The Female Genital System

Contents of Chapter 7 THE FEMALE GENITAL SYSTEM Anomalies of Development

The Ovary

Miscellaneous Lesions Traumatic Lesions of the Ovary and Bursal Adhesions Cystic Ovarian Degeneration in Cows Cystic Ovarian Degeneration in Other Species Neoplastic Diseases of the Ovary

The Fallopian Tubes The Uterus

Irregularities of Endometrial Growth Hydrometra and Mucometra Inflammatory Disease of the Uterus The Sequelae of Metritis and Endometritis Pyometra Specific Causative Types of Uterine Infection Diseases of the Pregnant Uterus

The Cervix The Vagina and Vulva

Neoplastic Diseases of the Tubular Genitalia

The Mammary Glands

Bovine Mastitis Mastitis in Sheep and Goats Mastitis in the Dog and Cat Mastitis in Swine Abnormalities of Mammary Growth— Hyperplasia and Neoplasia

BIBLIOGRAPHY

Agenesis of one or both ovaries is occasionally observed in ruminants, swine, and dogs. In bilateral agenesis, the tubular genitalia may be absent as part of the defect or, if present, are infantile or underdeveloped. Hypoplasia of the ovaries is studied in cattle only but probably occurs in other species. It is usually bilateral but varies considerably in its severity and symmetry, so that 'severe hypoplasia'" or "partial hypoplasia" may be applicable to one or both ovaries. In severe hypoplasia, the defective gonad varies in size from a cord-like thickening in the anterior border of the mesovarium to a flat smooth, firm bean-shaped structure in the normal position (Fig. 7.1 A). There are neither follicles nor luteal scars and, microscopically, the ovary is composed largely of medullary connective tissues and blood vessels. The ovarian cortex may be totally absent, or it may be only partially absent, forming then a thin or incomplete investment for the medulla. The cortical germinative stroma is much deficient in amount and is diluted with collagen. Ova are not detectable and there is no sign of organization into follicles (Fig. 7.IB). In hypoplasia of lesser severity, the germinative stroma is deficient but a few primary follicles can be found. Occasionally, a follicle grows to a large size and may become cystic, with luteal tissue in patches in the theca; size, however, is not a criterion of maturity and the life cycles of follicles in hypoplastic ovaries are not known. In association with ovarian hypoplasia, there is relative hypoplasia or infantilism of the remainder of the genital tract. Genital infantilism also occurs in young females in association with the nonfunctional ovaries of debility or malnutrition; these cases can be distinguished from those of hypoplasia by the presence of adequate amounts of cortical stroma, the presence of primordial follicles, and the responsiveness of the ovaries to gonadotrophins and improved nutrition. There is, in debility, a failure of release of hypophyseal gonadotrophins so that the follicles do not develop much past the antrum stage. Ovarian hypoplasia occurs in Swedish Highland cattle as a genetic defect conditioned by an autosomal recessive gene with incomplete penetrance. Elsewhere, the defect is not known to occur in any definite pattern or particular breed but is sporadic in incidence.

CHAPTER 7

The Female Genital System Prepared in collaboration with Dr. Kenneth McEntee ANOMALIES OF DEVELOPMENT

A

Mammary Glands

VARIETY of malformations of the mammary glands occur, but they are of little pathological importance. Aplasia and hypoplasia are infrequently seen. Supranumerary teats are common but only occasionally are they associated with polymastia. Fistulae of the teat and gland may be congenital or acquired, as may stenosis and atresia of the streak canal. The development of aberrant glandular tissue from the epithelium of the teat canal occurs in cows (Fig. 7.25A) and is of possible importance in the pathogenesis of some cases of mastitis. Enlargement of the gland in males (gynaecomastia) with secretion is a response to hormonal disturbances with oestrogenism; the oestrogen may be endogenous as in dogs with Sertoli-cell tumours of the testes, or it may be exogenous as in sheep grazing on clovers which produce compounds with oestrogenic activity. Vulva The vulva and vestibule are of ectodermal origin, being derived by partition from the urogenital sinus. Failure of proper partitioning allows the cloaca to persist. Hypoplasia of the vulva and vestibule is occasionally observed, sometimes alone but usually in association with hypoplasia of derivatives of the Müllerian ducts. Hypertrophy of the clitoris occurs in pseudohermaphroditism, in cows and sows with functional follicular cysts, and possibly, but rarely, in association with androgenic tumours of the adrenal gland.

Freemartin The bovine freemartin is a genetic female born co-twin with a male and the structural modifications of female genitalia are supposed to result from the influence of androgenic hormones produced by the male foetus. This supposition is based on the fact that there is fusion of the placental circulations, that the male gonad develops earlier than the female gonad, and that the entire female genital system is greatly suppressed and male vestiges are developed. This theory of pathogenesis is attractive in its simplicity but may not be correct; some nonandrogenic inducting substance may be the culprit. The gonad is usually only a cord-like thickening in the anterior border of the ovarian ligament. The ovarian tissue is typically hypoplastic and often contains vestigial seminiferous tubules. The tubular genitalia of Müllerianduct origin do not develop but remain as cord-like structures, usually without any lumen, in the edges of the liga-

Ovary The determination of sex is a genetic phenomenon and dependent on the chromosomal constitution of the zygote. Sex differentiation or the development of sexual dimorphism depends on the interaction between the genetic determinants of sex and the function of the foetal gonad. The proper development of the tubular genitalia of the female is, therefore, ovary-dependent, and disordered differentiation of the Müllerian-duct derivatives can be expected to accompany anomalous development of the ovaries. 389

390

7 . THE FEMALE G E N I T A L

ments. Vestigial seminal vesicles are probably always present, an epididymis may be present, the clitoris is enlarged, the vulva and vestibule are hypoplastic, and the vagina is hypoplastic or nonpatent with a complete hymen (Fig. 7.1C). The allantoic fusion in bovine twin pregnancies occurs at about the 10-mm. stage of development; approximately 90 per cent of females born cotwin with males are freemartins. Community of allantoic circulation is inferred on anatomical grounds from fusion of the blood supplies, and this fusion occurs before the stage of gonadal differentiation. Still indirect but perhaps the best evidence of the mingling of the blood supplies is the development of antigenic mosaicism of the erythrocytes and this latter provides a basis for the detection of freemartins by blood typing at an age when the only other practicable test is of vaginal patency. Arrests in the Development of the Müllerian-Duct System These defects are of significance only in cattle and swine. In other species they are rarely recorded and the degree of inhibited development is less. Thus in the bitch, uterus unicornis, partial fusion of the horns or reduction in length of one horn are probably the most severe defects recorded and are not associated with sterility. In swine and cattle on the other hand, segmental defects are not uncommon. In almost all instances, the anomaly is based on inhibited development of portions of the Müllerian ducts and their differentiated derivatives, or on aberrations of the pattern of fusion of the Müllerian ducts which produces the vagina, cervix, and uterine fundus. Segmental aplasia of the Müllerian-duct system has drawn frequent attention because of its rather common occurrence in white Shorthorn cattle. In this breed, the arrested development is thought to represent a pleomorphic action of a gene which, when homozygous, restricts the normal and basic pigmentation of the Shorthorn and produces a white coat colour. Probably, no breed of cattle is exempt from segmental aplasia and some may have genetic correlations such as occur in white Shorthorns. However, the anatomic expressions of any inhibitory influences will be comparable even though the influences themselves may be diverse; they are not necessarily genetic and not necessarily associated with coat colour. Familiarity with the developmental history of the Müllerian ducts should prevent any surprise concerning the wide variety of defects that can and do occur. As a rule, the ovaries, Fallopian tubes, and cornual apices are present and are normal except for retention of secretion in, and dilation of, the apices of the horns. Sows may provide an exception to the rule because, in this species, hydrosalpinx is relatively common amongst the gross genital abnormalities; the basis of the hydrosalpinx must be an obstruction to the tube, but whether the obstruction is developmental or acquired has not been fruitfully examined. If a total or large segmental defect of aplastic type is discovered in a salpinx, the basic defect is likely

SYSTEM

to be gonadal, either hermaphroditism, gonadal agenesis, or freemartin. The simplest defects involve only the caudal sections of the Müllerian ducts. If these fail to make patent connection with the urogenital sinus, an imperforate hymen persists. In association with imperforate hymen, the remainder of the genital tract may be normal but in time and with the accumulation of secretions (there may be two gallons or more) the vagina, cervix, and uterus become distended and atonic (Fig. 7.2A). If the hymen is perforated and the distension relieved early, the genital tract may function normally but prolonged and severe dilation leads to atrophy and permanent loss of tone of the walls. Bacteria may be fortuitously implanted in the uterine contents to produce pyometra. Lesser degrees of hymeneal persistence are common and usually of no significance. The perforated remnant may consist of a thin fenestrated membrane or dorsoventral bands. In some instances, the bands, especially those of sagittal disposition, may be remnants of the medial walls of the Müllerian ducts. The most severe defect is characterized by hymeneal constriction in association with absence or rudimentary development of the cranial vagina, cervix, or uterus including the horns, together or in any combination (Fig. 7.ID). Proximal to the segmental defect, the tubular structures become dilated cystic cavities filled with dark reddish-brown mucus which may, if inspissated, form hard rubbery masses. In the defective segment, there may be no trace of the Müllerian duct or there may be a pencilthick cord of connective tissue representing it. Uterus unicornis is quite common as an expression of segmental aplasia of one duct. The whole horn, excepting its apex, may be absent or the defect may be more limited, usually occurring then at the bifurcation of the uterus (Fig. 7.2B). In addition to aplastic or hypoplastic defects of the Müllerian ducts, there are common anomalies which result from failure of proper fusion of the caudal portions of the ducts. Complete failure of fusion leaves a double vagina, double cervix, and divided uterine fundus; this is rather rare. The more common failures of fusion occur in or adjacent to the cervix (Fig. 7.2C). The anterior vagina may be partitioned by a dorsoventral septum in conjunction with a double cervix. A dorsoventral band may be across the external os, the cervix and vagina being properly fused. The failure of fusion may involve only part of the cervix, chiefly the caudal part so that there is one uterine fundus, one internal os, and a bifurcated cervical canal with duplication of the external os. The cervix and uterine fundus may be completely divided, a condition known as uterus didelphys (Fig. 7.3A). The normal sequence of fusion involves the uterus last so that at an early stage of foetal development uterus didelphys is a normal formation. The gross anatomical form of the cervix, in terms of length, thickness, number, and disposition of rugae, length direction and tortuousity of the canal, and so on, is quite variable. The majority of these variations fall within a narrow range that is regarded as normal, but significant

THE

OVARY

Fig. 7.1. (A) Bilateral ovarian hypoplasia with uterine infantilism. Ox. (Courtesy of C. A. V. Barker.) (B) Ovarian hypoplasia. Ox. Paucity of germinal stroma and absence of follicular development. (C) Freemartin. Ox. (Courtesy of C. A. V. Barker.) (D) Segmental aplasia. Ox. The defect involves the anterior vagina, cervix, and uterine fundus. (Courtesy of C. A. V. Barker.)

391

392

7.

THE FEMALE G E N I T A L

SYSTEM

Fig. 7.2. (A) Segmentai aplasia. Ox. Imperforate hymen and distension of vagina and uterus with accumulated secretions. (B) Segmental aplasia. Ox. The defect involves the right uterine horn with dilation of proximal segment, and inspissation of secretions. (C) Double cervix in uterus didelphys. Ox.

THE

OVARY

Fig. 7.3. (A) Uterus didelphys. Ox. (B) Anomalous cervical rugae and short cervical canal. Ox. (C) Oophoritis caused by Corynebacterium ovis. Ewe. (D) Traumatic haemorrhage from ovary following expression of corpus luteum. Ox.

393

394

7 . THE FEMALE G E N I T A L SYSTEM

departures from normal are not uncommon, especially in heifers. Gross hypertrophy is observed occasionally, the structure being two or three times its normal length and thickness, and it may present an impenetrable barrier to the passage of sperm or the discharge of uterine secretions. Moderate hypoplasia of the cervix in which some rugae are absent and the canal widely patent (Fig. 7.3B) may militate against functional closure of the canal and predispose to persistent invasion of the uterus by microbes and chronic endometritis. Occasionally, the cervical canal is irregular in its course or even very tortuous and, although this may not interfere with conception following natural breeding, the insertion of an inseminating catheter may be difficult or impossible and persistent attempts to do so lead to cervical trauma occasionally complicated by abscessation or the formation of traumatic inclusion cysts. The Ovary MISCELLANEOUS LESIONS

Intrafollicular haemorrhage, for unknown reasons, occurs commonly in calves and in follicular cysts in the bitch. The only significant form of haemorrhage is that which follows manual squashing of the ovary in the course of "enucleating" a corpus luteum (Fig. 7.3D). Such haemorrhage is occasionally fatal. In some cases, organization of the clot leads to fibrous bursal adhesions. Oophoritis is relatively rare and when it occurs it is usually pyogenic (Fig. 7.3C). More common is localized serositis which is seen as red fibrin and serosal tags attached to the surface of the ovary, especially in heifers. These tags, which contain numerous leucocytes, correspond to points of previous ovulation. Fine bursal adhesions may result, but they are too delicate to interfere with ovulation. Serosal granulomas on the ovary occur in bovine peritoneal tuberculosis and porcine brucellosis, visible macroscopically as small reddish nodules or tags. Similar lesions are usually visible on adjacent serosal surfaces of the genital organs and adnexa. These infective granulomas remain strictly localized to the surface of the ovary and do not penetrate its substance. Paraovarian cysts are common in all species, may be single or multiple, and are often quite large (2 inches in diameter). They may be attached to the surface of the fimbriae, the salpinx, or the mesovarium. Sometimes pedunculated, they are clear with watery contents and a simple epithelial lining. Such cysts are remnants of the Wolffian system and their only significance is in the need to distinguish them from true ovarian cysts. Germinal inclusion cysts, small and of no importance, are common in the outer ovarian cortex. They arise by pinching off of surface indentations and are lined by peritoneum (or by germinal epithelium if there is truly such a structure). Cystadenomatous tumours of the ovary may arise focally in these cysts.

TRAUMATIC LESIONS OF THE OVARY AND BURSAL ADHESIONS

Fine bursal lesions have already been referred to above. More extensive adhesions, which obliterate the bursal sac or interfere with the motility of the fimbriae, result from trauma and inflammation. Man-made lesions of this type are fairly common following attempts to enucleate so-called retained corpora lutea with production of local haemorrhage and tissue injury. These tissues are especially vulnerable when inflamed, as in pyometra and salpingitis, because of friability and the tendency to release tubal inflammatory detritus into the bursa. Obliteration of the bursa by adhesions results in cystic degeneration of the follicles (Fig. 7.4A). CYSTIC OVARIAN DEGENERATION IN Cows

Ovarian cysts occur in all species. They are best known in the cow and scarcely anything of significance is known about them in other species. Accordingly, the major consideration here is of the bovine disease. The best-recognized facet of the problem is the follicular cyst associated with nymphomania, but luteal cysts are more common and of comparable importance. There have been many written contributions on the pathogenesis and nature of ovarian follicular cysts and nymphomania; many are delightfully but frustratingly imaginative, few are helpful, and probably none adheres to the Principle of Economy of Hypothesis, that is, the simplest hypothesis consistent with known facts. In the following discussion, separate consideration is given to four syndromes, the inference is not that they are pathogenetically distinct, but rather that the first three are gradations of the same dysfunction and the fourth is the end result of untreated cases of the second and third types. Absent is any separate consideration of adrenal virilism. In later years this has been accorded the status of an entity, clinically at least. Primary adrenal virilism occurs rarely in the bitch, but seldom if ever in other domestic species. It may also occur in the cow, but as yet there is no good reason to believe so. There is, however, good reason to expect that adrenal-cortical function will be altered in cows bearing functional follicular cysts and the degree of alteration and any resulting manifestations might well be correlated with the level of oestrogenism and, more importantly, the length of the period over which the oestrogens are continuously present. It is misleading, and emphasis misplaced, to classify any ascertainable manifestations of oestrogen-induced adrenal heterofunction as a separate syndrome of adrenal virilism; they are merely at one end of a broad spectrum of structural and behavioural responses to functional cystic follicles, the whole of which can be duplicated by the direct and indirect actions of parenterally administered oestrogens. The clinical and pathologic responses will be determined by the amount of oestrogen produced by the ovary, the period over which the oestrogen acts continuously, and the biologic variability of the individual.

THE

OVARY

Fig. 7.4. (A) Ovarian bursal adhesions. Ox. (Courtesy of C. A. V. Barker.) (B) Follicular cyst in ovary. Mare. (C) Cystic corpus luteum. Ox. (D) Atrophie follicular cysts with mucometra. Ox. Note dilation and apparent flaccidity of uterus. (E) Luteal tissue in theca in ovarian follicular cyst. Ox.

395

396

7 . T H E FEMALE G E N I T A L

Atretic follicles. Follicular atresia is a normal phenomenon and the destiny of any follicle which does not attain maturity. During the oestrus cycle of uniparous species many follicles develop, but only one is supposed to mature and ovulate; the remainder undergo atresia, degenerate, and disappear. In some species which are seasonally anoestrus, such as the ewe, cyclic follicular growth and atresia without maturation occur throughout the period of anoestrus. The same process is normal, at least in some species, during pregnancy. On the other hand, follicular atresia is pathologic when unnatural influences inhibit the final maturation. Such is the case in the anoestrus of debility and inanition. Follicular growth is independent of hypophyseal gonadotrophins up to the stage of antrum formation. Thereafter, growth and maturation depend on stimulation by hypophyseal gonadotrophins in proper proportion and sequence. Debilitated and malnourished animals are capable of synthesizing the gonadotrophins and the ovaries are capable of responding to them. The defect is in the pituitary gland, which either does not release its stored gonadotrophins, or does so in insufficient quantity. The affected follicles may cease to develop at any stage between that of the antrum and the finally mature. It is not known how long they may persist before degenerating. The form of atresia depends mainly on the stage of development of the follicle when degeneration begins. It is always preceded by degeneration of the ovum and its zona pellucida. In small follicles, the degeneration may be direct; a small cavity forms about the remnant of the zona pellucida, the granulosa cells show nuclear pycnosis and cytoplasmic vacuolation, and they desquamate into the cavity where they undergo complete disintegration. The ovum and zona pellucida are invaded by phagocytes of uncertain origin. In larger follicles, degeneration of the ovum and granulosa epithelium is followed by hypertrophy and ingrowth of theca, the cellular elements of which resemble immature lutein tissue, to enclose the degenerate remnants of the zona pellucida. This latter is rather persistent, but its presence does not always imply atresia as it is also found in cystic corpora lutea. The final process in atresia is infiltration by connective tissues which, when mature, form a collagenous core. An alternate form of degeneration of immature follicles results in the formation of cysts which, after degeneration of the ovum and granulosa epithelium, are lined by a single layer of epithelium. They may be very persistent and are common and multiple in pregnancy, much less frequent and solitary in debility. Cystic Graafian follicle. This is the best recognized and a common form of cystic ovarian degeneration. It arises from the failure of mature follicles to rupture and may or may not be associated with nymphomania. It is more common in heavy-producing mature cows, especially during the winter months. The pathogenesis is not clear, but there is good evidence that pituitary gonadotrophin is not released in early oestrus as it normally is and the mature follicle is

SYSTEM

not exposed to the ovujating and luteinizing action of the luteinizing hormone. One or more large follicles, an inch or more in diameter, are present on one or both ovaries. Apart from their greater size, they may be difficult to distinguish grossly from normal follicles without reference to the remainder of the genital tract. In the cow, the vulva is often oedematous, the clitoris may be enlarged, and there is almost invariably cystic formations in Bartholin's glands and Gartner's ducts. The cervix is enlarged, patent, and produces a characteristic tough grey-white mucus. The uterus is oedematous and flabby. The Fallopian tubes are usually normal. There will be no corpora lutea in the ovaries although orange remnants of old corpora may be present. The affected follicles are larger than normal ones with appreciably thicker walls and are under more tension. Histologically, the ovum is absent and most of the granulosa is either degenerate and lost or becoming so. The hillock persists longest and may be partially luteinized. Continued epithelial degeneration leaves a single-celled flat epithelium on a hyaline basement membrane outside of which is an oedematous and attenuated theca which may be partially luteinized. Cystic corpus luteum. Cystic corpora lutea in cattle occur in the younger age groups predominantly. There are aberrations of the oestrous cycle but, contrary to expectations, anoestrum is not always a feature of the condition. Oestrous cycles are often of normal length although periods of "silent" oestrus may be irregularly interspersed. Cystic corpora lutea may occur with successive cycles in the same animal. The duration of pro-oestrus and oestrus is, however, irregular. The pathogenesis of the cystic corpus luteum is very probably the same as that of the cystic follicle, that is by failure of the hypophysis to release adequate amounts of luteinizing hormone. Indeed, it is usual to find some evidence of luteinization, albeit microscopic, in follicular cysts, and the two conditions are assumed to be expressions of different degrees of the same dysfunction. Little or no luteinizing hormone, as assessed by cytochemical examination of hypophyses, is released in cows which develop follicular cysts; release of this hormone in cows which develop luteal cysts is slowed and not complete for some days. Small central cavities are common and normal in early corpora lutea and may be detectable for as long as 4-8 days after ovulation. They are not usually larger than 5 mm. When pathologic, luteal cysts usually are larger and measure 7—14 mm. They are readily differentiated from the normal when, as is usually so, ovulation has not occurred. There is then no ovulation papilla and the body of the corpus is smooth and rounded (Fig. 7.4C). One or more small blebs are usually present on the surface of a normal follicle which is about to ovulate and luteinization of these produces the ovulation papillae. The presence of papillae is usually but not invariably an indication that ovulation has occurred. In the rounded form of the cyst,

THE

the lutein tissue is present as a large or small crescent in the embedded portion and the cyst cavity is smooth and spherical. When ovulation papillae are present the cyst wall is completely luteinized and the cavity is irregular. Occasionally, an ovary bearing a cystic corpus luteum may also bear a cystic Graafian follicle or a mature and solid corpus luteum. The lutein tissue in the cyst wall does not differ, cytologically, from the normal but occurs primarily in the theca interna (Fig. 7.4E). The cavity has a well-developed lining offibroustissue, and remnants of the ovum and zona pellucida may be found.

OVARY

397

The oviducts are not significantly altered, showing at most some stromal oedema and epithelial hyperplasia. The uterus is invariably altered with differences in degree related to the duration of oestrogenism. In association with functionally active follicular cysts the uterus is enlarged, doughy or atonic, and the wall is oedematous. The cervix is enlarged, the external os patent, and the plicae oedematous. At the other extreme, in association with the atrophie variety of cyst, the uterus and cervix are small, the uterine wall is very thin, and there is atrophy of the myometrium, characterized by marked reduction in the amount of sarcoplasm relative to the volume of nuclei, to a degree comparable to that in castrates and prepubertal cows. The The atrophie cyst. Cows which bear follicular cysts for long endometrium may appear grossly normal: smooth, semiperiods, with or without nymphomania, ultimately develop transparent, greyish pink, and moist. In most cases, there permanent anoestrus. The cysts are then reduced in size is some degree of cystic endometrial hyperplasia, often and no longer dominate the contour of the ovary, the detectable by the naked eye as numerous grey-white tiny pressure within the cysts is reduced, and the walls are elevated "blisters" in the surface of the endometrium which appreciably thicker (Fig. 7.4D). These atrophie cysts are is overlain with a thin layer of clear viscous mucus. The usually multiple and bilateral; histologically, they do not accumulation of mucus (mucometra) and the development differ clearly from active follicular cysts. of cystic hyperplasia progress with time and are most striking in those animals which have been affected long The Extraovarian Lesions of Cystic Ovarian Degeneration enough for atrophy of the cyst and anoestrum to be present. in Cows By then, the endometrium may be of the descriptive "Swiss cheese" type and the volume of mucus be 100-1,000 ml. or The changes in other organs can be related to the direct even much more. Contrariwise, in other animals with these or indirect effects of hyperoestrogenism. The cyst fluid in atrophie cysts, the endometrium may be atrophie with very cows, especially those showing nymphomania, contains few dilated glands and no mucometra, but irrespective of oestrogenic substances in lesser quantities than does the the endometrial changes the myometrium will be atrophie. normal Graafian follicle. This has been advanced against In the early stage of the development of the cystic endothe theory of an oestrogenic pathogenesis for the lesions metrial change when the degree is not clearly in excess, the to be described. It should be remembered, however, that physiologic hyperplasia can be distinguished from the the toxicity of oestrogen depends not only on the level of pathologic by the fact that in the former the endometrial circulating oestrogen, but, and more importantly, on the activity is uniform and in the latter it is not. continuity of its action, even though exciting levels are relatively minute. In established cases of follicular cyst, The cervix may be hypertrophie or atrophie as described the anterior lobe of the pituitary gland is always enlarged, above. It usually contains thick, viscid, greyish-white and due partially to stromal hyperplasia and oedema, and cellular mucus. The epithelium undergoes squamous nonpartially to cellular hypertrophy. The gonadotrophinkeratinizing metaplasia of mild degree (Fig. 7.5C). producing basophils normally degranulate and release their The vagina is oedematous when the cysts are active but hormone in the first hours of oestrus; if a follicular cyst otherwise the most striking change is the formation of cysts develops there has been failure of this release of hormone in Gartner's ducts (Fig. 7.5B). These Wolffian vestiges and the gonadotrophin-producing cells remain fully granuwhich lie in the wall of the vagina, one on each side of its lated; if a luteal cyst occurs, the degranulation is delayed floor, are normally visible only macroscopically as conand incomplete and is more or less proportional to the tinuous or discontinuous ducts lined by a simple pavement degree of luteinization. With persistence of a follicular cyst, or cuboidal epithelium. When chronically stimulated by the degranulation of "gonadotrophs" proceeds slowly to oestrogen, the epithelium becomes squamous and the ducts completion and the acidophil cells hypertrophy and become cystic and visible or palpable as a series of blebs or as heavily granulated, the granules representing stored growth tubules up to 1.0 cm. in diameter on the floor of the vagina. hormone and prolactin. The thyroid gland is enlarged and The vulva may be oedematous when the cysts are active moderately hyperactive and the ultimobranchial residues and the clitoris may be enlarged in long-standing cases. show some degree of squamous metaplasia. The adrenal Cystic Gartner's ducts are usually accompanied by cystic cortex, especially the zona fasciculata, is widened, probably Bartholin's glands (Fig. 7.5D). Either may become abscessed. by cellular hypertrophy rather than hyperplasia. Just what Bartholin's glands, one on each side of the floor of the this means in terms of cortical function is not clear as there vulva, undergo cyclic secretory changes during the oestrous are neither adequate methods for estimating ketosteroids cycle and a squamous epithelium on the ducts is normal in in ruminants nor adequate histologie criteria of cellular oestrus. Exaggeration of this change in chronic oestroactivity in the adrenal cortex. There is sclerosis of the genism causes occlusion of the ducts and the formation of adrenal capsule. retention cysts.

398

7 . T H E FEMALE G E N I T A L

CYSTIC OVARIAN DEGENERATION IN OTHER SPECIES

In swine, atretic follicles are especially common and may be found in all stages of pregnancy as well as in nonpregnant sows and gilts. Single large cysts up to 2-3 cm. in diameter (the normal follicle is not more than 1.0 cm. in diameter) may be found during the oestrual phase of the cycle. They probably represent cysts that have failed to ovulate and are not significant. Cystic Graafian follicles are small and multiple, the number exceeding the number of normal follicles expected. These cysts are lined by granulosa epithelium and contain large amounts of oestrogen. There is hyperplasia of the endometrium of oestrogenic type. Cystic corpora lutea are large and the number is that of the expected number of follicles. The degree of luteinization varies from small crescents to a complete rim. The clitoris is enlarged and the endometrium is progestational. These cysts may persist indefinitely. No worth-while information is available on the disease in mares (Fig. 7.4B). It is worth noting, however, that follicles up to 3 inches in diameter are normal in the mare and that a number of developing follicles up to 2 inches in diameter may be present in each ovary. Further, that nymphomania in the mare appears not to be causatively associated with ovarian cysts and that the cause of cystic endometrial hyperplasia in this species is unknown. In the bitch, both cystic Graafian follicles and cystic corpora lutea are common in older age groups and both are important in canine medicine. The cysts are multiple and structurally similar to those described in cattle. Cysts of similar type occur in cats although perhaps with lesser frequency than in the bitch. The functional follicular cyst can be responsible for nymphomania, vulval tumefaction, cystic endometrial hyperplasia (Fig. 7.5A), cystic mammary hyperplasia (Fig. 7.30A), and genitalfibroleiomyomas(fibroids) (Fig. 7.23 A). The role of ovarian cysts in the history of mammary gland tumours in the bitch is also discussed later. The functional cystic corpora lutea cause exaggerated progestational proliferation of the endometrium. Both the retained corpus luteum of pseudopregnancy in the bitch and cat and the cystic corpus luteum, by virtue of excessive progestational activity, endow the uterus with a remarkable susceptibility to infection; pyometra is a common consequence. The pathogenesis of ovarian follicular and luteal cysts in the bitch and cat is not known in detail but presumably is comparable to that for this condition in cattle. Follicular cysts can be produced by the injection of pregnant-mare serum which contains follicle-stimulating hormone. Cysts not uncommonly result from incomplete oophorectomy, the viable remnants of ovarian tissue developing follicles which become cystic; larger remnants become hypertrophie and functional. NEOPLASTIC DISEASES OF THE OVARY

All the usual types of ovarian tumour occur in domestic animals but none is common. The classification is based on

SYSTEM

histology and evidence of function and is useful, at least for humans in which it has prognostic significance. (No one has yet built up a large enough series of animal ovarian tumours to know what their potentialities are.) But a purely histologie classification of any tumour is arbitrary and has often to be manipulated to allow many examples to fit, as is exemplified by the wide variations of nomenclature of any class of tumour. The only satisfactory classification is a histogenetic one based on recognition of the parent tissue and its embryologie relation to other tissue. For the ovary, this presents difficulties, for there is scant enough evidence on the embryogenesis of the normal ovary and opinions, but no really sound evidence, on the origin of oocytes or the lineal relationships of the cellular elements of the ovarian cortex. So far, these problems have been attacked only by the techniques of histology and these are not adequate to the task. The present histogenetic classification is into neoplasms (cystadenomas and carcinomas) derived from the coelomic germinal epithelium, and neoplasms (granulosa cell, theca cell, luteoma, arrhenoblastoma, dysgerminoma) derived from the specialized differentiation of the ovarian cortical stroma, the normal source of granulosa and theca cells. Unfortunately for this classification, it is not certain that there is such a tissue as germinal epithelium. An alternate and, at the moment, more satisfactory classification regards the cortical cells of the ovary as being as pluripotent in the determination of neoplasm as they probably are pluripotent in the determination of the form of the normal follicle and, further, that the specialized types of ovarian tumour are histogenetically related. Such a classification allows the inclusion of the wide gamut of histologie, including mixed, types of ovarian tumour. Ovarian tumours occur most frequently in the bitch and cow. In the bitch, they are often bilateral, especially the cystadenomatous types. In cattle, they are usually unilateral and of granulosa-cell type. Granulosa-cell tumours only are described in the mare and ewe. Apparently, the cat is more-or-less exempt from ovarian neoplasia; only one record was found. Tumours of specialized ovarian tissues are not reported in swine, but primary haemangiosarcomes of the ovary are occasionally observed in this species. The following classification is the one usually employed, it is based on the predominant structural form and on function and does not emphasize the variant and mixed types. The cystadenoma and it malignant counterpart are the least rare of the primary ovarian tumours. They occur in the bitch and some cause hyperoestrogenism. There is no important distinction between the serous and mucous types. The latter is rare in animals. These neoplasms may be unilateral or bilateral, unilocular or multilocular. The unilocular cysts are usually small and benign with a smooth lining of columnar epithelial cells which may bear cilia, resembling the epithelium of the Fallopian tube. The multiloculate tumours may be extraordinarily large, and complicated papillary processes project into the cysts (Fig. 7.6C). The presence of such papillae are to be regarded

THE

OVARY

Fig. 7.5. (A) Ovarian follicular cysts and endometrial hyperplasia. Bitch. (B) Cystic Gartner's ducts. Ox. (C) Squamous metaplasia of epithelium of cervix in hyperoestrogenism. Ox. (D) Cystic Bartholin's gland. Ox. (Courtesy of C. A. V. Barker.)

399

400

7.

THE FEMALE G E N I T A L

SYSTEM

Fig. 7.6. Papillary cystadenocarcinomas of ovaries. (A) Typical papillary structure of tumour when free of bursa. (B) Bilateral tumours. Bitch. Showing cauliflower appearance produced by growth within bursa, and cysts. (C) Architecture of papillary cystadenocarcinoma. Note diffuse involvement of ovary, papillary growth on surface and in cysts.

THE

OVARY

Fig. 7.7. (A) Luteinized granulosa-cell tumour. Ox. (B) Granulosa-cell tumour. Ox. (C) Solid and cystic granulosacell tumour. Mare. (D) Arrhenoblastoma. Bitch.

o

401

402

7.

THE FEMALE G E N I T A L

as indicative of malignancy. Some of these tumours are predominantly papilliferous rather than cystic, and in these there is almost always involvement over broad areas of the surface of the ovary by small nodularities or irregular papillae. Confinement of the papillary types within the rather complete ovarian bursa of the bitch, with consequent compression, gives them a typical cauliflower-like appearance (Fig. 7.6B). Once free of the bursa, the papillary nature becomes obvious (Fig. 7.6A) and peritoneal implantation occurs readily. This type of ovarian tumour should always be considered in the differential diagnosis of ascites in adult entire bitches. The ascites develops from obstruction of the diaphragmatic lymphatics by permeating tumour fragments with perhaps a contribution by secretion by the tumour epithelium. Spread of this tumour from the abdominal cavity is predominantly lymphatic and to the anterior sternal node before the lungs. Solid carcinoma is a solid epithelial tumour composed of the same cell type as the above with some papillary formation but no cysts. Solid carcinomas may be bilateral, are not large, and are composed of greyish-yellow friable tissue with focal areas of haemorrhage. They are to be regarded as less-differentiated types of cystadenocarcinoma and are observed occasionally in the bitch.

SYSTEM

Arrhenoblastomas are rare tumours with masculinizing properties. They are not distinctive histologically although some may produce patterns resembling testicular tubules. Their histogenesis is completely unclear although it may be from the ovarian rete. These tumours are unlikely to be correctly identified unless there is a history of masculinization. Without such history, even those tumours which produce almost perfect seminiferous tubules (Fig. 7.7D) may, with some doubt, be designated as arrhenoblastomas. The dysgerminoma is also of uncertain origin but in all other respects is analogous to the testicular seminoma. They are rare tumours, without endocrine effects, large, soft, and whitish, and composed of large and anaplastic epithelial cells. Like the seminomas, they may be malignant. Occasionally, they are bilateral. Secondary tumours of the ovary are probably not less rare than primary ones, the relatively high incidence being attributable largely to secondary deposits in lymphomatosis. Mammary carcinomas in the bitch and intestinal carcinomas in the cow may metastasize to the ovary and apparently have a curious affinity for corpora lutea. There is little doubt that they are of haematogenous origin, but this is controversial.

The Fallopian Tubes Primary lesions in the Fallopian tubes are uncommon. Granulosa-theca cell tumours are unilateral, usually non- Hydrosalpinx, pyosalpinx, and salpingitis are the only ones malignant tumours in any species. Part of their interest lies worthy of consideration, and these are usually secondary in the production of oestrogens by some of them with the to disease of the uterus or to manual manipulation of the usual consequences of hyperoestrogenism. At one time, the ovary. As regards incidence of salpingeal lesions, the only group was subdivided into granulosa-cell tumours, thecaagreement is that they are much more common than is the cell tumours, and luteomas on the basis of a similarity diagnosis of them. They are recognized to be important in between the predominating cell type and the cells of the the cow and sow, but not in other species. The low incidence Graafian follicle or corpus luteum. But many of these of salpingitis in the mare, even in the presence of metritis, tumours are mixtures, the lutein being merely luteinized is attributed, and probably rightly so, to the disposition of granulosa and theca cells. Small specimens are seldom sphincter muscle about the uterine ostium. observed; the larger ones may be up to 10 cm. in diameter. Hydrosalpinx The surface is smooth (Fig. 7.7A) and the cut surface may Distension of the Fallopian tube by fluid follows loss of be solid or cystic (Fig. 7.7A, C). The solid portions of the patency of the lumen (it is possible too that a condition tumour are white or yellow depending on the lipid content. akin to paralytic ileus may affect the tube when the The cells in these tumours do not differ much from normal, surrounding tissues are inflamed), and it does not matter but their histologie arrangement is quite various (Fig. 7.7B). whether the obstruction is to the abdominal ostium or the Diagnostic, when present, are gland-like or rosette patterns uterine ostium. The obstruction may have a congenital or of abortive follicles, some of which may contain a secretory inflammatory basis. Congenital anomalies involving the globule resembling an ovum and called a Call-Exner body. tubes are very rare, except in freemartins, but secondary This type of differentiation is, however, seldom observed hydrosalpinx can be associated with obstructions and in animals. Instead, the arrangement of cells is usually segmental aplasias of the uterine horns. In the latter diffuse with, in some tumours or parts of tumours, pseudoinstances, the apex of the horn is usually distended with alveolar or cylindromatous patterns, depending on the fluid also. In those cases which are of inflammatory origin, disposition of the stroma. The stroma consists of broad the inflammation may be traumatic or infective. The acute irregular bands of dense collagen. Cystic degeneration and infective inflammations are more likely to produce pyosalhaemorrhage are common. The more thecomatous portions pinx; the chronic infective inflammations tend to produce of such tumours may resemble normal theca cells and at loculations and stenosis of the lumen with secondary hydrothe other extreme be distinguishable from plump fibrosalpinx. As almost all infective inflammations are of blasts only by the demonstration of sudanophilic droplets ascending type from coexisting uterine inflammation, the in the cytoplasm or by histochemical techniques for steroids. most severe changes and the obstruction in such cases are The more purely lutein cells present no problem, being usually at or near the uterine end of the tube. similar to those in corpora lutea or vacuolated.

THE FALLOPIAN

A common form of inflammation which results in hydrosalpinx is traumatic following manual manipulation of the ovary. Uterine irrigations are somewhat less important, but, in either event, it is the adhesion between the tube and adnexa (usually the ovary with partial or complete obliteration of the bursal cavity) which causes obstruction of the abdominal ostium and secondary hydrosalpinx. Squashing of the normal dioestral corpus luteum (there is at best only partial expression of the body) is not difficult but, because of its vascularity, there is always some degree of haemorrhage, varying in extent from very slight to fatal in about 1:1000 cases. Small clots, which are usually retained in the bursa, can be completely resorbed. Larger clots must be organized, and this results in the formation of adhesions within the bursa and the fimbriated portion of the tube. With more extensive haemorrhage, adhesions may form to adjacent abdominal viscera and genital adnexa. Expression of pathologically persistent corpora lutea may result in little haemorrhage but a lot of tissue damage, and a more or less proportional degree of organization by fibrosis will result. The important types of persistent corpora lutea occur in association with pathological distension of the uterus. If this latter is pyometra, an additional complication is involved in that, as well as the manual trauma, there is liability to spillage of inflammatory products and extension of infection to traumatically devitalized tissue. Therapeutic uterine irrigation, especially if performed in the early postpartum period, has also caused the type of adhesion referred to and follows one of two complications : the irrigation fluid may leak through the tube into the bursa and provoke an inflammatory reaction, the usual types of irrigating fluid being irritative, or the infusion of an excessive volume of fluid causes rupture of the uterus and perimetritis. Uteri vary in the amount of fluid they may retain, but any amount in excess of 4 ounces is liable to cause uterine rupture, the rupture occurring on the lesser curvature at the mesometrial attachment with permeation of fluid through or beneath the serosa. Inflammatory thickening is the usual result and the development of serosal adhesions produces tubal obstruction and dilation. Hydrosalpinx is so called because the Fallopian tube is distended, uniformly or irregularly, up to 1.5 cm. or so with a clear watery mucus which fluctuates. The tube is also increased in length and tortuosity and is thin-walled. Histologically, there is extensive multilocular cyst formation in the mucosa with obliteration of the lumen and in some, chronically inflamed, mononuclear cell infiltrations of the substantia propria (Fig. 7.8A). Salpingitis Inflammation of the oviducts without significant enlargement is the commonest and most important tubal lesion, is usually bilateral, is usually not detectable macroscopically, and may show any of the usual forms of inflammation, either serous, catarrhal, or fibrinous. In the mildest forms of salpingitis, the mucosa alone is affected and changes of functional significance may be slight enough to be overlooked histologically. Congestion of the mucosal vessels,

TUBES

403

mononuclear-cell infiltration, loss of epithelial cilia, and some desquamation of epithelium may be the only changes detectable. With more severe infections, catarrhal exudate collects in the lumen, the mucosal folds are thickened by cellular infiltration and congestion, and the epithelium is in large part destroyed. Loss of epithelium occurs first on the free edges of the mucosal folds and these denuded areas tend to fuse and adhere to produce intramucosal cysts; or, alternately, in chronic catarrhal salpingitis the mucosa is virtually destroyed and replaced by proliferated connectivetissue and cellular infiltrations with more or less occlusion of the lumen. The Fallopian tube is a rather simple structure histologically, but even minor inflammatory changes evidenced by slight congestion or the presence of a few plasma cells appear to be important because of the readiness with which the epithelial cells desquamate or lose their cilia. The proper function of the living epithelium is necessary for the propulsion of the ovum, for the dissolution of the cumulus oophorus prior to fertilization, and for the maintenance of a luminal environment suitable to survival of the ovum. The salpingeal mucosa has a much lesser capacity for restitution than does the endometrium and, with the exception of mild serous inflammation, it is doubtful whether functional recovery occurs. Nonspecific infections causing salpingitis almost invariably do so by spread from the uterus. There is probably a 70-75 per cent association between uterine and salpingeal inflammation when diagnosis of the latter is based on histological evidence. In some cases, there will be a perimetritis with adhesions, pyosalpinx, or bursal abscess. Pyosalpinx This is less common than hydrosalpinx and typically follows metritis in the same manner as do other forms of salpingitis. The significant anatomic difference is the accumulation of pus in the tube following obstruction of the lumen. The obstruction may be of inspissated exudate, an inflammatory thickening and fusion of the mucosal folds, or chronic granulation tissue. The length of the tube is usually not uniformly involved by the inflammatory process; rather, there are segments in which the reaction is more acute or more advanced so that the obstruction tends to involve irregular segments with the in-between portions distended with exudate. The entire thickness of the wall of the duct is infiltrated with neutrophils, lymphocytes, and plasma cells and the same cells collect in the lumen and in the mucosal cysts formed by adhesions between the denuded epithelial folds. Surviving epithelium may be partly squamous (Fig. 7.8B). Eventually, the bacteria will be destroyed and the exudate converted to a watery fluid (hydrosalpinx). Frequently accompanying pyosalpinx are the bursal adhesions and local peritonitis described earlier. Among the organisms which may be found in inflammatory diseases of the oviduct are streptococci, staphylococci, Escherichia coli, and Corynebacterium pyogenes, and, of these, the latter is the more common and important.

404

7.

THE FEMALE G E N I T A L

SYSTEM

Fig. 7.8. (A) Chronic salpingitis and hydrosalpinx caused by Bmcella suis. Sow. (B) Pyosalpinx with squamous metaplasia. Sow. (C) Torsion and rupture of pregnant uterus with release of foetus into abdominal cavity. Bitch. (D) Lipid granuloma in broad ligament following rupture of uterus during irrigation. Ox.

THE

UTERUS

405

Bruceila suis in swine and Mycobacterium tuberculosis in oestrogenism which results from the ingestion of legumes cattle are responsible for specific forms of salpingitis; the with a high content of oestrogens. Uterine polyps may lead to prolapse of the involved horn in the bitch (Fig. 7.10A). lesions are as described for these infections in the uterus. In any species, usually only the previously gravid horn prolapses. In the cow and ewe the nongravid horn, and The Uterus sometimes intestine and bladder also, may be present Acquired Changes in Position within the everted horn. The pathologic sequelae of proOf the possible positional changes of the uterus only lapse are comparable to those of intestinal intussusception three—herniation, prolapse, and torsion—are important. with the added factor of trauma. Congestion and oedema Displacement of the uterus may occur in abdominal and are followed by haemorrhage, necrosis, and sepsis. Ganventral hernias in any species, but displacement into the grene may supervene. inguinal canal occurs only in the bitch. The sequelae depend Rupture of the uterus may occur spontaneously, but it is on whether or not the herniated uterus becomes incarusually a result of obstetrical manipulations. Most ruptures cerated by a developing pregnancy, pyometra, or traumatic occur in the fundus adjacent to the pelvic brim as irregular adhesions. tears which may involve the full width of the wall or only Torsion of the uterus is exceptional in species other than the mucosa. Mucosal ruptures are of no consequence. cattle. In almost all cases, such twisted uteri are pregnant Complete ruptures are often fatal either by virtue of but torsion may occur also with pyometra and hydrometra. haemorrhage, spread of uterine inflammation to the periThe torsion is of the same nature as an intestinal volvulus toneum, or displacement of retained membranes into the and occurs about the transverse axis of the organ with the abdominal cavity. The majority of ruptures occur in uteri mesovarium as onefixedpoint. In uniparous species (cow) which are devitalized as a result of torsion or prolonged in which a well-developed intercornual ligament does not dystocia. permit much independent movement of the horns, the Rupture may also follow acute distension of the uterus entire organ is involved in the torsion which is about the produced by infusion fluids. This is not an uncommon mesovarium and vagina or cervix as fixed points. In accident. The rupture occurs on the lesser curvature along multiparous species (bitch, cat) with long horns and no the line of attachment of the mesometrium and the irriintercornual ligament, the torsion will involve part of one gating fluids spread into the ligament. Many such fluids horn or the entire horn, the fixed points in the latter have an oily base and a granulomatous inflammatory instance being the mesovarium and the site of attachment response to the oil thickens the mesenteries of the uterus, of the horn to the uterine body. There seem to be no rules tube, and ovary (Figs. 7.8D; 7.9A). Complete sterility is a governing the direction of the twist. Minor degrees of common sequel to perimetritis. torsion (up to 90°) are fairly common in cows and apparently resolve themselves. The condition becomes of importance Circulatory Disturbances only when the torsion is 180° or more and results in dysEndometrial hyperaemia and oedema occur normally at tocia. Any twist in excess of 180° may result also in local oestrus and reach the greatest relative development in the circulatory embarrassment. The thinner-walled veins are bitch in proestrus. The resulting diapedesis and endometrial obstructed before the arteries and the uterus becomes conexfoliation account for the uterine haemorrhage at proesgested and oedematous, with oedema of the placenta and trus in this species. Haemorrhage is common in heifers, death of the foetus. The devitalized uterine wall becomes less common in older cows, and occurs immediately after friable and susceptible to rupture or, if Caesarean section oestrus. The source of the haemorrhage is the endometrial is performed, the friability of the wall makes suturing capillary bed immediately anterior to the cervix. It is difficult. Death of the foetus may be followed by mummiprobably an oestrogen-withdrawal effect and the nearest fication if the cervix remains closed; if air and infection thing to menstruation in domestic animals. Punctate enter the uterus, the foetus putrefies. In the bitch and cat, haemorrhages occur in the uterine serosa in heifers in transverse rupture of the twisted segment near parturition oestrus. Haemorrhage and haematoma formation in the releases the dead foetuses into the peritoneal cavity (Fig. centre and at the periphery of the placental zone are normal 7.8C). in the dog and cat; the breakdown products of the haemoProlapse of the uterus occurs fairly commonly in rumi- rrhage are responsible for the brown and greenish pigmentation in the normal pregnant uterus in these species. A nants, exceptionally in other species. Predisposing causes small degree of interplacental haemorrhage in the centre of in the cow are essentially those which cause or are assothe placentome is normal in the ewe. ciated with uterine hypotony and probably also with dysrhythmia of involutionary contractions. Amongst the Haemorrhage of pathologic import follows torsion and most common associations in the cow are prolonged dysinversion, by obvious mechanisms. Perhaps the most tocia relieved by forced traction, retained placenta, and common association of abnormal bleeding is endometrial postparturient hypocalcaemia. Probably the same sort of hyperplasia in the bitch, especially if there is superimposed influences operate in ewes and, in addition, uterine prolapse infection. A less common cause in this species is the uterine after parturition is a common complication of the hyperfibroleiomyoma (fibroid).

406

7 . THE FEMALE G E N I T A L SYSTEM

IRREGULARITIES OF ENDOMETRIAL GROWTH

Atrophy Atrophy of the endometrium results from loss of trophic ovarian function. Senile atrophy is not important in domestic animals and they retain their reproductive potential throughout their life span. Atrophy is of course most common after castration but may reflect hypopituitarism of chronic inanition or wasting disease or a primary hypophyseal lesion. The endometrium is flat, thin, and greyish in appearance, and in ruminants there are no evident primitive caruncles. The more superficial portions of the endometrium are the more atrophie and, in advanced atrophy, the lining mucosa covers a thin layer of condensed stroma in the depths of which are the inactive glandular remnants which are sometimes cystic. Hyperplasia Endometrial hyperplasia is usually called cystic hyperplasia of the endometrium or cystic hyperplastic endometritis. Both terms are misleading. Cystic hyperplasia, although perhaps the only form of endometrial hyperplasia which is recognizable as indubitably pathologic, is none the less the extreme degree of hyperplasia; lesser and earlier noncystic degrees of hyperplasia are also of pathologic importance. Cystic hyperplastic endometritis is really only an inflammatory complication of cystic hyperplasia. In the bitch and cat with endometrial hyperplasia, superimposed infectious inflammation is common, but in other species it is less common. The origin of endometrial hyperplasia can be attributed to excessive and prolonged oestrogenic activity. The mare is an exception to this generalization because in this species a source of excess oestrogen has not been recorded, or sought. Cystic endometrial hyperplasia in the cow is invariably associated with ovarian follicular cysts or granulosa-cell tumours, both of which are potential sources of hyperoestrogenism. In the ewe, the oestrogen is exogenous and derived from pasture legumes, subterranean clover {Trifolium subterraneum) and red clover {Trifolium pratense). The oestrogenic substance in these legumes is the isoflavone derivative genistein. Some oestrogenic activity is assayable in a variety of plant species, but to date only the above two have been found to have significant potency. There is a strong possibility that the excessive feeding of wheat-germ oil as a source of vitamin E may cause hyperoestrogenism in sheep. It has been suggested that the small amounts of oestrogenic activity in ordinary pasture grasses may have a galactopoietic effect. Ovarian follicular cysts are also present in the ovaries of the dog and cat although some few cases have instead granulosa-cell tumours or papillary cystadenocarcinomas. In the bitch, cystic corpora lutea often coexist with cystic follicles, and it appears that the additional activity of progesterone exaggerates the degree of endometrial hyperplasia and the susceptibility to infection and pyometra. This exaggerating influence of progesterone is especially evident during pseudopregnancy in the cat and bitch.

Noncystic endometrial hyperplasia is not recognizable macroscopically except as an equivocal thickening of the endometrium. The thickening is due to an increase in the size and number of glands which are irregular in their distribution and course, the normal parallel alignment being lost. The stroma is not hyperplastic but is oedematous. The glands may show both proliferative and secretory activity. In the bitch, when a cystic corpus luteum is also present the glands are tortuous and secretory, the mucosal epithelial cells are typically progestational, being hypertrophic with clear cytoplasm (Fig. 7.1 IB), the glands of the basal endometrium are also active, and there is little evidence of the normal partitioning of the endometrium into layers. There is usually some degree of adenomyosis. Cystic hyperplasia, the so-called "Swiss-cheese" endometrium, is the histologie extreme of the condition and is irreversible. It is probable that endometrial hyperplasia is but an exaggeration of the normal proliferative activity of the endometrium in response to ovarian hormones. The lesion can be produced in the bitch and other experimental species by prolonged oestrogen administration and by cyclic administration of oestrogen and progesterone, but the observation that the endometrium subjected to this abnormal stimulation, naturally or experimentally, does not respond uniformly clearly suggests that, although the lesion can be safely attributed to oestrogenic stimulation, there is still much to be learned of the complex relationship between hormonal factors and the local conditions in the uterus which govern its abnormal responsiveness. Cystic endometrial hyperplasia is recognizable grossly (Fig. 7.9B, C). In the mare, in which it is a rather rare condition, the uterine wall is soft, thick, and spongy; if the opened uterus is placed on a table and jarred, the endometrium shivers like a gelatinous mass. The lining has a glistening appearance and is moist; the numerous submucosal cysts, 1-5 cm. in diameter, bulge like blisters of clear fluid into the lumen. The uterus is usually uniformly involved. In the bitch and cat, the nondiffuse form is more common than the diffuse, but structurally they are similar. The cysts are up to 2 mm. in diameter with clear watery contents. In the more severe form in the bitch, there may be localized villous and papillary overgrowths which, histologically, are almost solely of epithelial tissue with scant connective-tissue stroma. Hydrometra is also occasionally present. In the cow, cystic hyperplasia is typically nonuniform and in long-standing cases is often associated with the presence of excess mucus (mucometra) or fluid (hydrometra) in the uterine lumen. Endometrial hyperplasia is a significant precancerous lesion in the human. In domestic animals, this is not so. Adenomyosis (Endometriosis) This term applies to the presence of endometrial glands and stroma between the muscle bundles of the myometrium (Fig. 7.1 OB). In some cases it is a malformation and in others it arises by hyperplastic overgrowth of the endometrium. It is not a common lesion in any domestic species but is seen in the bitch with cystic endometrial hyperplasia.

THE

UTERUS

Fig. 7.9. (A) Site of uterine rupture acquired during uterine irrigation for chronic endometritis. Ox. Note division of myometrium and lipid granuloma beneath serosa on left. (B) Cystic corpora lutea and cystic endometrial hyperplasia with mucometra. Bitch. (C) Closeup view of uterine horn in (B).

407

408

7 . THE FEMALE G E N I T A L

SYSTEM

Fig. 7.10. (A) Prolapse of uterine polyp with inversion of horn. Bitch. (B) Adenomyosis. Glands of normal configuration in myometrium. (C) Chronic endometritis. Ox. Dilated, atrophied glands with periglandular fibrosis.

THE

UTERUS

409

are to be sought then at either end of the gestation period. The normal nonpregnant uterus is endowed with a high degree of resistance to infection, and even in the case of the specific genital diseases—brucellosis, vibriosis, and trichoEndometrial Polyp moniasis—is incapable of supporting bacterial growth or This is a rare lesion seen only in the bitch. In contrast to even the persistence of bacteria for any extended period. the polypoid form of endometrial hyperplasia, the true Something is known of factors which render the uterus polyp contains a substantial connective-tissue stroma in susceptible, at least temporarily, to infection, but virtually addition to glands and is pedunculated. Polyps may be nothing is known of the mechanisms of its resistance. The multiple or isolated and their shape is moulded to the self-limiting nature of most infections, other than those uterine lumen (Fig. 7.10A). They tend to cause prolapse associated with pyometra, has been long recognized and of affected horn, the polyp then to be seen protruding from formed the basis for the recommendation of a period of the vagina. sexual rest for animals with uterine infections. Even the specific genital infections are self-limited in duration; active HYDROMETRA AND MUCOMETRA infection of a uterus with Vibrio foetus or Trichomonas foetus, in the absence of pregnancy, survives only for two The two conditions are considered together as the to three oestrual cycles : Bruceila abortus is an infection of difference is probably only in physical properties and the pregnant uterus and does not persist well in the nondepends on the degree of hydration of the mucin, which in pregnant uterus, although it is apparently capable of turn may be related to the relative activity of oestrogenic persisting in the mammary gland and lymph nodes of hormone. The accumulation of thin or viscid fluid in the infected cows. It is probable that local humoral factorsuterus is concurrent with the development of endometrial antibodies produced in the uterus and detectable in vaginal hyperplasia or is proximal to an obstruction of the lumen mucus—are important in limiting the duration of these of the uterus, cervix, or vagina. In the first instance, the specific infections. But undoubtedly other factors operate amount of fluid may be several litres and the greater the also. Many nonspecific infections are with organisms which volume of fluid, the less viscous it is. Small amounts of are not demonstrably antigenic. In any event, the production mucin give the mucosal surface a gummy stickiness. In of antibodies is too slow to account for the differential cows with cystic ovaries and endometrial hyperplasia, the bactericidal effects of the oestrus and the progestational large volumes offluidare usually associated with functional uterus. Luminal fluids of any phase are capable of supportcysts of the follicles. When terminal anoestrum occurs ing bacterial growth to a good and comparable degree, apparently much of the fluid is resorbed, leaving a small provided that the organisms do not contact the endoquantity of tenacious mucus. As described earlier, such metrium. It appears then, that the resistance of the oestrual uteri usually have thin atrophie walls and the ovarian uterus must depend in large measure on the normal cysts are multiple, small, and thick-walled. In the second uterine leucocytosis of oestrum and its rapid exaggeration instance, that of obstruction to the lumen, the volume of in the presence of infection. It has been well demonstrated fluid depends on the site of the obstruction; in uterus that the uterus which is under the influence of progesterone unicornus there may be 500 cc. ; in imperforate hymen there (which includes the pregnant uterus) is very susceptible to may be 10 litres or more. The fluid is slightly cloudy and many nonspecific bacteria and that a uterus not under the watery but, in some cases of segmental aplasia where the influence of progesterone is remarkably resistant to the volume of retained secretion is not great, it may be very same organisms even when their expulsion is prevented by viscid, ochre-coloured, and sometimes inspissated to ligation of the cervix. This comparison can be carried a rubbery masses of mucin and cellular detritus. In these step further to show that even greater susceptibility to cows the ovaries are normal. Animals with mucometra are infection is present at the implantation sites in the pregnant sterile. If affected uteri become infected an intractable uterus, but it is doubtful whether this can be applied as a pyometra results. An abnormally long and tortuous cervix generalization to all species and all types of infection. The may result in a form of mucometra caused by the retention uterus under the influence of oestrogen and the uterus of of uterine secretions. the castrate are resistant to infection to a comparable INFLAMMATORY DISEASE OF THE UTERUS degree, although in the cow it is suggested that resistance is General considerations. Inflammation limited in extent to increased by oestrogens. These known factors of susceptibility and resistance provide some insight into the the endometrium is termed endometritis; involvement of pathogenesis of the postcoital uterine infections, of the entire thickness of the wall is metritis; of the serosa, pyometra, and of the untoward results of entry into a perimetritis; and of the suspensory ligaments, parametritis. luteal-phase uterus. The classification is to some extent a useful index of the severity of reaction and of the pathogenesis. The great A different set of influences operate in the puerperium. majority of inflammatory conditions of the uterus do begin It is well recognized that uterine infections are likely to in the endometrium and are in some manner associated follow any abnormal parturition such as an abortion, with the reproductive process. The predisposing factors retained placenta, twin births, dystocia, and traumatic Adenomyosis is observed occasionally in cows as part of the local disarray of segmental aplasia. It may also be present as a malformation of the tips of the uterine horns in cows.

410

7.

THE FEMALE G E N I T A L

lacerations of the genital canal. A significant proportion of abortions indeed result from specific or nonspecific endometritides, but these are often complicated by the general factors that pertain to all postpartum infections of the uterus. Of the specific abortive agents in the cow, Vibrio foetus and Trichomonas foetus typically cause early abortion which is not complicated by placental retention or metritis. But with any of these causes, Br. abortus especially, abortion may occur later in pregnancy, at which time the well-developed and manifold interdigitations of the cotyledons favour retention of the placenta and acute metritis. Even in these instances, much of the evidence of infection is due to secondary invasion of the uterus; the specific bacteria are not endowed with any notable putrefactive properties. Granted then that some cases of postpartum metritis are a continuation and exaggeration of a gestational uterine infection, puerperal infection of the uterus is not too incorrectly viewed as analogous to wound infection with the organisms entering via the cervix. It has been stated that probably all mares have uterine infections by streptococci within 1-3 days after parturition but these do not persist for more than 2-3 days. In the cow, too, it has been observed that 25-30 per cent are infected in the normal puerperium but that most recover spontaneously from these infections with Corynebacteriumpyogenes, Escherichia coli, and other bacterial mixtures. Clearly, the outcome will be determined as much by the number and virulence of invading organisms as by the environment within the uterus. The recognized predisposing causes outlined above will all be associated with retarded uterine involution as will most cases of metritis. With the more virulent anaerobic bacteria such predisposition is not essential. The period necessary for normal involution varies with the species and is probably determined by the nature of placentation and the degree of epithelial reconstitution necessary. Apparently, it is well advanced in the mare within 9 days as judged by the capacity for fertile mating at that time. The conception rate is, however, not high in mares bred at this first postpartum oestrus, so that involution is probably not complete. In the cow on the other hand, involution cannot be considered complete until about 50 days postpartum. In the bitch, involution is occasionally much prolonged, with persistence of decidual remnants deep in the endometrium. The two main ingredients of involution are contraction to obliteration of the potential cavity and reconstitution of the epithelium: they proceed in parallel. Retarded postpartum contraction is an index of diminished myometrial tonus. This diminished tone may be part of general debility, it may be an exhaustion phenomenon consequent on prolonged dystocia, on excessive stretching as with twin births or hydrops allantois, or secondary in some obscure manner to already existing inflammation. Whatever the pre-existing cause, it is exacerbated by the establishment of postpartum infection. With significantly diminished tone and contractions, there is retention, beyond the normal period, of a patent lumen and retention within the lumen of autolyzing lochia—a

SYSTEM

mixture of blood, foetal fluid, mucus, and epithelial detritus, often including placental remnants. Involution of the bovine maternal placenta begins by vasoconstriction in the caruncular stalk with fatty degeneration and dissolution and desquamation of the entire superficial layer of the caruncle, complete in about 10 days. By 40-50 days, epithelial repair is complete, taking its origin from surviving epithelium and the glands. Functional closure of the cervix is present at 24-36 hours after parturition although it is still readily dilatable. The greatest volume of uterine lochia is present in the first 48 hours after parturition and is rapidly removed, partly by discharge and partially by résorption. Probably all factors predisposing to infection favour the accumulation of an excessive volume of lochia and its retention beyond the normal period and, by so doing, provide an excellent environment for all types of bacterial growth, of which the most devastating are the anaerobes. Their nutrient supply is increased and improved by the presence of decomposing placental remnants and, in some cases, macerated foetuses. Endometritis In endometritis, it is the endometrium or uterine mucosa which is mainly involved. The term should not be accepted too literally for, except with the very mild forms of infection, there is necessarily some effect of the inflammation on the remainder of the organ. Further, almost all uterine infections begin as an endometritis but may progress so rapidly to any of numerous variations and manifestations that definitions have little worth. The mildest forms are seen post coitus; they are caused by Trichomonas foetus and Vibrio foetus or pyogenic cocci and coliforms of low pathogenicity. It is doubtful if these last-named nonspecific infections will produce postcoital endometritis in adult cows as readily as they do in heifers; rather, it seems as if the virgin uterus requires exposure before acquiring resistance to the organisms ordinarily contained in semen. There are no gross lesions in this simple form of endometritis. A slight opacity of the normally crystal-clear oestrual mucus may be all that is seen. Histologically, the changes are not striking and consist for the most part of a diffuse but light infiltration of inflammatory cells with slight desquamation of the superficial epithelium and no significant vascular changes. Involvement of the glands is minimal. The significance of a few leucocytes in the stroma is always equivocal: they follow within 2-3 days after parturition and are present during oestrus. The best indications of mild endometritis are infiltrated plasma cells and foci of lymphocytes in the stroma (Fig. 7.9A). Resolution of this type of endometritis occurs with no more residue than a few cystic glands with periglandular fibrosis (Fig. 7.10C) although during its course it may be responsible for a series of aborted embryos. More severe grades of endometritis are common to the puerperium. Nothing of significance may be visible on the serosal surface, but the organ is enlarged and flabby, and collapsed rather than firm and contracted. The lumen

THE

contains chocolate-coloured lochia which is slightly tenacious and often without foul odour. With the admixture of inflammatory exudate and placental detritus, the uterine content becomes progressively dirty greyish-yellow in colour. The endometrium is congested and swollen and the intercotyledonary areas are ragged and tattered with shreds of mucosa free in the lumen. Small haemorrhages are common in the congested mucosa and there is a prominent leucocytic infiltration involving all mucosal elements, including the glands, and massing at the surface, where suppuration and superficial necrosis produce the tattered mucosa : the surface is comparable to a pyogenic membrane. The remainder of the genital canal may show nothing more than the traumatic lesions incident to parturition. If the uterus is paretic, there may be no discharge in the vagina. Metritis The distinction drawn here between endometritis and metritis for purposes of description is that in the latter all layers of the uterine wall show evidence of acute inflammation. The uterus is paretic and there may be little or no vaginal discharge. The wall of the uterus is thickened with suffused blood and oedema fluid and is very friable (Fig. 7.12A). The serosa is dull and finely granular with "paintbrush" haemorrhages and a thin deposition of fibrin, or the subserosal vessels may be darkly congested. Other than traumatic rupture, perforation with secondary peritonitis is not common except in anaerobic infections; death in untreated cases usually occurs first from toxaemia or septicaemia. The secretion may be scant or abundant, is foetid, and is dirty yellow to red-black in colour. The microscopic picture is that of a purulent inflammation. The subserosal connective tissues are oedematous and infiltrated with leucocytes, and the same process surrounds the blood vessels of the myometrium and permeates between bundles of, and individual, muscle fibres which themselves undergo granular degeneration. In metritis as in acute endometritis, the leucocytes mass on the mucosal surface and are associated with extensive haemorrhage, necrosis, and sloughing. Invasion of blood vessels, both arteriolar and venous, aggravates the lesion. Thrombosis may extend to the vessels of mesometrium with the usual sequelae.

411

UTERUS

ment by granulation scar tissue, the uterus takes on the nature of a fistulous tract. The changes depend on the duration and severity of the inflammation but consist essentially of productive fibrosis and leucocytosis in which plasma cells predominate. Thickening of the endometrium is by inflammatory tissue; the glands are depleted; those which survive are atrophie, flattened and attenuated, or cystic due to the periglandular fibrosis. The lining mucosa may be intact, denuded in places, or show foci of polypoid hyperplasia or squamous metaplasia (Fig. 7.12C) as do any chronically irritated mucous membranes. The exudate in the lumen is not copious and may be serous, catarrhal, or frankly purulent. Much of the labile endometrial stroma, especially that of caruncles, may be replaced by useless scar tissue, and dystrophic calcification of necrotic portions of the endometrium may sometimes be extensive enough that the lining of the uterus feels gravelly. Uterine Abscess This is not a common observation. The localization of an infection to one part of the uterine wall is thought to follow severe metritis or localized traumatic injury to the infected endometrium. Such an abscess may reach 6 inches in diameter and is usually well encapsulated although there may be some perimetrial adhesion and, in few instances, rupture into the peritoneal cavity or an adjacent hollow viscus. Parametritis and Perimetritis Chronic adhesive peritonitis involving the genital tract does not usually result from septic metritis because the uterine serosa offers an efficient barrier to the spread of infection, and spontaneous rupture of an infected uterus is not common. Few virulent infections spread to the supporting ligaments. Excluding an origin from an extragenital focus, perimetritis and parametritis follow manual manipulation of the ovary, pyosalpinx, obstetrical operations, removal of retained placenta, and uterine irrigations; in each of the latter three circumstances, there may be accidental perforation or rupture of the uterus. The extent of the adhesion may vary from a few fibrous bands to dense connective tissue which obscures the contour of the organs and fixes them to adjacent viscera (Fig. 7.12B). Abscesses may form in the adhesions of the ovarian bursa and the rectovaginal pouch.

THE SEQUELAE OF METRITIS AND ENDOMETRITIS

Many of the milder cases of endometritis recover health and fertility spontaneously; many of the acute cases of metritis are fatal in spite of therapy. Among the residual and complicating conditions are chronic endometritis, uterine abscess, parametritis, salpingitis, pyaemia, and pyometra. Pyelonephritis (see Diseases of the Kidney) is an occasional complication. Chronic Endometritis Recovery from the acute phase of the infection often results in chronic endometrial involvement. With greateror-lesser degrees of endometrial destruction and replace-

Salpingitis (see under Fallopian Tubes) Pyaemia Acute deaths from metritis usually result from toxaemia or septicaemia. In cases of longer standing and pyogenic infection, intermittent pyaemia may result in metastatic infection of other organs and tissues, Corynebacteriwn pyogenes being the organism most often incriminated. The tissues most often involved in the metastatic infection are the valvular endocardium, joints, myocardium, and lungs.

412

7 . T H E FEMALE G E N I T A L SYSTEM

PYOMETRA

Historically, pyometra may occur as a complicating sequel to uterine infections of the types described above, but as it is a pathologic entity with a number of other factors also entering into its pathogenesis, it is considered separately. Pyometra is an acute or chronic suppurative infection of the uterus with accumulation of pus in the uterine lumen in the presence of a closed cervix. The definition is usually extended to include those cases in which discharge is prevented by an acquired or congenital stenosis. Pyometra is an uncommon condition except in the cow, bitch, and cat, but it is probable that the same pathogenetic principles apply to all species. Pyometra in association with mechanical obstruction to discharge. This type of uterine infection is sometimes seen in the mare as a sequel to prolonged endometritis. The incriminated organisms are usually Strep, genitalium (syn. zooepidemicus) or Klebsiella pneumoniae var. genitalium. These genital infections in the mare typically produce vaginitis, cervicitis, and endometritis; in the course of chronicity the chronically inflamed cervix becomes indurated and may become stenotic, thereby preventing the expulsion of uterine exudate. Anomalous development of the uterus has been described earlier. In the segmental aplasias and with imperforate hymen, the lumen proximal to the site of obstruction becomes distended with mucus and cellular detritus. These closed cavities provide a satisfactory environment for bacterial growth, but this is not a frequent complication. When it does occur the source of the infecting organisms is probably haematogenous. Pyometra in association with functional obstruction to discharge. The great majority of cases of pyometra fall into this category and provide the basis for the definition of pyometra given above. The cervical closure may not be complete, but the discharge is never voluminous although it may appear at the vulval lips of the bitch and collect in the anterior vagina of the cow. An essential component of this classical type of pyometra is a solid or cystic corpus luteum which is retained beyond its normal cyclic span, and it is pertinent at this point to digress to a consideration of the retained corpus luteum. Following ovulation, a corpus luteum develops from the ruptured follicle and, when fully grown, dominates the contour of the ovary. In the absence of fertilization and pregnancy, the corpus luteum normally degenerates shortly before the next ovulation. If pregnancy occurs and proceeds normally, the corpus luteum persists throughout the period of gestation, normal or aborted (except for the mare among domestic species). The corpus luteum of pregnancy is not known to be different in any way from that of the oestrual cycle. A corpus luteum persistent beyond these physiological ranges is to be regarded as a retained corpus luteum with pathologic implications, although it is to be pointed out that its persistence in cows is usually, and perhaps always, secondary to other pathologic processes in the uterus.

Retained corpora lutea in the cow can be discussed in relation to the periods post coital and post partum. Following service or artificial insemination, many cows return to oestrus after a period in excess of the normal cycle length and the inference is made that this is due to early embryonic death following a brief period of implantation and before the conceptus is large enough to be recognized in discharge as an abortion. The inference is undoubtedly true in many instances and probably true in most, the exceptional instances being of failure of fertilization at service with one or more subsequent periods of unobserved or silent oestrum. Such instances are often diagnosed clinically as persistence or retention of the corpus luteum, but referring to events this is not so. However, death of the foetus at a later stage of development, if not followed by abortion, may be followed by maceration or mummification. Occasionally, such macerated or mummified foetuses are spontaneously expelled but often they are retained within the uterus, and under these circumstances the corpus luteum is retained and can be regarded as pathological. If the foetal death is due to existing infection of the uterus with pyogenic organisms, pyometra is likely to follow, necessarily with persistence of the corpus luteum. In some high-producing mature cows, the corpus luteum of pregnancy may persist after parturition. It is also possible, although the evidence is not conclusive, that the corpus luteum of the first postpartum oestrus may persist for 3 months or more. The retention of corpora lutea under these circumstances is not secondary to uterine disease although there may be some delay of uterine involution. However, uteri under this prolonged influence of a corpus luteum are highly susceptible for the initiation of infection or the exacerbation of a chronic or low-grade puerperal endometritis. Pyometra is a likely sequel and the further persistence of the corpus luteum becomes dependent on uterine abnormality. Summarizing then for the cow, it may be said that persistence of the corpus may occur for a restricted period postpartum without uterine abnormality, but in all circumstances of indefinite persistence this is initiated by some pathologic distension of the uterus and that, once initiated, the uterine and ovarian lesions are mutually interdependent: removal of the retained corpus luteum or neutralization of its influence by administered oestrogen is followed by expulsion of the macerated foetus or uterine pus and, conversely, evacuation of the uterus is followed by degeneration of the retained corpus luteum. Only occasionally does spontaneous recovery occur in cows. After persistence for some 6 months or more the retained corpus luteum becomes more deeply embedded in the ovary and smaller and more colourful; it is then no longer palpable. Persistent luteal tissue in the bitch is of dual origin. Cystic corpora lutea have been discussed with the ovaries. Although their natural history is not known, it is possible that they persist indefinitely or develop in overlapping series. The second type of persistent luteal tissue in the bitch, and the usual type in the cat, is that in the corpus

THE

UTERUS

Fig. 7.11. (A) Pyometra. Bitch. (B) Glandular hyperplasia with progestational change in epithelium. Pyometra. Bitch. (C) Cross section of uterus. Bitch. Cystic glandular hyperplasia and pyometra. (D) Caseous uterine tuberculosis. Ox.

413

414

7 . THE FEMALE G E N I T A L

luteum of pseudopregnancy, and this may persist for a month after oestrum. Both types of luteal persistence are important in the pathogenesis of pyometra in the bitch but, unlike the situation in the cow, their persistence is not due to abnormal uterine distension; why they form or persist is not known. The role of retained luteal tissue in the pathogenesis of pyometra appears clear. The secreted progesterone endows the uterus with a high degree of susceptibility to infection, maintains functional closure of the cervix, and inhibits myometrial contractility. The amount of pus retained in the uterus of a cow with pyometra varies from a few ounces to more than a gallon and is thick, rather mucinous, and cream or greyish green in colour. The cervix has no seal of mucus so, although contracted, there is usually escape of a small amount of pus into the anterior vagina. The wall of the uterus is thick, doughy, and paretic, but in long-standing cases, especially as complications of mucometra, the walls are thin or fibrosed. Pyosalpinx and perimetritis may coexist (Fig. 7.12D). There are no significant extragenital lesions and, apart from purely genital signs, the disease is asymptomatic. The histological changes do not differ significantly from those of endometritis of comparable duration and severity. Pyometra in the bitch and cat is a more acute lesion than in the cow and, typically, there is remarkable distension of the uterine horns which may come to occupy most of the peritoneal cavity (Fig. 7.11 A). Distension of the cornua may be symmetrical or asymmetrical, uniform or as ampulla-like dilatations as in the uterus of midpregnancy. The cervix is completely or almost completely closed as a functional response to the luteal hormone. The serosal surface of the uterus is dark in colour and the vessels are congested and prominent. The wall is friable and either rupture or perforation with secondary peritonitis is not uncommon. There may be obvious inflammation of the peritoneal serosa and suspensory ligaments but this is unusual. The nature of the uterine content is variable. In the more severe cases, usually those infected with Escherichia coli and Proteus spp., the exudate is thick, viscid, tenacious, opaque red-brown in colour, and with a characteristic foetid odour. In other cases, usually those infected with streptococci and staphylococci, the exudate is more typically purulent. When the exudate is removed, the mucosa is seen to be irregular in thickness, necrotic and ulcerated in portions with irregular superficial haemorrhages, and in other portions obviously hyperplastic, dull-white and dry in appearance with small cysts visible in these hyperplastic areas (Fig. 7.11C). Microscopically, the most significant feature is the remarkable endometrial hyperplasia and progestational proliferation in almost all cases (Fig. 7.1 IB). The cells of such progestational epithelium are enlarged, columnar, vacuolated and have a small pycnotic nucleus. In some cases, the normal single layer of cells piles up to produce pseudostratification or localized papillary proliferations. Whatever remains of the endometrial lining may show this

SYSTEM

development or it may be patchy and alternating with normal or even with metaplastic squamous epithelium which develops in response to irritation as a protective phenomenon. These changes are of the forerunning endocrine imbalance. The histological changes due to superimposed infection vary with the bacterial cause and time. Masses of neutrophil leucocytes collect in the uterine lumen and in the glands, although there is relative sparing of the latter unless they are cystic. The migrating leucocytes collect near the surface and then penetrate the epithelium, or, if in number, push it off to enter the lumen. In milder cases, there may be few neutrophils in the endometrial stroma, but they are not many when compared with the numerous plasma cells and lymphocytes. There may not be much vascular reaction over and above that of hormonal origin although perivascular reaction and leucocytosis of lymphatic vessels is almost constant in the myometrium. Sometimes the reaction is much more severe than that just described and in the endometrial stroma there are all the exudative phenomena of acute inflammation accompanied by the early reparative response of granulation tissue. The blood vessels are very congested and some show thrombosis, and about others there is diapedesis or larger haemorrhage. The stroma is oedematous and bullae often lift off the overlying epithelium. Numerous neutrophils infiltrate the stroma and collect in the lumen. There is little formation of fibrin, and rarely are there microabscesses in the mucosa although the surface may become a veritable pyogenic membrane. It is now generally accepted that most cases of pyometra in the bitch and cat are infective inflammations superimposed on endometrial hyperplasia and, therefore, secondary to prolonged hormonal imbalance. Most cases occur during pseudopregnancy. Some cases occurring during pseudopregnancy may be of the above type, but doubtless the pathogenesis of many cases is comparable to that of postpartum pyometra in the cow, being merely an altered course, under the influence of progesterone, of a pre-existing uterine infection. If the animal survives, the course may be modified by remissions and exacerbations which are to be related probably to cyclic changes in the ovary and periods of progesterone production with induced sensitivity to infection and functional closure of the cervix. In addition to these developmental types of pyometra in the bitch, some few cases will develop as complications of mechanical obstructions or congenital atresias of the genitalia. Extragenital lesions associated with pyometra in the bitch are common and due to severe intoxication and probably also to intermittent bacteraemia. Depression of bone marrow leads to anaemia and prominent extramedullary elaboration of leucocytes, especially in the liver, kidney, spleen, lymph nodes, lung, and adrenal glands, and there is typically a severe leucocytosis. A variety of degenerative and inflammatory lesions, including glomerulosclerosis, occur in the kidneys, and there may be haemorrhage and necrosis of the adrenal cortex and congestion of viscera.

THE

UTERUS

Fig. 7.12. (A) Acute metritis. Ewe. (B) Parauterine abscess. Ox. (Courtesy of C. A. V. Barker.) (C) Squamous endometrial metaplasia in chronic endometritis. Ox. (D) Pyometra with perimetrial and bursal adhesions. Ox.

415

416

7.

T H E FEMALE G E N I T A L SYSTEM

SPECIFIC CAUSATIVE TYPES OF UTERINE INFECTION

To be considered under this heading are three specific infections of the uterus, each of which is responsible for a characteristic anatomical form of metritis. Those infectious diseases in which abortion is a prominent feature are discussed under diseases of the pregnant uterus. NECROBACILLOSIS. Infection of the vagina and uterus with Fusiformis necrophorus is seen in post-parturient sheep and cows as an infection of contamination superimposed on traumatic or inflammatory genital disease. Necrobacillary metritis is usually fatal. The lesions are typical of those produced by this organism in any location and are characterized by dry coagulative necrosis separated by a narrow red zone of intense hyperaemia from surrounding viable tissue. An affected uterus is enlarged and the wall is thick and rigid. There is scant inflammatory exudate in the lumen although it may contain necrotic placental and caruncular remnants. The mucosa is thickened and folded and in large patches is necrotic, fragile, and ulcerated with a dark ragged surface. On section, the mucosal thickening is of a yellowish necrotic layer of tissue and this is separated by a zone of hyperaemia from an outer layer of firm grey granulation tissue which replaces the myometrium. Similar lesions are seen in the cervix and vagina. Typically, the masses of bacteria are found facing a wall of leucocytes at the advancing margin of the necrotic zone which is itself structureless. Extensive vasculitis with thrombosis is also characteristic of this infection. Thrombi can usually be found in the uterine veins and they may extend to the vena cava. TUBERCULOSIS. It is estimated that some 20 per cent of cows with generalized tuberculosis and 4 per cent of all tuberculous cows have involvement of the endometrium. There are three routes of infection, namely, haematogenous, via the Fallopian tubes from the peritoneum, and coital; of these, the last is exceptional. As in tuberculous lesions generally in cattle, there are two anatomical forms of the lesion, miliary tuberculosis and diffuse caseating tuberculosis, although transitional forms do exist. It is generally accepted that the disseminated miliary lesion is of haematogenous origin during the phase of early dissemination. In miliary tuberculosis, the uterus may appear normal externally. In the early stages, there may be no exudate in the lumen but later, as the granulomas enlarge, and ulcerate, the uterus will contain a yellow purulent exudate. The granulomas are visible as few or many nodules in the mucosa, usually the more superficial portions, and microscopically are of typical tuberculoid structure. A common site is near the bifurcation of the uterus or in the caruncles of the pregnant uterus. Caseous tuberculosis causes thickening and rigidity of the horns with serofibrinous or purulent fluid in the lumen. The endometrium is thickened, dry, and extensively caseous (Fig. 7.1 ID). There may be a marked exudative reaction with intense leucocytic infiltration. The caseated area is usually demarcated by a zone of epithelioid cells from a margin of connective tissue.

In association with the uterine lesion, there is often involvement of other portions of the genital tract. There may be multiple red granulations on the surface of the ovary and its ligaments or there may be enlargement of the ovaries with parenchymal tubercles. Tuberculous salpingitis or pyosalpinx is probably the rule when the Fallopian tubes are the portal of uterine infection. Similar lesions may be found infrequently in the lower genital tract. Infection of cows with the avian strain of the organism also produces a tuberculous metritis and placentitis with multiple small endometrial granulomas. STAPHYLOCOCCAL GRANULOMA. Staphylococcal infec-

tions of the sow's uterus appear to be common as a cause of postpartum metritis and also appear to respond readily to treatment. Granulomatous lesions occur occasionally in sows and cows but are quite uncommon. They have been reported following service by a boar with seminal vesiculitis caused by this organism. The lesion is a large node of fibrous connective tissue enclosing small abscesses in which colonies of the organism are demonstrable. DISEASES OF THE PREGNANT UTERUS

Embryonic Death There is little that can be said with profit of the pathology of the ovum, zygote, or early embryo, but a brief consideration is included here for purposes of orientation. When fertilized ova die, they undergo progressive cytolysis within the zona pellucida, which often remains intact after the cytoplasm and nucleus are dead. The whole then disintegrates and is resorbed or discharged at the next oestrum. It is rare to recover abnormal ova from the bovine Fallopian tube during the first 72 hours postoestrum. Presumably, in those cases in which oestrus occurs after a normal cycle, the ova die most commonly between the fourth and tenth day of the cycle. Most embryonic deaths in cows, however, are associated with prolongation of the interoestrual period, and it appears that, although the embryo may die at any period, it does so most commonly at about the sixteenth day. In the embryonic stage, the embryonic tissue proper disappears first and the trophoblast remains for a while before degenerating. The incidence of embryonic mortality is remarkably high in the species which have been studied, and probably in all species but authoritative answers to the whys and wherefores are not available; they are difficult and costly to obtain. Foetal Death A degenerate zygote or early embryo may be resorbed or expelled from the uterus. At a later stage in development, the dead foetus may be mummified, macerated, or aborted, an abortion being suitably defined as the recognized expulsion of a dead foetus prior to the time of expected viability. A dead foetus delivered within the period of expected viability is conveniently referred to as stillborn. In uniparous animals, death of the foetus is usually

THE

followed by abortion but sometimes the foetus is retained. The factors which determine the course of events are not clear. In multiparous species, if most of the foetuses die at the same time all are likely to be aborted, but it is more usual for one or several dead foetuses to be retained with the remaining viable ones and delivered at parturition, when it is often apparent that the deaths have occurred at different ages, the dead foetuses being of different sizes and degrees of mummification or maceration. Mummification of Foetus Mummification of a dead foetus is seen occasionally in any, but usually multiparous, species and most commonly in the sow. In the mare, it is typically one of twin foetuses which is macerated. A prerequisite for mummification is that infection not be present. The fluids are resorbed and the membranes become closely applied to the desiccated foetus. The whole becomes brown or black and rather leathery, moist on the surface with sticky mucus, but without odour or exudate. The time required for complete mummification will depend on the size of the foetus but probably requires as long as 6-8 months in the case of a 6-months bovine foetus, but all stages may be observed from the earliest of beginning separation of the placenta with haemoglobin staining of the tissues to the latest, when all that remains is a firm and shrunken remnant consisting almost wholly of dried skin and bones (Fig. 7.13A). Until the time of expulsion, which on occasion occurs spontaneously, or parturition in multipara which still carry some viable foetuses, the cervix remains closed and sealed. In uniparous animals, the mummified foetus is usually retained indefinitely or if aborted may only be delivered into the vagina. Animals which have had and recovered from a mummified foetus usually breed normally on subsequent occasions so there cannot be any serious uterine lesion accompanying the foetal death. A special example of mummification, referred to as bovine haemic mummification, is seen in cows of any breed but especially in Guernseys and is reported to be quite common. A recessive lethal gene is supposed to be operative. Separation of the placenta is effected by interplacental haemorrhage which begins about the centre of the placentome but spreads out over the organ until complete dehiscence occurs. The blood then spreads in the uterochorionic space between the placentomes and may be extensive enough that the foetus and its membranes are enveloped in a blood bath. Resorption of serum and foetal fluids progresses slowly leaving for a time a sticky red-brown remnant of the blood clot, but ultimately there is desiccation. The corpus luteum is retained. Maceration and Emphysema of Foetus Maceration and emphysema of the foetus depend on the presence of infection in the uterus. If the early embryo succumbs to uterine or embryonic infection, maceration is usually followed by résorption from the uterus or expulsion along with a small amount of purulent exudate.

UTERUS

417

Such, apparently, is the usual course of events in vibriosis and trichomoniasis of cows but is to be expected also with any sort of nonspecific endometrial infection. The causes of infectious death of the conceptus during the period of the foetus are the same as above, but the consequences, pyometra or acute endometritis, are usually more severe because of the presence of decomposing foetal remnants. The differences between pyometra and endometritis are as discussed earlier; in pyometra, the corpus luteum persists, the cervix remains sealed, and the uterus withholds its contents. If the corpus luteum and cervical seal break down there is a purulent discharge of the contents and, except for the presence of foetal remnants, this endometritis does not differ much from that of the puerperium. After about the third month of pregnancy in the cow, complete foetal maceration does not occur but the bones, either more-or-less complete or only the ossification centres, resist maceration (Fig. 7.13B). They may be discharged or be retained in the pus of pyometra indefinitely, often near the cervix. The uterine pus is usually thick and intensely foetid, but this depends on the nature of the infection; in trichomoniasis, the exudate is watery and odourless. The usual infectious causes of foetal death and endometritis are not potent gas formers; the development of foetal emphysema almost invariably depends on patency of the cervix and on invasion of the uterus and dead foetus by putrefactive organisms from the vagina. There are two common preludes to emphysema, dystocia at or near term, and incomplete abortion. In incomplete abortion, the cervix is open but not completely dilated and the foetus may be delivered into the cervix or anterior vagina or, because of malpresentation, uterine inertia, or inadequate dilation of the cervix, it may be retained in the uterus. The foetus putrefies, becomes distended with foul gas and crepitates. If the foetus is small, the dam may survive the initial acute episode of foetal emphysema after which maceration occurs in a chronic, foul purulent metritis. The cervix is not sealed but, because of uterine paresis, the pus is retained in the flaccid, dependent organ (septic metritis, suppurative metritis or pyometritis, as distinct from pyometra), and with it the foetal bones. Advanced uterine lesions accompany the macerated foetus. The uterine wall is thickened and the reaction within it varies from the acute exudative inflammation of pyometra to more-or-less complete sclerosis and replacement by granulation tissue in long-standing cases. In these, the uterus closes firmly about the bones, and the bones may cause perforation. Foetal emphysema, at or near term, complicating dystocia is fatal unless treated and maceration is not an expected sequel. In some cases of uterine torsion however, the twisted cervix and vagina produce an adequate seal against bacterial invasion of the dead foetus, and mummification, rather than maceration or emphysema, results. Worthy of mention is foetal emphysema in ewes caused by Clostridium feseri the organism responsible for blackleg. It affects foetuses near full term, causing acute tympanitic distension of the uterus, typical haemorrhagic

418

7.

THE FEMALE G E N I T A L

and necrotizing lesions of the foetus, and the accumulation of dark thin discharge in small amounts in the uterus. The pathogenesis of this special infection is not entirely clear, but there is usually a relation to rough handling such as at shearing. Cystic Placental Mole This is an extraordinary development that follows embryonic maceration. It is not common and should not be confused with hydatidiform mole. In the period of the embryo the foetal membranes are, in volume and mass, the greater part of the products of conception, and it is possible for the embryo to die and disappear while the membranes persist and possibly even continue to grow for a while. Most moles would correspond in size to a 3 or 4 months' pregnancy. The form of the membranes is retained and they may or may not bear small cotyledons, if they do, the cotyledons may be attached lightly or not at all to the caruncles of the uterus. There is usually no patent lumen to the mole, it being rather a mass of clear gelled fluid bound together by the surviving placental stroma, although in those cases showing placentary development the allantoic and amniotic epithelia may be present and apparently viable. Probably in all cases there is a thin purulent exudate in the uterus. The condition may persist as a pyometra with necrosis of the mole or it may be discharged with purulent exudate. Adventitial Placentation (Semiplacenta diffusa) The development of intercotyledonary placentation in ruminants is a mechanism of compensation for inadequate development of placentomes. The inadequate number of placentomes is primarily endometrial and may be congenital or acquired. There are normally between 75 and 120 caruncles in the cow and between 40 and 125 in the ewe and goat. Not all of them are utilized in a normal single pregnancy. Occasionally, the numbers are much less as a congenital disorder of endometrial organization; more commonly, the reduction in number is acquired by inflammatory destruction of portions of the endometrium. Compensation consists of a great increase in the size of remaining caruncles during pregnancy and many of them may fuse, and by the development of a more primitive villous placentation between the placentomes (Figs. 7.14; 7.15). The adventitous placenta develops first adjacent to the placentomes; the process may remain localized or involve virtually all of the intercotyledonary placenta, chiefly along the floor of the uterus. In the latter instances, pregnancy is insecure and may not proceed more than half way. Hydrallantois is a complication. Hydramnios and Hydrallantois The accumulation of excessive foetal fluid and oedema of the membranes are usually coincident and accompanied by foetal anasarca. Not rare in the cow, it is in other species. The accumulated foetal fluid is usually in both the amniotic and allantoic cavities although it may be disproportionately great in one or the other. There is normally

SYSTEM

6-15 litres of allantoic fluid in the cow and 3-6 litres of amniotic fluid, both volumes increasing to a maximum at about mid-gestation and then progressively decreasing to term. The excessive accumulation of fluid ought to have an obstructive origin, but in most cases the pathogenesis remains hypothetical. Such obstruction could be to the placental circulation of blood or the circulation and résorption of the fluid with, in the first instance, increased production of fluid and, in the second instance, retarded removal of fluids. Torsion of the uterus or umbilical cord (the latter not likely in cows) does result in oedema of the placenta, but there is no very significant increase in the foetal fluids. The two principal conditions under which the fluids accumulate to excess are foetal malformation and adventitial placentation. There is a high incidence of the condition in bison hybrids, in association with chondrodystrophic and muscle-contracture malformations of bovine and ovine foetuses, as well as other generalized types of foetal malformation. There is usually accompanying foetal anasarca. There is a variable quantity of excess fluid in the membranes, anything up to 50 gallons, and it is not notably different in quality from normal. The membranes themselves are usually not thickened more than a few centimetres. The fluid may accumulate slowly or begin to accumulate rapidly at any stage. Dystocia with uterine paresis, retention of placenta and acute metritis are important sequelae in those few cases that do not abort earlier in gestation. Amniotic Plaques and Placental Calcification These are normal and their inclusion here is warranted only to avoid confusion to anyone seeing them for the first time. Amniotic plaques are foci of squamous epithelium on the internal surface of the amnion. They are 2-4 mm. or so in diameter, flat, and resemble lesions of the poxes. They are especially concentrated on the umbilical stump where they are taller, cylindrical or papilliform. They seem to be constantly present on the bovine amnion during the middle trimester and they do also occur in other species but have not received much attention. The deposition of calcium, visible about the small blood vessels of the placenta as white streaks and spots, occurs in many species from about the end of the first to the middle of the second trimester. The degree of calcium deposition is quite variable and is more extensive in the allantois than in the amnion (Fig. 7.13C). Rarely, metaplastic ossification occurs. There is no indication of why the calcium is deposited nor what, if any, place it has in placental economy. Prolonged Gestation Syndromes characterized by abnormally long gestation periods occur in cattle and sheep. These syndromes have been only partially defined but, in cattle, two syndromes have been shown to have a genetic basis, the trait being governed by autosomal recessive genes, the defective foetus being homozygous.

THE

UTERUS

Fig. 7.13. (A) Mummifying foetuses. Pig. (B) Macerating foetus. Ox. (C) Calcium deposition. Placenta. Ox.

419

420

7.

THE FEMALE G E N I T A L

Fig. 7.14. Adventitial placentation. Uterus. Ox.

SYSTEM

THE

Fig. 7.15. Adventitial placentation. Placenta. Ox.

UTERUS

421

7 . THE FEMALE G E N I T A L SYSTEM

422

Two patterns of prolonged gestation in cattle are recognized : the first, which is most common in the Holstein and Aryshire breeds, produces a nonviable, large calf after a gestation period which is approximately 2 months longer than normal. The parturition is abnormal; the maternal preparations of relaxation of the pelvic ligaments and filling of the udder are minimal, and assistance is usually necessary. The calves are large, but of nearly normal proportions. Death is due to an uncontrollable hypoglycaemia. The only morphologic feature of these calves that seems related to the defect is lack of differentiation of the hypophyseal acidophils. In the second type of prolonged gestation, which is seen in the Guernsey, Jersey, and Swedish Red and White breeds, foetal monsters are common. These include animals with severe head anomalies of the cyclopian pattern, as well as some which lack only the adenohypophysis. Probably, adenohypophyseal aplasia is common to them. Many of these foetuses fail to develop after approximately the seventh month of gestation; in these cases the length of gestation appears to be determined by the viability of the foetus. Some gestation periods last 17 months; at this time, presumably, the placenta degenerates and the dead foetus, still developmentally immature, is expelled. Not all foetuses of this group follow this pattern; foetal growth continues in some, and in these the gestation period is extended by only a month or so and the calves are usually grossly deformed giants which die in utero. Prolonged gestation in sheep appears not to be an inherited tendency, and it is likely that not all cases are in cattle. The condition in sheep is associated with cyclopiantype malformations and absence of the pituitary gland. The lambs remain alive and continue to grow for as long as 2 months after term. The foetuses die without initiating parturition. Abortion and Stillbirth It will be apparent from the foregoing discussions that abortion or stillbirth are merely among the sequelae of intrauterine foetal death. The causes in general are the same irrespective of the period of gestation. It is to be remembered that diseases of the pregnant uterus do not always result in foetal death; on occasion the foetus may be delivered alive, either prematurely or at term, and live or be weak and succumb shortly after birth. A list of diseases—infectious, toxic, nutritional, physical—which are known to have resulted in specific or nonspecific and sporadic abortion would be a long one, and frequent mention is made throughout these volumes to abortion in relation to specific disease. Selected for description here are those infections which characteristically result in abortion as their chief manifestation. BRUCELLOSIS. Bacteria of the genus Bruceila are small, Gram-negative bacilli or coccobacilli which are strictly parasitic, prefer the intracellular habitat, and produce in animals chronic infections manifested typically by abortion. The three classical species of Bruceila, namely Br. abortus,

Br. suis, and Br. melitensis, are distinguishable to some extent by biochemical reactions but chiefly by serological means. The serological differences, however, are quantitive, not qualitative, and are related to the relative amounts of the A and M antigens possessed by the three species. Not infrequently, however, strains of Brucella are encountered which do not fit the classical scheme; the best-known example has been designated as Br. intermedia because it has the biochemical characters of Br. melitensis and the serological characters of Br. abortus. There are other examples of divergent types and probably still others can be accumulated. The fact that the differences between the various species and variants are quantitative but that each species and variant is rather fixed in its properties has led to the reasonable proposal by Renoux that all should be considered one species, Br. melitensis and that the present species and variants with fixed properties should be regarded as varieties of this one species. The biological similarities between the various strains of Brucella are in keeping with the remarkable similarities in the diseases produced in the different hosts by the various species of the organism. Brucella abortus is chiefly an infection of cattle, Br. melitensis prefers goats and sheep, and Br. suis is found chiefly in swine. Cross infections do, however, occur and almost all domestic species are susceptible. Brucella ovis is a new species which produces natural infection only in sheep. Bovine Brucellosis Caused by Brucella abortus. Brucellosis occurs in cattle in most parts of the world. Some countries are free of the disease either because of measures taken to prevent its entry or to eradicate it but, where the disease is endemic, the incidence may approach 20-30 per cent. The usual source of infection for cattle is an aborted foetus or placenta, or contaminated uterine discharges, and the usual route of infection is alimentary. Infection can occur per vaginum, via the conjunctiva, and through the broken or unbroken skin. The relative importance of these latter routes is not known. Coital infection can occur but is uncommon especially if genital infection in the male is long-standing, possibly because fewer organisms are excreted in semen from chronic lesions than from early lesions in the genitalia of bulls. Infection can be transmitted at artificial insemination if semen from infected bulls is used. Irrespective of the route of infection, the development and establishment of infection are probably comparable and will depend on the age and reproductive status of the animal, its inherent resistance, and on the dose and virulence of the infecting strain of the organism. Young cattle are relatively insusceptible up to about the age of puberty. They can be infected by the usual routes and means, including the ingestion of milk in which the organisms are intermittently excreted, but they throw off the infection in the course of a few months. Once infection is established in sexually-mature animals, females especially, it tends to persist indefinitely. Some,.

THE

perhaps many, animals will recover completely, but which ones will and when they will cannot be predicted. The organisms extend quickly to the lymph nodes regional to the point of entry, and there they provoke an acute lymphadenitis. The inflamed glands are enlarged, often much so, hyperplastic with no clear corticomedullary distinction, and frequently bear small or large medullary haemorrhages. The sinuses are infiltrated with neutrophils and eosinophils; germinal centres and proliferative activity become obvious ; and there is a slow but remarkable accumulation of plasma cells in the medullary sinusoids. The changes in the regional nodes take some weeks to develop fully and they persist for a prolonged period. There is no fibrosis or necrosis in the nodes. The infection may be overcome in the regional nodes but, once established, it is expected to spread during the phase of acute regional lymphadenitis. Spread is chiefly haematogenous and bacteraemia may persist for several months, the duration of persistence apparently depending on the susceptibility or resistance of the host. As the infection becomes chronic, bacteraemia becomes intermittent, ceases in some animals, and recurs irregularly for at least 2 years in 5-10 per cent of animals. Also, it tends to recur at parturition. It might be expected that the bacteraemic episodes would result in localization and persistence of the organism in many tissues but, curiously, localization is largely restricted to the spleen, mammary glands, mammary lymph nodes, and pregnant uterus of the female, and to the lymphoid tissues, testis, and accessory glands in the male, and such localizations occur in the early bacteraemic phases. The organism has little or no predilection for the kidney (although microscopic interstitial nephritis may be present), ovary, bone marrow, or mesenteric lymph nodes, and appears not to be excreted in the urine or faeces. Localization does occasionally occur in synovial structures to produce a purulent tendovaginitis, arthritis, or bursitis, but whether localization and persistence occur in a synovium which is healthy is not clear; some pre-existing inflammatory change may be necessary. Infected animals, almost without exception, excrete Bmcella abortus in the colostrum. Thereafter, excretion of the organism in milk may cease but, frequently, it continues, although intermittently, throughout the period of lactation. Organisms excreted in milk are an important source of infection for children : for calves also but they recover without significant effect. It is still not clear whether and to what extent Bmcella abortus causes anatomical changes in the mammary glands. Such must be expected, but they must also be mild and difficult to distinguish from the focal inflammatory reactions commonly present in mammary glands. Dense interstitial infiltrations of the interstitial tissue by plasma cells, lymphocytes, and histiocytes and exudation of neutrophils in acini probably constitute the usual changes. The mastitis is focal and not attended by gross changes. The cellular content of milk is increased. Bmcella abortus has special affinity for the pregnant

UTERUS

423

endometrium and foetal placenta to which it spreads haematogenously during the initial or later bacteraemic phases to produce extensive lesions. The lesions, to the naked eye, are characteristic but not pathognomonic; similar lesions of lesser severity may be caused by Vibrio foetus and other infections, and similar lesions, usually of greater severity, are produced by fungi. There is considerable variation in the severity of the uterine lesions and this is reflected to some extent in the course of the local infection; if the lesion is severe, abortion or premature birth is the likely outcome, and if the lesion is of minor severity the calf may be delivered normally at term and be viable or nonviable. The intrauterine lesions apparently progress very slowly because an interval of many months may elapse between infection and abortion or normal birth. Abortion occurs most often in the seventh and eighth months of gestation. Once the infection localizes in a pregnant uterus it almost certainly remains there and remains active until the foetus and placenta are delivered and for some time thereafter. The nonpregnant uterus is not particularly susceptible to Bmcella abortus and, following abortion or parturition, the organism is cleared from the uterus in a few weeks, or longer in some cases. The external appearance of an infected pregnant uterus is normal. Sometimes the placenta is normal. Typically, between the endometrium and chorion in the intercotyledonary area, there is a more-or-less abundant exudate which is odourless, dirty yellow in colour, slightly viscid and slimy, and which contains greyish yellow, pultaceous floccules of detritus. The foetal membranes and the umbilical cord are saturated with clear oedema fluid, and the membranes may be 1.0 cm. or more thick. The foetal fluids are usually normal although occasionally that in the amnion is viscid. The placental lesions are not uniform; some cotyledons may appear more-or-less normal and others be extensively necrotic, while still others are diseased to intermediate degrees; similarly, the intercotyledonary placenta varies in the extent to which it is changed, lesions being most prominent adjacent to the cotyledons. Affected areas of intercotyledonary placenta are thickened with a yellowish gelatinous fluid, opaque and tough, and the normal smooth glistening surface takes on an appearance resembling yellowish grey morocco leather with, on the surface, a patchy pultaceous coagulum of inflammatory exudate and desquamated, degenerate epithelial cells. Affected cotyledons or portions of them are necrotic, soft, yellow-grey in colour and may be covered with the sticky, odourless, brown exudate which is usually referred to as resembling soft caramel candy. The oedematous placental stroma contains increased numbers of leucocytes, largely mononuclear but some neutrophils, the chorionic epithelial cells are stuffed with bacteria (Fig. 7.16C) and many of them, with their inhabitants, desquamate into the uterochorionic space. The organisms in intact epithelial cells are coccoid but, free in the exudate, they assume a more elongate form even while still

424

7.

THE FEMALE G E N I T A L

contained within the ghosts of dead epithelial cells. Over the placentomes, the same sort of placentitis is present but the parasitism is not so extensive in the epithelial cells covering the cotyledonary villi, except at their base, or in the epithelium lining the caruncular crypts, although many of the placental giant cells may be necrotic. The intervillous portions of the placenta, the so-called placental arcades, are quite severely affected and exudate accumulates between the arcades and the expanded outer extremities of the maternal villi (Fig. 7.16B). There are normally some placental exudate and minor haemorrhages in these spaces, but this is greatly exaggerated in placentitis and contains infiltrated leucocytes, epithelial debris, and bacteria. The maternal portions of the placentome are not much involved except for the expanded ends of the maternal villi where these are bathed in the exudate of the placental arcades and, in consequence, become denuded and superficially necrotic. Beneath the necrotic tips of the maternal villi there is a more-or-less dense infiltration of leucocytes and a prominent productive inflammation, the fibrosis extending some distance along the cores of the villi. The inflammatory enlargement of the terminal portions of the maternal villi produces an increased degree of placental interlocking, and probably contributes to the retention of placenta. Adhesions, in the usual sense of connective-tissue fusion, between the placentae do not occur. The endometrium is relatively unscathed in the early infections. The zona basalis shows some increase in lymphocytes and plasma cells and there may be scattered microscopic granulomas of epithelioid cells. Even the intercaruncular epithelium may not be much disturbed. Later, there is severe endometritis. (For discussion of lesions in bulls caused by Br. abortus, see the chapter on the male genital system.) The foetus is usually somewhat oedematous with bloodtinged subcutaneous fluid. The same fluid is present in excess in the body cavities and the dorsal retroperitoneum. The normal abomasal content of a foetus is clear, translucent, thick, and viscid; in brucellosis, it often becomes very turbid, of a lemon-yellow colour, and flaky. The important foetal lesion in brucellosis is a pneumonia which is present to some degree in most cases aborted in the last half of pregnancy. The lungs may appear grossly normal, but histologie examination reveals scattered microscopic foci of bronchitis and bronchopneumonia (Fig. 7.16D). In severe cases, the lungs are enlarged and shaped to the thoracic contour, firm on palpation, reddened on the pleural surface or haemorrhagic, and fine yellow-white strands of fibrin are deposited on the pleura. Microscopically, there may be any stage from the minor changes mentioned through a well-developed catarrhal bronchopneumonia to the fibrinous variety. The reaction is centred on the bronchial ramifications suggesting these as the route of infection. The predominant inflammatory cells are mononuclear although many immature and mature neutrophils may be present in some areas. The septa may be oedematous and the perivascular lymphatics infiltrated with leucocytes. By the time the placentitis has advanced

SYSTEM

to an extent where abortion is inevitable an acute diffuse endometritis, without histologie specificity, has developed. Brucellosis in Swine Caused by Brucella suis. Pigs are susceptible to Br. melitensis and slightly susceptible to Br. abortus. The disease is usually caused by Br. suis, and this organism presents important problems in many countries. It does not occur in Great Britain or Canada and appears to have been eradicated from Denmark. There are some differences in the diseases produced by Br. suis and Br. abortus, and these depend largely on the frequency with which Br. suis in swine produces focal granulomatous lesions with coagulation necrosis, the affinity of this organism for the skeleton and joints, and its tendency to remain in granulomatous foci in the nonpregnant endometrium. The early stages of the pathogenesis of the infection are comparable with the early stages of bovine brucellosis. Infection can occur by the same variety of routes but, in swine, brucellosis is transmitted chiefly by coitus. Boars are as readily infected as sows, and the majority of infected boars develop lesions in the testes or accessory genitalia from which the organisms are shed in the semen, often for life. They may also be shed in the urine from a focus of infection in the bladder. Infected females may discharge the organism from the uterus for up to 2.5 years. Suckling piglets can be infected, although they are less susceptible than weaners or adults, and although most infected piglets cast off the infection, a few of them carry the infection into adulthood. With the development of lymphadenitis regional to the point of entry, the infection becomes bacteraemic. The bacteraemia may be transient or persist for many months or even for some years. Localization may occur in many organs but especially in the male and female genitalia, the skeleton including the vertebral column, synovial structures, mammary glands, lymph nodes, spleen, liver, kidney, bladder, and even in the brain. Brucella suis can grow and multiply in phagocytes, and the typical granulomatous lesion begins with the accumulation of histiocytes and epithelioid cells. Perhaps as a response to developing hypersensitivity to the organisms» as the lesion enlarges caseous necrosis occurs centrally and fibrous tissue forms a capsule. The granulomas enlarge progressively and the necrotic tissue attracts neutrophils. Giant cells are absent or scarce. Calcium may be deposited in the necrotic foci. Articular lesions caused by Br. suis are quite common. They begin as a synovitis and affect chiefly the compound and large joints of the limbs. The reaction is purulent or fibrinopurulent. Osteomyelitis in this disease is typically vertebral (or usually observed there). As with other causes of osteomyelitis, localization is typically in the vertebral epiphyses of the lumbar region. There is, however, an unusual tendency to involve and destroy the intervertébral cartilages. The smaller bony lesions are typically granulomatous with dry caseation necrosis, but the necrotic cores of larger lesions may liquefy and the suotmrative reaction

THE

UTERUS

Fig. 7.16. (A) Placentitis caused by Brucella ovis. Sheep. (Courtesy of W. J. Hartley.) (B) Placentitis caused by Brucella abortus. Ox. Cellular detritus detaching foetal placenta (right) from a caruncle. Necrosis of tips of maternal villi. (C) Colonies of Brucella abortus in cells of chorionic epithelium. Ox. (D) Foetal bronchoDneumonia in brucellosis. Ox.

425

426

7.

THE FEMALE G E N I T A L

extend to the méninges or fistulate to produce paravertebral abscesses. In the uterus and Fallopian tubes, there are often conspicuous and characteristic lesions which are not dependent on an association with pregnancy. They have been referred to as miliary uterine brucellosis and, as the name infers, there are few or very many yellowish-white nodules with an average diameter of 2-3 mm. seeded in the mucosa. When the nodules are numerous, they may coalesce to form irregular plaques and then are associated with thickening of the uterine wall and stricture of the lumen. The same lesion is usually present also in the Fallopian tubes where obstruction results in pyosalpinx (Fig. 7.8A, B). Incised, a small quantity of caseous exudate can be expressed from the nodules. Small, red, flat, and irregular granulomas are often scattered over the surface of the supporting ligaments ; grossly, they resemble foetal fat and are easily overlooked. There is some stromal fibrös is and a diffuse cellular ity in the tubes and endometrium due to infiltrated plasma and lymphoid cells with, in addition, well-developed and multiple hyperplastic lymphocytic nodules. There are few neutrophils in the stroma but, with the mononuclear cells, they can be seen pushing their way through the epithelium, and in places pushing it off, to collect in abundance in the lumen of the uterus and tube and in the more superficial glands. The glands are dilated and the leucocytes are enmeshed in strands of mucin and mixed with amorphous globs of mucus. The deeper glands are cystically dilated with an attenuated epithelium, a serous or thin mucinous content, and few or no inflammatory cells. The epithelium lining the lumen and superficial glands is in part retained, in part desquamated, and in part shows the development of a remarkable degree of epithelialization, even to the development of rete pegs and intercellular bridges. The organism is not visible in the lumen; apparently, and like Br. abortus, it prefers an intracellular habitat. The placentae of porcine foetuses aborted because of this infection are often covered with a rather slimy catarrhal exudate. Abortion usually occurs between the second and third months of pregnancy, but the incidence of abortion is relatively less than in the bovine disease; there is also a high incidence of stillborn and weak piglets born at term, and probably also a high incidence of early undetected embryonic deaths. Retention of the placenta may occur. The specific uterine lesions of porcine brucellosis are described above. Apparently, the miliary lesions may develop during pregnancy to a superimposed diffuse catarrhal type of endometritis with patchy congestion, haemorrhage, and oedema and a small amount of creamy-pink catarrhal exudate which contains large numbers of organisms. The foetal placenta may not show conspicuous changes but, as a rule, it is congested with small haemorrhages and patchy oedema. Usually too, there is a thin layer of exudate which is slimy, greyish-yellow or greyish-brown like muco-pus. It is more copious than the secretion normally present in the interplacental space and smears from it show numerous free organisms and many epithelioid cells, presumably chorionic, which contain clumps of bacteria. The foetus

SYSTEM

shows subcutaneous oedema, which is especially prominent about the umbilicus, and effusions into the body cavities. The oedema fluid is often blood stained. The stomach contents may appear normal or be slimy, turbid, or yellowish and may contain small flakes like curd. Brucellosis in Sheep Caused by Bruceila ovis. There is in Australia, New Zealand, and California, and probably elsewhere, a specific causative type of epididymitis in rams (see male genital system) and placentitis in pregnant ewes. Epididymitis is the more common and important of the manifestations and the main discussion of the disease is included in Chapter 6. The causative organism has been termed Brucella ovis, but there is doubt of the taxonomic validity. There are probably as many modes of transmission as there are for the Brucella in general but, in this disease, the coital route is important; infected rams excrete large numbers of the organism in the semen. The infection must pass through a stage of generalization, but the disease is never generalized. The organism is a humble one and not very pathogenic in the usual sense of capacity to provoke disease. It grows abundantly but harmlessly in the incubated egg and survives for a long time in the rat testis without provoking anything: even the epididymitis in rams is only an indirect effect, due to sperm stasis and sperm extravasation. In contrast to the capacity of this organism to avoid antagonizing the reticuloendothelial system, it is capable of parasitizing the placenta and producing abortion, but this is not common although it may be important in individual flocks. Although the manifestations of infection are solely genital, the organism can be cultured from the spleen and some other tissues in which it does not, however, produce lesions. Lesions have not been described in aborted lambs. The placenta, however, is grossly oedematous, being thickened to 2-5 cm. by a gelatinous fluid. Periarteritis and arteritis are distinctive features as in all forms of placentitis. The amnion is adherent to the chorioallantois and thickened in patches. The intercotyledonary placenta has plaque-like thickenings which may coalesce to resemble yellow-white chamois leather. (Fig. 7.16A). Diseased cotyledons may become partially detached; they are firmer than normal, enlarged and yellowish-white in colour. There is extensive necrosis of the epithelial elements of the cotyledons with oedema and cellular infiltration of the stroma. Organisms in abundance inhabit the epithelial cells of the chorion. Brucellosis in Sheep and Goats caused by Brucella melitensis. Brucella melitensis is the principal cause of brucellosis in sheep and goats, although natural infections with Br. abortus occur occasionally. Brucellosis in goats and sheep is prevalent in countries bordering the Mediterranean and in the Near East; it occurs also in southern parts of the United States and in South America. In most respects, the caprine disease resembles bovine brucellosis, but the disease in sheep is usually less protracted and spontaneous recovery is fairly common in a few weeks or months. In the early bacteraemic phases, goats may suffer severe illness and even die, but many

THE

infections are asymptomatic. The early signs of the disease may be referable to acute mastitis with palpable nodules in the gland and a secretion which is clotted and watery. The organism is excreted in the milk, usually only for a few weeks in sheep, but often for several months or even some years in goats. As is usual for ruminants, abortion may be the only sign observed and it tends to occur late in pregnancy. The uterine and vaginal discharges after pregnancy or parturition contain large numbers of organisms. Abortion or stillbirth may terminate successive pregnancies. Brucellosis in other Domestic Species. Bruceila abortus or Br. suis are regularly found in the bursal lesions described elsewhere as "poll evil" and "fistulous withers". There are other isolated reports of suppurative skeletal or synovial lesions in horses caused by these organisms. Cats are resistant to natural infection with Bmcella spp. Dogs are relatively resistant to brucellosis, but natural infections caused by all three species of the organism do occur. The majority of such infections are asymptomatic and detected serologically. Orchitis and epididymitis have been observed. Other lesions described in dogs with brucellosis are chiefly minute granulomas in liver, kidney and lymph nodes but are not specific, or necessarily related to the infection. GENITAL VIBRIOSIS. Specific genital infection caused by Vibrio foetus is common and widespread in cattle but less so in sheep. The incriminated organism in either host goes by the same name but, serologically, there is no relationship between ovine and bovine strains and, epidemiologically, there is little similarity between the two diseases. Genital Vibriosis in Cattle. The disease in cattle is a specific venereal disease, transmitted by coitus. Infected bulls may carry the organism indefinitely in the preputial cavity although some recover spontaneously. Infected cows develop an immunity and overcome the infection. The outstanding feature of bovine vibriosis is not observed abortion but temporary sterility or repeat-breeding with prolongation of the interoestrual periods. It is probable that the delayed return to oestrus is due to fertilization and early implantation followed by early embryonic death. Detectable abortions occur at any time but chiefly about the fourth to sixth month of gestation. The placenta is not usually retained. The endometrial lesions of vibriosis in cows which are repeat-breeders are mild and consist of lymphocytic infiltrations and nodules and scattered cystic glands. Aborted placentae are often autolyzed, indicating that foetal death occurs some while before expulsion. Placental lesions resemble those in brucellosis but are less severe. The intercotyledonary placenta is oedematous, opaque, and may be leathery; there is a diffuse infiltration of cells, which are mainly histiocytes. Diseased cotyledons are yellowish and pultaceous; many have yellow necrotic villi at the margins and in others these are scattered throughout. There may be dense accumulations of polymorphs among the denuded villi and in the stroma. The degree of placentitis is quite

UTERUS

427

variable and may be inconspicuous. The parasitism of the chorionic epithelium which is characteristic of Bmcella occurs but is less evident in vibrionic placentitis. Lesions in the foetus are nonspecific. There are commonly bloodstained effusions in the subcutis and body cavities with perhaps some loose deposits of fibrin on the serous membranes. The normal colourless thick viscid mucus of the stomach content becomes yellow, very turbid, and flaky. Genital Vibriosis in Sheep. The sole manifestations of Vibrio foetus infection in sheep are late abortion, premature birth, and the birth of weak lambs. The abortions occur late in pregnancy, and there is not usually retention of the placenta or sterility. Occasional maternal deaths occur as a result of metritis. Infection is not synonymous with disease as infected ewes may deliver infected but normal lambs. To the epidemiologist, the disease is characterized by an exasperating will-o'-the-wispishness, enzootics occurring suddenly in flocks here and there and then as suddenly disappearing again and only rarely recurring in successive years. The evidence so far is against the ewe remaining as a carrier. Some rams excrete the organism in the semen, but whether permanently or not is not clear. In any case, the ram is so far accorded only a minor role in transmission. The natural mode or modes of infection are not known, but, experimentally, the oral route of administration results in abortion in some cases and the intravenous route, if used in the last 4 months of gestation, will cause abortion in almost all cases. Opinions currently favour ingestion as the route of infection and the establishment of infection in the uterus as being dependent on relatively advanced pregnancy. The abortion rate in natural outbreaks varies between 5 per cent and 70 per cent but is usually about 25 per cent. The aborted foetuses may show nothing more than the usual oedematous changes of most abortions, but some do have rather specific hepatic lesions. Affected livers have few or many light tan areas, from 1-2 mm. up to 1-2 cm. in diameter and randomly distributed (Fig. 7.17A). Through the hepatic capsule, they are a little depressed and there is no surrounding reactionary zone. If the lamb has lived a while before succumbing, these lesions must be differentiated from those of putrefactive origin and from the focal necrobacillary hepatitis of umbilical origin. Histologically, the lesion is a focal necrotizing hepatitis without any special localization in the lobule. Much less characteristic are small renal cortical haemorrhages and bronchopneumonia. The cotyledons are enlarged, yellowish, dull and pultaceous, and covered with brownish exudate. The chorionic stroma is oedematous and infiltrated with leucocytes which are mainly histiocytes. There is a mild or acute endometritis with rather more prominent inflammatory exudation in the caruncular septa. The placental lesions are more severe over the placetomes than in the intercotyledonary areas and are qualitatively similar to the lesions described in the placenta in bovine brucellosis. LISTERIOSIS. Infections by Listeria monocytogenes in ruminants are traditionally associated with cerebral localization

428

7.

T H E FEMALE G E N I T A L SYSTEM

and encephalitis (for general discussion of the diseases associated with this organism see diseases of the nervous system). But localization can and does occur in the pregnant uterus and abortion or stillbirth is then the common sign. The syndromes of encephalitis and abortion may occur together in a herd or flock, but, rather surprisingly, this is the exception. More commonly one or the other syndrome occurs exclusively. The percentage of pregnant animals which may abort within any group is variable; usually the abortions produced are sporadic, but in some 50 per cent of pregnant animals may abort. The route of infection in natural cases is not known; ingestion is the most likely. This route, and others, have been shown experimentally to produce abortion. Cases of abortion in both cattle and sheep due to Listeria monocytogenes occur during the last trimester of pregnancy. If uterine infection develops during the early part of the last trimester, the placenta is quickly invaded by the organism and the foetus dies as a result of a septicaemia. The dead foetus is expelled in approximately 5 days; by this time autolytic changes mask the very minor lesions produced by the organism. The microscopic changes are slight; all organs teem with bacteria, but the only tissue alterations are small foci of hepatic necrosis. Abortions at this stage are not usually accompanied by severe systemic disease in the dam. The placenta is usually retained as a result of a mild metritis, but the organisms and associated inflammation are quickly cleared from the nonpregnant uterus. If the foetus is near term when the infection develops, an abnormal parturition is instituted in which dystocia is the rule, severe metritis and septicaemia being the most common complications. Lesions in the foetuses and placenta in this latter group are less likely to be obscured by autolytic changes but are still minimal in extent. They consist grossly of tiny pin-point yellow foci in the liver. Microscopically, in addition to these necrotic lesions in the liver, similar ones can be seen in the spleen. The placenta contains the most advanced lesions. The necrotic tips of the villi are covered by a purulent exudate in which many bacteria are present. Recovery of the organism is frequently difficult either because of contamination or because of some subtle vagary of the organism itself. These difficulties can sometimes be overcome by refrigerating the specimen (4° C.) and reculturing after a period of storage. This technique should be employed in cases of abortion in which there is reason to suspect this pathogen. SALMONELLOSIS

IN

HORSES

CAUSED

BY

Salmonella

abortus-equi. Six or so species of Salmonella are recorded as producing typhoid-like disease in horses, and of the infections S. typhi-murium occurs most frequently as a disease of foals and of adult horses after transportation (see Diseases of Stomach and Intestines). Salmonella abortus-equi has been described as a cause of sporadic and epidemic abortion in mares but there have been no reports of this in the United States for about 20 years, a period corresponding closely with that in which viral

causes of abortion have been recognized. This should imply reduction in the prevalence of the infection rather than a change in fashions of diagnosis because aborted equine foetuses are still routinely cultured in many centres. The infection continues to be of some importance in other parts of the world; the organisms can be readily cultivated from foetuses aborted by the infection, and placental lesions of some specificity are present. There is, however, some doubt whether S. abortus-equi is necessarily a primary pathogen for mares. The epidemiology of this infection probably resembles that of the salmonelloses in general, a discussion of which is given elsewhere, involving carrier animals, asymptomatic infections, and an altered host-parasite relation when the host is rendered susceptible by intercurrent disease or debility. The organism is often a saprophyte of the vagina and colon and is eliminated in uterine discharges. Although the evidence is contradictory on the efficacy of oral exposure in causing infection and abortion, this is probably the route of natural infection, the outcome of infection depending on the ecological factors suggested above and, probably also, on the stage of pregnancy. Infection is frequently followed by the development of substantial immunity. Abortion usually occurs late in gestation. The mare may be mildly ill or not. The foetus is oedematous and may have serosal haemorrhages, but there are no specific lesions. Acute placentitis is present and is of diphtheritic and haemorrhagic type. The allantoischorion is oedematous and studded with numerous haemorrhages, some of which may form intramural haematomas. Focal necroses surrounded by a distinct haemorrhagic reaction are regarded as characteristic. The umbilical cord shows a similar diffuse haemorrhagic purulent inflammation. Histologically, the chorionic epithelium is necrotic and desquamated and the surface covered with detritus in which numerous organisms are demonstrable. The chorionic stroma is permeated with red blood cells and leucocytes and the vessels are extensively thrombosed. Foals born alive but infected with this organism may die of septicaemia within a few days of birth, or they may survive a little longer and develop, in 1-3 days, suppurative omphalitis with metastatic suppurative polyarthritis and tendovaginitis. In some such cases the infection may be acquired immediately after birth, but infected foals can be born alive and most infections with this organism which cause death in the early neonatal period are probably acquired in utero. Extragenital infections in horses of either sex may be associated with this organism. Osteomyelitis and bursitis are described. Orchitis is recorded in stallions. SALMONELLOSIS OF SHEEP CAUSED BY Salmonella abortus-

ovis. Abortion caused by S. abortus-ovis in sheep is reported mainly from Europe and Great Britain. Epidemiologically, this infection probably resembles that in mares caused by S. abortus-equi, abortion being the classical and usually the only sign of infection, but there is good evidence that

THE

UTERUS

Fig. 7.17. (A) Focal hepatic necrosis in foetal lamb caused by Vibrio foetus. (Courtesy of W. J. Hartley.) (B) Embolie suppurative nephritis in shigellosis. Foal. (C) Placentitis in toxoplasmosis. Sheep. Note focal necrosis in cotyledons and normal intercotyledonary placenta. (Courtesy of W. J. Hartley.)

429

430

7 . THE FEMALE G E N I T A L

SYSTEM

Fig. 7.18. (A) Focal necrosis and calcification of cotyledon in toxoplasmosis. Sheep. (Courtesy of W. J. Hartley). (B) Dark foci of necrosis and calcification in placental toxoplasmosis. Sheep. (Courtesy of T. J. Hulland and Canadian Veterinary Journal.) (C) Typical congestive nodularity in liver of bovine foetus in abortion caused by a psittacoid agent. The lesion is not specific.

THE

transmission may also be coital, the organism being excreted in semen from apparent or inapparent latent testicular infections. There may, however, be signs of septicaemia, and it is probable that localization in the uterus follows an early bacteraemic phase. Salmonella abort us-ovis is relatively host specific. Sheep quite commonly develop salmonellosis caused by other species of the genus and, although these infections are usually characterized by acute gastroenteritis and septicaemia, abortion is sometimes the most prominent or only sign of infection. MISCELLANEOUS BACTERIAL INFECTIONS CAUSING ABOR-

TION IN MARES. That group of infections in foals producing the syndrome variously known as joint ill, navel ill, foal septicaemia, and pyosepticaemia neonatorum continue to be problems, although less frequently now than formerly. Klebsiella pneumoniae var. genitalium, Streptococcus zooepidemicus (syn. genitalium), Salmonella abortus-equi (see above), Corynebacterium equi, Escherichia coli, and Shigella equimlis may be found in any extended series of cases of neonatal septicaemia and polyarthritis in foals. Escherichia coli and C. equi are seldom responsible for abortion. The other species listed above do cause abortion as well as neonatal infections, but there is remarkably little information on their ecological features. Streptococcus zooepidemicus, and possibly Klebsiella genitalium also, is a common parasite on the vaginal mucosa of mares and is frequently responsible for chronic vaginitis, cervicitis, endometritis, and sterility. When an infected mare conceives, early abortion is a likely outcome, but some abortions occur late in pregnancy. The organism is readily cultured from the foetus, but there are no distinctive lesions. The neonatal infections may be septicaemic without distinctive lesions or less acute with fibrinopurulent polyarthritis and with or without omphalitis. Shigella equimlis is an important cause of neonatal death of foals in most countries. Foals may become infected in utero and be aborted, they may die of septicaemia in the early neonatal period, or they may survive days and develop lesions of localization in many tissues. It is probable that some infections are acquired during or after parturition. Aborted foals and those dying acutely of septicaemia do not have distinctive lesions. After a course of 3 or 4 days or more, localization of the infection with miliary microabscessations and polyarthritis develops. The microabscesses, which are embolie in type, may be found in many organs, and they are readily visible to the naked eye in the renal cortices (Fig. 7.17B). The renal abscesses are small, being only 1-3 mm. in diameter and they are numerous. Histologically, bacterial colonies are obvious in the glomeruli and intertubular capillaries and are enclosed in foci of intense suppuration. The arthritis is of fibrinopurulent type. There is little information on the epidemiology and pathogenesis of shigellosis. Mares which are caused to abort by this infection are not ill, and the organism does not persist for long in the uterus after abortion. However,

UTERUS

431

the same mare may abort successive pregnancies, a fact which suggests that the uterus can be reinfected from some endogenous asymptomatic focus. Shigella equimlis can occasionally be found in the intestine and tissues of healthy animals and occasionally also as an opportunist in pathological tissues such as verminous thromboses. It is, however, seldom of pathologic significance in adult animals although septicaemic infections have been observed. TOXOPLASMOSIS. Infection with Toxoplasmagondii appears to be very common in many species, but the disease toxoplasmosis is much less common and its diagnosis is still somewhat of an event. Like a number of other protozoan infections, toxoplasmosis has not become so well known or understood as to have earned the contempt of familiarity. The present discussion is limited to genital manifestations. A more complete discussion of the disease is given in Volume 2. The intrauterine transmission of infection is well established in the human and in a number of domestic species, but until recently T. gondii has not been ascribed any significant part in the general scheme of abortifacient infections although sporadic incidences of abortion and neonatal death have been observed. The capacity of this organism to induce abortion has recently been pointed out from New Zealand and the opinion expressed that although ovine abortion due to vibriosis, brucellosis, and listerellosis is well known, that due to toxoplasmosis is probably the most important and common of all. The abortions occur late in pregnancy and the incidence in an infected flock may be up to 15 per cent. The ewes are normal except for complications induced by mummification or incomplete abortion. The affected lambs show no significant gross lesions and in few only are lesions and parasites demonstrable histologically in myocardium, lung, and brain. The foetal placenta bears what are probably characteristic lesions. The cotyledons are bright to dark red as compared with a normal deep purple colour; scattered amongst the foetal villi are numerous white flecks or small soft white nodules 1-3 mm. in diameter (Figs 7.17C, 7.18A). The villi are oedematous and there is focal necrosis and desquamation of trophoblastic epithelium (Fig. 7.18B). In some, more extensive, there may be caseous and calcified cotyledonary nodules. The organism is readily identified either free or in pseudocysts. The intercotyledonary placenta shows oedema only. Information concerning the development of placental and foetal toxoplasmosis is scant. The infection in the dam is usually asymptomatic. Encysted organisms can frequently be found in the endometrium. It may be assumed that placental infection can occur at any time the infection is active and the organisms in theproliferative phase. Invasion of the placenta when the infection is chronic and encysted probably can occur only during the stage of implantation when endometrial pseudocysts are ruptured by the invading trophoblast. BOVINE ABORTION CAUSED BY PSITTACOID AGENTS.

A

432

7.

THE FEMALE G E N I T A L

seasonal incidence of abortion in cattle occurs in the foothill and mountainous portions of California. The disease affects heifers primarily and the losses are apt to be high: frequently, 60 per cent of the pregnant animals will abort. There is no acquired resistance which develops with age, and animals of any age may abort if pregnant when exposed for the first time to areas where the disease occurs. Subsequent pregnancies are safe. The geographic distribution of the disease is not known entirely but, where known, the limits of its distribution are strict, properties where the disease is a recurrent problem being adjacent to ranges free of the disease. A large, elementary body-producing agent of the psittacosis-lymphogranuloma group has been recovered from the aborted animals. This agent is capable of producing fever in susceptible animals and, after a latent period of some months during which the virus multiplies within the foetus, pregnant animals abort. There are few signs of impending abortion, delivery is uneventful, and the placenta is not retained. The foetuses which have been aborted in both the natural and experimental disease are distinctive. They are well developed and approximately the size of a term foetus. Usually, the foetus dies during delivery or shortly thereafter, but some premature calves suffering from the disease may survive. The foetal membranes are frequently thick and oedematous, but are not otherwise abnormal. Petechial haemorrhages are common on the mucous membranes and skin; these stand out vividly because the foetuses are pale and anaemic. The subcutaneous tissues are wet and oedematous, and a straw-coloured pleural and peritoneal effusion is regularly present. A variable feature, but an obvious one when present and well-developed, is a swollen, coarsely nodular liver (Fig. 7.18C) caused by chronic passive congestion. Petechial haemorrhages are apt to dominate the morbid picture, but they lack specificity. They are regularly seen in tongue, thymus, lymph nodes, and trachea. The lymphoid tissues throughout the body are enlarged, and there is associated lymph stasis. Tiny grey foci are irregularly scattered in all tissues, but their detection requires good light and a dark background of tissue, such as is best supplied by the myocardium or kidney. The histologie response of these foetuses is a diffuse or focal reticuloendothelial hyperplasia which involves all organs, although irregularly. The spleen, thymus (Fig. 7.19A) and lymph nodes (Fig. 7.19B) are likely to be most severely affected, but the presence and the nature of the lesion may be easier to appreciate in organs, such as brain (Fig. 7.19C), liver, and myocardium, which do not contain large amounts of reticuloendothelial tissue. The affects of the virus are not entirely proliferative, and small necrotic foci may develop in spleen or lymph nodes. The focal cutaneous lesions ulcerate (Fig. 7.19D). Two types of lesion are present in the livers of these foetuses. A vascular component, which produces the striking, but nonspecific, gross change, consists in dilation of the central veins and sinusoids and irregular necrosis of hepatic cells adjacent to these distended vessels. The

SYSTEM

second and more specific granulomatous lesion develops in the hepatic capsule, around the portal triads, and in the adventitia of the central veins. These inflammatory processes vary from small foci of proteinaceous exudate associated with slight neutrophil and macrophage infiltration to larger areas of epithelioid cells surrounded by fibrous tissue. Splenic enlargement is most commonly the result of chronic diffuse reticuloendothelial hyperplasia. Occasionally, it is the result of acute focal splenitis with necrosis. The size of these necrotic areas varies from minute foci in the areas of the pencillary capillaries to large segments of necrosis of the reticular elements surrounding the white pulp. These changes accompany congestion of the red pulp and moderate infiltration of the parenchyma by neutrophils. In advanced cases, the hyperplastic changes in the reticuloendothelial cells produce a blending of the splenic elements and loss of normal architecture. The changes in the lymph nodes are similar to those seen in the spleen. The normal pattern of the lymph node is distorted not only by the hyperplastic histocytes, but also by the infiltration of lymphocytes and neutrophils into the sinusoids. In the most obviously involved nodes, the pericapsular adventitia is similarly affected. It is in lymph nodes that Langhans-type giant cells are most apt to be found. The capsular and pericapsular infiltrations which are present in the lymph nodes are duplicated in the thymus in which the septa are frequently packed solidly with hyperplastic and infiltrating cells (Fig. 7.19A). Granulomatous lesions may be present in any organ; those in the kidney are similar to those produced in foetus by Bruceila abortus, but differentiation from abortions produced by Bruceila is afforded by the lung. In foetuses aborted by psittacoid agents the air passages are clear and, although the connective tissue stroma may be involved as elsewhere, the bronchopneumonia characteristic of Bruceila infection in the foetus is absent. The striated muscle throughout the body is apt to be mildly affected with oedematous separation of muscle fibres and small perivascular accumulations. The involvement of the myocardium is regularly more severe, both focal and diffuse myocarditis usually being present. Perhaps, the organ in which the nature of the lesion is clearest is the brain. Here the reaction occurs most commonly within the adventitia of the meningeal and parenchymal vessels. The cells consist of pleomorphic mononuclear cells which are arranged in eccentric accumulation about the vessels and also in small poorly defined foci in the parenchyma (Fig. 7.19C). Similar types of abortion have been reported from Germany and Italy. It is not clear precisely what relationship exists between these diseases and the Californian disease. A virus of the psittacosis-lymphogranuloma group has been incriminated as the cause of the disease in Germany. The virus of enzootic abortion of ewes, a psittacoid (see below), will, following experimental inoculation, cause placental infection and abortion in cows.

THE

UTERUS

Fig. 7.19. Abortion in cattle caused by psittacoid agent. (A) Reticuloendothelial hyperplasia in thymus. Foetus. (B) Proliferative lymphadenitis with giant cells in aborted calf. (C) Cerebral vasculitis. Foetus. (D) Acute focal dermatitis. Foetus.

433

434

7.

T H E FEMALE G E N I T A L SYSTEM

ENZOOTIC ABORTION IN EWES. This is a specific in-

fectious abortion of ewes first reported from Scotland, but since reported from Europe and the United States; it is an organism of the psittacosis-lymphogranuloma-venereum group. Late abortion and premature lambing are the only clinical manifestations of the disease. Retention of the foetal membranes may occur in some cases. Sterility is not a sequel, nor does this specific abortion terminate subsequent pregnancies. Little is known of the epidemiology of the disease, but it appears that infection may occur early in life and stimulate immunity and that abortion occurs when nonimmune ewes are exposed to infection. The ram is not a factor in dissemination of the disease. Aborted foetuses show only blood-stained oedematous transudates. The foetal placenta, however, resembles that seen in bovine brucellosis. Affected cotyledons are of a dull-clay or dark-red colour, firm, and matted with a dirty reddish exudate. The chorion shows irregular areas of oedema or a dry, leathery thickening. The histological nature of the placentitis is very similar to that in brucellosis, even to the characteristic parasitism of the chorionic epithelium, in this case by the elementary particles which are best demonstrated in smears stained by a briefly decolourized Ziehl-Neelsen stain or Giemsa. EQUINE VIRAL ABORTION.

There

are, as

presently

differentiated, two systemic viral infections of mares which cause abortion. The virus of "equine influenza", or, as it is now designated, "equine viral rhinopneumonitis" (see Respiratory System) is the cause of what was until recently the classic "equine virus abortion". The second viral disease is the newly differentiated "equine viral arteritis" (see Circulatory System) which as well as causing abortion, causes a rather severe and often fatal generalized infection of the dam. Abortion due to infection with rhinopneumonitis virus usually occurs in the ninth and tenth months ; it is prompt and uncomplicated. Death of the foetus does not occur until the onset of abortion and the dam shows no premonitory signs. Recovery from any influenza-like signs precedes the abortion. The aborted foetuses may show characteristic and diagnostic lesions which are variable in their development and may be absent. Oedema of the subcutis and fascia and accumulated fluid in the body cavities are common to aborted foetuses. There is often slight general icteric discolouration, and meconium staining of the foot pads and amnion. The most consistent gross lesion is severe oedema of the lungs, these organs being heavy and rubbery with a pitting response to pressure and oedema of the interlobular septa. Their colour may be darker or lighter than normal. Casts of fibrin are occasionally present in the bronchi (Fig. 7.20A). Beneath the capsule of the liver there are, in about 50 per cent of aborted foetuses, greyish-white foci of necrosis varying in size from minute up to 5 mm. in diameter. Such foci may be few or numerous. The spleen may be enlarged with petechial haemorrhages on the capsule and unusual prominence of the follicles. Haemorr-

hage of petechial or ecchymotic type may occur anywhere, but chiefly in the upper respiratory mucosae. Occasionally, there is haemorrhagic necrosis of the renal cortices. Histologically, the pulmonary interlobular septa are oedematous and infiltrated with mononuclear inflammatory cells. The oedema and spotty haemorrhage involve the whole organ uniformly, there is a fibrinous alveolar exudation and necrosis of bronchial and alveolar epithelial cells (Fig. 7.20B). Specific are the acidophilic inclusion bodies found in the nuclei of the bronchial and alveolar epithelium. The foci of hepatic necrosis are often minute and easily missed in a section. They are not so common as the changes in the lungs. Acidophilic inclusion bodies form in the nuclei of hepatic parenchymal cells, but they are not constant and are never numerous although they can usually be found about the areas of focal necrosis. There is oedema of the liver, and leucocytic infiltration in the necrotic foci and portal triads is common (Fig. 7.20C). Occasionally there is a diffuse hepatitis without focal necrosis. Necrosis of germinal centres occurs in all lymphocytic tissues, and intranuclear inclusion bodies may be found in the primitive reticular cells in such foci. There are haemorrhages in the splenic pulp and about the Malpighian corpuscles. The placenta is normal. Foals infected with this virus in utero may be born alive at or near term. Whether any survive or not is not known. Many of them die in the first few days with severe interstitial pneumonia and secondary bacterial septicaemia. Focal hepatic necroses are, as a rule, not present in these cases. Abortion caused by the equine arteritis virus occurs during the period of clinical disease or early in convalescence, and partial autolysis indicates that death of the foetus occurs before the onset of abortion, sometimes 2 or 3 days before. The aborted foetuses are oedematous, and there may be a few petechial haemorrhages in the respiratory mucosae and splenic capsule. In some, the spleen may contain one or more haemorrhagic infarcts but, apart from these, there are no anatomical changes in the foetus which permit a diagnosis of this infection. GENITAL TRICHOMONIASIS. This is a specific contagious venereal disease of cattle caused by the flagellated protozoan Trichomonas foetus and transmitted at coitus. Infection in the bull remains in the preputial cavity and must be considered, in the absence of effective treatment, as permanent. In early infections, there is a balanoposthitis of moderate severity with preputial swelling and a slight purulent discharge. As the infection becomes chronic, the inflammatory reaction disappears and the organisms become fewer in number. There is a tendency for them to concentrate on the glans penis and adjacent areas of the prepuce, but they are quite difficult to find in preputial washings and may be detected only by test-mating suspected bulls to susceptible heifers. Females are not readily infected, if at all, except by service and easily infected experimentally by placing a culture of the organism in the vagina. A few days after infection, an acute vaginitis with swelling of the vulva

THE

UTERUS

Fig. 7.20. Equine abortion caused by the equine rhinopneumonitis virus. (A) Fibrin casts in bronchi of aborted foetus. (Trachea, lower right.) (B) Acute necrotizing interstitial pneumonia in an aborted foetus. (C) Acute hepatitis with focal necrosis. Foetus.

435

436

7.

T H E FEMALE G E N I T A L SYSTEM

develops and there is a moderate amount of mucoid floccular discharge in the vagina. The protozoa may be easy or impossible to find in this exudate. The vaginitis resolves shortly, and the infection localizes in the uterus and cervix. Immediately prior to the oestrus which is subsequent to the infective service, large numbers of organisms can usually be found in exudate aspirated from the cervix, but as oestrus advances the number of protozoa is greatly reduced. The manifestations of established trichomoniasis in females are eervicitis and endometritis which result in repeat breeding, abortion, or pyometra. The inflammatory changes in the endometrium and cervix are relatively mild and nonspecific although the exudate, mucopurulent in character, may be rather copious. Discharge of exudate into the vagina may be more or less continuous or intermittent, and the numbers and activity of the trichomonads in the discharge varies considerably over short periods. The discharge may not be apparent at the vulva. The pattern of repeat breeding in trichomoniasis is the same as that in vibriosis, return to service occurring at irregular intervals, a fact which indicates that fertilization and implantation are followed by embryonic death. When the embryo or foetus dies it may be resorbed, aborted, or retained with the development of pyometra. Trichomonad abortions may occur at any time but mainly in the first half of pregnancy. There are no specific foetal lesions, but large numbers of protozoa may be found in the foetal fluids and stomach. The placenta is not severely altered as in brucellosis; it may be covered by a white or yellowish flocculent exudate in small amounts, thickened and slightly tough, and haemorrhage without much necrosis may be evident on the cotyledons. Pyometra is one of the remarkable changes of trichomoniasis, but it is a relatively uncommon complication. Its pathogenesis follows the scheme outlined earlier and its character is remarkable only for the copiousness of the exudate which is present. Any volume up to a gallon or more may be present and the exudate may be watery with floccules, colostrum-like, or brownish and sticky. It is without odour and swarms with trichomonads. MYCOTIC ABORTION IN CATTLE. Sporadic cases of bovine

abortion do occur due to infection with species of the rather ubiquitous genera, Aspergillus, Absidia, Mucor, and Rhizopus, their relative frequency in about this order. The portal of entry is not known, but that the initial development of lesions is in placentomes indicates haematogenous arrival. Probably the respiratory route is the portal of infection initiated by the inhalation of spores. With the exception of Rhizopus, these organisms are well-known secondary pathogens. Abortion occurs late in gestation, between the sixth and eighth month, and the placenta is often firmly retained. The foetus may appear normal, but often there are characteristic cutaneous lesions in the form of irregular elevated plaques resembling ichthyosis or extensive ringworm. These lesions are seen most commonly about the periorbit, occiput, shoulders, back, and sides (Fig. 7.21 A).

Affected areas are slightly elevated, greyish, irregular in outline and tend to coalesce. Histologically, the infection is seen to be superficial, involving the epidermis mainly, with parakeratosis, and oedema and inflammatory-cell infiltration of the underlying dermis. Sometimes the hair follicles and the dermis are invaded by the fungus but, with the exception of an occasional case of bronchopneumonia, there are no lesions in the internal organs, although the fungus can be isolated from the stomach contents (Fig. 7.21B). The placental lesions are remarkable. The gross appearance resembles that seen in brucellosis but is often much more severe. The allantois-chorion is then leathery with extensive superficial necrosis. The placentomes are greatly enlarged and necrotic with swollen margins and firmly incarcerated (Fig. 7.21 C). The infecting organisms are readily demonstrated in the necrotic tissue and typically extend along the blood vessels to produce necrotizing vasculitis. Lesser degrees of placentitis are probably quite common with the lesions restricted to placentomes as areas of haemorrhage, softening, and necrosis. The infection appears to begin in the placentomes with later spread to the interplacental space between the cotyledons, where a rich growth of hyphae occurs. With placentitis of lesser degree, there usually are no cutaneous lesions in the foetus although the fungi can be found in the gastric contents. The endometrial lesions are comparable in severity to those in the placenta. Secondary infections may follow retention of the placenta. The majority of cows with mycotic endometritis recover sufficiently after abortion to allow subsequent pregnancies to be carried to term, but in some endometrial destruction is severe. The Cervix Cysts of the cervix occur in cows, and probably all are retention cysts formed by fusion of the rugae. Loss of the original epithelium of the rugae is first necessary and may be incident to the lacerations of parturition, artificial insemination, or inflammation. The cysts are usually small and not significant. Larger ones may cause partial occlusion of the cervical canal, but this is seldom of importance. Stenosis of the cervix is extraordinary. It is acquired rather than congenital and consists of fusion across epithelial surfaces and scarification. It may follow severe laceration or long standing inflammation. Cervicitis is not in itself an entity but, instead, is to be regarded as an extension of an endometritis or vaginitis. The mucus-secreting epithelium provides good defence against bacterial invasion and if the epithelium breaks down it exposes densely arranged connective and muscular tissues which are not especially sensitive to the actions of bacteria. In the cow, the epithelium lining the external os and the adjacent few rugae is of the simple vaginal type, and this is more susceptible to irritation than the mucus-secreting surface anterior to it. Most inflammations then are superficial, but there are some exceptions such as necrobacillosis. The circumstances in which cervicitis occurs have been mentioned under diseases of the uterus or will be mentioned

THE

CERVIX

Fig. 7.21. Mycotic abortion. Ox. (A) Mycotic dermatitis. (B) Aspergillus spp. in smear from foetal stomach (phase). (C) Mycotic placentitis.

437

438

7 . THE FEMALE G E N I T A L SYSTEM

under diseases of the vagina. The usual form of bovine simple cervicitis is seen as a swelling of the first (caudal) annular rugae, which are oedematous and hyperaemic. They soon protrude through the external os into the vagina, and a thin mucopurulent exudate accumulates between the folds and collects in the vagina. Histologically, there is epithelial degeneration and desquamation and an infiltration by inflammatory cells which are predominantly mononuclear. Neutrophils in number penetrate the epithelium and become admixed with mucus, or in more acute cases there may be frank suppuration. Cervicitis is not usually more severe than this, although in older cows the prolapse and tumefaction of the rings may be quite gross. Although degrees of prolapse result from inflammation, they may also predispose to it. Slight but progressive degrees of eversion of the cervical rings occurs with succeeding pregnancies to expose portions of the cervical mucosa to the contaminated environment of the vagina. Chronic cervicitis may lead in time to enlargement and induration of the cervix with some stenosis, but enlargement is not a criterion of inflammatory sclerosis. Discrete cervical abscesses or suppurative fistulous tracts occasionally result from accidental injury acquired during uterine irrigation or artificial insemination. The Vagina and Vulva Cysts in the vagina or vulva are not important in themselves, but they do have some diagnostic significance. They occur as cystic dilations in Gartner's ducts and Bartholin's glands in cattle. Gartner's ducts are remnants of the embryonic Wolffian ducts; they lie, one on each side of the floor of the vagina, beneath the epithelium. They are invariably present to some degree in cattle although, when normal, they are only detectable microscopically as discontinuous ducts lined by a simple epithelium and found in the anterior vagina and petering out caudally. They become cystic in cows poisoned with highly chlorinated naphthalenes, in cows with ovarian follicular cysts, and occasionally following acute vaginitis. With lesser degrees of dilation, the cysts are more readily palpable than visible, but in well-developed instances they are clearly visible through the elevated and thinned vaginal walls (Fig. 7.5B). The cysts may be isolated or they may have a string-of-beads disposition, or the whole duct may be present, dilated to 1-2 cm. and tortuous. Cysts of Bartholin's glands occur under the same stimuli, but chiefly as a consequence of inflammation. The glands lie one on each side of the floor of the vestibule and normally are about 3 X 1.5 cm. in dimensions. They become visible when enlarged, especially if the vestibular mucosa is slightly everted (Fig. 7.5D). These glands are very sensitive to oestrogens, responding with the elaboration of a thin mucus and hyperplasia of the ductal epithelium. Gross exaggeration of responses in hyperoestrogenism accounts for the cystic development. Large retention cysts follow inflammatory stricture of the short excretory ducts. Abscessation may follow localization of infection in the cysts.

Ruptures of the vagina and vulva are quite frequently acquired as parturient injuries. The mucosa alone may be ruptured, or the entire thickness of the vaginal wall. Haemorrhages occur into the vagina or the perivaginal wall from foetal pressure or vascular disruption. Pelvic fat may herniate into the vagina; it is often mistaken for a neoplasm. Defects which extend deeper than the mucosa heal with cicatrization which may, in turn, result in partial stricture. Otherwise, the outcome depends on whether or not the lacerations become infected and, if so, with what. Occasionally, diffuse phlegmon, abscess, gangrene, or peritonitis are sequelae. Tumefaction of the vulva is a physiological response to oestrogens. It may be of exceptional development or persistence in prolonged hyperoestrogenism. A distinctive syndrome characterized by vulval tumefaction due to hyperaemia and oedema occurs in swine and is associated with the feeding of mouldy grains. The pathogenesis of the condition is still to be elucidated, but the lesions are suggestive of hyperoestrogenism. Young gilts are chiefly affected, older animals being resistant. There is remarkable oedematous swelling of the vulva and vagina, which may be severe enough to lead to eversion and prolapse of the mucosa. Prolapse of the vagina may occur in up to 30 per cent of cases and secondary rectal prolapse occurs in a lesser percentage. Gilts may also show mammary enlargement, and balanoposthitis develops in the males. Inflammatory Diseases of the Vagina and Vulva The mucous membrane of the vagina and vulva shares, with mucous membranes in general, a sensitivity to irritants. Although the vagina is of Müllerian duct origin, the original epithelium is replaced by stratified squamous epithelium from the urogenital sinus. This epithelium proliferates and matures under the influence of oestrogen and is then more resistant to infection. This enhanced resistance may be due to mechanical factors in the thickened keratinized epithelium and to local production of lactic acid from the glycogen which is deposited in the epithelium under the influence of oestrogens. There are probable additional ingredients in the recipe for resistance. We shall be concerned here only with the specific types of vaginitis and vulvitis although both are more commonly nonspecific and of simple catarrhal type. INFECTIOUS

BOVINE

CERVICOVAGINITIS

AND

EPIDI-

DYMITIS. This is a specific infectious disease of breeding cattle which so far has been described only from Africa. It is regarded there as the most important of the genital diseases of cattle, and for this reason should be borne in mind. The causative agent is unknown, but it is probably viral. Natural transmission is solely by coitus. Experimental transmission is easy if infective discharges are placed in the vagina or prepuce. After incubating for a few days, diffuse purplish inflammatory streaks or patches develop in the anterior vagina to be followed by the development of a copious tenacious creamy discharge in which there are large numbers of neutrophils but few or no organisms. The

THE VAGINA AND VULVA

infection spreads readily from the vagina to the cervix and uterus, also with the production there of the same copious pus. About 25 per cent of infected females are sterile because of the development of chronic salpingitis with hydrosalpinx and bursal adhesions. In the bull there is early but slight palpable enlargement of the spermatic cord and epididymis. The disease usually commences in one epididymis but later involves both organs and spreads from the tail of the epididymis to the head of it and ultimately to the testicle. The lesion is apparently an interstitial epididymitis with the production of excessive peritubular fibrosis and tubular obstruction. Testicular changes are probably secondary to those in the epididymis and to obliterative adhesions in the cavity of the tunica vaginalis. Similar productive inflammatory lesions occur in the ampullae and the seminal vesicles. CONTAGIOUS ANTERIOR VAGINITIS. This term as applied

here includes a vaginitis-cervicitis described from South Africa and also from California but, although the manifestations are the same, there is no evidence that the causative viruses are identical. In both cases, an agent can be isolated in eggs and adapted to suckling mice and is capable of transmitting the disease by intravaginal inoculation. Affected animals develop a vaginal exudate which is copious, nonodorous, yellow, and viscid. The anterior vaginal wall is intensely hyperaemic, and the epithelium erodes in a histologically nonspecific type of vaginal catarrh. The experimental incubation period is about 2 days, and the course is a few days to several weeks. Vaginitis of this type is more common as a sporadic event than reports would indicate but it is only rarely subjected to study. GRANULAR VENEREAL DISEASE. Papular eruptions of

the vulval mucosa are common in most domestic species but are best known in the bovine species by the above name or as "nodular venereal disease", "granular vaginitis", etc. The term vaginitis is a misnomer, as the papules are strictly limited to the vulval mucosa and are not found in the vagina, although in acute cases there may be an associated nonspecific vaginitis. Vulval granules may be found in any herd, affecting animals of any age but are usually more prominent in heifers bred naturally. They are much less common in pregnancy and are almost never present about the time of parturition. In severe cases, the papules may be found on all aspects of the vulval mucosa, but usually they are clustered in the ventral commissure about the clitoris as pale or pink elevations of a few millimetres' diameter and covered by a normal intact vulval mucosa. When numerous, they are likely also to be more active, larger, often coalescent, congested and red with a covering catarrhal vulvitis and vulval swelling. The overlying epithelium is then easily injured and bleeding occurs freely from the papules. The resting papules are composed of respectably organized lymphocytic follicles (Fig. 7.22D). When the vulval mucosa is irritated, these become congested with small intrafollicular haemorrhages and oedema, and hyper-

439

plastic, the mitotic frequency being quite high. The same lesions occur on the penis and prepuce of the bull and, as do those of the vulva, often persist for many months. These papules have never been shown to be caused by a specific agent and it is doubtful if a specific agent exists. The development of subepithelial lymphocytic foci is a characteristic response of mucous membranes to mild persistent or recurrent irritation and the simplest explanation of "granular venereal disease" is that it is a response to mild irritation of the vulval mucosa. INFECTIOUS PUSTULAR VULVOVAGINITIS OF CATTLE. We

are assuming for description here of infectious pustular vulvovaginitis that this is the disease (or perhaps more than one disease) which for many decades has been variously termed "vesicular venereal disease", "vesicular vaginitis", "coital exanthema", "coital vesicular exanthema", and "Bläschenausschlag". The assumption is probably valid, but proof is lacking and may no longer be obtainable. There is some evidence also that infectious pustular vulvovaginitis is caused by the same virus as that which causes infectious bovine rhinotracheitis (see, Respiratory System). As a rule, the nasal and vaginal infections behave epidemiologically as distinct diseases although occasionally the syndromes occur together in individual animals. Infectious pustular vulvovaginitis is highly contagious. It can be and frequently is transmitted by coitus, but it can also be transmitted by other mechanical means and is contagious by close contact. It may involve individual or few animals in a herd, but frequently spreads rapidly to involve all exposed females in a few days. The disease subsides in about 10 days, leaving immunity which is fragile and transient. Reinfection can occur but early reinfection produces only a mild disease. The incubation period is 1-3 days but may be as brief as 12 hours. The lesions are restricted to the genital tract, but a viraemic phase probably occurs because there is early fever and leucopaenia. Initially, there is hyperaemia of the vaginal and vulval mucosa with focal haemorrhages in the lymphocytic follicles of the submucosa. The severity of the vulvovaginitis increases rapidly and oedema of the vulva develops and mucopurulent vaginal discharge. The focal lesions replace the haemorrhages over the lymphoid follicles and consist of small (2-3 mm.) pock-like foci, slightly elevated, pale, soft, and friable (Fig. 7.22A). The focal lesions, being related to the lymphoid follicles, may be in short linear arrangements. The epithelium in the focal lesions erodes or ulcerates so that in a few days the foci are flat, grey, semitransparent plaques the size of the original lesions. The virus is epitheliotropic, the initial and most severe alterations occurring in the epithelium of the vagina and vulva. There is ballooning degeneration of the epithelial cells, and at about 24 hours intranuclear inclusions can be found in the epithelium (Fig. 7.22B, C). The inclusions are lightly acidophilic or bluish red and large; they can be found for 3 or 4 days, by which time the lesion has

440

7.

T H E FEMALE G E N I T A L SYSTEM

reached its zenith and is beginning to resolve. Some of the parasitized cells undergo necrosis, but epithelial disruption and ulcération are due largely to an intense infiltration by neutrophils. Vesicles and true pustules do not form. Acute inflammation occurs in the lamina propria with hyperaemia and oedema and the exudation of numerous plasma cells and lymphocytes. Many of the small vessels are occluded by adventitial and endothelial swelling. The lymphocytic follicles are remarkably hyperplastic and oedematous, and their outlines are obscured by the infiltrating cells in the lamina propria. Resolution occurs in about 8 days, with hyperplastic lymphoid follicles and slight epithelial thickening as residues. Mild cervicitis and endometritis accompany the vaginitis. There is focal loss of cervical and endometrial epithelium with slight cellular infiltration but no inclusion bodies. The Fallopian tubes are normal. NECROTIC VAGINITIS AND VULVITIS. Necrotic vaginitis

is a deep diphtheritic inflammation of the vaginal mucosa; it occurs in two fairly distinct syndromes, being either a vulvovaginitis or a cervicovaginitis. Necrotic vulvovaginitis is uncommon but many involve a number of cows in a herd. It is primarily traumatic with contamination and the result of direct injuries of various types and bite wounds, the latter either by pigs or dogs. Necrotic cervicovaginitis (Fig. 7.22E) is a complication of parturition and is observed chiefly in ewes and cows as a consequence of dystocia. A number of influences, mainly prolonged pressure necrosis, laceration, and abrasion, usually acting in combination are responsible for the lesion. Necrotic cervicovaginitis is frequently fatal either in association with direct extension of the inflammation to the peritoneum or in association with the uterine complications of prolonged dystocia and foetal emphysema. NEOPLASTIC DISEASES OF THE TUBULAR GENITALIA

Isolated reports have ascribed parentage of both benign and malignant tumours to all histologie components of the tubular genitalia, sometimes with doubtful credentials. Some of the least uncommon tumours warrant brief discussion. Leiomyoma (Clinical "Fibroid'") The leiomyoma is the most common tumour of the tubular genitalia of the bitch but is rarely met with in other species. Its origin is from the smooth muscle in the wall of the uterus, cervix, or vagina, and, although it may be solitary, usually there are multiple foci in each division. The tumour in the bitch is not malignant, nor wholly autonomous, being, in some unknown manner, endocrinedependent. It rarely occurs in the bitch earlier than middle age and is probably always associated with ovarian follicular cysts or oestrogen-secreting tumours, and often also with endometrial hyperplasia, mammary hyperplasia, and mammary neoplasia. Bitches castrated early in life are exempt, and established tumours regress following castration. This tumour has been provoked in guinea pigs

by continuous low-level doses of oestrogen but, for spontaneous leiomyomas as well as endometrial and mammary neoplasms, there is as yet no precise knowledge of the role of oestrogen. There are three possibilities which are usually considered, namely the maintenance of the above tissues to provide a site in which spontaneous neoplasia may occur, concerted action with other agents such as Bittner's milk factor, and gradation from hyperplasia to neoplasia with oestrogen as the sole excitant. At present there is little doubt that oestrogen is to some degree carcinogenic, and that it is fortunate that oestrus, in the absence of pregnancy, is cyclic, providing spontaneous remissions of oestrogen stimulation and a progestational phase which is antitumourigenic. The genital leiomyoma may grow to be as large as a grapefruit but is not invasive. The smaller tumours are fleshy but, as they enlarge, become firm or hard (hence the clinical "fibroid") due to the connective-tissue stroma. On cut surface, they have a watered silk appearance and the colour, whether more fleshy or white, depends on relative amounts of muscle and connective tissue. The tumour is not encapsulated but is well demarcated and easily shelled out. In almost all cases, the tumours project as globose or elliptical masses or as bulbous polyps into the lumen of the vagina, uterus, or cervix, but some project outward and few are found in the mesometrium (Fig. 7.23A). Degenerative changes occur in the larger tumours and are of two types, being either progressive replacement of myoma tissue by fibrous tissue of the stroma, or oedema and liquefaction with cyst formation. In the first type, the fibrosis may progress through hyalinization to calcification. The second type of degenerative change afflicts the vaginal leiomyomas especially, probably because these more often become pedunculated and susceptible to circulatory embarrassment. Histologically, the tumour is composed of whorling bundles of smooth muscle cells with abundant stroma but scant intercellular connective tissue. The organization does not depart much from normal and often the presence of neoplasm is best appreciated by the naked-eye appearance of the tissue (Fig. 7.23B). The overlying epithelium is intact. Malignant transformation has not been observed. In species other than the bitch, genital leiomyomas are uncommon, usually solitary, and not related in incidence to endocrine disturbances (Fig. 7.23C). Transmissible Venereal Tumour of Dogs This neoplasm, transmitted by coitus, occurs on the external genitalia of either sex. The noncommittal name of the tumour, in Europe often called "Sticker's sarcoma", is preferred to such terms as lymphosarcoma, histiocytoma, sarcoma, etc., which, suitably prefaced to indicate its transmissibility, have been used. But the histogenesis is obscure and, because the host's tissues do not contribute to the growth, is likely to remain so. This was the first neoplasm in the history of pathology to be transmitted

THE VAGINA

AND

VULVA

Fig. 7.22. (A) Vulva. Ox. White plaques of epithelial necrosis in infectious pustular vulvovaginitis. (Courtesy of Cornell Veterinarian.) (B) Histologie detail of (A) showing ballooning degeneration and ulcération of epithelium. (C) Intranuclear inclusions in vaginal epithelium in infectious pustular vulvovaginitis. (Courtesy of M. J. Studdert.) (D) "Granular vaginitis". Ox. Lymphoid follicles in submucosa. (E) Necrotic vaginitis of anterior vagina secondary to dystocia. Ox. (Courtesy of C. A. V. Barker.)

441

442

7 . THE FEMALE G E N I T A L

SYSTEM

Fig. 7.23. (A) Follicular and luteal cysts of ovaries with vaginal leiomyomas. Bitch. (C) Uterine leiomyoma. Ox.

(B) Uterine leiomyoma. Bitch.

THE VAGINA

experimentally, by the Russian veterinarian Novinsky in 1863. The tumour has been reported from Europe and the Orient as well as from the Americas, but there are geographical differences in its distribution which are liable to rather marked fluctuations in the course of a decade or so. In some parts of France, it occurs in epizootic proportions; in other European countries it is rare or absent. Once common in New York and Philadelphia, it is now an oddity there. Second only to mammary tumours as the most common tumour of dogs in some parts of Illinois, it is rare in some of the adjacent states. However, an abortive form of the disease, persisting only long enough to provoke immunity and passing unnoticed may be more common because a large percentage of dogs are refractory to artificial transmission. The tumour is not confined to the genitalia but in some few cases is found in other cutaneous locations. Metastasis sometimes occurs to regional lymph nodes but spontaneous regression usually occurs in less than 6 months. In the vagina, the tumour takes origin in the submucosa, usually of the dorsal wall, as one or more papular or papillary proliferations. Expansive growth also occurs mainly in the submucosa, and the overlying epithelium becomes stretched and attenuated. With rupture or penetration of the epithelium, the tumour projects into the vagina as an irregular, ulcerated, and friable mass which may protrude from the vulva. Histologically, the tumour is composed of round, oval or polyhedral cells with indistinct boundaries and a poorly stained or clear cytoplasm. The nuclei are large in proportion to cell size with a single, well-defined nucleolus and many chromatin granules. Variability in the size of the cells is rather characteristic and mitoses are frequent. There is no intercellular reticulum such as is seen in tumours of reticular origin, but an abundant and rather delicate vascular stroma may produce a pseudoalveolar or trabecular arrangement. In the skin also, the tumour seems to arise in the subcutis, and the epidermis is not usually penetrated. It is suggested that natural cutaneous implantation occurs in bite or other wounds. In any locale, the tumour shows a marked tendency to break down after a few months of rapid progression, and on incision the necrotic tissue resembles pus. Natural transmission is largely by coitus and requires the implantation of intact cells; it is not transmissible by filtrates. Apparently, an immunity is established to the tumour and resistance to reinfection follows spontaneous recovery. The tumour is transmissible to the fox but not to other species. Fibropapilloma of the Vulva This is probably the most common tumour of the bovine vulva and affects young animals primarily. It is, briefly, a wart growing on a mucous membrane, the nature of the host tissue apparently determining the reaction to the virus of bovine verrucae. This virus

AND

VULVA

443

infecting the keratinized bovine skin provokes the typical papilloma of relatively scant connective-tissue core and abundant epidermal overgrowth. Transplanted instead to the penile or vulval mucosa the contribution of the two moieties is reversed, the bulk of the tumour being of connective tissue with (barring accidents) just enough epithelium to cover it. Histologically, the bulk of the tumour consists of interlacing bundles of fibrocytes. In the younger tumours, there may be many mitotic figures and such cases have often been misdiagnosed as fibrosarcomas (see illustrations with male genitalia). Many of the plump spindle cells have large nuclei with bizarre nucleoli and sometimes pale, eosinophilic inclusion-like intranuclear structures. Collagen formation from the stroma is progressive with duration. Surface ulcération is followed by superficial inflammatory infiltration. The vulval tumours are usually sessile rounded growths when young, but become progressively more cauliflowerlike. Those attached to the penis are often pedunculated. The natural history of the genital fibropapilloma is the same as of the common cutaneous papilloma, spontaneous regression occurring in 1-6 months or so. Within this period, surgical excision may be followed by recurrence. Carcinoma of the Endometrium and Cervix These are rare neoplasms in domestic animals (Fig. 7.24A) and therein lies their interest. The rarity is real and not, as has been implied, apparent because of inadequate postmortem examination. The most popular current opinion on the pathogenesis of the endometrial carcinomas in women relates them to prolonged oestrogenism, with cystic endometrial hyperplasia of the same cause, as the precancerous lesion. There is very good evidence in support of such belief. In domestic animals on the other hand, cystic endometrial hyperplasia is common, but carcinoma is rare and when it does occur does not seem to require prior oestrogenic conditioning of the endometrium. Lymphomatosis The term lymphomatosis is here used in an inclusive sense to include all of the many forms of tumour of the lymphocytic series, excepting those which occasionally arise in the thymus and which behave more in accord with the usual concepts of a sarcoma. Involvement of the uterus is not uncommon in bovine lymphomatosis but is distinctly so in other species. As elsewhere, there are two anatomic forms of uterine involvement, diffuse and nodular. In either event, the initial deposition seems to occur in the endometrium. The diffuse nonnodular lesion involves both horns, body and occasionally the cervix in a more or less uniform thickening although the mucosa may be thrown into broad folds and the atrophie caruncles may still be easily recognized. The thickened wall loses its elasticity and on cut surface is rather structureless with an appearance like firm fat (Fig. 7.24B). Gentle pressure may expel small quantities of cloudy, highly cellular fluid. There is patchy ulcération

444

7.

THE FEMALE G E N I T A L SYSTEM

of the endometrial mucosa. There is nothing peculiar to the nodular form of the disease. These nodules, few or many, may attain large size and cause corresponding deformity. Central liquefactive necrosis is common in them. Microscopically, there is, with either form of the disease, gradual replacement of the normal uterine structures by infiltrating tumour cells. Lesions of corresponding type occur in the vagina, but do so less commonly. Metastatic Tumours With the exception of lymphomatosis, secondary neoplastic diseases of the tubular genitalia are rather rare. Serosal implantations occur in peritoneal carcinomatosis. Haematogenous métastases probably have a predilection for the endometrium (Fig. 7.24C). The Mammary Glands Old enemies like old friends are often taken for granted. There are few exceptions in the field of veterinary science and the two major classes of mammary disease—mastitis in the cow and other species, and mammary neoplasms in the bitch—are not among them. The inflammatory and neoplastic diseases of the mammary glands are the only conditions of significance to the pathologist although there are others of minor or surgical importance. BOVINE MASTITIS

Mastitis is an inflammation of the mammary glands of varied cause, course, and consequence, affecting all species although each has types peculiar to itself. By far the most important and common types of mastitis affect the dairy cows. But mastitis in any species is not one disease, the nature of the process, and probably also the pathogenesis, being dependent on the nature of the infectious agent. The main discussion here will be centred on bovine mastitis caused by Streptococcus agalactiae. Other causative types of bovine mastitis and mastitis in other species will be dealt with more summarily as being of lesser importance and because little is known of them beyond the facts of their occurrence. BOVINE MASTITIS DUE TO Streptococcus agalactiae. This type of mastitis was by far the most common and important of the forms of bovine mastitis until it was subdued by therapy. The causative agent has the mammary gland of the cow and goat as its natural and sole habitat; resistance to the extramammary environment is low although the organism may survive for a month or more on fomites, but environmental factors are important in the transfer of infection from cow to cow. Studies on the pathogenesis of mastitis have been hobbled by two misconceptions, the first of which overemphasized the environment as the source of infection, with relative de-emphasis of the true source of infection which is the infected mammary gland, and the second of which has equated significant infection with obvious disease. The latter has led to the neglect of factors controlling invasion through the teat canal, the persistence and multiplication in the sinuses, and the penetration of

tissue which results in the reactionary inflammation which we call mastitis. These three phases in the pathogenesis of mastitis can now be discussed. The only significant portal of entry of Strep, agalactiae into the mammary gland is through the teat canal. Mastitis is always a possible complication of traumatic teat injuries, but infection in such cases is more often due to environmental organisms than to Strep, agalactiae. It appears that the major and critical barrier to infection is some component or components of the teat canal. The establishment of a bacterial population in the teat cistern is usually followed by inflammation, but the application of even large numbers of bacteria to the teat orifice results in infection in only a few cases. The length of the teat canal seems not to be important. Its patency may be, but there is no good measure of this. There is contradictory evidence on the relationship between ease of milking and susceptibility to mastitis, but ease of milking is not a criterion of patency of the teat orifice. There is little doubt that structural factors of the teat orifice and canal are important in regulating the entry of organisms in some cases. Whether other factors are also involved is not known, but it seems likely that chemical factors within the teat canal are of primary importance in determining whether the infecting organisms shall be repulsed or permitted to proliferate and grow through the canal into the cistern. A purely mechanical progression is unlikely. Resistance to mastitis caused by Strep, agalactiae is rather strong in some cows so that it is possible to compare cows which are highly susceptible with those that are highly resistant. The difference between resistant and susceptible animals is apparent only if the infecting organism is applied to the teat orifice or within the teat canal; disposition of the organism, even in small numbers, within the sinus rather regularly results in infection— apparently the inherited mechanisms of resistance have been bypassed. Resistance is not an all-or-none phenomenon. It declines progressively with age and is, no doubt, subject to the general influence of body health, but at any single exposure to the teat orifice or canal it is all or none. In a susceptible animal, exposure of the canal to even small numbers of the organism is followed by their multiplication and entry into the cistern, whereas, in resistant animals, the inoculated organisms multiply briefly if at all in the teat canal, and disappear in the course of two or three milkings. But resistance to this sort of exposure, which most nearly parallels natural exposure, can be removed by removing the smegma of the teat canal. The teat canal is lined by a stratified squamous epithelium which is surfaced by a layer of keratin-like material and then an innermost layer of smegma—a waxy material composed probably of epithelial debris and milk solids. Although the lining of the teat canal is an invagination from the normal surface epithelium, its chemical composition, as judged by staining reactions, is quite different. It is possible that there is in the smegma of the teat orifice of resistant cows some substance which is actually inhibitory to the

THE

MAMMARY

GLANDS

Fig. 7.24. (A) Diffuse uterine endometrial adenocarcinoma with metastasis to right ovary. Ox. (B) Diffuse lymphomatosis of uterine wall. Ox. (C) Metastatic sarcoma of uterus. Mare. Pedunculation probably related to looseness of endometrium.

445

446

7.

THE FEMALE G E N I T A L

growth of Strep, agalactiae. The phenomenon of resistance can be demonstrated to operate also in infections by Staph. aureus, but with two differences. There is no increasing-with-age susceptibility to staphylococcal infections, and cows which are resistant to Strep, agalactiae are not necessarily resistant to Staph. aureus and vice versa; apparently, the ingredients of resistance to the two infections are not the same. The manner in which the teat canal determines resistance and susceptibility might reasonably be regarded as academic when strictly related to Strep, agalactiae infection because this organism is eradicable by present knowledge rationally applied. For the other important mammary infections still to be considered this is not so; these agents inhabit the environment where they are not vulnerable, and the achievement of a satisfactory degree of control over them may well require precise knowledge of factors governing invasion through the teat canal and these, in probability, will parallel the control exerted over the growth and entry of Srep. agalactiae. So much for the invasion phase. The infection phase is that in which the organism is present within the cisterns. It is often stressed that the presence of bacteria within the udder does not constitute mastitis, the presence of signs of inflammation being necessary for that diagnosis. Interpreted literally this is true. Interpreted instead in terms of the disease process such a statement constitutes an error in concept. There are necessarily three phases of the process of mastitis: the invasion phase already referred to, the infection phase in which the organism persists in the milk cistern and duct in more or less equilibrium with its host, and the inflammation phase which follows immediately on penetration of tissue from the ducts. Penetration of tissue is not an inevitable, but is a common, consequence of the infection phase and further it is unpredictable, occurring from time to time and being responsible for the clinical "flare-ups" or "crises" which are so characteristically part of the course of the disease process, especially when it is due to Strep, agalactiae. It is equally true for all the major causative forms of bovine mastitis, that each may, at any time, occur in a nonclinical form (detectable by bacteriological examination but not by the various tests such as strip cup, brom-thymol-blue, Whiteside test, cell count, and California mastitis test which are indicators of active mammary inflammation), and subsequently occur in a clinical form in which these tests are positive and there is often some systemic disturbance as well, and further that, following a clinical flare-up, there may be another period of quiescence. The initial multiplication of organisms within the cisterns and ducts, following their entry, is slightly delayed owing possibly to inhibitory factors in milk, but this inhibition is probably ineffectual in influencing the early course of the disease. When the milk is altered by the inflammatory reaction it may be more inhibitory, owing, it seems, to the presence of leucocytes. This is very probably the explanation for the occasional therapeutic success following infusion with nonspecific irritants and for the occasional observation

SYSTEM

that Strep, agalactiae infection is not easily superimposed on a mild mastitis caused by other organisms. Streptococcal mastitis is usually permanent. The organism is capable of maintaining its numbers in the cisterns in opposition to inflammatory products and the irrigative force of milking. How it remains in equilibrium with its host in the infection phase is not clear. At a variable period following the establishment of infection, the bacterial population may suddenly increase and the tissue become invaded for a brief period producing a clinical crisis. This proliferation of bacteria within the cisterns precedes tissue penetration and is associated with altered virulence of the organism as measured by mousepathogenicity tests. Whether there is also some change in the host system is not known, but change ought perhaps to be expected, because the detrimental effects of improper machine milking, in terms of height of vacuum, rate of pulsation, period of application, etc., are expressions, largely, of flare-ups of established quiescent infections. Repeated invasions usher in a series of inflammatory and reparative reactions, which if unchecked therapeutically, culminate in fibrosis and involution of the affected quarter. There are varying degrees of severity of the clinical reaction of streptococcal mastitis, the more acute cases being associated with systemic disturbances and the less acute ones not. The anatomic basis lies not in the acuteness of the inflammation, but in the amount of mammary tissue involved. A greater or lesser amount of normal uninflamed tissue is always present, the inflammatory reaction being confined to those areas in which the organisms manage to penetrate the duct epithelium. It appears that the streptococci are unable to penetrate the interstitial tissues to a significant degree, although sometimes they are found in leucocytes in the lymphatics and supramammary lymph node, and that the inflammatory reaction is due to diffusing toxic products of the organisms. This period of epithelial penetration is brief, being of only a few hours' duration, and the organism in tissue is rapidly destroyed by leucocytes. This destruction of the organism may at times sterilize the udder or so diminish numbers that bacterial cultures of milk taken during a crisis may be negative, a finding that applies also to other acute mammary infections. The first response to the penetration of streptococci is a remarkable interstitial oedema and an extensive migration of neutrophils into the interlobular tissue and secretory acini. The stromal lymphatics are widely dilated and contain numerous leucocytes which are delivered to the regional lymph node. The acinar epithelium becomes vacuolated and desquamated, or in places heaped up and ragged over accumulations of macrophages and fibroblasts which make their appearance very early in the course of the reaction. Streptococci are very numerous at this stage both within the ducts and acini and in and under the epithelium. The acute exudative reaction gives place to two processes which proceed together—pathologic fibrosis and involution. A few organisms still persist in the larger ducts and the neutrophil reaction is reduced, but macrophages and fibro-

T H E MAMMARY

GLANDS

447

Fig. 7.25. (A) Ectopic mammary tissue in wall of teat canal. Ox. (B) Acute streptococcal mastitis. Ox. (C) Chronic streptococcal mastitis with fibrosis, glandular atrophy and squamous metaplasia of duct. Ox.

blasts continue to increase in number (Fig. 7.25B) and eventually obliterate many of the acini. Lymphocytic foci begin to develop in the interstitial tissue. Other acini become dilated and rounded and contain a stringy coagulum with intact cells and cellular debris which constitutes the first indications of the involution which follows interruption of secretion and acinar stagnation. The involution affects lobules directly involved in the

exudative inflammation as well as those surrounded by interacinar tissue to which the fibroplasia has extended. Stagnation of secretion occurs also in many of the smaller ducts. It is pertinent to note that this is the stage which on palpation is swollen, firm, and painful and often referred to as fibrosed. But there is as yet little fibrosis, the "induration" being due instead to retained secretion. These nodular or diffuse "indurations" are firm and liver-like in

448

7.

T H E FEMALE G E N I T A L SYSTEM

consistency but of normal colour and are easily cut in contrast to the normal slack elasticity of mammary tissue which makes it difficult to cut. The processes of fibrosis and involution continue until the end stages when some lobules show normally involuted tissue, some are obliterated by fibrosis (Fig. 7.25C), and others show a varying balance between both processes. Such a gland is atrophie, dry and, because of the fibrosis, poorly elastic. Some lobules escape for a time, often a long time, only to be involved ultimately in a flare-up or by extension of the disease process. It is evident then that the many lobules involved are often out of phase with each other but that in each the succession of events proceeds rapidly. Adjacent to the spots where the streptococci invade the epithelium of the smaller ducts, granulation tissue develops rapidly and exuberantly and protrudes into the duct lumen which is dilated and contains stagnant milk, exudate, and numerous organisms. These polypoid proliferations may completely obstruct the duct or, by fusing with the opposite surface, produce loculations resembling abscess cavities which are clearly visible macroscopically. There is concomitant proliferation of periductal fibrous tissue spreading centrifugally to involve and obliterate large amounts of lobular tissue. Such granulation tissue in time cicatrizes and the duct epithelium is restored. Similar changes occur in the larger ducts and teat cisterns at points of bacterial penetration, but they are less exuberant and the epithelium is shortly transformed to a squamous, sometimes keratinizing, type which is later desquamated and reconstituted as the acute phase subsides to the chronic one of involution and as fibrosis supervenes. Involution has been regarded as a defence mechanism but this misconstrues its purely passive development as a consequence of stagnation. Such involuted lobules are capable of function at subsequent lactations. Whether there is any replacement of destroyed lobules by regeneration from persistent ducts has not been established, but it cannot amount to much. The gross appearances of streptococcal mastitis vary according to the stage of the disease. Usually more than one quarter is involved, but not uniformly, most of the change taking place in the distal portion of the gland about the cisterns and large ducts. The cisterns and ducts are filled with secretion in the early stage of the disease, the secretion being serous and floccular, or distinctly purulent. The mucous membrane of the cistern may not be appreciably altered or it may be hyperaemic and granular. The glandular tissue is swollen and turgid. It cuts easily with a knife and on the cut surface the lobulations are distinct because the swollen lobules protrude. It is not possible to recognize the interstitial oedema. The affected lobular tissue is greyish in colour and can be distinguished from the milky whiteness of normal lactating tissue, but not readily from involuted parenchyma. In the later stages of the disease, the most obvious changes occur in the cisterns and large ducts as a moderate thickening of the epithelium and small rounded polypoid proliferations into the lumen of the cistern and large ducts. Fibrosis is recognizable in these cases surrounding the

ducts, surrounding lobules and obliterating some, and diminishing in severity towards the base of the gland. BOVINE MASTITIS CAUSED BY STREPTOCOCCI OTHER THAN

Strep, agalactiae. Included in this category are Strep, dysgalactiae, Strep, überis, Strep, zooepidemicus, Strep, pyogenes, Strep, faecalis, and other unclassified streptococci of Lancefield's groups G and L, and pneumococci. Streptococcus uberis is usually associated with a mild and chronic disease, but the other species usually produce acute, but transient, inflammation, often accompanied by systemic signs of illness. The incidence of infection with any of these organisms tends to be sporadic, but occasionally there are severe outbreaks in individual herds. Any of the first three species may be present with Corynebacterium pyogenes in the severe "summer mastitis" of dry cows and heifers. Very little is known of the pathogenesis of these infections, although predisposing teat injuries are often incriminated; and little is known of the history of the lesions, although apparently it is similar to that of the lesions of Strep, agalactiae infection. With the exception of Strep, uberis, these infections do not persist as endemic infections. Mastitis caused by Strep, pyogenes is of some importance because the organism is a human pathogen; the secretion from infected quarters may contain enormous numbers of these organisms, but they proliferate barely, if at all, in drawn samples of milk. BOVINE MASTITIS CAUSED BY Staphylococcus

aureus.

Staphylococcal mastitis is predominantly an infection of the younger age groups and there is no increase in susceptibility with age. Pathogenic strains of staphylococci are always of human or animal origin and persist as permanent inhabitants of the skin and mucous membranes, although they are capable of more than average resistance to the general environment. It is generally accepted that the infection of the udder is contagious, and it seems probable that entry through the teat canal is, in general, subject to the same sort of local controls as is the entry of Strep, agalactiae. Strains of staphylococci are common as infections of the cisterns and ducts and without evidence of inflammation. Not all such strains, however, are pathogenic. The ability of a strain to produce coagulase and haemolysis is the best single criterion of its pathogenicity for animals. Mastitis paralleling the natural disease can be produced by infusing the udder with the alpha toxin; the beta toxin is nonirritant. Strains of the organism, not separable by other criteria, differ in their toxigenicity, but this is not necessarily related to pathogenicity; one strain may produce gangrenous mastitis on some occasions and only a mild disease on other occasions. Clinically, staphylococcal mastitis may be peracute and fulminating or milder and more chronic; the latter is the more common. The acute forms of the disease, typically, occur shortly after parturition and tend to produce gangrene of affected quarters and a high mortality. The

THE MAMMARY

affected quarters are swollen and tense, hot and firm, and very painful. There is almost complete stagnation of secretion and only a few millilitres of brownish bloodstained or straw-coloured watery fluid can be expressed from the teat. Uninfected quarters of the same udder are also swollen and tense and the secretion is reduced but otherwise normal, an effect probably due to the diffusion of toxins through the vascular bed of the gland. Gangrene usually affects first the teat and adjacent portions of the udder and may not be more extensive or it may extend even to involve the whole quarter. The tissues become blue and eventually black and are softer, insensitive, and cold. There is pitting oedema of the inguinal area, flank and ventre, and in a day or so the necrotic skin begins to exude serum and to slough, and crepitating gas bubbles develop beneath it. The changes are those of ordinary moist gangrene remarkable only for the abundance of fluid exudation and are attributable to the direct action of toxin on the acinar tissue and to venous thrombosis. The amount of tissue involved in the gangrenous process is quite variable and groups of necrotic lobules adjoin others which are near normal. Natural separation of the gangrenous areas begins about a week after the onset but proceeds slowly with the development of a suppurative surface and fistulae. The acute, nongangrenous, and mild forms of the disease progress more closely along the lines already described for streptococcal mastitis, but with some important differences which will be mentioned later. It appears that early events are comparable to those of streptococcal infection and that the bacterial population, resident in the ducts and cisterns during the infection phase, multiplies rapidly (Fig. 7.26A) and then penetrates through the duct wall to the interacinar tissue. If the penetration is massive and the organisms highly toxigenic, the acute and gangrenous forms of the disease occur. But the invasion, even if massive, is massive only in patches and intervening areas remain normal for some time (Fig. 7.26B). The differences in the manner of progression of streptococcal and the milder staphylococcal mastitis depend on different toxigenicity of the genera and the ability of the staphylococci to invade more deeply into the interacinar tissue and to establish themselves there as persistent foci of infection to provoke the granulomatous reaction known as "botryomycosis" (Fig. 7.26C, D). The initial reaction is necrotizing and these necrotic foci are soon surrounded by an intense leucocytic response and fibroplasia develops rapidly to wall off the irritant foci, thus obliterating large portions of the normal mammary structure. Each granulomatous focus may be no more than 1-2 cm. in diameter, but they may be numerous and involve a large proportion of the gland with, between them, a residuum of involuted lobules which are surrounded by septa greatly thickened by confluence of fibrosis. The thickened septa and the granulomas are readily visible to the naked eye and small amounts of pus can be expressed from them. Microscopically, the granulomas closely resemble those of actinomycosis and have been so called, but the coccal organisms are easily Q

GLANDS

449

visible in the microabscesses. Walled-off by connective tissue, the bacteria are not exposed to the action of antibiotics. The infection is always a localized one, and even in peracute cases bacteraemia does not occur. BOVINE MASTITIS CAUSED BY MISCELLANEOUS INFECTIONS.

These are more common and important than their treatment as a miscellany suggests, but very little is known of the pathogenesis and lesions. The bacteria usually grouped in this category include Escherichia coli, Pseudomonas aeruginosa, Pasteurella spp., Klebsiella pneumoniae, and Aerobacter aerogenes, and they occur in about that order of frequency. References to additional bacterial species as causes of mastitis will be found in the bibliography. Each usually produces a clinically acute form of the disease with systemic reaction and, especially in the case of E. coli, septicaemia. Acute tendovaginitis may also occur. Both E. coli and A. aerogenes may be associated with clinical "flare-ups" of the milder progressive type of disease with a history closely resembling that caused by Strep, agalactiae. With these infections also, negative cultures may be obtained during the acute phase. The pathology of the coliform infections has not been studied in detail. Indeed, there is even some debate on the pathogenesis of those infections produced by the enterobacteria, a haematogenous route of infection frequently being postulated because mastitis often coexists with puerperal infection of the uterus. It appears much more likely that infection is galactogenic because the cisterns and ducts bear the brunt of the injury and contain numerous bacteria whereas neither bacteria nor significant leucocytosis can be demonstrated in the interstitial tissue in the peracute infections which are the fatal ones. The infection is often limited to one quarter and, being of short course, the inflammation may be predominantly serous with much oedema or it may be severely haemorrhagic (Fig. 7.27B). The secretion in the cistern is scanty and may be watery, or cloudy and blood stained; it contains floccules of fibrin and coagulated casein. Similar floccules can often be seen as plugs in the milk ducts (Fig. 7.27A). There is usually severe oedema of the subcutis. Microscopically, the inflammatory reaction is seen to be centred on the ducts. The lining of the larger ducts is destroyed and replaced by fibrinocellular exudate. The lining of the smaller, intralobular, ducts is also destroyed and in these there are plugs of necrotic detritus (Fig. 7.27D). The acini are filled with a serous fluid in which there are vacuolated desquamated epithelial cells, but leucocytes are few or absent, either in the alveoli or in the septa. The septal tissues, especially the interlobular septa, are widened by oedema fluid and the lymphatics, which are greatly dilated, contain many plugs of fibrin. In areas of haemorrhagic inflammation, the septal vessels are suffused with blood and tortuous and there is extensive haemorrhage into the stroma (Fig. 7.27C) and into the acini. If the course of the peracute inflammation is prolonged beyond 1-2 days, extensive necrosis of tissue may occur. Gangrene is not produced by coliform bacilli alone. The

450

7.

THE FEMALE G E N I T A L

SYSTEM

Fig. 7.26. (A) Acute staphylococcal mastitis. Ox. Note colony of bacteria in duct at centre. (B) Acute staphylococcal mastitis showing patchy distribution of early invasion. Ox. (C) Granulomatous nodes and fibrosis in chronic staphylococcal mastitis of botryomycotic type. Ox. (D) Chronic staphylococcal granulomas. Ox.

THE

MAMMARY

GLANDS

Fig. 7.27. Coliform mastitis. Ox. (A) Haemorrhagic inflammation of gland cistern with plugs of exudate in ducts. (B) Typical haemorrhagic consolidation, sharply demarcated. (C) Interstitial haemorrhage in acute coliform mastitis. (D) Necrosis and desquamation in acini and fibrin plugs in lymphatics.

451

452

7.

THE FEMALE G E N I T A L

SYSTEM

with subsequent spread along the ducts (Fig. 7.28D). The anatomic form of the lesions is deductively explained on the basis of degrees of resistance and hypersensitivity but these are essentially imprecise (see Tuberculosis, Diseases of Lung). The disease may occur with outstanding duct BOVINE MASTITIS CAUSED BY Corynebacterium pyogenes. involvement following infusion with material conCorynebacterium pyogenes is found in normal udders taminated with Mycobacterium tuberculosis. Disseminated without evidence of inflammation, but it does cause sporadic miliary tuberculosis develops as part of an early generalizacases of acute mastitis as a complication of injury and, as an tion and is not common even in a highly infected comenzootic disease, is known in the United Kingdom as munity. The lesions are rather like those of miliary "summer mastitis" and in Europe as "Holstein uddertuberculosis elsewhere, occurring as nodules up to 1.0 cm. plague." Nonlactating and immature glands are affected or so in diameter which project above the cut surface. The as well as lactating glands. In the natural disease, one or tubercles are not evenly distributed, but rather tend to more of a variety of other organisms is also present and it is occur in groups in the deeper tissues. Some are caseous, not clear that C. pyogenes alone can initiate the inflamothers are caseous and calcified, and all are of typical matory phase. Affected quarters are swollen, bumpy, and tubercle structure, often with very heavy capsules. The foci hard; the secretion contains large amounts of pus and has a begin to develop in the interacinar connective tissue and foul odour. Abscesses form and they tend to rupture to the remain localized to lobules which are completely destroyed exterior near the base of the teat and then may heal or (Fig. 7.28C), but there is no direct progression between produce chronically discharging fistulae. In some cases adjacent lobules or encroachment on the interlobular there is extensive necrosis with sloughing of the necrotic connective tissue. The reaction is typically tuberculous, tissues. Nonfatal cases end in complete fibrosis and loss of and often there is more than one tubercle in each lobule function. affected. The sequence of events in corynebacterial mastitis have The interlobular ducts are also extensively involved and not been studied, but the lesion is clearly a necrotizing the dilated lumen is filled with cellular exudate. The wall suppurative galactophoritis with slight primary involveitself is greatly increased in thickness by tuberculous ment of the acinar tissue, and grossly visible abscesses form granulation tissue and epithelial hyperplasia. The suprawhere the exudate remains stagnant in the ducts. The mammary lymph nodes in such cases usually contain many smaller abscesses occur in the intralobular ducts and these typical tubercles. are associated with desquamative changes and the exudation Chronic organ tuberculosis is the most common form, of a few leucocytes into the acini, and with rapid fibrorepresenting 80-90 per cent of cases. It is rather different plasia and infiltration of leucocytes, including many from the ordinary tuberculous lesion and the regional plasma cells, in the septa. The small intralobular abscesses lymph nodes are not usually involved, although some may may heal with obliteration of the ducts and scarification show numerous microscopic foci of infection with few of the lobule. The large abscesses are centred on the larger organisms. The mammary tissue is very firm and cuts ducts the walls of which are remodelled by exuberant readily. The lobulated structure is exaggerated and, when granulation tissue although still lined in part by hypercut, projects above the surface of the organ giving a plastic and squamous epithelium (Fig. 7.28A, B). Bacteria smoothly bumpy appearance surrounded by the indenare numerous in the abscesses and in the secretions in other tation of the interlobular tissue. The lobules which are parts of the duct system. The walls of the teat canal and affected, and most of them tend to be, vary from greyish cistern are thickened by granulation tissue and the mucosa red to white in colour and the surface is dry. The lesions is ragged. The cistern is narrowed by the fibrosis and the begin as one or more foci of granulation tissue within the teat canal may be stenotic or atretic. lobules and they expand and coalesce to involve the entire lobule. A few of them break down and caseate. HistologicBOVINE TUBERCULOUS MASTITIS. Various figures have ally, the lobular outlines are retained and the interlobular been quoted for the incidence of mastitis in bovine septa are not involved. The process begins in the intratuberculosis, but no satisfactory estimation has so far been lobular septa, and the diffuse tuberculous granulation made. The most significant generalization is made by tissue overruns and obliterates the acinar tissue. Typical Nieberle to the effect that involvement of the mammary tubercles do not form although the cellular types involved glands is second only to that of the lungs. Its public health importance, however, depends not only on Nieberle's in the reaction are as usual. The intra- and interlobular generalization, but also on one by Stamp, who states that ducts are always involved and the walls are greatly thickened in all cases, irrespective of the age or activity of the lesion, by granulation tissue. The surface tends to caseate although the ducts are involved and, therefore, that every case of some epithelium, altered to a squamous type, may persist. mammary tuberculosis is an open case. Caseous exudate collects in the sinuses. In this form of the disease intramammary spread is entirely by way of the There are three major anatomical forms of mammary ducts and the reaction is typical of any chronic organ tuberculosis: disseminated miliary tuberculosis, chronic tuberculosis and of exogenous or endogenous reinfection organ tuberculosis, and caseous tuberculous mastitis. In the great majority of cases, the infection is blood borne, in an animal highly resistant by virtue of previous exposure.

necrosis is evident by the altered stainability of the tissues; the histoarchitecture of the tissue is retained for some time. If the animal survives, the necrotic tissue, usually most of one quarter, is sequestrated.

THE MAMMARY

GLANDS

Fig. 7.28. (A) Intraductal abscess in corynebacterial mastitis. Ox. (B) Bacterial colonies and exudate in duct lined by squamous epithelium. Ox. Corynebacterial mastitis. (C) Miliary tuberculous mastitis. Ox. (D) Tuberculous galactophoritis. Ox.

453

454

7.

THE FEMALE G E N I T A L SYSTEM

Caseous tuberculous mastitis causes great enlargement of affected glands and they are not nodular. The caseous areas are large and irregular with the dry yellowish caseous appearance and hyperaemic margin suggestive of ischaemic infarction. Other portions of the gland may show areas of chronic organ tuberculosis, often with commencing caseation and transformation to the diffuse type. Confluence is the rule and there is no limitation of spread by interlobular boundaries. The histological change is characterized by inflammatory exudation of fibrin and numerous leucocytes. The caseated areas are surrounded by a zone of hyperaemic granulation tissue of the sort that occurs in chronic organ tuberculosis, and haemorrhage in it occurs frequently. This form of the disease appears to develop from chronic organ tuberculosis, or possibly as part of an early generalization of the disease, in animals whose resistance is lowered by nonspecific factors or in which a high degree of sensitivity to the organism has developed. There is, in addition, a form of mammary tuberculosis in which the process centres on the interlobular ducts with subsequent spread to the larger ducts. In all cases of tuberculous mastitis there is duct involvement, but in the types already described duct involvement is by spread from initial foci in the intralobular tissues. In this last form, so-called tuberculous galactophoritis, there may be no discoverable acinar lesion, or, if lesions are present, they are more recent than, and obviously derived from, the duct infection. The glandular tissue in such cases retains its lobular character. The ducts are dilated and filled with an exudate of mixed inflammatory cells. The duct epithelium undergoes a patchy squamous or keratinizing metaplasia and the walls are greatly thickened by granulation tissue and infiltrated mononuclear cells but have few or no tubercles. The infectious process apparently begins in the walls of the larger interlobular ducts and extends up and down the duct system. Proximal progression leads to involvement of the smaller interlobular ducts and their obstruction, and this is followed by involution of the associated lobules. Tubercles occur in the supramammary lymph gland in this form of the disease. Mammary tuberculosis usually develops insidiously without signs of acute inflammation except in a few cases of the diffuse caseous type. The gland progressively increases in size and firmness. Rather importantly, the milk may be physically normal for a long period after the onset of the disease even although it contains the bacilli. In the later stages of the disease there is a reduction in the amount of the secretion and it is converted to a thin whey-like fluid which contains floccules of caseous exudate and very large numbers of bacilli. Because of the predominance of duct involvement, all cases are "open" and bacilli may be passed in the milk before gross lesions of tuberculosis are evident. ADDITIONAL INFECTIOUS CAUSES OF BOVINE GRANULO-

MATOUS MASTITIS. Included within this grouping are the organisms No cardia astéroïdes, Mycobacterium spp., and

Cryptococcus neoformans. With the exception of Nocardia astéroïdes, the infections develop only after infusion of the udder with compounds, usually penicillin, suspended in oil and tend, therefore, to involve a number of animals in isolated herds. Mastitis caused by N. astéroïdes (primarily a pathogen of man and dog) is sporadic although occasionally it reaches significant proportions in a herd. The source of infection is predominantly the soil, and under unknown circumstances entry is gained to the udder via the teat canal. Affected animals sometimes show a systemic reaction. Palpation of the gland typically reveals nodular formations up to 5 cm. in diameter with progressively developing diffuse fibrosis. Penetration of tissue occurs across the duct epithelium. The lining of the teat canal is thickened and corrugated by granulation tissue and the larger interlobular ducts are involved in the same manner. The glandular lesions remain fairly restricted to lobules without much coalescence across interlobular septa. The reaction is typically actinomycotic, although without club formation. Small abscesses contain tangled colonies of the organism and these are surrounded by a zone of epithelioid cells (giant cells are not present) and an expanding capsule of connective tissue which is infiltrated with a mixture of blood-borne leucocytes. Lymphocytes and plasma cells are abundant about the periphery of each lesion and in the surrounding lobular connective tissue. Affected lobules are obliterated. Cryptococcal mastitis caused by Cryptococcus neoformans has, in most reported instances, followed repeated udder infusion, usually with aqueous or oily penicillin. There is usually involvement of more than one quarter with, in the acute stages, rather severe swelling and an increased firmness of the gland and a subcutaneous oedema which when chronic produces tight adhesion of the skin to the gland. Changes in the milk occur after 2-3 weeks when it becomes watery and flaky, although the organism is excreted in number during the acute phase. The diseased tissue is abnormally fleshy, firm and greyish-white with spotty haemorrhages (Fig. 7.29C). Lobulation is exaggerated in the acute stages and the cut surface is very slimy with viscid greyish secretion that makes the gland hard to handle. Later the tissues become involuted and grey and contain numerous small granulomas. The histological picture is variable. In severely affected areas there tends to be complete liquefaction affecting epithelial cells, and the acini, in consequence, become distended and confined only by the skeleton of connective tissue (Fig. 7.29A). The organism is present in very large numbers and sometimes even the connective tissue is lysed to produce multilocular cystic acini. This far the inflammatory reaction is minor, but there develops a massive histiocytic response. Large vacuolated histiocytes infiltrate the acini and ductules and crowd beneath remaining epithelium, lifting it from its basement membrane. These cells engulf large numbers of yeasts and the histolytic effect of the organisms is no longer so obvious. More chronically, there develops extensive inter- and

THE

MAMMARY

GLANDS

Fig. 7.29. (A) Cryptococcal mastitis. Ox. (B) Cryptococci in typical soap-bubble lesion in supramammary node. (C) Cryptococcal mastitis. Ox. Note coarse nodular appearance of gland and cistern produced by mycotic granulomas. (A to C, Courtesy of J. R. M. Innes and the American Journal of Veterinary Research.) (D) Bovine mastitis produced by saprophytic mycobacteria.

455

456

7 . THE FEMALE G E N I T A L

intralobular fibrosis and a variable number of more typical granulomas. The corresponding lymph node is greatly enlarged and the lesions in it parallel those in the udder (Fig. 7.29B). The infection may metastasize to the lungs. Mastitis caused by Mycobacterium spp. other than M. tuberculosis also follows mammary infusion measures. These infections too cause a very marked enlargement of the gland, but there is no systemic reaction, nodularity, or subcutaneous oedema. The basic tissue reaction is granulomatous and well restricted to lobules. Giant cells are common, but the main infiltrating cells are histiocytes and lymphocytes organized in granulomatous formations which are often centred on oil droplets. Many of the lobules are completely destroyed by granulation tissue and there is considerable thickening and lymphocytic intiltration in the interlobular connective tissues (Fig. 7.29D). In the early stages, a ring of neutrophils may surround the oil droplets which contain large numbers of bacilli. Neither the organisms alone nor the oil alone is capable of provoking a granulomatous mastitis. Candida spp. infection has usually occurred under the same conditions of infusion. Mastitis caused by Trichosporon species is also reported. The tissue changes were not examined in either of these infections, but the infection produced by Candida spp. is often acute and transient, the infecting organism disappearing in about 3 weeks. The Mammary Secretion in Bovine Mastitis The major constituents of normal milk are: casein, lactalbumin, lactoglobulin, fat, lactose, salts, water, and cells. Changes in both the quality and quantity of these components occur during and following the inflammatory phase of mastitis, and a variety of examinations on milk have been proposed to discover the evidences of inflammation. However mastitis, according to the concept discussed previously, can be present without any evidence of inflammation and the only adequate test of its presence includes bacterial examination, remembering that during and following acute phases bacteria may not be detectable. The various other tests performed on milk have been devised for the detection of clinical cases and have considerable practical value. But the usefulness in such instances is limited by the inability of any clinical test to differentiate the causative types of the disease in all but very few cases. Physical alterations. The amount of secretion is reduced and, in the advanced stages of any form of the disease, tends to be a clear straw-coloured fluid. Clinical mastitis caused by Strep, agalactiae usually begins with the appearance of clots in a reduced volume of watery yellow secretion. In more chronic cases, the foremilk tends to be watery at all times and occasionally contains clots. Clots, as distinct from flakes of pus, indicate that an acute penetration phase has passed and that the altered duct epithelium and duct polyps are breaking down and desquamating. Rather similar changes occur in infections

SYSTEM

by the coliform group of bacteria, Nocardia astéroïdes, and the pathogenic fungi. In acute staphylococcal mastitis only a very small amount of secretion can be expressed, and this is watery and often blood stained, but with no clots or flakes. In acute corynebacterial mastitis the secretion is distinctly purulent. Milk from a tuberculous gland may, although containing bacilli, be normal for a long period. In the terminal stages of the disease it is greatly reduced in amount and converted to a thin wheylike fluid containing floccules of caseous exudate. Cellular content. Normal milk always contains numbers of cells, but the limits of normalcy are not precise and the cell count varies with the stage of lactation. During the early and late stages of lactation, there may be 500,000 to 1,000,000 cells per millilitre of milk, but during the middle stages, cell counts in excess of 100,000 should cause suspicion of inflammation. The cells normally present are epithelial cells, many of them disintegrated, and few leucocytes which are mainly polymorphs and lymphocytes. Differential cell counts are rarely performed because impractical. They are none the less valuable because, although total numbers vary with stage of lactation, the proportion of epithelial cells to leucocytes is relatively constant in normal milk. An obvious increase in the percentage of leucocytes is indicative of inflammation especially when they occur in clumps and mixed with fibres of fibrin. In the usual forms of inflammation the leucocytes are mainly polymorphs, but in the chronic phases mononuclear cells tend to predominate. In tuberculous mastitis, large mononuclear cells tend to occur in clumps, and the bacilli can be demonstrated in them with appropriate stains. The presence of erythrocytes in milk is of no significance for the diagnosis of mastitis unless accompanied by other evidence of inflammation. Chemical Changes. In mastitis, the acinar epithelium has altered permeability and function and, in the acute disease especially, the secretion shows some approach in constitution to that of plasma. Less casein is formed but the content of albumin and globulin is increased. Lactose is reduced but chlorides, of plasma origin, are increased. The pH changes from a normal of 6.4-6.8 to 7.0 or over. These alterations in the chemical state have provided a number of indirect tests of mammary inflammation. These tests include measurements of pH, electrical conductivity, and chloride level. The brom-thymol-blue indicator test is useful but will give false positives in early and late lactation. Bacteriological examinations. The great majority of cases of mastitis are caused by the streptococci, staphylococci, and coliform bacilli, but differentiation of the causative type cannot be made without bacteriological examination. Nor is it possible to detect nonclinical cases (the infection phase) by other than bacteriological means. A single cultural examination during the acute phase of the disease may not be enough, as cultures are often negative at that period; the more severe the disease the less likely are

THE MAMMARY G L A N D S

cultures to be positive. The examination of direct smears of unincubated milk samples is useful in some phases of the disease. It is a standard preliminary in the diagnosis of tuberculous mastitis and mycotic mastitis and is very useful for detecting infections by Nocardia astéroïdes and the Gram-positive cocci. Streptococcus agalactiae does not always form the typical long chains of eight to ten cells or more. The method of incubating the milk samples prior to examination magnifies the number of bacteria present, including contaminants, and gives a number of false positives; Strep, pyogenes, an uncommon but important infective agent, is destroyed by this procedure. The widespread use of penicillin in treating mammary infections has reduced the incidence of Strep, agalactiae and provided an increase in the percentage incidence of mastitis caused by other organisms. Their detection and differentiation requires the use of nonselective media capable of supporting the growth of all the usual types of infecting organisms. MASTITIS IN SHEEP AND GOATS

Mastitis in the ewe and goat is usually caused by Staphylococcus aureus or Pasteurella haemolytica. Corynebacterium ovis and C. pyogenes have been observed to cause "cold" abscesses and probably gain entrance through skin wounds. Staphylococcus aureus causes a galactogenic infection occurring very early in lactation with a course and consequences paralleling the disease in the cow. The morbidity, however, is higher and may approach 25 per cent of a flock. Pasteurella haemolytica causes mastitis in sheep on summer range at or near the end of lactation. It too is probably galactogenic and affects approximately 5 per cent of a flock. There is an early acute phase with systemic reaction, but in the course of 48 hours the systemic reaction has subsided. The affected gland, usually one side, is greatly enlarged and tense, and the secretion becomes watery and contains flakes. Later there may be developing bluish discolouration and widespread necrosis of tissue. Cases which do not terminate fatally develop abscesses in the course of a week or so with rupture and fistulation, and eventually most of the affected gland sloughs. Pneumonia in lambs has been reported to accompany this form of mastitis. CONTAGIOUS AGALACTIA OF SHEEP AND GOATS. This is

primarily a disease of goats, sheep being slightly less susceptible, and is caused by a pleuropneumonia-like organism Mycoplasma agalactiae. The proposed distinction between the various mycoplasmoses of goats is discussed under the section on arthritis. The disease is endemic in countries bordering on the Mediterranean Sea. The name, contagious agalactia, merely emphasizes one, although perhaps the most consistent, feature of the disease, namely mastitis. The disease is initially septicaemic, and often fatal in this phase. If the infected animal survives the acute stage there may develop signs of localization in the eyes and periarticular tissues and, in the case of a lactating female, in the mammary gland.

457

These are the sites in which localization is obvious, but it might be anticipated that M. agalactiae shares the affinity of this class of microorganism for connective tissues and lymphatics and that it localizes in other less obvious places. The organisms are eliminated in the secretions and discharges. Infection is probably by ingestion, but it can be galactogenic and per conjunctivum. Lactating females and kids are particularly susceptible to the infection and likely to succumb in the septicaemic phase of the disease. Pregnant females may abort or deliver live but infected foetuses. There are no specific lesions in the septicaemic phase, but the organism can be cultured from all tissues and from the blood. In infections of lesser severity or following recovery from the peracute disease, the febrile reaction subsides and lameness, keratoconjunctivitis, and alterations of the mammary secretion occur. This complete triad is not always present, and even when there are signs of localization the animal may continue to decline and die in 2 weeks or so. The mastitis apparently is an inflammation primarily of the interstitial tissue with secondary changes in the acini. Mild inflammations, although they cause cessation of lactation, may be followed by full functional recovery, but the more severe inflammations may lead to progressive fibrosis with parenchymal atrophy. The organisms are eliminated in the milk and in other discharges for many months in animals which survive the initial stages of the disease. Lameness is indicative of arthritis and periarthritis and this is more common at the carpal and tarsal joints than at others. Inflammatory oedema thickens the periarticular tissues. The synovial membranes may be normal or they may be hyperaemic or ulcerated with an increased volume of turbid fluid which may be blood stained. The ocular lesions, which are present in about 50 per cent of cases, consist of mucopurulent conjunctivitis and keratitis which may be complicated by ulcération and staphyloma. MASTITIS IN THE DOG AND CAT

In these species, inflammations of the breast are uncommon and nonspecific. The most important is nonspecific acute mastitis which is usually confined to early lactating or pseudopregnant periods. The exciting agents are staphylococci and streptococci, the former being the more common, and both are believed to gain entrance via fissures in the nipples and adjacent skin and to spread by way of both the ducts and the lymphatics. The staphylococci may cause gangrene, but they tend to localize in the course of a few days and form abscesses, while the streptococci tend to produce a more diffuse and spreading purulent inflammation. The acutely affected glands are large, firm, and oedematous, and the overlying skin becomes taut and shiny. Only a small amount of greyish secretion can be expressed; it may be blood tinged or contain pus. The chronic cases of mastitis in these species cannot be satisfactorily distinguished from neoplasm until examined cytologically. Indeed, mastitis is often superimposed on cystic mammary hyperplasia and on

458

7 . THE FEMALE G E N I T A L SYSTEM

mammary neoplasia, especially those tumours which involve the ducts. MASTITIS IN SWINE

Chronic granulomatous mastitis, affecting one or more glands, is occasionally observed in old sows. The lesions are of "botryomycotic" type, being suppurative granulomas, and the majority of them are produced by Staph. aureus. Actinomyces bovis was an important cause of this form of mastitis some decades ago but presently appears to be of very low incidence. It is true for sows as for cows that the designation "actinomycosis of the udder" refers more usually to staphylococcal than to actinomycotic infection. In either event, it appears that the infections are percutaneous, entry being gained through wounds of the skin. Mastitis caused by coliform bacteria is common as a very acute infection shortly after parturition. It may affect one or more glands and produces lesions which are similar to those in cows with this infection. The severe systemic reaction and the occasional presence of clinical synovitis indicates that septicaemia can occur. The pathogenesis is unknown, but overdistension of the udder may be predisposing. ABNORMALITIES OF MAMMARY

GROWTH—HYPERPLASIA

AND NEOPLASIA

Disorders of mammary growth of this type are very common in the bitch, of occasional occurrence in the cat, and very rare in the other domestic species. The two processes are considered under the one heading because it is difficult to avoid the conclusion that they are fundamentally alike, that hyperplasia is a precancerous lesion (although not an essential step in the development of mammary tumour) which grades indistinctly into cancer, and that hyperplasia is oestrogen dependent and mammary tumour often partially so. There are dissenting opinions on the relationship between the two processes in the human female: there are very few published opinions of any sort of the relationship in the bitch. The two lesions often coexist, but this alone does not imply a generative interrelationship because both lesions are rather common and both affect the older animals. On the other hand, there is quite good evidence that oestrogen has a leading role in provoking either lesion, and in the bitch both may coexist with endometrial hyperplasia and genital leiomyoma. It seems safe to accept that prolonged hyperplasia can pass into more or less autonomous growth, and sometimes there is direct histological evidence of such transformation. Mammary Hyperplasia This has gone by a very large number of misleading aliases, such as cystic mastitis, which contradict the essential nature of the process. Although the change is fundamentally one of epithelial and stromal hyperplasia, there is considerable structural pleomorphism both within and between affected glands, and this is determined in

part by the degree and pattern of the hyperplasia in the two components. In the bitch, usually more than one of the inguinal and caudal-abdominal glands are affected. The change is patchy in any affected gland but tends to involve the more superficial portions as poorly demarcated areas of an increased consistency and nodularity. It is not palpably distinguishable from neoplasia. A cystic form of the hyperplasia almost always predominates, the cysts are multiple and vary in size from microscopic to a diameter of 2 cm. or more (Fig. 7.30A). The larger cysts are usually thin walled and until opened have a bluish appearance. The content is watery or slightly viscid and grey or brownish in colour. The lining is typically a smooth shiny membrane and often there are thin spur-like projections from the wall or one or more large polypoid or cauliflowerlike proliferations into the lumen. The cystic changes probably involve the ducts more than the acini, but this is hard to determine. In the larger cysts the lining epithelium may be flattened or even absent, the wall then being of collagenous tissue. Papillary proliferations are common. The smaller cysts usually have an intact lining of cuboidal cells and in patches this may be multilayered or bear small papillae. Sometimes the epithelium assumes sebaceous characters. In all instances the basement membrane is intact. The lobules, although distorted in shape and size, usually remain recognizably intact with an increase in interlobular and to a lesser extent of the intralobular connective tissue. There may be cartilagenous metaplasia. A variant of this may be present in some areas of the gland or in some glands as an overgrowth of dense collagenous tissue obliterating most of the surrounding parenchyma but sparing a few ducts which on microscopic examination are found to be dilated and with a hyperplastic epithelium. This lesion is usually referred to as fibroadenoma. A variant of the epithelial pattern, which is usually termed adenosis, simulates very closely the pattern of neoplasia and, because of the difficulties that may attend diagnostic differentiation, the lesion is often diagnosed as adenoma or adenocarcinoma. If there are foci of necrosis within the lesion, the latter diagnosis is justified. The histologie features are very variable but consist generally of hyperplasia of the duct epithelium, proliferation of glands which become closely arranged, and an increase in stroma. Both ducts and acini become densely populated with lining cells, but these are rather regular in size, although not in shape, the nuclei are normochromic and the basement membranes are intact. Mitoses are rare and of normal configuration. Neoplasms of the Mammary Gland There are records of mammary cancer in all domesticated species, but it is rare in species other than the cat and bitch, and it is the latter with which we are primarily concerned. They are probably the most common neoplasms of the bitch; the incidence increases with age and is highest in nonparous females. There is no special breed incidence, but there are probably familial factors in

THE MAMMARY

GLANDS

Fig, 7.30. (A) Cystic mammary hyperplasia. Bitch. (B) Mammary adenocarcinoma with invasion and ulcération of skin. Cat. (C) Mammary adenocarcinoma. Bitch. Spindle-celled growth possibly of myoepithelial origin surrounding acini. (D) Mammary adenocarcinoma. Bitch. Mucin-producing type. (E) Mixed mammary tumour. Bitch.

459

460

7 . THE FEMALE G E N I T A L

susceptibility. There is a close correlation between mammary tumours in the bitch and the presence of oestrogen-secreting ovarian follicular cysts. Mammary tumour in castrate bitches is rare. But other than these associations, virtually nothing is known of the causation of mammary tumours in the bitch. In about 50 per cent of cases of mammary tumour there is multiple breast involvement and the incidence is higher for malignant than for benign tumours. The tumours may also be multiple in one gland. Both within and between glands in a particular animal, multiple tumours may be of diverse histologie type and malignancy. Degenerative changes are very common in mammary gland tumours, especially in the larger ones and those that are malignant. Extensive haemorrhage and necrosis with softening and cavitation produce a rather variegated picture on cut surface and histologically. The one remarkable feature about canine mammary gland tumours is the development of stromal fibrous tissue, cartilage, calcified cartilage, and bone (sometimes with bone marrow) (Fig. 7.30E). These definitive mesenchymal elements may all be present in some proportion in association with increased fibrous tissue and, as one type develops from another, this is not surprising. Not all mammary tumours contain apparent mesenchymal overgrowths, but many do, and these have been referred to as "mixed mammary tumours" and usually regarded as benign. Probably between 60 per cent and 75 per cent of mammary gland tumours in the bitch are "mixed" and the usual question of whether or not they are, as a class, benign or malignant has no pertinence; for malignancy, or lack of it, is a property of the different histologie elements, especially the epithelium, and except in frank cases of malignancy with metastasis can only be determined by histologie examination. Failure to appreciate this fact has led to a general opinion that tumours, which on palpation or gross examination contain bone or cartilage, are benign, and naturally to an underestimate of their capacity to produce a fatal outcome. The origin and significance of the stromal tissues is not at all clear. The theory that such tumour tissue arises from embryonic nests and is thus teratoid is unsatisfying. Other theories of origin will be considered briefly. Myoepithelial origin. The myoepithelial cells are contractile elements lying between the basement membrane and lining epithelium of the acini and ductules; their physiological role is to aid in milk ejection. The histogenesis of these cells is not clear, but they are usually regarded as being of neuroectodermal origin. If such is, in fact, their origin it is not difficult to accept that they may on occasion produce connective tissue and cartilage; Schwann cells of neural crest origin can do so. The presence of alkaline phosphatase in normal myoepithelial cells as well as in the cells of "mixed" tumours has also been advanced as an argument in favour of this histogenesis; but alkaline phosphatase is a rather universally distributed enzyme. Further, tumours which may be reasonably classified as

SYSTEM

myoepitheliomas do occur occasionally (Fig. 7.30C), and in these there is little connective tissue reaction and no cartilage or bone. Epithelial origin. This theory attributes to the neoplastic glandular epithelium, a direct parentage of the mucoid and chondroid stroma. There is little question that mammary adenocarcinomas may elaborate mucin (Fig. 7.30D). The intracellular origin of the mucin is obvious. There is no reason to believe that epithelium can produce cartilage, however. An alternative explanation which has been proposed is that the cartilagenous appearance of the stroma is due not to true cartilage, but rather to dissociated epithelial cells isolated in mucin; such a proposal, however, does not contain an explanation of the capacity of such chondroid to undergo rather normal endochondral ossification. Connective tissue origin. The simplest explanation of the presence of mucinous and chondromatous stroma is that it arises by metaplasia of stromal connective tissue and that bone develops as in the normal cartilage-bone evolution. Proliferation of stromal connective tissues is common in epithelial neoplasms of many sites. The metaplasia to cartilage is thought to be induced by the neoplastic epithelium. Experimentally, bone has been induced to develop under the influence of mammary epithelium. It is also of utmost pertinence that stromal changes of this sort also occur in mammary hyperplasia. Whatever the origin of stromal tissue there is little doubt that it too is often malignant and capable of metastasizing. A malignant "mixed" tumour may repeat the mixture in metastatic foci or the epithelial and mesenchymal moieties may metastasize independently. The problem of the occasional sarcoma, chondrosarcoma, or osteogenic sarcoma is not quite so easy. It is possible that, as has been claimed, such tumours with malignant overgrowth of the mesenchymal elements have not been fully examined—to do so adequately would require a very careful examination of each tumour for even very small islands of adenoma or carcinoma. Until such is accomplished it seems best to regard all mammary tumours, excepting of course those arising from auxiliary tissues, blood vessels, nerves, etc., as being of epithelial histogenesis with due qualification for stromal hyperplasia, metaplasia, or neoplasia. The macroscopic nature of mammary tumours is very variable, depending on the presence of coexisting cystic hyperplasia, the amount and nature of stromal tissue, the presence and degree of local infiltration, and the presence of degenerative changes—necrosis, haemorrhage, cyst formation, etc., and on the coexistence of different neoplastic patterns. Accordingly, no brief description can be accurate and sufficient, and it is proposed merely to present some features of the benign "mixed" tumours and of the malignant carcinomas with the memo that a variety of intermediate shades are common. The benign mixed tumours may be up to 10 cm. or more, located subcutaneously, and causing surface ulcération only when very large and bony. The tumour may form single

BIBLIOGRAPHY

or more or less closely aggregated multiple nodules of varying size. Boundary definition is sometimes clear but is obscured in lactating glands and by adjacent and contained areas of mammary hyperplasia. The hyperplasia is usually of the cystic type and its pattern has been described. Some of the tumours are rather homogeneous and solid on cut surface, white or grey in colour with apparent cartilage or bone or broad coarse septa of fibrous-tissue stroma. Some of them are well demarcated and bone hard, and these are usually spherical or oval with a core of cancellated bone and solid cortex capped to varying degree with cartilage. It is not possible to make any sort of gross distinction between the varieties of carcinoma. They may be single and involve one gland, but frequently they are multiple and involve more than one gland and in advanced cases may become confluent and very large. The consistency varies and may be soft or firm and nodules may be oval or irregular in shape, many are discoid or shield-like in early stages. Some are well demarcated from the surrounding compressed tissue, but they are not encapsulated, and others infiltrate adjacent tissue. Definition is also obscured by surrounding lactating or hyperplastic parenchyma. The cut surface is putty-coloured or whitish, and degenerative changes are common. The overlying skin is frequently fixed and it may be tense, ulcerated, or thickened and dimpled— the classical "peau d'orange". There is wide variation in the malignancy of mammary carcinomas, some being highly malignant from the outset and others pursuing a protracted course with late development of métastases. It is noteworthy also that late malignant transformation may occur in benign "mixed" tumours. Spread occurs by direct invasion and via the lymphatics and blood vessels. Involvement of the overlying skin by carcinomas is common and produces the fixation, thickening, and dimpling which develop to obvious ulcération or to a moist, weeping eczematous-like change, and the skin of the axial and inguinal regions and the corresponding limb may be similarly affected as a result of lymphatic obstruction. Nodal métastases occur by embolism and direct lymphatic permeation, and in due course the node itself is enlarged and hardened and may be fixed to adjacent tissue by capsular invasion. The nodes may, however, be enlarged in response to ulcération and degeneration of the primary tumour, and enlargement does not necessarily mean metastatic growth. Of more distant organs, the lungs are by far the most common site for secondary deposits. Metastasis to bone is rarely detected.

BIBLIOGRAPHY Anomalies Arthur, G. H. Some aspects of intersexuality in animals. Vet, Rec, 71:598-603, 1959.

461

Boyd, W. L. A clinical study of white heifer disease. Cornell Vet., 34: 337-345, 1944. (Segmentai aplasia.) Cantwell, G. E., Johnston, E. F. and Zeller, J. H. The sex chromatin of swine intersexes. / . Hered., 49: 199-202, 1958. Eriksson, K. Aerftlighetsundersökningar av genitalhypoplasi hos nötkreatur. (Investigations respecting the heredity of genital hypoplasia in cattle.) Skand. VetTidskr., 28: 419-423, 1938. Forbes, T. R. The origin of freemartin. Bull Hint. Med., 20: 461-466, 1946. Gibbons, W. J. Some congenital conditions interfering with fertility in cattle. Proc. 90th Ann. Meet. Amer. vet. Med. Ass., p. 399, 1953. Goethals, P. Studie van het geslachtsapparaat van zeugen met betrekking tot onvruchtbaarheid en verminderde vruchtbaarheid. (Study of genital system of sows in relation to sterility.) VlaamS diergeneesk. Tijdschr., 20: 155-165, 1951. Lagerlöf, N. and Settergren, I. Results of seventeen years' control of hereditary ovarian hypoplasia in cattle of the Swedish Highland breed. Cornell Vet., 43: 52-64, 1953. Lagerlöf, N. and Boyd, H. Ovarian hypoplasia and other abnormal conditions in the sexual organs of cattle of the Swedish Highland breed : Results of postmortem examination of over 6,000 cows. Cornell Vet., 43: 64-79, 1953. Lang, D. R. and Hansel, W. A sexual dimorphism in three somatic tissues of cattle. / . Dairy Sei., 42: 1330-1337, 1959. Lillie, F. R. The theory of the free-martin. Science, 43: 611-613, 1916. Lillie, F. R. The free-martin: a study of the action of sex hormones in fetal life of cattle. / . exp. Zool, 23: 371-452, 1917. Moore, K. L., Graham, M. A. and Barr, M. L. The sex chromatin of the bovine freemartin. / . exp. Zool, 135: 101-121, 1957. Murray, J. C. Cervix bifida in the domestic cow (Bos taurus). J. comp. Path., 52: 135-139, 1939. Revesz, C , Chappel, C. I. and Gaundry, R. Masculinization of female fetuses in the rat by progestational compounds. Endocrinology, 66: 140-144, 1960. Roberts, S. J. An unusual condition associated with uterus unicornus in cattle. Cornell Vet., 40: 358-363, 1950. Spriggs, D.N.Double external os in cattle. Vet.J.,101:138-143, 1945. Spriggs, D. N. White-heifer disease. Vet. Rec, 58: 405-409, 415-418, 1946. (Segmental aplasia.) Swett, W. W., Matthews, C. A. and Graves, R. R. Early recognition of the freemartin condition in heifers twinborn with bulls. / . agric. Res., 61: 587-623, 1940. Teige, J. Kongenitale hemningsmissdannelser av de Müllerske ganger og sinus urogenitalis hos storfe. (Congenital malformations of Mullerian ducts and urogenital sinus in cattle.) Nord. VetMed, 8: 289-319, 1956. Teige, J. Congenital malformations of the Mullerian ducts and sinus urogenitalis in pigs. Study of the genital organs from 9,250 gilts and 476 sows. Nord. VetMed., 9: 609-629, 1957. Wiggens, E. L., Casida, L. E. and Grummer, R. H. The incidence of female genital abnormalities in swine. / . Anim. Sei., 9: 269-276, 1950. Wilson, R. F., Nalbandov, A. V. and Krider, J. L. A study of impaired fertility in female swine. / . Anim. Sei., 8: 558-568, 1949. Cystic Ovarian Degeneration Arthur, G. H. An analysis of the reproductive functions of

462

7 . T H E FEMALE G E N I T A L

mares based on post-mortem examination. Vet. Rec, 70: 682-686, 1958. Casida, L. E. and Chapman, A. B. Factors affecting the incidence of cystic ovaries in a herd of Holstein cows. / . Dairy Sei., 34: 1200-1205, 1951. Dawson, F. L. M. Bovine cystic ovarian disease—a review of recent progress. Brit. vet. J., 113: 112-133, 1957. Dawson, F. L. M. The significance of cystic enlargement of the bovine corpus luteum. Brit. vet. J., 115: 46-54, 1959. Day, F. T. Sterility in the mare associated with irregularities of the oestrus cycle. Vet. Rec„ 51: 1113-1119, 1939. DeLange, M. The influence of delayed breeding on the fertility of beef heifers. Onderstepoort J. vet. Sei., 24: 126-354, 1950. Dow, C. Ovarian abnormalities in the bitch. / . comp. Path., 70: 59-69, 1960. Garm, O. A study on bovine nymphomania. Acta endocr., Copenhagen, 11: Suppl. 3, pp. 143, 1949. Hansel, W. and Wagner, W. C. Luteal inhibition in the bovine as a result of oxytocin injections, uterine dilatation, and intrauterine infusions of seminal and preputial fluids. / . Dairy Sei., 43: 796-805, 1960. Henricson, B. Genetical and statistical investigations into socalled cystic ovaries in cattle. Acta agric. Scand., 7:4-89,1956. McEntee, K. Cystic corpora lutea in cattle. Int. J. Fertil., 3: 120-128, 1958. Nalbandov, A. V. Anatomic and endocrine causes of sterility in female swine. Fertility & Sterility, 3: 100-119, 1952. Roberts, S. J. Clinical observations on cystic ovaries in dairy cattle. Cornell Vet., 45: 497-513, 1955. Van Rensburg, S. W. J. and Van Heerden, J. S. Infertility in mares caused by ovarian dysfunction. Onderstepoort J. vet. Sei., 26: 285-303, 1954. Williams, W. L. and Williams, W. W. Nymphomania in the cow. N. Amer. Vet., 4: 232-241, 305-315, 1923.

SYSTEM

hyperplasia, endometrial carcinoma, and endometriosis produced experimentally by oestrogen. Cancer, 10: 500-509, 1957. Schoop, G. Large-scale sterility due to estrogens in grass of pastures. 2nd int. Congr. Phys. Path. Anim. Reprod. & Artif. Insem., Copenhagen, 2: 87, 1952. Underwood, E. J. and Shier, F. L. The permanence of the oestrogenic effects of subterranean clover grazing on the ewe. Aust. vet. J., 27: 63-67, 1951. Underwood, E. J., Shier, F. L. and Peterson, J. E. Effects of prolonged injection of stilboestrol on the ewe. Aust. vet. J.,29: 206-211, 1953.

Salpingitis and Metritis Black, W. G., Simon, J., McNutt, S. H. and Casida, L. E. Investigations on the physiological basis for the differential response of estrous and pseudopregnant rabbit uteri to induced infection. Amer. J. vet. Res., 14: 318-323, 1953. Broome, A. W. J. and Lamming, G. E. The influence of ovarian hormones on resistance to uterine infections. Vet. Rec, 70: 603-604, 1958. Carpenter, C. M., Williams, W. W. and Gilman, H. L. Salpingitis in the cow. / . Amer. vet. med. Ass., 12: 173, 1921. Cembrowicz, H. J. Changes in the Fallopian tubes of the bovine as a cause of sterility. Vet. Rec, 62: 189, 1950. Dawson, F. L. M. Bovine endometritis—a review of literature to 1947, with special reference to the catarrhal type of the disease. Brit. vet. J., 106: 104-116, 1950. Dawson, F. L. M. The diagnosis and significance of bovine endosalpingitis and ovarian bursitis. Vet. Rec, 70: 487-493, 1958. Dow, C. The cystic hyperplasia—pyometra complex in the bitch. Vet. Rec, 70: 1102-1108, 1958. Dow, C. The cystic hyperplasia-pyometra complex in the bitch. / . comp. Path., 69: 237-250, 1959. Cystic Hyperplasia of Endometrium Dow, C. Experimental reproduction of the cystic hyperplasiaBartlett, S., Folley, S. J., Rowland, S. J., Curnow, D. H. and pyometra complex in the bitch. / . Path. Bact., 78: 267-278, Simpson, S. A. Oestrogens in grass and their possible effect 1959. on milk secretion. Nature, Lond., 162: 845, 1948. Erichsen, S. Follikkelcyster, hyperostrogenisme og pyometraBennetts, H. W., Underwood, E. J. and Shier, F. L. A specific patogenesen hos hund. (Follicular cysts, hyperoestrogenism breeding problem of sheep on subterranean clover pastures and the pathogenesis of pyometra in dog.) Nord. VetMed., in Western Australia. Aust. vet. J., 22: 2-12, 1946. 4: 1078-1089, 1952. Bennetts, H. W. Metaplasia in the sex organs of castrated male Fennestad, K. L., Pedersen, P. S. and Möller, T. Staphylosheep maintained on early subterranean clover pastures coccus aureus as a cause of reproductive failure and so-called Aust. vet. J., Ill 70-78, 1946. actinomycosis in swine. Nord. VetMed., 7: 929-947, 1955. Bennetts, H. W. A further note on metaplasia of the sex organs Lamming, G. E., Rowson, L. E. and Fry, R. M. Ovarian of castrated male sheep on subterranean clover pastures. hormones and uterine infection in cattle. Proc R. Soc Med., Aust. vet.J., 23: 10-15, 1947. 46: 387-391, 1953. Bradbury, R. B. and White, D. E. The chemistry of subterranean Lâszlo, F. Ueber die pathologishe Anatomie des Eileiters des clover. 1. Isolation of formononetin and genistein. /. ehem. Schweines. Dtsch. tierärztl. Wschr., 43: 673-675, 1935. Soc., 3447-3449, 1951. McDonald, L. E., Black, W. G., McNutt, S. and Casida, L. E. Cunningham, I. J. and Hogan, K. G. Oestrogens in New Response of rabbit uterus to instillation of semen at different Zealand pasture plants. N.Z. vet. J., 2: 128-134, 1954. phases of the estrus cycle. Amer. J. vet. Res., 13: 419-424, Curnow, D. H., Robinson, T. J. and Underwood, E. J. Oestro1952. genic action of extracts of subterranean clover (T. subterMoberg, R. Disease conditions in the Fallopian tubes and raneum L. var. Dwalganup). Aust. J. exp. Biol. med. Sei., 26: ovarian bursae of cattle. Vet. Rec, 66: 87-89, 1954. 171-180,1948. Rieck, G. W. Studien zur pathologischen Histologie, PathoDohan, F. C , Richardson, E. M., Stribley, R. C. and Gyorgy, P. genese und Atiologie des Pyometra-Endometritiskomplexes The estrogenic effects of extracts of spring rye grass and der Hündin. Zbl. VetMed, 6: 313-339, 1959. clover. / . Amer. vet. med. Ass., 118: 323-324, 1951. Rowson, L. E. A. Affections of the Fallopian tubes of cattle. Legg, S. P., Curnow, D. H. and Simpson, S. A. The seasonal Vet. Rec, 54:311-313, 1942. and species distribution of oestrogen in British plants. Rowson, L. E. A., Lamming, G. E. and Fry, R. M. The Biochem. J., 46: 19-20 (of Proceedings), 1950. relationship between ovarian hormones and uterine infection. Meissner, W. A., Sommers, S. C. and Sherman, G. Endometrial Vet. Rec, 65: 335-340, 1953.

BIBLIOGRAPHY

Simon, J. and McNutt, S. H. Histopathological alterations of the bovine uterus. 1. Studies with Vibrio foetus. Amer. J. vet. Res., 18: 53-66, 1957. Simon, J. and McNutt, S. H. Histopathological alterations of the bovine uterus. 2. Uterine tissue from cows of low fertility. Amer. J. vet. ReS., 18: 241-245, 1957. Spector, W. G. and Storey, E. A factor in the oestrogen treated uterus responsible for leucocyte migration. / . Path. Bact., 75: 387-397, 1958. Teunissen, G. H. B. The development of endometritis in the dog and the effect of oestradiol and progesterone on the uterus. Acta endocr., Copenhagen, 9: 407-420, 1952. Vallée, A. and Delrieu, A. Étude bactériologique des métrites de la chienne et de la chatte. Rec. Méd. vét., 13:195-198,1959. Weinstein, L., Gardner, W. U. and Allen, E. Bacteriology of the uterus with special reference to estrogenic hormones and the problem of pyometra. Proc. Soc. exp. Biol, N.Y., 37: 391-393, 1937. Diseases of the Pregnant Uterus Andres, J. 369 Tage Trächtigkeit bei der Kuh. Dtsch. tierärztl. Wschr., 39: 67-73, 83-85, 1931. Bearden, H. J. Fertilization and embryonic mortality rates for bulls with histories of either low or high fertility in artificial breeding. Thesis, Cornell University, 1954. Binns, W., Anderson, W. A. and Sullivan, D . J. Further observations on a congenital Cyclopian-type malformation in lambs. / . Amer. vet. med. Ass., 137: 515-521, 1960. Casida, L. E. Fertilization failure and embryonic death in domestic animals. In "Pregnancy Wastage", E. T. Engle (ed.), Springfield, Illinois, C. C Thomas, 1953. Casida, L. E. Prenatal death as a factor in the fertility of farm animals. Iowa St. Coll. J. Sei., 28: 119-126, 1953. Corner, G. W. The problem of embryonic pathology in mammals with observations upon uterine mortality in the pig. Amer. J. Anat., 3 1 : 524-545, 1923. Dimock, W. W. and Caslick, E. A. Sterility in mares. / . Amer. vet. med. Ass., 65: 141-159, 1924. Dimock, W. W., Edwards, P. R. and Bruner, D . W. Infections observed in equine fetuses and foals. Cornell Vet., 37: 89-99, 1947. Dollahite, J. W. and Anthony, W. V. Experimental production of abortion, premature calves and retained placentas by feeding a species of perennial broomweed. Sthwest. Vet., 10: 128-131, 1957. Dutt, R. H. Fertility rate and embryonic death loss in ewes early in the breeding season. / . Anim. Sei., 13: 464-473, 1954. Fincher, M. G., Evans, W. M. and Saunders, L. Z. Avian tuberculosis in a dairy cow. Cornell Vet., 44: 240-251, 1954. Firehammer, B. D . Bovine abortion due to Haemophilus species. / . Amer. vet. med. Ass., 135: 421-^422, 1959. Frost, J. N., Fincher, M. G. and Williams, W. L. Two severe cases of hydrops of amnion and allantois with a background of severe endometritis in primary gestation. Cornell Vet., 21:212-216, 1931. Good, E. S. and Corbett, L. S. Investigations of the etiology of infectious abortion of mares and jennets in Kentucky. / . infect. Dis., 13: 53-68, 1913. Good, E. S. and Smith, W. V. The Bacillus abortivus equinus as an etiological factor in infectious arthritis in colts. / . infect. Dis., 15: 347-349, 1914. Gregory, P. W., Mead, S. W. and Regan, W. M. A genetic analysis of prolonged gestation in cattle. Por tug. Acta biol, Ser. A: R. B. Goldschmidt Vol., pp. 861-882, 1951.

463

Hallgren, W. Abnormt lang dräktighet hos ko. (Abnormally long pregnancy in the cow.) Nord. VetMed., 3 : 1043-1060, 1951. Hawk, H. W., Wiltbank, J. N., Kidder, H. E. and Casida, L. E. Embryonic mortality between 16 and 34 days post-breeding in cows of low fertility. / . Dairy Sei., 38: 673-676, 1955. Kennedy, P. C , Kendrick, J. W. and Stormont, C. Adenohypophyseal aplasia, an inherited defect associated with abnormal gestation in Guernsey cattle. Cornell Vet., 47: 160-178, 1957. Laing, J. A. Infertility in cattle associated with death of ova at early stages after fertilization. / . comp. Path., 59: 97-108, 1949. Laing, J. A. Early embryonic mortality. 2nd. Int. Congr. Phys. Path. Anim. Reprod. & Artif Insem., Part 2, Pathology, Copenhagen, 1952, pp. 17-34. McEntee, K., Roberts, S. J. and Sears, R. M. Prolonged gestation in two Guernsey cows. Cornell Vet., 42: 355-359, 1952. M'Fadyean, J. and Edwards, J. T. Contagious abortion in mares and joint-ill in foals. / . comp. Path., 32: 42-71, 1919. Magnusson, H. Joint-ill in foals: etiology. / . comp. Path., 32: 143-182, 1919. Magnusson, H. Pyaemia in foals caused by Corynebacterium equi. Vet. Rec, 50: 1459-1468, 1938. Payne, J. M. Changes in the rat placenta and foetus following experimental infection with various species of bacteria. / . Path. Bact., 75: 367-385, 1958. Plum, N . Tuberculous abortion disease in cattle. Cornell Vet., 16: 237-249, 1926. Pullar, E. M. Nutritional abortion and stillbirths in Victorian pigs. Aust. vet. J., 26: 4-8, 1950. Simon, J., Sund, J. M., Wright, M. J., Winter, A. and Douglas, F. D . Pathological changes associated with the lowland abortion syndrome in Wisconsin. / . Amer. vet. med. Ass., 132: 164-169, 1958. Simon, J., Sund, J. M., Douglas, F . D., Wright, M. J. and Kowalczyk, T. The effect of nitrate or nitrite when placed in the rumens of pregnant dairy cattle. / . Amer. vet. med. Ass., 135:311-314, 1959. Simon, J., Sund, J. M., Wright, M. J. and Douglas, F. D . Prevention of noninfectious abortion in cattle by weed control and fertilization practices on lowland pastures. / . Amer. vet. med. Ass., 135: 315-317, 1959. Sorensen, A. M., Hansel, W., Hough, W. H., Armstrong, D . T., McEntee, K. and Bratton, R. W. Causes and prevention of reproductive failures in dairy cattle. Cornell Univ. agric. Exp. Sta. Bull., 936, 1959. Stamp, J. T. A review of the pathogenesis and pathology of bovine tuberculosis with special reference to practical problems. Vet. Rec, 56: 443-446, 1948. Stamp, J. T. and Watt, J. A. Tick-borne fever as a cause of abortion in sheep. Vet. Rec, 62: 465-468, 1950. Strieker, F. and Grunert, Z. B. pyosepticum viscosum equi (Shigella equirulis) v pripadoch akutneho horukcového ochorenia dospelych koni na Slovensku. (Isolation of Shigella equirulis from horse with an acute febrile disease.) Vet. Cas., 5 : 260-266, 1956. Teunissen, G. H. B. Steriliteit bij de merrie. (Sterility in the mare.) Tijdschr. Diergeneesk., 70: 42-64, 1945. Warnick, A. C , Grummer, R. H. and Casida, L. E. The nature of reproductive failures in repeat-breeder sows. / . Anim. Sei., 8: 569-577, 1949. Warwick, B. L., Turk, R. D . and Berry, R. O. Abortion in

464

7.

THE FEMALE GENITAL

sheep following the administration of phenothiazine. / . Amer. vet. med. Ass., 108: 41^2, 1946. Watson, W. A. and Hunter, D. The isolation of Pasteurella pseudotuberculosis from an ovine foetus. Vet. Rec, 72: 770-772, 1960. Wilson, A. L. and Young, G. B. Prolonged gestation in an Ayrshire herd. Vet. Rec, 70: 73-75, 1958. Brucellosis Anderson, W. A. and Davis, C. L. Nodular splenitis in swine associated with brucellosis. / . Amer. vet. med. Ass., 131: 141-145, 1957. Ariel, M. K patologiceskoj morfologii brucelleznogo aborta ovec. (On the morbid anatomy of abortion of sheep caused by Brucella melitensis.) In "Brucellosis in Sheep." Moscow, Viem Publ. Dept., 1937, pp. 129-149. Ariel, M. K patologiceskoj morfologii patentnogo brucelleza ovec. (On the pathological anatomy of latent sheep brucellosis.) In "Brucellosis in Sheep." Moscow, Viem Publ. Dept., 1937, pp. 157-176. Bang, B. The aetiology of epizootic abortion. / . comp. Path., 10: 125-149, 1897. (Brucellosis.) Bang, B. Infectious abortion in cattle. / . comp. Path., 19:191-202, 1906. Brown, I. W., Forbus, W. D. and Kerby, G. P. The reaction of the reticulo-endothelial system in experimental and naturally acquired brucellosis of swine. Amer. J. Path., 21:205-223,1945. Buddie, M. B. and Boyes, B. W. A Brucella mutant causing genital disease of sheep in New Zealand. Aust. vet. J., 29: 145-153, 1953. Cameron, H. S. Swine brucellosis. Advanc. vet. Sei., 3: 275-285, 1957. Creech, G. T. Organic lesions in swine caused by Brucella suis. J. Amer. vet. med. Ass., 86: 211-216, 1935. Doyle, T. M. Brucella abortus infection of goats. / . comp. Path., 52: 89-115, 1939. Feldman, W. H. and Olson, C. Spondylitis of swine associated with bacteria of the Brucella group. Arch. Path., 16: 195-210, 1933. Fitch, C. P., Bishop, L. M. and Kelly, M. D. The isolation of Brucella abortus from the blood-stream of cattle. Proc. Soc. exp. Bioi, N.Y., 34: 696-698, 1936. Forbus, W. D. and Davis, C. L. A chronic granulomatous disease of swine with striking resemblance to Hodgkin's disease. Amer. J. Path., 22: 35-69, 1946. Hallman, E. T. The pathology of Bact. abortus (Bang) infection in the bovine uterus. Cornell Vet., 14: 262-275, 1924. Huddleson, I. E. "Brucellosis in Man and Animals." New York, The Commonwealth Fund, 1943. Hutchings, L. M. "Brucellosis: A Symposium." American Association for the Advancement of Science, 1950. Jacob, K. Zur Pathologie des brucellenausscheidenden Rindereuters. Zbl. VetMed., 7: 779-793, 1960. James, W. A. and Graham, R. Porcine osteomyelitis, pyemic arthritis and pyemic bursitis associated with Brucella suis Traum. /. Amer. vet. med. Ass., 77: 774-782, 1930. Jones, L. M., Thomson, P. D. and Alton, G. G. Production of immunity against experimental Br. melitensis infection in goats. / . comp. Path., 68: 275-287, 1958. Keogh, J. and Doolette, J. B. The epidemiology of ovine brucellosis in South Australia. Aust. vet. J., 34:412-417,1958. Kernkamp, H. C. H., Roepke, M. H. and Jasper, D. E. Orchitis in swine due to Brucella suis. J. Amer. vet. med. Ass., 108: 215-221, 1946.

SYSTEM

Lowbeer, L. Skeletal and articular involvement in brucellosis of animals. Lab. Invest., 8: 1448-1455, 1959. MacFarlane, D., Salisbury, R. M., Osborne, H. J. and Jebson, J. L. Investigation into sheep abortion in New Zealand during the 1950 lambing season. (A description of Brucella ovis placental lesions.) Aust. vet. J., 28: 221-226, 1952. Manthei, C. A. Research on swine brucellosis by the Bureau of Animal Industry (1941-1947). Amer. J. vet. Res., 9: 40-45, 1948. Manthei, C. A. and Carter, R. W. Persistence of Brucella abortus infection in cattle. Amer. J. vet. Res., 11:173-180,1950. Meyer, M. E. and Cameron, H. S. Studies on the etiological agent of epididymitis in rams. Amer. J. vet. Res., 17: 495497, 1956. Morgan, W. J. and McDiarmid, A. The excretion of Brucella abortus in the milk of experimentally infected cattle. Res. vet. Set, 1:53-56, 1960. Morse, E. V. Canine brucellosis—a review of the literature. / . Amer. vet. med. Ass., 119: 304^308, 1951. Paulsen, M. and Moule, G. R. Infectious ovine abortion. Aust. vet. J., 29: 133-139, 1953. Payne, J. M. The pathogenesis of experimental brucellosis in the pregnant cow. / . Path. Bact., 78: 447-463, 1959. Renoux, G., Amarasinghe, A. and Sasquet, E. Sur la classification des Brucella. Arch. Inst. Pasteur Tunis, 32: 375-406, 1955. Renoux, G., Alton, G. G. and Mahaffey, L. W. Études sur la brucellose ovine et caprine. 7. Distribution de Br. melitensis dans les tissus de chèvres et de brebis artificiellement infectés. Arch. Inst. Pasteur Tunis, 33: 397-402, 1956. Renoux, G. Brucellosis in goats and sheep. Advanc. vet. Sei., 3: 242-273, 1957. Smith, T. A characteristic localisation of Bacillus abortus in the bovine fetal membranes. /. exp. Med., 29: 451-457, 1919. Smith, T. Pneumonia associated with Bacillus abortus Bang in fetuses and new-born calves. / . exp. Med., 41: 639-647, 1925. Stoenner, H. G. Isolation of Brucella abortus from sheep. /. Amer. vet. med. Ass., 118: 101-102, 1951. Thomsen, A. Brucella infection in swine. Ada path, microbiol. scand. Suppl. 21, 1934. Thomsen, A. The eradication of bovine brucellosis in Scandinavia. Advanc. vet. Sei., 3: 197-240, 1957. Wall, S. The alterations in the uterus in epizootic abortion and in some other infectious metrites in cows. \0th Int. vet. Congr., London, 1914, pp. 292-337. Watts, P. S. Genital infections in sheep with particular reference to Brucella-likc organisms. Aust. vet. J., 31: 1-6, 1955. Wipf, L., Morse, E. V., McNutt, S. H. and Glattli, H. R. Pathological aspects of canine brucellosis following oral exposure. Amer. J. vet. Res., 13: 366-372, 1952. Young, S. Preliminary report on a brucella infection in a ewe. (Brucella abortus). Vet. Rec, 65: 247-248, 1953. Vibriosis Adler, H. C. Genital vibriosis in the bovine. Experimental investigations with a special view to diagnosis, prophylaxis and treatment. Thesis, Copenhagen, Denmark, 1957. Eide, G. W. Studies on infertility and abortion in sheep and goats in Norway. 1. The occurrence of Listeria monocytogenes and Vibrio fetus in the sexual organs of normally fertile ewes. Nord. VetMed., 8: 437-445, 1956. Eide, G. W. and Helle, O. Studies on infertility and abortion in sheep and goats in Norway. 2. Genital vibriosis in sheep. Nord. VetMed., 9: 337-361, 1957.

BIBLIOGRAPHY

Eide, G. W. and Helle, O. Studies on genital vibriosis in sheep. Amer. J. vet. Res., 18: 868-871, 1957. Florent, A., Vandeplassche, M. and Huysman, A. Évolution de l'infection à Vibrio foetus chez la génisse à la suite d'une primo-infection unique. Rec. Méd. vét., 134: 97-104, 1958. Jensen, R., Miller, V. A., Hammarlund, M. A. and Graham, W. R. Vibrionic abortion in sheep. 1. Transmission and immunity. Amer. J. vet. Res., 18: 326-328, 1957. Jensen, R., Miller, V. A. and Molello, J. A. Placental pathology of sheep with vibriosis. Amer. J. vet. Res., 22: 169-185, 1961. King, E. Human infections with Vibrio foetus and a closely related Vibrio. J. infect. Dis., 101: 119-128, 1957. McEntee, K., Hughes, D. E. and Wagner, W. C. Failure to produce vibriosis in cattle by vulvar exposure. Cornell Vet., 49: 3Φ40, 1959. MacFarlane, D. Salisbury, R. M., Osborne, H. G. and Jebson, J. L. Investigation into sheep abortion in New Zealand during the 1950 lambing season. Aust. vet. J., 28: 221-226, 1952. Mitscherlich, E. and Liess, B. Die pathogène Bedeutung der bei Rind und Schaf isolierten Vibrionen. Mh. Tierheilk., 10: 351— 372, 1955. Plastridge, W. N., Williams, L. F., Easterbrooks, H. L., Walker, E. C. and Beccia, R. N. Vibriosis in cattle. Storrs (Conn.) agric. Exp. Sta. Bull No. 281, 1951. Plastridge, W. N. Vibriosis. Advanc. vet. Sei., 2: 327-374, 1955. Simon, J. and McNutt, S. H. Histopathological alterations of the bovine uterus. 1. Studies with Vibrio fetus. Amer. J. vet. Res., 18: 53-65, 1957. Willet, E. L., Ohms, J. I., Frank, A. H., Bryner, J. H. and Bartlett, D. E. Non-return rate and embryonic mortality from inseminations by bulls with Vibrio fetus. J. Dairy Sei., 38: 1369-1374, 1955. Listerial Abortion Diplock, P. T. Ovine listerial abortion. Aust. vet. J., 33: 68-70, 1957. Eveleth, D. F., Goldsby, A. I., Bolin, F. M., Holm, G. C. and Turn, J. Epizootiology of vibriosis and listeriosis of sheep and cattle. Vet. Med., 48: 321-323, 1953. Gray, M. L. and McWade, D. H. The isolation of Listeria monocytogenes from the bovine cervix. / . Bacteriol, 68: 634-635, 1954. Gray, M. L., Singh, C. and Thorp, F. Abortion and pre- or postnatal death of young due to Listeria monocytogenes. 3. Studies in ruminants. Amer. J. vet. Res., 17: 510-516,1956. Gray, M. L. Listeria monocytogenes bei Krankheiten der Fortpflanzungorgane von Haustieren. Berl. Münch. tierärztl. Wschr., 70: 134-135, 1957. Gray, M. L. Experimenial listeriosis in pregnant animals. Zbl. VetMed., Suppl. 1, 110-116, 1958. Osebold, J. W., Kendrick, J. W. and Njoku-Obi, A. Cattle abortion associated with natural Listeria monocytogenes infections. Abortion of cattle experimentally with Listeria monocytogenes. J. Amer. vet. med. Ass., 137: 221-226, 227-233, 1960. Paterson, J. S. Studies on organisms of the genus Listerella. 4. An outbreak of abortion with recovery of Listerella from the aborted foetuses. Vet. J., 96: 327-332, 1940. Smith, R. E., Reynolds, M. T. and Bennett, R. A. Listeria monocytogenes and abortion in a cow. / . Amer. vet. med. Ass., 126: 106-110, 1955. Stockton, J. J., Neu, L., Carpenter, W. S. and Gray, M. L. The

465

association of Listeria monocytogenes with abortion. / . Amer, vet. med. Ass., 124: 102-104, 1954. Young, S. and Firehammer, B. D. Abortion attributed to Listeria monocytogenes infection in a range herd. / . Amer. vet. med. Ass., 132: 434-^37, 1958. Trichomoniasis Andrews, J. Self-limitation and resistance in Trichomonas fetus infection in cattle. Amer. J. Hyg., 27: 149-154, 1938. Hammond, D. M. and Bartlett, D. E. The distribution of Trichomonas foetus in the preputial cavity of infected bulls. Amer. J. vet. Res., 4: 143-149, 1943. Kendrick, J. Trichomoniasis in bulls used for artificial insemination. Cornell Vet., 43: 230-240, 1953. Kerr, W. R. and Robertson, M. A study of the antibody response of cattle to Trichomonas foetus. J. comp. Path., 53: 280-297, 1945. Laing, J. A. Trichomonas foetus infection of cattle. F.A.O. agric. Studies No. 33, 39 pp. Rome, Food & Agric. Org. of United Nations, 1956. Morgan, B. B. "Bovine Trichomoniasis." Minneapolis, Burgess, 1946. Stableforth, A. W., Scorgie, N. J. and Gould, G. N. Trichomonas disease in cattle. Vet. Rec, 49:211-223,247-257,1937. Salmonella Abortion in Horses and Sheep Bartmann, E. Über das Vorkommen der Salmonella abortus ovis in den weiblichen und männlichen Geschlechtsorganen und im Euter des Schafes. Inaug. Diss. Univ. of Munich, 36 pp., 1957. Bosworth, T. J. and Glover, R. E. Contagious abortion in ewes. Vet.J., 81:319-334, 1925. Buxton, A. and Field, H. I. Salmonella infection in farm livestock. Proc. 14th int. vet. Congr., Lond., 2: 270, 1949. Calaprice, A. L'aborto ovino da salmonella in Campania. Contributo alla conoscenza délia diffusione e dell'importanza rivestita dal maschio riproduttore quale fonte e via di trasmissione naturale dell'infezione (Role of the male in the incidence of Salmonella abortion in sheep.) Ada med. vet. Napoli, 5: 277-285, 1959. Henning, M. W. On the aetiology of epizootic or infectious equine abortion. Onderstepoort J., 21: 17-40, 1946. Henning, M. W. and Mclntosh, B. M. An outbreak of tendovaginitis and bursitis due to Salmonella abortus-equi. J. S. Afr. vet. med. Ass., 17: 88-91, 1946. Jacob, W. K. Über zuchthygienische Untersuchungen in Schafherden (Breeding hygiene in sheep. Examination of flocks infected with Salmonella abortus-equi) Berl. Münch. tierärztl. Wschr., 72: 475-479, 1959. Köser, A. Salm. Abortus e^w-Infektionen bei Hengsten. Dtsch. tierärztl. Wschr., 63: 275-280, 1956. Lovell, R. A member of the Salmonella group causing abortion in sheep. / . Path. Bact., 34: 13-22, 1931. Manley, F. H. Contagious abortion of sheep and goats in Cyprus. / . comp. Path., 45: 293-300, 1932. (5. abortus-ovis.) Monteverde, J. J. and Garbers, G. V. Salmonella abortus equi infection in Argentina. Rev. Fac. Cienc. vet. La Plata, 1: 37-39, 1959. Mura, D. and Contini, A. Sorgenti e vie die trasmissione dell'infezione aborto ovino e caprino da Salmonella (importanza del maschio riproduttore). (The importance of the male in the transmission of Salmonella abortion in sheep and goats.) Vet. ital, 5: 787-802, 1954. Perrin, G., Saurat, P. and Verge, J. Les nouveaux aspects de

466

7.

THE FEMALE G E N I T A L

l'infection des Équidés par Salmonella abortus equi. Rec. Méd. vét., 126: 321-328, 1950. Rolle, M. Das Bact. abortus equi als Krankheitserreger bei Pferden. Dtsch. tierärztl. Wschr.jTierärztl. Rdsch., 52/50: 317-318,1944. Shearer, G. C. An outbreak of abortion in ewes due to Salmonella dublin. Vet. Rec., 69: 693-694, 1957. Watson, W. A. Salmonella dublin infection in a lambing flock. Vet. Rec., 72: 62-65, 1960. Abortion in Cattle and Sheep Associated with Psittacoid Agent Beer, J. and Martin, J. Nichtbakterieller Rinderabort mit fetaler Hepatopathie. Zuch. Fort. Bes. Haust., 3:97-107,1959. Boulanger, P. and Bannister, G. L. Abortion produced experimentally in cattle with an agent of the Psittacosis-Lymphogranuloma-Venereum group of viruses. Canad. J. comp. Med., 23: 259-265, 1959. Foggie, A. Immunological studies on the infection of ovine enzootic abortion in young lambs. /. comp. Path., 64:141-156, 1954. Howarth, J. A., Moulton, J. E. and Frazier, L. M. Epizootic bovine abortion characterized by fetal hepatopathy. /. Amer. yet. med. Ass., 128: 441-449, 1956. Kennedy, P. C , Olander, H. J. and Howarth, J. A. Pathology of epizootic bovine abortion. Cornell Vet., 50: 417-429, 1960. McEwen, A. D. and Foggie, A. Enzootic abortion in ewes. A note on the susceptibility of the pregnant bovine to infection and abortion. Vet. Rec, 67: 373, 1955. McEwen, A. D. and Holgate, S. Enzootic abortion in ewes. The recovery of the virus from the internal organs of the aborted foetus. Vet. Rec, 68: 690, 1956. Monsur, K. A. and Barwell, C. F. Observations on the antigenic relationship between the virus of enzootic abortion in ewes and viruses of the psittacosis-lymphogranuloma group. Brit. J. exp. Path., 32: 414-421, 1951. Parker, H. D. A virus of ovine abortion—isolation from sheep in the United States and characterization of the agent. Amer. J. Res., 21:243-250, 1960. Payne, J. M. and Belyavin, G. The experimental infection of pregnant rats with the virus of enzootic abortion of sheep. /. Path. Bact., 80: 215-223, 1960. Rossi, C. and Ghittino, P. Un focolaio di aborto bovino caratterizzato da epatopatia e cromatosi rinale dei feti. (Bovine abortion characterized by fetal renal chromatosis and hepatopathy.) Vet. ital, 11: 341-353, 1960. Schoop, G. and Kauker, E. Infektion eines Rinderbestandes durch ein Virus der Psittakosis-Lymphogranuloma-Gruppe gehäufte Aborte im Verlauf der Erkrankungen. Dtsch. tierärztl. Wschr., 63: 233-235,1956. Stamp, J. T., McEwen, A. D., Watt, J. A. A. and Nisbet, D. I. Enzootic abortion in ewes. 1. Transmission of the disease. Vet. Rec, 62: 251-255, 1950. Stamp, J. T. Developmental forms of the virus of ovine enzootic abortion. /. comp. Path., 61: 215-218, 1951. Stamp, J. T., Watt, J. A. A. and Cockburn, R. B. Enzootic abortion in ewes; complement fixation test. / . comp. Path., 62: 93-101, 1952. Storz, J., McKercher, D. G., Howarth, J. A. and Straub, O. C. The isolation of a viral agent from epizootic bovine abortion. /. Amer. vet. med. Ass., 137: 509-514, 1960. Tunnicliff, E. A. Ovine virus abortion. / . Amer. vet. med. Ass., 136: 132-134, 1960.

SYSTEM

Mycotic Abortion Austwick, P. K. C. and Venn, J. A. J. Routine investigations into mycotic abortion. Vet. Rec, 99: 488-^191, 1957. Bendixen, H. C. and Plum, N. Schimmelpilze (Aspergillus fumigatus und Absidia ramosa) als Abortusursache beim Rinde. Actapath. microbiol. scand., 6: 252-322, 1929. Francalanci, G. Sull'aborto micotico dei bovini. (Bovine mycotic abortion.) Vet. ital., 10: 278-291, 1959. Gilman, H. L. and Birch, R. R. A mold associated with abortion in cattle. Cornell Vet., 12: 81-89, 1925. Hörter, R. Aspergillus-Dermatomykose bei abortierten Rinderfeten. Dtsch. tierärztl. Wschr., 67: 380-383, 1960. Jungherr, E. Mycotic affections of the bovine reproductive system. /. Amer. vet. med. Ass., 86: 64-75, 1935. Van Uken, F. W. Schimmelabortus bij runderen. (Abortion in cows caused by fungi.) Tijdschr. Diergeenesk., 80: 1081-1088, 1955. Weidlich, N. Aspergillusabort und —Hautkrankeit bei einem Rinderfötus. Dtsch. tierärztl. Wschr., 59: 279-280, 1952. Toxoplasmosis Cole, C. R., Sänger, V. L., Farrell, R. L. and Kornder, J. D. The present status of toxoplasmosis in veterinary medicine. N. Amer. Vet., 35: 265-269, 1954. Hartley, W. J., Jebson, J. L. and McFarlane, D. New Zealand type 2 abortion in ewes. Aust. vet. J., 30: 216-218, 1954. Hartley, W. J. and Marshall, S. C. Toxoplasmosis as a cause of ovine perinatal mortality. N.Z. vet. J., 5: 119-124, 1957. Hartley, W. J. Experimental transmission of toxoplasmosis in sheep. N.Z. vet. J., 9: 1-6, 1961. Hoare, C. A. Toxoplasmosis in animals. Vet. Rev. & Annot., 2: 25-34, 1956. Hulland, T. J. and Tobe, S. B. Toxoplasmosis as a cause of abortion in Ontario sheep. Canad. vet. J., 2: 45-51, 1961. van der Waaij, D. Congenital transmission of avirulent Toxoplasma gondii after experimental infection in mice prior to gestation. Trop, geogr. Med., 12: 251-257, 1960. Werner, H. and Seidlitz, P. Experimenteller Beitrag zur connatalen Toxoplasmose. 1 and 2. Zbl. Bakt., 178: 250262, 393-406, 1960. Werner, H. Experimenteller Beitrag zur connatalen Toxoplasmose. 3. Zbl. Bakt., 180: 118-135, 1960. Vulvovaginitis Anderson, J., Plowright, W. and Purchase, H. S. Pathological and seminal changes in bulls affected with a specific venereal infection. / . comp. Path., 61: 219-230, 1951. Baker, J. A., McEntee, K. and Gillespie, J. H. Effects of infectious bovine rhinotracheitis—infectious pustular vulvovaginitis (IBR-IPV) virus on newborn calves. Cornell Vet., 50: 156-170, 1960. Conradi, H., Hubrig, T. and Wohanka, K. Untersuchungen und Beobachtungen zum Bläschenausschlag des Rindes. Berl. Münch. tierärztl. Wschr., 73: 46-52, 1960. Daubney, R., Hudson, J. R. and Anderson, J. Preliminary description of a form of sterility in cattle. E. Afr. agric J., 4: 31-34, 1938. Gillespie, J. H., McEntee, K., Kendrick, J. W. and Wagner, W. C. Comparison of infectious pustular vulvovaginitis virus with infectious bovine rhinotracheitis virus. Cornell Vet., 49: 288-297, 1959. Grieg, A. S., Bannister, G. L., Mitchell, D. and Barker, C. A. V. Cultivation in tissue culture of an infectious agent from

BIBLIOGRAPHY

coital exanthema of cattle. A preliminary report. Canad. J. comp. Med., 22: 119-122, 1958. Hudson, J. R. A specific venereal disease of cattle characterized by epididymitis in bulls and vaginitis in cows and heifers. Proc. 14th int. vet. Congr., Lond., 3: 487-491, 1949. Kendrick, J. W., McKercher, D. G. and Saito, J. Preliminary report of studies on a catarrhal vaginitis of cattle. / . Amer. vet. med. Ass., 128: 357-361, 1956. Kendrick, J. W., Gillespie, J. H. and McEntee, K. Infectious pustular vulvovaginitis of cattle. Cornell Vet., 48: 458-495, 1958. Koen, J. S. and Smith, H. C. An unusual case of genital involvement in swine associated with eating moldy corn. Vet. Med., 40: 131-133, 1945. McErlean, B. A. Vulvovaginitis of swine. Vet. Rec, 64: 539540, 1952. Mclntosh, B. M., Haig, D. A. and Alexander, R. A. Isolation in mice and embryonated hens' eggs of a virus associated with vaginitis of cattle. Onderstepoort J. Vet. Res., 26: 479484, 1954. McNutt, S. H., Purwin, P. and Murray, C. Vulvovaginitis in swine. /. Amer. vet. med. Ass., 73: 484-492, 1928. (Mouldycorn poisoning.) Millar, P. G. Viral infertility in cattle. Brit. vet. J., I l l : 309315, 1955. Mussill, J. Zum Seuchenverlauf beim Bläschenausschlag. Wien. tierärztl. Mschr., 36: 722-724, 1949. Pullar, E. M. and Lerew, W. M. Vulvovaginitis of swine. Aust. vet.J., 13:28-31, 1937. Van Rensburg, S. W. J. Bovine sterility caused by infectious disease in South Africa. Brit. vet. J., 109: 226-233, 1953. Neoplasms of the Female Genitalia Baumann, R. Das primäre Ovarialkarzinom des Rindes. Berl. Manch, tierärztl. Wschr./Wien. tierärztl. Mschr. 60/31:280-282, 1944. Casarosa, L. Contributo allo studio dei tumori a cellule della granulosa. Descrizione di un caso in ovaia di cagna. Nuova Vet., 26: 94-99, 1950. (Granulosa cell tumour in ewes.) Cotchin, E. Further observations on neoplasms in dogs, with particular reference to site of origin and malignancy. 1. Cutaneous, female genital and alimentary systems. Brit. vet. J., 110: 218-230, 1954. Formston, C. Fibropapillomatosis in cattle with special reference to external genitalia of the bull. Brit. vet. J., 109: 244-248, 1953. Guarda, F. Contributo allo studio dei tumori ovarici. L'arrenoblastoma nella varietà di adenoma tubulare nel suino. Ann. Fac. Med. vet., Torino, 8: 9-21, 1958. (Arrhenobblastoma in a pig.) Guthrie, M. J. Tumorigenesis in intrasplenic ovaries in mice. Cancer, Philad, 10: 190-203, 1957. Guthrie, M. J. Tumorigenesis in ovaries of mice after X-irradiation. Cancer, Philad., 11: 1226-1235, 1958. Jabara, H. G. Canine ovarian tumours following stilboestrol administration. Aust. J. exp. Biol. med. Sei., 37: 549-565, 1959. Kingman, H. E. and Davis, C. L. Granulosa-cell tumor of the ovary in a bovine associated with secondary changes. N. Amer, vet., 21: 42-46, 1940. Langham, R. F. and Clark, C. F. Granulosa cell tumor of a bovine ovary. Amer. J. vet. Res., 6: 81-83, 1945. Li, M. H. and Gardner, W. U. Experimental studies on the

467

pathogenesis and histogenesis of ovarian tumours in mice. Cancer Res., 7: 549-566, 1947. McEntee, K. and Zepp, C. P. Canine and bovine ovarian tumors. Proc. 1st World Congr. Fertil. & Steril, 2: 649-663, 1953. Monlux, A. W., Anderson, W. A., Davis, C. L. and Monlux, W. S. Adenocarcinoma of the uterus of the cow—differentiation of its pulmonary métastases from primary lung tumors. Amer. J. vet. Res., 17: 45-73, 1956. Montpellier, J. M., Samso, A. and Catanei, J. Le cancer de l'utérus en pathologie vétérinaire. Bull, algér. Cancer., 5: 45-56, 1952. Ottosen, H. E. Scirrhose adenokarcinomer i uterus hos koer. (Scirrhous adenocarcinoma of the uterus in cows.) Skand. VetTidskr., 33: 473^482, 1943. Wadsworth, J. R. The distribution of genital tumors in the bovine. Vet. Ext. Quart. Univ. Pa., No. 128, 133-137, 1952. Weyel, W. Ueber Granulosazelltumoren bei Tieren und ihr hormonales Verhalten. Dtsch. tierärztl. Wschr., 44: 550-553, 1936. Wilmes, H. Zum Vorkommen von Uterus—myomen beim Pferde. Dtsch. tierärztl. Wschr., 308-310, 1935. Mastitis Adams, E. W., Rickard, C. G. and Murphy, J. M. Some histological and histochemical observations on bovine teat epithelium. Cornell Vet., 51: 124-151, 1961. Adler, H. E. Mastitis in sows associated with Aerobacter infection. N. Amer. Vet., 32: 96-97, 1951. Albiston, H. E. Actinomycosis of the mammary glands of cows in Victoria. Aust. vet. J.,6: 2-22, 1930. (Staphylococcus.) Arnold, J. P. Anatomy and pathology of the bovine teat. / . Amer. vet. med. Ass., 116: 112-116, 1950. Awad, F. I. Nocardiosis of the bovine udder and testis. Vet. Rec, 72: 341-342, 1960. Barnum, D. A. and Fuller, D. S. Report of an outbreak of chronic mastitis in cattle caused by a streptococcus of Lancefield's group G. Canad. J. comp. Med., 17: 465-473, 1953. Barnum, D. A. A herd outbreak of mastitis caused by Pasteurella multocida. Canad. J. comp. Med., 18:113-119, 1954. Barnum, D. A., Thackeray, E. L. and Fish, N. A. An outbreak of mastitis caused by Serrâtia marcescens. Canad. J. comp. Med., 22: 392-395, 1958. Bendixen, H. C. and Minett, F. C. Excretion of Streptococcus pyogenes in the milk of naturally infected cows. / . Hyg., Camb., 38: 374-383, 1938. Brown, R. W. and Scherer, R. K. A report on two cases of acute mastitis caused by Bacillus cereus. Cornell Vet., 47: 226-240, 1957. Brown, R. W. and Scherer, R. K. A study of the necrotizing action of staphylococcic alpha toxin. Amer.J. vet. Res., 19: 354-362, 1958. Bryan, C. S. The bacterial contents of goat milk Amer. J. vet. Res., 3: 92-95, 1942. Burkhardt, S., Beach, B. A. and Spencer, G. R. Aerobacter aerogenes associated with acute toxaemic mastitis in eleven cows. / . Amer. vet. med. Ass., 103: 381, 1943. Christodoulou, T. and Tarlatzis, C. La maladie des oedèmes des chèvres de Sparta. Bull. Acad. vét. Fr., 27: 441-446, 1954. Derbyshire, J. B. The experimental production of staphylococcal mastitis in the goat. / . comp. Path., 68: 232-241,1958.

468

7 . THE FEMALE G E N I T A L

Emminger, A. C. and Schalm, O. W. The effect of Brucella abortus on the bovine udder and its secretion. Amer. J. vet. Res., 4: 100-109, 1943. Ferguson, J. A bacteriological study of the infections which follow injury to the bovine udder. Amer. J. vet. Res., 5: 87-92, 1944. Fey, H. and Stünzi, H. Colimastitis and Coli-Nekrotoxin. Schweiz. Arch. Tierheilk., 100: 325-329, 1958. Funke, H. Bovin mastit med fynd av jästsvampar i juversekretet. (Bovine mastitis associated with fungi.) Nord. VetMed., 12: 54-62, 1960. Helmboldt, C. F., Jungherr, E. L. and Plastridge, W. N. The histopathology of bovine mastitis. Storrs {Conn.) agric. Exp. Sta. Bull. No. 305, 1953. Holman, H. H., Smith, I. M. and Pattison, I. H. Experimental mastitis produced in the goat by Streptococcus dysgalactiae. J. comp. Path., 63: 199-210, 1953. Hughes, D. L. Some reflections on the mastitis problem. Vet. Rec, 66: 235-239, 1954. Innes, J. R. M., Seibold, H. R. and Arentzen, W. P. Pathology of bovine mastitis caused by Cryptococcus neoformans. Amer. J. vet. Res., 13: 469^75, 1952. Jacob, Kl. Zur Pathologie des brucellenausscheidenden Rindereuters. Zbl. VetMed., 6: 68-81, 1959. Jacob, Kl. Zur Pathologie des brucellenausscheidenden Rindereuters. 2. Mitt. Zbl. VetMed., 7: 779-793, 1960. Kujumgiev, I. Zur Aetiologie der infektiösen Agalaktie der Schafe und Ziegen. Zbl. VetMed., 6: 37^5, 1959. Little, R. B. and Plastridge, W. N. "Bovine Mastitis: A Symposium." New York and London, McGraw-Hill, 1946. M'Fadyean, J. Tuberculous mastitis in the cow; its pathogenesis, and morbid anatomy and histology. /. comp. Path., 30: 57-77, 139-172, 1917. Maclachlan, G. K., Wilson, C. D. and Stuart, P. A herd outbreak of mastitis associated with Streptococcus pneumoniae infection. Vet. Rec, 70: 987-988, 989, 1958. Maclay, M. H., Rankin, J. D., Loosmore, R. M. and Slavin, G. Experimental Staphylococcus aureus mastitis in sheep. / . comp. Path., 56: 139-147, 1946. Marsh, H. Mastitis in ewes caused by a Pasteurella. J. Amer. vet. med. Ass., 81: 376-382, 1932. Morgan, W. J. B. and McDiarmid, A. The excretion of Brucella abortus in the milk of experimentally infected cattle. Res. vet. Sei., 1: 53-56, 1960. Mosimann, W. Zur Anatomie der Rindermilchdruse und über die Morphologie ihrer sezernierenden Teile. Acta anat. (Basel), 8: 347-378, 1949. Munch-Peterson, E. Actinomyces (Nocardia) sp. from a bovine udder infection. Aust. vet. J., 30: 297-300,1954. Murphy, J. M. and Hanson, J. J. Infection of bovine udder with coliform bacteria. Cornell Vet., 33: 61-77, 1943. Murphy, J. M. and Drake, C. H. Infection of the bovine udder with yeastlike fungi. Amer. J. vet. Res., 8: 43-51, 1947. (Trichosporon.) Murphy, J. M., Stuart, O. M. and Reed, F. I. An evaluation of the camp test for the identification of Streptococcus agalactiae in routine mastitis testing. Cornell Vet., 42: 133147, 1952. Murphy, J. M. and Stuart, O. M. The syringe collection of milk via teat-wall puncture as an aid in the study of artificial infection of the bovine mammary gland. Cornell Vet., 44: 501-511, 1954. Nieberle, K. Tuberkulose und Fleischhygiene. Jena, Fischer, 1938.

SYSTEM

Pattison, I. H., Taylor, J. I. and Holman, H. H. Studies on experimental streptococcal mastitis. 1. Inoculation of large numbers of Str. agalactiae into teat canal of goats. / . comp. Path., 60: 71-92, 1950. Pattison, I. H. and Holman, H. H. Studies on experimental streptococcal mastitis. 4. The disease caused by the inoculation of Str. agalactiae strain 13 into the teat canal of goats. /. comp. Path., 61: 26-37, 1951. Pattison, I. H. Studies on experimental streptococcal mastitis. 5. Histological findings in experimental streptococcal mastitis in the goat. / . comp. Path., 61: 71-85, 1951. Pattison, I. H. Studies on experimental streptococcal mastitis. 6. Histological examination of the teats of affected goats. J. comp. Path., 62: 1-4, 1952. Pattison, I. H. and Smith, I. M. The histology of experimental Streptococcus dysgalactiae mastitis in goats. /. Path. Bact., 46: 247-250, 1953. Pattison, I. H. The progressive pathology of bacterial mastitis. Vet. Rec, 70: 114-117, 1958. Pier, A. C , Gray, D. M. and Fossatti, M. J. Nocardia astéroïdes —A newly recognized pathogen of the mastitis complex. Amer. J. Vet. Res., 19: 319-331, 1958. Plommet, M. Mammite staphylococcique de la brebis. Infection expérimentale. Ann. Inst. Pasteur, 98: 439-455, 1960. Pounden, W. D., Amberson, J. M. and Jaeger, R. F. A severe mastitis problem associated with Cryptococcus neoformans in a large dairy herd. Amer. J. vet. Res., 13: 121-128, 1952. Renk, W. Beiträge zur Diagnose und Pathogenese der akuten mastitiden. Zbl. VetMed., 4: 325-340, 1957. Simon, J., Nichols, R. E. and Morse, E. V. An outbreak of bovine cryptococcosis. / . Amer. vet. med. Ass., 122: 31-35, 1953. Smith, H. W. and Stables, J. W. An outbreak of bovine mastitis caused by Streptococcus pneumoniae. Vet. Rec, 70: 986-987, 1958. Smith, H. W. Staphylococcal diseases. In "Infectious Diseases of Animals." Stableforth, A. W. and Galloway, I. A. (eds.). London, Butterworths, 1959, Vol. 2, pp. 557-582; New York, Academic Press, 1960. Stableforth, A. W. Streptococcal diseases. In "Infectious Diseases of Animals", Stableforth, A. W. and Galloway, I. A. (eds.), London, Butterworths, 1959, Vol. 2, pp. 602-630. Stamp. J. T. Tuberculosis of the bovine udder. / . comp. Path., 53: 220-230, 1943. Stuart, P. An outbreak of bovine mastitis from which yeasts were isolated and attempts to reproduce the condition experimentally. Vet. Rec, 63: 314, 1951. (Candida.) Stuart, P. and Harvey, P. Bovine mastitis resembling tuberculosis caused by Mycobacterium lacticola and other rapidly growing acid-fast bacteria. Vet. Rec, 63: 881-885, 1951. Stuart, P. and Marshall, P. M. Avian type of tuberculosis of the bovine udder. Vet. Rec, 64: 309, 1952. Torrance, H. L. The paths of infection in udder tuberculosis. Vet. Rec, 49: 1441-1445, 1937. Tucker, E. W. Infection of the bovine udder with Mycobacterium species. Cornell Vet., 43: 576-599, 1953. Tunnicliff, E. A. Pasteurella mastitis in ewes. Vet. Med., 44: 498-502, 1949. van der Hoeden, J. and Shamir, A. Besmettelijke agalectia bij geiten en schapen. (Contagious agalactia in goats and sheep.) Tijdschr. Diergeneesk., 79: 705-714, 1954. Weir, J. and Barbour, D. Tuberculosis of the udder and its differential diagnosis. Vet. Rec, 62: 239-243, 1950. Winter, H. and O'Connor, R. F. Mastitis and generalised

BIBLIOGRAPHY

lesions in a cow produced by Pseudomonas pyocyanea. Aust. vet. /., 33: 83-87, 1957. Zavagli, V. L'agalaxie contagieuse des brebis et des chèvres. Bull. Off. int. Epizoot., 36: 336-362, 1951. Mammary Tumours Cotchin, E. Mammary neoplasms of the bitch. / . comp. Path., 68: 1-22, 1958.

469

Huggins, C. and Moulder, P. V. Studies on the mammary tumors of dogs. 1. Lactation and the influence of ovariectomy and suprarenalectomy thereon. /. exp. Med., 80: 441^54, 1944. Loeb, L. and Hesselberg, C. The cyclic changes in the mammary gland under normal and pathological conditions. /. exp. Med., 25: 285-322, 1917. Moulton, J. E. Histological classification of canine mammary tumors: Study of 107 cases. Cornell Vet., 44: 168-180, 1954.