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Functional Menstrual Disorders; Investigation and Endocrine Therapy
P:U NCTIONAL MENSTRUAL DISORDERS; INVESTIGA liON AND ENDOCRINE THERAPY ARTHUR FIRST,
M.D.,
F.A.C.S.*
MENSTRUATION
A PROPER understanding of menstruation is essential to an intelligent interpretation of the many phases of gynecologic physiology and pathology. The morphological processes concerned in menstruation are found to be closely governed by the fundamental physiological activities of (1) the anterior pituitary gland, (2) the ovaries, (3) the uterus and (4) the nervous system. Phases.-Generally a complete menstrual cycle averages about twenty-eight days and is divided into four phases: (1) The postmenstrual or period of recuperation, duration four to five days; (2) the preovulatory, proliferative or estrogen phase, average duration fourteen days; (3) the premenstrual, postovulatory, secretory or progestin phase, duration five days; (4) the menstrual period of dismantling, duration four days. The Postmenstrual Phase.-The postmenstrual characteristics of the uterine mucosa are well recognized. Reparative changes occur before the cessation of bleeding and this corresponds to a stage of reconstruction or involution. The rents in continuity of the surface epithelium are repaired by regeneration from the glandular tissue. The glands gradually resume their normal character as the endometrium returns to the proliferative type. The mucosa is· thin and contains widely separated, narrow, straight glands. In the ovary during this stage, ripening of a primordial follicle into a graafian follicle begins from the stimulating action of the anterior pituitary gland. The estrogenic hormone thus elaborated by the ovary induces growth and vascularity of the endometrium in direct ratio to the quantity produced. The Estrogen Phase.-At the beginning the glands are widely separated. On transverse section the space between these structures is about four times the diameter of the gland. Later in this phase they become rather closely packed, moderately tortuous, tubular in outline and extend into the basal layer. They are lined by low columnar epithelium. The nuclei of the cells are centrally placed and stain deeply. There is moderate secretion in the lumen of the glands. In the ovary about twelve to fifteen days after the beginning of menstruation, the graafian follicle reaches maturity and ovulation occurs. Upon rupture of the mature follicle. the follicular fluid and the mature egg cell surrounded by cells of the membrana granulosa are discharged into the peritoneal cavity. Large amounts of estrogenic hormone are transported by the blood stream to the uterus to promote growth and vascularity of the endometrium. Immediately following rupture of the follicle, the earliest stage of the new corpus luteum begins with * Diplomate of American Board of Obstetrics and Gynecology; Assistant Professor of Obstetrics, Jefferson Medical College; Attending Obstetrician, Jefferson Medical College Hospital, Philadelphia. 137;
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proliferation and differentiation of the granulosa cells and ingrowth of the theca lutein cells. The Progestin Phase.-In a dual capacity the corpus luteum continues the elaboration of estrogenic principle and also produces another hormone, termed progestin. This transforms the estrogen primed endometrium into a premenstrual state suitable, should an ovum become fertilized, for nidation. In this phase the mucosa becomes differentiated into three distinctive layers: (1) a compact surface layer, (2) an intervening spongy layer, and (3) immediately overlying the myometrium a basal layer. Marked secretory activity of the surface cells, but more particularly those of the glands, is evident. The epithelium lining the glands is composed of large cells with basal nuclei. The stroma also shows specific changes. A thin layer of lightly stained large polygonal stroma cells with large round nuclei forms the compact layer of the mucosa. These cells, however, are not equally developed in all areas. They are not unlike the decidual cells of early gestation and are termed pseudodecidual cells. In the middle or spongy layer are found characteristic markedly tortuous glands, closely packed, but separated from each other by strips of stroma cells. The gland lumen is filled with secretion. The basal layer is unchanged. The histology of the progestin endometrium is similar to that of a two weeks' gestation and only the absence of chorionic villi distinguishes it. The true premenstrual stage is the period from the cessation of actual production of progestin to the onset of bleeding and is only about forty-eight hours in duration. The coiled endometrial arteries constrict at the base with a peripheral ischemia and the stroma of the endometrium becomes dehydrated. Subepithelial hematomas appear coalescing into lacunae whieh begin to bleed into the lumen.
Types.-There are, according to the modern concept of menstruation, two different types of a menstruating mucosa: 1. N ormal.-In this type, the functional layers (compacta and spongiosa) are dismantled, leaving a raw wound, the base of which is formed by the altered basilar layer. This is the most common type. 2. Pseudomenstruation.-In this form, menstruation occurs from an inactive or almost resting mucosa. There is no evidence of the premenstrual phase in the mucosa, uterine bleeding occurring from an estrogenic endometrium. This periodic bleeding is not a genuine menstruation, because it is not associated with the characteristic preparatory endometrial changes nor with extensive endometrial desquamation. This inadequate preparation of the endometrium makes proper implan.tation of the fertilized ovum impossible and explains many cases of sterility in regularly menstruating women. Other possible causes of pseudomenstruation besides failure of ovulation are imbalance of the two ovarian hormones, estrogen and progestin, and a uterus which fails to respond to normal ovarian stimulation. In studying cases of menstrual disorders, a diagnostic premenstrual uterine curettage is important in that it shows the end result of the effect of both estrogen and progesterone activity on the endometrium. If the endometrium is normally responsive the type of ovarian dysfunction can be determined. Day-to-day vaginal smears also determine estrogenic effect and cyclic ovarian changes. The probable date of
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ovulation can often be elicited as well as the effectiveness of therapy. The interpretation of the smear consists in finding cells from the basal vaginal layer indicative of estrogen deficiency or cornification of cells from the superficial vaginal layer showing estrogen activity. Etiology.-As the result of anterior pituitary stimulation of the ovaries, estrogen is gradually concentrated in the endometrium. The premenstrual saturation of the follicular hormone in the uterine mucosa finally causes regressive endometrial changes with resultant bleeding. The role of the corpus luteum hormone is a passive one of maintaining the endometrium intact. Progestin is capable of nullifying the terminal effects of estrogen described above. When the corpus luteum regresses in the absence of pregnancy, the saturation effects of estrogen on the endometrium are uninhibited and bleeding results. This involution of the corpus luteum is probably brought about as increasing quantities of estrogenic hormone produced by the ovary gradually inhibit the pituitary gland which, therefore, withdraws its stimulation of the corpus luteum about two days before actual bleeding with resultant menstruation. In addition, an undetermined "bleeding factor" present in the endometrium of the adult woman only appears to be essential for the onset of menstruation. Thus "a child will rarely menstruate even though large quantities of both ovarian hormones are administered. Furthermore, women are occasionally encountered who do not menstruate, although they have a normal amount of estrogen in the blood and urine and an active secretory endometrium, indicating, perhaps, an absence of this so-called bleeding factor. AMENORRHEA
The term amenorrhea refers to a marked diminution or complete absence of the menstrual flow. It is classified as primary or secondary. The former refers to a total failure of menstruation to appear, and the latter to a cessation of the cycle after its establishment. Oligomenorrhea is applied to menstruation occurring at intervals of two or three months. Hypomenorrhea refers to regular though scanty menstruation. Physiological amenorrhea denotes the absence of menstruation during some physiologic process. Pathological amenorrhea refers to the absence of the period as a result of some anatomical disorder. Etiology.-PHYSIOLOGICAL AMENORRHEA.-Menstruation is nearly always absent during pregnancy and lactation. It is absent before the establishment of puberty, and after the menopause. PATHOLOGICAL AMENORRHEA.-The causes of pathological amenorrhea are both general and local. General Causes.-l. Constitutional Diseases.-The most common constitutional disorder associated with an absen<;:e of the menstrual flow i~
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advanced pulmonary tuberculosis. The primary anemias are generally associated with the condition, as may be diabetes, chronic nephritis, and tuberculous infections other than those involving the lungs. It may result from profound nervous shock, and it occurs in the advanced stages of organic nervous disease. In Manila it was recently reported that in many patients the menses stopped abruptly after the first bombing or soon after internment and before a food deficiency could have any effect. 2. Acute Infectious Diseases.-Amenorrhea is often present during convalescence from the acute exanthemas, typhoid fever, malaria and influenza. 3. Climatic Influence.-Exposure to wet and cold, with sudden chilling of the body or a simple change of environment may result in a temporary check of the menstrual process. Local Causes.-l. Primary.-The most common local cause of amenorrhea is congenital ill-development of the organs fundamentally concerned in menstruation. Usually the uterus and ovaries are involved, the hypoplastic alteration in the uterus being secondary to that in the ovaries. Hypoplasia of the latter organs may not be congenital, but may represent some pathologic alteration which had its inception in early adolescence. Irregular development of the genital organs, especially an imperforate hymen or stenosis of the vagina or cervix, results in a failure of the menstrual flow to appear. 2. Secondary.-Radical curettage or prolonged radium treatment may cause amenorrhea by destroying the endometrium. Follicle cysts of the ovary as a cause of amenorrhea are not infrequent. These may result from the inability of the ovum to penetrate an inflamed, thickened tunica albuginea, or more commonly, may be due to an insufficient hormonal stiQ1Ulation from the anterior pituitary gland, so that the follicle fails to rupture. If the follicle does not rupture, it becomes either atretic or distended with fluid and forms one or more retention cysts. Occasionally these cysts elaborate a sufficient quantity of estrogenic hormone to produce prolonged menstrual bleeding. Endocrinopathic Causes.-Disorders of the endocrine system may be associated with amenorrhea and this is especially true of the anterior pituitary gland and ovaries. These disturbances may be classified as: 1. Primary Pituitary Deficiency.-Primary deficiency of the anterior pituitary lobe is by far the most common form of endocrine disturbance encountered. Generally speaking, this condition, if not sufficiently severe to suppress totally ovarian function, is usually one of a mild Frohlich's syndrome (adiposogenital dystrophy). Clinically, these patients are rather short in stature and show distinct stigmas of underactivity of the hypophysis, manifested first by a characteristic mammary mons girdle obesity due to associated involvement of the hypothalamus, secondly by hypertrichosis with masculine distribution
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of pubic hair, and thirdly by genital hypoplasia with menstrual derangement. 2. Primary Ovarian Failure (Primary Hypogonadism).-Primary ovarian failure is due to inherent deficiency of the internal secretory portion of the ovary independent of the secondary effects of the diminution of function of other glands, notably the pituitary and thyroid. Clinically, these patients present a marked contrast to those of the hypopituitary type. They represent the superlatively feminine type. They are emotional to excess, underweight, visceroptotic and intolerant to food. They experience gastrointestinal spasticity, irritability of the nervous system and dysmenorrhea. Hypoplasia of the genital organs and irregular menstruation, or amenorrhea, are constant observations. Hormone studies reveal a uniformly low estrogenic level in the blood premenstrually. The most significant finding, however, is a demonstrable quantity of anterior pituitary gonadotropic hormone in the blood and urine in about 50 per cent of the patients. 3. Thyroid Derangement.-It is well known that the ovary depends on thyroid secretion to increase its chemical reactions. However, amenorrhea occurs more frequently with hyperfunction. Hypothyroidism is more often associated with an excessive flow. 4. Uterine Factor.-Amenorrhea sometimes is noted in patients with a normal level of blood and urine estrogen. In these women the uterus becomes atrophic and fails to respond to normal or increased ovarian function. Occasionally, however, one is surprised in obtaining on currettage a normal secretory endometrium. In these patients the absence of the so-called bleeding factor is, perhaps, responsible for the amenorrhea. Many of the disturbances associated with amenorrhea of endocrine origin are due to worry and anxiety over the nonappearance of the menses rather than to any direct effect of the amenorrhea itself. Most symptoms are relieved when the patient is reassured that amenorrhea does not mean the "retention" of harmful products. Treatment.-The treatment involves the employment of measures to correct the cause. We shall confine ourselves chiefly to a discussion of the endocrine therapy. QUANTITATIVE HORMONAL ASSAYS AS GUIDE TO TREATMENT.-Quantitative hormonal assays of anterior pimitary and ovarian excretion in the urine gives us the best means of determining endocrine function and therapy in both ameporrhea and dysfunctional uterine bleeding. The following hormonal assays are available for this purpose: 1. Gonadotropic Hormones.-Elaborated by the anterior pituitary gland, they stimulate the ovaries by means of two specific hormones: the follicle-stimulating and luteinizing hormone. In addition chorionic gonadotropin, somewhat resembling the above, is produced by the chorionic cells of the placenta. A twenty-four hour urine specimen is collected and the proteins precipitated by alcohol. Bio-assay is made by injection into infantile mice. These assays are of
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value in determining pituitary dysfunction in menstrual disorders and whether we are dealing with primary pituitary failure or primary hypogonadism. 2. Estrogenic Hormones.-For determination of estrogen in the urine, the urine is first hydrolyzed by boiling for fifteen minutes with 5 per cent hydrochloric acid or sulfuric acid. This releases about 95 per cent of the estrogenic hormone present by converting the inactive to active estrogen. During active sex life, except during pregnancy when there is a huge increase, a woman normally excretes in the urine 150 mouse units of estrogen in twenty-four hours. There is a rise in estrogen at the time of ovulation followed by a drop and then another rise premenstrually. The highest concentration is noted at the end of the premenstrual stage. A modification of the Allen-Doisy test is usually employed in which the extract is injected into castrated adult mice or rats and varying degrees of vaginal estrus observed. These are accurate and practical tests to determine the level of ovarian activity. They are of special value in the diagnosis of functional sterility in regularly menstruating women. At the premenstrual phase of the cycle, close to 90 per cent of normal fertile women show a demonstrable quantity of the hormone. In regularly menstruating sterile women, without pelvic disease, a positive reaction is much less frequent, thus indicating a deficiency of estrogenic production. 3. Progesterone and Its Excretion Product, Pregnandiol.-Progesterone is metabolized in the liver and excreted in the urine as a water-soluble compound, sodium pregnandiol glycuronate. Pregnandiol has no biologic action but can be determined in the urine by the gravimetric method of Venning and Browne. In menstrual disorders, the presence of pregnandiol in the urine immediately after ovulation in amounts of 3 to 10 mg. is indicative of a normal corpus luteum and ovulation. 4. Androgens and 17-Ketosteroids.-A woman normally excretes about threefourths as much androgen as the male. This is derived from the adrenal cortex. Biologic assay is difficult. Chemical assay for 17-ketosteroids is employed instead. The term "17-ketosteroids" refers to those steroids possessing a ketone group on the 17th carbon atom. The principle 17-ketosteroids that occur in the normal human urine are androgenic. Therefore they serve in the female as an index of adrenal function. In female hypogonadism, the 17-ketosteroids may be normal in primary ovarian failure but diminished if due to pituitary deficiency.
In considering endocrine therapy, functional amenorrhea and menorrhagia can practically be discussed together since both represent varying degrees of the same endocrine disturbance. To the woman suffering psychically from amenorrhea of functional origin, it makes no difference whether she is bleeding from a proliferative or a progestational endometrium. The mental relief is the same. To the woman, however, in whom amenorrhea and sterility coexist, the cure of the latter depends in great measure upon a physiological cure of the underlying uterine ovarian deficiency. We will therefore consider in order the specific therapeutic value of: (1) the gonadotropic hormones; (2) the estrogens; (3) progesterone; (4) androgens (testosterone); (5) thyroid. 1. Gonadotropic H ormOlles.-The gonadotropic hormones available are as follows: (a) Hypophyseal Gonadotropin.-Extracted from fresh anterior
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pituitary glands of s?eep and horse,. it contains bo~h .follic.l~-stimul~ting and luteinizing fractIOns. Its value lIes, therefore, III Its abIlIty to stImulate a hypofunctioning ovary if due to a pituitary gonadotropic deficiency. It does not cause ovulation. Injections should be stopped after three weeks of the cycle and after three months of cyclical administration due to the danger of producing follicle cysts of the ovary. It is employed in amenorrhea and in functional uterine bleeding due to deficient luteinization. The commercial preparations available contain 25 to 500 rat units per cubic centimeter. (b) Equine Gonadotropin.-Extracted from the serum of pregnant . mares, it is mostly a follicle-stimulating hormone and. only slightly a luteinizing hormone. In amenorrhea associated with genital hypoplasia, it is administered in doses of 200 to 400 I.U. intramuscularly three times a week for two weeks followed by a two weeks' rest or a course of chorionic gonadotropin. (c) Chorionic Gonadotropins.-Extracted from the urine and and placenta of pregnant women, its biologic effect is chiefly a luteinizing one. It has no value in the treatment of amenorrhea unless preceeded by hypophyseal gonadotropin in the first two weeks to cause follicle maturation. Then it may be given as 500 LU. daily for two weeks. In uterine bleeding due to progesterone deficiency 500 LU. are recommended three times weekly. (d) Combined Hypophyseal and Chorionic Gonadotropin.-This product is indicated in any disorder due to failure of ovulation. One cubic centimeter is given intramuscularly three times a week. Not more than 5 to 10 cc. should be given a month due to the danger of producing hemorrhagic and cystic ovaries. 2. Estrogens.-The estrogenic hormones are both natural and synthetic. Standardization is in terms of international unit defined as the estrogenic activity of 0.001 mg. of estrone; as rat unit-l R.u. being equivalent to 5-10 LU.; and by weight, in milligrams of active substance. It is administered intramuscularly, orally, locally and in decholin may be given intravenously. For amenorrhea 50,000 I.U. are given three times weekly for two weeks, followed by a course of progesterone and repeated monthly. The chief value of estrogens is to stimulate uterine growth in patients with primary ovarian deficiency. At best it is only substitution therapy. Its advocacy in functional bleeding is questionable except where an atrophic endometrium is present. Ovulation may be inhibited and bleeding stopped for a while but withdrawal bleeding may be sev.ere especially in a patient with a hyperplastic endometrium. Danger of prolonged usage inhibiting the pituitary and ovary should be emphasized. 3. Progesterone.-This may be administered intramuscularly or orally as pregneninolone, 1 mg. being equivalent to 0.2 mg. of progesterone by injection.
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Secondary amenorrheas respond after the administration of 20 mg. of progesterone given daily for three days (Zondek). It is better, however, especially if the amenorrhea is of longer duration than six months, to prime the endometrium first with large doses of estrogen. Zondek recommends 1 mg. of alpha-estradiol given together with 10 mg. of progesterone daily for five days. Progesterone may be of value in functional uterine bleeding if due to a progesterone deficiency such as is found in cases of hyperplasia of the endometrium. Ten mg. are injected twice weekly for the last two weeks of the cycle. 4. Androgens.-Testosterone may be given intramuscularly, sublingually, as a pellet under the skin or orally as methyl testosterone which is one-fifth as effective as the intramuscular injection. The danger of producing hirsutism should be kept in mind and may probably be avoided by limiting the dosage to 300 mg. per month and discontinuing it as soon as acne is evident. It is of great value in inhibiting some of the effects of estrogen on the endometrium and myometrium and in inhibiting the gonadotropic function of the pituitary. It tends to produce an atrophic endometrium. It is of special value, therefore, in functional uterine bleeding; 25 mg. are injected three times weekly. 5. Thyroid.- This is a valuable adjuvant in the treatment of functional amenorrhea and bleeding and may be used even when the basal metabolism is normal, or slightly subnormal. The administration of desiccated thyroid tissue, 0.09 or 0.13 gm. (l1h or 2 grains) daily, tends to increase cellular activity throughout the entire body, including the endocrine glands. In addition, it has been shown that thyroid extract neutralizes the action of estrogenic substance on the endometrium. This may explain the temporary beneficial effect of thyroid therapy in functional uterine bleeding when prolonged and unantagonized activity of estrogenic substance on the endometrium is the immediate cause of the abnormal uterine hemorrhage. Prostigmine has been used in the treatment of delayed menstruation. One mg. is injected on three consecutive days. Estrogenic substances release acetylcholine in the uterus which produces local hyperemia. Prostigmine is a nonspecific agent with a similar property of potentiating the action of acetylcholine. If no menstrual flow occurs within seventy-two hours after the last injection a tentative diagnosis of pregnancy is made. Insulin.- This drug may restore normal menstruation in some patients, especially those who are underweight and suffering with primary ovarian underactivity. Irradiation Therapy.-Low dosage irradiation of the pituitary gland and ovaries is a valuable measure in the treatment of functional amenOl,"rhea as well as menorrhagia of endocrine origin. The therapeutic action of irradiation is generally attributed to a transitory or permanent increase in cellular activity of the ovary. X-ray stimulation of the ovaries
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is contraindicated in the absence of a subthreshold quantity of blood estrogen, as it may induce permanent amenorrhea. Ovarian irradiation is only partially effective when the ovarian hypofunction is secondary to hypophyseal or thyroid underactivity. In such instances irradiation of the pituitary appears to have an adjuvant value. Low dosage irradiation of the pituitary gland and ovaries affords the best results in the treatment of menstrual disturbances with functional sterility associated. Strict adherence to the technic of the roentgenologist is most essential, i.e., from 50 to 80 roentgen units or about 10 per cent skin erythema dose being given once a week over a period of six weeks. The one menstrual disorder that almost invariably fails to respond is hypomenorrhea (scanty flow) in regularly menstruating women. The cause of the menstrual deficiency in these patients is apparently within the uterus itself. MENORRHAGIA
This term is applied to excessive menstruation, or to an undue prolongation of the flow. It may be anatomical or functional, the latter diagnosis being arrived at by exclusion. Etiology.-ANATOl\IIC TYPES.-The anatomical causes of menorrhagia are either general or local. These may be considered under the following: General Causes.-l. Blood Disease.-In patients with a hemorrhagic tendency, menorrhagia is commonly present. It may be the first symptom of purpura hemorrhagica, leukemia, aplastic anemia, and Hodgkin's disease. 2. Systemic Disease.-Disease of the cardiovascular apparatus, kidney or liver disease, resulting in a tardy return circulation, favors engorgement of the pelvic vessels. This naturally leads to uterine congestion and excessive menstruation. In addition, disorders of the arterial system associated with high tension or endarteritis may be a factor. ' 3. Hypothyroidism.-The menorrhagia often noted in myxedema and minor degrees of thyroid hypofunction illustrates the degree to which the ovary is dependent upon normal thyroid function. Local Causes.-l. Inflammation.-Inflammation, either acute, subacute or chronic, of the cervix, uterine body, fallopian tubes, ovaries, pelvic peritoneum, or pelvic cellular tissue, is nearly always associated with excessive menstrual discharge. 2. Ulcerations.-Ulcerations of the cervix or vagina, whether simple, tllberculous, syphilitic or malignant, provoke excessive menstrual discharge. In this category may be listed senile vaginitis, ill-fitting pessary and prolapse of the uterus. 3. Neoplasms.-Tumors, both benign and malignant, involving the cervix, endometrium, myometrium, or serous covering of the uterus may cause profuse and prolonged menstruation. Myomas of the inter-
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stitial type may be influential, but not to the same extent as those of the submucous variety. Subserous tumors, if small, do not cause bleeding, but if of large size, owing to pressure engorgement, abnormal hemorrhage may occur. DYSFUNCTIONAL UTERINE BLEEDlNG.-Bleeding of endocrine origin is termed functional bleeding. This term is a misnomer. More aptly it should be called dysfunctional uterine bleeding. An interv8.1 shorter than sixteen days or a flow lasting more than eight days is abnormal. The endocrine organs most commonly responsible for excessive menstruation are the pituitary gland and ovaries. Thyroid dysfunction may, likewise, provoke free menstrual bleeding. Functional menorrhagia is especially common (1) with the onset of puberty and (2) in the early menopause, although it not infrequently occurs in mature women under 40 years of age. Functional menstrual disorders result from an ovarian failure. This may be primary due to inherent ovarian disease or secondary to extraovarian causes such as pituitary disease or other endocrine lesions or various types of constitutional disease. The approximate degree of ovarian involvement is indicated by the endometrium. In patients with this symptom, uterine curettage usually reveals a hyperplastic endometrium characterized by a dense vascular stromal and epithelial overgrowth. The glands are large and cystic, representing the characteristic "Swiss cheese" pattern, large dilated glands being found side by side with others small and narrow. Many of these are lined by several layers of epithelial cells and show no secretion in the lumen. Functional bleeding is usually due to deficient activity of the anterior pituitary lobe. This deficiency results in an imbalance of the two hormones of the ovary manifested by a prolonged production of the estrogenic hormone. This is associated with an absence or deficiency of the corpus luteum hormone. The abnormal development of the unantagonized follicle due to the failure of luteinization results in follicular cysts of varying size. In the early menopause a certain number of women exhibit a tendency to menorrhagia or metrorrhagia. After eliminating carcinoma, myoma or polyps as causative factors by performing a diagnostic curettage, a functional origin must be considered. In these patients sclerotic changes in the ovarian parenchyma and the tunica albuginea render the follicle incapable of completing its cycle or of responding to a normal or even an increased pituit~ry function. Occasionally, postmenopausal uterine bleeding is encountered, due probably to a temporary reactivation of the graafian follicle. This condition must be distinguished from granulosa cell tumors of the ovary which produce similar clinical and endometrial changes. Treatment of Functional Uterine Bleeding.-In the treatment of bleeding of endocrine origin the mere removal of the hyperplastic en dome-
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trium does not bring about permanent cure. Unless the underlying endocrine disorder is overcome, the condition will recur. The treatment of functional uterine hemorrhage may be considered under three groups: (1) pubescent bleeding, (2) maturity bleeding and (3) menopausal bleeding. 1. Pubescent Bleeding.-In pubertal bleeding the ovary is usually at fault, i.e., there is an absence of progestin, except in the rare instances of Frohlich's disease. One generally finds a high gonadotropin and low estrogen curve. The endometrium may be hyperplastic or atrophic. The treatment recommended for the more serious cases is as follows: (a) The vagina should be packed through a Kelly cystoscope. (b) A blood transfusion.
Desiccated thyroid, ;2 grain three times daily. Insulin hypodermatically, 5 to 10 units, before the morning and evening meal, improves health and has a definite ovarian influence. (e) Progesterone, 10 mg. injected twice weekly. Occasionally this may precipitate bleeding. (f) Testosterone. This affords, as a rule, better results than other endocrine therapy. In the first week 150 mg. may be required followed by 50 mg. per week for several months, gradually reducing the dosage. (g) Low dosage irradiation of the ovaries (50 to 80 roentgen units per treatment) may be used as an adjunct in certain cases. (c) (d)
2. Maturity Bleeding.-During the childbearing period the administration of gonadotropic anterior pituitary-like hormone acts, it is claimed, as a specific. This hormone has a tencrency to complete luteinization and is, therefore, a logical form of treatment for women under 40. One thousand rat units are given hypodermically daily until the bleeding subsides and every other day for two months thereafter. In obstinate cases, low dosage irradiation of the pituitary gland and ovaries has proved of value. Snake venom has been recommended and favorable results have been reported following the administration of this material. . Biskind presents evidence that menorrhagia and. premenstrual tension related to an excess of estrogen, are caused by failure of the liver to inactivate estrogen because of deficiency of the vitamin B complex. Administration of B complex orally in daily doses of thiamine 9 mg., riboflavin 9 mg., nicotinamide 75 mg., led to prompt improvement of these conditions. 3. Menopausal Bleeding.-Patients approaching the menopause often show a compensatory excess of the gonadotropic hormone of the anterior hypophysis. The administration of gonadotropic hormone is, therefore, of no value. The injection of 300 mg. of testosterone propionate over a period of one month, it is claimed, is of value. Radium is the treatment of choice. Radium in Functional Bleeding.-If abnormal menstrual bleeding fails to respond to the simple measure outlined, radium may be used,
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but this should be employed only after ordinary means have failed. In the early menstrual life of women, only small doses of radium should be administered, and then, too, with extreme caution on account of the probability of inducing sterility or establishing a premature menopause. Temporary and even permanent amenorrhea may follow a 200 or 300 mg.-hr. dose. After the menopause, however, 600 to 1500 milligram-hours may be administered with impunity.
M.D.,
F.A.C.S.*
MENSTRUATION
A PROPER understanding of menstruation is essential to an intelligent interpretation of the many phases of gynecologic physiology and pathology. The morphological processes concerned in menstruation are found to be closely governed by the fundamental physiological activities of (1) the anterior pituitary gland, (2) the ovaries, (3) the uterus and (4) the nervous system. Phases.-Generally a complete menstrual cycle averages about twenty-eight days and is divided into four phases: (1) The postmenstrual or period of recuperation, duration four to five days; (2) the preovulatory, proliferative or estrogen phase, average duration fourteen days; (3) the premenstrual, postovulatory, secretory or progestin phase, duration five days; (4) the menstrual period of dismantling, duration four days. The Postmenstrual Phase.-The postmenstrual characteristics of the uterine mucosa are well recognized. Reparative changes occur before the cessation of bleeding and this corresponds to a stage of reconstruction or involution. The rents in continuity of the surface epithelium are repaired by regeneration from the glandular tissue. The glands gradually resume their normal character as the endometrium returns to the proliferative type. The mucosa is· thin and contains widely separated, narrow, straight glands. In the ovary during this stage, ripening of a primordial follicle into a graafian follicle begins from the stimulating action of the anterior pituitary gland. The estrogenic hormone thus elaborated by the ovary induces growth and vascularity of the endometrium in direct ratio to the quantity produced. The Estrogen Phase.-At the beginning the glands are widely separated. On transverse section the space between these structures is about four times the diameter of the gland. Later in this phase they become rather closely packed, moderately tortuous, tubular in outline and extend into the basal layer. They are lined by low columnar epithelium. The nuclei of the cells are centrally placed and stain deeply. There is moderate secretion in the lumen of the glands. In the ovary about twelve to fifteen days after the beginning of menstruation, the graafian follicle reaches maturity and ovulation occurs. Upon rupture of the mature follicle. the follicular fluid and the mature egg cell surrounded by cells of the membrana granulosa are discharged into the peritoneal cavity. Large amounts of estrogenic hormone are transported by the blood stream to the uterus to promote growth and vascularity of the endometrium. Immediately following rupture of the follicle, the earliest stage of the new corpus luteum begins with * Diplomate of American Board of Obstetrics and Gynecology; Assistant Professor of Obstetrics, Jefferson Medical College; Attending Obstetrician, Jefferson Medical College Hospital, Philadelphia. 137;
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proliferation and differentiation of the granulosa cells and ingrowth of the theca lutein cells. The Progestin Phase.-In a dual capacity the corpus luteum continues the elaboration of estrogenic principle and also produces another hormone, termed progestin. This transforms the estrogen primed endometrium into a premenstrual state suitable, should an ovum become fertilized, for nidation. In this phase the mucosa becomes differentiated into three distinctive layers: (1) a compact surface layer, (2) an intervening spongy layer, and (3) immediately overlying the myometrium a basal layer. Marked secretory activity of the surface cells, but more particularly those of the glands, is evident. The epithelium lining the glands is composed of large cells with basal nuclei. The stroma also shows specific changes. A thin layer of lightly stained large polygonal stroma cells with large round nuclei forms the compact layer of the mucosa. These cells, however, are not equally developed in all areas. They are not unlike the decidual cells of early gestation and are termed pseudodecidual cells. In the middle or spongy layer are found characteristic markedly tortuous glands, closely packed, but separated from each other by strips of stroma cells. The gland lumen is filled with secretion. The basal layer is unchanged. The histology of the progestin endometrium is similar to that of a two weeks' gestation and only the absence of chorionic villi distinguishes it. The true premenstrual stage is the period from the cessation of actual production of progestin to the onset of bleeding and is only about forty-eight hours in duration. The coiled endometrial arteries constrict at the base with a peripheral ischemia and the stroma of the endometrium becomes dehydrated. Subepithelial hematomas appear coalescing into lacunae whieh begin to bleed into the lumen.
Types.-There are, according to the modern concept of menstruation, two different types of a menstruating mucosa: 1. N ormal.-In this type, the functional layers (compacta and spongiosa) are dismantled, leaving a raw wound, the base of which is formed by the altered basilar layer. This is the most common type. 2. Pseudomenstruation.-In this form, menstruation occurs from an inactive or almost resting mucosa. There is no evidence of the premenstrual phase in the mucosa, uterine bleeding occurring from an estrogenic endometrium. This periodic bleeding is not a genuine menstruation, because it is not associated with the characteristic preparatory endometrial changes nor with extensive endometrial desquamation. This inadequate preparation of the endometrium makes proper implan.tation of the fertilized ovum impossible and explains many cases of sterility in regularly menstruating women. Other possible causes of pseudomenstruation besides failure of ovulation are imbalance of the two ovarian hormones, estrogen and progestin, and a uterus which fails to respond to normal ovarian stimulation. In studying cases of menstrual disorders, a diagnostic premenstrual uterine curettage is important in that it shows the end result of the effect of both estrogen and progesterone activity on the endometrium. If the endometrium is normally responsive the type of ovarian dysfunction can be determined. Day-to-day vaginal smears also determine estrogenic effect and cyclic ovarian changes. The probable date of
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ovulation can often be elicited as well as the effectiveness of therapy. The interpretation of the smear consists in finding cells from the basal vaginal layer indicative of estrogen deficiency or cornification of cells from the superficial vaginal layer showing estrogen activity. Etiology.-As the result of anterior pituitary stimulation of the ovaries, estrogen is gradually concentrated in the endometrium. The premenstrual saturation of the follicular hormone in the uterine mucosa finally causes regressive endometrial changes with resultant bleeding. The role of the corpus luteum hormone is a passive one of maintaining the endometrium intact. Progestin is capable of nullifying the terminal effects of estrogen described above. When the corpus luteum regresses in the absence of pregnancy, the saturation effects of estrogen on the endometrium are uninhibited and bleeding results. This involution of the corpus luteum is probably brought about as increasing quantities of estrogenic hormone produced by the ovary gradually inhibit the pituitary gland which, therefore, withdraws its stimulation of the corpus luteum about two days before actual bleeding with resultant menstruation. In addition, an undetermined "bleeding factor" present in the endometrium of the adult woman only appears to be essential for the onset of menstruation. Thus "a child will rarely menstruate even though large quantities of both ovarian hormones are administered. Furthermore, women are occasionally encountered who do not menstruate, although they have a normal amount of estrogen in the blood and urine and an active secretory endometrium, indicating, perhaps, an absence of this so-called bleeding factor. AMENORRHEA
The term amenorrhea refers to a marked diminution or complete absence of the menstrual flow. It is classified as primary or secondary. The former refers to a total failure of menstruation to appear, and the latter to a cessation of the cycle after its establishment. Oligomenorrhea is applied to menstruation occurring at intervals of two or three months. Hypomenorrhea refers to regular though scanty menstruation. Physiological amenorrhea denotes the absence of menstruation during some physiologic process. Pathological amenorrhea refers to the absence of the period as a result of some anatomical disorder. Etiology.-PHYSIOLOGICAL AMENORRHEA.-Menstruation is nearly always absent during pregnancy and lactation. It is absent before the establishment of puberty, and after the menopause. PATHOLOGICAL AMENORRHEA.-The causes of pathological amenorrhea are both general and local. General Causes.-l. Constitutional Diseases.-The most common constitutional disorder associated with an absen<;:e of the menstrual flow i~
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advanced pulmonary tuberculosis. The primary anemias are generally associated with the condition, as may be diabetes, chronic nephritis, and tuberculous infections other than those involving the lungs. It may result from profound nervous shock, and it occurs in the advanced stages of organic nervous disease. In Manila it was recently reported that in many patients the menses stopped abruptly after the first bombing or soon after internment and before a food deficiency could have any effect. 2. Acute Infectious Diseases.-Amenorrhea is often present during convalescence from the acute exanthemas, typhoid fever, malaria and influenza. 3. Climatic Influence.-Exposure to wet and cold, with sudden chilling of the body or a simple change of environment may result in a temporary check of the menstrual process. Local Causes.-l. Primary.-The most common local cause of amenorrhea is congenital ill-development of the organs fundamentally concerned in menstruation. Usually the uterus and ovaries are involved, the hypoplastic alteration in the uterus being secondary to that in the ovaries. Hypoplasia of the latter organs may not be congenital, but may represent some pathologic alteration which had its inception in early adolescence. Irregular development of the genital organs, especially an imperforate hymen or stenosis of the vagina or cervix, results in a failure of the menstrual flow to appear. 2. Secondary.-Radical curettage or prolonged radium treatment may cause amenorrhea by destroying the endometrium. Follicle cysts of the ovary as a cause of amenorrhea are not infrequent. These may result from the inability of the ovum to penetrate an inflamed, thickened tunica albuginea, or more commonly, may be due to an insufficient hormonal stiQ1Ulation from the anterior pituitary gland, so that the follicle fails to rupture. If the follicle does not rupture, it becomes either atretic or distended with fluid and forms one or more retention cysts. Occasionally these cysts elaborate a sufficient quantity of estrogenic hormone to produce prolonged menstrual bleeding. Endocrinopathic Causes.-Disorders of the endocrine system may be associated with amenorrhea and this is especially true of the anterior pituitary gland and ovaries. These disturbances may be classified as: 1. Primary Pituitary Deficiency.-Primary deficiency of the anterior pituitary lobe is by far the most common form of endocrine disturbance encountered. Generally speaking, this condition, if not sufficiently severe to suppress totally ovarian function, is usually one of a mild Frohlich's syndrome (adiposogenital dystrophy). Clinically, these patients are rather short in stature and show distinct stigmas of underactivity of the hypophysis, manifested first by a characteristic mammary mons girdle obesity due to associated involvement of the hypothalamus, secondly by hypertrichosis with masculine distribution
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of pubic hair, and thirdly by genital hypoplasia with menstrual derangement. 2. Primary Ovarian Failure (Primary Hypogonadism).-Primary ovarian failure is due to inherent deficiency of the internal secretory portion of the ovary independent of the secondary effects of the diminution of function of other glands, notably the pituitary and thyroid. Clinically, these patients present a marked contrast to those of the hypopituitary type. They represent the superlatively feminine type. They are emotional to excess, underweight, visceroptotic and intolerant to food. They experience gastrointestinal spasticity, irritability of the nervous system and dysmenorrhea. Hypoplasia of the genital organs and irregular menstruation, or amenorrhea, are constant observations. Hormone studies reveal a uniformly low estrogenic level in the blood premenstrually. The most significant finding, however, is a demonstrable quantity of anterior pituitary gonadotropic hormone in the blood and urine in about 50 per cent of the patients. 3. Thyroid Derangement.-It is well known that the ovary depends on thyroid secretion to increase its chemical reactions. However, amenorrhea occurs more frequently with hyperfunction. Hypothyroidism is more often associated with an excessive flow. 4. Uterine Factor.-Amenorrhea sometimes is noted in patients with a normal level of blood and urine estrogen. In these women the uterus becomes atrophic and fails to respond to normal or increased ovarian function. Occasionally, however, one is surprised in obtaining on currettage a normal secretory endometrium. In these patients the absence of the so-called bleeding factor is, perhaps, responsible for the amenorrhea. Many of the disturbances associated with amenorrhea of endocrine origin are due to worry and anxiety over the nonappearance of the menses rather than to any direct effect of the amenorrhea itself. Most symptoms are relieved when the patient is reassured that amenorrhea does not mean the "retention" of harmful products. Treatment.-The treatment involves the employment of measures to correct the cause. We shall confine ourselves chiefly to a discussion of the endocrine therapy. QUANTITATIVE HORMONAL ASSAYS AS GUIDE TO TREATMENT.-Quantitative hormonal assays of anterior pimitary and ovarian excretion in the urine gives us the best means of determining endocrine function and therapy in both ameporrhea and dysfunctional uterine bleeding. The following hormonal assays are available for this purpose: 1. Gonadotropic Hormones.-Elaborated by the anterior pituitary gland, they stimulate the ovaries by means of two specific hormones: the follicle-stimulating and luteinizing hormone. In addition chorionic gonadotropin, somewhat resembling the above, is produced by the chorionic cells of the placenta. A twenty-four hour urine specimen is collected and the proteins precipitated by alcohol. Bio-assay is made by injection into infantile mice. These assays are of
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value in determining pituitary dysfunction in menstrual disorders and whether we are dealing with primary pituitary failure or primary hypogonadism. 2. Estrogenic Hormones.-For determination of estrogen in the urine, the urine is first hydrolyzed by boiling for fifteen minutes with 5 per cent hydrochloric acid or sulfuric acid. This releases about 95 per cent of the estrogenic hormone present by converting the inactive to active estrogen. During active sex life, except during pregnancy when there is a huge increase, a woman normally excretes in the urine 150 mouse units of estrogen in twenty-four hours. There is a rise in estrogen at the time of ovulation followed by a drop and then another rise premenstrually. The highest concentration is noted at the end of the premenstrual stage. A modification of the Allen-Doisy test is usually employed in which the extract is injected into castrated adult mice or rats and varying degrees of vaginal estrus observed. These are accurate and practical tests to determine the level of ovarian activity. They are of special value in the diagnosis of functional sterility in regularly menstruating women. At the premenstrual phase of the cycle, close to 90 per cent of normal fertile women show a demonstrable quantity of the hormone. In regularly menstruating sterile women, without pelvic disease, a positive reaction is much less frequent, thus indicating a deficiency of estrogenic production. 3. Progesterone and Its Excretion Product, Pregnandiol.-Progesterone is metabolized in the liver and excreted in the urine as a water-soluble compound, sodium pregnandiol glycuronate. Pregnandiol has no biologic action but can be determined in the urine by the gravimetric method of Venning and Browne. In menstrual disorders, the presence of pregnandiol in the urine immediately after ovulation in amounts of 3 to 10 mg. is indicative of a normal corpus luteum and ovulation. 4. Androgens and 17-Ketosteroids.-A woman normally excretes about threefourths as much androgen as the male. This is derived from the adrenal cortex. Biologic assay is difficult. Chemical assay for 17-ketosteroids is employed instead. The term "17-ketosteroids" refers to those steroids possessing a ketone group on the 17th carbon atom. The principle 17-ketosteroids that occur in the normal human urine are androgenic. Therefore they serve in the female as an index of adrenal function. In female hypogonadism, the 17-ketosteroids may be normal in primary ovarian failure but diminished if due to pituitary deficiency.
In considering endocrine therapy, functional amenorrhea and menorrhagia can practically be discussed together since both represent varying degrees of the same endocrine disturbance. To the woman suffering psychically from amenorrhea of functional origin, it makes no difference whether she is bleeding from a proliferative or a progestational endometrium. The mental relief is the same. To the woman, however, in whom amenorrhea and sterility coexist, the cure of the latter depends in great measure upon a physiological cure of the underlying uterine ovarian deficiency. We will therefore consider in order the specific therapeutic value of: (1) the gonadotropic hormones; (2) the estrogens; (3) progesterone; (4) androgens (testosterone); (5) thyroid. 1. Gonadotropic H ormOlles.-The gonadotropic hormones available are as follows: (a) Hypophyseal Gonadotropin.-Extracted from fresh anterior
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pituitary glands of s?eep and horse,. it contains bo~h .follic.l~-stimul~ting and luteinizing fractIOns. Its value lIes, therefore, III Its abIlIty to stImulate a hypofunctioning ovary if due to a pituitary gonadotropic deficiency. It does not cause ovulation. Injections should be stopped after three weeks of the cycle and after three months of cyclical administration due to the danger of producing follicle cysts of the ovary. It is employed in amenorrhea and in functional uterine bleeding due to deficient luteinization. The commercial preparations available contain 25 to 500 rat units per cubic centimeter. (b) Equine Gonadotropin.-Extracted from the serum of pregnant . mares, it is mostly a follicle-stimulating hormone and. only slightly a luteinizing hormone. In amenorrhea associated with genital hypoplasia, it is administered in doses of 200 to 400 I.U. intramuscularly three times a week for two weeks followed by a two weeks' rest or a course of chorionic gonadotropin. (c) Chorionic Gonadotropins.-Extracted from the urine and and placenta of pregnant women, its biologic effect is chiefly a luteinizing one. It has no value in the treatment of amenorrhea unless preceeded by hypophyseal gonadotropin in the first two weeks to cause follicle maturation. Then it may be given as 500 LU. daily for two weeks. In uterine bleeding due to progesterone deficiency 500 LU. are recommended three times weekly. (d) Combined Hypophyseal and Chorionic Gonadotropin.-This product is indicated in any disorder due to failure of ovulation. One cubic centimeter is given intramuscularly three times a week. Not more than 5 to 10 cc. should be given a month due to the danger of producing hemorrhagic and cystic ovaries. 2. Estrogens.-The estrogenic hormones are both natural and synthetic. Standardization is in terms of international unit defined as the estrogenic activity of 0.001 mg. of estrone; as rat unit-l R.u. being equivalent to 5-10 LU.; and by weight, in milligrams of active substance. It is administered intramuscularly, orally, locally and in decholin may be given intravenously. For amenorrhea 50,000 I.U. are given three times weekly for two weeks, followed by a course of progesterone and repeated monthly. The chief value of estrogens is to stimulate uterine growth in patients with primary ovarian deficiency. At best it is only substitution therapy. Its advocacy in functional bleeding is questionable except where an atrophic endometrium is present. Ovulation may be inhibited and bleeding stopped for a while but withdrawal bleeding may be sev.ere especially in a patient with a hyperplastic endometrium. Danger of prolonged usage inhibiting the pituitary and ovary should be emphasized. 3. Progesterone.-This may be administered intramuscularly or orally as pregneninolone, 1 mg. being equivalent to 0.2 mg. of progesterone by injection.
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Secondary amenorrheas respond after the administration of 20 mg. of progesterone given daily for three days (Zondek). It is better, however, especially if the amenorrhea is of longer duration than six months, to prime the endometrium first with large doses of estrogen. Zondek recommends 1 mg. of alpha-estradiol given together with 10 mg. of progesterone daily for five days. Progesterone may be of value in functional uterine bleeding if due to a progesterone deficiency such as is found in cases of hyperplasia of the endometrium. Ten mg. are injected twice weekly for the last two weeks of the cycle. 4. Androgens.-Testosterone may be given intramuscularly, sublingually, as a pellet under the skin or orally as methyl testosterone which is one-fifth as effective as the intramuscular injection. The danger of producing hirsutism should be kept in mind and may probably be avoided by limiting the dosage to 300 mg. per month and discontinuing it as soon as acne is evident. It is of great value in inhibiting some of the effects of estrogen on the endometrium and myometrium and in inhibiting the gonadotropic function of the pituitary. It tends to produce an atrophic endometrium. It is of special value, therefore, in functional uterine bleeding; 25 mg. are injected three times weekly. 5. Thyroid.- This is a valuable adjuvant in the treatment of functional amenorrhea and bleeding and may be used even when the basal metabolism is normal, or slightly subnormal. The administration of desiccated thyroid tissue, 0.09 or 0.13 gm. (l1h or 2 grains) daily, tends to increase cellular activity throughout the entire body, including the endocrine glands. In addition, it has been shown that thyroid extract neutralizes the action of estrogenic substance on the endometrium. This may explain the temporary beneficial effect of thyroid therapy in functional uterine bleeding when prolonged and unantagonized activity of estrogenic substance on the endometrium is the immediate cause of the abnormal uterine hemorrhage. Prostigmine has been used in the treatment of delayed menstruation. One mg. is injected on three consecutive days. Estrogenic substances release acetylcholine in the uterus which produces local hyperemia. Prostigmine is a nonspecific agent with a similar property of potentiating the action of acetylcholine. If no menstrual flow occurs within seventy-two hours after the last injection a tentative diagnosis of pregnancy is made. Insulin.- This drug may restore normal menstruation in some patients, especially those who are underweight and suffering with primary ovarian underactivity. Irradiation Therapy.-Low dosage irradiation of the pituitary gland and ovaries is a valuable measure in the treatment of functional amenOl,"rhea as well as menorrhagia of endocrine origin. The therapeutic action of irradiation is generally attributed to a transitory or permanent increase in cellular activity of the ovary. X-ray stimulation of the ovaries
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is contraindicated in the absence of a subthreshold quantity of blood estrogen, as it may induce permanent amenorrhea. Ovarian irradiation is only partially effective when the ovarian hypofunction is secondary to hypophyseal or thyroid underactivity. In such instances irradiation of the pituitary appears to have an adjuvant value. Low dosage irradiation of the pituitary gland and ovaries affords the best results in the treatment of menstrual disturbances with functional sterility associated. Strict adherence to the technic of the roentgenologist is most essential, i.e., from 50 to 80 roentgen units or about 10 per cent skin erythema dose being given once a week over a period of six weeks. The one menstrual disorder that almost invariably fails to respond is hypomenorrhea (scanty flow) in regularly menstruating women. The cause of the menstrual deficiency in these patients is apparently within the uterus itself. MENORRHAGIA
This term is applied to excessive menstruation, or to an undue prolongation of the flow. It may be anatomical or functional, the latter diagnosis being arrived at by exclusion. Etiology.-ANATOl\IIC TYPES.-The anatomical causes of menorrhagia are either general or local. These may be considered under the following: General Causes.-l. Blood Disease.-In patients with a hemorrhagic tendency, menorrhagia is commonly present. It may be the first symptom of purpura hemorrhagica, leukemia, aplastic anemia, and Hodgkin's disease. 2. Systemic Disease.-Disease of the cardiovascular apparatus, kidney or liver disease, resulting in a tardy return circulation, favors engorgement of the pelvic vessels. This naturally leads to uterine congestion and excessive menstruation. In addition, disorders of the arterial system associated with high tension or endarteritis may be a factor. ' 3. Hypothyroidism.-The menorrhagia often noted in myxedema and minor degrees of thyroid hypofunction illustrates the degree to which the ovary is dependent upon normal thyroid function. Local Causes.-l. Inflammation.-Inflammation, either acute, subacute or chronic, of the cervix, uterine body, fallopian tubes, ovaries, pelvic peritoneum, or pelvic cellular tissue, is nearly always associated with excessive menstrual discharge. 2. Ulcerations.-Ulcerations of the cervix or vagina, whether simple, tllberculous, syphilitic or malignant, provoke excessive menstrual discharge. In this category may be listed senile vaginitis, ill-fitting pessary and prolapse of the uterus. 3. Neoplasms.-Tumors, both benign and malignant, involving the cervix, endometrium, myometrium, or serous covering of the uterus may cause profuse and prolonged menstruation. Myomas of the inter-
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stitial type may be influential, but not to the same extent as those of the submucous variety. Subserous tumors, if small, do not cause bleeding, but if of large size, owing to pressure engorgement, abnormal hemorrhage may occur. DYSFUNCTIONAL UTERINE BLEEDlNG.-Bleeding of endocrine origin is termed functional bleeding. This term is a misnomer. More aptly it should be called dysfunctional uterine bleeding. An interv8.1 shorter than sixteen days or a flow lasting more than eight days is abnormal. The endocrine organs most commonly responsible for excessive menstruation are the pituitary gland and ovaries. Thyroid dysfunction may, likewise, provoke free menstrual bleeding. Functional menorrhagia is especially common (1) with the onset of puberty and (2) in the early menopause, although it not infrequently occurs in mature women under 40 years of age. Functional menstrual disorders result from an ovarian failure. This may be primary due to inherent ovarian disease or secondary to extraovarian causes such as pituitary disease or other endocrine lesions or various types of constitutional disease. The approximate degree of ovarian involvement is indicated by the endometrium. In patients with this symptom, uterine curettage usually reveals a hyperplastic endometrium characterized by a dense vascular stromal and epithelial overgrowth. The glands are large and cystic, representing the characteristic "Swiss cheese" pattern, large dilated glands being found side by side with others small and narrow. Many of these are lined by several layers of epithelial cells and show no secretion in the lumen. Functional bleeding is usually due to deficient activity of the anterior pituitary lobe. This deficiency results in an imbalance of the two hormones of the ovary manifested by a prolonged production of the estrogenic hormone. This is associated with an absence or deficiency of the corpus luteum hormone. The abnormal development of the unantagonized follicle due to the failure of luteinization results in follicular cysts of varying size. In the early menopause a certain number of women exhibit a tendency to menorrhagia or metrorrhagia. After eliminating carcinoma, myoma or polyps as causative factors by performing a diagnostic curettage, a functional origin must be considered. In these patients sclerotic changes in the ovarian parenchyma and the tunica albuginea render the follicle incapable of completing its cycle or of responding to a normal or even an increased pituit~ry function. Occasionally, postmenopausal uterine bleeding is encountered, due probably to a temporary reactivation of the graafian follicle. This condition must be distinguished from granulosa cell tumors of the ovary which produce similar clinical and endometrial changes. Treatment of Functional Uterine Bleeding.-In the treatment of bleeding of endocrine origin the mere removal of the hyperplastic en dome-
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trium does not bring about permanent cure. Unless the underlying endocrine disorder is overcome, the condition will recur. The treatment of functional uterine hemorrhage may be considered under three groups: (1) pubescent bleeding, (2) maturity bleeding and (3) menopausal bleeding. 1. Pubescent Bleeding.-In pubertal bleeding the ovary is usually at fault, i.e., there is an absence of progestin, except in the rare instances of Frohlich's disease. One generally finds a high gonadotropin and low estrogen curve. The endometrium may be hyperplastic or atrophic. The treatment recommended for the more serious cases is as follows: (a) The vagina should be packed through a Kelly cystoscope. (b) A blood transfusion.
Desiccated thyroid, ;2 grain three times daily. Insulin hypodermatically, 5 to 10 units, before the morning and evening meal, improves health and has a definite ovarian influence. (e) Progesterone, 10 mg. injected twice weekly. Occasionally this may precipitate bleeding. (f) Testosterone. This affords, as a rule, better results than other endocrine therapy. In the first week 150 mg. may be required followed by 50 mg. per week for several months, gradually reducing the dosage. (g) Low dosage irradiation of the ovaries (50 to 80 roentgen units per treatment) may be used as an adjunct in certain cases. (c) (d)
2. Maturity Bleeding.-During the childbearing period the administration of gonadotropic anterior pituitary-like hormone acts, it is claimed, as a specific. This hormone has a tencrency to complete luteinization and is, therefore, a logical form of treatment for women under 40. One thousand rat units are given hypodermically daily until the bleeding subsides and every other day for two months thereafter. In obstinate cases, low dosage irradiation of the pituitary gland and ovaries has proved of value. Snake venom has been recommended and favorable results have been reported following the administration of this material. . Biskind presents evidence that menorrhagia and. premenstrual tension related to an excess of estrogen, are caused by failure of the liver to inactivate estrogen because of deficiency of the vitamin B complex. Administration of B complex orally in daily doses of thiamine 9 mg., riboflavin 9 mg., nicotinamide 75 mg., led to prompt improvement of these conditions. 3. Menopausal Bleeding.-Patients approaching the menopause often show a compensatory excess of the gonadotropic hormone of the anterior hypophysis. The administration of gonadotropic hormone is, therefore, of no value. The injection of 300 mg. of testosterone propionate over a period of one month, it is claimed, is of value. Radium is the treatment of choice. Radium in Functional Bleeding.-If abnormal menstrual bleeding fails to respond to the simple measure outlined, radium may be used,
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but this should be employed only after ordinary means have failed. In the early menstrual life of women, only small doses of radium should be administered, and then, too, with extreme caution on account of the probability of inducing sterility or establishing a premature menopause. Temporary and even permanent amenorrhea may follow a 200 or 300 mg.-hr. dose. After the menopause, however, 600 to 1500 milligram-hours may be administered with impunity.