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True Hermaphroditism: A Case Report, with Interpretations
TRUE HERMAPHRODITISM A
CASE REPORT' WITH INTERPRETATIONS
JOHN KINGSLEY LATTIMER, EARL T. ENGLE
AND
RALPH C. YEAW
From the Department of Urology and the Department of Anatomy, College of Physicians and Surgeons, Columbia University, and the Babies Hospital Service of the Squier Urological Clinic, New Yor/c City
An 11 year old negro child with hypospadias and no palpable testes was admitted to the Babies Hospital Service of the Squier Urological Clinic in New York · City. Internally, a left ovary and a right testis were found at either end of a broad ligament. Adjacent to the testis, and probably attached to it, was a tiny ovariotestis. The genital tract consisted of one large and one minute duct. The problem of hermaphroditism is thoroughly discussed in Young's monograph of 1937 on this and related subjects. Young reviews the records of 20 cases of true hermaphroditism for which satisfactory microscopical evidence of both ovarian and testicular tissue was presented. Since the publication of this monograph, additional reports have appeared. Although these reports have not been critically examined, there appear to be not more than 10 additional cases of true hermaphroditism. There are, therefore, reports of not more than 30 cases of hermaphroditism known to possess gonads of both sexes. CASE REPORT
This patient was an 11 year old negro child whose mother brought him to the clinic on October 27, 1942, for treatment of supposed cryptorchidism and hypospadias. The history revealed that the pregnancy and birth were uneventful. When the child was 1 month old, the mother noticed a tender mass in the right inguinal region, which appeared almost daily, and disappeared on pressure. The mass was assumed to be a testis, and at the age of 7 years, at the hospital of his birth, the child was given a course of about thirty injections with no effect. It has not been possible to learn the nature of the substance injected. The patient had experienced difficulty in urination, and prolonged dribbling. The explanation for this dribbling became evident later. There was no history of bleeding or of hematuria to suggest vicarious menstruation. There were 2 siblings, a brother of 18 who was very tall, and a sister of 13 who was very short. On physical examination, the parents and sister were found to be normal. The brother ,vas not available. There was no family history of genital abnormalities. The behavior of the patient had always been typically male. He skated and played basketball and football, although his father stated that he was always a little clumsy. He had progressed normally in school. The mother had observed the phallus to be erect on 1 occasion, at the age of 10 years. She had never observed any bloody spotting or evidence of nocturnal seminal emissions on the bed clothes. Physical examination. The child presented a preadolescent physique with no marked sexual differentiation, although the physical habitus was possibly more 481
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that of an 11 year old girl (fig. 1). The face could have been that of either a male or female, as is frequently true of normal preadolescents. The supraorbital ridges were not prominent but the Adam's apple was large. The voice was of medium timbre. The figure was stocky (4 ft. 11 in., 120 lbs.) with prominent mammary regions but small nipples. The thighs were heavy, with typical female fat distribution. The phallus was small and short and the glans was bound down in chordee (fig. 2). It was 1 inch in length and was encompassed at its base by 2 folds which resembled labia majora. A small amount of pubic
Fm. 1. Photographs of the 11 year old patient, T. S.
hair was present which was confined to 2 patches in the suprapubic region. The urine escaped through a hypospadic orifice at the base of the phallus. Continuous with this orifice was a groove which ran up the ventral surface of the phallus to its tip. A small, tender mass could be felt in the right inguinal canal, which was interpreted as a hernia. There was no evidence of a vaginal orifice externally and no testes could be palpated. X-rays. When contrast material was introduced into the urethral orifice with a catheter, the dye entered a long, tubular cul-de-sac connected vvith the urethra (fig. 3). The kidneys were normal, as shown by an intravenous pyelogram.
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During the taking of the intravenous pyelogram, urine leaked from the bladder and filled the cul-de-sac. The bony pelvis was more android than gynecoid (fig. 3). The bone age was not accelerated, as it is said to be in pseudoher-
Fm. 2. The phallus showing the hypospadias of the patient, T. S.
Fm. 3. X-ray of the pelvis, showing the cul-de-sac extending from the posterior urethra. The internal genital ducts are deflected from the midline to the right.
maphroditism associated -with adrenogenitalism. The sella turcica was normal. Cystoscopy. A Butterfield children's cystoscope was easily introduced into the bladder by follmving the roof of the urethra. A normal bladder with a prom-
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J. K. LATTIMER, E. T. ENGLE AND R. C. YEAW
inent, narrow trigone, suggestive of the male type, was seen. Upon withdrawing the cystoscope into the urethra, a structure resembling a verumontanum was visible, about 3 cm. distal to the bladder neck. This showed a prominent sinus pocularis, and although the cystoscope could not be passed into this orifice, a ureteral catheter was passed to 10 cm. and contrast material was injected. X-ray films again showed the tubular cul-de-sac located beneath the bladder and extending into the pelvis (fig. 3). This cul-de-sac was deflected toward the right from the mid-line. An external urethral sphincter was seen, distal to the verumontanum. Ko prostate or seminal vesicles could be palpated by rectal examination. Laboratory examination. The androgen output in the urine was normal for a male of this age. Seventeen-keto-steroids were excreted in the urine at the rate of 4.5 mg. in 24 hours. The estrogen output was 5 rat units in 24 hours. The urine and the blood chemistry were also normal. The patient's intelligence quotient was 100. Operative findings. The anatomical, hormonal and x-ray findings suggested that this was not the usual type of pseudohermaphroditism. On November 20, 1942, the patient was explored surgically with the object of determining the true status of the gonads. A suprapubic exposure (fig. 4) revealed a complete broad ligament in the normal position. Just to the right of the center of the broad ligament was a thickened ridge or cord suggestive of a rudimentary uterus. A fimbriated fallopian tube was present in the normal position, on each side, and each appeared to be connected with the thickened cord within the broad ligament. A gonad was present on each side, in the positions normally occupied by the ovaries. The one on the right was globular and measured 1 by 1.5 cm. No structure resembling an epididymis or vas deferens could be distinguished grossly. A fragment of the right gonad was excised from the ligamentous portion, and the cut surface showed the yellowish color of testicular parenchyma. However, no tubules extruded nor could any be secured by teasing. The gonad was entirely encapsulated in a firm tunica albuginea, and appeared to be a testis. The ovariotestis was not seen at this operation. The left gonad was smaller than the right. It was a flat structure, partially covered by fat. No follicles were evident from inspection of its surface. A fragment of this gonad was removed. From each gonad, a thin, white, cordlike structure extended to the internal inguinal ring, where an indirect hernia was present. The hernia on the right was the larger, and admitted the finger as far as the external ring. No gonad was palpable in either inguinal canal. The right gonad (testis) could be pushed into the internal ring, but its attachments anchored it firmly to the broad ligament. The blood vessels supplying each gonad were grouped in large cords and could be seen beneath the posterior parietal peritoneum. They resembled spermatic vessels in appearance, but they were not oriented towards the inguinal canals. Instead they were related to the gonads, as are the ovarian vessels. Palpation of the adrenal areas revealed no tumor masses, and both kidneys were normally situated. This child had always wanted to be a normal boy. He was brought up as a
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male, and his parents were anxious to have him continue as a male. His psychologic and sociologic adjustments were thoroughly masculine. This background was considered to be sufficient to justify the removal of the female structures. Therefore, on December 11, 1942, the tubes, the left gonad (ovary) and broad ligament, with the enclosed genital tract, were removed through a midline inc1s10n. The testis was mobilized and brought down through a right inguinal incision, into the fold of skin at the right side of the phallus. The hernia on the right side was then repaired.
Fm. 4. A drawing of the pelvic viscera found at operation
The structure which later proved to be an ovariotestis was discovered when the testis was mobilized at this operation. A scar, with omental adhesions was present at the lateral end of the testis, where the previous specimen had been removed. Adherent to this scar, and still farther laterally, was a small irregular nodule of grayish tissue, closely adjacent to the testis at its lateral end. This nodule proved to be an ovariotestis. No such structure had been seen at the time of the previous biopsy, which had also come from this end of the testis. Most of the ovariotestis was removed at this operation. The specimens were fixed in Bouin's solution and blocks of the genital tract
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were prepared for study. Sections were taken at intervals of 0.5-1.0 cm. throughout the length of the specimens. Sections were stained ,vith hematoxylin and eosin or Masson's trichrome stain. JJ/1icroscopic examination. The excised specimen from the right gonad had the characteristics of a testis of late childhood. It was covered with a thick tunica
Fm. 5 (Upper). Photomicrograph of the testis, obtained at biopsy Fm. 6 (Lower). Photomicrograph of the ovary, showing cortical ova and one large follicle with an ovum.
albuginea, with no marked area vasculosa. The seminiferous tubules were more sparsely distributed than is normal for an 11 year old boy. They were small, coiled, and each contained a definite lumen. Well differentiated Sertoli cells were abundant. The only other cellular component was the spermatogonia. Spermatogenesis was delayed since there were no primary spermatocytes or later
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developmental stages of germ cells. Since no mitotic figures were seen, chromosomal studies were not possible. Interstitial cells were relatively sparse, with small islands of apparently active cells and numerous cells interspersed among the fibroblasts, which might have been undifferentiated interstitial cells (fig. 5). The specimen from the left gonad showed a normal ovarian cortex which contained large numbers of primordial ova, remnants of atretic follicles and 1 follicle several millimeters in diameter which had been cut through at removal. The entire ovary, which was subsequently removed, was 17 mm. long and approximately 8 mm. thick. It had a thick cortical zone in which were a very large number of primordial follicles. The germinal epithelium was normal. . There were no noticeable invaginations nor ingrowths of the germinal epithelium, nor were there any transitional stages discernable between it and the primordial ova of the cortical area (fig. 6). There were numerous developing follicles, the largest normal one being 2.6 mm. in diameter. Several follicles of the same approximate size were undergoing atresia. Numerous follicles, in various stages of degeneration and replace-
Fm. 7. Photomicrograph of tissue from the ovariotestis, showing close proximity of the ovocytes to the seminiferous tubules.
ment by scar tissue, were present. There were no remnants of luteal tissue and ovulation, presumably, had not taken place. As is normally the case, atresia of follicles and their replacement had occurred without much development of theca lutein cells. The ovary had a normal vascular supply and there were no abnormal findings. This ovary was similar to that of a normal pubertal girl before the first ovulation. The tissue from the ovariotestis was fixed with special techniques for chromosome studies, in the hope of determining whether this individual was genetically male or female. This had been done successfully in a previous case with intersex characters (Severinghaus '42). Unfortunately, no mitotic figures were found in the present material. The ovariotestis was cut into small fragments to insure cytological fixation. The largest fragment was 5 by 1.5 mm. Several of the fragments showed a capsule of fibrous tissue structurally similar to a tunica albuginea. In the largest specimen, there were numerous ovocytes within and below this capsule, and immediately subjacent were seminiferous tubules which had the same structure as those of the testis (fig. 7). The ova were located peripherally, in a thin zone. Most of the ovocytes were surrounded by a single layer of follicular cells.
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J. K. LATTIMER, E. T. ENGLE AND R. C. YEAW
In I piece of tissue was a partly grown follicle with a normal egg, a granulosa which was about 8 cells thick and an antrum folliculi. Adjacent to this was an atretic follicle of the same size. Follicular growth thus had occurredlin this
Fm. 8. Drawing of a section of the distal portion of the genital ducts, near the urethra. The larger duct is the utriculus prostaticus, the smaller is the ductus deferens.
Fm. 9. Drawing of a section of the genital ducts from the middle segment
Fm. 10. Drawing of a section of the genital ducts of the proximal portion. The lumen of the utricle has narrowed, while the smaller deferential duct has an intrinsic musculature.
ovariotestis. It was not possible to determine precisely the topographical relationship, but the material available suggested that, in general, the ovarian elements were cortical, and the seminiferous tubules were medullary in position.
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TRUE HERMAPHRODITISM
Other sections showed tubules and ova in close relationship. In 1 piece of tissue the tubules were directly beneath the tunica albuginea and no ovarian structures were present in this cortical zone. The surgical specimen of the genital tract consisted of a broad ligament containing the thick tubular structure previously mentioned, which grossly resembled a vagina and uterus. When the structure was opened, it was found that the lower portion was a thin-walled duct 1 cm. in external diameter lined by a slightly rugose mucous membrane. The upper portion of the tract was slightly bulbous, with a heavy wall, and terminated in the left fallopian tube. The right fallopian tube had been removed separately at this operation. Microscopic examination revealed that in addition to the larger duct, there was a minute duct parallel to the large one, both being enclosed in a common envelope of smooth muscle and connective tissue (figs. 8, 9, 10). In cross secRIGHT
LEF"T
TESTIS
OVARY
WOLFFIAN DUCT D.DEFERENS
--'-i/f-J--?-1
UTRICULUS
Fm. 11. A schematic diagram showing the relations of the ducts within the broad ligament, and their relation to the gonads. The right fallopian tube was removed separately, and no lumen could be found in it.
tion, the lumen of the larger duct measured 7 by 2 mm. at the urethral, distal1 end. These internal dimensions were approximately maintained throughout the length of the specimen, although the thickness of the wall increased somewhat and the lumen was narrowed in the proximal1 half. The lumen of the smaller duct had a maximum diameter of about l mm. This duct paralleled the course of the larger duct, but its lumen did not communicate with that of the larger duct at any point. A schematic diagram is presented to indicate the relations of the ducts to the gonads (fig. 11). The cavity of the larger duct was lined by a stratified squamous epithelium which showed keratinization in many areas in the distal portion (fig. 12). The epithelium rested on a distinct basement membrane which was in contrast to the indefinite basement membrane of the adult vagina. The tunica propria, which 1 In the following description, the term distal refers to that portion of the specimen adjacent to the urethra. Proximal refers to those structures nearest to the gonads.
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was a thick layer of white fibrous connective tissue, lay beneath the mucous membrane. It had an abundant vascular supply. There were no smooth muscle fibers in it. Papillae of loose connective tissue carried blood vessels to the border of the epithelium. The stratified squamous epithelium which lined the duct continued to its proximal end, where the lumen abruptly narrowed) and connected with the lumen of the left fallopian tube. Except for the distinct basement membrane, the epithelium of the duct was characteristic of the vaginal epithelium. Its topographical relation to the urethra, however, was characteristic of the utriculus prostaticus. Since this duct conformed closely to the characteristics of the embryonic rudiment, it will be c~lled the utriculus prostaticus. There was no differentiation of either a cervix or a corpus uteri in either mucosa or musculature. The smaller duct continued as a separate structure throughout the specimen, and its essential structure remained the same (fig. 11). It was not possible to ascertain if this duct also joined the urethra as a separate duct, but it continued independently to the end of the surgical specimen, approximately 1 cm. from the urethra. In the most distal sections, nearest the junction with the urethra, the duct was narrow and had sacculated foldings, bearing a resemblance to the ejaculatory duct. The lumen was less than 1 mm. wide in its greatest diameter. The epithelium was high columnar, and was probably pseudostratified; the cells showed clear cytoplasm apically, and no specialized modification of the cell border. The nuclei of the cells were arranged in 2 rather uniform rows. A distinct basement membrane rested on a loosely organized tunica propria. At the more distal levels, there was no musculature related to the duct, although the connective tissue was arranged in an indistinct circular arrangement within the stroma. The course of this duct and its histology, especially in the proximal portions, were so similar to the ductus deferens that this structure will be referred to as the deferential or wolffian duct. In the distal portion, an outer layer of longitudinal and circular muscle surrounded the two ducts. The smaller duct had a circularly disposed connective tissue cover, but no related musculature (fig. 8). About 4 cni. proximally, the musculature lost all arrangement into longitudinal and circular layers, and the fasciculi were disposed in an interlacing manner. The muscle bundles were not compact, but loosely distributed, and were separated by an abundance of connective tissue. The deferential duct, however, at its proxi,-rnal end was completely surrounded by an intrinsic group of muscle bundles (fig. 10). The common outer muscular coat was lost, and each duct was surrounded by its own characteristic musculature. The outer coat of the utriculus was predominantly circular in arrangement. The outer coat of the deferential duct was composed of definite, narrow fasciculi of longitudinal fibers. Within this was a broad band of circularly disposed fibers. A rich vascular supply, accompanied by small nerves, penetrated the muscularis and continued into the tunica propria throughout the entire length of the genital tract. In the portion of the tract nearest the gonads, the two ducts were completely
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separated save for a loose fascial covering in which nerves and blood vessels were found. The deferential duct was larger than at the lower levels, and the saccula-
FIG. 12 (Upper). Photomicrograph of a section of the genital ducts, showing a portion of the mucosa of the utriculus and that of the deferential duct. FIG. 13 (Lower). Photomicrograph of the proximal portion of the duct us dcferens and the adjacent epididymis.
tions and foldings of the surface of the mucous membrane were deeper and more numerous. The outer longitudinal and inner circular layers of the smooth muscle were larger and more distinct than at lmver levels.
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Near the urethra, numerous laminated homogenous structures were scattered in the stroma on the right side of the specimen adjacent to the deferential duct on the "male" side of the genital tract. In structure and staining characteristics they resembled closely the corpora amylacea of the prostate gland and were immediately surrounded by a layer of dense white fibrous connective tissue. In the normal human prostate gland, however, these structures are always found in an acinus of the gland. In the specimen being described, there was no glandular tissue in these areas. Topographically, these bodies were in the position of the embryonic prostatic anlagen. A typical fallopian tube with fimbriae was removed with the left gonad, the ovary. The cavity of this tube was traced in step sections to the upper portion of the utriculus which was lined by stratified squamous epithelium. The cavity of the fallopian tube was lined by columnar epithelium which was thrown into many folds by the stroma. The transition from the columnar epithelium of the tube to the stratified squamous epithelium of the utriculus was abrupt. The lumen of the larger duct was continuous with that of the left fallopian tube. In the broad ligament adjacent to the left fallopian tube and the ovary was another series of ducts. These were minute and lined by a layer of low cuboidal epithelium. A cyst of 1 mm. diameter which was structurally the same as the smaller ducts was found in the same area. These ducts were similar to the epoi:iphoron frequently found near the hilus of the ovary, or in the ovarian ligament of the adult. They are reported to be the rete ovarii, or embryonic rests of the mesonephric tubules which persist, frequently as small cysts, in the adult female. These were isolated ducts located within this circumscribed area and could not be tra.ced to any continuity with either of the main ducts described above. The material at hand did not permit a similar identification of the continuity of ducts on the right side of the g~nital tract with the testis. After removal of a uterine tube from the area of the right testis at the second surgical operation, the remaining structures were translocated through the internal abdominal ring to a position into the right labium or scrotal fold. In the tissue adjacent to the testis was a series of coiled ducts which resembled a rudimentary or incompletely differentiated epididymis. This structure was minute in size, but the ductuli were structurally much more differentiated than the series of structures in proximity to the ovary and described as rests of the mesonephric tubules. These apparently homologous structures on the right side appeared to be an undeveloped epididymis, and on the left side were believed to be a rete ovarii or epoi:iphoron. The ducts were small, but in general organization they resembled the adult epididymis, both because of the definite circular muscle and the characteristic cellular arrangement of the ductuli efferentia, with alternating groups of low and tall columnar epithelium. No cilia could be demonstrated. The ductus deferens (fig. 11), passed through the broad ligament and terminatednear the epididymis (fig.12). It did not unite with the ducts of the epididymis, but ended blindly in a small cyst, 1 mm. in diameter, about 1.5 mm. from
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the nearest tubules of the epididymis (fig. 13). A smaller cyst was located superiorly and near to the cystic end of the duct but did not communicate with it. The specimen which grossly resembled a right fallopian tube, when examined in the fresh state was an almost round cord of tissue about 5 mm. in diameter. On microscopic examination the muscular organization suggested a uterine tube but there was no lumen. The center of the cord was filled with a very loosely arranged connective tissue traversed by large thin-walled blood vessels. There was no evidence that a lumen lined by a mucous membrane was ever present and no vestige of one was to be found in the tissue available for study. Possible embryological interpretations. The left gonad was indubitably an ovary which was approaching structural and functional maturity. There was no remnant of the primitive male duct system on the left side. The epoophoron, a residue of the embryonic mesonephric tubules, was present which frequently is the case in adult mammalian and human ovaries. Interpretation of the right gonad and the ovariotestis was more difficult, because 2 excised specimens only were available. The small nodule lateral to the testis, of which only an excised specimen was secured, might have been entirely separate from the testis, or might have represented a lobulation of the same organ. The specimen showed the cortical ova, small follicles and seminiferous tubules. In certain sections the ova and tubules might have been adjacent (fig. 7). In others, the ova were cortical in position and the tubules were located more deeply. At the first operation, the testis was seen to be discreet, globular and entirely enclosed in a tunica albuginea. No ovariotestis was seen at this time. At the second operation, a biopsy from the tissue immediately lateral and adjacent to the testis revealed a small ovariotestis. Even though the ovariotestis was not morphologically a part of the adjacent testis, it was probably derived from the same embryological anlagen. The ducts. Several possible embryological interpretations are discussed to account for the distribution of the genital duct system of this case. There were 2 characteristic fallopian tubes observed at the time of operation, and during the preparation of the blocks for microscopic study. Therefore, a miillerian duct system was anticipated. However, the discovery of the smaller deferential duct, and its relation to the epididymis, and the histological similarity of this duct in its upper levels to the adult ductus deferens, showed that l side of the wolffian system was present. It would be feasible to consider this a case of internal or pelvic gynandromorphism. Thus, the left gonad or ovary was accompanied by a left miillerian duct. The right gonad or testis was accompanied by a right wolffian duct, or ductus deferens, and the epididymis. If this were a case of internal gynandromorphism, it would be assumed that the left wolffian duct had completely degenerated, and that all of the right miillerian duct had atrophied save the distal portion which remained as an obliterated tube. In view of the evidence, it was believed that the right duct, related to the testis and the epididymis, represented the right wolffian duct, or, in the matured form, the ductus deferens and epididy-
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mis. In normal development, the ductuli efferentes develop separately, being derived from mesonephric tubules. Secondary union is then established between these tubules and the ductus epididymis and its continuation, the ductus deferens. In the case reported, union between the wolffian duct and the mesonephric tubules (mesonephric ducts) failed to occur, and the wolffian duct ended blindly in a cystic dilatation. The left duct at its ovarian end was morphologically a fallopian tube and was derived from the left mullerian duct. In the development of the normal female genital tract, the mullerian ducts, paired at first, fuse for some distance proximal to the locus of entrance into the urogenital sinus. These fused ducts form the upper portion of the vagina and the entire uterus. In the male, a remnant of the upper portion of these fused ducts is known as the utriculus prostaticus, or uterus masculinus. In older terminology, this utriculus was referred to as the vagina masculinus, but later interpretations regarded it as the upper portion of the fused mullerian ducts, homologous to the uterus in the female. In the case reported here, it appears proper to regard the left duct not as a rudimentary vagina, but as a true, though enlarged utriculus prostaticus representing the fusion of the upper segments of the paired mullerian ducts. It can hardly be considered as a vagina, because of its topographical relation to the "prostatic" urethra, and because there was no uterus intervening between the vagina and the fallopian tube. In this case the left fallopian tube, in relation to the ovary, was in communication with the utriculus or homologue of the uterus. The right fallopian tube, although it had no lumen communicating with the uterine homologue, was the upper portion of the right mullerian duct. Added morphological evidence for considering this fused mullerian segment as it entered the urethra, homologous with the uterus or prostatic utricle, was the presence of corpora amalacea near the prostatic anlagen on the right side. It is hardly possible that all of the right mullerian duct had disappeared except at the tubal end, as had the left wolffian duct. The mullerian ducts do fuse for most of their length in normal development or in most pseudohermaphrodites with female organs. The wolffian ducts normally do not fuse but remain as separate bilateral structures. In this interpretation it is, therefore, assumed that both mullerian ducts persisted, as fused ducts distally, as paired ducts proximally, but only the right wolffian duct remained. There was no trace of the left wolffian duct. It is known that in the rat, the genital tract of the fetus may be greatly modified by administration of estrogens or androgens. This literature is too extensive to be discussed here, but has been competently reviewed by Greene (1942). More pertinent to the present case are the observations of Zuckerman (1940), subsequently confirmed by many others. In these experiments it was reported that the utriculus prostaticus of the immature male monkey could be selectively affected by injection of estrogen into the monkey. The normally columnar, secretory epithelium of the utriculus could be changed to a stratified squamous epithelium.
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In the female monkey of any age, the columnar epithelium lining the lumen and the glands of the uterine cervix can be changed completely by estrogen administration, into the stratified squamous epithelium characteristic of the portio vaginalis of the cervix. In no instance in the monkey has the epithelium of the body and fundus of the uterus been changed to a keratinized squamous epithelium. In estrogen treated male monkeys, the prostate gland is unaffected and the epithelium of the ductus deferens is unchanged. Only the epithelium of the prostatic utricle changes to a stratified squamous epithelium. The findings in the case here reported are quite analagous to the effects produced by estrogen injection in female monkeys. That duct which is interpreted as being the ductus deferens had the characteristic structure of the adult male ductus, deferens, though it was not as completely developed or differentiated. The epithelium of the duct which had been interpreted to be a utriculus prostaticus, did not have the undifferentiated columnar epithelium of the normal utriculus prostaticus, nor did it have the epithelium or musculature of any part of the uterus. The ovary of this individual had numerous growing follicles which were producing estrogen. There is no assurance that this estrogen had been produced in sufficient quantities, or over the required time, to produce squamous cell transformation of the utriculus prostaticus. The analogy of estrinized immature male monkeys is suggestive, however. The use of estrogen has been suggested by Zuckerman and by Burns to aid in classifying homologous structures in the genital tract. Burns (1941, 1942) has studied the homologies of the genital ducts and derivatives of the urogenit11l sinus in the opossum. He reports that "All epithelia in the urinogenital tract of the opposum which respond to estrogens by squamous metaplasia and cornification have a common origin from the urinogenital sinus." In the case reported here, the epithelium of the miillerian tract, which was the same type as is found in the normal mature vagina, extended the entire length of the duct up to its union with the fallopian tube. This appeared to be a stratified squamous cell conversion of an embryonic genital duct. It was difficult, however, to apply Burns' observation on the opossum to the present case, as this entire duct, from the urethra to the fallopian tube cannot be considered a derivative of the urinogenital sinus on the basis of present embryological information. Clinical resume. The findings in this case correlated closely with observed conditions. The hormones of both sexes were present, but only in amounts normal for a preadolescent of either sex, and the bone age was not advanced. This was a point of differentiation from adrenogenital pseudohermaphroditism, where the excess of androgens would have advanced the bone age. The child's urinary symptoms were partly related to the abnormal anatomy of the urethra. The delay in initiating the urinary stream was due to the fact that the urine filled the cul-de-sac before any began to flow from the meatuso The dribbling after urination was caused by the slow emptying of the utriculus into the posterior urethra, with a resultant urgency and leakage. The clinical management of this child has been started by the surgical removal
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of the female structures, and by the injection of 6,000 units of chorionic gonadotropin, postoperatively, to sustain the transplanted testis. The testis has shown no sign of atrophy and is easily palpable in the right scrotal (labial) fold. The child subsequently received 75 mg. testosterone propionate intramuscularly each week to increase the size of the penis so that a satisfactory repair of the hypospadias can be done. A further report on the progress of this patient will await the completion of hormonal and surgical procedures, and an adequate follow-up period. SUMMARY
An additional case of true hermaphroditism is reported in an 11 year old negro child who showed hypospadias and no palpable testes. On the right side a rudimentary ductus deferens, epididymis and juvenile testis were found in the abdomen. Structures resembling prostatic corpora amylacea were found where the prostate should have been. On the left side a rudimentary fused mullerian duct, a patent fallopian tube and a prepubertal ovary were present. The miillerian system emptied into the posterior urethra. In addition, there was a small ovariotestis and a remnant of a fallopian tube on the right side. The ovary and the duct systems were operatively removed and an orchidopexy performed. After the period of gonadotropic and androgen hormone treatment, the hypospadias will be corrected. REFERENCES BURNS, RoBERT K., JR.: The origin and differentiation of the epithelium of the urinogenital sinus in the opossum with a study of the modifications induced by estrogens. Carnegie Inst. Washington Publ. 541, Contributions to Embryo!. No. 191, pp. 68-83, 1942. GREENE, R.R.: Hormonal factors in sex inversion: The effects of sex hormones on embryonic sexual structures of the rat. Biol. Symposia, 9: 105-124, 1942. SEVERINGHAUS, A. E.: Sex chromosomes in human intersex. Am. J. Anat., 70: 73-93, 1942. YOUNG, H. H.: Hermaphroditism, Genital Abnormalities and the Adrenal Genital syndrome. Baltimore: Williams & Wilkins Co., 1937. ZUCKERMAN, S.: The histogenesis of tissues sensitive to estrogens. Biol. Review, 15: 231271, 1940.
CASE REPORT' WITH INTERPRETATIONS
JOHN KINGSLEY LATTIMER, EARL T. ENGLE
AND
RALPH C. YEAW
From the Department of Urology and the Department of Anatomy, College of Physicians and Surgeons, Columbia University, and the Babies Hospital Service of the Squier Urological Clinic, New Yor/c City
An 11 year old negro child with hypospadias and no palpable testes was admitted to the Babies Hospital Service of the Squier Urological Clinic in New York · City. Internally, a left ovary and a right testis were found at either end of a broad ligament. Adjacent to the testis, and probably attached to it, was a tiny ovariotestis. The genital tract consisted of one large and one minute duct. The problem of hermaphroditism is thoroughly discussed in Young's monograph of 1937 on this and related subjects. Young reviews the records of 20 cases of true hermaphroditism for which satisfactory microscopical evidence of both ovarian and testicular tissue was presented. Since the publication of this monograph, additional reports have appeared. Although these reports have not been critically examined, there appear to be not more than 10 additional cases of true hermaphroditism. There are, therefore, reports of not more than 30 cases of hermaphroditism known to possess gonads of both sexes. CASE REPORT
This patient was an 11 year old negro child whose mother brought him to the clinic on October 27, 1942, for treatment of supposed cryptorchidism and hypospadias. The history revealed that the pregnancy and birth were uneventful. When the child was 1 month old, the mother noticed a tender mass in the right inguinal region, which appeared almost daily, and disappeared on pressure. The mass was assumed to be a testis, and at the age of 7 years, at the hospital of his birth, the child was given a course of about thirty injections with no effect. It has not been possible to learn the nature of the substance injected. The patient had experienced difficulty in urination, and prolonged dribbling. The explanation for this dribbling became evident later. There was no history of bleeding or of hematuria to suggest vicarious menstruation. There were 2 siblings, a brother of 18 who was very tall, and a sister of 13 who was very short. On physical examination, the parents and sister were found to be normal. The brother ,vas not available. There was no family history of genital abnormalities. The behavior of the patient had always been typically male. He skated and played basketball and football, although his father stated that he was always a little clumsy. He had progressed normally in school. The mother had observed the phallus to be erect on 1 occasion, at the age of 10 years. She had never observed any bloody spotting or evidence of nocturnal seminal emissions on the bed clothes. Physical examination. The child presented a preadolescent physique with no marked sexual differentiation, although the physical habitus was possibly more 481
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J. K. LATTIMER, E. T. ENGLE AND R. C. YEAW
that of an 11 year old girl (fig. 1). The face could have been that of either a male or female, as is frequently true of normal preadolescents. The supraorbital ridges were not prominent but the Adam's apple was large. The voice was of medium timbre. The figure was stocky (4 ft. 11 in., 120 lbs.) with prominent mammary regions but small nipples. The thighs were heavy, with typical female fat distribution. The phallus was small and short and the glans was bound down in chordee (fig. 2). It was 1 inch in length and was encompassed at its base by 2 folds which resembled labia majora. A small amount of pubic
Fm. 1. Photographs of the 11 year old patient, T. S.
hair was present which was confined to 2 patches in the suprapubic region. The urine escaped through a hypospadic orifice at the base of the phallus. Continuous with this orifice was a groove which ran up the ventral surface of the phallus to its tip. A small, tender mass could be felt in the right inguinal canal, which was interpreted as a hernia. There was no evidence of a vaginal orifice externally and no testes could be palpated. X-rays. When contrast material was introduced into the urethral orifice with a catheter, the dye entered a long, tubular cul-de-sac connected vvith the urethra (fig. 3). The kidneys were normal, as shown by an intravenous pyelogram.
TRUE HERMAPHRODITISM
483
During the taking of the intravenous pyelogram, urine leaked from the bladder and filled the cul-de-sac. The bony pelvis was more android than gynecoid (fig. 3). The bone age was not accelerated, as it is said to be in pseudoher-
Fm. 2. The phallus showing the hypospadias of the patient, T. S.
Fm. 3. X-ray of the pelvis, showing the cul-de-sac extending from the posterior urethra. The internal genital ducts are deflected from the midline to the right.
maphroditism associated -with adrenogenitalism. The sella turcica was normal. Cystoscopy. A Butterfield children's cystoscope was easily introduced into the bladder by follmving the roof of the urethra. A normal bladder with a prom-
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J. K. LATTIMER, E. T. ENGLE AND R. C. YEAW
inent, narrow trigone, suggestive of the male type, was seen. Upon withdrawing the cystoscope into the urethra, a structure resembling a verumontanum was visible, about 3 cm. distal to the bladder neck. This showed a prominent sinus pocularis, and although the cystoscope could not be passed into this orifice, a ureteral catheter was passed to 10 cm. and contrast material was injected. X-ray films again showed the tubular cul-de-sac located beneath the bladder and extending into the pelvis (fig. 3). This cul-de-sac was deflected toward the right from the mid-line. An external urethral sphincter was seen, distal to the verumontanum. Ko prostate or seminal vesicles could be palpated by rectal examination. Laboratory examination. The androgen output in the urine was normal for a male of this age. Seventeen-keto-steroids were excreted in the urine at the rate of 4.5 mg. in 24 hours. The estrogen output was 5 rat units in 24 hours. The urine and the blood chemistry were also normal. The patient's intelligence quotient was 100. Operative findings. The anatomical, hormonal and x-ray findings suggested that this was not the usual type of pseudohermaphroditism. On November 20, 1942, the patient was explored surgically with the object of determining the true status of the gonads. A suprapubic exposure (fig. 4) revealed a complete broad ligament in the normal position. Just to the right of the center of the broad ligament was a thickened ridge or cord suggestive of a rudimentary uterus. A fimbriated fallopian tube was present in the normal position, on each side, and each appeared to be connected with the thickened cord within the broad ligament. A gonad was present on each side, in the positions normally occupied by the ovaries. The one on the right was globular and measured 1 by 1.5 cm. No structure resembling an epididymis or vas deferens could be distinguished grossly. A fragment of the right gonad was excised from the ligamentous portion, and the cut surface showed the yellowish color of testicular parenchyma. However, no tubules extruded nor could any be secured by teasing. The gonad was entirely encapsulated in a firm tunica albuginea, and appeared to be a testis. The ovariotestis was not seen at this operation. The left gonad was smaller than the right. It was a flat structure, partially covered by fat. No follicles were evident from inspection of its surface. A fragment of this gonad was removed. From each gonad, a thin, white, cordlike structure extended to the internal inguinal ring, where an indirect hernia was present. The hernia on the right was the larger, and admitted the finger as far as the external ring. No gonad was palpable in either inguinal canal. The right gonad (testis) could be pushed into the internal ring, but its attachments anchored it firmly to the broad ligament. The blood vessels supplying each gonad were grouped in large cords and could be seen beneath the posterior parietal peritoneum. They resembled spermatic vessels in appearance, but they were not oriented towards the inguinal canals. Instead they were related to the gonads, as are the ovarian vessels. Palpation of the adrenal areas revealed no tumor masses, and both kidneys were normally situated. This child had always wanted to be a normal boy. He was brought up as a
TRUE HERMAPHRODITISM
485
male, and his parents were anxious to have him continue as a male. His psychologic and sociologic adjustments were thoroughly masculine. This background was considered to be sufficient to justify the removal of the female structures. Therefore, on December 11, 1942, the tubes, the left gonad (ovary) and broad ligament, with the enclosed genital tract, were removed through a midline inc1s10n. The testis was mobilized and brought down through a right inguinal incision, into the fold of skin at the right side of the phallus. The hernia on the right side was then repaired.
Fm. 4. A drawing of the pelvic viscera found at operation
The structure which later proved to be an ovariotestis was discovered when the testis was mobilized at this operation. A scar, with omental adhesions was present at the lateral end of the testis, where the previous specimen had been removed. Adherent to this scar, and still farther laterally, was a small irregular nodule of grayish tissue, closely adjacent to the testis at its lateral end. This nodule proved to be an ovariotestis. No such structure had been seen at the time of the previous biopsy, which had also come from this end of the testis. Most of the ovariotestis was removed at this operation. The specimens were fixed in Bouin's solution and blocks of the genital tract
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were prepared for study. Sections were taken at intervals of 0.5-1.0 cm. throughout the length of the specimens. Sections were stained ,vith hematoxylin and eosin or Masson's trichrome stain. JJ/1icroscopic examination. The excised specimen from the right gonad had the characteristics of a testis of late childhood. It was covered with a thick tunica
Fm. 5 (Upper). Photomicrograph of the testis, obtained at biopsy Fm. 6 (Lower). Photomicrograph of the ovary, showing cortical ova and one large follicle with an ovum.
albuginea, with no marked area vasculosa. The seminiferous tubules were more sparsely distributed than is normal for an 11 year old boy. They were small, coiled, and each contained a definite lumen. Well differentiated Sertoli cells were abundant. The only other cellular component was the spermatogonia. Spermatogenesis was delayed since there were no primary spermatocytes or later
TRUE HERMAPHRODITISM
487
developmental stages of germ cells. Since no mitotic figures were seen, chromosomal studies were not possible. Interstitial cells were relatively sparse, with small islands of apparently active cells and numerous cells interspersed among the fibroblasts, which might have been undifferentiated interstitial cells (fig. 5). The specimen from the left gonad showed a normal ovarian cortex which contained large numbers of primordial ova, remnants of atretic follicles and 1 follicle several millimeters in diameter which had been cut through at removal. The entire ovary, which was subsequently removed, was 17 mm. long and approximately 8 mm. thick. It had a thick cortical zone in which were a very large number of primordial follicles. The germinal epithelium was normal. . There were no noticeable invaginations nor ingrowths of the germinal epithelium, nor were there any transitional stages discernable between it and the primordial ova of the cortical area (fig. 6). There were numerous developing follicles, the largest normal one being 2.6 mm. in diameter. Several follicles of the same approximate size were undergoing atresia. Numerous follicles, in various stages of degeneration and replace-
Fm. 7. Photomicrograph of tissue from the ovariotestis, showing close proximity of the ovocytes to the seminiferous tubules.
ment by scar tissue, were present. There were no remnants of luteal tissue and ovulation, presumably, had not taken place. As is normally the case, atresia of follicles and their replacement had occurred without much development of theca lutein cells. The ovary had a normal vascular supply and there were no abnormal findings. This ovary was similar to that of a normal pubertal girl before the first ovulation. The tissue from the ovariotestis was fixed with special techniques for chromosome studies, in the hope of determining whether this individual was genetically male or female. This had been done successfully in a previous case with intersex characters (Severinghaus '42). Unfortunately, no mitotic figures were found in the present material. The ovariotestis was cut into small fragments to insure cytological fixation. The largest fragment was 5 by 1.5 mm. Several of the fragments showed a capsule of fibrous tissue structurally similar to a tunica albuginea. In the largest specimen, there were numerous ovocytes within and below this capsule, and immediately subjacent were seminiferous tubules which had the same structure as those of the testis (fig. 7). The ova were located peripherally, in a thin zone. Most of the ovocytes were surrounded by a single layer of follicular cells.
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J. K. LATTIMER, E. T. ENGLE AND R. C. YEAW
In I piece of tissue was a partly grown follicle with a normal egg, a granulosa which was about 8 cells thick and an antrum folliculi. Adjacent to this was an atretic follicle of the same size. Follicular growth thus had occurredlin this
Fm. 8. Drawing of a section of the distal portion of the genital ducts, near the urethra. The larger duct is the utriculus prostaticus, the smaller is the ductus deferens.
Fm. 9. Drawing of a section of the genital ducts from the middle segment
Fm. 10. Drawing of a section of the genital ducts of the proximal portion. The lumen of the utricle has narrowed, while the smaller deferential duct has an intrinsic musculature.
ovariotestis. It was not possible to determine precisely the topographical relationship, but the material available suggested that, in general, the ovarian elements were cortical, and the seminiferous tubules were medullary in position.
489
TRUE HERMAPHRODITISM
Other sections showed tubules and ova in close relationship. In 1 piece of tissue the tubules were directly beneath the tunica albuginea and no ovarian structures were present in this cortical zone. The surgical specimen of the genital tract consisted of a broad ligament containing the thick tubular structure previously mentioned, which grossly resembled a vagina and uterus. When the structure was opened, it was found that the lower portion was a thin-walled duct 1 cm. in external diameter lined by a slightly rugose mucous membrane. The upper portion of the tract was slightly bulbous, with a heavy wall, and terminated in the left fallopian tube. The right fallopian tube had been removed separately at this operation. Microscopic examination revealed that in addition to the larger duct, there was a minute duct parallel to the large one, both being enclosed in a common envelope of smooth muscle and connective tissue (figs. 8, 9, 10). In cross secRIGHT
LEF"T
TESTIS
OVARY
WOLFFIAN DUCT D.DEFERENS
--'-i/f-J--?-1
UTRICULUS
Fm. 11. A schematic diagram showing the relations of the ducts within the broad ligament, and their relation to the gonads. The right fallopian tube was removed separately, and no lumen could be found in it.
tion, the lumen of the larger duct measured 7 by 2 mm. at the urethral, distal1 end. These internal dimensions were approximately maintained throughout the length of the specimen, although the thickness of the wall increased somewhat and the lumen was narrowed in the proximal1 half. The lumen of the smaller duct had a maximum diameter of about l mm. This duct paralleled the course of the larger duct, but its lumen did not communicate with that of the larger duct at any point. A schematic diagram is presented to indicate the relations of the ducts to the gonads (fig. 11). The cavity of the larger duct was lined by a stratified squamous epithelium which showed keratinization in many areas in the distal portion (fig. 12). The epithelium rested on a distinct basement membrane which was in contrast to the indefinite basement membrane of the adult vagina. The tunica propria, which 1 In the following description, the term distal refers to that portion of the specimen adjacent to the urethra. Proximal refers to those structures nearest to the gonads.
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J. K. LATTIMER, E. T. ENGLE AND R. C. YEAW
was a thick layer of white fibrous connective tissue, lay beneath the mucous membrane. It had an abundant vascular supply. There were no smooth muscle fibers in it. Papillae of loose connective tissue carried blood vessels to the border of the epithelium. The stratified squamous epithelium which lined the duct continued to its proximal end, where the lumen abruptly narrowed) and connected with the lumen of the left fallopian tube. Except for the distinct basement membrane, the epithelium of the duct was characteristic of the vaginal epithelium. Its topographical relation to the urethra, however, was characteristic of the utriculus prostaticus. Since this duct conformed closely to the characteristics of the embryonic rudiment, it will be c~lled the utriculus prostaticus. There was no differentiation of either a cervix or a corpus uteri in either mucosa or musculature. The smaller duct continued as a separate structure throughout the specimen, and its essential structure remained the same (fig. 11). It was not possible to ascertain if this duct also joined the urethra as a separate duct, but it continued independently to the end of the surgical specimen, approximately 1 cm. from the urethra. In the most distal sections, nearest the junction with the urethra, the duct was narrow and had sacculated foldings, bearing a resemblance to the ejaculatory duct. The lumen was less than 1 mm. wide in its greatest diameter. The epithelium was high columnar, and was probably pseudostratified; the cells showed clear cytoplasm apically, and no specialized modification of the cell border. The nuclei of the cells were arranged in 2 rather uniform rows. A distinct basement membrane rested on a loosely organized tunica propria. At the more distal levels, there was no musculature related to the duct, although the connective tissue was arranged in an indistinct circular arrangement within the stroma. The course of this duct and its histology, especially in the proximal portions, were so similar to the ductus deferens that this structure will be referred to as the deferential or wolffian duct. In the distal portion, an outer layer of longitudinal and circular muscle surrounded the two ducts. The smaller duct had a circularly disposed connective tissue cover, but no related musculature (fig. 8). About 4 cni. proximally, the musculature lost all arrangement into longitudinal and circular layers, and the fasciculi were disposed in an interlacing manner. The muscle bundles were not compact, but loosely distributed, and were separated by an abundance of connective tissue. The deferential duct, however, at its proxi,-rnal end was completely surrounded by an intrinsic group of muscle bundles (fig. 10). The common outer muscular coat was lost, and each duct was surrounded by its own characteristic musculature. The outer coat of the utriculus was predominantly circular in arrangement. The outer coat of the deferential duct was composed of definite, narrow fasciculi of longitudinal fibers. Within this was a broad band of circularly disposed fibers. A rich vascular supply, accompanied by small nerves, penetrated the muscularis and continued into the tunica propria throughout the entire length of the genital tract. In the portion of the tract nearest the gonads, the two ducts were completely
TRUE HERMAPHRODITISM
491
separated save for a loose fascial covering in which nerves and blood vessels were found. The deferential duct was larger than at the lower levels, and the saccula-
FIG. 12 (Upper). Photomicrograph of a section of the genital ducts, showing a portion of the mucosa of the utriculus and that of the deferential duct. FIG. 13 (Lower). Photomicrograph of the proximal portion of the duct us dcferens and the adjacent epididymis.
tions and foldings of the surface of the mucous membrane were deeper and more numerous. The outer longitudinal and inner circular layers of the smooth muscle were larger and more distinct than at lmver levels.
492
J. K. LATTIMER, E. T. ENGLE AND R. C. YEAW
Near the urethra, numerous laminated homogenous structures were scattered in the stroma on the right side of the specimen adjacent to the deferential duct on the "male" side of the genital tract. In structure and staining characteristics they resembled closely the corpora amylacea of the prostate gland and were immediately surrounded by a layer of dense white fibrous connective tissue. In the normal human prostate gland, however, these structures are always found in an acinus of the gland. In the specimen being described, there was no glandular tissue in these areas. Topographically, these bodies were in the position of the embryonic prostatic anlagen. A typical fallopian tube with fimbriae was removed with the left gonad, the ovary. The cavity of this tube was traced in step sections to the upper portion of the utriculus which was lined by stratified squamous epithelium. The cavity of the fallopian tube was lined by columnar epithelium which was thrown into many folds by the stroma. The transition from the columnar epithelium of the tube to the stratified squamous epithelium of the utriculus was abrupt. The lumen of the larger duct was continuous with that of the left fallopian tube. In the broad ligament adjacent to the left fallopian tube and the ovary was another series of ducts. These were minute and lined by a layer of low cuboidal epithelium. A cyst of 1 mm. diameter which was structurally the same as the smaller ducts was found in the same area. These ducts were similar to the epoi:iphoron frequently found near the hilus of the ovary, or in the ovarian ligament of the adult. They are reported to be the rete ovarii, or embryonic rests of the mesonephric tubules which persist, frequently as small cysts, in the adult female. These were isolated ducts located within this circumscribed area and could not be tra.ced to any continuity with either of the main ducts described above. The material at hand did not permit a similar identification of the continuity of ducts on the right side of the g~nital tract with the testis. After removal of a uterine tube from the area of the right testis at the second surgical operation, the remaining structures were translocated through the internal abdominal ring to a position into the right labium or scrotal fold. In the tissue adjacent to the testis was a series of coiled ducts which resembled a rudimentary or incompletely differentiated epididymis. This structure was minute in size, but the ductuli were structurally much more differentiated than the series of structures in proximity to the ovary and described as rests of the mesonephric tubules. These apparently homologous structures on the right side appeared to be an undeveloped epididymis, and on the left side were believed to be a rete ovarii or epoi:iphoron. The ducts were small, but in general organization they resembled the adult epididymis, both because of the definite circular muscle and the characteristic cellular arrangement of the ductuli efferentia, with alternating groups of low and tall columnar epithelium. No cilia could be demonstrated. The ductus deferens (fig. 11), passed through the broad ligament and terminatednear the epididymis (fig.12). It did not unite with the ducts of the epididymis, but ended blindly in a small cyst, 1 mm. in diameter, about 1.5 mm. from
TRUE HERMAPHRODITISM
493
the nearest tubules of the epididymis (fig. 13). A smaller cyst was located superiorly and near to the cystic end of the duct but did not communicate with it. The specimen which grossly resembled a right fallopian tube, when examined in the fresh state was an almost round cord of tissue about 5 mm. in diameter. On microscopic examination the muscular organization suggested a uterine tube but there was no lumen. The center of the cord was filled with a very loosely arranged connective tissue traversed by large thin-walled blood vessels. There was no evidence that a lumen lined by a mucous membrane was ever present and no vestige of one was to be found in the tissue available for study. Possible embryological interpretations. The left gonad was indubitably an ovary which was approaching structural and functional maturity. There was no remnant of the primitive male duct system on the left side. The epoophoron, a residue of the embryonic mesonephric tubules, was present which frequently is the case in adult mammalian and human ovaries. Interpretation of the right gonad and the ovariotestis was more difficult, because 2 excised specimens only were available. The small nodule lateral to the testis, of which only an excised specimen was secured, might have been entirely separate from the testis, or might have represented a lobulation of the same organ. The specimen showed the cortical ova, small follicles and seminiferous tubules. In certain sections the ova and tubules might have been adjacent (fig. 7). In others, the ova were cortical in position and the tubules were located more deeply. At the first operation, the testis was seen to be discreet, globular and entirely enclosed in a tunica albuginea. No ovariotestis was seen at this time. At the second operation, a biopsy from the tissue immediately lateral and adjacent to the testis revealed a small ovariotestis. Even though the ovariotestis was not morphologically a part of the adjacent testis, it was probably derived from the same embryological anlagen. The ducts. Several possible embryological interpretations are discussed to account for the distribution of the genital duct system of this case. There were 2 characteristic fallopian tubes observed at the time of operation, and during the preparation of the blocks for microscopic study. Therefore, a miillerian duct system was anticipated. However, the discovery of the smaller deferential duct, and its relation to the epididymis, and the histological similarity of this duct in its upper levels to the adult ductus deferens, showed that l side of the wolffian system was present. It would be feasible to consider this a case of internal or pelvic gynandromorphism. Thus, the left gonad or ovary was accompanied by a left miillerian duct. The right gonad or testis was accompanied by a right wolffian duct, or ductus deferens, and the epididymis. If this were a case of internal gynandromorphism, it would be assumed that the left wolffian duct had completely degenerated, and that all of the right miillerian duct had atrophied save the distal portion which remained as an obliterated tube. In view of the evidence, it was believed that the right duct, related to the testis and the epididymis, represented the right wolffian duct, or, in the matured form, the ductus deferens and epididy-
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mis. In normal development, the ductuli efferentes develop separately, being derived from mesonephric tubules. Secondary union is then established between these tubules and the ductus epididymis and its continuation, the ductus deferens. In the case reported, union between the wolffian duct and the mesonephric tubules (mesonephric ducts) failed to occur, and the wolffian duct ended blindly in a cystic dilatation. The left duct at its ovarian end was morphologically a fallopian tube and was derived from the left mullerian duct. In the development of the normal female genital tract, the mullerian ducts, paired at first, fuse for some distance proximal to the locus of entrance into the urogenital sinus. These fused ducts form the upper portion of the vagina and the entire uterus. In the male, a remnant of the upper portion of these fused ducts is known as the utriculus prostaticus, or uterus masculinus. In older terminology, this utriculus was referred to as the vagina masculinus, but later interpretations regarded it as the upper portion of the fused mullerian ducts, homologous to the uterus in the female. In the case reported here, it appears proper to regard the left duct not as a rudimentary vagina, but as a true, though enlarged utriculus prostaticus representing the fusion of the upper segments of the paired mullerian ducts. It can hardly be considered as a vagina, because of its topographical relation to the "prostatic" urethra, and because there was no uterus intervening between the vagina and the fallopian tube. In this case the left fallopian tube, in relation to the ovary, was in communication with the utriculus or homologue of the uterus. The right fallopian tube, although it had no lumen communicating with the uterine homologue, was the upper portion of the right mullerian duct. Added morphological evidence for considering this fused mullerian segment as it entered the urethra, homologous with the uterus or prostatic utricle, was the presence of corpora amalacea near the prostatic anlagen on the right side. It is hardly possible that all of the right mullerian duct had disappeared except at the tubal end, as had the left wolffian duct. The mullerian ducts do fuse for most of their length in normal development or in most pseudohermaphrodites with female organs. The wolffian ducts normally do not fuse but remain as separate bilateral structures. In this interpretation it is, therefore, assumed that both mullerian ducts persisted, as fused ducts distally, as paired ducts proximally, but only the right wolffian duct remained. There was no trace of the left wolffian duct. It is known that in the rat, the genital tract of the fetus may be greatly modified by administration of estrogens or androgens. This literature is too extensive to be discussed here, but has been competently reviewed by Greene (1942). More pertinent to the present case are the observations of Zuckerman (1940), subsequently confirmed by many others. In these experiments it was reported that the utriculus prostaticus of the immature male monkey could be selectively affected by injection of estrogen into the monkey. The normally columnar, secretory epithelium of the utriculus could be changed to a stratified squamous epithelium.
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In the female monkey of any age, the columnar epithelium lining the lumen and the glands of the uterine cervix can be changed completely by estrogen administration, into the stratified squamous epithelium characteristic of the portio vaginalis of the cervix. In no instance in the monkey has the epithelium of the body and fundus of the uterus been changed to a keratinized squamous epithelium. In estrogen treated male monkeys, the prostate gland is unaffected and the epithelium of the ductus deferens is unchanged. Only the epithelium of the prostatic utricle changes to a stratified squamous epithelium. The findings in the case here reported are quite analagous to the effects produced by estrogen injection in female monkeys. That duct which is interpreted as being the ductus deferens had the characteristic structure of the adult male ductus, deferens, though it was not as completely developed or differentiated. The epithelium of the duct which had been interpreted to be a utriculus prostaticus, did not have the undifferentiated columnar epithelium of the normal utriculus prostaticus, nor did it have the epithelium or musculature of any part of the uterus. The ovary of this individual had numerous growing follicles which were producing estrogen. There is no assurance that this estrogen had been produced in sufficient quantities, or over the required time, to produce squamous cell transformation of the utriculus prostaticus. The analogy of estrinized immature male monkeys is suggestive, however. The use of estrogen has been suggested by Zuckerman and by Burns to aid in classifying homologous structures in the genital tract. Burns (1941, 1942) has studied the homologies of the genital ducts and derivatives of the urogenit11l sinus in the opossum. He reports that "All epithelia in the urinogenital tract of the opposum which respond to estrogens by squamous metaplasia and cornification have a common origin from the urinogenital sinus." In the case reported here, the epithelium of the miillerian tract, which was the same type as is found in the normal mature vagina, extended the entire length of the duct up to its union with the fallopian tube. This appeared to be a stratified squamous cell conversion of an embryonic genital duct. It was difficult, however, to apply Burns' observation on the opossum to the present case, as this entire duct, from the urethra to the fallopian tube cannot be considered a derivative of the urinogenital sinus on the basis of present embryological information. Clinical resume. The findings in this case correlated closely with observed conditions. The hormones of both sexes were present, but only in amounts normal for a preadolescent of either sex, and the bone age was not advanced. This was a point of differentiation from adrenogenital pseudohermaphroditism, where the excess of androgens would have advanced the bone age. The child's urinary symptoms were partly related to the abnormal anatomy of the urethra. The delay in initiating the urinary stream was due to the fact that the urine filled the cul-de-sac before any began to flow from the meatuso The dribbling after urination was caused by the slow emptying of the utriculus into the posterior urethra, with a resultant urgency and leakage. The clinical management of this child has been started by the surgical removal
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J. K. LATTIMER, E. T. ENGLE AND R. C, YEAW
of the female structures, and by the injection of 6,000 units of chorionic gonadotropin, postoperatively, to sustain the transplanted testis. The testis has shown no sign of atrophy and is easily palpable in the right scrotal (labial) fold. The child subsequently received 75 mg. testosterone propionate intramuscularly each week to increase the size of the penis so that a satisfactory repair of the hypospadias can be done. A further report on the progress of this patient will await the completion of hormonal and surgical procedures, and an adequate follow-up period. SUMMARY
An additional case of true hermaphroditism is reported in an 11 year old negro child who showed hypospadias and no palpable testes. On the right side a rudimentary ductus deferens, epididymis and juvenile testis were found in the abdomen. Structures resembling prostatic corpora amylacea were found where the prostate should have been. On the left side a rudimentary fused mullerian duct, a patent fallopian tube and a prepubertal ovary were present. The miillerian system emptied into the posterior urethra. In addition, there was a small ovariotestis and a remnant of a fallopian tube on the right side. The ovary and the duct systems were operatively removed and an orchidopexy performed. After the period of gonadotropic and androgen hormone treatment, the hypospadias will be corrected. REFERENCES BURNS, RoBERT K., JR.: The origin and differentiation of the epithelium of the urinogenital sinus in the opossum with a study of the modifications induced by estrogens. Carnegie Inst. Washington Publ. 541, Contributions to Embryo!. No. 191, pp. 68-83, 1942. GREENE, R.R.: Hormonal factors in sex inversion: The effects of sex hormones on embryonic sexual structures of the rat. Biol. Symposia, 9: 105-124, 1942. SEVERINGHAUS, A. E.: Sex chromosomes in human intersex. Am. J. Anat., 70: 73-93, 1942. YOUNG, H. H.: Hermaphroditism, Genital Abnormalities and the Adrenal Genital syndrome. Baltimore: Williams & Wilkins Co., 1937. ZUCKERMAN, S.: The histogenesis of tissues sensitive to estrogens. Biol. Review, 15: 231271, 1940.