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Female Pseudohermaphroditism in a Neonate Born to a Mother with Polycystic Ovarian Disease
0022-534 7/86/1365-1098$02.00/0 Vol. 136, November
THE JOURNAL OF UROLOGY
Copyright© 1986 by The Williams & Wilkins Co.
Printed in U.S.A.
FEMALE PSEUDOHERMAPHRODITISM IN A NEONATE BORN TO A MOTHER WITH POLYCYSTIC OVARIAN DISEASE MARK BILOWUS, VAL ABBASSI
AND
M. DAVID GIBBONS
From the Departments of Pediatrics (Endocrinology) and Surgery (Pediatric Urology), Georgetown University Medical Center, Washington, D. C.
ABSTRACT
A newborn with female pseudohermaphroditism (profound masculinization of the external genitalia and preservation of the internal female genitalia) is presented. During pregnancy progressive hirsutism was noted in the mother, and polycystic ovaries were found at cesarean section. The serum testosterone level in the cord blood was elevated markedly (1,232 ng./dl.). After birth the serum testosterone levels of the mother and newborn decreased dramatically. Over-all it appears that the polycystic ovaries were the source of the excessive androgen secretion that caused maternal and fetal masculinization during the pregnancy. Female pseudohermaphroditism commonly is caused by congenital adrenal hyperplasia. Although virilization of the female fetus also can occur as the result of androgens arising endogenously within the mother, only 11 cases of fetal virilization attributable to maternal androgen-producing ovarian tumors had been reported by 19731 and only 2 cases of fetal virilization as a consequence of maternal adrenal disease, one owing to a maternal adrenal tumor and one caused by maternal congenital adrenal hyperplasia,3 have been described. We report a case that is unique not only because of the apparent source of maternal androgen but also because of the severe degree of masculinization of the female fetus, which included agenesis of the vagina. CASE REPORT
A. A. was delivered at term by cesarean section to a mother in whom ovulation had been induced by clomiphene citrate. The mother suffered progressive hirsutism and cystic acne during the pregnancy. She took no medication. At cesarean section the maternal gonads had the characteristic appearance of polycystic ovaries. At birth the neonate was noted to have ambiguous genitalia. The labioscrotal folµs were fused and rugated (fig. 1, A), the phallus was 20 mm. long, the meatus opened at the base of the shaft (fig. 1, B) and~· no gonads were palpable. The newborn was healthy except £ r the ambiguous genitalia. A genitogram demonstrated an elo gated urethra without a utricle (fig. 2) and pelvic ultrasound showed no evidence of a vaginal structure. A karyotype rev aled a normal 46; XX chromosomal pattern. Cord serum t~tosterone was elevated markedly at 1,232 ng./dl. (normal v lue for female newborn is 25.8 ± 7.1 ng./dl. 4 ). Cord serum 1 -a-hydroxyprogesterone and cortisol concentrations were noripal at 2,700 ng./dl. and 16.0 µg./dl., respectively. Urinary 17-tetosteroids (0.5 mg./24 hours), 17ketogenic steroids (0.3 mg./24 hours), and serum and urinary electrolytes were normal. \;i'he normal values for urinary steroids and cord serum 17-a\hydroxyprogesterone excluded the common varieties of congenital adrenal hyperplasia from further consideration. 5 When 'the newborn was 7 days old the serum testosterone level had decreased to 41 ng./dl. and the 17-a-hydroxyprogesterone value to 210 ng./dl., both normal values for age. Maternal serum testosterone 9 days post partum was 468 ng./dl. and it decreased to 82 ng./dl. by 15 days, although the free testosterone values remained markedly elevated during this period (see table). A trial of 6,000 units human chorionic gonadotropin administered parenterally to the mother for 3 Accepted for publication May 21, 1986.
days failed to cause an increase in serum testosterone, although the androstenedione level increased significantly from 384 to 680 µg.jdl. Dehydroepiandrosterone sulfate concentration also increased in response to human chorionic gonadotropin but it remained within the normal range. Prednisone administration for 2 months did not affect the hormonal values significantly except for depressing free testosterone slightly. However, the administration of 1 ± 50 norethindrone with mestranol caused a dramatic decrease in the maternal serum levels of testosterone to 10 ng./dl. (see table). The free testosterone similarly decreased to 1.6 pg./ml. as did dehydroepiandrosterone sulfate (27 µg./dl.). After endocrine and genetic evaluation the 7-week-old infant was hospitalized for cystourethroscopy, exploratory (pelvic) laparotomy and genitoplasty. Endoscopic findings revealed no true utricle, although there was a small elevation below the bladder neck at the 6 o'clock position, which resembled a verumontanum but catheterization was unsuccessful. The bladder and ureteral orifices were normal. Bimanual examination disclosed a midline uterus that was confirmed at laparotomy. The uterus, tubes and normal-appearing bilateral ovaries also were noted with no evidence of ovotestes or vasal structures. Following laparotomy a clitoral reduction (corporeal resection, preserving glans and neurovascular structures) and labioplasty (creating labia minora from dorsal clitoral hood) were performed. DISCUSSION
It is well known that there is considerable variability in the fetal response to endogenous fetal or maternal androgens. The time of exposure to this hormone in relation to fetal age appears to determine the degree of virilization that occurs in the fetus regardless of the genetic sex. According to Grumbach and Ducharme, fetal virilization occurs during 8 and 13 weeks of gestation, and results in labioscrotal fusion and urogenital sinus formation. 6 Beyond week 13 clitoromegaly and rugation of the labia majora are seen. Experiments with pregnant animals, such as guinea pigs, rats and mice, have shown that androgens given at a specific time during pregnancy produce predictable sexual development of the female embryo.7 It is generally agreed that testosterone causes preservation of the wolffian duct derivatives in the genetic male subject without inhibition of the miillerian duct derivatives, completely inhibits feminine development of the urogenital sinus, and through its conversion to 5-a-dihydrotestosterone stimulates the typical masculinized development of the urogenital sinus and external genitalia. The lower twothirds of the vagina, which is formed from the urogenital sinus,
1098
FEMALE PSEUDOHERlvIAPHRODITISM IN NEONATE
FIG. 1.
A, external genitalia. B, external genitalia showing scrotal hypospadias
Postpartum maternal hormone values before and after therapeutic interventions Total Testosterone (µg./dl.) 9 Days post partum 15 Days post partum Before human chorionic gonadotropin After human chorionic gonadotropin After 2 mos. prednisone After 1 + 50 norethidrone with mestranol Normal range
1099
Free AndrosTestostenedione terone (ng./dl.) (pg./ml.)
Dehydroepiandrosterone (ng./dl.)
Dehydroepiandrosterone Sulfate (µg./dl.)
389
162.0
780
212.0
Not determined
274.0
468.5 82.0
14.8
98
18.6
Not determined 384
87
20.0
680
60
7.2
226
440
217.0
10
1.6
Not determined
Not determined
27.0
28-80
1.4-11.8
70-:310
150-700
9:3-327
then would not develop under these circumstances. However, mu.llerian duct regression would occur only if a mu.llerian inhibitor was secreted by the Bertoli cells of the fetal testes. 8 · 9 It would appear in our case that the fetal exposure to maternal androgens occurred early in the course of the pregnancy, since the newborn was virilized severely and the entire vagina, including the upper (mu.llerian origin) and lower (urogenital sinus origin) portions, was completely absent. However, the uterus and fallopian tubes developed normally, which indicates that functioning testicular tissue was not likely to have been the cause of the masculinization. The production of testosterone by the mother was tested with human chorionic gonadotropin manipulation during the early puerperal state. Testosterone levels did not increase, although androstenedione, the immediate precursor of testosterone, did increase markedly. Maternal androgens are converted to estrogenic compounds within the placenta-a mechanism thought to protect the female fetus from the masculinizing effect of androgens. When the capacity of the placenta to aromatize these androgens is exceeded, for example as in the
case of an androgen secreting maternal tumor, the androgen may cross the placenta and induce masculinization of the female fetus. It is well known that the ability of the placenta to protect the fetus from this maternal androgenic environment is enhanced with gestational age as the activity of the aromatase enzyme increases. 10 Therefore, in early pregnancy the protective capability of the placenta could be exceeded if the levels of androgens were elevated sufficiently, and these compounds would then cross the placenta and masculinize the developing androgen sensitive primordial genital structures. Since the mother had no tumor, and the testosterone levels in the mother and newborn decreased precipitously post partum, it is reasonable to assume that excessive testosterone production was of maternal origin and was related to the pregnancy. The only abnormality that was noted during cesarean section was the presence of polycystic ovaries. The production of testosterone declined gradually postpartum. Prednisone and estrogen suppression therapy was undertaken to evaluate further the source of the androgen excess. Two months of prednisone therapy had no effect on maternal androgen values. Norethindrone with mestranol did suppress the androgen levels (dehydroepiandrosterone sulfate and testosterone), presumably by its action on gonadotropin suppression and induction of sexhormone binding globulin. This case is unusual in that the cause of the pseudohermaphroditism appeared to be related to the excessive androgen production commonly associated with polycystic ovarian disease. These findings raise an important question for this couple of whether other female fetuses will risk virilization if the mother becomes pregnant again. REFERENCES
1. Novak, D. J., Lauchlan, S. C., McCawley, J. C. and Faiman, C.:
Virilization during pregnancy. Case report and review of literature. Amer. J. Med., 49: 281, 1970. 2. Murset, G., Zachmann, M., Prader, A., Fischer, J. and Labhart, A.: Male external genitalia of a girl caused by virilizing adrenal tumour in the mother. Case report and steroid studies. Acta Endocr., 65: 627, 1970. 3. Kai, H., Nose, 0., Iida, Y., Ono, J., Harada, T. and Yabuuchi, H.: Female pseudohermaphroditism caused by maternal congenital adrenal hyperplasia. J. Ped., 95: 418, 1979. 4. Penny, R., Parlow, A. F. and Frasier, S. D.: Testosterone and estradiol concentrations in paired maternal and cord sera and
1100
BILOWUS, ABBASSI AND GIBBONS
5. 6.
7.
8.
9.
10. FIG. 2. Genitogram shows bladder, urethral tract and no evidence of vagina
their correlation with the concentration of chorionic gonadotropin. Pediatrics, 64: 604, 1979. Ziirbriigg, R. P.: Diseases and tumours associated with virilization: pediatric aspects. Prog. Ped. Surg., 16: 77, 1983. Grumbach, M. M. and Ducharme, J. R.: The effects of androgens on fetal sexual development: androgen-induced female pseudohermaphroditism. Fertil. Steril., 11: 157, 1960. Greene, R. R., Burrill, M. W. and Ivy, A. C.: Experimental intersexuality: effects of estrogens on antenatal sexual development of the rat. Amer. J. Anat., 67: 305, 1940. Jasso, N.: Permeability of membranes to the miillerian-inhibiting substance synthesized by the human fetal testis in vitro: a clue to its biochemical nature. J. Clin. Endocr. Metab., 34: 265, 1972. Jasso, N.: Activite inhibitrice du testicule de foetus de veau sur le canal de Muller de foetus de rat, en culture organotypique: role des tubes seminiferes. C.R. Acad. Sci., 274: 3573, 1973. Smith, S. W. and Axelrod, L. R.: Studies on the metabolism of steroid hormones and their precursors by the human placenta at various stages of gestation. II. In vitro metabolism of 3 betahydroxyandrost-5-en-17-one. J. Clin. Endocr., 29: 1182, 1969.
THE JOURNAL OF UROLOGY
Copyright© 1986 by The Williams & Wilkins Co.
Printed in U.S.A.
FEMALE PSEUDOHERMAPHRODITISM IN A NEONATE BORN TO A MOTHER WITH POLYCYSTIC OVARIAN DISEASE MARK BILOWUS, VAL ABBASSI
AND
M. DAVID GIBBONS
From the Departments of Pediatrics (Endocrinology) and Surgery (Pediatric Urology), Georgetown University Medical Center, Washington, D. C.
ABSTRACT
A newborn with female pseudohermaphroditism (profound masculinization of the external genitalia and preservation of the internal female genitalia) is presented. During pregnancy progressive hirsutism was noted in the mother, and polycystic ovaries were found at cesarean section. The serum testosterone level in the cord blood was elevated markedly (1,232 ng./dl.). After birth the serum testosterone levels of the mother and newborn decreased dramatically. Over-all it appears that the polycystic ovaries were the source of the excessive androgen secretion that caused maternal and fetal masculinization during the pregnancy. Female pseudohermaphroditism commonly is caused by congenital adrenal hyperplasia. Although virilization of the female fetus also can occur as the result of androgens arising endogenously within the mother, only 11 cases of fetal virilization attributable to maternal androgen-producing ovarian tumors had been reported by 19731 and only 2 cases of fetal virilization as a consequence of maternal adrenal disease, one owing to a maternal adrenal tumor and one caused by maternal congenital adrenal hyperplasia,3 have been described. We report a case that is unique not only because of the apparent source of maternal androgen but also because of the severe degree of masculinization of the female fetus, which included agenesis of the vagina. CASE REPORT
A. A. was delivered at term by cesarean section to a mother in whom ovulation had been induced by clomiphene citrate. The mother suffered progressive hirsutism and cystic acne during the pregnancy. She took no medication. At cesarean section the maternal gonads had the characteristic appearance of polycystic ovaries. At birth the neonate was noted to have ambiguous genitalia. The labioscrotal folµs were fused and rugated (fig. 1, A), the phallus was 20 mm. long, the meatus opened at the base of the shaft (fig. 1, B) and~· no gonads were palpable. The newborn was healthy except £ r the ambiguous genitalia. A genitogram demonstrated an elo gated urethra without a utricle (fig. 2) and pelvic ultrasound showed no evidence of a vaginal structure. A karyotype rev aled a normal 46; XX chromosomal pattern. Cord serum t~tosterone was elevated markedly at 1,232 ng./dl. (normal v lue for female newborn is 25.8 ± 7.1 ng./dl. 4 ). Cord serum 1 -a-hydroxyprogesterone and cortisol concentrations were noripal at 2,700 ng./dl. and 16.0 µg./dl., respectively. Urinary 17-tetosteroids (0.5 mg./24 hours), 17ketogenic steroids (0.3 mg./24 hours), and serum and urinary electrolytes were normal. \;i'he normal values for urinary steroids and cord serum 17-a\hydroxyprogesterone excluded the common varieties of congenital adrenal hyperplasia from further consideration. 5 When 'the newborn was 7 days old the serum testosterone level had decreased to 41 ng./dl. and the 17-a-hydroxyprogesterone value to 210 ng./dl., both normal values for age. Maternal serum testosterone 9 days post partum was 468 ng./dl. and it decreased to 82 ng./dl. by 15 days, although the free testosterone values remained markedly elevated during this period (see table). A trial of 6,000 units human chorionic gonadotropin administered parenterally to the mother for 3 Accepted for publication May 21, 1986.
days failed to cause an increase in serum testosterone, although the androstenedione level increased significantly from 384 to 680 µg.jdl. Dehydroepiandrosterone sulfate concentration also increased in response to human chorionic gonadotropin but it remained within the normal range. Prednisone administration for 2 months did not affect the hormonal values significantly except for depressing free testosterone slightly. However, the administration of 1 ± 50 norethindrone with mestranol caused a dramatic decrease in the maternal serum levels of testosterone to 10 ng./dl. (see table). The free testosterone similarly decreased to 1.6 pg./ml. as did dehydroepiandrosterone sulfate (27 µg./dl.). After endocrine and genetic evaluation the 7-week-old infant was hospitalized for cystourethroscopy, exploratory (pelvic) laparotomy and genitoplasty. Endoscopic findings revealed no true utricle, although there was a small elevation below the bladder neck at the 6 o'clock position, which resembled a verumontanum but catheterization was unsuccessful. The bladder and ureteral orifices were normal. Bimanual examination disclosed a midline uterus that was confirmed at laparotomy. The uterus, tubes and normal-appearing bilateral ovaries also were noted with no evidence of ovotestes or vasal structures. Following laparotomy a clitoral reduction (corporeal resection, preserving glans and neurovascular structures) and labioplasty (creating labia minora from dorsal clitoral hood) were performed. DISCUSSION
It is well known that there is considerable variability in the fetal response to endogenous fetal or maternal androgens. The time of exposure to this hormone in relation to fetal age appears to determine the degree of virilization that occurs in the fetus regardless of the genetic sex. According to Grumbach and Ducharme, fetal virilization occurs during 8 and 13 weeks of gestation, and results in labioscrotal fusion and urogenital sinus formation. 6 Beyond week 13 clitoromegaly and rugation of the labia majora are seen. Experiments with pregnant animals, such as guinea pigs, rats and mice, have shown that androgens given at a specific time during pregnancy produce predictable sexual development of the female embryo.7 It is generally agreed that testosterone causes preservation of the wolffian duct derivatives in the genetic male subject without inhibition of the miillerian duct derivatives, completely inhibits feminine development of the urogenital sinus, and through its conversion to 5-a-dihydrotestosterone stimulates the typical masculinized development of the urogenital sinus and external genitalia. The lower twothirds of the vagina, which is formed from the urogenital sinus,
1098
FEMALE PSEUDOHERlvIAPHRODITISM IN NEONATE
FIG. 1.
A, external genitalia. B, external genitalia showing scrotal hypospadias
Postpartum maternal hormone values before and after therapeutic interventions Total Testosterone (µg./dl.) 9 Days post partum 15 Days post partum Before human chorionic gonadotropin After human chorionic gonadotropin After 2 mos. prednisone After 1 + 50 norethidrone with mestranol Normal range
1099
Free AndrosTestostenedione terone (ng./dl.) (pg./ml.)
Dehydroepiandrosterone (ng./dl.)
Dehydroepiandrosterone Sulfate (µg./dl.)
389
162.0
780
212.0
Not determined
274.0
468.5 82.0
14.8
98
18.6
Not determined 384
87
20.0
680
60
7.2
226
440
217.0
10
1.6
Not determined
Not determined
27.0
28-80
1.4-11.8
70-:310
150-700
9:3-327
then would not develop under these circumstances. However, mu.llerian duct regression would occur only if a mu.llerian inhibitor was secreted by the Bertoli cells of the fetal testes. 8 · 9 It would appear in our case that the fetal exposure to maternal androgens occurred early in the course of the pregnancy, since the newborn was virilized severely and the entire vagina, including the upper (mu.llerian origin) and lower (urogenital sinus origin) portions, was completely absent. However, the uterus and fallopian tubes developed normally, which indicates that functioning testicular tissue was not likely to have been the cause of the masculinization. The production of testosterone by the mother was tested with human chorionic gonadotropin manipulation during the early puerperal state. Testosterone levels did not increase, although androstenedione, the immediate precursor of testosterone, did increase markedly. Maternal androgens are converted to estrogenic compounds within the placenta-a mechanism thought to protect the female fetus from the masculinizing effect of androgens. When the capacity of the placenta to aromatize these androgens is exceeded, for example as in the
case of an androgen secreting maternal tumor, the androgen may cross the placenta and induce masculinization of the female fetus. It is well known that the ability of the placenta to protect the fetus from this maternal androgenic environment is enhanced with gestational age as the activity of the aromatase enzyme increases. 10 Therefore, in early pregnancy the protective capability of the placenta could be exceeded if the levels of androgens were elevated sufficiently, and these compounds would then cross the placenta and masculinize the developing androgen sensitive primordial genital structures. Since the mother had no tumor, and the testosterone levels in the mother and newborn decreased precipitously post partum, it is reasonable to assume that excessive testosterone production was of maternal origin and was related to the pregnancy. The only abnormality that was noted during cesarean section was the presence of polycystic ovaries. The production of testosterone declined gradually postpartum. Prednisone and estrogen suppression therapy was undertaken to evaluate further the source of the androgen excess. Two months of prednisone therapy had no effect on maternal androgen values. Norethindrone with mestranol did suppress the androgen levels (dehydroepiandrosterone sulfate and testosterone), presumably by its action on gonadotropin suppression and induction of sexhormone binding globulin. This case is unusual in that the cause of the pseudohermaphroditism appeared to be related to the excessive androgen production commonly associated with polycystic ovarian disease. These findings raise an important question for this couple of whether other female fetuses will risk virilization if the mother becomes pregnant again. REFERENCES
1. Novak, D. J., Lauchlan, S. C., McCawley, J. C. and Faiman, C.:
Virilization during pregnancy. Case report and review of literature. Amer. J. Med., 49: 281, 1970. 2. Murset, G., Zachmann, M., Prader, A., Fischer, J. and Labhart, A.: Male external genitalia of a girl caused by virilizing adrenal tumour in the mother. Case report and steroid studies. Acta Endocr., 65: 627, 1970. 3. Kai, H., Nose, 0., Iida, Y., Ono, J., Harada, T. and Yabuuchi, H.: Female pseudohermaphroditism caused by maternal congenital adrenal hyperplasia. J. Ped., 95: 418, 1979. 4. Penny, R., Parlow, A. F. and Frasier, S. D.: Testosterone and estradiol concentrations in paired maternal and cord sera and
1100
BILOWUS, ABBASSI AND GIBBONS
5. 6.
7.
8.
9.
10. FIG. 2. Genitogram shows bladder, urethral tract and no evidence of vagina
their correlation with the concentration of chorionic gonadotropin. Pediatrics, 64: 604, 1979. Ziirbriigg, R. P.: Diseases and tumours associated with virilization: pediatric aspects. Prog. Ped. Surg., 16: 77, 1983. Grumbach, M. M. and Ducharme, J. R.: The effects of androgens on fetal sexual development: androgen-induced female pseudohermaphroditism. Fertil. Steril., 11: 157, 1960. Greene, R. R., Burrill, M. W. and Ivy, A. C.: Experimental intersexuality: effects of estrogens on antenatal sexual development of the rat. Amer. J. Anat., 67: 305, 1940. Jasso, N.: Permeability of membranes to the miillerian-inhibiting substance synthesized by the human fetal testis in vitro: a clue to its biochemical nature. J. Clin. Endocr. Metab., 34: 265, 1972. Jasso, N.: Activite inhibitrice du testicule de foetus de veau sur le canal de Muller de foetus de rat, en culture organotypique: role des tubes seminiferes. C.R. Acad. Sci., 274: 3573, 1973. Smith, S. W. and Axelrod, L. R.: Studies on the metabolism of steroid hormones and their precursors by the human placenta at various stages of gestation. II. In vitro metabolism of 3 betahydroxyandrost-5-en-17-one. J. Clin. Endocr., 29: 1182, 1969.