Adrenogenital Syndrome Producing Female Pseudohermaphroditism with a Phallic Urethra

Vol. 103, Apr. Printed in U.S.A.

THE JOURNAL OF UROLOGY

Copyright© 1970 by The Williams & Wilkins Co.

ADRENOGENITAL SYNDROME PRODUCING :FEMALE PSEUDOHERMAPHRODITISM WITH A PHALLIC URETHRA JAY Y. GILLENWATER,* ARTHUR W. WYKER, McLEMORE BIRDSONG _rnD W. NORMAN THORNTON From the Departments of Urology, Pediatrics and Obstetrics, The University of Virginia Medical Center, Charlottesville, Virginia

Female pseudohermaphroditism is seen in patients whose gonads are ovaries and who have varying degrees of masculinization. The most common cause of this disorder is the adrenogenital syndrome due to adrenal cortical hyperplasia secondary to a heritable inborn error of metabolism. The incidence suggests that an autosomal recessive genetic factor is responsible. The basic defect is a congenital partial or complete absence of one or several adrenal enzymes necessary for cortisol production with the accumulation of androgenic steroidal precursors. The adrenal hyperplasia is secondary to increased adrenocorticotropic hormone (ACTH) production by the pituitary because of deficient cortisol production disrupting the adrenal-hypothalmic pituitary feedback mechanisms. The virilization is due to over-production of adrenal androgens. Thirty per cent of the cases have a sufficient decrease in cortisol and aldosterone to be threatened by an addisonism. 1 Masculinization of the female to such an extent that there is a well-developed penis with a urethral opening at the tip of the penis is rare. Such a case is herein reported and the literature is reviewed. REVIEW OF LITERATURE

We found 16 documented cases of complete phallic urethra (type 5-Prader) 2 in patients with female pseudohermaphroditism secondary to the adrenogenital syndrome. 3 - 6 In 9 cases the diagAccepted for publication March 4, 1969. * Requests for reprints: Department of Urology, The University of Virginia Medical Center, Charlottesville, Virginia 22901. 1 Bongiovanni, A. M. and Root, A. W.: The adrenogenital syndrome. New Engl. J. Med., 268: 1283, 1342 and 1391, 1963. 2 Prader, A.: Vollkommen mannliche aubere Genitalentwicklung und Salzverlustsyndrom bei Madchen mit kongenitalem andrenogenitalem Syndrom. Helvet. Paediat. Acta, 13: 5, 1958. 3 Reilly, W. A., Hinman, F., Jr., Pickering, D. E. and Crane, J. T.: Phallic urethra in female pseudohermaphroditism. Amer. J. Dis. Child., 95: 9, 1958. 4

Peris, L. A.: Congenital adrenal hyperplasia

nosis was made at autopsy; these infants died of adrenal insufficiency with severe dehydration caused by vomiting and diarrhea. Diagnosis in the remaining cases was made in patients ranging in age from infancy to adulthood with presenting complaints of cryptorchism and hematuria. Reilly found 8 cases of complete phallic urethra in non-adrenogenital syndrome patients and described an additional case. 3 He thought that this group of patients represents a developmental anomaly from some unknown stimulus. There have been 3 cases of complete phallic urethra in female pseudohermaphroditism in patients secondary to exogenous androgen administration to mothers during pregnancy .7 Two cases cf phallic urethras have been reported in female pseudohermaphrodites whose mothers had arrhenobJastoma during pregnancy. CASE REPORT

S.2\/I., UVH No. 35 75 49, was admitted to the hospital in 1953 at the age of 4 years because of marked masculinization with facial, pubic and axillary hair (fig. 1). The patient had a large penis ·with a normal urethral opening and the urinary ketosteroids ranged between 56 and 76 mg. per 24 hours and suppressed to 4 mg. per 24 hours on cortisone. Blood pressure was 150/90 mm. Hg. An excretory urogram (IVP) and skull x-ray were normal. A skin biopsy was interpreted as chromatin negative with no Barr bodies and was compatible with a male pattern. The diagnosis was adrenogenital syndrome and cortisone was given. The patient was followed producing female hermaphroditism with phallic urethra. Obstet. Gynec., 16: 156, 1960. 5 Rook, G. D., Green, M. and Sard, J. T.: Adrenogenital syndrome with phallic urethra. Amer. J. Dis. Child., 101: 645, 1961. 6 Madsen, P. 0.: Familial female pseudohermaphroditism with hypertension and penile urethra. J. Urol., 90: 466, 1963. 7 Goldman, A. S. and Bongiovanni, A. M.: Induced genital anomalies. Ann. N. Y. Acad. Sci., 142: 755, 1967. 500

I<'EMALE PSEUDOHERi\IAPHHODITISi\I

Frn. I. Patient, 4 years old, mascnlinization and increased growth can be seen.

verumontanum. The patient was operated 011 for cryptorchism througl1 a left Gibson incision and the retroperitoneal area from the bladder to the kidney was explored without locating a vas deferens or testes. The incision was enlarged, the peritoneal cavity was opened and enlarged adrenals were found but no testes could be located. The patient continued to have intermittent hematuria. In August 1959, he was reevaluated. Cystoendoscopy revealed a complete penile urethra and a blood-filled vagina opening into the posterior urethra. This finding was confirmed by methrograms. With bimanual pelvic examination a uterus and gonads were palpated. Buccal mucosa! smears and review of the patient's old ~kin biopsy revealed a chromatin positive pattern. The patient was evaluated by the psychiatrists and was found to have a definite male gender role. Abdominal exploration revealed a uterus and 2 normal ovaries. Hysterectomy and bilateral oophorectomy were performed (fig. 3). The patient has continued on cortisone and has had some problems of recurrent backache and emotional adjustment. KORMAL SEXUAL DEVELOPME:s/T

The undifferentiated gonad appears in the fetus as a genital ridge medial to the mesonephros and may develop into an ovary or a testis. The germ cells migrate from the wall of the primitive gut to the gonad in the 8 mm. embryo. The genetic sex is believed to determine gonadal sex by inhibiting one part of the gonad. The cortex of the gonad with the germ cells it encloses develops into the ovary and the medulla into a testis. This differentiation is first evident at about the 15 mm, (7th \\'eek) in the embryo, FIG. 2. Patient, 7 years old, prominent breast development, large phal! us and recent surgical incision are seen.

closely in our outpatient department as well as his pediatrician. The patient was re-admitted to the hospital in l\Iarch 1956 at the age of 7 because of intermittent hematuria. examination showed adult male hair distribution, some enlargement of the breasts, bilateral undescended testes and adult-sized phallus with the urethral opening at the end of the glans penis (fig. 2). An IVP was normal and the bone age was 14 years. Cystoendoscopy was interpreted a~ showing normal bladder and congestion of the prostatic urethra and

Frn. 3. Uterus, ovaries and well-developed penis with normal-appearing urethra.

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The further differentiation of the internal genitalia is delayed until the 25 to 30 mm. (8 to 9 weeks) stage. According to the work of Jost, this differentiation is dependent upon whether a normally functioning testis is present. 8 In a series of experiments on rabbits Jost found that if the gonad was removed (either testis or ovary) prior to this stage of differentiation of the internal genitalia, the wolffian duct system was inhibited and the internal and external genitalia developed toward female organogenesis. If the testis was removed from one side then onlythat side developed along female lines. If a testis was transplanted to one side that side developed along male lines. He found that no synthetic androgen could cause these local changes of the fetal internal genitalia thus postulating that the fetal testes have some other masculinizing hormone which causes local effects of stimulating the wolffian duct and inhibiting the miillerian duct in the fetus. The external genitalia remain in an undifferentiated state until 12 fetal weeks. The genitalia tubercle is apparent at 6 weeks and by 8 weeks the urethral folds, urethral groove and genital swellings are apparent in both sexes. Between 12 and 16 weeks in the male fetus there is development of the penis, progressive fusion of the urethral folds, the urogenital sinus extends to the tip of the penis and the genital swellings become located toward the anus. In the female fetus during the same period the urethral groove remains open and the genital swellings elongate and flank the base of the phallus. The urethra becomes clearly female by 16 weeks and by 20 weeks the canalization of the female genital tract is complete. EFFECT OF ANDROGEN ON FETAL SEXUAL DEVELOPMENT

The age of the fetus is a critical factor in the response of the sex primordia to androgens since the capacity to stimulate the external genitalia, urogenital sinus and development of the wolffian duct is limited to a specific period of life. For the development of a complete phallic urethra in the female fetus the androgenic stimulus must be given before 11 weeks. 9 This concept is supported 8 Jost, A.: Embryonic sexual differentiation. In: Hermaphroditism, Genital Anomalies and Related Endocrine Disorders. Edited by H. W. Jones, Jr. and W. W. Scott. Baltimore: The Williams & Wilkins Co., 1958. 9 Grumbach, M. M. and Ducharme, J. R.: The effects of androgens on fetal sexual development: androgen-induced female pseudohermaphroditism. Fertil. Steril., 11: 157, 1960.

by experimental work and by observations in humans. Androgens have been found to be readily transmitted across the placental barrier in humans. They can modify development in the female fetus of the external genitalia, urogenital sinus and, rarely, the wolffian duct. Overzier states that the differentiation of the genital ducts is almost complete at the time the fetal adrenal cortex begins to produce androgens but seminal vesicles and prostatic glands have been found in patients with marked virilism. 10 It is of interest that 4 cases of masculinization of the female infant after the mother had received stilbestrol during pregnancy have been reported.11 It was postulated that perhaps this effect was due to adrenal hyperplasia consequent to the administration of estrogens. Conversely feminization of the male fetus leading to a severe hypospadias has been reported after maternal administration of estrogens and progesterones. 8 Prader has divided the different degrees of masculinization of urogenital sinus into 5 types dependent upon when the androgen is administered (fig. 4): Type 1-androgen administration after 20 weeks of fetal life. The vulva has been formed and only clitoral hypertrophy results. Type 2-androgen administration after 19 weeks of fetal life. The vulva gapes but is funnel-shaped and the clitoris is enlarged. The vagina and urethra open separately. Type 3effect of androgens at about 14 to 15 weeks of fetal life. The vagina and urethra open into a common urogenital sinus. The clitoris is larger and penis-like. Type 4-effect of androgens at about 12 to 13 weeks of fetal life. The perineum is thrust forward, the narrow urogenital sinus is formed and the labia form a bifid scrotum. The urogenital sinus opens at the base of the penis corresponding to a hypospadiac penis. Type 5effect of androgens at about 11 weeks of fetal life. The external genitalia have a male appearance except for the absence of testes in the scrotum.2 DIAGNOSIS AND MANAGEMENT

The diagnosis of a female pseudohermaphrodite encompasses the differential diagnosis of intersex 10 Overzier, C.: Induzierter Pseudohermaphroditism. In: Die Intersexualitiit. Edited by C. Overzier, Stuttgart: Georg Thieme Verlag, pp.

394-408, 1961.

11 Bongiovanni, A. M., DiGeorge, A. M. and Grumbach, M. M.: Masculinization of the female infant associated with estrogenic therapy alone during gestation: four cases. J. Clin. Endocr.,

19: 1004, 1959.

FE:\IALE PSEUDOHEHMAPHRODITIS:\I

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20 WEEKS

URETERAL BUD WOLFFIAN DUCT

19 WEEKS

TESTINE

CLOACA

8th WEEK

UROGENITAL SINUS

11 WEEKS

MULLERIAN DUCT

Fm. 4. Effects of androgenic hormones on development of miillerian and wolffian ducts. Adapted from original description by Prader.'

problen1s. It is important to recognize the adrenogenital syndrome not only to assign the correct sex but also to prevent death from adrenal insufficiency. The clinician must be alert to any abnormality of the urogenital system suggesting a possible intersex problem. In the usual case of adrenogenital syndrome the female infant will have ambiguous genitalia at birth and the male infant will usually exhibit macrogenitosomia praecox within the first 3 or 4 years of life. The adrenogenital syndrome is difficult to recognize in the male infant because of the difficulty in determining excessive development of the penis. The diagnosis can be made when the male shows increased growth, rapid sexnal development or signs of pseudohermaphroditism. In either sex the recognition of the salt-losing defect could lead to the diagnosis. The rare defect of the enzymes, 3-beta-hydroxysteroid dehydrogenase or 20-hydroxylase, will transform the external genitalia of the male into an equally

ambiguous state. Male subjects with variabie degrees of hypospadias or frank feminization of the external genitalia may be the result of deficiency of this enzyme. The bilateral cryptorchid child with ambiguous genitalia or precocious development should certainly be suspected of having an intersex problem. Thus in almost any intersex problem the adrenogenital should be ruled out. vVhen an intersex problem is i1 is desirable to define the 5 morphologic criteria of sex: 1) sex chromatin 2) structure, 3) internal genitalia, 4) external genitalia and 5) hormonal status. The sex chromatin pattern should be determined by the buccal or blood smear. If the sex chromatin is positive the female sex role can usuaJ!y be safely assigned. In the female pseudohermaphrodite the chromatin pattern will be positive. The external genitalia, urogenital sinus and sometimes the internal genitalia can be defined by

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endoscopy and urethrograms. The 24-hour urinary excretion of 17-ketosteroids, pregnanediol, 11-ketopregnanediol and 17-ketogenic steroids (these are elevated because they include pregnanediol and 11-ketopregnanediol) will be above normal in congenital adrenal hyperplasia. Occasionally the 17 -ketosteroids are normally elevated during the first week of life and it will be necessary to repeat them when the child is 2 or 3 weeks old. The gonad and sometimes the internal genitalia can only be differentiated by surgical exploration. As illustrated by our case, the correct diagnosis and proper assig11ment of sex can be made by correct interpretation of the nuclear sex and through surgical exploration. In the classic case of congenital adrenal hyperplasia with increased 17-ketosteroids, female sex chromatin and internal female structures, surgical exploration is not necessary. However to diagnose true hermaphroditism it is always necessary to biopsy the gonads. Unless the problem is clearly delineated, surgical exploration should be performed but preferably delayed until the child is 2 to 3 months old. Management of patients with intersex problems must be individualized. Patients with adrenogenital syndrome should receive the physiologic requirements of cortisone and possibly a mineralo-corticoid to suppress the increased ACTH and the resultant adrenal hyperplasia, The female pseudohermaphrodite resulting from the adrenogenital syndrome is not only influenced by androgens but also by the lack of estrogens due to pituitary inhibition of gonadotropins. If the bone age is more than 12 years, as soon as cortisone is started there is breast development and menstruation as was seen in our patient

(fig. 2). Prader found that the adrenogenital syndrome with phallic urethra was usually present in infants with the most severe salt-losing defects. 3 This certainly was not true in our case nor in the cases of Peris4 and Madsen. 6 Surgical aspects of treatment are concerned with restoration of external genitalia and removing conflicting internal genitalia. This problem is seen principally in the female with masculinization of external genitalia and normal internal genitalia. It is important to recognize the true sex as soon as possible and to restore the genitalia to normal conditions. This procedure is probably best deferred until the patient is several month, old. The deferral simplifies the surgical procedure and enables control of the adrenogenital syndrome by cortisone. In some patients medical therapy may cause the enlarged clitoris to become relatively decreased in size, eliminating the need for an operation. In special circumstances, such as those in our case in which the patient ha5 been incorrectly reared as a boy, it is best to continue the assigned sex.12 SUMMARY

The seventeenth case of a complete phallic urethra with female pseudohermaphroditism secondary to the adrenogenital syndrome is reported. The normal fetal sexual development and the effects of androgen on sexual development are reviewed. Patient referral and followup care were by Dr. 0. Watts Booth, Newport News, Virginia. 12 Money, J., Hampson, J. G. and Hampson, J. L.: Hermaphroditism: recommendations concerning assignment of sex, change of sex and psychologic management. Bull. Johns Hopkins Hosp., 97: 284, 1955.