P&S Medical Review: August 1996, Vol.3, No.2
True Hermaphroditism: Considerations in the Management of Patients Presenting in Early and Adult Life

Abstract

A twenty-seven year old man with penoscrotal hypospadias and unilateral undescended gonad was diagnosed with lateral true hermaphroditism during an evaluation for infertility. Phenotype male true hermaphrodites seldom present in adult life, and rarely for infertility. This case illustrates how diagnosis and treatment may be delayed until a significant personal event, such as infertility, prompts medical evaluation.

Introduction

True hermaphroditism is a rare disorder of intersexuality, which if not diagnosed in neonatal life, usually manifests during adolescence.1 True hermaphroditism refers to the presence of both testicular and ovarian tissue in the same individual. The external genitalia in these individuals may range from normal male to normal female, however, most phenotypic males have hypospadias. Ambiguous genitalia or severe hypospadias in a patient without two palpable gonads should be evaluated further for the presence of an intersex state.2

In infancy, genetic counseling and determination of the dominant phenotype are crucial to gender assignment and rearing. Late diagnosis, however, poses additional dilemmas for the patient in that the malignant potential of undescended or dysmorphic gonads is greater and issues of fertility may become significant. We report the second case of true hermaphroditism presenting as infertility in a phenotype male patient. A discussion of early and late diagnosis, potential for fertility, and risk of malignancy in patients with true hermaphroditism is offered.

Case Report

A twenty seven year old Mexican man was referred to Harlem Hospital Center clinic for the evaluation of infertility and intermittent right groin pain. No obvious cause of infertility was found in his wife. The patient's past history was significant for intermittent right inguinal swelling and right lower abdominal pain occurring monthly since the age of 17. The couple reported normal sexual intercourse. The patient was raised with a normal male gender identity and had no significant family history. He denied dysuria, urolithiasis, flank pain, hematuria, or urinary tract infections.

Physical examination revealed a normally developed phenotype male with short stature (153 cm). Hair pattern was generally male with sparse hair between the breasts and a normal male hair escutcheon. He did not have gynecomastia or breast tenderness. As illustrated in figure 1, the penis was foreshortened (6 cm) and he had penoscrotal hypospadias with ventral curvature, and mild transposition of the scrotum. The left testis was of normal size (3.5 cm x 2.5 cm) and consistency, and the vas deferens was palpable. The right hemiscrotum was empty and poorly developed. A right sided gonad was not palpable. The prostate was estimated to be 10 15 grams and was normal to palpation. A right inguinal hernia was noted.

Laboratory studies including urinalysis, blood chemistry, and complete blood count were normal. Evaluation of serum hormone assays revealed the following: testosterone 613 ng/dl (normal, 300 990 ng/dl); estradiol 70 ng/dl (normal 0 50 ng/dl); follicle stimulating hormone (FSH) 3.4 MlU/ml, (normal, 425 MlU/ml) and leutinizing hormone (LH) 4.2 MlU/ml (normal, 6 23 MlU/ml). Cytogenetic analyses, including fluorescein in situ hybridization and examination of phytohemoagglutinin stimulated peripheral blood, showed a 46 XX/46 XY mosaic chromosomal pattern (fig. 2). Semen analysis revealed a volume of 0.4 ml, low fructose, 1% normal forms, 0% motility, and oligo azospermia.

Intravenous urogram revealed a filling defect in the proximal right ureter which appeared to be intrinsic to the ureter (fig. 3). There was no evidence of obstruction. An abdominal computerized tomography (CT) scan showed the right gonad to be in the inguinal canal. The above mentioned ureteral defect was not seen on CT scan, however, the kidneys appeared normal.

Cystoscopic examination revealed a normal appearing prostate, urethra, and utricle. No cystoscopic or radiographic evidence of a vagina was found. Ureteroscopy was carried out to the right ureteropelvic junction where a fleshy soft tissue mass was seen to be freely movable. No other lesions were seen. Basket retrieval and pathologic examination showed the tissue to be composed of keratinized desquamative metaplastic tissue (cholesteatoma).

Right groin exploration was performed and no gonad was identified. However, a large empty hernia sac was found. The peritoneum was entered via the hernia sac and a well developed fallopian tube was identified. At abdominal exploration through a Pfannensteil incision, a polycystic ovary and unicornuate uterus were seen (fig. 4). Therefore, removal of all female internal organs was performed. The patient was informed of his condition and inpatient psychiatric counseling was provided.

Histologic sections through the ovary showed mature follicles, ova, and corpus luteum, with evidence of polycystic disease. The uterine cavity communicated with the fallopian tube and was lined by a thin endometrium composed of pseudostratified columnar epithelium with few glands. No evidence of a cervix was found.

Postoperatively, left testicular sonography revealed a normal sized testis (3.7 x 1.3 x 2.9 cm) with normal echotexture. One month following surgery, serum testosterone was 522 ng/dl and estradiol decreased to 39 ng/dl. FSH and LH increased to 17.1 and 14.3 MlU/ml, respectively.

Discussion

Classification. True hermaphroditism, although rare, has been reported in nearly 500 patients.3 The disorder may be classified according to the histology and location of the gonads: Lateral, testis and contralateral ovary (30%); bilateral, testicular and ovarian tissue identified on both sides, usually as ovotestes (20%); unilateral, ovotestis on one side and testis or ovary on the other side (50%).4

Pathology. The ovotestis is the most common gonad in true hermaphrodites,

followed by the ovary, and last by the testis.3 Despite the varied appearance of the external genitalia, the development of the ipsilateral ductal system is consistent with that of the gonad.

Complete absence of the uterine horn is commonly found on the side of a functional testis. A fallopian tube usually develops normally next to a functional ovary. However, ductal abnormalities result when the ipsilateral testicular tissue component (from an ovotestis) secretes androgen or Müllerian inhibiting substance (MIS). Müllerian regression begins at 8 weeks of fetal life due to production of MIS. Josso et al, 5 have found detectable but low levels of MIS in true hermaphrodites. Similarly, abnormalities of the vas deferens and seminal vesicles may result from ipsilateral estradiol secretion and lower MIS titer.

Associated abnormalities. Although histologic confirmation of both testicular and ovarian tissue is required to make the diagnosis of true hermaphroditism, several clinical findings suggest the diagnosis. Hypospadias, often associated with bifid scrotal folds, is the most common anomaly found in patients with true hermaphroditism. This is consistent with the overall increase in intersexuality in patients with and without ambiguous genitalia and both hypospadias and cryptorchidism reported by Rajfer and Walsh.6 Most authors agree that any patient with hypospadias and one or more undescended gonads should undergo exploration and biopsy of all gonadal tissue early in life.3 As first suggested by Olsson et al.,7 the expression "cryptogonadism" should replace the term cryptorchidism until biopsy evidence of testis tissue is available. This term is a useful reminder to physicians that the true histology of the gonad should be determined in order to properly manage patients.

Breast development, often associated with a low testosterone to estradiol ratio, occurs in over 90% of all patients with true hermaphroditism.1 The absence of gynecomastia in the current case reflects his normal testosterone and estradiol levels. Cyclic hematuria may result from menstruation from endometrial tissue into the urinary tract.8,9 The presence of periodic right groin pain in the absence of hematuria in our patient is consistent with the findings of polycystic ovary disease and a hypoplastic unicornuate uterus. Inguinal hernias, noted in about 50% of all true hermaphrodites,4,7 may contain a gonad or uterus in many cases. Suspicion of intersexuality in a presumed female patient with a palpable groin mass is appropriate.

Cytogenetics. There appears to be geographic differences in the karyotype of true hermaphrodites throughout the world. The most common findings are 46XX, 46XX/46XY mosaicism, and 46XY in South Africa,10 Europe,11 and Japan,12 respectively. The Y chromosome predisposes to a male phenotype, but as in the case of XX male syndrome, a 46XX karyotype does not necessarily promote a female phenotype.13 The testis-determining factor (TDF), equivalent to the sex-determining region Y (SRY), activates Sertoli cells to produce MIS, leading to Müllerian degeneration and stimulation at the gonadal ridge for the production of Leydig cells. The etiology of 46XX true hermaphroditism has implicated various mechanisms including translocated Y-chromosomal sequences including SRY (possibly a paternal meiotic exchange between X and Y) or a mutation that allows testis determination without the SRY gene.14 46XX/46XY mosaicism is thought to result from chimerism the existence of two or more cell lines, each of which has a different genetic origin. Although beyond the scope of this report, Ford offers a complete discussion on how chimerism can occur. 15

Malignancy potential. There is an increased incidence of seminomas, gonadoblastomas, and teratomas in male hermaphrodite patients.16 The risk of developing germ cell neoplasms correlates with the presence of the Y chromosome. The incidence of gonadal neoplasia is considerably higher in pseudohermaphrodites with dysgenetic gonads (nearly 25%) than in true hermaphrodites. The 1.9 to 2.6 percent risk of malignant degeneration in true hermaphroditism usually occurs in phenotype males and exclusively in mosaics;1,11,17 the risk may reflect the ectopic location of the gonads in these individuals.18 The chance of malignancy may be minimized by preserving those gonads that are easily palpable (scrotal), and excising all ectopically located gonads. Thereafter, frequent sonographic examinations should be performed.

Fertility potential. The diagnosis of true hermaphroditism must be distinguished from mixed gonadal dysgenesis. In the latter, histologic confirmation of dysgenetic gonads with the absence of germinal epithelium makes fertility impossible in these patients. In contrast, fertility potential does exist in true hermaphrodites. Phenotypic male true hermaphrodites, however, seldom produce adequate quality sperm to be considered fertile. While ovulation is not uncommon, spermatogenesis has been reported in only 12% of cases of true hermaphroditism.3 Testicular tissue from whole testes or ovotestes may show tubular atrophy and increases in interstitial tissue in over half the cases reported by Aaronson.19 Furthermore, only two cases of male hermaphrodites fathering children have been reported.20 Hypoplastic testes are usually found and therefore, infertility should be considered the rule. It is likely that fertile true hermaphrodites do not seek medical attention and are thus under reported in the literature. Only one other case of male factor infertility as the initial presentation of true hermaphroditism has been reported in the literature.21 Our case illustrates that diagnosis may not be made unless a significant medical problem (i.e. infertility) prompts medical intervention. Had he been fertile, his condition may not have been identified. In vitro fertilization technology may afford some otherwise infertile patients the ability to father children.

In phenotype female true hermaphrodites, twelve living offspring have resulted from fourteen individual pregnancies.11 Uterine maldevelopment and stenosis of the cervix or fallopian tubes, however, renders normal childbirth improbable.

Treatment. Several variables must be considered in managing patients with true hermaphroditism. These include age at diagnosis, location and histology of gonads, and phenotypic and functional aspects of the external genitalia. Sex assignment made prior to the age of two years may avoid psychosocial damage in the patient.1 Female rearing is advisable if the phallus is less than 2 cm or if the vagina is large.23 A three month trial of intramuscular testosterone enanthate may be given to phenotype males with microphallus to ascertain phallic growth potential.24 Burstein et al.25 reported successful phallic growth in fourteen boys treated in this fashion. Androgen therapy during childhood, however, is felt to postpone and not prevent the development of psychological problems in patients with microphallus.22 Furthermore, a recent animal study26 and several clinical investigations22,27-29 have shown early hormonal therapy to only foster early phallic growth, with no further growth potential at the time of puberty.

After sex assignment has been made, removal of all contradictory gonadal tissue should be done to allow for maximal gender specific development, as well as to increase fertility potential. The latter point may be more appropriate in female assigned patients where the chances of fertility may be greater. Since 80% of ovotestes are considered to be polar in nature, partial excision of ovarian or testicular tissue has been reported to preserve hormonal function.11,27 Based on histologic studies by Aaronson,19 however, complete removal of contradictory tissue may not be possible in many patients using this method. Furthermore, since infertility is common in patients with ovotestes (only one case of fertility has been reported31 in a patient with bilateral ovotestes) and hormone replacement may be given at puberty, the necessity of partial excision is questionable.

Our case illustrates how identification of true hermaphroditism can be made initially in adult life. Ideally, diagnosis and management of patients should begin at birth to avoid gender identity disturbances. Late management should consider both the risk of malignancy and the potential for fertility in affected individuals. Complete investigations including chromosomal studies should be performed in all patients with true hermaphroditism. Psychological counseling, cosmetic, and extirpative surgery all play important roles in patients initially diagnosed in adult life.

List of Figures:

Figure 1: Appearance of external genitalia. Note penoscrotal hypospadias, empty right scrotum, and normal appearing left testis.

Figure 2. Chromosome analysis shows 46 XX (A) and 46 XY (B) mosaic karyotype.

Figure 3: Intravenous urogram shows filling defect in right upper ureter.

Figure 4: Intraoperative photograph. Note polycystic ovary (o), fallopian tube with fimbria (f), and right uterine horn (u). A Babcock clamp is seen encircling the round ligament.

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