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Male pseudohermaphroditism in a 6 month old boy, due to congenital 3β-hydroxysteroid dehydrogenase deficiency, associated with atrial septal defect, is reported. At 2 weeks he required therapy for severe dehydration and projectile vomiting. The parents were first cousins and one female sibling had died suddenly at 2 months. The patient presented with melanoderma, perineal hypospadias with testicles in a bifid scrotum and atrial septal defect (ostium secundum). Complete cytogenetic studies showed a 46,XY karyotype. Serum sodium ranged from 129 to 140 mEq/l and serum potassium from 5.1 to 4.6 mEq/l. Basal plasma hormonal studies showed normal androstenedione (Δ4A), decreased cortisol (F), slightly elevated ACTH, 17-hydroxy-progesterone (17-OH-P) and testosterone (T), and highly increased dehydroepiandrosterone-sulphate (DHEA-S) levels. ACTH stimulation increased and DXM suppression decreased the plasma levels of DHEA-S, 17-OH-P and T but not that of F; hCG stimulation during cortisone therapy did not change the levels of DHEA-S and T. Corticosteroid therapy normalized electrolyte levels and reduced melanoderma and hormonal hypersecretion. Moderately elevated plasma levels of 17-OH-P and T suggest a partial testicular 3β-HSD deficiency. The multifactorial inheritance and the relatively high prevalence of atrial septal defect vs the rarity of adrenal enzymatic defect suggest a causal association even if a common genetic factor cannot be excluded.

A study of steroid metabolism by a tumour of the specific gonadal stroma was carried out in a 10 year old boy. Tumours developed in the two testes from multiple foci, and clinically, no signs of sexual development were evident. Four testicular enzymes necessary for testosterone biosynthesis were estimated in the child, in two adult controls, and in three pre-pubertal boys with male pseudohermaphroditism but normal tests of Leydig cell function. 17α-Hydroxylase and 17β-hydroxysteroid dehydrogenase were similar in the five controls and in the gonad with the tumour, while 17,20-desmolase and 3β-hydroxysteroid dehydrogenase were grossly deficient in the child with the tumour. These enzyme deficiencies might explain the absence of peripheral virilization in a boy with a tumour of Leydig and Sertoli cells.

A 27 year old female is described who had 46,XY chromosome complement, ambiguous external genitalia with elevated LH, slightly above normal FSH and low testosterone. Her plasma testosterone level increased 15–20 fold after HCG stimulation (5000 IU × 3). then returned to pre-stimulation level 3 months later. This was possibly due to the secretion of an abnormal LH molecule which is immunoreactive but biologically inactive in the human.

The histochemistry of the gonads of three cases of male pseudohermaphroditism was studied. The histological and histochemical findings are integrated with the clinical and laboratory data. The study enables us to differentiates the histological picture of the gonads of these patients from those of prepuberal or primary undescended testes. A histochemical study was used to differentiate the Leydig cells in the cases without feminization, from the feminized cases. The feminized patients had a testicular interstitial tissue filled with a pigment identified as a lipofuscin. 3β-ol-dehydrogenase activity was markedly positive in these pigmented cells, suggesting their active functional condition.

The anatomic findings and gonadal histology of 41 patients who had atypical forms of gonadal dysgenesis or of male pseudohermaphroditism are described. Fourteen of these cases were classified as atypical gonadal dysgenesis because there were gross evidences of abnormal gonadal development, differing from those of classical Turner's syndrome. In this group there was no incidence of familial inheritance but there were evidences of chromosomal aberrations. Two patients diagnosed as »gonadal dysplasia« had primitive genital streaks differing from those of typical gonadal aplasia (Turner's Syndrome) only in the presence of masses of Leydig-like cells. That this condition is a variant of gonadal aplasia is suggested by the association of short stature in one case and by the demonstration in the other case of chromosomal mosaicism of XO/XX pattern, with the XO cell type predominant as in chromatin-negative Turner's Syndrome. Ten patients had »asymmetrical gonadal differentiation« with a testis on one side and on the other side either no gonad (2 cases), a primitive genital streak (6 cases) or an undifferentiated gonad (2 cases). Among these mosaicism of XO/XY type was demonstrated in one case and it is suspected that more intensive chromosomal studies in the future may show a high incidence of mosaicism or other chromosomal aberration in this group. In addition 2 cases of true hermaphroditism are described. There were 27 male pseudohermaphrodites who had two testes with no histological evidences of dysgenesis. Eight of these patients had female external genitalia and 19 had genitalia which were ambiguous or resembled the male. In 4 patients of the latter group there were completely developed uterus and Fallopian tubes. Since the testes of all the male hermaphrodites showed good development of the medullary components believed to be responsible for male differentiation, it must be assumed that there was a defect in the biosynthesis of the »male organizing substances« of the foetal testes. Normal male XY chromosomal patterns were found in all of our cases which were studied and have been reported by other workers. The high familial incidence of this disorder suggests that an enzyme defect is transmitted by a mutant gene. In the »syndrome of feminizing testes« the demonstration of oestrogenic manifestations after puberty is further evidence of an abnormality of synthesis of testicular hormones. The correlation of gonadal pathology and the sex differentiation of gonaducts and external genitalia is compatible with the theory of Jost that normal masculinization is dependant upon the production of adequate amounts of masculinizing substances by the foetal testes. Discordances between the degree of masculinization (or feminization) of the gonaducts and the external genitalia can be explained only by postulating that there are at least two substances concerned; one causing masculinization of the Wolffian ducts and external genitalia and the other causing disappearance of the Mullerian ducts.

Pituitary and testicular function was studied in pubertal and adult rabbits with pseudohermaphroditism secondary to immunization of mothers against testosterone. Circulating testosterone, LH and FSH levels showed a developmental pattern during sexual maturation, similar to that observed in controls. Plasma FSH levels were elevated in male pseudohermaphrodites despite normal plasma testosterone concentrations. Fighting, male sexual behaviour and coitus occurred normally as in controls. The testicular response to endogenous elevated LH levels and the pituitary LH and FSH responses to LRH injection and to castration were similar in affected males and in controls. These observations suggest that inhibition of the central effects of androgens during the embryonic and perinatal period has little or no effect on the differentiation and maturation of the hypothalamo-pituitary-testicular axis in rabbit.

Male pseudohermaphroditism due to 17β-hydroxysteroid dehydrogenase (17β-HSD) deficiency has a high prevalence within the Arab population of the Gaza strip and is characterised by marked virilization at puberty, leading in many cases to the spontaneous adoption of a male gender role. As a result of this, parents of 7 affected male infants (aged 1– 10 months) born with female phenotype requested early gender reassignment. Diagnosis was suspected in 5 on the basis of a positive family history, but confirmed in all cases by the finding of low to normal testosterone levels (30–184 ng/dl) with high Δ4-androstenedione levels (188–808 ng/dl), after hCG. Treatment with im testosterone oenanthate (25–50 mg/dose) was given in one to three 3-months courses and penile size was increased into the normal range without evoking a significant increase in height velocity or skeletal maturation. Five patients underwent the first stage of male genitoplasty between 2 and 3 years of age. This consisted of bilateral orchidopexy, chordee release and penile lengthening – yielding finally an anatomically normal-sized and shaped penis. Androgen responsive male pseudohermaphroditism due to 17β-HSD deficiency or a similar defect and diagnosed in infancy should be treated as soon as possible with systemic testosterone before considering any sex change, and in preparation for male genitoplasty. Early gender reassignment according to genetic and gonadal sex is probably the management of choice for these cases since this may result in a normal adjustment to the male gender role, particularly after puberty.

An inherited form of incomplete male pseudohermaphroditism was studied in two post-pubertal and one pre-pubertal sibling. All patients presented a 46XY karyotype, infantile female external genitalia, lack of breast development and sexual hair. Persistently elevated serum levels of gonadotrophins with normal pituitary responsiveness to LRH were found. Serum 17-OH progesterone, androstenedione, and testosterone levels were extremely low before and after gonadal stimulation with hCG. Laparotomy revealed absence of Wolffian and Mullerian derivatives. Testes were small and cryptorchidic. Microscopic and ultrastructural examination revealed seminiferous tubules with absence of spermatogenesis and normal Sertoli cells. The interstitial spaces were mainly occupied by poorly differentiated cells although in the post-pubertal patients there were small and randomly distributed nodules of Leydig cells without crystaloids. Incubation of testicular tissue from one post-pubertal patient with [14C]acetate showed lack of 14C-incorporation into appropriate steroid carriers. These data were interpreted as demonstrating that gonadotrophin resistance was the underlying abnormality of this syndrome, representing the human counterpart of the 'vet' pseudohermaphroditic rat.

A 17 year old patient with female phenotype and 46,XY karyotype presented because of primary amenorrhoea. Enlarged clitoris and pubic hair were observed and no breast development. Gonadotrophin values were greatly raised into the castrate range, while testosterone was at the upper limit of the normal range for females. No uterus, Fallopian tubes or remnants of Mullerian and Wolffian products were found at laparotomy. Bilateral inguinal masses were removed and proved to be testicular tissue. This case report shows that gonads can be present in patients with the clinical and endocrinological characteristics of the syndrome of 'true agonadism'.

A family is presented in which all males of the second generation died at birth, and in which two out of four individuals of the third generation exhibited ambiguous external genitalia. All members of the third generation, one brother and one sister in one sibship, and two brothers in another sibship, were studied from both a clinical and a cytogenetical point of view. In the two boys with ambiguous external genitalia the legal sex was designated female at birth but was later changed to male. Histological examination of their gonads revealed testicular dysgenesis. The girl was clinically normal, and the third male had a small penis and cryptorchid testes. All the boys had an apparently normal 46/XY karyotype without any evidence of mosaicism. It could not be decided from studies on the Xg blood group and some other sex-linked characters whether the condition described was inherited as an X-linked recessive or an autosomal dominant, sex-limited trait.

The authors studied the gonads of 20 children presenting different types of pseudohermaphroditism with the object of comparing the histological findings with those observed in cases of simple cryptorchidism. The picture seen in: Miscellaneous male pseudohermaphroditism is identical to that of simple cryptorchidism. The feminizing testicular syndrome shows a distinct difference from that seen in the undescended testis of children of the same age. There is proliferation of spindle cells resembling ovarian stroma, but with no follicular derivatives. After puberty there is a discrepancy between the presence of large groups of Leydig cells and an immaturity of the seminiferous tubules. The testicular lesion in mixed gonadal dysgenesis resembles that of cryptorchidism. However, serial sectioning of entire streaks allowed the demonstration in 3 cases of a tumour entirely composed of germinal cells. In one of these cases a biopsy taken one year previously had revealed no abnormalities. The tumour somewhat resembles a gonadoblastoma but with a difference. No previous reference to such a tumour in children at puberty has been found. Similar lesions were seen in the opposite testicle in two cases. In the light of these findings, it is considered that in such cases the streak and also the testicle should be completely removed to avoid a possible later development of a generalised seminoma.