Teofilo Gautier

Steroid 5α-Reductase Deficiency in Man: An Inherited Form of Male Pseudohermaphroditism

In male pseudohermaphrodites born with ambiguity of the external genitalia but with marked virilization at puberty, biochemical evaluation reveals a marked decrease in plasma dihydrotestosterone secondary to a decrease in steroid 5α-reductase activity. In utero the decrease in dihydrotestosterone results in incomplete masculinization of the external genitalia. Inheritance is autosomal recessive.

Androgens and the Evolution of Male-Gender Identity among Male Pseudohermaphrodites with 5α-Reductase Deficiency

Abstract To determine the contribution of androgens to the formation of male-gender identity, we studied male pseudohermaphrodites who had decreased dihydrotestosterone production due to 5α-reducta...

Male pseudohermaphroditism due to steroid 5α-reductase deficiency

Abstract A new inherited form of male pseudohermaphroditism has been investigated in a pedigree of 24 families with 38 affected males. At birth, the affected males (46 XY) have a clitoral-like phallus, bifid scrotum and urogenital sinus. The testes are in the inguinal canals or labial-scrotal folds. The Wolffian structures are normally differentiated; there are no Mullerian structures. At puberty a muscular male habitus develops with growth of the phallus and scrotum, voice change and no gynecomastia. The subjects have erections, ejaculations and a libido directed towards females. They have decreased body hair, a scant to absent beard, no temporal hair line recession and a small prostate. Testicular biopsy reveals a normal testis. The mean plasma T levels in affected adults are significantly higher, and the mean plasma DHT levels are significantly lower when compared to those in normal subjects. The plasma T:DHT ratios range from 35 to 84 compared to 8 to 16 in normal subjects. After the administration of hCG, the T:DHT ratios in affected male children range from 74 to 162 compared to 3 to 26 in the control subjects. In affected adults, mean plasma LH and FSH levels are significantly higher than in normal subjects. In the affected subjects, the metabolic clearance rates of T and DHT are normal, but the conversion ratio of T to DHT is less than 1 per cent. The endogenous mean urinary E:A and E-OH:A-OH ratios, and the urinary E:A and E-OH:A-OH ratios after the infusion of radioactive T are significantly higher than in normal males. Inheritance is autosomal recessive with some sibling sisters showing the same biochemical defect, and obligate carrier parents showing an intermediate defect. These data support our thesis that the defect in these male pseudohermaphrodites is secondary to decreased steroid Δ 4 -5α-reductase activity. The affected subjects provide a clinical model for delineating the roles of T and DHT in sexual differentiation and development. This entity also demonstrates an inherited disorder of steroid metabolism in which the basic enzyme deficiency resides in the target tissues.

Male pseudohermaphroditism due to multiple defects in steroid-biosynthetic microsomal mixed-function oxidases: a new variant of congenital adrenal hyperplasia

A six-month-old 46,XY infant with a female phenotype and ambiguous genitalia was evaluated for male pseudohermaphroditism. The principal findings were (1) low basal plasma levels of all measured C19 steroids and their sulfates, which were unchanged or only minimally increased after stimulation with human chorionic gonadotropin or ACTH, (2) no urinary metabolites of C19 11-deoxy steroids, and decreased amounts of C19 11-oxosteroids, (3) normal basal plasma cortisol levels and normal urinary excretion of cortisol metabolites, (4) high plasma corticosterone and deoxycorticosterone levels and elevated urinary excretion of their metabolites, (5) high plasma progesterone and pregnenolone levels and increased urinary excretion of pregnanediol and pregnenediol, (6) high plasma 17 alpha-hydroxyprogesterone and 21-deoxycortisol levels and increased urinary excretion of pregnanetriol, 17 alpha-hydroxypregnanolone, and pregnenetriolone, (7) high plasma and urinary levels of 5-pregnene-3 beta,20 alpha-diol sulfate, (8) low plasma levels of 21-hydroxy-pregnenolone and 5-pregnene-3 beta,17 alpha, 20 alpha-triol sulfate, (9) high plasma ACTH levels, and (10) suppression of the high plasma steroid levels by dexamethasone. The unusual pattern of plasma and urinary steroids indicated that this child had multiple abnormalities of steroid-biosynthetic microsomal mixed-function oxidases--21-hydroxylase, 17 alpha-hydroxylase, and 17,20 desmolase. The deficit in the activities of the first two enzymes resulted in decreased cortisol synthesis with subsequent increased ACTH secretion and adrenocortical hyperplasia. The male pseudohermaphroditism resulted from deficient testosterone synthesis due to deficiency of 17 alpha-hydroxylase and 17,20 desmolase. The mother and two sisters of the affected child had evidence of mild 17 alpha-hydroxylase deficiency.

Male pseudohermaphroditism secondary to 5α-reductase deficiency—A model for the role of androgens in both the development of the male phenotype and the evolution of a male gender identity

Abstract Male pseudohermaphroditism secondary to 5α-reductase deficiency is reviewed. At birth, the affected males (46 XY) have a clitoral-like phallus, bifid scrotum and urogenital sinus with the testes in the inguinal canals or labial-scrotal folds. At puberty, a muscular male habitus develops with growth of the phallus and without gynecomastia. When compared to aged matched male controls the mean plasm testosterone (T) levels in affected adults are significantly higher; while the mean plasma 5α-dihydrotestosterone (DHT) levels are significantly lower. The plasma T:DHT ratios range from 24 to 84, compared to a normal range of 8–16. After administration of hCG, the T:DHT ratios in the affected prepubertal male children range from 35 to 172 compared to a range of 3–26 in the controls. The metabolic clearance rates of T and DHT are normal, but the conversion ratio of T to DHT is decreased to less than 1%. The endogenous mean urinary etiocholanolone (5β) to androsterone (5α) ratios, and the urinary 5β to 5α ratios after infusion of radioactive T are significantly higher than in normal males. Studies with cortisol and corticosterone (11-oxo, C-21) Δ4–11β-hydroxyandrostenedione (11-deoxy, C-19) and testosterone and androstenedione (11-deoxy, C-19) have shown that the fractional conversion of the infused parent steroids to 5α reduced produced products is markedly decreased in individuals with 5α-reductase deficiency and may reflect a generalized defect in steroid metabolism. Decreased 5α-reductase activity has been demonstrated in fibroblasts cultured from nongenital and genital skin of affected subjects, in cell free extracts from epididymis and fibroblasts cultured from genital skin and in genital skin slices. Characterization of the enzyme activity in four kindreds reveals that 5α-reductase enzyme activity in each kindred has different properties. Pedigree analysis from the large Dominican kindred reveals inheritance to be autosomal recessive. This model of inheritance is further documented by the fact that some sibling sisters show the same biochemical defect, and obligate carrier parents show an intermediate defect. The affected subjects provide a clinical model for delineating the roles of T and DHT in sexual differentiation and development. Because of the appearance of the genitalia at birth, 18 of the affected males from the Dominican kindred were raised as girls. Extensive psychosexual evaluation was conducted by interviewing the affected subjects, parents, siblings and wives, and it was found that in spite of the rearing as female throughout childhood 16 of 18 changed gender identity and role with puberty. We conclude that in the formation of male gender identity, normal T exposures of the brain in utero and at puberty are major contributing factors. Thus, in normal males the formation of gender identity is at least partially androgen induced.

Inherited 5α-reductase deficiency in man

Abstract Study of the syndrome of 5α-reductase deficiency in man has elucidated the importance of testosterone conversion to dihydrotestosterone in sexual differentiation of the male fetus. Insights into specific actions for testosterone and dihydrotestosterone in the fetal and adult male are suggested, as well as a role for androgens in male gender identity formation. Pedigree analysis and biochemical studies have elucidated the mode of inheritance of this gene defect.

URINARY STEROID METABOLITES IN SUBJECTS WITH MALE PSEUDOHERMAPHRODITISM DUE TO 5α‐REDUCTASE DEFICIENCY

To investigate the enzymatic basis for abnormal steroid metabolism in subjects with male pseudohermaphroditism due to 5α‐reductase deficiency, the ring A reduced urinary 5β and 5α metabolites of testosterone, androstenedione, 11β‐hydroxyandrostenedione, cortisol and corticosterone were measured by gas chromatography. Assays of the four pairs of urinary 5β and 5α steroid metabolites revealed decreased conversion of the parent steroids to 5α‐reduced urinary metabolites, with increased 5β to 5α urinary steroid metabolite ratios. These studies establish that increased urinary 5β/5α ratios are distinctive for this disorder, and represent the most reliable method for confirming the diagnosis of primary inherited 5α‐reductase deficiency. These data also suggest that the conversion on the many Δ4‐3 ketosteroids to 5α‐reduced steroids may be due to a single enzyme with broad specificity, or multiple enzyme reductases with a common regulator.

Testicular function in 2 cases of penile agenesis.

AbstractTwo cases of congenital absence of the penis are presented. In both cases testicular androgen function was adequate, as judged by measurements of plasma androgens after administration of human chorionic gonadotropin

The Impact of Androgens on the Evolution of Male Gender Identity

Sex differences in behavior from infancy through adulthood have been documented in humans (Ounsted and Taylor 1972; Hutt, 1972) and animals (Reinisch, 1974; Goy and Goldfoot 1973). In animals, sexually dimorphic behavior is secondary to sex steroid induced differentiation and activation of the brain at critical periods. In humans, however, controversy exists as to whether gender identity formation is influenced by sex steroid “imprinting” of the brain at critical periods.

The Prevalence of 5α-Reductase Deficiency in Children with Ambiguous Genitalia in the Dominican Republic

During a 10-year period 65 children and adolescents with ambiguous genitalia from the Dominican Republic, not known through kindred studies of 5 alpha-reductase deficiency, were evaluated. Plasma androgen determinations were performed before and/or after Leydig cell stimulation of the testes with human chorionic gonadotropin. Of the children there were 24 female pseudohermaphrodites, 21 of whom had 21-hydroxylase deficiency, 1 true hermaphrodite and 40 (62 per cent) male pseudohermaphrodites. One child had a human chorionic gonadotropin response suggestive of 17-20 desmolase deficiency, and on further evaluation he also had partial deficiencies of the enzymes 21-hydroxylase and 17 alpha-hydroxylase. Five subjects had a female phenotype and subnormal androgen responses to human chorionic gonadotropin. In 5 of 33 male pseudohermaphrodites with a normal testosterone response to human chorionic gonadotropin 5 alpha-reductase deficiency was suspected by elevated plasma testosterone/dihydrotestosterone ratios before and/or after human chorionic gonadotropin stimulation. The diagnosis of 5 alpha-reductase deficiency was confirmed by elevated 5 beta/5 alpha urinary C19 and C21 steroid metabolite ratios. One subject with 5 alpha-reductase deficiency was traced to the original Dominican kindred of 38 affected subjects. Pedigree analysis of another proband revealed 3 additional affected relatives. Four subjects with a normal testosterone response to human chorionic gonadotropin had XO/XY gonadal dysgenesis. There were 25 male pseudohermaphrodites with normal plasma testosterone and dihydrotestosterone responses to human chorionic gonadotropin, who were not diagnosed by this methodology. This study reveals that 5 alpha-reductase deficiency occurs with a frequency of 13 per cent as a cause of male pseudohermaphroditism in the Dominican Republic with approximately the same frequency as XO/XY gonadal dysgenesis. Unlike female pseudohermaphrodites, the majority of male subjects with pseudohermaphroditism remain unclassified by these techniques.