Male pseudohermaphroditism due to 17-hydroxylase deficiency

A 27-year-old phenotypic female presented with primary amenorrhea, severe hypertension, and hypokalemia. At the age of puberty sexual development had not occurred; in particular, sexual hair had not grown. Past history revealed an episode of subarachnoid hemorrhage and several episodes of ventricular tachyarrhythmia. Karyotype was 46, XY. The steroids requiring 17-hydroxylation (cortisol, testosterone, pregnanetriol, 17-ketosteroids, 17-hydroxycorticosteroids) were low, while those not requiring 17-hydroxylation (progesterone, deoxycorticosterone, corticosterone) were high, demonstrating 17-hydroxylase deficiency. The corticosterone/deoxycorticosterone ratio was relatively low, suggesting an associated partial deficiency of 11-hydroxylase.     

Two types of male pseudohermaphroditism due to 17, 20-desmolase deficiency

Three patients with male pseudohermaphroditism due to 17,20-desmolase deficiency were studied at a pubertal age. Patients 1 and 2 (first cousins, raised as males) had inter-sexual external genitalia, some spontaneous male pubertal development, some response of plasma testosterone to hCG, low plasma dehydroepiandrosterone, and pregnanetriolone (3 alpha, 17 alpha, 20 alpha-trihydroxypregnan-11-one) in urine. Patient 3 (unrelated, raised as a female) had female external genitalia, no spontaneous pubertal development, no response of plasma testosterone to hCG, normal plasma dehydroepiandrosterone, and no pregnanetriolone in urine. It is concluded that two types of 17,20-desmolase deficiency exist: one with an incomplete defect in both, the delta 4- and the delta 5-pathway (patients 1 and 2), and one with a complete defect in the delta 4-pathway only (patient 3).     

17 alpha-hydroxylase deficiency: mineralocorticoid hormone profiles in an affected family

The plasma concentrations of mineralocorticoid hormones, basal and after stimulation and suppression with ACTH, can identify the heterozygotes in a family with two siblings with 17 alpha-hydroxylase deficiency. Both parents and one sibling had elevated levels of plasma deoxycorticosterone, corticosterone, 18-hydroxydeoxycorticosterone, and 18-hydroxycorticosterone, but normal cortisol and aldosterone concentrations. Stimulation with ACTH effected additional increases in the elevated steroid and cortisol levels, but not in aldosterone, further increasing the discrepancy and the ratio between 18-hydroxycorticosterone and aldosterone. One sibling had normal steroid patterns and an 18-hydroxycorticosterone to aldosterone ratio. Suppression of ACTH restored the steroids to low normal levels. In addition, the ratio of the gas chromatographic analysis of the total major urinary metabolites of corticosterone to total metabolites of cortisol was greater, and the sum of urinary androsterone and etiocholanolone to total corticosterone and cortisol metabolites was less in the heterozygotes than in normal subjects. This identifies deficient 17-hydroxylation, which is required for the production of cortisol and C-19 steroids. These criteria appear unique for the 17 alpha-hydroxylase defect in the heterozygote.     

Mechanisms of androgen production in male pseudohermaphroditism due to 17 beta-hydroxysteroid dehydrogenase deficiency.

17 beta-Hydroxysteroid dehydrogenase (17 beta HSD) deficiency is a rare cause of male pseudohermaphroditism, but is a frequent disorder among a highly inbred Arab population in the Gaza strip. Affected individuals are born and reared as females until puberty, when marked virilization occurs, leading in many cases to the spontaneous adoption of a male gender role. To investigate the mechanisms and site(s) of androgen production, we determined the gonadal and extragonadal steroid patterns in two postpubertal male pseudohermaphroditism patients, who were castrated and reared as females. Before castration, both patients had very high plasma levels of androstenedione (delta 4-A), normal or moderately low levels of testosterone (T), and significantly elevated delta 4-A/T ratios (P less than 0.01). Dihydrotestosterone (DHT) levels were normal or high, while the DHT/T ratios were lower than normal (P less than 0.01), suggesting enhanced 5 alpha-reductase activity. These abnormalities were much more severe in spermatic venous blood. 17 beta HSD deficiency was also found in the delta 5-pathway, by high dehydroepiandrosterone (DHEA) levels and very high dehydroxyepiandrosterone/delta 5-androstenediol (DHEA/delta 5-diol) ratios, and in peripheral tissue metabolites, by very high androsterone glucuronide/3 alpha-androstanediol glucuronide ratios (P less than 0.01). The estrogen pathway was also impaired (P less than 0.01), even though both estrone and estradiol levels were elevated. Gonadectomy significantly reduced all androgens and estrogens (P less than 0.01), but when compared to 42 castrated controls, both patients had lower delta 4-A and higher T levels. The delta 4-A/T ratio was lower than that in controls, indicating normal to enhanced extragonadal 17 beta HSD activity. A similar pattern was observed in the delta 5- and estrogen pathways. DHT levels were within normal limits, and 3 alpha-diol was moderately decreased. These data suggest that testicular 17 beta HSD activity is under a different genetic control from that in extragonadal tissues. Affected males lack the testicular enzyme, but their extragonadal 17 beta HSD activity is normal or enhanced. Together with enhanced 5 alpha-reductase activity, this represents a highly efficient compensatory mechanism for androgen and estrogen production after puberty.     

Study of a new case of male pseudohermaphroditism due to 17-ketosteroid reductase deficiency (author's transl)]

We studied a 17 year old patient with primary amenorrhea, hirsutixm, clitoral enlargment, poor breast development and 46, XY karyotype. The results shown in table clearly indicate a 17-ketosteroid reductase deficiency. In the view of previously described patients we can conclude that: 1) intensity of virilisation depends on both plasma testosterone and androstenedione levels; 2) importance of gynecomastia depends on plasma E2 but not E1 levels; 3) FSH levels are not correlated with circulating androgens or estrogens but presumably depends on importance of seminiferous tubules' lesions.     

男性假两性畸形——17β-羟类固醇脱氢酶3型缺陷症研究

目的 本研究通过对一例l7β-羟类固醇脱氢酶(1713-HSD)3型缺陷症的临床诊断及基因检测,探讨其病理生理及发病机制.方法 总结分析该家系临床资料,通过激素测定和hCG兴奋试验确认其临床诊断;收集该家系先证者及其父母的外周血,通过PCR扩增产物直接测序和亚克隆方法检测其基因突变,确认其基因诊断.结果 该患者社会性别为女性,以"原发性闭经"就诊;染色体核型为46,XY,双侧腹股沟隐睾,呈男性假两性畸形.激素测定显示睾酮合成前体物质如硫酸脱氢表雄酮、雄烯二酮明显升高,而睾酮却低于正常.hCG兴奋试验提示雄烯二酮转化为睾酮过程受阻,即17β-HSD3活性缺陷.基因诊断证实HSD17B3 基因第一外显子存在4个碱基缺失(172-175del).结论 青春期出现男性化表现伴乳腺发育时应考虑该症可能,hCG试验可提供临床依据,基因诊断可进一步确诊.     

Familial male pseudohermaphroditism due to 5-alpha-reductase deficiency in a Turkish village

Twelve persons with sexual ambiguity were identified in an isolated village in southern Turkey. Eleven were examined and had pseudovaginal perineoscrotal hypospadias; eight were studied. Serum and urine samples from five affected males and urine samples from three affected children were analyzed. Urine samples from another 26 villagers, mostly parents and siblings, were also analyzed. In all but one of the affected adult subjects, serum testosterone levels were either normal or increased, and in all adults, the dihydrotestosterone levels were low (8 to 20 ng/dl) and the testosterone/dihydrotestosterone ratios were elevated (to 36 or more); the levels of 4-androstenedione were normal. Thirty-four urine samples were analyzed for etiocholanolone/androsterone, 11-beta-hydroxyetiocholanolone/11-beta-hydroxyandrosterone, tetrahydrocorticosterone/5-alpha-tetrahydrocorticosterone and tetrahydrocortisol/5-alpha-tetrahydrocortisol ratios. In affected persons, all 5-beta/5-alpha urinary C19 and C21 steroid metabolite ratios measured were elevated. These findings are compatible with the diagnosis of male pseudohermaphroditism due to 5-alpha-reductase deficiency. In parents and some of the siblings of the affected subjects, the 5-beta/5-alpha urinary ratios were between affected and normal levels. The intermediate 5-beta/5-alpha ratios of the parents who were phenotypically normal, together with documented consanguinity, confirm an autosomal recessive mode of inheritance and are useful in identification of the carrier state. The urinary tetrahydrocortisol/5-alpha-tetrahydrocortisol ratios provided the highest index of discrimination between homozygotes (mean +/- SD, adults: 35.80 +/- 20.10; children: 15.48 +/- 7.91), heterozygotes (parents: 4.56 +/- 1.61; siblings and other relatives: 5.97 +/- 3.68), and normal subjects (1.07 +/- 0.36). Thus, this study identified a second community with inherited male pseudohermaphroditism due to 5-alpha-reductase deficiency, confirming the autosomal recessive inheritance of this condition and the generalized abnormality in both C19 and C21 steroid 5-alpha metabolism.     

Combined 17 alpha-hydroxylase/17,20-lyase deficiency due to a stop codon in the N-terminal region of 17 alpha-hydroxylase cytochrome P-450

Steroid 17 alpha-hydroxylase (cytochrome P-450(17)alpha) mediates both 17 alpha-hydroxylase and 17,20-lyase activities. A relatively rare disease, 17 alpha-hydroxylase deficiency is characterized by defects in either or both of these activities. The molecular basis for variability of the defect is not well understood. We have determined the exonic sequence of the mutant P-450(17)alpha gene from one Japanese patient with combined 17 alpha-hydroxylase/17,20-lyase deficiencies. A stop codon (TGA) due to a single point mutation was found at the position of amino acid 17 in exon 1 of the P-450(17)alpha gene. The presence of a stop codon in the N-terminal region of this gene leads to the absence of a functional P-450(17)alpha protein in adrenal cortex and ovary, and consequently hypertension, primary amenorrhea and osteoporosis in this patient.     

A case of 17alpha-hydroxylase deficiency with symptoms mimicking testicular feminization

A case of 17alpha-hydroxylase deficiency mimicking testicular feminization is reported. Different from the complete form of testicular feminization in which androgens are normal or elevated and end-organ insensitivity to androgens is supposed, this case had a negligible amount of androgens and responded to the injection of testosterone propionate with a positive nitrogen and phosphate balance.     

Male pseudohermaphroditism due to 17 beta-hydroxysteroid dehydrogenase deficiency: gender reassignment in early infancy

Male pseudohermaphroditism due to 17 beta-hydroxysteroid dehydrogenase (17 beta-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 delta 4-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 17 beta-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.     

Prepubertal male pseudohermaphroditism due to 17-ketosteroid reductase deficiency: diagnostic value of a hCG test and lack of HLA association

Most patients with male pseudohermaphroditism (MPH) due to 17-ketosteroid reductase (17-KSR) deficiency were diagnosed at or after puberty when significant virilization occurred. We report 2 prepubertal sibs (Case 1, 4 yr and Case 2, 10 yr) unambiguously raised as females, with clitoral enlargement, separate urethral and vaginal orifices and gonads palpable at the inguinal canal bilaterally. Basal serum LH, FSH, 17-hydroxyprogesterone, testosterone (T), dihydrotestosterone and dehydroepiandrosterone (DHEA) were normal for age. delta 4-Androstenedione (delta 4-A) was slightly elevated in Case 2 but nondiagnostic. Steroid measurements after human chorionic gonadotropin (hCG) stimulation were compared with those of boys with male external genitalia submitted to the same hCG protocol: peak T was subnormal (Case 1, 80, Case 2, 91, vs normal 329 +/- 129 ng/dl, mean +/- 1SD), peak delta 4-A elevated (Case 1, 477, Case 2, 264, vs normal 44 +/- 26 ng/dl) resulting in an abnormally elevated delta 4-A/T ratio (Case 1, 6.0, Case 2, 2.9, vs normal 0.12 +/- 0.09) and establishing the diagnosis of 17-KSR deficiency. This diagnosis was confirmed in vitro by minimal T production when testicular tissue of both patients was incubated with tritiated delta 4-A. The 2 sibs did not share a single haplotype for the HLA complex indicating lack of association between HLA and the locus of the gene for 17-KSR. In conclusion, in 2 sibs with MPH the subnormal T and elevated delta 4-A response to the hCG test indicated the diagnosis of 17-KSR deficiency followed by orchiectomy to avoid later virilization at puberty.     

Neutral 17β-hydroxysteroid oxidoreductase deficiency in testes causing male pseudohermaphroditism in an infant

A deficiency of neutral 17-hydroxysteroid oxidoreductase activity in tests has been diagnosed in an infant with male pseudohermaphroditism.In vivo stimulation tests of testicular endocrine function with human chorionic gonadotrophin provided an accurate diagnosis in contrast to estimates of enzymic activityin vitro in testes and other tissues. The discrepancy in testes may be due to the absence of gonadotrophin stimulation in the latter studies. Thein vitro studies show that there are at least two forms of 17-hydroxysteroid oxidoreductase under independent genetic control and that only one form is localized to the testes. The diagnosis before puberty has allowed early treatment by removal of the abnormal testes which should prevent the usual presenting clinical signs of marked masculinization and hirsutism at puberty.     

A novel compound heterozygous mutation in the CYP17 (P450 17alpha-hydroxylase) gene leading to 17alpha-hydroxylase/17,20-lyase deficiency

Mutations in the CYP17 gene impair steroid biosynthesis in the adrenals and gonads and often cause 17alpha-hydroxylase/17,20-lyase deficiency, leading to amenorrhea, sexual infantilism, and hypokalemic low aldosterone hypertension. Several CYP17 mutations resulting in 17alpha-hydroxylase/17,20-lyase deficiency have been reported previously. In the present study, we found a novel CYP17 mutation from the molecular analysis of a Korean patient with primary amenorrhea with a 46,XX karyotype, and hypokalemic hypertension. We sequenced all 8 exons of the CYP17 gene that were amplified from patient's genomic DNA using polymerase chain reaction (PCR) and found a compound heterozygous mutation in the CYP17 structural gene; a 1-base deletion and a 1-base transversion (TAC-->AA) at codon 329, leading to the production of a truncated protein (1-417 amino acids), and a 3-base deletion (TCC, either 350-351 or 351-352 codon) in the other allele. Restriction enzyme digestion analysis of patient's and parental DNA showed that the 1-base deletion and the 3-base deletion are inherited from mother and father, respectively. Here we conclude that these novel compound heterozygous mutations might account for the patient's clinical manifestations of 17alpha-hydroxylase/17,20-lyase deficiency.     

Male pseudohermaphroditism due to 17 beta-hydroxysteroid dehydrogenase 3 deficiency. Diagnosis, psychological evaluation, and management

Ten male pseudohermaphrodites with 17 beta-hydroxysteroid dehydrogenase 3 (17 beta-HSD3) deficiency were evaluated in 1 clinic with an average follow-up of 10.1 years. The diagnoses were made by demonstrating low to normal serum testosterone levels, high androstenedione levels, and high ratios of serum androstenedione to testosterone in the basal state or after treatment with human chorionic gonadotropin. The molecular features of the underlying mutations were identified in all 7 families. Two additional males in the same families are believed to be affected on the basis of history obtained from family members. All of the 46,XY individuals in these families were registered at birth and raised as females (despite the presence of ambiguous genitalia in all or most), and all virilized after the time of expected puberty due to a rise in serum testosterone to or toward the normal male range. The age at diagnosis varied from 4 to 37 years. Ten individuals were studied by the same psychologist, and change of gender role (social sex) from female to male occurred in 3 subjects and in the 2 presumed affected subjects not studied. The individual with the highest serum testosterone level maintained female sexual identity, and in 2 families some of the affected males changed gender role and others did not. Thus, while androgen action plays a role in the process, additional undefined psychological, social, and/or biologic factors must be determinants of gender identity/role behavior. Management of the 7 individuals who chose to maintain female sex roles included castration, clitoroplasty, vaginal enlargement procedures when appropriate, treatment of hirsutism, cricoid cartilage reduction, and estrogen replacement. Three of the 7 are married (2 twice), 1 is involved in a long-term heterosexual relationship, 1 is engaged to be married, and the other 2 are not married and not believed to be sexually active. The 3 subjects who changed gender role behavior to male underwent hypospadias repair, and 1 was given supplemental testosterone therapy. One of these men is divorced, and the other 2 (aged 29 and 35 years) are unmarried. The diagnosis in 8 of these subjects was made after the time of expected puberty; it is unclear whether the functional and social outcomes would have been different if the diagnosis had been made and therapy begun earlier in life.     

Combined 17 alpha- and 18-hydroxylase deficiency associated with complete male pseudohermaphroditism and hypoaldosteronism.

A 15-year-old phenotypic female with XY genotype presented with male pseudohermaphroditism, gynecomastia, hypokalemic alkalosis, and hypertension. Being raised as a girl, the patient failed to menstruate and developed no sexual hair. At laparatomy no Müllerian structures were found but testes were removed which showed histologically atrophy of seminiferous tubules and abundant Leydig cells. Deoxycorticosterone (2.0 mg/24 h) and corticosterone (117 mg/24 h) secretion rates were extremely elevated, whereas those of aldosterone (17 micrograms/24 h), deoxycortisol (22 micrograms/24 h), and cortisol (23 micrograms/24 h) were almost unmeasurable. The excretion rates of 18-OH-deoxycorticosterone (less than 0.25 microgram/24 h) and 18-OH-corticosterone (3.0 microgram/24 h) were subnormal in spite of high plasma ACTH levels (200 pg/ml), and deoxycorticosterone (32.2 micrograms/24 h) and corticosterone (269 micrograms/24 h) excess. Gonadotropins were elevated. Deficient 17 alpha-hydroxylation was suspected because of: 1) low levels of 17 alpha-OH-progesterone; 2) diminished excretion rates of both 17 alpha-OH-progesterone and pregnanetriol; and 3) reduced concentrations of dehydroepiandrosterone, androstenedione, and testosterone in testicular tissue. We conclude that this male pseudohermaphrodite with complete female phenotype had 17 alpha-hydroxylase deficiency. The enzymatic defect was linked with an associated 18-hydroxylase deficiency.