Persistent testicular delta5-isomerase-3beta-hydroxysteroid dehydrogenase (delta5-3beta-HSD) deficiency in the delta5-3beta-HSD form of congenital adrenal hyperplasia (original) (raw)
Related papers
Journal of Pediatric Endocrinology and Metabolism, 1987
r f An 11 year old child with hypertension and male pseudohermaphroditism due to 17«-hydroxylase deficiency [corticosterone > 25,000 ng/dL (N < 820); Sbortisol < 1 ug/dL; 11-desoxyCortisol 734 ng/dL (N < K00)] has been followed for seven years. GnRH infusion at age 3 8/12 years provoked a castrate gonadotropin Secretory response (LH: 19 ^ 518 mlU/mL, FSH: 15 015 mlU/mL, basal peak). In vitro incubation of testicular tissue revealed conversion of [H 3 ]-17<*-hydrofryprogesterone to testosterone (59 pmol/20 mg tissue) [but not of [H 3 ]-pregnenolone (0.23 pmol/20 mg tissue) ^documenting deficiency of 17<*-hydroxylase activity in [the gonad. Persistently elevated serum concentrations of corticosterone appeared to prevent signs and symptoms of adrenal insufficiency despite negligible Cortisol levels, and provided some inhibitory feedback on ACTH secretion. Although blood pressure measurements were only mildly elevated, at age 11 years there was electrocardiographic evidence of moderate to severe left ventricular hypertrophy. Despite very low concentrations of adrenal and gonadal sex steroids bone age maturation progressed normally suggesting that gonadal and adrenal sex steroids are not critical for the maturation of the prepubertal skeleton.
Molecular and Cellular Endocrinology, 1991
The isolation, cloning and expression of a DNA insert complementary to mRNA encoding rat testis 3@-hydroxysteroid dehydrogenase/A5 + 4-isomerase (3P-HSD) is reported. The insert contains an open reading frame encoding a protein of 373 amino acids, which exhibits 73% and 78% identity to the cDNA encoding the human placental form at the amino acid and nucleotide levels respectively. Northern blot analysis of total RNA of rat tissues using as probe a specific radiolabeled cDNA insert encoding rat testis 3/3-HSD demonstrated high levels of 1.6 kb mRNA species in ovary, adrenal and Leydig tumor, with lower but detectable message in testis and adult male liver, while the probe also hybridized to a 2.1 kb mRNA species in liver. The cDNA was inserted into a modified pCMV vector and expressed in COS-1 monkey kidney tumor cells. The expressed protein was similar in size to 3P-HSD present in H540 Leydig tumor cell homogenate and human placental microsomal 3@-HSD, as detected by immunoblot analysis, and catalyzed the conversion of pregnenolone to progesterone, 17a-hydroxypregnenolone to 17cu-hydroxyprogesterone, and dehydroepiandrosterone to androstenedione. Transfected COS cell homogenates, supplemented with NAD+, but not NADP+, converted pregnenolone to progesterone and dehydroepiandrosterone to androstenedione with apparent K, values of 0.13 and 0.09 PM, respectively. Immunoblot analysis of various rat tissues using a polyclonal antibody directed against human placental 3/3-HSD, in addition to immunoreactivity in the adrenal and testis, demonstrated immunoreactive 3P-HSD protein in adult male liver, but not in adult female or fetal liver. We conclude that while one gene product is highly expressed in testicular Leydig cells, and probably adrenal and ovary, accounting for their 3P-HSD content, a 3P-HSD is also expressed in liver in a sex-specific manner.
The Journal of Clinical Endocrinology & Metabolism, 2002
To define the hormonal criteria via genotypic proof for 3hydroxysteroid dehydrogenase (3-HSD) deficiency in the adrenals and gonads, we investigated the type II 3-HSD genotype in 55 patients with clinical and/or hormonal presentation suggesting compromised adrenal with or without gonadal 3-HSD activity. Fourteen patients (11 males and 3 females) had ambiguous genitalia with or without salt wasting and with or without premature pubarche. One female neonate had salt wasting only. Twenty-five children (4 males and 21 females) had premature pubarche only. Fifteen adolescent and adult females had hirsutism with or without menstrual disorder. The type II 3-HSD gene, including the promoter region up to ؊1053 base, all exons I, II, III, IV, and exon and intron boundaries, was sequenced in all subjects. Eight patients had a proven or predictably deleterious mutation in both alleles of the type II 3-HSD gene, and 47 patients had no apparent mutation in the gene. ACTHstimulated (1 h post iv bolus of 250 g Cortrosyn) serum 17hydroxypregnenolone (⌬5-17P) levels and basal and ACTHstimulated ratios of ⌬5-17P to cortisol (F) in the genotypic proven patients were unequivocally higher than those of agematched or pubic hair stage matched genotype-normal patients or control subjects (n ؍ 7-30 for each group). All other baseline and ACTH-stimulated hormone parameters, including dehydroepiandrosterone (DHEA) levels, ratios of ⌬5-17P to 17-OHP and DHEA to androstenedione in the genotype-proven patients, overlapped with the genotype-normal patients or control subjects. The hormonal findings in the genotype-proven patients suggest that the following hormonal criteria are compatible with 3-HSD deficiency congenital adrenal hyperplasia (numeric and graphic reference standards from infancy to adulthood are provided): ACTH-stimulated ⌬5-17P levels in 1) neonatal infants with ambiguous genitalia at or greater than 378 nmol/ liter equivalent to or greater than 5.3 SD above the control mean level [95 ؎ 53 (SD) nmol/liter]; 2) Tanner I children with ambiguous genitalia at or greater than 165 nmol/liter equivalent to or greater than 35 SD above the control mean level [12 ؎ 4.3 (SD) nmol/liter]; 3) children with premature pubarche at or greater than 294 nmol/liter equivalent to or greater than 54 SD above Tanner II pubic hair stage matched control mean level [17 ؎ 5 (SD) nmol/liter]; and 4) adults with at or greater than 289 nmol/ liter equivalent to or greater than 21 SD above the normal mean level [25 ؎ 12 (SD) nmol/liter]. ACTH-stimulated ratio of ⌬5-17P to F in 1) neonatal infants at or greater than 434 equivalent to or greater than 6.4 SD above the control mean ratio [88 ؎ 54 (SD)]; 2) Tanner I children at or greater than 216 equivalent to or greater than 23 SD above the control mean ratio [12 ؎ 9 (SD)]; 3) children with premature pubarche at or greater than 363 equivalent to or greater than 38 SD above the control mean ratio [20 ؎ 9 (SD)]; and 4) adults at or greater than 4010 equivalent to or greater than 221 SD above the normal mean ratio [29 ؎ 18 (SD)]. Conversely, the hormonal data in the genotype-normal patients suggest the following hormonal criteria are not consistent with 3-HSD deficiency congenital adrenal hyperplasia: ACTH-stimulated ⌬5-17P levels in children with premature pubarche up to 72 nmol/liter equivalent to up to 11 SD above the control mean level, and in hirsute females up to 150 nmol/liter equivalent to up to 12 SD above the normal female mean level [28 ؎ 10 (SD) nmol/ liter]; and ACTH-stimulated ⌬5-17P to F ratio in children with premature pubarche up to 67 equivalent to up to 5 SD above the control mean ratio, and in hirsute females up to 151 equivalent to up to 10 SD above the normal mean ratio [32 ؎ 12 (SD)]. These findings help define newly proposed hormonal criteria to accurately predict inherited 3-HSD deficiency.
International Journal of Molecular Sciences, 2019
The term 'differences of sex development' (DSD) refers to a group of congenital conditions that are associated with atypical development of chromosomal, gonadal, or anatomical sex. Disorders of steroidogenesis comprise autosomal recessive conditions that affect adrenal and gonadal enzymes and are responsible for some conditions of 46,XX DSD where hyperandrogenism interferes with chromosomal and gonadal sex development. Congenital adrenal hyperplasias (CAHs) are disorders of steroidogenesis that mainly involve the adrenals (21-hydroxylase and 11hydroxylase deficiencies) and sometimes the gonads (3-beta-hydroxysteroidodehydrogenase and P450-oxidoreductase); in contrast, aromatase deficiency mainly involves the steroidogenetic activity of the gonads. This review describes the main genetic, biochemical, and clinical features that apply to the abovementioned conditions. The activities of the steroidogenetic enzymes are modulated by post-translational modifications and cofactors, particularly electron-donating redox partners. The incidences of the rare forms of CAH vary with ethnicity and geography. The elucidation of the precise roles of these enzymes and cofactors has been significantly facilitated by the identification of the genetic bases of rare disorders of steroidogenesis. Understanding steroidogenesis is important to our comprehension of differences in sexual development and other processes that are related to human reproduction and fertility, particularly those that involve androgen excess as consequence of their impairment.
Biochimica et Biophysica Acta
for 17a-hydroxylation of pregnenolone and 1.5 -10s6 M for progesterone. Since formation of these 20-ketone reduced steroids was mediated by 2Oa-hydroxysteroid dehydrogenase, it is postulated that the role of 20a-hydroxysteroid dehydrogenase in regulating androgen formation in the human testis is by competing with steroid 17n-hydroxylase to utilize pregnenolone and progesterone and by inhibiting steroid 17a-hydroxylase by its reaction products, 2Oadihydropregnenolone and 2Oadihydroprogesterone.
Testicular adrenal rest hyperplasia due to 21-hydroxylase deficiency: a case report
Endocrine pathology, 2006
Bilateral testicular tumors are a rare complication of congenital adrenal hyperplasia. It can be extremely difficult to distinguish histologically between Leydig cell tumors and adrenocortical rest hyperplasia, which may lead in some cases to unnecessary orchidectomy. A 7-yr-old boy was admitted because of precocious puberty and enlargement of testicles. Hormonal studies established the diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Testicular biopsy revealed interlacing strands, cords, and rests of cells resembling interstitial (Leydig) cells but with no Reinke crystalloids. Here we report a case of testicular adrenal rest hyperplasia in congenital adrenal hyperplasia and discuss the pathological and clinical features and origin of this rare lesion by using immunohistochemical evaluation.