Deficiência combinada de 17α-hidroxilase/17,20 liase devido à mutação p.R96W no gene CYP17 em um paciente brasileiro

Congenital adrenal hyperplasia (CAH) resulting from 17α-hydroxylase/17,20-lyase deficiency is a rare autosomal recessive disease and the second most common form of CAH in Brazil. We describe the case of a Brazilian patient with CYP17 deficiency (17α-hydroxylase/17,20-lyase deficiency) caused by a homozygous p.R96W mutation on exon 1 of the CYP17 gene, an unusual genotype in Brazilian patients with this form of CAH. The patient, raised as a normal female, sought medical care for lack of pubertal signs and primary amenorrhea at the age of 16 years. At evaluation, the presence of a 46,XY karyotype, hypertension and hypokalemia were observed. We emphasize the recognition of CYP17 deficiency in the differential diagnosis of cases of hypergonadotrophic hypogonadism and hypertension in young patients who need specific treatment for both situations.A hiperplasia adrenal congênita (HAC), em razão da deficiência de 17α-hidroxilase/17,20-liase, é uma doença autossômica recessiva rara e a segunda causa mais comum de HAC no Brasil. Descrevemos o caso de um paciente brasileiro portador da deficiência 17α-hidroxilase/17,20- liase (CYP17) em homozigose para a mutação p.R96W no éxon 1 do gene da CYP17A1, uma mutação incomum entre os casos brasileiros descritos com essa forma de HAC. Esse paciente, criado como um indivíduo normal do sexo feminino, procurou atendimento por ausência de sinais puberais e amenorreia primária aos 16 anos de idade. Durante a avaliação, constataram-se um cariótipo 46,XY e a presença de hipertensão e hipocalemia. Enfatizamos o reconhecimento da deficiência da CYP17 dentre os possíveis diagnósticos em um paciente jovem com hipogonadismo hipergonadotrófico e hipertensão, os quais necessitam de tratamento particularizado para ambas as situações.Universidade Federal do Rio Grande do Sul Hospital de Clínicas de Porto AlegreUniversidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Department of MedicineUniversity of Texas Southwestern Medical Center Department of Internal MedicineUNIFESP, EPM, Department of MedicineSciEL

3beta-Hydroxysteroid Dehydrogenase is a Possible Pharmacological Target in the Treatment of Castration-Resistant Prostate Cancer

Prostate cancer usually responds to androgen deprivation therapy, although the response in metastatic disease is almost always transient and tumors eventually progress as castration-resistant prostate cancer (CRPC). CRPC continues to be driven by testosterone or dihydrotestosterone from intratumoral metabolism of 19-carbon adrenal steroids from circulation, and/or de novo intratumoral steroidogenesis. Both mechanisms require 3beta-hydroxysteroid dehydrogenase (3betaHSD) metabolism of Delta(5)-steroids, including dehydroepiandrosterone (DHEA) and Delta(5)-androstenediol (A5diol), to testosterone. In contrast, reports that DHEA and A5diol directly activate the androgen receptor (AR) suggest that 3betaHSD metabolism is not required and that 3betaHSD inhibitors would be ineffective in the treatment of CRPC. We hypothesized that activation of AR in prostate cancer by DHEA and A5diol requires their conversion via 3betaHSD to androstenedione and testosterone, respectively. Here, we show that DHEA and A5diol induce AR chromatin occupancy and AR-regulated genes. Furthermore, we show that Delta(5)-androgens undergo 3beta-dehydrogenation in prostate cancer and that induction of AR nuclear translocation, AR chromatin occupancy, transcription of PSA, TMPRSS2, and FKBP5, as well as cell proliferation by DHEA and A5diol, are all blocked by inhibitors of 3betaHSD. These findings demonstrate that DHEA and A5diol must be metabolized by 3betaHSD to activate AR in these models of CRPC. Furthermore, this work suggests that 3betaHSD may be exploited as a pharmacologic target in the treatment of CRPC

Deficiência combinada de 17α -hidroxilase/17,20 liase devido à mutação p.R96W no gene CYP17 em um paciente brasileiro

A hiperplasia adrenal congênita (HAC), em razão da deficiência de 17α -hidroxilase/17,20-liase, é uma doença autossômica recessiva rara e a segunda causa mais comum de HAC no Brasil. Descrevemos o caso de um paciente brasileiro portador da deficiência 17α -hidroxilase/17,20- liase (CYP17) em homozigose para a mutação p.R96W no éxon 1 do gene da CYP17A1, uma mutação incomum entre os casos brasileiros descritos com essa forma de HAC. Esse paciente, criado como um indivíduo normal do sexo feminino, procurou atendimento por ausência de sinais puberais e amenorreia primária aos 16 anos de idade. Durante a avaliação, constataram-se um cariótipo 46,XY e a presença de hipertensão e hipocalemia. Enfatizamos o reconhecimento da deficiência da CYP17 dentre os possíveis diagnósticos em um paciente jovem com hipogonadismo hipergonadotrófico e hipertensão, os quais necessitam de tratamento particularizado para ambas as situações.Congenital adrenal hyperplasia (CAH) resulting from 17α -hydroxylase/17,20-lyase deficiency is a rare autosomal recessive disease and the second most common form of CAH in Brazil. We describe the case of a Brazilian patient with CYP17 deficiency (17α -hydroxylase/17,20-lyase deficiency) caused by a homozygous p.R96W mutation on exon 1 of the CYP17 gene, an unusual genotype in Brazilian patients with this form of CAH. The patient, raised as a normal female, sought medical care for lack of pubertal signs and primary amenorrhea at the age of 16 years. At evaluation, the presence of a 46,XY karyotype, hypertension and hypokalemia were observed. We emphasize the recognition of CYP17 deficiency in the differential diagnosis of cases of hypergonadotrophic hypogonadism and hypertension in young patients who need specific treatment for both situations

Biochemical Factors Governing the Steady-State Estrone/Estradiol Ratios Catalyzed by Human 17β-Hydroxysteroid Dehydrogenases Types 1 and 2 in HEK-293 Cells

Human 17β-hydroxysteroid dehydrogenase types 1 and 2 (17βHSD1 and 17βHSD2) regulate estrogen potency by catalyzing the interconversion of estrone (E1) and estradiol (E2) using nicotinamide adenine dinucleotide (phosphate) cofactors NAD(P)(H). In intact cells, 17βHSD1 and 17βHSD2 establish pseudo-equilibria favoring E1 reduction or E2 oxidation, respectively. The vulnerability of these equilibrium steroid distributions to mutations and to altered intracellular cofactor abundance and redox state, however, is not known. We demonstrate that the equilibrium E2/E1 ratio achieved by 17βHSD1 in intact HEK-293 cell lines is progressively reduced from 94:6 to 10:90 after mutagenesis of R38, which interacts with the 2′-phosphate of NADP(H), and by glucose deprivation, which lowers the NADPH/NADP+ ratio. The shift to E2 oxidation parallels changes in apparent Km values for purified 17βHSD1 proteins to favor NAD(H) over NADP(H). In contrast, mutagenesis of E116 (corresponding to R38 in 17βHSD1) and changes in intracellular cofactor ratios do not alter the greater than 90:10 E1/E2 ratio catalyzed by 17βHSD2, and these mutations lower the apparent Km of recombinant 17βHSD2 for NADP(H) only less than 3-fold. We conclude that the equilibrium E1/E2 ratio maintained by human 17βHSD1 in intact cells is governed by NADPH saturation, which is strongly dependent on both R38 and high intracellular NADPH/NADP+ ratios. In contrast, the preference of 17βHSD2 for E2 oxidation strongly resists alteration by genetic and metabolic manipulations. These findings suggest that additional structural features, beyond the lack of a specific arginine residue, disfavor NADPH binding and thus support E2 oxidation by 17βHSD2 in intact cells