The Hormonal Phenotype of Nonclassic 3β-Hydroxysteroid Dehydrogenase (HSD3B) Deficiency in Hyperandrogenic Females Is Associated with Insulin-Resistant Polycystic Ovary Syndrome and Is Not a Variant of Inherited HSD3B2 Deficiency

Abstract

To test our hypothesis that the hormonal phenotype of mild 3beta-hydroxysteroid dehydrogenase (HSD3B) deficiency in hyperandrogenic females (HF) is related to insulin-resistant polycystic ovary syndrome (PCOS), we compared insulin sensitivity and gonadotropin secretion in HF with compromised ( downward arrow ) adrenal HSD3B phenotype despite normal HSD3B2 genes (n = 6) to those in HF with classic PCOS (n = 9) of similar ages (14-36 yr). The same was examined in premature pubarche (PP) girls with (n = 4) and without the descending HSD3B phenotype (n = 5). The descending HSD3B phenotype was defined by ACTH-stimulated Delta(5)-precursor steroid levels and Delta(5)-precursors to Delta(4)-product steroid ratios higher than those in normal females (n = 30 for adult, n = 12 for pubertal). Classic PCOS HF had elevated testosterone levels and normal ACTH-stimulated hormonal profiles. The insulin sensitivity index determined by the frequently sampled iv glucose-tolbutamide test (FSIVGTT) in all HF with descending HSD3B phenotype and in all HF with classic PCOS, regardless of body mass index (BMI), was lower than in all eight normal BMI and five high BMI normal females. Integrated incremental insulin determined by FSIVGTT, the area under the curve for insulin, and fasting and 2 h glucose load insulin levels determined by an oral glucose tolerance test in both HF groups were higher (P < 0.01-0.0001) than those in normal females with normal or high BMI. LHRH-stimulated LH levels and LH/FSH ratios in both HF groups were higher (P < 0.01) than those in normal females. No statistical differences were found in the insulin sensitivity and gonadotropin parameter between the two PP girl groups. The insulin sensitivity index in each half of PP girls with the descending HSD3B phenotype was lower than or similar to that in control PP girls with a similar weight length index. The fasting glucose to insulin ratio in three of four PP girls with the descending HSD3B phenotype was lower than that in control PP girls, but one of four with the descending HSD3B phenotype had a higher fasting glucose to insulin ratio than the control PP girls. The findings of insulin sensitivity and gonadotropin data in both HF with the descending HSD3B phenotype and classic PCOS indicate significant insulin resistance and LH hypersecretion in both. These suggest that the descending HSD3B phenotype in HF is associated with a variant of insulin-resistant PCOS. The variable insulin sensitivity parameter in the small number of PP girls with the descending HSD3B phenotype warrants a further large scale study to examine this phenotype association with childhood insulin resistance.

Management Approaches to Congenital Adrenal Hyperplasia in Adolescents and Adults; Latest Therapeutic Developments

“…Ambroziak et al reported that adult patients with classical 21-hydroxylase deficiency have obesity, hyperinsulinemia, insulin resistance, and hyperleptinemia more frequently than age/sex matched controls (Ambroziak et al, 2010). Carbunaru et al have reported that the hormonal phenotype of non-classic 3--ol dehydrogenase deficiency in hyperandrogenemic females is associated with insulin-resistant PCOS and is not a variant of genetic HSD3B2 deficiency (Carbunaru et al, 2004). This article is consistent with a publication by (Lutfallah et al, 2002) that proposed new hormonal criteria for the diagnosis of those patients with mutations in the Type II 3-beta-ol dehydrogenase exon.…”

“…Gene therapy, wherein the defective gene is supplemented with a functional one should, theoretically, be the ideal therapy for every form of CAH, with the possible exception of non-classical 3--ol dehydrogenase deficiency, for which no mutation in the exon has been identified (Carbunaru et al, 2004).…”

The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report

“…However, in patients who develop this form of hyperandrogenism during adult life, no specific genetic defect has been detected, and it has been suggested that these patients may have a functional enzymatic deficiency (143,144). In practice, these patients may be considered affected by PCOS because they generally have anovulation and menstrual irregularities and have similar phenotypic features, including insulin resistance and LH hypersecretion, as patients of classic PCOS (142,144).…”

The adrenal and polycystic ovary syndrome

“…Circulating DHEAS levels are positively, albeit weakly, associated with the degree of hypersecretion. The adrenocortical dysfunction observed does not appear to be the result of genetic defects affecting 21-OH (P450c21, encoded by CYP21) [49,50], 11β-hydroxylase (11-OH; P450c11, encoded by CYP11B1) [51], or 3β-hydroxysteroid dehydrogenase (3β-HSD, encoded by HSD3B2) [52,53]. In fact, the single steroidogenic difference observed between PCOS women and healthy controls appears to be a greater estimated Δ 5 17-OH activity [50], primarily observed in PCOS patients with high DHEAS levels [43].…”