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

Department of Pediatrics, Division of Pediatric Endocrinology, and Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, University of Illinois College of Medicine (G.C., P.P., B.S., P.S., F.Z., Y.T.C., S.P.), Chicago, Illinois 60612; Department of Pediatrics, Division of Pediatric Endocrinology, University of Michigan (N.H.), Ann Arbor, Michigan 48109; Department of Pediatrics, Division of Pediatric Endocrinology, St. Louis University (S.E.M.), St. Louis, Missouri 63104; and Division of Reproductive and Developmental Sciences (Clinical Biochemistry), University of Edinburgh (J.I.M.), Edinburgh, Scotland EH16 4SB

Address all correspondence and requests for reprints to: Dr. Songya Pang, Department of Pediatrics, University of Illinois College of Medicine, 840 South Wood Street, M/C 856, Chicago, Illinois 60612. E-mail: spang{at}tigger.cc.uic.edu.

To test our hypothesis that the hormonal phenotype of mild 3ß-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 () 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 HSD3B phenotype (n = 5). The HSD3B phenotype was defined by ACTH-stimulated ⁵-precursor steroid levels and ⁵-precursors to 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 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 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 HSD3B phenotype was lower than that in control PP girls, but one of four with the 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 HSD3B phenotype and classic PCOS indicate significant insulin resistance and LH hypersecretion in both. These suggest that the 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 HSD3B phenotype warrants a further large scale study to examine this phenotype association with childhood insulin resistance.

This work was supported by USPHS Grant R01-HD-36399 (to S.P.) and in part by a USPHS grant for the General Clinical Research Center to University of Illinois (Chicago, IL).

Abbreviations: ⁴-A, Androstenedione; AUCg, area under the curve for glucose; AUCi, area under the curve for insulin; BMI, body mass index; , compromised; ⁵-17P, 17-hydroxypregnenolone; DHEA, dehydroepiandrosterone; F, cortisol; FSIVGTT, frequently sampled iv glucose-tolbutamide test; HF, hyperandrogenic female; HSD3B, 3ß-hydroxysteroid dehydrogenase; IIIns, integrated incremental insulin; OGTT, oral glucose tolerance test; 17-OHP, 17-hydroxyprogesterone; PCOS, polycystic ovary syndrome; PP, premature pubarche; S_I, insulin sensitivity index; T, testosterone; WLI, weight-length index.

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