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.