INSULIN INFUSION AMPLIFIES 17-ALPHA-HYDROXYCORTICOSTEROID INTERMEDIATES RESPONSE TO ADRENOCORTICOTROPIN IN HYPERANDROGENIC WOMEN - APPARENTRELATIVE IMPAIRMENT OF 17,20-LYASE ACTIVITY

Recent data suggest that insulin is a modulator of ovarian and adrenal steroidogenesis and that, in the ovary of hyperandrogenic women, hype rinsulinemia might cause dysregulation of cytochrome P450c17 alpha act ivity. To further assess in vivo the effects of insulin on adrenal ste roidogenesis, ACTH stimulation was carried out in 21 hyperandrogenic w omen during a 3-h hyperinsulinemic (80 mU/m(2) . min) euglycemic clamp . In all of these women the procedure was repeated during saline infus ion as a control. In nonamenorrheic patients, the tests were performed in the early follicular phase of two different menstrual cycles. Seru m cortisol, progesterone, 17-hydroxypregnenolone (17-OHPREG), 17-hydro xyprogesterone (17-OHP), dehydroepiandrosterone (DHEA), and androstene dione (A) were measured after 2 h of insulin or saline infusion (zero time) and, subsequently, 30 and 60 min after an iv bolus of 0.25 mg AC TH-(1-24). At zero time, no difference was found in the serum steroid concentrations between the two protocols. ACTH-stimulated serum 17-OHP REG and, to a lesser extent, 17-OHP were significantly higher during i nsulin than during saline infusion (peaks, 60.6 +/- 9.0 vs. 40.7 +/- 7 .9 and 7.7 +/- 0.7 vs. 6.6 +/- 0.6 nmol/L; P < 0.005 and P < 0.01, res pectively). Serum DHEA was also slightly higher during hyperinsulinemi a, although only after 30 min (54.5 +/- 3.0 vs. 48.2 +/- 4.2 nmol/L; P < 0.05). No statistically significant difference in the cortisol, pro gesterone, or androstenedione response to ACTH was found between the t wo protocols. ACTH-stimulated 17-OHPREG/DHEA and 17-OHP/A molar ratios , indexes of apparent 17,20-lyase activity, were significantly higher during the clamp studies than during saline infusion (by ANOVA, F = 12 .8; P < 0.001 and F = 8.7; P < 0.005, respectively), suggesting an imp aired enzyme activity. These in vivo data support the hypothesis that insulin potentiates ACTH-stimulated steroidogenesis. This effect of in sulin seems to be associated with a relative impairment of 17,20-lyase activity.