Clinical evidence for predominance of delta-5 steroid production in women with polycystic ovary syndrome

Abstract

Context: In women with polycystic ovary syndrome (PCOS), the basis for ovarian androgen overproduction involves an overall increase of steroidogenesis, notably in the delta-4 pathway. However, in vitro studies have suggested that excessive androgen production occurs predominantly through the delta-5 pathway.

Objective: This study was performed to assess androgen dose-responses after human chorionic gonadotropin (hCG) stimulation in PCOS and normal women.

Design: We conducted a prospective study to compare androgen production after iv hCG in PCOS and normal women.

Setting: The study was conducted in a General Clinical Research Center in an academic medical center.

Participants: Women with PCOS (age, 18-37 yr; n = 10) and normal ovulatory controls (age, 18-37 yr; n = 11) were recruited.

Interventions: For dose-response studies, blood samples were obtained before and at 0.5, 24, and 48 h after iv recombinant hCG (1, 10, 25, 100, and 250 μg). A subset of subjects underwent frequent blood sampling over 24 h after iv injection of 25 μg of recombinant hCG.

Main outcome measure(s): We measured basal and stimulated serum 17-hydroxyprogesterone (17-OHP), androstenedione (A), testosterone (T), dehydroepiandrosterone, estradiol, and progesterone responses after hCG administration.

Results: In PCOS women, maximal A and T production was observed at the lowest doses of hCG, whereas responses were minimal in normal women. Incremental responses of 17-OHP, estradiol, and progesterone were greater in PCOS compared to normal women.

Conclusion: In PCOS women, maximal A and T responses to hCG relative to those of 17-OHP are consistent with ovarian androgen overproduction via the delta-5 pathway.

Trial registration: ClinicalTrials.gov NCT00747617.

Figures

Fig. 1.

Mean serum hCG concentrations after iv administration of r-hCG in a combined group of five PCOS and five normal women. The baseline hCG levels in all subjects were undetectable. The early maximal increase at each dose represents the mean serum hCG value 30 min after injection.

Fig. 2.

Mean (±se) baseline and 24-h serum 17-OHP, A, T, DHEA, E2, and P4 responses to iv administration of 1, 10, 25, 100, and 250 ìg of r-hCG in PCOS and normal women. Using linear mixed-effect models analyses, significant increases of 17-OHP, E2, and P4 were observed in both groups. By comparison, incremental A responses were significant only in PCOS women. Between groups, 17-OHP and A responses were significantly greater in PCOS women. Serum T responses were also higher compared to normal women, but the difference did not achieve statistical significance. As determined by MMRM, significant differences between groups in response to a fixed dose of hCG are indicated by a (P < 0.05), b (P < 0.01), and c (P < 0.001).

Fig. 3.

Mean (±se) serum levels of 17-OHP, A, T, DHEA, E2, and P4 over 24 h after iv administration of 25 ìg r-hCG in five PCOS women and four normal controls.

Fig. 4.

Mean (±se) serum levels of 17-OHP, A, and T at baseline, 24, and 48 h after iv administration of 250 ìg r-hCG in PCOS and normal women.

Fig. 5.

Serum 17-OHP, A, and T responses in individual women with PCOS (black triangles) and normal controls (open circles) before and 24 h after iv administration of 25 μg r-hCG. Variable androgen responsiveness in PCOS women was similar at all doses of r-hCG.