Reproductive and metabolic determinants of granulosa cell dysfunction in normal-weight women with polycystic ovary syndrome

Abstract

Objective: To determine the degree to which E₂ hyperresponsiveness to FSH and antimüllerian hormone (AMH) overproduction in normal-weight women with polycystic ovary syndrome (PCOS) correlate with increased antral follicle number (AFN), hyperandrogenism, and/or metabolic dysfunction.

Design: Prospective cohort study.

Setting: Academic medical center.

Patient(s): Seven normal-weight women with PCOS (1990 National Institutes of Health criteria) ages 20-34 years and 13 age- and body mass index- (BMI-; 18.5-25 kg/m²) matched normoandrogenic ovulatory women were studied.

Intervention(s): All women underwent basal serum hormone and metabolic measurements, FSH stimulation testing with transvaginal ovarian sonography, frequently sampled IV glucose tolerance testing, and whole-body dual-energy x-ray absorptiometry.

Main outcome measure(s): Serum hormone/metabolite levels, 24-hour serum E₂ response to 150 IU recombinant human (rh) FSH infusion, AFN, insulin sensitivity, and body mass measurements.

Result(s): Serum E₂ responsiveness to rhFSH and AMH levels were greater in women with PCOS than in BMI- and age-matched control women, as were serum androgen levels, AFN, and abdominal fat mass. In all women combined, serum E₂ responsiveness to rhFSH was associated with AFN. Serum AMH levels, however, positively correlated with AFN but remained positively correlated with serum LH and free T levels and negatively correlated with total body fat and percent body fat, adjusting for AFN.

Conclusion(s): In normal-weight women with PCOS, serum E₂ hyperresponsiveness to rhFSH represents increased AFN, while elevated serum AMH levels reflect opposing effects of stimulatory reproductive (hyperandrogenism and increased AFN) versus inhibitory metabolic (body fat) factors. Given the small number of subjects reported, additional follow-up studies are required to confirm these data.

Keywords: Antimüllerian hormone; PCOS; adiposity; estradiol; hyperandrogenism.

Figure 1

Twenty-four-hour (24-hr) area under the curve (AUC) determinations for serum E2 and FSH responses to 150 IU rhFSH intravenous infusion. The serum E2 response to rhFSH was significantly greater in PCOS (N=7) than BMI- and age-matched control (N=13) women (A) despite similar serum FSH responses to rhFSH injection in both female groups (B). The initial rise of serum E2 in all women occurred 4–6 hours after rhFSH injection, with the subsequent rise thereafter to maximal serum E2 levels at 16 hours being greater in PCOS than the control women (C). Serum FSH levels rose to maximal levels approximately 6 hours after 150 IU rhFSH intravenous infusion and then declined from these levels thereafter (D). *, P=0.009 vs. BMI- and age-matched control (mean ± SEM).

Figure 2

Serum E2 response to rhFSH positively correlated with (A) percent android fat, (B) serum total T level and (C) log AFN in all women combined (13 BMI- and age-matched controls [open circles], 7 PCOS [dark circles]: total, 20 women).

Figure 3

Serum AMH levels positively correlated with (A) percent android fat; serum levels of (B) total T, (C) free T, (D) A4 and (E) LH; as well as (F) log AFN in all women combined (13 BMI- and age-matched controls [open circles], 6 PCOS [dark circles]: total, 19 women).