These results indicate that the absolute LH increment following GnRH is largely dependent on baseline LH levels and may account for the well-documented difference in LH responsiveness between PCOS and normal women. That neither LH responses to GnRH nor LH pulse amplitude were correlated to LH pulse frequency suggests involvement of other factors along with GnRH to account for increased LH secretion in PCOS. In addition to E2 and BMI, serum testosterone appears to be, at least in part, responsible for differences in LH secretion and release between PCOS and normal women.

Women with polycystic ovary syndrome (PCOS) undergoing ovulation induction appear to be extremely sensitive to gonadotropin stimulation and at increased risk for ovarian hyperstimulation syndrome. To determine granulosa cell responsiveness to recombinant human FSH (r-hFSH), dose-response studies were conducted in 16 individual PCOS patients and 7 normal women. Each subject received an iv injection of r-hFSH at doses of 0, 37.5, 75, or 150 IU in a randomized fashion on four separate occasions. Blood samples were obtained at frequent intervals before and for 24 h after r-hFSH administration for measurement of gonadotropins and steroid hormones. Our results showed that administration of r-hFSH produced instantaneous and equivalent dose-related increases in serum FSH in PCOS and normal women, which were followed by similar exponential decreases to baseline levels within 24 h in both groups. In PCOS subjects, the peak mean incremental response of serum estradiol (E(2)) to 150 IU of r-hFSH was 1.8-fold greater (P < 0.0001) and considerably accelerated compared with that found in normal women. In contrast, E(2) responses to 37.5 IU and 75 IU were similar between groups. Regression analysis of maximal E(2) concentrations in response to r-hFSH in each individual subject revealed that the slope of the linear trend line in the group of women with PCOS (r = 0.82) was significantly greater (P < 0.01) than that of normal controls (r = 0.71). The time-course of response revealed that in PCOS women, increases of E(2) were not sustained, compared with those of normal controls, because peak concentrations were followed by an estimated 40% decrement in circulating levels, whereas E(2) levels in normal women persisted for 24 h after reaching maximal values. These findings indicate that women with PCOS exhibit a significantly greater capacity for E(2) production in response to iv r-hFSH, compared with normal women. In PCOS, E(2) production was relatively transient because after peak concentrations a marked decline was detected at each dose, unlike normal women who exhibited persistent elevations of E(2) for up to 24 h. That this distinction was dose-dependent supports the concept of an FSH dose-response threshold, beyond which PCOS but not normal women are susceptible to ovarian hyperresponsiveness.

These findings suggest that in PCOS and normal women, acute exposure to FSH does not appear to exert an effect on AMH production.

Women with polycystic ovary syndrome (PCOS) are known to exhibit insulin resistance with compensatory hyperinsulinemia. To determine the role of hyperinsulinemia on follicle function in PCOS, we examined 24-h estradiol (E(2)) responses to recombinant human FSH (r-hFSH), 75 IU, before and during insulin infusion both before and after administration of pioglitazone (30 mg/d) in seven PCOS women. Each subject underwent two 10-h hyperinsulinemic-euglycemic clamps at rates of 30 (low dose) and 200 (high dose) mU/m(2).min, respectively. During both low- and high-dose insulin infusions, E(2) responses to r-hFSH were unaltered compared with that observed in the absence of insulin. Pioglitazone administration for 5 months improved insulin sensitivity as indicated by significantly (P < 0.05) increased glucose infusion rates during the clamp studies. At 3 months of treatment, r-hFSH-stimulated E(2) responses were not different from those observed before treatment. With pioglitazone treatment, E(2) responses to r-hFSH remained unchanged during low-dose insulin infusion, whereas a highly significant (P < 0.02) increased response was noted with the high-dose hyperinsulinemic-euglycemic clamp. In addition to a greater magnitude of response, peak levels of E(2) were sustained longer compared with that seen before treatment. The data indicate that granulosa cell responsiveness to FSH was enhanced by insulin after improved insulin sensitivity induced by pioglitazone. These findings are consistent with the possibility that PCOS granulosa cells are insulin resistant.

These findings provide evidence that, in PCOS women, theca cell androgen production is enhanced by FSH administration and suggest a granulosa-theca cell paracrine mechanism.

Assisted reproduction technologies and ovulation induction for treatment of infertility continue to cause high order multiple gestations. Increased perinatal morbidity and mortality, as well as maternal morbidity, may complicate these pregnancies. Selective fetal reduction, an acceptable therapeutic approach in these cases, is usually performed at or after the ninth week of gestation, with KCl injected in the vicinity of the fetal heart, and is associated with a total pregnancy loss rate of 11.7%. We report our experience with 90 women who underwent early (mean 7.5 weeks gestation, range 7. 0-8.0 weeks) transvaginal selective embryo aspiration. The mean number of viable embryos before and after reduction was 3.5 and 2.1 respectively. Six (6.7%) pregnancies were lost before 24 gestational weeks. One miscarriage occurred at the tenth gestational week. The other five pregnancies were aborted at 17.3-21.6 weeks gestation. Additional interventions were performed in three of these pregnancies: genetic amniocentesis in two cases and cervical suture in one case. In the subset of 39 patients with>/=4 embryos, only one (2.6%) pregnancy loss was recorded. This loss rate is significantly lower (P < 0.05) than the 15.3% loss rate in patients with >/=4 fetuses calculated from other work. Four (4.4%) other pregnancies were complicated by premature delivery (25-28 weeks gestation). Mean gestational age of delivered pregnancies in our series was 35.7 weeks. In conclusion, early transvaginal embryo aspiration is a simple and relatively safe method for multiple pregnancy reduction. The overall pregnancy loss rate associated with early embryo aspiration is similar to that of procedures performed at later gestational age, but is significantly lower when the initial number of embryos is four or greater.

In PCOS women with insulin resistance, hyperinsulinemia may contribute to inappropriate gonadotropin secretion. To determine whether insulin influences gonadotropin release in PCOS, pulsatile LH secretion and gonadotropin responses to GnRH were evaluated before (phase 1) and during (phase 2) insulin infusion. In phase 1, 11 PCOS and 9 normal women on separate days underwent 1) frequent blood sampling (q 10 min) for 12 h and 2) gonadotropin stimulation by successive doses of GnRH, 2 microg, 10 microg, and 20 microg, administered i.v. at 4 h intervals over a continuous 12 h. In phase 2, studies were repeated 2 h after initiation of a 12-h hyperinsulinemic-euglycemic clamp (80 mU/m(2).min). Administration of insulin to both groups failed to alter mean serum gonadotropin concentrations, LH pulse frequency, or LH pulse amplitude. Moreover, gonadotropin responses to GnRH were unchanged by insulin infusion. In PCOS and normal women, a significant reduction of serum androstenedione was associated with insulin administration, whereas no differences were noted for the remaining androgens and estrogens measured. These findings demonstrated that in PCOS women, LH secretion and gonadotropin responses to GnRH were not influenced by insulin administration. Insulin infusion had little effect on steroid hormone production with the possible exception of androstenedione. These results suggest that inappropriate LH secretion in PCOS is not a direct consequence of insulin resistance and compensatory hyperinsulinemia.

FSH-stimulated inhibin B responses may be employed to assess the functional capacity of granulosa cells in PCOS and normal women.