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Evidence for Abnormal Granulosa Cell Responsiveness to Follicle-Stimulating Hormone in Women with Polycystic Ovary Syndrome

Departments of Reproductive Medicine (M.S.C., K.P., M.H.D., P.J.M., R.J.C.) and Family and Preventive Medicine (R.D.), University of California, San Diego, La Jolla, California 92093; and San Diego State University (T.K.), San Diego, California 92182

Address all correspondence and requests for reprints to: R. Jeffrey Chang, M.D., Department of Reproductive Medicine, University of California, San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, California 92093-0633. E-mail: rjchang{at}ucsd.edu.

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 (E₂) 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, E₂ responses to 37.5 IU and 75 IU were similar between groups. Regression analysis of maximal E₂ 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 E₂ were not sustained, compared with those of normal controls, because peak concentrations were followed by an estimated 40% decrement in circulating levels, whereas E₂ 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 E₂ production in response to iv r-hFSH, compared with normal women. In PCOS, E₂ production was relatively transient because after peak concentrations a marked decline was detected at each dose, unlike normal women who exhibited persistent elevations of E₂ 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.

This research was supported by National Institute of Child Health and Human Development/National Institutes of Health (NIH) through a cooperative agreement (U54 HD12303-20) as part of the Specialized Cooperative Centers Program in Reproduction Research and in part by NIH Grant M01 RR00827.

Abbreviations: A, Androstenedione; CV, coefficient(s) of variation; DHEAS, dehydroepiandrosterone sulfate; E₁, estrone; E₂, estradiol; IGFBP, IGF binding protein; 17-OHP, 17-hydroxyprogesterone; PCOS, polycystic ovary syndrome; P₄, progesterone; r-hFSH, recombinant human FSH; T, testosterone.

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