The Impact of Insulin Secretion on the Ovarian Response to Exogenous Gonadotropins in PCOS

ABSTRACT & COMMENTARY

Synopsis: Hyperinsulinemia is a risk factor for ovarian hyperresponsivity during ovulation induction with exogenous FSH.

Source: Fulghesu AM, et al. J Clin Endocrinol Metab 1997;82:644-648.

A subset of women with polycystic ovary syndrome (PCOS), regardless of body mass index, have insulin resistance. Insulin increases LH-mediated androgen production by ovarian thecal-stromal cells and the aromatase activity of granulosa cells. Given these considerations, Fulghesu et al wondered if women with PCOS who were hyperinsulinemic would respond differently to FSH stimulation than those who were found to meet criteria for normoinsulinemia. Thirty-four women with polycystic ovary syndrome underwent 52 cycles of superovulation with exogenous FSH (Metrodin). The presence or absence of hyperinsulinemia was determined in response to a standard oral glucose tolerance test. All of the PCOS women in the study had failed to conceive after six cycles of clomiphene citrate. The increase in ovarian volume in response to exogenous FSH delivered in a standard format was greater in women designated as hyperinsulinemic. This was caused by the development of a larger number of immature follicles. The estradiol level and the estradiol/androstenedione ratio were higher in the hyperinsulinemic group.

Because the androstenedione levels were similar in both groups, the greater estradiol/androstenedione level was interpreted as indicating greater aromatization of the androgen precursor in the women with hyperinsulinemia. About 50% of the stimulation cycles resulted in ovarian hyperstimulation syndrome that ranged from mild to severe in the hyperinsulinemic group as contrasted to 25% in the normoinsulinemic group, in whom the severity was never more than moderate. Fulghesu et al thus conclude that hyperinsulinemia is a risk factor for ovarian hyperresponsivity during ovulation induction with exogenous FSH.

COMMENT BY SARAH L. BERGA, MD

The present study provides yet another rationale for needing a diagnosis prior to instituting treatment in anovulatory women. No one quite understands how women who are resistant to insulin’s actions in terms of glucose disposal can be so sensitive to its actions at the ovarian level. However, the present study confirms that insulin alters intraovarian events. In the scenario of ovulation induction with FSH, elevated insulin levels enhance ovarian responsivity. The sample size was too small to examine pregnancy outcome, but presumably these women are more at risk for multiple gestation as well as ovarian hyperstimulation syndrome. Others have shown that hyperinsulinemic women have an increased lifetime risk of noninsulin- dependent diabetes mellitus. One worries that resulting pregnancies will be complicated by gestational diabetes. If one knows about these risks ahead of time, it may be possible to ameliorate them to some degree.

Although nonobese women with PCOS may have insulin resistance, excess weight will only aggravate this diathesis. Ovulation induction should be undertaken with extreme caution, perhaps with the use of twice daily injections to provide a more physiological FSH signal. If conception occurs, monitoring for gestational diabetes is mandatory. Ovarian hyperstimulation can become life-threatening in women who conceive as hCG levels rise, and it is sometimes necessary to resort to pregnancy termination. Since women with PCOS who hyperstimulate once are at risk for more of the same in subsequent cycles, it may be worth a trial of weight reduction prior to the next cycle if the woman is overweight. It is puzzling and frustrating for physician and patient alike when multiple cycles of ovulation induction result in too great of an ovarian response. Now at least we have a potential culprit, and one that we may be able to modify if the new insulin-sensitizing agents prove efficacious or weight loss is possible.