Increases FSH Receptors and Estradriol Release
Whether increased granulosa cell sensitivity to FSH arises primarily from the ovary or secondarily as a result of non ovarian factors is unknown. Studies have shown that granulosa cells from PCOS have greater binding of FSH compared with normal ovaries.
1. FSH Receptor Hyper-responsiveness and HyperstimulationDespite a lack of ovulation, studies have demonstrated that PCOS granulosa cells are extremely sensitive to follicle-stimulating hormone (FSH) stimulation when compared with normal cells. Studies find women with PCOS have estradiol secretion in response to FSH (during stimulation) that is comparable to normal women. Yet, beyond a certain threshold of increasing levels of FSH stimulation, estrogen production was clearly greater in women with PCOS. In this study, the heightened estrogen response to the highest dose of FSH is consistent with the clinical observation of ovarian hyper-responsiveness to gonadotropin stimulation during ovulation induction. Of interest was the observation that all FSH doses uniformly (in both normal and PCOS women) induced rises in estradiol levels within 3 hours of administration, which suggests that any aromatase inhibition, previously suspected in PCOS, is relatively mild.
2. FSH Receptors Hyper-responsiveness and Androgens EnhancementMechanisms that lead to increased FSH receptors in granulosa cells might contribute to increased ovarian responsiveness to FSH. Although a primary role of androgens is to provide substrate for conversion to estrogens, androgens also seem to enhance estrogen production in response to FSH stimulation. Studies showed that androgens can enhance FSH-induced activity and suggests involvement of the FSH receptor. Subsequent studies conducted in nonhuman primates receiving testosterone implants showed that androgen, acting through its own receptor, induced increases in FSH-receptor expression in granulosa cells, which probably accounted for greater ovarian size and increased follicle number observed in these animals. Possibility excess ovarian androgen might be responsible, at least in part, for increased granulosa cell responsiveness to FSH.
FSH Receptors and Insulin Resistance
Another factor that might impact granulosa cell function is insulin as it acts as a ‘co-gonadotropin’ within the ovary. Women with PCOS are assumed to have granulosa cells which might be insulin resistant. Studies have shown that PCOS granulosa cells are extremely sensitive to insulin whether in the presence or absence of gonadotropin stimulation. In PCOS, granulosa cells are less responsive to insulin since insulin receptors (on the granulosa cells) are unable to recognize or be activated by insulin. Thus the receptors do not get “turned on” to produce FSH sensitivity. In women who have PCOS and are treated with metformin, (an insulin sensitizer which help the insulin receptor to be activated by insulin) granulosa cell responsiveness to FSH was significantly increased. Whether granulosa cells in women with PCOS are insulin resistant as a primary or secondary effect has not been addressed.Collectively, these findings might be relevant to women who have PCOS and are undergoing ovarian stimulation to achieve pregnancy. During ovulation-induction therapy in women with PCOS, estrogen levels and follicle growth are reduced compared with normal women. That PCOS granulosa cells might be insulin-resistant could, at least in part, account for decreased ovarian response to FSH. Reduced follicle responsiveness might be overcome with increased FSH administration; this implicates decreased FSH secretion as the reason for the lack of ovulation. Once sufficient ovarian stimulation has been achieved and follicle growth is observed, the use of low-dose FSH is preferred compared with escalation of the daily dose as PCOS are hyper-responsive to high doses of FSH, which increases the risk of ovarian hyperstimulation syndrome.
Inappropriate gonadotropin Release
In women with PCOS, the pituitary secretes excessive amounts of LH resulting in high levels of androgens. Plus, in PCOS the secretion of LH in response to GnRH is higher than normal women. Because LH secretion reflects GnRH activity, these observations indicate that corresponding release of hypothalamic GnRH is increased. Recent studies have indicated that excess androgen production can have a profound influence on LH pulse frequency in women with PCOS. It has been shown that administration of progesterone and estrogen to women with PCOS failed to slow the LH pulse frequency, whereas in normal women a significant reduction in the LH pulse was noted. Subsequently, studies were conducted in which women with PCOS were pretreated with an androgen-blocking agent before administration of estrogen and progesterone; the result was restoration of normal LH pulse frequency. These findings suggest that, in PCOS, high circulating levels of androgen prevent the negative feedback effects of estrogen and progesterone on the release of LH.
Insulin and Inappropriate Gonadotropin Secretion
The interaction between hyperinsulinemia and inappropriate gonadotropin secretion in PCOS is not completely clear. Previous studies have shown that insulin enhanced LH secretion in response to GnRH. Yet, efforts to determine an effect of insulin in PCOS women have not documented consistent alterations in LH secretion following GnRH stimulation.
Lowered FSH Levels
FSH secretion in women with PCOS is decreased, as indicated by significantly lower serum concentrations compared with those found in normal women. The mechanism for decreased FSH secretion in PCOS has not been determined, although the negative feedback effect of chronic unopposed estrogen secretion (possibly coming from other places in the body besides ovary, i.e.: abdominal fat) in these women has been implicated as the problem. Alternatively, reduced serum FSH levels might reflect the activity of hypothalamic GnRH, which at increased secretion favors the malfunction of the hypersensitive LH receptor expression compared to the less responsive FSH receptor.