Effect of Increased Circulating Androgens on Granulosa Cell Responses to FSH.
Effect of Increased Circulating Androgens on Granulosa Cell Responses to FSH.
The purpose of this study is to evaluate the effect of increased circulating androgens on
 estradiol production by the granulosa cells in response to FSH stimulus.
Various previous studies have demonstrated that androgens enhance granulosa cell function in
 a variety of animal species including rodents and non-human primates. In vitro studies have
 shown that granulosa cells exposed to either testosterone or dihydrotestosterone exhibit
 increased production of estrogen, progesterone and inhibin in response to FSH. Studies done
 in non-human primates have also shown that androgen increases the numbers of preantral and
 antral follicles as well as increases FSH receptor mRNA expression in granulosa cells. This
 suggests that granulosa cell hyperresponsiveness to FSH in polycystic ovary syndrome (PCOS)
 may be related to androgen excess. The investigators plan to address this possibility by
 performing a series of in vivo studies. In one of the investigator's prior studies androgen
 blockade was done by administration of flutamide and E2 responses to FSH assessed. This study
 has been completed and the manuscript is being prepared for publication. In the present
 protocol, the investigators propose to further study the role of androgens with a 2 phase
 study. In the first phase the investigators plan to suppress endogenous steroid hormone
 production by the ovaries via treatment with the GnRH analog Lupron for 4 weeks beyond which
 a gradual resumption of ovarian activity will occur. Granulosa cell (inhibin B) responses to
 FSH will be examined before and after ovarian suppression as well as during early and
 moderate recovery of ovarian steroidogenesis. These results will provide control data to
 which comparisons can be made from results of the next phase.

 In the second phase, after a 2 month washout interval, the same subjects will again receive
 Lupron to suppress endogenous steroid production. After 4 weeks, at the beginning of ovarian
 activity resumption, the investigators will administer Letrozole 5mg for 14 days and again
 examine granulosa cell responses to FSH during recovery. Letrozole is a 3rd generation
 aromatase inhibitor which results in suppression of E2 production and increase in circulating
 serum androgen levels to about 40% greater than pre-treatment values. It is now also being
 used for ovulation induction. It has minimal side effects and is in general very well
 tolerated. By using Letrozole for 2 weeks after GnRH suppression of the ovaries, the
 investigators will more effectively increase the amount of circulating androgen while keeping
 estrogen at low levels, thereby allowing the investigators to more completely study the
 effects of isolated and elevated androgen levels on granulosa cell responses to FSH. By
 comparing results obtained in phase 1, the investigators will be able to determine if there
 is an androgen mediated response by granulosa cells to FSH stimulation in the absence of
 other ovarian steroids. Also, the addition of a control group will allow investigators to
 determine if the granulosa cell response is different between PCOS and normals.

 It is hypothesized that there will be a significant rise in inhibin B production by the
 granulosa cells in PCOS women in response to FSH after treatment with Letrozole as compared
 to both the control group and to responses observed in the control phase of study. This would
 confirm that androgens are indeed responsible at least in part for the hyperresponsiveness to
 FSH seen in women with PCOS.
Inclusion Criteria:

 -  Subjects will be determined to have PCOS based on clinical criteria such as history of
 irregular menses and clinical or laboratory evidence of hyperandrogenism.

 -  Subjects should not have been on any hormonal therapy or metformin for at least 2
 months prior to study start.

 Exclusion Criteria:

 -  Women with hemoglobin less than 11gm/dl at screening evaluation.

 -  Women with untreated thyroid abnormalities

 -  Pregnant women

 -  Women with BMI>37

 -  Women with known sensitivity to the agent being used.