Effect of Increased Circulating Androgens on Granulosa Cell Responses to FSH.
Condition: Polycystic Ovary Syndrome
MeSH terms: Polycystic Ovary Syndrome
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Letrozole
Intervention type(s): Drug
Intervention description(s): In Phase II, letrozole, 5 mg/day, will be given for 14 days
Other intervention name(s): Femora
Intervention MeSH terms: Letrozole
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Health Services Research
Keywords: Granulosa Cell; Androgens; FSH; Ovary