In women with polycystic ovary syndrome (PCOS) androgen excess is fundamental to the clinical and physiological alterations of this disorder. In particular, androgen overproduction induces distinctive PCO morphology and appears to influence follicle function. Studies conducted in animals and nonhuman primates have demonstrated that androgens increase follicle number and in small antral follicles enhance granulosa cell (GC) responsiveness to gonadotropin stimulation. However, androgens also have been shown to clearly inhibit GC aromatase activity, and in PCOS follicular fluid, androgen content is abnormally increased. Efforts to reconcile these differences are nonexistent. Moreover, appropriate clinical studies to examine the effects of androgen on follicle health in women are lacking. Excessive androgen exposure in women due to functional tumors or high-dose testosterone treatment in F-M transsexuals has been associated with PCO morphology. Use of androgen therapy to promote follicle growth prior to ovarian hyperstimulation in women undergoing in vitro fertilization has not provided consistent results. However, in these studies GC responses to FSH were not carefully assessed, study populations were exclusively women with previously poor ovarian responses to FSH, and women with PCOS were not included. In fact, there are essentially no clinical studies that have addressed in detail the impact of androgen on follicle function in normal or PCOS women. We hypothesize that androgen facilitates GC responses to FSH in normal women and androgen excess further amplifies follicle growth and function in women with PCOS.
In Aim 1, we propose to study the effect of increased ovarian androgen on follicle function by increasing intraovarian androgen accumulation using aromatase inhibition followed by FSH stimulation.
In Aim 2, we will examine potential mechanisms of androgen-follicle interaction in PCOS as 17- hydroxyprogesterone and androgen responses to hCG stimulation are highly variable and in some women overlap with those of normal controls. These studies will include association with follicle cohort size, effect of hyperinsulinemia, and impact of hyperandrogenemia by assessment of follicle stimulation after long-term androgen suppression. These clinical studies will be complemented by investigation of the intrafollicular, paracrine relationship between excess TC androgen production and GC factors in Aim 3, in which we will create transgenic mice overexpressing Cyp17 in TCs and determine the effects on ovarian morphology, folliculogenesis and fertility. These studies will also examine paracrine mechanisms that may associate with androgen excess in cultured follicles. The experiments in this project are designed to provide insight into whether androgen excess facilitates or interferes with follicle function and ovulation in women with PCOS.
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