Sex Steroids Program Premature Ovarian Failure

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Each woman is endowed with a finite number of primordial follicles at birth. Most of this initial endowment is depleted during normal reproductive life, mainly through atresia. The length of reproductive life is largely defined by the rate of follicular depletion. The variability in the length of reproductive life suggests variability in the initial endowment of primordial follicles and/or rate of follicle loss. Reproductive life span can be shortened by factors that reduce primordial follicular endowment, accelerate the rate of recruitment/atresia of follicles, and/or induce follicular deficiencies leading to developmental arrest of follicles. Increasing evidence suggests that the environment to which the fetus is exposed can alter the path of reproductive organ differentiation. The use of animal models offers exciting potential for delineating the mechanisms by which human fertility disorders can be programmed in fetal life. Our studies found that prenatal exposure of sheep to testosterone results in altered neuroendocrine feedback, hyperandrogenism, multifollicular ovarian morphology, increased follicular atresia and reproductive cycle defects culminating in early reproductive failure. The objective of this proposal is to delineate the ovarian programming that occurs as a consequence of in utero sex steroid exposure that is responsible for reproductive failure later in life. The working hypothesis is as follows: Exposure of fetuses to excess testosterone during critical stages of ovarian follicular development alters normal developmental trajectories by changing the expression patterns of key growth factors, androgen/estrogen receptors, and ratio of anti- to proapoptotic Bcl-2 members, resulting in accelerated recruitment of primordial to primary follicles, accelerated growth of primary follicles to antral stage and enhanced incidences of atresia or arrest of antral follicles. These alterations eventually, lead to premature depletion of ovarian follicular reserve and ovarian failure. The deleterious effects of testosterone are mediated either by its androgenic action, estrogenic action due to its conversion to estradiol, or both. Further, prenatal exposure to steroids alters ovarian follicular susceptibility to postnatal steroids leading to premature ovarian failure. The outcome of these studies is of relevance to 3 of the targeted NIH missions, fetal antecedents of disease, developmental biology and reproductive health for the 21st century.