Due to recent demographic and socioeconomic trends, a large number of women are delaying childbearing until their late 30s and early 40s when their fertility is significantly compromised. Whereas there is a clear age-related decline in female fertility, many questions remain regarding its etiology. This grant proposes to address several of the questions, which remain regarding the physiology of reproductive aging in women. Human females are endowed with a finite number of ovarian follicles, the majority of which expire secondary to atresia. Ultimate depletion coincides with the onset of menopause therefore, the rate of ovarian follicle depletion is the final determinant of the duration of the reproductive life span. The scant data, that are available (based on data generated from only 103 subjects from newborn to menopause), suggest that there is a steady decline in primordial follicle number and that there may be a threshold number below which the rate of atresia escalates, signaling a significant decline in reproductive capacity. These data are based on old morphometric techniques with inherent inaccuracies due both to sampling errors and to assumptions that are made to estimate follicle number. In addition, these older studies did not attempt to correlate primordial follicle number or rate of atresia with any endocrine parameters. We propose to employ modern morphometric techniques to count primordial follicle number in 300 pairs of human ovaries from females ages 0 to 55. In addition, we will obtain serum samples in a subgroup of these subjects for determination of gonadotropins, estradiol and inhibins. Specific aims of this proposal are: 1) to determine whether the duration of the reproductive lifespan is more dependent on initial follicle endowment or rate of loss; 2) to more accurately determine the normal decay curve for follicle loss from fetus to menopause; 3) to determine whether there is a critical threshold(s) of non-growing and early antral follicle number below which there are changes in hormone secretion (specifically inhibin B and FSH) and/or menstrual cyclicity; 4) to determine whether circulating levels of these hormones predict (or reflect) the number of follicles remaining; 5) to begin to determine the minimum size of an ovarian sample (biopsy) that is sufficient to accurately approximate the total number of follicles present. These studies will increase our understanding of the natural history of follicle atresia and provide insight into the factors, which determine the duration of the reproductive lifespan. Such an understanding is vital to our ultimate goal to be able to predict, recognize and treat age-related infertility.