FSH is the key inducer of ovarian follicle and testis tubule development, and is released in an orchestrated fashion subject to endocrine control. However, the microheterogeneity of the FSH molecule suggests that studies on circulating FSH bioactivity are essential to understanding gonadal development and function. The study of paracrine modulators (estrogens, androgens and growth factors) that could enhance FSH action in granulosa cells led to the development of a granulosa cell aromatase bioassay (GAB) highly sensitive to FSH. This sensitive assay is hormone-specific and species-nonspecific. Applications of this assay to serum and urine samples from various species reveal that physiologic levels of FSH can be measured. Although changes in bio-FSH levels basically confirm earlier RIA results during the human menstrual cycle, dramatic decreases in bio- to immuno- ratio of FSH were found in men and women treated with GnRH antagonists. In this proposal, the GAB assay will be applied to different animal species as well as to various physiologic and pathophysiologic states in humans. The assay will be adapted and further improved to measure bio-FSH in serum, urine and amniotic fluid samples in various species. Emphasis will be placed upon the understanding of reproductive cyclicity and basis of follicle recruitment in different models, as well as the initiation and cessation of ovarian function during physiologic states. In addition to revealing the reproductive cycles in human, rat and several exotic species (e.g., gorilla, whale and elephant), the basis of multiple ovulation will be evaluated in genetically selected Booroola Merino sheep and different species of lemurs. Potential changes in the B/I ratio of FSH will also be studied during the preovulatory period, luteal- follicular transition, puberty onset, pregnancy, postmenopause and aging in human beings and other animals. Pharmacologic studies will focus on changes in bio-FSH level following treatment with GnRH antagonists and agonists, gonadal steroids, as well as clomiphene citrate; whereas pathologic studies will reveal FSH changes during precocious puberty, premature ovarian failure and oligospermia. Differences in the bio- to immuno- ratio of FSH will be further characterized using chromatofocusing and in vitro cultures of rat anterior pituitary cells. The proposed studies should provide a better understanding on the role of bioactive FSH in reproduction.
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