To understand the regulatory mechanisms involved in controlling the vertebrate reproductive cycle, it is important to identify the hierarchy of extragonadal (pituitary gonadotropic hormones) and intragonadal (steroid hormones and gonadal peptides) molecules and to decipher how their episodic releases stimulate gonadal development. Derangements in the episodic secretion of gonadotropins (GTHs) frequently cause infertility in humans. The etiologies, and the developmental and molecular aspects of the pulsatile GTHs release are largely unknown. The understanding of the relationship of several gonadal peptides to the signals for gonadal function is still very elementary. The long-term goal of this project is to characterize the developmental and dynamic interaction between the release of GTHs and the rhythmic secretion of ovarian steroids and gonadal peptides at the molecular level. The periodic release of 17beta-estradiol (E2) throughout the reproductive cycle appears to have a programming role in the modulation of GTHs secretion. Although the most important physiological determinant of circulating gonadotropin levels in animals and humans appears to be the steroid status, the hypothesis that gonadal peptides also play a critical role cannot be ruled out. This proposal is designed to test the experimental paradigms that both estradiol and gonadal peptides (inhibin and actin) preferentially modulate gonadotropins mRNA subunits expression. Regulation of GTH subunit mRNA expressions by sex-steroids (in particular the action of E2) and gonadal peptides on the pituitary gland will be assessed using Norther blot analysis and ribonuclease protection assay. Antibodies against the GTH subunits will be generated in order to develop a homologous radioimmunoassay to measure GTH levels and to test the hypothesis that the cyclic production of GTHs is under both gonadal peptides and steroids influence. In addition to the inhibin effects at the pituitary level, the hypothesis that gonadal peptides may play a crucial role as paracrine and autocrine regulator of ovarian functions will be assessed using ovarian follicle cell cultures. The elucidation of the molecular and biological mechanisms by which gonadotropins, gonadal peptides and steroids control episodic reproductive activities may provide new insights for understanding not only the basic productive process, but also very possibly unravel the etiologies of menstrual dysfunction in humans.
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