DIFFERENTIATION IN HUMAN GRANULOSA CELLS

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The purpose of this investigation is to examine periovulatory changes in the human follicle to better define the sequence of events surrounding ovulation and culminating in the differentiation of an adequately funtioning corpus luteum. Most of our knowledge about the sequence of steroidogenic and receptor-mediated events surrounding ovulation is derived from animal investigations and extended by analogy to the human. Increasing experimental evidence suggests that this may be a faulty analogy. Specifically, we propose to evaluate the ability of adenosine, androgens and prolactin to modulate gonadotropin effects in both pre- and periovulatory cultured human granulosa cells. Adenosine amplification of FSH- and LH-mediated cAMP and steroid production in preovulatory cells will be examined as well as the relationship of follicular fluid purines to folliculogenesis. Androgen-induced inhibitory effects on steroidogenesis and LH-receptor appearance will be investigated in both preovulatory cells and periovulatory granulosa-luteal cells. Finally, inhibition of luteal development by prolactin will be assessed. In addition to steroidogenesis we will examine granulosa-luteal cells to determine the role of LH, prolactin and androgen in the expression of LH-receptors as a measure of adequate luteal differentiation. The sensitivity of luteal LH-receptor appearance to inhibitors of both protein and RNA synthesis will be determined. This proposal is designed to answer the follwoing questions. In addition to gonadotropins are there other important modulators of steroidongenesis, such as adenosine, androgen and prolactin, which affect human follicular development and differentiation? What role do known putative effectors of ovarian function such as gonadotropins, prolactin, Ca2++ mediated-phosphorylation and protein or RNA synthesis play in periovulatory luteal differentiation as manifested by the appearance of LH-receptors and steroidogenesis? Answers to these questions will illuminate the events surrounding ovulation and luteal differentation in the human ovary which are critical to the regulation of our fertility and reproduction.