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Autocrine/paracrine regulation of steroidogenesis in human ovarian cells

University of British Columbia

This study investigated the hypothesis that local ovarian substances regulate gonadotropin-dependent steroidogenesis in the human ovary and form a paracrine and autocrine network for granulosa cell responses to endocrine stimulation. The specific substances investigated were inhibin, activin, follistatin, angiotensin II and Ill (A II and A III), prostaglandin F₂α (PGF₂α) and GnRH. Inhibin-related peptides were isolated in follicular fluid and were stimulated by FSH. Inhibin-A had no effect on basal and gonadotropin-stimulated progesterone production in human granulosa-luteal cells. Activin-A inhibited hCG/FSH-stimulated but not basal progesterone production, suggesting its role as an inhibitor of luteinization. Follistatin stimulated basal progesterone production, suggesting its antagonistic role for activin-A. Intracellular cAMP levels were inhibited by activin and stimulated by foffistatin. Follistatin may induce the preovulatory progesterone peak which is necessary to trigger the LH surge. Activin-A and follistatin form a balanced autocrine network to regulate proper progesterone production from granulosa cells around the ovulatory phase. Inhibin BAsubunit mRNA expression was increased by hCG treatment in cultured human granulosa cells, suggesting inhibin and activin production are subject to endocrine regulation. For comparison with another steroidogenic tissue, inhibin subunit mRNA expression in human trophoblast cells was also studied. GnRH and cAMP stimulated inhibin α and βB mRNA expression in human term placental cells. cAMP also stimulated inhibin βA mRNA expression. These results provide evidence for the interaction of local regulators and gonadotropins within the human ovary and placenta. A renin-angiotensin system exists in human ovary and was stimulated by LH. Effects of A II and A Ill on steroidogenesis of granulosa-luteal cells were examined. A II and A III bound to the granulosa-luteal cell surface. A III but not A II inhibited hCG- stimulated progesterone production. A III had an additive effect on PMA, a diacylglycerol analog, inhibited progesterone production response to hCG and PMA pretreatment did not block the inhibitory action of A Ill. These suggested that inhibitory effect of A III was not modulated by protein kinase C pathway. A III may play a luteolytic role during the luteal phase. Effects of GnRH and PGF on hCG-stimulated progesterone production were studied. GnRH had no effect on basal and hCG-stimulated progesterone production. PGF₂α failed to have consistent effects on basal and hCG- stimulated progesterone production. These results are different from those observed in the rat ovary and may be due to species difference in the cellular response to PGF₂α. Taken together, the results of this study showed that ovarian local regulators play key roles in the control of steroidogenesis by granulosa-luteal cells. The physiological significance of the actions of these local regulators might be that they interact with each other to fine-tune the endocrine response of the ovary to the robust actions of the gonadotropins.

Thesis/Dissertation

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2009-04-08

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http://hdl.handle.net/2429/6968

Reproductive and Developmental Sciences

University of British Columbia

UBCV

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