Luteinizing hormone acts directly at granulosa cells to stimulate periovulatory processesModulation of luteinizing hormone effects by prostaglandins

The midcycle surge of luteinizing hormone (LH) triggers events within the primate periovulatory follicle that culminate in follicle rupture and luteinization of the follicle wall; these events include the shift from primarily estrogen to primarily progesterone production, vascularization of the granulosa cell layer, and expression of matrix metalloproteinases and their inhibitors (MMPs and TIMPs) thought to be necessary for follicle rupture. However, it is unknown if LH acts directly at granulosa cells to regulate these important periovulatory processes. The ovulatory LH surge also stimulates the production of prostaglandins (PGs) by the follicle just before follicle rupture, suggesting that LH may have both PG-dependent and PG-independent actions. To address these questions, gonadotropins were administered to adult female rhesus monkeys to stimulate the development of multiple, large preovulatory follicles. Granulosa cells were aspirated and maintained in vitro for up to 48 h in serum-free, chemically defined medium. Granulosa cells were cultured with LH alone or in combination with PGs to determine if these hormones act directly at granulosa cells to induce the production of factors implicated in periovulatory processes. LH treatment increased media progesterone (p<0.05) and vascular endothelial growth factor (VEGF; p<0.05) levels as well as stimulating expression of mRNAs for MMP-1 (p=0.05), MMP-9 (p<0.05), and TIMP-1 (p<0.05), similar to the effects of an ovulatory dose of gonadotropin in vivo. PGE2 alone elevated media progesterone levels but decreased LH stimulation of MMP-1 mRNA (p<0.05). PGF2α reduced LH-stimulated TIMP-1 mRNA (p<0.05) levels. These studies suggest a direct action of LH on granulosa cells to stimulate the processes involved in tissue remodeling and neovascularization, i.e., MMPs/TIMPs and angiogenic factors, as well as steroidogenesis. LH-stimulated PGs may have a regulatory role to modulate some effects of the LH surge, such as MMP/TIMP expression.