Progesterone produced by the mammalian corpus luteum (CL) is required for maintenance of pregnancy. Formation of an inadequate CL is a clinically recognized cause of infertility, termed luteal phase defect. At the end of the luteal phase, prostaglandin F2alpha (PGF2alpha) in most species, including the ewe, induces functional (decreased progesterone production) and structural (demise of the tissue) luteolysis. The mechanism is not clearly understood. The CL of many species (including humans and ewes) contains two morphologically and functionally distinct steroidogenic cell types, designated small and large. A signal for luteolysis appears to be mediated by large cells, which contain receptors for PGF2alpha. Oxytocin (produced by large cells) is also thought to be involved in luteal regression. Responses to luteolysis appears to be regulated by calcium-mediated intracellular pathways. The proposed studies will investigate whether PGF2alpha-induced luteolysis in large cells is mediated via increased [Ca2+]i and decreased intracellular pH; and if oxytocin (produced by large cells) also provides a signal for luteolysis in small cells. To test these hypotheses, the specific aims will 1) investigate mechanisms by which PGF2alpha alters [Ca2+]i in large cells 2) correlate secretion of progesterone and oxytocin (functional effect) and cellular viability (structural effect) with these alterations 3) measure changes in responsiveness of these mechanisms as the cyclic CL physiologically approaches regression 4) examine whether oxytocin produced by large cells in response to PGF2alpha can provide a luteolytic signal for small 5) evaluate the ability of varying extracellular pH to alter large cell responsiveness to PGF2alpha. The results of these studies will provide a novel approach to understanding cellular mechanisms of luteolysis, hence valuable insight as to the role of the large cell in regulating luteal function. This improved understanding will provide a better approach to treating infertility and developing new methods of birth control.
