FUNCTIONAL REGULATION IN OVINE LARGE LUTEAL CELLS

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.