Regulation of progesterone and prostaglandin F_2α production in the CL

After the luteinizing hormone (LH) surge, the cells that remain from the ovulated follicle undergo a process of differentiation termed luteinization. Two key features of the cells after luteinization are the capacity for tremendous production of progesterone [10¹⁶ molecules of progesterone per (min/(g of CL))] and the capacity to undergo regression or death of the cells at the appropriate time. There are two steroidogenic cell types, the small and large luteal cells that are regulated by different mechanisms. In small luteal cells, production of progesterone is stimulated by LH through the protein kinase A (PKA) pathway. The large luteal cells of ruminants produce large quantities of progesterone that is independent of LH stimulation. Although luteotrophins clearly regulate luteal function, much of luteal progesterone production in some species appears to be constitutive, consistent with the autonomous aspects of the large luteal cell. The key regulated step in luteal progesterone production appears to be regulation of transport of cholesterol to the inner mitochondrial membrane apparently mediated by the steroidogenic acute regulatory protein (StAR). In addition, our recent research indicates that PKA is tonically active in large luteal cells and this may be responsible for the high, relatively autonomous nature of luteal progesterone production. Regression of the corpus luteum (CL) in many species is initiated by prostaglandin (PG) F_2α secreted from the uterus. Luteal cells also have the capacity for production of PGF_2α. Luteal PGF_2α production can be regulated by a variety of substances including inhibition by progesterone and stimulation by cytokines. We have also characterized a positive feedback pathway in ruminant and porcine CL in which small amounts of uterine PGF_2α stimulate intraluteal production of PGF_2α due to induction of the cycloxygenase-2 (Cox-2) enzyme in large luteal cells. This positive feedback pathway is only present in CL that has acquired the capacity for luteal regression (∼day 7 in cow, ∼day 13 in pig). Regulation by protein kinase C (PKC) of transcriptional factors interacting with an E-box in the 5′ flanking region of the Cox-2 gene is the critical regulatory element involved in this positive feedback pathway. Thus, luteinization in some species appears to change specific gene transcription such that progesterone production becomes relatively independent of acute luteotrophic regulation and intraluteal PGF_2α synthesis is induced by the second messenger pathways that are activated by PGF_2α.