The overall goal of the proposed studies is to better define the relative contributions of pathways that provide cholesterol precursor for P4 production during primate gestation. The proposed studies will utilize the baboon as the model for study of the endocrinology of human pregnancy. Three major experiments are proposed. In the first series of experiments, the relative contributions of pathways that provide cholesterol precursor for placental P4 biosynthesis will be studied during normal gestation. Baboons will also be treated after administration of an inhibitor of hepatic lipoprotein secretion 4-aminopyrazolo [3-4-d]pyrimidine (4-APP). mRNA concentrations for LDL, acLDL receptors, and LDL receptor-related protein (LRP) will be assessed by RT-PCR. The resultant proteins synthesized will be quantitated by Western blots and key enzymes that regulate de novo cholesterol synthesis will be quantitated by radioenzymatic techniques. The second series of experiments will examine the influence of estrogen on the cholesterol pathway. Placental LDL uptake will be inhibited by 4-APP and elimination of the stimulatory effect of estrogen by removal of fetal androgen precursors after fetectomy. The last series of experiments will examine the capacity of the corpus luteum for P4 biosynthesis after fetectomy and or 4-APP treatment. The knowledge gained from these experiments will provide an increased understanding of the important physiologic events underlying the P4 mediated maintenance of pregnancy and the initiation of normal labor in the primate.
