The major objective of the proposed research is to gain a better understanding of the role of female endocrine status in the regulation of Ca homeostasis throughout normal development and during pregnancy and lactation. In order to approach this broad topic in a systematic fashion, the experimental work will focus on four rat models in which sex differences or pregnancy and lactation have been found to affect Ca metabolism. Each of these models will be studied to learn what sex- or pregnancy-related factors are involved. Once this is known and can be manipulated in controlled experiments, related changes will be investigated in blood, bone, kidney and intestine. Circulating levels of Ca, Mg, P04, parathyroid hormones, calcitonin and in appropriate experiments, estradiol, estriol, progesterone, prolactin and vitamin D metabolites will be measured. In order to determine the target tissues involved in each of the specific cases a series of techniques will be used to study each of the three major tissues involved in Ca homeostasis: 1) bone responsiveness to PTH will be evaluated in vivo by measuring the hypercalcemic response and the elevation in bone cyclic AMP content following PTH injection. 2) Urinary excretion of Ca, Mg, P04, and cyclic AMP will be measured. In addition, renal cortical slices will be used to study conversion of 25-hydroxycholecalcificol to more polar metabolites, and the hormone-dependent adenylate cyclase system. 3) Active transport of Ca by everted gut sacs will be used in conjunction with measurements of intestinal calcium-binding protein, and in appropriate cases evaluation of fractional Ca absorption, to study the role of intestinal Ca absorption in the specific sex-related alterations in Ca homeostasis. The results of this work will greatly expand our overall understanding of the regulation of Ca homeostasis and may contribute significantly to our understanding of the pathogenesis of postmenopausal osteoporosis.
