Title of project

Direct effects of the Calcium Sensing Receptor on pituitary function: A translational approach

Abstract

The age of pubertal onset has been decreasing in the last three decades implying changes in regulation of the hypothalamic-pituitary-gonadal (HGP)-axis. The underlying causes are largely unknown, but obesity, environmental and lifestyle changes have been suggested to be responsible for this decrease. A double blinded randomized clinical trial, originally looking into the effect on bone mineral density during puberty, surprisingly showed that calcium supplementation to prepubertal girls induced earlier puberty compared to placebo. However, the putative direct effect of calcium on pituitary function has never been characterized. The Calcium-Sensing Receptor (CaSR) plays a major role in maintaining serum calcium levels and is primarily expressed in the parathyroid gland and kidney, but we have detected robust CaSR expression in the hypothalamus, pituitary and in the gonads, which supports a regulatory role on the HPG-axis. In the pituitary we find CaSR expression in the Alpha-GSU positive pituitary cells, which is the cells that produce the two gonadotropins luteinizing hormone (LH) and follicle stimulating hormone (FSH). The aim of this project is to study whether CaSR directly influence production of luteinizing hormone (LH) and follicle stimulating hormone (FSH), which are essential for pubertal entry. We will use a translational approach and characterize the pituitary, reproductive and endocrine phenotype of mice with a specific deletion of CaSR exclusively in the anterior pituitary as well as look into intracellular signaling in a pituitary cell line. This basic and functional data will be extrapolated into the human setting by looking at pituitary tests in healthy volunteers and patients with CaSR mutations, supported by an observational study of calcium homeostasis in adolescents going through puberty and infertile men. This grant will be used to provide novel insights into basic physiology, with the potential of high clinical relevance, as it is possible to manipulate CaSR by an agonist (Cincalcet) that is already in clinical use.