Endocrine Abstracts

JOINT643

Introduction: A clinical study showed that calcium supplementation to prepubertal girls induced earlier puberty compared with placebo treatment. The calcium-sensing receptor (CaSR) is important for maintaining serum calcium concentrations within a narrow range. CaSR activity can be allosteric modulated by cinacalcet, commonly used in the clinic to treat hyperparathyroidism. CaSR has previously been identified in the pituitary gland of both humans and rodents, and we have found CaSR to be specifically expressed in α-glycoprotein subunit (αGSU)-positive cells in the anterior pituitary of mice. Gonadotropic cells of the anterior pituitary secrete luteinizing hormone (LH) and follicle-stimulating hormone (FSH) which promote e.g. pubertal onset, production of sex steroids, gametogenesis, and ovulation. The presence of CaSR in the pituitary suggest a direct regulatory role of calcium, which implies that the effect of calcium supplementation on pubertal timing, could potentially be caused by a direct effect of calcium on the pituitary. This study aims to elucidate the effect of CaSR modulation on pituitary function and male reproductive outcomes using pharmaceutical and genetic approaches.

Methods: Initially, the role of CaSR in pituitary function was examined by treating wildtype male mice of the reproductive age with cinacalcet (100 mg/kg) daily for two weeks. To explore further, a pituitary specific Casr-deficient mouse model was generated utilizing the Cre-LoxP system, and further validated through immunohistochemistry (IHC). The endocrine and reproductive phenotypes of both mouse models was examined through mass spectrometry and enzyme-linked immunosorbent assay (ELISA).

Results: Wildtype male mice treated with cinacalcet had a 64% decrease of LH serum levels compared with the control group (p=0.039). Furthermore, testosterone levels were reduced with 97% in mice treated with cinacalcet compared with vehicle-treated mice (p=<0.0001). The pituitary specific Casr-deficient mouse model was evaluated at 8-weeks of age, and there was a tendency towards higher LH serum levels.

Conclusion: Together, these preliminary findings suggest that modulation of CaSR activity can influence gonadotrophic cell function, thus highlighting a potential link between CaSR function and reproductive health. Further investigation of the phenotypic traits of the Casr-deficient mouse model is needed to fully understand the mechanisms underlying these observations.