Endocrine Abstracts

JOINT2063

Introduction: In a previous randomized clinical trial (RCT), prepubertal children were given calcium supplementation or placebo. Girls in the intervention group entered puberty 5 months earlier than the placebo group, but no effect on pubertal timing were detected in the boys who participated in the RCT. CaSR is the main receptor for systemic calcium homeostasis, and its presence has been established in the anterior pituitary. The aim of this study was to investigate if the effect of calcium on pubertal timing seen in the RCT was due to a direct effect on pituitary function through CaSR.

Methods: A mouse model was generated using the Cre-LoxP method, to introduce a deletion of CaSR specifically in the anterior pituitary. Female knock-down (KD) and control mice (n = 13, both groups) were sacrificed at 8 weeks and blood samples and reproductive organs were collected. Hormone levels were measured using both commercially available and in-house ELISAs. Collected organs were weighted and stored either at -80°C or was formalin and paraffin embedded.

Results: Female reproductive organs showed significantly lower weight when comparing CaSR knock-down to control mice (organ weight/total body weight%): This included ovary weight (0.02176 vs. 0,03534; P = 0.0035) and uterus weight (0.1788 vs. 0.3826; P = 0.0023). No difference in Fsh expression was detected between the two groups. However, a tendency towards lower Lhbeta levels was observed in the KD group with a relative expression level of 0.33 compared to control set to 1 (P = 0.0544). Accordingly, a trend toward lower serum LH was detected in the KD mice (0.7619 ng/mL) compared to control littermates (0.9887 ng/mL), however this was not statistically significant (P = 0.0845). There was no difference in serum AMH or Inhibin-B levels between the two groups.

Conclusion: Female mice with a KD of CaSR in the anterior pituitary have lower ovary and uterus weight compared to littermate controls. No change in AMH og Inhibin B levels between the groups, but a slight tendency towards lower LH serum levels and Lhbeta expression levels in the KD group. Further characterization of the phenotype in this mouse model is ongoing, and the evaluation of puberty timing in these mice are still pending. If CaSR proves to be important for the regulation of the Hypothalamic-Pituitary-Gonadal (HPG) axis, it has a clinical perspective since CaSR can be modulated by the drug Cinacalcet, an allosteric agonist of CaSR, already in clinical use.