Yale School of Medicine Thesis Award Recipient — 2012

Purpose: To investigate the expression and exogenous effect of leptin hormone in diseased parathyroid glands at a basic science and clinical level. Introduction: Hyperparathyroidism (HPTH) is a common endocrine problem affecting 1 in 500 individuals who are typically female and over the age of 60. Combined effects of low calcium and vitamin D stimulating parathyroid activity and excess PTH secretion are well established, especially in secondary HPTH. Unclear is the mechanism behind the development of hyper secreting parathyroid adenomas, responsible for nearly 90 percent of primary HPTH. Discovered in 1994 as a class I cytokine receptor, leptin has mounted considerable interest as a mitogenic factor involved in the stimulation and growth of tumors. Also, leptin has been implicated in multiple calcium-related metabolic processes, which have led to numerous evaluations of the connections between vitamin-D, PTH, and obesity. Ultimately, these scientific findings, the prevalence of higher leptin levels in women with HPTH, and our hypothesis that leptin found with increased body weight contributes to the pathogenesis of HPTH has led to our study on endogenous leptin production and its ex-ogenous effect in diseased parathyroid glands. Furthermore, with routine serum calcium screening now, many patients are treated with minimally invasive parathyroidectomy (MIP) before hypercalcemic sequelae develop; we also wished to clarify the clinical relationship between PTH, leptin, and BMI in a cohort of patients with HPTH undergoing surgery. Methods: We enrolled 96 patients with HPTH undergoing MIPs in a prospective study to collect tissue and co-localize leptin hormone and PTH by in situ hybridization (ISH), im-munohistochemistry (IHC), immunofluorescence (IF), and electronmicroscopy (EM). Cell culture and whole organ explant experiments in which surgically removed human parathy-roid tissue were exposed to recombinant human leptin to functionally characterize the effect of leptin on PTH secretion. Parathyroid adenomas and hyperplasia were xenografted into nude rats and evaluated for the production of human leptin. Blood was also collected to assess subsequent perioperative changes to serum leptin levels. Patients without HPTH undergoing hemithyroidectomies under identical surgical conditions were enrolled as control subjects. Wilcoxon signed-rank test, non-parametric version of paired t-test, and Pear-son correlation were used to compare leptin level changes with different clinical variables using SAS 9.2. Results: Leptin, leptin receptor, and PTH mRNA transcripts and protein were detected in an overlapping fashion in secretory (chief) cells in parathyroid hyperplasia and adenoma samples by ISH, IHC, IF, and EM studies. Immunofluorescence studies under spinning disc confocal microscopy and …