TR11 Differential TSH receptor signaling induced by luteinizing hormone and human chorionic gonadotropin

Abstract

Human chorionic gonadotropin (hCG) shares structural homology with thyroid-stimulating hormone (TSH) and contributes to thyroid hormone production during pregnancy through activation of the TSH receptor (TSHR). Although hCG and luteinizing hormone (LH) bind the same receptor (LHCGR), their effects on TSHR signaling remain poorly understood. To compare hCG- and LH-mediated activation of TSHR signaling pathways. COS7 cells overexpressing human TSHR were exposed to increasing concentrations of hCG or LH. Gs- and Gq-mediated signaling was assessed by measuring intracellular cyclic adenosine monophosphate (cAMP) and inositol monophosphate (IP1) using bioluminescence resonance energy transfer and homogeneous time-resolved fluorescence assays. cAMP response element-dependent transcriptional activity was evaluated using a luciferase reporter assay. Human thyroid organoids were used to validate the findings in native tissue. Statistical analyses were performed using the Kruskal–Wallis test with Dunn’s post hoc test (n = 4; P < 0.05). At a concentration of 1 μM, hCG significantly increased intracellular cAMP and activated cAMP response element-dependent transcription, demonstrating activation of the TSHR–Gs–cAMP signaling pathway. In contrast, LH did not stimulate cAMP accumulation or transcriptional activation and, at the same concentration, inhibited both responses. Neither hormone increased IP1 concentrations; however, LH significantly reduced TSH-induced IP1 accumulation, suggesting antagonistic effects on TSHR–Gq signaling. These findings were confirmed in human thyroid organoids, in which hCG maintained organoid viability and preserved TSH responsiveness. Human chorionic gonadotropin selectively activates TSHR-dependent Gs/cAMP signaling, supporting its physiological role in thyroid regulation during pregnancy. In contrast, luteinizing hormone acts as a functional antagonist of TSHR, negatively modulating both Gs- and Gq-mediated signaling pathways. These findings identify TSHR as a potential novel target of gonadotropin action in the thyroid.