Human Luteinizing Hormone and Chorionic Gonadotropin Display Biased Agonism at the LH and LH/CG Receptors

TL;DR

This study reveals that human luteinizing hormone and chorionic gonadotropin act as biased agonists at the LH/CG receptor, eliciting different intracellular responses and steroidogenesis, which could inform personalized reproductive treatments.

Contribution

The paper demonstrates that recombinant LH and hCG exhibit biased agonism at the LH/CG receptor, showing differential signaling and efficacy, advancing understanding of gonadotropin receptor pharmacology.

Findings

rhCG is more potent than rhLH in activating responses.

rhLH shows partial effects on rrestin recruitment and progesterone production.

rhLH and rhCG act as natural biased agonists at LH/CG receptor.

Abstract

Human luteinizing hormone (LH) and chorionic gonadotropin (hCG) have been considered biologically equivalent because of their structural similarities and their binding to the same receptor; the LH/CGR. However, accumulating evidence suggest that LH/CGR differentially responds to the two hormones triggering differential intracellular signaling and steroidogenesis. The mechanistic basis of such differential responses remains mostly unknown. Here, we compared the abilities of recombinant rhLH and rhCG to elicit cAMP, \beta-arrestin 2 activation, and steroidogenesis in HEK293 cells and mouse Leydig tumor cells (mLTC-1). For this, BRET and FRET technologies were used allowing quantitative analyses of hormone activities in real-time and in living cells. Our data indicate that rhLH and rhCG differentially promote cell responses mediated by LH/CGR revealing interesting divergences in their potencies, efficacies and kinetics: rhCG was more potent than rhLH in both HEK293 and mLTC-1 cells. Interestingly, partial effects of rhLH were found on \beta-arrestin recruitment and on progesterone production compared to rhCG. Such a link was further supported by knockdown experiments. These pharmacological differences demonstrate that rhLH and rhCG act as natural biased agonists. The discovery of novel mechanisms associated with gonadotropin-specific action may ultimately help improve and personalize assisted reproduction technologies