  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
