Endocrine Abstracts

Background and Purpose: Infertility affects 15% of couples globally, and only few treatment options are available. Gonadotropins are classic and potent regulators of ovarian and female reproductive function, but novel endocrine crosstalk appears to exist between gonads and the skeleton that may influence female fertility. One of the new players include the RANKL signalling system, which consists of the receptor activator of nuclear factor κβ ligand (RANKL), the receptor RANK, and the decoy receptor osteoprotegerin (OPG). Recent studies suggest that the RANKL system is expressed in testis and is a novel regulator of germ cell proliferation and maturation. However, little is known about the role of the RANKL system in female gonads and whether it affects reproductive function, which is explored in the present study.

Methods: QPCR, immunohistochemistry and in situ hybridisation were performed to investigate the expression pattern of the RANKL system in mouse and human female reproductive organs. To explore the role of RANKL in ovaries, we utilised the Cre-loxP system to generate a granulosa cell-specific Rankl knockdown mouse model. The phenotype of the reproductive system was evaluated on sexually mature female mice. To extrapolate the data into the human setting RANKL and OPG were measured in serum and follicular fluid and associated with live birth rate after assisted reproductive techniques.

Results: The present study indicates that RANKL, RANK, and OPG are expressed in the female gonads. We validated that the Amh promotor can be exploited to achieve selective Cre recombinase activity in granulosa cells in female gonads. Pilot data indicate a higher pregnancy and birth rate in mice when RANKL is genetically suppressed in granulosa cells. In humans, we found that follicular fluid levels of RANKL and OPG are linked with number of stimulated follicles and live birth rate in women undergoing assisted reproductive techniques.

Conclusion: These preliminary findings suggest a role of RANKL in ovarian physiology and future investigations may untangle the exact role of RANKL for female reproductive function.