Endocrine Abstracts

JOINT1403

Novel treatment options for male infertility are highly warranted, as male-factor infertility is involved in up to 50% of all infertile couples. Yet for the vast majority (90%) of affected men no treatment options exist. The RANKL/RANK/OPG signaling pathway, known for its role in bone resorption, is also active in the testis of both men and mice. In previous studies, we have demonstrated that inhibition of RANKL with denosumab in mice resulted in higher sperm count and testis weight. Additionally, increased germ cell proliferation was found in ex vivo cultures of adult mouse testis tissue following denosumab treatment and a randomized control trial showed that denosumab treatment enhanced sperm concentration in infertile men with serum AMH levels above 38 pmol/l. These findings suggest that RANKL inhibition may be a potential treatment option for some infertile men. Here, the potential beneficial effects of pre-treatment with selected compounds (e.g. prostaglandins, gonadotropins) prior to denosumab treatment was examined. A humanized RANKL mouse model enables the use of the RANKL inhibitor denosumab in mice, and testicular tissue fragments (1.5 mm³) from these mice were cultured ex vivo. The first 24 hours with agents such as hCG, and Ibuprofen, followed by treatment with 100 ng/mL denosumab for 48 hours. Germ cell proliferation was assessed via quantification of BrdU incorporation. Pre-treatment with vehicle, hCG, ibuprofen, or dexamethasone was examined, and a significantly increased germ cell proliferation was found after pre-treatment with hCG (82%, P = 0.0042) and ibuprofen (92%, P = 0.0017) when compared to vehicle treated tissue. No effect on germ cell apoptosis was observed. This study suggests that pre-treatment of adult testicular tissue with hCG and ibuprofen prior to denosumab administration may enhance the stimulatory effect of denosumab on germ cell proliferation. However, further research is needed to understand the effects of RANKL inhibition on the interplay between Sertoli and germ cells and the implications for improvement of spermatogenesis.