Endocrine Abstracts

Currently, no treatment options exist to improve semen quality for the majority of infertile men. Proper interaction between germ and Sertoli cells in the testis is critical for sperm production, and a recent study suggested that Denosumab, an inhibitor of RANKL signaling, may stimulate sperm production in some infertile men. Here, we show in animal and human studies how expression of the RANKL signaling system is critical for both Sertoli cell function and the testicular response to Denosumab. RANKL was removed globally in mice using the Cre-LoxP system. qPCR and immunohistochemistry were used to investigate OPG expression in human testis with full spermatogenesis or Sertoli cell-only (SCO) syndrome, fetal testis, as well as cultures of human testis tissue treated with Denosumab. Reproductive hormones, semen quality, and anti-Müllerian hormone (AMH) levels were measured in 100 infertile men, who subsequently were randomized to a single subcutaneous injection with Denosumab (60 mg) or placebo (1 mL NaCl). After 80 and 160 days, semen samples were analyzed, and blood samples collected. Mice with global RANKL deletion had increased testicular and epididymal weight. OPG expression was high in Sertoli cells from human testis with SCO in contrast to testis with full spermatogenesis or fetal testis. In human testicular cultures with low or moderate OPG expression Denosumab increased germ cell proliferation and decreased apoptosis, while Denosumab had no effect in testis with spermatogenic arrest or high expression of OPG in Sertoli cells. In infertile men, low serum AMH was associated with poor Sertoli cell function and decreased semen quality. In the randomized placebo-controlled clinical trial one dose of Denosumab did not increase semen quality compared to placebo. However, in a sub-group of men with baseline serum AMH>35 pmol/l Denosumab increased the inhibin B/FSH ratio and number of motile sperm cells, which is the best predictor of male fertility potential. This translational study suggests that the effect of Denosumab depends on the function of Sertoli cells with high OPG expression being a marker of dysfunction. AMH may be used to select the sub-group of infertile men who may benefit from Denosumab treatment; however, further investigation is critical for understanding the interplay between Sertoli cell function, spermatogenesis, and RANKL inhibition.