P-102 Inhibition of RANKL increases the number of motile sperm in a subgroup of infertile men

Abstract

Abstract Study question Does inhibition of RANKL increase semen quality in infertile men? Summary answer Overall, inhibition of RANKL (Denosumab) did not affect semen quality. However, in a subgroup of men with high serum AMH sperm production was significantly increased. What is known already Currently, there is no treatment available for male infertility, but studies in animal and preclinical human data have suggested a role for RANKL in male reproduction. Study design, size, duration A single-center, double-blinded, randomized clinical trial in 100 infertile men randomly assigned (1:1) to s.c. injection with 60 mg/mL Denosumab or s.c. saline injection 1 mL (0.9%) (placebo). The primary endpoint was changes in semen production, though the study was designed as an explorative study, with the aim of investigating the profile of which infertile men who would have a beneficial treatment outcome of Denosumab. Participants/materials, setting, methods All participants were infertile men referred to our andrological clinic due to impaired semen quality. Blood and semen samples were collected at baseline and after one and two cycles of spermatogenesis on day 80 and day 160, respectively. Main results and the role of chance There were no differences in semen quality or reproductive hormones at day 80 or day 160 between men treated with Denosumab or placebo. However, men with a serum AMH ≥ 40 pmol/L had a significant increase in total motile sperm (143% (SD 116%); p = 0.011), progressive motile sperm (133% (SD 100%); p = 0.039) and a borderline increase in sperm concentration (64% (SD 95%); p = 0.056) at day 80 compared to baseline. Further stratifying men according to both serum AMH (≥ 40 pmol/L) and serum RANKL (highest 50%), showed a significantly higher increase in sperm concentration (107% (SD 111%) vs. -8% (SD 68%); p = 0.009), total motile sperm (256% (SD 270%) vs. 31% (SD 125%); p = 0.039) and progressive motile sperm (191% (SD 194%) vs. 18% (SD 134%) p = 0.013) at day 80 in men treated with Denosumab compared to placebo treated men. Furthermore, serum FSH (-28% (SD 33%) vs. 0%, (SD 22%); p = 0.041) and serum LH (-29% (SD 28%) vs. 20% (SD 51%), p = 0.048) were significantly lower and testosterone/LH ratio (50% (SD 51%) vs. -7% (SD 43%); p = 0.024) significantly higher at day 80 in men treated with Denosumab compared to placebo treatment. Limitations, reasons for caution This is a report from a randomized clinical trial, with an explorative design. Randomized clinical trials in a predefined group of infertile men with high serum AMH, are needed to explore if inhibition of RANKL improves semen quality and pregnancy rate in infertile couples with male factor infertility. Wider implications of the findings The increase in sperm production after Denosumab treatment in infertile men with preserved Sertoli cell function needs to be validated, in a trial selecting men based on serum AMH. Ultimately, Denosumab may be a potential breakthrough in treating male infertility at least in some infertile men with high serum AMH. Trial registration number NCT03030196