Denosumab stimulates spermatogenesis in infertile men with preserved Sertoli cell capacity
Sperm production depends on proper Sertoli-germ cell interaction, and we hypothesized that receptor activator of nuclear factor κB ligand (RANKL) activity in Sertoli cells may influence spermatogenesis. Treatment with the RANKL inhibitor denosumab, normally used to treat osteoporosis, increased testicular weight, inhibin B, and germ cell proliferation in ex vivo testis cultures and in vivo in a humanized RANKL mouse. The effect on germ cell proliferation was positively associated with baseline serum concentrations of anti-müllerian hormone (AMH). In accordance, denosumab increased germ cell proliferation in ex vivo human testis cultures with low/moderate but not severe impairment of Sertoli cell function. In a placebo-controlled randomized clinical trial, denosumab had no effect on semen quality but increased sperm concentration in a subgroup of infertile men with serum AMH ≥38 pmol/L at baseline. In conclusion, high serum AMH may increase the probability of a beneficial response to denosumab treatment in infertile men, thus suggesting a possible venue for precision medicine in male infertility.
Authors
- Zhihui Cui (ORCID: https://orcid.org/0000-0001-7970-4585)
- Martin Blomberg Jensen (ORCID: https://orcid.org/0000-0003-3800-4253)
- Birgitte Grønkær Toft
- Christine Hjorth Andreassen (ORCID: https://orcid.org/0000-0002-3643-6426)
- Ida Marie Boisen (ORCID: https://orcid.org/0000-0003-2401-2877)
- Charles A. O’Brien (ORCID: https://orcid.org/0000-0002-5286-6821)
- Anne Jørgensen (ORCID: https://orcid.org/0000-0002-6409-198X)
- Nadia Nicholine Poulsen (ORCID: https://orcid.org/0000-0002-0625-1770)
- Thomas Hasselager
- Nadia Krarup Knudsen (ORCID: https://orcid.org/0009-0005-1591-343X)
- Anders Juul (ORCID: https://orcid.org/0000-0002-0534-4350)
- Daniel J. Bernard (ORCID: https://orcid.org/0000-0001-5365-5586)
- Niklas Rye Jørgensen (ORCID: https://orcid.org/0000-0001-9624-5210)
- Luisina Ongaro (ORCID: https://orcid.org/0000-0002-5449-2894)
- Li Juel Mortensen (ORCID: https://orcid.org/0000-0002-8995-9116)
- Rune Holt (ORCID: https://orcid.org/0000-0002-2489-3216)
- Sam Kafai Yahyavi (ORCID: https://orcid.org/0000-0002-6658-5094)
- Jasmin P. Hjerresen
- John E. Nielsen
Institutions
- University of Copenhagen (DK)
- Novo Nordisk Foundation (DK)
- Copenhagen University Hospital (DK)
- Gentofte Hospital (DK)
- Rigshospitalet (DK)
- McGill University (CA)
- University of Arkansas for Medical Sciences (US)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2024-10-01
- DOI
- https://doi.org/10.1016/j.xcrm.2024.101783
- Citations
- 5
- Primary Topic
- Sperm and Testicular Function
- Type
- article
- Field-Weighted Citation Impact
- 2.69
Funders
- Innovationsfonden
- Novo Nordisk
- Danmarks Frie Forskningsfond
- Læge Sophus Carl Emil Friis og hustru Olga Doris Friis' Legat
- Novo Nordisk Fonden
- Beckett-Fonden
- Hartmann Fonden
- Candys Foundation