2. Academic Validation
  3. Denosumab stimulates spermatogenesis in infertile men with preserved Sertoli cell capacity

Denosumab stimulates spermatogenesis in infertile men with preserved Sertoli cell capacity

  • Cell Rep Med. 2024 Oct 15;5(10):101783. doi: 10.1016/j.xcrm.2024.101783.
Christine H Andreassen 1,  Rune Holt 1,  Li Juel Mortensen 2,  Nadia Krarup Knudsen 1,  John E Nielsen 3,  Nadia Nicholine Poulsen 1,  Sam K Yahyavi 1,  Ida M Boisen 4,  Zhihui Cui 1,  Luisina Ongaro 5,  Jasmin P Hjerresen 1,  Birgitte G Toft 6,  Thomas Hasselager 7,  Niklas R Jørgensen 8,  Daniel J Bernard 5,  Anders Juul 9,  Charles O'Brien 10,  Anne Jørgensen 1,  Martin Blomberg Jensen 11
Affiliations

Affiliations

  • 1 Division of Translational Endocrinology, Department of Endocrinology and Internal Medicine, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark.
  • 2 Division of Translational Endocrinology, Department of Endocrinology and Internal Medicine, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark; Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
  • 3 Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
  • 4 Division of Translational Endocrinology, Department of Endocrinology and Internal Medicine, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
  • 5 Department of Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada.
  • 6 Department of Pathology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
  • 7 Department of Pathology, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark.
  • 8 Department of Clinical Biochemistry, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
  • 9 Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
  • 10 Center for Musculoskeletal Disease Research, Division of Endocrinology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
  • 11 Division of Translational Endocrinology, Department of Endocrinology and Internal Medicine, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. Electronic address: martin.blomberg.jensen@regionh.dk.
PMID: 39383870 DOI: 10.1016/j.xcrm.2024.101783
Abstract

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.

Keywords

AMH; RANKL activity; bone; denosumab; male infertility; personalized medicine; randomized clinical trial; spermatogenesis.

Figures
Products