RANKL regulates male reproductive function 

Infertility is a worldwide health issue that impacts 17.5% of couples globally (1). Although male infertility is quite prevalent, there are limited treatment options available (2).

RANKL regulates male reproductive function 

A study published by Blomberg Jensen M et al, identified RANKL as a regulator of male reproductive function: RANKL regulates male reproductive function. Nat Commun. 2021; 12(1):2450.

Abstract

Infertile men have few treatment options. Here, we demonstrate that the transmembrane receptor activator of NF-kB ligand (RANKL) signaling system is active in mouse and human testis. RANKL is highly expressed in Sertoli cells and signals through RANK, expressed in most germ cells, whereas the RANKL-inhibitor osteoprotegerin (OPG) is expressed in germ and peritubular cells. OPG treatment increases wild-type mouse sperm counts, and mice with global or Sertoli-specific genetic suppression of Rankl have increased male fertility and sperm counts. Moreover, RANKL levels in seminal fluid are high and distinguishes normal from infertile men with higher specificity than total sperm count. In infertile men, one dose of Denosumab decreases RANKL seminal fluid concentration and increases serum Inhibin-B and anti-Müllerian-hormone levels, but semen quality only in a subgroup. This translational study suggests that RANKL is a regulator of male reproductive function, however, predictive biomarkers for treatment-outcome requires further investigation in placebo-controlled studies.

In a more recent study by Andreassen CH et al , Denosumab, a RANKL inhibitor to treat osteoporosis, showed a beneficial response to treat infertile men in a subgroup of individuals: Denosumab stimulates spermatogenesis in infertile men with preserved Sertoli cell capacity. M.Cell Rep Med. 2024; 5(10):101783.

Summary

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.

The BIOMEDICA soluble RANKL (sRANKL) ELISA assay (cat. no. BI-20462) and Osteoprotegerin – OPG ELISA assay (cat. no. BI-20403) was utilized in both studies to quantify soluble RANKL and OPG levels in human serum and seminal fluid.

 

Key findings

• Infertile men had significant higher seminal sRANKL concentration and lower serum sRANKL levels than healthy men.
• Seminal fluid levels of sRANKL were approx. 100-fold higher than corresponding serum levels.
• High RANKL levels in seminal fluid distinguishes normal from infertile men with higher specificity than total sperm count.
• One dose of Denosumab, a RANKL inhibitor, decreases RANKL seminal fluid concentration.
• Denosumamb treatment in infertile men suggests a potential approach in addressing male infertility.

 

Soluble RANKL HS ELISA assay kit (cat. no. BI-20462)

• High sensitivity – measurable concentrations in healthy subjects
• Only ELISA that measures free, uncomplexed soluble RANKL
• Widely cited in more than 320 publications

 

OSTEOPROTEGERIN (OPG) ELISA assay kit (cat. no. BI-20403)

• Reliable – validated according to international guidelines
• Most referenced human OPG ELISA – 270 citations
• Only 20µl sample volume required 

 

Literature

1. World Health Organization. 2023. Infertility prevalence estimates 1990-2021 .
2. Denosumab stimulates spermatogenesis in infertile men with preserved Sertoli cell capacity. Andreassen CH, Holt R, Juel Mortensen L, Knudsen NK, Nielsen JE, Poulsen NN, Yahyavi SK, Boisen IM, Cui Z, Ongaro L, Hjerresen JP, Toft BG, Hasselager T, Jørgensen NR, Bernard DJ, Juul A, O’Brien C, Jørgensen A, Blomberg Jensen M.Cell Rep Med. 2024 Oct 15;5(10):101783. doi: 10.1016/j.xcrm.2024.101783. PMID: 39383870.
3. RANKL regulates male reproductive function. Blomberg Jensen M, Andreassen CH, Jørgensen A, Nielsen JE, Juel Mortensen L, Boisen IM, Schwarz P, Toppari J, Baron R, Lanske B, Juul A. Nat Commun. 2021 Apr 23;12(1):2450. doi: 10.1038/s41467-021-22734-8. PMID: 33893301; PMCID: PMC8065035.