Clinical Relevance of Modifying RANKL Signaling During Folliculogenesis

Female infertility presents a significant societal challenge that will be aggravated in the future due to delayed parenthood. Our translational research suggests that receptor activator of NF-κB ligand (RANKL) is a novel treatment target, during assisted reproductive techniques and that inhibition of this pathway may reduce the impact of aging on the ovary. RANKL is a regulator of bone health, and an antibody (denosumab) blocking RANKL activity is used clinically to treat osteoporosis. Previously, we have shown that inhibition of RANKL increases sperm production in rodents, in human tissue models, and in a subpopulation of infertile men. Now, we show that all factors of the RANKL signalling system are expressed in human and mouse ovaries. Granulosa cell-specific Rankl knockdown lowers the number of primordial follicles, which suggests that RANKL has an important role during early stages of folliculogenesis. Additionally, our data from women undergoing in vitro fertilisation show that follicular fluid concentrations of RANKL and OPG are associated with age and the number of matured follicles, and RANKL inhibition promoted maturation of human oocytes in vitro, which suggests an effect also late in folliculogenesis. Thus, the proposed project aims to: 1) Clarify the role of RANKL in ovaries of mice and humans 2) Determine the reproductive effect of modulating RANKL activity systemically or locally in mice and monkeys 3) Investigate whether manipulation of RANKL can optimise in vitro maturation and rescue of immature human oocytes and 4) Determine whether follicular fluid concentrations of soluble RANKL and OPG may serve as markers of ovarian pathophysiology. The overall aim of this project is to uncover how RANKL regulates follicle reserve and oocyte maturation during the final stages of follicle development. Thereby, determining whether this pathway may be a target for optimisation of IVF treatment and a future treatment option for female infertility.

Study Overview

• Status: Recruiting
• Conditions: Osteoporosis; Follicle Development; Female Infertility; NF-κB Ligand; RANKL
• Intervention / Treatment: Other: Denosumab; Other: PBS

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Midt Jylland
    • Skive, Midt Jylland, Denmark, 7800
      • Recruiting
      • Regionshospitalet, Skive, Midt Jylland 7800
      • Contact: Peter Humaidan PH Professior, Professor; Phone Number: +4578445760; Email: peter.humaidan@midt.rm.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Female in the age of 18 or above, Normal AMH-value, able to give concent

Exclusion Criteria:

• Patients who have had autotransplanted ovarian tissue

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Study group; DENOSUMAB medical preparation	Other: Denosumab; DENOSUMAB facilitates maturation of immature occytes in stage GV and MI
Active Comparator: Control group; PBS medical preparation	Other: PBS; PBS facilitates maturation of immature occytes in stage GV and MI

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Evaluate and compare the reproductive phenotype of granulosa cell-specific Rankl knock down mice, global Rankl knock out mice, and a humanized RANKL mouse model treated with denosumab.	From enrollment to the end of the study
Investigate the effects of manipulating RANKL activity on ovarian function in human adult ovaries ex vivo and in xenotransplanted human ovarian cortex tissue.	From enrollment to the end of the study
Investigate the reproductive effect of pharmacological RANKL inhibition in higher primates	From enrollment to the end of the study

Collaborators and Investigators

• Sponsor: Peter Humaidan
• Collaborators: Herlev Hospital

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2025
• Primary Completion (Estimated): March 15, 2028
• Study Completion (Estimated): March 15, 2028

Study Registration Dates

• First Submitted: March 26, 2026
• First Submitted That Met QC Criteria: April 16, 2026
• First Posted (Actual): April 22, 2026

Study Record Updates

• Last Update Posted (Actual): April 22, 2026
• Last Update Submitted That Met QC Criteria: April 16, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Bone Diseases; Musculoskeletal Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Metabolic Diseases; Genital Diseases, Female; Bone Diseases, Metabolic; Infertility; Nutritional and Metabolic Diseases; Osteoporosis; Infertility, Female; Amino Acids, Peptides, and Proteins; Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Denosumab
• Other Study ID Numbers: RANKL

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No