Clinical Relevance of Modifying RANKL Signaling During Folliculogenesis

NCT07546552 | Recruiting

• 1 other identifier: RANKL
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Female Infertility; NF-κB Ligand; RANKL; Osteoporosis; Follicle Development

Outcome Measures

Primary Outcomes (3)

• 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

Study Arms (2)

Study group

EXPERIMENTAL

DENOSUMAB medical preparation

Other: Denosumab

Control group

ACTIVE COMPARATOR

PBS medical preparation

Other: PBS

Interventions

Denosumab OTHER

DENOSUMAB facilitates maturation of immature occytes in stage GV and MI

Study group

PBS OTHER

PBS facilitates maturation of immature occytes in stage GV and MI

Control group

Eligibility Criteria

• Age: 18 Years+
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• Patients who have had autotransplanted ovarian tissue

Sponsors & Collaborators

• Peter Humaidan: lead
• Herlev Hospital: collaborator

Study Sites (1)

Regionshospitalet, Skive, Midt Jylland 7800

Skive, Midt Jylland, 7800, Denmark

RECRUITING

MeSH Terms

Conditions

Infertility, Female; Osteoporosis

Interventions

Denosumab

Condition Hierarchy (Ancestors)

Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Infertility; Bone Diseases, Metabolic; Bone Diseases; Musculoskeletal Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: March 26, 2026
• First Posted: April 22, 2026
• Study Start: August 1, 2025
• Primary Completion (Estimated): March 15, 2028
• Study Completion (Estimated): March 15, 2028
• Last Updated: April 22, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)