Female Infertility, NF-κB Ligand, RANKL, Osteoporosis, Follicle Development
Conditions
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.
Interventions
OTHERDenosumab
DENOSUMAB facilitates maturation of immature occytes in stage GV and MI
OTHERPBS
PBS facilitates maturation of immature occytes in stage GV and MI
Sponsors
Peter Humaidan
Herlev Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
Yes
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
Design outcomes
Primary
| 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 |
Countries
Denmark
Outcome results
None listed