TNFSF11 Inhibition and Fertility: a Prospective Study

• Status: Completed
• Trial end date: 2019-01-01
• Target enrollment: 0
• Participant gender: Male

Summary

The receptor activator of NF-kB ligand (RANKL) system is considered important for bone homeostasis and comprises three important factors. RANKL exist in three isoforms but the predominant function is mediated by the transmembrane ligand that binds to a specific receptor (receptor activator of NF-KB (RANK)) on a neighbour cell that subsequently activates NFKB and regulates cell cycle OPG is an endogenous secreted protein that binds RANKL and inhibits its signalling.

Thus, the RANK/RANKL system is vital for activation of the bone resorbing cells (osteoclasts). In bone the bone synthesizing cells (osteoblasts) express RANKL that signals to RANK on the immature osteoclasts. This induces proliferation and activation of the cells they start to proliferate and resorp bone. OPG is produced by somatic cells in the bone and this production is regulated by sex hormones, TGF-B and various other substances. Today a human made recombinant antibody against RANKL, Denosumab is used to treat osteoporosis as it inhibits RANKL signalling and thus causes less bone resorption in humans.

RANKL, RANK and OPG are expressed in the testis and this pathway appears to be a novel regulator of germ cell proliferation. Decreased semen quality is a major factor of male infertility. Semen quality is a measure of the ability of the sperm to accomplish fertilization. Evaluation of male fertility potential is today basically conducted through semen analysis. There is no treatment for men with no sperm in the ejaculate and there exist no drug that can increase sperm counts.Therefore, drugs that can lower RANKL expression/activity for instance an antibody against RANKL such as Denosumab may be used for this new indication: A new treatment option of infertile men with impaired semen quality.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Martin Blomberg Jensen
• Treatments: Denosumab

Criteria

Infertile men referred for evaluation of male infertility at department of growth and reproduction or infertile men interested in participation in clinical trials.

Inclusion Criteria:

• Male with an age > 18 years old

• Referred for male infertility with sperm concentration >= 0.1 million/ml.

• Additionally, all men must have either sperm concentration < 20 million/ml or < 50% progressive motile spermatozoa or < 12% morphological normal spermatozoa using strict criteria

Exclusion Criteria:

Men with chronic diseases such as

• diabetes mellitus

• Thyroid disease

• endocrine disturbances in need of treatment

• malignant disease

• or diseases known to interfere with calcium homeostasis (such as inflammatory disease with granuloma: sarcoidoses, tuberculosis, Wegeners, vasculitis, inflammatory bowel disease (Crohn's and colitis ulcerosa etc).

• Men with previous testis cancer

• If there is an indication for testis biopsy and it is planned or conducted within the next 6 months

• Serum 25-hydroxy-D3 < 50 nmol/l

• Serum Calcium ion < 1,18 or > 1,35 mmol/l

• Serum OPG >4 pg/ml

• Serum PTH <1.6 or >6 pmol/l

• Inhibin-B < 50 pg/ml

• Latex Allergy

• no good oral condition or major implants

• BMD < -1,5 in columna lumbalis and collum femoris

Criteria for drop out:

• Abrogation of the treatment

• Newly diagnosed endocrine, calcium metabolic disease, parathyroid, thyroid, diabetes or other endocrine disease in need of treatment

• New malignant disease

• Treatment with chemotherapy, immunomodulating therapy, salazopyrin

• Oral or iv treatment with steroid hormones

• New treatment with diuretics, antihypertensive treatment, treatment the heart, calcium channel blockers

• If testis biopsy is performed or other surgery in the genital region during the trial

• Prolia Intoxication