Researchers from the Department of Growth and Reproduction at Rigshospitalet and the Division of Bone and Mineral Research at Harvard University are behind the new and exciting research, which could potentially improve sperm quality in 40-60% of infertile men worldwide, thus significantly increasing these men's chances of reproducing.
The initial research results have recently been published in the prestigious journal Nature Communication, and the researchers are now ready to move forward with a large randomised study of men with reduced sperm quality. All infertile men are invited to take part in the study.
The researchers at Rigshospitalet and Harvard University are the first in the world to document the presence of the RANKL protein in male testicles and to document that the protein helps regulate fertility. RANKL is a protein best known for its presence in bones, where it affects the degradation of the bones and may lead to osteoporosis. One of the most well-known drugs to prevent this is the RANKL inhibitor Denosumab, which is used throughout the world to treat osteoporosis.
When the researchers discovered the RANKL protein by coincidence in connection with other studies of the male testicles, they immediately tested the effect of adding the Denosumab RANKL inhibitor to testicle tissue in the laboratory. The result was a significantly higher number of cells, so there was good reason to believe that Denosumab could increase the sperm count in men with poor sperm quality.
The researchers went on to study the effect in mouse and testicle tissue models and, most recently, in 12 infertile men. The hypothesis soon proved correct in all studies, so now the researchers are putting all of their energy into a randomised trial to determine which infertile men will benefit most from the treatment and what are the possible side effects.
The surprising RANKL protein
Martin Blomberg from the Department of Growth and Reproduction at Rigshospitalet and head of the study said:
"For many years, we've been researching the role of vitamin D in fertility. Then one of the studies suddenly identified the RANKL protein in the testicles, and this was very surprising, since RANKL has not been observed in the testicles before," explained Martin Blomberg.
"Based on the preliminary study of the effect of Denosumab on men's sperm count, we have reason to believe that, for a significant number of men with mildly to moderately poor sperm quality, a single injection with the Denosumab drug will be enough to increase the sperm count for a period of up to several months, significantly increasing these men's chances of impregnating a woman, and so we're looking forward to studying this further," he said.
Martin Blomberg is very excited about the new discovery and the prospects of contributing to the development of an actual treatment for men with poor sperm quality, because no such treatment exists today.
If a couple cannot conceive because the man has poor sperm quality, in most cases we can only offer to treat the woman through artificial insemination, even though she has no problems conceiving. With the new discovery and what is hopefully a new treatment method, we hope to be able to treat the man instead, so that the woman does not have to go through treatment to make up for their male partner's poor sperm quality. However, there are many causes of low sperm quality and we therefore have to examine how to best identify the men who will benefit the most from the treatment, Martin Blomberg explained.
"It's our hypothesis that by taking a blood sample and analysing it for two different hormones, we can select the patients who will benefit from the treatment. We’re therefore encouraging infertile couples in which the male has poor sperm quality to join the study. We also hope that general practitioners and Danish fertility clinics will refer men to us, so that we can determine whether they could benefit from the treatment," he said.
The new study will include 380 men, who will have a blood sample taken and who will then draw lots to either receive a dose of Denosumab or a placebo drug.
A patent on using Denosumab to treat poor sperm quality
The research results so far are already so significant and promising that Rigshospitalet has taken out a patent throughout most of the world on the use of Denosumab and similar drugs in fertility treatment, and the hospital aims to further develop a drug as a new treatment option for male infertility. The patent is licenced to the company XY Therapeutics, which will take care of the next step in the development of the project.
Patenting and further development of the project has taken place as a collaborative effort with Research and Innovation, a unit under the Capital Region of Denmark, which also sees great perspectives for the project and the potential new treatment:
"The project has unique potential as a new treatment for a group of patients that previously had no treatment option available. We’d like to support this, so that the research can be disseminated and implemented as patient treatment," explained Chief Advisor Bjarke Poulsen from Research and Innovation.
The Bioinnovation Institute has also supported the project, both during the initial research phase and, now, with DKK 3.5 million for the further project, because they believe there is a potential that the project will provide a new treatment for a group of men who otherwise have no treatment options.
"The success of the project is due to the unique research carried out and the collaborative efforts on further development and commercialisation between the parties involved and XY Therapeutics, the new company. We believe and hope that the project will lead to a new, world-class treatment to meet a significant, unmet demand," explained Giles Dudley, who is the business portfolio manager at the Bioinnovation Institute.
The picture shows, from left to right: Bjarke Poulsen, Martin Blomberg and Giles Dudley
Facts about the new randomised study
• Will include 380 infertile men over a period of two years
• The participating men will have a blood sample taken to identify biomarkers for who will benefit the most from the treatment
• After the blood sample, participants will either be administered a dose of Denosumab or a dose of placebo, by drawing of lots.
• Participants will subsequently be monitored for 150 days to see the effect on their sperm quality and the couple's chances of conceiving
• The study will end in 2024
• The study is being carried out by Rigshospitalet with financial support from the Bioinnovatoin Institute, XY Therapeutics and research grants.