Effects on Offspring
Another open question about GLP-1 RAs and male fertility is their potential effects on the offspring, said Sriram Machineni, MBBS, associate professor of endocrinology at the Albert Einstein College of Medicine in New York City. The clinical trials involving the drugs for treating type 2 diabetes and obesity required both men and women to use contraception. If sperm contributing to a pregnancy are exposed to a GLP-1 agent, “we don’t know what the consequences could be,” Dr. Machineni said. “Just increasing the fertility of the man is not enough. We need to make sure it’s safe long-term for the fetus.”
Dr. Bole also pointed out the need for understanding potential effects in the fetus.
“We know that there are epigenetic changes that can happen to sperm that are influenced by the lifestyle and the physical health and environment of the parent,” Dr. Bole said. “So how could these drugs potentially affect those epigenetic changes that then potentially are passed on to the offspring? We don’t know that.”
An ideal source for that data would be a cohort registry of people who are taking the medication and then cause a pregnancy. “They have a registry for pregnant women,” Dr. Machineni said, “but we need something similar for men.”
Dr. Sadeghi-Nejad said that he and his coauthors are working on developing a registry for men who take GLP-1 RAs that would enable long-term tracking of multiple andrologic outcomes, including fertility and sexual dysfunction. Such a registry could theoretically be useful in tracking pregnancy and offspring outcomes as well.
Too Soon for Prescribing
Additional options for treating fertility in men with obesity would be welcome. Current treatments include the selective estrogen receptor modulator (SERM) clomiphene citrate and the aromatase inhibitor anastrozole. But these have their drawbacks, Dr. Sadeghi-Nejad pointed out; in the overweight population in particular, they “are not necessarily ideal,” he said.
“Although both are viable treatments for enhancing hormonal balance and semen parameters, clomiphene citrate has rare but documented side effects, including thromboembolism, gastrointestinal distress and occasional weight gain in men,” Dr. Sadeghi-Nejad and his colleagues wrote. “Furthermore, despite clomiphene citrate’s association with significant increases in sperm concentration, it is not universally effective, with a meta-analysis indicating a significant increase in sperm concentration in approximately 60% of men.”
For men who have obesity and oligospermia but normal levels of testosterone and estradiol, “conventional pharmaceutical approaches like clomiphene may not be suitable,” the authors wrote.
Still, GLP-1 RAs may have a role to play for this population.
“I think it is within the wheelhouse of a reproductive urologist to consider those types of medications,” Dr. Lindsey said. For example, for a patient who has overweight or obesity, “does it make sense to think about doing clomiphene therapy, which we often do for someone who has low testosterone, in conjunction [with a GLP-1 agonist]? Maybe there’s a kind of an additive effect of having both on board.”
Dr. Ramasamy similarly noted that GLP-1 agonists cannot replace SERMs but may work “synergistically” with them.
“Despite the established popularity of GLP-1 receptor agonists, there may be some reluctance among urologists and fertility specialists to prescribe them, with some others advocating for their use to enhance semen parameters,” Dr. Ramasamy said. “However, robust scientific evidence is still lacking, necessitating caution and a wait for more substantial data.”
Even if GLP-1 RAs prove to have therapeutic benefit for fertility, considerations such as availability and cost may affect prescribing.
“We do currently have safe and effective drugs that we use for male fertility, and those are generally nowhere near as expensive,” Dr. Bole said. “When we start talking about another drug that we can add, we have to think about the efficacy and the potential side effect but also, is this affordable for patients?”
Eventually, once more evidence become available, all of the urologists who spoke with this news organization said that they expect discussion about the possible therapeutic utility of GLP-1 agonists to make its way into clinical guidelines.
“Obesity is such a huge impediment for fertility in the modern environment,” Dr. Machineni said. “We will have to clarify the use of these agents, so I think this will be a part of the guidelines some point, but I think we need more information.”
The research was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the American Cancer Society. The review authors and other quoted physicians reported no disclosures. Dr. Machineni has consulted for Novo Nordisk and Lilly and has conducted clinical trials with semaglutide and tirzepatide for those companies.
A version of this article appeared on Medscape.com.