New Test Might Transform Male Infertility

A new study suggests that, at least for certain male patients, the answer to infertility might lie with epigenetics.

According to the study, a commercially-available test of epigenetic anomalies — factors that affect how genes express themselves — can grade the likelihood that sperm are viable for conception.

“The uniqueness of epigenetics is that some of the abnormalities detected have the potential to be modified with lifestyle,” said Larry I. Lipshultz, MD, head of the Division of Male Reproductive Medicine and Surgery at Baylor College of Medicine, Houston, Texas, who presented the new findings at the 2022 annual meeting of the American Urological Association.

For decades, semen analysis has been based on motility, morphology, and concentration. But these measures, while useful, are limited. Semen can still have low capacity for producing a pregnancy even when all three parameters are normal, Lipshultz told Medscape Medical News.

The test, called Path SpermQT (Inherent Biosciences) detects unstable gene promotors, which are the epigenetic markers for gene expression. In previous work with more than 1300 gene samples, expression of the specific genes regulated by these promoters were linked to a wide variety of functions relevant to fertilization, such as spermatogenesis.

The test does not attempt to look for expression of specific unstable promoters, but rather quantifies them to characterize sperm quality as excellent (≤ 10 unstable promoters), average (11 to 42), or poor (≥ 43).

In the studies that led to development of the SpermQT test, the number of unstable promoters correlated with pregnancy success. Pregnancy was achieved even among those in the group with poor sperm quality, but at very low rates.

Of the 172 semen samples collected so far in the ongoing analysis, sperm quality was characterized as excellent in 31%, average in 59%, and poor in 10%.

The stratifications for sperm quality were not significantly correlated with common measures of sperm viability, such as concentration, Lipshultz reported.

Certain patient characteristics were associated with greater sperm quality. These included use of antioxidant supplementation and low estrogen levels, as seen in men who had taken aromatase inhibitors.

So far, only one natural conception has occurred in the group with poor sperm versus eight in those with average or excellent quality.

The prognostic role of the test is only part of the picture.

“The exciting thing about this area of research is that epigenetics can be changed,” Lipshultz told Medscape. Based on the data so far, he said he is already starting to consider antioxidant supplementation and hormone modifications when sperm quality is poor.

The value of the Path SpermQT test for identifying treatment targets might eventually revolutionize the management of male infertility, Lipshultz said, but it has more immediate potential in helping couples decide whether to proceed with in vitro fertilization (IVF).

“We often see patients at an impasse when they are trying to decide to move to IVF,” he said. “A test like this could provide some direction. If sperm quality is good, the advice might be to keep trying. If poor, then a couple might want to move to IVF more quickly.”

A test of sperm quality on the basis of epigenetics “could change how we look at couples attempting to conceive,” agreed Peter N. Schlegel, MD, professor of urology and reproductive medicine, Weill Cornell Medicine, New York City.

Schlegel praised several characteristics of the epigenetics test, including that 70% to 80% of men with poor quality with SpermQT have normal results on standard assessments of semen. This finding suggests the tool is providing unique information about patients. He also noted that the studies so far indicate that sperm of poor quality for natural conception is still viable for IVF fertilization — which could be useful for couples weighing their options.

However, while the test is already available, Schlegel cautioned that much of the promise has yet to be documented.

“The results to date, despite being statistically significant, have only been gleamed from a small group of patients,” he said. “Much larger studies are needed before a change in practice is warranted.”

The value of SpermQT for identifying modifiable risks might be even further away.

“It is well recognized that environmental and lifestyle changes can affect methylation, but it is not known if the abnormalities seen so far could be influenced by lifestyle changes,” Schlegel said. Among the numerous steps needed to answer this question, he suggested that it might be first important “to evaluate why such changes in methylation occur.”

Lipshultz has financial relationships with several pharmaceutical companies, including Inherent Biosciences, which is marketing the SpermQT test. Schlegel has financial relationships with Theralogix, Posterity Health, and Roman Health.

American Urological Association (AUA) 2022 Annual Meeting: Abstract P09-02. Presented May 13, 2022.

Ted Bosworth is a medical writer in New York City.

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