Dysfunction Junction

New research challenges traditional approaches to male reproductive aging

One of the posters presented as part of ENDO 2025’s Reproductive Endocrinology tract gained a lot of attention because it shed light on a heretofore unheralded link between men’s sexual well-being and metabolic health. Lead author Michael Zitzmann, MD, PhD, talks to Endocrine News about his team’s findings that could potentially have a huge impact on treating aging men’s reproductive function.  

Even though ENDO 2025 wrapped at the end of July, the research presented there will continue to reverberate for years to come. The field sits at the intersection of so many critical health issues that the immediate buzz around poster sessions and keynote presentations was just the beginning of much longer scientific conversations.

Michael Zitzmann, MD, PhD, professor and doctor of medicine at University Hospital in Muenster, Germany, presented one such study that promises to have long-term implications for men’s health as they age. The research builds on his earlier work published in Ageing Cell in 2020 on the effects of aging on male reproductive health investigated during the FAMe 1 (Fertility and Ageing in Healthy Men) trial. “FAMe 2.0, which formed the basis of our ENDO 2025 presentation,” says Zitzmann, “is currently in preparation for submission to a high-impact peer-reviewed journal. We are incorporating additional stratified analyses and extended follow-up data to ensure a comprehensive publication.”

For FAMe 1, 197 healthy men aged 18 – 84 years were assessed for andrological parameters at baseline, with 117 participants returning for FAMe 2 about six years later. This follow-up trial specifically zeroes in on how body mass index (BMI) and glycated hemoglobin (HbA1c) contribute to reproductive aging, given the well-known association between metabolic disorders and certain reproductive parameters such as testosterone decline and erectile dysfunction (ED).

Glucose vs. Testosterone

What emerged from the longitudinal analysis was both striking and clinically significant. While total and free testosterone levels declined significantly over the six-year period in men older than 25 years at baseline (p < 0.05), and follicle-stimulating hormone levels increased in men older than age 35 years (with luteinizing hormone and sex hormone–binding globulin levels not changing), these hormonal changes told only part of the story. The more compelling finding centered on erectile function, which exhibited a moderate but progressive decline throughout the study period (p < 0.001). Moreover, despite declining, testosterone levels remained within normal range.

“When men present with sexual complaints — especially erectile dysfunction — clinicians should not only consider testosterone levels but must also assess metabolic health comprehensively. Our findings strongly support the view that sexual function can serve as a sentinel marker for broader metabolic disturbances.” – Michael Zitzmann, MD, PhD, professor and doctor of medicine, University Hospital, Muenster, Germany

“This is indeed one of the most striking and clinically relevant findings from our study,” Zitzmann explains. In men older than age 45 years, neither age (p = 0.13) nor testosterone levels (p = 0.52) influenced erectile function. Instead, incremental increases in HbA1c levels were significantly associated with deteriorating erectile function (p = 0.002). Similarly, Aging Males’ Symptoms (AMS) scores increased significantly after age 45, correlating strongly with higher HbA1c levels (p = 0.001).

“While testosterone certainly influences libido and general sexual well-being, its role in erectile function is less direct. Erections depend primarily on vascular and neurological integrity,” Zitzmann notes.
“In our study, testosterone levels declined modestly over time but remained within the physiologic range. Meanwhile, erectile function declined more sharply — and this decline correlated much more strongly with metabolic markers such as HbA1c than with testosterone.”

Underlying Mechanisms

Although this finding — that metabolic factors are the primary drivers of ED in aging men, not declining testosterone — is revelatory, it certainly stands to reason. “The mechanism lies in the vascular and neural damage induced by elevated blood glucose levels, even before clinical diabetes manifests,” Zitzmann explains. “Hyperglycemia promotes endothelial dysfunction, reduces nitric oxide bioavailability, and accelerates atherosclerosis — all of which impair penile blood flow and erectile capacity.”

The research also suggests that advanced glycation end products (AGEs) play a role in the pathophysiology. AGEs may damage peripheral nerves and contribute to diabetic neuropathy, thus affecting erectile function. Perhaps most clinically relevant is the timing of these effects. “What’s important to note is that this effect becomes measurable even at prediabetic levels of HbA1c, suggesting that sexual dysfunction can serve as an early warning sign of metabolic compromise — often before cardiovascular events occur,” Zitzmann emphasizes.

This finding aligns with epidemiologic trends showing increasing prevalence of impaired glucose regulation with age. “While this can begin in the fourth decade of life, it becomes particularly prominent from the age of 45 onward,” Zitzmann observes. “In our study, men over 45 showed a significantly stronger correlation between increasing HbA1c and deteriorating erectile function, independent of age and testosterone levels.”

Clinical Practice Implications

For Zitzmann, who has been conducting research in male contraception and reproductive endocrinology since 1999 and has published more than 160 papers on male reproductive health, these findings represent much more than scientific interest. “What fascinates me is how intricately these systems interact — not only biologically, but also psychologically and socioculturally. Despite its relevance to public health, male reproductive health remains comparatively underrepresented in both research and funding.”

He says this research may prompt a paradigm shift in clinical practice toward integrated metabolic-reproductive health management, insofar as even modest elevations in HbA1c within the prediabetic range were linked with worsening erectile function and increased hypogonadism-like symptoms such as fatigue, mood changes, and reduced muscle mass, despite normal testosterone levels. “When men present with sexual complaints — especially erectile dysfunction — clinicians should not only consider testosterone levels but must also assess metabolic health comprehensively,” Zitzmann says. “Our findings strongly support the view that sexual function can serve as a sentinel marker for broader metabolic disturbances.”

Zitzmann advocates for effective sexual health maintenance plans that include routine metabolic screening with fasting glucose, HbA1c, lipids, and blood pressure assessment. Early lifestyle interventions focusing on dietary changes, weight management, and exercise programs to improve insulin sensitivity and vascular health form the cornerstone of this approach.

Patient education also plays a crucial role. “Helping men understand the link between metabolism and sexual function” can motivate engagement with preventive care strategies. Perhaps most importantly, Zitzmann emphasizes the need for multidisciplinary collaboration, involving endocrinologists, cardiologists, and urologists to provide integrated care.

“While testosterone certainly influences libido and general sexual well-being, its role in erectile function is less direct. Erections depend primarily on vascular and neurological integrity. In our study, testosterone levels declined modestly over time but remained within the physiologic range. Meanwhile, erectile function declined more sharply — and this decline correlated much more strongly with metabolic markers such as HbA1c than with testosterone.” – Michael Zitzmann, MD, PhD, professor and doctor of medicine, University Hospital, Muenster, Germany

“By taking this broader approach, we can detect subclinical disease earlier, tailor interventions more precisely, and ultimately improve quality of life and long-term outcomes for men,” he concludes.

Looking Forward

The impact of Zitzmann’s ENDO 2025 presentation is clear. “This year’s meeting was outstanding, and our poster presentation received considerable attention — not only from academic attendees, but also from the media, including coverage in German outlets. The resonance of the topic shows how relevant men’s health and reproductive aging have become, particularly as they intersect with broader issues like metabolic health and preventive medicine.”

As we await the published FAMe 2.0 data, clinicians can begin implementing some of the changes it will demand now. Sexual dysfunction, particularly ED, may represent one of the earliest and most sensitive indicators of metabolic compromise — preceding cardiovascular events and offering a critical window for intervention. For endocrinologists, this research reinforces the interconnected nature of metabolic health and provides compelling evidence for comprehensive screening approaches that extend beyond traditional reproductive hormone assessment.

Zitzmann has attended ENDO annually since 2001. What will he bring to ENDO 2026?

Horvath is a freelance writer based in Baltimore, Md. She wrote about the 2025 Transatlantic Alliance Award winner Ashley Grossman, FMedSci, in the July issue.