The Effect of Metformin on Male Reproductive Function and Prostate: An Updated Review

Abstract

Metformin is the first-line oral antidiabetic drug that shows multiple pleiotropic effects of anti-inflamation, anti-cancer, anti-aging, anti-microbia, anti-atherosclerosis, and immune modulation. Metformin's effects on men's related health are reviewed here, focusing on reproductive health under subtitles of erectile dysfunction (ED), steroidogenesis and spermatogenesis; and on prostate-related health under subtitles of prostate specific antigen (PSA), prostatitis, benign prostate hyperplasia (BPH), and prostate cancer (PCa). Updated literature suggests a potential role of metformin on arteriogenic ED but controversial and contradictory effects (either protective or harmful) on testicular functions of testosterone synthesis and spermatogenesis. With regards to prostate-related health, metformin use may be associated with lower levels of PSA in humans, but its clinical implications require more research. Although there is a lack of research on metform's effect on prostatitis, it may have potential benefits through its anti-microbial and anti-inflammatory properties. Metformin may reduce the risk of BPH by inhibiting the insulin-like growth factor 1 pathway and some but not all studies suggest a protective role of metformin on the risk of PCa. Many clinical trials are being conducted to investigate the use of metformin as an adjuvant therapy for PCa but results currently available are not conclusive. While some trials suggest a benefit in reducing the metastasis and recurrence of PCa, others do not show any benefit. More research works are warranted to illuminate the potential usefulness of metformin in the promotion of men's health.

Metformin: Sex/Gender Differences in Its Uses and Effects—Narrative Review

“…In small (and—apparently—underpowered) studies, the effects of MTF solely on men have been observed. This medication has been reported to be of benefit in non-diabetic men with erectile dysfunction who had not responded to sildenafil [ 75 ]. The mechanisms are obscure: they may be direct, via endothelium-dependent vasodilatation or attenuation of sympathetic nerve activity, and indirect, via MTF’s effect on blood pressure [ 75 ].…”

Diabetes as a potential compounding factor in COVID-19-mediated male subfertility

“…Given its nature as a glucose-lowering and anti-inflammatory drug [ 93 ], and that both high glucose and excessive inflammation cause male hypogonadism based on our studies [ 42 , 79 ], we would speculate that metformin could, at least to a certain extent, protect male diabetic patients from COVID-19-induced subfertility. However, various factors, including severity of diabetes, other complications such as obesity, hypertension and hyperlipidaemia, as well as dosage and duration of metformin treatment, which are reported to influence the effectiveness of metformin on male fertility in diabetic subjects [ 94 ], could complicate the unique circumstances in COVID-19.…”

Hallmarks of Testicular Aging: The Challenge of Anti-Inflammatory and Antioxidant Therapies Using Natural and/or Pharmacological Compounds to Improve the Physiopathological Status of the Aged Male Gonad

“…However, longevity was extended by metformin administration only in Caenorhabditis elegans, reviewed by [195], and in only one of the tested strains of mice [196]. An extensive review by Tseng [197] summarized the effects of metformin on male reproductive health, specifically on erectile dysfunction, steroidogenesis, and spermatogenesis (showing beneficial effects on all issues, mostly in animal models). However, none of the studies were performed in aged animals or aged men.…”