madman
Super Moderator
Metformin is the first-line oral antidiabetic drug that shows multiple pleiotropic effects of anti-inflammation, anti-cancer, antiaging, anti-microbiota, 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 metformin'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 adjuvant therapy for PCa but the 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.
Introduction
Metformin is an oral anti-diabetic drug that has been recommended as the first-line therapy for patients with type 2 diabetes mellitus (T2DM) since 2012 [1]. It is now the most prescribed glucose-lowering drug and more than 150 million people in the world are prescribed metformin annually [2]. Metformin exerts various beneficial effects beyond glucose-lowering, including immune modulation, anti-atherosclerosis, anticancer, anti-aging, anti-microbiota, and anti-inflammation [3,4]. Recently, by using the nation-wide database of the National Health Insurance in Taiwan, we also showed that metformin use is associated with a lower risk of hypertension [5], hospitalization for heart failure [6], hospitalization for atrial fibrillation [7], chronic obstructive pulmonary disease [8], varicose veins [9], hemorrhoid [10], dementia [11,12], nodular goiter [13], uterine leiomyoma [14], osteoporosis/vertebral fracture [15], and inflammatory bowel disease [16].
Metformin can cross the placenta and distribute to various tissues including the salivary gland, tongue, stomach, intestine, colon, appendix, heart, muscle, liver, pancreas, kidney, adipose tissue, spinal cord, hypothalamus, pituitary gland, adrenal gland, thyroid, ovary, uterus, testes, and prostate [17-20]. Metformin is hydrophilic and, depending on cell types, it enters the cell via the plasma membrane monoamine transporter and the organic cation transporter (OCT) 1–3 and is excreted from the cell through OCT1 or multidrug and toxic compound extrusion type transporters (MATE1 and MATE2) [2]. Its serum half-life is approximately 5 hours and is excreted from the kidney without being metabolized [2]. It is rapidly transported and eliminated and may appear in the bladder 10 minutes after its oral intake [2]. It inhibits the activity of respiratory electron transport in mitochondria by binding to the mitochondrial complex I, leading to a decrease of adenosine triphosphate and thus activating the 5' adenosine monophosphate-activated protein kinase (AMPK) [2,17]. Metformin may also exert various activities via AMPK-independent pathways by modulating the expressions and actions of hormones, cytokines, and growth factors [2,21].
Metformin has been researched for its potential usefulness for the treatment of polycystic ovary syndrome (PCOS) in women and is currently recommended as an adjunct to ovulation induction for the treatment of infertility in female patients with PCOS [22]. Metformin’s benefits in men’s health have been a focus of recent research, but more work needs to be done to confirm its usefulness in clinical practice. This article aims at reviewing the updated information published in related literature in the following two categories: men’s reproductive health (penis and testes) and prostate-related health. Men’s reproductive health will be discussed under three subtitles: erectile dysfunction (ED), steroidogenesis, and spermatogenesis. Prostate-related health will be discussed under four subtitles: prostate-specific antigen (PSA), prostatitis, benign prostate hyperplasia (BPH), and prostate cancer (PCa).
MEN’S REPRODUCTIVE HEALTH
Men’s reproductive health and fertility are related to the erectile function of the penis and the testicular functions of steroidogenesis (testosterone synthesis) and spermatogenesis. Over the past decades, some studies have been conducted to investigate the effects of metformin on related issues and several review articles can be seen in the literature [17,22-24]. This topic will be discussed under the following three subtitles: ED, steroidogenesis (testosterone synthesis), and spermatogenesis
1. Erectile dysfunction
2. Steroidogenesis
3. Spermatogenesis
PROSTATE-RELATED HEALTH
The prostate has the most abundant expression of OCT3 for the uptake of metformin [19,20]. Therefore, metformin may potentially have an effect on prostate-related health. These issues will be discussed under the following subtitles: PSA, prostatitis, BPH, and PCa.
1. Prostate-specific antigen
2. Prostatitis
3. Benign prostate hyperplasia
4. Prostate cancer
1) Cellular and animal studies
2) Diabetes mellitus and prostate cancer risk
3) Metformin use and prostate cancer risk
4) Metformin use as adjuvant therapy for prostate cancer
CONCLUSIONS
This narrative review focuses on the effects of metformin on men’s reproductive health and prostate-related health. Main findings from updated literature are summarized in Table 1-6 and the potential mechanisms are depicted in Table 7. In summary, metformin may exert potential benefits on arteriogenic ED but its effects on testicular steroidogenesis and spermatogenesis are controversial. While some suggest a protective effect on testicular injury with increased testosterone synthesis and improvement of sperm quality and quantity, others concluded with a harmful effect. With regards to prostate-related health, metformin use in humans is associated with a lower level of PSA, but its clinical implications are not clear. Metformin’s effect on prostatitis has not been researched, but it may potentially reduce prostate infection and inflammation. Metformin may reduce the risk of BPH by inhibiting the IGF-1 pathway or by improving insulin resistance and metabolic syndrome. Because of a potential anticancer effect of metformin, the benefits of metformin use on PCa risk, therapy, and prognosis are hot topics currently under enthusiastic research. However, its clinical applications remain to be confirmed.
Introduction
Metformin is an oral anti-diabetic drug that has been recommended as the first-line therapy for patients with type 2 diabetes mellitus (T2DM) since 2012 [1]. It is now the most prescribed glucose-lowering drug and more than 150 million people in the world are prescribed metformin annually [2]. Metformin exerts various beneficial effects beyond glucose-lowering, including immune modulation, anti-atherosclerosis, anticancer, anti-aging, anti-microbiota, and anti-inflammation [3,4]. Recently, by using the nation-wide database of the National Health Insurance in Taiwan, we also showed that metformin use is associated with a lower risk of hypertension [5], hospitalization for heart failure [6], hospitalization for atrial fibrillation [7], chronic obstructive pulmonary disease [8], varicose veins [9], hemorrhoid [10], dementia [11,12], nodular goiter [13], uterine leiomyoma [14], osteoporosis/vertebral fracture [15], and inflammatory bowel disease [16].
Metformin can cross the placenta and distribute to various tissues including the salivary gland, tongue, stomach, intestine, colon, appendix, heart, muscle, liver, pancreas, kidney, adipose tissue, spinal cord, hypothalamus, pituitary gland, adrenal gland, thyroid, ovary, uterus, testes, and prostate [17-20]. Metformin is hydrophilic and, depending on cell types, it enters the cell via the plasma membrane monoamine transporter and the organic cation transporter (OCT) 1–3 and is excreted from the cell through OCT1 or multidrug and toxic compound extrusion type transporters (MATE1 and MATE2) [2]. Its serum half-life is approximately 5 hours and is excreted from the kidney without being metabolized [2]. It is rapidly transported and eliminated and may appear in the bladder 10 minutes after its oral intake [2]. It inhibits the activity of respiratory electron transport in mitochondria by binding to the mitochondrial complex I, leading to a decrease of adenosine triphosphate and thus activating the 5' adenosine monophosphate-activated protein kinase (AMPK) [2,17]. Metformin may also exert various activities via AMPK-independent pathways by modulating the expressions and actions of hormones, cytokines, and growth factors [2,21].
Metformin has been researched for its potential usefulness for the treatment of polycystic ovary syndrome (PCOS) in women and is currently recommended as an adjunct to ovulation induction for the treatment of infertility in female patients with PCOS [22]. Metformin’s benefits in men’s health have been a focus of recent research, but more work needs to be done to confirm its usefulness in clinical practice. This article aims at reviewing the updated information published in related literature in the following two categories: men’s reproductive health (penis and testes) and prostate-related health. Men’s reproductive health will be discussed under three subtitles: erectile dysfunction (ED), steroidogenesis, and spermatogenesis. Prostate-related health will be discussed under four subtitles: prostate-specific antigen (PSA), prostatitis, benign prostate hyperplasia (BPH), and prostate cancer (PCa).
MEN’S REPRODUCTIVE HEALTH
Men’s reproductive health and fertility are related to the erectile function of the penis and the testicular functions of steroidogenesis (testosterone synthesis) and spermatogenesis. Over the past decades, some studies have been conducted to investigate the effects of metformin on related issues and several review articles can be seen in the literature [17,22-24]. This topic will be discussed under the following three subtitles: ED, steroidogenesis (testosterone synthesis), and spermatogenesis
1. Erectile dysfunction
2. Steroidogenesis
3. Spermatogenesis
PROSTATE-RELATED HEALTH
The prostate has the most abundant expression of OCT3 for the uptake of metformin [19,20]. Therefore, metformin may potentially have an effect on prostate-related health. These issues will be discussed under the following subtitles: PSA, prostatitis, BPH, and PCa.
1. Prostate-specific antigen
2. Prostatitis
3. Benign prostate hyperplasia
4. Prostate cancer
1) Cellular and animal studies
2) Diabetes mellitus and prostate cancer risk
3) Metformin use and prostate cancer risk
4) Metformin use as adjuvant therapy for prostate cancer
CONCLUSIONS
This narrative review focuses on the effects of metformin on men’s reproductive health and prostate-related health. Main findings from updated literature are summarized in Table 1-6 and the potential mechanisms are depicted in Table 7. In summary, metformin may exert potential benefits on arteriogenic ED but its effects on testicular steroidogenesis and spermatogenesis are controversial. While some suggest a protective effect on testicular injury with increased testosterone synthesis and improvement of sperm quality and quantity, others concluded with a harmful effect. With regards to prostate-related health, metformin use in humans is associated with a lower level of PSA, but its clinical implications are not clear. Metformin’s effect on prostatitis has not been researched, but it may potentially reduce prostate infection and inflammation. Metformin may reduce the risk of BPH by inhibiting the IGF-1 pathway or by improving insulin resistance and metabolic syndrome. Because of a potential anticancer effect of metformin, the benefits of metformin use on PCa risk, therapy, and prognosis are hot topics currently under enthusiastic research. However, its clinical applications remain to be confirmed.
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