Hypothesis: Metformin is a potential reproductive toxicant

Abstract

Metformin is the first-line oral treatment for type 2 diabetes mellitus and is prescribed to more than 150 million people worldwide. Metformin's effect as a glucose-lowering drug is well documented but the precise mechanism of action is unknown. A recent finding of an association between paternal metformin treatment and increased numbers of genital birth defects in sons and a tendency towards a skewed secondary sex ratio with less male offspring prompted us to focus on other evidence of reproductive side effects of this drug. Metformin in humans is documented to reduce the circulating level of testosterone in both men and women. In experimental animal models, metformin exposure in utero induced sex-specific reproductive changes in adult rat male offspring with reduced fertility manifested as a 30% decrease in litter size and metformin exposure to fish, induced intersex documented in testicular tissue. Metformin is excreted unchanged into urine and feces and is present in wastewater and even in the effluent of wastewater treatment plants from where it spreads to rivers, lakes, and drinking water. It is documented to be present in numerous freshwater samples throughout the world - and even in drinking water. We here present the hypothesis that metformin needs to be considered a potential reproductive toxicant for humans, and probably also for wildlife. There is an urgent need for studies exploring the association between metformin exposure and reproductive outcomes in humans, experimental animals, and aquatic wildlife.

Keywords: development; endocrine disruptor; environment; metformin; reproductive toxicant; testosterone; wildlife.

Figure 1

Metformin’s path from the synthesis of the drug from petrochemicals to contamination of the environment via wastewater. 1) Metformin derives from petrochemicals, which again derive from fossil fuels such as oil. 2) From petrochemicals there is a production of the drug, metformin which is 3) prescribed to more than 150 million people, including a large proportion of patients with diabetes 2, who thus are directly exposed through therapeutic treatment. 4) As metformin is not metabolized in the human body, it enters the environment unchanged through urine and feces, and 5) metformin thus reaches wastewater treatment plants and later 6) freshwaters as rivers and lakes and drinking water. 7) Metformin, therefore, contaminates our environment affecting the aquatic wildlife and potentially exists as indirect exposure to human populations all over the world.

Figure 2

Metformin’s processes of potential interference with fetal development. Metformin may interfere with fetal development through effects on steroidogenesis (38), epigenetics (39), metabolism (40), and gamete development and maturation (27). The mechanism behind these effects remains poorly understood, but data suggest that the AMP-induced protein kinase (AMPK) pathway might play a central role except for effects on steroidogenesis that might be AMPK-independent (38).