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.

Metabolic disorders in prediabetes: From mechanisms to therapeutic management

“…Metformin use may also cause lactic acidosis or even death in patients with severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m). Additionally, metformin is a biologically active molecule with a low environmental decomposition capacity and may cause aquatic environmental contamination[ 51 ].…”

Metformin use in pregnancy: What about long‐term effects in offspring?

“…11 Metformin is not being metabolized, and hence, it is excreted unmodified through feces and urine to wastewaters. 12 Despite decades of research, the details of metformin's effects at the cellular level are incompletely understood. However, it is evident that metformin has multiple sites of action and that several molecular pathways are involved.…”

“…Moreover, metformin inhibits intestinal absorption of dietary glucose and alters the composition and metabolic profile of the gut microbiota 11 . Metformin is not being metabolized, and hence, it is excreted unmodified through feces and urine to wastewaters 12 …”

“… 11 Metformin is not being metabolized, and hence, it is excreted unmodified through feces and urine to wastewaters. 12 …”

UiO-66@Fe3O4 nanocomposite as an adsorbent in dispersive solid phase extraction of metformin in surface water and wastewater

“…The international diabetes federation (IDF) also states that almost 2.3 million metformin prescriptions are made annually [7]. According to toxicological studies, metformin is a potential endocrine disruptor [8], and hence, the stability of this drug in water shows the need for its removal [9]. Therefore, to safeguard the health of human beings and aquatic life and maintain a good ecological balance, there is a need to monitor the presence of MET in water bodies.…”