Preconception Antidiabetic Drugs in Men and Birth Defects in Offspring

Abstract

Background: Diabetes reduces semen quality and increasingly occurs during reproductive years. Diabetes medications, such as metformin, have glucose-independent effects on the male reproductive system. Associations with birth defects in offspring are unknown.Objective: To evaluate whether the risk for birth defects in offspring varies with preconceptional pharmacologic treatment of fathers with diabetes.Design: Nationwide prospective registry-based cohort study.

Metformin: Is it a drug for all reasons and diseases?

“…Metformin is used for the treatment of polycystic ovary syndrome (PCOS) with its benefits attributed to improving insulin sensitivity, reducing insulin levels and thereby reducing the activity of steroidogenic enzymes. Conversely, in males the use of metformin has been linked to genital defects in male offspring [36] that may be linked to reports of effects of metformin on human and mouse testicular cells, lowers testosterone levels, and also reports in fish that it is an endocrine disruptor [464][465][466][467][468][469] The effects of metformin on the microbiota in the gut where the release of GLP-1 from L-cells that in turn enhances the release of insulin from ß-cells in the pancreas. The anti-cancer effects of metformin have been attributed to the activation of AMPK and subsequent inhibition of mTOR.…”

“…A conservative estimate based on 150 million people taking 1 g/day of metformin is that potentially 150,000 kg/day of the drug are voided in the urine reflecting an increasing concern on the health of numerous species including Homo sapiens. Possibly related to the effects of metformin in fish are the data from the nationwide cohort study in Denmark from Wensink et al (2022), which has provided evidence that treatment of men with metformin is linked to genital birth defects in their male offspring [36]. This finding promoted the comment from Allan Brett, Editor in Chief NEJM Journal Watch: "This observational study suggests a relation between paternal pre-pregnancy metformin use and birth defects.…”

“…Vitamin B12 deficiency could offset putative benefits associated with using metformin for the treatment of neurodegenerative diseases [35]. Concerns over reproductive health in males have also been raised and are discussed in the conclusions section together with the risk of environmental contamination [36]. Metformin is also being increasingly used in gestational diabetes and is considered a safe alternative to insulin [37,38].…”

“…Concerns have also been expressed that metformin at the equivalent of comparatively high therapeutic concentrations (50-100 μM) negatively affects pancreatic beta-cell differentiation from human embryonic stem cells resulting in metabolic dysfunction in later life [47,48]. These concerns add to those raised in the study from Denmark linking metformin use in men with genital defects in male offspring [36].…”

Learning by reading: A review of recent diabetes articles

“…In a study of 1 116 779 Danish offspring from 1997 to 2016, among 5298, 1451, and 647 whose fathers were treated with insulin, metformin, and a sulfonylurea risk of birth defects 0.98‐, 1.40‐, and 1.34‐fold greater than the remainder of the population 22 . Although the increased likelihood was statistically significant for metformin and not for sulfonylureas, the suggested interpretation that paternal exposure to metformin might predispose to birth defects seems unlikely given the similar risk ratio for the two classes of oral hypoglycemic agents, so that if such an association exists it may be one of paternal T2D with birth defects.…”