Metformin in Reproductive Biology

Abstract

Initially produced in Europe in 1958, metformin is still one of the most widely prescribed drugs to treat type II diabetes and other comorbidities associated with insulin resistance. Metformin has been shown to improve fertility outcomes in females with insulin resistance associated with polycystic ovary syndrome (PCOS) and in obese males with reduced fertility. Metformin treatment reinstates menstrual cyclicity, decreases the incidence of cesareans, and limits the number of premature births. Notably, metformin reduces steroid levels in conditions associated with hyperandrogenism (e.g., PCOS and precocious puberty) in females and improves fertility of adult men with metabolic syndrome through increased testosterone production. While the therapeutical use of metformin is considered to be safe, in the last 10 years some epidemiological studies have described phenotypic differences after prenatal exposure to metformin. The goals of this review are to briefly summarize the current knowledge on metformin focusing on its effects on the female and male reproductive organs, safety concerns, including the potential for modulating fetal imprinting via epigenetics.

Keywords: metformin; oocytes; ovary; spermatogenesis; testis.

Figure 1

Metformin-induced inhibition of mitochondrial Complex I. The direct inhibition of Complex I by metformin decreases the production of ATP ensuing in increases in AMP. The increase in the [AMP] to [ATP] ratio signals energy resulting in inhibition of high-energy demanding gluconeogenesis process. This ratio leads to the activation of the AMPK complex leading to a decrease in lipogenesis, increase in fatty acid beta-oxidation with an improvement in insulin sensitivity which allows the restoration of gluconeogenesis. The inhibition of metformin on mGDP prevents the use of lactate or glycerol for gluconeogenesis. OCT1: Organic Cation Ttransporter 1; LKB1: Liver Kinase B1; Glut2: GLUcose Transporter 2. mGPD: mitochondrial glycerophosphate dehydrogenase. Adapted from (20).

Figure 2

Metformin effect on AMPK. Indirectly metformin activates AMPK. This activation results in mitochondrial biogenesis and glycolysis.

Figure 3

Interaction network between AMPK and proteins expressed in Sertoli cells. The network was created using the Elsevier Pathway Studio program. Green arrows indicate activation while red arrows indicate inhibition.