Metformin inhibits human spermatozoa motility and signalling pathways mediated by protein kinase A and tyrosine phosphorylation without affecting mitochondrial function
V. Calle-Guisado A , L. Gonzalez-Fernandez A , D. Martin-Hidalgo A , L. J. Garcia-Marin A * and M. J. Bragado A B *
+ Author Affiliations
- Author Affiliations
A Research Group of Intracellular Signalling and Technology of Reproduction (SINTREP), Institute of Biotechnology in Agriculture and Livestock (INBIO G+C), Avda Universidad, University of Extremadura, 10003 Caceres, Spain.
B Corresponding author. Email: jbragado@unex.es
Reproduction, Fertility and Development 31(4) 787-795 https://doi.org/10.1071/RD18256
Submitted: 6 July 2018 Accepted: 12 November 2018 Published: 19 December 2018
Abstract
Metformin is a leading antidiabetic drug that is used worldwide in the treatment of diabetes mellitus. This biguanide exerts metabolic and pleiotropic effects in somatic cells, although its in vitro actions on human spermatozoa remain unknown. The present study investigated the effects of metformin on human sperm function. Human spermatozoa were incubated in the presence or absence of 10 mM metformin for 8 or 20 h, and motility was measured by computer-aided sperm analysis (CASA); other parameters were evaluated by flow cytometry. Metformin significantly reduced the percentage of motile, progressive and rapid spermatozoa and significantly decreased sperm velocity. Metformin did not affect viability, mitochondrial membrane potential (MMP) or mitochondrial superoxide anion generation of human spermatozoa at any time studied. However, metformin clearly inhibited the protein kinase (PK) A pathway and protein tyrosine phosphorylation at 8 and 20 h, key regulatory pathways for correct sperm function. In summary, metformin treatment of human spermatozoa had a detrimental effect on motility and inhibited essential sperm signalling pathways, namely PKA and protein tyrosine phosphorylation, without affecting physiological parameters (viability, MMP, mitochondrial superoxide anion generation). Given the growing clinical use of metformin in different pathologies in addition to diabetes, this study highlights an adverse effect of metformin on spermatozoa and its relevance in terms of human fertility in patients who potentially could be treated with metformin in the future.
Additional keywords: antidiabetic drug, progressive motility, superoxide generation, viability.
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