Faiza Alam ( Department of Physiology, University of Karachi, Pakistan )
Nida Farooqui, ( Department of Biological Biomedical Sciences Aga Khan University, Karachi )
Rehana Rehman ( Department of Biological and Biomedical Sciences, Aga Khan University, Karachi, Pakistan )
February-B 2021, Volume 71, Issue 2
Letter to the Editor
DOI: https://doi.org/10.47391/JPMA.11-1318
Madam, There is an increased prevalence of infertility in male population. With reference to a variety of mechanisms, oxidative stress (OS) is responsible for alteration in structural and functional integrity of sperm leading to altered sperm parameters, hence leading to infertility1.
Metformin though proved to be a first-line hypoglycaemic agent has demonstrated antioxidant properties in numerous tissues. It inhibits the mitochondrial respiratory chain in the liver, which leads to stimulation of AMP-activated protein kinase (AMPK)-dependent as well as AMPK-independent mechanisms2. Metformin triggers alanine production within the Sertoli cells (SCs,) balances the NADH/NAD+ equilibrium and provides antioxidant environment. This drug is a treatment of choice in treating females with Polycystic Ovaries (PCOS) on the basis of its capability to reduce insulin sensitivity as well as angiogenesis through the nuclear factor κB (NF-κB) pathway which renders it to reduce oxidant species, thus improving the reproductive environment3.
Study on obese mice model reveals that Metformin improved male fertility by decreasing accumulation of lipid in the testis and increasing follicle stimulating hormone (FSH) levels. The drug improved OS by reviving NF-κB activity in SCs, remodeling of the BTB structure and rebuilding the tangled BTB-related proteins3. Furthermore, it improves fertility by inhibiting OS hence alleviating damage of blood test barrier (BTB) in testis of infertile males4 as illustrated in Figure.
Recently metformin has proved to improve semen quality in men with hyperinsulinaemia, but the underlying molecular mechanism is unclear4.
We have proposed the possible mechanism of Metformin to maintain the microenvironment of the granulosa cells for restoration of fertility in females5.
In order to determine impact of metformin on OS and male infertility, we plan to isolate spermatozoa from infertile males by density gradient centrifugation, induce OS with H2O2 after incubating for 24 hours, Metformin will be added in the stressed cells and again incubated for 24 hours. To determine the OS activity, the isolated cells will be lysed, and Mishra Oxidative assay will be applied to detect changes in absorbance at 480nm6. Difference in expression of markers of OS will be compared before and after exposure by (OD experimental group – OD blank)/ (OD control group – OD blank) × 100%.). We hypothesize that OS will be reduced with Metformin treatment. The expected reduced levels of oxidative markers in the semen specimen /betterment of the sperm parameters after Metformin would reflect its probable role.
Disclaimer: None to declare.
Conflict of Interest: None to declare.
Funding Sources: Pakistan Science Foundation, grant #PSF/Res/SAKU/Med.
References
1. Bisht S, Faiq M, Tolahunase M, Dada R. Oxidative stress and male infertility. Nat Rev Urol 2017;14:470-85. doi: 10.1038/nrurol.2017.69.
2. Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia 2017;60:1577-85. doi: 10.1007/s00125-017-4342-z.
3. Ye J, Luo D, Xu X, Sun M, Su X, Tian Z, et al. Metformin Improves Fertility in Obese Males by Alleviating Oxidative Stress-Induced Blood-Testis Barrier Damage. Oxid Med Cell Longev 2019;2019:e9151067. doi: 10.1155/2019/9151067.
4. Tan BK, Adya R, Chen J, Farhatullah S, Heutling D, Mitchell D, et al. Metformin decreases angiogenesis via NF-kappaB and Erk1/2/Erk5 pathways by increasing the antiangiogenic thrombospondin-1. Cardiovasc Res 2009;83:566-74. doi: 10.1093/cvr/cvp131.
5. Rehman R, Abidi SH, Alam F. Metformin, Oxidative Stress, and Infertility: A Way Forward. Front Physiol 2018;9:e1722. doi: 10.3389/fphys.2018.01722.
6. Misra HP, Fridovich I. Superoxide dismutase: "positive" spectrophotometric assays. Anal Biochem 1977;79:553-60. doi: 10.1016/0003-2697(77)90429-8
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