Metformin and Male Reproduction: Comparison
Please note this is a comparison between Version 2 by Lily Guo and Version 1 by Alexander Shpakov.

Metformin (MF), a first-line drug to treat type 2 diabetes mellitus (T2DM), alone and in combination with other drugs, shows positive effect on steroidogenesis and spermatogenesis in men with T2DM and metabolic syndrome, thus MF treatment indicates prospective use for improvement of male reproductive functions and fertility in these disorders. The entry is focused on use of MF therapy for restoration of male reproductive functions in metabolic and endocrine disorders. 

  • Metformin and Male reproduction
Please wait, diff process is still running!

References

  1. Rena, G.; Hardie, D.G.; Pearson, E.R. The mechanisms of action of metformin. Diabetologia 2017, 60, 1577–1585, doi:10.1007/s00125-017-4342-z.
  2. Li, M.; Li, X.; Zhang, H.; Lu, Y. Molecular Mechanisms of Metformin for Diabetes and Cancer Treatment. Front. Physiol. 2018, 9, 1039, doi:10.3389/fphys.2018.01039.
  3. Agius, L.; Ford, B.E.; Chachra, S.S. The Metformin Mechanism on Gluconeogenesis and AMPK Activation: The Metabolite Perspective. Int. J. Mol. Sci. 2020, 21, 3240, doi:10.3390/ijms21093240.
  4. An, H.; He, L. Current understanding of metformin effect on the control of hyperglycemia in diabetes. J. Endocrinol. 2016, 228, R97–R106, doi:10.1530/JOE-15-0447.
  5. He, L. Metformin and Systemic Metabolism. Trends Pharm. Sci. 2020, 41, 868–881, doi:10.1016/j.tips.2020.09.001.
  6. Cioce, M.; Pulito, C.; Strano, S.; Blandino, G.; Fazio, V.M. Metformin: Metabolic Rewiring Faces Tumor Heterogeneity. Cells 2020, 9, 2439, doi:10.3390/cells9112439.
  7. Chan, P.; Shao, L.; Tomlinson, B.; Zhang, Y.; Liu, Z.M. Metformin transporter pharmacogenomics: Insights into drug dispo-sition-where are we now? Expert Opin. Drug Metab. Toxicol. 2018, 14, 1149–1159, doi:10.1080/17425255.2018.1541981.
  8. Hardie, D.G.; Ross, F.A.; Hawley, S.A. AMPK: A nutrient and energy sensor that maintains energy homeostasis. Nat. Rev. Mol. Cell Biol. 2012, 13, 251–262, doi:10.1038/nrm3311.
  9. Hardie, D.G.; Schaffer, B.E.; Brunet, A. AMPK: An Energy-Sensing Pathway with Multiple Inputs and Outputs. Trends Cell Biol. 2016, 27, 190–201, doi:10.1016/j.tcb.2015.10.013.
  10. Lin, S.C.; Hardie, D.G. AMPK: Sensing Glucose as well as Cellular Energy Status. Cell Metab. 2018, 27, 299–313, doi:10.1016/j.cmet.2017.10.009.
  11. Hardie, D.G. AMPK: A key regulator of energy balance in the single cell and the whole organism. Int. J. Obes. 2008, 32, S7–S12, doi:10.1038/ijo.2008.116.
  12. Hardie, DG. Keeping the home fires burning: AMP-activated protein kinase. J. R. Soc. Interface. 2018, 15, 20170774, doi:10.1098/rsif.2017.0774.
  13. Lizcano, J.M.; Göransson, O.; Toth, R.; Deak, M.; Morrice, N.A.; Boudeau, J.; Hawley, S.A.; Udd, L.; Mäkelä, T.P.; Hardie, D.G.; et al. LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. EMBO J. 2004, 23, 833–843, doi:10.1038/sj.emboj.7600110.
  14. Hawley, S.A.; Pan, D.A.; Mustard, K.J.; Ross, L.; Bain, J.; Edelman, A.M.; Frenguelli, B.G.; Hardie, D.G. Calmodu-lin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab. 2005, 2, 9–19, doi:10.1016/j.cmet.2005.05.009.
  15. Woods, A.; Dickerson, K.; Heath, R.; Hong, S.P.; Momcilovic, M.; Johnstone, S.R.; Carlson, M.; Carling, D. Ca2+/calmodulin-dependent protein kinase kinase-beta acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab. 2005, 2, 21–33, doi:10.1016/j.cmet.2005.06.005.
  16. Momcilovic, M.; Hong, S.P.; Carlson, M. Mammalian TAK1 activates Snf1 protein kinase in yeast and phosphorylates AMP-activated protein kinase in vitro. J. Biol. Chem. 2006, 281, 25336–25343, doi:10.1074/jbc.M604399200.
  17. Jia, J.; Abudu, Y.P.; Claude-Taupin, A.; Gu, Y.; Kumar, S.; Choi, S.W.; Peters, R.; Mudd, M.H.; Allers, L.; Salemi, M.; et al. Ga-lectins Control mTOR in Response to Endomembrane Damage. Mol. Cell 2018, 70, 120–135, doi:10.1016/j.molcel.2018.03.009.
  18. Jia, J.; Bissa, B.; Brecht, L.; Allers, L.; Choi, S.W.; Gu, Y.; Zbinden, M.; Burge, M.R.; Timmins, G.; Hallows, K.; et al. AMPK, a Regulator of Metabolism and Autophagy, Is Activated by Lysosomal Damage via a Novel Galectin-Directed Ubiquitin Sig-nal Transduction System. Mol. Cell. 2020, 77, 951–969, doi:10.1016/j.molcel.2019.12.028.
  19. Zhou, G.; Myers, R.; Li, Y.; Chen, Y.; Shen, X.; Fenyk-Melody, J.; Wu, M.; Ventre, J.; Doebber, T.; Fujii, N.; et al. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 2001, 108, 1167–1174, doi:10.1172/JCI13505.
  20. Woods, A.; Johnstone, S.R.; Dickerson, K.; Leiper, F.C.; Fryer, L.G.; Neumann, D.; Schlattner, U.; Wallimann, T.; Carlson, M.; Carling, D. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr. Biol. 2003, 13, 2004–2008, doi:10.1016/j.cub.2003.10.031.
  21. Cao, J.; Meng, S.; Chang, E.; Beckwith-Fickas, K.; Xiong, L.; Cole, R.N.; Radovick, S.; Wondisford, F.E.; He, L. Low concentra-tions of metformin suppress glucose production in hepatocytes through AMP-activated protein kinase (AMPK). J. Biol. Chem. 2014, 289, 20435–20446, doi:10.1074/jbc.M114.567271.
  22. Oakhill, J.S.; Steel, R.; Chen, Z.P.; Scott, J.W.; Ling, N.; Tam, S.; Kemp, B.E. AMPK is a direct adenylate charge-regulated pro-tein kinase. Science 2011, 332, 1433–1435, doi:10.1126/science.1200094.
  23. Xiao, B.; Sanders, M.J.; Underwood, E.; Heath, R.; Mayer, F.V.; Carmena, D.; Jing, C.; Walker, P.A.; Eccleston, J.F.; Haire, L.F.; et al. Structure of mammalian AMPK and its regulation by ADP. Nature 2011, 472, 230–233, doi:10.1038/nature09932.
  24. Ross, F.A.; Jensen, T.E.; Hardie, D.G. Differential regulation by AMP and ADP of AMPK complexes containing different γ subunit isoforms. Biochem. J. 2016, 473, 189–199, doi:10.1042/BJ20150910.
  25. Zhang, C.S.; Hawley, S.A.; Zong, Y.; Li, M.; Wang, Z.; Gray, A.; Ma, T.; Cui, J.; Feng, J.W.; Zhu, M.; et al. Fruc-tose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK. Nature 2017, 548, 112–116, doi:10.1038/nature23275.
  26. Zong, Y.; Zhang, C.S.; Li, M.; Wang, W.; Wang, Z.; Hawley, S.A.; Ma, T.; Feng, J.W.; Tian, X.; Qi, Q.; et al. Hierarchical activa-tion of compartmentalized pools of AMPK depends on severity of nutrient or energy stress. Cell Res. 2019, 29, 460–473, doi:10.1038/s41422-019-0163-6.
  27. Davies, S.P.; Helps, N.R.; Cohen, P.T.; Hardie, D.G. 5’-AMP inhibits dephosphorylation, as well as promoting phosphoryla-tion, of the AMP-activated protein kinase. Studies using bacterially expressed human protein phosphatase-2C alpha and na-tive bovine protein phosphatase-2AC. FEBS Lett. 1995, 377, 421–425, doi:10.1016/0014-5793(95)01368-7.
  28. Suter, M.; Riek, U.; Tuerk, R.; Schlattner, U.; Wallimann, T.; Neumann, D. Dissecting the role of 5’-AMP for allosteric stimu-lation, activation, and deactivation of AMP-activated protein kinase. J. Biol. Chem. 2006, 281, 32207–32216, doi:10.1074/jbc.M606357200.
  29. El-Mir, M.Y.; Nogueira, V.; Fontaine, E.; Averet, N.; Rigoulet, M.; Leverve, X. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J. Biol. Chem. 2000, 275, 223–228, doi:10.1074/jbc.275.1.223.
  30. Owen, M.R.; Doran, E.; Halestrap, A.P. Evidence that metformin exerts its anti-diabetic effects through inhibition of com-plex 1 of the mitochondrial respiratory chain. Biochem. J. 2000, 348, 607–614, doi:10.1042/bj3480607.
  31. Foretz, M.; Hébrard, S.; Leclerc, J.; Zarrinpashneh, E.; Soty, M.; Mithieux, G.; Sakamoto, K.; Andreelli, F.; Viollet, B. Metfor-min inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J. Clin. Investig. 2010, 120, 2355–2369, doi:10.1172/JCI40671.
  32. Bridges, H.R.; Jones, A.J.; Pollak, M.N.; Hirst, J. Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria. Biochem. J. 2014, 462, 475–487, doi:10.1042/BJ20140620.
  33. Ouyang, J.; Parakhia, R.A.; Ochs, R.S. Metformin activates AMP kinase through inhibition of AMP deaminase. J. Biol. Chem. 2011, 286, 1–11, doi:10.1074/jbc.M110.121806.
  34. Meng, S.; Cao, J.; He, Q.; Xiong, L.; Chang, E.; Radovick, S.; Wondisford, F.E.; He, L. Metformin activates AMP-activated protein kinase by promoting formation of the αβγ heterotrimeric complex. J. Biol. Chem. 2015, 290, 3793–3802, doi:10.1074/jbc.M114.604421.
  35. Foretz, M.; Guigas, B.; Viollet, B. Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus. Nat. Rev. Endocrinol. 2019, 15, 569.
  36. Sliwinska, A.; Drzewoski, J. Molecular action of metformin in hepatocytes: An updated insight. Curr. Diabetes Rev. 2015, 11, 175–181, doi:10.2174/1573399811666150325233108.
  37. He, L.; Wondisford, F.E. Metformin action: Concentrations matter. Cell Metab. 2015, 21, 159–162, doi:10.1016/j.cmet.2015.01.003.
  38. Karnewar, S.; Neeli, P.K.; Panuganti, D.; Kotagiri, S.; Mallappa, S.; Jain, N.; Jerald, M.K.; Kotamraju, S. Metformin regulates mitochondrial biogenesis and senescence through AMPK mediated H3K79 methylation: Relevance in age-associated vascu-lar dysfunction. Biochim. Biophys. Acta Mol. Basis Dis. 2018, 1864, 1115–1128, doi:10.1016/j.bbadis.2018.01.018.
  39. Rattan, R.; Giri, S.; Hartmann, L.C.; Shridhar, V. Metformin attenuates ovarian cancer cell growth in an AMP-kinase dispen-sable manner. J. Cell. Mol. Med. 2011, 15, 166–178, doi:10.1111/j.1582-4934.2009.00954.x
  40. Fullerton, M.D.; Galic, S.; Marcinko, K.; Sikkema, S.; Pulinilkunnil, T.; Chen, Z.P.; O’Neill, H.M.; Ford, R.J.; Palanivel, R.; O’Brien, M.; et al. Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing ef-fects of metformin. Nat. Med. 2013, 19, 1649–1654, doi:10.1038/nm.3372.
  41. Kim, J.; Yang, G.; Kim, Y.; Kim, J.; Ha, J. AMPK activators: Mechanisms of action and physiological activities. Exp. Mol. Med. 2016, 48, e224, doi:10.1038/emm.2016.16.
  42. Motoshima, H.; Goldstein, B.J.; Igata, M.; Araki, E. AMPK and cell proliferation—AMPK as a therapeutic target for athero-sclerosis and cancer. J. Physiol. 2006, 574, 63–71, doi:10.1113/jphysiol.2006.108324.
  43. Choi, Y.K.; Park, K.G. Metabolic roles of AMPK and metformin in cancer cells. Mol. Cells 2013, 36, 279–87, doi:10.1007/s10059-013-0169-8.
  44. Gao, F.; Chen, J.; Zhu, H. A potential strategy for treating atherosclerosis: Improving endothelial function via AMP-activated protein kinase. Sci. China Life Sci. 2018, 61, 1024–1029, doi:10.1007/s11427-017-9285-1.
  45. Lyons, C.L.; Roche. H.M. Nutritional Modulation of AMPK-Impact upon Metabolic-Inflammation. Int. J. Mol. Sci. 2018, 19, 3092, doi:10.3390/ijms19103092.
  46. Viollet, B.; Foretz, M. Revisiting the mechanisms of metformin action in the liver. Ann. Endocrinol. 2013, 74, 123–129, doi:10.1016/j.ando.2013.03.006.
  47. Miller, R.A.; Chu, Q.; Xie, J.; Foretz, M.; Viollet, B.; Birnbaum, M.J. Biguanides suppress hepatic glucagon signalling by de-creasing production of cyclic AMP. Nature 2013, 494, 256–260, doi:10.1038/nature11808.
  48. He, L.; Sabet, A.; Djedjos, S.; Miller, R.; Sun, X.; Hussain, M.A.; Radovick, S.; Wondisford, F.E. Metformin and insulin sup-press hepatic gluconeogenesis through phosphorylation of CREB binding protein. Cell 2009, 137, 635–646, doi:10.1016/j.cell.2009.03.016.
  49. Madiraju, A.K.; Erion, D.M.; Rahimi, Y.; Zhang, X.M.; Braddock, D.T.; Albright, R.A.; Prigaro, B.J.; Wood, J.L.; Bhanot, S.; MacDonald, M.J.; et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogen-ase. Nature 2014, 510, 542–546, doi:10.1038/nature13270.
  50. Madiraju, A.K.; Qiu, Y.; Perry, R.J.; Rahimi, Y.; Zhang, X.M.; Zhang, D.; Camporez, J.G.; Cline, G.W.; Butrico, G.M.; Kemp, B.E.; et al. Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo. Nat. Med. 2018, 24, 1384–1394, doi:10.1038/s41591-018-0125-4.
  51. Cuyàs, E.; Verdura, S.; Llorach-Pares, L.; Fernández-Arroyo, S.; Luciano-Mateo, F.; Cabré, N.; Stursa, J.; Werner, L.; Mar-tin-Castillo, B.; Viollet, B.; et al. Metformin directly targets the H3K27me3 demethylase KDM6A/UTX. Aging Cell. 2018, 17, e12772, doi:10.1111/acel.12772.
  52. Wu, H.; Esteve, E.; Tremaroli, V.; Khan, M.T.; Caesar, R.; Mannerås-Holm, L.; Ståhlman, M.; Olsson, L.M.; Serino, M.; Planas-Fèlix, M.; et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contrib-uting to the therapeutic effects of the drug. Nat. Med. 2017, 23, 850–858, doi:10.1038/nm.4345.
  53. Shin, N.R.; Lee, J.C.; Lee, H.Y.; Kim, M.S.; Whon, T.W.; Lee, M.S.; Bae, J.W. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut 2014, 63, 727–735, doi:10.1136/gutjnl-2012-303839.
  54. Duca, F.A.; Côté, C.D.; Rasmussen, B.A.; Zadeh-Tahmasebi, M.; Rutter, G.A.; Filippi, B.M.; Lam, T.K. Metformin activates a duodenal Ampk-dependent pathway to lower hepatic glucose production in rats. Nat. Med. 2015, 21, 506–511, doi:10.1038/nm.3787.
  55. Hattori, Y.; Suzuki, K.; Hattori, S.; Kasai, K. Metformin inhibits cytokine-induced nuclear factor kappaB activation via AMP-activated protein kinase activation in vascular endothelial cells. Hypertension 2006, 47, 1183–1188, doi:10.1161/01.HYP.0000221429.94591.72.
  56. Huang, N.L.; Chiang, S.H.; Hsueh, C.H.; Liang, Y.J.; Chen, Y.J.; Lai, L.P. Metformin inhibits TNF-alpha-induced IkappaB ki-nase phosphorylation, IkappaB-alpha degradation and IL-6 production in endothelial cells through PI3K-dependent AMPK phosphorylation. Int. J. Cardiol. 2009, 134, 169–175, doi:10.1016/j.ijcard.2008.04.010.
  57. Okamura, H.; Yoshida, K.; Sasaki, E.; Qiu, L.; Amorim, B.R.; Morimoto, H.; Haneji, T. Expression of PTEN and Akt phos-phorylation in lipopolysaccharide-treated NIH3T3 cells. Cell Biol. Int. 2007, 31, 119–125, doi:10.1016/j.cellbi.2006.09.014.
  58. Lee, S.K.; Lee, J.O.; Kim, J.H.; Kim, S.J.; You, G.Y.; Moon, J.W.; Jung, J.H.; Park, S.H.; Uhm, K.O.; Park, J.M.; et al. Metformin sensitizes insulin signaling through AMPK-mediated PTEN down-regulation in preadipocyte 3T3-L1 cells. J. Cell. Biochem. 2011, 112, 1259–1267, doi:10.1002/jcb.23000.
  59. Chavarro, J.E.; Toth, T.L.; Wright, D.L.; Meeker, J.D.; Hauser, R. Body mass index in relation to semen quality, sperm DNA integrity, and serum reproductive hormone levels among men attending an infertility clinic. Fertil. Steril. 2010, 93, 2222–2231, doi:10.1016/j.fertnstert.2009.01.100.
  60. Hofny, E.R.; Ali, M.E.; Abdel-Hafez, H.Z.; Kamal Eel, D.; Mohamed, E.E.; Abd El-Azeem, H.G.; Mostafa, T. Semen parame-ters and hormonal profile in obese fertile and infertile males. Fertil. Steril. 2010, 94, 581–584, doi:10.1016/j.fertnstert.2009.03.085.
  61. Brand, J.S.; van der Tweel, I.; Grobbee, D.E.; Emmelot-Vonk, M.H.; van der Schouw, Y.T. Testosterone, sex hormone-binding globulin and the metabolic syndrome: A systematic review and meta-analysis of observational studies. Int. J. Epidemiol. 2011, 40, 189–207, doi:10.1093/ije/dyq158.
  62. La Vignera, S.; Condorelli, R.; Vicari, E.; D’Agata, R.; Calogero, A.E. Diabetes mellitus and sperm parameters. J. Androl. 2012, 33, 145–153, doi:10.2164/jandrol.111.013193.
  63. Dupont, C.; Faure, C.; Sermondade, N.; Boubaya, M.; Eustache, F.; Clément, P.; Briot, P.; Berthaut, I.; Levy, V.; Cedrin-Durnerin, I.; et al. Obesity leads to higher risk of sperm DNA damage in infertile patients. Asian J. Androl. 2013, 15, 622–625, doi:10.1038/aja.2013.65.
  64. Corona, G.; Bianchini, S.; Sforza, A.; Vignozzi, L.; Maggi, M. Hypogonadism as a possible link between metabolic diseases and erectile dysfunction in aging men. Hormones 2015, 14, 569–578, doi:10.14310/horm.2002.1635.
  65. Pergialiotis, V.; Prodromidou, A.; Frountzas, M.; Korou, L.M.; Vlachos, G.D.; Perrea, D. Diabetes mellitus and functional sperm characteristics: A meta-analysis of observational studies. J. Diabetes Complicat. 2016, 30, 1167–1176, doi:10.1016/j.jdiacomp.2016.04.002.
  66. Lu, X.; Huang, Y.; Zhang, H.; Zhao, J. Effect of diabetes mellitus on the quality and cytokine content of human semen. J. Re-prod. Immunol. 2017, 123, 1–2, doi:10.1016/j.jri.2017.08.007.
  67. Condorelli, R.A.; La Vignera, S.; Mongioì, L.M.; Alamo, A.; Calogero, A.E. Diabetes Mellitus and Infertility: Different Path-ophysiological Effects in Type 1 and Type 2 on Sperm Function. Front. Endocrinol. 2018, 9, 268, doi:10.3389/fendo.2018.00268.
  68. Dhindsa, S.; Ghanim, H.; Batra, M.; Dandona, P. Hypogonadotropic Hypogonadism in Men with Diabesity. Diabetes Care 2018, 41, 1516–1525, doi:10.2337/dc17-2510.
  69. Rastrelli, G.; Filippi, S.; Sforza, A.; Maggi, M.; Corona, G. Metabolic Syndrome in Male Hypogonadism. Front. Horm. Res. 2018, 49, 131–155, doi:10.1159/000485999.
  70. Martins, A.D.; Majzoub, A.; Agawal, A. Metabolic Syndrome and Male Fertility. World J. Men’s Health 2019, 37, 113–127, doi:10.5534/wjmh.180055.
  71. Agarwal, A.; Said, T.M. Oxidative stress, DNA damage and apoptosis in male infertility: A clinical approach. BJU Int. 2005, 95, 503–507, doi:10.1111/j.1464-410X.2005.05328.x.
  72. Hagiuda, J.; Ishikawa, H.; Furuuchi, T.; Hanawa, Y.; Marumo, K. Relationship between dyslipidaemia and semen quality and serum sex hormone levels: An infertility study of 167 Japanese patients. Andrologia 2014, 46, 131–135, doi:10.1111/and.12057.
  73. Alahmar, A.T. Role of Oxidative Stress in Male Infertility: An Updated Review. J. Hum. Reprod. Sci. 2019, 12, 4–18, doi:10.4103/jhrs.JHRS_150_18.
  74. Zhao, L.; Pang, A. Effects of Metabolic Syndrome on Semen Quality and Circulating Sex Hormones: A Systematic Review and Meta-Analysis. Front. Endocrinol. 2020, 11, 428, doi:10.3389/fendo.2020.00428.
  75. Bhattacharya, S.M.; Ghosh, M.; Nandi, N. Diabetes mellitus and abnormalities in semen analysis. J. Obstet. Gynaecol. Res. 2014, 40, 167–171, doi:10.1111/jog.12149.
  76. Colli, L.G.; Belardin, L.B.; Echem, C.; Akamine, E.H.; Antoniassi, M.P.; Andretta, R.R.; Mathias, L.S.; Rodrigues, S.F.P.; Ber-tolla, R.P.; de Carvalho, M.H.C. Systemic arterial hypertension leads to decreased semen quality and alterations in the tes-ticular microcirculation in rats. Sci. Rep. 2019, 9, 11047, doi:10.1038/s41598-019-47157-w.
  77. Faure, M.; Bertoldo, M.J.; Khoueiry, R.; Bongrani, A.; Brion, F.; Giulivi, C.; Dupont, J.; Froment, P. Metformin in Reproduc-tive Biology. Front. Endocrinol. 2018, 9, 675, doi:10.3389/fendo.2018.00675.
  78. Stokes, V.J.; Anderson, R.A.; George, J.T. How does obesity affect fertility in men–and what are the treatment options? Clin. Endocrinol. 2015, 82, 633–638, doi:10.1111/cen.12591.
  79. Morgante, G.; Tosti, C.; Orvieto, R.; Musacchio, M.C.; Piomboni, P.; De Leo, V. Metformin improves semen characteristics of oligo-terato-asthenozoospermic men with metabolic syndrome. Fertil. Steril. 2011, 95, 2150–2152, doi:10.1016/j.fertnstert.2010.12.009.
  80. Liu, C.Y.; Chang, T.C.; Lin, S.H.; Wu, S.T.; Cha, T.L.; Tsao, C.W. Metformin Ameliorates Testicular Function and Spermato-genesis in Male Mice with High-Fat and High-Cholesterol Diet-Induced Obesity. Nutrients 2020, 12, 1932, doi:10.3390/nu12071932.
  81. Ozata, M.; Oktenli, C.; Bingol, N.; Ozdemir, I.C. The effects of metformin and diet on plasma testosterone and leptin levels in obese men. Obes. Res. 2001, 9, 662–667, doi:10.1038/oby.2001.90.
  82. Al-Kuraishy, H.M.; Al-Gareeb, A.I. Erectile Dysfunction and Low Sex Drive in Men with Type 2 DM: The Potential Role of Diabetic Pharmacotherapy. J. Clin. Diagn. Res. 2016, 10, FC21–FC26, doi:10.7860/JCDR/2016/19971.8996.
  83. Pelusi, C.; Giagulli, V.A.; Baccini, M.; Fanelli, F.; Mezzullo, M.; Fazzini, A.; Bianchi, N.; Carbone, M.D.; De Pergola, G.; Mastroroberto, M.; et al. Clomiphene citrate effect in obese men with low serum testosterone treated with metformin due to dysmetabolic disorders: A randomized, double-blind, placebo-controlled study. PLoS ONE 2017, 12, e0183369, doi:10.1371/journal.pone.0183369.
  84. Tosca, L.; Froment, P.; Rame, C.; McNeilly, J.R.; McNeilly, A.S.; Maillard, V.; Dupont, J. Metformin decreases GnRH- and activin-induced gonadotropin secretion in rat pituitary cells: Potential involvement of adenosine 5’ monophos-phate-activated protein kinase (PRKA). Biol. Reprod. 2011, 84, 351–362, doi:10.1095/biolreprod.110.087023.
  85. Casulari, L.A.; Caldas, A.D.; Domingues Casulari Motta, L.; Lofrano-Porto, A. Effects of metformin and short-term lifestyle modification on the improvement of male hypogonadism associated with metabolic syndrome. Minerva Endocrinol. 2010, 35, 145–151.
  86. Guay, A.T.; Bansal, S.; Heatley, G.J. Effect of raising endogenous testosterone levels in impotent men with secondary hy-pogonadism: Double blind placebo-controlled trial with clomiphene citrate. J. Clin. Endocrinol. Metab. 1995, 80, 3546–3552, doi:10.1210/jcem.80.12.8530597.
  87. Giagulli, V.A.; Silvestrini, A.; Bruno, C.; Triggiani, V.; Mordente, A.; Mancini, A. Is There Room for SERMs or SARMs as Alternative Therapies for Adult Male Hypogonadism? Int. J. Endocrinol. 2020, 2020, 9649838, doi:10.1155/2020/9649838.
  88. Aggerholm, A.S.; Thulstrup, A.M.; Toft, G.; Ramlau-Hansen, C.H.; Bonde, J.P. Is overweight a risk factor for reduced semen quality and altered serum sex hormone profile? Fertil. Steril. 2008, 90, 619–626, doi:10.1016/j.fertnstert.2007.07.1292.
  89. Hammoud, A.O.; Wilde, N.; Gibson, M.; Parks, A.; Carrell, D.T.; Meikle, A.W. Male obesity and alteration in sperm param-eters. Fertil. Steril. 2008, 90, 2222–2225, doi:10.1016/j.fertnstert.2007.10.011.
  90. Allan, C.A.; McLachlan, R.I. Androgens and obesity. Curr. Opin. Endocrinol. Diabetes Obes. 2010, 17, 224–232, doi:10.1097/MED.0b013e3283398ee2.
  91. Mah, P.M.; Wittert, G.A. Obesity and testicular function. Mol. Cell. Endocrinol. 2010, 316, 180–186, doi:10.1016/j.mce.2009.06.007.
  92. Bellastella, G.; Menafra, D.; Puliani, G.; Colao, A.; Savastano, S.; Obesity Programs of nutrition, Education, Research and Assessment (OPERA) Group. How much does obesity affect the male reproductive function? Int. J. Obes. Suppl. 2019, 9, 50–64, doi:10.1038/s41367-019-0008-2.
  93. Lee, Y.; Dang, J.T.; Switzer, N.; Yu, J.; Tian, C.; Birch, D.W.; Karmali, S. Impact of Bariatric Surgery on Male Sex Hormones and Sperm Quality: A Systematic Review and Meta-Analysis. Obes. Surg. 2019, 29, 334–346, doi:10.1007/s11695-018-3557-5.
  94. Hart, R.J.; Doherty, D.A.; Mori, T.A.; Adams, L.A.; Huang, R.C.; Minaee, N.; Handelsman, D.J.; McLachlan, R.; Norman, R.J.; Dickinson, J.E.; et al. Features of the metabolic syndrome in late adolescence are associated with impaired testicular func-tion at 20 years of age. Hum. Reprod. 2019, 34, 389–402, doi:10.1093/humrep/dey371.
  95. Kapoor, D.; Channer, K.S.; Jones, T.H. Rosiglitazone increases bioactive testosterone and reduces waist circumference in hypogonadal men with type 2 diabetes. Diab. Vasc. Dis. Res. 2008, 5, 135–137, doi:10.3132/dvdr.2008.022.
  96. Wong, L.; Chen, H.M.; Lai, S.Q.; Yang, H.Z.; Kuang, J.; Pei, J.H. Effects of sulfonylurea as initial treatment on testosterone of middle-aged men with type 2 diabetes: A 16-week, pilot study. J. Diabetes Investig. 2015, 6, 454–459, doi:10.1111/jdi.12324.
  97. Attia, S.M.; Helal, G.K.; Alhaider, A.A. Assessment of genomic instability in normal and diabetic rats treated with metfor-min. Chem. Biol. Interact. 2009, 180, 296–304, doi:10.1016/j.cbi.2009.03.001.
  98. Rabbani, S.I.; Devi, K.; Khanam, S. Role of Pioglitazone with Metformin or Glimepiride on Oxidative Stress-induced Nucle-ar Damage and Reproductive Toxicity in Diabetic Rats. Malays. J. Med. Sci. 2010, 17, 3–11.
  99. Yan, W.J.; Mu, Y.; Yu, N.; Yi, T.L.; Zhang, Y.; Pang, X.L.; Cheng, D.; Yang, J. Protective effects of metformin on reproductive function in obese male rats induced by high-fat diet. J. Assist. Reprod. Genet. 2015, 32, 1097–1104, doi:10.1007/s10815-015-0506-2.
  100. Ghasemnejad-Berenji, M.; Ghazi-Khansari, M.; Yazdani, I.; Nobakht, M.; Abdollahi, A.; Ghasemnejad-Berenji, H.; Mohajer Ansari, J.; Pashapour, S.; Dehpour, A.R. Effect of metformin on germ cell-specific apoptosis, oxidative stress and epididymal sperm quality after testicular torsion/detorsion in rats. Andrologia 2018, 50, doi:10.1111/and.12846.
  101. Nna, V.U.; Bakar, A.B.A.; Ahmad, A.; Mohamed, M. Diabetes-induced testicular oxidative stress, inflammation, and caspa-se-dependent apoptosis: The protective role of metformin. Arch. Physiol. Biochem. 2018, 4, 1–12, doi:10.1080/13813455.2018.1543329.
  102. Nna, V.U.; Abu Bakar, A.B.; Ahmad, A.; Eleazu, C.O.; Mohamed, M. Oxidative Stress, NF-κB-Mediated Inflammation and Apoptosis in the Testes of Streptozotocin-Induced Diabetic Rats: Combined Protective Effects of Malaysian Propolis and Metformin. Antioxidants 2019, 8, 465, doi:10.3390/antiox8100465.
  103. Annie, L.; Jeremy, M.; Gurusubramanian, G.; Derkach, K.V.; Shpakov, A.O.; Roy, V.K. Effect of metformin on testicular ex-pression and localization of leptin receptor and levels of leptin in the diabetic mice. Mol. Reprod. Dev. 2020, 87, 620–629, doi:10.1002/mrd.23342.
  104. Derkach, K.V.; Bakhtyukov, A.A.; Romanova, I.V.; Zorina, I.I.; Bayunova, L.V.; Bondareva, V.M.; Morina, I.Yu.; Kumar Roy, V.; Shpakov, A.O. The effect of metformin treatment on the basal and gonadotropin-stimulated steroidogenesis in male rats with type 2 diabetes mellitus. Andrologia 2020, e13816, doi:10.1111/and.13816.
  105. Ayuob, N.N.; Murad, H.A.; Ali, S.S. Impaired expression of sex hormone receptors in male reproductive organs of diabetic rat in response to oral antidiabetic drugs. Folia Histochem. Cytobiol. 2015, 53, 35–48, doi:10.5603/FHC.a2015.0005.
  106. Nna, V.U.; Bakar, A.B.A.; Ahmad, A.; Mohamed, M. Diabetes-induced testicular oxidative stress, inflammation, and caspase-dependent apoptosis: The protective role of metformin. Arch. Physiol. Biochem. 2018, 4, 1–12, doi:10.1080/13813455.2018.1543329.
  107. Annie, L.; Jeremy, M.; Gurusubramanian, G.; Derkach, K.V.; Shpakov, A.O.; Roy, V.K. Effect of metformin on testicular expression and localization of leptin receptor and levels of leptin in the diabetic mice. Mol. Reprod. Dev. 2020, 87, 620–629, doi:10.1002/mrd.23342.
  108. Nna, V.U.; Bakar, A.B.A.; Ahmad, A.; Mohamed, M. Down-regulation of steroidogenesis-related genes and its accompanying fertility decline in streptozotocin-induced diabetic male rats: Ameliorative effect of metformin. Andrology 2019, 7, 110–123, doi:10.1111/andr.12567.
  109. Morgan, D.H.; Ghribi, O.; Hui, L.; Geiger, J.D.; Chen, X. Cholesterol-enriched diet disrupts the blood-testis barrier in rab-bits. Am. J. Physiol. Endocrinol. Metab. 2014, 307, E1125–E1130, doi:10.1152/ajpendo.00416.2014.
  110. Yu, C.; Jiang, F.; Zhang, M.; Luo, D.; Shao, S.; Zhao, J.; Gao, L.; Zuo, C.; Guan, Q. HC diet inhibited testosterone synthesis by activating endoplasmic reticulum stress in testicular Leydig cells. J. Cell Mol. Med. 2019, 23, 3140–3150, doi:10.1111/jcmm.14143.
  111. Fejes, I.; Koloszár, S.; Závaczki, Z.; Daru, J.; Szöllösi, J.; Pál, A. Effect of body weight on testosterone/estradiol ratio in oli-gozoospermic patients. Arch. Androl. 2006, 52, 97–102, doi:10.1080/01485010500315479.
  112. Rice, S.; Pellatt, L.; Ramanathan, K.; Whitehead, S.A.; Mason, H.D. Metformin inhibits aromatase via an extracellular signal-regulated kinase-mediated pathway. Endocrinology 2009, 150, 4794–4801, doi:10.1210/en.2009-0540.
  113. Fuhrmeister, I.P.; Branchini, G.; Pimentel, A.M.; Ferreira, G.D.; Capp, E.; Brum, I.S.; von Eye Corleta, H. Human granulosa cells: Insulin and insulin-like growth factor-1 receptors and aromatase expression modulation by metformin. Gynecol. Obstet. Invest. 2014, 77, 156–162, doi:10.1159/000358829.
  114. Asghari, A.; Akbari, G.; Meghdadi, A.; Mortazavi, P. Protective effect of metformin on testicular ischemia/reperfusion injury in rats. Acta Cir. Bras. 2016, 31, 411–416, doi:10.1590/S0102-865020160060000008.
  115. Asghari, A.; Akbari, G.; Meghdadi, A.; Mortazavi, P. Effects of melatonin and metformin co-administration on testicular ischemia/reperfusion injury in rats. J. Pediatr. Urol. 2016, 12, 410.e1–410.e7, doi:10.1016/j.jpurol.2016.06.017.
  116. Nasrolahi, O.; Khaneshi, F.; Rahmani, F.; Razi, M. Honey and metformin ameliorated diabetes-induced damages in testes of rat; correlation with hormonal changes. Iran. J. Reprod. Med. 2013, 11, 1013–1020.
  117. Nna, V.U.; Bakar, A.B.A.; Ahmad, A.; Umar, U.Z.; Suleiman, J.B.; Zakaria, Z.; Othman, Z.A.; Mohamed, M. Malaysian propolis and metformin mitigate subfertility in streptozotocin-induced diabetic male rats by targeting steroidogenesis, testicular lactate transport, spermatogenesis and mating behaviour. Andrology 2020, 8, 731–746, doi:10.1111/andr.12739.
  118. Mardanshahi, T.; Rezaei, N.; Zare, Z.; Malekzadeh Shafaroudi, M.; Mohammadi, H. Effects of L-Carnitine on the sperm pa-rameters disorders, apoptosis of spermatogenic cells and testis histopathology in diabetic Rats. Int. J. Reprod. Biomed. 2018, 17, 325–336, doi:10.18502/ijrm.v17i5.4600.
  119. Hurtado de Llera, A.; Martin-Hidalgo, D.; Gil, M.C.; Garcia-Marin, L.J.; Bragado, M.J. AMP-activated kinase AMPK is ex-pressed in boar spermatozoa and regulates motility. PLoS ONE 2012, 7, e38840, doi:10.1371/journal.pone.0038840.
  120. Calle-Guisado, V.; de Llera, A.H.; Martin-Hidalgo, D.; Mijares, J.; Gil, M.C.; Alvarez, I.S.; Bragado, M.J.; Garcia-Marin, L.J. AMP-activated kinase in human spermatozoa: Identification, intracellular localization, and key function in the regulation of sperm motility. Asian J. Androl. 2017, 19, 707–714, doi:10.4103/1008-682X.185848.
  121. Nguyen, T.M. Impact of 5’-amp-activated Protein Kinase on Male Gonad and Spermatozoa Functions. Front. Cell Dev. Biol. 2017, 5, 25, doi:10.3389/fcell.2017.00025.
  122. Nguyen, T.M.D. Role of AMPK in mammals reproduction: Specific controls and whole-body energy sensing. Comptes Ren-dus Biol. 2019, 342, 1–6, doi:10.1016/j.crvi.2018.10.003.
  123. Martin-Hidalgo, D.; de Llera, H.A.; Calle-Guisado, V.; Gonzalez-Fernandez, L.; Garcia-Marin, L.; Bragado, M.J. AMPK Func-tion in Mammalian Spermatozoa. Int. J. Mol. Sci. 2018, 19, 3293, doi:10.3390/ijms19113293.
  124. Kwon, O.; Kim, K.W.; Kim, M.S. Leptin signalling pathways in hypothalamic neurons. Cell. Mol. Life Sci. 2016, 73, 1457–1477, doi:10.1007/s00018-016-2133-1.
  125. Wang, B.; Cheng, K.K. Hypothalamic AMPK as a Mediator of Hormonal Regulation of Energy Balance. Int. J. Mol. Sci. 2018, 19, 3552, doi:10.3390/ijms19113552.
  126. Tosca, L.; Chabrolle, C.; Dupont, J. L’AMPK: Un lien entre métabolisme et reproduction? [AMPK: A link between metabo-lism and reproduction?]. Med. Sci. 2008, 24, 297–300, doi:10.1051/medsci/2008243297.
  127. Wang, B.; Cheng, K.K. Hypothalamic AMPK as a Mediator of Hormonal Regulation of Energy Balance. Int. J. Mol. Sci. 2018, 19, 3552, doi:10.3390/ijms19113552.
  128. Tosca, L.; Chabrolle, C.; Dupont, J. L’AMPK: Un lien entre métabolisme et reproduction? [AMPK: A link between metabo-lism and reproduction?]. Med. Sci. 2008, 24, 297–300, doi:10.1051/medsci/2008243297.
More