Physiological disturbances and histological damages of reproductive system in male rats resulted by metformin

Document Type : Research Paper


Biology Department, College of Education for Pure Sciences, University of Thi-Qar, Iraq



The current study was designed to evaluate the effects of metformin in some physiological and histological parameters of reproductive system in the diabetic male rats experimentally.  Forty rats were randomly divided into four groups. The (control) first group was treated with normal saline; the second was infected group which included rats diabetic experimentally treated by alloxan; the third and fourth groups were induced diabetic experimentally and received metformin suspension (150 mg kg-1 daily) at one and two doses respectively. Twelve hours was time between these two doses. Reproductive ability was measured by determination of some physiological parameters as count sperm, malformations, motility, dead sperm, weights of sex organs (testes, epididymis, prostate glands and seminal vesicles) and the damaged testicular structure. The present results indicated that the administrated metformin at high doses led to significant decrease (p < 0.05) in total count of sperm, motility and in weights of all sex organs such as testes, epididymis, prostate glands and seminal vesicle, while significant increase (p < 0.05) in sperm abnormalities and dead sperm. Also, the results showed that the diabetes and exposure to metformin caused many malformations of sperm such as shattered sperm, the lacking, hooked and quirky tail, while the abnormalities of head included the lacking, Globozoospermia and elliptical head. The histological damages in testicular structure were observed including the destroyed and raised thickness of connective tissue among seminiferous tubules, necrosis and reduction numbers of spermatocytes along with the congestion of blood vessels. Many histological alterations occurred clearly due to treated with high dose of metformin after diabetic experimentally including the most affected structural troubles as large fracture of seminiferous tubules, expansion of bloody congestion and raise of necrosis in testicular structure.                                 


Ahmed, BG 2005, The physiological and biochemical effects on the balance between oxidative stress and antioxidant defence systems. Medical Journal of Islamic World Academy of Sciences, 15: 34-42.
Alarcon Aguilara, FJ, Romas, R, Perez Gutierrez, S, Aguilar Contreras, A, Contreras Weber, CC & Flores Saenz, JL 2002, Study of anti-hyperglycaemic effect of plant used of antidiabetic. Journal of Ethnopharmacology, 61: 101-110.
Alves, MG, Martins, AD, Rato, L, Moreira, PI, Socorro, S & Oliveira, PF 2013, Molecular mechanisms beyond glucose transport in diabetes-related male infertility, Biochimica et Biophysica Acta, 1832: 626-635.
Assi, MA, Mohammed, MH, Abdulkahaleq, LA 2022, Evaluate the effect of alcoholic extraction of walnut on gonadal hormones of treated rats. Caspian Journal of Environmental Sciences, 20: 145-153.
Bancroft, JD & Gamble, M 2008, Theory and practices of histological technique. 2nd edition. Churchill Elsevier. London, 56 p.                                                                          
 Broadhurst, CL, Polansky, MM & Anderson, RA 2000, Insulin like biological activity of culinary and medicinal plants aqueous extracts in vitro. Journal of Agricultural and Food Chemistry, 48: 849-852.                                                                                                                                    
Chemineau, PY, Cogine, Y, Cuerin, Y, Orgeure, P & Valtet, JC 1991, Training manual on artificial insemination in sheep and goats. FAO. Animal Production & Health, 83 p.
Chowhury, M & Steinberger, E 1976, Differences of the effects of testosterone propionate on the production of LH and FSH. Acta Endocrinologica, 82: 688-690.       
Dujic, T, Zhou, K, Tavendale, R, Palmer, CN & Pearson, ER 2016, Effect of serotonin transporter 5-HTTLPR polymorphism on gastrointestinal intolerance to metformin: A GoDARTS study. Diabetes Care, 39: 1896-1901.                                
George, D & Mallery, P 2011, IBM SPSS statistics 19 step by step: A simple guide and reference (12th edition).                                                                                            
Ghosh, SA, Bartke, P, Grasso, LE, Reichert, L & Russell, D 1992, Structural manifestation of the rat sertoli cell to hypophysectomy. A correlative morphometric and endocrine study. Journal of Endocrinology, 131:  85-497.
 Hazratian, L, Naderi, M & Mollashahi, M    2017, Norway rat, Rattus norvegicus in metropolitans, a bio-indicator for heavy metal pollution (Case study: Tehran, Iran) Caspian Journal of Environmental Sciences, 15: 58-92.
 Humaidan Al-Moussawi, NH 2022, Hormonal and enzymatic analysis for pancreas of diabetic and obese mice in Iraq. Caspian Journal of Environmental Sciences, 20: 337-349.                                                   
Kamal, AK, Sarmad, RK & Ismail, SK 2012, Role of green tea extract in reducing pathological changes of induced diabetes mellitus in rats. Journal of the Science of Food and Agriculture, 24: 1-12.
 Liu, Y, Yang, Z, Kong, D, Zhang, Y, Yu, W & Zha, W 2019, Metformin ameliorates testicular damage in male mice with streptozotocin-Induced type 1 diabetes through the PK2/PKR Pathway. Oxidative Medicine and Cellular Longevity. pp: 1-14.
 Madiraju, AK 2014, Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature, 26,510: 542.                                  
Majithiya, JB & Balaraman, R 2006, Metformin reduces blood pressure and restores endothelial functions in aorta as streptozotocin - induced diabetic rats. Life Sciences, 78: 2615-2624.                                                                                                         
Manonmani, M & Manimekalai, K 2018, A study of serum magnesium level in Type 4 diabetes mellitus patients. Journal of Diabetes Mellitus, 8: 20.                                           
 Mitra, S, Srivastava, A & Khandelwal, S 2013, Tributyltin chloride induced testicular toxicity by JNK and p38 activation, redox imbalance and cell death in sertoli- germ cell co-culture. Toxicology, 314: 39-50.                                                              
 Mohamed, A, Khaled, H, Fadhel, G, Ali, B, Asma, O, Abdelaziz, K & Abdelfattah, F 2009, Testicular toxicity in mercuric chloride treated rats:     Association with oxidative stress. Répertoire toxicologique. 28: 81- 89.                                                             
Neha, K, Anupam, B, Shweta, V & Basant, S 2013, Design, synthesis of guanidine derivatives and their anti-hyperglycemic evaluation. Der Pharma Chemica, 5: 59-66.
Oishi, K, Barchi, M, Au, AC, Gelb, BD & Diaz, GA 2004, Male infertility due to germ cell apoptosis in mice lacking the thiamine carrier, Tht1. A new insight into the critical role of thiamine in spermatogenesis. Developmental Biology, 266: 299-309. 
  Qasim Alkafajy, SA 2022, Effect of Ibuprofen, Ponstan and Panadol oral suspensions on the gastrointestinal mucosal layer in mice. Caspian Journal of Environmental Sciences, 20: 539-544.                                                                                                      
Robb, GW, Amann, RP & Killian, GJ 1978, Daily sperm production and epididymal sperm reserves of puberty and adult rats. Journal of Reproduction & Infertility, 54: 103-107.                
 Sajal, G, Lucky, S, Nabil, A & Ashok, A 2008, The impact of oxidative stress on female reproduction and art: An evidence-based review. Cambridge Up, 86: 629- 641.
Saravanan, R & Pari, L 2006, Effect of a novel insulin tropic agent, succinic acid monoethyl ester, on lipids and lipoproteins levels in rats with streptozotocin nicotinamide- induced Type 2 diabetes. Journal of Biological Science, 3: 581-587.                                       
 Sato, S, Kataoka, S, Kimura, A & Mukai, Y 2016, Azuki bean (Vigna angularis) extract reduces oxidative stress and stimulates autophagy in the kidneys of streptozotocin- induced early diabetic rats. Canadian Journal of Physiology and Pharmacology, 94: 1298-1303.                                                                                                             
Soto, B 1983, Effect of agents genotoxic in morphology of spermatozoid in testis. PhD Dissertation, University of Valparaiso, Chile.                                                                      
Standl, E & Schnell, O 2012, Alpha-glucosidase inhibitors cardiovascular considerations and trial evaluation. Diabetes and Vascular Disease Research, 9: 163-169.                                                      
Tartarin1, P, Moison, D, Guibert, E, Dupont, J, Habert, R, Rouiller fabre, V, Frydman, N, Pozzi5, S, Frydman, R, Lecureuil, C & Froment, P 2012, Metformin exposure affects human and mouse fetal testicular cells.  Human Reproduction, 27: 3304-3314.                                                                                         
 Ugbenyen Anthony, M & Odetola Adebimpe, A 2009, Hypoglycemic potential of the young leave methanolic extract of Magnifera indica in alloxan induced diabetic rat. Pakistan Journal of Nutrition, 8: 239-241.                                                                 
William, KW 2000, Hormones and hormone antagonists in Remington.  The Science and Practice of Pharmacy, 20th Edition, 77: 1390-1391.                                                     
Wyrobek, A & Bruce, W 1975, Chemical induction of sperm abnormalities in mice. Proceedings of the National Academy of Sciences, 72: 4425 - 4429.                                                                    
 Xiao, Y, Liu, H & Yu, J 2016, MAPK1/3 regulate hepatic lipid metabolism via ATG7-dependent autophagy. Autophagy, 12: 592-593.