Voluntary exercise could reduce sperm malformations by improving hypothalamus-hypophysis-gonadal axis and kisspeptin/leptin signaling in type 2 diabetic rats

Document Type : Original Article

Authors

1 Student Research Committee, Tabriz University of Medical Sciences

2 Department of Physiology, Faculty of Medicine, Tabriz University of medical sciences, Tabriz, Iran

3 Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

4 Medical Education research center, Tabriz University of Medical sciences, Tabriz, Iran

5 Department of Basic Sciences, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran

6 Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

Abstract

Objective(s): Most male patients with type 2 diabetes mellitus (T2DM) experience infertility. It is well established that regular physical activity could alleviate diabetic infertility symptoms. This study was designed to determine the effect of voluntary exercise on sperm malformation.  
Materials and Methods: Thirty-two male Wistar rats were randomly divided into control (C), diabetic (D), voluntary exercise (Ex), and diabetic-voluntary exercise (D-Ex) groups. Diabetes was induced by an intraperitoneal injection of streptozotocin (35 mg/kg) followed by a high-fat diet for four weeks. Voluntary exercise was performed by placing the animals in the rotary wheel cages for ten weeks. Sperm malformations were analyzed. Moreover, the hypothalamic leptin, kisspeptin, kisspeptin receptors (KissR), as well as plasma LH, FSH, testosterone, and leptin levels were evaluated. 
Results: Results showed that induction of T2DM caused increased sperm malformation, plasma, and hypothalamic leptin as well as decreased hypothalamic kisspeptin, KissR, and plasma LH levels compared with the C group (P<0.001 to P<0.01). Voluntary exercise in the Ex group increased hypothalamic KissR, plasma FSH, LH, and testosterone levels compared with the C group; however, it decreased sperm malformation and hypothalamic leptin levels (P<0.001 to P<0.05). Voluntary exercise in the D-Ex group reduced sperm malformation, hypothalamic leptin, and plasma testosterone while elevated hypothalamic kisspeptin and KissR protein levels compared with the D group (P<0.001 to P<0.01). 
Conclusion: The results illustrated voluntary exercise reduces sperm malformations by improving the HHG axis and kisspeptin/leptin signaling in rats with T2DM. 

Keywords

References

1. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004; 27:1047-1053.
2. Agbaje I M, Rogers D A, McVicar C M, McClure N, Atkinson A B, Mallidis C, et al. Insulin dependant diabetes mellitus: implications for male reproductive function. Hum Reprod 2007; 22:1871-1877.
3. Agarwal A, Mulgund A, Hamada A, Chyatte M R. A unique view on male infertility around the globe. Reprod Biol Endocrinol 2015; 13:37-46.
4. Ombelet W, Cooke I, Dyer S, Serour G, Devroey P. Infertility and the provision of infertility medical services in developing countries. Hum Reprod Update 2008; 14:605-621.
5. Alves M G, Martins A D, Rato L, Moreira P I, Socorro S, Oliveira P F. Molecular mechanisms beyond glucose transport in diabetes-related male infertility. Biochim Biophys Acta Mol Basis Dis 2013; 1832:626-635.
6. Kuiri-Hänninen T, Sankilampi U, Dunkel L. Activation of the hypothalamic-pituitary-gonadal axis in infancy: Minipuberty. Horm Res Paediatr 2014; 82:73-80.
7. Thompson E L, Patterson M, Murphy K G, Smith K L, Dhillo W S, Todd J F, et al. Central and peripheral administration of kisspeptin-10 stimulates the hypothalamic-pituitary-gonadal axis. J Neuroendocrinol 2004; 16:850-858.
8. True C, Kirigiti M A, Kievit P, Grove K L, Smith M S. Leptin is not the critical signal for kisspeptin or luteinising hormone restoration during exit from negative energy balance. J Neuroendocrinol 2011; 23:1099-1112.
9. Abbara A, Eng P C, Phylactou M, Clarke S A, Mills E, Chia G, et al. Kisspeptin-54 accurately identifies hypothalamic gonadotropin-releasing hormone neuronal dysfunction in men with congenital hypogonadotropic hypogonadism. Neuroendocrinol 2020; 111:1176-1186.
10. Mantzoros C S, Magkos F, Brinkoetter M, Sienkiewicz E, Dardeno T A, Kim S Y, et al. Leptin in human physiology and pathophysiology. Am J Physiol Endocrinol Metab 2011; 301:567-584.
11. Garcia-Galiano D, Allen S J, Elias C  F. Role of the adipocyte-derived hormone leptin in reproductive control. Horm Mol Biol Clin Investig 2014; 19:141-149.
12. Heydari H, Ghiasi R, Hamidian G, Ghaderpour S, Keyhanmanesh R. Voluntary exercise improves sperm parameters in high fat diet receiving rats through alteration in testicular oxidative stress, mir-34a/SIRT1/p53 and apoptosis. Horm Mol Biol Clin Invest 2021; 42:253-263 .
13. Gaderpour S, Ghiasi R, Hamidian G, Heydari H, Keyhanmanesh R. Voluntary exercise improves spermatogenesis and testicular apoptosis in type 2 diabetic rats through alteration in oxidative stress and mir-34a/SIRT1/p53 pathway. Iran J Basic Med Sci 2021; 24:1-8.
14. Ghiasi R, Naderi R, Sheervalilou R, Alipour M R. Swimming training by affecting the pancreatic Sirtuin1 (SIRT1) and oxidative stress, improves insulin sensitivity in diabetic male rats. Horm Mol Biol Clin Invest 2019; 40:1-12.
15. Shing C M, Fassett R G, Peake J M, Coombes J S. Voluntary exercise decreases atherosclerosis in nephrectomised ApoE knockout mice. PLoS One 2015; 10:1-12.
16. Salehi M S, Namavar M R, Jafarzadeh-Shirazi M R, Rahmanifar F, Tamadon A. A simple method for isolation of the anteroventral periventricular and arcuate nuclei of the rat hypothalamus. J Anat 2012; 7:48-51.
17.Cao D, Ma X, Zhang W J, Xie Z. Dissection and coronal slice preparation of developing mouse pituitary gland. J Vis Exp 2017; 16:1-5.
18. Keyhanmanesh R, Hamidian G, Alipour M, Oghbaei H. Beneficial treatment effects of dietary nitrate supplementation on testicular injury in streptozotocin-induced diabetic male rats. Reprod Biomed Online 2019; 38:857-871.
19. Aziz N, Saleh R A, Sharma R K, Lewis-Jones I, Esfandiari N, Thomas Jr AJ, et al. Novel association between sperm reactive oxygen species production, sperm morphological defects, and the sperm deformity index. Fertil Steril 2004; 81:349-354.
20. Aziz N, Said T, Paasch U, Agarwal A. The relationship between human sperm apoptosis, morphology and the sperm deformity index. Hum Reprod 2007; 22:1413-1419.
21. Oskuye Z, Bavil F, Hamidian G, Mehri K, Qadiri A, Ahmadi M, et al. Troxerutin affects the male fertility in prepubertal type 1 diabetic male rats. Iran J Basic Med Sci 2019; 22:197-205.
22. Dudek M, Kołodziejski P, Pruszyńska-Oszmałek E, Sassek M, Ziarniak K, Nowak K, et al. Effects of high-fat diet-induced obesity and diabetes on Kiss1 and GPR54 expression in the hypothalamic–pituitary–gonadal (HPG) axis and peripheral organs (fat, pancreas and liver) in male rats. Neuropeptides 2016; 56:41-49.
23. Cooper T G. Reply: WHO reference values for human semen. Hum Reprod Update 2010; 16:559-559.
24. Guzick D S, Overstreet J W, Factor-Litvak P, Brazil C K, Nakajima S T, Coutifaris C, et al. Sperm morphology, motility, and concentration in fertile and infertile men. N Engl J Med 2001; 345:1388-1393.
25. Maneesh M, Jayalekshmi H. Role of reactive oxygen species and antioxidants on pathophysiology of male reproduction. Indian J Clin Biochem 2006; 21:80-89.
26. Agarwal A, Saleh R A, Bedaiwy M A. Role of reactive oxygen species in the pathophysiology of human reproduction. Fertil Steril 2003; 79:829-843.
27. Lavranos G, Balla M, Tzortzopoulou A, Syriou V, Angelopoulou R. Investigating ROS sources in male infertility: a common end for numerous pathways. Reprod Toxicol 2012; 34:298-307.
28. Guthrie H D, Welch G R. Effects of reactive oxygen species on sperm function. Theriogenol 2012; 78:1700-1708.
29. Oghbaei H, Alipour M, Hamidian G, Ahmadi M, Ghorbanzadeh V, Keyhanmanesh R. Two months sodium nitrate supplementation alleviates testicular injury in streptozotocin-induced diabetic male rats. Exp Physiol 2018; 103:1603-1617.
30. Keyhanmanesh R, Hamidian G, Alipour M, Ranjbar M, Oghbaei H. Protective effects of sodium nitrate against testicular apoptosis and spermatogenesis impairments in streptozotocin-induced diabetic male rats. Life Sci 2018; 211:63-73.
31. Oghbaei H, Hamidian G, Alipour MR, Alipour S, Keyhanmanesh R. The effect of prolonged dietary sodium nitrate treatment on the hypothalamus-pituitary-gonadal axis and testicular structure and function in streptozotocin-induced diabetic male rats. Food func 2020; 11:2451-2465.
32. Delfino M, Imbrogno N, Elia J, Capogreco F, Mazzilli F. Prevalence of diabetes mellitus in male partners of infertile couples. Minerva Urol Nefrol 2007; 59:131-135.
33. Condorelli R A, La Vignera S, Mongioì L M, Alamo A, Calogero A E. Diabetes mellitus and infertility: different pathophysiological effects in type 1 and type 2 on sperm function. Frontiers endocrinol 2018; 9:268-277.
34. Parastesh M, Heidarianpour A, Bayat M, Saremi A. Effects of resistance training on serum level of reproductive hormones and sperm parameters in type 2 diabetes rats. Majallahi Ilmipizhuhishii Danishgahilumi Pizishki Va Khadamati Bihdashti Darmanii Arak 2016; 19:26-36.
35. Pelliccione F, Verratti V, D’Angeli A, Micillo A, Doria C, Pezzella A, et al. Physical exercise at high altitude is associated with a testicular dysfunction leading to reduced sperm concentration but healthy sperm quality. Fertil Steril 2011; 96:28-33.
36. Vaamonde D, Da Silva-Grigoletto M E, García-Manso J M, Barrera N, Vaamonde-Lemos R. Physically active men show better semen parameters and hormone values than sedentary men. Eur J Appl Physiol 2012; 112:3267-3273.
37. Dhillo W S, Chaudhri O B, Patterson M, Thompson E L, Murphy K G, Badman M K, et al. Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males. J Clin Endocrinol Metab 2005; 90:6609-6615.
38. Navarro V M, Castellano J M, Fernández-Fernández R, Barreiro M L, Roa J, Sanchez-Criado J E, et al. Developmental and hormonally regulated messenger ribonucleic acid expression of KiSS-1 and its putative receptor, GPR54, in rat hypothalamus and potent luteinizing hormone-releasing activity of KiSS-1 peptide. Endocrinol 2004; 145:4565-4574.
39. Asare-Anane H, Ofori E K, Kwao-Zigah G, Ateko R O, Annan B D R T, Adjei A B, et al. Lower circulating kisspeptin and primary hypogonadism in men with type 2 diabetes. Endocrinol Diabetes Metab 2019; 2:1-6.
40. Arisha A H, Moustafa A. Potential inhibitory effect of swimming exercise on the Kisspeptin-GnRH signaling pathway in male rats. Theriogenol 2019; 133:87-96.
41. Ghosh D, Das U, Ghosh S, Mallick M, Debnath J. Testicular gametogenic and steroidogenic activities in cyclophosphamide treated rat: a correlative study with testicular oxidative stress. Drug Chem Toxicol 2002; 25:281-292.
42. Manna I, Jana K, Samanta P. Effect of intensive exercise‐induced testicular gametogenic and steroidogenic disorders in mature male Wistar strain rats: a correlative approach to oxidative stress. Acta Physiol Scand 2003; 178:33-40.
43. S du Plessis S, Kashou A, Vaamonde D, Agarwal A. Is there a link between exercise and male factor infertility? Open Reprod Sci J 2011; 3:105-113.
44. Samanta P K, Manna I, Jana K. Effect of L-ascorbic add supplementation on testicular oxidative stress and endocrine disorders in mature male rats exposed to intensive swimming exercise. Reprod Med Biol 2006; 5:145-153.
45.Erdemir F, Atilgan D, Markoc F, Boztepe O, Suha-Parlaktas B, Sahin S. The effect of diet induced obesity on testicular tissue and serum oxidative stress parameters. Actas Urol Esp (English Edition) 2012; 36:153-159.
46. Quennell J H, Howell C S, Roa J, Augustine R A, Grattan D R, Anderson G M. Leptin deficiency and diet-induced obesity reduce hypothalamic kisspeptin expression in mice. Endocrinol 2011; 152:1541-1550.
47.Wauters M, Considine R V, Yudkin J S, Peiffer F, De Leeuw I, Van Gaal L F. Leptin levels in type 2 diabetes: associations with measures of insulin resistance and insulin secretion. Horm Metab Res 2003; 35:92-96.
48. Haskell‐Luevano C, Schaub J W, Andreasen A, Haskell K R, Moore M C, Koerper L M, et al. Voluntary exercise prevents the obese and diabetic metabolic syndrome of the melanocortin‐4 receptor knockout mouse. FASEB J 2009; 23:642-655.
49. Girard I, Rezende E L, Garland Jr T. Leptin levels and body composition of mice selectively bred for high voluntary locomotor activity. Physiol Biochem Zool 2007; 80:568-579.
50. Dandona P, Dhindsa S. Update: hypogonadotropic hypogonadism in type 2 diabetes and obesity. Clin Endocrinol Metab 2011; 96:2643-2651.
51. De Gendt K, Swinnen J V, Saunders P T, Schoonjans L, Dewerchin M, Devos A, et al. A sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis. Proc Natl Acad Sci 2004; 101:1327-1332.
52. Dhindsa S, Prabhakar S, Sethi M, Bandyopadhyay A, Chaudhuri A, Dandona P. Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. Clin Endocrinol Metab 2004; 89:5462-5468.
53. Hackney A. Endurance exercise training and reproductive endocrine dysfunction in men alterations in the hypothalamic-pituitary-testicular axis. Curr pharm des 2001; 7:261-273.
54. Raastad T, Bjøro T, Hallen J. Hormonal responses to high-and moderate-intensity strength exercise. Eur J Appl Physiol 2000; 82:121-128.
55. Hackney A, Sinning W, Bruot B. Reproductive hormonal profiles of endurance-trained and untrained males. Med Sci Sports Exerc 1988; 20:60-65.
56. Chainy G, Samantaray S, Samanta L. Testosterone‐induced changes in testicular antioxidant system. Andrologia 1997; 29:343-349.
57. Powers S K, Ji L L, Leeuwenburgh C. Exercise training-induced alterations in skeletal muscle antioxidant capacity: a brief review. Med Sci Sports Exerc 1999; 31:987-997.
58. Manna I, Jana K, Samanta P K. Effect of intensive exercise-induced testicular gametogenic and steroidogenic disorders in mature male wistar strain rats: a correlative approach to oxidative stress. Acta Physiol Scand 2003; 178:33-40.
59. Ramzan M H, Ramzan M, Ramzan F, Wahab F, Jillani M, Khan MA, et al. Insight into the serum kisspeptin levels in infertile males. Arch Iran Med 2015; 18:12-17.
60. Agarwal A, Prabakaran S A, Said T M. Prevention of oxidative stress injury to sperm. J Androl 2005; 26:654-660.
Iranian Journal of Basic Medical Sciences
Volume 24, Issue 12
December 2021
Pages 1624-1631

Files

Share

How to cite

Statistics