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Licensed Unlicensed Requires Authentication Published by De Gruyter November 13, 2020

Adverse effects of metabolic disorders in childhood on adult reproductive function and fertility in the male

Isabel Viola Wagner ORCID logo, Elizabeth Oliver, Jörg Dötsch and Olle Söder


Over the last 50 years, there has been a steady decline in fertility rates in humans, which has occurred in parallel with an increasing incidence of obesity and metabolic disorders. The potential impact of these disorders and plausible mechanisms by which they negatively influence male reproduction are only partly understood and published data are often controversial. Obesity is one of the most important health challenges worldwide and is becoming more prevalent in children and adolescents. Obesity, the metabolic syndrome and related co-morbidities can lead to impaired male reproductive function, including adverse effects on spermatogenesis and steroidogenesis as illustrated by reduced sperm number and quality, decreased testosterone levels and elevated inflammatory markers. The incidence of diabetes mellitus type I is also dramatically increasing and may negatively impact spermatogenesis and testicular function, resulting in decreased serum testosterone and epididymal weight. In this review, we summarize and discuss the effects of metabolic diseases that typically develop during childhood and adolescence on later reproductive function and fertility. While impact on reproductive health is likely observed in both sexes, we have chosen to focus on the male in the current review. Specifically, we illustrate adverse effects of obesity, type 1 diabetes, the metabolic syndrome and insulin resistance on sperm function and testosterone metabolism. Identification of pathophysiological mechanisms during childhood may open up new avenues for early prevention and treatment resulting in better reproductive outcomes and improved fertility rates during adulthood.

Corresponding author: Isabel Viola Wagner, MD, Karolinska Institutet, Department of Women’s and Children’s Health, Pediatric Endocrinology Unit, Stockholm, Sweden; Department of Pediatrics, Medical Faculty, University of Cologne, Pediatric Endocrinology Unit, Cologne, Germany; and Division of Pediatric Endocrinology and Diabetes, Department of Paediatrics, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, Germany, Phone: +49 (0) 451/50042827, E-mail:


The authors wishes to thank all the children, adolescents and families and adults who participated in the cited studies.

  1. Research funding: We did not get financial support or funding for writing this review.

  2. Author Contributions: All four authors contributed in writing and revising the review.

  3. Competing interests: The authors have no conflicts of interest to the preparation or content of the manuscript.

  4. Ethical approval: The authors have no ethical conflicts to disclose.


1. Hammoud, AO, Gibson, M, Peterson, CM, Hamilton, BD, Carrell, DT. Obesity and male reproductive potential. J Androl 2006;27:619–26. in Google Scholar

2. Hammoud, AO, Meikle, AW, Reis, LO, Gibson, M, Peterson, CM, Carrell, DT. Obesity and male infertility: a practical approach. Semin Reprod Med 2012;30:486–95. in Google Scholar

3. Morrison, C. Interaction between exercise and leptin in the treatment of obesity. Diabetes 2008;57:534–5. in Google Scholar

4. Pinhas-Hamiel, O, Zeitler, P. Insulin resistance, obesity, and related disorders among black adolescents. J Pediatr 1996;129:319–20. in Google Scholar

5. Palmer, NO, Bakos, HW, Fullston, T, Lane, M. Impact of obesity on male fertility, sperm function and molecular composition. Spermatogenesis 2012;2:253–63. in Google Scholar PubMed PubMed Central

6. 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 2012;36:153–9. in Google Scholar

7. Schoeller, EL, Schon, S, Moley, KH. The effects of type 1 diabetes on the hypothalamic, pituitary and testes axis. Cell Tissue Res 2012;349:839–47. in Google Scholar PubMed PubMed Central

8. Ballester, J, Munoz, MC, Dominguez, J, Rigau, T, Guinovart, JJ, Rodriguez-Gil, JE. Insulin-dependent diabetes affects testicular function by FSH- and LH-linked mechanisms. J Androl 2004;25:706–19. in Google Scholar PubMed

9. Kelnar, CJ, McKinnell, C, Walker, M, Morris, KD, Wallace, WH, Saunders, PT, et al.. Testicular changes during infantile ‘quiescence’ in the marmoset and their gonadotrophin dependence: a model for investigating susceptibility of the prepubertal human testis to cancer therapy?. Hum Reprod 2002;17:1367–78. in Google Scholar PubMed

10. Sliwowska, JH, Ziarniak, K, Dudek, M, Matuszewska, J, Tena-Sempere, M. Dangerous liaisons for pubertal maturation: the impact of alcohol consumption and obesity on the timing of puberty. Biol Reprod 2018;100:25–40.10.1093/biolre/ioy168Search in Google Scholar PubMed

11. Davidson, LM, Millar, K, Jones, C, Fatum, M, Coward, K. Deleterious effects of obesity upon the hormonal and molecular mechanisms controlling spermatogenesis and male fertility. Hum Fertil 2015;18:184–93. in Google Scholar

12. Hajshafiha, M, Ghareaghaji, R, Salemi, S, Sadegh-Asadi, N, Sadeghi-Bazargani, H. Association of body mass index with some fertility markers among male partners of infertile couples. Int J Gen Med 2013;6:447–51. in Google Scholar

13. Hong, CY, Park, JH, Ahn, RS, Im, SY, Choi, HS, Soh, J, et al.. Molecular mechanism of suppression of testicular steroidogenesis by proinflammatory cytokine tumor necrosis factor alpha. Mol Cell Biol 2004;24:2593–604. in Google Scholar

14. Wagner, IV, Kloting, N, Atanassova, N, Savchuk, I, Sprote, C, Kiess, W, et al.. Prepubertal onset of obesity negatively impacts on testicular steroidogenesis in rats. Mol Cell Endocrinol 2016;437:154–62. in Google Scholar

15. Hales, DB. Testicular macrophage modulation of Leydig cell steroidogenesis. J Reprod Immunol 2002;57:3–18. in Google Scholar

16. Hales, DB. Another piece in the maddening puzzle of declining steroidogenesis in aging Leydig cells. J Androl 2002;23:327–8; discussion 9.Search in Google Scholar

17. Mealy, K, Robinson, B, Millette, CF, Majzoub, J, Wilmore, DW. The testicular effects of tumor necrosis factor. Ann Surg 1990;211:470–5. in Google Scholar PubMed PubMed Central

18. Hales, DB. Interleukin-1 inhibits Leydig cell steroidogenesis primarily by decreasing 17 alpha-hydroxylase/C17-20 lyase cytochrome P450 expression. Endocrinology 1992;131:2165–72. in Google Scholar PubMed

19. Li, X, Hales, KH, Watanabe, G, Lee, RJ, Pestell, RG, Hales, DB. The effect of tumor necrosis factor-alpha and cAMP on induction of AP-1 activity in MA-10 tumor Leydig cells. Endocrine 1997;6:317–24. in Google Scholar

20. Vettor, R, De Pergola, G, Pagano, C, Englaro, P, Laudadio, E, Giorgino, F, et al.. Gender differences in serum leptin in obese people: relationships with testosterone, body fat distribution and insulin sensitivity. Eur J Clin Invest 1997;27:1016–24. in Google Scholar PubMed

21. Paasch, U, Grunewald, S, Kratzsch, J, Glander, HJ. Obesity and age affect male fertility potential. Fertil Steril 2010;94:2898–901. in Google Scholar PubMed

22. Trayhurn, P, Wood, IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 2004;92:347–55. in Google Scholar PubMed

23. Ikeda, Y, Hama, S, Kajimoto, K, Okuno, T, Tsuchiya, H, Kogure, K. Quantitative comparison of adipocytokine gene expression during adipocyte maturation in non-obese and obese rats. Biol Pharm Bull 2011;34:865–70. in Google Scholar PubMed

24. Thomas, S, Kratzsch, D, Schaab, M, Scholz, M, Grunewald, S, Thiery, J, et al.. Seminal plasma adipokine levels are correlated with functional characteristics of spermatozoa. Fertil Steril 2013;99:1256–63 e3. in Google Scholar PubMed

25. Li, L, Ma, P, Huang, C, Liu, Y, Zhang, Y, Gao, C, et al.. Expression of chemerin and its receptors in rat testes and its action on testosterone secretion. J Endocrinol 2014;220:155–63. in Google Scholar PubMed PubMed Central

26. Nogueiras, R, Barreiro, ML, Caminos, JE, Gaytan, F, Suominen, JS, Navarro, VM, et al.. Novel expression of resistin in rat testis: functional role and regulation by nutritional status and hormonal factors. J Cell Sci 2004;117:3247–57. in Google Scholar PubMed

27. Caminos, JE, Nogueiras, R, Gaytan, F, Pineda, R, Gonzalez, CR, Barreiro, ML, et al.. Novel expression and direct effects of adiponectin in the rat testis. Endocrinology 2008;149:3390–402. in Google Scholar PubMed

28. Ocon-Grove, OM, Krzysik-Walker, SM, Maddineni, SR, Hendricks, GL3rd, Ramachandran, R. Adiponectin and its receptors are expressed in the chicken testis: influence of sexual maturation on testicular ADIPOR1 and ADIPOR2 mRNA abundance. Reproduction 2008;136:627–38. in Google Scholar

29. Wagner, IV, Yango, P, Svechnikov, K, Tran, ND, Soder, O. Adipocytokines may delay pubertal maturation of human Sertoli cells. Reprod Fertil Dev 2019;31:1395–400. doi: in Google Scholar PubMed

30. Blazquez, M, Medina, P, Crespo, B, Gomez, A, Zanuy, S. Identification of conserved genes triggering puberty in European sea bass males (Dicentrarchus labrax) by microarray expression profiling. BMC Genom 2017;18:441. in Google Scholar PubMed PubMed Central

31. Rodriguez-Mari, A, Canestro, C, BreMiller, RA, Catchen, JM, Yan, YL, Postlethwait, JH. Retinoic acid metabolic genes, meiosis, and gonadal sex differentiation in zebrafish. PLoS One 2013;8:e73951. in Google Scholar PubMed PubMed Central

32. Martins, FF, Aguila, MB, Mandarim-de-Lacerda, CA. Impaired steroidogenesis in the testis of leptin-deficient mice (ob/ob −/−). Acta Histochem 2017;119:508–15. in Google Scholar PubMed

33. Bhat, GK, Sea, TL, Olatinwo, MO, Simorangkir, D, Ford, GD, Ford, BD, et al.. Influence of a leptin deficiency on testicular morphology, germ cell apoptosis, and expression levels of apoptosis-related genes in the mouse. J Androl 2006;27:302–10. in Google Scholar PubMed

34. Farooqi, IS, Bullmore, E, Keogh, J, Gillard, J, O’Rahilly, S, Fletcher, PC. Leptin regulates striatal regions and human eating behavior. Science 2007;317:1355. in Google Scholar PubMed PubMed Central

35. Maffei, M, Halaas, J, Ravussin, E, Pratley, RE, Lee, GH, Zhang, Y, et al.. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1995;1:1155–61. in Google Scholar PubMed

36. Barash, IA, Cheung, CC, Weigle, DS, Ren, H, Kabigting, EB, Kuijper, JL, et al.. Leptin is a metabolic signal to the reproductive system. Endocrinology 1996;137:3144–7. in Google Scholar PubMed

37. Mounzih, K, Lu, R, Chehab, FF. Leptin treatment rescues the sterility of genetically obese ob/ob males. Endocrinology 1997;138:1190–3. in Google Scholar PubMed

38. Jun, JY, Ma, Z, Pyla, R, Segar, L. Leptin treatment inhibits the progression of atherosclerosis by attenuating hypercholesterolemia in type 1 diabetic Ins2(+/Akita):apoE(−/−) mice. Atherosclerosis 2012;225:341–7. in Google Scholar PubMed PubMed Central

39. Yu, WH, Walczewska, A, Karanth, S, McCann, SM. Nitric oxide mediates leptin-induced luteinizing hormone-releasing hormone (LHRH) and LHRH and leptin-induced LH release from the pituitary gland. Endocrinology 1997;138:5055–8. in Google Scholar PubMed

40. Hoffmann, A, Manjowk, GM, Wagner, IV, Kloting, N, Ebert, T, Jessnitzer, B, et al.. Leptin within the subphysiological to physiological range dose dependently improves male reproductive function in an obesity mouse model. Endocrinology 2016;157:2461–8. in Google Scholar PubMed

41. Luo, L, Chen, H, Stocco, DM, Zirkin, BR. Leydig cell protein synthesis and steroidogenesis in response to acute stimulation by luteinizing hormone in rats. Biol Reprod 1998;59:263–70. in Google Scholar PubMed

42. Clark, BJ, Wells, J, King, SR, Stocco, DM. The purification, cloning, and expression of a novel luteinizing hormone-induced mitochondrial protein in MA-10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR). J Biol Chem 1994;269:28314–22.10.1016/S0021-9258(18)46930-XSearch in Google Scholar

43. Ivell, R, Wade, JD, Anand-Ivell, R. INSL3 as a biomarker of Leydig cell functionality. Biol Reprod 2013;88:147. in Google Scholar PubMed

44. Lampiao, F, du Plessis, SS. Insulin and leptin enhance human sperm motility, acrosome reaction and nitric oxide production. Asian J Androl 2008;10:799–807. in Google Scholar PubMed

45. Wagner, IV, Sabin, MA, Pfaffle, RW, Hiemisch, A, Sergeyev, E, Korner, A, et al.. Effects of obesity on human sexual development. Nat Rev Endocrinol 2012;8:246–54. in Google Scholar PubMed

46. Yoon, YS, Shin, SA, Noh, JH, Oh, SW. Burden of type 2 diabetes in young Korean adults owing to obesity. Diabetes Care 2005;28:2329. in Google Scholar PubMed

47. Sowers, JR, Epstein, M, Frohlich, ED. Diabetes, hypertension, and cardiovascular disease: an update. Hypertension 2001;37:1053–9. in Google Scholar PubMed

48. Said, G. Diabetic neuropathy–a review. Nat Clin Pract Neurol 2007;3:331–40. in Google Scholar PubMed

49. Jangir, RN, Jain, GC. Diabetes mellitus induced impairment of male reproductive functions: a review. Curr Diabetes Rev 2014;10:147–57. in Google Scholar PubMed

50. Whiting, DR, Guariguata, L, Weil, C, Shaw, J. IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract 2011;94:311–21. in Google Scholar PubMed

51. Lutz, W. Fertility rates and future population trends: will Europe’s birth rate recover or continue to decline?. Int J Androl 2006;29:25–33. in Google Scholar PubMed

52. Maresch, CC, Stute, DC, Alves, MG, Oliveira, PF, de Kretser, DM, Linn, T. Diabetes-induced hyperglycemia impairs male reproductive function: a systematic review. Hum Reprod Update 2018;24:86–105. in Google Scholar PubMed

53. Agbaje, IM, Rogers, DA, McVicar, CM, McClure, N, Atkinson, AB, Mallidis, C, et al.. Insulin dependant diabetes mellitus: implications for male reproductive function. Hum Reprod 2007;22:1871–7. in Google Scholar PubMed

54. Alves, MG, Martins, AD, Cavaco, JE, Socorro, S, Oliveira, PF. Diabetes, insulin-mediated glucose metabolism and Sertoli/blood-testis barrier function. Tissue Barriers 2013;1:e23992. in Google Scholar PubMed PubMed Central

55. Baccetti, B, La Marca, A, Piomboni, P, Capitani, S, Bruni, E, Petraglia, F, et al.. Insulin-dependent diabetes in men is associated with hypothalamo-pituitary derangement and with impairment in semen quality. Hum Reprod 2002;17:2673–7. in Google Scholar PubMed

56. El Baba, K, Azar, ST. Low testosterone and diabetes. Curr Diabetes Rev 2013;9:418–21. in Google Scholar PubMed

57. Gazzaruso, C, Coppola, A, Giustina, A. Erectile dysfunction and coronary artery disease in patients with diabetes. Curr Diabetes Rev 2011;7:143–7. in Google Scholar PubMed

58. La Vignera, S, Condorelli, R, Vicari, E, D’Agata, R, Calogero, AE. Diabetes mellitus and sperm parameters. J Androl 2012;33:145–53. in Google Scholar PubMed

59. Mallidis, C, Agbaje, I, McClure, N, Kliesch, S. The influence of diabetes mellitus on male reproductive function: a poorly investigated aspect of male infertility. Urologe A 2011;50:33–7. in Google Scholar PubMed

60. Ricci, G, Catizone, A, Esposito, R, Pisanti, FA, Vietri, MT, Galdieri, M. Diabetic rat testes: morphological and functional alterations. Andrologia 2009;41:361–8. in Google Scholar PubMed

61. Scarano, WR, Messias, AG, Oliva, SU, Klinefelter, GR, Kempinas, WG. Sexual behaviour, sperm quantity and quality after short-term streptozotocin-induced hyperglycaemia in rats. Int J Androl 2006;29:482–8. in Google Scholar PubMed

62. Sexton, WJ, Jarow, JP. Effect of diabetes mellitus upon male reproductive function. Urology 1997;49:508–13. in Google Scholar

63. Alves, MG, Martins, AD, Jarak, I, Barros, A, Silva, J, Sousa, M, et al.. Testicular lactate content is compromised in men with Klinefelter Syndrome. Mol Reprod Dev 2016;83:208–16. in Google Scholar

64. Amaral, S, Oliveira, PJ, Ramalho-Santos, J. Diabetes and the impairment of reproductive function: possible role of mitochondria and reactive oxygen species. Curr Diabetes Rev 2008;4:46–54. in Google Scholar

65. Gomez, O, Ballester, B, Romero, A, Arnal, E, Almansa, I, Miranda, M, et al.. Expression and regulation of insulin and the glucose transporter GLUT8 in the testes of diabetic rats. Horm Metab Res 2009;41:343–9. in Google Scholar

66. Seethalakshmi, L, Menon, M, Diamond, D. The effect of streptozotocin-induced diabetes on the neuroendocrine-male reproductive tract axis of the adult rat. J Urol 1987;138:190–4. in Google Scholar

67. Benitez, A, Perez Diaz, J. Effect of streptozotocin-diabetes and insulin treatment on regulation of Leydig cell function in the rat. Horm Metab Res 1985;17:5–7. in Google Scholar PubMed

68. Sudha, S, Sankar, BR, Valli, G, Govindarajulu, P, Balasubramanian, K. Streptozotocin-diabetes impairs prolactin binding to Leydig cells in prepubertal and pubertal rats. Horm Metab Res 1999;31:583–6. in Google Scholar PubMed

69. Hutson, JC, Stocco, DM, Campbell, GT, Wagoner, J. Sertoli cell function in diabetic, insulin-treated diabetic, and semi-starved rats. Diabetes 1983;32:112–6. in Google Scholar PubMed

70. Martins, AD, Majzoub, A, Agawal, A. Metabolic syndrome and male fertility. World J Mens Health 2019;37:113–27. in Google Scholar PubMed PubMed Central

71. Lotti, F, Corona, G, Degli Innocenti, S, Filimberti, E, Scognamiglio, V, Vignozzi, L, et al.. Seminal, ultrasound and psychobiological parameters correlate with metabolic syndrome in male members of infertile couples. Andrology 2013;1:229–39. in Google Scholar PubMed

72. Leisegang, K, Udodong, A, Bouic, PJ, Henkel, RR. Effect of the metabolic syndrome on male reproductive function: a case-controlled pilot study. Andrologia 2014;46:167–76. in Google Scholar PubMed

73. Ventimiglia, E, Capogrosso, P, Colicchia, M, Boeri, L, Serino, A, Castagna, G, et al.. Metabolic syndrome in white European men presenting for primary couple’s infertility: investigation of the clinical and reproductive burden. Andrology 2016;4:944–51. in Google Scholar PubMed

74. An, T, Wang, YF, Liu, JX, Pan, YY, Liu, YF, He, ZC, et al.. Comparative analysis of proteomes between diabetic and normal human sperm: insights into the effects of diabetes on male reproduction based on the regulation of mitochondria-related proteins. Mol Reprod Dev 2018;85:7–16. in Google Scholar PubMed

75. Singh, AK, Tomarz, S, Chaudhari, AR, Sinqh, R, Verma, N. Type 2 diabetes mellitus affects male fertility potential. Indian J Physiol Pharmacol 2014;58:403–6.Search in Google Scholar

76. Oliveira, PF, Alves, MG, Rato, L, Silva, J, Sa, R, Barros, A, et al.. Influence of 5 alpha-dihydrotestosterone and 17 beta-estradiol on human Sertoli cells metabolism. Int J Androl 2011;34:e612–20. in Google Scholar PubMed

77. Shrilatha, B, Muralidhara. Early oxidative stress in testis and epididymal sperm in streptozotocin-induced diabetic mice: its progression and genotoxic consequences. Reprod Toxicol 2007;23:578–87. in Google Scholar PubMed

78. Fedder, J, Kaspersen, MD, Brandslund, I, Hojgaard, A. Retrograde ejaculation and sexual dysfunction in men with diabetes mellitus: a prospective, controlled study. Andrology 2013;1:602–6. in Google Scholar PubMed

79. Schisterman, EF, Mumford, SL, Chen, Z, Browne, RW, Boyd Barr, D, Kim, S, et al.. Lipid concentrations and semen quality: the LIFE study. Andrology 2014;2:408–15. in Google Scholar PubMed PubMed Central

80. Ergun, A, Kose, SK, Aydos, K, Ata, A, Avci, A. Correlation of seminal parameters with serum lipid profile and sex hormones. Arch Androl 2007;53:21–3. in Google Scholar PubMed

81. Shalaby, MA, el-Zorba, HY, Kamel, GM. Effect of alpha-tocopherol and simvastatin on male fertility in hypercholesterolemic rats. Pharmacol Res 2004;50:137–42. in Google Scholar PubMed

82. Guo, D, Li, S, Behr, B, Eisenberg, ML. Hypertension and male fertility. World J Mens Health 2017;35:59–64. in Google Scholar PubMed PubMed Central

83. Svartberg, J, von Muhlen, D, Schirmer, H, Barrett-Connor, E, Sundfjord, J, Jorde, R. Association of endogenous testosterone with blood pressure and left ventricular mass in men. The Tromso Study. Eur J Endocrinol 2004;150:65–71. in Google Scholar PubMed

Received: 2020-05-15
Accepted: 2020-09-21
Published Online: 2020-11-13
Published in Print: 2021-01-27

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