Оценка влияния коррекции углеводного обмена и массы тела на эндогенную продукцию тестостерона у мужчин с сахарным диабетом 2 типа, ожирением и синдромом гипогонадизма

Синдром гипогонадизма и сахарный диабет 2 типа (СД2) у мужчин нередко сочетаются и взаимно отягощают друг друга. Учитывая патогенетическую взаимосвязь с компонентами метаболического синдрома (гипергликемия, инсулинорезистентность, ожирение) и потенциальную обратимость дефицита тестостерона, а также настороженность врачей и пациентов в отношении заместительной терапии тестостероном, интересным является изучения влияния различных методик коррекции углеводного обмена и ожирения на эндогенную продукцию тестостерона. При анализе влияния коррекции образа жизни, медикаментозной терапии СД2 и ожирения, а также метаболической хирургии на выработку тестостерона, обнадеживающие результаты получены в отношении методик, обеспечивающих, в первую очередь, значимое снижение массы тела (препараты из группы агонистов рецепторов глюкагоноподобного пептида-1 и бариатрическая хирургия). Что касается иных классов новых противодиабетических препаратов, вполне вероятно, что все они могут оказывать прямое или косвенное благотворное воздействие на мужскую половую функцию, главным образом за счет снижения глюкозотоксичности и воспаления. Однако данная гипотеза требует проведения исследований на больших по объему выборках пациентов. Кроме того, до сих пор нет убедительных данных о значимости коррекции углеводного обмена вне зависимости от снижения массы тела в отношении эндогенной продукции тестостерона, а также отсутствуют данные о степени улучшения гликемического контроля, необходимой для клинически значимого повышения уровня тестостерона сыворотки крови.

1. Corona G, Vena W, Pizzocaro A, et al. Testosterone therapy in diabetes and pre-diabetes. Andrology. 2023;11:204-214. https://doi.org/10.1111/andr.13367

2. Muraleedharan V, Marsh H, Kapoor D, et al. Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. Eur. J. Endocrinol. 2013;169(6):725-733. https://doi.org/10.1530/EJE-13-0321

3. Kumari N, Khan A, Shaikh U, et al. Comparison of Testosterone Levels in Patients With and Without Type 2 Diabetes. Cureus. 2021;78(3):151-158. https://doi.org/10.7759/cureus.16288

4. Li S, Zhao Y, Yang Y, et al. Metabolic Effects of Testosterone Replacement Therapy in Patients with Type 2 Diabetes Mellitus or Metabolic Syndrome: A Meta-Analysis. Int J Endocrinol. 2020;2020(3):1-12. https://doi.org/10.1155/2020/4732021

5. Saad F, Haider A, Doros G, Traish A. Long-term treatment of hypogonadal men with testosterone produces substantial and sustained weight loss. Obesity. 2013;21:1975-81. https://doi.org/10.1002/oby.20407

6. Haider A, Yassin A, Doros G, Saad F. Effects of long-term testosterone therapy on patients with ‘diabesity’: results of observational studies of pooled analyses in obese hypogonadal men with type 2 diabetes. Int J Endocrinol. 2014:683515. https://doi.org/10.1155/2014/683515

7. Haider A, Yassin A, Doros G, Traish AM, Saad F. Reductions of weight and waist size in 362 hypogonadal men with obesity grades I to III under longterm treatment with testosterone undecanoate. (TU): observational data from two registry studies. In: Abstract (SAT-0940) Presented at the Endocrine Society’s 96th Annual Meeting. 2014.

8. Yassin A, Doros G. Testosterone therapy in hypogonadal men results in sustained and clinically meaningful weight loss. Clin Obes. 2013;3:73-83. https://doi.org/10.1111/cob.12022

9. Saad F, Yassin A, Doros G, Haider A. Effects of long-term treatment with testosterone on weight and waist size in 411 hypogonadal men with obesity classes I-III: observational data from two registry studies. Int J Obes. 2016;40:162-70. https://doi.org/10.1038/ijo.2015.139

10. Lincoff AM, Bhasin S, Flevaris P, et al. Cardiovascular Safety of Testosterone-Replacement Therapy. N Engl J Med. 2023;389(2):107-117. https://doi.org/10.1056/NEJMoa2215025

11. Sukegawa G, Tsuji Y. Risk of male infertility due to testosterone replacement therapy for late-onset hypogonadism (LOH). Acta Urol Jpn. 2020. https://doi.org/10.14989/ActaUrolJap_66_11_407

12. Tan RBW, Guay AT, Hellstrom WJG. Clinical Use of Aromatase Inhibitors in Adult Males. Sex Med Rev. 2014;2(2):79-90. https://doi.org/10.1002/smrj.23

13. Camacho EM, Huhtaniemi IT, O’Neill TW, et al. Age-associated changes in hypothalamic-pituitary-testicular function in middle-aged and older men are modified by weight change and lifestyle factors: longitudinal results from the European Male Ageing Study. Eur J Endocrinol. 2013;168(3):445-455. https://doi.org/10.1530/EJE-12-0890

14. La Vignera S, Cannarella R, Galvano F, et al. The ketogenic diet corrects metabolic hypogonadism and preserves pancreatic ß-cell function in overweight/obese men: a singlearm uncontrolled study. Endocrine. 2021;72(2):392-399. https://doi.org/10.1007/s12020-020-02518-8

15. Mongioì LM, Cimino L, Condorelli RA, et al. Effectiveness of a very low calorie ketogenic diet on testicular function in overweight/obese men. Nutrients. 2020. https://doi.org/10.3390/nu12102967

16. Mongioì LM, Cimino L, Greco E, et al. Very-low-calorie ketogenic diet: An alternative to a pharmacological approach to improve glycometabolic and gonadal profile in men with obesity. Curr Opin Pharmacol. 2021;60:72-82. https://doi.org/10.1016/j.coph.2021.06.013

17. Sahebkar A, Simental-Mendía LE, Reiner Ž, et al. Effect of orlistat on plasma lipids and body weight: A systematic review and meta-analysis of 33 randomized controlled trials. Pharmacol Res. 2017;122:53-65. https://doi.org/10.1016/j.phrs.2017.05.022

18. Suleiman JB, Nna VU, Othman ZA, Zakaria Z, Bakar ABA, Mohamed M. Orlistat attenuates obesity‐induced decline in steroidogenesis and spermatogenesis by up‐regulating steroidogenic genes. Andrology. 2020;8(5):1471-1485. https://doi.org/10.1111/andr.12824

19. Suleiman JB, Nna VU, Zakaria Z, et al. Orlistat reverses intratesticular lactate transport decline and infertility in male obese rats. Reproduction. 2020;160(6):863-872. https://doi.org/10.1530/REP-20-0381

20. Van Cauwenberghe J, De Block C, Vanderschueren D, Antonio L. Effects of treatment for diabetes mellitus on testosterone concentrations: A systematic review. Andrology. 2023;11:225-233. https://doi.org/10.1111/andr.13318

21. Giagulli VA, Castellana M, Carbone MD, et al. Weight loss more than glycemic control may improve testosterone in obese type 2 diabetes mellitus men with hypogonadism. Andrology. 2020;8(3):654-662

22. Tan S, Ignatenko S, Wagner F, et al. Licogliflozin versus placebo in women with polycystic ovary syndrome: A randomized, double‐blind, phase 2 trial. Diabetes, Obes Metab. 2021;23(11):2595-2599. https://doi.org/10.1111/dom.14495

23. Ayuob NN, Murad HAS, Ali SS. Impaired expression of sex hormone receptors in male reproductive organs of diabetic rat in response to oral antidiabetic drugs. Folia Histochem Cytobiol. 2015;53(1):35-48. https://doi.org/10.5603/FHC.a2015.0005

24. Hibi H, Ohori T, Yamada Y. DPP-IV inhibitor may affect spermatogenesis. Diabetes Res Clin Pract. 2011;93(2):e74-e75. https://doi.org/10.1016/j.diabres.2011.04.022

25. Abdelzaher WY, Rofaeil RR, Ali DME, Attya ME. Protective effect of dipeptidyl peptidase-4 inhibitors in testicular torsion/ detorsion in rats: a possible role of HIF-1α and nitric oxide. Naunyn Schmiedebergs Arch Pharmacol. 2020;393(4):603-614. https://doi.org/10.1007/s00210-019-01765-5

26. Abdel‐Aziz AM, Naguib Abdel Hafez SM. Sitagliptin protects male albino rats with testicular ischaemia/reperfusion damage: Modulation of VCAM‐1 and VEGF‐A. Andrologia. 2020;52(2). https://doi.org/10.1111/and.13472

27. Ahmed ZA, Abtar AN, Othman HH, Aziz TA. Effects of quercetin, sitagliptin alone or in combination in testicular toxicity induced by doxorubicin in rats. Drug Des Devel Ther. 2019;Volume 13:3321-3329. https://doi.org/10.2147/DDDT.S222127

28. Altabas V, Altabas K. DPP-4 inhibition improves a sexual condition? Med Hypotheses. 2015;85(2):124-126. https://doi.org/10.1016/j.mehy.2015.04.011

29. Daneshjou D, Soleimani Mehranjani M, Zadeh Modarres S, Shariatzadeh MA. Sitagliptin/Metformin: A New Medical Treatment in Polycystic Ovary Syndrome. Trends Endocrinol Metab. 2020;31(12):890-892. https://doi.org/10.1016/j.tem.2020.09.002

30. Santilli F, Simeone PG, Guagnano MT, et al. Effects of Liraglutide on Weight Loss, Fat Distribution, and β-Cell Function in Obese Subjects With Prediabetes or Early Type 2 Diabetes. Diabetes Care. 2017;40(11):1556-1564. https://doi.org/10.2337/dc17-0589

31. Potts JE, Gray LJ, Brady EM, Khunti K, Davies MJ, Bodicoat DH. The effect of glucagon-like peptide 1 receptor agonists on weight loss in type 2 diabetes: A systematic review and mixed treatment comparison meta-analysis. PLoS One. 2015. https://doi.org/10.1371/journal.pone.0126769

32. Halawi H, Khemani D, Eckert D, et al. Effects of liraglutide on weight, satiation, and gastric functions in obesity: a randomised, placebocontrolled pilot trial. Lancet Gastroenterol Hepatol. 2017;2(12):890-899. https://doi.org/10.1016/S2468-1253(17)30285-6

33. Cignarelli A, Genchi VA, D’Oria R, et al. Role of Glucose-Lowering Medications in Erectile Dysfunction. J Clin Med. 2021;10(11):2501. https://doi.org/10.3390/jcm10112501

34. Cannarella R, Calogero AE, Condorelli RA, Greco EA, Aversa A, La Vignera S. Is there a role for glucagon-like peptide-1 receptor agonists in the treatment of male infertility? Andrology. 2021. https://doi.org/10.1111/andr.13015

35. Giagulli VA, Carbone MD, Ramunni MI, et al. Adding liraglutide to lifestyle changes, metformin and testosterone therapy boosts erectile function in diabetic obese men with overt hypogonadism. Andrology. 2015;3(6):1094-1103. https://doi.org/10.1111/andr.12099

36. Shao N, Yu XY, Yu YM, et al. Short-term combined treatment with exenatide and metformin is superior to glimepiride combined metformin in improvement of serum testosterone levels in type 2 diabetic patients with obesity. Andrologia. 2018. https://doi.org/10.1111/and.13039

37. Model JFA, Lima MV, Ohlweiler R, et al. Liraglutide treatment counteracts alterations in adipose tissue metabolism induced by orchiectomy in rats. Life Sci. 2021;278:119586. https://doi.org/10.1016/j.lfs.2021.119586

38. Zhang E, Xu F, Liang H, et al. GLP‐1 Receptor Agonist Exenatide Attenuates the Detrimental Effects of Obesity on Inflammatory Profile in Testis and Sperm Quality in Mice. Am J Reprod Immunol. 2015;74(5):457-466. https://doi.org/10.1111/aji.12420

39. Jensterle M, Podbregar A, Goricar K, Gregoric N, Janez A. Effects of liraglutide on obesity-associated functional hypogonadism in men. Endocr Connect. 2019;8(3):195-202. https://doi.org/10.1530/EC-18-0514

40. Caltabiano R, Condorelli D, Panza S, et al. Glucagon-like peptide-1 receptor is expressed in human and rodent testis. Andrology. 2020. https://doi.org/10.1111/andr.12871

41. Ahangarpour A, Oroojan AA, Heidari H. Effects of Exendin-4 on Male Reproductive Parameters of D-Galactose Induced Aging Mouse Model. World J Mens Health. 2014;32(3):176. https://doi.org/10.5534/wjmh.2014.32.3.176

42. Grossmann M, Thomas MC, Panagiotopoulos S, et al. Lowtestosterone levels are common and associated with insulin resistance in men with diabetes. J Clin Endocrinol Metab. 2008;93(5):1834-1840

43. Capoccia D, Coccia F, Guarisco G, et al. Long-term Metabolic Effects of Laparoscopic Sleeve Gastrectomy. Obes Surg. 2018;28(8):2289-2296. https://doi.org/10.1007/s11695-018-3153-8

44. Corona G, Vignozzi L, Sforza A, Mannucci E, Maggi M. Obesity and late-onset hypogonadism. Mol Cell Endocrinol. 2015;418:120-133. https://doi.org/10.1016/j.mce.2015.06.031

45. Escobar-Morreale HF, Santacruz E, Luque-Ramírez M, Botella Carretero JI. Prevalence of ‘obesity-associated gonadal dysfunction’ in severely obese men and women and its resolution after bariatric surgery: a systematic review and meta-analysis. Hum Reprod Update. 2017;23(4):390-408. https://doi.org/10.1093/humupd/dmx012

46. Liu F, Tu Y, Zhang P, Bao Y, Han J, Jia W. Decreased visceral fat area correlates with improved total testosterone levels after Rouxen-Y gastric bypass in obese Chinese males with type 2 diabetes: a 12-month follow-up. Surg Obes Relat Dis. 2018;14(4):462-468. https://doi.org/10.1016/j.soard.2017.11.009

47. Zhu C, Mei F, Gao J, Zhou D, Lu L, Qu S. Changes in inflammatory markers correlated with increased testosterone after laparoscopic sleeve gastrectomy in obese Chinese men with acanthosis nigricans. J Dermatol. 2019. https://doi.org/10.1111/1346-8138.14783

48. Facchiano E, Scaringi S, Veltri M, et al. Age as a Predictive Factor of Testosterone Improvement in Male Patients After Bariatric Surgery: Preliminary Results of a Monocentric Prospective Study. Obes Surg. 2013;23(2):167-172. https://doi.org/10.1007/s11695-012-0753-6

49. Neunhaeuserer D, Gasperetti A, Savalla F, et al. Functional Evaluation in Obese Patients Before and After Sleeve Gastrectomy. Obes Surg. 2017;27(12):3230-3239. https://doi.org/10.1007/s11695-017-2763-x

50. Liao M, Guo X, Yu X, et al. Role of Metabolic Factors in the Association Between Osteocalcin and Testosterone in Chinese Men. J Clin Endocrinol Metab. 2013;98(8):3463-3469. https://doi.org/10.1210/jc.2013-1805

51. Samavat J, Facchiano E, Cantini G, et al. Osteocalcin increase after bariatric surgery predicts androgen recovery in hypogonadal obese males. Int J Obes. 2014. https://doi.org/10.1038/ijo.2013.228

52. Hammoud A, Gibson M, Hunt SC, et al. Effect of Roux-en-Y Gastric Bypass Surgery on the Sex Steroids and Quality of Life in Obese Men. J Clin Endocrinol Metab. 2009;94(4):1329-1332. https://doi.org/10.1210/jc.2008-1598

53. Boonchaya-anant P, Laichuthai N, Suwannasrisuk P, Houngngam N, Udomsawaengsup S, Snabboon T. Changes in Testosterone Levels and Sex Hormone-Binding Globulin Levels in Extremely Obese Men after Bariatric Surgery. Int J Endocrinol. 2016;2016:1-5. https://doi.org/10.1155/2016/1416503

54. Calderón B, Galdón A, Calañas A, et al. Effects of Bariatric Surgery on Male Obesity-Associated Secondary Hypogonadism: Comparison of Laparoscopic Gastric Bypass with Restrictive Procedures. Obes Surg. 2014;24(10):1686-1692. https://doi.org/10.1007/s11695-014-1233-y

55. Di Vincenzo A, Silvestrin V, Bertoli E, et al. Short-term effects of surgical weight loss after sleeve gastrectomy on sex steroids plasma levels and PSA concentration in men with severe obesity. Aging Male. 2021. https://doi.org/10.1080/13685538.2018.1528445

56. Pham NH, Bena J, Bhatt DL, Kennedy L, Schauer PR, Kashyap SR. Increased Free Testosterone Levels in Men with Uncontrolled Type 2 Diabetes Five Years After Randomization to Bariatric Surgery. Obes Surg. 2018. https://doi.org/10.1007/s11695-017-2881-5

57. Glina FPA, de Freitas Barboza JW, Nunes VM, Glina S, Bernardo WM. What Is the Impact of Bariatric Surgery on Erectile Function? A Systematic Review and Meta-Analysis. Sex Med Rev. 2017;5(3):393-402. https://doi.org/10.1016/j.sxmr.2017.03.008

58. Sarhan MD, Khattab M, Sarhan MD, Maurice KK, Hassan H. Impact of Bariatric Surgery on Male Sexual Health: a Prospective Study. Obes Surg. 2021;31(9):4064- 4069. https://doi.org/10.1007/s11695-021-05522-7

59. Kun L, Pin Z, Jianzhong D, et al. Significant Improvement of Erectile Function after Roux-en-Y Gastric Bypass Surgery in Obese Chinese Men with Erectile Dysfunction. Obes Surg. 2015;25(5):838-844. https://doi.org/10.1007/s11695-014-1465-x

60. Carette C, Levy R, Eustache F, et al. Changes in total sperm count after gastric bypass and sleeve gastrectomy: the BARIASPERM prospective study. Surg Obes Relat Dis. 2019;15(8):1271-1279. https://doi.org/10.1016/j.soard.2019.04.019