Influence of androgen deprivation therapy on glucose metabolism and ambulatory glucose profile

Introduction. Androgen deprivation, used to treat prostate cancer, leads to metabolic disorders, including glucose metabolism disorders. The timing of development and the characteristics of these changes have not been sufficiently studied. The expansion of the possibilities for assessing glycemia makes it possible to obtain changes in glucose.

Objective. To study the dynamics of the effect of long-term androgen-deprivation therapy with gonadotropin-releasing hormone agonists (GnRH agonists) on the parameters of glucose metabolism and ambulatory glucose profile in patients with locally advanced prostate cancer (La PCa).

Materials and methods. The study included 99 patients with La PCa receiving androgendeprivation therapy (ADT) with (GnRH agonists) for at least 12 months. The study of fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) levels was performed at baseline, after 3, 6 and 12 months of ADT, and constant self-monitoring of glycemia was recommended using portable glucometers. Flash glucose monitoring systems (FreeStyle Libre) were installed in ten patients with a detected increase in glycemia on the background of ADT, allowing them to obtain data on the ambulatory glucose profile (AGP).

Results and discussion. Long-term ADT in patients with La PCa, regardless of baseline age, BMI, WC, was accompanied by an early, progressive deterioration in parameters of glucose metabolism. The proportion of patients with prediabetic FPG values after 12 months becames 66% according ADA criteria. We found that 12-month ADT changes the AGP: an increase area under the curve and postprandial glycemic levels, an increase in blood glucose variability with an increase in the CONGA index to 6.817 (p < 0.001).

Conclusion. ADT by GnRH agonists in patients with La PCa is accompanied by a predisposition to early disorders of glucose metabolism with a high risk of rapid development of prediabetes regardless of baseline age, BMI, and WC. The AGP of patients is characterized by an increase in the total glycemic load, and glycemic variability.

1. Dedov I.I., Shestakova M.V., Mayorov A.Y. (eds.). Standards of Specialized Diabetes Care. 9th edition. Saharnyy diabet = Diabetes Mellitus. 2019; 22(1 Suppl.):1-144. (In Russ.) doi: 10.14341/DM221S1.

2. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care. 2003;26(1 Suppl.): s5-s20. doi: 10.2337/diacare.26.2007.s5.

3. Chen C., Zhao X.L., Li Z.H., Zhu Z.G., Qian S.H., Flewitt A.J. Current and Emerging Technology for Continuous Glucose Monitoring. Sensors (Basel). 2017;19;17(1):182. doi: 10.3390/s17010182.

4. Mian Z., Hermayer K.L., Jenkins A. Continuous Glucose Monitoring: Review of an Innovation in Diabetes Management. Am J Med Sci. 2019;358(5): 332-339. doi: 10.1016/j.amjms.2019.07.003.

5. Ang E., Lee Z.X., Moore S., Nana M. Flash glucose monitoring (FGM): A clinical review on glycaemic outcomes and impact on quality of life. J Diabetes Complications. 2020;34(6):107559. doi: 10.1016/j.jdiacomp.2020.107559.

6. Huggins C., Hodges C.V. Studies on prostatic cancer: I. The effect of castration, of estogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate. J Urology. 1941;1:293-297.

7. Bell K.J., Del Mar C., Wright G., Dickinson J., Glasziou P. Prevalence of incidental prostate cancer: A systematic review of autopsy studies. Int J Cancer. 2015;1;137(7):1749-1757. doi: 10.1002/ijc.29538.

8. Ferlay J., Colombet M., Soerjomataram I., Mathers C., Parkin D.M., Pineros M. et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer. 2019;144(8):1941-1953. doi: 10.1002/ijc.31937.

9. Kaprin A.D., Starinskiy V.V., Shakhzadova A.O. (eds.). The state of cancer care for the population of Russia in 2019. Moscow : P.A. Herzen Moscow Oncology Research Institute, a branch of the National Medical Research Radiological Center of the Ministry of Health of the Russian Federation; 2020. 239 p. (In Russ.) Available at: https//glavonco.ru/cancer_register/Pomoshch%202019.pdf.

10. Stellato R.K., Feldman H.A., Hamdy O., Horton E.S., McKinlay J.B. Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts male aging study. Diabetes Care. 2000;23(4):490-494. doi: 10.2337/diacare.23.4.490.

11. Oh J.Y., Barrett-Connor E., Wedick N.M., Wingard D.L. Rancho Bernardo Study. Endogenous sex hormones and the development of type 2 diabetes in older men and women: the Rancho Bernardo study. Diabetes Care. 2002;25(1):55-60. doi: 10.2337/diacare.25.1.55.

12. Jones T.H., Arver S., Behre H.M., Buvat J., Meuleman E., Moncada I. et al. TIMES2 Investigators. Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care. 2011;34(4):828-837. doi: 10.2337/dc10-1233.

13. Hackett G., Cole N., Bhartia M., Kennedy D., Raju J., Wilkinson P. Testosterone replacement therapy improves metabolic parameters in hypogonadal men with type 2 diabetes but not in men with coexisting depression: the BLAST study. J Sex Med. 2014;11(3):840-856. doi: 10.1111/jsm.12404.

14. Keating N.L., O'Malley A.J., Smith M.R. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol. 2006;24(27):4448-4456. doi: 10.1200/JCO.2006.06.2497.

15. Smith J.C., Bennett S., Evans L.M., Kynaston H.G., Parmar M., Mason M.D. et al. The effects of induced hypogonadism on arterial stiffness, body composition, and metabolic parameters in males with prostate cancer. J Clin Endocrinol Metab. 2001;86(9):4261-4267. doi: 10.1210/jcem.86.9.7851.

16. Hamilton E.J., Gianatti E., Strauss B.J., Wentworth J., Lim-Joon D., Bolton D. et al. Increase in visceral and subcutaneous abdominal fat in men with prostate cancer treated with androgen deprivation therapy. Clin Endocrinol (Oxf). 2011;74(3):377-383. doi: 10.1111/j.1365-2265.2010.03942.x.

17. Mitsuzuka K., Kyan A., Sato T., Orikasa K., Miyazato M., Aoki H. et al. Influence of 1 year of androgen deprivation therapy on lipid and glucose metabolism and fat accumulation in Japanese patients with prostate cancer. Prostate Cancer Prostatic Dis. 2016;19(1):57-62. doi: 10.1038/pcan.2015.50.

18. Emerging Risk Factors Collaboration, Sarwar N., Gao P., Seshasai S.R., Gobin R., Kaptoge S., Di Angelantonio E et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010:26;375(9733):2215-2222. doi: 10.1016/S0140-6736(10)60484-9.

19. Vistisen D., Witte D.R., Brunner E.J., Kivimäki M., Tabák A., Jørgensen M.E., Færch K. Risk of cardiovascular disease and death in individuals with prediabetes defined by different criteria: the whitehall II study. Diabetes Care. 2018;41(4):899-906. doi: 10.2337/dc17-2530.

20. Tang X., Li S., Wang Y., Wang M., Yin Q., Mu P. et al. Glycemic variability evaluated by continuous glucose monitoring system is associated with the 10-y cardiovascular risk of diabetic patients with well-controlled HbA1c. Clin Chim Acta. 2016;461:146-150. doi: 10.1016/j.cca.2016.08.004.

21. Salukhov V.V., Kiteyshin V.P., Ulupova E.O., Titov D.G. Rationale of glycemic variability measurement in the practice of endocrinologist. Medline. ru. Rossiyskiy biomeditsinskiy zhurnal = Medline.ru. Russian Biomedical Journal. 2018;19:819-831. (In Russ.) Available at: http://www.medline.ru/public/art/tom19/art60.html.

22. Cheung A.S., Hoermann R., Dupuis P., Joon D.L., Zajac J.D., Grossmann M. Relationships between insulin resistance and frailty with body composition and testosterone in men undergoing androgen deprivation therapy for prostate cancer. Eur J Endocrinol. 2016;175(3):229-237. doi: 10.1530/EJE-16-0200.

23. Marin P., Oden B., Bjorntorp P. Assimilation and mobilization of triglycerides in subcutaneous abdominal and femoral adipose tissue in vivo in men: effects of androgens. J Clin Endocrinol Metab. 1995;80(1):239-243. doi: 10.1210/jcem.80.1.7829619.

24. Gupta V., Bhasin S., Guo W., Singh R., Miki R., Chauhan P. et al. Effects of dihydrotestosterone on differentiation and proliferation of human mesenchymal stem cells and preadipocytes. Mol Cell Endocrinol. 2008;296(1-2): 32-40. doi: 10.1016/j.mce.2008.08.019.

25. Chang D., Joseph DJ., Ebert M.A., Galvao D.A., Taaffe D.R., Denham J.W. et al. Effect of androgen deprivation therapy on muscle attenuation in men with prostate cancer. J Med Imaging Radiat Oncol. 2014;58(2):223-228. doi: 10.1111/1754-9485.12124.

26. Hegarty B.D., Furler S.M., Ye J., Cooney G.J., Kraegen E.W. The role of intramuscular lipid in insulin resistance. Acta Physiol Scand. 2003;178(4):373-383. doi: 10.1046/j.1365-201X.2003.01162.x.

27. Navarro G., Xu W., Jacobson D.A., Wicksteed B., Allard C., Zhanget G. et al. Extranuclear actions of the androgen receptor enhance glucose-stimulated insulin secretion in the male. Cell Metab. 2016;23(5):837-851. doi: 10.1016/j.cmet.2016.03.015.

28. Sezer H., Yazici D., Copur S., Dagel T., Deyneli O., Kanbay M. The relationship between glycemic variability and blood pressure variability in normoglycemic normotensive individuals. Blood Press Monit. 2021;26(2): 102-107. doi: 10.1097/MBP.0000000000000491.

29. Alatawi Z., Mirghani H. The Association Between Glycemic Variability and Myocardial Infarction: A Review and Meta-Analysis of Prospective Studies and Randomized Trials. Cureus. 2020;12(11):e11556. doi: 10.7759/cureus.11556.

30. Demidova T.Yu., Kishkovich Yu.S. Prediabetes: the current state of the problem and the adjustment possibility. RMZh. Meditsinskoe obozrenie = RMJ. Medical Review. 2019;10(II):60-67. Available at: https://www.rmj.ru/articles/endokrinologiya/Prediabet_sovremennoe_sostoyanie_problemy_i_vozmoghnosti_korrekcii/#ixzz6t9gCA73S.

31. Margel D., Urbach D.R., Lipscombe L.L., Bell C.M., Kulkarni G., Austin P.C. et al. Metformin use and all-cause and prostate cancer-specific mortality among men with diabetes. J Clin Oncol. 2013;31(25):3069-3075. doi: 10.1200/JCO.2012.46.7043.

32. Richards K.A., Liou J.I., Cryns V.L., Downs T.M., Abel E.J., Jarrard D.F. Metformin Use is Associated with Improved Survival for Patients with Advanced Prostate Cancer on Androgen Deprivation Therapy. J Urol. 2018;200(6):1256-1263. doi: 10.1016/j.juro.2018.06.031.

33. Lee M.J., Jayalath V., Xu W., Lu L., Freedland S.J., Fleshner N.E. et al. Association between metformin medication, genetic variation and prostate cancer risk. Prostate Cancer Prostatic Dis. 2021;24(1):96-105. doi: 10.1038/s41391-020-0238-y.

34. Nobes J.P., Langley S.E., Klopper T., Russell-Jones D., Laing R.W. A prospective, randomized pilot study evaluating the effects of metformin and lifestyle intervention on patients with prostate cancer receiving androgen deprivation therapy. BJU Int. 2012;109(10):1495-1502. doi: 10.1111/j.1464-410X.2011.10555.x.