Vol 68, No 3 (2017)
Original paper
Published online: 2017-02-22

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Effect of testosterone replacement therapy on vitamin D and FGF-23 levels in congenital hypogonadism

Cem Haymana1, Alper Sonmez1, Aydogan Aydogdu1, Serkan Tapan2, Yalcin Basaran1, Coskun Meric1, Kamil Baskoy3, Abdullah Taslipinar1, Mahmut Ilker Yilmaz4, Omer Azal1
Pubmed: 28230890
Endokrynol Pol 2017;68(3):311-616.


Introduction: Patients with hypogonadism are at increased risk of cardiac and metabolic diseases and osteoporosis. Vitamin D and Fibroblast growth factor-23 (FGF-23) play role in the regulation of bone mineral metabolism and endothelial functions. Low vitamin D levels are reported in hypogonadism, while there is no data about the effect of testosterone replacement therapy (TRT). We investigated the effect of TRT on vitamin D and FGF-23 levels along with endothelial functions and insulin resistance in hypogonadal patients.

Material and methods: Patients with congenital hypogonadotrophic hypogonadism (CHH) (n=32, age 20.6 ±1.58 years) were enrolled. TRT was implemented in transdermal form. The demographic parameters, FGF-23, 25(OH)D3, Asymmetric dimethylarginine (ADMA) and homeostatic model assessment of insulin resistance (HOMA-IR) levels were measured both before and after TRT.

Results: After a follow-up period of 3.63±1.33 months, ADMA and FGF-23 levels were significantly increased (p=0.03 and p=0.005 respectively), while the 25(OH)D3 and HOMA-IR index were not significantly changed. The body mass index and waist circumference levels of the patients were also increased (p<0.001 and p=0.02) along with a significant decrease in the HDL cholesterol levels (p=0.006).

Conclusions: The results show that a short term TRT increases plasma FGF-23 and ADMA levels, in young, treatment naive patients with CHH. Whether this is an early implication of TRT related adverse effects in this very young and treatment naïve population of CHH is not clear. Future prospective studies are required to find out the long-term effects of TRT on cardio-metabolic morbidity and mortality in this specific population.


  1. Laaksonen DE, Niskanen L, Punnonen K, et al. Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care. 2004; 27(5): 1036–1041.
  2. Traish AM, Saad F, Feeley RJ, et al. The dark side of testosterone deficiency: III. Cardiovascular disease. J Androl. 2009; 30(5): 477–494.
  3. Overvad S, Bay K, Bojesen A, et al. Low INSL3 in Klinefelter syndrome is related to osteocalcin, testosterone treatment and body composition, as well as measures of the hypothalamic-pituitary-gonadal axis. Andrology. 2014; 2(3): 421–427.
  4. Foresta C, Ruzza G, Mioni R, et al. Testosterone and bone loss in Klinefelter syndrome. Horm Metab Res. 1983; 15(1): 56–57.
  5. Finkelstein JS, Klibanski A, Neer RM, et al. Osteoporosis in men with idiopathic hypogonadotropic hypogonadism. Ann Intern Med. 1987; 106(3): 354–361.
  6. Lee DM, Tajar A, Pye SR, et al. EMAS study group. Association of hypogonadism with vitamin D status: the European Male Ageing Study. Eur J Endocrinol. 2012; 166(1): 77–85.
  7. Tak YJ, Lee JG, Kim YJ, et al. Serum 25-hydroxyvitamin D levels and testosterone deficiency in middle-aged Korean men: a cross-sectional study. Asian J Androl. 2015; 17(2): 324–328.
  8. Nimptsch K, Platz EA, Willett WC, et al. Association between plasma 25-OH vitamin D and testosterone levels in men. Clin Endocrinol (Oxf). 2012; 77(1): 106–112.
  9. Arisaka O, Arisaka M, Nakayama Y, et al. Effect of testosterone on bone density and bone metabolism in adolescent male hypogonadism. Metabolism. 1995; 44(4): 419–423.
  10. Shimada T, Hasegawa H, Yamazaki Y, et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res. 2004; 19(3): 429–435.
  11. Shimada T, Yamazaki Y, Takahashi M, et al. Vitamin D receptor-independent FGF23 actions in regulating phosphate and vitamin D metabolism. Am J Physiol Renal Physiol. 2005; 289(5): F1088–F1095.
  12. Liu S, Quarles LD. How fibroblast growth factor 23 works. J Am Soc Nephrol. 2007; 18(6): 1637–1647.
  13. Mirza MAI, Hansen T, Johansson L, et al. Relationship between circulating FGF23 and total body atherosclerosis in the community. Nephrol Dial Transplant. 2009; 24(10): 3125–3131.
  14. Mirza MAI, Larsson A, Lind L, et al. Circulating fibroblast growth factor-23 is associated with vascular dysfunction in the community. Atherosclerosis. 2009; 205(2): 385–390.
  15. Tripepi G, Kollerits B, Leonardis D, et al. Competitive interaction between fibroblast growth factor 23 and asymmetric dimethylarginine in patients with CKD. J Am Soc Nephrol. 2015; 26(4): 935–944.
  16. Burnett-Bowie SAM, Mendoza N, Leder BZ. Effects of gonadal steroid withdrawal on serum phosphate and FGF-23 levels in men. Bone. 2007; 40(4): 913–918.
  17. Meric C, Sonmez A, Aydogdu A, et al. Osteoprotegerin, fibroblast growth factor 23, and vitamin D3 levels in male patients with hypogonadism. Horm Metab Res. 2014; 46(13): 955–958.
  18. Aydogdu A, Bolu E, Sonmez A, et al. Effects of three different medications on metabolic parameters and testicular volume in patients with hypogonadotropic hypogonadism: 3-year experience. Clin Endocrinol (Oxf). 2013; 79(2): 243–251.
  19. Sonmez A, Haymana C, Bolu E, et al. Metabolic syndrome and the effect of testosterone treatment in young men with congenital hypogonadotropic hypogonadism. Eur J Endocrinol. 2011; 164(5): 759–764.
  20. Sonmez A, Haymana C, Aydogdu A, et al. Endothelial dysfunction, insulin resistance and inflammation in congenital hypogonadism, and the effect of testosterone replacement. Endocr J. 2015; 62(7): 605–613.
  21. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972; 18(6): 499–502.
  22. Wallace TM, Matthews DR. The assessment of insulin resistance in man. Diabet Med. 2002; 19(7): 527–534.
  23. Dupree K, Dobs A. Osteopenia and male hypogonadism. Rev Urol. 2004; 6 Suppl 6: S30–S34.
  24. Jackson JA, Kleerekoper M, Parfitt AM, et al. Bone histomorphometry in hypogonadal and eugonadal men with spinal osteoporosis. J Clin Endocrinol Metab. 1987; 65(1): 53–58.
  25. Finkelstein JS, Klibanski A, Neer RM, et al. Osteoporosis in men with idiopathic hypogonadotropic hypogonadism. Ann Intern Med. 1987; 106(3): 354–361.
  26. Mittan D, Lee S, Miller E, et al. Bone loss following hypogonadism in men with prostate cancer treated with GnRH analogs. J Clin Endocrinol Metab. 2002; 87(8): 3656–3661.
  27. Irwig MS, Irwig MS. Male hypogonadism and skeletal health. Curr Opin Endocrinol Diabetes Obes. 2013; 20(6): 517–522.
  28. Blomberg Jensen M, Nielsen JE, Jørgensen A, et al. Vitamin D receptor and vitamin D metabolizing enzymes are expressed in the human male reproductive tract. Hum Reprod. 2010; 25(5): 1303–1311.
  29. Francis RM, Peacock M, Aaron JE, et al. Osteoporosis in hypogonadal men: role of decreased plasma 1,25-dihydroxyvitamin D, calcium malabsorption, and low bone formation. Bone. 1986; 7(4): 261–268.
  30. Corona G, Rastrelli G, Vignozzi L, et al. Testosterone, cardiovascular disease and the metabolic syndrome. Best Pract Res Clin Endocrinol Metab. 2011; 25(2): 337–353.
  31. Rosano GMC, Sheiban I, Massaro R, et al. Low testosterone levels are associated with coronary artery disease in male patients with angina. Int J Impot Res. 2007; 19(2): 176–182.
  32. Rabijewski M, Papierska L, Kozakowski J, et al. [The relationship between testosterone and dehydroepiandrosterone sulfate concentrations, insulin resistance and visceral obesity in elderly men]. Endokrynol Pol. 2005; 56(6): 897–903.
  33. Laaksonen DE, Niskanen L, Punnonen K, et al. Sex hormones, inflammation and the metabolic syndrome: a population-based study. Eur J Endocrinol. 2003; 149(6): 601–608.
  34. Kapoor D, Goodwin E, Channer KS, et al. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol. 2006; 154(6): 899–906.
  35. Mårin P, Holmäng S, Gustafsson C, et al. Androgen treatment of abdominally obese men. Obes Res. 1993; 1(4): 245–251.
  36. Li JY, Zhu JC, Dou JT, et al. Effects of androgen supplementation therapy on partial androgen deficiency in the aging male: a preliminary study. Aging Male. 2002; 5(1): 47–51.
  37. Sonmez A, Taslipinar A, Tapan S, et al. Comment on: Jones et al. Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 Study). Diabetes Care 2011;34:828-837. Diabetes Care. 2011; 34(11): e172; author's reply e173.
  38. Travison TG, Basaria S, Storer TW, et al. Adverse events associated with testosterone administration. N Engl J Med. 2010; 363(2): 109–122.
  39. Xu L, Freeman G, Cowling BJ, et al. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC Med. 2013; 11: 108.
  40. Vigen R, O'Donnell CI, Barón AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013; 310(17): 1829–1836.
  41. Glueck CJ, Wang P. Testosterone therapy, thrombosis, thrombophilia, cardiovascular events. Metabolism. 2014; 63(8): 989–994.
  42. Li G, Oparil S, Kelpke SS, et al. Fibroblast growth factor receptor-1 signaling induces osteopontin expression and vascular smooth muscle cell-dependent adventitial fibroblast migration in vitro. Circulation. 2002; 106(7): 854–859.
  43. Yilmaz MI, Sonmez A, Saglam M, et al. FGF-23 and vascular dysfunction in patients with stage 3 and 4 chronic kidney disease. Kidney Int. 2010; 78(7): 679–685.
  44. Gutiérrez OM, Januzzi JL, Isakova T, et al. Fibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease. Circulation. 2009; 119(19): 2545–2552.
  45. Bouras G, Deftereos S, Tousoulis D, et al. Asymmetric Dimethylarginine (ADMA): a promising biomarker for cardiovascular disease? Curr Top Med Chem. 2013; 13(2): 180–200.
  46. Cakir E, Ozcan O, Yaman H, et al. Elevated plasma concentration of asymmetric dimethylarginine that is reduced by single dose testosterone administration in idiopathic hypogonadotropic hypogonadism patients. J Clin Endocrinol Metab. 2005; 90(3): 1651–1654.
  47. Leifke E, Kinzel M, Tsikas D, et al. Effects of normalization of plasma testosterone levels in hypogonadal men on plasma levels and urinary excretion of asymmetric dimethylarginine (ADMA). Horm Metab Res. 2008; 40(1): 56–59.