Osteocalcin Levels in Male Idiopathic Hypogonadotropic Hypogonadism: Relationship With the Testosterone Secretion and Metabolic Profiles

Yu-Ying Yang, Si-Chang Zheng, Wen-Cui Wang, Zu-Wei Yang, Chang Shan, Yu-Wen Zhang, Yan Qi, Yu-Hong Chen, Wei-Qiong Gu, Wei-Qing Wang, Hong-Yan Zhao, Jian-Min Liu, Shou-Yue Sun, Yu-Ying Yang, Si-Chang Zheng, Wen-Cui Wang, Zu-Wei Yang, Chang Shan, Yu-Wen Zhang, Yan Qi, Yu-Hong Chen, Wei-Qiong Gu, Wei-Qing Wang, Hong-Yan Zhao, Jian-Min Liu, Shou-Yue Sun

Abstract

Idiopathic hypogonadotropic hypogonadism (IHH) patients are characterized by the absence of puberty and varying degrees of deteriorated metabolic conditions. Osteocalcin (OC) could regulate testosterone secretion and energy metabolism, but it remains unknown whether such an effect exists in IHH patients. Our study is aimed to examine the relationship between serum OC levels with testosterone and its responsiveness to gonadotropin stimulation and metabolic profiles in male IHH patients. A total of 99 male patients aged 18-37 years and diagnosed with IHH were enrolled in the current study, and the relationships between OC and testicular volume, baseline total testosterone (TT), free testosterone (FT), and peak TT (Tmax) levels after human chorionic gonadotropin (hCG) stimulation, gonadotropin responsiveness index (GRI), which is calculated by dividing Tmax by testicular volume, as well as metabolic profiles, such as 2-h post-challenge glucose (2hPG) and fat percentage (fat%), were analyzed. The results showed that OC had an independent negative relationship with testicular volume (r = -0.253, P = 0.012) and a positive association with Tmax (r = 0.262, P = 0.014) after adjusting for confounders. In addition, OC was a major determinant of GRI (adjusted R 2 for the model = 0.164, P = 0.012), fat% (adjusted R 2 for the model = 0.100, P = 0.004), and 2hPG (adjusted R 2 for the model = 0.054, P = 0.013) in IHH patients. In conclusion, OC is associated with testosterone secretion upon gonadotropin stimulation, glucose metabolism, and fat mass variations in IHH. This study was registered at clinicaltrials.gov (NCT02310074).

Keywords: gonadotropin; idiopathic hypogonadotropic hypogonadism; metabolism; osteocalcin; testosterone.

Copyright © 2019 Yang, Zheng, Wang, Yang, Shan, Zhang, Qi, Chen, Gu, Wang, Zhao, Liu and Sun.

Figures

Figure 1
Figure 1
(A) The simple correlation between OC and testicular volume. (B) Partial correlation between OC and Tmax adjusted for age and testicular volume. The y-axis represents the residuals obtained after fitting a linear regression model using Tmax as a dependent variable, and age and testicular volume as the independent variables. The x-axis represents the residuals obtained after fitting a linear regression model using osteocalcin as a dependent variable, and age and testicular volume as the independent variables. (C) The simple correlation between OC and GRI.

References

    1. Bianco SDC, Kaiser UB. The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism. Nat Rev Endocrinol. (2009) 5:569–76. 10.1038/nrendo.2009.177
    1. Santen RJ, Paulsen CA. Hypogonadotropic eunuchoidism. I. Clinical study of the mode of inheritance. J Clin Endocrinol Metab. (1973) 36:47–54. 10.1210/jcem-36-1-47
    1. Segal TY, Mehta A, Anazodo A, Hindmarsh PC, Dattani MT. Role of gonadotropin-releasing hormone and human chorionic gonadotropin stimulation tests in differentiating patients with hypogonadotropic hypogonadism from those with constitutional delay of growth and puberty. J Clin Endocrinol Metab. (2009) 94:780–5. 10.1210/jc.2008-0302
    1. Liu Z, Mao J, Wu X, Xu H, Wang X, Huang B, et al. . Efficacy and outcome predictors of gonadotropin treatment for male congenital hypogonadotropic hypogonadism. Medicine. (2016) 95:e2867. 10.1097/MD.0000000000002867
    1. Rastrelli G, Corona G, Mannucci E, Maggi M. Factors affecting spermatogenesis upon gonadotropin-replacement therapy: a meta-analytic study. Andrology. (2014) 2:794–808. 10.1111/andr.262
    1. Wang W-B, She F, Xie L-F, Yan W-H, Ouyang J-Z, Wang B-A, et al. . Evaluation of basal serum adrenocorticotropic hormone and cortisol levels and their relationship with nonalcoholic fatty liver disease in male patients with idiopathic hypogonadotropic hypogonadism. Chin Med J. (2016) 129:1147–53. 10.4103/0366-6999.181967
    1. Naharci MI, Bolu E, Karadurmus N, Basaran Y. The relationship between ghrelin levels and insulin resistance in men with idiopathic hypogonadotrophic hypogonadism at diagnosis and after therapy. Endokrynol Pol. (2012) 61:351–8. Available online at:
    1. Bayram F, Elbuken G, Korkmaz C, Aydogdu A, Karaca Z, Cakir I. The effects of gonadotropin replacement therapy on metabolic parameters and body composition in men with idiopathic hypogonadotropic hypogonadism. Horm Metab Res. (2015) 48:112–7. 10.1055/s-0035-1564252
    1. De Rosa M, Paesano L, Nuzzo V, Zarrilli S, Del Puente A, Oriente P, et al. . Bone mineral density and bone markers in hypogonadotropic and hypergonadotropic hypogonadal men after prolonged testosterone treatment. J Endocrinol Invest. (2001) 24:246–52. 10.1007/BF03343854
    1. Shabsigh R, Katz M, Yan G, Makhsida N. Cardiovascular issues in hypogonadism and testosterone therapy. Am J Cardiol. (2005) 96:67–72. 10.1016/j.amjcard.2005.10.009
    1. Naharci M, Pinar M, Bolu E, Olgun A. Effect of testosterone on insulin sensitivity in men with idiopathic hypogonadotropic hypogonadism. Endocr Pract. (2013) 13:629–35. 10.4158/EP.13.6.629
    1. Jones TH. Effects of testosterone on Type 2 diabetes and components of the metabolic syndrome. J Diabetes. (2010) 2:146–56. 10.1111/j.1753-0407.2010.00085.x
    1. Liu S, Sun Q. Sex differences, endogenous sex-hormone hormones, sex-hormone binding globulin, and exogenous disruptors in diabetes and related metabolic outcomes. J Diabetes. (2018) 10:428–41. 10.1111/1753-0407.12517
    1. Karsenty G. The mutual dependence between bone and gonads. J Endocrinol. (2012) 213:107–14. 10.1530/JOE-11-0452
    1. Oury F. A crosstalk between bone and gonads. Ann N Y Acad Sci. (2012) 1260:1–7. 10.1111/j.1749-6632.2011.06360.x
    1. Oury F, Sumara G, Sumara O, Ferron M, Chang H, Smith CE, et al. . Endocrine regulation of male fertility by the skeleton. Cell. (2011) 144:796–809. 10.1016/j.cell.2011.02.004
    1. Wei J, Karsenty G. An overview of the metabolic functions of osteocalcin. Curr Osteoporos Rep. (2015) 13:180–5. 10.1007/s11914-015-0267-y
    1. Oury F, Ferron M, Huizhen W, Confavreux C, Xu L, Lacombe J, et al. . Osteocalcin regulates murine and human fertility through a pancreas–bone–testis axis. J Clin Invest. (2015) 125:2180. 10.1172/JCI81812
    1. Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, et al. . Endocrine regulation of energy metabolism by the skeleton. Cell. (2007) 130:456–69. 10.1016/j.cell.2007.05.047
    1. Ferron M, McKee MD, Levine RL, Ducy P, Karsenty G. Intermittent injections of osteocalcin improve glucose metabolism and prevent type 2 diabetes in mice. Bone. (2012) 50:568–75. 10.1016/j.bone.2011.04.017
    1. Karsenty G, Oury F. Biology without walls: the novel endocrinology of bone. Annu Rev Physiol. (2012) 74:87–105. 10.1146/annurev-physiol-020911-153233
    1. Petak SM, Nankin HR, Spark RF, Swerdloff RS, Rodriguez-Rigau LJ, American Association of Clinical Endocrinologists . American Association of Clinical Endocrinologists Medical Guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients−2002 update. Endocr Pract. (2002) 8:440–56. 10.4158/EP.8.6.439
    1. Sakamoto H, Saito K, Oohta M, Inoue K, Ogawa Y, Yoshida H. Testicular volume measurement: comparison of ultrasonography, orchidometry, and water displacement. Urology. (2007) 69:152–7. 10.1016/j.urology.2006.09.012
    1. Anawalt BD. Serum inhibin B levels reflect Sertoli cell function in normal men and men with testicular dysfunction. J Clin Endocrinol Metab. (1996) 81:3341–5. 10.1210/jc.81.9.3341
    1. Oury F, Ferron M, Huizhen W, Confavreux C, Xu L, Lacombe J, et al. . Osteocalcin regulates murine and human fertility through a pancreas–bone–testis axis. J Clin Invest. (2013) 123:2421–33. 10.1172/JCI65952
    1. Ammini A, Gupta N, Khadgawat R, Kulshreshtha B. Progression of puberty after initiation of androgen therapy in patients with idiopathic hypogonadotropic hypogonadism. Indian J Endocrinol Metab. (2013) 17:851. 10.4103/2230-8210.117245
    1. Zhang M, Tong G, Liu Y, Mu Y, Weng J, Xue Y, et al. . Sequential versus continual purified urinary FSH/hCG in men with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. (2015) 100:2449–55. 10.1210/jc.2014-3802
    1. Aydogdu A, Bolu E, Sonmez A, Tasci I, Haymana C, Acar R, et al. . Effects of three different medications on metabolic parameters and testicular volume in patients with hypogonadotropic hypogonadism: 3-year experience. Clin Endocrinol. (2013) 79:243–51. 10.1111/cen.12135
    1. Kanazawa I, Tanaka K, Ogawa N, Yamauchi M, Yamaguchi T, Sugimoto T. Undercarboxylated osteocalcin is positively associated with free testosterone in male patients with type 2 diabetes mellitus. Osteoporos Int. (2013) 24:1115–9. 10.1007/s00198-012-2017-7
    1. Zhong N, Xu B, Cui R, Xu M, Su J, Zhang Z, et al. . Positive correlation between serum osteocalcin and testosterone in male hyperthyroidism patients with high bone turnover. Exp Clin Endocrinol Diabetes. (2016) 124:452–6. 10.1055/s-0042-107944
    1. Samavat J, Facchiano E, Cantini G, Di Franco A, Alpigiano G, Poli G, et al. . Osteocalcin increase after bariatric surgery predicts androgen recovery in hypogonadal obese males. Int J Obes. (2014) 38:357–63. 10.1038/ijo.2013.228
    1. Schwetz V, Gumpold R, Graupp M, Hacker N, Schweighofer N, Trummer O, et al. Osteocalcin is not a strong determinant of serum testosterone and sperm count in men from infertile couples. Andrology. (2013) 1:590–4. 10.1111/j.2047-2927.2013.00095.x
    1. Degros V, Cortet-Rudelli C, Soudan B, Dewailly D. The human chorionic gonadotropin test is more powerful than the gonadotropin-releasing hormone agonist test to discriminate male isolated hypogonadotropic hypogonadism from constitutional delayed puberty. Eur J Endocrinol. (2003) 149:23–9. 10.1530/eje.0.1490023
    1. Christiansen P, Andersson A-M, Skakkebaek NE, Juul A. Serum inhibin B, FSH, LH and testosterone levels before and after human chorionic gonadotropin stimulation in prepubertal boys with cryptorchidism. Eur J Endocrinol. (2002) 147:95–101. 10.1530/eje.0.1470095
    1. Saez JM, Forest MG. Kinetics of human chorionic gonadotropin-induced steroidogenic response of the human testis. I. Plasma testosterone: implications for human chorionic gonadotropin stimulation test*. J Clin Endocrinol Metab. (1979) 49:278–83. 10.1210/jcem-49-2-278
    1. Liu JM, Rosen CJ, Ducy P, Kousteni S, Karsenty G. Regulation of glucose handling by the skeleton: insights from mouse and human studies. Diabetes. (2016) 65:3225–32. 10.2337/db16-0053
    1. Liu JM, Zhao HY, Zhao L, Chen Y, Zhang LZ, Tao B, et al. . An independent positive relationship between the serum total osteocalcin level and fat-free mass in healthy premenopausal women. J Clin Endocrinol Metab. (2013) 98:2146–52. 10.1210/jc.2013-1112
    1. Booth SL, Centi A, Smith SR, Gundberg C. The role of osteocalcin in human glucose metabolism: marker or mediator? Nat Rev Endocrinol. (2013) 9:43–55. 10.1038/nrendo.2012.201
    1. Kotan LD, Isik E, Turan I, Mengen E, Akkus G, Tastan M, et al. . Prevalence and associated phenotypes of PLXNA1 variants in normosmic and anosmic idiopathic hypogonadotropic hypogonadism. Clin Genet. (2019) 95:320–4. 10.1111/cge.13482

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel