3,350
Views
1
CrossRef citations to date
0
Altmetric
Articles

Male subclinical hypogonadism and late-onset hypergonadotrophic hypogonadism: mechanisms, endothelial function, and interplay between reproductive hormones, undercarboxylated osteocalcin, and endothelial dysfunction

ORCID Icon, , &
Pages 79-94 | Received 01 Nov 2021, Accepted 28 Feb 2022, Published online: 15 Mar 2022

References

  • Tajar A, Forti G, O'Neill TW, the EMAS Group, et al. Characteristics of secondary, primary, and compensated hypogonadism in aging men: evidence from the European Male Ageing study. J Clin Endocrinol Metab. 2010;95(4):1810–1818.
  • Corradi PF, Corradi RB, Greene LW. Physiology of the hypothalamic pituitary gonadal axis in the male. Urol Clin North Am. 2016;25(1):151–162.
  • Hiort O, Holterhus PM, Horter T, et al. Significance of mutations in the androgen receptor gene in males with idiopathic infertility. J Clin Endocrinol Metab. 2000;85(8):2810–2815.
  • de Ronde W, van der Schouw YT, Muller M, et al. Associations of sex-hormone-binding globulin (SHBG) with non-SHBG-bound levels of testosterone and estradiol in independently living men. J Clin Endocrinol Metab. 2005;90(1):157–162.
  • Giannetta E, Gianfrilli D, Barbagallo F, et al. Subclinical male hypogonadism. Best Pract Res Clin Endocrinol Metab. 2012;26(4):539–550.
  • Tajar A, O'Connell MD, Mitnitski AB, European Male Aging Study Group, et al. Frailty in relation to variations in hormone levels of the hypothalamic-pituitary-testicular axis in older men: results from the European male aging study. J Am Geriatr Soc. 2011;59(5):814–821.
  • Corona G, Maseroli E, Rastrelli G, et al. Characteristics of compensated hypogonadism in patients with sexual dysfunction. J Sex Med. 2014;11(7):1823–1834.
  • van den Beld AW, Huhtaniemi IT, Pettersson KSL, et al. Luteinizing hormone and different genetic variants, as indicators of frailty in healthy elderly men. J Clin Endocrinol Metab. 1999;84(4):1334–1339.
  • Hyde Z, Norman PE, Flicker L, et al. Elevated LH predicts ischaemic heart disease events in older men: the health in men study. Eur J Endocrinol. 2011;164(4):569–577.
  • Komori T. Functions of osteocalcin in bone, pancreas, testis, and muscle. IJMS. 2020;21(20):7513.
  • Millar SA, Patel H, Anderson SI, et al. Osteocalcin, vascular calcification, and atherosclerosis: a systematic review and meta-analysis. Front Endocrinol. 2017;8:183.
  • Tacey A, Qaradakhi T, Brennan-Speranza T, et al. Potential role for osteocalcin in the development of atherosclerosis and blood vessel disease. Nutrients. 2018;10(10):1426.
  • Tacey A, Millar S, Qaradakhi T, et al. Undercarboxylated osteocalcin has no adverse effect on endothelial function in rabbit aorta or human vascular cells. J Cell Physiol. 2021;236(4):2840–2849.
  • Eendebak RJAH, Ahern T, Swiecicka A, EMAS Group, et al. Elevated luteinizing hormone despite normal testosterone levels in older men-natural history, risk factors and clinical features. Clin Endocrinol (Oxf). 2018;88(3):479–490.
  • Chen W, Liu ZY, Wang LH, et al. Are the aging male's symptoms (AMS) scale and the androgen deficiency in the aging male (ADAM) questionnaire suitable for the screening of late-onset hypogonadism in aging Chinese men? Aging Male. 2013;16(3):92–96.
  • Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab. 1999;84(10):3666–3672.
  • Aiman J, Griffin JE, Gazak JM, et al. Androgen insensitivity as a cause of infertility in otherwise normal men. N Engl J Med. 1979;300(5):223–227.
  • Touboul PJ, Hennerici MG, Meairs S, et al. Mannheim carotid intima-media thickness consensus (2004–2006). an update on behalf of the advisory board of the 3rd and 4th watching the risk symposium, 13th and 15th European Stroke Conferences, Mannheim, Germany, 2004, and Brussels, Belgium, 2006. Cerebrovasc Dis. 2007;23(1):75–80.
  • Celermajer DS, Sorensen KE, Gooch VM, et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992;340(8828):1111–1115.
  • Stefanadis C, Dernellis J, Tsiamis E, et al. Aortic stiffness as a risk factor for recurrent acute coronary events in patients with ischaemic heart disease. Eur Heart J. 2000;21(5):390–396.
  • Rochira V, Carani C. Aromatase deficiency in men: a clinical perspective. Nat Rev Endocrinol. 2009;5(10):559–568.
  • Crabbe P, Bogaert V, De Bacquer D, et al. Part of the interindividual variation in serum testosterone levels in healthy men reflects differences in androgen sensitivity and feedback set point: contribution of the androgen receptor polyglutamine tract polymorphism. J Clin Endocrinol Metab. 2007;92(9):3604–3610.
  • Mulligan T, Iranmanesh A, Johnson ML, et al. Aging alters feed-forward and feedback linkages between LH and testosterone in healthy men. Am J Physiol. 1997;273(4):R1407–R1413.
  • McBride JA, Carson CC, Coward RM. Testosterone deficiency in the aging male. Ther Adv Urol. 2016;8(1):47–60.
  • Yang YY, Zheng SC, Wang WC, et al. Osteocalcin levels in male idiopathic hypogonadotropic hypogonadism: relationship with the testosterone secretion and metabolic profiles. Front Endocrinol. 2019;10:687.
  • Karsenty G, Oury F. Regulation of male fertility by the bone-derived hormone osteocalcin. Mol Cell Endocrinol. 2014;382(1):521–526.
  • Nah K, Jung S, Kim BT. Uncarboxyolated osteocalcin inversely correlated with total testosterone level in elderly man. Korean J Fam Pract. 2017;7(5):781–785.
  • Posielski N, Krieger J, Madison W, et al. Osteocalcin as a novel regulator of testosterone production: a bench to bedside study in rats and humans. J Urol. 2019;201(4S):e855 MP58–08.
  • De Toni L, Guidolin D, De Filippis V, et al. Osteocalcin and sex hormone binding globulin compete on a specific binding site of GPRC6A. Endocrinology. 2016;157(11):4473–4486.
  • Kanazawa I, Tanaka K, Ogawa N, et al. Undercarboxylated osteocalcin is positively associated with free testosterone in male patients with type 2 diabetes mellitus. Osteoporos Int. 2013;24(3):1115–1119.
  • Samavat J, Facchiano E, Cantini G, et al. Osteocalcin increase after bariatric surgery predicts androgen recovery in hypogonadal obese males. Int J Obes. 2014;38(3):357–363.
  • Zhong N, Xu B, Cui R, et al. Positive correlation between serum osteocalcin and testosterone in male hyperthyroidism patients with high bone turnover. Exp Clin Endocrinol Diabetes. 2016;124(07):452–456.
  • Schwetz V, Gumpold R, Graupp M, et al. Osteocalcin is not a strong determinant of serum testosterone and sperm count in men from infertile couples. Andrology. 2013;1(4):590–594.
  • Yeap BB, Alfonso H, Chubb SA, et al. Higher serum undercarboxylated osteocalcin and other bone turnover markers are associated with reduced diabetes risk and lower estradiol concentrations in older men. J Clin Endocrinol Metab. 2015;100(1):63–71.
  • Morley JE, Perry HM III, Kaiser FE, et al. Effects of testosterone replacement therapy in old hypogonadal males: a preliminary study. J Am Geriatr Soc. 1993;41(2):149–152.
  • Ghanim H, Dhindsa S, Green K, et al. Increase in osteocalcin following testosterone therapy in men with type 2 diabetes and subnormal free testosterone. J Endocr Soc. 2019;3(8):1617–1630.
  • Taxel P, Kennedy DG, Fall PM, et al. The effect of aromatase inhibition on sex steroids, gonadotropins, and markers of bone turnover in older men. J Clin Endocrinol Metab. 2001;86(6):2869–2874.
  • Leder BZ, Finkelstein JS. Effect of aromatase inhibition on bone metabolism in elderly hypogonadal men. Osteoporos Int. 2005;16(12):1487–1494.
  • Merlotti D, Gennari L, Stolakis K, et al. Aromatase activity and bone loss in men. J Osteoporos. 2011;2011:230671.
  • Holmboe SA, Vradi E, Jensen TK, et al. The association of reproductive hormone levels and all-cause, cancer, and cardiovascular disease mortality in Men. J Clin Endocrinol Metab. 2015;100(12):4472–4480.
  • Kelly DM, Jones TH. Testosterone and cardiovascular risk in men. Front Horm Res. 2014;43:1–20.
  • Thirumalai A, Rubinow KB, Page ST. An update on testosterone, HDL and cardiovascular risk in men. Clin Lipidol. 2015;10(3):251–258.
  • Mohler ER, Ellenberg SS, Lewis CE, et al. The effect of testosterone on cardiovascular biomarkers in the testosterone trials. J Clin Endocrinol Metab. 2018;103(2):681–688. [published correction appears in J Clin Endocrinol Metab. 2020;105(1)].
  • Whitsel EA, Boyko EJ, Matsumoto AM, et al. Intramuscular testosterone esters and plasma lipids in hypogonadal men: a meta-analysis. Am J Med. 2001;111(4):261–269.
  • Cai Z, Xi H, Pan Y, et al. Effect of testosterone deficiency on cholesterol metabolism in pigs fed a high-fat and high-cholesterol diet. Lipids Health Dis. 2015;14:18–20.
  • Isidori AM, Giannetta E, Greco EA, et al. Effects of testosterone on body composition, bone metabolism and serum lipid profile in Middle-aged men: a meta-analysis. Clin Endocrinol. 2005;63(3):280–293.
  • Haddad RM, Kennedy CC, Caples SM, et al. Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc. 2007;82(1):29–39.
  • Haring R, Xanthakis V, Coviello A, et al. Clinical correlates of sex steroids and gonadotropins in men over the late adulthood: the Framingham heart study. Int J Androl. 2012;35(6):775–782.
  • Adorni MP, Zimetti F, Cangiano B, et al. High-density lipoprotein function is reduced in patients affected by genetic or idiopathic hypogonadism. J Clin Endocrinol Metab. 2019;104(8):3097–3107.
  • Jones ME, Boon WC, Proietto J, et al. Of mice and men: the evolving phenotype of aromatase deficiency. Trends Endocrinol Metab. 2006;17(2):55–64.
  • Papageorgiou N, Briasoulis A, Androulakis E, et al. Imaging subclinical atherosclerosis: where do we stand? Curr Cardiol Rev. 2017;13(1):47–55.
  • Huhtaniemi I, Mäkinen JI, Perheentupa A, et al. Late-onset hypogonadism in men. Experience from the Turku male ageing study (TuMAS). Hormones. 2008;7(1):36–45. PMID: 18359743
  • Hsu B, Cumming RG, Naganathan V, et al. Temporal changes in androgens and estrogens are associated with all-cause and cause-specific mortality in older men. J Clin Endocrinol Metab. 2016;101(5):2201–2210.
  • Toth P, Li X, Rao CV, et al. Expression of functional human chorionic gonadotropin/human luteinizing hormone receptor gene in human uterine arteries. J Clin Endocrinol Metab. 1994;79(1):307–315.
  • Berndt S, Perrier d'Hauterive S, Blacher S, et al. Angiogenic activity of human chorionic gonadotropin through LH receptor activation on endothelial and epithelial cells of the endometrium. Faseb J. 2006;20(14):2630–2263.
  • Lu M, Yang CB, Gao L, et al. Mechanism of subclinical hypothyroidism accelerating endothelial dysfunction (review). Exp Ther Med. 2015;9(1):3–10.
  • Empen K, Lorbeer R, Dörr M, et al. Association of testosterone levels with endothelial function in men: results from a population-based study. Arterioscler Thromb Vasc Biol. 2012;32(2):481–486.
  • Stanhewicz AE, Wenner MM, Stachenfeld NS. Sex differences in endothelial function important to vascular health and overall cardiovascular disease risk across the lifespan. Am J Physiol Heart Circ Physiol. 2018;315(6):H1569–H1588.
  • Fukui M, Kitagawa Y, Kamiuchi K, et al. Association between serum estradiol concentrations and carotid atherosclerosis in men with type 2 diabetes mellitus. Metabolism. 2008;57(2):285–289.
  • Brand JS, den Ouden ME, Schuurmans MJ, et al. Endogenous sex hormones and subclinical atherosclerosis in middle-aged and older men. Int J Cardiol. 2013;168(1):574–576.
  • Chan YX, Knuiman MW, Hung J, et al. Testosterone, dihydrotestosterone and estradiol are differentially associated with carotid intima-media thickness and the presence of carotid plaque in men with and without coronary artery disease. Endocr J. 2015;62(9):777–786.
  • Stelmaszewska J, Chrusciel M, Doroszko M, et al. Revisiting the expression and function of follicle-stimulation hormone receptor in human umbilical vein endothelial cells. Sci Rep. 2016;6:37095.
  • Melloni C, Roe MT. Androgen deprivation therapy and cardiovascular disease. Urol Oncol. 2020;38(2):45–52.
  • Wallace IR, McKinley MC, Bell PM, et al. Sex hormone binding globulin and insulin resistance. Clin Endocrinol. 2013;78(3):321–329.
  • Yeap BB, Marriott RJ, Antonio L, et al. Serum testosterone is inversely and sex hormone-binding globulin is directly associated with all-cause mortality in men. JCEM. 2021;106(2):e625–e637.
  • Gyawali P, Martin SA, Heilbronn LK, et al. Cross-sectional and longitudinal determinants of serum sex hormone binding globulin (SHBG) in a cohort of community-dwelling men. PLoS One. 2018;13(7):e0200078.
  • Mathews L, Subramanya V, Zhao D, et al. Endogenous sex hormones and endothelial function in postmenopausal women and men: the multi-ethnic study of atherosclerosis. J Womens Health. 2019;28(7):900–909.
  • Prats-Puig A, Osiniri I, Soriano-Rodriguez P, et al. Undercarboxylated osteocalcin relates to cardiovascular risk markers in offspring of families with metabolic syndrome. Atherosclerosis. 2014;233(1):272–277. atherosclerosis.2014.01.002
  • Zhang M, Ni Z, Zhou W, et al. Undercarboxylated osteocalcin as a biomarker of subclinical atherosclerosis in non-dialysis patients with chronic kidney disease. J Biomed Sci. 2015;22:75.
  • Tacey A, Smith C, Woessner MN, et al. Undercarboxylated osteocalcin is associated with vascular function in female older adults but does not influence vascular function in male rabbit carotid artery ex vivo. PLoS One. 2020;15(11):e0242774.
  • Choi BH, Joo NS, Kim MJ, et al. Coronary artery calcification is associated with high serum concentration of undercarboxylated osteocalcin in asymptomatic Korean men. Clin Endocrinol. 2015;83(3):320–326.
  • Smith C, Voisin S, Al Saedi A, et al. Osteocalcin and its forms across the lifespan in adult men. Bone. 2020;130:115085.
  • Kanazawa I, Yamaguchi T, Sugimoto T. Relationship between bone biochemical markers versus glucose/lipid metabolism and atherosclerosis; a longitudinal study in type 2 diabetes mellitus. Diabetes Res Clin Pract. 2011;92(3):393–399.
  • Dhore CR, Cleutjens JP, Lutgens E, et al. Differential expression of bone matrix regulatory proteins in human atherosclerotic plaques. Arterioscler Thromb Vasc Biol. 2001;21(12):1998–2003.
  • Foresta C, De Toni L, Selice R, et al. Increased osteocalcin-positive endothelial progenitor cells in hypogonadal male patients. J Endocrinol Invest. 2010;33(7):439–442.