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Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Cardiovascular Complications in Patients with Klinefelter’s Syndrome

Author(s): Franz Sesti , Riccardo Pofi , Carlotta Pozza, Marianna Minnetti , Daniele Gianfrilli and George A. Kanakis *

Volume 26 , Issue 43 , 2020

Page: [5556 - 5563] Pages: 8

DOI: 10.2174/1381612826666201102105408

Price: $65

Abstract

More than 70 years have passed since the first description of Klinefelter Syndrome (KS), the most frequent chromosome disorder causing male infertility and hypogonadism. KS is associated with increased cardiovascular (CV) mortality due to several comorbidities, including hypogonadism, as well as metabolic syndrome and type 2 diabetes, which are highly prevalent in these patients. Aside from metabolic disturbances, patients with KS suffer from both acquired and congenital CV abnormalities, cerebrovascular thromboembolic disease, subclinical atherosclerosis and endothelial dysfunction, which may all contribute to increased CV mortality. The mechanisms involved in this increased risk of CV morbidity and mortality are not entirely understood. More research is needed to better characterise the CV manifestations, elucidate the pathophysiological mechanisms and define the contribution of testosterone replacement to restoring CV health in KS patients. This review explores the complex association between KS, metabolic syndrome and CV risk in order to plan future studies and improve strategies to reduce mortality in this high-risk population.

Keywords: Klinefelter syndrome, cardiovascular diseases, hypogonadism, cardiac abnormalities, metabolic syndrome, cardiovascular risk, thromboembolic disease.

[1]
Jacobs PA, Strong JA. A case of human intersexuality having a possible XXY sex-determining mechanism. Nature 1959; 183(4657): 302-3.
[http://dx.doi.org/10.1038/183302a0] [PMID: 13632697]
[2]
Morris JK, Alberman E, Scott C, Jacobs P. Is the prevalence of Klinefelter syndrome increasing? Eur J Hum Genet 2008; 16(2): 163-70.
[http://dx.doi.org/10.1038/sj.ejhg.5201956] [PMID: 18000523]
[3]
Bojesen A, Juul S, Gravholt CH. Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study. J Clin Endocrinol Metab 2003; 88(2): 622-6.
[http://dx.doi.org/10.1210/jc.2002-021491] [PMID: 12574191]
[4]
Kanakis GA, Nieschlag E. Klinefelter syndrome: more than hypogonadism. Metabolism 2018; 86: 135-44.
[http://dx.doi.org/10.1016/j.metabol.2017.09.017] [PMID: 29382506]
[5]
Bonomi M, Rochira V, Pasquali D, et al. Klinefelter syndrome (KS): genetics, clinical phenotype and hypogonadism. J Endocrinol Invest 2017; 40(2): 123-34.
[http://dx.doi.org/10.1007/s40618-016-0541-6] [PMID: 27644703]
[6]
Vincent MC, Daudin M, De MP, et al. Cytogenetic investigations of infertile men with low sperm counts: a 25-year experience. J Androl 2002; 23(1): 18-22.
[http://dx.doi.org/10.1002/j.1939-4640.2002.tb02597.x] [PMID: 11780918]
[7]
Van Assche E, Bonduelle M, Tournaye H, et al. Cytogenetics of infertile men. Hum Reprod 1996; 11(Suppl. 4): 1-24.
[http://dx.doi.org/10.1093/humrep/11.suppl_4.1] [PMID: 9147109]
[8]
Bojesen A, Gravholt CH. Morbidity and mortality in Klinefelter syndrome (47,XXY). Acta Paediatr 2011; 100(6): 807-13.
[http://dx.doi.org/10.1111/j.1651-2227.2011.02274.x] [PMID: 21414026]
[9]
Di Minno MN, Esposito D, Di Minno A, et al. Increased platelet reactivity in Klinefelter men: something new to consider. Andrology 2015; 3(5): 876-81.
[http://dx.doi.org/10.1111/andr.12080] [PMID: 26216452]
[10]
Bojesen A, Juul S, Birkebaek N, Gravholt CH. Increased mortality in Klinefelter syndrome. J Clin Endocrinol Metab 2004; 89(8): 3830-4.
[http://dx.doi.org/10.1210/jc.2004-0777] [PMID: 15292313]
[11]
Swerdlow AJ, Higgins CD, Schoemaker MJ, Wright AF, Jacobs PA. Mortality in patients with Klinefelter syndrome in Britain: a cohort study. J Clin Endocrinol Metab 2005; 90(12): 6516-22.
[http://dx.doi.org/10.1210/jc.2005-1077] [PMID: 16204366]
[12]
Bojesen A, Juul S, Birkebaek NH, Gravholt CH. Morbidity in Klinefelter syndrome: a Danish register study based on hospital discharge diagnoses. J Clin Endocrinol Metab 2006; 91(4): 1254-60.
[http://dx.doi.org/10.1210/jc.2005-0697] [PMID: 16394093]
[13]
Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001; 24(4): 683-9.
[http://dx.doi.org/10.2337/diacare.24.4.683] [PMID: 11315831]
[14]
Ford ES. Risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome: a summary of the evidence. Diabetes Care 2005; 28(7): 1769-78.
[http://dx.doi.org/10.2337/diacare.28.7.1769] [PMID: 15983333]
[15]
Bojesen A, Kristensen K, Birkebaek NH, et al. The metabolic syndrome is frequent in Klinefelter’s syndrome and is associated with abdominal obesity and hypogonadism. Diabetes Care 2006; 29(7): 1591-8.
[http://dx.doi.org/10.2337/dc06-0145] [PMID: 16801584]
[16]
Ishikawa T, Yamaguchi K, Kondo Y, Takenaka A, Fujisawa M. Metabolic syndrome in men with Klinefelter’s syndrome. Urology 2008; 71(6): 1109-13.
[http://dx.doi.org/10.1016/j.urology.2008.01.051] [PMID: 18455766]
[17]
Jiang-Feng M, Hong-Li X, Xue-Yan W, et al. Prevalence and risk factors of diabetes in patients with Klinefelter syndrome: a longitudinal observational study. Fertil Steril 2012; 98(5): 1331-5.
[http://dx.doi.org/10.1016/j.fertnstert.2012.07.1122] [PMID: 22940087]
[18]
Pasquali D, Arcopinto M, Renzullo A, et al. Cardiovascular abnormalities in Klinefelter syndrome. Int J Cardiol 2013; 168(2): 754-9.
[http://dx.doi.org/10.1016/j.ijcard.2012.09.215] [PMID: 23092857]
[19]
Bardsley MZ, Falkner B, Kowal K, Ross JL. Insulin resistance and metabolic syndrome in prepubertal boys with Klinefelter syndrome. Acta Paediatr 2011; 100(6): 866-70.
[http://dx.doi.org/10.1111/j.1651-2227.2011.02161.x] [PMID: 21251059]
[20]
Davis S, Lahlou N, Bardsley M, et al. Gonadal function is associated with cardiometabolic health in pre-pubertal boys with Klinefelter syndrome. Andrology 2016; 4(6): 1169-77.
[http://dx.doi.org/10.1111/andr.12275
] [PMID: 27637014]
[21]
Davis SM, Cox-Martin MG, Bardsley MZ, Kowal K, Zeitler PS, Ross JL. Effects of Oxandrolone on Cardiometabolic Health in Boys With Klinefelter Syndrome: A Randomized Controlled Trial. J Clin Endocrinol Metab 2017; 102(1): 176-84.
[PMID: 27802097]
[22]
Strain WD, Paldánius PM. Diabetes, cardiovascular disease and the microcirculation. Cardiovasc Diabetol 2018; 17(1): 57.
[http://dx.doi.org/10.1186/s12933-018-0703-2] [PMID: 29669543]
[23]
Langeron L, Lamelin P, Routier G. Klinefelter syndrome and diabetes. J Sci Med Lille 1958; 76(11): 440-4.
[PMID: 13611784]
[24]
Salzano A, D’Assante R, Heaney LM, et al. Klinefelter syndrome, insulin resistance, metabolic syndrome, and diabetes: review of literature and clinical perspectives. Endocrine 2018; 61(2): 194-203.
[http://dx.doi.org/10.1007/s12020-018-1584-6] [PMID: 29572708]
[25]
Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009; 120(16): 1640-5.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.109.192644] [PMID: 19805654]
[26]
Lindberg S, Jensen JS, Bjerre M, et al. Adiponectin, type 2 diabetes and cardiovascular risk. Eur J Prev Cardiol 2015; 22(3): 276-83.
[http://dx.doi.org/10.1177/2047487313514894
] [PMID: 24265290]
[27]
Nishizawa H, Shimomura I, Kishida K, et al. Androgens decrease plasma adiponectin, an insulin-sensitizing adipocyte-derived protein. Diabetes 2002; 51(9): 2734-41.
[http://dx.doi.org/10.2337/diabetes.51.9.2734
] [PMID: 12196466]
[28]
Díez JJ, Iglesias P. The role of the novel adipocyte-derived hormone adiponectin in human disease. Eur J Endocrinol 2003; 148(3): 293-300.
[http://dx.doi.org/10.1530/eje.0.1480293] [PMID: 12611609]
[29]
Bojesen A, Høst C, Gravholt CH. Klinefelter’s syndrome, type 2 diabetes and the metabolic syndrome: the impact of body composition. Mol Hum Reprod 2010; 16(6): 396-401.
[http://dx.doi.org/10.1093/molehr/gaq016] [PMID: 20231162]
[30]
Haider A, Saad F, Doros G, Gooren L. Hypogonadal obese men with and without diabetes mellitus type 2 lose weight and show improvement in cardiovascular risk factors when treated with testosterone: an observational study. Obes Res Clin Pract 2014; 8(4): e339-49.
[http://dx.doi.org/10.1016/j.orcp.2013.10.005] [PMID: 25091355]
[31]
Corona G, Giagulli VA, Maseroli E, et al. Testosterone supplementation and body composition: results from a meta-analysis of observational studies. J Endocrinol Invest 2016; 39(9): 967-81.
[http://dx.doi.org/10.1007/s40618-016-0480-2] [PMID: 27241317]
[32]
Corona G, Vignozzi L, Sforza A, Maggi M. Risks and benefits of late onset hypogonadism treatment: an expert opinion. World J Mens Health 2013; 31(2): 103-25.
[http://dx.doi.org/10.5534/wjmh.2013.31.2.103] [PMID: 24044106]
[33]
Goodale T, Sadhu A, Petak S, Robbins R. Testosterone and the Heart. Methodist DeBakey Cardiovasc J 2017; 13(2): 68-72.
[http://dx.doi.org/10.14797/mdcj-13-2-68] [PMID: 28740585]
[34]
Høst C, Bojesen A, Erlandsen M, et al. A placebo-controlled randomized study with testosterone in Klinefelter syndrome: beneficial effects on body composition. Endocr Connect 2019; 8(9): 1250-61.
[http://dx.doi.org/10.1530/EC-19-0323] [PMID: 31394497]
[35]
Pizzocaro A, Vena W, Condorelli R, et al. Testosterone treatment in male patients with Klinefelter syndrome: a systematic review and meta-analysis J Endocrinol Invest 2020; 43(12): 1675-87.
[36]
Adatia I, Coe JY, Harder J. Transposition of the great arteries in a neonate with Klinefelter’s syndrome. Pediatr Cardiol 1987; 8(4): 285-6.
[http://dx.doi.org/10.1007/BF02427544] [PMID: 3432120]
[37]
Liu J, Moulick A, Mesia CI, Ge S, Obiri N, Anderson CE. Transposition of the great arteries in a neonate with Klinefelter syndrome-an incidental finding or a true association. Am J Med Genet A 2015; 167A(1): 268-70.
[http://dx.doi.org/10.1002/ajmg.a.36814] [PMID: 25339114]
[38]
Velagaleti GV, Kumar A, Lockhart LH, Matalon R. Patent ductus arteriosus and microdeletion 22q11 in a patient with Klinefelter syndrome. Ann Genet 2000; 43(2): 105-7.
[http://dx.doi.org/10.1016/S0003-3995(00)01013-3] [PMID: 10998453]
[39]
Zhang Y. Congenital defect of the partial atrioventricular canal with Klinefelter syndrome. BMJ Case Rep 2009; 2009: bcr10.2008.1121.
[http://dx.doi.org/10.1136/bcr.10.2008.1121]
[40]
Gautier M, Nouaille J. Systematic study of the Barr body in 500 infants with severe congenital heart diseases. Arch Fr Pediatr 1967; 24(1): 109.
[PMID: 6031448]
[41]
Yoshida K, Ryu T, Ogata T, et al. An elderly man with Klinefelter syndrome associated with hypertrophic cardiomyopathy, sick sinus syndrome, and coronary arteriovenous fistula. Jpn Circ J 1998; 62(3): 222-4.
[http://dx.doi.org/10.1253/jcj.62.222] [PMID: 9583452]
[42]
Agarwal S, Dekam MJ. Multiple cardiac anomalies in an elderly man with Klinefelter’s syndrome. Singapore Med J 2011; 52(1): e15-7.
[PMID: 21298229]
[43]
Peet J, Weaver DD, Vance GH. 49,XXXXY: a distinct phenotype. Three new cases and review. J Med Genet 1998; 35(5): 420-4.
[http://dx.doi.org/10.1136/jmg.35.5.420] [PMID: 9610808]
[44]
Hou JW. 49, XXXXY syndrome. Chang Gung Med J 2004; 27(7): 551-4.
[PMID: 15508879]
[45]
Shen Z, Zou CC, Shang SQ, Jiang KW. Down-Klinefelter syndrome (48,XXY,+21) in a child with congenital heart disease: case report and literature review. Intern Med 2012; 51(11): 1371-4.
[http://dx.doi.org/10.2169/internalmedicine.51.7097] [PMID: 22687844]
[46]
Hustinx TW, Eberle P, Geerts SJ, Woltring LM. Mongoloid twins with 48 chromosomes (AA plus A21XXY). Ann Hum Genet 1961; 25: 111-5.
[http://dx.doi.org/10.1111/j.1469-1809.1961.tb01507.x] [PMID: 14450218]
[47]
Serra W, De Iaco G, Reverberi C, Gherli T. Pulmonary embolism and patent foramen ovale thrombosis: the key role of TEE. Cardiovasc Ultrasound 2007; 5: 26.
[http://dx.doi.org/10.1186/1476-7120-5-26
] [PMID: 17718903]
[48]
Hecht F, Nievaard JE, Duncanson N, et al. Double aneuploidy: the frequency of XXY in males with Down’s syndrome. Am J Hum Genet 1969; 21(4): 352-9.
[PMID: 4240108]
[49]
Erdtmann B, de Freitas AA, de Souza RP, Salzano FM. Klinefelter’s syndrome and G trisomy. J Med Genet 1971; 8(3): 364-8.
[http://dx.doi.org/10.1136/jmg.8.3.364
] [PMID: 5097144]
[50]
Akbas E, Soylemez F, Savasoglu K, Halliogluand O, Balci S. A male case with double aneuploidy (48,XXY,+21). Genet Couns 2008; 19(1): 59-63.
[PMID: 18564502]
[51]
Gerretsen MF, Peelen W, Rammeloo LA, Koolbergen DR, Hruda J. Double aortic arch with double aneuploidy--rare anomaly in combined Down and Klinefelter syndrome. Eur J Pediatr 2009; 168(12): 1479-81.
[http://dx.doi.org/10.1007/s00431-009-0958-4] [PMID: 19263078]
[52]
Jeanty C, Turner C. Prenatal diagnosis of double aneuploidy, 48,XXY,+21, and review of the literature. J Ultrasound Med 2009; 28(5): 673-81.
[http://dx.doi.org/10.7863/jum.2009.28.5.673] [PMID: 19389908]
[53]
Said SA, Bucx JJ, van de Weel FA. Coronary-cameral fistula in association with Klinefelter syndrome: exercise-induced ventricular tachycardia late after surgical ligation. Int J Cardiol 1992; 36(1): 111-4.
[http://dx.doi.org/10.1016/0167-5273(92)90117-L] [PMID: 1428242]
[54]
Rodrigues MA, Morgade LF, Dias LFA, et al. Down-Klinefelter syndrome (48,XXY,+21) in a neonate associated with congenital heart disease. Genet Mol Res 2017; 16(3): 16.
[http://dx.doi.org/10.4238/gmr16039780] [PMID: 28973759]
[55]
Fricke GR, Mattern HJ, Schweikert HU, Schwanitz G. Klinefelter’s syndrome and mitral valve prolapse. an echocardiographic study in twenty-two patients. Biomed Pharmacother 1984; 38(2): 88-97.
[PMID: 6743777]
[56]
Fricke GR, Mattern HJ, Schweikert HU. Mitral valve prolapse in Klinefelter syndrome. Lancet 1981; 2(8260-61): 1414.
[http://dx.doi.org/10.1016/S0140-6736(81)92821-X] [PMID: 6118776]
[57]
Katsumata T, Tomizawa Y, Okoshi T, et al. A case of Klinefelter’s syndrome with acute mitral regurgitation caused by idiopathic chordal rupture. Kyobu Geka 1991; 44(10): 867-70.
[PMID: 1921008]
[58]
Andersen NH, Bojesen A, Kristensen K, et al. Left ventricular dysfunction in Klinefelter syndrome is associated to insulin resistance, abdominal adiposity and hypogonadism. Clin Endocrinol (Oxf) 2008; 69(5): 785-91.
[http://dx.doi.org/10.1111/j.1365-2265.2008.03211.x] [PMID: 18248650]
[59]
Brubaker PH, Kitzman DW. Chronotropic incompetence: causes, consequences, and management. Circulation 2011; 123(9): 1010-20.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.110.940577] [PMID: 21382903]
[60]
Jørgensen IN, Skakkebaek A, Andersen NH, et al. Short QTc interval in males with klinefelter syndrome-influence of CAG repeat length, body composition, and testosterone replacement therapy. Pacing Clin Electrophysiol 2015; 38(4): 472-82.
[http://dx.doi.org/10.1111/pace.12580] [PMID: 25615644]
[61]
Zitzmann M, Bongers R, Werler S, et al. Gene expression patterns in relation to the clinical phenotype in Klinefelter syndrome. J Clin Endocrinol Metab 2015; 100(3): E518-23.
[http://dx.doi.org/10.1210/jc.2014-2780] [PMID: 25532039]
[62]
O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK Jr. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. N Engl J Med 1999; 340(1): 14-22.
[http://dx.doi.org/10.1056/NEJM199901073400103] [PMID: 9878640]
[63]
Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation 2007; 115(4): 459-67.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.106.628875] [PMID: 17242284]
[64]
Maruhashi T, Iwamoto Y, Kajikawa M, et al. Interrelationships Among Flow-Mediated Vasodilation, Nitroglycerine-Induced Vasodilation, Baseline Brachial Artery Diameter, Hyperemic Shear Stress, and Cardiovascular Risk Factors. J Am Heart Assoc 2017; 7(1): 7.
[PMID: 29288158]
[65]
Maruhashi T, Kajikawa M, Kishimoto S, et al. Diagnostic Criteria of Flow-Mediated Vasodilation for Normal Endothelial Function and Nitroglycerin-Induced Vasodilation for Normal Vascular Smooth Muscle Function of the Brachial Artery. J Am Heart Assoc 2020; 9(2): e013915.
[http://dx.doi.org/10.1161/JAHA.119.013915] [PMID: 31910779]
[66]
Foresta C, Caretta N, Palego P, et al. Reduced artery diameters in Klinefelter syndrome. Int J Androl 2012; 35(5): 720-5.
[http://dx.doi.org/10.1111/j.1365-2605.2012.01269.x] [PMID: 22489599]
[67]
Badimon L, Peña E, Arderiu G, et al. C-Reactive Protein in Atherothrombosis and Angiogenesis. Front Immunol 2018; 9: 430.
[http://dx.doi.org/10.3389/fimmu.2018.00430] [PMID: 29552019]
[68]
Kaptoge S, Di Angelantonio E, Pennells L, et al. C-reactive protein, fibrinogen, and cardiovascular disease prediction. N Engl J Med 2012; 367(14): 1310-20.
[http://dx.doi.org/10.1056/NEJMoa1107477] [PMID: 23034020]
[69]
Vasa M, Fichtlscherer S, Aicher A, et al. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res 2001; 89(1): E1-7.
[http://dx.doi.org/10.1161/hh1301.093953
] [PMID: 11440984]
[70]
Schmidt-Lucke C, Rössig L, Fichtlscherer S, et al. Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events: proof of concept for the clinical importance of endogenous vascular repair. Circulation 2005; 111(22): 2981-7.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.104.504340] [PMID: 15927972]
[71]
Di Mambro A, Ferlin A, De Toni L, Selice R, Caretta N, Foresta C. Endothelial progenitor cells as a new cardiovascular risk factor in Klinefelter’s syndrome. Mol Hum Reprod 2010; 16(6): 411-7.
[http://dx.doi.org/10.1093/molehr/gaq015
] [PMID: 20228052]
[72]
Ru BZ, Gao XC, Yue WW, Hu P. Testosterone level not significantly correlates to endothelial progenitor cells in Klinefelter’s syndrome patients. Zhonghua Nan Ke Xue 2012; 18(1): 67-9.
[PMID: 22295853]
[73]
Campbell WA, Price WH. Venous thromboembolic disease in Klinefelter’s syndrome. Clin Genet 1981; 19(4): 275-80.
[http://dx.doi.org/10.1111/j.1399-0004.1981.tb00709.x] [PMID: 7273469]
[74]
Zöller B, Ji J, Sundquist J, Sundquist K. High Risk of Venous Thromboembolism in Klinefelter Syndrome. J Am Heart Assoc 2016; 5(5): 5.
[http://dx.doi.org/10.1161/JAHA.116.003567] [PMID: 27208002]
[75]
Chang S, Christiansen CF, Bojesen A, Juul S, Münster AB, Gravholt CH. Klinefelter syndrome and testosterone treatment: a national cohort study on thrombosis risk. Endocr Connect 2020; 9(1): 34-43.
[http://dx.doi.org/10.1530/EC-19-0433] [PMID: 31829966]
[76]
Salzano A, Arcopinto M, Marra AM, et al. Klinefelter syndrome, cardiovascular system, and thromboembolic disease: review of literature and clinical perspectives. Eur J Endocrinol 2016; 175(1): R27-40.
[http://dx.doi.org/10.1530/EJE-15-1025
] [PMID: 26850445]
[77]
Forti G, Corona G, Vignozzi L, Krausz C, Maggi M. Klinefelter’s syndrome: a clinical and therapeutical update. Sex Dev 2010; 4(4-5): 249-58.
[http://dx.doi.org/10.1159/000316604] [PMID: 20664188]
[78]
Corona G, Rastrelli G, Di Pasquale G, Sforza A, Mannucci E, Maggi M. Endogenous Testosterone Levels and Cardiovascular Risk: Meta-Analysis of Observational Studies. J Sex Med 2018; 15(9): 1260-71.
[http://dx.doi.org/10.1016/j.jsxm.2018.06.012] [PMID: 30145097]
[79]
Isidori AM, Giannetta E, Gianfrilli D, et al. Effects of testosterone on sexual function in men: results of a meta-analysis. Clin Endocrinol (Oxf) 2005; 63(4): 381-94.
[http://dx.doi.org/10.1111/j.1365-2265.2005.02350.x] [PMID: 16181230]
[80]
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 (Oxf) 2005; 63(3): 280-93.
[http://dx.doi.org/10.1111/j.1365-2265.2005.02339.x] [PMID: 16117815]
[81]
Radicioni AF, Ferlin A, Balercia G, et al. Consensus statement on diagnosis and clinical management of Klinefelter syndrome. J Endocrinol Invest 2010; 33(11): 839-50.
[http://dx.doi.org/10.1007/BF03350351] [PMID: 21293172]
[82]
Radicioni AF, De Marco E, Gianfrilli D, et al. Strategies and advantages of early diagnosis in Klinefelter’s syndrome. Mol Hum Reprod 2010; 16(6): 434-40.
[http://dx.doi.org/10.1093/molehr/gaq027] [PMID: 20392711]

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