Skip to main content

Klinefelter syndrome, insulin resistance, metabolic syndrome, and diabetes: review of literature and clinical perspectives



Klinefelter syndrome (KS), the most frequent chromosomic abnormality in males, is associated with hypergonadotropic hypogonadism and an increased risk of cardiovascular diseases (CVD). The mechanisms involved in increasing risk of cardiovascular morbidity and mortality are not completely understood. This review summarises the current understandings of the complex relationship between KS, metabolic syndrome and cardiovascular risk in order to plan future studies and improve current strategies to reduce mortality in this high-risk population.


We searched PubMed, Web of Science, and Scopus for manuscripts published prior to November 2017 using key words "Klinefelter syndrome" AND "insulin resistance" OR "metabolic syndrome" OR "diabetes mellitus" OR "cardiovascular disease" OR "testosterone". Manuscripts were collated, studied and carried forward for discussion where appropriate.


Insulin resistance, metabolic syndrome, and type 2 diabetes are more frequently diagnosed in KS than in the general population; however, the contribution of hypogonadism to metabolic derangement is highly controversial. Whether this dangerous combination of risk factors fully explains the CVD burden of KS patients remains unclear. In addition, testosterone replacement therapy only exerts a marginal action on the CVD system.


Since fat accumulation and distribution seem to play a relevant role in triggering metabolic abnormalities, an early diagnosis and a tailored intervention strategy with drugs aimed at targeting excessive visceral fat deposition appear necessary in patients with KS.

This is a preview of subscription content, access via your institution.

Fig. 1


  1. 1.

    H.F. Klinefelter, E.C. Reifenstein, F. Albright, Syndrome characterized by gynaecomastia, aspermatogenesis without a-Leydigism, and increased excretion of follicle stimulating hormone. J. Clin. Endocrinol. 2(11), 615–627 (1942)

    Article  CAS  Google Scholar 

  2. 2.

    J.K. Morris, E. Alberman, C. Scott, P. Jacobs, Is the prevalence of Klinefelter syndrome increasing? Eur. J. Hum. Genet. 16(2), 163–170 (2008).

    Article  PubMed  CAS  Google Scholar 

  3. 3.

    A. Bojesen, S. Juul, C.H. Gravholt, Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study. J. Clin. Endocrinol. Metab. 88(2), 622–626 (2003).

    Article  PubMed  CAS  Google Scholar 

  4. 4.

    G. Forti, G. Corona, L. Vignozzi, C. Krausz, M. Maggi, Klinefelter’s syndrome: a clinical and therapeutical update. Sex Dev. 4(4-5), 249–258 (2010).

    Article  PubMed  CAS  Google Scholar 

  5. 5.

    A. Ropke, F. Tuttelmann, Mechanisms in endocrinology: aberrations of the X chromosome as cause of male infertility. Eur. J. Endocrinol. 177(5), R249–R259 (2017).

    Article  PubMed  Google Scholar 

  6. 6.

    E.V. Albuquerque, R.C. Scalco, A.A. Jorge, Management of endocrine disease: diagnostic and therapeutic approach of tall stature. Eur. J. Endocrinol. 176(6), R339–R353 (2017).

    Article  PubMed  CAS  Google Scholar 

  7. 7.

    A. Sansone, F. Romanelli, M. Sansone, A. Lenzi, L. Di Luigi, Gynecomastia and hormones. Endocrine 55(1), 37–44 (2017).

    Article  PubMed  CAS  Google Scholar 

  8. 8.

    J. Rohayem, A. Luberto, E. Nieschlag, M. Zitzmann, S. Kliesch, Delayed treatment of undescended testes may promote hypogonadism and infertility. Endocrine 55(3), 914–924 (2017).

    Article  PubMed  CAS  Google Scholar 

  9. 9.

    A. Sansone, F. Romanelli, D. Gianfrilli, A. Lenzi, Endocrine evaluation of erectile dysfunction. Endocrine 46(3), 423–430 (2014).

    Article  PubMed  CAS  Google Scholar 

  10. 10.

    A.F. Radicioni, E. De Marco, D. Gianfrilli, S. Granato, L. Gandini, A.M. Isidori, A. Lenzi, Strategies and advantages of early diagnosis in Klinefelter’s syndrome. Mol. Hum. Reprod. 16(6), 434–440 (2010).

    Article  PubMed  CAS  Google Scholar 

  11. 11.

    F. Lanfranco, A. Kamischke, M. Zitzmann, E. Nieschlag, Klinefelter’s syndrome. Lancet 364(9430), 273–283 (2004).

    Article  PubMed  CAS  Google Scholar 

  12. 12.

    D. Liberato, S. Granato, D. Grimaldi, F.M. Rossi, N. Tahani, D. Gianfrilli, A. Anzuini, A. Lenzi, G. Cavaggioni, A.F. Radicioni, Fluid intelligence, traits of personality and personality disorders in a cohort of adult KS patients with the classic 47, XXY karyotype. J. Endocrinol. Invest. 40(11), 1191–1199 (2017).

    Article  PubMed  CAS  Google Scholar 

  13. 13.

    A. Bojesen, S. Juul, N.H. Birkebaek, C.H. Gravholt, Morbidity in Klinefelter syndrome: a Danish register study based on hospital discharge diagnoses. J. Clin. Endocrinol. Metab. 91(4), 1254–1260 (2006).

    Article  PubMed  CAS  Google Scholar 

  14. 14.

    A. Bojesen, S. Juul, N. Birkebaek, C.H. Gravholt, Increased mortality in Klinefelter syndrome. J. Clin. Endocrinol. Metab. 89(8), 3830–3834 (2004).

    Article  PubMed  CAS  Google Scholar 

  15. 15.

    A.J. Swerdlow, C.D. Higgins, M.J. Schoemaker, A.F. Wright, P.A. Jacobs, G.United Kingdom Clinical Cytogenetics, Mortality in patients with Klinefelter syndrome in Britain: a cohort study. J. Clin. Endocrinol. Metab. 90(12), 6516–6522 (2005).

    Article  PubMed  CAS  Google Scholar 

  16. 16.

    A. Bojesen, C.H. Gravholt, Morbidity and mortality in Klinefelter syndrome (47,XXY). Acta Paediatr. 100(6), 807–813 (2011).

    Article  PubMed  Google Scholar 

  17. 17.

    W.H. Price, J.F. Clayton, S. Collyer, R. de Mey, Mortality ratios and life expectancy in X chromatin positive males. J. Epidemiol. Community Health 39(1), 33–38 (1985)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. 18.

    A. Salzano, M. Arcopinto, A.M. Marra, E. Bobbio, D. Esposito, G. Accardo, F. Giallauria, E. Bossone, C. Vigorito, A. Lenzi, D. Pasquali, A.M. Isidori, A. Cittadini, Klinefelter syndrome, cardiovascular system, and thromboembolic disease: review of literature and clinical perspectives. Eur. J. Endocrinol. 175(1), R27–R40 (2016).

    PubMed  CAS  Article  Google Scholar 

  19. 19.

    A.E. Calogero, V.A. Giagulli, L.M. Mongioi, V. Triggiani, A.F. Radicioni, E.A. Jannini, D. Pasquali, N.G. Klinefelter Italia, Klinefelter syndrome: cardiovascular abnormalities and metabolic disorders. J. Endocrinol. Invest. 40(7), 705–712 (2017).

    Article  PubMed  CAS  Google Scholar 

  20. 20.

    National Cholesterol Education Program Expert Panel on Detection, E., Treatment of High Blood Cholesterol in, A., Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 106(25), 3143–3421 (2002)

    Article  Google Scholar 

  21. 21.

    E.S. Ford, Prevalence of the metabolic syndrome defined by the International Diabetes Federation among adults in the U.S. Diabetes Care 28(11), 2745–2749 (2005)

    Article  PubMed  Google Scholar 

  22. 22.

    K.G. Alberti, R.H. Eckel, S.M. Grundy, P.Z. Zimmet, J.I. Cleeman, K.A. Donato, J.C. Fruchart, W.P. James, C.M. Loria, S.C. Smith Jr.; International Diabetes Federation Task Force on, E., Prevention, L. Hational Heart, I. Blood; American Heart, A., World Heart, F., International Atherosclerosis, S., International Association for the Study of, O., 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 120(16), 1640–1645 (2009).

    Article  PubMed  CAS  Google Scholar 

  23. 23.

    S.D. de Ferranti, K. Gauvreau, D.S. Ludwig, E.J. Neufeld, J.W. Newburger, N. Rifai, Prevalence of the metabolic syndrome in American adolescents: findings from the Third National Health and Nutrition Examination Survey. Circulation 110(16), 2494–2497 (2004).

    Article  PubMed  Google Scholar 

  24. 24.

    A. Bojesen, K. Kristensen, N.H. Birkebaek, J. Fedder, L. Mosekilde, P. Bennett, P. Laurberg, J. Frystyk, A. Flyvbjerg, J.S. Christiansen, C.H. Gravholt, The metabolic syndrome is frequent in Klinefelter’s syndrome and is associated with abdominal obesity and hypogonadism. Diabetes Care 29(7), 1591–1598 (2006).

    Article  PubMed  Google Scholar 

  25. 25.

    T. Ishikawa, K. Yamaguchi, Y. Kondo, A. Takenaka, M. Fujisawa, Metabolic syndrome in men with Klinefelter’s syndrome. Urology 71(6), 1109–1113 (2008).

    Article  PubMed  Google Scholar 

  26. 26.

    Z. Yesilova, C. Oktenli, S.Y. Sanisoglu, U. Musabak, E. Cakir, M. Ozata, K. Dagalp, Evaluation of insulin sensitivity in patients with Klinefelter’s syndrome: a hyperinsulinemic euglycemic clamp study. Endocrine 27(1), 11–15 (2005).

    Article  PubMed  CAS  Google Scholar 

  27. 27.

    D. Pei, W.H. Sheu, C.Y. Jeng, W.K. Liao, M.M. Fuh, Insulin resistance in patients with Klinefelter’s syndrome and idiopathic gonadotropin deficiency. J. Formos. Med. Assoc. 97(8), 534–540 (1998)

    PubMed  CAS  Google Scholar 

  28. 28.

    D. Pasquali, M. Arcopinto, A. Renzullo, M. Rotondi, G. Accardo, A. Salzano, D. Esposito, L. Saldamarco, A.M. Isidori, A.M. Marra, A. Ruvolo, R. Napoli, E. Bossone, A. Lenzi, R.R. Baliga, L. Sacca, A. Cittadini, Cardiovascular abnormalities in Klinefelter syndrome. Int. J. Cardiol. 168(2), 754–759 (2013).

    Article  PubMed  Google Scholar 

  29. 29.

    J.S. Brand, I. van der Tweel, D.E. Grobbee, M.H. Emmelot-Vonk, Y.T. van der Schouw, Testosterone, sex hormone-binding globulin and the metabolic syndrome: a systematic review and meta-analysis of observational studies. Int. J. Epidemiol. 40(1), 189–207 (2011).

    Article  PubMed  Google Scholar 

  30. 30.

    D.M. Kelly, S. Akhtar, D.J. Sellers, V. Muraleedharan, K.S. Channer, T.H. Jones, Testosterone differentially regulates targets of lipid and glucose metabolism in liver, muscle and adipose tissues of the testicular feminised mouse. Endocrine 54(2), 504–515 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. 31.

    K. Mitsuhashi, T. Senmaru, T. Fukuda, M. Yamazaki, K. Shinomiya, M. Ueno, S. Kinoshita, J. Kitawaki, M. Katsuyama, M. Tsujikawa, H. Obayashi, N. Nakamura, M. Fukui, Testosterone stimulates glucose uptake and GLUT4 translocation through LKB1/AMPK signaling in 3T3-L1 adipocytes. Endocrine 51(1), 174–184 (2016).

    Article  PubMed  CAS  Google Scholar 

  32. 32.

    E.M. Camacho, I.T. Huhtaniemi, T.W. O’Neill, J.D. Finn, S.R. Pye, D.M. Lee, A. Tajar, G. Bartfai, S. Boonen, F.F. Casanueva, G. Forti, A. Giwercman, T.S. Han, K. Kula, B. Keevil, M.E. Lean, N. Pendleton, M. Punab, D. Vanderschueren, F.C. Wu, E. Group, Age-associated changes in hypothalamic-pituitary-testicular function in middle-aged and older men are modified by weight change and lifestyle factors: longitudinal results from the European Male Ageing Study. Eur. J. Endocrinol. 168(3), 445–455 (2013).

    Article  PubMed  CAS  Google Scholar 

  33. 33.

    D. Landry, A. Pare, S. Jean, L.J. Martin, Adiponectin influences progesterone production from MA-10 Leydig cells in a dose-dependent manner. Endocrine 48(3), 957–967 (2015).

    Article  PubMed  CAS  Google Scholar 

  34. 34.

    A.M. Isidori, G. Balercia, A.E. Calogero, G. Corona, A. Ferlin, S. Francavilla, D. Santi, M. Maggi, Outcomes of androgen replacement therapy in adult male hypogonadism: recommendations from the Italian society of endocrinology. J. Endocrinol. Invest. 38(1), 103–112 (2015).

    Article  PubMed  CAS  Google Scholar 

  35. 35.

    M. Bekaert, Y. Van Nieuwenhove, P. Calders, C.A. Cuvelier, A.H. Batens, J.M. Kaufman, D.M. Ouwens, J.B. Ruige, Determinants of testosterone levels in human male obesity. Endocrine 50(1), 202–211 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. 36.

    I. Gies, D. Unuane, B. Velkeniers, J. De Schepper, Management of Klinefelter syndrome during transition. Eur. J. Endocrinol. 171(2), R67–R77 (2014).

    Article  PubMed  CAS  Google Scholar 

  37. 37.

    M.Z. Bardsley, B. Falkner, K. Kowal, J.L. Ross, Insulin resistance and metabolic syndrome in prepubertal boys with Klinefelter syndrome. Acta Paediatr. 100(6), 866–870 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    S. Davis, N. Lahlou, M. Bardsley, M.C. Temple, K. Kowal, L. Pyle, P. Zeitler, J. Ross, Gonadal function is associated with cardiometabolic health in pre-pubertal boys with Klinefelter syndrome. Andrology 4(6), 1169–1177 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. 39.

    S.M. Davis, M.G. Cox-Martin, M.Z. Bardsley, K. Kowal, P.S. Zeitler, J.L. Ross, Effects of oxandrolone on cardiometabolic health in boys with Klinefelter syndrome: a randomized controlled trial. J. Clin. Endocrinol. Metab. 102(1), 176–184 (2017).

    PubMed  Article  Google Scholar 

  40. 40.

    S. Iwatsuki, S. Sasaki, K. Taguchi, T. Hamakawa, K. Mizuno, A. Okada, Y. Kubota, Y. Umemoto, Y. Hayashi, T. Yasui, Effect of obesity on sperm retrieval outcome and reproductive hormone levels in Japanese azoospermic men with and without Klinefelter syndrome. Andrology 5(1), 82–86 (2017).

    Article  PubMed  CAS  Google Scholar 

  41. 41.

    L. Aksglaede, C. Molgaard, N.E. Skakkebaek, A. Juul, Normal bone mineral content but unfavourable muscle/fat ratio in Klinefelter syndrome. Arch. Dis. Child 93(1), 30–34 (2008).

    Article  PubMed  CAS  Google Scholar 

  42. 42.

    V.A. Giagulli, M.D. Carbone, M.I. Ramunni, B. Licchelli, G. De Pergola, C. Sabba, E. Guastamacchia, V. Triggiani, Adding liraglutide to lifestyle changes, metformin and testosterone therapy boosts erectile function in diabetic obese men with overt hypogonadism. Andrology 3(6), 1094–1103 (2015).

    Article  PubMed  CAS  Google Scholar 

  43. 43.

    S.J. Han, K.S. Kim, W. Kim, J.H. Kim, Y.H. Lee, J.S. Nam, J.A. Seo, B.K. Kim, J. Lee, J.O. Chung, M.H. Kim, T.S. Sohn, H.S. Choi, S.B. Hong, Y.S. Chung, Obesity and hyperglycemia in korean men with Klinefelter syndrome: the Korean Endocrine Society Registry. Endocrinol. Metab. 31(4), 598–603 (2016).

    Article  CAS  Google Scholar 

  44. 44.

    L. Aksglaede, K. Link, A. Giwercman, N. Jorgensen, N.E. Skakkebaek, A. Juul, 47,XXY Klinefelter syndrome: clinical characteristics and age-specific recommendations for medical management. Am. J. Med. Genet. C Semin. Med. Genet. 163C(1), 55–63 (2013).

    Article  PubMed  Google Scholar 

  45. 45.

    M. Arcopinto, C.A. Cella, R. Wesolowski, A. Salzano, E. Bossone, A. Cittadini, R.R. Baliga, Primary prevention of cancer-related thrombosis: special focus on ambulatory patients. Int. J. Cardiol. 173(3), 583–584 (2014).

    Article  PubMed  Google Scholar 

  46. 46.

    A. Salzano, P. Demelo-Rodriguez, A.M. Marra, M. Proietti, A. Focused, Review of gender differences in antithrombotic therapy. Curr. Med. Chem. 24(24), 2576–2588 (2017).

    Article  PubMed  CAS  Google Scholar 

  47. 47.

    M. Rotondi, F. Coperchini, A. Renzullo, G. Accardo, D. Esposito, G. Groppelli, F. Magri, A. Cittadini, A.M. Isidori, L. Chiovato, D. Pasquali, High circulating levels of CCL2 in patients with Klinefelter’s syndrome. Clin. Endocrinol. 80(3), 465–467 (2014).

    Article  CAS  Google Scholar 

  48. 48.

    S. Belli, D. Santi, E. Leoni, E. Dall’Olio, F. Fanelli, M. Mezzullo, C. Pelusi, L. Roli, S. Tagliavini, T. Trenti, A.R. Granata, U. Pagotto, R. Pasquali, V. Rochira, C. Carani, M. Simoni, Human chorionic gonadotropin stimulation gives evidence of differences in testicular steroidogenesis in Klinefelter syndrome, as assessed by liquid chromatography-tandem mass spectrometry. Eur. J. Endocrinol. 174(6), 801–811 (2016).

    Article  PubMed  CAS  Google Scholar 

  49. 49.

    N.H. Andersen, A. Bojesen, J.S. Christiansen, C.H. Gravholt, Glycemia, lipidemia and systolic left ventricular function evaluated by myocardial strain rate: a tissue Doppler echocardiographic study. Ultrasound Med. Biol. 34(1), 151–154 (2008).

    Article  PubMed  Google Scholar 

  50. 50.

    D. Daneman, Type 1 diabetes. Lancet 367(9513), 847–858 (2006).

    Article  PubMed  CAS  Google Scholar 

  51. 51.

    F. Panimolle, C. Tiberti, S. Granato, A. Semeraro, D. Gianfrilli, A. Anzuini, A. Lenzi, A. Radicioni, Screening of endocrine organ-specific humoral autoimmunity in 47,XXY Klinefelter’s syndrome reveals a significant increase in diabetes-specific immunoreactivity in comparison with healthy control men. Endocrine 52(1), 157–164 (2016).

    Article  PubMed  CAS  Google Scholar 

  52. 52.

    L. Langeron, P. Lamelin, G. Routier, Klinefelter syndrome and diabetes. J. Sci. Med. Lille 76(11), 440–444 (1958)

    PubMed  CAS  Google Scholar 

  53. 53.

    Y. Takeuchi, Y. Murata, J. Sintani, H. Masukawa, R. Nakamura, K. Oi, Y. Kato, M. Niinomi, Klinefelter’s syndrome accompanied by mixed connective tissue disease and diabetes mellitus. Intern. Med. 38(11), 875–881 (1999)

    Article  PubMed  CAS  Google Scholar 

  54. 54.

    S.M. Milcou, B. Ionesco, A. Bucur, Glucide metabolism in Klinefelter’s disease. Rev. Fr. Endocrinol. Clin. 12(4), 305–314 (1971)

    PubMed  CAS  Google Scholar 

  55. 55.

    V. Esmann, J. Nielsen, G.B. Petersen, A case of Klinefelter’s syndrome with 48,XXXY and diabetes mellitus. Acta Med. Scand. 186(1-2), 27–33 (1969)

    PubMed  CAS  Google Scholar 

  56. 56.

    J. Nielsen, K. Johansen, H. Yde, Frequency of diabetes mellitus in patients with Klinefelter’s syndrome of different chromosome constitutions and the XYY syndrome. Plasma insulin and growth hormone level after a glucose load. J. Clin. Endocrinol. Metab. 29(8), 1062–1073 (1969).

    Article  PubMed  CAS  Google Scholar 

  57. 57.

    J. Mirouze, C. Jaffiol, C. Bernard, E. Cartry, The prediabetes of Klinefelter’s syndrome. Diabete 14(2), 57–59 (1966)

    PubMed  CAS  Google Scholar 

  58. 58.

    I.M. Jackson, K.D. Buchanan, M.T. McKiddie, C.R. Prentice, Carbohydrate metabolism in Klinefelter’s syndrome. J. Endocrinol. 35(2), 169–172 (1966)

    Article  PubMed  CAS  Google Scholar 

  59. 59.

    K.L. Becker, D.L. Hoffman, L.O. Underdahl, H.L. Mason, Klinefelter’s syndrome. Clinical and laboratory findings in 50 patients. Arch. Intern. Med. 118(4), 314–321 (1966)

    Article  PubMed  CAS  Google Scholar 

  60. 60.

    J. Nielsen, Diabetes mellitus in parents of patients with Klinefelter’s syndrome. Lancet 287, 1376 (1966)

    Article  Google Scholar 

  61. 61.

    A.P. Forbes, E. Engel, The high incidence of diabetes mellitus in 41 patients with gonadal dysgenesis, and their close relatives. Metabolism 12, 428–439 (1963)

    PubMed  CAS  Google Scholar 

  62. 62.

    M. Jiang-Feng, X. Hong-Li, W. Xue-Yan, N. Min, L. Shuang-Yu, X. Hong-Ding, L. Liang-Ming, Prevalence and risk factors of diabetes in patients with Klinefelter syndrome: a longitudinal observational study. Fertil. Steril. 98(5), 1331–1335 (2012).

    Article  PubMed  Google Scholar 

  63. 63.

    K. Zuppinger, E. Engel, A.P. Forbes, L. Mantooth, J. Claffey, Klinefelter’s syndrome, a clinical and cytogenetic study in twenty-four cases. Acta Endocrinol. 54(Suppl 113), 115+ (1967)

    Google Scholar 

  64. 64.

    M. Sagara, M. Nakasono, I. Makino, K. Takebe, Two cases of Klinefelter’s syndrome associated with diabetes mellitus, and analysing the clinical features of all domestic reported cases. J. Jpn. Diab. Soc. 28(5), 677–686 (1986)

    Google Scholar 

  65. 65.

    K. Ota, T. Suehiro, Y. Ikeda, K. Arii, Y. Kumon, K. Hashimoto, Diabetes mellitus associated with Klinefelter’s syndrome: a case report and review in Japan. Intern. Med. 41(10), 842–847 (2002)

    Article  PubMed  Google Scholar 

  66. 66.

    C. Lichiardopol, M. Mota, C. Panus, Metabolic changes in Klinefelter syndrome. Rom. J. Intern. Med. 42(2), 415–422 (2004)

    PubMed  Google Scholar 

  67. 67.

    M. Zitzmann, R. Bongers, S. Werler, N. Bogdanova, J. Wistuba, S. Kliesch, J. Gromoll, F. Tuttelmann, Gene expression patterns in relation to the clinical phenotype in Klinefelter syndrome. J. Clin. Endocrinol. Metab. 100(3), E518–E523 (2015).

    Article  PubMed  CAS  Google Scholar 

  68. 68.

    A. Bojesen, J.M. Hertz, C.H. Gravholt, Genotype and phenotype in Klinefelter syndrome—impact of androgen receptor polymorphism and skewed X inactivation. Int. J. Androl. 34(6 Pt 2), e642–e648 (2011).

    Article  PubMed  CAS  Google Scholar 

  69. 69.

    M. Arcopinto, A. Salzano, E. Bossone, F. Ferrara, E. Bobbio, D. Sirico, O. Vriz, C. De Vincentiis, M. Matarazzo, L. Saldamarco, F. Sacca, R. Napoli, M. Iacoviello, V. Triggiani, A.M. Isidori, C. Vigorito, J. Isgaard, A. Cittadini, Multiple hormone deficiencies in chronic heart failure. Int. J. Cardiol. 184, 421–423 (2015).

    Article  PubMed  Google Scholar 

  70. 70.

    M. Arcopinto, A. Salzano, J. Isgaard, A. Cittadini, Hormone replacement therapy in heart failure. Curr. Opin. Cardiol. 30(3), 277–284 (2015).

    Article  PubMed  Google Scholar 

  71. 71.

    A.M. Marra, M. Arcopinto, E. Bobbio, A. Salzano, L. Sacca, A. Cittadini, An unusual case of dilated cardiomyopathy associated with partial hypopituitarism. Intern. Emerg. Med. 7(Suppl 2), S85–S87 (2012).

    Article  PubMed  Google Scholar 

  72. 72.

    A. Salzano, A.M. Marra, F. Ferrara, M. Arcopinto, E. Bobbio, P. Valente, R. Polizzi, C. De Vincentiis, M. Matarazzo, L. Saldamarco, F. Sacca, R. Napoli, M.G. Monti, R. D’Assante, A.M. Isidori, J. Isgaard, N. Ferrara, P.P. Filardi, F. Perticone, C. Vigorito, E. Bossone, A. Cittadini, T.O.S.C. investigators, Multiple hormone deficiency syndrome in heart failure with preserved ejection fraction. Int. J. Cardiol. 225, 1–3 (2016).

    Article  PubMed  Google Scholar 

  73. 73.

    American Diabetes, A., 2. Classification and diagnosis of diabetes. Diabetes Care 40(Suppl 1), S11–S24 (2017).

    Article  Google Scholar 

  74. 74.

    S. Davis, S. Howell, R. Wilson, T. Tanda, J. Ross, P. Zeitler, N. Tartaglia, Advances in the interdisciplinary care of children with Klinefelter syndrome. Adv. Pediatr. 63(1), 15–46 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  75. 75.

    American Diabetes, A., 5. Prevention or delay of type 2 diabetes: standards of medical care in diabetes-2018. Diabetes Care 41(Suppl 1), S51–S54 (2018).

    Article  Google Scholar 

  76. 76.

    W.C. Knowler, E. Barrett-Connor, S.E. Fowler, R.F. Hamman, J.M. Lachin, E.A. Walker, D.M. Nathan, G.Diabetes Prevention Program Research, Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N. Engl. J. Med. 346(6), 393–403 (2002).

    Article  PubMed  CAS  Google Scholar 

  77. 77.

    American Diabetes, A., 4. Lifestyle management: standards of medical care in diabetes-2018. Diabetes Care 41(Suppl 1), S38–S50 (2018).

    Article  Google Scholar 

  78. 78.

    N. Pitteloud, M. Hardin, A.A. Dwyer, E. Valassi, M. Yialamas, D. Elahi, F.J. Hayes, Increasing insulin resistance is associated with a decrease in Leydig cell testosterone secretion in men. J. Clin. Endocrinol. Metab. 90(5), 2636–2641 (2005).

    Article  PubMed  CAS  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to Antonio Cittadini.

Ethics declarations

Conflict of interest

Dr. A.S. receives research grant support from Cardiopath. The remaining authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Additional information

These authors contributed equally: Andrea Salzano and Roberta D’Assante.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Salzano, A., D’Assante, R., Heaney, L.M. et al. Klinefelter syndrome, insulin resistance, metabolic syndrome, and diabetes: review of literature and clinical perspectives. Endocrine 61, 194–203 (2018).

Download citation


  • Klinefelter syndrome
  • Diabetes mellitus
  • Metabolic syndrome
  • Insulin resistance
  • Testosterone therapy
  • Cardiovascular diseases