The role of hypogonadism in Klinefelter Syndrome

Asian Journal of Andrology

Volumn 16, Issue 2, 2014, Pages 185-191

  Høst, Christian ^a   Skakkebæk, Anne ^a   Groth, Kristian A ^a   Bojesen, Anders ^b,c  

^a AARHUS UNIVERSITY HOSPITAL   (Denmark)

^b LILLEBAELT HOSPITAL   (Denmark)

^c UNIVERSITY OF SOUTHERN DENMARK   (Denmark)

Author keywords

Androgen receptor; Body composition; Bone density; Hypogonadism; Infertility; Klinefelter syndrome; Learning disorders; Male; Testosterone

Indexed keywords

TESTOSTERONE;

ANDROGEN THERAPY; AZOOSPERMIA; BODY COMPOSITION; BODY FAT; BONE MINERAL; CHROMOSOME DISORDER; DEATH; GENE DOSAGE; HOSPITALIZATION; HUMAN; HYPOGONADISM; INFERTILITY; KLINEFELTER SYNDROME; LEARNING DISORDER; MASCULINITY; MENTAL DISEASE; METABOLIC SYNDROME X; MUSCLE MASS; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PUBERTY; REVIEW; RISK FACTOR;

BODY COMPOSITION; BRAIN; COGNITION; FERTILITY; HORMONE REPLACEMENT THERAPY; HUMANS; HYPOGONADISM; INSULIN RESISTANCE; KLINEFELTER SYNDROME; MALE; OSTEOPOROSIS; TESTIS; TESTOSTERONE;

EID: 84896767167     PISSN: 1008682X     EISSN: 17457262     Source Type: Journal    
DOI: 10.4103/1008-682X.122201     Document Type: Review

References (110)

1. Bojesen A, Juul S, Gravholt CH. Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study. J Clin Endocrinol Metab 2003; 88: 622-6. (Pubitemid 36207801)
2. Herlihy AS, Halliday JL, Cock ML, McLachlan RI. The prevalence and diagnosis rates of Klinefelter syndrome: an Australian comparison. Med J Aust 2011; 194: 24-8.
3. Coffee B, Keith K, Albizua I, Malone T, Mowrey J, et al. Incidence of fragile X syndrome by newborn screening for methylated FMR1 DNA. Am J Hum Genet 2009; 85: 503-14.
4. Klinefelter HF, Reifenstein EC, Albright F. Syndrome characterized by gynecomastia, aspermatogenesis without a-leydigsm and increased secretion of follicle-stimulating hormone. J Clin Endocrinol Metab 1942: 615-22.
5. Smyth CM, Bremner WJ. Klinefelter syndrome. Arch Intern Med 1998; 158: 1309-14. (Pubitemid 28287523)
6. Simpson JL, de la CF, Swerdloff RS, Samango-Sprouse C, Skakkebaek NE, et al. Klinefelter syndrome: expanding the phenotype and identifying new research directions. Genet Med 2003; 5: 460-8. (Pubitemid 37483416)
7. Bojesen A, Gravholt CH. Klinefelter syndrome in clinical practice. Nat Clin Pract Urol 2007; 4: 192-204. (Pubitemid 46567152)
8. 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: 1254-60.
9. Bojesen A, Juul S, Birkebaek N, Gravholt CH. Increased mortality in klinefelter syndrome. J Clin Endocrinol Metab 2004; 89: 3830-4. (Pubitemid 39071480)
10. 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: 6516-22. (Pubitemid 41759307)
11. Bojesen A, Stochholm K, Juul S, Gravholt CH. Socioeconomic trajectories affect mortality in Klinefelter syndrome. J Clin Endocrinol Metab 2011; 96: 2098-104.
12. Stochholm K, Bojesen A, Jensen AS, Juul S, Gravholt CH. Criminality in men with Klinefelter's syndrome and XYY syndrome: a cohort study. BMJ Open 2012; 2: e000650.
13. Aksglaede L, Wikstrom M, Meyts ER, Dunkel L, Skakkebaek E, et al. Natural history of seminiferous tubule degeneration in Klinefelter syndrome. Hum Reprod Update 2005; 12: 39-48.
14. Ratcliffe SG, Butler GE, Jones M. Edinburgh study of growth and development of children with sex chromosome abnormalities. IV. Birth Defects Orig Artic Ser 1990; 26: 1-44.
15. Lahlou N, Fennoy I, Ross JL, Bouvattier C, Roger M. Clinical and hormonal status of infants with nonmosaic XXY karyotype. Acta Paediatr 2011; 100: 824-9.
16. Fennoy I. Testosterone and the child (0-12 years) with Klinefelter syndrome (47XXY): a review. Acta Paediatr 2011; 100: 846-50.
17. Lahlou N, Fennoy I, Carel JC, Roger M. Inhibin B and anti-Mullerian hormone, but not testosterone levels, are normal in infants with nonmosaic Klinefelter syndrome. J Clin Endocrinol Metab 2004; 89: 1864-8. (Pubitemid 38507946)
18. Aksglaede L, Petersen JH, Main KM, Skakkebaek NE, Juul A. High normal testosterone levels in infants with non-mosaic Klinefelter's syndrome. Eur J Endocrinol 2007; 157: 345-50. (Pubitemid 47603540)
19. Cabrol S, Ross JL, Fennoy I, Bouvattier C, Roger M, et al. Assessment of Leydig and Sertoli cell functions in infants with nonmosaic Klinefelter syndrome: insulin-like peptide 3 levels are normal and positively correlated with LH levels. J Clin Endocrinol Metab 2011; 96: E746-53.
20. Samango-Sprouse CA, Sadeghin T, Mitchell FL, Dixon T, Stapleton E, et al. Positive effects of short course androgen therapy on the neurodevelopmental outcome in boys with 47, XXY syndrome at 36 and 72 months of age. Am J Med Genet A 2013; 161: 501-8.
21. Christiansen P, Andersson AM, Skakkebaek NE. Longitudinal studies of inhibin B levels in boys and young adults with Klinefelter syndrome. J Clin Endocrinol Metab 2003; 88: 888-91. (Pubitemid 36207838)
22. Aksglaede L, Wikstrom AM, Rajpert-De Meyts E, Dunkel L, Skakkebaek NE, et al. Natural history of seminiferous tubule degeneration in Klinefelter syndrome. Hum Reprod Update 2006; 12: 39-48. (Pubitemid 43013745)
23. Lanfranco F, Kamischke A, Zitzmann M, Nieschlag E. Klinefelter's syndrome. Lancet 2004; 364: 273-83. (Pubitemid 38942818)
24. Bojesen A, Kristensen K, Birkebaek NH, Fedder J, Mosekilde L, et al. The metabolic syndrome is frequent in Klinefelter's syndrome and is associated with abdominal obesity and hypogonadism. Diabetes Care 2006; 29: 1591-8. (Pubitemid 44127586)
25. Laron Z, Dickerman Z, Zamir R, Galatzer A. Paternity in Klinefelter's syndrome: a case report. Arch Androl 1982; 8: 149-51. (Pubitemid 12061642)
26. Aksglaede L, Juul A. Testicular function and fertility in men with Klinefelter syndrome: a review. Eur J Endocrinol 2013; 168: R67-76.
27. Schiff JD, Palermo GD, Veeck LL, Goldstein M, Rosenwaks Z, et al. Success of testicular sperm extraction [corrected] and intracytoplasmic sperm injection in men with Klinefelter syndrome. J Clin Endocrinol Metab 2005; 90: 6263-7. (Pubitemid 41606554)
28. Cruger D, Toft B, Agerholm I, Fedder J, Hald F, et al. Birth of a healthy girl after ICSI with ejaculated spermatozoa from a man with non-mosaic Klinefelter's syndrome: case report. Hum Reprod 2001; 16: 1909-11. (Pubitemid 32916221)
29. Komori S, Horiuchi I, Hamada Y, Hasegawa A, Kasumi H, et al. Birth of healthy neonates after intracytoplasmic injection of ejaculated or testicular spermatozoa from men with nonmosaic Klinefelter's syndrome: a report of 2 cases. J Reprod Med 2004; 49: 126-30. (Pubitemid 38229145)
30. Staessen C, Tournaye H, Van Assche E, Michiels A, Van Landuyt L, et al. PGD in 47, XXY Klinefelter's syndrome patients. Hum Reprod Update 2003; 9: 319-30. (Pubitemid 36987281)
31. Ron-El R, Strassburger D, Gelman-Kohan S, Friedler S, Raziel A, et al. A 47, XXY fetus conceived after ICSI of spermatozoa from a patient with non-mosaic Klinefelter's syndrome: case report. Hum Reprod 2000; 15: 1804-6. (Pubitemid 30636073)
32. Bender BG, Linden MG, Robinson A. Neuropsychological impairment in 42 adolescents with sex chromosome abnormalities. Am J Med Genet 1993; 48: 169-73. (Pubitemid 23292014)
33. Ratcliffe S. Long-term outcome in children of sex chromosome abnormalities. Arch Dis Child 1999; 80: 192-5. (Pubitemid 29119739)
34. Ross JL, Roeltgen DP, Stefanatos G, Benecke R, Zeger MP, et al. Cognitive and motor development during childhood in boys with Klinefelter syndrome. Am J Med Genet A 2008; 146A: 708-19. (Pubitemid 351354146)
35. Fales CL, Knowlton BJ, Holyoak KJ, Geschwind DH, Swerdloff RS, et al. Working memory and relational reasoning in Klinefelter syndrome. J Int Neuropsychol Soc 2003; 9: 839-46. (Pubitemid 37139013)
36. Graham JM Jr, Bashir AS, Stark RE, Silbert A, Walzer S. Oral and written language abilities of XXY boys: implications for anticipatory guidance. Pediatrics 1988; 81: 795-806.
37. Kompus K, Westerhausen R, Nilsson LG, Hugdahl K, Jongstra S, et al. Deficits in inhibitory executive functions in Klinefelter (47, XXY) syndrome. Psychiatry Res 2011; 189: 135-40.
38. Lee NR, Wallace GL, Clasen LS, Lenroot RK, Blumenthal JD, et al. Executive function in young males with klinefelter (XXY) syndrome with and without comorbid attention-deficit/hyperactivity disorder. J Int Neuropsychol Soc 2011: 1-9.
39. Temple CM, Sanfilippo PM. Executive skills in Klinefelter's syndrome. Neuropsychologia 2003; 41: 1547-59. (Pubitemid 36808828)
40. Bender BG, Harmon RJ, Linden MG, Robinson A. Psychosocial adaptation of 39 adolescents with sex chromosome abnormalities. Pediatrics 1995; 96: 302-8.
41. Boks MP, de Vette MH, Sommer IE, van Rijn S, Giltay JC, et al. Psychiatric morbidity and X-chromosomal origin in a Klinefelter sample. Schizophr Res 2007; 93: 399-402. (Pubitemid 46817961)
42. Bruining H, Swaab H, Kas M, van Engeland H. Psychiatric characteristics in a self-selected sample of boys with Klinefelter syndrome. Pediatrics 2009; 123: e865-70.
43. Bryant DM, Hoeft F, Lai S, Lackey J, Roeltgen D, et al. Neuroanatomical phenotype of Klinefelter syndrome in childhood: a voxel-based morphometry study. J Neurosci 2011; 31: 6654-60.
44. Giedd JN, Clasen LS, Wallace GL, Lenroot RK, Lerch JP, et al. XXY (Klinefelter syndrome): a pediatric quantitative brain magnetic resonance imaging case-control study. Pediatrics 2007; 119: e232-40. (Pubitemid 46397830)
45. Shen D, Liu D, Liu H, Clasen L, Giedd J, et al. Automated morphometric study of brain variation in XXY males. Neuroimage 2004; 23: 648-53. (Pubitemid 39377730)
46. Patwardhan AJ, Eliez S, Bender B, Linden MG, Reiss AL. Brain morphology in Klinefelter syndrome: extra X chromosome and testosterone supplementation. Neurology 2000; 54: 2218-23. (Pubitemid 30416270)
47. Delisi LE, Maurizio AM, Svetina C, Ardekani B, Szulc K, et al. Klinefelter's syndrome (XXY) as a genetic model for psychotic disorders. Am J Med Genet B Neuropsychiatr Genet 2005; 135: 15-23. (Pubitemid 40577849)
48. Knickmeyer RC, Baron-Cohen S. Fetal testosterone and sex differences in typical social development and in autism. J Child Neurol 2006; 21: 825-45. (Pubitemid 46099268)
49. Skakkebak A, Gravholt CH, Rasmussen PM, Bojesen A, Jensen JS, et al. Neuroanatomical correlates of Klinefelter syndrome studied in relation to the neuropsychological profile. NeuroImage: Clinical 2013; in press.
50. Merke DP, Fields JD, Keil MF, Vaituzis AC, Chrousos GP, et al. Children with classic congenital adrenal hyperplasia have decreased amygdala volume: potential prenatal and postnatal hormonal effects. J Clin Endocrinol Metab 2003; 88: 1760-5. (Pubitemid 36623401)
51. Warwick MM, Doody GA, Lawrie SM, Kestelman JN, Best JJ, et al. Volumetric magnetic resonance imaging study of the brain in subjects with sex chromosome aneuploidies. J Neurol Neurosurg Psychiatry 1999; 66: 628-32. (Pubitemid 29186970)
52. Lombardo MV, Ashwin E, Auyeung B, Chakrabarti B, Taylor K, et al. Fetal testosterone influences sexually dimorphic gray matter in the human brain. J Neurosci 2012; 32: 674-80.
53. Annell AL, Gustavson KH, Tenstam J. Symtomatology in schoolboys with positive sex chromatin (the klinefelter syndrome). Acta Psychiatr Scand 1970; 46: 71-80.
54. Nielsen J, Pelsen B. Follow-up 20 years later of 34 Klinefelter males with karyotype 47, XXY and 16 hypogonadal males with karyotype 46, XY. Hum Genet 1987; 77: 188-92. (Pubitemid 17160067)
55. Skakkebak AP, Bojesen A, Kristensen MK, Hertz JM, Ostergaard JR, et al. Personality, psychological distress and autism traits-key players in the neuropsychological phenotype of Klinefelter syndrome. Submitted 2013.
56. Itti E, Gaw Gonzalo IT, Pawlikowska-Haddal A, Boone KB, Mlikotic A, et al. The structural brain correlates of cognitive deficits in adults with Klinefelter's syndrome. J Clin Endocrinol Metab 2006; 91: 1423-7.
57. Tsai EC, Boyko EJ, Leonetti DL, Fujimoto WY. Low serum testosterone level as a predictor of increased visceral fat in Japanese-American men. Int J Obes Relat Metab Disord 2000; 24: 485-91. (Pubitemid 30198102)
58. Marin P, Holmang S, Jonsson L, Sjostrom L, Kvist H, et al. The effects of testosterone treatment on body composition and metabolism in middle-aged obese men. Int J Obes Relat Metab Disord 1992; 16: 991-7. (Pubitemid 23010023)
59. Hamilton EJ, Gianatti E, Strauss BJ, Wentworth J, Lim-Joon D, et al. Increase in visceral and subcutaneous abdominal fat in men with prostate cancer treated with androgen deprivation therapy. Clin Endocrinol (Oxf) 2011; 74: 377-83.
60. Aksglaede L, Molgaard C, Skakkebaek NE, Juul A. Normal bone mineral content but unfavourable muscle/fat ratio in Klinefelter syndrome. Arch Dis Child 2008; 93: 30-4.
61. Bojesen A, Birkebaek N, Kristensen K, Heickendorff L, Mosekilde L, et al. Bone mineral density in Klinefelter syndrome is reduced and primarily determined by muscle strength and resorptive markers, but not directly by testosterone. Osteoporos Int 2010; 22: 1441-50.
62. Page ST, Amory JK, Bowman FD, Anawalt BD, Matsumoto AM, et al. Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T. J Clin Endocrinol Metab 2005; 90: 1502-10. (Pubitemid 40464011)
63. Sheffield-Moore M, Dillon EL, Casperson SL, Gilkison CR, Paddon-Jones D, et al. A randomized pilot study of monthly cycled testosterone replacement or continuous testosterone replacement versus placebo in older men. J Clin Endocrinol Metab 2011; 96: E1831-7.
64. Srinivas-Shankar U, Roberts SA, Connolly MJ, O'Connell MD, Adams JE, et al. Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab 2010; 95: 639-50.
65. Ishikawa T, Yamaguchi K, Kondo Y, Takenaka A, Fujisawa M. Metabolic syndrome in men with Klinefelter's syndrome. Urology 2008; 71: 1109-13.
66. Jiang-Feng M, Hong-Li X, Xue-Yan W, Min N, Shuang-Yu L, et al. Prevalence and risk factors of diabetes in patients with Klinefelter syndrome: a longitudinal observational study. Fertil Steril 2012; 98: 1331-5.
67. Yesilova Z, Oktenli C, Sanisoglu SY, Musabak U, Cakir E, et al. Evaluation of insulin sensitivity in patients with klinefelter's syndrome: a hyperinsulinemic euglycemic clamp study. Endocrine 2005; 27: 11-6.
68. Bardsley MZ, Falkner B, Kowal K, Ross JL. Insulin resistance and metabolic syndrome in prepubertal boys with Klinefelter syndrome. Acta Paediatr 2011; 100: 866-70.
69. Laaksonen DE, Niskanen L, Punnonen K, Nyyssonen K, Tuomainen TP, et al. Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care 2004; 27: 1036-41. (Pubitemid 38579762)
70. Stellato RK, Feldman HA, Hamdy O, Horton ES, McKinlay JB. Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts male aging study. Diabetes Care 2000; 23: 490.
71. Grossmann M, Thomas MC, Panagiotopoulos S, Sharpe K, Macisaac RJ, et al. Low testosterone levels are common and associated with insulin resistance in men with diabetes. J Clin Endocrinol Metab 2008; 93: 1834-40. (Pubitemid 351656526)
72. Grossmann M, Gianatti EJ, Zajac JD. Testosterone and type 2 diabetes. Curr Opin Endocrinol Diabetes Obes 2010; 17: 247-56.
73. Selvin E, Feinleib M, Zhang L, Rohrmann S, Rifai N, et al. Androgens and diabetes in men: results from the Third National Health and Nutrition Examination Survey (NHANES III). Diabetes Care 2007; 30: 234-8. (Pubitemid 46198324)
74. Heufelder AE, Saad F, Bunck MC, Gooren L. Fifty-two-week treatment with diet and exercise plus transdermal testosterone reverses the metabolic syndrome and improves glycemic control in men with newly diagnosed type 2 diabetes and subnormal plasma testosterone. J Androl 2009; 30: 726-33.
75. Kapoor D, Goodwin E, Channer KS, Jones TH. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol 2006; 154: 899-906. (Pubitemid 43997730)
76. Gopal RA, Bothra N, Acharya SV, Ganesh HK, Bandgar TR, et al. Treatment of hypogonadism with testosterone in patients with type 2 diabetes mellitus. Endocr Pract 2010; 16: 570-6.
77. Corrales JJ, Burgo RM, Garca-Berrocal B, Almeida M, Alberca I, et al. Partial androgen deficiency in aging type 2 diabetic men and its relationship to glycemic control. Metabolism 2004; 53: 666-72. (Pubitemid 38596543)
78. Marin P, Krotkiewski M, Bjorntorp P. Androgen treatment of middle-aged, obese men: effects on metabolism, muscle and adipose tissues. Eur J Med 1992; 1: 329-36.
79. Yialamas MA, Dwyer AA, Hanley E, Lee H, Pitteloud N, et al. Acute sex steroid withdrawal reduces insulin sensitivity in healthy men with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2007; 92: 4254-9. (Pubitemid 350074740)
80. Lapauw B, Ouwens M, t Hart LM, Wuyts B, Holst JJ, et al. Sex steroids affect triglyceride handling, glucose-dependent insulinotropic polypeptide, and insulin sensitivity: a 1-week randomized clinical trial in healthy young men. Diabetes Care 2010; 33: 1831-3.
81. Laaksonen DE, Niskanen L, Punnonen K, Nyyssonen K, Tuomainen TP, et al. Sex hormones, inflammation and the metabolic syndrome: a population-based study. Eur J Endocrinol 2003; 149: 601-8. (Pubitemid 38054707)
82. Nishizawa H, Shimomura I, Kishida K, Maeda N, Kuriyama H, et al. Androgens decrease plasma adiponectin, an insulin-sensitizing adipocyte-derived protein. Diabetes 2002; 51: 2734-41. (Pubitemid 34970926)
83. Page ST, Herbst KL, Amory JK, Coviello AD, Anawalt BD, et al. Testosterone administration suppresses adiponectin levels in men. J Androl 2005; 26: 85-92. (Pubitemid 39665280)
84. Xu A, Chan KW, Hoo RL, Wang Y, Tan KC, et al. Testosterone selectively reduces the high molecular weight form of adiponectin by inhibiting its secretion from adipocytes. J Biol Chem 2005; 280: 18073-80. (Pubitemid 41389052)
85. Lanfranco F, Zitzmann M, Simoni M, Nieschlag E. Serum adiponectin levels in hypogonadal males: influence of testosterone replacement therapy. Clin Endocrinol (Oxf) 2004; 60: 500-7. (Pubitemid 38482514)
86. Host C, Bojesen A, Frystyk J, Flyvbjerg A, Christiansen JS, et al. Effect of sex hormone treatment on circulating adiponectin and subforms in Turner and Klinefelter syndrome. Eur J Clin Invest 2010; 40: 211-9.
87. Basaria S, Coviello AD, Travison TG, Storer TW, Farwell WR, et al. Adverse events associated with testosterone administration. N Engl J Med 2010; 363: 109-22.
88. Hyde Z, Norman PE, Flicker L, Hankey GJ, McCaul KA, et al. Elevated LH predicts ischaemic heart disease events in older men: the Health in Men Study. Eur J Endocrinol 2011; 164: 569-77.
89. Traish AM, Miner MM, Morgentaler A, Zitzmann M. Testosterone deficiency. Am J Med 2011; 124: 578-87.
90. Zitzmann M. Testosterone deficiency, insulin resistance and the metabolic syndrome. Nat Rev Endocrinol 2009; 5: 673-81.
91. Sinnesael M, Claessens F, Boonen S, Vanderschueren D. Novel insights in the regulation and mechanism of androgen action on bone. Curr Opin Endocrinol Diabetes Obes 2013; 20: 240-4.
92. Luisetto G, Mastrogiacomo I, Bonanni G, Pozzan G, Botteon S, et al. Bone mass and mineral metabolism in Klinefelter's syndrome. Osteoporos Int 1995; 5: 455-61.
93. Foresta C, Ruzza G, Mioni R, Meneghello A, Baccichetti C. Testosterone and bone loss in Klinefelter syndrome. Horm Metab Res 1983; 15: 56-7. (Pubitemid 13175046)
94. Choi HR, Lim SK, Lee MS. Site-specific effect of testosterone on bone mineral density in male hypogonadism. J Korean Med Sci 1995; 10: 431-5.
95. Smith DA, Walker MS. Changes in plasma steroids and bone density in Klinefelter's syndrome. Calcif Tissue Res 1977; 22 Suppl: 225-8.
96. Horowitz M, Wishart JM, O'Loughlin PD, Morris HA, Need AG, et al. Osteoporosis and Klinefelter's syndrome. Clin Endocrinol (Oxf) 1992; 36: 113-8.
97. Ferlin A, Schipilliti M, Vinanzi C, Garolla A, Di Mambro A, et al. Bone mass in subjects with Klinefelter syndrome: role of testosterone levels and androgen receptor gene CAG polymorphism. J Clin Endocrinol Metab 2011; 96: E739-45.
98. van den Bergh JP, Hermus AR, Spruyt AI, Sweep CG, Corstens FH, et al. Bone mineral density and quantitative ultrasound parameters in patients with Klinefelter's yndrome after long-term testosterone substitution. Osteoporos Int 2001; 12: 55-62. (Pubitemid 32233659)
99. Kubler A, Schulz G, Cordes U, Beyer J, Krause U. The influence of testosterone substitution on bone mineral density in patients with Klinefelter's syndrome. Exp Clin Endocrinol 1992; 100: 129-32. (Pubitemid 23135781)
100. Zitzmann M, Depenbusch M, Gromoll J, Nieschlag E. X-chromosome inactivation patterns and androgen receptor functionality influence phenotype and social characteristics as well as pharmacogenetics of testosterone therapy in Klinefelter patients. J Clin Endocrinol Metab 2004; 89: 6208-17. (Pubitemid 39628435)
101. Bojesen A, Hertz JM, Gravholt CH. Genotype and phenotype in Klinefelter syndrome-impact of androgen receptor polymorphism and skewed X inactivation. Int J Androl 2011; 34: e642-8.
102. Nielsen J, Pelsen B, Sorensen K. Follow-up of 30 Klinefelter males treated with testosterone. Clin Genet 1988; 33: 262-9.
103. Meikle AW, Dobs AS, Arver S, Caramelli KE, Sanders SW, et al. Androgen replacement in the treatment of Klinefelter's syndrome: efficacy and safety of a nonscrotal permeation-enhanced testosterone transdermal system. Endocr Pract 1998; 4: 17-22.
104. Lunenfeld B, Arver S, Moncada I, Rees DA, Schulte HM. How to help the aging male? Current approaches to hypogonadism in primary care. Aging Male 2012; 15: 187-97.
105. Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2010; 95: 2536-59.
106. Steidle C, Schwartz S, Jacoby K, Sebree T, Smith T, et al. AA2500 Testosterone Gel Normalizes Androgen Levels in Aging Males with Improvements in Body Composition and Sexual Function. J Clin Endocrinol Metab 2003; 88: 2673.
107. McNicholas TA, Dean JD, Mulder H, Carnegie C, Jones NA. A novel testosterone gel formulation normalizes androgen levels in hypogonadal men, with improvements in body composition and sexual function. BJU Int 2003; 91: 69-74.
108. de Ronde W. Hyperandrogenism after transfer of topical testosterone gel: case report and review of published and unpublished studies. Hum Reprod 2009; 24: 425-8.
109. Yin A, Swerdloff R. Treating hypogonadism in younger males. Expert Opin Pharmacother 2010; 11: 1529-40.
110. Groth KA, Skakkebaek A, Host C, Gravholt CH, Bojesen A. Clinical review: klinefelter syndrome: a clinical update. J Clin Endocrinol Metab 2012; 98: 20-30.