, Volume 41, Issue 2, pp 200–219 | Cite as

Sex hormone replacement in Turner syndrome

  • Christian Trolle
  • Britta Hjerrild
  • Line Cleemann
  • Kristian H. Mortensen
  • Claus H. Gravholt


The cardinal features of Turner syndrome (TS) are short stature, congenital abnormalities, infertility due to gonadal dysgenesis, with sex hormone insufficiency ensuing from premature ovarian failure, which is involved in lack of proper development of secondary sex characteristics and the frequent osteoporosis seen in Turner syndrome. But sex hormone insufficiency is also involved in the increased cardiovascular risk, state of physical fitness, insulin resistance, body composition, and may play a role in the increased incidence of autoimmunity. Severe morbidity and mortality affects females with Turner syndrome. Recent research emphasizes the need for proper sex hormone replacement therapy (HRT) during the entire lifespan of females with TS and new hypotheses concerning estrogen receptors, genetics and the timing of HRT offers valuable new information. In this review, we will discuss the effects of estrogen and androgen insufficiency as well as the effects of sex HRT on morbidity and mortality with special emphasis on evidence based research and areas needing further studies.


  1. 1.
    K. Stochholm, S. Juul, K. Juel, R.W. Naeraa, C.H. Gravholt, Prevalence, incidence, diagnostic delay, and mortality in Turner syndrome. J. Clin. Endocrinol. Metab. 91, 3897–3902 (2006). doi: 10.1210/jc.2006-0558 PubMedCrossRefGoogle Scholar
  2. 2.
    M.J. Schoemaker, A.J. Swerdlow, C.D. Higgins, A.F. Wright, P.A. Jacobs, Mortality in women with turner syndrome in Great Britain: a national cohort study. J. Clin. Endocrinol. Metab. 93, 4735–4742 (2008). doi: 10.1210/jc.2008-1049 PubMedCrossRefGoogle Scholar
  3. 3.
    C.H. Gravholt, S. Juul, R.W. Naeraa, J. Hansen, Morbidity in Turner syndrome. J. Clin. Epidemiol. 51, 147–158 (1998)PubMedCrossRefGoogle Scholar
  4. 4.
    V.M. De, P. Devroey, B.C. Fauser, Primary ovarian insufficiency. Lancet 376, 911–921 (2010). doi: 10.1016/S0140-6736(10)60355-8 CrossRefGoogle Scholar
  5. 5.
    F.A. Conte, M.M. Grumbach, S.L. Kaplan, A diphasic pattern of gonadotropin secretion in patients with the syndrome of gonadal dysgenesis. J. Clin. Endocrinol. Metab. 40, 670–674 (1975)PubMedCrossRefGoogle Scholar
  6. 6.
    C. Heinrichs, P. Bourdoux, C. Saussez, H.L. Vis, J.P. Bourguignon, Blood spot follicle-stimulating hormone during early postnatal life in normal girls and Turner’s syndrome. J. Clin. Endocrinol. Metab. 78, 978–981 (1994)PubMedCrossRefGoogle Scholar
  7. 7.
    D. Apter, H.L. Lenko, J. Perheentupa, A. Soderholm, R. Vihko, Subnormal pubertal increases of serum androgens in Turner’s syndrome. Horm. Res. 16, 164–173 (1982)PubMedCrossRefGoogle Scholar
  8. 8.
    C.H. Gravholt, B. Svenstrup, P. Bennett, C.J. Sandahl, Reduced androgen levels in adult turner syndrome: influence of female sex steroids and growth hormone status. Clin. Endocrinol. (Oxf.) 50, 791–800 (1999)CrossRefGoogle Scholar
  9. 9.
    A.M. Boot, M.A. de Ridder, H.A. Pols, E.P. Krenning, S.M. de Muinck Keizer-Schrama, Bone mineral density in children and adolescents: relation to puberty, calcium intake, and physical activity. J. Clin. Endocrinol. Metab. 82, 57–62 (1997)PubMedCrossRefGoogle Scholar
  10. 10.
    J.C. Prior, Y.M. Vigna, J.D. Wark, D.R. Eyre, B.C. Lentle, D.K. Li, P.R. Ebeling, L. Atley, Premenopausal ovariectomy-related bone loss: a randomized, double-blind, one-year trial of conjugated estrogen or medroxyprogesterone acetate. J. Bone Miner. Res. 12, 1851–1863 (1997). doi: 10.1359/jbmr.1997.12.11.1851 PubMedCrossRefGoogle Scholar
  11. 11.
    G. Theintz, B. Buchs, R. Rizzoli, D. Slosman, H. Clavien, P.C. Sizonenko, J.P. Bonjour, Longitudinal monitoring of bone mass accumulation in healthy adolescents: evidence for a marked reduction after 16 years of age at the levels of lumbar spine and femoral neck in female subjects. J. Clin. Endocrinol. Metab. 75, 1060–1065 (1992)PubMedCrossRefGoogle Scholar
  12. 12.
    C.H. Gravholt, P. Vestergaard, A.P. Hermann, L. Mosekilde, K. Brixen, J.S. Christiansen, Increased fracture rates in Turner’s syndrome: a nationwide questionnaire survey. Clin. Endocrinol. (Oxf.) 59, 89–96 (2003)CrossRefGoogle Scholar
  13. 13.
    K. Landin-Wilhelmsen, I. Bryman, M. Windh, L. Wilhelmsen, Osteoporosis and fractures in Turner syndrome-importance of growth promoting and oestrogen therapy. Clin. Endocrinol. (Oxf.) 51, 497–502 (1999)CrossRefGoogle Scholar
  14. 14.
    V.K. Bakalov, T. Shawker, I. Ceniceros, C.A. Bondy, Uterine development in Turner syndrome. J. Pediatr. 151, 528–531 (2007). doi: 10.1016/j.jpeds.2007.04.031 PubMedCrossRefGoogle Scholar
  15. 15.
    G. Khastgir, H. Abdalla, A. Thomas, L. Korea, L. Latarche, J. Studd, Oocyte donation in Turner’s syndrome: an analysis of the factors affecting the outcome. Hum. Reprod. 12, 279–285 (1997)PubMedCrossRefGoogle Scholar
  16. 16.
    J.L. Ross, G. Stefanatos, D. Roeltgen, H. Kushner, G.B. Cutler Jr., Ullrich–Turner syndrome: neurodevelopmental changes from childhood through adolescence. Am. J. Med. Genet. 58, 74–82 (1995). doi: 10.1002/ajmg.1320580115 PubMedCrossRefGoogle Scholar
  17. 17.
    C. Cunniff, K.L. Jones, K. Benirschke, Ovarian dysgenesis in individuals with chromosomal abnormalities. Hum. Genet. 86, 552–556 (1991)PubMedCrossRefGoogle Scholar
  18. 18.
    A.R. Zinn, V.S. Tonk, Z. Chen, W.L. Flejter, H.A. Gardner, R. Guerra, H. Kushner, S. Schwartz, V.P. Sybert, D.L. Van Dyke, J.L. Ross, Evidence for a Turner syndrome locus or loci at Xp11.2–p22.1. Am. J. Hum. Genet. 63, 1757–1766 (1998). doi: 10.1086/302152 PubMedCrossRefGoogle Scholar
  19. 19.
    D. Toniolo, F. Rizzolio, X chromosome and ovarian failure. Semin. Reprod. Med. 25, 264–271 (2007). doi: 10.1055/s-2007-980220 PubMedCrossRefGoogle Scholar
  20. 20.
    F. Rizzolio, S. Bione, C. Sala, M. Goegan, M. Gentile, G. Gregato, E. Rossi, T. Pramparo, O. Zuffardi, D. Toniolo, Chromosomal rearrangements in Xq and premature ovarian failure: mapping of 25 new cases and review of the literature. Hum. Reprod. 21, 1477–1483 (2006). doi: 10.1093/humrep/dei495 PubMedCrossRefGoogle Scholar
  21. 21.
    R.S. James, B. Coppin, P. Dalton, N.R. Dennis, C. Mitchell, A.J. Sharp, D.H. Skuse, N.S. Thomas, P.A. Jacobs, A study of females with deletions of the short arm of the X chromosome. Hum. Genet. 102, 507–516 (1998)PubMedCrossRefGoogle Scholar
  22. 22.
    N.H. Birkebaek, D. Cruger, J. Hansen, J. Nielsen, G. Bruun-Petersen, Fertility and pregnancy outcome in Danish women with Turner syndrome. Clin. Genet. 61, 35–39 (2002)PubMedCrossRefGoogle Scholar
  23. 23.
    M.I. Boechat, S.J. Westra, B. Lippe, Normal US appearance of ovaries and uterus in four patients with Turner’s syndrome and 45, X karyotype. Pediatr. Radiol. 26, 37–39 (1996)PubMedCrossRefGoogle Scholar
  24. 24.
    I. Bryman, L. Sylven, K. Berntorp, E. Innala, I. Bergstrom, C. Hanson, M. Oxholm, K. Landin-Wilhelmsen, Pregnancy rate and outcome in Swedish women with Turner syndrome. Fertil. Steril. 95, 2507–2510 (2011). doi: 10.1016/j.fertnstert.2010.12.039 PubMedCrossRefGoogle Scholar
  25. 25.
    O. Hovatta, Pregnancies in women with Turner’s syndrome. Ann. Med. 31, 106–110 (1999)PubMedGoogle Scholar
  26. 26.
    A.M. Pasquino, F. Passeri, I. Pucarelli, M. Segni, G. Municchi, Spontaneous pubertal development in Turner’s syndrome. Italian Study Group for Turner’s Syndrome. J. Clin. Endocrinol. Metab. 82, 1810–1813 (1997)PubMedCrossRefGoogle Scholar
  27. 27.
    K.H. Mortensen, M.D. Rohde, N. Uldbjerg, C.H. Gravholt, Repeated spontaneous pregnancies in 45,X Turner syndrome. Obstet. Gynecol. 115, 446–449 (2010). doi: 10.1097/AOG.0b013e3181cb5b2a PubMedCrossRefGoogle Scholar
  28. 28.
    T.N. Hadnott, H.N. Gould, A.M. Gharib, C.A. Bondy, Outcomes of spontaneous and assisted pregnancies in Turner syndrome: the U.S. National Institutes of Health experience. Fertil. Steril. 95, 2251–2256 (2011). doi: 10.1016/j.fertnstert.2011.03.085 PubMedCrossRefGoogle Scholar
  29. 29.
    C.A. Bondy, Care of girls and women with Turner syndrome: a guideline of the Turner Syndrome Study Group. J. Clin. Endocrinol. Metab. 92, 10–25 (2007). doi: 10.1210/jc.2006-1374 PubMedCrossRefGoogle Scholar
  30. 30.
    M. Schumacher, R. Guennoun, A. Ghoumari, C. Massaad, F. Robert, M. El-Etr, Y. Akwa, K. Rajkowski, E.E. Baulieu, Novel perspectives for progesterone in hormone replacement therapy, with special reference to the nervous system. Endocr. Rev. 28, 387–439 (2007). doi: 10.1210/er.2006-0050 PubMedCrossRefGoogle Scholar
  31. 31.
    Y. Yaron, Y. Ochshorn, A. Amit, I. Yovel, A. Kogosowki, J.B. Lessing, Patients with Turner’s syndrome may have an inherent endometrial abnormality affecting receptivity in oocyte donation. Fertil. Steril. 65, 1249–1252 (1996)PubMedGoogle Scholar
  32. 32.
    T. Foudila, V. Soderstrom-Anttila, O. Hovatta, Turner’s syndrome and pregnancies after oocyte donation. Hum. Reprod. 14, 532–535 (1999)PubMedCrossRefGoogle Scholar
  33. 33.
    M. Snajderova, T. Mardesic, J. Lebl, H. Gerzova, L. Teslik, J. Zapletalova, The uterine length in women with Turner syndrome reflects the postmenarcheal daily estrogen dose. Horm. Res. 60, 198–204 (2003). doi: 10.1159/000073233 PubMedCrossRefGoogle Scholar
  34. 34.
    L. Cleemann, K. Holm, E. Fallentin, S.O. Skouby, H. Smedegaard, N. Moller, H. Borch-Christensen, E.M. Jeppesen, S.B. Wieslander, A.M. Andersson, A. Cohen, G.C. Hojbjerg, Uterus and ovaries in girls and young women with Turner syndrome evaluated by ultrasound and magnetic resonance imaging. Clin. Endocrinol. (Oxf.) 74, 756–761 (2011). doi: 10.1111/j.1365-2265.2011.03995.x CrossRefGoogle Scholar
  35. 35.
    W.F. Paterson, A.S. Hollman, M.D. Donaldson, Poor uterine development in Turner syndrome with oral oestrogen therapy. Clin. Endocrinol. (Oxf.) 56, 359–365 (2002)CrossRefGoogle Scholar
  36. 36.
    J.G. Hreinsson, M. Otala, M. Fridstrom, B. Borgstrom, C. Rasmussen, M. Lundqvist, T. Tuuri, N. Simberg, M. Mikkola, L. Dunkel, O. Hovatta, Follicles are found in the ovaries of adolescent girls with Turner’s syndrome. J. Clin. Endocrinol. Metab. 87, 3618–3623 (2002)PubMedCrossRefGoogle Scholar
  37. 37.
    B. Borgstrom, J. Hreinsson, C. Rasmussen, M. Sheikhi, G. Fried, V. Keros, M. Fridstrom, O. Hovatta, Fertility preservation in girls with turner syndrome: prognostic signs of the presence of ovarian follicles. J. Clin. Endocrinol. Metab. 94, 74–80 (2009). doi: 10.1210/jc.2008-0708 PubMedGoogle Scholar
  38. 38.
    M.L. Davenport, N. Punyasavatsut, D. Gunther, L. Savendahl, P.W. Stewart, Turner syndrome: a pattern of early growth failure. Acta Paediatr. Suppl. 88, 118–121 (1999)PubMedCrossRefGoogle Scholar
  39. 39.
    A.J. Lyon, M.A. Preece, D.B. Grant, Growth curve for girls with Turner syndrome. Arch. Dis. Child. 60, 932–935 (1985)PubMedCrossRefGoogle Scholar
  40. 40.
    C.H. Gravholt, N.R. Weis, Reference values for body proportions and body composition in adult women with Ullrich–Turner syndrome. Am. J. Med. Genet. 72, 403–408 (1997). doi: 10.1002/(SICI)1096-8628(19971112)72:4<403:AID-AJMG6>3.0.CO;2-R PubMedCrossRefGoogle Scholar
  41. 41.
    C. Rongen-Westerlaken, L. Corel, J. van den Broeck, G. Massa, J. Karlberg, K. Albertsson-Wikland, J.M. Wit, Reference values for height, height velocity and weight in Turner’s syndrome. Swedish Study Group for GH treatment. Acta Paediatr. 86, 937–942 (1997)PubMedCrossRefGoogle Scholar
  42. 42.
    P. Rochiccioli, M. David, G. Malpuech, M. Colle, J.M. Limal, J. Battin, R. Mariani, C. Sultan, J.L. Nivelon, G. Simonin, Study of final height in Turner’s syndrome: ethnic and genetic influences. Acta Paediatr. 83, 305–308 (1994)PubMedCrossRefGoogle Scholar
  43. 43.
    L.C. Low, C. Sham, E. Kwan, J. Karlberg, G. Tang, P.T. Cheung, H. Pang, W. Tse, B. But, C.M. Yu, S.T. Lam, Spontaneous growth in Chinese patients with Turner’s syndrome and influence of karyotype. Acta Paediatr. 86, 18–21 (1997)PubMedCrossRefGoogle Scholar
  44. 44.
    T. Kosho, K. Muroya, T. Nagai, M. Fujimoto, S. Yokoya, H. Sakamoto, T. Hirano, H. Terasaki, H. Ohashi, G. Nishimura, S. Sato, N. Matsuo, T. Ogata, Skeletal features and growth patterns in 14 patients with haploinsufficiency of SHOX: implications for the development of Turner syndrome. J. Clin. Endocrinol. Metab. 84, 4613–4621 (1999)PubMedCrossRefGoogle Scholar
  45. 45.
    M. Westwood, S.H. Tajbakhsh, K.W. Siddals, A.J. Whatmore, P.E. Clayton, Reduced pericellular sensitivity to IGF-I in fibroblasts from girls with Turner syndrome: a mechanism to impair clinical responses to GH. Pediatr. Res. 70, 25–30 (2011). doi: 10.1203/PDR.0b013e31821b570b PubMedCrossRefGoogle Scholar
  46. 46.
    A.J. Whatmore, L. Patel, P.E. Clayton, A pilot study to evaluate gene expression profiles in peripheral blood mononuclear cells (PBMCs) from children with GH deficiency and Turner syndrome in response to GH treatment. Clin. Endocrinol. (Oxf.) 70, 429–434 (2009). doi: 10.1111/j.1365-2265.2008.03477.x CrossRefGoogle Scholar
  47. 47.
    A. Barreca, D. Larizza, G. Damonte, M. Arvigo, P. Ponzani, A. Cesarone, C.F. Lo, F. Severi, G. Giordano, F. Minuto, Insulin-like growth factors (IGF-I and IGF-II) and IGF-binding protein-3 production by fibroblasts of patients with Turner’s syndrome in culture. J. Clin. Endocrinol. Metab. 82, 1041–1046 (1997)PubMedCrossRefGoogle Scholar
  48. 48.
    C.H. Gravholt, J.W. Chen, C. Oxvig, M.T. Overgaard, J.S. Christiansen, J. Frystyk, A. Flyvbjerg, The GH-IGF-IGFBP axis is changed in Turner syndrome: partial normalization by HRT. Growth Horm. IGF Res. 16, 332–339 (2006). doi: 10.1016/j.ghir.2006.09.001 PubMedCrossRefGoogle Scholar
  49. 49.
    T.C. Sas, S.M. de Muinck Keizer-Schrama, T. Stijnen, M. Jansen, B.J. Otten, J. Hoorweg-Nijman, T. Vulsma, G.G. Massa, C.W. Rouwe, H.M. Reeser, W.J. Gerver, J.J. Gosen, C. Rongen-Westerlaken, S.L. Drop, Normalization of height in girls with Turner syndrome after long-term growth hormone treatment: results of a randomized dose-response trial. J. Clin. Endocrinol. Metab. 84, 4607–4612 (1999)PubMedCrossRefGoogle Scholar
  50. 50.
    J.C. Carel, L. Mathivon, C. Gendrel, J.P. Ducret, J.L. Chaussain, Near normalization of final height with adapted doses of growth hormone in Turner’s syndrome. J. Clin. Endocrinol. Metab. 83, 1462–1466 (1998)PubMedCrossRefGoogle Scholar
  51. 51.
    E.M. Bannink, R.L. van der Palen, P.G. Mulder, S.M. de Muinck Keizer-Schrama, Long-term follow-up of GH-treated girls with Turner syndrome: BMI, blood pressure, body proportions. Horm. Res. 71, 336–342 (2009). doi: 10.1159/000223418 PubMedCrossRefGoogle Scholar
  52. 52.
    M.L. Davenport, B.J. Crowe, S.H. Travers, K. Rubin, J.L. Ross, P.Y. Fechner, D.F. Gunther, C. Liu, M.E. Geffner, K. Thrailkill, C. Huseman, A.J. Zagar, C.A. Quigley, Growth hormone treatment of early growth failure in toddlers with Turner syndrome: a randomized, controlled, multicenter trial. J. Clin. Endocrinol. Metab. 92, 3406–3416 (2007). doi: 10.1210/jc.2006-2874 PubMedCrossRefGoogle Scholar
  53. 53.
    C.A. Quigley, B.J. Crowe, D.G. Anglin, J.J. Chipman, Growth hormone and low dose estrogen in Turner syndrome: results of a United States multi-center trial to near-final height. J. Clin. Endocrinol. Metab. 87, 2033–2041 (2002)PubMedCrossRefGoogle Scholar
  54. 54.
    R. Eastell, Role of oestrogen in the regulation of bone turnover at the menarche. J. Endocrinol. 185, 223–234 (2005). doi: 10.1677/joe.1.06059 PubMedCrossRefGoogle Scholar
  55. 55.
    S.D. Chernausek, K.M. Attie, J.F. Cara, R.G. Rosenfeld, J. Frane, Growth hormone therapy of Turner syndrome: the impact of age of estrogen replacement on final height. Genentech, Inc., Collaborative Study Group. J. Clin. Endocrinol. Metab. 85, 2439–2445 (2000)PubMedCrossRefGoogle Scholar
  56. 56.
    Y.K. Van Pareren, S.M. de Muinck Keizer-Schrama, T. Stijnen, T.C. Sas, M. Jansen, B.J. Otten, J.J. Hoorweg-Nijman, T. Vulsma, W.H. Stokvis-Brantsma, C.W. Rouwe, H.M. Reeser, W.J. Gerver, J.J. Gosen, C. Rongen-Westerlaken, S.L. Drop, Final height in girls with turner syndrome after long-term growth hormone treatment in three dosages and low dose estrogens. J. Clin. Endocrinol. Metab. 88, 1119–1125 (2003)PubMedCrossRefGoogle Scholar
  57. 57.
    A.J. Weissberger, K.K. Ho, L. Lazarus, Contrasting effects of oral and transdermal routes of estrogen replacement therapy on 24-hour growth hormone (GH) secretion, insulin-like growth factor I, and GH-binding protein in postmenopausal women. J. Clin. Endocrinol. Metab. 72, 374–381 (1991)PubMedCrossRefGoogle Scholar
  58. 58.
    Y.J. Janssen, F. Helmerhorst, M. Frolich, F. Roelfsema, A switch from oral (2 mg/day) to transdermal (50 microg/day) 17beta-estradiol therapy increases serum insulin-like growth factor-I levels in recombinant human growth hormone (GH)-substituted women with GH deficiency. J. Clin. Endocrinol. Metab. 85, 464–467 (2000)PubMedCrossRefGoogle Scholar
  59. 59.
    R.L. Rosenfield, N. Devine, J.J. Hunold, N. Mauras, T. Moshang Jr., A.W. Root, Salutary effects of combining early very low-dose systemic estradiol with growth hormone therapy in girls with Turner syndrome. J. Clin. Endocrinol. Metab. 90, 6424–6430 (2005). doi: 10.1210/jc.2005-1081 PubMedCrossRefGoogle Scholar
  60. 60.
    L. Soriano-Guillen, J. Coste, E. Ecosse, J. Leger, M. Tauber, S. Cabrol, M. Nicolino, R. Brauner, J.L. Chaussain, J.C. Carel, Adult height and pubertal growth in Turner syndrome after treatment with recombinant growth hormone. J. Clin. Endocrinol. Metab. 90, 5197–5204 (2005). doi: 10.1210/jc.2005-0470 PubMedCrossRefGoogle Scholar
  61. 61.
    M. Taboada, R. Santenm, J. Lima, J. Hossain, R. Singh, K.O. Klein, N. Mauras, Pharmacokinetics and pharmacodynamics of oral and transdermal 17{beta} estradiol in girls with Turner syndrome. J. Clin. Endocrinol. Metab. (2011). doi: 10.1210/jc.2011-1449
  62. 62.
    C.H. Gravholt, R.W. Naeraa, S. Fisker, J.S. Christiansen, Body composition and physical fitness are major determinants of the growth hormone-insulin-like growth factor axis aberrations in adult Turner’s syndrome, with important modulations by treatment with 17 beta-estradiol. J. Clin. Endocrinol. Metab. 82, 2570–2577 (1997)PubMedCrossRefGoogle Scholar
  63. 63.
    E.R. Prossnitz, M. Barton, The G-protein-coupled estrogen receptor GPER in health and disease. Nat. Rev. Endocrinol. (2011). doi: 10.1038/nrendo.2011.122
  64. 64.
    J.L. Ross, D. Roeltgen, P. Feuillan, H. Kushner, G.B. Cutler Jr., Effects of estrogen on nonverbal processing speed and motor function in girls with Turner’s syndrome. J. Clin. Endocrinol. Metab. 83, 3198–3204 (1998)PubMedCrossRefGoogle Scholar
  65. 65.
    J.L. Ross, D. Roeltgen, P. Feuillan, H. Kushner, G.B. Cutler Jr., Use of estrogen in young girls with Turner syndrome: effects on memory. Neurology 54, 164–170 (2000)PubMedGoogle Scholar
  66. 66.
    J.L. Ross, C.A. Quigley, D. Cao, P. Feuillan, K. Kowal, J.J. Chipman, G.B. Cutler Jr., Growth hormone plus childhood low-dose estrogen in Turner’s syndrome. N. Engl. J. Med. 364, 1230–1242 (2011). doi: 10.1056/NEJMoa1005669 PubMedCrossRefGoogle Scholar
  67. 67.
    L. Cuttler, V.G. Van, F.A. Conte, S.L. Kaplan, M.M. Grumbach, Somatomedin-C levels in children and adolescents with gonadal dysgenesis: differences from age-matched normal females and effect of chronic estrogen replacement therapy. J. Clin. Endocrinol. Metab. 60, 1087–1092 (1985)PubMedCrossRefGoogle Scholar
  68. 68.
    P. Vestergaard, A.P. Hermann, H. Orskov, L. Mosekilde, Effect of sex hormone replacement on the insulin-like growth factor system and bone mineral: a cross-sectional and longitudinal study in 595 perimenopausal women participating in the Danish Osteoporosis Prevention Study. J. Clin. Endocrinol. Metab. 84, 2286–2290 (1999)PubMedCrossRefGoogle Scholar
  69. 69.
    K.C. Leung, G. Johannsson, G.M. Leong, K.K. Ho, Estrogen regulation of growth hormone action. Endocr. Rev. 25, 693–721 (2004). doi: 10.1210/er.2003-0035 PubMedCrossRefGoogle Scholar
  70. 70.
    D.S. Huang, A.J. O’Sullivan, Short-term oral oestrogen therapy dissociates the growth hormone/insulin-like growth factor-I axis without altering energy metabolism in premenopausal women. Growth Horm. IGF Res. 19, 162–167 (2009). doi: 10.1016/j.ghir.2008.08.009 PubMedCrossRefGoogle Scholar
  71. 71.
    A. Cano, C. Castelo-Branco, J.J. Tarin, Effect of menopause and different combined estradiol-progestin regimens on basal and growth hormone-releasing hormone-stimulated serum growth hormone, insulin-like growth factor-1, insulin-like growth factor binding protein (IGFBP)-1, and IGFBP-3 levels. Fertil. Steril. 71, 261–267 (1999)PubMedCrossRefGoogle Scholar
  72. 72.
    F. Bidlingmaier, T.M. Strom, H.G. Dorr, W. Eisenmenger, D. Knorr, Estrone and estradiol concentrations in human ovaries, testes, and adrenals during the first two years of life. J. Clin. Endocrinol. Metab. 65, 862–867 (1987)PubMedCrossRefGoogle Scholar
  73. 73.
    B.S. McEwen, How do sex and stress hormones affect nerve cells? Ann. N Y Acad. Sci. 743, 1–16 (1994)PubMedCrossRefGoogle Scholar
  74. 74.
    S.M. Romans, G. Stefanatos, D.P. Roeltgen, H. Kushner, J.L. Ross, Transition to young adulthood in Ullrich–Turner syndrome: neurodevelopmental changes. Am. J. Med. Genet. 79, 140–147 (1998). doi: 10.1002/(SICI)1096-8628(19980901)79:2<140:AID-AJMG10>3.0.CO;2-J PubMedCrossRefGoogle Scholar
  75. 75.
    J. Downey, E.J. Elkin, A.A. Ehrhardt, H.F. Meyer-Bahlburg, J.J. Bell, A. Morishima, Cognitive ability and everyday functioning in women with Turner syndrome. J. Learn. Disabil. 24, 32–39 (1991)PubMedCrossRefGoogle Scholar
  76. 76.
    A. Swillen, J.P. Fryns, A. Kleczkowska, G. Massa, M. Vanderschueren-Lodeweyckx, H. Van den Berghe, Intelligence, behaviour and psychosocial development in Turner syndrome. A cross-sectional study of 50 pre-adolescent and adolescent girls (4–20 years). Genet. Couns. 4, 7–18 (1993)PubMedGoogle Scholar
  77. 77.
    B.B. Sherwin, Estrogenic effects on memory in women. Ann. N Y Acad. Sci. 743, 213–230 (1994)PubMedCrossRefGoogle Scholar
  78. 78.
    R. Schmidt, F. Fazekas, B. Reinhart, P. Kapeller, G. Fazekas, H. Offenbacher, B. Eber, M. Schumacher, W. Freidl, ) Estrogen replacement therapy in older women: a neuropsychological and brain MRI study. J. Am. Geriatr. Soc. 44, 1307–1313 (1996)PubMedGoogle Scholar
  79. 79.
    D.M. Jacobs, M.X. Tang, Y. Stern, M. Sano, K. Marder, K.L. Bell, P. Schofield, G. Dooneief, B. Gurland, R. Mayeux, Cognitive function in nondemented older women who took estrogen after menopause. Neurology 50, 368–373 (1998)PubMedGoogle Scholar
  80. 80.
    J. Ross, D. Roeltgen, A. Zinn, Cognition and the sex chromosomes: studies in Turner syndrome. Horm. Res. 65, 47–56 (2006). doi: 10.1159/000090698 PubMedCrossRefGoogle Scholar
  81. 81.
    J.L. Ross, D. Roeltgen, G.A. Stefanatos, P. Feuillan, H. Kushner, C. Bondy, G. B. J. Cutler Jr, Androgen-responsive aspects of cognition in girls with Turner syndrome. J. Clin. Endocrinol. Metab. 88, 292–296 (2003)PubMedCrossRefGoogle Scholar
  82. 82.
    J.L. Ross, M.M. Mazzocco, H. Kushner, K. Kowal Jr., G.B. Cutler, D. Roeltgen, Effects of treatment with oxandrolone for 4 years on the frequency of severe arithmetic learning disability in girls with Turner syndrome. J. Pediatr. 155, 714–720 (2009). doi: 10.1016/j.jpeds.2009.05.031 PubMedCrossRefGoogle Scholar
  83. 83.
    L.A. Menke, T.C. Sas, M. Visser, B.P. Kreukels, T. Stijnen, G.R. Zandwijken, S.M. de Muinck Keizer-Schrama, B.J. Otten, J.M. Wit, P.T. Cohen-Kettenis, The effect of the weak androgen oxandrolone on psychological and behavioral characteristics in growth hormone-treated girls with Turner syndrome. Horm. Behav. 57, 297–305 (2010). doi: 10.1016/j.yhbeh.2009.12.011 PubMedCrossRefGoogle Scholar
  84. 84.
    L. Sylven, C. Magnusson, K. Hagenfeldt, von, S. B., Life with Turner’s syndrome—a psychosocial report from 22 middle-aged women. Acta Endocrinol. (Cph.) 129, 188–194 (1993)Google Scholar
  85. 85.
    N. Stahnke, E. Keller, H. Landy, Favorable final height outcome in girls with Ullrich–Turner syndrome treated with low-dose growth hormone together with oxandrolone despite starting treatment after 10 years of age. J. Pediatr. Endocrinol. Metab. 15, 129–138 (2002)PubMedCrossRefGoogle Scholar
  86. 86.
    R.G. Rosenfeld, J. Frane, K.M. Attie, J.A. Brasel, S. Burstein, J.F. Cara, S. Chernausek, R.W. Gotlin, J. Kuntze, B.M. Lippe et al., Six-year results of a randomized, prospective trial of human growth hormone and oxandrolone in Turner syndrome. J. Pediatr. 121, 49–55 (1992)PubMedCrossRefGoogle Scholar
  87. 87.
    R.G. Rosenfeld, K.M. Attie, J. Frane, J.A. Brasel, S. Burstein, J.F. Cara, S. Chernausek, R.W. Gotlin, J. Kuntze, B.M. Lippe, C.P. Mahoney, W.V. Moore, P. Saenger, A.J. Johanson, Growth hormone therapy of Turner’s syndrome: beneficial effect on adult height. J. Pediatr. 132, 319–324 (1998)PubMedCrossRefGoogle Scholar
  88. 88.
    K.O. Nilsson, K. Albertsson-Wikland, J. Alm, S. Aronson, J. Gustafsson, L. Hagenas, A. Hager, S.A. Ivarsson, J. Karlberg, B. Kristrom, C. Marcus, C. Moell, M. Ritzen, T. Tuvemo, C. Wattsgard, U. Westgren, O. Westphal, J. Aman, Improved final height in girls with Turner’s syndrome treated with growth hormone and oxandrolone. J. Clin. Endocrinol. Metab. 81, 635–640 (1996)PubMedCrossRefGoogle Scholar
  89. 89.
    R.W. Naeraa, J. Nielsen, I.L. Pedersen, K. Sorensen, Effect of oxandrolone on growth and final height in Turner’s syndrome. Acta Paediatr. Scand. 79, 784–789 (1990)PubMedCrossRefGoogle Scholar
  90. 90.
    E. Joss, K. Zuppinger, Oxandrolone in girls with Turner’s syndrome. A pair-matched controlled study up to final height. Acta Paediatr. Scand. 73, 674–679 (1984)PubMedCrossRefGoogle Scholar
  91. 91.
    G. Haeusler, K. Schmitt, P. Blumel, E. Plochl, T. Waldhor, H. Frisch, Growth hormone in combination with anabolic steroids in patients with Turner syndrome: effect on bone maturation and final height. Acta Paediatr. 85, 1408–1414 (1996)PubMedGoogle Scholar
  92. 92.
    E.J. Gault, R.J. Perry, T.J. Cole, S. Casey, W.F. Paterson, P.C. Hindmarsh, P. Betts, D.B. Dunger, M.D. Donaldson, Effect of oxandrolone and timing of pubertal induction on final height in Turner’s syndrome: randomised, double blind, placebo controlled trial. BMJ 342, d1980 (2011)PubMedCrossRefGoogle Scholar
  93. 93.
    V.P. Sybert, Adult height in Turner syndrome with and without androgen therapy. J. Pediatr. 104, 365–369 (1984)PubMedCrossRefGoogle Scholar
  94. 94.
    G. Haeusler, K. Schmitt, P. Blumel, E. Plochl, T. Waldhor, H. Frisch, Insulin, insulin-like growth factor-binding protein-1, and sex hormone-binding globulin in patients with Turner’s syndrome: course over age in untreated patients and effect of therapy with growth hormone alone and in combination with oxandrolone. J. Clin. Endocrinol. Metab. 81, 536–541 (1996)PubMedCrossRefGoogle Scholar
  95. 95.
    L.A. Menke, T.C. Sas, S.M. de Muinck Keizer-Schrama, G.R. Zandwijken, M.A. de Ridder, R.J. Odink, M. Jansen, H.A. Delemarre-van de Waal, W.H. Stokvis-Brantsma, J.J. Waelkens, C. Westerlaken, H.M. Reeser, A.S. van Trotsenburg, E.F. Gevers, S. van Buuren, P.H. Dejonckere, A.C. Hokken-Koelega, B.J. Otten, J.M. Wit, Efficacy and safety of oxandrolone in growth hormone-treated girls with turner syndrome. J. Clin. Endocrinol. Metab. 95, 1151–1160 (2010). doi: 10.1210/jc.2009-1821 PubMedCrossRefGoogle Scholar
  96. 96.
    L.A. Menke, T.C. Sas, T. Stijnen, G.R. Zandwijken, S.M. de Muinck Keizer-Schrama, B.J. Otten, J.M. Wit, Effect of oxandrolone on glucose metabolism in growth hormone-treated girls with Turner syndrome. Horm. Res. Paediatr. 75, 115–122 (2011). doi: 10.1159/000319313 PubMedCrossRefGoogle Scholar
  97. 97.
    M.P. Zeger, K. Shah, K. Kowal Jr., G.B. Cutler, H. Kushner, J.L. Ross, Prospective study confirms oxandrolone-associated improvement in height in growth hormone-treated adolescent girls with Turner syndrome. Horm. Res. Paediatr. 75, 38–46 (2011). doi: 10.1159/000317529 PubMedCrossRefGoogle Scholar
  98. 98.
    N. Zuckerman-Levin, T. Frolova-Bishara, D. Militianu, M. Levin, J. Aharon-Peretz, Z. Hochberg, Androgen replacement therapy in Turner syndrome: a pilot study. J. Clin. Endocrinol. Metab. 94, 4820–4827 (2009). doi: 10.1210/jc.2009-0514 PubMedCrossRefGoogle Scholar
  99. 99.
    G. Andersson-Wallgren, K. Albertsson-Wikland, Change in speaking fundamental frequency in hormone-treated patients with Turner’s syndrome—a longitudinal study of four cases. Acta Paediatr. 83, 452–455 (1994)PubMedCrossRefGoogle Scholar
  100. 100.
    L.A. Menke, T.C. Sas, G.R. Zandwijken, M.A. de Ridde, T. Stijnen, S.M. de MuinckKeizer-Schrama, B.J. Otten, J.M. Wit, The effect of oxandrolone on body proportions and body composition in growth hormone-treated girls with Turner syndrome. Clin. Endocrinol. (Oxf.) 73, 212–219 (2010). doi: 10.1111/j.1365-2265.2010.03789.x Google Scholar
  101. 101.
    M.C. Davies, B. Gulekli, H.S. Jacobs, Osteoporosis in Turner’s syndrome and other forms of primary amenorrhoea. Clin. Endocrinol. (Oxf.) 43, 741–746 (1995)CrossRefGoogle Scholar
  102. 102.
    J.L. Ross, L.M. Long, P. Feuillan, F. Cassorla, G.B. Cutler Jr., Normal bone density of the wrist and spine and increased wrist fractures in girls with Turner’s syndrome. J. Clin. Endocrinol. Metab. 73, 355–359 (1991)PubMedCrossRefGoogle Scholar
  103. 103.
    N. Zuckerman-Levin, I. Yaniv, T. Schwartz, H. Guttmann, Z. Hochberg, Normal DXA bone mineral density but frail cortical bone in Turner’s syndrome. Clin. Endocrinol. (Oxf.) 67, 60–64 (2007). doi: 10.1111/j.1365-2265.2007.02835.x CrossRefGoogle Scholar
  104. 104.
    V.K. Bakalov, L. Axelrod, J. Baron, L. Hanton, L.M. Nelson, J.C. Reynolds, S. Hill, J. Troendle, C.A. Bondy, Selective reduction in cortical bone mineral density in turner syndrome independent of ovarian hormone deficiency. J. Clin. Endocrinol. Metab. 88, 5717–5722 (2003)PubMedCrossRefGoogle Scholar
  105. 105.
    C.H. Gravholt, A.L. Lauridsen, K. Brixen, L. Mosekilde, L. Heickendorff, J.S. Christiansen, Marked disproportionality in bone size and mineral, and distinct abnormalities in bone markers and calcitropic hormones in adult turner syndrome: a cross-sectional study. J. Clin. Endocrinol. Metab. 87, 2798–2808 (2002)PubMedCrossRefGoogle Scholar
  106. 106.
    R.W. Naeraa, K. Brixen, R.M. Hansen, C. Hasling, L. Mosekilde, J.H. Andresen, P. Charles, J. Nielsen, Skeletal size and bone mineral content in Turner’s syndrome: relation to karyotype, estrogen treatment, physical fitness, and bone turnover. Calcif. Tissue Int. 49, 77–83 (1991)PubMedCrossRefGoogle Scholar
  107. 107.
    A. Carrascosa, M. Gussinye, P. Terradas, D. Yeste, L. Audi, E. Vicens-Calvet, Spontaneous, but not induced, puberty permits adequate bone mass acquisition in adolescent Turner syndrome patients. J. Bone Miner. Res. 15, 2005–2010 (2000). doi: 10.1359/jbmr.2000.15.10.2005 PubMedCrossRefGoogle Scholar
  108. 108.
    S.J. Emans, E. Grace, F.A. Hoffer, C. Gundberg, V. Ravnikar, E.R. Woods, Estrogen deficiency in adolescents and young adults: impact on bone mineral content and effects of estrogen replacement therapy. Obstet. Gynecol. 76, 585–592 (1990)PubMedGoogle Scholar
  109. 109.
    J.P. Sabatier, G. Guaydier-Souquieres, D. Laroche, A. Benmalek, L. Fournier, F. Guillon-Metz, J. Delavenne, A.Y. Denis, Bone mineral acquisition during adolescence and early adulthood: a study in 574 healthy females 10–24 years of age. Osteoporos. Int. 6, 141–148 (1996)PubMedCrossRefGoogle Scholar
  110. 110.
    Z. Harel, M. Gold, B. Cromer, A. Bruner, M. Stager, L. Bachrach, K. Wolter, C. Reid, P. Hertweck, A. Nelson, D. Nelson, S. Coupey, C. Johnson, R. Burkman, H. Bone, Bone mineral density in postmenarchal adolescent girls in the United States: associated biopsychosocial variables and bone turnover markers. J. Adolesc. Health 40, 44–53 (2007). doi: 10.1016/j.jadohealth.2006.08.013 PubMedCrossRefGoogle Scholar
  111. 111.
    D.M. Brown, J. Jowsey, D.S. Bradford, Osteoporosis in ovarian dysgenesis. J. Pediatr. 84, 816–820 (1974)PubMedCrossRefGoogle Scholar
  112. 112.
    A.S. Garden, M.J. Diver, W.D. Fraser, Undiagnosed morbidity in adult women with Turner’s syndrome. Clin. Endocrinol. (Oxf.) 45, 589–593 (1996)CrossRefGoogle Scholar
  113. 113.
    S. Pors Nielsen, N. Kolthoff, O. Barenholdt, B. Kristensen, B. Abrahamsen, A.P. Hermann, C. Brot, Diagnosis of osteoporosis by planar bone densitometry: can body size be disregarded? Br. J. Radiol. 71, 934–943 (1998)PubMedGoogle Scholar
  114. 114.
    R.M. Shore, R.W. Chesney, R.B. Mazess, P.G. Rose, G.J. Bargman, Skeletal demineralization in Turner’s syndrome. Calcif. Tissue Int. 34, 519–522 (1982)PubMedCrossRefGoogle Scholar
  115. 115.
    J.J. Stepan, J. Musilova, V. Pacovsky, Bone demineralization, biochemical indices of bone remodeling, and estrogen replacement therapy in adults with Turner’s syndrome. J. Bone Miner. Res. 4, 193–198 (1989). doi: 10.1002/jbmr.5650040210 PubMedCrossRefGoogle Scholar
  116. 116.
    L. Sylven, K. Hagenfeldt, H. Ringertz, Bone mineral density in middle-aged women with Turner’s syndrome. Eur. J. Endocrinol. 132, 47–52 (1995)PubMedCrossRefGoogle Scholar
  117. 117.
    S. Mora, G. Weber, M.P. Guarneri, G. Nizzoli, D. Pasolini, G. Chiumello, Effect of estrogen replacement therapy on bone mineral content in girls with Turner syndrome. Obstet. Gynecol. 79, 747–751 (1992)PubMedGoogle Scholar
  118. 118.
    N. Mauras, N.E. Vieira, A.L. Yergey, Estrogen therapy enhances calcium absorption and retention and diminishes bone turnover in young girls with Turner’s syndrome: a calcium kinetic study. Metabolism 46, 908–913 (1997)PubMedCrossRefGoogle Scholar
  119. 119.
    S. Bertelloni, L. Cinquanta, G.I. Baroncelli, P. Simi, S. Rossi, G. Saggese, Volumetric bone mineral density in young women with Turner’s syndrome treated with estrogens or estrogens plus growth hormone. Horm. Res. 53, 72–76 (2000)PubMedCrossRefGoogle Scholar
  120. 120.
    T.C. Sas, S.M. de Muinck Keizer-Schrama, T. Stijnen, A. van Teunenbroek, W.J. van Leeuwen, A. Asarfi, R.R. van Rijn, S.L. Drop, Bone mineral density assessed by phalangeal radiographic absorptiometry before and during long-term growth hormone treatment in girls with Turner’s syndrome participating in a randomized dose-response study. Pediatr. Res. 50, 417–422 (2001)PubMedCrossRefGoogle Scholar
  121. 121.
    W. Hogler, J. Briody, B. Moore, S. Garnett, P.W. Lu, C.T. Cowell, Importance of estrogen on bone health in Turner syndrome: a cross-sectional and longitudinal study using dual-energy X-ray absorptiometry. J. Clin. Endocrinol. Metab. 89, 193–199 (2004)PubMedCrossRefGoogle Scholar
  122. 122.
    O. Soucek, J. Lebl, M. Snajderova, S. Kolouskova, M. Rocek, Z. Hlavka, O. Cinek, J. Rittweger, Z. Sumnik, Bone geometry and volumetric bone mineral density in girls with Turner syndrome of different pubertal stages. Clin. Endocrinol. (Oxf.) 74, 445–452 (2011). doi: 10.1111/j.1365-2265.2010.03955.x CrossRefGoogle Scholar
  123. 123.
    M.A. Smith, J. Wilson, W.H. Price, Bone demineralisation in patients with Turner’s syndrome. J. Med. Genet. 19, 100–103 (1982)PubMedCrossRefGoogle Scholar
  124. 124.
    V.K. Bakalov, M.L. Chen, J. Baron, L.B. Hanton, J.C. Reynolds, C.A. Stratakis, L.E. Axelrod, C.A. Bondy, Bone mineral density and fractures in Turner syndrome. Am. J. Med. 115, 259–264 (2003)PubMedCrossRefGoogle Scholar
  125. 125.
    T.S. Han, B. Cadge, G.S. Conway, Hearing impairment and low bone mineral density increase the risk of bone fractures in women with Turner’s syndrome. Clin. Endocrinol. (Oxf.) 65, 643–647 (2006). doi: 10.1111/j.1365-2265.2006.02643.x CrossRefGoogle Scholar
  126. 126.
    P. Pitukcheewanont, N. Numbenjapon, D. Safani, S. Rossmiller, V. Gilsanz, G. Costin, Bone size and density measurements in prepubertal children with Turner syndrome prior to growth hormone therapy. Osteoporos. Int. 22, 1709–1715 (2011). doi: 10.1007/s00198-010-1375-2 PubMedCrossRefGoogle Scholar
  127. 127.
    N. Nissen, C.H. Gravholt, B. Abrahamsen, E.M. Hauge, J.E. Jensen, L. Mosekilde, K. Brixen, Disproportional geometry of the proximal femur in patients with Turner syndrome: a cross-sectional study. Clin. Endocrinol. (Oxf.) 67, 897–903 (2007). doi: 10.1111/j.1365-2265.2007.02984.x CrossRefGoogle Scholar
  128. 128.
    S. Bechtold, F. Rauch, V. Noelle, S. Donhauser, C.M. Neu, E. Schoenau, H.P. Schwarz, Musculoskeletal analyses of the forearm in young women with Turner syndrome: a study using peripheral quantitative computed tomography. J. Clin. Endocrinol. Metab. 86, 5819–5823 (2001)PubMedCrossRefGoogle Scholar
  129. 129.
    F. Buzi, G. Maccarinelli, B. Guaragni, F. Ruggeri, G. Radetti, A. Meini, E. Mazzolari, D. Cocchi, Serum osteoprotegerin and receptor activator of nuclear factors kB (RANKL) concentrations in normal children and in children with pubertal precocity, Turner’s syndrome and rheumatoid arthritis. Clin. Endocrinol. (Oxf.) 60, 87–91 (2004)CrossRefGoogle Scholar
  130. 130.
    G. Khastgir, J.W. Studd, S.W. Fox, J. Jones, J. Alaghband-Zadeh, J.W. Chow, A longitudinal study of the effect of subcutaneous estrogen replacement on bone in young women with Turner’s syndrome. J. Bone Miner. Res. 18, 925–932 (2003). doi: 10.1359/jbmr.2003.18.5.925 PubMedCrossRefGoogle Scholar
  131. 131.
    L. Cleemann, B.E. Hjerrild, A.L. Lauridsen, L. Heickendorff, J.S. Christiansen, L. Mosekilde, C.H. Gravholt, Long-term hormone replacement therapy preserves bone mineral density in Turner syndrome. Eur. J. Endocrinol. 161, 251–257 (2009). doi: 10.1530/EJE-09-0020 PubMedCrossRefGoogle Scholar
  132. 132.
    L. Cleemann, K. Holm, H. Kobbernagel, S.O., Skouby, B., Kristensen, H., Smedegaard, A.M., Andersson, A., Cohen, C.H. Gravholt, Normal tempo of bone formation in Turner syndrome despite signs of accelerated bone resorption. Horm. Res. Paediatr. (2011). doi: 10.1159/000329046
  133. 133.
    H.M. Frost, On the estrogen–bone relationship and postmenopausal bone loss: a new model. J. Bone Miner. Res. 14, 1473–1477 (1999). doi: 10.1359/jbmr.1999.14.9.1473 PubMedCrossRefGoogle Scholar
  134. 134.
    W. Hogler, N. Shaw, Childhood growth hormone deficiency, bone density, structures and fractures: scrutinizing the evidence. Clin. Endocrinol. (Oxf.) 72, 281–289 (2010). doi: 10.1111/j.1365-2265.2009.03686.x CrossRefGoogle Scholar
  135. 135.
    J.R. Buchanan, C. Myers, T. Lloyd, P. Leuenberger, L.M. Demers, Determinants of peak trabecular bone density in women: the role of androgens, estrogen, and exercise. J. Bone Miner. Res. 3, 673–680 (1988). doi: 10.1002/jbmr.5650030613 PubMedCrossRefGoogle Scholar
  136. 136.
    V.K. Bakalov, M.M. Cooley, M.J. Quon, M.L. Luo, J.A. Yanovski, L.M. Nelson, G. Sullivan, C.A. Bondy, Impaired insulin secretion in the Turner metabolic syndrome. J. Clin. Endocrinol. Metab. 89, 3516–3520 (2004). doi: 10.1210/jc.2004-0122 PubMedCrossRefGoogle Scholar
  137. 137.
    R. Giordano, D. Forno, F. Lanfranco, C. Manieri, L. Ghizzoni, E. Ghigo, Metabolic and cardiovascular outcomes in a group of adult patients with Turner’s syndrome under hormonal replacement therapy. Eur. J. Endocrinol. 164, 819–826 (2011). doi: 10.1530/EJE-11-0002 PubMedCrossRefGoogle Scholar
  138. 138.
    C.H. Gravholt, R.W. Naeraa, B. Nyholm, L.U. Gerdes, E. Christiansen, O. Schmitz, J.S. Christiansen, Glucose metabolism, lipid metabolism, and cardiovascular risk factors in adult Turner’s syndrome. The impact of sex hormone replacement. Diabetes Care 21, 1062–1070 (1998)PubMedCrossRefGoogle Scholar
  139. 139.
    R.W. Holl, D. Kunze, H. Etzrodt, W. Teller, E. Heinze, Turner syndrome: final height, glucose tolerance, bone density and psychosocial status in 25 adult patients. Eur. J. Pediatr. 153, 11–16 (1994)PubMedCrossRefGoogle Scholar
  140. 140.
    C.H. Gravholt, Epidemiological, endocrine and metabolic features in Turner syndrome. Eur. J. Endocrinol. 151, 657–687 (2004)PubMedCrossRefGoogle Scholar
  141. 141.
    S. Caprio, S. Boulware, M. Diamond, R.S. Sherwin, T.O. Carpenter, K. Rubin, S. Amiel, M. Press, W.V. Tamborlane, Insulin resistance: an early metabolic defect of Turner’s syndrome. J. Clin. Endocrinol. Metab. 72, 832–836 (1991)PubMedCrossRefGoogle Scholar
  142. 142.
    B.E. Hjerrild, J.J. Holst, C.B. Juhl, J.S. Christiansen, O. Schmitz, C.H. Gravholt, Delayed beta-cell response and glucose intolerance in young women with Turner syndrome. BMC Endocr. Disord. 11, 6 (2011). doi: 10.1186/1472-6823-11-6 PubMedCrossRefGoogle Scholar
  143. 143.
    L. Sylven, K. Hagenfeldt, K. Brondum-Nielsen, B. von Schoultz, Middle-aged women with Turner’s syndrome. Medical status, hormonal treatment and social life. Acta Endocrinol. (Cph.) 125, 359–365 (1991)Google Scholar
  144. 144.
    M. El-Mansoury, K. Berntorp, I. Bryman, C. Hanson, E. Innala, A. Karlsson, K. Landin-Wilhelmsen, Elevated liver enzymes in Turner syndrome during a 5-year follow-up study. Clin. Endocrinol. (Oxf.) 68, 485–490 (2008). doi: 10.1111/j.1365-2265.2007.03166.x CrossRefGoogle Scholar
  145. 145.
    R.J. Chetkowski, D.R. Meldrum, K.A. Steingold, D. Randle, J.K. Lu, P. Eggena, J.M. Hershman, N.K. Alkjaersig, A.P. Fletcher, H.L. Judd, Biologic effects of transdermal estradiol. N. Engl. J. Med. 314, 1615–1620 (1986). doi: 10.1056/NEJM198606193142505 PubMedCrossRefGoogle Scholar
  146. 146.
    N. Jospe, C.C. Orlowski, R.W. Furlanetto, Comparison of transdermal and oral estrogen therapy in girls with Turner’s syndrome. J. Pediatr. Endocrinol. Metab. 8, 111–116 (1995)PubMedCrossRefGoogle Scholar
  147. 147.
    H. Guttmann, Z. Weiner, E. Nikolski, S. Ish-Shalom, J. Itskovitz-Eldor, M. Aviram, S. Reisner, Z. Hochberg, Choosing an oestrogen replacement therapy in young adult women with Turner syndrome. Clin. Endocrinol. (Oxf.) 54, 159–164 (2001)CrossRefGoogle Scholar
  148. 148.
    O. Koulouri, J. Ostberg, G.S. Conway, Liver dysfunction in Turner’s syndrome: prevalence, natural history and effect of exogenous oestrogen. Clin. Endocrinol. (Oxf.) 69, 306–310 (2008). doi: 10.1111/j.1365-2265.2008.03203.x CrossRefGoogle Scholar
  149. 149.
    M. Elsheikh, H.J. Hodgson, J.A. Wass, G.S. Conway, Hormone replacement therapy may improve hepatic function in women with Turner’s syndrome. Clin. Endocrinol. (Oxf.) 55, 227–231 (2001)CrossRefGoogle Scholar
  150. 150.
    C. Host, J.J. Christiansen, J.S. Christiansen, J.O. Jorgensen, C.H. Gravholt, Discontinuation of hormone replacement therapy in young GH-treated hypopituitary women increases liver enzymes. Growth Horm. IGF Res. 20, 26–30 (2010). doi: 10.1016/j.ghir.2009.07.001 PubMedCrossRefGoogle Scholar
  151. 151.
    J. McKenzie, B.M. Fisher, A.J. Jaap, A. Stanley, K. Paterson, N. Sattar, Effects of HRT on liver enzyme levels in women with type 2 diabetes: a randomized placebo-controlled trial. Clin. Endocrinol. (Oxf.) 65, 40–44 (2006). doi: 10.1111/j.1365-2265.2006.02543.x CrossRefGoogle Scholar
  152. 152.
    C.H. Gravholt, H.E. Poulsen, P. Ott, J.S. Christiansen, H. Vilstrup, Quantitative liver functions in Turner syndrome with and without hormone replacement therapy. Eur. J. Endocrinol. 156, 679–686 (2007). doi: 10.1530/EJE-07-0070 PubMedCrossRefGoogle Scholar
  153. 153.
    D. Roulot, C. Degott, O. Chazouilleres, F. Oberti, P. Cales, N. Carbonell, S. Benferhat, S. Bresson-Hadni, D. Valla, Vascular involvement of the liver in Turner’s syndrome. Hepatology 39, 239–247 (2004). doi: 10.1002/hep.20026 PubMedCrossRefGoogle Scholar
  154. 154.
    S. Sipila, D.R. Taaffe, S. Cheng, J. Puolakka, J. Toivanen, H. Suominen, Effects of hormone replacement therapy and high-impact physical exercise on skeletal muscle in post-menopausal women: a randomized placebo-controlled study. Clin. Sci. (Lond.) 101, 147–157 (2001)CrossRefGoogle Scholar
  155. 155.
    S.K. Phillips, K.M. Rook, N.C. Siddle, S.A. Bruce, R.C. Woledge, Muscle weakness in women occurs at an earlier age than in men, but strength is preserved by hormone replacement therapy. Clin. Sci. (Lond.) 84, 95–98 (1993)Google Scholar
  156. 156.
    C.H. Gravholt, B.E. Hjerrild, L. Mosekilde, T.K. Hansen, L.M. Rasmussen, J. Frystyk, A. Flyvbjerg, J.S. Christiansen, Body composition is distinctly altered in Turner syndrome: relations to glucose metabolism, circulating adipokines, and endothelial adhesion molecules. Eur. J. Endocrinol. 155, 583–592 (2006). doi: 10.1530/eje.1.02267 PubMedCrossRefGoogle Scholar
  157. 157.
    J.E. Rossouw, G.L. Anderson, R.L. Prentice, A.Z. LaCroix, C. Kooperberg, M.L. Stefanick, R.D. Jackson, S.A. Beresford, B.V. Howard, K.C. Johnson, J.M. Kotchen, J. Ockene, Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 288, 321–333 (2002)PubMedCrossRefGoogle Scholar
  158. 158.
    G.L. Anderson, M. Limacher, A.R. Assaf, T. Bassford, S.A. Beresford, H. Black, D. Bonds, R. Brunner, R. Brzyski, B. Caan, R. Chlebowski, D. Curb, M. Gass, J. Hays, G. Heiss, S. Hendrix, B.V. Howard, J. Hsia, A. Hubbell, R. Jackson, K.C. Johnson, H. Judd, J.M. Kotchen, L. Kuller, A.Z. LaCroix, D. Lane, R.D. Langer, N. Lasser, C.E. Lewis, J. Manson, K. Margolis, J. Ockene, M.J. O’Sullivan, L. Phillips, R.L. Prentice, C. Ritenbaugh, J. Robbins, J.E. Rossouw, G. Sarto, M.L. Stefanick, H.L. Van, J. Wactawski-Wende, R. Wallace, S. Wassertheil-Smoller, Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 291, 1701–1712 (2004). doi: 10.1001/jama.291.14.1701 PubMedCrossRefGoogle Scholar
  159. 159.
    J.L. Turgeon, M.C. Carr, P.M. Maki, M.E. Mendelsohn, P.M. Wise, Complex actions of sex steroids in adipose tissue, the cardiovascular system, and brain: Insights from basic science and clinical studies. Endocr. Rev. 27, 575–605 (2006). doi: 10.1210/er.2005-0020 PubMedCrossRefGoogle Scholar
  160. 160.
    S.M. Harman, E. Vittinghoff, E.A. Brinton, M.J. Budoff, M.I. Cedars, R.A. Lobo, G.R. Merriam, V.M. Miller, F. Naftolin, L. Pal, N. Santoro, H.S. Taylor, D.M. Black, Timing and duration of menopausal hormone treatment may affect cardiovascular outcomes. Am. J. Med. 124, 199–205 (2011). doi: 10.1016/j.amjmed.2010.09.021 PubMedCrossRefGoogle Scholar
  161. 161.
    M.N. Sack, D.J. Rader, R.O. Cannon III, Oestrogen and inhibition of oxidation of low-density lipoproteins in postmenopausal women. Lancet 343, 269–270 (1994)PubMedCrossRefGoogle Scholar
  162. 162.
    D.W. Losordo, M. Kearney, E.A. Kim, J. Jekanowski, J.M. Isner, Variable expression of the estrogen receptor in normal and atherosclerotic coronary arteries of premenopausal women. Circulation 89, 1501–1510 (1994)PubMedGoogle Scholar
  163. 163.
    K. Komukai, S. Mochizuki, M. Yoshimura, Gender and the renin-angiotensin-aldosterone system. Fundam. Clin. Pharmacol. 24, 687–698 (2010). doi: 10.1111/j.1472-8206.2010.00854.x PubMedCrossRefGoogle Scholar
  164. 164.
    N.C. Nathwani, R. Unwin, C.G. Brook, P.C. Hindmarsh, Blood pressure and Turner syndrome. Clin. Endocrinol. (Oxf.) 52, 363–370 (2000)CrossRefGoogle Scholar
  165. 165.
    K.H. Mortensen, K.W. Hansen, M. Erlandsen, J.S. Christiansen, C.H. Gravholt, Ambulatory arterial stiffness index in Turner syndrome: the impact of sex hormone replacement therapy. Horm. Res. 72, 184–189 (2009). doi: 10.1159/000232495 PubMedCrossRefGoogle Scholar
  166. 166.
    J.E. Ostberg, C. Storry, A.E. Donald, M.J. Attar, J.P. Halcox, G.S. Conway, A dose-response study of hormone replacement in young hypogonadal women: effects on intima media thickness and metabolism. Clin. Endocrinol. (Oxf.) 66, 557–564 (2007). doi: 10.1111/j.1365-2265.2007.02772.x Google Scholar
  167. 167.
    C.A. Bondy, P.L. Van, V.K. Bakalov, V. Sachdev, C.A. Malone, V.B. Ho, D.R. Rosing, Prolongation of the cardiac QTc interval in Turner syndrome. Medicine 85, 75–81 (2006). doi: 10.1097/01.md.0000205629.16302.bc PubMedCrossRefGoogle Scholar
  168. 168.
    P.R. Dalla, S. Bechtold, S. Kaab, M. Buckl, S. Urschel, H. Netz, H.P. Schwarz, QTc interval prolongation in children with Ulrich–Turner syndrome. Eur. J. Pediatr. 165, 831–837 (2006). doi: 10.1007/s00431-006-0194-0 CrossRefGoogle Scholar
  169. 169.
    Y. Zhang, P. Ouyang, W.S. Post, D. Dalal, D. Vaidya, E. Blasco-Colmenares, E.Z. Soliman, G.F. Tomaselli, E. Guallar, Sex-steroid hormones and electrocardiographic QT-interval duration: findings from the third national health and nutrition examination survey and the multi-ethnic study of atherosclerosis. Am. J. Epidemiol. 174, 403–411 (2011). doi: 10.1093/aje/kwr172 PubMedCrossRefGoogle Scholar
  170. 170.
    C. van Noord, E.M. Rodenburg, B.H. Striker, Invited commentary: sex-steroid hormones and QT-interval duration. Am. J. Epidemiol. 174, 412–415 (2011). doi: 10.1093/aje/kwr170 PubMedCrossRefGoogle Scholar
  171. 171.
    Y.M. Shuba, V.E. Degtiar, V.N. Osipenko, V.G. Naidenov, R.L. Woosley, Testosterone-mediated modulation of HERG blockade by proarrhythmic agents. Biochem. Pharmacol. 62, 41–49 (2001)PubMedCrossRefGoogle Scholar
  172. 172.
    K.T. Jorgensen, K. Rostgaard, I. Bache, R.J. Biggar, N.M. Nielsen, N. Tommerup, M. Frisch, Autoimmune diseases in women with Turner’s syndrome. Arthritis Rheum. 62, 658–666 (2010). doi: 10.1002/art.27270 PubMedCrossRefGoogle Scholar
  173. 173.
    K.H. Mortensen, L. Cleemann, B.E. Hjerrild, E. Nexo, H. Locht, E.M. Jeppesen, C.H. Gravholt, Increased prevalence of autoimmunity in Turner syndrome—influence of age. Clin. Exp. Immunol. 156, 205–210 (2009). doi: 10.1111/j.1365-2249.2009.03895.x PubMedCrossRefGoogle Scholar
  174. 174.
    M. Elsheikh, J.A. Wass, G.S. Conway, Autoimmune thyroid syndrome in women with Turner’s syndrome—the association with karyotype. Clin. Endocrinol. (Oxf.) 55, 223–226 (2001)CrossRefGoogle Scholar
  175. 175.
    A.B. Pernis, Estrogen and CD4+ T cells. Curr. Opin. Rheumatol. 19, 414–420 (2007). doi: 10.1097/BOR.0b013e328277ef2a PubMedCrossRefGoogle Scholar
  176. 176.
    R.H. Straub, The complex role of estrogens in inflammation. Endocr. Rev. 28, 521–574 (2007). doi: 10.1210/er.2007-0001 PubMedCrossRefGoogle Scholar
  177. 177.
    S.P. Taback, V.G. Van, Health-related quality of life of young adults with Turner syndrome following a long-term randomized controlled trial of recombinant human growth hormone. BMC Pediatr. 11, 49 (2011). doi: 10.1186/1471-2431-11-49 PubMedCrossRefGoogle Scholar
  178. 178.
    L. Lasaite, D. Lasiene, L. Lasas, Cognition, emotions and quality of life in Lithuanian girls with Turner syndrome after growth hormone therapy discontinuation. J. Pediatr. Endocrinol. Metab. 23, 443–450 (2010)PubMedCrossRefGoogle Scholar
  179. 179.
    E. Amundson, U.W. Boman, M.L. Barrenas, I. Bryman, K. Landin-Wilhelmsen, Impact of growth hormone therapy on quality of life in adults with turner syndrome. J. Clin. Endocrinol. Metab. 95, 1355–1359 (2010). doi: 10.1210/jc.2009-1754 PubMedCrossRefGoogle Scholar
  180. 180.
    L. Baxter, J. Bryant, C.B. Cave, R. Milne, Recombinant growth hormone for children and adolescents with Turner syndrome. Cochrane Database Syst. Rev. CD003887 (2007). doi:10.1002/14651858.CD003887.pub2
  181. 181.
    B.R. Bhavnani, Pharmacokinetics and pharmacodynamics of conjugated equine estrogens: chemistry and metabolism. Proc. Soc. Exp. Biol. Med. 217, 6–16 (1998)PubMedGoogle Scholar
  182. 182.
    S. Drobac, K. Rubin, A.D. Rogol, R.L. Rosenfield, A workshop on pubertal hormone replacement options in the United States. J. Pediatr. Endocrinol. Metab. 19, 55–64 (2006)PubMedCrossRefGoogle Scholar
  183. 183.
    M.L. Davenport, Evidence for early initiation of growth hormone and transdermal estradiol therapies in girls with Turner syndrome. Growth Horm. IGF Res. 16(Suppl A), S91–S97 (2006). doi: 10.1016/j.ghir.2006.04.002 PubMedCrossRefGoogle Scholar
  184. 184.
    C.H. Gravholt, J. Frystyk, A. Flyvbjerg, H. Orskov, J.S. Christiansen, Reduced free IGF-I and increased IGFBP-3 proteolysis in Turner syndrome: modulation by female sex steroids. Am. J. Physiol. Endocrinol. Metab. 280, E308–E314 (2001)PubMedGoogle Scholar
  185. 185.
    N. Mauras, D. Shulman, H.Y. Hsiang, P. Balagopal, S. Welch, Metabolic effects of oral versus transdermal estrogen in growth hormone-treated girls with turner syndrome. J. Clin. Endocrinol. Metab. 92, 4154–4160 (2007). doi: 10.1210/jc.2007-0671 PubMedCrossRefGoogle Scholar
  186. 186.
    R.W. Naeraa, C.H. Gravholt, K.W. Kastrup, B. Svenstrup, J.S. Christiansen, Morning versus evening administration of estradiol to girls with turner syndrome receiving growth hormone: impact on growth hormone and metabolism. A randomized placebo-controlled crossover study. Acta Paediatr. 90, 526–531 (2001)PubMedCrossRefGoogle Scholar
  187. 187.
    M.J. Schoemaker, A.J. Swerdlow, C.D. Higgins, A.F. Wright, P.A. Jacobs, Cancer incidence in women with Turner syndrome in Great Britain: a national cohort study. Lancet Oncol. 9, 239–246 (2008). doi: 10.1016/S1470-2045(08)70033-0 PubMedCrossRefGoogle Scholar
  188. 188.
    K. Freriks, J. Timmermans, C.C. Beerendonk, C.M. Verhaak, R.T. Netea-Maier, B.J. Otten, D.D. Braat, D.F. Smeets, D.H. Kunst, A.R. Hermus, H.J. Timmers, Standardized multidisciplinary evaluation yields significant previously undiagnosed morbidity in adult women with turner syndrome. J. Clin. Endocrinol. Metab. 96, E1517–E1526 (2011). doi: 10.1210/jc.2011-0346 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Christian Trolle
    • 1
  • Britta Hjerrild
    • 1
  • Line Cleemann
    • 2
  • Kristian H. Mortensen
    • 1
    • 3
  • Claus H. Gravholt
    • 1
    • 4
  1. 1.Department of Endocrinology and Internal Medicine and Medical Research LaboratoriesAarhus University HospitalAarhus CDenmark
  2. 2.Department of PediatricsHillerød HospitalHillerødDenmark
  3. 3.Department of RadiologyCambridge University HospitalsCambridgeUK
  4. 4.Department of Molecular MedicineAarhus University HospitalAarhus NDenmark

Personalised recommendations