Advertisement

Endocrine

, Volume 55, Issue 2, pp 366–375 | Cite as

Effect of estrogen replacement therapy on bone and cardiovascular outcomes in women with turner syndrome: a systematic review and meta-analysis

  • Dahima Cintron
  • Rene Rodriguez-Gutierrez
  • Valentina Serrano
  • Paula Latortue-Albino
  • Patricia J Erwin
  • Mohammad Hassan Murad
Meta-Analysis

Abstract

Patients with Turner syndrome have adverse bone and cardiovascular outcomes from chronic estrogen deficiency. Hence, long-term estrogen replacement therapy is the cornerstone treatment. The estimates of its effect and optimal use, however, remain uncertain. We aimed to summarize the benefits and harms of estrogen replacement therapy on bone, cardiovascular, vasomotor and quality of life outcomes in patients with Turner syndrome. A comprehensive search of four databases was performed from inception through January 2016. Randomized clinical trials and observational cohort studies studying the effect of estrogen replacement therapy in patients with Turner syndrome under the age of 40 were included. Independently and in duplicate reviewers selected studies, extracted data and assessed risk of bias. Subgroup analyses were based on route of administration and type of estrogen formulation. Twenty-five studies at moderate to high risk of bias (12 randomized trials, 13 cohort studies) with 771 patients were included. Using random-effects models, estrogen replacement therapy showed an increase in bone mineral density [weighted mean change from baseline 0.09 g/cm2 (0.04–0.14)] that differed by type of estrogen but not route of administration. Oral estrogen replacement therapy showed a higher increase in high density lipoprotein cholesterol levels when compared to transdermal [weighted mean difference 9.33 mg/dl (4.82–13.85)] with no significant effect on other lipid fractions. The current evidence suggests possible benefit of estrogen replacement therapy on bone mineral density and high density lipoprotein cholesterol. Whether this improvement translates into changes in patient important outcomes (cardiovascular events or fractures) remains uncertain. Larger randomized clinical trials with direct comparisons on patient important outcomes are necessary.

Keywords

Estrogen Lipids Fractures Vasomotor symptoms Quality of life Adverse events 

Notes

Funding

DC was supported by TL1 TR000137 from the National Center for Advancing Translational Science, a component of the National Institutes of Health.

Compliance with ethical standards

Conflicts of interest

The authors declare that they have no conflicts of interest.

Supplementary material

12020_2016_1046_MOESM1_ESM.docx (77 kb)
Supplementary Information

References

  1. 1.
    C.H. Gravholt, Aspects of the treatment of Turner syndrome. Expert Opin Pharmacother 2(10), 1633–1647 (2001). doi: 10.1517/14656566.2.10.1633 CrossRefPubMedGoogle Scholar
  2. 2.
    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(1), 89–96 (2003)CrossRefGoogle Scholar
  3. 3.
    W.H. Price, J.F. Clayton, S. Collyer, R. De Mey, J. Wilson, Mortality ratios, life expectancy, and causes of death in patients with Turner’s syndrome. J. Epidemiol Community Health 40(2), 97–102 (1986)CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    E.J. Turtle, A.A. Sule, L.E. Bath, M. Denvir, A. Gebbie, S. Mirsadraee, D.J. Webb, Assessing and addressing cardiovascular risk in adults with Turner syndrome. Clin Endocrinol (Oxf) 78(5), 639–645 (2013). doi: 10.1111/cen.12104 CrossRefGoogle Scholar
  5. 5.
    U.W. Boman, A. Moller, K. Albertsson-Wikland, Psychological aspects of Turner syndrome. J. Psychosom Obstet Gynaecol 19(1), 1–18 (1998)CrossRefPubMedGoogle Scholar
  6. 6.
    L. Zhu, X. Jiang, Y. Sun, W. Shu, Effect of hormone therapy on the risk of bone fractures: a systematic review and meta-analysis of randomized controlled trials. Menopause 23(4), 461–470 (2016). doi: 10.1097/gme.0000000000000519 PubMedGoogle Scholar
  7. 7.
    G.E. Hale, C.L. Shufelt, Hormone therapy in menopause: an update on cardiovascular disease considerations. Trends Cardiovasc Med 25(6), 540–549 (2015). doi: 10.1016/j.tcm.2015.01.008 CrossRefPubMedGoogle Scholar
  8. 8.
    S.T. Alves, C.T. Gallichio, M.M. Guimaraes, Insulin resistance and body composition in Turner syndrome: effect of sequential change in the route of estrogen administration. Gynecol Endocrinol 22(10), 590–594 (2006). doi: 10.1080/08916930600929586 CrossRefPubMedGoogle Scholar
  9. 9.
    R.W. Naeraa, J. Nielsen, K.W. Kastrup, Growth hormone and 17 beta-oestradiol treatment of Turner girls---2-year results. Eur. J. Pediatr. 153(2), 72–77 (1994)PubMedGoogle Scholar
  10. 10.
    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 54(2), 159–164 (2001)CrossRefGoogle Scholar
  11. 11.
    K. Rubin, Turner syndrome and osteoporosis: mechanisms and prognosis. Pediatrics 102(2 Pt 3), 481–485 (1998)PubMedGoogle Scholar
  12. 12.
    S. Drobac, K. Rubin, A.D. Rogol, R.L. Rosenfield, A workshop on pubertal hormone replacement options in the United States. J. Pediatr. Endocrinol. Metabol. 19(1), 55–64 (2006)CrossRefGoogle Scholar
  13. 13.
    A. Gawlik, B. Kaczor, H. Kaminska, A. Zachurzok-Buczynska, T. Gawlik, E. Malecka-Tendera, Quality of medical follow-up of young women with Turner syndrome treated in one clinical center. Horm. Res. Paediatr. 77(4), 222–228 (2012). doi: 10.1159/000337780 CrossRefPubMedGoogle Scholar
  14. 14.
    V.K. Bakalov, T. Shawker, I. Ceniceros, C.A. Bondy, Uterine development in Turner syndrome. J. Pediatr. 151(5), 528–531, 531.e521 (2007). doi: 10.1016/j.jpeds.2007.04.031 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    T. McGinn, P.C. Wyer, T.B. Newman, S. Keitz, R. Leipzig, G.G. For, Tips for learners of evidence-based medicine: 3. Measures of observer variability (kappa statistic). CMAJ 171(11), 1369–1373 (2004). doi: 10.1503/cmaj.1031981 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    J. Pitkin, M.C. Rees, S. Gray, M.A. Lumsden, J. Marsden, J.C. Stevenson, J. Williamson, Management of premature menopause. Menopause. Int. 13(1), 44–45 (2007). doi: 10.1258/175404507780456719 PubMedGoogle Scholar
  17. 17.
    J.P. Higgins, D.G. Altman, P.C. Gotzsche, P. Juni, D. Moher, A.D. Oxman, J. Savovic, K.F. Schulz, L. Weeks, J.A. Sterne, The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 343, d5928 (2011)CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    A. Stang, Critical evaluation of the Newcastle--Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur. J. Epidemiol 25(9), 603–605 (2010). doi: 10.1007/s10654-010-9491-z CrossRefPubMedGoogle Scholar
  19. 19.
    J.A. Sterne, M. Egger, D. Moher, Chapter 10: addressing reporting biases. In: Higgins, J.P.T., Green, S. (eds.) Cochrane Handbook for Systematic Reviews of Interventions. Wiley, Cichester (2008)Google Scholar
  20. 20.
    M.H. Murad, V.M. Montori, J.P. Ioannidis, R. Jaeschke, P.J. Devereaux, K. Prasad, I. Neumann, A. Carrasco-Labra, T. Agoritsas, R. Hatala, M.O. Meade, P. Wyer, D.J. Cook, G. Guyatt, How to read a systematic review and meta-analysis and apply the results to patient care: users’ guides to the medical literature. JAMA 312(2), 171–179 (2014). doi: 10.1001/jama.2014.5559s CrossRefPubMedGoogle Scholar
  21. 21.
    J.P.T. Higgins, J.J. Deeks, D.G. Atlman, Chapter 16: special topics in statistics. In: Higgings, J.P.T., Green, S. (eds.) Chochrane Handbook for Systematic Reviews of Interventions. Wiley, Chichester (2008)Google Scholar
  22. 22.
    J.P. Higgins, S.G. Thompson, J.J. Deeks, D.G. Altman, Measuring inconsistency in meta-analyses. BMJ 327(7414), 557–560 (2003). doi: 10.1136/bmj.327.7414.557 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    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. Metabol. 92(11), 4154–4160 (2007). doi: 10.1210/jc.2007-0671 CrossRefGoogle Scholar
  24. 24.
    Z.M. Nabhan, L.A. DiMeglio, R. Qi, S.M. Perkins, E.A. Eugster, Conjugated oral versus transdermal estrogen replacement in girls with Turner syndrome: a pilot comparative study. J. Clin. Endocrinol. Metabol. 94(6), 2009–2014 (2009). doi: 10.1210/jc.2008-2123 CrossRefGoogle Scholar
  25. 25.
    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(13), 1230–1242 (2011). doi: 10.1056/NEJMoa1005669 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    N. Jospe, C.C. Orlowski, R.W. Furlanetto, Comparison of transdermal and oral estrogen therapy in girls with Turner’s syndrome. J. Pediatr. Endocrinol. 8(2), 111–116 (1995)CrossRefGoogle Scholar
  27. 27.
    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(3), 184–189 (2009). doi: 10.1159/000232495 CrossRefPubMedGoogle Scholar
  28. 28.
    S.P. Taback, G. Van Vliet, 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 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    S. Shah, N. Forghani, E. Durham, E.K. Neely, A randomized trial of transdermal and oral estrogen therapy in adolescent girls with hypogonadism. Int. J. Pediatr. Endocrinol. 2014(1) (2014). doi: 10.1186/1687-9856-2014-12
  30. 30.
    L. Torres-Santiago, V. Mericq, M. Taboada, N. Unanue, K.O. Klein, R. Singh, J. Hossain, R.J. Santen, J.L. Ross, N. Mauras, Metabolic effects of oral versus transdermal 17beta-estradiol (E2): a randomized clinical trial in girls with Turner syndrome. J. Clin. Endocrinol. Metabol. 98(7), 2716–2724 (2013). doi: 10.1210/jc.2012-4243 CrossRefGoogle Scholar
  31. 31.
    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. Metabol. 94(12), 4820–4827 (2009). doi:http://dx.doi.org/10.1210/jc.2009-0514 CrossRefGoogle Scholar
  32. 32.
    P.M. Crofton, N. Evans, L.E. Bath, P. Warner, T.J. Whitehead, H.O. Critchley, C.J. Kelnar, W.H. Wallace, Physiological versus standard sex steroid replacement in young women with premature ovarian failure: effects on bone mass acquisition and turnover. Clin. Endocrinol. 73(6), 707–714 (2010). doi: 10.1111/j.1365-2265.2010.03868.x CrossRefGoogle Scholar
  33. 33.
    L. Cleemann, K. Holm, H. Kobbernagel, B. Kristensen, S.O. Skouby, A.E.K. Jensen, C. Gravholt, The effect of high dose oral 17s estradiol on bone mineralization and body composition in young women with turner syndrome-a 5 year randomized controlled clinical trial. Horm. Res. Paediatr. 84, 159 (2015). doi: 10.1159/000437032 CrossRefGoogle Scholar
  34. 34.
    N.Y. Kim, D.Y. Lee, M.J. Kim, B.K. Yoon, D. Choi, Estrogen requirements in girls with Turner syndrome; how low is enough for initiating puberty and uterine development? Gynecol Endocrinol 28(2), 130–133 (2012). doi: 10.3109/09513590.2011.588752 CrossRefPubMedGoogle Scholar
  35. 35.
    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(4), 585–592 (1990)PubMedGoogle Scholar
  36. 36.
    V. Papagianni, E. Deligeoroglou, E. Makrakis, D. Botsis, G. Creatsas, Response to hormonal treatment of young females with primary or very premature ovarian failure. Gynecol Endocrinol 27(5), 291–299 (2011). doi: 10.3109/09513591003632274 CrossRefPubMedGoogle Scholar
  37. 37.
    R. Lanes, P. Gunczler, A. Palacios, O. Villaroel, Serum lipids, lipoprotein lp(a), and plasminogen activator inhibitor-1 in patients with Turner’s syndrome before and during growth hormone and estrogen therapy. Fertil Steril 68(3), 473–477 (1997)CrossRefPubMedGoogle Scholar
  38. 38.
    R. Lanes, P. Gunczler, S. Esaa, R. Martinis, O. Villaroel, J.R. Weisinger, Decreased bone mass despite long-term estrogen replacement therapy in young women with Turner’s syndrome and previously normal bone density. Fertil Steril 72(5), 896–899 (1999)CrossRefPubMedGoogle Scholar
  39. 39.
    M. Gussinye, P. Terrades, D. Yeste, E. Vicens-Calvet, A. Carrascosa, Low areal bone mineral density values in adolescents and young adult turner syndrome patients increase after long-term transdermal estradiol therapy. Horm. Res. 54(3), 131–135 (2000). doi: 10.1159/000053246 PubMedGoogle Scholar
  40. 40.
    N.J. Shaw, V.K. Rehan, S. Husain, T. Marshall, C.S. Smith, Bone mineral density in Turner’s syndrome---a longitudinal study. Clin. Endocrinol. 47(3), 367–370 (1997)CrossRefGoogle Scholar
  41. 41.
    E. Sowinska-Przepiera, E. Andrysiak-Mamos, Z. Friebe, K. Kapczuk, K. Pilarska, The effect of primary lack of estrogens and the influence of the age at the beginning of estrogen therapy on bone mineral density in patients with Turner’s syndrome. Endokrynol Pol. 56(2), 145–153 (2005)PubMedGoogle Scholar
  42. 42.
    M. Kodama, H. Komura, T. Kodama, Y. Nishio, T. Kimura, Estrogen therapy initiated at an early age increases bone mineral density in Turner syndrome patients. Endocr. J. 59(2), 153–159 (2012)CrossRefPubMedGoogle Scholar
  43. 43.
    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(2), 72–76 (2000)PubMedGoogle Scholar
  44. 44.
    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(5), 925–932 (2003)CrossRefPubMedGoogle Scholar
  45. 45.
    N. Suganuma, M. Furuhashi, T. Hirooka, T. Moriwaki, Y. Hasegawa, O. Mori, M. Ogawa, Bone mineral density in adult patients with Turner’s syndrome: analyses of the effectiveness of GH and ovarian steroid hormone replacement therapies. Endocr. J. 50(3), 263–269 (2003)CrossRefPubMedGoogle Scholar
  46. 46.
    A.C. Looker, L.G. Borrud, J.P. Hughes, Lumbar spine and proximal femur bone mineral density, bone mineral content, and bone area: United States, 2005–2008. Vital. Health. Stat. 11, 13–14 (2012)Google Scholar
  47. 47.
    J.T. Schousboe, J.A. Shepherd, J.P. Bilezikian, S. Baim, Executive summary of the 2013 International Society for Clinical Densitometry Position Development Conference on bone densitometry. J. Clin. Densitom. 16(4), 455–466 (2013). doi: 10.1016/j.jocd.2013.08.004 CrossRefPubMedGoogle Scholar
  48. 48.
    A. Prentice, T.J. Parsons, T.J. Cole, Uncritical use of bone mineral density in absorptiometry may lead to size-related artifacts in the identification of bone mineral determinants. Am. J. Clin. Nutr. 60(6), 837–842 (1994)PubMedGoogle Scholar
  49. 49.
    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. Metabol. 75(4), 1060–1065 (1992). doi: 10.1210/jcem.75.4.1400871 Google Scholar
  50. 50.
    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(4), 557–564 (2007). doi: 10.1111/j.1365-2265.2007.02772.x Google Scholar
  51. 51.
    J.C. Carel, C. Elie, E. Ecosse, M. Tauber, J. Leger, S. Cabrol, M. Nicolino, R. Brauner, J.L. Chaussain, J. Coste, Self-esteem and social adjustment in young women with Turner syndrome---influence of pubertal management and sexuality: population-based cohort study. J. Clin. Endocrinol. Metabol. 91(8), 2972–2979 (2006). doi: 10.1210/jc.2005-2652 CrossRefGoogle Scholar
  52. 52.
    E.M. Bannink, H. Raat, P.G. Mulder, S.M. de Muinck Keizer-Schrama, Quality of life after growth hormone therapy and induced puberty in women with Turner syndrome. J. Pediatr. 148(1), 95–101 (2006). doi: 10.1016/j.jpeds.2005.08.043 CrossRefPubMedGoogle Scholar
  53. 53.
    H.C Buscher, D.J. Cook, A.M. Holbrook, G. Guyatt, Chapter 13.4: surrogate outcomes. In: Gordon Guyatt, D.R., Maureen O. Meade, Deborah J. Cook (ed.) Users’ Guides to the Medical Literature: A Manual for Evidence-Based Clinical Practice 3 edition. McGraw-Hill Education, New York (2015)Google Scholar
  54. 54.
    M.J. Pletcher, K. Bibbins-Domingo, K. Liu, S. Sidney, F. Lin, E. Vittinghoff, S.B. Hulley, Nonoptimal lipids commonly present in young adults and coronary calcium later in life: the Coronary Artery Risk Development in Young Adults (CARDIA) study. Ann. Intern. Med. 153(3), 137–146 (2010). doi: 10.7326/0003-4819-153-3-201008030-00004 CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    S. Ferrari, M.L. Bianchi, J.A. Eisman, A.J. Foldes, S. Adami, D.A. Wahl, J.J. Stepan, M.C. de Vernejoul, J.M. Kaufman, Osteoporosis in young adults: pathophysiology, diagnosis, and management. Osteoporos Int. 23(12), 2735–2748 (2012). doi: 10.1007/s00198-012-2030-x CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Mayo Graduate SchoolMayo ClinicRochesterUSA
  2. 2.Knowledge and Evaluation Research Unit in Endocrinology, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Department of MedicineMayo ClinicRochesterUSA
  3. 3.Division of Endocrinology, Diabetes, Metabolism and Nutrition, Department of MedicineMayo ClinicRochesterUSA
  4. 4.Division of Endocrinology, Department of Internal MedicineUniversity Hospital “Dr. Jose E. Gonzalez”, Autonomous University of Nuevo LeonMonterreyMexico
  5. 5.Department of Nutrition, Diabetes and MetabolismPontifical Catholic University of ChileSantiagoChile
  6. 6.University of Puerto Rico- Medical Sciences CampusSan JuanPuerto Rico
  7. 7.Mayo Clinic LibrariesRochesterUSA
  8. 8.Division of Preventive, Occupational, and Aerospace Medicine, Department of MedicineMayo ClinicRochesterUSA

Personalised recommendations