Effect of estrogen replacement therapy on bone and cardiovascular outcomes in women with turner syndrome: a systematic review and meta-analysis
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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.
KeywordsEstrogen Lipids Fractures Vasomotor symptoms Quality of life Adverse events
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.
- 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.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.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
- 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.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
- 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.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
- 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
- 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
- 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
- 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
- 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.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