Long Term Effects of Oral Versus Transdermal Estrogen Replacement Therapy in Turner Syndrome

Summary

This 14-month, phase IV, randomized controlled crossover trial aims to compare the effects of oral versus transdermal estrogen replacement therapy (ERT) in women with Turner syndrome (TS). The study's objectives are to clarify endocrine, metabolic, cardiovascular, and thromboembolic risk factors in TS after a wash-out period without estrogen (E2) treatment; compare the effects of oral versus transdermal (TD) ERT regimens; and examine the long-term effects of E2 administration via these two routes. The study involves 50 TS women aged 18-50 years and 50 control participants. TS participants are randomized to receive either oral or TD ERT for six months, followed by crossover to the alternate treatment for another six months. Prior to randomization, any existing ERT will be discontinued for a 1-month washout period. A second 1-month washout period will occur between the two 6-month treatment phases. Laboratory analyses and clinical investigations are performed after the first wash-out period, after the first six months of treatment, and after the last six months of treatment. We anticipate that this study may provide a basis for new and improved recommendations for sex hormone replacement therapy in TS.

Timeline

Start

2021-11-29

Primary completion

2026-12-31

Completion

2026-12-31

Publications

• Background Stochholm K, Juul S, Juel K, Naeraa RW, Gravholt CH. Prevalence, incidence, diagnostic delay, and mortality in Turner syndrome. J Clin Endocrinol Metab. 2006 Oct;91(10):3897-902. doi: 10.1210/jc.2006-0558. Epub 2006 Jul 18.
• Background Gravholt CH, Andersen NH, Conway GS, Dekkers OM, Geffner ME, Klein KO, Lin AE, Mauras N, Quigley CA, Rubin K, Sandberg DE, Sas TCJ, Silberbach M, Soderstrom-Anttila V, Stochholm K, van Alfen-van derVelden JA, Woelfle J, Backeljauw PF; International Turner Syndrome Consensus Group. Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting. Eur J Endocrinol. 2017 Sep;177(3):G1-G70. doi: 10.1530/EJE-17-0430.
• Background Hjerrild BE, Mortensen KH, Gravholt CH. Turner syndrome and clinical treatment. Br Med Bull. 2008;86:77-93. doi: 10.1093/bmb/ldn015. Epub 2008 Apr 9.
• Background Gravholt CH, Landin-Wilhelmsen K, Stochholm K, Hjerrild BE, Ledet T, Djurhuus CB, Sylven L, Baandrup U, Kristensen BO, Christiansen JS. Clinical and epidemiological description of aortic dissection in Turner's syndrome. Cardiol Young. 2006 Oct;16(5):430-6. doi: 10.1017/S1047951106000928.
• Background Mortensen KH, Andersen NH, Hjerrild BE, Horlyck A, Stochholm K, Hojbjerg Gravholt C. Carotid intima-media thickness is increased in Turner syndrome: multifactorial pathogenesis depending on age, blood pressure, cholesterol and oestrogen treatment. Clin Endocrinol (Oxf). 2012 Dec;77(6):844-51. doi: 10.1111/j.1365-2265.2012.04337.x.
• Background Mauger C, Lancelot C, Roy A, Coutant R, Cantisano N, Le Gall D. Executive Functions in Children and Adolescents with Turner Syndrome: A Systematic Review and Meta-Analysis. Neuropsychol Rev. 2018 Jun;28(2):188-215. doi: 10.1007/s11065-018-9372-x. Epub 2018 Apr 27.
• Background Hansen M. Female hormones: do they influence muscle and tendon protein metabolism? Proc Nutr Soc. 2018 Feb;77(1):32-41. doi: 10.1017/S0029665117001951. Epub 2017 Aug 29.
• Background Greising SM, Baltgalvis KA, Lowe DA, Warren GL. Hormone therapy and skeletal muscle strength: a meta-analysis. J Gerontol A Biol Sci Med Sci. 2009 Oct;64(10):1071-81. doi: 10.1093/gerona/glp082. Epub 2009 Jun 26.
• Background Canonico M, Plu-Bureau G, Lowe GD, Scarabin PY. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. BMJ. 2008 May 31;336(7655):1227-31. doi: 10.1136/bmj.39555.441944.BE. Epub 2008 May 20.
• Background Renoux C, Dell'aniello S, Garbe E, Suissa S. Transdermal and oral hormone replacement therapy and the risk of stroke: a nested case-control study. BMJ. 2010 Jun 3;340:c2519. doi: 10.1136/bmj.c2519.
• Background Sweetland S, Beral V, Balkwill A, Liu B, Benson VS, Canonico M, Green J, Reeves GK; Million Women Study Collaborators. Venous thromboembolism risk in relation to use of different types of postmenopausal hormone therapy in a large prospective study. J Thromb Haemost. 2012 Nov;10(11):2277-86. doi: 10.1111/j.1538-7836.2012.04919.x.
• Background Gravholt CH, Naeraa RW, Fisker S, Christiansen JS. 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. 1997 Aug;82(8):2570-7. doi: 10.1210/jcem.82.8.4127.
• Background Taboada M, Santen R, Lima J, Hossain J, Singh R, Klein KO, Mauras N. Pharmacokinetics and pharmacodynamics of oral and transdermal 17beta estradiol in girls with Turner syndrome. J Clin Endocrinol Metab. 2011 Nov;96(11):3502-10. doi: 10.1210/jc.2011-1449. Epub 2011 Aug 31.
• Background Torres-Santiago L, Mericq V, Taboada M, Unanue N, Klein KO, Singh R, Hossain J, Santen RJ, Ross JL, Mauras N. Metabolic effects of oral versus transdermal 17beta-estradiol (E(2)): a randomized clinical trial in girls with Turner syndrome. J Clin Endocrinol Metab. 2013 Jul;98(7):2716-24. doi: 10.1210/jc.2012-4243. Epub 2013 May 15.
• Background Gravholt CH, Naeraa RW, Nyholm B, Gerdes LU, Christiansen E, Schmitz O, Christiansen JS. Glucose metabolism, lipid metabolism, and cardiovascular risk factors in adult Turner's syndrome. The impact of sex hormone replacement. Diabetes Care. 1998 Jul;21(7):1062-70. doi: 10.2337/diacare.21.7.1062.
• Background Klein KO, Baron J, Colli MJ, McDonnell DP, Cutler GB Jr. Estrogen levels in childhood determined by an ultrasensitive recombinant cell bioassay. J Clin Invest. 1994 Dec;94(6):2475-80. doi: 10.1172/JCI117616.
• Background Klein KO, Rosenfield RL, Santen RJ, Gawlik AM, Backeljauw PF, Gravholt CH, Sas TCJ, Mauras N. Estrogen Replacement in Turner Syndrome: Literature Review and Practical Considerations. J Clin Endocrinol Metab. 2018 May 1;103(5):1790-1803. doi: 10.1210/jc.2017-02183.
• Background Berglund A, Stochholm K, Gravholt CH. The epidemiology of sex chromosome abnormalities. Am J Med Genet C Semin Med Genet. 2020 Jun;184(2):202-215. doi: 10.1002/ajmg.c.31805. Epub 2020 Jun 7.

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Indications