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

NCT06570460 | Recruiting Phase 4 DMC

• 1 other identifier: AU2019TS2
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Turner Syndrome; Hypogonadism; Ovarian; Hormone Replacement Therapy; Estrogen Replacement Therapy; Estrogen Deficiency

Keywords

Turner syndrome; Hormone replacement therapy; Estrogen replacement therapy; Estrogen treatment; Long term side effects

Outcome Measures

Primary Outcomes (9)

• Blood test values

  Changes in blood test values of follicle stimulating hormone and luthenizing hormone from baseline

  After 1 month of wash-out, 6 months of oral and six months of transdermal treatment

• Blood test values

  Changes in blood test values of estradiol from baseline

  After 1 month of wash-out, 6 months of oral and six months of transdermal treatment

• Dual energy X-ray absorptiometry

  Changes in body composition and bone mineral density

  After 6 months of oral and six months of transdermal treatment

• Cardiovascular status

  Changes in 24-hour blood pressure measurements

  After 6 months of oral and six months of transdermal treatment

• Cardiovascular status

  Changes in arterial stiffness measured by SphygmoCor

  After 6 months of oral and six months of transdermal treatment

• Muscle quality (quadriceps femoris)

  MR scan of both quadriceps measuring muscle cross-sectional area (CSA) and fat content of the muscle. Maximal isometric muscle strength of both quadriceps (functional muscle tests). Muscle quality = maximum quadriceps strength measured in nM/muscle CSA.

  After 6 months of oral and six months of transdermal treatment

• Functional muscle tests

  Changes in maximal jumping height

  After 6 months of oral and six months of transdermal treatment

• Isometric muscle tests

  Changes in maximal isometric hand strength

  After 6 months of oral and six months of transdermal treatment

• Maximal oxygen uptake test (VO2 max)

  Changes in maximal oxygen uptake

  After 6 months of oral and six months of transdermal treatment

Secondary Outcomes (3)

• Self-reported health-related quality of life and functioning (SF-36)

  After 6 months of oral and six months of transdermal treatment

• Self-reported quality of life (WHOQoL-Bref)

  After 6 months of oral and six months of transdermal treatment

• Subjective medication assesment

  After 6 months of oral and six months of transdermal treatment

Study Arms (3)

Oral estrogen treatment

ACTIVE COMPARATOR

Turner syndrome patients receiving oral estrogen treatment (Estrofem®)

Drug: 17-beta estradiol

Transdermal estrogen treatment

ACTIVE COMPARATOR

Turner syndrome patients receiving transdermal estrogen treatment (Divigel)

Drug: 17-beta estradiol

Controls

NO INTERVENTION

Healthy age-matched controls receiving no treatment

Interventions

17-beta estradiol DRUG

Treatment with orally administered estrogen for 6 months

Also known as: Estrofem

Oral estrogen treatment

Eligibility Criteria

• Age: 18 Years - 50 Years
• Gender Eligibility Details: Only patients with Turner syndrome can participate and age mathed healthy controls (women)
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• For participants with TS:
• Diagnosis of TS regardless of karyotype
• Age 18-50 years
• Already receiving estrogen treatment
• For healthy controls:
• Female
• Age 18-50 years
• Previously healthy
• Not receiving any medication
• Not using any form of contraceptive pills
• No mental or psychiatric disorders

You may not qualify if:

• Active systemic chronic diseases
• Known or suspected breast cancer
• Known or suspected estradiol-dependent tumors (endometrial cancer or similar)
• Untreated endometrial hyperplasia
• Current or previous venous thromboembolism
• Acute or previous liver disease where liver enzymes are still elevated by a factor 3 or more
• Known hypersensitivity to the medications used
• Pregnancy
• Menopause (for the control group only)

Sponsors & Collaborators

• Aarhus University Hospital: lead
• University of Aarhus: collaborator

Study Sites (1)

Department of Endocrinology and Internal Medicine, Aarhus University Hospital

Aarhus, Aarhus N, 8200, Denmark

RECRUITING

Related Publications (18)

• 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.

  PMID: 16849410 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.

  PMID: 28705803 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.

  PMID: 18400842 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.

  PMID: 16984695 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.

  PMID: 22233516 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.

  PMID: 29704077 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.

  PMID: 28847313 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.

  PMID: 19561145 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.

  PMID: 18495631 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.

  PMID: 20525678 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.

  PMID: 22963114 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.

  PMID: 9253336 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.

  PMID: 21880799 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.

  PMID: 23678038 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.

  PMID: 9653596 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.

  PMID: 7989605 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.

  PMID: 29438552 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.

  PMID: 32506765 BACKGROUND

MeSH Terms

Conditions

Turner Syndrome; Hypogonadism

Interventions

Estradiol; estradiol, estriol drug combination

Condition Hierarchy (Ancestors)

Gonadal Dysgenesis; Disorders of Sex Development; Urogenital Abnormalities; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Sex Chromosome Disorders of Sex Development; Male Urogenital Diseases; Heart Defects, Congenital; Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Sex Chromosome Disorders; Chromosome Disorders; Genetic Diseases, Inborn; Gonadal Disorders; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Study Officials

• Claus H Gravholt, Professor

  Aarhus University Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Camilla M Balle, Ph.d.-student

CONTACT

40769623; camibl@clin.au.dk

Claus H Gravholt, Professor

CONTACT

78455470; claus.gravholt@clin.au.dk

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: The patients with TS will be randomized to receive either oral (tablet) or transdermal (gel) estrogen replacement therapy. The study is not blinded, as both investigator and study participants know which medication, they are receiving.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: A randomized controlled trial

Study Record Dates

• First Submitted: December 4, 2019
• First Posted: August 26, 2024
• Study Start: November 29, 2021
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026
• Last Updated: August 26, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)