Turner SyndromePhase 4NCT06570460
Long Term Effects of Oral Versus Transdermal Estrogen Replacement Therapy in Turner Syndrome
A Phase 4 study testing 17-beta estradiol in people with Turner Syndrome and Hypogonadism; Ovarian, run by Aarhus University Hospital at 1 site in Denmark.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 to 50 years, women onlyHealthy volunteers can take part
- Conditions the study is for
- Turner Syndrome, Hypogonadism; Ovarian, Hormone Replacement Therapy
- What is being tested?
- 17-beta estradiol
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 50 participants
- Where
- 1 siteDenmark
- Study dates
- 29 Nov 2021to 31 Dec 2026
- Phase
- Phase 4
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 50 years
- Women only
- Healthy volunteers accepted
- Adult
Who may be able to join
- For participants with TS:
- Diagnosis of TS regardless of karyotype
- Age 18-50 years
- Already receiving estrogen treatment
- For healthy controls:
- Female
Show all 11Show fewer
- Age 18-50 years
- Previously healthy
- Not receiving any medication
- Not using any form of contraceptive pills
- No mental or psychiatric disorders
Who cannot join
- 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
Show all 9Show fewer
- Known hypersensitivity to the medications used
- Pregnancy
- Menopause (for the control group only)
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Denmark1 site, 1 recruiting
- Recruiting
Department of Endocrinology and Internal Medicine, Aarhus University Hospital
Aarhus, Aarhus N, 8200
Camilla M Balle, Ph.d.-student, 40769623, camibl@clin.au.dk
About this study
Official title: Long Term Effects of Oral Versus Transdermal Estrogen Replacement Therapy in Turner Syndrome - A Randomized Trial
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.
Read the detailed description
OBJECTIVES
- Clarify endocrine, metabolic, cardiovascular and thromboembolic risk factors in Turner syndrome (TS) after a wash out period
- Compare the effects of oral versus transdermal (TD) estrogen replacement therapy (ERT) in women with Turner syndrome
- Examine long term effects of ERT via the two routes on endocrine, metabolic, cardiovascular, physiologic and thromboembolic risk endpoints
BACKGROUND Turner syndrome (TS) is a rare genetic condition affecting approximately 1 in 2,000 female births. A hallmark of TS is ovarian dysgenesis, leading to hypogonadism, premature ovarian failure, and infertility. Consequently, estrogen replacement therapy (ERT) is typically initiated around age 11-12 to induce puberty and continued until the average age of menopause (50-55 years), aiming for at least 42 years of adequate estrogen exposure.
Hypogonadism in TS is associated with various health complications. Importantly, estradiol (E2) replacement may mitigate these risks. Estrogen deficiency in TS affects cardiovascular health (hypertension, congenital cardiac disease, altered lipid profiles), metabolic function (diabetes, thyroid dysfunction, hepatic disorders, kidney disease, skeletal abnormalities), and is linked to neurocognitive and social challenges.
E2 can be administered orally or transdermally (TD), but it remains unclear whether either route offers specific advantages. There is ongoing debate regarding a potential increased thromboembolic risk in TS patients treated with oral E2. Epidemiological studies in postmenopausal women have reported an elevated thromboembolic risk associated with oral estrogen treatment, but to a lesser extent with TD administration. However, extrapolating data from postmenopausal women to TS patients is inappropriate, as women with TS receive estrogen as replacement therapy due to inadequate endogenous production. Furthermore, limited knowledge exists regarding the side effects of oral versus TD estrogen replacement therapy for TS patients.
MATERIALS AND METHODS
Study group:
Women aged 18-50 years with TS recruited primarily from the Department of Endocrinology at Aarhus University Hospital (n=50); 300 patients with TS are currently followed in the outpatient clinic. The investigators also have the opportunity to recruit from the Turner Association in Denmark, and finally the investigators do have contact with other outpatient clinics with TS patients in Denmark from where the investigators have previously recruited TS patients.
An age-matched control group of healthy women is included by advertisement (n=50).
Inclusion criteria:
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
Exclusion criteria:
- 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)
Design:
A 14-month, phase IV, randomized controlled crossover study involving women with Turner Syndrome (TS) (n=50) and healthy, age-matched controls (n=50). 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. Healthy controls will not receive any treatment. They will undergo a single set of assessments for comparison.
Laboratory analyses and clinical investigations will be conducted at the Department of Endocrinology and the associated Medical Research Unit at Aarhus University Hospital. These will include blood and urine sample collection, as well as specific clinical investigations. At baseline, both TS patients and healthy controls will undergo these assessments. Only TS patients will undergo follow-up assesments.
Clinical investigations:
- Insulin sensitivity assessment
- 24-hour blood pressure monitoring
- DEXA scan (Dual-Energy X-ray Absorptiometry)
- Bioelectrical impedance analysis (Multiplate)
- Comprehensive clinical examination
- Quality of life assessments using questionnaires
- SphygmoCor analysis
- VO2 max test using a stationary bike
- MRI of the thigh muscles to measure muscle cross-sectional area (CSA) and intramuscular fat content
- Isometric muscle strength testing and functional testing
STATISTICS Data will be summarized by treatment group and assessment time point. The investigators will use a mixed model with repeated measures analysis of variance (ANOVA) to compare the mean changes in each of the study variables between treatments over time. When appropriate, transformations or nonparametric methods will be used. All tests are two-tailed with a 5% level of significance. Data are presented as mean ± SE or median with CI for metrics not normally distributed.
PERSPECTIVES Patients with TS undergo hormone replacement therapy from puberty to menopause, spanning more than 40 years of treatment. To date, only two experimental studies have compared oral and TD ERT in TS, focusing solely on metabolic parameters and finding no differences between the two regimens. If the investigators' hypotheses are correct and if the side effects, including increased thromboembolic risk, are higher with oral than TD ERT, this project could be crucial for optimizing treatment, improving quality of life, and reducing morbidity and mortality in TS. The investigators aim for this study to provide a basis for new and improved national and international recommendations for ERT in TS patients and to contribute new knowledge about hormonal treatment for the general population as well.
- Conditions
- Turner Syndrome, Hypogonadism; Ovarian, Hormone Replacement Therapy, Estrogen Replacement Therapy, Estrogen Deficiency
- Being tested
- 17-beta estradiol
- Keywords
- Turner syndrome, Hormone replacement therapy, Estrogen replacement therapy, Estrogen treatment, Long term side effects
- Medical subject headings
- Turner Syndrome, Hypogonadism
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
17-beta estradiolDrug
Also called Estrofem
Treatment with orally administered estrogen for 6 months
17-beta estradiolDrug
Also called Divigel
Treatment with transdermally administered estrogen for 6 months
| Study group | Role | What they receive |
|---|---|---|
| Oral estrogen treatment | Active comparator | Turner syndrome patients receiving oral estrogen treatment (Estrofem®) Receives: Drug: 17-beta estradiol |
| Transdermal estrogen treatment | Active comparator | Turner syndrome patients receiving transdermal estrogen treatment (Divigel) Receives: Drug: 17-beta estradiol |
| Controls | No intervention | Healthy age-matched controls receiving no treatment |
What is being measured
The primary outcome is the main question the study is designed to answer.
Blood test values
Changes in blood test values of follicle stimulating hormone and luthenizing hormone from baseline
Measured: 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
Measured: 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
Measured: After 6 months of oral and six months of transdermal treatment
Cardiovascular status
Changes in 24-hour blood pressure measurements
Measured: After 6 months of oral and six months of transdermal treatment
Cardiovascular status
Changes in arterial stiffness measured by SphygmoCor
Measured: 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.
Measured: After 6 months of oral and six months of transdermal treatment
Functional muscle tests
Changes in maximal jumping height
Measured: After 6 months of oral and six months of transdermal treatment
Isometric muscle tests
Changes in maximal isometric hand strength
Measured: After 6 months of oral and six months of transdermal treatment
Maximal oxygen uptake test (VO2 max)
Changes in maximal oxygen uptake
Measured: 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)
The Short Form 36 Health Survey is a self-reported quality of life questionnaire consisting of eight scaled scores. Each scale is transformed directly into a 0-100 scale, where a lower score indicates greater difficulty.
Measured: After 6 months of oral and six months of transdermal treatment
Self-reported quality of life (WHOQoL-Bref)
The WHOQoL-Bref is a questionnaire where the participant's answers to 26 questions are used to create an overall quality of life profile. This profile includes scores for each dimension of the questionnaire: physical health, mental health, social relationships, and the participant's environment.
Measured: After 6 months of oral and six months of transdermal treatment
Subjective medication assesment
Subjective assesment of the medication after 6 months of use
Measured: After 6 months of oral and six months of transdermal treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Aug 2024
- Study start29 Nov 2021
- Primary completion31 Dec 2026 (estimated)
- Study completion31 Dec 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (18)Papers the sponsor has linked to this study.
- Other trials for Turner SyndromeStudies of the same condition, open and under way.
- More trials run by Aarhus University HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- A randomized controlled trial
- Masking
- None (open label)
- Enrolment
- 50 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Aarhus University Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- University of Aarhus
- Responsible party
- Sponsor
- Investigators
- Claus H Gravholt, Professor, Principal investigator, Aarhus University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06570460
- Sponsor's protocol ID
- AU2019TS2
- Status last verified
- Jul 2024
- First submitted
- 4 Dec 2019
- Last updated
- 26 Aug 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 16849410Gravholt 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.
PubMed 28705803Hjerrild 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.
PubMed 18400842Gravholt 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.
PubMed 16984695Mortensen 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.
PubMed 22233516Mauger 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.
PubMed 29704077Hansen 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.
PubMed 28847313Greising 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.
PubMed 19561145Canonico 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.
PubMed 18495631Renoux 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.
PubMed 20525678Sweetland 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.
PubMed 22963114Gravholt 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.
PubMed 9253336Taboada 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.
PubMed 21880799Torres-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.
PubMed 23678038Gravholt 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.
PubMed 9653596
Study at a glance
From the registry record, last updated by the sponsor on 26 Aug 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Long Term Effects of Oral Versus Transdermal Estrogen Replacement Therapy in Turner Syndrome - A Randomized Trial
- ClinicalTrials.gov ID
- NCT06570460
- Acronym / sponsor ID
- AU2019TS2
- 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
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 50 participants (estimated)
- Lead sponsor
- Aarhus University HospitalUniversity, hospital or other
- Collaborators
- University of Aarhus
- Study start
- 29 Nov 2021 (actual)
- Primary completion
- 31 Dec 2026 (estimated)
- Study completion
- 31 Dec 2026 (estimated)
- First posted
- 26 Aug 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
OBJECTIVES
- Clarify endocrine, metabolic, cardiovascular and thromboembolic risk factors in Turner syndrome (TS) after a wash out period
- Compare the effects of oral versus transdermal (TD) estrogen replacement therapy (ERT) in women with Turner syndrome
- Examine long term effects of ERT via the two routes on endocrine, metabolic, cardiovascular, physiologic and thromboembolic risk endpoints
BACKGROUND Turner syndrome (TS) is a rare genetic condition affecting approximately 1 in 2,000 female births. A hallmark of TS is ovarian dysgenesis, leading to hypogonadism, premature ovarian failure, and infertility. Consequently, estrogen replacement therapy (ERT) is typically initiated around age 11-12 to induce puberty and continued until the average age of menopause (50-55 years), aiming for at least 42 years of adequate estrogen exposure.
Hypogonadism in TS is associated with various health complications. Importantly, estradiol (E2) replacement may mitigate these risks. Estrogen deficiency in TS affects cardiovascular health (hypertension, congenital cardiac disease, altered lipid profiles), metabolic function (diabetes, thyroid dysfunction, hepatic disorders, kidney disease, skeletal abnormalities), and is linked to neurocognitive and social challenges.
E2 can be administered orally or transdermally (TD), but it remains unclear whether either route offers specific advantages. There is ongoing debate regarding a potential increased thromboembolic risk in TS patients treated with oral E2. Epidemiological studies in postmenopausal women have reported an elevated thromboembolic risk associated with oral estrogen treatment, but to a lesser extent with TD administration. However, extrapolating data from postmenopausal women to TS patients is inappropriate, as women with TS receive estrogen as replacement therapy due to inadequate endogenous production. Furthermore, limited knowledge exists regarding the side effects of oral versus TD estrogen replacement therapy for TS patients.
MATERIALS AND METHODS
Study group:
Women aged 18-50 years with TS recruited primarily from the Department of Endocrinology at Aarhus University Hospital (n=50); 300 patients with TS are currently followed in the outpatient clinic. The investigators also have the opportunity to recruit from the Turner Association in Denmark, and finally the investigators do have contact with other outpatient clinics with TS patients in Denmark from where the investigators have previously recruited TS patients.
An age-matched control group of healthy women is included by advertisement (n=50).
Inclusion criteria:
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
Exclusion criteria:
- 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)
Design:
A 14-month, phase IV, randomized controlled crossover study involving women with Turner Syndrome (TS) (n=50) and healthy, age-matched controls (n=50). 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. Healthy controls will not receive any treatment. They will undergo a single set of assessments for comparison.
Laboratory analyses and clinical investigations will be conducted at the Department of Endocrinology and the associated Medical Research Unit at Aarhus University Hospital. These will include blood and urine sample collection, as well as specific clinical investigations. At baseline, both TS patients and healthy controls will undergo these assessments. Only TS patients will undergo follow-up assesments.
Clinical investigations:
- Insulin sensitivity assessment
- 24-hour blood pressure monitoring
- DEXA scan (Dual-Energy X-ray Absorptiometry)
- Bioelectrical impedance analysis (Multiplate)
- Comprehensive clinical examination
- Quality of life assessments using questionnaires
- SphygmoCor analysis
- VO2 max test using a stationary bike
- MRI of the thigh muscles to measure muscle cross-sectional area (CSA) and intramuscular fat content
- Isometric muscle strength testing and functional testing
STATISTICS Data will be summarized by treatment group and assessment time point. The investigators will use a mixed model with repeated measures analysis of variance (ANOVA) to compare the mean changes in each of the study variables between treatments over time. When appropriate, transformations or nonparametric methods will be used. All tests are two-tailed with a 5% level of significance. Data are presented as mean ± SE or median with CI for metrics not normally distributed.
PERSPECTIVES Patients with TS undergo hormone replacement therapy from puberty to menopause, spanning more than 40 years of treatment. To date, only two experimental studies have compared oral and TD ERT in TS, focusing solely on metabolic parameters and finding no differences between the two regimens. If the investigators' hypotheses are correct and if the side effects, including increased thromboembolic risk, are higher with oral than TD ERT, this project could be crucial for optimizing treatment, improving quality of life, and reducing morbidity and mortality in TS. The investigators aim for this study to provide a basis for new and improved national and international recommendations for ERT in TS patients and to contribute new knowledge about hormonal treatment for the general population as well.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 3
- Model description
- A randomized controlled trial
| Arm | Type | Receives |
|---|---|---|
| Oral estrogen treatment | Active comparator | Drug: 17-beta estradiolTurner syndrome patients receiving oral estrogen treatment (Estrofem®) |
| Transdermal estrogen treatment | Active comparator | Drug: 17-beta estradiolTurner syndrome patients receiving transdermal estrogen treatment (Divigel) |
| Controls | No intervention | –Healthy age-matched controls receiving no treatment |
Who may qualify
- Ages
- 18 to 50 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (11 listed)
- Diagnosis of TS regardless of karyotype
- Age 18-50 years
- Already receiving estrogen treatment
- Female
- Age 18-50 years
Key exclusion criteria (9 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| 17-beta estradiolAlso: EstrofemTreatment with orally administered estrogen for 6 months | Drug | Oral estrogen treatment |
| 17-beta estradiolAlso: DivigelTreatment with transdermally administered estrogen for 6 months | Drug | Transdermal estrogen treatment |
Primary outcome
Blood test values
Time frame: After 1 month of wash-out, 6 months of oral and six months of transdermal treatment
Changes in blood test values of follicle stimulating hormone and luthenizing hormone from baseline
Blood test values
Time frame: After 1 month of wash-out, 6 months of oral and six months of transdermal treatment
Changes in blood test values of estradiol from baseline
Dual energy X-ray absorptiometry
Time frame: After 6 months of oral and six months of transdermal treatment
Changes in body composition and bone mineral density
Cardiovascular status
Time frame: After 6 months of oral and six months of transdermal treatment
Changes in 24-hour blood pressure measurements
Cardiovascular status
Time frame: After 6 months of oral and six months of transdermal treatment
Changes in arterial stiffness measured by SphygmoCor
Muscle quality (quadriceps femoris)
Time frame: After 6 months of oral and six months of transdermal treatment
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.
Functional muscle tests
Time frame: After 6 months of oral and six months of transdermal treatment
Changes in maximal jumping height
Isometric muscle tests
Time frame: After 6 months of oral and six months of transdermal treatment
Changes in maximal isometric hand strength
Maximal oxygen uptake test (VO2 max)
Time frame: After 6 months of oral and six months of transdermal treatment
Changes in maximal oxygen uptake
3 secondary outcomes
Self-reported health-related quality of life and functioning (SF-36)
Time frame: After 6 months of oral and six months of transdermal treatment
Self-reported quality of life (WHOQoL-Bref)
Time frame: After 6 months of oral and six months of transdermal treatment
Subjective medication assesment
Time frame: After 6 months of oral and six months of transdermal treatment
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Aug 2024.
- Background: PubMed 16849410Stochholm 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: PubMed 28705803Gravholt 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: PubMed 18400842Hjerrild 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: PubMed 16984695Gravholt 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: PubMed 22233516Mortensen 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: PubMed 29704077Mauger 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: PubMed 28847313Hansen 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: PubMed 19561145Greising 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: PubMed 18495631Canonico 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: PubMed 20525678Renoux 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: PubMed 22963114Sweetland 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: PubMed 9253336Gravholt 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Claus H Gravholt, Professor principal investigator
Aarhus University Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing 17-beta estradiol in people with Turner Syndrome and Hypogonadism; Ovarian, run by Aarhus University Hospital at 1 site in Denmark.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 26 Aug 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Camilla M Balle, Ph.d.-student (40769623 ext. 0045, camibl@clin.au.dk), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Blood test values (time frame: After 1 month of wash-out, 6 months of oral and six months of transdermal treatment). The study lists 9 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06570460, which also lists 18 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Aug 2024.