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

August 22, 2024 updated by: Aarhus University Hospital

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

OBJECTIVES

  1. Clarify endocrine, metabolic, cardiovascular and thromboembolic risk factors in Turner syndrome (TS) after a wash out period
  2. Compare the effects of oral versus transdermal (TD) estrogen replacement therapy (ERT) in women with Turner syndrome
  3. 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 Type

Interventional

Enrollment (Estimated)

50

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Camilla M Balle, Ph.d.-student
  • Phone Number: 0045 40769623
  • Email: camibl@clin.au.dk

Study Contact Backup

Study Locations

  • Denmark
    • Aarhus N
      • Aarhus, Aarhus N, Denmark, 8200
        • Recruiting
        • Department of Endocrinology and Internal Medicine, Aarhus University Hospital
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult

Accepts Healthy Volunteers

Yes

Description

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)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Oral estrogen treatment
Turner syndrome patients receiving oral estrogen treatment (Estrofem®)
Drug: 17-beta estradiol
Treatment with orally administered estrogen for 6 months
Other Names:
  • Estrofem
Drug: 17-beta estradiol
Treatment with transdermally administered estrogen for 6 months
Other Names:
  • Divigel
Active Comparator: Transdermal estrogen treatment
Turner syndrome patients receiving transdermal estrogen treatment (Divigel)
Drug: 17-beta estradiol
Treatment with orally administered estrogen for 6 months
Other Names:
  • Estrofem
Drug: 17-beta estradiol
Treatment with transdermally administered estrogen for 6 months
Other Names:
  • Divigel
No Intervention: Controls
Healthy age-matched controls receiving no treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
After 1 month of wash-out, 6 months of oral and six months of transdermal treatment
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
After 1 month of wash-out, 6 months of oral and six months of transdermal treatment
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
After 6 months of oral and six months of transdermal treatment
Cardiovascular status
Time Frame: After 6 months of oral and six months of transdermal treatment
Changes in 24-hour blood pressure measurements
After 6 months of oral and six months of transdermal treatment
Cardiovascular status
Time Frame: After 6 months of oral and six months of transdermal treatment
Changes in arterial stiffness measured by SphygmoCor
After 6 months of oral and six months of transdermal treatment
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.
After 6 months of oral and six months of transdermal treatment
Functional muscle tests
Time Frame: After 6 months of oral and six months of transdermal treatment
Changes in maximal jumping height
After 6 months of oral and six months of transdermal treatment
Isometric muscle tests
Time Frame: After 6 months of oral and six months of transdermal treatment
Changes in maximal isometric hand strength
After 6 months of oral and six months of transdermal treatment
Maximal oxygen uptake test (VO2 max)
Time Frame: After 6 months of oral and six months of transdermal treatment
Changes in maximal oxygen uptake
After 6 months of oral and six months of transdermal treatment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Self-reported health-related quality of life and functioning (SF-36)
Time Frame: After 6 months of oral and six months of transdermal treatment
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.
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
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.
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
Subjective assesment of the medication after 6 months of use
After 6 months of oral and six months of transdermal treatment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Aarhus University Hospital

Collaborators

University of Aarhus

Investigators

  • Principal Investigator: Claus H Gravholt, Professor, Aarhus University Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 29, 2021

Primary Completion (Estimated)

December 31, 2026

Study Completion (Estimated)

December 31, 2026

Study Registration Dates

First Submitted

December 4, 2019

First Submitted That Met QC Criteria

August 22, 2024

First Posted (Actual)

August 26, 2024

Study Record Updates

Last Update Posted (Actual)

August 26, 2024

Last Update Submitted That Met QC Criteria

August 22, 2024

Last Verified

July 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • AU2019TS2

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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