Determining Dose Equivalence Between Oral and Transdermal Estrogen Treatment in Women With Turner Syndrome

August 22, 2024 updated by: Aarhus University Hospital

Determining Dose Equivalence Between Oral and Transdermal Estrogen Treatment in Women With Turner Syndrome - A Randomized Study

This 5-week, phase IV randomized crossover trial aims to compare the effects of oral versus transdermal estrogen replacement therapy (ERT) in women with Turner syndrome (TS). The objective is to establish the equipotency between the two estradiol regimens by evaluating various estradiol-dependent surrogate markers. The study involves 50 women with TS, aged 18-50 years, who are randomized to receive either oral or transdermal ERT for 14 days, followed by a crossover to the alternate treatment for another 14 days, with a one-week washout period in between. Blood tests are conducted at baseline, after the first 14 days of treatment, after the washout period, and after the final 14 days of treatment. The investigators anticipate that this study will provide clinicians with a better understanding of ERT in treating women with TS.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

OBJECTIVE

1. To determine the equipotency of two different estradiol regimens (oral versus transdermal administration) using various estradiol-dependent surrogate markers.

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

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.

Design:

A 5-week, phase IV randomized crossover trial involving 50 women with TS. Participants are randomized to receive E2 for 14 days, either as oral or TD treatment, followed by a crossover to the alternate treatment for another 14 days, with a one-week washout period in between.

Laboratory analyses:

Blood samples are collected at baseline, after the first 14 days of treatment, after the washout period, and after the final 14 days of treatment.

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. The investigators aim for this study to provide clinicians with a better understanding of ERT in treating women with TS, and to contribute with 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:
          • Camilla M Balle, Ph.d.-student
          • Phone Number: 0045 40769623
          • Email: camibl@rm.dk

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

No

Description

Inclusion Criteria:

  • Diagnosis of TS regardless of karyotype
  • Age 18-50 years
  • Already receiving estrogen treatment

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

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 14 days
Other Names:
  • Estrofem
Drug: 17-beta estradiol
Treatment with transdermally administered estrogen for 14 days
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 14 days
Other Names:
  • Estrofem
Drug: 17-beta estradiol
Treatment with transdermally administered estrogen for 14 days
Other Names:
  • Divigel

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Equipotency
Time Frame: After 14 days
Levels of luthenizing hormone and follicle stimulating hormone are measured at different doses
After 14 days

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

August 5, 2024

First Submitted That Met QC Criteria

August 5, 2024

First Posted (Actual)

August 9, 2024

Study Record Updates

Last Update Posted (Actual)

August 23, 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

  • AU2019TS1

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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