- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00837616
Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
April 20, 2023 updated by: Nelly Mauras, Nemours Children's Clinic
Estrogen Dosing in Turner Syndrome:Pharmacology & Metabolism
Estrogen is necessary for feminization during puberty and to decrease bone resorption, the latter critical for the achievement of peak bone mass and normal bone health in the female.
The practicing pediatric endocrinologist often faces the dilemma of how to best feminize girls with hypogonadism (lack of estrogen), manifested as delayed or arrested puberty, due to disorders of the brain or the ovaries.
We propose a series of studies to address which type, dose, and route of delivery of estrogen are suitable choices in feminizing and sustaining estrogen concentrations in adolescent girls with Turner syndrome.
To accomplish this we will study girls/young woman between the ages of 13 to 20 with Turner Syndrome in 2 protocols.
In Protocol # 1 we will study 24 girls with TS, they will receive 3 different estrogen preparations, either by mouth or via a patch for a total of 6 weeks.
They will come to the clinical research center for blood draws after 2 wks of taking the estrogen.
With this study, we hope to learn how the body responds to estrogen differently, depending on the form estrogen is given and how high, estrogen levels gets in the blood in these girls with Turner Syndrome.
We will be comparing these patients estrogen levels to girls that menstruate normally and do not have Turner Syndrome.
In Protocol #2, 40 patients with TS will be recruited; these patients will take estrogen for 1 year, either by mouth or via a patch.
Patients will come to the lab for blood drawn in 7 occasions and we will measure estrogen levels as well as other hormones and lipid levels.
We will also perform a Dual-energy X-ray absorptiometry (DXA) study (like an X ray) to assess body composition and bone mineralization.
We will adjust doses based on the estrogen levels we find.
With this study we hope to learn how estrogen affects body composition, i.e., the amount of fat vs. muscle, and how different forms of estrogen affect blood cholesterol and other hormones.
This study will allow us to understand better how to best replace young woman with Turner Syndrome with estrogen.
Study Overview
Status
Completed
Conditions
Intervention / Treatment
Detailed Description
Data on the specific effects and bioequivalency of the different forms of estrogen are lacking, and in the young adolescent age group in particular, virtually non-existent.
This has been complicated further by the difficulty in accurately interpreting estradiol assay results as the conventional radioimmunoassays (RIA) for estradiol are inaccurate and insensitive measuring very small concentrations in plasma.
There is wide variation in the types of estrogens used for estrogen replacement, as well as doses and route of administration.
Girls with Turner syndrome (TS) represent an important case study for these issues as they have early primary gonadal insufficiency or failure many years before the achievement of peak bone mass.
Hence, a study of the effects of different estrogen compounds in this patient population offers a unique model that eliminates the confounding effects of other products produced by the intact gonad.
Since in this condition it is imperative that estrogen replacement is started during the adolescent years and continued for several decades, this issue becomes highly relevant to these young women's health.Our specific aims are to: 1. to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) and relative biological potency of different oral vs. transdermal preparations of estradiol using state-of-the-art tandem mass spectrometry assays and recombinant cell bioassays; 2. to investigate the differential, long term metabolic effects of oral vs. transdermal estrogen replacement, specifically the effects on lipid and protein metabolism as well as body composition in this patient population; 3. to determine feasibility of estrogen concentration-based dosing in puberty and 4. To characterize the metabolic profile of TS girls previously treated with GH.
To accomplish this we will study girls/young woman between ages 13 to 20 with TS in 2 protocols.
Protocol #1 will be a study of the pharmacokinetic/pharmacodynamic (PK/PD) of 3 different preparations of estrogen in different doses.
Protocol #2 will be a one year longitudinal study of the effects of oral vs. transdermal (TD) estrogen on body composition, hormones and growth factors.
Study Type
Interventional
Enrollment (Actual)
41
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 Locations
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Santiago, Chile
- University of Chile/Clinica las Condes
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Florida
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Jacksonville, Florida, United States, 32207
- Nemours Children's Clinic
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Pennsylvania
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Philadelphia, Pennsylvania, United States, 19107
- Jefferson Medical College of Thomas Jefferson University
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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
11 years to 18 years (Child, Adult)
Accepts Healthy Volunteers
Yes
Description
Inclusion Criteria:
- Girls with Turner Syndrome (45X, or related karyotypes) diagnosed clinically and cytogenetically
- Female subjects with Y material will be allowed providing gonadectomies have been performed previously
- Age: 13-20 years
- Subjects have completed or nearly completed their linear growth
- Previous growth hormone (GH) therapy discontinued at least 6 months prior to study participation
- Stable thyroid replacement therapy will be allowed
- Celiac disease on stable diets will be allowed
- Any previous hormone replacement therapy (HRT) will be allowed
Exclusion Criteria:
- Diabetes Mellitus on insulin therapy, insulin sensitizers or oral hypoglycemics
- Inflammatory Bowel Disease (ulcerative colitis or Crohn's disease), celiac disease
- Cigarette smoking
- Any other chronic conditions, that, in the opinion of investigators could impair the metabolism of nutrients
- Severe obesity, i.e., Body Mass Index (BMI) >95th centile
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: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Active Comparator: Group A
Group A will receive the oral estradiol for 12 months
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Group A will be given estrogen by mouth daily(0.5 mg or 1mg or 2 mg of 17B Estradiol.
Doses will vary depending on the blood levels of estrogen starting with the lower doses and adjusting these doses up as needed to keep the levels in the normal range.
The estrogen will be taken for 21 days.
In order to have a menstrual cycle progesterone will be given for 7 days, starting from day 14 through day 21 of each cycle.
Then both medications are stopped on day 21 for a total of 7 days.
Labs will be obtained at baseline, 1,2,3,6,9 and 12 months.
Dual-energy X-ray absorptiometry (DXA) scan and calorimetry will be done at baseline and at 6 and 12 month.
Other Names:
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Active Comparator: Group B
Group B will receive the transdermal estradiol for 12 months
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Group B will be given estrogen via a patch applied to the skin twice a week (0.375mg or 0.05mg or 0.075mg) Doses will vary depending on the blood levels of estrogen starting with the lower doses and adjusting these doses up as needed to keep the levels in the normal range.
The estrogen will be taken for 21 days.
In order to have a menstrual cycle progesterone will be given for 7 days, starting from day 14 through day 21 of each cycle.
Then both medications are stopped on day 21 for a total of 7 days.
Labs will be obtained at baseline, 1,2,3,6,9 and 12 months.
Dual-energy X-ray absorptiometry (DXA) scan and calorimetry will be done at baseline and at 6 and 12 month.
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
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Change in Weight From Baseline at 12 Months
Time Frame: 12 months
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12 months
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Change in Body Mass Index From Baseline at 12 Months
Time Frame: 12 months
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12 months
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Change in Percent Fat Mass From Baseline in 12 Months
Time Frame: 12 months
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12 months
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Change in Fat Free Mass From Baseline at 12 Months
Time Frame: 12 months
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12 months
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Secondary Outcome Measures
Outcome Measure |
Time Frame |
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Changes in Insulin Growth Factor-I From Baseline at 12 Months
Time Frame: 12 months
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12 months
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Lipids Concentrations After Using Oral Versus Transdermal 17B Estradiol Replacement for 12 Months
Time Frame: 12 months
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12 months
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Rates of Lipid Oxidation After Using Oral Versus Transdermal 17B Estradiol Replacement for 12 Months
Time Frame: 12 months
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12 months
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Serum 17B Estradiol Concentrations After Using Oral Versus Transdermal 17B Estradiol Replacement for 12 Months
Time Frame: 12 months
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12 months
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Serum Estrone Concentrations After Using Oral Versus Transdermal 17B Estradiol Replacement for 12 Months
Time Frame: 12 months
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12 months
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Serum Estrone Sulfate Concentrations After Using Oral Versus Transdermal 17B Estradiol Replacement for 12 Months
Time Frame: 12 months
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12 months
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Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Collaborators
Investigators
- Principal Investigator: Nelly Mauras, MD, Nemours Children's Clinic
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
- 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.
- 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.
Helpful Links
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
January 1, 2009
Primary Completion (Actual)
June 1, 2012
Study Completion (Actual)
December 1, 2012
Study Registration Dates
First Submitted
February 3, 2009
First Submitted That Met QC Criteria
February 4, 2009
First Posted (Estimate)
February 5, 2009
Study Record Updates
Last Update Posted (Actual)
May 16, 2023
Last Update Submitted That Met QC Criteria
April 20, 2023
Last Verified
April 1, 2023
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Pathologic Processes
- Heart Diseases
- Cardiovascular Diseases
- Endocrine System Diseases
- Disease
- Ovarian Diseases
- Adnexal Diseases
- Gonadal Disorders
- Disorders of Sex Development
- Urogenital Abnormalities
- Congenital Abnormalities
- Genetic Diseases, Inborn
- Heart Defects, Congenital
- Cardiovascular Abnormalities
- Chromosome Disorders
- Sex Chromosome Disorders
- Sex Chromosome Disorders of Sex Development
- Syndrome
- Hypogonadism
- Primary Ovarian Insufficiency
- Menopause, Premature
- Turner Syndrome
- Gonadal Dysgenesis
- Physiological Effects of Drugs
- Hormones
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Estrogens
- Contraceptive Agents, Hormonal
- Contraceptive Agents
- Reproductive Control Agents
- Contraceptive Agents, Female
- Estradiol
- Estradiol 17 beta-cypionate
- Estradiol 3-benzoate
- Polyestradiol phosphate
Other Study ID Numbers
- 908-M01
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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