Turner SyndromePhase 4NCT00837616
Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
A Phase 4 study testing 17 B estradiol orally and 17 B estradiol in people with Turner Syndrome and Hypogonadism, run by Nemours Children's Clinic at 3 sites in 2 countries.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 13 to 20 years, women onlyHealthy volunteers can take part
- Conditions the study is for
- Turner Syndrome, Hypogonadism, Premature Ovarian Failure
- What is being tested?
- 17 B estradiol orally and 17 B estradiol
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 41 participants
- Where
- 3 sitesin 2 countries
- Study dates
- Jan 2009to Dec 2012
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 13 to 20 years
- Women only
- Healthy volunteers accepted
- Child, Adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
3 sites in 2 countries.
3 sites in 2 countries
United States2 sites
Nemours Children's Clinic
Jacksonville, Florida, 32207
Jefferson Medical College of Thomas Jefferson University
Philadelphia, Pennsylvania, 19107
About this study
Official title: 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.
Read the 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.
- Conditions
- Turner Syndrome, Hypogonadism, Premature Ovarian Failure
- Being tested
- 17 B estradiol orally, 17 B estradiol
- Keywords
- Turner Syndrome, Hypogonadism, GH, Estrogen, Estrogen Patches, IGF-I, Body Composition, Protein Metabolism, Lipid Oxidation, Estradiol assay by LCMSMS, Recombinant Cell Bioassay
- Medical subject headings
- Turner Syndrome, Hypogonadism, Primary Ovarian Insufficiency
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
17 B estradiol orallyDrug
Also called Estrace
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.
17 B estradiolDrug
Also called Vivelle
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.
| Study group | Role | What they receive |
|---|---|---|
| Group A | Active comparator | Group A will receive the oral estradiol for 12 months Receives: Drug: 17 B estradiol orally |
| Group B | Active comparator | Group B will receive the transdermal estradiol for 12 months Receives: Drug: 17 B estradiol |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Weight From Baseline at 12 Months
Measured: 12 months
Change in Body Mass Index From Baseline at 12 Months
Measured: 12 months
Change in Percent Fat Mass From Baseline in 12 Months
Measured: 12 months
Change in Fat Free Mass From Baseline at 12 Months
Measured: 12 months
Secondary outcomes (6)
Changes in Insulin Growth Factor-I From Baseline at 12 Months
Measured: 12 months
Lipids Concentrations After Using Oral Versus Transdermal 17B Estradiol Replacement for 12 Months
Measured: 12 months
Rates of Lipid Oxidation After Using Oral Versus Transdermal 17B Estradiol Replacement for 12 Months
Measured: 12 months
Serum 17B Estradiol Concentrations After Using Oral Versus Transdermal 17B Estradiol Replacement for 12 Months
Measured: 12 months
Serum Estrone Concentrations After Using Oral Versus Transdermal 17B Estradiol Replacement for 12 Months
Measured: 12 months
Serum Estrone Sulfate Concentrations After Using Oral Versus Transdermal 17B Estradiol Replacement for 12 Months
Measured: 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Feb 2009 (estimated)
- Study startJan 2009
- Primary completionJun 2012
- Study completionDec 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Turner SyndromeStudies of the same condition, open and under way.
- 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
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 41 participants (actual)
Sponsor and investigators
- Lead sponsor
- Nemours Children's Clinic
- Sponsor type
- University, hospital or other
- Collaborators
- Genentech, Inc.
- Responsible party
- Principal investigator, Nelly Mauras, Nemours Children's Clinic
- Investigators
- Nelly Mauras, MD, Principal investigator, Nemours Children's Clinic
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00837616
- Sponsor's protocol ID
- 908-M01
- Status last verified
- Apr 2023
- First submitted
- 3 Feb 2009
- Last updated
- 16 May 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
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.
PubMed 23678038Taboada 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 21880799
Study at a glance
From the registry record, last updated by the sponsor on 16 May 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Estrogen Dosing in Turner Syndrome:Pharmacology & Metabolism
- ClinicalTrials.gov ID
- NCT00837616
- Acronym / sponsor ID
- 908-M01
- Conditions
- Turner Syndrome, Hypogonadism, Premature Ovarian Failure
- Keywords
- Turner Syndrome, Hypogonadism, GH, Estrogen, Estrogen Patches, IGF-I, Body Composition, Protein Metabolism
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 41 participants (actual)
- Lead sponsor
- Nemours Children's ClinicUniversity, hospital or other
- Collaborators
- Genentech, Inc.
- Study start
- Jan 2009
- Primary completion
- Jun 2012 (actual)
- Study completion
- Dec 2012 (actual)
- First posted
- 5 Feb 2009 (estimated)
- Results
- Posted 10 Feb 2014
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Group A | Active comparator | Drug: 17 B estradiol orallyGroup A will receive the oral estradiol for 12 months |
| Group B | Active comparator | Drug: 17 B estradiolGroup B will receive the transdermal estradiol for 12 months |
Who may qualify
- Ages
- 13 to 20 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult
Key inclusion criteria (8 listed)
- 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
Key exclusion criteria (5 listed)
- 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
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 B estradiol orallyAlso: EstraceGroup 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. | Drug | Group A |
| 17 B estradiolAlso: VivelleGroup 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. | Drug | Group B |
Primary outcome
Change in Weight From Baseline at 12 Months
Time frame: 12 months
Change in Body Mass Index From Baseline at 12 Months
Time frame: 12 months
Change in Percent Fat Mass From Baseline in 12 Months
Time frame: 12 months
Change in Fat Free Mass From Baseline at 12 Months
Time frame: 12 months
6 secondary outcomes
Changes in Insulin Growth Factor-I From Baseline at 12 Months
Time frame: 12 months
Lipids Concentrations After Using Oral Versus Transdermal 17B Estradiol Replacement for 12 Months
Time frame: 12 months
Rates of Lipid Oxidation After Using Oral Versus Transdermal 17B Estradiol Replacement for 12 Months
Time frame: 12 months
Serum 17B Estradiol Concentrations After Using Oral Versus Transdermal 17B Estradiol Replacement for 12 Months
Time frame: 12 months
Serum Estrone Concentrations After Using Oral Versus Transdermal 17B Estradiol Replacement for 12 Months
Time frame: 12 months
Serum Estrone Sulfate Concentrations After Using Oral Versus Transdermal 17B Estradiol Replacement for 12 Months
Time frame: 12 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 May 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 23678038Torres-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.
- Results publication: PubMed 21880799Taboada 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.
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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. This study is not recruiting at the moment.
Nelly Mauras, MD principal investigator
Nemours Children's Clinic
3 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing 17 B estradiol orally and 17 B estradiol in people with Turner Syndrome and Hypogonadism, run by Nemours Children's Clinic at 3 sites in 2 countries.
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 8 inclusion and 5 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: finished, as of the sponsor's last update on 16 May 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in United States, Chile. 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?
Yes. Results are posted in the registry (first posted 10 Feb 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Weight From Baseline at 12 Months (time frame: 12 months). The study lists 4 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 NCT00837616, which also lists 2 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 16 May 2023.