Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism

This study has been completed.
Sponsor:
Collaborator:
Genentech
Information provided by (Responsible Party):
Nelly Mauras, Nemours Children's Clinic
ClinicalTrials.gov Identifier:
NCT00837616
First received: February 3, 2009
Last updated: February 26, 2014
Last verified: February 2014
  Purpose

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.


Condition Intervention Phase
Turner Syndrome
Hypogonadism
Premature Ovarian Failure
Drug: 17 B estradiol orally
Drug: 17 B estradiol
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Estrogen Dosing in Turner Syndrome:Pharmacology & Metabolism

Resource links provided by NLM:


Further study details as provided by Nemours Children's Clinic:

Primary Outcome Measures:
  • Change in Weight From Baseline at 12 Months [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • Change in Body Mass Index From Baseline at 12 Months [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • Change in Percent Fat Mass From Baseline in 12 Months [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • Change in Fat Free Mass From Baseline at 12 Months [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • Characterize PK/PD and Relative Biological Potency of Different Oral vs TD Estrogen Preparations [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Changes in Insulin Growth Factor-I From Baseline at 12 Months [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • Lipids Concentrations After Using Oral Versus Transdermal 17B Estradiol Replacement for 12 Months [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • Rates of Lipid Oxidation After Using Oral Versus Transdermal 17B Estradiol Replacement for 12 Months [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • Serum 17B Estradiol Concentrations After Using Oral Versus Transdermal 17B Estradiol Replacement for 12 Months [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • Serum Estrone Concentrations After Using Oral Versus Transdermal 17B Estradiol Replacement for 12 Months [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • Serum Estrone Sulfate Concentrations After Using Oral Versus Transdermal 17B Estradiol Replacement for 12 Months [ Time Frame: 12 months ] [ Designated as safety issue: No ]

Enrollment: 41
Study Start Date: January 2009
Study Completion Date: December 2012
Primary Completion Date: June 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Group A
Group A will receive the oral estradiol for 12 months
Drug: 17 B estradiol orally
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 Name: Estrace
Active Comparator: Group B
Group B will receive the transdermal estradiol for 12 months
Drug: 17 B estradiol
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 Name: Vivelle

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.

  Eligibility

Ages Eligible for Study:   13 Years to 20 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00837616

Locations
United States, Florida
Nemours Children's Clinic
Jacksonville, Florida, United States, 32207
United States, Pennsylvania
Jefferson Medical College of Thomas Jefferson University
Philadelphia, Pennsylvania, United States, 19107
Chile
University of Chile/Clinica las Condes
Santiago, Chile
Sponsors and Collaborators
Nemours Children's Clinic
Genentech
Investigators
Principal Investigator: Nelly Mauras, MD Nemours Children's Clinic
  More Information

Additional Information:
Publications:
Responsible Party: Nelly Mauras, Chief, Division of Endocrinology, Diabetes & Metabolism, Nemours Children's Clinic
ClinicalTrials.gov Identifier: NCT00837616     History of Changes
Other Study ID Numbers: 908-M01
Study First Received: February 3, 2009
Results First Received: May 28, 2013
Last Updated: February 26, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Nemours Children's Clinic:
Turner Syndrome
Hypogonadism
GH
Estrogen
Estrogen Patches
IGF-I
Body Composition
Protein Metabolism
Lipid Oxidation
Estradiol assay by LCMSMS
Recombinant Cell Bioassay

Additional relevant MeSH terms:
Primary Ovarian Insufficiency
Turner Syndrome
Gonadal Dysgenesis
Hypogonadism
Menopause, Premature
Gonadal Disorders
Endocrine System Diseases
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Disorders of Sex Development
Urogenital Abnormalities
Sex Chromosome Disorders of Sex Development
Heart Defects, Congenital
Cardiovascular Abnormalities
Cardiovascular Diseases
Heart Diseases
Congenital Abnormalities
Sex Chromosome Disorders
Chromosome Disorders
Genetic Diseases, Inborn
Estradiol
Polyestradiol phosphate
Estrogens
Estradiol valerate
Estradiol 17 beta-cypionate
Estradiol 3-benzoate
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on August 01, 2014