Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
Condition: Turner Syndrome; Hypogonadism; Premature Ovarian Failure
MeSH terms: Turner Syndrome; Gonadal Dysgenesis; Primary Ovarian Insufficiency; Menopause, Premature; Hypogonadism; Syndrome
Intervention: 17 B estradiol orally; 17 B estradiol
Intervention description: 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.; 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.
Intervention MeSH terms: Estradiol 17 beta-cypionate; Estradiol 3-benzoate; Estradiol; Polyestradiol phosphate
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 41.0
Sex: Female
Minimum age: 13 Years
Maximum age: 20 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Turner Syndrome; Hypogonadism; GH; Estrogen; Estrogen Patches; IGF-I; Body Composition; Protein Metabolism; Lipid Oxidation; Estradiol assay by LCMSMS; Recombinant Cell Bioassay

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.
      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.
    

Eligibility 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