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
Study type: Interventional
Phase: Phase 4

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.
    

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.
    

Intervention name(s): 17 B estradiol orally; 17 B estradiol
Intervention type(s): Drug; Drug
Intervention description(s): 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.
Other intervention name(s): Estrace; Vivelle
Intervention MeSH terms: Estradiol 17 beta-cypionate; Estradiol 3-benzoate; Estradiol; Polyestradiol phosphate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Turner Syndrome; Hypogonadism; GH; Estrogen; Estrogen Patches; IGF-I; Body Composition; Protein Metabolism; Lipid Oxidation; Estradiol assay by LCMSMS; Recombinant Cell Bioassay