Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
Estrogen Dosing in Turner Syndrome: Pharmacology and 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.
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.
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