Clinical trial NCT00837616: Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
Official title: Estrogen Dosing in Turner Syndrome:Pharmacology & Metabolism
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Turner Syndrome
Hypogonadism
Premature Ovarian Failure
Keywords: Turner Syndrome
Hypogonadism
GH
Estrogen
Estrogen Patches
IGF-I
Body Composition
Protein Metabolism
Lipid Oxidation
Estradiol assay by LCMSMS
Recombinant Cell Bioassay
Lead sponsor: Nemours Children's Clinic
Sponsor class: OTHER
Collaborators: name: Genentech, Inc.
First posted: 2009-02-05
Enrollment: 41
Sex: FEMALE
Minimum age (years): 13
Maximum age (years): 20
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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

Primary outcomes:
measure: Change in Weight From Baseline at 12 Months
timeFrame: 12 months
measure: Change in Body Mass Index From Baseline at 12 Months
timeFrame: 12 months
measure: Change in Percent Fat Mass From Baseline in 12 Months
timeFrame: 12 months
measure: Change in Fat Free Mass From Baseline at 12 Months
timeFrame: 12 months
Secondary outcomes:
measure: Changes in Insulin Growth Factor-I From Baseline at 12 Months
timeFrame: 12 months
measure: Lipids Concentrations After Using Oral Versus Transdermal 17B Estradiol Replacement for 12 Months
timeFrame: 12 months
measure: Rates of Lipid Oxidation After Using Oral Versus Transdermal 17B Estradiol Replacement for 12 Months
timeFrame: 12 months
measure: Serum 17B Estradiol Concentrations After Using Oral Versus Transdermal 17B Estradiol Replacement for 12 Months
timeFrame: 12 months
measure: Serum Estrone Concentrations After Using Oral Versus Transdermal 17B Estradiol Replacement for 12 Months
timeFrame: 12 months
measure: Serum Estrone Sulfate Concentrations After Using Oral Versus Transdermal 17B Estradiol Replacement for 12 Months
timeFrame: 12 months
Other outcomes:
Locations:
city: Jacksonville
country: United States
facility: Nemours Children's Clinic
state: Florida
city: Philadelphia
country: United States
facility: Jefferson Medical College of Thomas Jefferson University
state: Pennsylvania
city: Santiago
country: Chile
facility: University of Chile/Clinica las Condes
Study officials:
affiliation: Nemours Children's Clinic
name: Nelly Mauras, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: Taboada 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.