Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism

NCT00837616 | Completed Phase 4 Results

• 1 other identifier: 908-M01
• Study Type: interventional
• Target: 41
• Locations: 2 countries
• Sites: 3

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.

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

Outcome Measures

Primary Outcomes (4)

• Change in Weight From Baseline at 12 Months

  12 months

• Change in Body Mass Index From Baseline at 12 Months

  12 months

• Change in Percent Fat Mass From Baseline in 12 Months

  12 months

• Change in Fat Free Mass From Baseline at 12 Months

  12 months

Secondary Outcomes (6)

• Changes in Insulin Growth Factor-I From Baseline at 12 Months

  12 months

• Lipids Concentrations After Using Oral Versus Transdermal 17B Estradiol Replacement for 12 Months

  12 months

• Rates of Lipid Oxidation After Using Oral Versus Transdermal 17B Estradiol Replacement for 12 Months

  12 months

• Serum 17B Estradiol Concentrations After Using Oral Versus Transdermal 17B Estradiol Replacement for 12 Months

  12 months

• Serum Estrone Concentrations After Using Oral Versus Transdermal 17B Estradiol Replacement for 12 Months

  12 months

Study Arms (2)

Group A

ACTIVE COMPARATOR

Group A will receive the oral estradiol for 12 months

Drug: 17 B estradiol orally

Group B

ACTIVE COMPARATOR

Group B will receive the transdermal estradiol for 12 months

Drug: 17 B estradiol

Interventions

17 B estradiol orally DRUG

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.

Also known as: Estrace

Group A

17 B estradiol DRUG

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.

Also known as: Vivelle

Group B

Eligibility Criteria

• Age: 13 Years - 20 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Nemours Children's Clinic: lead
• Genentech, Inc.: collaborator

Study Sites (3)

Nemours Children's Clinic

Jacksonville, Florida, 32207, United States

Location

Jefferson Medical College of Thomas Jefferson University

Philadelphia, Pennsylvania, 19107, United States

Location

University of Chile/Clinica las Condes

Santiago, Chile

Location

Related Publications (2)

• 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.

  PMID: 23678038 RESULT

• 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.

  PMID: 21880799 RESULT

MeSH Terms

Conditions

Turner Syndrome; Hypogonadism; Primary Ovarian Insufficiency

Interventions

Estradiol

Condition Hierarchy (Ancestors)

Gonadal Dysgenesis; Disorders of Sex Development; Urogenital Abnormalities; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Sex Chromosome Disorders of Sex Development; Male Urogenital Diseases; Heart Defects, Congenital; Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Sex Chromosome Disorders; Chromosome Disorders; Genetic Diseases, Inborn; Gonadal Disorders; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Genital Diseases

Intervention Hierarchy (Ancestors)

Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Results Point of Contact

• Title: Dr. Nelly Mauras
• Organization: Nemours Children's Clinic

nmauras@nemours.org

(904) 697-3674

Study Officials

• Nelly Mauras, MD

  Nemours Children's Clinic

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Chief, Division of Endocrinology, Diabetes & Metabolism

Study Record Dates

• First Submitted: February 3, 2009
• First Posted: February 5, 2009
• Study Start: January 1, 2009
• Primary Completion: June 1, 2012
• Study Completion: December 1, 2012
• Last Updated: May 16, 2023
• Results First Posted: February 10, 2014

Record last verified: 2023-04

Locations

CL (1); US (2)