Prevention of Obesity in Women Via Estradiol Regulation - Full Text View

Purpose

The purpose of this study is to evaluate potential mechanisms by which estradiol deficiency accelerates fat gain and abdominal fat accumulation in women.

Condition	Intervention	Phase
Obesity	Drug: leuprolide acetate Drug: Estradiol Transdermal Behavioral: progressive resistance exercise training	Phase 3

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Investigator, Outcomes Assessor) Primary Purpose: Treatment
Official Title:	Estrogen Deficiency and Mechanisms of Fat Accumulation

Resource links provided by NLM:

MedlinePlus related topics: Diabetes Medicines Exercise and Physical Fitness Obesity

Drug Information available for: Estradiol Estradiol cypionate Estradiol valerate Estradiol acetate Estradiol hemihydrate Leuprolide acetate

U.S. FDA Resources

Further study details as provided by University of Colorado, Denver:

Primary Outcome Measures:

Resting Energy Expenditure (REE) Resting Metabolic Rate (RMR) [ Time Frame: Baseline, after 5 months of treatment, and 4 months post-treatment ] [ Designated as safety issue: No ]
DEX/CRH stimulation test (dexamethasone-suppressed CRH test)to measure stress-induced HPA axis activity [ Time Frame: Baseline, after 5 months of treatment, and 4 months post-treatment ] [ Designated as safety issue: No ]
Cortisol response to Corticotropin Releasing Hormone under Dexamethasone suppression

Secondary Outcome Measures:

Energy Expenditure (EE) and Total Energy Expenditure (TEE) [ Time Frame: Baseline, 5 months of treatment, and 4 months post-treatment ] [ Designated as safety issue: No ]

Estimated Enrollment:	300
Study Start Date:	May 2008
Estimated Study Completion Date:	June 2014
Estimated Primary Completion Date:	June 2014 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Placebo Comparator: 1 GnRH agonist + placebo	Drug: leuprolide acetate 3.75 mg for depot suspension delivered by monthly intramuscular injection for 5 months Other Name: Lupron
Active Comparator: 2 GnRH agonist + placebo + exercise	Drug: leuprolide acetate 3.75 mg for depot suspension delivered by monthly intramuscular injection for 5 months Other Name: Lupron Behavioral: progressive resistance exercise training 45 minute exercise sessions 4 times per week for 5 months
Experimental: 3 GnRH agonist + E2	Drug: leuprolide acetate 3.75 mg for depot suspension delivered by monthly intramuscular injection for 5 months Other Name: Lupron Drug: Estradiol Transdermal 0.075 mg patch per day for 5 months Other Name: Climara
Experimental: 4 GnRH agonist + E2 + exercise	Drug: leuprolide acetate 3.75 mg for depot suspension delivered by monthly intramuscular injection for 5 months Other Name: Lupron Drug: Estradiol Transdermal 0.075 mg patch per day for 5 months Other Name: Climara Behavioral: progressive resistance exercise training 45 minute exercise sessions 4 times per week for 5 months

Detailed Description:

Many factors contribute to the current epidemic of obesity. Although estrogen status is not commonly recognized as a determinant of obesity risk in women, there is strong evidence from large randomized controlled trials that estradiol (E2)-based hormone therapy (HT) reduces weight gain by about 40% in postmenopausal women. Importantly, there is also strong evidence that E2 reduces abdominal fat accumulation, a fundamental component of the Metabolic Syndrome. Some studies suggest risks of HT outweigh the benefits for some women. However, this does not negate the importance of learning the mechanisms by which E2 influences energy balance and fat patterning.

This study uses gonadotropin releasing hormone (GnRH) analog therapy to determine the effects of chronic (5-month) sex hormone suppression on resting energy expenditure (REE), altered hypothalamic-pituitary-adrenal (HPA) axis activity, and fat gain.

It is hypothesized that REE will be reduced in response to chronic sex hormone suppression, promoting fat gain. It is also hypothesized that stress-induced hypothalamic-pituitary-adrenal (HPA)axis activity will be amplified during sex hormone suppression; altered HPA axis activity leading to cortisol excess causes abdominal fat accumulation. Finally, it is hypothesized that E2 add-back therapy will lessen these responses.

Participants will be randomized so that half of the women in each treatment arm will participate in an exercise training program, consisting of progressive resistance exercise to prevent the decline in fat-free mass (FFM) and the increase in fat mass that has been observed in young women in response to GnRH analog therapy.

Eligibility

Ages Eligible for Study:	18 Years to 49 Years
Genders Eligible for Study:	Female
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

Healthy premenopausal women, aged 18 to 49 years
Regular menses (no missed cycles in previous year; cycle length 25-35 days)
Positive luteinizing hormone test or a mid-luteal serum progesterone greater than 3 ng/mL
Nonsmokers
Willing to receive all study interventions
Physically able and willing to be randomized to participate in a supervised resistance exercise training program

Exclusion Criteria:

Already performing high-intensity resistance exercise training more than 1 day per week
On diabetes medications
Use of hormonal contraception in the past 3 months
On oral or inhaled glucocorticoids
Positive pregnancy test
Intention to become pregnant or start hormonal contraceptive therapy during the period of study
Lactation
Hypersensitivity to extrinsic peptide hormones, mannitol, Gonadotropin-releasing hormone (GnRH), leuprolide acetate, benzyl alcohol (the vehicle for injection of leuprolide acetate), or transdermal patch
Score greater than 16 on the Center for Epidemiologic Studies Depression Scale and Beck Depression Inventory-II score greater than 18, or clinician recommendation to exclude
Severe osteopenia or osteoporosis (proximal femur or lumbar spine t scores < -2.0)
BMI greater than 40 kg/m2, weight change of more than ± 2 kg in last 6 months, or weight-reduced by more than 5 kg from maximal body weight
Abnormal vaginal bleeding
History of breast cancer or other estrogen-dependent neoplasms
History of venous thromboembolic events
Moderate or severe renal impairment (creatinine clearance <50 mL/min by Cockcroft-Gault)
Chronic hepatobiliary disease, defined as liver function tests (AST, ALT, alkaline phosphatase, total bilirubin) greater than 1.5 times the upper limit of normal
Thyroid dysfunction, defined as ultra sensitive TSH less than 0.5 or greater than 5.0 mU/L
Uncontrolled hypertension, defined as resting BP greater than 150/90 mmHg
Cardiovascular disease, including indicators of ischemic heart disease or serious arrhythmias at rest or during the graded exercise test; follow-up diagnostic testing to rule out cardiovascular disease by a cardiologist will be allowed
Orthopedic or other problems that would interfere with participation in the exercise program

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00687739

Contacts

Contact: Ellie Gibbons, BA

720-848-6408

Ellie.Gibbons@UCHSC.edu

Locations

United States, Colorado
University of Colorado Denver	Recruiting
Aurora, Colorado, United States, 80045
Contact: Ellie Gibbons, BA 720-848-6408 Ellie.Gibbons@UCHSC.edu
Principal Investigator: Wendy M Kohrt, PhD
Sub-Investigator: Wendolyn S Gozansky, MD, MPH

Sponsors and Collaborators

University of Colorado, Denver

National Institute on Aging (NIA)

Investigators

Principal Investigator:

Wendy M Kohrt, PhD

University of Colorado, Denver

More Information

Publications:

Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, Bonds D, Brunner R, Brzyski R, Caan B, Chlebowski R, Curb D, Gass M, Hays J, Heiss G, Hendrix S, Howard BV, Hsia J, Hubbell A, Jackson R, Johnson KC, Judd H, Kotchen JM, Kuller L, LaCroix AZ, Lane D, Langer RD, Lasser N, Lewis CE, Manson J, Margolis K, Ockene J, O'Sullivan MJ, Phillips L, Prentice RL, Ritenbaugh C, Robbins J, Rossouw JE, Sarto G, Stefanick ML, Van Horn L, Wactawski-Wende J, Wallace R, Wassertheil-Smoller S; Women's Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA. 2004 Apr 14;291(14):1701-12.

Sites CK, L'Hommedieu GD, Toth MJ, Brochu M, Cooper BC, Fairhurst PA. The effect of hormone replacement therapy on body composition, body fat distribution, and insulin sensitivity in menopausal women: a randomized, double-blind, placebo-controlled trial. J Clin Endocrinol Metab. 2005 May;90(5):2701-7. Epub 2005 Feb 1.

Utian WH, Gass ML, Pickar JH. Body mass index does not influence response to treatment, nor does body weight change with lower doses of conjugated estrogens and medroxyprogesterone acetate in early postmenopausal women. Menopause. 2004 May-Jun;11(3):306-14.

Responsible Party:	University of Colorado, Denver
ClinicalTrials.gov Identifier:	NCT00687739 History of Changes
Other Study ID Numbers:	06-0512, R01AG018198
Study First Received:	May 29, 2008
Last Updated:	January 10, 2013
Health Authority:	United States: Federal Government

Keywords provided by University of Colorado, Denver:

hormone therapy
obesity
postmenopause
disease /disorder proneness /risk

insulin sensitivity /resistance
metabolic syndrome
women's health

Additional relevant MeSH terms:

Obesity
Overnutrition
Nutrition Disorders
Overweight
Body Weight
Signs and Symptoms
Estradiol
Polyestradiol phosphate
Estradiol valerate
Estradiol 3-benzoate
Estradiol 17 beta-cypionate
Leuprolide
Estrogens

Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions
Contraceptive Agents
Reproductive Control Agents
Therapeutic Uses
Contraceptive Agents, Female
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Fertility Agents, Female
Fertility Agents

ClinicalTrials.gov processed this record on May 22, 2013

Prevention of Obesity in Women Via Estradiol Regulation (POWER)