Clinical trial NCT00687739: Prevention of Obesity in Women Via Estradiol Regulation
Official title: Estrogen Deficiency and Mechanisms of Fat Accumulation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Obesity
Keywords: hormone therapy
obesity
postmenopause
disease /disorder proneness /risk
insulin sensitivity /resistance
metabolic syndrome
women's health
Lead sponsor: University of Colorado, Denver
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
First posted: 2008-06-02
Enrollment: 79
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 49
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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 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

Primary outcomes:
measure: Resting Energy Expenditure (REE)
timeFrame: Before and after 5 months of treatment
measure: Cortisol Response (Area Under the Curve) to CRH Under DEX Suppression
timeFrame: Before and after 5 months of treatment
Secondary outcomes:
measure: Total Energy Expenditure (TEE)
timeFrame: Before and after 5 months of treatment
measure: Fat Mass
timeFrame: Before and after 5 months of treatment
measure: Fat-free Mass
timeFrame: Before and after 5 months of treatment
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado Denver
state: Colorado
Study officials:
affiliation: University of Colorado, Denver
name: Wendy M Kohrt, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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. doi: 10.1001/jama.291.14.1701.
citation: 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. doi: 10.1210/jc.2004-1479. Epub 2005 Feb 1.
citation: 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. doi: 10.1097/01.gme.0000117062.54779.bd.
citation: Gavin KM, Shea KL, Gibbons E, Wolfe P, Schwartz RS, Wierman ME, Kohrt WM. Gonadotropin-releasing hormone agonist in premenopausal women does not alter hypothalamic-pituitary-adrenal axis response to corticotropin-releasing hormone. Am J Physiol Endocrinol Metab. 2018 Aug 1;315(2):E316-E325. doi: 10.1152/ajpendo.00221.2017. Epub 2018 Apr 6.