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CompletedNCT00687739POWERUpdated Apr 1, 2025Results posted

Prevention of Obesity in Women Via Estradiol Regulation

A Phase 3 interventional study of leuprolide acetate and Estradiol Transdermal in Obesity, sponsored by University of Colorado, Denver. Completed at 1 site in United States. Open to female participants aged 18 Years to 49 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2025-04-01.

Sponsored by University of Colorado, Denver · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
79
Allocation
Randomized
Ages
18 Years to 49 Years
Sex
Female
01

Study summary

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

Read the 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.

02

Conditions studied

  • Obesity

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Keywords

  • hormone therapy
  • obesity
  • postmenopause
  • disease /disorder proneness /risk
  • insulin sensitivity /resistance
  • metabolic syndrome
  • women's health
03

In context

Obesity

6,296 studies on the registry are indexed under Obesity; 1,692 are open to participants now.

This study's enrollment of 79 is close to the median of 78 across 4,878 interventional studies indexed under Obesity.

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Lead sponsor

University of Colorado, Denver is the lead sponsor of 1,499 studies on the registry; 315 are open to participants now.

Of its 139 completed or terminated interventional studies of FDA-regulated products, 89 (64%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years to 49 Years
Sexes eligible
Female
Accepts healthy volunteers
Yes

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

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
05

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Triple (Participant, Investigator, Outcomes assessor)
Enrollment
79 participants (actual)

Study arms

  • Placebo comparator
    1

    GnRH agonist + placebo

    Drug: leuprolide acetate

  • Active comparator
    2

    GnRH agonist + placebo + exercise

    Drug: leuprolide acetate · Behavioral: progressive resistance exercise training

  • Experimental
    3

    GnRH agonist + Estradiol

    Drug: leuprolide acetate · Drug: Estradiol Transdermal

  • Experimental
    4

    GnRH agonist + Estradiol + exercise

    Drug: leuprolide acetate · Drug: Estradiol Transdermal · Behavioral: progressive resistance exercise training

Interventions

  • Drugleuprolide acetate

    3.75 mg for depot suspension delivered by monthly intramuscular injection for 5 months

    Also known as: Lupron

  • DrugEstradiol Transdermal

    0.075 mg patch per day for 5 months

    Also known as: Climara

  • Behavioralprogressive resistance exercise training

    45 minute exercise sessions 4 times per week for 5 months

06

What researchers measure

Primary outcomes

  1. Resting Energy Expenditure (REE)

    Resting energy expenditure measured by indirect calorimeter at baseline and after 5 months of treatment.

    Time frame: Before and after 5 months of treatment

  2. Cortisol Response (Area Under the Curve) to CRH Under DEX Suppression

    Cortisol response to corticotropin releasing hormone (CRH) during dexamethasone (DEX) suppression; DEX/CRH stimulation test

    Time frame: Before and after 5 months of treatment

Secondary outcomes

  1. Total Energy Expenditure (TEE)

    24-hour energy expenditure measured by indirect calorimetry in a room calorimeter

    Time frame: Before and after 5 months of treatment

  2. Fat Mass

    Total body fat mass measured by DXA

    Time frame: Before and after 5 months of treatment

  3. Fat-free Mass

    Total body fat-free mass measured by DXA

    Time frame: Before and after 5 months of treatment

07

Results

Posted Dec 9, 2019
Limitations and caveats
This was a mechanistically driven study to isolate the effects of estradiol on bioenergetics and HPA axis activity. It was not a therapeutic clinical trial.

Participant flow

Participant flow — Overall Study
MilestoneGnRH Agonist + PlaceboGnRH Agonist + Placebo + ExerciseGnRH Agonist + EstradiolGnRH Agonist + Estradiol + Exercise
Started25152514
Completed23122312
Not completed2322
Withdrew: Lost to follow-up2212
Withdrew: Adverse event0110

Outcome measures

PrimaryResting Energy Expenditure (REE)

Resting energy expenditure measured by indirect calorimeter at baseline and after 5 months of treatment.

Time frame:
Before and after 5 months of treatment
Reported as:
Mean · kcal/d
Resting Energy Expenditure (REE)
kcal/dGnRHag+PLGnRHag+PL+exGnRHag+E2GnRHag+E2+ex
Resting Energy Expenditure (REE)-37.8 (-88.7 to 13.0)-87.2 (-185.9 to 11.4)14.6 (-34.8 to 64.0)-19.3 (-95.1 to 56.4)
Statistical analysis
  • GnRHag+PL vs GnRHag+PL+ex vs GnRHag+E2 vs GnRHag+E2+ex · ANCOVA · p = <0.05 (The p value was calculated)
PrimaryCortisol Response (Area Under the Curve) to CRH Under DEX Suppression

Cortisol response to corticotropin releasing hormone (CRH) during dexamethasone (DEX) suppression; DEX/CRH stimulation test

Time frame:
Before and after 5 months of treatment
Reported as:
Mean · ng/mL x min
Cortisol Response (Area Under the Curve) to CRH Under DEX Suppression
ng/mL x minGnRHag+PLGnRHag+E2
Cortisol Response (Area Under the Curve) to CRH Under DEX Suppression189 (-2481 to 2859)-3115 (-5322 to -907)
Statistical analysis
  • GnRHag+PL vs GnRHag+E2 · ANCOVA · p = <0.05 (The p value was calculated)
SecondaryTotal Energy Expenditure (TEE)

24-hour energy expenditure measured by indirect calorimetry in a room calorimeter

Time frame:
Before and after 5 months of treatment
Reported as:
Mean · kcal/d
Total Energy Expenditure (TEE)
kcal/dGnRHag+PLGnRHag+PL+exGnRHag+E2GnRHag+E2+Ex
Total Energy Expenditure (TEE)-108.8 (-201.1 to -16.5)-166.5 (-388.1 to 55.1)-92.7 (-167.1 to -18.4)-107.4 (-298.3 to 83.5)
Statistical analysis
  • GnRHag+PL vs GnRHag+PL+ex vs GnRHag+E2 vs GnRHag+E2+Ex · ANCOVA · p = <0.05 (The p value was calculated)
SecondaryFat Mass

Total body fat mass measured by DXA

Time frame:
Before and after 5 months of treatment
Reported as:
Mean · kg
Fat Mass
kgGnRHag+PLGnRHag+PL+exGnRHag+E2GnRHag+E2+ex
Fat Mass0.5 (-0.5 to 1.4)-0.6 (-1.7 to 0.5)0.4 (-0.7 to 1.5)-0.8 (-2.9 to 1.2)
SecondaryFat-free Mass

Total body fat-free mass measured by DXA

Time frame:
Before and after 5 months of treatment
Reported as:
Mean · kg
Fat-free Mass
kgGnRHag+PLGnRHag+PL+exGnRHag+E2GnRHag+E2+ex
Fat-free Mass-1.0 (-1.5 to -0.6)0.1 (-0.6 to 0.7)0.0 (-0.5 to 0.4)1.0 (-0.3 to 2.2)

Adverse events

Collected over Adverse events were collected from the time eligibility was established through the completion of the study, over approximately 1 year.. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
GnRH Agonist + Placebo—0/23 (0%)0/23 (0%)
GnRH Agonist + Placebo + Exercise—0/12 (0%)0/12 (0%)
GnRH Agonist + Estradiol—1/23 (4.3%)0/23 (0%)
GnRH Agonist + Estradiol + Exercise—0/12 (0%)0/12 (0%)
Most frequent serious events
Most frequent serious events
EventGnRH Agonist + PlaceboGnRH Agonist + Placebo + ExerciseGnRH Agonist + EstradiolGnRH Agonist + Estradiol + Exercise
HospitalizationProduct Issues0/230/121/230/12

Baseline characteristics

Of the 79 women enrolled, 9 discontinued. Baseline and outcome measure data are reported for the 70 participants who completed the study. Ethnic data (Hispanic or Latino) are not distinct from racial data. 9 women who identified as Hispanic or Latino are also included in one of the race categories

Age, Continuous
Age, Continuous(years)GnRH Agonist + PlaceboGnRH Agonist + Placebo + ExerciseGnRH Agonist + EstradiolGnRH Agonist + Estradiol + ExerciseTotal
Mean36 ± 836 ± 835 ± 935 ± 935.5 ± 8.5
Sex: Female, Male
Sex: Female, Male(Participants)GnRH Agonist + PlaceboGnRH Agonist + Placebo + ExerciseGnRH Agonist + EstradiolGnRH Agonist + Estradiol + ExerciseTotal
Female2312231270
Male00000
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)GnRH Agonist + PlaceboGnRH Agonist + Placebo + ExerciseGnRH Agonist + EstradiolGnRH Agonist + Estradiol + ExerciseTotal
Asian11002
Native American10001
Black21429
Caucasian15917950
More than one race41016
Refused to answer00202
Hispanic or Latino42129
Region of Enrollment
Region of Enrollment(participants)GnRH Agonist + PlaceboGnRH Agonist + Placebo + ExerciseGnRH Agonist + EstradiolGnRH Agonist + Estradiol + ExerciseTotal
United States2312231270
Body Mass Index (BMI)
Body Mass Index (BMI)(kg/m^2)GnRH Agonist + PlaceboGnRH Agonist + Placebo + ExerciseGnRH Agonist + EstradiolGnRH Agonist + Estradiol + ExerciseTotal
Mean28 ± 628 ± 628 ± 628 ± 628 ± 6
Body Composition Total Mass
Body Composition Total Mass(kilograms)GnRH Agonist + PlaceboGnRH Agonist + Placebo + ExerciseGnRH Agonist + EstradiolGnRH Agonist + Estradiol + ExerciseTotal
Mean74.4 ± 2.774.4 ± 2.776.6 ± 376.6 ± 375.5 ± 2.8
Body Composition Fat Mass
Body Composition Fat Mass(kilograms)GnRH Agonist + PlaceboGnRH Agonist + Placebo + ExerciseGnRH Agonist + EstradiolGnRH Agonist + Estradiol + ExerciseTotal
Mean27.8 ± 1.927.8 ± 1.928.2 ± 228.2 ± 228 ± 2
08

Study locations

1 site
  • University of Colorado Denver
    Aurora, Colorado 80045, United States
09

References and documents

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. doi: 10.1001/jama.291.14.1701. PubMed 15082697 ↗
  • 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. PubMed 15687338 ↗
  • 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. PubMed 15167310 ↗
  • 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. PubMed 29631362 ↗
10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Apr 1, 2025, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT00687739
Lead sponsor
University of Colorado, Denver
Collaborators
National Institute on Aging (NIA)
Responsible party
Sponsor
First posted
Jun 2, 2008
Start date
May 2008
Primary completion
Jun 2014
Completion
Jun 2014
Results posted
Dec 9, 2019
Last update
Apr 1, 2025

Study contacts

Wendy M Kohrt, PhD
principal investigator · University of Colorado, Denver

Oversight

Data monitoring committee
Yes
View the source record on ClinicalTrials.gov ↗

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