Menopause
Conditions
Keywords
menopause, sleep fragmentation, leuprolide, adipokine, weight gain, leptin
Brief summary
This study aims to investigate the impact of menopause-related sleep fragmentation on metabolic biomarkers of body fat gain. The investigators hypothesize that experimental sleep fragmentation will result in an adverse leptin response as a metabolic biomarker for body fat gain.
Detailed description
While obesity is highly prevalent in midlife and older women, with rates increasing markedly after age 40 and body fat increasing in half of women during and after the menopause transition, factors causing these changes are not well understood. Reduced total sleep time has been shown to adversely impact biomarkers of obesity, but the effect of the highly prevalent menopause-related sleep fragmentation secondary to hot flashes on metabolism and eating behaviors in humans is not known. We will use experimental paradigms to isolate the impact of menopause-related sleep disruption, as well as that of hot flashes and estrogen withdrawal, metabolic biomarkers of body fat gain and on eating behaviors, results of which will inform strategies to prevent body fat gain and improve cardio-metabolic health outcomes in women.
Interventions
DRUGEstradiol withdrawal
one injection of open-label intramuscular dose of leuprolide (3.75-mg depot), a gonadotropin-releasing hormone agonist that rapidly suppresses estradiol and temporarily achieves ovarian suppression.
OTHERFragmented sleep
Fragmented sleep will be experimentally induced.
Sponsors
National Institute on Aging (NIA)
Brigham and Women's Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy premenopausal women 18-45 years old * Regular sleep schedule * Limited alcohol and caffeine intake * Regular monthly menstrual cycles * No lifetime history of hot flashes * Willingness to use approved methods of contraception during study * Not obese * Good general health
Exclusion criteria
* Contraindication, hypersensitivity or previous adverse reaction to gonadotropin releasing hormone agonists * Pregnancy * Breastfeeding * Tobacco use * Contraindicated systemic hormone medications or centrally active medications * Shift workers or recent/expected time zone travel * Obstructive sleep apnea * Insomnia symptoms * Diagnosis of osteoporosis or osteopenia * Hypothalamic-pituitary-adrenal axis disorders * Diabetes * Gastric bypass, metabolic disorders, or other related conditions * Abnormalities on screening laboratory tests * Substantial hearing impairment * Cardiovascular illness * Neurological illness * Recent psychiatric illness or substance-use disorder
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Normalized Serum Leptin Levels | pre/post sleep fragmentation (3 days); pre/post estradiol withdrawal (~5 weeks) | 12-hr overnight fasted AM (morning) blood samples were assayed for leptin levels on study days 2-6 under both estrogenized and estradiol-withdrawal conditions \[total: 10 samples\]. For each individual, leptin values were normalized relative to the mean baseline leptin value. Baseline was defined as the unfragmented estrogenized condition (avg. of study days 2-3 in the estrogenized condition). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Normalized Satiety Scores | pre/post sleep fragmentation (3 days); pre/post estradiol withdrawal (~5 weeks) | 12-hr overnight fasted AM satiety scores were collected on study days 2-6 under both estrogenized and estradiol-withdrawal conditions \[total: 10 scores\]. For each individual, satiety scores were normalized relative to the mean baseline satiety score. Baseline was defined as the unfragmented estrogenized condition (avg. of study days 2-3 in the estrogenized condition). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Baseline Study Arm All participants who completed Sleep Block 1 | 38 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Sleep Block 1 | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Baseline Study Arm |
|---|---|
| Age, Continuous | 29.4 years STANDARD_DEVIATION 6.3 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 22 Participants |
| Sex: Female, Male Female | 38 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 41 |
| other Total, other adverse events | 32 / 41 |
| serious Total, serious adverse events | 0 / 41 |
Outcome results
Primary
Normalized Serum Leptin Levels
12-hr overnight fasted AM (morning) blood samples were assayed for leptin levels on study days 2-6 under both estrogenized and estradiol-withdrawal conditions \[total: 10 samples\]. For each individual, leptin values were normalized relative to the mean baseline leptin value. Baseline was defined as the unfragmented estrogenized condition (avg. of study days 2-3 in the estrogenized condition).
Time frame: pre/post sleep fragmentation (3 days); pre/post estradiol withdrawal (~5 weeks)
Population: To compare between study conditions, leptin levels \[12-hr overnight fasted AM samples\] were averaged across 2 samples \[on study days 2-3\] before 2 nights of sleep fragmentation and across 3 samples \[on study days 4-6\] after 3 nights of sleep fragmentation. Leptin levels were averaged across 5 samples \[on study days 2-6\] \~1 week before leuprolide administration (pre-estradiol withdrawal) and across 5 samples \[on study days 2-6\] \~4 weeks after leuprolide administration (post-estradiol withdrawal)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sleep Fragmentation - Active | Normalized Serum Leptin Levels | 96.7 percentage of mean baseline leptin | Standard Error 2.5 |
| Sleep Fragmentation - Control | Normalized Serum Leptin Levels | 94.0 percentage of mean baseline leptin | Standard Error 1.5 |
| Estradiol Withdrawal - Active | Normalized Serum Leptin Levels | 90.0 percentage of mean baseline leptin | Standard Error 3 |
| Estradiol Withdrawal - Control | Normalized Serum Leptin Levels | 101.0 percentage of mean baseline leptin | Standard Error 1.1 |
p-value: 0.22Mixed Models Analysis
p-value: 0.001Mixed Models Analysis
Secondary
Normalized Satiety Scores
12-hr overnight fasted AM satiety scores were collected on study days 2-6 under both estrogenized and estradiol-withdrawal conditions \[total: 10 scores\]. For each individual, satiety scores were normalized relative to the mean baseline satiety score. Baseline was defined as the unfragmented estrogenized condition (avg. of study days 2-3 in the estrogenized condition).
Time frame: pre/post sleep fragmentation (3 days); pre/post estradiol withdrawal (~5 weeks)
Population: To compare between study conditions, satiety scores \[12-hr overnight fasted AM satiety scores\] were averaged across 2 scores \[on study days 2-3\] before sleep fragmentation and across 3 scores \[on study days 4-6\] after 3 nights of sleep fragmentation. Satiety scores were averaged across 5 scores \[on study days 2-6\] \~1 week before leuprolide administration (pre-estradiol withdrawal) and across 5 scores \[on study days 2-6\] \~4 weeks after leuprolide administration (post-estradiol withdrawal).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sleep Fragmentation - Active | Normalized Satiety Scores | 99.2 percentage of mean baseline satiety | Standard Error 11.9 |
| Sleep Fragmentation - Control | Normalized Satiety Scores | 113.1 percentage of mean baseline satiety | Standard Error 11 |
| Estradiol Withdrawal - Active | Normalized Satiety Scores | 102.6 percentage of mean baseline satiety | Standard Error 15.6 |
| Estradiol Withdrawal - Control | Normalized Satiety Scores | 109.3 percentage of mean baseline satiety | Standard Error 7.8 |
p-value: 0.048Mixed Models Analysis
p-value: 0.58Mixed Models Analysis