Perimenopausal Disorder, Stress, Emotional
Conditions
Keywords
perimenopause, menopause transition, estrogen, stress, mood
Brief summary
Women in the menopause transition ('perimenopause') are exposed to extreme hormone variability, tend to experience a unique set of severe stressors (e.g., divorce, death of loved ones), and are also at substantially elevated risk to suffer from mood and anxiety disorders. The purpose of this research is to understand the mechanisms by which variability in estradiol (E2) is associated with the symptoms of anxiety and anhedonia (loss of interest and pleasure - a common symptom of depression). By stabilizing E2 variability with a hormonal manipulation, this research will determine the degree to which the E2 variability (or E2 levels) plays a causal role in perimenopausal anxiety and anhedonia symptoms and whether it does so by affecting biological responses to stress.
Detailed description
Framed within a diathesis-stress model, the primary objective of this research is to determine the pathophysiological mechanisms of estradiol (E2) in the clinical anxiety and anhedonia seen in the menopause transition (MT). Specifically whether E2 variability or E2 levels predict exaggerated hypothalamic-pituitary-adrenal (HPA) axis reactivity and impaired recovery to stress and, in turn, deficits in behavioral indices of threat responsivity and approach motivation and symptoms of anxiety and anhedonia. The secondary objective of the research is to use a hormonal manipulation as a mechanistic probe to stabilize E2 variability in premenopausal ranges and determine if: a) HPA axis reactivity/recovery represents a biomarker of behavioral and symptom responses to E2 stabilization; b) whether recent severe life stress predicts the HPA axis response to hormone stabilization. A total of 170 women in the early or late MT who are eligible for the hormonal probe will be recruited to reflect the full continuum of anxiety and anhedonia symptoms based on self-report to the State-Trait Anxiety Inventory and the Snaith-Hamilton Pleasure Scale, respectively. However, the investigators will over-represent the clinically impairing end of the anxious and anhedonic phenotype (75% of the sample). Over an 8-week baseline, anxiety and anhedonia symptoms and serum E2 measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) will be assessed on a weekly basis. At baseline week 8, HPA axis (plasma cortisol and ACTH) response to the Trier Social Stress Test and behavioral measures of threat responsivity (via Dot-Probe task) and approach motivation (Effort Expenditure for Rewards Task 'EEfRT') will be determined. Using transdermal E2 as a pharmacological probe to stabilize variability of E2 in premenopausal ranges, women will then be randomized to transdermal E2 (0.10 mg) or placebo for 16 weeks. This is not a clinical efficacy trial. The investigators will use an randomized control trial (RCT) design with a hormonal manipulation in order to investigate the pathophysiologic role of E2 variability (or E2 levels) in HPA axis dysregulation and, in turn, threat responsivity and approach motivation. Serum E2 will be assessed weekly during weeks 9-16, and HPA axis reactivity to stress and behavioral responses to the Dot-Probe and EEfRT tasks will be assessed every four weeks during the 16 week probe.
Interventions
Transdermal Estradiol worn daily for 16 weeks (patch changed every 7 days).
DRUGPlacebo Patch
Matching placebo patches to be worn every day for 16 weeks (patch changed every 7 days).
DRUGProgesterone Capsule
Micronized progesterone (200 mg) will be administered every day for 12 days during the 9th week of randomization and again following randomization at the 17th week
DRUGPlacebo Oral Capsule
Matching placebo capsules will be administered orally every day for 12 days during the 9th week of randomization and again following randomization at the 17th week.
Sponsors
National Institute of Mental Health (NIMH)
University of North Carolina, Chapel Hill
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
45 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
* Perimenopausal (either early perimenopause, defined as menstrual cycle length 7+ days longer or shorter than usual; or the late perimenopause, defined as ≥2 skipped cycles and an interval of amenorrhea ≥60 days but within one year of the last menstrual period) * 45 to 60 years of age * must be medically healthy
Exclusion criteria
* a history of cardiovascular disease (CVD) including coronary artery disease, arteriosclerosis, heart attack, or stroke * Type I or II diabetes * personal history of thrombotic events * personal or family history suggesting elevated risk for E2-related cancer * currently experiencing migraine headaches with aura
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change Over Time in the Anxiety Score From State-Trait Anxiety Inventory | Baseline (Week 8), Weeks 16, 20 and 24 | The State-Trait anxiety inventory is consists of 20 questions on a 4-point force-choice Likert-type response scales (scores 0 - 3). The 20 questions are summed together for final score. The score can range from 0 to 60 with higher scores representing higher levels of anxiety. Change over time is defined as the difference in the least square means between timepoints and 95% confidence interval limits. |
| Change Over Time in Anhedonia Score From Snaith-Hamilton Pleasure Scale | Baseline (Week 8), Weeks 16, 20 and 24 | Anhedonia will be assessed using SHAPS scores which range from 14-56, with higher scores corresponding to higher levels of anhedonia. Change over time is defined as the difference in least square means between time points and 95% confidence interval limits. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change Over Time in AUC Cortisol Stress Response | Baseline (Week 8), Weeks 16, 20 and 24 | The stress biomarker cortisol (µg/dL) assessed at rest and in response to the Trier Social Stress test (AUC with respect to ground) at baseline (Week 8) and again post-randomization at weeks 16, 20 and 24. Blood serum samples for measuring cortisol are taken at immediately before the Trier Social Stress test and at 10, 20, 30, and 45 minutes post test. Change over time is defined as the difference in least square means between timepoints and with 95% confidence interval limits. |
| Change Over Time in Threat Bias Score From Dot Probe Task | up to 24 weeks | Changes in threat bias scores assessed using Dot Probe task during labs at weeks 8, 16, 20 and 24. The bias measurement protocol consists of 144 trials (48 threat congruent, 48 threat incongruent, 48 neutral presentations). Participants indicate the probe letter via button press. Angry face location, probe location, probe type and actor are all fully counterbalanced in presentation. The threat bias score equals the mean of reaction time on threat congruent from threat incongruent trials. A threat bias scores \>0 indicate a bias towards threat, whereas scores \<0 mean that the participant is slower to respond to threatening stimuli than neutral stimuli. Reaction times were measured in milliseconds. Change over time is defined as the difference in least square means between timepoints with 95% confidence interval limits. |
| Change Over Time in Percent of Hard Task Choice in EEfRT | up to 24 weeks | Effort Expenditure for Rewards Task (EEfRT) measures approach motivation that indexes the willingness to expend effort to obtain monetary rewards under varying conditions of reward probability and magnitude. On each trial, participants choose between an easy task and a hard task and are presented with information about the probability of winning (i.e., 12%, 50%, or 88%), and the magnitude of the potential reward if they complete the button-press task successfully (range: $1.24 - $4.12). Completion of the easy task requires 30 button presses in 7 seconds using the dominant index finger, whereas completion of the hard task requires 100 presses with the non-dominant pinky finger in 21 seconds. The percent of hard task choices is the dependent measure. Change over time is defined as the difference in least square means between time points with 95% confidence interval limits. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Patch and Placebo Capsule Placebo patches worn for 16 weeks. On the 9th week of patch, oral placebo capsule taken daily for 12 days. Following the 16 weeks of patch use oral placebo capsule taken daily for 12 days.
Placebo Patch: Matching placebo patches to be worn every day for 16 weeks (patch changed every 7 days).
Placebo Oral Capsule: Matching placebo capsules will be administered orally every day for 12 days during the 9th week of randomization and again following randomization at the 17th week. | 40 |
| Estradiol Patch and Progesterone Capsule Estradiol patches worn for 16 weeks. On the 9th week of patch, oral progesterone capsule taken daily for 12 days. Following the 16 weeks of estradiol patch use oral progesterone capsule taken daily for 12 days.
Estradiol Patch, 0.1 Mg/24 Hours Weekly Transdermal Film, Extended Release: Transdermal Estradiol worn daily for 16 weeks (patch changed every 7 days).
Progesterone Capsule: Micronized progesterone (200 mg) will be administered every day for 12 days during the 9th week of randomization and again following randomization at the 17th week | 42 |
| Total | 82 |
Baseline characteristics
| Characteristic | Placebo Patch and Placebo Capsule | Total | Estradiol Patch and Progesterone Capsule |
|---|---|---|---|
| Age, Continuous | 50.40 years STANDARD_DEVIATION 2.52 | 49.88 years STANDARD_DEVIATION 2.83 | 49.39 years STANDARD_DEVIATION 3.04 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 6 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 37 Participants | 76 Participants | 39 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 15 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 34 Participants | 64 Participants | 30 Participants |
| Region of Enrollment United States | 40 Participants | 82 Participants | 42 Participants |
| Sex: Female, Male Female | 40 Participants | 82 Participants | 42 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 40 | 0 / 42 |
| other Total, other adverse events | 39 / 40 | 39 / 42 |
| serious Total, serious adverse events | 0 / 40 | 0 / 42 |
Outcome results
Primary
Change Over Time in Anhedonia Score From Snaith-Hamilton Pleasure Scale
Anhedonia will be assessed using SHAPS scores which range from 14-56, with higher scores corresponding to higher levels of anhedonia. Change over time is defined as the difference in least square means between time points and 95% confidence interval limits.
Time frame: Baseline (Week 8), Weeks 16, 20 and 24
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo Patch and Placebo Capsule | Change Over Time in Anhedonia Score From Snaith-Hamilton Pleasure Scale | Baseline (Week 8) to Week 16 | -0.01 score on a scale |
| Placebo Patch and Placebo Capsule | Change Over Time in Anhedonia Score From Snaith-Hamilton Pleasure Scale | Week 16 to Week 20 | 0.12 score on a scale |
| Placebo Patch and Placebo Capsule | Change Over Time in Anhedonia Score From Snaith-Hamilton Pleasure Scale | Week 20 to Week 24 | 0.29 score on a scale |
| Estradiol Patch and Progesterone Capsule | Change Over Time in Anhedonia Score From Snaith-Hamilton Pleasure Scale | Baseline (Week 8) to Week 16 | -0.63 score on a scale |
| Estradiol Patch and Progesterone Capsule | Change Over Time in Anhedonia Score From Snaith-Hamilton Pleasure Scale | Week 16 to Week 20 | 0.88 score on a scale |
| Estradiol Patch and Progesterone Capsule | Change Over Time in Anhedonia Score From Snaith-Hamilton Pleasure Scale | Week 20 to Week 24 | -0.07 score on a scale |
Primary
Change Over Time in the Anxiety Score From State-Trait Anxiety Inventory
The State-Trait anxiety inventory is consists of 20 questions on a 4-point force-choice Likert-type response scales (scores 0 - 3). The 20 questions are summed together for final score. The score can range from 0 to 60 with higher scores representing higher levels of anxiety. Change over time is defined as the difference in the least square means between timepoints and 95% confidence interval limits.
Time frame: Baseline (Week 8), Weeks 16, 20 and 24
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo Patch and Placebo Capsule | Change Over Time in the Anxiety Score From State-Trait Anxiety Inventory | Baseline (Week 8) to Week 16 | 2.74 score on a scale |
| Placebo Patch and Placebo Capsule | Change Over Time in the Anxiety Score From State-Trait Anxiety Inventory | Week 16 to Week 20 | -3.50 score on a scale |
| Placebo Patch and Placebo Capsule | Change Over Time in the Anxiety Score From State-Trait Anxiety Inventory | Week 20 to Week 24 | 3.63 score on a scale |
| Estradiol Patch and Progesterone Capsule | Change Over Time in the Anxiety Score From State-Trait Anxiety Inventory | Baseline (Week 8) to Week 16 | -0.89 score on a scale |
| Estradiol Patch and Progesterone Capsule | Change Over Time in the Anxiety Score From State-Trait Anxiety Inventory | Week 16 to Week 20 | 0.19 score on a scale |
| Estradiol Patch and Progesterone Capsule | Change Over Time in the Anxiety Score From State-Trait Anxiety Inventory | Week 20 to Week 24 | 3.75 score on a scale |
Secondary
Change Over Time in AUC Cortisol Stress Response
The stress biomarker cortisol (µg/dL) assessed at rest and in response to the Trier Social Stress test (AUC with respect to ground) at baseline (Week 8) and again post-randomization at weeks 16, 20 and 24. Blood serum samples for measuring cortisol are taken at immediately before the Trier Social Stress test and at 10, 20, 30, and 45 minutes post test. Change over time is defined as the difference in least square means between timepoints and with 95% confidence interval limits.
Time frame: Baseline (Week 8), Weeks 16, 20 and 24
Population: Data reported for all samples collected.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo Patch and Placebo Capsule | Change Over Time in AUC Cortisol Stress Response | Baseline (Week 8) to Week 16 | 33.77 µg/dL |
| Placebo Patch and Placebo Capsule | Change Over Time in AUC Cortisol Stress Response | Week 16 to Week 20 | -7.30 µg/dL |
| Placebo Patch and Placebo Capsule | Change Over Time in AUC Cortisol Stress Response | Week 20 to Week 24 | 53.40 µg/dL |
| Estradiol Patch and Progesterone Capsule | Change Over Time in AUC Cortisol Stress Response | Week 16 to Week 20 | -244.20 µg/dL |
| Estradiol Patch and Progesterone Capsule | Change Over Time in AUC Cortisol Stress Response | Baseline (Week 8) to Week 16 | 245.50 µg/dL |
| Estradiol Patch and Progesterone Capsule | Change Over Time in AUC Cortisol Stress Response | Week 20 to Week 24 | 88.80 µg/dL |
Secondary
Change Over Time in Percent of Hard Task Choice in EEfRT
Effort Expenditure for Rewards Task (EEfRT) measures approach motivation that indexes the willingness to expend effort to obtain monetary rewards under varying conditions of reward probability and magnitude. On each trial, participants choose between an easy task and a hard task and are presented with information about the probability of winning (i.e., 12%, 50%, or 88%), and the magnitude of the potential reward if they complete the button-press task successfully (range: $1.24 - $4.12). Completion of the easy task requires 30 button presses in 7 seconds using the dominant index finger, whereas completion of the hard task requires 100 presses with the non-dominant pinky finger in 21 seconds. The percent of hard task choices is the dependent measure. Change over time is defined as the difference in least square means between time points with 95% confidence interval limits.
Time frame: up to 24 weeks
Population: Data reported from tasks completed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo Patch and Placebo Capsule | Change Over Time in Percent of Hard Task Choice in EEfRT | Baseline (Week 8) to Week 16 | -0.0044 percentage of hard task choices |
| Placebo Patch and Placebo Capsule | Change Over Time in Percent of Hard Task Choice in EEfRT | Week 16 to Week 20 | 0.0019 percentage of hard task choices |
| Placebo Patch and Placebo Capsule | Change Over Time in Percent of Hard Task Choice in EEfRT | Week 20 to Week 24 | -0.0045 percentage of hard task choices |
| Estradiol Patch and Progesterone Capsule | Change Over Time in Percent of Hard Task Choice in EEfRT | Baseline (Week 8) to Week 16 | 0.0086 percentage of hard task choices |
| Estradiol Patch and Progesterone Capsule | Change Over Time in Percent of Hard Task Choice in EEfRT | Week 16 to Week 20 | 0.0289 percentage of hard task choices |
| Estradiol Patch and Progesterone Capsule | Change Over Time in Percent of Hard Task Choice in EEfRT | Week 20 to Week 24 | 0.0200 percentage of hard task choices |
Secondary
Change Over Time in Threat Bias Score From Dot Probe Task
Changes in threat bias scores assessed using Dot Probe task during labs at weeks 8, 16, 20 and 24. The bias measurement protocol consists of 144 trials (48 threat congruent, 48 threat incongruent, 48 neutral presentations). Participants indicate the probe letter via button press. Angry face location, probe location, probe type and actor are all fully counterbalanced in presentation. The threat bias score equals the mean of reaction time on threat congruent from threat incongruent trials. A threat bias scores \>0 indicate a bias towards threat, whereas scores \<0 mean that the participant is slower to respond to threatening stimuli than neutral stimuli. Reaction times were measured in milliseconds. Change over time is defined as the difference in least square means between timepoints with 95% confidence interval limits.
Time frame: up to 24 weeks
Population: Data reported from tasks completed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo Patch and Placebo Capsule | Change Over Time in Threat Bias Score From Dot Probe Task | Baseline (Week 8) to Week 16 | -5.23 milliseconds |
| Placebo Patch and Placebo Capsule | Change Over Time in Threat Bias Score From Dot Probe Task | Week 16 to Week 20 | -2.49 milliseconds |
| Placebo Patch and Placebo Capsule | Change Over Time in Threat Bias Score From Dot Probe Task | Week 20 to Week 24 | -0.92 milliseconds |
| Estradiol Patch and Progesterone Capsule | Change Over Time in Threat Bias Score From Dot Probe Task | Baseline (Week 8) to Week 16 | -3.75 milliseconds |
| Estradiol Patch and Progesterone Capsule | Change Over Time in Threat Bias Score From Dot Probe Task | Week 16 to Week 20 | -3.81 milliseconds |
| Estradiol Patch and Progesterone Capsule | Change Over Time in Threat Bias Score From Dot Probe Task | Week 20 to Week 24 | 7.25 milliseconds |