PERT: Perimenopausal Estrogen Replacement Therapy Study

• Sponsor: University of North Carolina, Chapel Hill (Other)
• Overall Status: Completed
• CT.gov ID: NCT01308814
• Collaborator: National Institute of Mental Health (NIMH) (NIH)
• Enrollment: 172
• Location: 1
• Arms: 2
• Duration (Months): 65
• Patients Per Site Per Month: 2.6

Study Details

Study Description

Brief Summary

Study Background and Objectives: In the U.S. the majority of heart disease deaths are in women, not men. Much of the gender disparity in CVD rates relate to the burden of CV risk in women after the menopause. Depression has been associated with an increased risk for CVD morbidity and mortality. Even histories of recurrent depression in euthymic individuals are associated with elevated CV risk. Understanding the depression-CVD link may have particular relevance for women since women experience depression at a rate twice that of men. Substantial convergent evidence indicates that ovarian failure (estrogen deprivation) is one likely mechanism contributing to both CVD and depression in women. The perimenopause, a time associated with a two-fold increase in rates of depression, may provide an ideal opportunity for studying the pathophysiology of CV risk and depression in women.

The primary objective of this study is to examine the prophylactic role of estradiol in the development of depressive symptoms and the progression of cardiovascular risk in perimenopausal women with or without histories of depression. The investigators predict that women susceptible to depression will be particularly vulnerable to the acceleration of CVD in the context of the perimenopause and, consequently, will show differentially greater benefit of estradiol treatment during the menopause transition for both indices of CV risk (e.g. inflammation, endothelial function, stress reactivity), as well as depressive symptoms.

Condition or Disease	Intervention/Treatment	Phase
Perimenopause; Menopause; Depression	Drug: Estradiol; Drug: Placebo	Phase 2/Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 172 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Depression, Estrogen Replacement, and Cardiovascular Health in the Perimenopause
• Study Start Date: Oct 1, 2010
• Actual Primary Completion Date: Mar 1, 2016
• Actual Study Completion Date: Mar 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo patches for 12 months and placebo pills for 12 days every 2 months.	Drug: Placebo; Placebo patches for 12 months, to be worn continuously and replaced once a week. Also, placebo pills will be administered for 12 days every 2 months.
Experimental: Estradiol Transdermal 17β-estradiol (100 ug/day) for 12 months and oral micronized progesterone (200 mg/day) for 12 days every two months.	Drug: Estradiol; Transdermal 17β-estradiol (100 ug/day) for 12 months, administered as patches to be worn continuously and replaced once a week. Also, every 2 months, oral micronized progesterone (200 mg/day x 12 days) will be administered.; Other Names: Climara and Prometrium.

Outcome Measures

Primary Outcome Measures

1. Change in Depressive Symptoms as Indicated by The Center for Epidemiologic Studies Depression Scale (CES-D) [Baseline, month 12]

   Change from pre-trial (baseline) to post-trial (month 12) in the Center for Epidemiologic Studies Depression Scale (CES-D). The CES-D has a Range from 0-60, with higher scores indicating the presence of more symptomatology. A score of 16 or greater is indicative of clinically significant symptoms of depression.

2. Change in Psychiatric Diagnosis as Assessed by the Structured Clinical Interview for DSM Disorders I/NP [Baseline and when prompted by CES-D score]

3. Change in Stress Reactivity During Laboratory Session Including Trier Social Stress Test [Baseline, month 12]

   Primary measures reflecting stress reactivity will consist of mean arterial pressure (MAP), vascular resistance index (VRI), plasma cortisol, and plasma IL-6. For each of these four measures, a delta score (change from rest to stress) will be calculated and then standardized as Z scores. The individual Z scores will then be averaged to yield a single Stress Reactivity profile measure (average z score) - a composite Z score reflecting magnitude of activation in the four primary stress-responsive pathways. This composite z score at baseline will be subtracted from the composite z score at 12 months to yield this outcome measure.

Secondary Outcome Measures

1. Change in Functional Well-being as Assessed by the Medical Outcomes Study 36-item Short Form (SF-36) [Baseline, month 12]

   The Medical Outcomes Study 36-item Short Form (SF-36) is a measure of functional well-being, including physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to emotional health problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. The range of this scale is 0-100, where higher scores indicates a more favorable health state.

2. Percentage Meeting Criteria for Metabolic Risk [Baseline and Month 12] [Baseline, month 12]

   Subjects will be classified as having metabolic risk if they either meet standard criteria for the metabolic syndrome (based on 3 of 5 risk factors: elevated blood pressure, fasting triglycerides, fasting glucose, waist circumference and low HDL-cholesterol) or they exhibit insulin resistance based on the homeostatic model assessment (HOMA) to derive HOMA-IR based on fasting insulin and glucose levels using the equation: HOMA-IR = fasting glucose (mmol/L) × fasting insulin (μU/mL)/22.5

3. Change in Percentage of Brachial Artery Diameter [Baseline, month 12]

   Change (from Baseline-to-12 Month) in flow mediated dilatation (FMD) test of the brachial artery, dilatation occurs following an acute increase in blood flow, induced by via circulatory arrest in the arm for a period of time. Measured using high resolution ultrasound, yielding a measure of endothelial-dependent vasodilatation. The increase in brachial arterial diameter as a consequence of reactive hyperemia is compared to the baseline diameter of the artery and expressed as a percentage of the baseline diameter (% FMD). Flow-mediated vasodilatation at each time point was calculated as diameter of the brachial artery under reactive hyperemia minus baseline diameter of the brachial artery. The change presented here is calculated as 12 month %FMD minus baseline month %FMD.

4. Change in Baroreceptor Sensitivity [Baseline, month 12]

   A finometer noninvasive blood pressure devise (FMS) was used to collect a 10 minute recording of beat-to-beat blood pressure and pulse rate during spontaneous breathing under quiet recumbent conditions. baroreflex sensitivity was computed from the most stable 5-minute segment of this 10-minute period. Cross-spectral analysis was used to estimate the average transfer function modulus (i.e., gain) between systemic blood pressure oscillations and R-R interval oscillations in the frequency range of 0.07-0.14 Hz, also known as the low frequency band. The units of this baroreflex sensitivity (BRS) were msec/mmHg. The outcome presented here is the 12 month BRS minus baseline BRS.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 45 Years to 60 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• must be between 45 and 60 years of age

• must be in the menopause transition (irregular/ absent menstrual cycles or hot flashes)

• must be are medically healthy

Exclusion Criteria:

• currently taking antidepressant medication

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of North Carolina	Chapel Hill	North Carolina	United States	27599

Sponsors and Collaborators

• University of North Carolina, Chapel Hill
• National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: Susan Girdler, PH.D., UNC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Susan Girdler, PhD, Principal Investigator, University of North Carolina, Chapel Hill
• ClinicalTrials.gov Identifier: NCT01308814
• Other Study ID Numbers: 10-0542; R01MH087619
• First Posted: Mar 4, 2011
• Last Update Posted: Aug 22, 2017
• Last Verified: Jul 1, 2017

• Keywords provided by Susan Girdler, PhD, Principal Investigator, University of North Carolina, Chapel Hill: Perimenopause; Menopause; Depression; Cardiovascular health
• Additional relevant MeSH terms: Depression; Depressive Disorder; Estradiol

Study Results

Participant Flow

Arm/Group Title	Placebo	Estradiol
Arm/Group Description	Placebo patches for 12 months and placebo pills for 12 days every 2 months. Placebo: Placebo patches for 12 months, to be worn continuously and replaced once a week. Also, placebo pills will be administered for 12 days every 2 months.	Transdermal 17β-estradiol (100 ug/day) for 12 months and oral micronized progesterone (200 mg/day) for 12 days every two months. Estradiol: Transdermal 17β-estradiol (100 ug/day) for 12 months, administered as patches to be worn continuously and replaced once a week. Also, every 2 months, oral micronized progesterone (200 mg/day x 12 days) will be administered.
Period Title: Overall Study
STARTED	86	86
COMPLETED	69	63
NOT COMPLETED	17	23

Baseline Characteristics

Arm/Group Title	Placebo	Estradiol	Total
Arm/Group Description	Placebo patches for 12 months and placebo pills for 12 days every 2 months. Placebo: Placebo patches for 12 months, to be worn continuously and replaced once a week. Also, placebo pills will be administered for 12 days every 2 months.	Transdermal 17β-estradiol (100 ug/day) for 12 months and oral micronized progesterone (200 mg/day) for 12 days every two months. Estradiol: Transdermal 17β-estradiol (100 ug/day) for 12 months, administered as patches to be worn continuously and replaced once a week. Also, every 2 months, oral micronized progesterone (200 mg/day x 12 days) will be administered.	Total of all reporting groups
Overall Participants	86	86	172
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	86 100%	86 100%	172 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.5 (3.0)	50.5 (3.0)	50.5 (3.0)
Sex: Female, Male (Count of Participants)
Female	86 100%	86 100%	172 100%
Male	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	86 100%	86 100%	172 100%

Outcome Measures

1. Primary Outcome

Title	Change in Depressive Symptoms as Indicated by The Center for Epidemiologic Studies Depression Scale (CES-D)
Description	Change from pre-trial (baseline) to post-trial (month 12) in the Center for Epidemiologic Studies Depression Scale (CES-D). The CES-D has a Range from 0-60, with higher scores indicating the presence of more symptomatology. A score of 16 or greater is indicative of clinically significant symptoms of depression.
Time Frame	Baseline, month 12

Outcome Measure Data

Analysis Population Description

The data presented here are based on individuals who completed the study and provided useable data for this particular measure at the time point reported.

Arm/Group Title	Placebo	Estradiol
Arm/Group Description	Placebo patches for 12 months and placebo pills for 12 days every 2 months. Placebo: Placebo patches for 12 months, to be worn continuously and replaced once a week. Also, placebo pills will be administered for 12 days every 2 months.	Transdermal 17β-estradiol (100 ug/day) for 12 months and oral micronized progesterone (200 mg/day) for 12 days every two months. Estradiol: Transdermal 17β-estradiol (100 ug/day) for 12 months, administered as patches to be worn continuously and replaced once a week. Also, every 2 months, oral micronized progesterone (200 mg/day x 12 days) will be administered.
Measure Participants	69	63
Mean (Standard Deviation) [units on a scale]	1.04 (7.56)	-1.02 (4.89)

2. Primary Outcome

Title	Change in Psychiatric Diagnosis as Assessed by the Structured Clinical Interview for DSM Disorders I/NP
Time Frame	Baseline and when prompted by CES-D score

Outcome Measure Data

Analysis Population Description

These data were not collected because this measure is no longer the preferred method for characterizing change in depression risk. The preferred method is now to measure depressive symptoms continuously, which was done. These continuous results can be found for the CESD score in this record.

Arm/Group Title	Placebo	Estradiol
Arm/Group Description	Placebo patches for 12 months and placebo pills for 12 days every 2 months. Placebo: Placebo patches for 12 months, to be worn continuously and replaced once a week. Also, placebo pills will be administered for 12 days every 2 months.	Transdermal 17β-estradiol (100 ug/day) for 12 months and oral micronized progesterone (200 mg/day) for 12 days every two months. Estradiol: Transdermal 17β-estradiol (100 ug/day) for 12 months, administered as patches to be worn continuously and replaced once a week. Also, every 2 months, oral micronized progesterone (200 mg/day x 12 days) will be administered.
Measure Participants	0	0

3. Primary Outcome

Title	Change in Stress Reactivity During Laboratory Session Including Trier Social Stress Test
Description	Primary measures reflecting stress reactivity will consist of mean arterial pressure (MAP), vascular resistance index (VRI), plasma cortisol, and plasma IL-6. For each of these four measures, a delta score (change from rest to stress) will be calculated and then standardized as Z scores. The individual Z scores will then be averaged to yield a single Stress Reactivity profile measure (average z score) - a composite Z score reflecting magnitude of activation in the four primary stress-responsive pathways. This composite z score at baseline will be subtracted from the composite z score at 12 months to yield this outcome measure.
Time Frame	Baseline, month 12

Outcome Measure Data

Analysis Population Description

The data presented here are based on individuals who completed the study and provided useable data for this particular measure at the time point reported.

Arm/Group Title	Placebo	Estradiol
Arm/Group Description	Placebo patches for 12 months and placebo pills for 12 days every 2 months. Placebo: Placebo patches for 12 months, to be worn continuously and replaced once a week. Also, placebo pills will be administered for 12 days every 2 months.	Transdermal 17β-estradiol (100 ug/day) for 12 months and oral micronized progesterone (200 mg/day) for 12 days every two months. Estradiol: Transdermal 17β-estradiol (100 ug/day) for 12 months, administered as patches to be worn continuously and replaced once a week. Also, every 2 months, oral micronized progesterone (200 mg/day x 12 days) will be administered.
Measure Participants	66	63
Mean (Standard Deviation) [composite Z score]	0.02 (0.67)	-0.18 (0.54)

4. Secondary Outcome

Title	Change in Functional Well-being as Assessed by the Medical Outcomes Study 36-item Short Form (SF-36)
Description	The Medical Outcomes Study 36-item Short Form (SF-36) is a measure of functional well-being, including physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to emotional health problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. The range of this scale is 0-100, where higher scores indicates a more favorable health state.
Time Frame	Baseline, month 12

Outcome Measure Data

Analysis Population Description

The data presented here are based on individuals who completed the study and provided useable data for this particular measure at the time point reported.

Arm/Group Title	Placebo	Estradiol
Arm/Group Description	Placebo patches for 12 months and placebo pills for 12 days every 2 months. Placebo: Placebo patches for 12 months, to be worn continuously and replaced once a week. Also, placebo pills will be administered for 12 days every 2 months.	Transdermal 17β-estradiol (100 ug/day) for 12 months and oral micronized progesterone (200 mg/day) for 12 days every two months. Estradiol: Transdermal 17β-estradiol (100 ug/day) for 12 months, administered as patches to be worn continuously and replaced once a week. Also, every 2 months, oral micronized progesterone (200 mg/day x 12 days) will be administered.
Measure Participants	67	59
Mean (Standard Deviation) [units on a scale]	0.94 (13.60)	2.32 (11.32)

5. Secondary Outcome

Title	Percentage Meeting Criteria for Metabolic Risk [Baseline and Month 12]
Description	Subjects will be classified as having metabolic risk if they either meet standard criteria for the metabolic syndrome (based on 3 of 5 risk factors: elevated blood pressure, fasting triglycerides, fasting glucose, waist circumference and low HDL-cholesterol) or they exhibit insulin resistance based on the homeostatic model assessment (HOMA) to derive HOMA-IR based on fasting insulin and glucose levels using the equation: HOMA-IR = fasting glucose (mmol/L) × fasting insulin (μU/mL)/22.5
Time Frame	Baseline, month 12

Outcome Measure Data

Analysis Population Description

The data presented here are based on individuals who completed the study and provided useable data for this particular measure at the time point reported.

Arm/Group Title	Placebo	Estradiol
Arm/Group Description	Placebo patches for 12 months and placebo pills for 12 days every 2 months. Placebo: Placebo patches for 12 months, to be worn continuously and replaced once a week. Also, placebo pills will be administered for 12 days every 2 months.	Transdermal 17β-estradiol (100 ug/day) for 12 months and oral micronized progesterone (200 mg/day) for 12 days every two months. Estradiol: Transdermal 17β-estradiol (100 ug/day) for 12 months, administered as patches to be worn continuously and replaced once a week. Also, every 2 months, oral micronized progesterone (200 mg/day x 12 days) will be administered.
Measure Participants	86	86
baseline with metabolic risk	17 19.8%	17 19.8%
12 month with metabolic risk	10 11.6%	9 10.5%

6. Secondary Outcome

Title	Change in Percentage of Brachial Artery Diameter
Description	Change (from Baseline-to-12 Month) in flow mediated dilatation (FMD) test of the brachial artery, dilatation occurs following an acute increase in blood flow, induced by via circulatory arrest in the arm for a period of time. Measured using high resolution ultrasound, yielding a measure of endothelial-dependent vasodilatation. The increase in brachial arterial diameter as a consequence of reactive hyperemia is compared to the baseline diameter of the artery and expressed as a percentage of the baseline diameter (% FMD). Flow-mediated vasodilatation at each time point was calculated as diameter of the brachial artery under reactive hyperemia minus baseline diameter of the brachial artery. The change presented here is calculated as 12 month %FMD minus baseline month %FMD.
Time Frame	Baseline, month 12

Outcome Measure Data

Analysis Population Description

The data presented here are based on individuals who completed the study and provided useable data for this particular measure at the time point reported.

Arm/Group Title	Placebo	Estradiol
Arm/Group Description	Placebo patches for 12 months and placebo pills for 12 days every 2 months. Placebo: Placebo patches for 12 months, to be worn continuously and replaced once a week. Also, placebo pills will be administered for 12 days every 2 months.	Transdermal 17β-estradiol (100 ug/day) for 12 months and oral micronized progesterone (200 mg/day) for 12 days every two months. Estradiol: Transdermal 17β-estradiol (100 ug/day) for 12 months, administered as patches to be worn continuously and replaced once a week. Also, every 2 months, oral micronized progesterone (200 mg/day x 12 days) will be administered.
Measure Participants	86	85
Mean (Standard Deviation) [percent flow mediated dilatation]	-0.65 (4.75)	0.56 (4.91)

7. Secondary Outcome

Title	Change in Baroreceptor Sensitivity
Description	A finometer noninvasive blood pressure devise (FMS) was used to collect a 10 minute recording of beat-to-beat blood pressure and pulse rate during spontaneous breathing under quiet recumbent conditions. baroreflex sensitivity was computed from the most stable 5-minute segment of this 10-minute period. Cross-spectral analysis was used to estimate the average transfer function modulus (i.e., gain) between systemic blood pressure oscillations and R-R interval oscillations in the frequency range of 0.07-0.14 Hz, also known as the low frequency band. The units of this baroreflex sensitivity (BRS) were msec/mmHg. The outcome presented here is the 12 month BRS minus baseline BRS.
Time Frame	Baseline, month 12

Outcome Measure Data

Analysis Population Description

The data presented here are based on individuals who completed the study and provided useable data for this particular measure at the time point reported.

Arm/Group Title	Placebo	Estradiol
Arm/Group Description	Placebo patches for 12 months and placebo pills for 12 days every 2 months. Placebo: Placebo patches for 12 months, to be worn continuously and replaced once a week. Also, placebo pills will be administered for 12 days every 2 months.	Transdermal 17β-estradiol (100 ug/day) for 12 months and oral micronized progesterone (200 mg/day) for 12 days every two months. Estradiol: Transdermal 17β-estradiol (100 ug/day) for 12 months, administered as patches to be worn continuously and replaced once a week. Also, every 2 months, oral micronized progesterone (200 mg/day x 12 days) will be administered.
Measure Participants	85	85
Mean (Standard Deviation) [msec/mmHg]	0.19 (2.74)	0.43 (2.52)

Adverse Events

Arm/Group Title	Placebo		Estradiol
Arm/Group Description	Placebo patches for 12 months and placebo pills for 12 days every 2 months. Placebo: Placebo patches for 12 months, to be worn continuously and replaced once a week. Also, placebo pills will be administered for 12 days every 2 months.		Transdermal 17β-estradiol (100 ug/day) for 12 months and oral micronized progesterone (200 mg/day) for 12 days every two months. Estradiol: Transdermal 17β-estradiol (100 ug/day) for 12 months, administered as patches to be worn continuously and replaced once a week. Also, every 2 months, oral micronized progesterone (200 mg/day x 12 days) will be administered.
All Cause Mortality
	Placebo		Estradiol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/86 (0%)		0/86 (0%)
Serious Adverse Events
	Placebo		Estradiol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/86 (0%)		0/86 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Estradiol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	81/86 (94.2%)		83/86 (96.5%)
Blood and lymphatic system disorders
Bleeding changes, heavy bleeding	11/86 (12.8%)		32/86 (37.2%)
Bleeding changes, prolonged bleeding	1/86 (1.2%)		13/86 (15.1%)
Eye disorders
Vision changes or issues	28/86 (32.6%)		26/86 (30.2%)
Gastrointestinal disorders
Bloating	2/86 (2.3%)		8/86 (9.3%)
GI Symptoms	23/86 (26.7%)		18/86 (20.9%)
General disorders
Fatigue	5/86 (5.8%)		12/86 (14%)
Headache, not migraine	58/86 (67.4%)		52/86 (60.5%)
Headache, migraine with no aura	9/86 (10.5%)		9/86 (10.5%)
Sleep issues	12/86 (14%)		9/86 (10.5%)
Weight gain	53/86 (61.6%)		50/86 (58.1%)
Other	48/86 (55.8%)		43/86 (50%)
Infections and infestations
Bacterial or viral infection	23/86 (26.7%)		28/86 (32.6%)
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	25/86 (29.1%)		30/86 (34.9%)
Leg or calf discomfort, swelling, or pain	38/86 (44.2%)		42/86 (48.8%)
Psychiatric disorders
High CES-D depression scale score without major or minor depression	24/86 (27.9%)		13/86 (15.1%)
Anxiety	5/86 (5.8%)		2/86 (2.3%)
Irritability	14/86 (16.3%)		15/86 (17.4%)
Negative mood changes	25/86 (29.1%)		20/86 (23.3%)
Reproductive system and breast disorders
Bleeding changes, spotting	29/86 (33.7%)		55/86 (64%)
Bleeding changes, mild or moderate bleeding	38/86 (44.2%)		69/86 (80.2%)
Breast tenderness	33/86 (38.4%)		46/86 (53.5%)
Hot flushes	15/86 (17.4%)		4/86 (4.7%)
Respiratory, thoracic and mediastinal disorders
Shortness of breath or chest pain	10/86 (11.6%)		15/86 (17.4%)
Skin and subcutaneous tissue disorders
Skin irritation	31/86 (36%)		32/86 (37.2%)
Vascular disorders
Stage 1 hypertension	10/86 (11.6%)		4/86 (4.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.