PerimenopausePhase 2/3PERTNCT01308814
Perimenopausal Estrogen Replacement Therapy Study
A Phase 2/3 study testing Estradiol in people with Perimenopause and Menopause, run by University of North Carolina, Chapel Hill at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 45 to 60 years, women onlyHealthy volunteers can take part
- Conditions the study is for
- Perimenopause, Menopause, Depression
- What is being tested?
- Estradiol
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 172 participants
- Where
- 1 siteUnited States
- Study dates
- Oct 2010to Mar 2016
- Phase
- Phase 2/3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 45 to 60 years
- Women only
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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
Who cannot join
- currently taking antidepressant medication
Trial locations and contacts
1 site in 1 country.
United States1 site
University of North Carolina
Chapel Hill, North Carolina, 27599
About this study
Official title: Depression, Estrogen Replacement, and Cardiovascular Health in the Perimenopause
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.
- Conditions
- Perimenopause, Menopause, Depression
- Being tested
- Estradiol, Placebo
- Keywords
- Perimenopause, Menopause, Depression, Cardiovascular health
- Medical subject headings
- Depression
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EstradiolDrug
Also called Climara and Prometrium.
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.
PlaceboDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| Placebo | Placebo comparator | Placebo patches for 12 months and placebo pills for 12 days every 2 months. Receives: Drug: Placebo |
| Estradiol | Experimental | Transdermal 17β-estradiol (100 ug/day) for 12 months and oral micronized progesterone (200 mg/day) for 12 days every two months. Receives: Drug: Estradiol |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Depressive Symptoms as Indicated by The Center for Epidemiologic Studies Depression Scale (CES-D)
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.
Measured: Baseline, month 12
Change in Psychiatric Diagnosis as Assessed by the Structured Clinical Interview for DSM Disorders I/NP
Measured: Baseline and when prompted by CES-D score
Change in Stress Reactivity During Laboratory Session Including Trier Social Stress Test
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.
Measured: Baseline, month 12
Secondary outcomes (4)
Change in Functional Well-being as Assessed by the Medical Outcomes Study 36-item Short Form (SF-36)
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.
Measured: Baseline, month 12
Percentage Meeting Criteria for Metabolic Risk [Baseline and 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
Measured: Baseline, month 12
Change in Percentage of Brachial Artery Diameter
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.
Measured: Baseline, month 12
Change in Baroreceptor Sensitivity
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.
Measured: Baseline, month 12
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Mar 2011 (estimated)
- Study startOct 2010
- Primary completionMar 2016
- Study completionMar 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for PerimenopauseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 172 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of North Carolina, Chapel Hill
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute of Mental Health (NIMH)
- Responsible party
- Principal investigator, Susan Girdler, PhD, University of North Carolina, Chapel Hill
- Investigators
- Susan Girdler, PH.D., Principal investigator, UNC
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01308814
- Sponsor's protocol ID
- 10-0542
- Other IDs
- R01MH087619
- Acronym
- PERT
- Status last verified
- Jul 2017
- First submitted
- 28 Feb 2011
- Last updated
- 22 Aug 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Vaisar T, Gordon JL, Wimberger J, Heinecke JW, Hinderliter AL, Rubinow DR, Girdler SS, Rubinow KB. Perimenopausal transdermal estradiol replacement reduces serum HDL cholesterol efflux capacity but improves cardiovascular risk factors. J Clin Lipidol. 2021 Jan-Feb;15(1):151-161.e0. doi: 10.1016/j.jacl.2020.11.009. Epub 2020 Nov 24.
PubMed 33288437Zannas AS, Gordon JL, Hinderliter AL, Girdler SS, Rubinow DR. IL-6 Response to Psychosocial Stress Predicts 12-month Changes in Cardiometabolic Biomarkers in Perimenopausal Women. J Clin Endocrinol Metab. 2020 Oct 1;105(10):e3757-65. doi: 10.1210/clinem/dgaa476.
PubMed 32706883Gordon JL, Rubinow DR, Watkins L, Hinderliter AL, Caughey MC, Girdler SS. The Effect of Perimenopausal Transdermal Estradiol and Micronized Progesterone on Markers of Risk for Arterial Disease. J Clin Endocrinol Metab. 2020 May 1;105(5):e2050-60. doi: 10.1210/clinem/dgz262.
PubMed 31838497Gordon JL, Rubinow DR, Eisenlohr-Moul TA, Xia K, Schmidt PJ, Girdler SS. Efficacy of Transdermal Estradiol and Micronized Progesterone in the Prevention of Depressive Symptoms in the Menopause Transition: A Randomized Clinical Trial. JAMA Psychiatry. 2018 Feb 1;75(2):149-157. doi: 10.1001/jamapsychiatry.2017.3998.
PubMed 29322164
Study at a glance
From the registry record, last updated by the sponsor on 22 Aug 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Depression, Estrogen Replacement, and Cardiovascular Health in the Perimenopause
- ClinicalTrials.gov ID
- NCT01308814
- Acronym / sponsor ID
- PERT / 10-0542
- Conditions
- Perimenopause, Menopause, Depression
- Keywords
- Perimenopause, Menopause, Depression, Cardiovascular health
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 172 participants (actual)
- Lead sponsor
- University of North Carolina, Chapel HillUniversity, hospital or other
- Collaborators
- National Institute of Mental Health (NIMH)
- Study start
- Oct 2010
- Primary completion
- Mar 2016 (actual)
- Study completion
- Mar 2016 (actual)
- First posted
- 4 Mar 2011 (estimated)
- Results
- Posted 22 Aug 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Placebo | Placebo comparator | Drug: PlaceboPlacebo patches for 12 months and placebo pills for 12 days every 2 months. |
| Estradiol | Experimental | Drug: EstradiolTransdermal 17β-estradiol (100 ug/day) for 12 months and oral micronized progesterone (200 mg/day) for 12 days every two months. |
Who may qualify
- Ages
- 45 to 60 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (3 listed)
- 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
Key exclusion criteria (1 listed)
- currently taking antidepressant medication
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| EstradiolAlso: Climara and Prometrium.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. | Drug | Estradiol |
| PlaceboPlacebo 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. | Drug | Placebo |
Primary outcome
Change in Depressive Symptoms as Indicated by The Center for Epidemiologic Studies Depression Scale (CES-D)
Time frame: 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.
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
Change in Stress Reactivity During Laboratory Session Including Trier Social Stress Test
Time frame: 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.
4 secondary outcomes
Change in Functional Well-being as Assessed by the Medical Outcomes Study 36-item Short Form (SF-36)
Time frame: Baseline, month 12
Percentage Meeting Criteria for Metabolic Risk [Baseline and Month 12]
Time frame: Baseline, month 12
Change in Percentage of Brachial Artery Diameter
Time frame: Baseline, month 12
Change in Baroreceptor Sensitivity
Time frame: Baseline, month 12
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Aug 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 33288437Vaisar T, Gordon JL, Wimberger J, Heinecke JW, Hinderliter AL, Rubinow DR, Girdler SS, Rubinow KB. Perimenopausal transdermal estradiol replacement reduces serum HDL cholesterol efflux capacity but improves cardiovascular risk factors. J Clin Lipidol. 2021 Jan-Feb;15(1):151-161.e0. doi: 10.1016/j.jacl.2020.11.009. Epub 2020 Nov 24.
- Derived from this study: PubMed 32706883Zannas AS, Gordon JL, Hinderliter AL, Girdler SS, Rubinow DR. IL-6 Response to Psychosocial Stress Predicts 12-month Changes in Cardiometabolic Biomarkers in Perimenopausal Women. J Clin Endocrinol Metab. 2020 Oct 1;105(10):e3757-65. doi: 10.1210/clinem/dgaa476.
- Derived from this study: PubMed 31838497Gordon JL, Rubinow DR, Watkins L, Hinderliter AL, Caughey MC, Girdler SS. The Effect of Perimenopausal Transdermal Estradiol and Micronized Progesterone on Markers of Risk for Arterial Disease. J Clin Endocrinol Metab. 2020 May 1;105(5):e2050-60. doi: 10.1210/clinem/dgz262.
- Derived from this study: PubMed 29322164Gordon JL, Rubinow DR, Eisenlohr-Moul TA, Xia K, Schmidt PJ, Girdler SS. Efficacy of Transdermal Estradiol and Micronized Progesterone in the Prevention of Depressive Symptoms in the Menopause Transition: A Randomized Clinical Trial. JAMA Psychiatry. 2018 Feb 1;75(2):149-157. doi: 10.1001/jamapsychiatry.2017.3998.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Susan Girdler, PH.D. principal investigator
UNC
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Estradiol in people with Perimenopause and Menopause, run by University of North Carolina, Chapel Hill at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 22 Aug 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 22 Aug 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Depressive Symptoms as Indicated by The Center for Epidemiologic Studies Depression Scale (CES-D) (time frame: Baseline, month 12). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01308814, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Aug 2017; AzTrials last refreshed its copy on 26 Oct 2026.