Atherosclerosis, Immune Mediated Inflammation and Hypoestrogenemia in Young Women

February 24, 2025 updated by: Chrisandra Shufelt, Cedars-Sinai Medical Center

The purpose of this study is to determine whether young women with functional hypothalamic amenorrhea (premenopausal HypoE) is associated with risk factors for pre-clinical cardiovascular disease (CVD).

For this study, the investigators will measuring vascular function and inflammatory markers on:

  • young women with functional hypothalamic amenorrhea (>3 months of no menstrual cycle due to low estrogen)
  • young women with regular menstrual cycles not on hormone therapy.
  • recently menopausal women (<3 years from final menstrual period) not on hormone therapy.

Premenopausal HypoE participants (women with functional hypothalamic amenorrhea) will be randomized to use either an estrogen patch or a placebo patch (no active medicine) for 12 weeks, followed by estrogen or placebo patch plus progesterone or placebo pills for 2 additional weeks. The investigators are looking to see if estrogen improves vascular and inflammation.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Study Aims:

  1. To test the hypothesis premenopausal HypoE (women with FHA) is associated with pre-clinical CVD as determined by reductions in vascular endothelial function.
  2. To test the hypothesis premenopausal HypoE (women with FHA) is associated with increased immune-mediated inflammation.
  3. To test the hypothesis whether estrogen replacement can reduce inflammation and improve vascular endothelial function in premenopausal HypoE women (women with FHA).

In a randomized, double-blind placebo-controlled trial in premenopausal HypoE women (women with FHA) the investigators will test 12 weeks of transdermal estradiol 0.1 mg/day patch or placebo followed by 2 weeks of estradiol plus progesterone 200mg (for endometrial safety) on vascular endothelial function and immune-mediated inflammation versus placebo. Patches will be applied by the participant to the lower abdomen twice weekly, alternating sides.

The investigators will be using non-invasive tests to measure vascular function to measures reactive hyperemic index (RHI) using peripheral arterial tonometry (PAT)

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
29

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • Los Angeles, California, United States, 90048
        • Cedars-Sinai Barbra Streisand Women's Heart Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 60 years (Adult)

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

For premenopausal Hypo E and normal control women, inclusions include:

  • Premenopausal currently not on hormone therapy,
  • English speaking (for the purposes of complete psychosocial assessment)
  • able to give informed consent
  • a gynecological age (age since menarche) > 10 and < 25 years, and chronological age > 18 years
  • Within 90-110% of ideal body weight as determined by the 1983 Metropolitan Height and weight table for women
  • All participants with hypothalamic amenorrhea will be diagnosed based on exclusion of other etiologies for their amenorrhea, including pregnancy, thyroid dysfunction, hyperprolactinemia, premature ovarian insufficiency, and polycystic ovary disease

For recently menopausal women inclusions include:

  • Follicle stimulating hormones (FSH) >30 and 12 months of amenorrhea, within 3 years of final menstrual period with natural menopausal not on hormone therapy
  • English speaking
  • Able to give informed consent
  • Within 90-110% of ideal body weight

Exclusion Criteria:

For premenopausal Hypo E and normal control women exclusions include:

  • Smoking
  • Hypertension
  • Hyperlipidemia
  • Diabetes
  • Medications including psychotropic or illicit drugs, medical, neurological
  • Ophthalmologic disease except acuity problems
  • Major Axis I disorder other than depression
  • Pregnancy in the last 12 months and/or lactating in the last 6 months
  • Current use of hormone contraceptive or any estrogen or progestin therapy

For HypoE women, exclusion criteria include:

- Allergy to adhesive or tape

For recently menopausal women exclusions also include:

  • Previous or current use of hormone therapy, estrogen or progestin
  • Surgical or chemotherapy induced menopause
  • Premature ovarian failure

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Placebo Comparator: Transdermal Placebo Patch, Placebo Pill
Placebo Transdermal Patch, Placebo Pill
Drug: Transdermal placebo patch
Participants will use a dose of placebo patches for 12 weeks +/- 1 week. Placebos will be applied by the participant to the lower abdomen twice weekly, alternating sides.
Drug: Placebo Pill
After 12 weeks +/- 1week of transdermal placebo patch, participants will use placebo patch plus placebo pill for 2 additional weeks +/- 3 days.
Other Names:
  • Placebo Oral Pill
Active Comparator: 17Beta Estradiol, Progesterone
17Beta Estradiol (0.1mg/day) , Progesterone (100mg) or Medroxyprogesterone (10mg) for patient with a peanut allergy because progesterone 100mg is a peanut based product
Drug: 17beta Estradiol
Participants will use a dose of transdermal estradiol 0.1 mg/day patch for 12 weeks +/- 1week. PAT index vascular measures and serum immune markers will be measured after 6 and 12 weeks +/- 1week on estrogen patches. Patches will be applied by the participant to the lower abdomen twice weekly, alternating sides.
Other Names:
  • Vivelle-Dot
  • Estradiol Transdermal Patch
Drug: Progesterone
After 12 weeks +/- 1week of transdermal estradiol patch, participants will use estrogen patch plus progesterone for 2 additional weeks +/- 3 days. Progesterone is a peanut based product and for patients with a peanut allergy we will replace this with a synthetic progestin at an equivalent dose, medroxyprogesterone 10mg.
Other Names:
  • Prometrium

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Rate of Change of Reactive Hyperemia Index (RHI) by Peripheral Arterial Tonometry
Time Frame: Baseline, week 12 on trial
Change in PAT measured as reactive hyperemia index (RHI) from baseline to week 12 on treatment or placebo. Reactive hyperemia index (RHI) is the post-to-pre occlusion PAT signal ratio in the occluded arm, relative to the same ratio in the control arm, corrected for baseline vascular tone of the occluded arm calculated by taking the ratio of the pulse amplitude during the hyperemic phase (after a period of blood flow occlusion) to the baseline pulse amplitude. The values below <1.67 are abnormal and suggest impaired endothelial function or endothelial dysfunction.
Baseline, week 12 on trial

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Serum Inflammatory Markers
Time Frame: Change in serum cortisol from baseline to week 12 on treatment or placebo
Change in serum cortisol from baseline to week 12 on treatment or placebo
Change in serum cortisol from baseline to week 12 on treatment or placebo
Serum Estradiol Levels
Time Frame: Serum estradiol levels after 12 week of treatment vs placebo
Week 12 serum estradiol levels
Serum estradiol levels after 12 week of treatment vs placebo
Quality of Life (Questionnaire)
Time Frame: Change in quality of life scores after 12 week of treatment vs placebo
Short-Form Health Survey 12 (SF-12) was reported as the mental component score (MCS) and physical component score (PCS). Each scale ranges from 0 to 100. For both PCS and MCS, higher values represent better outcomes, indicating superior physical or mental health, respectively. Lower scores suggest poorer outcomes in the respective domains. Scores above 50 for either PCS or MCS are generally considered above the population average for health-related quality of life, as the scales are often normed to a mean of 50 with a standard deviation of 10 in general population studies. Scores below 50 suggest below-average physical or mental health, with the degree of deviation providing further insight into the severity of physical or mental health challenges.
Change in quality of life scores after 12 week of treatment vs placebo
Depression
Time Frame: Change in PHQ-9 Scores after 12 week of treatment vs placebo

Patient Health Questionnaire (PHQ-9) total score ranges from 0 to 27. Each item is scored on a scale of 0 (not at all) to 3 (nearly every day), with higher scores indicating greater severity of depressive symptoms.

Interpretation of Scores:

  • 0-4: Minimal or no depression
  • 5-9: Mild depression
  • 10-14: Moderate depression
  • 15-19: Moderately severe depression
  • 20-27: Severe depression
Change in PHQ-9 Scores after 12 week of treatment vs placebo
Anxiety
Time Frame: Change in Anxiety Scores after 12 week of treatment vs placebo

Overall Anxiety Severity and Impairment Scale (OASIS) total score ranges from 0 to 20, with each of the 5 items scored on a scale of 0 (no anxiety or impairment) to 4 (extreme anxiety or impairment). Higher scores indicate greater severity and functional impairment related to anxiety.

The OASIS scores can be categorized as follows:

  • 0-4: Minimal or no anxiety
  • 5-9: Mild anxiety
  • 10-14: Moderate anxiety with some functional impairment
  • 15-20: Severe anxiety with significant functional impairment.
Change in Anxiety Scores after 12 week of treatment vs placebo
Stress
Time Frame: Change in stress scores after 12 week of treatment vs placebo

Cohen Perceived Stress Scale (PSS) ranges from 0 to 40, with each of the 10 items scored on a scale of 0 (never) to 4 (very often). Higher scores reflect higher levels of perceived stress.

The PSS scores can be categorized as follows:

  • 0-13: Low perceived stress
  • 14-26: Moderate perceived stress
  • 27-40: High perceived stress
Change in stress scores after 12 week of treatment vs placebo
Change in Serum Estradiol Levels
Time Frame: change in estradiol after 12 week of treatment vs placebo
Change from Baseline to week 12 serum estradiol levels
change in estradiol after 12 week of treatment vs placebo
Serum Inflammatory Markers
Time Frame: Change in serum hsCRP from baseline to week 12 on treatment or placebo
Change in serum hsCRP from baseline to week 12 on treatment or placebo
Change in serum hsCRP from baseline to week 12 on treatment or placebo
Change in Insomnia Severity Index After 12 Week of Treatment vs Placebo
Time Frame: Insomnia score after 12 week of treatment vs placebo
Change in Insomnia Severity Index after 12 week of treatment vs placebo. Insomnia Severity Index (ISI) total score ranges from 0 to 28.
Insomnia score after 12 week of treatment vs placebo

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Cedars-Sinai Medical Center

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Chrisandra Shufelt, MD, Cedars-Sinai Medical Center
  • Study Director: Noel Bairey-Merz, MD, Cedars-Sinai Medical Center

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
January 1, 2017

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
February 1, 2023

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
February 1, 2023

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
December 1, 2016

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 10, 2017

First Posted (Estimated)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
January 12, 2017

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
March 25, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
February 24, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
February 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • PRO26081

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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