Estrogen DeficiencyPhase 2NCT03018366
Atherosclerosis, Immune Mediated Inflammation and Hypoestrogenemia in Young Women
A Phase 2 study testing 17beta Estradiol and Progesterone in people with Estrogen Deficiency and Cardiovascular Disease (CVD), run by Cedars-Sinai Medical Center at 1 site in United States.
Trial summary
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). Read more about this study
- Who is it for?
- Ages 18 to 60 years, women onlyHealthy volunteers can take part
- Conditions the study is for
- Estrogen Deficiency, Cardiovascular Disease (CVD), Functional Hypothalamic Amenorrhea
- What is being tested?
- 17beta Estradiol and Progesterone
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 29 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Jan 2017to 1 Feb 2023
- Phase
- Phase 2
- 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 18 to 60 years
- Women only
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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
Show all 12Show fewer
- 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
Who cannot join
- For premenopausal Hypo E and normal control women exclusions include:
- Smoking
- Hypertension
- Hyperlipidemia
- Diabetes
- Medications including psychotropic or illicit drugs, medical, neurological
Show all 16Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Cedars-Sinai Barbra Streisand Women's Heart Center
Los Angeles, California, 90048
About this study
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:
Read more
- 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.
Read the detailed description
Study Aims:
- To test the hypothesis premenopausal HypoE (women with FHA) is associated with pre-clinical CVD as determined by reductions in vascular endothelial function.
- To test the hypothesis premenopausal HypoE (women with FHA) is associated with increased immune-mediated inflammation.
- 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)
- Conditions
- Estrogen Deficiency, Cardiovascular Disease (CVD), Functional Hypothalamic Amenorrhea, Endothelial Dysfunction
- Being tested
- 17beta Estradiol, Transdermal placebo patch, Progesterone, Placebo Pill
- Keywords
- estrogen, premenopause, menopause, amenorrhea
- Medical subject headings
- Cardiovascular Diseases, Amenorrhea
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
17beta EstradiolDrug
Also called Estradiol Transdermal Patch, Vivelle-Dot
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.
Transdermal placebo patchDrug
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.
ProgesteroneDrug
Also called Prometrium
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.
Placebo PillDrug
Also called Placebo Oral Pill
After 12 weeks +/- 1week of transdermal placebo patch, participants will use placebo patch plus placebo pill for 2 additional weeks +/- 3 days.
| Study group | Role | What they receive |
|---|---|---|
| 17Beta Estradiol, Progesterone | Active comparator | 17Beta Estradiol (0.1mg/day) , Progesterone (100mg) or Medroxyprogesterone (10mg) for patient with a peanut allergy because progesterone 100mg is a peanut based product Receives: Drug: 17beta Estradiol; Drug: Progesterone |
| Transdermal Placebo Patch, Placebo Pill | Placebo comparator | Placebo Transdermal Patch, Placebo Pill Receives: Drug: Transdermal placebo patch; Drug: Placebo Pill |
What is being measured
The primary outcome is the main question the study is designed to answer.
Rate of Change of Reactive Hyperemia Index (RHI) by Peripheral Arterial Tonometry
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.
Measured: Baseline, week 12 on trial
Secondary outcomes (9)
Serum Inflammatory Markers
Change in serum cortisol from baseline to week 12 on treatment or placebo
Measured: Change in serum cortisol from baseline to week 12 on treatment or placebo
Serum Estradiol Levels
Week 12 serum estradiol levels
Measured: Serum estradiol levels after 12 week of treatment vs placebo
Quality of Life (Questionnaire)
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.
Measured: Change in quality of life scores after 12 week of treatment vs placebo
Depression
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
Measured: Change in PHQ-9 Scores after 12 week of treatment vs placebo
Change in Insomnia Severity Index 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.
Measured: Insomnia score after 12 week of treatment vs placebo
Anxiety
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.
Measured: Change in Anxiety Scores after 12 week of treatment vs placebo
Stress
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
Measured: Change in stress scores after 12 week of treatment vs placebo
Change in Serum Estradiol Levels
Change from Baseline to week 12 serum estradiol levels
Measured: change in estradiol after 12 week of treatment vs placebo
Serum Inflammatory Markers
Change in serum hsCRP from baseline to week 12 on treatment or placebo
Measured: Change in serum hsCRP from baseline to week 12 on treatment or placebo
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Jan 2017 (estimated)
- Study start1 Jan 2017
- Primary completion1 Feb 2023
- Study completion1 Feb 2023
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 (1)Papers the sponsor has linked to this study.
- Other trials for Estrogen DeficiencyStudies of the same condition, open and under way.
- More trials run by Cedars-Sinai Medical CenterThe sponsor's other registered studies.
- 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
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 29 participants (actual)
Sponsor and investigators
- Lead sponsor
- Cedars-Sinai Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Chrisandra Shufelt, Mayo Clinic
- Investigators
- Chrisandra Shufelt, MD, Principal investigator, Cedars-Sinai Medical CenterNoel Bairey-Merz, MD, Study director, Cedars-Sinai Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03018366
- Sponsor's protocol ID
- PRO26081
- Status last verified
- Feb 2025
- First submitted
- 1 Dec 2016
- Last updated
- 13 Mar 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Shufelt CL, Saadedine M, Cook-Wiens G, Pisarska MD, Manson JE, Berga SL, Arditi M, Shah PK, Bairey Merz CN. Functional Hypothalamic Amenorrhea and Preclinical Cardiovascular Disease. J Clin Endocrinol Metab. 2023 Dec 21;109(1):e51-e57. doi: 10.1210/clinem/dgad498.
PubMed 37610989
Study at a glance
From the registry record, last updated by the sponsor on 13 Mar 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Atherosclerosis, Immune Mediated Inflammation and Hypoestrogenemia in Young Women
- ClinicalTrials.gov ID
- NCT03018366
- Acronym / sponsor ID
- PRO26081
- Conditions
- Estrogen Deficiency, Cardiovascular Disease (CVD), Functional Hypothalamic Amenorrhea, Endothelial Dysfunction
- Keywords
- estrogen, premenopause, menopause, amenorrhea
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 29 participants (actual)
- Lead sponsor
- Cedars-Sinai Medical CenterUniversity, hospital or other
- Study start
- 1 Jan 2017 (actual)
- Primary completion
- 1 Feb 2023 (actual)
- Study completion
- 1 Feb 2023 (actual)
- First posted
- 12 Jan 2017 (estimated)
- Results
- Posted 24 Feb 2025
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Study Aims:
- To test the hypothesis premenopausal HypoE (women with FHA) is associated with pre-clinical CVD as determined by reductions in vascular endothelial function.
- To test the hypothesis premenopausal HypoE (women with FHA) is associated with increased immune-mediated inflammation.
- 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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 17Beta Estradiol, Progesterone | Active comparator | Drug: 17beta Estradiol, Drug: Progesterone17Beta Estradiol (0.1mg/day) , Progesterone (100mg) or Medroxyprogesterone (10mg) for patient with a peanut allergy because progesterone 100mg is a peanut based product |
| Transdermal Placebo Patch, Placebo Pill | Placebo comparator | Drug: Transdermal placebo patch, Drug: Placebo PillPlacebo Transdermal Patch, Placebo Pill |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (12 listed)
- 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
Key exclusion criteria (16 listed)
- Smoking
- Hypertension
- Hyperlipidemia
- Diabetes
- Medications including psychotropic or illicit drugs, medical, neurological
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 |
|---|---|---|
| 17beta EstradiolAlso: Estradiol Transdermal Patch, Vivelle-DotParticipants 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. | Drug | 17Beta Estradiol, Progesterone |
| Transdermal placebo patchParticipants 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 | Transdermal Placebo Patch, Placebo Pill |
| ProgesteroneAlso: PrometriumAfter 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. | Drug | 17Beta Estradiol, Progesterone |
| Placebo PillAlso: Placebo Oral PillAfter 12 weeks +/- 1week of transdermal placebo patch, participants will use placebo patch plus placebo pill for 2 additional weeks +/- 3 days. | Drug | Transdermal Placebo Patch, Placebo Pill |
Primary outcome
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.
9 secondary outcomes
Serum Inflammatory Markers
Time frame: 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
Quality of Life (Questionnaire)
Time frame: 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
Change in Insomnia Severity Index After 12 Week of Treatment vs Placebo
Time frame: Insomnia score after 12 week of treatment vs placebo
Anxiety
Time frame: 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
Change in Serum Estradiol Levels
Time frame: 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
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Mar 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 37610989Shufelt CL, Saadedine M, Cook-Wiens G, Pisarska MD, Manson JE, Berga SL, Arditi M, Shah PK, Bairey Merz CN. Functional Hypothalamic Amenorrhea and Preclinical Cardiovascular Disease. J Clin Endocrinol Metab. 2023 Dec 21;109(1):e51-e57. doi: 10.1210/clinem/dgad498.
- Individual participant dataSharing planned: No
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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.
Chrisandra Shufelt, MD principal investigator
Cedars-Sinai Medical Center
Noel Bairey-Merz, MD study director
Cedars-Sinai Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing 17beta Estradiol and Progesterone in people with Estrogen Deficiency and Cardiovascular Disease (CVD), run by Cedars-Sinai Medical Center 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 12 inclusion and 16 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 13 Mar 2025. 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 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.
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 24 Feb 2025). 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?
Rate of Change of Reactive Hyperemia Index (RHI) by Peripheral Arterial Tonometry (time frame: Baseline, week 12 on trial). 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 NCT03018366, which also lists 1 linked publication.
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 13 Mar 2025.