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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:
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 Aims:
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)
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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 |
|
| Transdermal Placebo Patch, Placebo Pill | Placebo Comparator | Placebo Transdermal Patch, Placebo Pill |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 17beta Estradiol | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Baseline, week 12 on trial |
| Measure | Description | Time Frame |
|---|---|---|
| Serum Inflammatory Markers | 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 |
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Inclusion Criteria:
For premenopausal Hypo E and normal control women, inclusions include:
For recently menopausal women inclusions include:
Exclusion Criteria:
For premenopausal Hypo E and normal control women exclusions include:
For HypoE women, exclusion criteria include:
- Allergy to adhesive or tape
For recently menopausal women exclusions also include:
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| Name | Affiliation | Role |
|---|---|---|
| Chrisandra Shufelt, MD | Cedars-Sinai Medical Center | Principal Investigator |
| Noel Bairey-Merz, MD | Cedars-Sinai Medical Center | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Cedars-Sinai Barbra Streisand Women's Heart Center | Los Angeles | California | 90048 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37610989 | Derived | 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. |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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 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. 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. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jun 3, 2022 |
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| Transdermal placebo patch | Drug | 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. |
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| Progesterone | Drug | 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. |
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| Placebo Pill | Drug | After 12 weeks +/- 1week of transdermal placebo patch, participants will use placebo patch plus placebo pill for 2 additional weeks +/- 3 days. |
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Week 12 serum estradiol levels
| 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. | 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:
| 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. | 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:
| 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:
| 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 | 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 | Change in serum hsCRP from baseline to week 12 on treatment or placebo |
| FG001 | Transdermal Placebo Patch, Placebo Pill | Placebo Transdermal Patch, Placebo Pill 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. Placebo Pill: After 12 weeks +/- 1week of transdermal placebo patch, participants will use placebo patch plus placebo pill for 2 additional weeks +/- 3 days. |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 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. 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. |
| BG001 | Transdermal Placebo Patch, Placebo Pill | Placebo Transdermal Patch, Placebo Pill 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. Placebo Pill: After 12 weeks +/- 1week of transdermal placebo patch, participants will use placebo patch plus placebo pill for 2 additional weeks +/- 3 days. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
| |||||||||||||||
| Sex/Gender, Customized | Count of Participants | Participants |
| ||||||||||||||||
| Race (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||
| BMI | Mean | Standard Deviation | kg/m^2 |
| |||||||||||||||
| Waist | Mean | Standard Deviation | inches |
| |||||||||||||||
| Hip | Mean | Standard Deviation | inches |
| |||||||||||||||
| Age at Menarche | Mean | Standard Deviation | years |
| |||||||||||||||
| Serum Estradiol | Median | Inter-Quartile Range | pg/mL |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Our results represent the change (delta) in RHI after 12 week of treatment vs placebo | Posted | Mean | Standard Deviation | change of RHI | Baseline, week 12 on trial |
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| ||||||||||||||||||||||||||||
| Secondary | Serum Inflammatory Markers | Change in serum cortisol from baseline to week 12 on treatment or placebo | Posted | Median | Inter-Quartile Range | µg/dL | Change in serum cortisol from baseline to week 12 on treatment or placebo |
|
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| Secondary | Serum Estradiol Levels | Week 12 serum estradiol levels | Posted | Median | Inter-Quartile Range | pg/mL | Serum estradiol levels after 12 week of treatment vs placebo |
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| Secondary | 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. | Our results represent the change (delta) in quality of life scores after 12 week of treatment vs placebo for MCS and PCS. | Posted | Mean | Standard Deviation | score on a scale | Change in quality of life scores after 12 week of treatment vs placebo |
| ||||||||||||||||||||||||||||||
| Secondary | 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:
| Our results report the change (delta) in PHQ-9 after 12 week of estrogen treatment vs placebo. | Posted | Mean | Standard Deviation | score on a scale | Change in PHQ-9 Scores after 12 week of treatment vs placebo |
|
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| Secondary | 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. | Our results report the change (delta) of the insomnia severity index after 12 week of estrogen treatment vs placebo | Posted | Mean | Standard Deviation | score on a scale | Insomnia score after 12 week of treatment vs placebo |
|
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| Secondary | 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:
| Our results report the change (delta) in Anxiety Scores after 12 week of estrogen treatment vs placebo | Posted | Mean | Standard Deviation | score on a scale | Change in Anxiety Scores after 12 week of treatment vs placebo |
|
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| Secondary | 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:
| Our results indicate the change (delta) in stress scores after 12 week of estrogen treatment vs placebo. | Posted | Mean | Standard Deviation | score on a scale | Change in stress scores after 12 week of treatment vs placebo |
|
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| Secondary | Change in Serum Estradiol Levels | Change from Baseline to week 12 serum estradiol levels | Posted | Median | Inter-Quartile Range | pg/mL | change in estradiol after 12 week of treatment vs placebo |
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| Secondary | Serum Inflammatory Markers | Change in serum hsCRP from baseline to week 12 on treatment or placebo | Posted | Median | Inter-Quartile Range | mg/L | Change in serum hsCRP from baseline to week 12 on treatment or placebo |
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For the length of the study enrollment, 14 weeks.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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 | 0 | 14 | 0 | 14 | 0 | 14 |
| EG001 | Transdermal Placebo Patch, Placebo Pill | Placebo Transdermal Patch, Placebo Pill for 12 weeks +/- 1 week. Placebos will be applied by the participant to the lower abdomen twice weekly, alternating sides. | 0 | 15 | 0 | 15 | 0 | 15 |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Chrisandra Shufelt | Mayo Clinic | 904-953-7224 | shufelt.chrisandra@mayo.edu |
| Dec 19, 2024 |
| Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D002318 | Cardiovascular Diseases |
| D000568 | Amenorrhea |
| ID | Term |
|---|---|
| D008599 | Menstruation Disturbances |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D004958 | Estradiol |
| D011374 | Progesterone |
| ID | Term |
|---|---|
| D004963 | Estrenes |
| D004962 | Estranes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D045166 | Estradiol Congeners |
| D012739 | Gonadal Steroid Hormones |
| D042341 | Gonadal Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D011282 | Pregnenediones |
| D011283 | Pregnenes |
| D011278 | Pregnanes |
| D003339 | Corpus Luteum Hormones |
| D045167 | Progesterone Congeners |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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