Estrogen Deficiency, Cardiovascular Disease (CVD), Functional Hypothalamic Amenorrhea, Endothelial Dysfunction
Conditions
Keywords
estrogen, premenopause, menopause, amenorrhea
Brief 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). 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: 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)
Interventions
DRUG17beta 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.
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.
DRUGProgesterone
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.
DRUGPlacebo Pill
After 12 weeks +/- 1week of transdermal placebo patch, participants will use placebo patch plus placebo pill for 2 additional weeks +/- 3 days.
Sponsors
Cedars-Sinai Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 60 Years
Healthy volunteers
Yes
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,
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Change of Reactive Hyperemia Index (RHI) by Peripheral Arterial Tonometry | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Serum Estradiol Levels | Serum estradiol levels after 12 week of treatment vs placebo | Week 12 serum estradiol levels |
| Quality of Life (Questionnaire) | 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. |
| Depression | 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 |
| 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 |
| Anxiety | 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. |
| Stress | 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 Serum Estradiol Levels | change in estradiol after 12 week of treatment vs placebo | Change from Baseline to week 12 serum estradiol levels |
| Change in Insomnia Severity Index After 12 Week of Treatment vs Placebo | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 14 |
| 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. | 15 |
| Total | 29 |
Baseline characteristics
| Characteristic | Total | Transdermal Placebo Patch, Placebo Pill | 17Beta Estradiol, Progesterone |
|---|---|---|---|
| Age at Menarche | 12.96 years STANDARD_DEVIATION 1.6 | 12.9 years STANDARD_DEVIATION 1.4 | 13.1 years STANDARD_DEVIATION 1.8 |
| Age, Continuous | 26.0 years STANDARD_DEVIATION 6.3 | 25.1 years STANDARD_DEVIATION 6.1 | 27 years STANDARD_DEVIATION 6.7 |
| BMI | 21.5 kg/m^2 STANDARD_DEVIATION 3.3 | 21.4 kg/m^2 STANDARD_DEVIATION 3.1 | 21.7 kg/m^2 STANDARD_DEVIATION 3.7 |
| Hip | 34.2 inches STANDARD_DEVIATION 3 | 34.4 inches STANDARD_DEVIATION 3.7 | 34.0 inches STANDARD_DEVIATION 2.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 6 Participants | 5 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 18 Participants | 8 Participants | 10 Participants |
| Serum Estradiol | 25 pg/mL | 30 pg/mL | 24 pg/mL |
| Sex/Gender, Customized Female | 29 Participants | 15 Participants | 14 Participants |
| Waist | 27.1 inches STANDARD_DEVIATION 2.99 | 27.1 inches STANDARD_DEVIATION 3.7 | 27.1 inches STANDARD_DEVIATION 2.1 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 15 |
| other Total, other adverse events | 0 / 14 | 0 / 15 |
| serious Total, serious adverse events | 0 / 14 | 0 / 15 |
Outcome results
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.
Time frame: Baseline, week 12 on trial
Population: Our results represent the change (delta) in RHI after 12 week of treatment vs placebo
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 17Beta Estradiol, Progesterone | Rate of Change of Reactive Hyperemia Index (RHI) by Peripheral Arterial Tonometry | 0.20 change of RHI | Standard Deviation 0.52 |
| Transdermal Placebo Patch, Placebo Pill | Rate of Change of Reactive Hyperemia Index (RHI) by Peripheral Arterial Tonometry | 0.25 change of RHI | Standard Deviation 0.64 |
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: * 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.
Time frame: Change in Anxiety Scores after 12 week of treatment vs placebo
Population: Our results report the change (delta) in Anxiety Scores after 12 week of estrogen treatment vs placebo
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 17Beta Estradiol, Progesterone | Anxiety | -0.31 score on a scale | Standard Deviation 3.3 |
| Transdermal Placebo Patch, Placebo Pill | Anxiety | -0.54 score on a scale | Standard Deviation 2.07 |
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.
Time frame: Insomnia score after 12 week of treatment vs placebo
Population: Our results report the change (delta) of the insomnia severity index after 12 week of estrogen treatment vs placebo
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 17Beta Estradiol, Progesterone | Change in Insomnia Severity Index After 12 Week of Treatment vs Placebo | 8.0 score on a scale | Standard Deviation 5.7 |
| Transdermal Placebo Patch, Placebo Pill | Change in Insomnia Severity Index After 12 Week of Treatment vs Placebo | 3.9 score on a scale | Standard Deviation 4 |
Secondary
Change in Serum Estradiol Levels
Change from Baseline to week 12 serum estradiol levels
Time frame: change in estradiol after 12 week of treatment vs placebo
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 17Beta Estradiol, Progesterone | Change in Serum Estradiol Levels | 84 pg/mL |
| Transdermal Placebo Patch, Placebo Pill | Change in Serum Estradiol Levels | -4.7 pg/mL |
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: * 0-4: Minimal or no depression * 5-9: Mild depression * 10-14: Moderate depression * 15-19: Moderately severe depression * 20-27: Severe depression
Time frame: Change in PHQ-9 Scores after 12 week of treatment vs placebo
Population: Our results report the change (delta) in PHQ-9 after 12 week of estrogen treatment vs placebo.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 17Beta Estradiol, Progesterone | Depression | -0.67 score on a scale | Standard Deviation 3.52 |
| Transdermal Placebo Patch, Placebo Pill | Depression | -0.08 score on a scale | Standard Deviation 2.09 |
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.
Time frame: Change in quality of life scores after 12 week of treatment vs placebo
Population: Our results represent the change (delta) in quality of life scores after 12 week of treatment vs placebo for MCS and PCS.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 17Beta Estradiol, Progesterone | Quality of Life (Questionnaire) | SF12-PCS | 2.14 score on a scale | Standard Deviation 7.97 |
| 17Beta Estradiol, Progesterone | Quality of Life (Questionnaire) | SF12-MCS | 1.83 score on a scale | Standard Deviation 11.66 |
| Transdermal Placebo Patch, Placebo Pill | Quality of Life (Questionnaire) | SF12-PCS | -0.45 score on a scale | Standard Deviation 4.44 |
| Transdermal Placebo Patch, Placebo Pill | Quality of Life (Questionnaire) | SF12-MCS | 2.69 score on a scale | Standard Deviation 5.99 |
Secondary
Serum Estradiol Levels
Week 12 serum estradiol levels
Time frame: Serum estradiol levels after 12 week of treatment vs placebo
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 17Beta Estradiol, Progesterone | Serum Estradiol Levels | 108.0 pg/mL |
| Transdermal Placebo Patch, Placebo Pill | Serum Estradiol Levels | 36.5 pg/mL |
Secondary
Serum Inflammatory Markers
Change in serum cortisol from baseline to week 12 on treatment or placebo
Time frame: Change in serum cortisol from baseline to week 12 on treatment or placebo
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 17Beta Estradiol, Progesterone | Serum Inflammatory Markers | -0.4 µg/dL |
| Transdermal Placebo Patch, Placebo Pill | Serum Inflammatory Markers | 3.1 µg/dL |
Secondary
Serum Inflammatory Markers
Change in serum hsCRP from baseline to week 12 on treatment or placebo
Time frame: Change in serum hsCRP from baseline to week 12 on treatment or placebo
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 17Beta Estradiol, Progesterone | Serum Inflammatory Markers | 0.0857 mg/L |
| Transdermal Placebo Patch, Placebo Pill | Serum Inflammatory Markers | 0.0322 mg/L |
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: * 0-13: Low perceived stress * 14-26: Moderate perceived stress * 27-40: High perceived stress
Time frame: Change in stress scores after 12 week of treatment vs placebo
Population: Our results indicate the change (delta) in stress scores after 12 week of estrogen treatment vs placebo.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 17Beta Estradiol, Progesterone | Stress | -0.49 score on a scale | Standard Deviation 3.69 |
| Transdermal Placebo Patch, Placebo Pill | Stress | -0.46 score on a scale | Standard Deviation 3.41 |