Atherosclerosis, Immune Mediated Inflammation and Hypoestrogenemia in Young Women

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: Completed
• Conditions: Endothelial Dysfunction; Estrogen Deficiency; Cardiovascular Disease (CVD); Functional Hypothalamic Amenorrhea
• Intervention / Treatment: Drug: Transdermal placebo patch; Drug: Placebo Pill; Drug: 17beta Estradiol; Drug: Progesterone

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: Interventional
• Enrollment (Actual): 29
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• 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

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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

Outcome Measure	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

Secondary Outcome Measures

Outcome Measure	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	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: 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	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	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	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
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

Collaborators and Investigators

• Sponsor: Cedars-Sinai Medical Center
• Investigators: Principal Investigator: Chrisandra Shufelt, MD, Cedars-Sinai Medical Center; Study Director: Noel Bairey-Merz, MD, Cedars-Sinai Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2017
• Primary Completion (Actual): February 1, 2023
• Study Completion (Actual): February 1, 2023

Study Registration Dates

• First Submitted: December 1, 2016
• First Submitted That Met QC Criteria: January 10, 2017
• First Posted (Estimated): January 12, 2017

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 24, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: menopause; estrogen; amenorrhea; premenopause
• Additional Relevant MeSH Terms: Vascular Diseases; Pathologic Processes; Arteriosclerosis; Arterial Occlusive Diseases; Menstruation Disturbances; Cardiovascular Diseases; Inflammation; Atherosclerosis; Amenorrhea; Contraceptive Agents, Hormonal; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Reproductive Control Agents; Contraceptive Agents, Female; Contraceptive Agents; Estrogens; Progestins; Estradiol 17 beta-cypionate; Estradiol 3-benzoate; Estradiol; Polyestradiol phosphate; Progesterone
• Other Study ID 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