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Completed

NCT Number: NCT03018366

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.

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Key information

Conditions

Estrogen Deficiency Amenorrhea Cardiovascular Disease (CVD) Cardiovascular Diseases Endothelial Dysfunction Functional Hypothalamic Amenorrhea Menstruation Disturbances Pathologic Processes Pathological Conditions, Signs and Symptoms

Age range

18 year–60 year

Sex eligibility

Female

Study type

Interventional

Phase

Phase 2

Primary location

Cedars-Sinai Barbra Streisand Women's Heart Center

Los Angeles, California, 90048, United States

About this study

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)

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

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.

Other names: Estradiol Transdermal Patch, Vivelle-Dot

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.

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.

Other names: Prometrium

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.

Other names: Placebo Oral Pill

Primary outcomes

  1. 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.

Secondary outcomes

  1. 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

  2. Serum Estradiol Levels

    Time frame: Serum estradiol levels after 12 week of treatment vs placebo

    Week 12 serum estradiol levels

  3. 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.

  4. 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

  5. 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.

  6. 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.

  7. 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

  8. 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

  9. 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

Sponsors and collaborators

Lead sponsor

Cedars-Sinai Medical Center

Other

Registry information

Important dates

Study start
2017
Primary completion
2023
Study completion
2023
First posted
Jan 12, 2017
Registry last updated
Mar 13, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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