Atherosclerosis, Immune Mediated Inflammation and Hypoestrogenemia in Young Women

The purpose of this study is to determine whether low estrogen levels in young women with hypothalamic amenorrhea (premenopausal HypoE) is associated with risk factors for cardiovascular disease.

For this study, the investigators will measuring vascular function and immune markers on:

• young women with 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 will then be randomized to use either an estrogen patch or a placebo patch (no active medicine) for 3 months, 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 immune function.

Study Overview

• Status: Completed
• Conditions: Hypothalamic Amenorrhea; Estrogen Deficiency; Cardiovascular Disease (CVD)
• 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 is associated with pre-clinical CVD as determined by reductions in vascular endothelial function and increased central arterial stiffness.
2. To test the hypothesis premenopausal HypoE is associated with increased immune-mediated inflammation.
3. To test the hypothesis estrogens can reduce inflammation, improve vascular endothelial function and central arterial stiffness in premenopausal HypoE women.

In a randomized, double-blind placebo-controlled trial in premenopausal HypoE women 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 on vascular endothelial function, arterial stiffness 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 including:

• Peripheral arterial tonometry (PAT)
• SphygmoCor measurements of central blood pressure
• Carotid intima-media thickness (CIMT)

• 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 peripheral arterial tonometry (PAT)	PAT measured as reactive hyperemia index (RHI%)	Baseline, week 6, 12, and 14 on trial

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of change of pulse wave analysis	SphymoCor measured as augmentation index	Baseline, week 6, 12, and 14 on trial
Rate of change of pulse wave velocity	SphymoCor measured as meters/second	Baseline, week 6, 12, and 14 on trial
Serum Inflammatory Markers		Baseline, week 6, 12, and 14 on trial
Hormone levels		Baseline, week 6, 12, and 14 on trial
Quality of life (questionnaire)	Short-Form Health Survey 12	Baseline, week 6, 12, and 14 on trial
Depression	Patient Health Questionnaire (PHQ-9)	Baseline, week 6, 12, and 14 on trial
Sleep changes	Insomnia Severity Index	Baseline, week 6, 12, and 14 on trial
Anxiety	Overall Anxiety Severity and Impairment Scale (OASIS)	Baseline, week 6, 12, and 14 on trial
Stress	Cohen Perceived Stress Scale	Baseline, week 6, 12, and 14 on trial
DEXA Scan	dual-energy x-ray absorptiometry (DEXA) bone mass	Baseline

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 (Estimated): February 15, 2024
• Last Update Submitted That Met QC Criteria: January 24, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

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