Atherosclerosis, Immune Mediated Inflammation and Hypoestrogenemia in Young Women

NCT ID: NCT03018366

Last Updated: 2025-03-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 29 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-01-01
• Study Completion Date: 2023-02-01

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)

Conditions

Estrogen Deficiency; Cardiovascular Disease (CVD); Functional Hypothalamic Amenorrhea; Endothelial Dysfunction

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

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

Group Type: ACTIVE_COMPARATOR

17beta Estradiol

Intervention Type: 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.

Progesterone

Intervention Type: 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.

Transdermal Placebo Patch, Placebo Pill

Placebo Transdermal Patch, Placebo Pill

Group Type: PLACEBO_COMPARATOR

Transdermal placebo patch

Intervention Type: 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.

Placebo Pill

Intervention Type: DRUG

After 12 weeks +/- 1week of transdermal placebo patch, participants will use placebo patch plus placebo pill for 2 additional weeks +/- 3 days.

Interventions

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.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Estradiol Transdermal Patch; Vivelle-Dot; Prometrium; Placebo Oral Pill

Eligibility Criteria

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

• 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: Yes

Sponsors

Cedars-Sinai Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Chrisandra Shufelt

Professor and Chair, Division of General Internal Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Chrisandra Shufelt, MD

Role: PRINCIPAL_INVESTIGATOR

Cedars-Sinai Medical Center

Noel Bairey-Merz, MD

Role: STUDY_DIRECTOR

Cedars-Sinai Medical Center

Locations

Cedars-Sinai Barbra Streisand Women's Heart Center

Los Angeles, California, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 37610989 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

PRO26081

Identifier Type: -

Identifier Source: org_study_id