Atherosclerosis, Immune Mediated Inflammation and Hypoestrogenemia in Young Women

NCT03018366 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: PRO26081
• Study Type: interventional
• Target: 29
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Keywords

estrogen; premenopause; menopause; amenorrhea

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (9)

• Serum Inflammatory Markers

  Change in serum cortisol from baseline to week 12 on treatment or placebo

• Serum Estradiol Levels

  Serum estradiol levels after 12 week of treatment vs placebo

• Quality of Life (Questionnaire)

  Change in quality of life scores after 12 week of treatment vs placebo

• Depression

  Change in PHQ-9 Scores after 12 week of treatment vs placebo

• Change in Insomnia Severity Index After 12 Week of Treatment vs Placebo

  Insomnia score after 12 week of treatment vs placebo

Study Arms (2)

17Beta Estradiol, Progesterone

ACTIVE COMPARATOR

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; Drug: Progesterone

Transdermal Placebo Patch, Placebo Pill

PLACEBO COMPARATOR

Placebo Transdermal Patch, Placebo Pill

Drug: Transdermal placebo patch; Drug: Placebo Pill

Interventions

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.

Also known as: Estradiol Transdermal Patch, Vivelle-Dot

17Beta Estradiol, Progesterone

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.

Transdermal Placebo Patch, Placebo Pill

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.

Also known as: Prometrium

17Beta Estradiol, Progesterone

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.

Also known as: Placebo Oral Pill

Transdermal Placebo Patch, Placebo Pill

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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
• Previous or current use of hormone therapy, estrogen or progestin
• Surgical or chemotherapy induced menopause
• Premature ovarian failure

Sponsors & Collaborators

• Cedars-Sinai Medical Center: lead

Study Sites (1)

Cedars-Sinai Barbra Streisand Women's Heart Center

Los Angeles, California, 90048, United States

Location

Related Publications (1)

• 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.

  PMID: 37610989 DERIVED

MeSH Terms

Conditions

Cardiovascular Diseases; Amenorrhea

Interventions

Estradiol; Progesterone

Condition Hierarchy (Ancestors)

Menstruation Disturbances; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Pregnenediones; Pregnenes; Pregnanes; Corpus Luteum Hormones; Progesterone Congeners

Results Point of Contact

• Title: Dr. Chrisandra Shufelt
• Organization: Mayo Clinic

shufelt.chrisandra@mayo.edu

904-953-7224

Study Officials

• Chrisandra Shufelt, MD

  Cedars-Sinai Medical Center

  PRINCIPAL INVESTIGATOR

• Noel Bairey-Merz, MD

  Cedars-Sinai Medical Center

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor and Chair, Division of General Internal Medicine

Study Record Dates

• First Submitted: December 1, 2016
• First Posted: January 12, 2017
• Study Start: January 1, 2017
• Primary Completion: February 1, 2023
• Study Completion: February 1, 2023
• Last Updated: March 13, 2025
• Results First Posted: February 24, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)