Atherosclerosis, Immune Mediated Inflammation and Hypoestrogenemia in Young Women

Phase 2

Completed

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

Interventions: Drug: Transdermal placebo patch
Drug: 17beta Estradiol
Drug: Placebo Pill
Drug: Progesterone

Registration Number: NCT03018366

Lead Sponsor: Cedars-Sinai Medical Center

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)

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 29

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Transdermal Placebo Patch, Placebo Pill	Transdermal placebo patch	Placebo Transdermal Patch, Placebo Pill
Transdermal Placebo Patch, Placebo Pill	Placebo Pill	Placebo Transdermal Patch, Placebo Pill
17Beta Estradiol, Progesterone	17beta Estradiol	17Beta Estradiol (0.1mg/day) , Progesterone (100mg) or Medroxyprogesterone (10mg) for patient with a peanut allergy because progesterone 100mg is a peanut based product
17Beta Estradiol, Progesterone	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

Primary Outcome Measures

Name	Time	Method
Rate of Change of Reactive Hyperemia Index (RHI) by Peripheral Arterial Tonometry	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 Outcome Measures

Name	Time	Method
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
Serum Estradiol Levels	Serum estradiol levels after 12 week of treatment vs placebo	Week 12 serum estradiol levels
Quality of Life (Questionnaire)	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.
Depression	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
Change in Insomnia Severity Index After 12 Week of Treatment vs Placebo	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.
Anxiety	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.
Stress	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
Change in Serum Estradiol Levels	change in estradiol after 12 week of treatment vs placebo	Change from Baseline to week 12 serum estradiol levels