Atherosclerosis, Immune Mediated Inflammation and Hypoestrogenemia in Young Women

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
Study Aims: 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. To test the hypothesis premenopausal HypoE is associated with increased immune-mediated inflammation. 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)

Official Title
-----------------
Atherosclerosis, Immune Mediated Inflammation and Hypoestrogenemia in Young Women

Conditions
-----------------
Estrogen Deficiency, Cardiovascular Disease (CVD), Hypothalamic Amenorrhea

Intervention / Treatment
-----------------
* Drug: 17beta Estradiol
* Drug: Transdermal placebo patch
* Drug: Progesterone
* Drug: Placebo Pill


Participation Criteria
=================
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 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 17Beta Estradiol, Progesterone<br>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<br>* 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.<br>* Other names: Vivelle-Dot;Drug: Progesterone<br>* 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.<br>* Other names: Prometrium;|
| Placebo Comparator: Transdermal Placebo Patch, Placebo Pill<br>Placebo Transdermal Patch, Placebo Pill | Drug: Transdermal placebo patch<br>* 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.<br>Drug: Placebo Pill<br>* After 12 weeks +/- 1week of transdermal placebo patch, participants will use placebo patch plus placebo pill for 2 additional weeks +/- 3 days.<br>* Other names: Placebo Oral Pill;|

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
estrogen, premenopause, menopause, amenorrhea