Atherosclerosis, Immune Mediated Inflammation and Hypoestrogenemia in Young Women

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.

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)

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