Role of Endogenous Estrogen in Growth-Hormone Regulation in Postmenopausal Women

Participants are being asked to take part in this research study to learn why growth hormone(GH) levels decline when estrogen production falls at the time of menopause. GH is a hormone released from the pituitary gland that affects bone, muscle, and fat. Estrogen is a female hormone. Doctors believe that lower estrogen is one of the reasons that GH diminishes in postmenopausal women. However, estrogen does not fall completely. This raises the question whether the little bit of estrogen that is left is doing anything. Lack of GH makes bones thinner, muscles weaker, and fat stores larger. To learn whether the low amount of the body's own estrogen maintains GH secretion after menopause, the investigators need to stop any estrogen you might be taking and then partially block the effect, if any, of your own estrogen. The investigators will use a new estrogen-blocking drug (fulvestrant). Fulvestrant(which also goes by the tradename, Faslodex) was recently approved by the Food and Drug Administration (FDA) to treat breast cancer. Fulvestrant is being used in a non-FDA approved manner in this study (not to treat breast cancer, but to study the effect on Growth Hormone secretion). The drug interferes with how estrogen works in the body, except in the brain. The study that you are considering now tests whether your own estrogen works outside the brain to maintain GH secretion in postmenopausal women. This concept is important, because the brain controls how the pituitary gland secretes GH.

Hypotheses: Endogenous estrogen concentrations contribute significantly to maintaining postmenopausal growth-hormone (GH) secretion and; (b) systemic vis-à-vis CNS actions of endogenous estrogen differentially control the outflow of somatotropic hormones (viz., GH, IGF-I, IGFBP-1).

Approach: contrast regulation of the GH axis in postmenopausal women pretreated with the CNS-excluded selective estrogen-receptor antagonist, fulvestrant, versus placebo.

Background: fulvestrant was released recently by the FDA for therapy of estrogen-sensitive postmenopausal breast cancer. The drug acts as a mechanistically novel inhibitor of estradiol-receptor dimerization, thereby depleting nuclear estrogen receptors. Fulvestrant does not gain access to the CNS. Thus, inhibition of estrogen action will be restricted to non hypothalamic sites of GH-axis control, such as the pituitary gland, liver and fat cells. In contrast, endogenous estrogens have access to both CNS and peripheral sites.

Premise: selective blockade of peripheral estradiol receptors will reduce GH secretion if endogenous estrogens maintain GH secretion via systemic effects.

Eligibility Criteria:
Inclusion Criteria:

* healthy postmenopausal women (ages 50 to 80 y), wherein menopause is defined by the absence of spontaneous menses for 1 y and a serum concentration of FSH \> 30 IU/L and of (ultrasensitive) estradiol \< 20 pg/mL and verified by medical history and screening blood work;
* normal hemoglobin of \>11.0 g/dL in women (a ferritin level will be drawn, and must be normal, if Hgb is 11.0 - 11.5) , Platelets greater than 200 x 109/L, AST 8-48 U/L.
* Subjects (age 50 and above) will have a screening baseline ECG if not on record from the past year.

Exclusion Criteria:

* exposure to psychotropic or neuroactive drug within five biological half- lives;
* undesirability, disinclination or ill advisability of withholding estrogen supplements (e.g. under treatment for symptomatic hot flushes; primary physician recommendation);
* BMI \< 19 or \> 35
* drug or alcohol abuse; psychosis, depression, mania or anorexia nervosa;
* acute or chronic organ or systemic inflammatory disease;
* endocrinopathy, other than primary thyroidal failure receiving replacement;
* although fulvestrant has no known intrinsic estrogenicity, for safety reasons we include contraindication to short-term estrogen exposure; e.g.,estrogen-sensitive neoplasia, undiagnosed vaginal bleeding, deep-venous thrombosis, stroke or threatened stroke, clinical evidence of atherosclerotic heart disease, including myocardial infarction and/or angina, refractory high blood pressure, severe type IV hyperlipidemia:
* nightshift work or recent transmeridian travel (exceeding 3 time zones within 5 days of admission);
* systemic anticoagulation other than anti platelet therapy (in view of i.m. injections of fulvestrant); history of bleeding diathesis (ie; disseminated coagulation (DIC), clotting factor deficiency
* acute weight change (\> 3 kg in 6 weeks); and/or
* unwillingness to provide written informed consent.
* Platelets less than 200 x 109 /L
* International normalization ratio(INR) (Prothrombin time) greater than 1.6
* Total bilirubin greater than 1.5 x ULRR
* ALT or AST greater than 2.5 xULRR if no demonstrable liver metastases or greater
* History or hypersensitivity to active or inactive excipients of fulvestrant (ie; castor oil or Mannitol).