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

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.

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).