Role of Endogenous Estrogen in Growth-Hormone Regulation in Postmenopausal Women
Condition: Healthy
Intervention: Fulvestrant
Intervention description: Secretagogue combinations are assigned in randomized double-blind order within-subject to include the following four conditions:
(i)L-arginine (30 gm i.v. over 30 min from 0930 h to 1000 h) followed by 5 mL bolus of NS at 1000 h; (ii) L-arginine (30 gm i.v. over 30 min from 0930 h to 1000 h) followed by GHRH and Ghrelin (both at dose of 0.3 mcg/kg bolus i.v.) at 1000 h; (iii) L-arginine (30 gm i.v. over 30 min from 0930 h to 1000 h) followed by GHRH (0.3 μg/kg bolus i.v.) at 1000 h; (iv) L-arginine infusion (30 gm i.v. over 30 min from 0930 h to 1000 h) followed by Ghrelin (0.3 μg/kg bolus i.v.) at 1000 h.
**Ghrelin dosage is based on 70 kg subject.Total exposure of Ghrelin will be 42 mcg total dose for 2 subject visits (21 mcg per visit).
Intervention MeSH terms: Fulvestrant
Phase: Phase 1
Study type: Interventional
Primary purpose: Basic Science
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Enrollment: 30.0
Sex: Female
Minimum age: 50 Years
Maximum age: 80 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Women; Fulvestrant Study; Post Menopausal Women; Hormones; Healthy Adult Women

Summary:

      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.
    

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).