Role of Endogenous Estrogen in Growth-Hormone Regulation in Postmenopausal Women
Condition: Healthy
Study type: Interventional
Phase: Phase 1

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.
    

Detailed description: 
      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.
    

Intervention name(s): Fulvestrant
Intervention type(s): Drug
Intervention description(s): 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
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Basic Science
Keywords: Women; Fulvestrant Study; Post Menopausal Women; Hormones; Healthy Adult Women