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.
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Subject)
Primary Purpose: Basic Science
|Official Title:||Role of Endogenous Estrogen in Growth-Hormone Regulation in Postmenopausal Women|
- BioStatistical Analysis [ Time Frame: Withdrawal of blood samples (2.5 mL each) every 10 min for 6 hr. Sampling will begin at 0800 h and conclude at 1400 h. ] [ Designated as safety issue: Yes ]GH concentrations decrease with age gradually in premenopausal women and rapidly in ovariprival individuals. A prime focus of our clinical studies is how estradiol availability governs GH secretion via combined central and peripheral regulation of neuropeptide signaling. The present investigation extends this theme by assessing whether endogenous estrogen maintains GH output and, if so, whether estrogen acts via CNS or systemic mechanisms in postmenopausal individuals.
- BioStatistical Analysis [ Time Frame: Withdrawal of blood samples (2.5 mL each) every 10 min for 6 hr. Sampling will begin at 0800 h and conclude at 1400 h. ] [ Designated as safety issue: Yes ]The present study will utilize a highly specific ER antagonist, fulvestrant, which inhibits ER-dependent pathways in peripheral tissues but not in the CNS. The study subjects are postmenopausal women, for whom fulvestrant was developed as a treatment for estrogen-responsive breast cancer. The premise is that fulvestrant will impede the effects of estradiol at systemic sites (e.g. liver, pituitary gland and fat cells), but not in drug-inaccessible CNS sites (e.g. hypothalamic nuclei), thereby unveiling which sites are important in regulating GH secretion.
|Study Start Date:||June 2009|
|Study Completion Date:||June 2013|
|Primary Completion Date:||June 2013 (Final data collection date for primary outcome measure)|
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).
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01186796
|United States, Minnesota|
|Rochester, Minnesota, United States, 55905|
|Principal Investigator:||Johannes Veldhuis, M.D.||Mayo Clinic|