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

This study has been completed.
Sponsor:
Collaborators:
National Institutes of Health (NIH)
AstraZeneca
Information provided by (Responsible Party):
Johannes D. Veldhuis, Mayo Clinic
ClinicalTrials.gov Identifier:
NCT01186796
First received: August 16, 2010
Last updated: March 24, 2015
Last verified: March 2015
  Purpose
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.

Condition Intervention Phase
Healthy
Drug: Fulvestrant
Phase 1

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by Mayo Clinic:

Primary Outcome Measures:
  • Mean Baseline GH Concentration [ 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: No ]
    Averaged over 90-min baseline on the saline day.


Secondary Outcome Measures:
  • Mean GH Concentration (Pulsatile) in Response to Secretagogue [ 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: No ]
    Subjects were administered 4 different secretagogues: (i) L-arginine/Saline, (ii) L-arginine/Ghrelin, (iii) L-arginine/GHRH, and (iv) L-arginine / GHRH + Ghrelin. The result was calculated by averaging values over the 6 hour collection timeframe.

  • Mean Mass of GH Released Per Burst in Response to Secretagogue [ 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: No ]
    Subjects were administered 4 different secretagogues: (i) L-arginine/Saline, (ii) L-arginine/Ghrelin, (iii) L-arginine/GHRH, and (iv) L-arginine / GHRH + Ghrelin. The result was calculated on each 6-hr pool of data by utilizing a previously published deconvolution method and analyzed via two-way ANOVA.

  • Mean Duration of GH Bursts (Mode) in Response to Secretagogue [ 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: No ]
    Subjects were administered 4 different secretagogues: (i) L-arginine/Saline, (ii) L-arginine/Ghrelin, (iii) L-arginine/GHRH, and (iv) L-arginine / GHRH + Ghrelin. The result was calculated on each 6-hr pool of data by utilizing a previously published deconvolution method and analyzed via two-way ANOVA.

  • Mean GH Half-Life in Response to Secretagogue [ 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: No ]
    Subjects were administered 4 different secretagogues: (i) L-arginine/Saline, (ii) L-arginine/Ghrelin, (iii) L-arginine/GHRH, and (iv) L-arginine / GHRH + Ghrelin. The result was calculated on each 6-hr pool of data by utilizing a previously published deconvolution method and analyzed via two-way ANOVA.


Enrollment: 30
Study Start Date: June 2009
Study Completion Date: June 2013
Primary Completion Date: June 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Fulvestrant Drug: Fulvestrant

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).


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.

  Eligibility

Ages Eligible for Study:   50 Years to 80 Years   (Adult, Senior)
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
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).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01186796

Locations
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
Sponsors and Collaborators
Mayo Clinic
National Institutes of Health (NIH)
AstraZeneca
Investigators
Principal Investigator: Johannes Veldhuis, M.D. Mayo Clinic
  More Information

Responsible Party: Johannes D. Veldhuis, Johannes D. Veldhuis, MD, Mayo Clinic
ClinicalTrials.gov Identifier: NCT01186796     History of Changes
Other Study ID Numbers: 07-003036 
Study First Received: August 16, 2010
Results First Received: February 24, 2015
Last Updated: March 24, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by Mayo Clinic:
Women
Fulvestrant Study
Post Menopausal Women
Hormones
Healthy Adult Women

Additional relevant MeSH terms:
Hormones
Estradiol
Estrogens
Fulvestrant
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Estrogen Receptor Antagonists
Estrogen Antagonists
Hormone Antagonists

ClinicalTrials.gov processed this record on August 28, 2016