- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01186796
Role of Endogenous Estrogen in Growth-Hormone Regulation in Postmenopausal Women
Study Overview
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.
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
-
-
Minnesota
-
Rochester, Minnesota, United States, 55905
- Mayo Clinic
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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).
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Single
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: 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). |
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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.
|
Averaged over 90-min baseline on the saline day.
|
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.
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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.
|
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.
|
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.
|
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.
|
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.
|
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.
|
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.
|
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.
|
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.
|
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.
|
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.
|
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.
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Johannes Veldhuis, M.D., Mayo Clinic
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 07-003036
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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