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| Name | Class |
|---|---|
| National Institutes of Health (NIH) | NIH |
| AstraZeneca | INDUSTRY |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Fulvestrant | Experimental |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Fulvestrant | Drug | 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). |
| Measure | Description | Time Frame |
|---|---|---|
| Mean Baseline GH Concentration | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Mean GH Concentration (Pulsatile) in Response to Secretagogue | 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Johannes Veldhuis, M.D. | Mayo Clinic | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Mayo Clinic | Rochester | Minnesota | 55905 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | Fulvestrant Group | Subjects are given 3 consecutive weekly injections of Fulvestrant 250mg. On days 22-26 after the initial injection, secretagogue combinations are assigned in randomized double-blind order within-subject to include the following 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. |
| FG001 | Saline Placebo Group | Subjects are given 3 consecutive weekly injections of saline. On days 22-26 after the initial injection, secretagogue combinations are assigned in randomized double-blind order within-subject to include the following 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. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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All subjects are healthy post-menopausal women from the community.
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| ID | Title | Description |
|---|---|---|
| BG000 | Fulvestrant Group | Subjects are given 3 consecutive weekly injections of Fulvestrant 250mg. On days 22-26 after the initial injection, secretagogue combinations are assigned in randomized double-blind order within-subject to include the following 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Mean Baseline GH Concentration | Averaged over 90-min baseline on the saline day. | Posted | Mean | Standard Error | ug/L | 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. |
|
Total adverse event data for the study was collected from 2009-2013 - or the duration of the study. For each individual, adverse event data was collected over approximately one month.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Fulvestrant Group | Subjects are given 3 consecutive weekly injections of Fulvestrant 250mg. On days 22-26 after the initial injection, secretagogue combinations are assigned in randomized double-blind order within-subject to include the following 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Vasovagal reaction with syncope | Surgical and medical procedures | Subject had a syncopal episode while on her way home after a study visit. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Generalized malaise | Surgical and medical procedures |
Strengths and limitations of the study include the potentially confounding effects of body composition (not studied here except at the level of BMI), underlying physical fitness of subjects, size of the cohort, and the brevity of the study (2 months)
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Johannes. D. Veldhuis, M.D. | Mayo Clinic | 507-255-0902 | Veldhuis.Johannes@mayo.edu |
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| ID | Term |
|---|---|
| D000077267 | Fulvestrant |
| ID | Term |
|---|---|
| D004958 | Estradiol |
| D004963 | Estrenes |
| D004962 | Estranes |
| D013256 | Steroids |
| D000072473 |
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| Mean Mass of GH Released Per Burst in Response to Secretagogue | 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 | 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 | 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. |
| Protocol Violation |
|
| BG001 | Saline Group | Subjects are given 3 consecutive weekly injections of Saline. On days 22-26 after the initial injection, secretagogue combinations are assigned in randomized double-blind order within-subject to include the following 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. |
| BG002 | Total | Total of all reporting groups |
| Participants |
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| Sex: Female, Male | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
|
| OG001 | Saline Placebo Group | Subjects are given 3 consecutive weekly injections of saline. On days 22-26 after the initial injection, secretagogue combinations are assigned in randomized double-blind order within-subject to include the following 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. |
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| Secondary | Mean GH Concentration (Pulsatile) in Response to Secretagogue | 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. | Posted | Mean | Standard Error | ug/L/6h | 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. |
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| Secondary | Mean Mass of GH Released Per Burst in Response to Secretagogue | 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. | Posted | Mean | Standard Error | ug/L | 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. |
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| Secondary | Mean Duration of GH Bursts (Mode) in Response to Secretagogue | 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. | Posted | Mean | Standard Error | min | 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. |
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| Secondary | Mean GH Half-Life in Response to Secretagogue | 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. | Posted | Mean | Standard Error | min | 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. |
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| 1 |
| 14 |
| 2 |
| 14 |
| EG001 | Saline Placebo Group | Subjects are given 3 consecutive weekly injections of saline. On days 22-26 after the initial injection, secretagogue combinations are assigned in randomized double-blind order within-subject to include the following 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. | 0 | 15 | 0 | 15 |
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| Erythema post Fulvestrant injections | Surgical and medical procedures | Developed small 3-4cm erythematoses on bilateral wrists/forearms 3 days after Fulvestrant injection |
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| Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D045166 | Estradiol Congeners |
| D012739 | Gonadal Steroid Hormones |
| D042341 | Gonadal Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| Pulsatile GH Response to L-arg/ghrelin |
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| Pulsatile GH Response to L-arg/ghrelin + GHRH |
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| Mean Mass of GH per Burst post L-Arg/Ghrelin |
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| Mean Mass of GH per Burst post L-Arg/GHRH+Ghrelin |
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| Mean Duration of GH Bursts post L-Arg/Ghrelin |
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| Mean Duration of GH Bursts post L-Arg/GHRH+Ghrelin |
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| Mean GH Half-life duration post L-Arg/Ghrelin |
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| Mean GH Half-life duration post L-Arg/GHRH+Ghrelin |
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