Growth Hormone Secretion Abnormality, Obese
Conditions
Keywords
Growth hormone, GH, Obesity, Mitochondrial function, reduced growth hormone secretion
Brief summary
Obesity is associated with reduced growth hormone (GH) secretion. Reduced GH secretion in obesity is associated with increased cardiovascular disease risk. However, it is not yet known how reduced GH increases cardiovascular disease risk in obesity. The investigators hypothesize that reduced GH contributes to dysfunction of the mitochondria. Therefore, the investigators hypothesize that treatment of obese subjects with reduced GH secretion with GH will improve mitochondrial function and that this improvement in mitochondrial function will contribute, in part, to the effects of GH to improve metabolic parameters in obesity. The investigators propose to study skeletal muscle mitochondria in obese subjects with reduced GH secretion using magnetic resonance spectroscopy and muscle biopsies before and after treatment with GH.
Interventions
DRUGGrowth hormone treatment
Growth hormone 0.4 mg once daily (titrated to IGF-1) by sub-cutaneous injection for 12 weeks.
Sponsors
Pfizer
Massachusetts General Hospital
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
1. Men age 18-60 years old 2. BMI ≥ 30 kg/m2 3. Waist circumference ≥ 102 cm 4. Peak GH value of ≤ 4.2 μg/l on standard GHRH-arginine stimulation test
Exclusion criteria
1. Obesity due to a known secondary cause (Cushing's syndrome, hypothyroidism, etc) or a history of gastric bypass procedure. 2. Subjects who have a known history of diabetes, fasting blood sugar \>125 mg/dl or using any anti-diabetic drugs. 3. Use of Aspirin, Clopidogrel (Plavix), Warfarin (Coumadin) or other anti-coagulants 4. Subjects on testosterone, glucocorticoids, anabolic steroids, GHRH, GH or IGF-1 within 3 months of enrollment. 5. Changes in lipid lowering or anti-hypertensive regimen within 3 months of screening 6. History of pituitary tumor, hypopituitarism, pituitary surgery, pituitary/brain radiation or traumatic brain injury or any other condition known to affect the GH axis. 7. Severe chronic illness including HIV, active malignancy or history of colon cancer. 8. Hemoglobin \< 9.0 g/dL, SGOT \> 2.5 x upper limit normal, Creatinine \>1.5 mg/dL, or PSA \>5 ng/ml. 9. Subject is currently enrolled in another investigational device or drug trial(s), or subject has received other investigational agent(s) within 28 days of baseline visit. 10. Any condition judged by the patient's physician to cause this clinical trial to be detrimental to the patient. 11. Contraindications to MRI scanning.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phosphocreatine Recovery | 12-weeks | The primary objective of this study is to determine the effects of growth hormone on mitochondrial function as assessed by 31P-MRS in obese subjects with reduced GH secretion. Mitochondrial function was represented by ViPCr, a measure of phosphocreatine recovery after sub-maximal exercise. Univariate regression analyses was performed to assess the relationship between the change in skeletal muscle IGF-1 mRNA after 12 weeks treatment with rhGH to change in ViPCr. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Skeletal Muscle IGF-1 Gene Expression | Baseline and 12-weeks | Change in skeletal muscle IGF-1 gene mRNA expression from Baseline to 12-weeks is reported. |
| Change in Body Composition | Baseline and 12-weeks | Change in waist circumference from Baseline to 12-weeks is reported. |
| Change in Circulating IGF-1 Concentration | Baseline and 12-weeks | Change in circulating IGF-1 from Baseline to 12-weeks is reported. |
| Change in Insulin Sensitivity | Baseline and 12-weeks | Change in fasting glucose from Baseline to 12-weeks is reported. |
| Change in Phosphocreatine Recovery | Baseline and 12-weeks | Change in phosphocreatine recovery, represented by ViPCr, from Baseline to 12-weeks is reported. |
| Change in Inflammatory Marker | Baseline and 12-weeks | Change in high sensitivity C-reactive protein (hsCRP) from Baseline to 12-weeks is reported. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Growth Hormone Growth hormone treatment: Growth hormone 0.4 mg once daily (titrated to IGF-1) by sub-cutaneous injection for 12 weeks. | 15 |
| Total | 15 |
Baseline characteristics
| Characteristic | Growth Hormone |
|---|---|
| Age, Continuous | 47.9 years STANDARD_DEVIATION 8.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 10 Participants |
| Region of Enrollment United States | 15 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 11 / 15 |
| serious Total, serious adverse events | 0 / 15 |
Outcome results
Primary
Phosphocreatine Recovery
The primary objective of this study is to determine the effects of growth hormone on mitochondrial function as assessed by 31P-MRS in obese subjects with reduced GH secretion. Mitochondrial function was represented by ViPCr, a measure of phosphocreatine recovery after sub-maximal exercise. Univariate regression analyses was performed to assess the relationship between the change in skeletal muscle IGF-1 mRNA after 12 weeks treatment with rhGH to change in ViPCr.
Time frame: 12-weeks
Population: All 15 subjects underwent 31P-MRS, however, two scans were not evaluable due to technical difficulties. In addition, paired analyses (both Baseline and 12-weeks) from only 10 subjects were available for gene expression analyses. Therefore univariate regression analyses between IGF-1 mRNA and PCr recovery could only be performed in 10 subjects.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Growth Hormone Treatment | Phosphocreatine Recovery | 0.74 correlation coefficient | 5.4 |
Comparison: Univariate regression analyses was performed to assess the relationship between change in skeletal muscle IGF-1 mRNA expression after 12 weeks treatment with rhGH and change in ViPCr.p-value: 0.02Regression, Linear
Secondary
Change in Body Composition
Change in waist circumference from Baseline to 12-weeks is reported.
Time frame: Baseline and 12-weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Growth Hormone Treatment | Change in Body Composition | -3 cm | Standard Error 1 |
p-value: <0.05t-test, 2 sided
Secondary
Change in Circulating IGF-1 Concentration
Change in circulating IGF-1 from Baseline to 12-weeks is reported.
Time frame: Baseline and 12-weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Growth Hormone Treatment | Change in Circulating IGF-1 Concentration | 218 ug/l | Standard Error 29 |
p-value: <0.0001t-test, 2 sided
Secondary
Change in Inflammatory Marker
Change in high sensitivity C-reactive protein (hsCRP) from Baseline to 12-weeks is reported.
Time frame: Baseline and 12-weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Growth Hormone Treatment | Change in Inflammatory Marker | -1.78 mg/l | Standard Error 0.57 |
p-value: <0.05t-test, 2 sided
Secondary
Change in Insulin Sensitivity
Change in fasting glucose from Baseline to 12-weeks is reported.
Time frame: Baseline and 12-weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Growth Hormone Treatment | Change in Insulin Sensitivity | 6 mg/dl | Standard Error 3 |
p-value: <0.05t-test, 2 sided
Secondary
Change in Phosphocreatine Recovery
Change in phosphocreatine recovery, represented by ViPCr, from Baseline to 12-weeks is reported.
Time frame: Baseline and 12-weeks
Population: Obese men with reduced GH secretion were treated with rhGH for 12 weeks. All 15 subjects underwent 31P-MRS, however, two scans were not evaluable due to technical difficulties.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Growth Hormone Treatment | Change in Phosphocreatine Recovery | -10.2 mM/min | Standard Error 7.5 |
p-value: >0.05t-test, 2 sided
Secondary
Change in Skeletal Muscle IGF-1 Gene Expression
Change in skeletal muscle IGF-1 gene mRNA expression from Baseline to 12-weeks is reported.
Time frame: Baseline and 12-weeks
Population: Paired analyses (both Baseline and 12-weeks) from only 10 subjects are available for gene expression
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Growth Hormone Treatment | Change in Skeletal Muscle IGF-1 Gene Expression | 2.1 fold change | Standard Error 0.3 |
p-value: <0.05t-test, 2 sided