tenn0titan
New member
Found some articles and was wondering if anyone has tried it?
The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency
F Salomon, RC Cuneo, R Hesp, and PH Sonksen
Abstract
In a double-blind, placebo-controlled trial, we studied the effects of six months of growth hormone replacement in 24 adults with growth hormone deficiency. Most of the patients had acquired growth hormone deficiency during adulthood as a consequence of treatment for pituitary tumors, and all were receiving appropriate thyroid, adrenal, and gonadal hormone replacement. The daily dose of recombinant human growth hormone (rhGH) was 0.07 U per kilogram of body weight, given subcutaneously at bedtime. The mean (+/- SE) plasma concentration of insulin-like growth factor I increased from 0.41 +/- 0.05 to 1.53 +/- 0.16 U per liter during rhGH treatment. Treatment with rhGH had no effect on body weight. The mean lean body mass, however, increased by 5.5 +/- 1.1 kg (P less than 0.0001), and the fat mass decreased by 5.7 +/- 0.9 kg (P less than 0.0001) in the group treated with growth hormone; neither changed significantly in the placebo group. The basal metabolic rate, measured at base line and after one and six months of rhGH administration, increased significantly; the respective values were 32.4 +/- 1.4, 37.2 +/- 2.2, and 34.4 +/- 1.6 kcal per kilogram of lean body mass per day (P less than 0.001 for both comparisons). Fasting plasma cholesterol levels were lower (P less than 0.05) in the rhGH-treated group than in the placebo group, whereas plasma triglyceride values were similar in the two groups throughout the study. We conclude that growth hormone has a role in the regulation of body composition in adults, probably through its anabolic and lipolytic actions.
Whither Recombinant Human Growth Hormone?
Christos S. Mantzoros, MD, DSc and Alan C. Moses, MD
Growth hormone and insulin-like growth factor 1 (IGF-1) are important anabolic hormones. They enhance intestinal absorption of calcium and phosphate and may play a direct role in DNA synthesis in bone, proliferation of osteoblasts, and accumulation of procollagen messenger RNA [1,2]. Although the actions of growth hormone were thought to be caused by circulating IGF-1 alone, recent evidence [1,2] suggests that growth hormone and other hormones stimulate local production of IGF-1, which acts in a paracrine-autocrine fashion in some tissues.
Starvation and cachexia (including that seen in patients with wasting associated with the acquired immunodeficiency syndrome [AIDS]) are associated with functional resistance to growth hormone and IGF-1 [1,2]. In addition, secretion of growth hormone substantially declines with age and results in concentrations of IGF-1 that are approximately 50% lower in elderly men than in younger men [1,3] and are associated with clinical manifestations of the insulin resistance syndrome [4].
Since the introduction of recombinant human growth hormone, impressive data have accrued on its ability to promote linear growth in children with growth hormone deficiency or advanced renal failure [1,4,5]. The embracing of recombinant human growth hormone as a therapeutic tool in pediatric endocrinology has been accompanied by a search for further indications for its use. Although parenteral injection of recombinant human growth hormone by athletes and body builders is acknowledged as abuse [6], recent studies have explored its use (and that of IGF-1) as medically appropriate therapy in adults with acquired growth hormone deficiency, in older adults with physiologic deficiency of growth hormone, in patients in severely catabolic states (such as those who have had trauma, burns, or extensive surgery) [1,3,7,8] and in persons with AIDS-associated wasting [9]. What is the rationale for these treatments, and how strongly do the data support replacement therapy with recombinant human growth hormone in these situations?
Earlier studies [1] have shown that short-term recombinant human growth hormone therapy increases lean body mass and muscle mass and reduces fat mass in young athletes, malnourished patients, patients who have had surgery, patients with renal failure, patients with burns, and adults with childhood-onset growth hormone deficiency [1]. Preliminary studies of elderly persons and patients with AIDS-associated cachexia [1,10,11] show that short-term therapy with high doses of recombinant human growth hormone (0.1 mg/kg of body weight per day) increases oxidation of fat and improves nitrogen balance, protein synthesis, and body mass. In the longest study to date [8], recombinant human growth hormone increased lean body mass by 8.8% and decreased adipose tissue mass by 14.4%. Moreover, short-term therapy with low doses of recombinant human IGF-1 (4 micro gram/kg centered dot hr-1 intravenously for 12 hours a day for 10 days) produced transient nitrogen retention in patients with cachexia associated with human immunodeficiency virus (HIV) infection, although no clear anabolic effect was seen [12].
In this issue, Waters and colleagues [9] report the results of their recent 12-week randomized clinical trial of recombinant human growth hormone (1.4 mg/d), recombinant human IGF-1 (5 mg twice daily), or both in patients with HIV-associated wasting. Therapy resulted in modest weight gain, an increase in lean body mass, and an increase in muscle strength but inconsistent improvements in quality of life. The study concluded that such therapy was not warranted until further evidence of efficacy (including improved survival) becomes available. Moreover, two recent studies [13,14] showed that recombinant human growth hormone (0.68 mg/d) plus recombinant human IGF-1 (10 mg/d) could not produce sustained anabolic responses in HIV-infected patients [13,14].
Growth hormone replacement improves muscle volume, strength, and exercise capacity in young adults with hypopituitarism [15], but no changes in strength or functional ability have been seen in healthy older men receiving an average dosage of 1.8 mg/d [3]. Thus, in patients with AIDS-associated cachexia and elderly persons with growth hormone deficiency, it is still unclear whether changes in body composition include increases in muscle mass or correlate with clinically important improvements in strength, physical mobility, ability to exercise, metabolic values, cardiovascular function, or quality of life.
Bone formation and resorption appear to increase during treatment with recombinant human growth hormone [1]. In a 30-month study [16] of replacement therapy in adults with childhood-onset growth hormone deficiency, bone turnover markers peaked at 6 months and bone density continued to increase. Treatment of older men for 6 months increased bone mineral density in the lumbar vertebrae by 1.6% but did not increase bone mineral density in the radius or proximal femur, a result similar to that seen in nonelderly, growth hormone-deficient adults [8]. The effect of growth hormone treatment on risk for fractures in elderly persons remains unknown.
In a study reported in this issue, Schambelan and colleagues [17] investigated 178 patients with HIV-associated wasting. Patients who received recombinant human growth hormone at an average dose of 6 mg/d (4.3-fold more than the dose used by Waters and colleagues [9]) for 12 weeks had a sustained increase in body weight and lean body mass, a decrease in fat, and an increase in treadmill work output. Quality of life, days of disability, and use of medical resources were the same in patients who did and those who did not receive growth hormone. No adverse effects on immune function or changes in mortality rate were seen, but the study was not designed (and probably lacked the power) to detect differences in these outcome measures.
The increase in lean body mass may represent water retention, increased protein synthesis, both, or neither. Accuracy of measurement of body mass may be altered by rapid hydration of water-depleted intracellular compartments in patients with chronic malnutrition [18]. Rapid weight gain in patients treated with exogenous recombinant human growth hormone suggests that fluid retention has the potential to skew measurements of lean body mass. In addition, although only 22% of the increase in exercise capacity (workload multiplied by body weight) induced by growth hormone could be attributed to increased weight, the marginal statistical significance might still reflect the increase in weight. Improved exercise capacity and body weight were not associated with better quality of life or less-frequent use of medical resources.
An advisory committee of the Food and Drug Administration (FDA) recently examined these and other data and heard testimony about treatment with recombinant human growth hormone for AIDS-associated wasting [19]. Although the data reported by Schambelan and colleagues showed a weight gain of 1.6 kg after treatment, a second study by the same investigators did not duplicate these results, thereby failing to meet a condition of FDA approval [19]. Nonetheless, the FDA approved this treatment of AIDS-associated wasting under the auspices of an expanded access program.
Also in this issue, Baum and colleagues [20] address the effects of 18 months of low-dose recombinant human growth hormone replacement therapy (initial average dose, 0.6 mg/d [10% of the dose used by Schambelan and colleagues], adjusted to normalize IGF-1 levels) on bone mineral density, body mass, and body composition in patients with adult-onset growth hormone deficiency. Therapy increased lean body mass by 2.5 kg, decreased fat mass by 3.6%, stimulated bone turnover, and increased bone mineral density by 2.4% to 5.1%. Left ventricular mass, left ventricular performance, and exercise capacity did not change with therapy.
Baum and colleagues' study provides further support for the use of dose hormone replacement therapy in growth hormone-deficient adults. It also shows that adjusting therapy according to the circulating level of IGF-1 can avoid significant side effects that have been seen in other studies, probably without decreasing the benefits.
Growth hormone therapy may cause dose-dependent sodium and fluid retention and lead to clinically significant edema, arthralgia, hypertension, and the carpal tunnel syndrome [1]. The mitogenic effects of growth hormone and IGF-1 in vivo remain controversial, but no compelling data show that giving growth factors in physiologic doses to children with growth hormone deficiency leads to increased incidence of cancer [1]. Whether the same is true for elderly patients and patients with AIDS (both of whom have an increased risk for cancer) remains unknown. Thus, although short-term adverse effects of growth factor therapy can be minimized by dose reduction, its long-term safety in elderly persons and patients with AIDS remains unclear. Finally, the cost of treatment at the doses used for patients with AIDS-associated wasting is substantial (approximately $1000 per week), and the appropriate duration of treatment remains undefined [19].
What are the implications of the above findings? Is growth factor treatment cost effective? Unfortunately, the jury is still out. The data presented in this issue do not provide unequivocal evidence that treatment with growth factor increases muscle mass in patients with AIDS-associated cachexia. Two studies [9,17] with similar data in AIDS-associated wasting (that is, small beneficial changes in body composition induced by recombinant human growth hormone, recombinant human IGF-1, or both) came to opposite conclusions about the advisability of these therapies. There have also been no cost-effectiveness analysis and no survival analysis. In contrast, the situation with growth hormone-deficient adults is more promising. Thus, we can be optimistic if persons can be identified who respond to therapy with recombinant human growth hormone with improved quality or duration of life. The clinical challenge will be to identify these persons prospectively (that is, to define inclusion and exclusion criteria for current therapy and future studies).
Failure to achieve more dramatic results in these studies probably stems from many causes. The appropriate dosing regimen (replacement therapy compared with pharmacologic doses) has not been established and probably differs among patient groups. Recent studies are limited because they have not examined dose response in patients in catabolic states.
The end points used for treatment have not been definitively established. Does normalization of circulating IGF-1 levels accurately reflect the tissue action of growth factors? How do we accurately measure lean body mass in sick patients and determine changes in lean body mass? Is increased lean body mass a reasonable surrogate for enhanced survival in patients with AIDS-associated wasting or for improved function in growth hormone-deficient adults? We also need to know whether a role exists for pulsatile recombinant human growth hormone and whether growth hormone-releasing hormone or growth hormone-stimulating secretagogues are alternative and more physiologic approaches. We must decide whether to step back and do smaller studies with better-defined populations and more accurate outcome measures to address the above concerns before beginning large and costly clinical trials. We need to determine whether administration of recombinant human growth hormone or recombinant human IGF-1 is cost-effective and, if so, for whom. Finally, if treatment is effective under these circumstances, studies comparing its effectiveness with that of other treatments (such as exercise and increased nutritional intake) should be done, emphasizing possible effects of combination therapy.
In conclusion, despite the excitement and promise of treatment with recombinant human growth hormone for HIV-associated wasting and for growth hormone deficiency in adults, many questions remain unanswered--a frustrating situation for those desperately in need of help. Although some recent data are inconclusive, we are making progress. The studies on AIDS-associated wasting in this issue should provide a strong impetus for additional studies to define precisely who will and will not benefit from administration of recombinant human growth hormone or recombinant IGF-1.
So would you guys take this stuff? I can get it 1mg for a great price. But not too sure about if it is as good as HGH.
Peace
TT
The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency
F Salomon, RC Cuneo, R Hesp, and PH Sonksen
Abstract
In a double-blind, placebo-controlled trial, we studied the effects of six months of growth hormone replacement in 24 adults with growth hormone deficiency. Most of the patients had acquired growth hormone deficiency during adulthood as a consequence of treatment for pituitary tumors, and all were receiving appropriate thyroid, adrenal, and gonadal hormone replacement. The daily dose of recombinant human growth hormone (rhGH) was 0.07 U per kilogram of body weight, given subcutaneously at bedtime. The mean (+/- SE) plasma concentration of insulin-like growth factor I increased from 0.41 +/- 0.05 to 1.53 +/- 0.16 U per liter during rhGH treatment. Treatment with rhGH had no effect on body weight. The mean lean body mass, however, increased by 5.5 +/- 1.1 kg (P less than 0.0001), and the fat mass decreased by 5.7 +/- 0.9 kg (P less than 0.0001) in the group treated with growth hormone; neither changed significantly in the placebo group. The basal metabolic rate, measured at base line and after one and six months of rhGH administration, increased significantly; the respective values were 32.4 +/- 1.4, 37.2 +/- 2.2, and 34.4 +/- 1.6 kcal per kilogram of lean body mass per day (P less than 0.001 for both comparisons). Fasting plasma cholesterol levels were lower (P less than 0.05) in the rhGH-treated group than in the placebo group, whereas plasma triglyceride values were similar in the two groups throughout the study. We conclude that growth hormone has a role in the regulation of body composition in adults, probably through its anabolic and lipolytic actions.
Whither Recombinant Human Growth Hormone?
Christos S. Mantzoros, MD, DSc and Alan C. Moses, MD
Growth hormone and insulin-like growth factor 1 (IGF-1) are important anabolic hormones. They enhance intestinal absorption of calcium and phosphate and may play a direct role in DNA synthesis in bone, proliferation of osteoblasts, and accumulation of procollagen messenger RNA [1,2]. Although the actions of growth hormone were thought to be caused by circulating IGF-1 alone, recent evidence [1,2] suggests that growth hormone and other hormones stimulate local production of IGF-1, which acts in a paracrine-autocrine fashion in some tissues.
Starvation and cachexia (including that seen in patients with wasting associated with the acquired immunodeficiency syndrome [AIDS]) are associated with functional resistance to growth hormone and IGF-1 [1,2]. In addition, secretion of growth hormone substantially declines with age and results in concentrations of IGF-1 that are approximately 50% lower in elderly men than in younger men [1,3] and are associated with clinical manifestations of the insulin resistance syndrome [4].
Since the introduction of recombinant human growth hormone, impressive data have accrued on its ability to promote linear growth in children with growth hormone deficiency or advanced renal failure [1,4,5]. The embracing of recombinant human growth hormone as a therapeutic tool in pediatric endocrinology has been accompanied by a search for further indications for its use. Although parenteral injection of recombinant human growth hormone by athletes and body builders is acknowledged as abuse [6], recent studies have explored its use (and that of IGF-1) as medically appropriate therapy in adults with acquired growth hormone deficiency, in older adults with physiologic deficiency of growth hormone, in patients in severely catabolic states (such as those who have had trauma, burns, or extensive surgery) [1,3,7,8] and in persons with AIDS-associated wasting [9]. What is the rationale for these treatments, and how strongly do the data support replacement therapy with recombinant human growth hormone in these situations?
Earlier studies [1] have shown that short-term recombinant human growth hormone therapy increases lean body mass and muscle mass and reduces fat mass in young athletes, malnourished patients, patients who have had surgery, patients with renal failure, patients with burns, and adults with childhood-onset growth hormone deficiency [1]. Preliminary studies of elderly persons and patients with AIDS-associated cachexia [1,10,11] show that short-term therapy with high doses of recombinant human growth hormone (0.1 mg/kg of body weight per day) increases oxidation of fat and improves nitrogen balance, protein synthesis, and body mass. In the longest study to date [8], recombinant human growth hormone increased lean body mass by 8.8% and decreased adipose tissue mass by 14.4%. Moreover, short-term therapy with low doses of recombinant human IGF-1 (4 micro gram/kg centered dot hr-1 intravenously for 12 hours a day for 10 days) produced transient nitrogen retention in patients with cachexia associated with human immunodeficiency virus (HIV) infection, although no clear anabolic effect was seen [12].
In this issue, Waters and colleagues [9] report the results of their recent 12-week randomized clinical trial of recombinant human growth hormone (1.4 mg/d), recombinant human IGF-1 (5 mg twice daily), or both in patients with HIV-associated wasting. Therapy resulted in modest weight gain, an increase in lean body mass, and an increase in muscle strength but inconsistent improvements in quality of life. The study concluded that such therapy was not warranted until further evidence of efficacy (including improved survival) becomes available. Moreover, two recent studies [13,14] showed that recombinant human growth hormone (0.68 mg/d) plus recombinant human IGF-1 (10 mg/d) could not produce sustained anabolic responses in HIV-infected patients [13,14].
Growth hormone replacement improves muscle volume, strength, and exercise capacity in young adults with hypopituitarism [15], but no changes in strength or functional ability have been seen in healthy older men receiving an average dosage of 1.8 mg/d [3]. Thus, in patients with AIDS-associated cachexia and elderly persons with growth hormone deficiency, it is still unclear whether changes in body composition include increases in muscle mass or correlate with clinically important improvements in strength, physical mobility, ability to exercise, metabolic values, cardiovascular function, or quality of life.
Bone formation and resorption appear to increase during treatment with recombinant human growth hormone [1]. In a 30-month study [16] of replacement therapy in adults with childhood-onset growth hormone deficiency, bone turnover markers peaked at 6 months and bone density continued to increase. Treatment of older men for 6 months increased bone mineral density in the lumbar vertebrae by 1.6% but did not increase bone mineral density in the radius or proximal femur, a result similar to that seen in nonelderly, growth hormone-deficient adults [8]. The effect of growth hormone treatment on risk for fractures in elderly persons remains unknown.
In a study reported in this issue, Schambelan and colleagues [17] investigated 178 patients with HIV-associated wasting. Patients who received recombinant human growth hormone at an average dose of 6 mg/d (4.3-fold more than the dose used by Waters and colleagues [9]) for 12 weeks had a sustained increase in body weight and lean body mass, a decrease in fat, and an increase in treadmill work output. Quality of life, days of disability, and use of medical resources were the same in patients who did and those who did not receive growth hormone. No adverse effects on immune function or changes in mortality rate were seen, but the study was not designed (and probably lacked the power) to detect differences in these outcome measures.
The increase in lean body mass may represent water retention, increased protein synthesis, both, or neither. Accuracy of measurement of body mass may be altered by rapid hydration of water-depleted intracellular compartments in patients with chronic malnutrition [18]. Rapid weight gain in patients treated with exogenous recombinant human growth hormone suggests that fluid retention has the potential to skew measurements of lean body mass. In addition, although only 22% of the increase in exercise capacity (workload multiplied by body weight) induced by growth hormone could be attributed to increased weight, the marginal statistical significance might still reflect the increase in weight. Improved exercise capacity and body weight were not associated with better quality of life or less-frequent use of medical resources.
An advisory committee of the Food and Drug Administration (FDA) recently examined these and other data and heard testimony about treatment with recombinant human growth hormone for AIDS-associated wasting [19]. Although the data reported by Schambelan and colleagues showed a weight gain of 1.6 kg after treatment, a second study by the same investigators did not duplicate these results, thereby failing to meet a condition of FDA approval [19]. Nonetheless, the FDA approved this treatment of AIDS-associated wasting under the auspices of an expanded access program.
Also in this issue, Baum and colleagues [20] address the effects of 18 months of low-dose recombinant human growth hormone replacement therapy (initial average dose, 0.6 mg/d [10% of the dose used by Schambelan and colleagues], adjusted to normalize IGF-1 levels) on bone mineral density, body mass, and body composition in patients with adult-onset growth hormone deficiency. Therapy increased lean body mass by 2.5 kg, decreased fat mass by 3.6%, stimulated bone turnover, and increased bone mineral density by 2.4% to 5.1%. Left ventricular mass, left ventricular performance, and exercise capacity did not change with therapy.
Baum and colleagues' study provides further support for the use of dose hormone replacement therapy in growth hormone-deficient adults. It also shows that adjusting therapy according to the circulating level of IGF-1 can avoid significant side effects that have been seen in other studies, probably without decreasing the benefits.
Growth hormone therapy may cause dose-dependent sodium and fluid retention and lead to clinically significant edema, arthralgia, hypertension, and the carpal tunnel syndrome [1]. The mitogenic effects of growth hormone and IGF-1 in vivo remain controversial, but no compelling data show that giving growth factors in physiologic doses to children with growth hormone deficiency leads to increased incidence of cancer [1]. Whether the same is true for elderly patients and patients with AIDS (both of whom have an increased risk for cancer) remains unknown. Thus, although short-term adverse effects of growth factor therapy can be minimized by dose reduction, its long-term safety in elderly persons and patients with AIDS remains unclear. Finally, the cost of treatment at the doses used for patients with AIDS-associated wasting is substantial (approximately $1000 per week), and the appropriate duration of treatment remains undefined [19].
What are the implications of the above findings? Is growth factor treatment cost effective? Unfortunately, the jury is still out. The data presented in this issue do not provide unequivocal evidence that treatment with growth factor increases muscle mass in patients with AIDS-associated cachexia. Two studies [9,17] with similar data in AIDS-associated wasting (that is, small beneficial changes in body composition induced by recombinant human growth hormone, recombinant human IGF-1, or both) came to opposite conclusions about the advisability of these therapies. There have also been no cost-effectiveness analysis and no survival analysis. In contrast, the situation with growth hormone-deficient adults is more promising. Thus, we can be optimistic if persons can be identified who respond to therapy with recombinant human growth hormone with improved quality or duration of life. The clinical challenge will be to identify these persons prospectively (that is, to define inclusion and exclusion criteria for current therapy and future studies).
Failure to achieve more dramatic results in these studies probably stems from many causes. The appropriate dosing regimen (replacement therapy compared with pharmacologic doses) has not been established and probably differs among patient groups. Recent studies are limited because they have not examined dose response in patients in catabolic states.
The end points used for treatment have not been definitively established. Does normalization of circulating IGF-1 levels accurately reflect the tissue action of growth factors? How do we accurately measure lean body mass in sick patients and determine changes in lean body mass? Is increased lean body mass a reasonable surrogate for enhanced survival in patients with AIDS-associated wasting or for improved function in growth hormone-deficient adults? We also need to know whether a role exists for pulsatile recombinant human growth hormone and whether growth hormone-releasing hormone or growth hormone-stimulating secretagogues are alternative and more physiologic approaches. We must decide whether to step back and do smaller studies with better-defined populations and more accurate outcome measures to address the above concerns before beginning large and costly clinical trials. We need to determine whether administration of recombinant human growth hormone or recombinant human IGF-1 is cost-effective and, if so, for whom. Finally, if treatment is effective under these circumstances, studies comparing its effectiveness with that of other treatments (such as exercise and increased nutritional intake) should be done, emphasizing possible effects of combination therapy.
In conclusion, despite the excitement and promise of treatment with recombinant human growth hormone for HIV-associated wasting and for growth hormone deficiency in adults, many questions remain unanswered--a frustrating situation for those desperately in need of help. Although some recent data are inconclusive, we are making progress. The studies on AIDS-associated wasting in this issue should provide a strong impetus for additional studies to define precisely who will and will not benefit from administration of recombinant human growth hormone or recombinant IGF-1.
So would you guys take this stuff? I can get it 1mg for a great price. But not too sure about if it is as good as HGH.
Peace
TT
