After reading this, I feel that everyone should incorporate HGH into their Hormone Replacement Therapy (HRT) or performance enhancement program.
A Canadian Perspective on ENDO 2003: The 85th Annual Meeting of the Endocrine Society
Therapeutic Benefits of Growth Hormone Replacement
June 19-22, 2003; Philadelphia, Pennsylvania
from Medscape Diabetes & Endocrinology
Posted 07/17/2003
Shereen Ezzat, MD
Growth hormone (GH) replacement therapy in adult GH-deficient (GHD) patients is today an established form of hormone therapy. More than 100 clinical trials have been published characterising the GHD syndrome in adults, determining the effects of replacement therapy with recombinant human GH, and providing the basis for optimisation of treatment in order to maximize benefits and minimise potential risks. Numerous reviews[1,2] have described the diversity of effects of GH replacement therapy.
GH replacement aims to normalize the features of GHD, but the functional and long-term outcomes of the therapy are relatively less well documented. As a consequence, different clinical practices have developed in different countries on the rationale and approach to GH replacement therapy.[2] GH replacement in the adult population aims to alleviate the symptoms of GHD and/or target the GHD-associated abnormal markers such as those for osteoporosis and cardiovascular disease. There is indirect evidence that GHD is related to the increased morbidity and mortality in cardiovascular disease demonstrated amongst hypopituitary patients who receive conventional hormonal replacement therapy without GH substitution.[3-6] Higher frequencies of sick leave and disability pension amongst patients with a history of pituitary tumor have been reported compared with the general population.[7]
There is ample and robust evidence supporting the remedial effects of GH replacement on body composition, including gradual normalisation of lean body mass and reduction in fat mass.[8,9] A number of studies have also demonstrated improvements in psychological well-being, with specific improvements in energy, emotional reactions, and social isolation.[10,11] Moreover, healthcare consumption decreases in parallel with enhanced psychological well-being.[12]
These findings were echoed in a poster presentation[13] at ENDO 2003: The 85th Annual Meeting of the Endocrine Society, in which a group of researchers from The Netherlands investigated the effects of GH replacement therapy on healthcare utilisation and quality of life among GHD adults receiving long-term therapy. After 1 year of GH replacement therapy, 61.6% of subjects reported a subjective improvement in personal well-being, and after 2 years of treatment there was an increase to 65.7% of treated patients. Leisure-time physical activity significantly improved, and visits to the doctor, days in hospital, and sick days decreased. The investigators noted that after 2 years of therapy, the quality of life and healthcare utilisation measures for GHD patients were comparable to the general Dutch population.
Improvements in muscle strength, exercise capacity, and respiratory function have also been observed in some studies.[14,15] In a poster presented at ENDO 2003,[16] GH treatment of GHD adults was associated with improved sleep quality (fewer awakenings, increased duration of deep sleep), which the authors speculated might contribute to better quality of life.
The characteristic features of longstanding GHD on cardiac structural and functional abnormalities, dyslipidemia, endothelial dysfunction, abnormal coagulation, and abnormalities of the cardiac autonomic system were extensively reported at ENDO 2003.
These effects on cardiac changes may not be restricted to elderly subjects with GHD. In a study from Italy,[17] echocardiography was performed in 15 children with GHD before and after 6 and 12 months of GH treatment (0.2 mg/kg/week); the left ventricular mass index (LVMi), the ejection fraction (EF), and the ratio between the maximum early diastolic flow velocity (E) and maximum late diastolic flow velocity (A) (E/A) were measured. Healthy children with familial short stature and normal response to GH provocative tests having comparable age, sex, height, and weight were used as controls.
Interestingly, LVMi (gr/m) was significantly lower in GHD children (48.18 ± 0.4) compared with controls (58.61 ± 3.1; P < .02). After 6 months of GH therapy, LVMi increased significantly with respect to pretreatment values (P < .05), becoming similar to controls; a further significant increase in LVMi was observed after 12 months of treatment (69.31 ± 4.8; P < .001). The increase in LVMi during GH treatment paralleled the increase in serum IGF-1 levels (r = 0.55; P = .0002). No differences in cardiac performance were observed between GHD patients and controls. The EF (%) in children with GHD was 64.0 ± 5.9 before GH therapy -- not different from controls (62.94 ± 0.9). During GH treatment, EF did not show any change compared with pretreatment values (63.8 ± 3.9 after 6 months and 62.8 ± 5.9 after 12 months of therapy). The E/A ratio in GHD children was 1.70 ± 0.4 before treatment, 1.9 ± 0.4 after 6 months of treatment, and 1.6 ± 0.4 after 12 months of treatment, without any difference vs controls (1.9 ± 0.4).
These data are consistent with the notion that GHD children have reduced LV mass, whereas LV performance is not impaired. LVMi improves after 6 months of GH treatment. Although after 1 year of replacement therapy LVMi is higher than in controls, none of the patients developed cardiac hypertrophy. Further longitudinal studies are needed to evaluate whether cardiac impairment during childhood may contribute to an increased cardiovascular risk in adults with GHD.
Pharmacologic approaches to enhance endogenous GH secretion were also presented. It was previously reported that hexarelin (HEX), a member of the growth hormone-releasing peptides (GHRPs), binds to CD36, a scavenger receptor involved in the scavenging of oxidized low-density lipoproteins (oxLDL) in monocytes/macrophages, leading to foam-cell formation. To determine whether GHRPs may interfere with CD36 function/expression in monocytes/macrophages, thereby hampering the uptake of oxLDL by macrophages and foam-cell development, long-term studies of the effects of GHRPs on atherosclerotic lesion development were conducted in ApoE null mice and in ApoE/CD36 double null mice.[18] Mice were placed on a high-fat, high-cholesterol (HFHC) diet for 12 weeks and given daily subcutaneous injections of 0.9% NaCl or either HEX (100 g/kg) or EP 80317 (300g/kg). At 18 weeks, mice were anaesthetized and cardiac blood withdrawn for plasma cholesterol profiles analysis. Peritoneal macrophages were collected for measurement of CD36 expression by flow cytometry analysis and by Western blotting as well as for RNA extraction for RT- PCR analysis of PPAR-LXR-ABCA1. The aortic trees were dissected and the aortic arch was opened longitudinally. The aortic lesion area was evaluated after staining with Oil Red-O. Interestingly, a significant reduction of lesion area, by 28% and 47%, was observed following treatment with HEX and EP 80317, respectively, in ApoE null mice. Further, the reduced lesion area in ApoE null mice was associated with a decrease in total plasma cholesterol (31%) and non-HDL cholesterol, compared with controls. HDL cholesterol tended to increase in ApoE null mice by 65% and 73%, respectively, following treatment with HEX and EP 80317. Both GHRPs reduced ox-LDL induced peritoneal macrophage accumulation by 39% in ApoE null mice. This reduction was paralleled by the increase of the expression of genes PPAR, LXR, and ABCA1. These findings would indicate that GHRPs can protect ApoE null mice from developing fatty streaks lesions. Moreover, the antiatherosclerotic effect of GHRPs appears to be mediated through the negative modulation of the expression of CD36 in macrophages and the increase of expression of genes involved in the cellular cholesterol removal. Finally, the protective effects of GHRPs are associated with favourable modulation in plasma lipid profile. GHRPs might be an interesting alternative in the treatment of atherosclerosis and hypercholesterolemia.
Unfortunately, these new and exciting findings are not widely appreciated. For example, research conducted in May 2002 surveyed 250 office-based physicians,[19] including primary care physicians (100), cardiologists (75), and endocrinologists (75). Sampling within each specialty group included physicians from all major regions of the United States. Eighty percent of physicians surveyed were not aware that adult GHD can produce conditions associated with increased cardiovascular risk such as elevated cholesterol, high blood pressure, insulin resistance, and abdominal obesity. Interestingly, physicians surveyed were more likely to perceive lack of exercise (90%), metabolic syndrome (90%), diabetes (89%), and poor diet (88%) as causes of the aforementioned conditions associated with increased cardiovascular risk. In marked contrast, only 38% of primary care physicians and cardiologists surveyed were aware that GHD can first develop during adulthood, compared with 84% of endocrinologists surveyed. However, nearly 70% of primary care physicians and cardiologists were able to identify conditions such as pituitary tumors and traumatic brain injury as potential causes of GHD. Ninety-two percent of primary care physicians and cardiologists said they would ultimately refer patients diagnosed with GHD to an endocrinologist for medical care; however, 5% of primary care physicians and cardiologists said they would treat patients with GHD themselves; 3% said they would do nothing. These observations emphasize the need for greater awareness of the GH-deficiency state and its implications for adult patients among physicians in general and nonendocrinologists in particular.
A Canadian Perspective on ENDO 2003: The 85th Annual Meeting of the Endocrine Society
Therapeutic Benefits of Growth Hormone Replacement
June 19-22, 2003; Philadelphia, Pennsylvania
from Medscape Diabetes & Endocrinology
Posted 07/17/2003
Shereen Ezzat, MD
Growth hormone (GH) replacement therapy in adult GH-deficient (GHD) patients is today an established form of hormone therapy. More than 100 clinical trials have been published characterising the GHD syndrome in adults, determining the effects of replacement therapy with recombinant human GH, and providing the basis for optimisation of treatment in order to maximize benefits and minimise potential risks. Numerous reviews[1,2] have described the diversity of effects of GH replacement therapy.
GH replacement aims to normalize the features of GHD, but the functional and long-term outcomes of the therapy are relatively less well documented. As a consequence, different clinical practices have developed in different countries on the rationale and approach to GH replacement therapy.[2] GH replacement in the adult population aims to alleviate the symptoms of GHD and/or target the GHD-associated abnormal markers such as those for osteoporosis and cardiovascular disease. There is indirect evidence that GHD is related to the increased morbidity and mortality in cardiovascular disease demonstrated amongst hypopituitary patients who receive conventional hormonal replacement therapy without GH substitution.[3-6] Higher frequencies of sick leave and disability pension amongst patients with a history of pituitary tumor have been reported compared with the general population.[7]
There is ample and robust evidence supporting the remedial effects of GH replacement on body composition, including gradual normalisation of lean body mass and reduction in fat mass.[8,9] A number of studies have also demonstrated improvements in psychological well-being, with specific improvements in energy, emotional reactions, and social isolation.[10,11] Moreover, healthcare consumption decreases in parallel with enhanced psychological well-being.[12]
These findings were echoed in a poster presentation[13] at ENDO 2003: The 85th Annual Meeting of the Endocrine Society, in which a group of researchers from The Netherlands investigated the effects of GH replacement therapy on healthcare utilisation and quality of life among GHD adults receiving long-term therapy. After 1 year of GH replacement therapy, 61.6% of subjects reported a subjective improvement in personal well-being, and after 2 years of treatment there was an increase to 65.7% of treated patients. Leisure-time physical activity significantly improved, and visits to the doctor, days in hospital, and sick days decreased. The investigators noted that after 2 years of therapy, the quality of life and healthcare utilisation measures for GHD patients were comparable to the general Dutch population.
Improvements in muscle strength, exercise capacity, and respiratory function have also been observed in some studies.[14,15] In a poster presented at ENDO 2003,[16] GH treatment of GHD adults was associated with improved sleep quality (fewer awakenings, increased duration of deep sleep), which the authors speculated might contribute to better quality of life.
The characteristic features of longstanding GHD on cardiac structural and functional abnormalities, dyslipidemia, endothelial dysfunction, abnormal coagulation, and abnormalities of the cardiac autonomic system were extensively reported at ENDO 2003.
These effects on cardiac changes may not be restricted to elderly subjects with GHD. In a study from Italy,[17] echocardiography was performed in 15 children with GHD before and after 6 and 12 months of GH treatment (0.2 mg/kg/week); the left ventricular mass index (LVMi), the ejection fraction (EF), and the ratio between the maximum early diastolic flow velocity (E) and maximum late diastolic flow velocity (A) (E/A) were measured. Healthy children with familial short stature and normal response to GH provocative tests having comparable age, sex, height, and weight were used as controls.
Interestingly, LVMi (gr/m) was significantly lower in GHD children (48.18 ± 0.4) compared with controls (58.61 ± 3.1; P < .02). After 6 months of GH therapy, LVMi increased significantly with respect to pretreatment values (P < .05), becoming similar to controls; a further significant increase in LVMi was observed after 12 months of treatment (69.31 ± 4.8; P < .001). The increase in LVMi during GH treatment paralleled the increase in serum IGF-1 levels (r = 0.55; P = .0002). No differences in cardiac performance were observed between GHD patients and controls. The EF (%) in children with GHD was 64.0 ± 5.9 before GH therapy -- not different from controls (62.94 ± 0.9). During GH treatment, EF did not show any change compared with pretreatment values (63.8 ± 3.9 after 6 months and 62.8 ± 5.9 after 12 months of therapy). The E/A ratio in GHD children was 1.70 ± 0.4 before treatment, 1.9 ± 0.4 after 6 months of treatment, and 1.6 ± 0.4 after 12 months of treatment, without any difference vs controls (1.9 ± 0.4).
These data are consistent with the notion that GHD children have reduced LV mass, whereas LV performance is not impaired. LVMi improves after 6 months of GH treatment. Although after 1 year of replacement therapy LVMi is higher than in controls, none of the patients developed cardiac hypertrophy. Further longitudinal studies are needed to evaluate whether cardiac impairment during childhood may contribute to an increased cardiovascular risk in adults with GHD.
Pharmacologic approaches to enhance endogenous GH secretion were also presented. It was previously reported that hexarelin (HEX), a member of the growth hormone-releasing peptides (GHRPs), binds to CD36, a scavenger receptor involved in the scavenging of oxidized low-density lipoproteins (oxLDL) in monocytes/macrophages, leading to foam-cell formation. To determine whether GHRPs may interfere with CD36 function/expression in monocytes/macrophages, thereby hampering the uptake of oxLDL by macrophages and foam-cell development, long-term studies of the effects of GHRPs on atherosclerotic lesion development were conducted in ApoE null mice and in ApoE/CD36 double null mice.[18] Mice were placed on a high-fat, high-cholesterol (HFHC) diet for 12 weeks and given daily subcutaneous injections of 0.9% NaCl or either HEX (100 g/kg) or EP 80317 (300g/kg). At 18 weeks, mice were anaesthetized and cardiac blood withdrawn for plasma cholesterol profiles analysis. Peritoneal macrophages were collected for measurement of CD36 expression by flow cytometry analysis and by Western blotting as well as for RNA extraction for RT- PCR analysis of PPAR-LXR-ABCA1. The aortic trees were dissected and the aortic arch was opened longitudinally. The aortic lesion area was evaluated after staining with Oil Red-O. Interestingly, a significant reduction of lesion area, by 28% and 47%, was observed following treatment with HEX and EP 80317, respectively, in ApoE null mice. Further, the reduced lesion area in ApoE null mice was associated with a decrease in total plasma cholesterol (31%) and non-HDL cholesterol, compared with controls. HDL cholesterol tended to increase in ApoE null mice by 65% and 73%, respectively, following treatment with HEX and EP 80317. Both GHRPs reduced ox-LDL induced peritoneal macrophage accumulation by 39% in ApoE null mice. This reduction was paralleled by the increase of the expression of genes PPAR, LXR, and ABCA1. These findings would indicate that GHRPs can protect ApoE null mice from developing fatty streaks lesions. Moreover, the antiatherosclerotic effect of GHRPs appears to be mediated through the negative modulation of the expression of CD36 in macrophages and the increase of expression of genes involved in the cellular cholesterol removal. Finally, the protective effects of GHRPs are associated with favourable modulation in plasma lipid profile. GHRPs might be an interesting alternative in the treatment of atherosclerosis and hypercholesterolemia.
Unfortunately, these new and exciting findings are not widely appreciated. For example, research conducted in May 2002 surveyed 250 office-based physicians,[19] including primary care physicians (100), cardiologists (75), and endocrinologists (75). Sampling within each specialty group included physicians from all major regions of the United States. Eighty percent of physicians surveyed were not aware that adult GHD can produce conditions associated with increased cardiovascular risk such as elevated cholesterol, high blood pressure, insulin resistance, and abdominal obesity. Interestingly, physicians surveyed were more likely to perceive lack of exercise (90%), metabolic syndrome (90%), diabetes (89%), and poor diet (88%) as causes of the aforementioned conditions associated with increased cardiovascular risk. In marked contrast, only 38% of primary care physicians and cardiologists surveyed were aware that GHD can first develop during adulthood, compared with 84% of endocrinologists surveyed. However, nearly 70% of primary care physicians and cardiologists were able to identify conditions such as pituitary tumors and traumatic brain injury as potential causes of GHD. Ninety-two percent of primary care physicians and cardiologists said they would ultimately refer patients diagnosed with GHD to an endocrinologist for medical care; however, 5% of primary care physicians and cardiologists said they would treat patients with GHD themselves; 3% said they would do nothing. These observations emphasize the need for greater awareness of the GH-deficiency state and its implications for adult patients among physicians in general and nonendocrinologists in particular.
