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Growth Hormone, Cardiovascular Risk & Malignancy OR20-3 Low-Dose Growth Hormone (GH) as an Adjuvant to Life Style Modifications in the Therapy of Obesity. Stewart G Albert*1, Arshag D Mooradian1, Angela T Cestia1, Linda S Hackney1. 1Div of Endocrinology, Dept of Intern Med, St Louis Univ Sch of Med, Saint Louis, MO. Background: An optimal goal in therapy of obesity is to lose body fat (BF) and retain lean body mass (LBM). GH is anabolic and lipolytic; obese subjects have reduced GH and insulin-like growth factor-I (IGF-I) levels. Low-dose (L-D) GH therapy, aimed at normalizing IGF-I, was added to life style modifications in therapy of obesity. The study was powered for endpoints of weight (Wt) and BF loss. Methods: 59 subjects (36±7 yrs, BMI 36.9±5.0 kg/m²) were randomized in a double-blind, placebo-controlled trial of L-D GH (Genotropin ™) for a 6-month intervention phase (6-m) followed by 3-month drug-free retention phase (9-m); 40 completed 6-m and 39 completed 9-m. Twenty-three (16w, 7m) self administered GH 200 mcg daily; after 1-month GH was increased to 400 mcg in (m) and 600 mcg daily in (w). Controls (Con) of 17 subjects (12w, 5m) administered placebo injections. Body composition was assessed by dual energy x-ray absorptiometry. All received instruction in diet, behavioral, and exercise modifications starting at baseline (0-m). Results: Wt decreased in the GH group from 100.4±13.2 at 0-m, to 98.0±15.6 at 6-m (p=0.04), and was sustained at 98.1±16.6kg at 9-m (p=0.02). Wt loss in Con was not significant. Wt loss due to GH was entirely due to loss of BF, which was greater in GH vs. Con at 6-m (-3.5±4.1 vs.-1.6±2.7 kg, p=0.0002) and at 9-m (2.8±4.4 vs.1.3±2.8 kg, p=0.002). LBM did not change in either group. GH increased IGF-I from -0.85 standard deviations (SD) (Z-score) at 0-m, to +0.09 (SD) at 6-m (p=0.0002). IGF-I did not change in Con. The IGF-I (Z-score) at 6-m correlated with change in BF(r=0.38, p=0.014). HDL cholesterol increased in the GH group from 43±13 at 0-m, to 51±11 at 6-m (p<0.001) with a return to 46±9 mg/dL at 9-m. HDL was higher in GH vs.Con at 6-m (p=0.02). In both groups, there were no changes in triglycerides, LDL, VLDL, glucose, insulin, insulin sensitivity (HOMA or QUICKI), resting energy expenditure, or blood pressure. GH was well tolerated; 1 subject dropped out due to edema. Conclusions: Normalization of IGF-I levels with L-D GH therapy was well tolerated, and associated with weight loss of BF, no change in LBM, and improved lipid profile. The weight effects were retained for 3-m after discontinuation of therapy. L-D GH therapy may be considered as an adjuvant to a clinically necessary weight loss program. This trial was supported by a clinical grant from Pharmacia & Upjohn CLINICAL ORAL: Growth Hormone, Cardiovascular Risk & Malignancy (1:00 PM - 2:30 PM) Presentation Date: 6/20/2003, Time: 1:30 PM; Location: Ballroom A
Growth Hormone, Cardiovascular Risk & Malignancy OR20-3 News Summary Growth hormone helps obese people lose weight and improves cholesterol levels Obese people who took moderate doses of growth hormone lost weight, composed solely of body fat, and maintained muscle mass, according to a new study being presented on Friday, June 20, at The Endocrine Society’s 85th Annual Meeting in Philadelphia. In addition, levels of high-density lipoprotein (HDL) cholesterol – the “good” cholesterol – increased, which may offer some protection against developing heart disease. Obesity is a major health risk in the United States and may affect as much as 30 percent of the population. It is associated with complications of liver, lung and heart disease and increases the risk for diabetes. Several medicines are approved for weight loss, and researchers believe that growth hormone holds future potential to join these drugs as weight-loss therapy in the obese. When people are obese, their bodies re-adjust their hormone balance. One of the hormones to go down is growth hormone. When growth hormone is low, the body tends to accumulate body fat, and lose lean body mass like muscle. When people try to lose weight, the low levels of growth hormone may interfere with their goals. If they lose muscle, they may not have the energy to exercise. In the past when doctors used growth hormone as a medicine to restore the body levels, the doses were too high. People had side effects and did not want to continue the therapy. Therefore, researchers at St. Louis University School of Medicine in St. Louis, Mo., led by Dr. Stewart G. Albert, wanted to study the effects of providing growth hormone at a more balanced dose. They screened 59 people between the ages of 20 and 45 (with an average of 36 years) with obesity, and 39 people completed the study. The participants were about 40 percent over weight, as calculated as a body mass index of 37. They were randomized to receive either human growth hormone or a placebo by nightly injection for six months, followed by three months of receiving no drugs. There were 23 participants (16 women and 7 men) who received the drug, and 17 (12 women and 5 men) received the placebo. The dose of growth hormone was calculated to replace the normal amount of growth hormone the body would make if there were no obesity. Body weight, body fat, and resting metabolic weight were measured. Those who took growth hormone lost total body weight of about 2.4 kg (about 5.25 pounds). This weight loss was all due to the loss of body fat; they did not lose any muscle mass. Of the fat loss, most of it was due to loss of fat in the abdominal area. HDL levels increased in the group taking growth hormone by about 19 percent. There was no change in the low-density lipoprotein (LDL) cholesterol, the “bad” cholesterol. Only one study participant had a side effect – swelling – from taking growth hormone, and the drug was discontinued. The researchers do not know why people lost weight – whether their appetite decreased or their energy increased because they maintained their muscle mass and were able to exercise. The research was supported by a clinical grant from Pharmacia.
Growth Hormone, Cardiovascular Risk & Malignancy OR20-5 Does GH Treatment Increase the Risk To Develop a Malignant Neoplasm? Experience from KIGS. Patrick Wilton*1, Anders Mattsson1, Kerstin Albertsson-Wikland2, Christopher Cowell3, Anthony Price4, Edward 0 Reiter5, Michael B Ranke6. 1KIGS/KIMS Outcomes Res, Pharmacia AB, Stockholm, Sweden; 2Dept of Peds, Univ of Gothenburg, Gothenburg, Sweden; 3Inst of Endocrinology, The Children’s Hosp at Westmead, Westmead, Australia; 4Dept of Peds, Royal Mancherster Children’s Hosp, Manchester, United Kingdom; 5Dept of Peds, Baystate Med Ctr Children’s Hosp, Springfield, MA; 6Kinderklinik Sek Paed Endokrinology, Klinikum Schnarrenberg, Tuebingen, Germany. Based on two cases each of colon cancer and Hodgkin disease in children treated with pituitary growth hormone Swerdlow et al (The Lancet 2002; 360:273) suggested that there was an increased mortality of neoplasms associated with GH treatment. The aim of the present study was to analyse the risk of de novo neoplasms in KIGS (Pharmacia International Growth Database). By January 2003 there were 40 451 non-tumour patients included in KIGS with at least a baseline and one return visit on GH, idiopathic GHD (n= 22 511), Turner syndrome (TS) (n=4 923), Langerhans cell histiocytosis (LCH) (n=162), kidney transplanted (n=123) and other diagnoses (n=12 957) and with a total GH treatment time of 140 816 years of which 110 177 years were in KIGS. There were in total 26 patients reported with a de novo neoplasm, eight in IGHD, two in organic GHD, five in TS, four in LCH, three in renal transplant group and four in four other diagnosis. There were four renal carcinomas of which three were in renal transplants, three lymphomas, three germinomas of which two were in LCH, two acute myelocytic leukemias and 14 other single neoplasms. Standardized incidence ratio for the whole cohort, but patients with LCH or renal transplants and in three big subgroups has been calculated age, sex and country adjusted and is shown in Table. Conclusions: There was no evidence of an increased incidence of neoplasm in GH trated patients, but longer follow-up is recommended. CLINICAL ORAL: Growth Hormone, Cardiovascular Risk & Malignancy (1:00 PM - 2:30 PM) Presentation Date: 6/20/2003, Time: 2:00 PM; Location: Ballroom A
Growth Hormone, Cardiovascular Risk & Malignancy OR20-5 News Summary Growth hormone use in children does not increase risk of cancer A database that collects information about growth hormone use among children shows that the rate of cancer in this group is no greater than that of similar children not taking this therapy, putting to rest an ongoing concern, according to a new study being presented on Friday, June 20, at The Endocrine Society’s 85th Annual Meeting in Philadelphia. The researchers believe that this finding will be of great interest to physicians treating children with growth hormone. Children and adolescents with diseases that disturb the growth hormone release from the pituitary gland have been treated with biosynthetic growth hormone since 1985. The hormone is identical to that produced in the gland; therefore, it is not surprising that very few side effects are reported. When a child develops cancer, however, researchers have wondered if growth hormone could encourage faster growth. KIGS, the Pharmacia International Growth Database, is a database where physicians from all over the world can send in data on their growth hormone–treated patients, after permission from the patient and parents. Information, which could identify a specific patient, is never submitted to the database. The aim of the current multi-center, international study, led by Dr. Patrick Wilton, was to evaluate the risk of developing cancer in growth hormone–treated children and adolescents. As of January 2003, there were data on 40,451 patients in the KIGS database. Patients who had been treated for cancer before starting growth hormone were not included. The patients were treated for an average of 2.7 years. Nineteen were diagnosed with a form of cancer, which was the expected number that would have been diagnosed among children of the same ages without growth hormone treatment during a similar period of time. This study was supported by Pharmacia Corporation.
Growth Hormone, Cardiovascular Risk & Malignancy OR20-6 Neoplasms Reported during Growth Hormone Replacement in KIMS. Patrick Wilton*1, Anders Mattsson1, Roger Abs2, Bengt-Ake Bengtsson4, Ulla Feldt-Rasmussen3, Miklos Goth5, John Monson6, for KIMS International Board. 1KIGS/KIMS Outcomes Res, Pharmacia AB, Stockholm, Sweden; 2Univ Hosp, Antwerp, Belgium; 3RigsHosp., Copenhagen, Denmark; 4Sahlgrenska Hosp, Gothenburg, Sweden; 5Natl Med Ctr, Budapest, Hungary; 6St Bart.’s Hosp, London, UK Does growth hormone treatment increase the risk of neoplasia in adult with GHD? The controversial issue of the role of growth hormone (GH) in neoplasia still exists. The aim of the present study was to analyse the risk of de novo neoplasms in adult patients with GHD substituted with growth hormone enrolled in KIMS (Pharmacia International Metabolic Database). By July 2002 there were 6 428 patients (3 281 males) with at least one baseline and one return visit on GH enrolled in KIMS. Median age was 44.4 years. Total duration on GH in KIMS was 14 073 years. Etiology to GHD was NFPA (n=1 683), non-secreting adenomas (n=1 219), craniopharyngioma (n=765), other cranial tumours (n=428), idiopathic GHD (n=981) and miscellaneous (n=1 532). 118 neoplasms were reported in 115 patients. (Table). The increased standardized incidence ratio found in skin cancers and cranial tumours were most likely because the patients were under close surveillance, but also that in the largest group of patients in KIMS, pituitary adenomas, there is an inherent increased risk of neoplasia. The high SIR based on two cases of carcinoid is influenced by an inherent risk and not associated with GH replacement. Conclusions: There is no evidence in KIMS that GH replacement in adult GHD increases the risk to develop a malignant neoplasm. However, longer follow-up is recommended. CLINICAL ORAL: Growth Hormone, Cardiovascular Risk & Malignancy (1:00 PM - 2:30 PM) Presentation Date: 6/20/2003, Time: 2:15 PM; Location: Ballroom A
Growth Hormone, Cardiovascular Risk & Malignancy OR20-6 News Summary Lifelong use of growth hormone does not appear to increase risk of cancer A registry of adults taking growth hormone shows that the incidence of cancer is not significantly higher in this group than in the general population, which answers a question that has been proposed by researchers, according to a new study being presented on Friday, June 20, at The Endocrine Society’s 85th Annual Meeting in Philadelphia. Growth hormone was originally used to treat children with a disease of the pituitary gland, which normally produces this hormone. Among other symptoms of a growth hormone deficiency, these children increase very slowly in height and can end up one or two feet below normal height as adults. Research has shown that growth hormone has to be injected also in adult life to keep a normal metabolism. Nowadays, ten thousands of adults around the world are treated with growth hormone. There are very few side effects reported with biosynthetic growth hormone, which is not surprising because the compound is an exact copy of the growth hormone produced in normal pituitary glands. However, in the case of a growth hormone–deficient patient developing cancer, researchers have questioned if growth hormone could help the cancer to grow faster. The aim of the current multi-center, international study, led by Dr. Patrick Wilton, was to investigate whether adults with growth hormone deficiency and treated with biosynthetic hormone develop symptoms of cancer more often than people without a growth hormone disease. Physicians from 28 countries around the world who are treating patients with growth hormone are sending data, with patient consent, about possible side effects, including cancer, to a database called KIMS, Pharmacia International Metabolic Database. Information that could identify a specific patient is not submitted to the database. As of July 2002, there were data from 6,428 patients collected. The average time on growth hormone treatment was 2.2 years. A cancer was diagnosed after the first six months of growth hormone treatment in 82 patients, which was not more than would be diagnosed in the same number of normal people of the same ages during the same number of years of observation. Two types of cancers, skin cancers and brain tumors, were, however, found in higher numbers than expected. The most likely explanation of this is that the patients were on regular follow-up visits to their doctors, and small cancers with no symptoms were found. In normal people, most cancers are found when there are symptoms compelling them to see the doctor or through a standard screening program, such as for breast cancer. The researchers note that a longer follow-up period is needed to confirm these early conclusions. This study was supported by Pharmacia Corporation.
Growth Hormones I P2-344 The Incidence of Malignant Disease and Cardiovascular Morbidity in Hypopituitary Patients with or without Growth Hormone Replacement Therapy. Johan Svensson*1, Bengt-Ake Bengtsson1, Thord Rosen1, Anders Oden2, Gudmundur Johannsson1. 1Res Ctr for Endocrinology and Metab, Sahlgrenska Univ Hosp, Goteborg, Sweden; 2Kungalv, Valler, Romelanda, Sweden. Background: Methods. Results. Conclusion. CLINICAL POSTER: Growth Hormones I (11:00 AM - 12:00 PM and 2:30 PM - 3:30 PM) Presentation Date: Friday, June 20, 2003
Growth Hormones I P2-344 News Summary Growth hormone treatment shows lower risk of cancer and heart problems for people with pituitary hormone deficiency, strokes still an issue In patients with low levels of pituitary hormones, those who were treated with growth hormone had a lower risk of cancer, heart disease and strokes, according to a study being presented on Friday, June 20, at The Endocrine Society’s 85th Annual Meeting in Philadelphia. Even so, say researchers, strokes were still slighly increased in those taking growth hormone when compared to the general population. Hypopituitarism often causes deficiency of several hormones, including growth hormone. The effects of growth hormone replacement therapy in adults on overall mortality, cardiovascular morbidity and the rate of malignancies are unknown. To study this issue, Dr. Johan Svensson and colleagues in Göteborg and Romelanda, Sweden, conducted a retrospective comparison of 1,411 hypopituitary adults and the normal population in terms of fatal and non-fatal health problems. In addition, a similar prospective comparison was made between 289 hypopituitary patients on long-term growth hormone replacement therapy and the general population. Average length of treatment was 60 months. The researchers found that hypopituitary patients without growth hormone replacement had an increased rate of malignancies, with a predominance of colorectal cancer, suggesting that factors other than growth hormone is of importance for the risk of cancer in this patient group. In hypopituitary women, growth hormone replacement appeared to be protective against fatal heart attacks with rapid time courses. The rate of cerebrovascular events, such as strokes, was increased in hypopituitary adults without growth hormone replacement therapy and also tended to be increased in hypopituitary adults on growth hormone replacement therapy, demonstrating that factors other than growth hormone in the overall treatment are of importance for the outcome of this patient group. This work was sponsored by the Swedish Medical Research Council.
Growth Hormones II P3-495 Body Mass Index Determines Evoked GH Responsiveness in 57 Normal Healthy Male Subjects: A Novel Diagnostic Challenge. Vivien S Bonert*1,2, Janet D Elashoff3, Rhodora G Enriquez1, Shlomo Melmed1,2. 1Endocrinology/Med, Cedars-Sinai Med Ctr, Los Angeles, CA; 2UCLA Sch of Med, Los Angeles, CA; 3Biostatistics Core Services, Research Inst, Cedars- Sinai Med Ctr, Los Angeles, CA. Normal spontaneous and evoked GH secretion are determined by multiple factors including gender, age, ethnicity and body mass index (BMI). GH responses to GH secretagogs, as well as spontaneous 24 -hr GH release are decreased in obesity. However, IGF-1 concentrations are within the age-adjusted normal range, despite GH insufficiency associated with obesity . Evoked GH levels in obese normal subjects may be as low as those in panhypopituitary patients with severe GH deficiency (GHD).The mean GH peak after provocative GH stimulation with growth hormone releasing hormone/arginine (GHRH+ARG) is 70% lower in obese subjects(BMI>30kg/m²) than in normal individuals(1). This study evaluates the clinical utility of provocative GH testing for the diagnosis of GHD in normal healthy male subjects. Peak GH responses to GHRH+ARG were evaluated in fifty-seven healthy normal male subjects aged 20-60 years, with BMI from 21-40.7. BMI< 25 is defined as normal, 25-29.9 as overweight, >30 as obese. After an overnight fast, GHRH (1ug/kg iv) and arginine (0.5g/kg iv over 30 mins) were administered to subjects and GH levels measured at -30, 0, +30, +60, +90, +120 mins. BMI correlated significantly with peak GH response at 30 (Pearson r = -0.50) and 60 minutes (r = -0.59) after GHRH+ARG. Age correlated moderately with both BMI (r=0.35) and peak GH responses at 30 (r=-0.33) and 60 min(r=-0.39), but did not contribute significantly to the prediction of GH response after BMI was entered into the regression.Using the maximum of the 30 min and 60 min GH responses to GHRH+ARG and classifying peak values < 9 ng/ml as abnormal, 35% of subjects with BMI > 25 failed to respond. In contrast only 1 of 20 subjects with normal BMI (< 25) failed to evoke GH. Normalized IGF-1 values (derived by subtracting the mean for their decade divided by the standard deviation) did not correlate with BMI (r=0.19). Conclusion: These results indicate that BMI is a major determinant of evoked GH response. Peak GH responses are significantly suppressed in normal subjects with even very mildly elevated BMI (i. e. slightly overweight subjects) . GH provocative testing for diagnosis of GH deficiency in patients with elevated BMI will not accurately distinguish normal from deficient GH responses. BMI should be measured and evoked GH responses appropriately interpreted for all adult subjects undergoing GH testing for GH deficiency. Supported by Pharmacia CLINICAL POSTER: Growth Hormones II (11:00 AM - 12:00 PM and 2:30 PM - 3:30 PM) Presentation Date: Saturday, June 21, 2003
Growth Hormones II P3-495 News Summary Growth hormone test is not reliable measure in overweight and obese The growth hormone (GH) stimulation test, which measures for appropriate levels of naturally occurring GH, may not be a reliable predictor of GH deficiency in healthy people with any amount of elevated body mass index (BMI), according to a new study being presented on Saturday, June 21, at The Endocrine Society’s 85th Annual Meeting in Philadelphia. Several factors – including, age, ethnic origin and obesity – influence the level GH in the bloodstream. Individuals with GH resistance or known pituitary disease may not produce enough GH. In children. this can cause short stature; in adults, GH insufficiency can lead to changes in muscle mass, cholesterol levels and bone strength. GH administration is advised only for people who are truly GH deficient. Patients suspected of producing too little GH can undergo testing by injecting substances that stimulate the pituitary gland to secrete GH. Evoked GH levels in response to these stimulants are then measured. It has been shown, however, that obesity can decrease GH levels in the body to values as low as in patients with pituitary damage. Dr. Vivien Bonert and colleagues at Cedars-Sinai Medical Center and the UCLA School of Medicine, both in Los Angeles, designed a study to establish the degree of obesity that would affect GH levels. Sixty healthy males, with a body mass index (BMI) ranging from 21–40.7 were given GH stimulation tests, with subsequent measurement of GH levels. BMI relates weight to height. A BMI of less than 25 is defined as normal, 25–29.9 is overweight and greater than 30 is considered obese. The researchers found that even a slight increase in weight can markedly decrease the GH response to stimulation, which they believe should be an important consideration in interpreting test results. The stimulation test may not be a valid diagnostic predictor of GH deficiency in healthy people with any BMI elevation because of the incidence of the false test response caused by being overweight. This research is supported by Pharmacia.
Growth Hormone Measurement & Secretion OR32-5 A Multicenter, Open-Label Study of Pegvisomant in Patients with Acromegaly Converting from Long-Acting Octreotide. Peter J Trainer*1, Pamela U Freda2, Michael O Thorner3, Aart J van der Lely4, David L Kleinberg5, Pia Burman6, Keith E Friend7. 1Dept of Endocrinology, Christie Hosp, Manchester, United Kingdom; 2Dept of Med, Columbia Univ, Coll of Physicians & Surgeons, New York, NY; 3Dept of Intern Med, Univ of Virginia Hlth Syst, Charlottesville, VA; 4Dept of Intern Med, Erasmus Med Ctr, Rotterdam, Netherlands; 5Dept of Med, New York Univ Med Ctr, New York, NY; 6Global Med Affairs, Endocrine Care, Pharmacia Corp, Stockholm, Sweden; 7Global Med Affairs, Endocrine Care, Pharmacia Corp, Peapack, NJ. Goals of acromegaly therapy include adequate biochemical control and reducing signs and symptoms. The major classes of compounds available to achieve these clinical objectives are somatostatin analogues such as octreotide, and GH receptor antagonists, represented by the recently approved agent, pegvisomant (Somavert®). We report the efficacy of pegvisomant to decrease total serum IGF-I levels in a cohort of 48 patients with acromegaly (23 women, median age 46.5, range 21-78) who were on treatment with the long-acting octreotide, Sandostatin LAR® (LAR). During pegvisomant treatment at each monthly visit, IGF-I was measured (Nichols acid extraction), a sign and symptoms score (SSS) completed (5 features of acromegaly each rated on a scale of 0 to 8; total score out of 40, higher score=more symptoms), and ring size measured. All patients initially participated in a placebo-controlled trial of pegvisomant (limb 1, L1). The patients were then placed on LAR (L2). Thereafter, patients were converted back to pegvisomant (L3). The minimum duration of each treatment limb was 3 months. CLINICAL ORAL: Growth Hormone Measurement & Secretion (1:00 PM - 2:30 PM) Presentation Date: 6/21/2003, Time: 2:00 PM; Location: Exhibit Hall C
Growth Hormone Measurement & Secretion OR32-5 News Summary New drug shows improvements over existing therapy to treat life-shortening disease In people with a life-shortening disease called acromegaly, a newly approved medication effectively controlled levels of a hormone that contributes to the disabling symptoms and the long-term health problems associated with the disease, according to a study being presented on Saturday, June 21, at The Endocrine Society’s 85th Annual Meeting in Philadelphia. The drug, pegvisomant (Somavert®), controlled levels of this hormone, insulin-like growth factor I (IGF-I), even in patients who did not respond to another drug used to treat acromegaly. Acromegaly is a serious, life-shortening disease triggered by over-secretion of growth hormone, most often caused by a pituitary tumor. This excess of growth hormone leads to overproduction of a second hormone, IGF-I, that contributes to the disabling symptoms and the long-term health problems associated with the disorder. Patients with acromegaly often suffer from headaches, excessive sweating, soft-tissue swelling, joint disorders and, perhaps most striking, a progressive coarsening of facial features and enlargement of the hands, feet and jaw. Patients with acromegaly face a death rate two-to-four times higher than the average person, due to such serious long-term complications as heart and respiratory disease, diabetes and some forms of cancer. Pegvisomant is the first in a new class of medicines called growth hormone receptor antagonists and the only medicine designed to specifically block the effects of excess growth hormone in acromegaly. Pegvisomant was approved on March 2003 by the U.S. Food and Drug Administration for the treatment of acromegaly. Dr. Peter Trainer and colleagues from multiple institutions studied 48 men and women with acromegaly. Patients included in the study initially received pegvisomant as part of a previous clinical trial. Then they were given long-acting octreotide (Sandostatin LAR®) – also used to treat acromegaly – for at least three months. This study evaluated the efficacy of converting these patients from long-acting octreotide to pegvisomant. Levels of IGF-I, the severity of five clinical signs and symptoms and the ring size of the patients were measured once a month. After six months of pegvisomant treatment, 88 percent of patients had normal levels of IGF-I, compared with 46 percent of patients in the octreotide phase and 96 percent of patients in the previous pegvisomant trial. Patients also had significantly fewer signs and symptoms and smaller ring size during pegvisomant therapy compared to octreotide therapy. Results of this study, say researchers, also indicate that measuring the levels of IGF-I in the blood of acromegaly patients provides an accurate marker of disease activity, as these levels were closely correlated with clinical markers of the disease, such as signs and symptoms and ring size. This study was supported by Pharmacia Corporation.
Growth Hormone Measurement & Secretion OR32-3 Development of Ultra Sensitive Human Growth Hormone (hGH) Isoform Specific Immunoassays and Their Use To Detect Doping with Recombinant hGH. Zida Wu*1, Martin Bidlingmaier1, Alexandra Keller2, Eberhard Keller2, Christian J Strasburger1. 1Intern Med, Klinikum der Ludwig-Maximilians-Univ, Munich, Bavaria, Germany; 2Klinik fur Kinder und Jugendliche, Univ Leipzig, Leipzig, Saxonia, Germany. Immunoassays specific for hGH isoforms have been shown to be useful tools in the detection of doping with recombinant hGH (rhGH) (1, 2). To improve the approach, ultra sensitive immunoassays specific for 22 kD-, 20 kD- and pituitary derived-hGH have been established using enhanced chemiluminescence techniques. Combined with biotinylated high affinity mAbs, streptavidin conjugated to multiple horseradish peroxidase molecules on a dextran backbone and sensitive substrates, it was possible to quantify hGH at concentrations as low as 1 pg/ml. Linear working range of these ultra sensitive immunoassays is between 1-1000 pg/ml, intra- and inter-assay CVs are 3.2-5.8% and 4.5-7.2% respectively. To test the power of such ultra sensitive immunoassays in doping detection, we used 35 serum samples taken from 7 subjects between 10 and 18 hours after a single injection of rhGH. These samples have low “total hGH” concentrations (<0.2 ng/ml) as determined by conventional hGH assays and the treatment with rhGH could not be detected previously. 20 serum samples from 15 normal, untreated subjects with similar concentrations of hGH were used as controls. Using the ultra sensitive 22 kD- and pituitary derived-hGH specific immuoassays, 6 out of 7 subjects treated with rhGH could be identified. The analytical methods were adapted for the analysis of urine samples, and preliminary experiments showed that 20 kDa accounted for less than 0.6% of total hGH in urine samples from rhGH treated patients (n=7), whereas 1.2-4.1% of total hGH were 20 kD hGH in urine samples from controls (n=8, p<0.01). Reference: (1) Detection of doping with human growth hormone, Wu et al., Lancet, 353: 895, 1999. (2) Development of human growth hormone (hGH) isoform specific monoclonal antibodies and their use in a possible test to detect hGH doping in sports, Wu et al., Proc 84th Meeting of the Endocrine Society, San Francisco, P3-527, 2002. This study was supported by grants from BISp (Cologne, Germany, VF 0408/03/01) and the IOC (Lausanne, Switzerland). CLINICAL ORAL: Growth Hormone Measurement & Secretion (1:00 PM - 2:30 PM) Presentation Date: 6/21/2003, Time: 1:30 PM; Location: Exhibit Hall C
Growth Hormone Measurement & Secretion OR32-3 News Summary Improved method for detecting growth hormone use by athletes may put stop to abuse A new method to differentiate naturally occurring growth hormone (hGH) from biosynthetic growth hormone (rhGH), used in doping in sports, is now more sensitive and can potentially be used to identify rhGH abuse among athletes, according to a new study being presented on Saturday, June 21, at The Endocrine Society’s 85th Annual Meeting in Philadelphia. Growth hormone has been estimated as one of the most frequently abused drugs in sport. Although hGH, as produced by the human pituitary gland, is listed as an prohibited class E substance by the International Olympic Committee (IOC), no official test for the detection of GH abuse has been implemented to date. Due to the similarities between rhGH and endogenous GH, differences have been believed to be undetectable. With the support of the IOC and the German National Institute for Sport Science, Dr. Zida Wu and colleagues in Munich and Leipzig, Germany, are developing methods to detect the abuse of human growth hormone for doping in sports. One of their strategies is developing monoclonal antibodies and immunoassays able to recognize the difference between rhGH and hGH. The most widely abused form of growth hormone is the pure preparation produced by recombinant DNA technology. This protein has a molecular mass of 22 kilo Dalton (kDa). Human pituitary glands, however, produce not only a form, called an isoform, of GH that has identical or very similar amino acid sequences to those of rhGH but also hGH dimers – two molecules of hGH complex – and 20 kDa hGH – hGH lacking 15 amino acid residues. These researchers have developed monoclonal antibodies (mAbs) that can recognize growth hormone, distinguishing natural from biosynthetic, even though the differences are very minor. They selected monoclonal antibodies with a high affinity to recombinant 22 kDa hGH but with low affinity to pituitary-derived hGH. They also selected monoclonal antibodies with a high affinity to pituitary-derived hGH but low affinity to recombinant 22 kDa hGH, and monoclonal antibodies that only bind 20 kD GH or hGH dimers. By using these mAbs, it was possible to establish immunoassays with high discriminatory potency. In this study, they have developed a new analysis method, with up to a 100-fold increase in sensitivity. They examined 35 blood samples taken from seven subjects between 20 and 36 hours after a single injection of rhGH. These samples have low “total hGH” concentrations, and the treatment with rhGH could not be detected previously. Using the ultra sensitive 22 kD- and pituitary derived-hGH specific immuoassays, six out of seven subjects treated with rhGH could be identified. Furthermore, the ultrasensitive assays enable them, for the first time, to analyze the hGH isoforms in urine samples. Preliminary experiments showed that 20 kDa accounted for less than 0.6 percent of total hGH in urine samples from seven rhGH treated patients, whereas 1.2–4.1 percent of total hGH were 20 kD hGH in urine samples from eight controls. This research is supported by the IOC and the German National Institute for Sport Science.
Lipids P2-223 Growth Hormone-Releasing Peptides as Inhibitors of Fatty Streaks Formation:A New Therapy for Atherosclerosis. Huy Ong*1,2, Andre Tremblay3,4, Maria Febbraio5, Roy Silverstein5, Roberta Avallone1,3, Khadija Iken1, Yanfe Wang1, Kim Bujold1, Annie Demers1, Martin G Sirois6, Romano Deghenghi7, Sylvie Marleau1. 1Fac of Pharmacy, Univ de Montreal, Montreal, QC, Canada; 2Dept of Pharmacol, Univ de Montreal, Montreal, QC, Canada; 3Ctr de Recherche, Hosp Ste Justine, Montreal, QC, Canada; 4Dept Gynecol&Ob, Univ de Montreal, Montreal, QC, Canada; 5Weill Med Coll, Cornell Univ, New York, NY; 6Montreal Heart Inst, Montreal, QC, Canada; 7Europeptides, Argenteuil, France. We have 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 cells development, long term studies of the effects of GHRPs administration on atherosclerotic lesion development were conducted in ApoE null mice, and in ApoE/CD36 double null mice. Methods: Mice were put on a high fat high cholesterol (HFHC) diet for a period of 12 weeks.and received daily s.c. injections of 0,9% NaCl or either HEX (100 mg/kg) or EP 80317 (300µg/kg). At 18 weeks, mice were anesthetized 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 blot.as well as for RNA extraction for RT- PCR analysis of PPARg-LXRa-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. Results: A significant reduction of lesion area, by 28% and 47%, was observed following treatment with HEX and EP 80317, in ApoE null mice respectively.The reduced lesion area in ApoE null mice was associated with a decrease in total plasma cholesterol (31%) and non HDL cholesterol as compared to controls. HDL cholesterol tended to increase in ApoE null mice by 65% and 73% following treatment with HEX and EP 80317, respectively. Both GHRPs reduced ox-LDL induced peritoneal macrophage accumulation by 39% in ApoE null mice. This reduction was paralleled with the increase of the expression of genes PPARg, LXRa and ABCA1. Conclusions: 1)GHRPs protect ApoE null mice from developing fatty streaks lesions. 2)The anti-atherosclerotic effect of GHRPs is 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.3).The protective effect of GHRPs are associated with favourable modulation in plasma lipid profile. GHRPs might be an interesting alternative in the treatment of atherosclerosis and hypercholesterolemia. BASIC POSTER: Lipids (11:00 AM - 12:00 PM and 2:30 PM - 3:30 PM) Presentation Date: Friday, June 20, 2003
Lipids P2-223 News Summary New family of drugs shows success in preventing atherosclerosis in early studies Growth hormone–releasing peptides (GHRPs) prevent fatty streaks and atherosclerotic lesions –precursors to heart disease – from forming in mice, according to a new study being presented on Friday, June 20, at The Endocrine Society’s 85th Annual Meeting in Philadelphia. This discovery may open new perspectives for the treatment of atherosclerosis, also known as hardening of the arteries. In recent years, the inflammatory component of atherosclerosis has been revealed. This inflammatory component is associated with the migration of white blood cell subtypes, the monocytes, into the inner lining of arteries. In the arterial-prone sites, the monocytes are transformed into resident cells named macrophages and acquire the ability to engulf lipids – fat or fat-like substances. Lipid-laden macrophages are known as foam cells and are key elements of the atherosclerotic lesion. Oxidized lipoproteins are the major lipids taken up by macrophages through their binding to scavenger receptors, called CD36. The GHRPs that have initially developed as growth hormone secretagogues – which stimulate secretion of growth hormone –have shown to exert a protective effect in preventing the foam cell formation. Researchers in Montreal, New York City and Argenteuil, France, led by Dr. Huy Ong, have uncovered that GHRPs – a family of small synthetic peptides that are ligands of CD36 – exert a negative modulatory effect on fatty streak formation and lesion development in ApoE-null mice, a genetic model of atherosclerosis. They arrived at this conclusion by studying the mice, which were put on a high fat, high cholesterol (HFHC) diet starting at six weeks of age. The mice received daily injections for 12 weeks of 0.9 percent NaCl (control) or either one of the two GHRPs, hexarelin (100 μg/kg) and EP80317 (300 μg/kg). At 18 weeks, blood was collected for plasma lipid profile analysis and aortic lesions were evaluated. The effect of GHRPs was associated with a decrease in CD36 expression on macrophages and an increase in the expression of factors involved in the metabolism and flow of cholesterol from the macrophages. This protective effect also parallels with a favourable modulation of plasma lipid and cholesterol profiles. This is the first report on the clear-cut inhibitory effect of GHRPs on fatty streak formation. The potential use of these small synthetic peptides as antiatherogenic agents alone or in combination with statins, say the researchers, might offer a unique alternative for the reduction of atherosclerotic plaque formation, thus reducing the acute clinical complications of atherosclerosis, including heart attack and stroke. This study is supported by the Canadian Institutes of Health Research program and by Europeptides of Argenteuil, France.
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