Still, costs of treatment in terms of money, effort, and perhaps quality of life are substantial. Treatment of children usually involves daily injections of growth hormone, usually for as long as the child is growing. Lifelong continuation may be recommended for those most severely deficient as adults. Most pediatric endocrinologists monitor growth and adjust dose every 3–4 months. Assessing the psychological value of treatment is difficult, but most children and families are enthusiastic once the physical benefits begin to be seen. Treatment costs vary by country and by size of child, but $US 10,000 to 30,000 a year is common. Little except the cost of treating severely deficient children is controversial, and most children with severe growth hormone deficiency in the developed world are offered treatment, although most accept. HGH deficiency in adults The Endocrine Society has recommended that adult patients diagnosed with growth hormone deficiency (GHd) be administered an individualized GH treatment regimen.Molitch ME et al. (2011) Evaluation and Treatment of Adult Growth Hormone Deficiency:An Endocrine Society Clinical Practice Guideline The Endocrine Society, 2011. First published in Journal of Clinical Endocrinology & Metabolism, 96(6):1587–1609. With respect to diagnosis, their guidelines state that "adults patients with structural hypothalamic/pituitary disease, surgery or irradiation in these areas, head trauma, or evidence of other pituitary hormone deficiencies be considered for evaluation for acquired GHd" and that "idiopathic GHd in adults is very rare, and stringent criteria are necessary to make this diagnosis. Because in the absence of suggestive clinical circumstances there is a significant false-positive error rate in the response to a single GH stimulation test, we suggest the use of two tests before making this diagnosis." GH replacement therapy can provide a number of measurable benefits to GH-deficient adults. These include improved bone density, increased muscle mass, decrease of adipose tissue, faster hair and nail growth, strengthened immune system, increased circulatory system, and improved blood lipid levels, but long term mortality benefit has not yet been demonstrated. A peer-reviewed article published in 2010 indicates that "Growth hormone (GH) replacement unequivocally benefits growth, body composition, cardiovascular risk factors and quality of life. Less is known about the effects of GH on learning and memory." Other As of 2004, GH has been approved by the U.S. Food and Drug Administration for treatment of other conditions such as: In adults, wasting (or cachexia) caused by AIDS. Turner syndrome epitomizes the response of non-deficient shortness. At doses 20\% higher than those used in GH deficiency, growth accelerates. With several years of treatment the median gain in adult height is about on this dose. The gains appear to be dose-dependent. It has been used successfully in toddlers with Turner syndrome, as well as in older girls. Short-stature homeobox gene deficiency Chronic kidney failure results in many problems, including growth failure. GH treatment for several years both before and after transplantation may prevent further deceleration of growth and may narrow the height deficit, though even with treatment net adult height loss may be about Prader–Willi syndrome, a generally non-hereditary genetic condition, is a case where GH is prescribed for benefits in addition to height. GH is one of the treatment options an experienced endocrinologist may use when treating a child with PWS. GH can help children with PWS in height, weight, body mass, strength, and agility. . Reports have indicated increase of growth rate (especially in the first year of treatment) and a variety of other positive effects, including improved body composition (higher muscle mass, lower fat mass); improved weight management; increased energy and physical activity; improved strength, agility, and endurance; and improved respiratory function. The Prader-Willi Syndrome Association (USA) recommends that a sleep study be conducted before initiating GH treatment in a child with PWS. At this time there is no direct evidence of a causative link between growth hormone and the respiratory problems seen in PWS (among both those receiving and those not receiving GH treatment), including sudden death. A follow-up sleep study after one year of GH treatment may also be indicated. GH (specifically Pfizer's version, Genotropin) is the only treatment that has received an FDA indication for children with PWS. The FDA indication only applies to children. Children short because of intrauterine growth retardation are small for gestational age at birth for a variety of reasons. If early catch-up growth does not occur and their heights remain below the third percentile by 2 or 3 years of age, adult height is likely to be similarly low. High-dose GH treatment has been shown to accelerate growth, but data on long term benefits and risks are limited. Idiopathic short stature (ISS) is one of the most controversial indications for GH as pediatric endocrinologists do not agree on its definition, diagnostic criteria, or limits. The term has been applied to children with severe unexplained shortness that will result in an adult height below the 3rd percentile. In the late 1990s, the pharmaceutical manufacturer Eli Lilly and Company sponsored trials of their brand of rHGH (Humatrope) in children with extreme ISS, those at least 2.25 standard deviations below mean (in the lowest 1.2 percent of the population). These boys and girls appeared to be headed toward heights of less than 63" (160 cm) and 59" (150 cm) respectively. They were treated for about 4 years and gained in adult height. Controversy has arisen as to whether all of these children were truly "short normal" children, since the average IGF1 was low. Approval of HGH for the treatment of this extreme degree of shortness led to an increase in the number of parents seeking its use to make otherwise normal children a little taller.is Adverse effects The New England Journal of Medicine published two editorials in 2003 expressing concern about off-label uses of HGH and the proliferation of advertisements for "HGH-Releasing" dietary supplements, and emphasized that there is no evidence that use of HGH in healthy adults or in geriatric patients is safe and effective - and especially emphasized that risks of long-term HGH treatment are unknown. One editorial was by Jeffrey M. Drazen, M.D., the editor-in-chief of the journal; the other one was by Dr. Mary Lee Vance, who provided the NEJM's editorial original, cautious comment on a much cited 1990 study on the use of HGH in geriatric patients with low growth hormone levels. A small but controlled study of GH given to severely ill adults in an intensive care unit setting for the purpose of increasing strength and reducing the muscle wasting of critical illness showed a higher mortality rate for the patients having received GH. The reason is unknown, but GH is now rarely used in ICU patients unless they have severe growth hormone deficiency. GH treatment usually decreases insulin sensitivity, but some studies showed no evidence for increased diabetes incidence in GH-treated adult hypopituitary patients. In past it was believed that GH treatment could increase the cancer risk; a large study recently concluded that "With relatively short follow-up, the overall primary cancer risk in 6840 patients receiving GH as adults was not increased. Elevated SIRs (which is risk of getting cancer) were found for subgroups in the USA cohort defined by age <35 years or childhood onset GH deficiency." The FDA issued a Safety Alert in August 2011, communicating the fact that a French study found that persons with certain kinds of short stature (idiopathic growth hormone deficiency and idiopathic or gestational short stature) treated with recombinant human growth hormone during childhood and who were followed over a long period of time, were at a small increased risk of death when compared to individuals in the general population of France. History Perhaps the most famous person who exemplified the appearance of untreated congenital growth hormone deficiency was Charles Sherwood Stratton (1838–1883), who was exhibited by P. T. Barnum as General Tom Thumb, and married Lavinia Warren. Pictures of the couple show the typical adult features of untreated severe growth hormone deficiency. Despite the severe shortness, limbs and trunks are proportional. By the middle of the twentieth century, endocrinologists understood the clinical features of growth hormone deficiency. GH is a protein hormone, like insulin, which had been purified from pig and cow pancreases for treatment of type 1 diabetes since the 1920s. However, pig and cow GH did not work at all in humans, due to greater species-to-species variation of molecular structure (i.e., insulin is considered more "evolutionarily conserved" than GH). Extraction for treatment Extracted growth hormone was used since the late 1950s until the late 1980s when its use was replaced by recombinant GH. In the late 1950s, Maurice Raben purified enough GH from human pituitary glands to successfully treat a GH-deficient boy. A few endocrinologists began to help parents of severely GH-deficient children to make arrangements with local pathologists to collect human pituitary glands after removal at autopsy. Parents would then contract with a biochemist to purify enough growth hormone to treat their child. Few families could manage such a complicated undertaking. In 1960, the National Pituitary Agency was formed as a branch of the U.S. National Institutes of Health. The purpose of this agency was to supervise the collection of human pituitary glands when autopsies were performed, arrange for large-scale extraction and purification of GH, and distribute it to a limited number of pediatric endocrinologists for treating GH-deficient children under research protocols. Canada, UK, Australia, New Zealand, France, Israel, and other countries establish similar government-sponsored agencies to collect pituitaries, purify GH, and distribute it for treatment of severely GH-deficient children. Supplies of this “cadaver growth hormone” were limited, and only the most severely deficient children were treated. From 1963 to 1985 about 7700 children in the U.S. and 27,000 children worldwide were given GH extracted from human pituitary glands to treat severe GH deficiency. Physicians trained in the relatively new specialty of pediatric endocrinology provided most of this care, but in the late 1960s there were only a hundred of these physicians in a few dozen of the largest university medical centers around the world. In 1977, the NPA GH extraction and purification procedure was refined and improved. A shortage of available cadaver GH worsened in the late 1970s as the autopsy rate in the U.S. declined, while the number of pediatric endocrinologists able to diagnose and treat GH deficiency increased. GH was "rationed." Often, treatment would be stopped when a child reached an arbitrary minimal height, such as . Children who were short for reasons other than severe GH deficiency were lied to and told that they would not benefit from treatment. Only those pediatric endocrinologists that remained at university medical centers with departments able to support a research program had access to NPA growth hormone. In the late 1970s, a Swedish pharmaceutical company, Kabi, contracted with a number of hospitals in Europe to buy pituitary glands for the first commercial GH product, Crescormon. Although an additional source of GH was welcomed, Crescormon was greeted with ambivalence by pediatric endocrinologists in the United States. The first concern was that Kabi would begin to purchase pituitaries in the U.S., which would quickly undermine the NPA, which relied on a donation system like blood transfusion. As the number of autopsies continued to shrink, would pathologists sell pituitaries to a higher bidder? The second offense was Kabi-Pharmacia’s marketing campaign, which was directed at primary care physicians under the slogan, “Now, you determine the need,” implying that the services of a specialist were not needed for growth hormone treatment anymore and that any short child might be a candidate for treatment. Although the Crescormon controversy in the U.S. is long forgotten, Kabi’s pituitary purchase program continued to generate scandal in Europe as recently as 2000. Recombinant human growth hormone (rHGH) In 1981, the new American corporation Genentech, after collaboration with Kabi, developed and started trials of recombinant human growth hormone (rHGH) made by a new technology (recombinant DNA) in which human genes were inserted into bacteria so that they could produce unlimited amounts of the protein. Because this was new technology, approval was deferred as lengthy safety trials continued over the next four years. In 1985, four young adults in the U.S. having received NPA growth hormone in the 1960s developed CJD (Creutzfeldt–Jakob disease). The connection was recognized within a few months, and use of human pituitary GH rapidly ceased. Between 1985 and 2003, a total of 26 cases of CJD occurred in adults having received NPA GH before 1977 (out of 7700), comparable numbers of cases occurred around the world. By 2003 there had been no cases in people who received only GH purified by the improved 1977 methods. Discontinuation of human cadaver growth hormone led to rapid Food and Drug Administration approval of Genentech’s recombinant human growth hormone, which was introduced in 1985 as Protropin in the United States. Although this previously scarce commodity was suddenly available in "bucketfuls", the price of treatment (US$ 10,000–30,000 per year) was the highest at the time. Genentech justified it by the prolonged research and development investment, orphan drug status, and a pioneering post-marketing surveillance registry for tracking safety and effectiveness (National Cooperative Growth Study).
Still, costs of treatment in terms of money, effort, and perhaps quality of life are substantial. Treatment of children usually involves daily injections of growth hormone, usually for as long as the child is growing. Lifelong continuation may be recommended for those most severely deficient as adults. Most pediatric endocrinologists monitor growth and adjust dose every 3–4 months. Assessing the psychological value of treatment is difficult, but most children and families are enthusiastic once the physical benefits begin to be seen. Treatment costs vary by country and by size of child, but $US 10,000 to 30,000 a year is common. Little except the cost of treating severely deficient children is controversial, and most children with severe growth hormone deficiency in the developed world are offered treatment, although most accept. HGH deficiency in adults The Endocrine Society has recommended that adult patients diagnosed with growth hormone deficiency (GHd) be administered an individualized GH treatment regimen.Molitch ME et al. (2011) Evaluation and Treatment of Adult Growth Hormone Deficiency:An Endocrine Society Clinical Practice Guideline The Endocrine Society, 2011. First published in Journal of Clinical Endocrinology & Metabolism, 96(6):1587–1609. With respect to diagnosis, their guidelines state that "adults patients with structural hypothalamic/pituitary disease, surgery or irradiation in these areas, head trauma, or evidence of other pituitary hormone deficiencies be considered for evaluation for acquired GHd" and that "idiopathic GHd in adults is very rare, and stringent criteria are necessary to make this diagnosis. Because in the absence of suggestive clinical circumstances there is a significant false-positive error rate in the response to a single GH stimulation test, we suggest the use of two tests before making this diagnosis." GH replacement therapy can provide a number of measurable benefits to GH-deficient adults. These include improved bone density, increased muscle mass, decrease of adipose tissue, faster hair and nail growth, strengthened immune system, increased circulatory system, and improved blood lipid levels, but long term mortality benefit has not yet been demonstrated. A peer-reviewed article published in 2010 indicates that "Growth hormone (GH) replacement unequivocally benefits growth, body composition, cardiovascular risk factors and quality of life. Less is known about the effects of GH on learning and memory." Other As of 2004, GH has been approved by the U.S. Food and Drug Administration for treatment of other conditions such as: In adults, wasting (or cachexia) caused by AIDS. Turner syndrome epitomizes the response of non-deficient shortness. At doses 20\% higher than those used in GH deficiency, growth accelerates. With several years of treatment the median gain in adult height is about on this dose. The gains appear to be dose-dependent. It has been used successfully in toddlers with Turner syndrome, as well as in older girls. Short-stature homeobox gene deficiency Chronic kidney failure results in many problems, including growth failure. GH treatment for several years both before and after transplantation may prevent further deceleration of growth and may narrow the height deficit, though even with treatment net adult height loss may be about Prader–Willi syndrome, a generally non-hereditary genetic condition, is a case where GH is prescribed for benefits in addition to height. GH is one of the treatment options an experienced endocrinologist may use when treating a child with PWS. GH can help children with PWS in height, weight, body mass, strength, and agility. . Reports have indicated increase of growth rate (especially in the first year of treatment) and a variety of other positive effects, including improved body composition (higher muscle mass, lower fat mass); improved weight management; increased energy and physical activity; improved strength, agility, and endurance; and improved respiratory function. The Prader-Willi Syndrome Association (USA) recommends that a sleep study be conducted before initiating GH treatment in a child with PWS. At this time there is no direct evidence of a causative link between growth hormone and the respiratory problems seen in PWS (among both those receiving and those not receiving GH treatment), including sudden death. A follow-up sleep study after one year of GH treatment may also be indicated. GH (specifically Pfizer's version, Genotropin) is the only treatment that has received an FDA indication for children with PWS. The FDA indication only applies to children. Children short because of intrauterine growth retardation are small for gestational age at birth for a variety of reasons. If early catch-up growth does not occur and their heights remain below the third percentile by 2 or 3 years of age, adult height is likely to be similarly low. High-dose GH treatment has been shown to accelerate growth, but data on long term benefits and risks are limited. Idiopathic short stature (ISS) is one of the most controversial indications for GH as pediatric endocrinologists do not agree on its definition, diagnostic criteria, or limits. The term has been applied to children with severe unexplained shortness that will result in an adult height below the 3rd percentile. In the late 1990s, the pharmaceutical manufacturer Eli Lilly and Company sponsored trials of their brand of rHGH (Humatrope) in children with extreme ISS, those at least 2.25 standard deviations below mean (in the lowest 1.2 percent of the population). These boys and girls appeared to be headed toward heights of less than 63" (160 cm) and 59" (150 cm) respectively. They were treated for about 4 years and gained in adult height. Controversy has arisen as to whether all of these children were truly "short normal" children, since the average IGF1 was low. Approval of HGH for the treatment of this extreme degree of shortness led to an increase in the number of parents seeking its use to make otherwise normal children a little taller.is Adverse effects The New England Journal of Medicine published two editorials in 2003 expressing concern about off-label uses of HGH and the proliferation of advertisements for "HGH-Releasing" dietary supplements, and emphasized that there is no evidence that use of HGH in healthy adults or in geriatric patients is safe and effective - and especially emphasized that risks of long-term HGH treatment are unknown. One editorial was by Jeffrey M. Drazen, M.D., the editor-in-chief of the journal; the other one was by Dr. Mary Lee Vance, who provided the NEJM's editorial original, cautious comment on a much cited 1990 study on the use of HGH in geriatric patients with low growth hormone levels. A small but controlled study of GH given to severely ill adults in an intensive care unit setting for the purpose of increasing strength and reducing the muscle wasting of critical illness showed a higher mortality rate for the patients having received GH. The reason is unknown, but GH is now rarely used in ICU patients unless they have severe growth hormone deficiency. GH treatment usually decreases insulin sensitivity, but some studies showed no evidence for increased diabetes incidence in GH-treated adult hypopituitary patients. In past it was believed that GH treatment could increase the cancer risk; a large study recently concluded that "With relatively short follow-up, the overall primary cancer risk in 6840 patients receiving GH as adults was not increased. Elevated SIRs (which is risk of getting cancer) were found for subgroups in the USA cohort defined by age <35 years or childhood onset GH deficiency." The FDA issued a Safety Communication in August 2011, stating that the evidence regarding recombinant human growth hormone and increased risk of death is inconclusive after reviewing sources including a French study found that persons with certain kinds of short stature (idiopathic growth hormone deficiency and idiopathic or gestational short stature) treated with recombinant human growth hormone during childhood and who were followed over a long period of time, compared to individuals in the general population of France. History Perhaps the most famous person who exemplified the appearance of untreated congenital growth hormone deficiency was Charles Sherwood Stratton (1838–1883), who was exhibited by P. T. Barnum as General Tom Thumb, and married Lavinia Warren. Pictures of the couple show the typical adult features of untreated severe growth hormone deficiency. Despite the severe shortness, limbs and trunks are proportional. By the middle of the twentieth century, endocrinologists understood the clinical features of growth hormone deficiency. GH is a protein hormone, like insulin, which had been purified from pig and cow pancreases for treatment of type 1 diabetes since the 1920s. However, pig and cow GH did not work at all in humans, due to greater species-to-species variation of molecular structure (i.e., insulin is considered more "evolutionarily conserved" than GH). Extraction for treatment Extracted growth hormone was used since the late 1950s until the late 1980s when its use was replaced by recombinant GH. In the late 1950s, Maurice Raben purified enough GH from human pituitary glands to successfully treat a GH-deficient boy. A few endocrinologists began to help parents of severely GH-deficient children to make arrangements with local pathologists to collect human pituitary glands after removal at autopsy. Parents would then contract with a biochemist to purify enough growth hormone to treat their child. Few families could manage such a complicated undertaking. In 1960, the National Pituitary Agency was formed as a branch of the U.S. National Institutes of Health. The purpose of this agency was to supervise the collection of human pituitary glands when autopsies were performed, arrange for large-scale extraction and purification of GH, and distribute it to a limited number of pediatric endocrinologists for treating GH-deficient children under research protocols. Canada, UK, Australia, New Zealand, France, Israel, and other countries establish similar government-sponsored agencies to collect pituitaries, purify GH, and distribute it for treatment of severely GH-deficient children. Supplies of this “cadaver growth hormone” were limited, and only the most severely deficient children were treated. From 1963 to 1985 about 7700 children in the U.S. and 27,000 children worldwide were given GH extracted from human pituitary glands to treat severe GH deficiency. Physicians trained in the relatively new specialty of pediatric endocrinology provided most of this care, but in the late 1960s there were only a hundred of these physicians in a few dozen of the largest university medical centers around the world. In 1977, the NPA GH extraction and purification procedure was refined and improved. A shortage of available cadaver GH worsened in the late 1970s as the autopsy rate in the U.S. declined, while the number of pediatric endocrinologists able to diagnose and treat GH deficiency increased. GH was "rationed." Often, treatment would be stopped when a child reached an arbitrary minimal height, such as . Children who were short for reasons other than severe GH deficiency were lied to and told that they would not benefit from treatment. Only those pediatric endocrinologists that remained at university medical centers with departments able to support a research program had access to NPA growth hormone. In the late 1970s, a Swedish pharmaceutical company, Kabi, contracted with a number of hospitals in Europe to buy pituitary glands for the first commercial GH product, Crescormon. Although an additional source of GH was welcomed, Crescormon was greeted with ambivalence by pediatric endocrinologists in the United States. The first concern was that Kabi would begin to purchase pituitaries in the U.S., which would quickly undermine the NPA, which relied on a donation system like blood transfusion. As the number of autopsies continued to shrink, would pathologists sell pituitaries to a higher bidder? The second offense was Kabi-Pharmacia’s marketing campaign, which was directed at primary care physicians under the slogan, “Now, you determine the need,” implying that the services of a specialist were not needed for growth hormone treatment anymore and that any short child might be a candidate for treatment. Although the Crescormon controversy in the U.S. is long forgotten, Kabi’s pituitary purchase program continued to generate scandal in Europe as recently as 2000. Recombinant human growth hormone (rHGH) In 1981, the new American corporation Genentech, after collaboration with Kabi, developed and started trials of recombinant human growth hormone (rHGH) made by a new technology (recombinant DNA) in which human genes were inserted into bacteria so that they could produce unlimited amounts of the protein. Because this was new technology, approval was deferred as lengthy safety trials continued over the next four years. In 1985, four young adults in the U.S. having received NPA growth hormone in the 1960s developed CJD (Creutzfeldt–Jakob disease). The connection was recognized within a few months, and use of human pituitary GH rapidly ceased. Between 1985 and 2003, a total of 26 cases of CJD occurred in adults having received NPA GH before 1977 (out of 7700), comparable numbers of cases occurred around the world. By 2003 there had been no cases in people who received only GH purified by the improved 1977 methods. Discontinuation of human cadaver growth hormone led to rapid Food and Drug Administration approval of Genentech’s recombinant human growth hormone, which was introduced in 1985 as Protropin in the United States. Although this previously scarce commodity was suddenly available in "bucketfuls", the price of treatment (US$ 10,000–30,000 per year) was the highest at the time. Genentech justified it by the prolonged research and development investment, orphan drug status, and a pioneering post-marketing surveillance registry for tracking safety and effectiveness (National Cooperative Growth Study).
R
$US 10,000 to 30,000 a year is common. Little except the cost of treating severely deficient children is controversial, and most children with severe growth hormone deficiency in the developed world are offered treatment, although most accept. HGH deficiency in adults The Endocrine Society has recommended that adult patients diagnosed with growth hormone deficiency (GHd) be administered an individualized GH treatment regimen.Molitch ME et al. (2011) Evaluation and Treatment of Adult Growth Hormone Deficiency:An Endocrine Society Clinical Practice Guideline The Endocrine Society, 2011. First published in Journal of Clinical Endocrinology & Metabolism, 96(6):1587–1609. With respect to diagnosis, their guidelines state that "adults patients with structural hypothalamic/pituitary disease, surgery or irradiation in these areas, head trauma, or evidence of other pituitary hormone deficiencies be considered for evaluation for acquired GHd" and that "idiopathic GHd in adults is very rare, and stringent criteria are necessary to make this diagnosis. Because in the absence of suggestive clinical circumstances there is a significant false-positive error rate in the response to a single GH stimulation test, we suggest the use of two tests before making this diagnosis." GH replacement therapy can provide a number of measurable benefits to GH-deficient adults. These include improved bone density, increased muscle mass, decrease of adipose tissue, faster hair and nail growth, strengthened immune system, increased circulatory system, and improved blood lipid levels, but long term mortality benefit has not yet been demonstrated. A peer-reviewed article published in 2010 indicates that "Growth hormone (GH) replacement unequivocally benefits growth, body composition, cardiovascular risk factors and quality of life. Less is known about the effects of GH on learning and memory." Other As of 2004, GH has been approved by the U.S. Food and Drug Administration for treatment of other conditions such as: In adults, wasting (or cachexia) caused by AIDS. Turner syndrome epitomizes the response of non-deficient shortness. At doses 20\% higher than those used in GH deficiency, growth accelerates. With several years of treatment the median gain in adult height is about on this dose. The gains appear to be dose-dependent. It has been used successfully in toddlers with Turner syndrome, as well as in older girls. Short-stature homeobox gene deficiency Chronic kidney failure results in many problems, including growth failure. GH treatment for several years both before and after transplantation may prevent further deceleration of growth and may narrow the height deficit, though even with treatment net adult height loss may be about Prader–Willi syndrome, a generally non-hereditary genetic condition, is a case where GH is prescribed for benefits in addition to height. GH is one of the treatment options an experienced endocrinologist may use when treating a child with PWS. GH can help children with PWS in height, weight, body mass, strength, and agility. . Reports have indicated increase of growth rate (especially in the first year of treatment) and a variety of other positive effects, including improved body composition (higher muscle mass, lower fat mass); improved weight management; increased energy and physical activity; improved strength, agility, and endurance; and improved respiratory function. The Prader-Willi Syndrome Association (USA) recommends that a sleep study be conducted before initiating GH treatment in a child with PWS. At this time there is no direct evidence of a causative link between growth hormone and the respiratory problems seen in PWS (among both those receiving and those not receiving GH treatment), including sudden death. A follow-up sleep study after one year of GH treatment may also be indicated. GH (specifically Pfizer's version, Genotropin) is the only treatment that has received an FDA indication for children with PWS. The FDA indication only applies to children. Children short because of intrauterine growth retardation are small for gestational age at birth for a variety of reasons. If early catch-up growth does not occur and their heights remain below the third percentile by 2 or 3 years of age, adult height is likely to be similarly low. High-dose GH treatment has been shown to accelerate growth, but data on long term benefits and risks are limited. Idiopathic short stature (ISS) is one of the most controversial indications for GH as pediatric endocrinologists do not agree on its definition, diagnostic criteria, or limits. The term has been applied to children with severe unexplained shortness that will result in an adult height below the 3rd percentile. In the late 1990s, the pharmaceutical manufacturer Eli Lilly and Company sponsored trials of their brand of rHGH (Humatrope) in children with extreme ISS, those at least 2.25 standard deviations below mean (in the lowest 1.2 percent of the population). These boys and girls appeared to be headed toward heights of less than 63" (160 cm) and 59" (150 cm) respectively. They were treated for about 4 years and gained in adult height. Controversy has arisen as to whether all of these children were truly "short normal" children, since the average IGF1 was low. Approval of HGH for the treatment of this extreme degree of shortness led to an increase in the number of parents seeking its use to make otherwise normal children a little taller.is Adverse effects The New England Journal of Medicine published two editorials in 2003 expressing concern about off-label uses of HGH and the proliferation of advertisements for "HGH-Releasing" dietary supplements, and emphasized that there is no evidence that use of HGH in healthy adults or in geriatric patients is safe and effective - and especially emphasized that risks of long-term HGH treatment are unknown. One editorial was by Jeffrey M. Drazen, M.D., the editor-in-chief of the journal; the other one was by Dr. Mary Lee Vance, who provided the NEJM's editorial original, cautious comment on a much cited 1990 study on the use of HGH in geriatric patients with low growth hormone levels. A small but controlled study of GH given to severely ill adults in an intensive care unit setting for the purpose of increasing strength and reducing the muscle wasting of critical illness showed a higher mortality rate for the patients having received GH. The reason is unknown, but GH is now rarely used in ICU patients unless they have severe growth hormone deficiency. GH treatment usually decreases insulin sensitivity, but some studies showed no evidence for increased diabetes incidence in GH-treated adult hypopituitary patients. In past it was believed that GH treatment could increase the cancer risk; a large study recently concluded that "With relatively short follow-up, the overall primary cancer risk in 6840 patients receiving GH as adults was not increased. Elevated SIRs (which is risk of getting cancer) were found for subgroups in the USA cohort defined by age <35 years or childhood onset GH deficiency." The FDA issued a Safety Alert in August 2011, communicating the fact that a French study found that persons with certain kinds of short stature (idiopathic growth hormone deficiency and idiopathic or gestational short stature) treated with recombinant human growth hormone during childhood and who were followed over a long period of time, were at a small increased risk of death when compared to individuals in the general population of France. History Perhaps the most famous person who exemplified the appearance of untreated congenital growth hormone deficiency was Charles Sherwood Stratton (1838–1883), who was exhibited by P. T. Barnum as General Tom Thumb, and married Lavinia Warren. Pictures of the couple show the typical adult features of untreated severe growth hormone deficiency. Despite the severe shortness, limbs and trunks are proportional. By the middle of the twentieth century, endocrinologists understood the clinical features of growth hormone deficiency. GH is a protein hormone, like insulin, which had been purified from pig and cow pancreases for treatment of type 1 diabetes since the 1920s. However, pig and cow GH did not work at all in humans, due to greater species-to-species variation of molecular structure (i.e., insulin is considered more "evolutionarily conserved" than GH). Extraction for treatment Extracted growth hormone was used since the late 1950s until the late 1980s when its use was replaced by recombinant GH. In the late 1950s, Maurice Raben purified enough GH from human pituitary glands to successfully treat a GH-deficient boy. A few endocrinologists began to help parents of severely GH-deficient children to make arrangements with local pathologists to collect human pituitary glands after removal at autopsy. Parents would then contract with a biochemist to purify enough growth hormone to treat their child. Few families could manage such a complicated undertaking. In 1960, the National Pituitary Agency was formed as a branch of the U.S. National Institutes of Health. The purpose of this agency was to supervise the collection of human pituitary glands when autopsies were performed, arrange for large-scale extraction and purification of GH, and distribute it to a limited number of pediatric endocrinologists for treating GH-deficient children under research protocols. Canada, UK, Australia, New Zealand, France, Israel, and other countries establish similar government-sponsored agencies to collect pituitaries, purify GH, and distribute it for treatment of severely GH-deficient children. Supplies of this “cadaver growth hormone” were limited, and only the most severely deficient children were treated. From 1963 to 1985 about 7700 children in the U.S. and 27,000 children worldwide were given GH extracted from human pituitary glands to treat severe GH deficiency. Physicians trained in the relatively new specialty of pediatric endocrinology provided most of this care, but in the late 1960s there were only a hundred of these physicians in a few dozen of the largest university medical centers around the world. In 1977, the NPA GH extraction and purification procedure was refined and improved. A shortage of available cadaver GH worsened in the late 1970s as the autopsy rate in the U.S. declined, while the number of pediatric endocrinologists able to diagnose and treat GH deficiency increased. GH was "rationed." Often, treatment would be stopped when a child reached an arbitrary minimal height, such as . Children who were short for reasons other than severe GH deficiency were lied to and told that they would not benefit from treatment. Only those pediatric endocrinologists that remained at university medical centers with departments able to support a research program had access to NPA growth hormone. In the late 1970s, a Swedish pharmaceutical company, Kabi, contracted with a number of hospitals in Europe to buy pituitary glands for the first commercial GH product, Crescormon. Although an additional source of GH was welcomed, Crescormon was greeted with ambivalence by pediatric endocrinologists in the United States. The first concern was that Kabi would begin to purchase pituitaries in the U.S., which would quickly undermine the NPA, which relied on a donation system like blood transfusion. As the number of autopsies continued to shrink, would pathologists sell pituitaries to a higher bidder? The second offense was Kabi-Pharmacia’s marketing campaign, which was directed at primary care physicians under the slogan, “Now, you determine the need,” implying that the services of a specialist were not needed for growth hormone treatment anymore and that any short child might be a candidate for treatment. Although the Crescormon controversy in the U.S. is long forgotten, Kabi’s pituitary purchase program continued to generate scandal in Europe as recently as 2000. Recombinant human growth hormone (rHGH) In 1981, the new American corporation Genentech, after collaboration with Kabi, developed and started trials of recombinant human growth hormone (rHGH) made by a new technology (recombinant DNA) in which human genes were inserted into bacteria so that they could produce unlimited amounts of the protein. Because this was new technology, approval was deferred as lengthy safety trials continued over the next four years. In 1985, four young adults in the U.S. having received NPA growth hormone in the 1960s developed CJD (Creutzfeldt–Jakob disease). The connection was recognized within a few months, and use of human pituitary GH rapidly ceased. Between 1985 and 2003, a total of 26 cases of CJD occurred in adults having received NPA GH before 1977 (out of 7700), comparable numbers of cases occurred around the world. By 2003 there had been no cases in people who received only GH purified by the improved 1977 methods. Discontinuation of human cadaver growth hormone led to rapid Food and Drug Administration approval of Genentech’s recombinant human growth hormone, which was introduced in 1985 as Protropin in the United States. Although this previously scarce commodity was suddenly available in "bucketfuls", the price of treatment (US$
$US 10,000 to 30,000 a year is common. Little except the cost of treating severely deficient children is controversial, and most children with severe growth hormone deficiency in the developed world are offered treatment, although most accept. HGH deficiency in adults The Endocrine Society has recommended that adult patients diagnosed with growth hormone deficiency (GHd) be administered an individualized GH treatment regimen.Molitch ME et al. (2011) Evaluation and Treatment of Adult Growth Hormone Deficiency:An Endocrine Society Clinical Practice Guideline The Endocrine Society, 2011. First published in Journal of Clinical Endocrinology & Metabolism, 96(6):1587–1609. With respect to diagnosis, their guidelines state that "adults patients with structural hypothalamic/pituitary disease, surgery or irradiation in these areas, head trauma, or evidence of other pituitary hormone deficiencies be considered for evaluation for acquired GHd" and that "idiopathic GHd in adults is very rare, and stringent criteria are necessary to make this diagnosis. Because in the absence of suggestive clinical circumstances there is a significant false-positive error rate in the response to a single GH stimulation test, we suggest the use of two tests before making this diagnosis." GH replacement therapy can provide a number of measurable benefits to GH-deficient adults. These include improved bone density, increased muscle mass, decrease of adipose tissue, faster hair and nail growth, strengthened immune system, increased circulatory system, and improved blood lipid levels, but long term mortality benefit has not yet been demonstrated. A peer-reviewed article published in 2010 indicates that "Growth hormone (GH) replacement unequivocally benefits growth, body composition, cardiovascular risk factors and quality of life. Less is known about the effects of GH on learning and memory." Other As of 2004, GH has been approved by the U.S. Food and Drug Administration for treatment of other conditions such as: In adults, wasting (or cachexia) caused by AIDS. Turner syndrome epitomizes the response of non-deficient shortness. At doses 20\% higher than those used in GH deficiency, growth accelerates. With several years of treatment the median gain in adult height is about on this dose. The gains appear to be dose-dependent. It has been used successfully in toddlers with Turner syndrome, as well as in older girls. Short-stature homeobox gene deficiency Chronic kidney failure results in many problems, including growth failure. GH treatment for several years both before and after transplantation may prevent further deceleration of growth and may narrow the height deficit, though even with treatment net adult height loss may be about Prader–Willi syndrome, a generally non-hereditary genetic condition, is a case where GH is prescribed for benefits in addition to height. GH is one of the treatment options an experienced endocrinologist may use when treating a child with PWS. GH can help children with PWS in height, weight, body mass, strength, and agility. . Reports have indicated increase of growth rate (especially in the first year of treatment) and a variety of other positive effects, including improved body composition (higher muscle mass, lower fat mass); improved weight management; increased energy and physical activity; improved strength, agility, and endurance; and improved respiratory function. The Prader-Willi Syndrome Association (USA) recommends that a sleep study be conducted before initiating GH treatment in a child with PWS. At this time there is no direct evidence of a causative link between growth hormone and the respiratory problems seen in PWS (among both those receiving and those not receiving GH treatment), including sudden death. A follow-up sleep study after one year of GH treatment may also be indicated. GH (specifically Pfizer's version, Genotropin) is the only treatment that has received an FDA indication for children with PWS. The FDA indication only applies to children. Children short because of intrauterine growth retardation are small for gestational age at birth for a variety of reasons. If early catch-up growth does not occur and their heights remain below the third percentile by 2 or 3 years of age, adult height is likely to be similarly low. High-dose GH treatment has been shown to accelerate growth, but data on long term benefits and risks are limited. Idiopathic short stature (ISS) is one of the most controversial indications for GH as pediatric endocrinologists do not agree on its definition, diagnostic criteria, or limits. The term has been applied to children with severe unexplained shortness that will result in an adult height below the 3rd percentile. In the late 1990s, the pharmaceutical manufacturer Eli Lilly and Company sponsored trials of their brand of rHGH (Humatrope) in children with extreme ISS, those at least 2.25 standard deviations below mean (in the lowest 1.2 percent of the population). These boys and girls appeared to be headed toward heights of less than 63" (160 cm) and 59" (150 cm) respectively. They were treated for about 4 years and gained in adult height. Controversy has arisen as to whether all of these children were truly "short normal" children, since the average IGF1 was low. Approval of HGH for the treatment of this extreme degree of shortness led to an increase in the number of parents seeking its use to make otherwise normal children a little taller.is Adverse effects The New England Journal of Medicine published two editorials in 2003 expressing concern about off-label uses of HGH and the proliferation of advertisements for "HGH-Releasing" dietary supplements, and emphasized that there is no evidence that use of HGH in healthy adults or in geriatric patients is safe and effective - and especially emphasized that risks of long-term HGH treatment are unknown. One editorial was by Jeffrey M. Drazen, M.D., the editor-in-chief of the journal; the other one was by Dr. Mary Lee Vance, who provided the NEJM's editorial original, cautious comment on a much cited 1990 study on the use of HGH in geriatric patients with low growth hormone levels. A small but controlled study of GH given to severely ill adults in an intensive care unit setting for the purpose of increasing strength and reducing the muscle wasting of critical illness showed a higher mortality rate for the patients having received GH. The reason is unknown, but GH is now rarely used in ICU patients unless they have severe growth hormone deficiency. GH treatment usually decreases insulin sensitivity, but some studies showed no evidence for increased diabetes incidence in GH-treated adult hypopituitary patients. In past it was believed that GH treatment could increase the cancer risk; a large study recently concluded that "With relatively short follow-up, the overall primary cancer risk in 6840 patients receiving GH as adults was not increased. Elevated SIRs (which is risk of getting cancer) were found for subgroups in the USA cohort defined by age <35 years or childhood onset GH deficiency." The FDA issued a Safety Communication in August 2011, stating that the evidence regarding recombinant human growth hormone and increased risk of death is inconclusive after reviewing sources including a French study found that persons with certain kinds of short stature (idiopathic growth hormone deficiency and idiopathic or gestational short stature) treated with recombinant human growth hormone during childhood and who were followed over a long period of time, compared to individuals in the general population of France. History Perhaps the most famous person who exemplified the appearance of untreated congenital growth hormone deficiency was Charles Sherwood Stratton (1838–1883), who was exhibited by P. T. Barnum as General Tom Thumb, and married Lavinia Warren. Pictures of the couple show the typical adult features of untreated severe growth hormone deficiency. Despite the severe shortness, limbs and trunks are proportional. By the middle of the twentieth century, endocrinologists understood the clinical features of growth hormone deficiency. GH is a protein hormone, like insulin, which had been purified from pig and cow pancreases for treatment of type 1 diabetes since the 1920s. However, pig and cow GH did not work at all in humans, due to greater species-to-species variation of molecular structure (i.e., insulin is considered more "evolutionarily conserved" than GH). Extraction for treatment Extracted growth hormone was used since the late 1950s until the late 1980s when its use was replaced by recombinant GH. In the late 1950s, Maurice Raben purified enough GH from human pituitary glands to successfully treat a GH-deficient boy. A few endocrinologists began to help parents of severely GH-deficient children to make arrangements with local pathologists to collect human pituitary glands after removal at autopsy. Parents would then contract with a biochemist to purify enough growth hormone to treat their child. Few families could manage such a complicated undertaking. In 1960, the National Pituitary Agency was formed as a branch of the U.S. National Institutes of Health. The purpose of this agency was to supervise the collection of human pituitary glands when autopsies were performed, arrange for large-scale extraction and purification of GH, and distribute it to a limited number of pediatric endocrinologists for treating GH-deficient children under research protocols. Canada, UK, Australia, New Zealand, France, Israel, and other countries establish similar government-sponsored agencies to collect pituitaries, purify GH, and distribute it for treatment of severely GH-deficient children. Supplies of this “cadaver growth hormone” were limited, and only the most severely deficient children were treated. From 1963 to 1985 about 7700 children in the U.S. and 27,000 children worldwide were given GH extracted from human pituitary glands to treat severe GH deficiency. Physicians trained in the relatively new specialty of pediatric endocrinology provided most of this care, but in the late 1960s there were only a hundred of these physicians in a few dozen of the largest university medical centers around the world. In 1977, the NPA GH extraction and purification procedure was refined and improved. A shortage of available cadaver GH worsened in the late 1970s as the autopsy rate in the U.S. declined, while the number of pediatric endocrinologists able to diagnose and treat GH deficiency increased. GH was "rationed." Often, treatment would be stopped when a child reached an arbitrary minimal height, such as . Children who were short for reasons other than severe GH deficiency were lied to and told that they would not benefit from treatment. Only those pediatric endocrinologists that remained at university medical centers with departments able to support a research program had access to NPA growth hormone. In the late 1970s, a Swedish pharmaceutical company, Kabi, contracted with a number of hospitals in Europe to buy pituitary glands for the first commercial GH product, Crescormon. Although an additional source of GH was welcomed, Crescormon was greeted with ambivalence by pediatric endocrinologists in the United States. The first concern was that Kabi would begin to purchase pituitaries in the U.S., which would quickly undermine the NPA, which relied on a donation system like blood transfusion. As the number of autopsies continued to shrink, would pathologists sell pituitaries to a higher bidder? The second offense was Kabi-Pharmacia’s marketing campaign, which was directed at primary care physicians under the slogan, “Now, you determine the need,” implying that the services of a specialist were not needed for growth hormone treatment anymore and that any short child might be a candidate for treatment. Although the Crescormon controversy in the U.S. is long forgotten, Kabi’s pituitary purchase program continued to generate scandal in Europe as recently as 2000. Recombinant human growth hormone (rHGH) In 1981, the new American corporation Genentech, after collaboration with Kabi, developed and started trials of recombinant human growth hormone (rHGH) made by a new technology (recombinant DNA) in which human genes were inserted into bacteria so that they could produce unlimited amounts of the protein. Because this was new technology, approval was deferred as lengthy safety trials continued over the next four years. In 1985, four young adults in the U.S. having received NPA growth hormone in the 1960s developed CJD (Creutzfeldt–Jakob disease). The connection was recognized within a few months, and use of human pituitary GH rapidly ceased. Between 1985 and 2003, a total of 26 cases of CJD occurred in adults having received NPA GH before 1977 (out of 7700), comparable numbers of cases occurred around the world. By 2003 there had been no cases in people who received only GH purified by the improved 1977 methods. Discontinuation of human cadaver growth hormone led to rapid Food and Drug Administration approval of Genentech’s recombinant human growth hormone, which was introduced in 1985 as Protropin in the United States. Although this previously scarce commodity was suddenly available in "bucketfuls", the price of treatment (US$