Growth hormone deficiency medical therapy: Difference between revisions

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=== Children treatment ===
=== Children treatment ===


==== '''Indications'''<ref name="pmid3481175">{{cite journal| author=Albertsson-Wikland K| title=The effect of human growth hormone injection frequency on linear growth rate. | journal=Acta Paediatr Scand Suppl | year= 1987 | volume= 337 | issue=  | pages= 110-6 | pmid=3481175 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3481175  }}</ref> ====
=== '''Indications'''<ref name="pmid3481175">{{cite journal| author=Albertsson-Wikland K| title=The effect of human growth hormone injection frequency on linear growth rate. | journal=Acta Paediatr Scand Suppl | year= 1987 | volume= 337 | issue=  | pages= 110-6 | pmid=3481175 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3481175  }}</ref> ===
* Treatment with [[Growth hormone|Growth hormone (GH)]] is indicated for children with [[Growth hormone|GH]] deficiency whose [[Epiphysis|epiphyses]] are open.  
* Treatment with [[Growth hormone|Growth hormone (GH)]] is indicated for children with [[Growth hormone|GH]] deficiency whose [[Epiphysis|epiphyses]] are open.  
* Treatment should be continued until linear growth ceases or even beyond.
* Treatment should be continued after linear growth ceases until full skeletal development.


==== Dosing ====
=== Dosing ===
* The dose for children is between 0.16 and 0.24 mg/kg/week, divided into once daily injections.
* The dose for children is between 0.16 and 0.24 mg/kg/week, divided into once daily injections.
* The dose for patients with severe [[Growth hormone|GH]] deficiency is 20 micrograms/kg/day.
* The dose for patients with severe [[Growth hormone|GH]] deficiency is 20 micrograms/kg/day.
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* Although, effective treatment with GH before [[puberty]] is more efficacious than efforts to treat patients during [[puberty]].
* Although, effective treatment with GH before [[puberty]] is more efficacious than efforts to treat patients during [[puberty]].


==== '''Monitoring''' ====
=== '''Monitoring''' ===
* Serum levels of [[Insulin-like growth factor 1|insulin-like growth factor I]] (IGF-I) should be measured several weeks after beginning [[Growth hormone|GH]] treatment or making a dose adjustment.
* Serum levels of [[Insulin-like growth factor 1|insulin-like growth factor I]] (IGF-I) should be measured several weeks after beginning [[Growth hormone|GH]] treatment or making a dose adjustment.
* This helps to avoid very high [[Insulin-like growth factor-I|IGF-I]] levels, which are thought to be associated with some of the drug's toxicity as recommended in guidelines from the Pediatric Endocrine Society (PES):<ref name="pmid27884013">{{cite journal| author=Grimberg A, DiVall SA, Polychronakos C, Allen DB, Cohen LE, Quintos JB et al.| title=Guidelines for Growth Hormone and Insulin-Like Growth Factor-I Treatment in Children and Adolescents: Growth Hormone Deficiency, Idiopathic Short Stature, and Primary Insulin-Like Growth Factor-I Deficiency. | journal=Horm Res Paediatr | year= 2016 | volume= 86 | issue= 6 | pages= 361-397 | pmid=27884013 | doi=10.1159/000452150 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27884013  }}</ref>
* This helps to avoid very high [[Insulin-like growth factor-I|IGF-I]] levels, which are thought to be associated with some of the drug's toxicity as recommended in guidelines from the Pediatric Endocrine Society (PES):<ref name="pmid27884013">{{cite journal| author=Grimberg A, DiVall SA, Polychronakos C, Allen DB, Cohen LE, Quintos JB et al.| title=Guidelines for Growth Hormone and Insulin-Like Growth Factor-I Treatment in Children and Adolescents: Growth Hormone Deficiency, Idiopathic Short Stature, and Primary Insulin-Like Growth Factor-I Deficiency. | journal=Horm Res Paediatr | year= 2016 | volume= 86 | issue= 6 | pages= 361-397 | pmid=27884013 | doi=10.1159/000452150 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27884013  }}</ref>
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* For patients with multiple [[pituitary hormone]] deficiencies, [[Adrenal gland|adrenal]] and [[thyroid]] function should be reassessed a few months after initiation of [[Growth hormone|GH]] therapy.<ref name="pmid27884013" />
* For patients with multiple [[pituitary hormone]] deficiencies, [[Adrenal gland|adrenal]] and [[thyroid]] function should be reassessed a few months after initiation of [[Growth hormone|GH]] therapy.<ref name="pmid27884013" />


==== '''Duration of therapy''' ====
=== '''Duration of therapy''' ===
* Treatment is continued at least until linear growth decreases to less than 2.0 to 2.5 cm.<ref name="pmid27884013" />
* Treatment is continued at least until linear growth decreases to less than 2.0 to 2.5 cm.<ref name="pmid27884013" />
* More than two-thirds of patients have normal results when retested for [[Growth hormone|GH]] deficiency as adults.  
* More than two-thirds of patients have normal results when retested for [[Growth hormone|GH]] deficiency as adults.  
* It is important to repeat the [[Growth hormone|GH]] stimulation test during the transition period to determine if they will require ongoing therapy.
* It is important to repeat the [[Growth hormone|GH]] stimulation test during the transition period to determine if they will require ongoing therapy.


* If GH is administered at an early age, patients can achieve [[adult]] height.<ref name="pmid16537676">{{cite journal| author=Reiter EO, Price DA, Wilton P, Albertsson-Wikland K, Ranke MB| title=Effect of growth hormone (GH) treatment on the near-final height of 1258 patients with idiopathic GH deficiency: analysis of a large international database. | journal=J Clin Endocrinol Metab | year= 2006 | volume= 91 | issue= 6 | pages= 2047-54 | pmid=16537676 | doi=10.1210/jc.2005-2284 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16537676  }}</ref>
* Patients can achieve [[adult]] height if treatment is administered at an early age.<ref name="pmid16537676">{{cite journal| author=Reiter EO, Price DA, Wilton P, Albertsson-Wikland K, Ranke MB| title=Effect of growth hormone (GH) treatment on the near-final height of 1258 patients with idiopathic GH deficiency: analysis of a large international database. | journal=J Clin Endocrinol Metab | year= 2006 | volume= 91 | issue= 6 | pages= 2047-54 | pmid=16537676 | doi=10.1210/jc.2005-2284 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16537676  }}</ref>
* Patients heights should be rechecked every four to six months to determine if the growth response is adequate.
* Patients heights should be reevaluated every four to six months to determine if the growth response is adequate.
* During the initial growth period, the 75<sup>th</sup> percentile curve for height velocity is an appropriate target to define an adequate growth response to [[Growth hormone|GH]].  
* During the initial growth period, the 75<sup>th</sup> percentile curve for height velocity is an appropriate target as an adequate growth response to [[Growth hormone|GH]].  


==== Effect of treatment ====
=== Effect of treatment ===


===== '''Growth''' =====
===== '''Growth''' =====
* Results usually better if [[Growth hormone|GH]] therapy is started in early childhood.<ref name="pmid12114235">{{cite journal| author=Carel JC, Ecosse E, Nicolino M, Tauber M, Leger J, Cabrol S et al.| title=Adult height after long term treatment with recombinant growth hormone for idiopathic isolated growth hormone deficiency: observational follow up study of the French population based registry. | journal=BMJ | year= 2002 | volume= 325 | issue= 7355 | pages= 70 | pmid=12114235 | doi= | pmc=117125 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12114235  }}</ref>The gain in height observed in children with ISS by GH treatment was maintained during 2 years of follow-up after interruption of treatment.<ref>{{Cite journal
* Results usually better if [[Growth hormone|GH]] therapy is started in early childhood.<ref name="pmid12114235">{{cite journal| author=Carel JC, Ecosse E, Nicolino M, Tauber M, Leger J, Cabrol S et al.| title=Adult height after long term treatment with recombinant growth hormone for idiopathic isolated growth hormone deficiency: observational follow up study of the French population based registry. | journal=BMJ | year= 2002 | volume= 325 | issue= 7355 | pages= 70 | pmid=12114235 | doi= | pmc=117125 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12114235  }}</ref>Increase in height observed during 2 years of follow-up after interruption of treatment.<ref>{{Cite journal


  | author = [[Z. Laron]], [[B. Klinger]], [[S. Anin]], [[A. Pertzelan]] & [[P. Lilos]]
  | author = [[Z. Laron]], [[B. Klinger]], [[S. Anin]], [[A. Pertzelan]] & [[P. Lilos]]
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===== '''Bone mass''' =====
===== '''Bone mass''' =====
* Children with [[Growth hormone|GH]] deficiency have low bone mass compared with control children.  
* Children with [[Growth hormone|GH]] deficiency have low [[bone mass]] compared with normal children.  
* To maximize bone mass, it is important to consider the continuation of GH treatment even after linear growth has ceased until full skeletal.<ref name="pmid19324976">{{cite journal| author=Conway GS, Szarras-Czapnik M, Racz K, Keller A, Chanson P, Tauber M et al.| title=Treatment for 24 months with recombinant human GH has a beneficial effect on bone mineral density in young adults with childhood-onset GH deficiency. | journal=Eur J Endocrinol | year= 2009 | volume= 160 | issue= 6 | pages= 899-907 | pmid=19324976 | doi=10.1530/EJE-08-0436 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19324976  }}</ref>  
* To maximize [[bone mass]], it is important to consider the continuation of treatment even after linear growth has ceased until full skeletal development.<ref name="pmid19324976">{{cite journal| author=Conway GS, Szarras-Czapnik M, Racz K, Keller A, Chanson P, Tauber M et al.| title=Treatment for 24 months with recombinant human GH has a beneficial effect on bone mineral density in young adults with childhood-onset GH deficiency. | journal=Eur J Endocrinol | year= 2009 | volume= 160 | issue= 6 | pages= 899-907 | pmid=19324976 | doi=10.1530/EJE-08-0436 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19324976  }}</ref>  
* GH therapy increases bone mass.<ref name="pmid1874933">{{cite journal| author=Bonjour JP, Theintz G, Buchs B, Slosman D, Rizzoli R| title=Critical years and stages of puberty for spinal and femoral bone mass accumulation during adolescence. | journal=J Clin Endocrinol Metab | year= 1991 | volume= 73 | issue= 3 | pages= 555-63 | pmid=1874933 | doi=10.1210/jcem-73-3-555 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1874933  }}</ref>Without adequate GH replacement, GH deficiency can be associated with low bone mass during adulthood.<ref name="pmid8126140">{{cite journal| author=Holmes SJ, Economou G, Whitehouse RW, Adams JE, Shalet SM| title=Reduced bone mineral density in patients with adult onset growth hormone deficiency. | journal=J Clin Endocrinol Metab | year= 1994 | volume= 78 | issue= 3 | pages= 669-74 | pmid=8126140 | doi=10.1210/jcem.78.3.8126140 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8126140  }}</ref>
* [[Growth hormone|GH]] therapy increases bone mass.<ref name="pmid1874933">{{cite journal| author=Bonjour JP, Theintz G, Buchs B, Slosman D, Rizzoli R| title=Critical years and stages of puberty for spinal and femoral bone mass accumulation during adolescence. | journal=J Clin Endocrinol Metab | year= 1991 | volume= 73 | issue= 3 | pages= 555-63 | pmid=1874933 | doi=10.1210/jcem-73-3-555 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1874933  }}</ref>Without adequate GH replacement, [[Growth hormone|GH]] deficiency can be associated with low [[bone mass]] during adulthood.<ref name="pmid8126140">{{cite journal| author=Holmes SJ, Economou G, Whitehouse RW, Adams JE, Shalet SM| title=Reduced bone mineral density in patients with adult onset growth hormone deficiency. | journal=J Clin Endocrinol Metab | year= 1994 | volume= 78 | issue= 3 | pages= 669-74 | pmid=8126140 | doi=10.1210/jcem.78.3.8126140 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8126140  }}</ref>


==== '''ADVERSE EFFECTS OF GROWTH HORMONE THERAPY''' ====
==== '''ADVERSE EFFECTS OF GROWTH HORMONE THERAPY''' ====
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===== '''Acute effects''' =====
===== '''Acute effects''' =====
* [[Headache|Headaches]] which usually are benign.
* [[Headache|Headaches]] which usually are benign.
* [[Idiopathic intracranial hypertension]] (formerly known as [[Idiopathic intracranial hypertension|pseudotumor cerebri]]), increased [[Intraocular pressure (IOP)|intraocular pressure]] usually resolves with discontinuation of [[Growth hormone|GH]] therapy. Treatment can often be resumed at a lower dose without the return of symptoms back up to standard doses.<ref name="pmid22727870">{{cite journal| author=Youngster I, Rachmiel R, Pinhas-Hamiel O, Bistritzer T, Zuckerman-Levin N, de Vries L et al.| title=Treatment with recombinant human growth hormone during childhood is associated with increased intraocular pressure. | journal=J Pediatr | year= 2012 | volume= 161 | issue= 6 | pages= 1116-9 | pmid=22727870 | doi=10.1016/j.jpeds.2012.05.024 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22727870  }}</ref>  
* [[Idiopathic intracranial hypertension]] (known as [[Idiopathic intracranial hypertension|pseudotumor cerebri]]), increased [[Intraocular pressure (IOP)|intraocular pressure]] usually resolves with discontinuation of [[Growth hormone|GH]] therapy. Treatment can often be resumed at a lower dose without the return of symptoms back up to standard doses.<ref name="pmid22727870">{{cite journal| author=Youngster I, Rachmiel R, Pinhas-Hamiel O, Bistritzer T, Zuckerman-Levin N, de Vries L et al.| title=Treatment with recombinant human growth hormone during childhood is associated with increased intraocular pressure. | journal=J Pediatr | year= 2012 | volume= 161 | issue= 6 | pages= 1116-9 | pmid=22727870 | doi=10.1016/j.jpeds.2012.05.024 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22727870  }}</ref>  
* [[Slipped capital femoral epiphysis]]: routine monitoring is recommended for suggestive symptoms such as hip and/or [[knee pain]], and changes in [[gait]]. This condition usually requires surgical pinning of the [[Epiphysis|capital femoral epiphysis]].<ref name="pmid18174706">{{cite journal| author=Darendeliler F, Karagiannis G, Wilton P| title=Headache, idiopathic intracranial hypertension and slipped capital femoral epiphysis during growth hormone treatment: a safety update from the KIGS database. | journal=Horm Res | year= 2007 | volume= 68 Suppl 5 | issue=  | pages= 41-7 | pmid=18174706 | doi=10.1159/000110474 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18174706  }}</ref>  
* [[Slipped capital femoral epiphysis]]: routine monitoring is recommended for suggestive symptoms such as hip and/or [[knee pain]], and changes in [[gait]]. This condition requires surgical pinning of the [[Epiphysis|capital femoral epiphysis]].<ref name="pmid18174706">{{cite journal| author=Darendeliler F, Karagiannis G, Wilton P| title=Headache, idiopathic intracranial hypertension and slipped capital femoral epiphysis during growth hormone treatment: a safety update from the KIGS database. | journal=Horm Res | year= 2007 | volume= 68 Suppl 5 | issue=  | pages= 41-7 | pmid=18174706 | doi=10.1159/000110474 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18174706  }}</ref>  
* Worsening of existing [[scoliosis]].<ref name="pmid8626820">{{cite journal| author=Blethen SL, Allen DB, Graves D, August G, Moshang T, Rosenfeld R| title=Safety of recombinant deoxyribonucleic acid-derived growth hormone: The National Cooperative Growth Study experience. | journal=J Clin Endocrinol Metab | year= 1996 | volume= 81 | issue= 5 | pages= 1704-10 | pmid=8626820 | doi=10.1210/jcem.81.5.8626820 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8626820  }}</ref>  
* Worsening of existing [[scoliosis]].<ref name="pmid8626820">{{cite journal| author=Blethen SL, Allen DB, Graves D, August G, Moshang T, Rosenfeld R| title=Safety of recombinant deoxyribonucleic acid-derived growth hormone: The National Cooperative Growth Study experience. | journal=J Clin Endocrinol Metab | year= 1996 | volume= 81 | issue= 5 | pages= 1704-10 | pmid=8626820 | doi=10.1210/jcem.81.5.8626820 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8626820  }}</ref>  
* [[Pancreatitis]]
* [[Pancreatitis]]
* [[Gynecomastia]]
* [[Gynecomastia]]
* Increase in the growth and pigmentation of [[Nevus|nevi,]] without [[malignant]] degeneration.<ref name="pmid8099381">{{cite journal| author=Bourguignon JP, Piérard GE, Ernould C, Heinrichs C, Craen M, Rochiccioli P et al.| title=Effects of human growth hormone therapy on melanocytic naevi. | journal=Lancet | year= 1993 | volume= 341 | issue= 8859 | pages= 1505-6 | pmid=8099381 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8099381  }}</ref>
* Increase in the growth and [[pigmentation]] of [[Nevus|nevi]].<ref name="pmid8099381">{{cite journal| author=Bourguignon JP, Piérard GE, Ernould C, Heinrichs C, Craen M, Rochiccioli P et al.| title=Effects of human growth hormone therapy on melanocytic naevi. | journal=Lancet | year= 1993 | volume= 341 | issue= 8859 | pages= 1505-6 | pmid=8099381 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8099381  }}</ref>
* [[Carpal tunnel syndrome]], [[edema]], and [[arthralgia]] are more common in adults undergoing [[Growth hormone|GH]] treatment but are unusual in children.
* [[Carpal tunnel syndrome]], [[edema]], and [[arthralgia]] are more common in adults than in children.
* Most usually occur soon after therapy is initiated, and some of these effects are probably caused by sodium and water retention.  
* Most usually occur soon after therapy is initiated, and some of these effects are probably caused by [[sodium]] and water retention.  
* [[Antibodies|Neutralizing antibodies]] against [[Growth hormone|GH]] may be formed resulting in loss of efficacy.<ref name="pmid12014526">{{cite journal| author=Pitukcheewanont P, Schwarzbach L, Kaufman FR| title=Resumption of growth after methionyl-free human growth hormone therapy in a patient with neutralizing antibodies to methionyl human growth hormone. | journal=J Pediatr Endocrinol Metab | year= 2002 | volume= 15 | issue= 5 | pages= 653-7 | pmid=12014526 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12014526  }}</ref>
* [[Antibodies|Neutralizing antibodies]] against [[Growth hormone|GH]] may be formed resulting in loss of [[efficacy]].<ref name="pmid12014526">{{cite journal| author=Pitukcheewanont P, Schwarzbach L, Kaufman FR| title=Resumption of growth after methionyl-free human growth hormone therapy in a patient with neutralizing antibodies to methionyl human growth hormone. | journal=J Pediatr Endocrinol Metab | year= 2002 | volume= 15 | issue= 5 | pages= 653-7 | pmid=12014526 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12014526  }}</ref>
* Development of [[insulin resistance]] and disorders of [[glucose intolerance]] may occur in children receiving [[Growth hormone|GH]] therapy.<ref name="pmid10696981">{{cite journal| author=Cutfield WS, Wilton P, Bennmarker H, Albertsson-Wikland K, Chatelain P, Ranke MB et al.| title=Incidence of diabetes mellitus and impaired glucose tolerance in children and adolescents receiving growth-hormone treatment. | journal=Lancet | year= 2000 | volume= 355 | issue= 9204 | pages= 610-3 | pmid=10696981 | doi=10.1016/S0140-6736(99)04055-6 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10696981  }}</ref>
* Development of [[insulin resistance]] and [[glucose intolerance]] may occur in children receiving [[Growth hormone|GH]] therapy.<ref name="pmid10696981">{{cite journal| author=Cutfield WS, Wilton P, Bennmarker H, Albertsson-Wikland K, Chatelain P, Ranke MB et al.| title=Incidence of diabetes mellitus and impaired glucose tolerance in children and adolescents receiving growth-hormone treatment. | journal=Lancet | year= 2000 | volume= 355 | issue= 9204 | pages= 610-3 | pmid=10696981 | doi=10.1016/S0140-6736(99)04055-6 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10696981  }}</ref>


===== Chronic effects =====
===== Chronic effects =====
* There is a possible role for [[Growth hormone|GH]] in cancer risk especially [[prostate cancer]].<ref name="pmid12147365">{{cite journal| author=Giovannucci E, Pollak M| title=Risk of cancer after growth-hormone treatment. | journal=Lancet | year= 2002 | volume= 360 | issue= 9329 | pages= 268-9 | pmid=12147365 | doi=10.1016/S0140-6736(02)09561-2 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12147365  }}</ref><ref name="pmid26227295">{{cite journal| author=Swerdlow AJ, Cooke R, Albertsson-Wikland K, Borgström B, Butler G, Cianfarani S et al.| title=Description of the SAGhE Cohort: A Large European Study of Mortality and Cancer Incidence Risks after Childhood Treatment with Recombinant Growth Hormone. | journal=Horm Res Paediatr | year= 2015 | volume= 84 | issue= 3 | pages= 172-83 | pmid=26227295 | doi=10.1159/000435856 | pmc=4611066 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26227295  }}</ref>
* There is a possible role for [[Growth hormone|GH]] in cancer risk especially [[prostate cancer]].<ref name="pmid12147365">{{cite journal| author=Giovannucci E, Pollak M| title=Risk of cancer after growth-hormone treatment. | journal=Lancet | year= 2002 | volume= 360 | issue= 9329 | pages= 268-9 | pmid=12147365 | doi=10.1016/S0140-6736(02)09561-2 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12147365  }}</ref><ref name="pmid26227295">{{cite journal| author=Swerdlow AJ, Cooke R, Albertsson-Wikland K, Borgström B, Butler G, Cianfarani S et al.| title=Description of the SAGhE Cohort: A Large European Study of Mortality and Cancer Incidence Risks after Childhood Treatment with Recombinant Growth Hormone. | journal=Horm Res Paediatr | year= 2015 | volume= 84 | issue= 3 | pages= 172-83 | pmid=26227295 | doi=10.1159/000435856 | pmc=4611066 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26227295  }}</ref>
* [[Growth hormone|GH]] therapy does not increase the risk of leukemia or other cancers compared with the general population.<ref name="pmid281872252">{{cite journal| author=Swerdlow AJ, Cooke R, Beckers D, Borgström B, Butler G, Carel JC et al.| title=Cancer Risks in Patients Treated With Growth Hormone in Childhood: The SAGhE European Cohort Study. | journal=J Clin Endocrinol Metab | year= 2017 | volume= 102 | issue= 5 | pages= 1661-1672 | pmid=28187225 | doi=10.1210/jc.2016-2046 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28187225  }}</ref>
* [[Growth hormone|GH]] therapy does not increase the risk of [[leukemia]] or other cancers compared with the general population.<ref name="pmid281872252">{{cite journal| author=Swerdlow AJ, Cooke R, Beckers D, Borgström B, Butler G, Carel JC et al.| title=Cancer Risks in Patients Treated With Growth Hormone in Childhood: The SAGhE European Cohort Study. | journal=J Clin Endocrinol Metab | year= 2017 | volume= 102 | issue= 5 | pages= 1661-1672 | pmid=28187225 | doi=10.1210/jc.2016-2046 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28187225  }}</ref>However, a lack of association with [[cancer]] was also found in other studies.<ref name="pmid25839904">{{cite journal| author=Raman S, Grimberg A, Waguespack SG, Miller BS, Sklar CA, Meacham LR et al.| title=Risk of Neoplasia in Pediatric Patients Receiving Growth Hormone Therapy--A Report From the Pediatric Endocrine Society Drug and Therapeutics Committee. | journal=J Clin Endocrinol Metab | year= 2015 | volume= 100 | issue= 6 | pages= 2192-203 | pmid=25839904 | doi=10.1210/jc.2015-1002 | pmc=5393518 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25839904  }}</ref>
* However, a lack of association with cancer was also found in other studies.<ref name="pmid25839904">{{cite journal| author=Raman S, Grimberg A, Waguespack SG, Miller BS, Sklar CA, Meacham LR et al.| title=Risk of Neoplasia in Pediatric Patients Receiving Growth Hormone Therapy--A Report From the Pediatric Endocrine Society Drug and Therapeutics Committee. | journal=J Clin Endocrinol Metab | year= 2015 | volume= 100 | issue= 6 | pages= 2192-203 | pmid=25839904 | doi=10.1210/jc.2015-1002 | pmc=5393518 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25839904  }}</ref>
* For patients with a primary cancer diagnosis that led to the [[Growth hormone|GH]] treatment, [[recombinant]] [[GH]] was associated with an increase in risk for [[cancer]].<ref name="pmid281872252" />
* For patients with a primary cancer diagnosis that led to the [[Growth hormone|GH]] treatment, recombinant GH was associated with a modest increase in risk for secondary cancer.<ref name="pmid281872252" />
* The increased risk was significant for a variety of secondary cancers including [[Bone|bone,]] [[melanoma]], [[kidney]], [[brain]], [[thyroid]] cancer and [[leukemia]].  
* The increased risk was significant for a variety of secondary cancers including [[Bone|bone,]] [[melanoma]], [[kidney]], [[brain]], [[thyroid]] cancer and [[leukemia]].  
* Cancer mortality increased with [[Growth hormone|GH]] dose and duration of treatment.
* For children with [[cancer]], guidelines suggest a 12-month period after completion of cancer-directed therapy to confirm that the [[cancer]] was eradicated before initiating [[Growth hormone|GH therapy]].
* For children with cancer, guidelines suggest a 12-month period after completion of cancer-directed therapy to confirm that the cancer was eradicated before initiating GH therapy.


==== Transition of GH treatment from childhood to adults<ref name="pmid21270511">{{cite journal| author=Molitch ME| title=Growth hormone treatment in adults with growth hormone deficiency: the transition. | journal=J Endocrinol Invest | year= 2011 | volume= 34 | issue= 2 | pages= 150-4 | pmid=21270511 | doi=10.3275/7483 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21270511  }}</ref> ====
==== Transition of GH treatment from childhood to adults<ref name="pmid21270511">{{cite journal| author=Molitch ME| title=Growth hormone treatment in adults with growth hormone deficiency: the transition. | journal=J Endocrinol Invest | year= 2011 | volume= 34 | issue= 2 | pages= 150-4 | pmid=21270511 | doi=10.3275/7483 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21270511  }}</ref> ====
* The transition period between childhood treatment and adults treatment begins in late [[puberty]] and ends with full adult maturation.
* The transition period between childhood treatment and adults treatment begins in late [[puberty]] and ends with full adult maturation.
* Children treated with [[Growth hormone|GH]] should be retested near the time of reaching the adult height to determine if they have persistence of GHD.
* Children treated with [[Growth hormone|GH]] should be retested if they have persistence of GHD near the time of reaching adulthood.
* Patients with idiopathic GHD usually do not need [[Growth hormone|GH]] treatment anymore, children with organic causes of GHD usually are found to have GHD on retesting.  
* Patients with idiopathic GHD usually do not need [[Growth hormone|GH]] treatment anymore, children with organic causes of GHD usually are found to have GHD on retesting.  
* Retesting involves measurement of [[Insulin-like growth factor-I|IGF-I]] and stimulation with [[insulin]]-induced [[hypoglycemia]] or [[arginine]].
* Retesting involves measurement of [[Insulin-like growth factor-I|IGF-I]] and stimulation with [[insulin]]-induced [[hypoglycemia]] or [[arginine]].
* Most studies have shown the benefit of [[Growth hormone|GH]] treatment in young adults with GHD in body composition, especially the achievement of peak [[bone mass]].  
* Most studies have shown the benefit of [[Growth hormone|GH]] treatment in young adults with GHD in [[body composition]], especially the achievement of peak [[bone mass]].  


=== Adult-type GH deficiency treatment ===
=== Adult-type GH deficiency treatment ===
Line 101: Line 99:


==== Dosing ====
==== Dosing ====
The starting dose should be 2 to 5 mcg/kg body weight once daily.
* The starting dose should be 2 to 5 mcg/kg body weight once daily.


==== '''Duration of therapy''' ====
==== '''Duration of therapy''' ====
* Treatment should be continued indefinitely.<ref name="pmid23572082">{{cite journal| author=Appelman-Dijkstra NM, Claessen KM, Roelfsema F, Pereira AM, Biermasz NR| title=Long-term effects of recombinant human GH replacement in adults with GH deficiency: a systematic review. | journal=Eur J Endocrinol | year= 2013 | volume= 169 | issue= 1 | pages= R1-14 | pmid=23572082 | doi=10.1530/EJE-12-1088 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23572082  }}</ref>
* Treatment should be continued indefinitely.<ref name="pmid23572082">{{cite journal| author=Appelman-Dijkstra NM, Claessen KM, Roelfsema F, Pereira AM, Biermasz NR| title=Long-term effects of recombinant human GH replacement in adults with GH deficiency: a systematic review. | journal=Eur J Endocrinol | year= 2013 | volume= 169 | issue= 1 | pages= R1-14 | pmid=23572082 | doi=10.1530/EJE-12-1088 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23572082  }}</ref>
* Stopping the treatment causes an increase in [[C-reactive protein (CRP)|C-reactive protein]] and increases in both [[LDL Cholesterol|LDL]] and [[HDL Cholesterol|HDL]] cholesterol but improved insulin sensitivity and decreased glycated hemoglobin [[Hemoglobin A1c|(A1C]]).<ref name="pmid22791760">{{cite journal| author=Filipsson Nyström H, Barbosa EJ, Nilsson AG, Norrman LL, Ragnarsson O, Johannsson G| title=Discontinuing long-term GH replacement therapy--a randomized, placebo-controlled crossover trial in adult GH deficiency. | journal=J Clin Endocrinol Metab | year= 2012 | volume= 97 | issue= 9 | pages= 3185-95 | pmid=22791760 | doi=10.1210/jc.2012-2006 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22791760  }}</ref>
* Stopping the treatment causes an increase in [[C-reactive protein (CRP)|C-reactive protein]] and increases in both [[LDL Cholesterol|LDL]] and [[HDL Cholesterol|HDL]] cholesterol but improved [[insulin]] [[sensitivity]] and decreased glycated [[hemoglobin]] [[Hemoglobin A1c|(A1C]]).<ref name="pmid22791760">{{cite journal| author=Filipsson Nyström H, Barbosa EJ, Nilsson AG, Norrman LL, Ragnarsson O, Johannsson G| title=Discontinuing long-term GH replacement therapy--a randomized, placebo-controlled crossover trial in adult GH deficiency. | journal=J Clin Endocrinol Metab | year= 2012 | volume= 97 | issue= 9 | pages= 3185-95 | pmid=22791760 | doi=10.1210/jc.2012-2006 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22791760  }}</ref>


==== '''Monitoring''' ====
==== '''Monitoring''' ====

Revision as of 14:34, 27 September 2017

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammed Abdelwahed M.D[2]

Overview

Growth hormone (GH) is indicated for children with GH deficiency whose epiphyses are open. The dose for children is between 0.16 and 0.24 mg/kg/week, divided into once daily injections. Serum levels of insulin-like growth factor I (IGF-I) should be measured several weeks after beginning GH treatment or making a dose adjustment. GH side effects include headaches, Idiopathic intracranial hypertension, Slipped capital femoral epiphysis, worsening of existing scoliosis, Pancreatitis, and Gynecomastia. There is a possible role for GH in cancer risk.

Medical Therapy

Children treatment

Indications[1]

  • Treatment with Growth hormone (GH) is indicated for children with GH deficiency whose epiphyses are open.
  • Treatment should be continued after linear growth ceases until full skeletal development.

Dosing

  • The dose for children is between 0.16 and 0.24 mg/kg/week, divided into once daily injections.
  • The dose for patients with severe GH deficiency is 20 micrograms/kg/day.

Dosing during puberty[2] 

  • A temporary increase in GH dose is preferred if the patient failed to respond to normal doses.
  • Although, effective treatment with GH before puberty is more efficacious than efforts to treat patients during puberty.

Monitoring 

  • Serum levels of insulin-like growth factor I (IGF-I) should be measured several weeks after beginning GH treatment or making a dose adjustment.
  • This helps to avoid very high IGF-I levels, which are thought to be associated with some of the drug's toxicity as recommended in guidelines from the Pediatric Endocrine Society (PES):[3]
  • If the IGF-I level is below this target range, increase the dose of GH because GH is unlikely to be efficacious if IGF-I levels are very low.
  • If the IGF-I level is above this target range, we reduce the GH dose to prevent GH toxicity.
  • For patients with multiple pituitary hormone deficiencies, adrenal and thyroid function should be reassessed a few months after initiation of GH therapy.[3]

Duration of therapy 

  • Treatment is continued at least until linear growth decreases to less than 2.0 to 2.5 cm.[3]
  • More than two-thirds of patients have normal results when retested for GH deficiency as adults.
  • It is important to repeat the GH stimulation test during the transition period to determine if they will require ongoing therapy.
  • Patients can achieve adult height if treatment is administered at an early age.[4]
  • Patients heights should be reevaluated every four to six months to determine if the growth response is adequate.
  • During the initial growth period, the 75th percentile curve for height velocity is an appropriate target as an adequate growth response to GH.

Effect of treatment

Growth 
  • Results usually better if GH therapy is started in early childhood.[5]Increase in height observed during 2 years of follow-up after interruption of treatment.[6]
Bone mass 
  • Children with GH deficiency have low bone mass compared with normal children.
  • To maximize bone mass, it is important to consider the continuation of treatment even after linear growth has ceased until full skeletal development.[7]
  • GH therapy increases bone mass.[8]Without adequate GH replacement, GH deficiency can be associated with low bone mass during adulthood.[9]

ADVERSE EFFECTS OF GROWTH HORMONE THERAPY 

Treatment of children with recombinant human GH has generally been safe.[10][11]

Acute effects 
Chronic effects
  • There is a possible role for GH in cancer risk especially prostate cancer.[18][19]
  • GH therapy does not increase the risk of leukemia or other cancers compared with the general population.[20]However, a lack of association with cancer was also found in other studies.[21]
  • For patients with a primary cancer diagnosis that led to the GH treatment, recombinant GH was associated with an increase in risk for cancer.[20]
  • The increased risk was significant for a variety of secondary cancers including bone, melanoma, kidney, brain, thyroid cancer and leukemia.
  • For children with cancer, guidelines suggest a 12-month period after completion of cancer-directed therapy to confirm that the cancer was eradicated before initiating GH therapy.

Transition of GH treatment from childhood to adults[22]

  • The transition period between childhood treatment and adults treatment begins in late puberty and ends with full adult maturation.
  • Children treated with GH should be retested if they have persistence of GHD near the time of reaching adulthood.
  • Patients with idiopathic GHD usually do not need GH treatment anymore, children with organic causes of GHD usually are found to have GHD on retesting.
  • Retesting involves measurement of IGF-I and stimulation with insulin-induced hypoglycemia or arginine.
  • Most studies have shown the benefit of GH treatment in young adults with GHD in body composition, especially the achievement of peak bone mass.

Adult-type GH deficiency treatment

Treatment protocol

  • GH is administered by subcutaneous injection once a day, usually in the evening.
  • The goal should be to start with low doses and increase gradually until the serum IGF-1 concentration is normal.
  • The eventual goal is to find the GH dose that maintains the serum IGF-1 concentration within the middle of the age-adjusted normal range.[23]
  • If side effects occur or the serum IGF-1 concentration increases to above normal at any dose, the dose should be decreased.

Dosing

  • The starting dose should be 2 to 5 mcg/kg body weight once daily.

Duration of therapy

Monitoring

  • Measurement of serum IGF-1 is probably the best single test of the adequacy of GH treatment.[26]
  • We suggest measuring a serum IGF-1 two months after starting therapy.
  • GH treatment should increase the serum IGF-1 concentration to within, but not higher than, the age-specific range of normal to avoid over replacement.
  • Once serum IGF-1 is in the normal range, we suggest repeating it every 6 to 12 months.
  • If IGF-1 is ever above normal, the GH dose should be decreased by 1 to 2 mcg/kg increments and serum IGF-1 should be repeated every two months until it returns to the normal range.

References

  1. ↑ Albertsson-Wikland K (1987). "The effect of human growth hormone injection frequency on linear growth rate". Acta Paediatr Scand Suppl. 337: 110–6. PMID 3481175.
  2. ↑ Allen DB (1999). "Issues in the transition from childhood to adult growth hormone therapy". Pediatrics. 104 (4 Pt 2): 1004–10. PMID 10506252.
  3. ↑ 3.0 3.1 3.2 Grimberg A, DiVall SA, Polychronakos C, Allen DB, Cohen LE, Quintos JB; et al. (2016). "Guidelines for Growth Hormone and Insulin-Like Growth Factor-I Treatment in Children and Adolescents: Growth Hormone Deficiency, Idiopathic Short Stature, and Primary Insulin-Like Growth Factor-I Deficiency". Horm Res Paediatr. 86 (6): 361–397. doi:10.1159/000452150. PMID 27884013.
  4. ↑ Reiter EO, Price DA, Wilton P, Albertsson-Wikland K, Ranke MB (2006). "Effect of growth hormone (GH) treatment on the near-final height of 1258 patients with idiopathic GH deficiency: analysis of a large international database". J Clin Endocrinol Metab. 91 (6): 2047–54. doi:10.1210/jc.2005-2284. PMID 16537676.
  5. ↑ Carel JC, Ecosse E, Nicolino M, Tauber M, Leger J, Cabrol S; et al. (2002). "Adult height after long term treatment with recombinant growth hormone for idiopathic isolated growth hormone deficiency: observational follow up study of the French population based registry". BMJ. 325 (7355): 70. PMC 117125. PMID 12114235.
  6. ↑ Z. Laron, B. Klinger, S. Anin, A. Pertzelan & P. Lilos (1997). "Growth during and 2 years after stopping GH treatment in prepubertal children with idiopathic short stature". Journal of pediatric endocrinology & metabolism : JPEM. 10 (2): 191–196. PMID 9364352. Unknown parameter |month= ignored (help)
  7. ↑ Conway GS, Szarras-Czapnik M, Racz K, Keller A, Chanson P, Tauber M; et al. (2009). "Treatment for 24 months with recombinant human GH has a beneficial effect on bone mineral density in young adults with childhood-onset GH deficiency". Eur J Endocrinol. 160 (6): 899–907. doi:10.1530/EJE-08-0436. PMID 19324976.
  8. ↑ Bonjour JP, Theintz G, Buchs B, Slosman D, Rizzoli R (1991). "Critical years and stages of puberty for spinal and femoral bone mass accumulation during adolescence". J Clin Endocrinol Metab. 73 (3): 555–63. doi:10.1210/jcem-73-3-555. PMID 1874933.
  9. ↑ Holmes SJ, Economou G, Whitehouse RW, Adams JE, Shalet SM (1994). "Reduced bone mineral density in patients with adult onset growth hormone deficiency". J Clin Endocrinol Metab. 78 (3): 669–74. doi:10.1210/jcem.78.3.8126140. PMID 8126140.
  10. ↑ Saenger P, Attie KM, DiMartino-Nardi J, Hintz R, Frahm L, Frane JW (1998). "Metabolic consequences of 5-year growth hormone (GH) therapy in children treated with GH for idiopathic short stature. Genentech Collaborative Study Group". J Clin Endocrinol Metab. 83 (9): 3115–20. doi:10.1210/jcem.83.9.5089. PMID 9745413.
  11. ↑ Carel JC, Butler G (2010). "Safety of recombinant human growth hormone". Endocr Dev. 18: 40–54. doi:10.1159/000316126. PMID 20523016.
  12. ↑ Youngster I, Rachmiel R, Pinhas-Hamiel O, Bistritzer T, Zuckerman-Levin N, de Vries L; et al. (2012). "Treatment with recombinant human growth hormone during childhood is associated with increased intraocular pressure". J Pediatr. 161 (6): 1116–9. doi:10.1016/j.jpeds.2012.05.024. PMID 22727870.
  13. ↑ Darendeliler F, Karagiannis G, Wilton P (2007). "Headache, idiopathic intracranial hypertension and slipped capital femoral epiphysis during growth hormone treatment: a safety update from the KIGS database". Horm Res. 68 Suppl 5: 41–7. doi:10.1159/000110474. PMID 18174706.
  14. ↑ Blethen SL, Allen DB, Graves D, August G, Moshang T, Rosenfeld R (1996). "Safety of recombinant deoxyribonucleic acid-derived growth hormone: The National Cooperative Growth Study experience". J Clin Endocrinol Metab. 81 (5): 1704–10. doi:10.1210/jcem.81.5.8626820. PMID 8626820.
  15. ↑ Bourguignon JP, Piérard GE, Ernould C, Heinrichs C, Craen M, Rochiccioli P; et al. (1993). "Effects of human growth hormone therapy on melanocytic naevi". Lancet. 341 (8859): 1505–6. PMID 8099381.
  16. ↑ Pitukcheewanont P, Schwarzbach L, Kaufman FR (2002). "Resumption of growth after methionyl-free human growth hormone therapy in a patient with neutralizing antibodies to methionyl human growth hormone". J Pediatr Endocrinol Metab. 15 (5): 653–7. PMID 12014526.
  17. ↑ Cutfield WS, Wilton P, Bennmarker H, Albertsson-Wikland K, Chatelain P, Ranke MB; et al. (2000). "Incidence of diabetes mellitus and impaired glucose tolerance in children and adolescents receiving growth-hormone treatment". Lancet. 355 (9204): 610–3. doi:10.1016/S0140-6736(99)04055-6. PMID 10696981.
  18. ↑ Giovannucci E, Pollak M (2002). "Risk of cancer after growth-hormone treatment". Lancet. 360 (9329): 268–9. doi:10.1016/S0140-6736(02)09561-2. PMID 12147365.
  19. ↑ Swerdlow AJ, Cooke R, Albertsson-Wikland K, Borgström B, Butler G, Cianfarani S; et al. (2015). "Description of the SAGhE Cohort: A Large European Study of Mortality and Cancer Incidence Risks after Childhood Treatment with Recombinant Growth Hormone". Horm Res Paediatr. 84 (3): 172–83. doi:10.1159/000435856. PMC 4611066. PMID 26227295.
  20. ↑ 20.0 20.1 Swerdlow AJ, Cooke R, Beckers D, Borgström B, Butler G, Carel JC; et al. (2017). "Cancer Risks in Patients Treated With Growth Hormone in Childhood: The SAGhE European Cohort Study". J Clin Endocrinol Metab. 102 (5): 1661–1672. doi:10.1210/jc.2016-2046. PMID 28187225.
  21. ↑ Raman S, Grimberg A, Waguespack SG, Miller BS, Sklar CA, Meacham LR; et al. (2015). "Risk of Neoplasia in Pediatric Patients Receiving Growth Hormone Therapy--A Report From the Pediatric Endocrine Society Drug and Therapeutics Committee". J Clin Endocrinol Metab. 100 (6): 2192–203. doi:10.1210/jc.2015-1002. PMC 5393518. PMID 25839904.
  22. ↑ Molitch ME (2011). "Growth hormone treatment in adults with growth hormone deficiency: the transition". J Endocrinol Invest. 34 (2): 150–4. doi:10.3275/7483. PMID 21270511.
  23. ↑ Fleseriu M, Hashim IA, Karavitaki N, Melmed S, Murad MH, Salvatori R; et al. (2016). "Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline". J Clin Endocrinol Metab. 101 (11): 3888–3921. doi:10.1210/jc.2016-2118. PMID 27736313.
  24. ↑ Appelman-Dijkstra NM, Claessen KM, Roelfsema F, Pereira AM, Biermasz NR (2013). "Long-term effects of recombinant human GH replacement in adults with GH deficiency: a systematic review". Eur J Endocrinol. 169 (1): R1–14. doi:10.1530/EJE-12-1088. PMID 23572082.
  25. ↑ Filipsson Nyström H, Barbosa EJ, Nilsson AG, Norrman LL, Ragnarsson O, Johannsson G (2012). "Discontinuing long-term GH replacement therapy--a randomized, placebo-controlled crossover trial in adult GH deficiency". J Clin Endocrinol Metab. 97 (9): 3185–95. doi:10.1210/jc.2012-2006. PMID 22791760.
  26. ↑ de Boer H, Blok GJ, Popp-Snijders C, Stuurman L, Baxter RC, van der Veen E (1996). "Monitoring of growth hormone replacement therapy in adults, based on measurement of serum markers". J Clin Endocrinol Metab. 81 (4): 1371–7. doi:10.1210/jcem.81.4.8636336. PMID 8636336.

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