Growth hormone deficiency medical therapy: Difference between revisions

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==== '''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|GH]] is indicated for children with 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 until linear growth ceases or even beyond.


==== 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 GH deficiency is 20 micrograms/kg/day.
* The dose for patients with severe [[Growth hormone|GH]] deficiency is 20 micrograms/kg/day.


==== '''Dosing during puberty''' ====
==== '''Dosing during puberty''' ====
* A temporary increase in GH dose (eg, to 70 to 100 micrograms/kg/day) has been suggested in case of failed proper response to treatment.  
* A temporary increase in [[Growth hormone|GH]] dose is preferred if the patient failed to respond to normal doses.  
* Although, effective treatment with GH prior to puberty is more efficacious and cost-effective than efforts to boost growth 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 I (IGF-I) should be measured several weeks after beginning 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 IGF-I levels, which are thought to be associated with some of the drug's toxicity.
* 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>
* 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>


* 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 [[Insulin-like growth factor-I|IGF-I]] level is below this target range, increase the dose of [[Growth hormone|GH]] because [[Growth hormone|GH]] is unlikely to be efficacious if [[Insulin-like growth factor-I|IGF-I]] levels are very low.
* If the IGF-I level is above this target range (ie, >+2 SD), we reduce the GH dose to prevent GH toxicity.
* If the [[Insulin-like growth factor-I|IGF-I]] level is above this target range, we reduce the [[Growth hormone|GH]] dose to prevent [[Growth hormone|GH]] toxicity.
* For patients with multiple pituitary hormone deficiencies, adrenal and thyroid function should be reassessed a few months after initiation of GH therapy and periodically by measuring 8 to 9 AM serum cortisol and free T4, respectively.<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 (0.8 to 1 inch)/year.<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 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 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.
* GH deficiency is usually permanent in patients with genetic causes of GH deficiency (recognized by a family history of GH deficiency), structural causes of GH deficiency (eg, optic nerve hypoplasia), or organic GH deficiency (eg, caused by brain surgery, brain tumors, intracranial irradiation, or associated with multiple pituitary hormone deficiencies).


==== '''Growth response to GH 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>
* if GH is administered at an early age, patients can achieve adult height within the midparental target height range.<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.
* recheck length or height at least every four to six months and calculate the height velocity to determine whether 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 GH.  
* During the initial "catch-up" growth period, the 75<sup>th</sup> percentile curve for height velocity is an appropriate target to define an adequate growth response to GH.
* Catch-up growth should continue until the child's height percentile is in the expected range Children who have an inadequate growth response to GH therapy should be reevaluated. The causes can be categorized by the IGF-I level.


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


===== '''Growth''' =====
===== '''Growth''' =====
* Results usually better if 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>
* 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>


===== '''Bone mass''' =====
===== '''Bone mass''' =====
* Children with GH deficiency have low bone mass compared with age- and size-matched control children.  
* Children with [[Growth hormone|GH]] deficiency have low bone mass compared with control children.  
* To maximize peak 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 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>  
* These findings suggest that GH therapy increases bone mass and the progression toward peak 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, either childhood- or adult-onset 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>
* These findings suggest that GH therapy increases bone mass and the progression toward peak 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, either childhood- or adult-onset 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''' ====
Treatment of children with recombinant human GH has generally been safe.<ref name="pmid9745413">{{cite journal| author=Saenger P, Attie KM, DiMartino-Nardi J, Hintz R, Frahm L, Frane JW| title=Metabolic consequences of 5-year growth hormone (GH) therapy in children treated with GH for idiopathic short stature. Genentech Collaborative Study Group. | journal=J Clin Endocrinol Metab | year= 1998 | volume= 83 | issue= 9 | pages= 3115-20 | pmid=9745413 | doi=10.1210/jcem.83.9.5089 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9745413  }}</ref>
Treatment of children with [[Recombinant DNA|recombinant]] human [[Growth hormone|GH]] has generally been safe.<ref name="pmid9745413">{{cite journal| author=Saenger P, Attie KM, DiMartino-Nardi J, Hintz R, Frahm L, Frane JW| title=Metabolic consequences of 5-year growth hormone (GH) therapy in children treated with GH for idiopathic short stature. Genentech Collaborative Study Group. | journal=J Clin Endocrinol Metab | year= 1998 | volume= 83 | issue= 9 | pages= 3115-20 | pmid=9745413 | doi=10.1210/jcem.83.9.5089 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9745413  }}</ref>


===== '''Acute effects''' =====
===== '''Acute effects''' =====
* Headaches which usually are benign.
* [[Headache|Headaches]] which usually are benign.
* Idiopathic intracranial hypertension (formerly known as pseudotumor cerebri), increased intraocular pressure usually resolves with discontinuation of 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]] (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>  
* 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 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 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>  
* 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 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,]] 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>
* Carpal tunnel syndrome, edema, and arthralgia are more common in adults undergoing GH treatment but are unusual in children.
* [[Carpal tunnel syndrome]], [[edema]], and [[arthralgia]] are more common in adults undergoing [[Growth hormone|GH]] treatment but are unusual in children.
* Most usually occur soon after therapy is initiated, and some of these effects are probably caused by sodium and water retention. Rarely, a child treated with GH develops neutralizing antibodies, 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>
* Most usually occur soon after therapy is initiated, and some of these effects are probably caused by sodium and water retention.  
* Development of insulin resistance and disorders of glucose intolerance may occur in children receiving 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>
* [[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>


===== Chronic effects =====
===== Chronic effects =====
* There is a possible role for 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>
* 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>
* 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 GH treatment, recombinant GH was associated with a modest increase in risk for secondary 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, melanoma, kidney, brain, thyroid, 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 GH dose and duration of treatment.  
* Cancer mortality increased with [[Growth hormone|GH]] dose and duration of treatment.  
* For children with cancer (including craniopharyngioma) who develop GH deficiency, guidelines suggest a 12-month waiting period after completion of cancer-directed therapy to confirm that the cancer was eradicated before initiating GH therapy. 14
* 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. 14


=== Adult-type GH deficiency treatment ===
=== Adult-type GH deficiency treatment ===


==== '''Treatment protocol''' ====
==== '''Treatment protocol''' ====
* GH is administered by subcutaneous injection once a day, usually in the evening.
* [[Growth hormone|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 goal should be to start with low doses and increase gradually until the serum [[Insulin-like growth factor-I|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.<ref name="pmid27736313">{{cite journal| author=Fleseriu M, Hashim IA, Karavitaki N, Melmed S, Murad MH, Salvatori R et al.| title=Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline. | journal=J Clin Endocrinol Metab | year= 2016 | volume= 101 | issue= 11 | pages= 3888-3921 | pmid=27736313 | doi=10.1210/jc.2016-2118 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27736313  }}</ref>
* The eventual goal is to find the [[Growth hormone|GH]] dose that maintains the serum [[Insulin-like growth factor-I|IGF-1]] concentration within the middle of the age-adjusted normal range.<ref name="pmid27736313">{{cite journal| author=Fleseriu M, Hashim IA, Karavitaki N, Melmed S, Murad MH, Salvatori R et al.| title=Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline. | journal=J Clin Endocrinol Metab | year= 2016 | volume= 101 | issue= 11 | pages= 3888-3921 | pmid=27736313 | doi=10.1210/jc.2016-2118 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27736313  }}</ref>
* If side effects occur or the serum IGF-1 concentration increases to above normal at any dose, the dose should be decreased.
* If side effects occur or the serum [[Insulin-like growth factor-I|IGF-1]] concentration increases to above normal at any dose, the dose should be decreased.


==== Dosing ====
==== Dosing ====
Line 88: Line 85:
==== '''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 and increases in both LDL and HDL cholesterol but improved insulin sensitivity and decreased glycated hemoglobin (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''' ====
* Measurement of serum IGF-1 is probably the best single test of the adequacy of GH treatment.<ref name="pmid8636336">{{cite journal| author=de Boer H, Blok GJ, Popp-Snijders C, Stuurman L, Baxter RC, van der Veen E| title=Monitoring of growth hormone replacement therapy in adults, based on measurement of serum markers. | journal=J Clin Endocrinol Metab | year= 1996 | volume= 81 | issue= 4 | pages= 1371-7 | pmid=8636336 | doi=10.1210/jcem.81.4.8636336 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8636336  }}</ref>
* Measurement of serum [[Insulin-like growth factor-I|IGF-1]] is probably the best single test of the adequacy of [[Growth hormone|GH]] treatment.<ref name="pmid8636336">{{cite journal| author=de Boer H, Blok GJ, Popp-Snijders C, Stuurman L, Baxter RC, van der Veen E| title=Monitoring of growth hormone replacement therapy in adults, based on measurement of serum markers. | journal=J Clin Endocrinol Metab | year= 1996 | volume= 81 | issue= 4 | pages= 1371-7 | pmid=8636336 | doi=10.1210/jcem.81.4.8636336 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8636336  }}</ref>
* We suggest measuring a serum IGF-1 two months after starting therapy.
* We suggest measuring a serum [[Insulin-like growth factor-I|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.
* GH treatment should increase the serum [[Insulin-like growth factor-I|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.  
* Once serum [[Insulin-like growth factor-I|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.
* If [[Insulin-like growth factor-I|IGF-1]] is ever above normal, the [[Growth hormone|GH]] dose should be decreased by 1 to 2 mcg/kg increments and serum [[Insulin-like growth factor-I|IGF-1]] should be repeated every two months until it returns to the normal range.


==References==
==References==

Revision as of 20:36, 16 August 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

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 until linear growth ceases or even beyond.

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 

  • 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):[2]
  • 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.[2]

Duration of therapy 

  • Treatment is continued at least until linear growth decreases to less than 2.0 to 2.5 cm.[2]
  • 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.
  • if GH is administered at an early age, patients can achieve adult height.[3]
  • Patients heights should be rechecked 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 to define an adequate growth response to GH.

Effect of treatment

Growth 
  • Results usually better if GH therapy is started in early childhood.[4]
Bone mass 
  • Children with GH deficiency have low bone mass compared with control children.
  • To maximize bone mass, it is important to consider the continuation of GH treatment even after linear growth has ceased until full skeletal.[5]
  • These findings suggest that GH therapy increases bone mass and the progression toward peak bone mass.[6]Without adequate GH replacement, either childhood- or adult-onset GH deficiency can be associated with low bone mass during adulthood.[7]

ADVERSE EFFECTS OF GROWTH HORMONE THERAPY 

Treatment of children with recombinant human GH has generally been safe.[8]

Acute effects 
Chronic effects
  • There is a possible role for GH in cancer risk especially prostate cancer.[15]
  • GH therapy does not increase the risk of leukemia or other cancers compared with the general population.[16]
  • However, a lack of association with cancer was also found in other studies.[17]
  • For patients with a primary cancer diagnosis that led to the GH treatment, recombinant GH was associated with a modest increase in risk for secondary cancer.[16]
  • The increased risk was significant for a variety of secondary cancers including bone, melanoma, kidney, brain, thyroid cancer and leukemia.
  • Cancer mortality increased with 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 GH therapy. 14

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.[18]
  • 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

  • Treatment should be continued indefinitely.[19]
  • Stopping the treatment causes an increase in C-reactive protein and increases in both LDL and HDL cholesterol but improved insulin sensitivity and decreased glycated hemoglobin (A1C).[20]

Monitoring

  • Measurement of serum IGF-1 is probably the best single test of the adequacy of GH treatment.[21]
  • 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. ↑ 2.0 2.1 2.2 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 16.0 16.1 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 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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