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==Overview==
==Overview==
An immediate investigation should be started in severe [[short stature]] defined as a short child more than 3 sd below the mean of children at the same age. Measurement of a random serum [[Growth hormone|GH]] level alone is not helpful. Measurement of [[Insulin-like growth factor 1|Insulin-like growth factor I]] (IGF-I) and [[Insulin-like growth factor binding protein 3|Insulin-like growth factor binding protein-3]] ([[IGFBP3|IGFBP-3]]) is more helpful than GH level alone.  
An immediate investigation should be started in severe [[short stature]] defined as a short child more than 3 [[standard deviation]]<nowiki/>s below the mean of children at the same age. Measurement of a random serum [[Growth hormone|GH]] level alone is not helpful. Measurement of [[Insulin-like growth factor 1|Insulin-like growth factor I]] (IGF-I) and [[Insulin-like growth factor binding protein 3|Insulin-like growth factor binding protein-3]] ([[IGFBP3|IGFBP-3]]) is more helpful than GH level alone. GH stimulation tests are indicated for most patients suspected to have GHD. If the clinical and other laboratory criteria are sufficient to make the diagnosis of GHD, there is no need to perform the test. Pharmacologic stimuli include [[clonidine]], [[glucagon]], [[arginine]], and [[insulin]]-induced [[hypoglycemia]]. Administration of [[sex steroids]] for a few days prior to the provocative [[Growth hormone|GH]] testing reduces the chance of a [[false-positive]] result.  
 
GH stimulation tests is indicated for most patients suspected to have GHD. If the clinical and other laboratory criteria are sufficient to make the diagnosis of GHD, there is no need to perform the test. Pharmacologic stimuli include [[clonidine]], [[glucagon]], [[arginine]], and [[insulin]]-induced [[hypoglycemia]]. Administration of [[sex steroids]] for a few days prior to the provocative [[Growth hormone|GH]] testing reduces the chance of a false-positive result.


==Laboratory Findings==
==Laboratory Findings==


=== ''Neonatal evaluation'' ===
=== Neonatal evaluation ===
* A [[Growth hormone|GH level]] should always be measured:
* Always measure GH levels:
**In the presence of [[Hypoglycemia|neonatal hypoglycemia]]
**In the presence of neonatal hypoglycemia  
**In the absence of a metabolic disorder.  
**In the absence of a metabolic disorder.  
**A random [[Growth hormone|GH]] measurement in a [[polyclonal]] RIA of less than 20 mg/L would suggest GHD in the newborn.  
**A random GH measurement in a polyclonal RIA of less than 20 mg/L would suggest GHD within the newborn.  
**An [[IGFBP3|IGFBP-3]] measurement is of value for the diagnosis of GHD in infancy.
**An IGFBP-3 measurement is of value for the diagnosis of GHD in infancy.


=== Children evaluation ===
=== Children evaluation ===
Criteria to initiate immediate investigation include:
The evaluation for GHD in a short child can not be initiated until exclusion of other causes of growth failure, which include hypothyroidism, chronic systemic disease, and Turner syndrome.
* Severe [[short stature]], defined as a short child more than 3 sd below the mean of children at the same age
 
* Height more than 1.5 sd below the mid-parental height;
Indications for immediate investigation include:
* Height more than 2 sd below the mean and a height velocity over 1 yr more than 1 sd below the mean for chronological age, or a decrease in height sd of more than 0.5 over 1 yr in children over 2 yr of age;
* Severe [[short stature|short stature:]] a short child more than 3 [[Standard deviation|standard deviations]] (SD) below the mean height of children of the same age
* In the absence of [[short stature]], a height velocity more than 2 sd below the mean over 1 yr or more than 1.5 sd sustained over 2 yr; this may occur in GHD, presenting in infancy, or in organic GHD.
* In the absence of [[short stature]]: a height velocity more than 2 SD below the mean height for more than 1 year or more than 1.5 SD sustained over 2 years
* Height more than 1.5 SD below the mid-parental height
* Height more than 2 SD below the mean height and a height velocity of 1 or more SD below the [[mean]] height for chronological age sustained for more than a year
* A decrease in height SD of more than 0.5 over 1 year in children over 2 years of age
* Signs indicative of an [[Intracranial mass|intracranial lesion]]
* Signs indicative of an [[Intracranial mass|intracranial lesion]]
The evaluation for GHD in a short child should not be initiated until other causes of [[growth failure]], such as [[hypothyroidism]], chronic systemic disease, [[Turner syndrome]] have been considered excluded.
=== Adult evaluation ===
 
Indications for immediate investigation include:
=== '''Adults evaluation''' ===
* Adults with known [[hypothalamic]] or [[pituitary disease]] such as:  
Criteria to initiate immediate investigation include:
**[[Panhypopituitarism]] with documented deficiency of [[thyroid-stimulating hormone]] (TSH), [[corticotropin]] (ACTH), and [[Gonadotropins|gonadotropins.]]   
* Adults with known [[hypothalamic]] or [[pituitary disease]]:  
**Multiple deficiencies of other pituitary hormones correlated highly with a subnormal GH response to a stimulation test.<ref>{{Cite journal
* [[Panhypopituitarism]] is documented deficiencies of [[thyroid-stimulating hormone]] (TSH), [[corticotropin]] (ACTH), and [[Gonadotropins|gonadotropins.]]   
* Multiple deficiencies of other pituitary hormones correlated highly with a subnormal GH response to a stimulation test.<ref>{{Cite journal


  | author = [[Mark L. Hartman]], [[Brenda J. Crowe]], [[Beverly M. K. Biller]], [[Ken K. Y. Ho]], [[David R. Clemmons]] & [[John J. Chipman]]
  | author = [[Mark L. Hartman]], [[Brenda J. Crowe]], [[Beverly M. K. Biller]], [[Ken K. Y. Ho]], [[David R. Clemmons]] & [[John J. Chipman]]
Line 43: Line 42:
  | pmid = 11836272
  | pmid = 11836272
}}</ref>  
}}</ref>  
* A low serum [[Insulin-like growth factor-I|IGF-1]] concentration confirms the diagnosis of GH deficiency in these patients; provocative testing is not required.<ref>{{Cite journal
**A low serum [[Insulin-like growth factor-I|IGF-1]] concentration confirms the diagnosis of GH deficiency in these patients; provocative testing is not required.<ref>{{Cite journal


  | author = [[Maria Fleseriu]], [[Ibrahim A. Hashim]], [[Niki Karavitaki]], [[Shlomo Melmed]], [[M. Hassan Murad]], [[Roberto Salvatori]] & [[Mary H. Samuels]]
  | author = [[Maria Fleseriu]], [[Ibrahim A. Hashim]], [[Niki Karavitaki]], [[Shlomo Melmed]], [[M. Hassan Murad]], [[Roberto Salvatori]] & [[Mary H. Samuels]]
Line 56: Line 55:
  | pmid = 27736313
  | pmid = 27736313
}}</ref>  
}}</ref>  
* Adults with a history of GH deficiency in childhood. Some will be found to have normal [[Growth hormone|GH]] secretion as adults, although this is not likely in those with GH deficiency due to an organic such as [[pituitary adenoma]]
* Adults with a history of GH deficiency in childhood. Some will be found to have normal [[Growth hormone|GH]] secretion as adults, although patients with GH deficiency due to an organic cause such as [[pituitary adenoma]] never show normal [[Growth hormone|GH]] level.


=== What to measure? ===
=== What to measure ===
GH secretion is pulsatile and its secretion is regulated by two [[Hypothalamus|hypothalamic]] factors; growth hormone-releasing hormone and [[somatostatin]].<ref name="pmid20161791">{{cite journal| author=Osterstock G, Escobar P, Mitutsova V, Gouty-Colomer LA, Fontanaud P, Molino F et al.| title=Ghrelin stimulation of growth hormone-releasing hormone neurons is direct in the arcuate nucleus. | journal=PLoS One | year= 2010 | volume= 5 | issue= 2 | pages= e9159 | pmid=20161791 | doi=10.1371/journal.pone.0009159 | pmc=2820089 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20161791  }}</ref>
GH secretion is pulsatile and its secretion is regulated by way of  hypothalamic factors; growth hormone releasing hormone (GHRH) and somatostatin.<ref name="pmid20161791">{{cite journal| author=Osterstock G, Escobar P, Mitutsova V, Gouty-Colomer LA, Fontanaud P, Molino F et al.| title=Ghrelin stimulation of growth hormone-releasing hormone neurons is direct in the arcuate nucleus. | journal=PLoS One | year= 2010 | volume= 5 | issue= 2 | pages= e9159 | pmid=20161791 | doi=10.1371/journal.pone.0009159 | pmc=2820089 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20161791  }}</ref> Measurement of a random serum GH level alone isn't always beneficial, other tests which can be used in the diagnosis include:
 
So, measurement of a random serum [[Growth hormone|GH]] level alone is not helpful and usually other tests used with it:
* [[Insulin-like growth factor 1|Insulin-like growth factor I]] (IGF-I)
* [[Insulin-like growth factor 1|Insulin-like growth factor I]] (IGF-I)
* [[Insulin-like growth factor binding protein 3|Insulin-like growth factor binding protein-3]] ([[IGFBP3|IGFBP-3]]) levels: it is the major serum carrier protein for [[Insulin-like growth factor-I|IGF-I]] and the most [[Growth hormone|GH]] dependent.<ref name="pmid2431001">{{cite journal| author=Baxter RC, Martin JL| title=Radioimmunoassay of growth hormone-dependent insulinlike growth factor binding protein in human plasma. | journal=J Clin Invest | year= 1986 | volume= 78 | issue= 6 | pages= 1504-12 | pmid=2431001 | doi=10.1172/JCI112742 | pmc=423906 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2431001  }}</ref>
* [[Insulin-like growth factor binding protein 3|Insulin-like growth factor binding protein-3]] ([[IGFBP3|IGFBP-3]]) levels: it is the major serum carrier protein for [[Insulin-like growth factor-I|IGF-I]] and the most [[Growth hormone|GH]] dependent.<ref name="pmid2431001">{{cite journal| author=Baxter RC, Martin JL| title=Radioimmunoassay of growth hormone-dependent insulinlike growth factor binding protein in human plasma. | journal=J Clin Invest | year= 1986 | volume= 78 | issue= 6 | pages= 1504-12 | pmid=2431001 | doi=10.1172/JCI112742 | pmc=423906 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2431001  }}</ref>
* Their concentrations often reflect the concentration of secreted [[Growth hormone|GH]].<ref name="pmid8626859">{{cite journal| author=Nunez SB, Municchi G, Barnes KM, Rose SR| title=Insulin-like growth factor I (IGF-I) and IGF-binding protein-3 concentrations compared to stimulated and night growth hormone in the evaluation of short children--a clinical research center study. | journal=J Clin Endocrinol Metab | year= 1996 | volume= 81 | issue= 5 | pages= 1927-32 | pmid=8626859 | doi=10.1210/jcem.81.5.8626859 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8626859  }}</ref>They are better tests than [[Growth hormone|GH]] level because they are stable during the day and not pulsatile.<ref name="pmid2760171">{{cite journal| author=Martha PM, Rogol AD, Veldhuis JD, Kerrigan JR, Goodman DW, Blizzard RM| title=Alterations in the pulsatile properties of circulating growth hormone concentrations during puberty in boys. | journal=J Clin Endocrinol Metab | year= 1989 | volume= 69 | issue= 3 | pages= 563-70 | pmid=2760171 | doi=10.1210/jcem-69-3-563 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2760171  }}</ref>


==== Limitations ====
==== Limitations ====
Serum [[Insulin-like growth factor-I|IGF-I]] levels may be low in conditions other than GHD such as [[Growth hormone insensitivity syndrome|growth hormone insensitivity]], [[hypothyroidism]], [[renal failure]], [[Diabetes mellitus|diabetes]], and [[cancer]].<ref name="pmid3760118">{{cite journal| author=Powell DR, Rosenfeld RG, Baker BK, Liu F, Hintz RL| title=Serum somatomedin levels in adults with chronic renal failure: the importance of measuring insulin-like growth factor I (IGF-I) and IGF-II in acid-chromatographed uremic serum. | journal=J Clin Endocrinol Metab | year= 1986 | volume= 63 | issue= 5 | pages= 1186-92 | pmid=3760118 | doi=10.1210/jcem-63-5-1186 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3760118  }}</ref>
* Serum [[Insulin-like growth factor-I|IGF-I]] levels may be low in other conditions such as [[Growth hormone insensitivity syndrome|growth hormone insensitivity]], [[hypothyroidism]], [[renal failure]], [[Diabetes mellitus|diabetes]], and [[cancer]].<ref name="pmid3760118">{{cite journal| author=Powell DR, Rosenfeld RG, Baker BK, Liu F, Hintz RL| title=Serum somatomedin levels in adults with chronic renal failure: the importance of measuring insulin-like growth factor I (IGF-I) and IGF-II in acid-chromatographed uremic serum. | journal=J Clin Endocrinol Metab | year= 1986 | volume= 63 | issue= 5 | pages= 1186-92 | pmid=3760118 | doi=10.1210/jcem-63-5-1186 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3760118  }}</ref>


==== Interpretation ====
==== Interpretation ====
Line 77: Line 72:
=== '''GH stimulation tests''' ===
=== '''GH stimulation tests''' ===
* It is indicated for most patients suspected to have GHD.
* It is indicated for most patients suspected to have GHD.
* The results should be interpreted in the context of [[bone age]], and [[Insulin-like growth factor-I|IGF-1]] and [[IGFBP3|IGFBP-3]] concentrations.
* The results should be interpreted in the context of [[bone age]], [[Insulin-like growth factor-I|IGF-1]] and [[IGFBP3|IGFBP-3]] concentrations.


* If the clinical and other laboratory criteria are sufficient to make the diagnosis of GHD, there is no need to perform the test. 
* If the clinical and other laboratory criteria are sufficient to make the diagnosis of GHD, there is no need to perform the test. 


* A serum GH concentration of >10 mcg/L, but a cutoff of 7.5 mcg/L is often used for modern assays.
* A serum GH concentration of >10 mcg/L with a cutoff of 7.5 mcg/L is often used for modern assays.


* The stimulation tests are performed after an overnight fast. Serum samples are collected at intervals to capture the peak [[Growth hormone|GH]] level.
* The stimulation tests are performed after an overnight fast. Serum samples are collected at intervals to capture the peak [[Growth hormone|GH]] level.
Line 95: Line 90:
!Side effect
!Side effect
|-
|-
|Clonidine 
|[[Clonidine]] 
|stimulation of GHRH via alpha-adrenergic pathways
|stimulation of [[Growth hormone-releasing hormone|GHRH]] via [[Alpha-adrenergic receptor|alpha-adrenergic]] pathways<ref>{{Cite journal
 
| author = [[N. C. Fraser]], [[J. Seth]] & [[N. S. Brown]]
| title = Clonidine is a better test for growth hormone deficiency than insulin hypoglycaemia
| journal = [[Archives of disease in childhood]]
| volume = 58
| issue = 5
| pages = 355–358
| year = 1983
| month = May
| pmid = 6344804
}}</ref>
|5 mcg/kg 
|5 mcg/kg 
|One hour
|One hour
|Hypotension and hypoglycemia   
|[[Hypotension]] and hypoglycemia<ref>{{Cite journal
 
| author = [[Monika Obara-Moszynska]], [[Andrzej Kedzia]], [[Eugeniusz Korman]] & [[Marek Niedziela]]
| title = Usefulness of growth hormone (GH) stimulation tests and IGF-I concentration measurement in GH deficiency diagnosis
| journal = [[Journal of pediatric endocrinology & metabolism : JPEM]]
| volume = 21
| issue = 6
| pages = 569–579
| year = 2008
| month = June
| pmid = 18717243
}}</ref>   
|-
|-
|Arginine
|[[Arginine]]
|
|Stimulates [[Growth hormone|GH]] release
|0.5 g/kg 
|0.5 g/kg 
|One hour
|One hour
|No side effects 
|No side effects 
|-
|-
|Glucagon 
|[[Glucagon]]<ref>{{Cite journal
|Transient hyperglycemia  
 
| author = [[K. S. Leong]], [[A. B. Walker]], [[I. Martin]], [[D. Wile]], [[J. Wilding]] & [[I. A. MacFarlane]]
| title = An audit of 500 subcutaneous glucagon stimulation tests to assess growth hormone and ACTH secretion in patients with hypothalamic-pituitary disease
| journal = [[Clinical endocrinology]]
| volume = 54
| issue = 4
| pages = 463–468
| year = 2001
| month = April
| pmid = 11318781
}}</ref> 
|Transient [[hyperglycemia]]
|0.03 mg/kg 
|0.03 mg/kg 
|Three hours 
|Three hours 
|Nausea, vomiting, sweating, and headache
|[[Nausea]], [[vomiting]], [[sweating]], and [[headache]]
|-
|-
|Insulin
|[[Insulin]]<ref>{{Cite journal
|Insulin-induced hypoglycemia is a potent stimulant of GH release
 
| title = Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society. GH Research Society
| journal = [[The Journal of clinical endocrinology and metabolism]]
| volume = 85
| issue = 11
| pages = 3990–3993
| year = 2000
| month = November
| doi = 10.1210/jcem.85.11.6984
| pmid = 11095419
}}</ref>
|Insulin-induced [[hypoglycemia]] is a potent stimulant of [[Growth hormone|GH]] release
|
|
|
|
|Hypoglycemia
|[[Hypoglycemia]]
|}
|}


Latest revision as of 14:08, 27 October 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

An immediate investigation should be started in severe short stature defined as a short child more than 3 standard deviations below the mean of children at the same age. Measurement of a random serum GH level alone is not helpful. Measurement of Insulin-like growth factor I (IGF-I) and Insulin-like growth factor binding protein-3 (IGFBP-3) is more helpful than GH level alone. GH stimulation tests are indicated for most patients suspected to have GHD. If the clinical and other laboratory criteria are sufficient to make the diagnosis of GHD, there is no need to perform the test. Pharmacologic stimuli include clonidine, glucagon, arginine, and insulin-induced hypoglycemia. Administration of sex steroids for a few days prior to the provocative GH testing reduces the chance of a false-positive result.

Laboratory Findings

Neonatal evaluation

  • Always measure GH levels:
    • In the presence of neonatal hypoglycemia
    • In the absence of a metabolic disorder.
    • A random GH measurement in a polyclonal RIA of less than 20 mg/L would suggest GHD within the newborn.
    • An IGFBP-3 measurement is of value for the diagnosis of GHD in infancy.

Children evaluation

The evaluation for GHD in a short child can not be initiated until exclusion of other causes of growth failure, which include hypothyroidism, chronic systemic disease, and Turner syndrome.

Indications for immediate investigation include:

  • Severe short stature: a short child more than 3 standard deviations (SD) below the mean height of children of the same age
  • In the absence of short stature: a height velocity more than 2 SD below the mean height for more than 1 year or more than 1.5 SD sustained over 2 years
  • Height more than 1.5 SD below the mid-parental height
  • Height more than 2 SD below the mean height and a height velocity of 1 or more SD below the mean height for chronological age sustained for more than a year
  • A decrease in height SD of more than 0.5 over 1 year in children over 2 years of age
  • Signs indicative of an intracranial lesion

Adult evaluation

Indications for immediate investigation include:

  • Adults with known hypothalamic or pituitary disease such as:
  • Adults with a history of GH deficiency in childhood. Some will be found to have normal GH secretion as adults, although patients with GH deficiency due to an organic cause such as pituitary adenoma never show normal GH level.

What to measure

GH secretion is pulsatile and its secretion is regulated by way of  hypothalamic factors; growth hormone releasing hormone (GHRH) and somatostatin.[3] Measurement of a random serum GH level alone isn't always beneficial, other tests which can be used in the diagnosis include:

Limitations

Interpretation

GH stimulation tests

  • It is indicated for most patients suspected to have GHD.
  • The results should be interpreted in the context of bone age, IGF-1 and IGFBP-3 concentrations.
  • If the clinical and other laboratory criteria are sufficient to make the diagnosis of GHD, there is no need to perform the test. 
  • A serum GH concentration of >10 mcg/L with a cutoff of 7.5 mcg/L is often used for modern assays.
  • The stimulation tests are performed after an overnight fast. Serum samples are collected at intervals to capture the peak GH level.
Test Mechanism Dose Peak of effect Side effect
Clonidine  stimulation of GHRH via alpha-adrenergic pathways[9] 5 mcg/kg  One hour Hypotension and hypoglycemia[10]   
Arginine Stimulates GH release 0.5 g/kg  One hour No side effects 
Glucagon[11]  Transient hyperglycemia 0.03 mg/kg  Three hours  Nausea, vomiting, sweating, and headache
Insulin[12] Insulin-induced hypoglycemia is a potent stimulant of GH release Hypoglycemia

Interpretation

  • The interpretation of the test results depends upon age and sex hormone concentrations.
  • Children with constitutional delay of growth and puberty may have low GH results on provocative testing in the absence of true GHD.
  • Administration of sex steroids for a few days prior to the provocative GH testing reduces the chance of a false-positive result.

References

  1. ↑ Mark L. Hartman, Brenda J. Crowe, Beverly M. K. Biller, Ken K. Y. Ho, David R. Clemmons & John J. Chipman (2002). "Which patients do not require a GH stimulation test for the diagnosis of adult GH deficiency?". The Journal of clinical endocrinology and metabolism. 87 (2): 477–485. doi:10.1210/jcem.87.2.8216. PMID 11836272. Unknown parameter |month= ignored (help)
  2. ↑ Maria Fleseriu, Ibrahim A. Hashim, Niki Karavitaki, Shlomo Melmed, M. Hassan Murad, Roberto Salvatori & Mary H. Samuels (2016). "Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline". The Journal of clinical endocrinology and metabolism. 101 (11): 3888–3921. doi:10.1210/jc.2016-2118. PMID 27736313. Unknown parameter |month= ignored (help)
  3. ↑ Osterstock G, Escobar P, Mitutsova V, Gouty-Colomer LA, Fontanaud P, Molino F; et al. (2010). "Ghrelin stimulation of growth hormone-releasing hormone neurons is direct in the arcuate nucleus". PLoS One. 5 (2): e9159. doi:10.1371/journal.pone.0009159. PMC 2820089. PMID 20161791.
  4. ↑ Baxter RC, Martin JL (1986). "Radioimmunoassay of growth hormone-dependent insulinlike growth factor binding protein in human plasma". J Clin Invest. 78 (6): 1504–12. doi:10.1172/JCI112742. PMC 423906. PMID 2431001.
  5. ↑ Powell DR, Rosenfeld RG, Baker BK, Liu F, Hintz RL (1986). "Serum somatomedin levels in adults with chronic renal failure: the importance of measuring insulin-like growth factor I (IGF-I) and IGF-II in acid-chromatographed uremic serum". J Clin Endocrinol Metab. 63 (5): 1186–92. doi:10.1210/jcem-63-5-1186. PMID 3760118.
  6. ↑ 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.
  7. ↑ Richmond EJ, Rogol AD (2008). "Growth hormone deficiency in children". Pituitary. 11 (2): 115–20. doi:10.1007/s11102-008-0105-7. PMID 18425584.
  8. ↑ "Stimulation of growth hormone secretion by levodopa-propranolol in children and adolescents". Pediatrics. 56 (2): 262–6. 1975. PMID 169508.
  9. ↑ N. C. Fraser, J. Seth & N. S. Brown (1983). "Clonidine is a better test for growth hormone deficiency than insulin hypoglycaemia". Archives of disease in childhood. 58 (5): 355–358. PMID 6344804. Unknown parameter |month= ignored (help)
  10. ↑ Monika Obara-Moszynska, Andrzej Kedzia, Eugeniusz Korman & Marek Niedziela (2008). "Usefulness of growth hormone (GH) stimulation tests and IGF-I concentration measurement in GH deficiency diagnosis". Journal of pediatric endocrinology & metabolism : JPEM. 21 (6): 569–579. PMID 18717243. Unknown parameter |month= ignored (help)
  11. ↑ K. S. Leong, A. B. Walker, I. Martin, D. Wile, J. Wilding & I. A. MacFarlane (2001). "An audit of 500 subcutaneous glucagon stimulation tests to assess growth hormone and ACTH secretion in patients with hypothalamic-pituitary disease". Clinical endocrinology. 54 (4): 463–468. PMID 11318781. Unknown parameter |month= ignored (help)
  12. ↑ "Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society. GH Research Society". The Journal of clinical endocrinology and metabolism. 85 (11): 3990–3993. 2000. doi:10.1210/jcem.85.11.6984. PMID 11095419. Unknown parameter |month= ignored (help)
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