Growth hormone deficiency pathophysiology: Difference between revisions
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==Overview== | ==Overview == | ||
The [[ | The [[Somatotrophs|somatotroph cells]] of the [[Anterior pituitary gland|anterior pituitary organ]] produce [[growth hormone]] ([[Growth hormone|GH]]). The most widely studied impact of growth hormone is increasing [[weight]]. [[Growth hormone|GH]] causes [[epiphyseal plate]] broadening and [[ligament]] development. [[Growth hormone|GH]] deficiency results in alterations in the [[physiology]] of different systems of the body, manifesting as altered [[lipid metabolism]], increased [[Subcutaneous tissue|subcutaneous]] [[visceral]] [[fat]], decreased [[muscle mass]], decreased [[bone density]], low exercise performance, and reduced quality of life. The hereditary premise of inborn growth hormone deficiency relies upon numerous factors; POU1F1 quality transformations are the most widely recognized hereditary reason for the joined [[pituitary hormone]] lack. Quality [[Deletion (genetics)|deletions]], [[Frameshift mutation|frameshift]] transformations, and jabber changes of GH1 quality have been described as reasons for familial GHD. | ||
==Pathophysiology== | ==Pathophysiology== | ||
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* They are regulated by two [[Hypothalamus|hypothalamic]] hormones; [[GHRH|GH-releasing hormone]] ([[GHRH]]) stimulates and [[somatostatin]] inhibits them. | * They are regulated by two [[Hypothalamus|hypothalamic]] hormones; [[GHRH|GH-releasing hormone]] ([[GHRH]]) stimulates and [[somatostatin]] inhibits them. | ||
* GH | * GH increases [[body mass]] by: | ||
** | **Increasing total body [[protein]] content and is associated with an increase in [[amino acid]] incorporation into [[cartilage]] and [[bone]].<ref name="pmid13319878">{{cite journal| author=MURPHY WR, DAUGHADAY WH, HARTNETT C| title=The effect of hypophysectomy and growth hormone on the incorporation of labeled sulfate into tibial epiphyseal and nasal cartilage of the rat. | journal=J Lab Clin Med | year= 1956 | volume= 47 | issue= 5 | pages= 715-22 | pmid=13319878 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13319878 }}</ref> | ||
** | **Stimulation of l[[Lipolysis|ipolysis]] decreasing total body [[fat]] content. | ||
** | **Increasing [[bone mass]] by stimulating skeletal [[insulin-like growth factor-I]], causing [[hypertrophy]] of [[osteoblasts]], bone remodeling, and [[mineralization]]. | ||
**Decreasing the expression of [[adipocyte]] maturation regulators ([[CEBPA|''C/EBPα'',]] ''[[PPAR|PPARγ]]'') and prominent genes related to [[lipid]] synthesis such as ''[[FAS ligand|FAS]]'' and ''[[FABP1|FABP]].'' | |||
**Increasing the [[Messenger RNA|mRNA]] expression of ''[[adiponectin]]'' and ''[[UCP1]]'' in mature [[adipocytes]] causing [[epiphyseal plate]] widening and [[cartilage]] growth.<ref name="pmid15689575">{{cite journal| author=Veldhuis JD, Roemmich JN, Richmond EJ, Rogol AD, Lovejoy JC, Sheffield-Moore M et al.| title=Endocrine control of body composition in infancy, childhood, and puberty. | journal=Endocr Rev | year= 2005 | volume= 26 | issue= 1 | pages= 114-46 | pmid=15689575 | doi=10.1210/er.2003-0038 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15689575 }}</ref> | |||
*[[Growth hormone|GH]] deficiency results in alterations in the physiology of different systems of the body, manifesting as altered [[lipid metabolism]], increased subcutaneous visceral [[fat]], decreased [[muscle mass]], decreased [[bone density]], low exercise performance, and reduced quality of life. | *[[Growth hormone|GH]] deficiency results in alterations in the [[physiology]] of different systems of the body, manifesting as altered [[lipid metabolism]], increased [[Subcutaneous tissue|subcutaneous]] [[visceral]] [[fat]], decreased [[muscle mass]], decreased [[bone density]], low exercise performance, and reduced quality of life. | ||
== | == Regulation of growth hormone secretion == | ||
* The secretion of [[growth hormone]] is controlled by a complex regulatory system. Primarily, it is controlled by two [[hormones]]; [[Growth hormone releasing hormone|GH-releasing hormone]] and [[somatostatin]]. | |||
* The [[adenylate cyclase]]-[[cyclic AMP]]-[[protein kinase A]] plays a major role in the control of GH secretion by [[Growth hormone releasing hormone|GH-releasing hormone]]. | |||
* GH gene expression is also of importance in determining the [[Growth hormone|GH]] response. | |||
* GH secretion is [[Pulsatile flow|pulsatile]]; between pulses, serum GH concentration may be undetectable. It is thought that the pulses of GH release are mediated by the reduction in inhibition by [[somatostatin]] with an increase of [[GHRH]]. | |||
* The [[glucocorticoids]] play a principal role in the functional maturation of [[Growth hormone|GH]] cells in the fetal [[Pituitary gland|pituitary glands]], inducing [[Growth hormone|GH]] and [[Growth hormone-releasing hormone|GHRH-receptor]] [[gene expression]], and development of the [[Growth hormone|GH]] secretory system. | |||
* During [[puberty]], there is a temporary increase in [[Growth hormone|GH]] secretion with a subsequent return to the normal values in early adulthood. | |||
[[File:1809 Hormonal Regulation of Growth.jpg|500px|center|thumb|Growth hormone secretion regulations, source: By OpenStax College - Anatomy & Physiology, Connexions Web site. httpcnx.orgcontentcol114961.6, Jun 19, 2013., CC BY 3.0, httpscommons.wikimedia.orgwindex.phpcurid=30148146]] | |||
== Molecular effects of growth hormone on cells == | |||
* [[Growth hormone]] acts by binding to the [[Receptor (biochemistry)|receptor]] [[homodimer]] in the [[liver]]. | |||
* The [[Receptor (biochemistry)|receptor]] consists of an [[extracellular]] [[Ligand (biochemistry)|ligand-binding]] [[Domain (biology)|domain]] and a [[Cytoplasm|cytoplasmic]] signaling part. | |||
* GH acts to stimulate hepatic synthesis and secretion of [[Insulin-like growth factor-I|insulin-like growth factor-1]] ([[Insulin-like growth factor-I|IGF-1]]). | |||
* [[Insulin-like growth factor-I|IGF-1]] is a [[protein]] responsible for most of the growth-promoting activities of [[Growth hormone|GH]]. | |||
* [[Insulin-like growth factor-I|IGF-1]] directly inhibits [[Growth hormone|GH]] secretion and GH [[Receptor (biochemistry)|receptor]] function by a negative feedback effect. | |||
* [[Growth hormone|GH]] stimulates [[cell proliferation]] in [[osteoblasts]]. Human [[Trabecular bone|trabecular]] [[osteoblasts]] produce mainly [[Insulin-like growth factor 2|IGF-II]], IGFBP-3 and fewer quantities of [[IGF-I]] in culture. | |||
* IGFs and their binding [[proteins]] may exert important regulatory effects on the [[Growth hormone|GH]] effect on [[osteoblasts]]. | |||
[[File:Growth liver.png|300px|center|thumb| Growth hormone peripheral action, source: By Mikael Häggström.When using this image in external works, it may be cited asHäggström, Mikael (2014). Medical gallery of Mikael Häggström 2014. WikiJournal of Medicine 1 (2). DOI10.15347wjm2014.008. ISSN 2002-4436]] | |||
== Growth Hormone signaling == | |||
* A single [[Growth hormone|GH]] molecule binds with two GH [[Receptor (biochemistry)|receptor]] molecules, followed by activation of [[Janus kinase|JAK2 tyrosine kinase]] by [[phosphorylation]]. | |||
* [[Phosphorylation]] of [[JAK2]] leads to [[phosphorylation]] of intracellular proteins called [[STAT protein|STAT proteins]], [[MAP kinases|MAP kinase]] activation, and induction of [[gene expression]]. | |||
* These [[STAT protein|STAT proteins]] are [[phosphorylated]] by [[JAK2]] and directly translocated to the [[cell nucleus]], where they play the major control of [[Growth hormone|GH]]-specific [[gene]] effects by binding to [[nuclear DNA]]. | |||
* [[STAT5]] plays an important role in the regulation of expression of some [[Gene|genes]] in the [[liver]] [[Cell (biology)|cells.]] | |||
* A defect in [[Growth hormone|GH]]-mediated [[JAK-STAT signaling pathway|JAK-STAT]] signal [[transduction]] could be a cause of the [[Growth hormone|GH]] resistance. | |||
[[File:Growth Hormone-pathway-3.gif|350px|center|thumb|GH signaling]] | |||
==Genetic basis of growth hormone deficiency== | |||
==== ''[[POU1F1]]'' gene mutations ==== | ==== ''[[POU1F1]]'' gene mutations ==== | ||
* | * This is the most common known genetic cause of the combined [[Pituitary gland|pituitary]] hormone deficiency.<ref name="pmid26608600">{{cite journal| author=Ziemnicka K, Budny B, Drobnik K, Baszko-Błaszyk D, Stajgis M, Katulska K et al.| title=Two coexisting heterozygous frameshift mutations in PROP1 are responsible for a different phenotype of combined pituitary hormone deficiency. | journal=J Appl Genet | year= 2016 | volume= 57 | issue= 3 | pages= 373-81 | pmid=26608600 | doi=10.1007/s13353-015-0328-z | pmc=4963446 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26608600 }}</ref> | ||
* It is responsible for [[Pituitary gland|pituitary]]-specific [[Transcription (genetics)|transcription]] of [[Gene|genes]] for GH, [[prolactin]], [[thyrotropin]], and the [[growth hormone releasing hormone|growth hormone-releasing hormone]] ([[GHRH]]) receptor.<ref name="pmid1977085">{{cite journal| author=Li S, Crenshaw EB, Rawson EJ, Simmons DM, Swanson LW, Rosenfeld MG| title=Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU-domain gene pit-1. | journal=Nature | year= 1990 | volume= 347 | issue= 6293 | pages= 528-33 | pmid=1977085 | doi=10.1038/347528a0 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1977085 }}</ref> | * It is responsible for [[Pituitary gland|pituitary]]-specific [[Transcription (genetics)|transcription]] of [[Gene|genes]] for GH, [[prolactin]], [[thyrotropin]], and the [[growth hormone releasing hormone|growth hormone-releasing hormone]] ([[GHRH]]) receptor.<ref name="pmid1977085">{{cite journal| author=Li S, Crenshaw EB, Rawson EJ, Simmons DM, Swanson LW, Rosenfeld MG| title=Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU-domain gene pit-1. | journal=Nature | year= 1990 | volume= 347 | issue= 6293 | pages= 528-33 | pmid=1977085 | doi=10.1038/347528a0 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1977085 }}</ref> | ||
* ''PROP1'' [[mutations]] result in failure to activate ''POU1F1/Pit1'' [[gene expression]] and probably cause [[Pituitary gland|pituitary]] hypoplasia.<ref name="pmid9462743">{{cite journal| author=Wu W, Cogan JD, Pfäffle RW, Dasen JS, Frisch H, O'Connell SM et al.| title=Mutations in PROP1 cause familial combined pituitary hormone deficiency. | journal=Nat Genet | year= 1998 | volume= 18 | issue= 2 | pages= 147-9 | pmid=9462743 | doi=10.1038/ng0298-147 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9462743 }}</ref> | * ''PROP1'' [[mutations]] result in failure to activate ''POU1F1/Pit1'' [[gene expression]] and probably cause [[Pituitary gland|pituitary]] hypoplasia.<ref name="pmid9462743">{{cite journal| author=Wu W, Cogan JD, Pfäffle RW, Dasen JS, Frisch H, O'Connell SM et al.| title=Mutations in PROP1 cause familial combined pituitary hormone deficiency. | journal=Nat Genet | year= 1998 | volume= 18 | issue= 2 | pages= 147-9 | pmid=9462743 | doi=10.1038/ng0298-147 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9462743 }}</ref> | ||
==== GH1 gene mutations ==== | ==== GH1 gene mutations ==== | ||
* | * ''GH1'' gene encoding GH is located on [[chromosome 17]]. | ||
* [[Gene deletion|Gene deletions]], f[[Frameshift mutation|rameshift]] mutations, and [[nonsense mutations]] of ''GH1'' have been described as causes of familial GHD. | * [[Gene deletion|Gene deletions]], f[[Frameshift mutation|rameshift]] mutations, and [[nonsense mutations]] of ''GH1'' have been described as causes of familial GHD. | ||
| Line 41: | Line 69: | ||
==== '''Defective stabilization of circulating [[Insulin-like growth factor-I|IGF-I]]''' ==== | ==== '''Defective stabilization of circulating [[Insulin-like growth factor-I|IGF-I]]''' ==== | ||
* Acid-labile subunit is important for the stabilization of the [[Insulin-like growth factor-I|IGF-I]]. | * Acid-labile subunit is important for the stabilization of the [[Insulin-like growth factor-I|IGF-I]]. | ||
* [[Mutations]] in the [[gene]] coding for it causes less stable and subsequently less | * [[Mutations]] in the [[gene]] coding for it causes less stable and subsequently less effective end product.<ref name="pmid19729943">{{cite journal| author=Domené HM, Hwa V, Argente J, Wit JM, Wit JM, Camacho-Hübner C et al.| title=Human acid-labile subunit deficiency: clinical, endocrine and metabolic consequences. | journal=Horm Res | year= 2009 | volume= 72 | issue= 3 | pages= 129-41 | pmid=19729943 | doi=10.1159/000232486 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19729943 }}</ref> | ||
==== '''[[Insulin-like growth factor-I|IGF-I]] receptor mutations''' ==== | ==== '''[[Insulin-like growth factor-I|IGF-I]] receptor mutations''' ==== | ||
Latest revision as of 16:15, 30 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
The somatotroph cells of the anterior pituitary organ produce growth hormone (GH). The most widely studied impact of growth hormone is increasing weight. GH causes epiphyseal plate broadening and ligament development. GH deficiency results in alterations in the physiology of different systems of the body, manifesting as altered lipid metabolism, increased subcutaneous visceral fat, decreased muscle mass, decreased bone density, low exercise performance, and reduced quality of life. The hereditary premise of inborn growth hormone deficiency relies upon numerous factors; POU1F1 quality transformations are the most widely recognized hereditary reason for the joined pituitary hormone lack. Quality deletions, frameshift transformations, and jabber changes of GH1 quality have been described as reasons for familial GHD.
Pathophysiology
- The somatotroph cells of the anterior pituitary gland produce growth hormone.[1]
- They are regulated by two hypothalamic hormones; GH-releasing hormone (GHRH) stimulates and somatostatin inhibits them.
- GH increases body mass by:
- Increasing total body protein content and is associated with an increase in amino acid incorporation into cartilage and bone.[2]
- Stimulation of lipolysis decreasing total body fat content.
- Increasing bone mass by stimulating skeletal insulin-like growth factor-I, causing hypertrophy of osteoblasts, bone remodeling, and mineralization.
- Decreasing the expression of adipocyte maturation regulators (C/EBPα, PPARγ) and prominent genes related to lipid synthesis such as FAS and FABP.
- Increasing the mRNA expression of adiponectin and UCP1 in mature adipocytes causing epiphyseal plate widening and cartilage growth.[3]
- GH deficiency results in alterations in the physiology of different systems of the body, manifesting as altered lipid metabolism, increased subcutaneous visceral fat, decreased muscle mass, decreased bone density, low exercise performance, and reduced quality of life.
Regulation of growth hormone secretion
- The secretion of growth hormone is controlled by a complex regulatory system. Primarily, it is controlled by two hormones; GH-releasing hormone and somatostatin.
- The adenylate cyclase-cyclic AMP-protein kinase A plays a major role in the control of GH secretion by GH-releasing hormone.
- GH gene expression is also of importance in determining the GH response.
- GH secretion is pulsatile; between pulses, serum GH concentration may be undetectable. It is thought that the pulses of GH release are mediated by the reduction in inhibition by somatostatin with an increase of GHRH.
- The glucocorticoids play a principal role in the functional maturation of GH cells in the fetal pituitary glands, inducing GH and GHRH-receptor gene expression, and development of the GH secretory system.
- During puberty, there is a temporary increase in GH secretion with a subsequent return to the normal values in early adulthood.
Molecular effects of growth hormone on cells
- Growth hormone acts by binding to the receptor homodimer in the liver.
- The receptor consists of an extracellular ligand-binding domain and a cytoplasmic signaling part.
- GH acts to stimulate hepatic synthesis and secretion of insulin-like growth factor-1 (IGF-1).
- IGF-1 is a protein responsible for most of the growth-promoting activities of GH.
- IGF-1 directly inhibits GH secretion and GH receptor function by a negative feedback effect.
- GH stimulates cell proliferation in osteoblasts. Human trabecular osteoblasts produce mainly IGF-II, IGFBP-3 and fewer quantities of IGF-I in culture.
- IGFs and their binding proteins may exert important regulatory effects on the GH effect on osteoblasts.
Growth Hormone signaling
- A single GH molecule binds with two GH receptor molecules, followed by activation of JAK2 tyrosine kinase by phosphorylation.
- Phosphorylation of JAK2 leads to phosphorylation of intracellular proteins called STAT proteins, MAP kinase activation, and induction of gene expression.
- These STAT proteins are phosphorylated by JAK2 and directly translocated to the cell nucleus, where they play the major control of GH-specific gene effects by binding to nuclear DNA.
- STAT5 plays an important role in the regulation of expression of some genes in the liver cells.
- A defect in GH-mediated JAK-STAT signal transduction could be a cause of the GH resistance.
Genetic basis of growth hormone deficiency
POU1F1 gene mutations
- This is the most common known genetic cause of the combined pituitary hormone deficiency.[4]
- It is responsible for pituitary-specific transcription of genes for GH, prolactin, thyrotropin, and the growth hormone-releasing hormone (GHRH) receptor.[5]
- PROP1 mutations result in failure to activate POU1F1/Pit1 gene expression and probably cause pituitary hypoplasia.[6]
GH1 gene mutations
- GH1 gene encoding GH is located on chromosome 17.
- Gene deletions, frameshift mutations, and nonsense mutations of GH1 have been described as causes of familial GHD.
Syndrome of bioinactive GH
- Bioinactive GH has the main symptoms and signs of isolated GHD with normal basal GH levels and low insulin-like growth factor I concentrations.[7]
GH receptor signal transduction
- It is essential for normal signaling of the GH receptor. Mutations in the gene encoding signal transducer decrease the response of receptors to GH.[8]
IGF-I gene mutations
- Mutations in the gene encoding IGF-I cause a unique syndrome of GHD.[9]
- Patients with IGF-I gene mutations have prenatal growth failure, microcephaly, significant neurocognitive deficits, and sensorineural hearing loss.
Defective stabilization of circulating IGF-I
- Acid-labile subunit is important for the stabilization of the IGF-I.
- Mutations in the gene coding for it causes less stable and subsequently less effective end product.[10]
IGF-I receptor mutations
- Mutations in the gene encoding the receptor for the IGF-I result in partial loss of function of the IGF-I receptor.[11]
References
- ↑ Cuttler L (1996). "The regulation of growth hormone secretion". Endocrinol Metab Clin North Am. 25 (3): 541–71. PMID 8879986.
- ↑ MURPHY WR, DAUGHADAY WH, HARTNETT C (1956). "The effect of hypophysectomy and growth hormone on the incorporation of labeled sulfate into tibial epiphyseal and nasal cartilage of the rat". J Lab Clin Med. 47 (5): 715–22. PMID 13319878.
- ↑ Veldhuis JD, Roemmich JN, Richmond EJ, Rogol AD, Lovejoy JC, Sheffield-Moore M; et al. (2005). "Endocrine control of body composition in infancy, childhood, and puberty". Endocr Rev. 26 (1): 114–46. doi:10.1210/er.2003-0038. PMID 15689575.
- ↑ Ziemnicka K, Budny B, Drobnik K, Baszko-Błaszyk D, Stajgis M, Katulska K; et al. (2016). "Two coexisting heterozygous frameshift mutations in PROP1 are responsible for a different phenotype of combined pituitary hormone deficiency". J Appl Genet. 57 (3): 373–81. doi:10.1007/s13353-015-0328-z. PMC 4963446. PMID 26608600.
- ↑ Li S, Crenshaw EB, Rawson EJ, Simmons DM, Swanson LW, Rosenfeld MG (1990). "Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU-domain gene pit-1". Nature. 347 (6293): 528–33. doi:10.1038/347528a0. PMID 1977085.
- ↑ Wu W, Cogan JD, Pfäffle RW, Dasen JS, Frisch H, O'Connell SM; et al. (1998). "Mutations in PROP1 cause familial combined pituitary hormone deficiency". Nat Genet. 18 (2): 147–9. doi:10.1038/ng0298-147. PMID 9462743.
- ↑ Besson A, Salemi S, Deladoëy J, Vuissoz JM, Eblé A, Bidlingmaier M; et al. (2005). "Short stature caused by a biologically inactive mutant growth hormone (GH-C53S)". J Clin Endocrinol Metab. 90 (5): 2493–9. doi:10.1210/jc.2004-1838. PMID 15713716.
- ↑ Hwa V, Camacho-Hübner C, Little BM, David A, Metherell LA, El-Khatib N; et al. (2007). "Growth hormone insensitivity and severe short stature in siblings: a novel mutation at the exon 13-intron 13 junction of the STAT5b gene". Horm Res. 68 (5): 218–24. doi:10.1159/000101334. PMID 17389811.
- ↑ Batey L, Moon JE, Yu Y, Wu B, Hirschhorn JN, Shen Y; et al. (2014). "A novel deletion of IGF1 in a patient with idiopathic short stature provides insight Into IGF1 haploinsufficiency". J Clin Endocrinol Metab. 99 (1): E153–9. doi:10.1210/jc.2013-3106. PMC 3879666. PMID 24243634.
- ↑ Domené HM, Hwa V, Argente J, Wit JM, Wit JM, Camacho-Hübner C; et al. (2009). "Human acid-labile subunit deficiency: clinical, endocrine and metabolic consequences". Horm Res. 72 (3): 129–41. doi:10.1159/000232486. PMID 19729943.
- ↑ Kawashima Y, Higaki K, Fukushima T, Hakuno F, Nagaishi J, Hanaki K; et al. (2012). "Novel missense mutation in the IGF-I receptor L2 domain results in intrauterine and postnatal growth retardation". Clin Endocrinol (Oxf). 77 (2): 246–54. doi:10.1111/j.1365-2265.2012.04357.x. PMID 22309212.