81.Growth Hormone & Disease Therapy

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81.Growth Hormone & Disease Therapy

 

 

 

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Syllabus

Part I Physiology

1 Growth Hormone Receptor in Growth………………………………………… 3

Vivian Hwa

2 Ghrelin in the Regulation of GH Secretion

and Other Pituitary Hormones……………………………………………………. 17

Fabio Lanfranco, Matteo Baldi, Giovanna Motta,

Marco Alessandro Minetto, Filippa Marotta,

Valentina Gasco, and Ezio Ghigo

3 Growth Hormone Pulsatility and its Impact on Growth

and Metabolism in Humans ………………………………………………………… 33

Antonio Ribeiro-Oliveira Jr. and Ariel L. Barkan

4 Metabolic Actions of Growth Hormone……………………………………….. 57

Morton G. Burt

Part II Genetics

5 Molecular Genetics of Congenital Growth

Hormone Deficiency……………………………………………………………………. 83

Christopher J. Romero, Elyse Pine-Twaddell,

and Sally Radovick

6 Structural Abnormalities in Congenital Growth

Hormone Deficiency……………………………………………………………………. 103

Andrea Secco, Natascia Di Iorgi, and Mohamad Maghnie

7 Genetic Causes of Familial Pituitary Adenomas…………………………… 137

Silvia Vandeva, Sabina Zacharieva, Adrian F. Daly,

and Albert Beckers

Part III Growth Hormone Deficiency

8 The Epidemiology of Growth Hormone Deficiency………………………. 153

Kirstine Stochholm and Jens Sandahl Christiansen

9 Diagnosis of Growth Hormone Deficiency in Adults …………………….. 169

Sandra Pekic and Vera Popovic

10 Transition from Puberty to Adulthood ………………………………………… 187

Helena Gleeson

11 Issues in Long-Term Management of Adults

with Growth Hormone Deficiency……………………………………………….. 211

Anne McGowan and James Gibney

12 Quality of Life in Acromegaly and Growth

Hormone Deficiency……………………………………………………………………. 237

Susan M. Webb, Eugenia Resmini, Alicia Santos,

and Xavier Badia

Part IV Acromegaly

13 The Value of GH and IGF-I Measurements

in the Management of Acromegaly………………………………………………. 253

Pamela U. Freda

14 The Role of Somatostatin Analogues in Treatment

of Acromegaly…………………………………………………………………………….. 271

Haliza Haniff and Robert D. Murray

15 The Role of External Beam Radiation Therapy

and Stereotactic Radiosurgery in Acromegaly……………………………… 303

Bruce E. Pollock

16 Mortality and Morbidity in Acromegaly:

Impact of Disease Control …………………………………………………………… 317

Ian M. Holdaway

17 GHR Antagonist: Efficacy and Safety………………………………………….. 339

Claire E. Higham and Peter J. Trainer

Part V Use of Growth Hormone

18 Long-Acting Growth Hormone Analogues…………………………………… 361

Alice Thorpe, Helen Freeman, Sarbendra L. Pradhananga,

Ian R. Wilkinson, and Richard J.M. Ross

19 Growth Hormone Supplementation in the Elderly……………………….. 375

Ralf Nass and Jennifer Park

20 Growth Hormone in Sports: Is There Evidence of Benefit? ………….. 389

Anne E. Nelson, Ken Ho, and Vita Birzniece

Index…………………………………………………………………………………………………. 405

 

Growth Hormone & Disease Therapy


Growth hormone (GH) is synthesised and secreted by the somatotroph cells of the anterior lobe of the pituitary gland. Its actions involve multiple organs and systems, affecting postnatal longitudinal growth as well as protein, lipid, and carbohydrate metabolism. GH hypersecretion results in gigantism or acromegaly, a condition associated with significant morbidity and mortality, while GH deficiency results in growth retardation in children and the GH deficiency syndrome in adults. This article, aimed at non‐paediatric physicians, examines the clinical features, diagnosis, and current concepts in the management of these conditions.


Growth hormone (GH) is an anabolic hormone that is synthesised and secreted by the somatotroph cells of the anterior lobe of the pituitary gland. It is a member of the GH gene family, which includes prolactin and the placental lactogens. Using x ray crystallography, the three dimensional structure of human GH has been shown to consist of two disulfide bridges, four α‐helices arranged in an “up‐up‐down‐down” topology, and three shorter connective helices.1


GH exerts its biological effects by binding to the extracellular domain of the GH receptor, a single pass protein that also contains transmembrane and intracellular regions. A single GH molecule binds to two GH receptor molecules, resulting in dimerisation of the receptor.2 This GH induced GH receptor dimerisation is thought to be the first step in the signal pathway that ultimately results in the various biological effects associated with GH.3


GH actions involve multiple organs and systems. Postnatal longitudinal growth and development, but not intrauterine growth, are dependent on normal pulsatile GH secretion.4 GH is also responsible for changes in protein, lipid, and carbohydrate metabolism.5


The somatomedin hypothesis postulated that the observed effects of GH are mediated via a growth factor, initially labelled “somatomedin”6,7 and subsequently identified as insulin‐like growth factor (IGF) 1.8 However, recent evidence suggests that not all actions of GH are mediated by IGF1 and many factors other than GH contribute to the expression of serum IGF1 including nutritional state, liver function, serum protease activity, IGF1 binding proteins, and sex hormones.5


GH secretion is regulated by the hypothalamus and the mediators of GH actions. Regulatory factors include GH releasing hormone (GHRH), somatostatin, GH releasing peptide (ghrelin), and IGF1. Disorders of the GH/IGF1 system result either from GH hypersecretion (gigantism, acromegaly) or GH deficiency. This article, aimed at non‐paediatric physicians, examines the clinical features, diagnosis, and current concepts in the management of these conditions.


The term acromegaly is derived from the Greek words akron, meaning extremity, and megas meaning great. Acromegaly is a chronic endocrine disease first described by the French neurologist Pierre Marie in 1886. It is caused almost invariably by a GH secreting pituitary adenoma, although rarely it may be attributable to a hypothalamic tumour secreting GHRH or ectopic GHRH secretion from a carcinoid tumour (predominantly of the pancreas or bronchus). It is a rare condition, with an estimated prevalence of around 60 per million and an annual incidence of 3–4 per million,9 but active acromegaly is associated with significant morbidity and an increase in mortality compared with the general population.10,11,12,13,14


Molecular pathogenesis
Pituitary adenomas generally result from dysregulated monoclonal expansion of a mutated cell, pointing to an intrinsic defect as the primary neoplastic event in pituitary tumourigenesis.15 Tumour formation is most probably the ultimate result of a series of genetic changes involving tumour suppressor gene inactivation and oncogene activation. Stimulatory G protein (Gs) is involved in the mediation of GHRH action and contains an α‐subunit; an activating mutation of the α‐subunit gene (gsp) leads to persistently activated stimulatory G protein and high intracellular levels of cyclic AMP. This defect mimics stimulation of adenylyl cyclase by GHRH receptor activation, resulting in autonomous GH secretion.15 The gsp mutation has been found in 40% of human GH secreting pituitary adenomas, and is comparatively specific for somatotroph tumourigenesis.


Clinical features
The clinical features of acromegaly are attributable to the somatic and metabolic effects of prolonged excess GH exposure or to local effects of an expanding pituitary mass.16 They often develop insidiously over many years, resulting in delayed diagnosis.17 Most patients experience headaches and sweating. The most typical clinical signs are the coarse facial features, large, spade shaped hands and enlarged feet resulting from soft tissue swelling and bony enlargement. The facial features include deep nasolabial furrows, prominent supraorbital ridges, and enlargement of the lips and nose. Growth of the mandible results in prognathism, malocclusion, and widened inter‐dental spaces. Other common features include enlargement of the tongue (macroglossia), swelling of the nasopharyngeal tissue, sleep apnoea, lethargy, skin tags, goitre, and colonic polyps. The expanding pituitary mass may cause hypopituitarism, reproductive disorders, and visual symptoms. GH hypersecretion occurring before the epiphyses have fused results in excess linear bone growth and gigantism.


Complications
Musculoskeletal complications
The most significant cause of functional disability in acromegaly is arthropathy. Acromegalic arthropathy affects up to 70% of patients and involves both the axial and peripheral skeleton.18,19 The underlying pathophysiology is not entirely understood, but it has been hypothesised that GH excess stimulates local production of IGF1 in cartilage, resulting in thickening of the cartilage, change of the normal joint geometry, and joint hypermobility.18 Radiological findings include narrowing of the joint spaces, osteophytes, and other features seen in osteoarthritis. Symptomatic carpal tunnel syndrome is also a frequent finding, affecting up to 60% of patients, and is thought to be attributable to oedema of the median nerve in the carpal tunnel, rather than extrinsic nerve compression.18,20


Cardiovascular complications
Acromegaly is characterised by a high incidence of cardiovascular disease, which contributes significantly to morbidity and mortality. Hypertension occurs in around a third of all patients, ranging in some series up to 60%.21 The mechanisms underlying the development of hypertension in acromegaly remain unclear although experimental and clinical studies suggest possible roles for the anti‐natriuretic action of GH, changed sympathetic tone, and direct effects of vascular growth factors.21 Acromegalic cardiomyopathy is caused by the effects of chronic GH excess on the heart. It is characterised by biventricular concentric hypertrophy, with thickened ventricle walls but normal sized chambers.18 The cardiac hypertrophy is associated with functional changes (decreased ejection fraction in response to exercise), valve abnormalities, and a high incidence of arrhythmias.22,23,24,25 The incidence and severity of the abnormalities increase in elderly patients with long disease duration.26,27


Metabolic complications
GH counteracts the effects of insulin on glucose and lipid metabolism, resulting in metabolic complications in patients with acromegaly. The most frequent of these is changed glucose metabolism. The prevalence of overt diabetes mellitus ranges from 19% to 56% in patients with active acromegaly, with impaired glucose tolerance (IGT) occurring in up to 46%.18,28 Studies investigating the pathogenesis of changed glucose metabolism in acromegaly suggest GH excess induces insulin resistance by impairing the ability of insulin to suppress gluconeogenesis, decreasing peripheral glucose utilisation, and reducing insulin receptor numbers and binding affinity.

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