24

REVIEW

Growth hormone and its disorders

J Ayuk, M C Sheppard
...............................................................................................................................

Postgrad Med J 2006;82:24–30. doi: 10.1136/pgmj.2005.036087

Growth hormone (GH) is synthesised and secreted by the factors include GH releasing hormone (GHRH),
somatostatin, GH releasing peptide (ghrelin),
somatotroph cells of the anterior lobe of the pituitary gland. and IGF1. Disorders of the GH/IGF1 system
Its actions involve multiple organs and systems, affecting result either from GH hypersecretion (gigantism,
postnatal longitudinal growth as well as protein, lipid, and acromegaly) or GH deficiency. This article, aimed
at non-paediatric physicians, examines the clin-
carbohydrate metabolism. GH hypersecretion results in ical features, diagnosis, and current concepts in
gigantism or acromegaly, a condition associated with the management of these conditions.
significant morbidity and mortality, while GH deficiency
results in growth retardation in children and the GH ACROMEGALY
The term acromegaly is derived from the Greek
deficiency syndrome in adults. This article, aimed at non- words akron, meaning extremity, and megas
paediatric physicians, examines the clinical features, meaning great. Acromegaly is a chronic endo-
crine disease first described by the French
diagnosis, and current concepts in the management of neurologist Pierre Marie in 1886. It is caused
these conditions. 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

G
rowth hormone (GH) is an anabolic
(predominantly of the pancreas or bronchus). It
hormone that is synthesised and secreted is a rare condition, with an estimated prevalence
by the somatotroph cells of the anterior of around 60 per million and an annual incidence
lobe of the pituitary gland. It is a member of the of 3–4 per million,9 but active acromegaly is
GH gene family, which includes prolactin and associated with significant morbidity and an
the placental lactogens. Using x ray crystal- increase in mortality compared with the general
lography, the three dimensional structure of population.10–14
human GH has been shown to consist of two
disulfide bridges, four a-helices arranged in an Molecular pathogenesis
‘‘up-up-down-down’’ topology, and three shorter Pituitary adenomas generally result from dysre-
connective helices.1 gulated monoclonal expansion of a mutated cell,
GH exerts its biological effects by binding to pointing to an intrinsic defect as the primary
the extracellular domain of the GH receptor, a neoplastic event in pituitary tumourigenesis.15
single pass protein that also contains transmem- Tumour formation is most probably the ultimate
brane and intracellular regions. A single GH result of a series of genetic changes involving
molecule binds to two GH receptor molecules, tumour suppressor gene inactivation and onco-
resulting in dimerisation of the receptor.2 This gene activation. Stimulatory G protein (Gs) is
GH induced GH receptor dimerisation is thought involved in the mediation of GHRH action and
to be the first step in the signal pathway that contains an a-subunit; an activating mutation of
ultimately results in the various biological effects the a-subunit gene (gsp) leads to persistently
associated with GH.3 activated stimulatory G protein and high intra-
GH actions involve multiple organs and cellular levels of cyclic AMP. This defect mimics
systems. Postnatal longitudinal growth and stimulation of adenylyl cyclase by GHRH recep-
development, but not intrauterine growth, are tor activation, resulting in autonomous GH
dependent on normal pulsatile GH secretion.4 GH secretion.15 The gsp mutation has been found in
is also responsible for changes in protein, lipid, 40% of human GH secreting pituitary adenomas,
and carbohydrate metabolism.5 and is comparatively specific for somatotroph
The somatomedin hypothesis postulated that tumourigenesis.
See end of article for the observed effects of GH are mediated via a
authors’ affiliations growth factor, initially labelled ‘‘somatome- Clinical features
....................... The clinical features of acromegaly are attribu-
din’’6 7 and subsequently identified as insulin-
Correspondence to: like growth factor (IGF) 1.8 However, recent table to the somatic and metabolic effects of
Dr J Ayuk, Division of evidence suggests that not all actions of GH are prolonged excess GH exposure or to local effects
Medical Sciences, Queen of an expanding pituitary mass.16 They often
Elizabeth Hospital, mediated by IGF1 and many factors other than
Edgbaston, Birmingham GH contribute to the expression of serum IGF1
B15 2TH, UK; j.ayuk@ including nutritional state, liver function, serum Abbreviations: GH, growth hormone; IGF, insulin-like
bham.ac.uk protease activity, IGF1 binding proteins, and sex growth factor; OGTT, oral glucose tolerance test; IGT,
impaired glucose intolerance; GHRH, GH releasing
Submitted 14 April 2005 hormones.5 hormone; TRH, thyrotropin releasing hormone; MRI,
Accepted 10 May 2005 GH secretion is regulated by the hypothalamus magnetic resonance imaging; CT, computed tomography;
....................... and the mediators of GH actions. Regulatory TSS, transsphenoidal surgery

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Growth hormone disorders 25

Growth hormone (GH) Acromegaly

N An anabolic hormone N Attributable to GH excess

N Synthesised in the anterior lobe of the pituitary gland N Annual incidence 3–4 per million
N Acts by binding to two GH receptor molecules N Prevalence 60 per million
N Responsible for longitudinal growth N Associated with significant morbidity and mortality
N Modulates protein, lipid, and carbohydrate metabo- N Treatment modalities; surgery, radiotherapy, medical
lism therapy
N Secretion regulated by the hypothalamus

Clinical features of acromegaly

develop insidiously over many years, resulting in delayed
diagnosis.17 Most patients experience headaches and sweat-
ing. The most typical clinical signs are the coarse facial N Coarse facial features
features, large, spade shaped hands and enlarged feet N Large, spade shaped hands
resulting from soft tissue swelling and bony enlargement. N Large feet
The facial features include deep nasolabial furrows, promi- N Prognathism and macroglossia
nent supraorbital ridges, and enlargement of the lips and
nose. Growth of the mandible results in prognathism, N Sleep apnoea
malocclusion, and widened inter-dental spaces. Other com- N Goitre
mon features include enlargement of the tongue (macro- N Colonic polyps
glossia), swelling of the nasopharyngeal tissue, sleep apnoea,
lethargy, skin tags, goitre, and colonic polyps. The expanding
pituitary mass may cause hypopituitarism, reproductive with acromegaly. The most frequent of these is changed
disorders, and visual symptoms. GH hypersecretion occurring glucose metabolism. The prevalence of overt diabetes mellitus
before the epiphyses have fused results in excess linear bone ranges from 19% to 56% in patients with active acromegaly,
growth and gigantism. with impaired glucose tolerance (IGT) occurring in up to
46%.18 28 Studies investigating the pathogenesis of changed
Complications glucose metabolism in acromegaly suggest GH excess induces
Musculoskeletal complications insulin resistance by impairing the ability of insulin to
The most significant cause of functional disability in suppress gluconeogenesis, decreasing peripheral glucose
acromegaly is arthropathy. Acromegalic arthropathy affects utilisation, and reducing insulin receptor numbers and
up to 70% of patients and involves both the axial and binding affinity.18
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, Neoplastic complications
resulting in thickening of the cartilage, change of the normal The association between the GH/IGF1 axis and neoplasia
joint geometry, and joint hypermobility.18 Radiological find- such as breast, prostate, and colon cancer has been the
ings include narrowing of the joint spaces, osteophytes, and subject of basic and clinical research for many years. Data
other features seen in osteoarthritis. Symptomatic carpal linking IGFs to tumourigenesis and neoplastic growth have
tunnel syndrome is also a frequent finding, affecting up to been extensively reviewed by Khandwala et al.29 However,
60% of patients, and is thought to be attributable to oedema epidemiological studies exploring the link between acrome-
of the median nerve in the carpal tunnel, rather than galy, cancer incidence, and mortality have given rise to
extrinsic nerve compression.18 20 conflicting data, leading to significant debate. Early studies
suggested an increased incidence of neoplasia overall,
Cardiovascular complications particularly of the breast17 and colon,30 in patients with
Acromegaly is characterised by a high incidence of cardio- acromegaly. Evidence from more recent studies, however, has
vascular disease, which contributes significantly to morbidity failed to confirm these findings, and suggests overall cancer
and mortality. Hypertension occurs in around a third of all incidence is not increased in acromegaly.31 32 What has
patients, ranging in some series up to 60%.21 The mechanisms emerged is that patients with acromegaly have an increased
underlying the development of hypertension in acromegaly risk of developing colorectal cancer, although the exact
remain unclear although experimental and clinical studies magnitude of this risk and the role of screening programmes
suggest possible roles for the anti-natriuretic action of GH, remain the subject of much debate.33–36 In addition, recent
changed sympathetic tone, and direct effects of vascular epidemiological studies found cancer death rates in cohorts
growth factors.21 Acromegalic cardiomyopathy is caused by of patients with acromegaly were similar to those in the
the effects of chronic GH excess on the heart. It is general population, suggesting malignancy is not a signifi-
characterised by biventricular concentric hypertrophy, with cant cause of mortality in patients with acromegaly.14 37 38
thickened ventricle walls but normal sized chambers.18 The
cardiac hypertrophy is associated with functional changes Diagnostic investigations
(decreased ejection fraction in response to exercise), valve Biochemical diagnosis
abnormalities, and a high incidence of arrhythmias.22–25 The The clinical features of acromegaly are outlined above, but as
incidence and severity of the abnormalities increase in elderly it often develops insidiously, few patients present immedi-
patients with long disease duration.26 27 ately at the time of onset of symptoms and the most common
mode of presentation is as an incidental finding by a
Metabolic complications healthcare professional.39 Biochemical confirmation relies
GH counteracts the effects of insulin on glucose and lipid on the demonstration of excessive GH secretion. Baseline
metabolism, resulting in metabolic complications in patients biochemical assessment includes a fasting or random GH and

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26 Ayuk, Sheppard

Complications of acromegaly Diagnostic tests

N Musculoskeletal; arthropathy, carpal tunnel syndrome N Biochemical; oral glucose tolerance test, serum IGF1
N Cardiovascular; hypertension, cardiomyopathy, N Radiological; pituitary MRI (CT if MRI not possible)
arrhythmias N Visual field assessment
N Metabolic; impaired glucose and lipid metabolism N Assessment of other anterior pituitary hormones
N Neoplastic; colorectal cancer

predominantly attributable to vascular disease, respiratory

IGF1 measurement, with a random GH level less than 0.4 mg/ disease and, in the earlier studies, malignancy.10–
12 14 17 31 37 45 46
l (0.8 mU/l) and a normal age and sex matched IGF1 However, results from the more recent studies
excluding the diagnosis of acromegaly.40 However, as GH is also showed that the increased mortality associated with
secreted in a pulsatile manner, single GH measurements acromegaly can be diminished if treatment is successful in
provide inadequate information regarding GH increase and reducing GH hypersecretion to less than 2–2.5 mg/l (4–5 mU/
therefore if either of these levels is not achieved or index of l), whether this is measured as the mean of a growth
suspicion is high, an oral glucose tolerance test (OGTT) hormone day profile or as a random growth hormone
should be performed with 75 g oral glucose and subsequent level.11 12 14 31 37 38 This has resulted in the publication of a
measurements of glucose and GH every 30 minutes over two consensus statement defining the criteria for cure of
hours. Failure of GH suppression to less than 1 mg/l (2 mU/l) acromegaly as a normal age matched serum IGF1 level and
during an OGTT suggests the diagnosis of acromegaly, but a GH nadir of less than 1 mg/l (2 mU/l) during an oral glucose
the results should always be considered in conjunction with tolerance test.40
an IGF1 measurement as other conditions (for example, The main aims of treatment of acromegaly are reversing
diabetes mellitus, renal disease) can cause discordantly the symptoms and signs of the disease, treating the under-
increased GH levels.40 Twenty four hour mean GH levels lying cause, preventing disease recurrence, and improving
can also be used in the diagnosis of acromegaly (mean 24 long term survival. This entails the use of surgery, radio-
hour GH less than 2.5 mg/l (5 mU/l) excludes acromegaly), therapy, and/or medical therapy.
but 24 hour sampling is time consuming and less cost
effective than an OGTT, and is now usually reserved for Surgery
research purposes or for patients with equivocal OGTT or Transsphenoidal surgery (TSS) is still considered first line
IGF1 results.39 Thyrotropin releasing hormone (TRH), GHRH, treatment for acromegaly in most patients. Based on strict
or gonadotrophin releasing hormone (GnRH) stimulation biochemical criteria (mean GH less than 2.5 mg/l (5 mU/l),
tests and measurement of IGF binding protein 3 offer no suppressed GH during an OGTT and/or normal IGF1), the
additional information for the diagnosis of acromegaly. overall remission rate after TSS ranges from 55% to 70%.13 46–
50
A number of factors have emerged as crucial in determining
Radiological investigation outcome after TSS, including tumour size, extrasellar exten-
Magnetic resonance imaging (MRI) is now considered the sion, dural invasion, and pre-treatment GH levels. Remission
gold standard for investigating pituitary adenomas, providing rates for microadenomas are around 80% to 90%, while those
invaluable information about tumour size and extension, and for macroadenomas are around 50%.13 46–48 The expertise of
permitting accurate delineation of parasellar structures.41 42 the pituitary surgeon also plays a key part in determining
The information obtained is improved if this is performed at a outcome, as has been illustrated by data from our centre in
centre specialised in examination of the pituitary fossa.43 For Birmingham; surgical outcome improved significantly when
patients in whom it is not possible to perform MRI, computed surgery was performed by a single dedicated pituitary
tomography (CT) offers a reasonable alternative. surgeon rather than eight different surgeons, as had been
the case previously.48
Other investigations Surgical complications such as cerebrospinal fluid (CSF)
Visual field defects occur in up to 20% of patients with leaks, diabetes insipidus, and development of new hypopi-
acromegaly, predominantly in those with larger tumours, tuitarism are infrequent, occurring in less than 7% of cases,
suprasellar extension, and higher GH levels.44 A bitemporal while recurrence after initial surgical remission occurs in
hemianopia is the most common defect but other forms may around 6%.13 47 50
also be seen. Visual fields should be tested by confrontation
during initial assessment, and if necessary this should be Radiotherapy
followed by formal documentation using Goldman perimetry. Radiotherapy has been used in the management of acrome-
Over 50% of patients with acromegaly have pituitary galy for nearly a century, with conventional fractionated
dysfunction affecting the secretion of at least one other radiotherapy lowering GH levels over 20 years to less than
anterior pituitary hormone,39 therefore basal pituitary func- 5 mg/l (10 mU/l) in 70% to 90% of patients.51 Radiotherapy is
tion should be assessed by measuring serum prolactin, also effective at controlling tumour growth as shown by
gonadotrophins, testosterone/oestradiol, thyroid stimulating Brada et al, with progression free survival of 94% at 10 years
hormone (TSH), free T3, free T4, and serum cortisol, although and 88% at 20 years in patients with pituitary adenomas
dynamic testing of the hypothalamo-pituitary-adrenal axis treated with external beam radiotherapy.52 However, a
may be necessary. number of factors have led to a re-evaluation of the role of
In rare cases where a GHRH secreting tumour is suspected, radiotherapy in the management of acromegaly. Apart from
serum GHRH levels can be measured. the long lag time to clinical effect, during which the patients
continue to suffer the effects of GH hypersecretion, a number
Management of studies have shown that IGF1 levels remain raised in a
Several retrospective studies have shown a twofold to significant proportion of patients whose GH levels are
threefold increased mortality in acromegalic patients com- reduced to 2–2.5 mg/l (4–5 mU/l) after treatment with radio-
pared with age and sex matched controls, with death therapy.51 53 Hypopituitarism, which itself has been linked to

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Growth hormone disorders 27

premature mortality,54 is a significant problem, and at 10 extent to that seen in patients who received the drugs after
years, around half of all patients treated with radiotherapy surgery.69 71–74 These findings have led the authors to conclude
will have developed new anterior hormone deficiencies.55 In that if the possibility of surgical cure is low, and if there is no
addition, it is now well recognised that patients treated with visual compromise, then medical treatment with somatosta-
radiotherapy have a significantly increased risk of cerebro- tin analogues alone is as effective biochemically and clinically
vascular events and cerebrovascular mortality compared with as the combination of surgery followed by medical therapy,
the general population.14 56 57 Radiation induced visual dete- and offers a reasonable primary therapeutic modality.
rioration and the development of second brain tumours occur Given the recognised efficacy of somatostatin analogues in
in a small proportion of patients,52 and although cognitive improving biochemical parameters and reducing tumour size,
dysfunction is listed as a side effect of radiotherapy, recent a number of studies have investigated the impact of pre-
evidence suggests it occurs in patients with pituitary tumours treatment with these drugs on surgical outcome. While some
regardless of treatment modality.58 have shown no clear benefits, others have found improve-
Gamma knife radiosurgery, which permits a highly precise ments in terms of remission rates and clinical conditions,
circumscribed delivery of radiation to a target in a single including preoperative blood pressure, cardiac function,
session, has also been used to treat acromegaly.59 In a recent glucose metabolism, and shorter hospital stays.75 76
study, around 25% of patients treated with gamma knife There are a number of side effects associated with
radiosurgery achieved GH less than 2.5 mg/l (5 mU/l) and somatostatin analogue therapy, but these are rarely severe
IGF1 normalisation within five years, with significant and in general do not limit treatment. Around 50% of
tumour shrinkage.60 However, more long term follow up data patients experience gastrointestinal symptoms including
are required to fully assess its role in the management of diarrhoea, nausea, and abdominal discomfort, but these are
acromegaly.
usually transient.64 New gallstone formation (usually asymp-
At present, radiotherapy should be reserved for patients in
tomatic) occurs in 10%–20% of patients and a small number
whom satisfactory control of tumour growth, GH, and IGF1
develop impaired glucose metabolism.73
has not been achieved by surgery and/or medical therapy.

Medical therapy GH receptor antagonists

Traditionally, TSS and/or radiotherapy have been considered Pegvisomant is a novel, genetically engineered GH receptor
first line treatment for acromegaly, but despite recent antagonist that, in contrast with dopamine agonists and
advances in both these forms of treatment, the overall somatostatin analogues, inhibits GH action rather than
surgical cure rate remains around 60% and radiotherapy is secretion. It exerts its biological actions by preventing
characterised by delayed effect and a high incidence of functional dimerisation of the GH receptor.77 Clinical studies
hypopituitarism, as discussed above. This means medical have shown that pegvisomant is remarkably effective,
therapy is necessary in a significant proportion of patients, improving clinical symptoms and signs and resulting in
and current options include dopamine agonists, somatostatin IGF1 normalisation in over 90% of patients.78–80 The drug
analogues, and more recently GH receptor antagonists. seems to be safe and well tolerated. Because pegvisomant
works by blocking the actions of GH, efficacy is independent
Dopamine agonists of tumour characteristics, such as the density of somatostatin
The dopamine agonist bromocriptine was the first effective receptors. Despite normalised IGF1 levels, GH levels remain
medical treatment for acromegaly, but it lowers GH secretion raised in these patients, albeit with minimal or neutralised
to the desired levels in less than 20% of cases and is bioactivity because of receptor block. Concerns of the raised
associated with a number of side effects including nausea, GH concentrations being reflected in tumour growth need to
dizziness, and headaches.61 Newer dopamine agonists like be clarified by additional long term monitoring studies.
cabergoline are better tolerated and more efficacious, low-
ering GH levels to less than 2 mg/l (4 mU/l) in up to 46% of There is now overwhelming evidence that the clinical
cases, with greater responses in patients with tumours co- outcome in patients with acromegaly can be improved
secreting GH and prolactin.62 This is not uncommon, as up to substantially by means of earlier diagnosis, better surgical
one third of these adenomas are plurihormonal acidophil cell expertise, a multidisciplinary approach to management, and
derived tumours and co-secrete both hormones.63 effective medical therapies used in a flexible manner. The
factors that are important in choosing an optimal strategy
Somatostatin analogues
The use of dopamine agonists has largely been superseded by
the introduction of somatostatin analogues, which exert their
biological effects by activating somatostatin receptors (pre-
dominantly sub-receptor types 2 and 5) in the pituitary.64
Octreotide, a long acting synthetic somatostatin analogue,
has been used to treat acromegaly for two decades, and since
Mortality (SMR)

the mid-1990s, three slow release depot preparations have

been introduced; Sandostatin LAR (Novartis), Lanreotide LA
(Ipsen), and Lanreotide Autogel (Ipsen). These have been
shown to be both effective and safe, suppressing GH levels to
less than 2–2.5 mg/l (4–5 mU/l) and normalising serum IGF1
levels in 50%–70% of cases.64–67 In addition, tumour shrinkage
1
by 20%–50% has been reported in around 30% of patients pre-
selected for octreotide responsiveness.64 68–70
Although somatostatin analogues have traditionally been AGHD 2–2.5 µg/l
used as an adjunct to surgery and radiotherapy, they are
increasingly being used as first line therapy in the treatment Figure 1 U shaped curve showing the optimal level of circulating GH
of acromegaly. Several studies in which somatostatin required to maintain normal health. Both GH excess and GH deficiency
analogues were given to previously untreated (de novo) seem to be associated with an increase in mortality. AGHD, adult growth
patients showed suppression of GH and IGF1 to a similar hormone deficiency; SMR, standardised mortality ratio.

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28 Ayuk, Sheppard

now increasingly include patient preference, coincidental pathognomonic. Although GH response to a number of
comorbidity, and cost-benefit analyses. pharmacological stimuli including clonidine, glucagon, argi-
nine, and GHRH have been used to diagnose GH deficiency,82
GROWTH HORMONE DEFICIENCY the insulin tolerance test is currently considered the
Growth hormone deficiency in adulthood can result from diagnostic test of choice,87 with a peak GH response of less
onset during childhood or later in life. Idiopathic GH than 3 mg/l confirming the diagnosis. This test can, however,
deficiency is the most common cause of GH deficiency in be unpleasant for patients and is contraindicated in those
children.81 It is a poorly defined and often reversible with epilepsy and ischaemic heart disease, resulting in an
condition that presents with short stature and low growth ongoing search for newer and safer tests to diagnose GH
velocity for age. In contrast, adult onset GH deficiency deficiency. Recently developed strategies include the com-
generally presents as part of a combined pituitary hormone bined arginine and GHRH stimulation test and the combined
deficiency phenotype (hypopituitarism) and is commonly GHRH and GH releasing peptide 6 stimulation test.88
attributable to a pituitary adenoma and/or treatment with
surgery or radiotherapy.82 GH is usually the first anterior Growth hormone deficiency and mortality
pituitary hormone to be affected in patients with large A number of studies have examined mortality in patients
pituitary adenomas or after pituitary surgery and radio- with hypopituitarism and all have confirmed increased
therapy. Other causes of GH deficiency are listed in the box. mortality compared with age matched controls, predomi-
nantly attributable to respiratory, cardiovascular, and cere-
Growth hormone deficiency syndrome brovascular disease.54 89–91 The extent to which GH deficiency
There is no single symptom or sign that is pathognomonic of influences this increased mortality remains unclear and has
GH deficiency in adult life, but a well defined constellation of been the subject of much debate. Although adult GH
symptoms and signs has been identified in adults with GH deficiency has been implicated as having a vital role in
deficiency, leading to the recognition of a ‘‘GH deficiency mediating increased vascular mortality in hypopituitarism,92
syndrome’’. In adult life, GH deficiency is associated with the largest study examining mortality in hypopituitarism
changed body composition, changed metabolism, reduced reported that the only hormone deficiency that was
exercise capacity, and impaired quality of life.82 83 Adults with conclusively implicated in the excess mortality was untreated
GH deficiency have reduced skeletal muscle, reduced lean gonadotrophin deficiency.54 Furthermore, evidence is lacking
body mass and increased fat mass, particularly distributed in that GH replacement in GH deficiency patients leads to
the truncal region, mostly in visceral tissue. In addition, these improved survival. In fact, untreated patients with isolated
patients have reduced bone mass compared with matched GH deficiency due to GH gene deletion, patients with
healthy controls, and are at increased risk of sustaining multiple pituitary hormone deficiency due to PROP1 gene
osteoporotic fractures.84 mutation, and patients with isolated IGF1 deficiency due to
Adult GH deficiency and hypopituitarism have been GH receptor gene mutation (Laron syndrome) can survive to
associated with a number of risk factors for cardiovascular an advanced age, reaching ages of 80–90 years.93 By contrast,
disease, including vascular endothelial dysfunction, dyslipi- a recent study of 11 subjects living in a Swiss valley with
daemia, and insulin resistance.85 Reduced left ventricular isolated GH deficiency due to deletion of the GH1 gene
mass, impaired cardiac systolic function, and impaired reported a significantly reduced life span in comparison with
response to peak exercise have also been reported.86 These siblings, as well as with the normal population living in the
findings, along with the reduced lean body mass, result in valley.94
reduced muscle strength and exercise capacity.
Using validated questionnaires, several studies have GH replacement
reported reduced self perceived psychological wellbeing and Replacement therapy with GH has consistently been shown
quality of life in adults with GH deficiency.83 Characteristic to have beneficial effects on body composition, bone turn-
features include depressed mood, anxiety, lack of energy, over, cardiovascular risk factors, and quality of life.83 In
social isolation, and impaired wellbeing. studies investigating the effects of GH replacement on body
Diagnosing GH deficiency in children is straightforward, as composition, lean body mass increased by 2 to 5.5 kg, while
it is associated with growth retardation. However, diagnosis (predominantly abdominal) fat mass was reduced by 4 to
of adult onset GH deficiency is much more challenging, as 6 kg after six months. Longer term treatment (12 months or
none of the features associated with the condition are more) led to increases in bone mineral density and
biochemical evidence of bone remodelling.
The effects of GH replacement on cardiac morphology and
Causes of GH deficiency function are well described, with a number of studies
showing a significant increase in left ventricular mass and
N Pituitary tumours stroke volume.86 This results in improved cardiac perfor-
N Genetic causes; Laron syndrome, pituitary transcription mance.
GH therapy leads to an improvement in vascular risk due
factor 1 (Pit1), and prophet of Pit1 (PROP1) mutations
to a number of factors including changed nitric oxide
N Septo-optic dysplasia
N Parapituitary tumours; craniopharyngiomas, menin-
giomas, metastases Growth hormone deficiency syndrome
N Radiotherapy; pituitary, cranial
N Traumatic brain injury N Reduced lean body mass, increased fat mass
N Pituitary infarction; apoplexy, Sheehan’s syndrome N Dyslipidaemia, insulin resistance, vascular endothelial
N Pituitary infiltration; sarcoidosis, lymphocytic hypophy- dysfunction
sitis N Reduced left ventricular mass, impaired systolic func-
N Infection; tuberculosis tion
N Chemotherapy N Impaired quality of life

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Growth hormone disorders 29

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