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Acromegaly

, M.D. and , M.D.

Author Information

Last Update: February 1, 2016.

ABSTRACT

Acromegaly is a rare condition with an approximate incidence of 3-4 new cases per million of population per year and a prevalence of 60 per million (1). There are approximately 3000 identified cases in the UK and 15000 in the USA, although it is possible that more cases exist but do not come to clinical attention. The condition was named by Pierre Marie in 1886 using the Greek words akron- extremities and megas- large to describe the typical clinical appearance of the condition (2).The disease occurs as a result of excessive secretion of growth hormone. In more than 99% of cases this is due to a benign pituitary growth hormone secreting adenoma. Pituitary carcinomas are exceedingly rare. Extremely infrequently acromegaly occurs as a result of ectopic secretion of growth hormone releasing hormone (GHRH) from a peripheral neuroendocrine tumour (3), or from excessive hypothalamic GHRH secretion (4). Approximately 5% of cases are associated with familial syndromes, most commonly multiple endocrine neoplasia type 1 (MEN1) syndrome, but also McCune Albright syndrome, familial acromegaly, Carney’s syndrome and Familial Isolated Pituitary Adenoma (FIPA). Both genders are equally affected and the diagnosis is typically made in adults aged 40-60 years of age. Younger patients often have more aggressive disease due to more rapidly growing adenomas. For complete coverage of this and all related areas of Endocrinology, please visit our FREE on-line web-textbook, www.endotext.org.

GROWTH HORMONE- STRUCTURE AND PHYSIOLOGY

Growth hormone is a 191 amino acid single chain protein containing two disulphide bonds. It has considerable structural homology with prolactin. Approximately 70% circulates as a 22 kD protein, 10% as a 20 kD isoform and the remainder as dimers or sulphated and glycosylated isoforms. Growth hormone secretion occurs in pulsatile bursts, numbering between 4 and 11 in 24 hours, especially at night, with extremely low or undetectable levels occurring in the nadir between pulses. Thus, a random single serum measurement is very limited as a means of assessing the overall level of secretion, which requires either frequent sampling over a 24 hour period, or more pragmatically, the mean level of a number of serum measurements taken over 10-12 hours – a growth hormone day curve (5). Assessment of urinary growth hormone secretion is inaccurate. Secretion of growth hormone is governed by both secretory and inhibitory hypothalamic factors. GHRH (growth hormone releasing hormone) and ghrelin act to stimulate release, whereas hypothalamic somatostatin (a 14 amino acid peptide) exerts marked inhibitory effects on GH release. Both of these stimulatory and inhibitory factors are subject not only to higher influences within the brain but also to peripheral signals such that the overall secretion of growth hormone can vary widely under different physiological conditions (6). These are summarised in Table 1.

Image acromegaly_neuroendo5e_image002_0004.jpg

Figure 1. The 2-D structure of human growth hormone

Table 1. PHYSIOLOGICAL FACTORS INCREASING GROWTH HORMONE SECRETION

1. Sleep (slow waves)

2. Malnutrition and fasting (IGF-I is low)

3. Stress

4. Exercise

5. Fall in blood glucose (hypoglycaemia)6. Type 1 diabetes mellitus, if uncontrolled (IGF-1 is low)7. Cirrhosis of the liver

Growth hormone circulates in blood bound to a specific binding protein, called GHBP. This protein comprises the extracelluar portion of the growth hormone receptor (GHR), which is widely distributed and present in most tissues. Activation of the growth hormone receptor occurs when the growth hormone molecule binds two adjacent receptors resulting in dimerisation of the growth hormone receptors. Dimerisation of the growth hormone receptor results in its activation and binding of the intracellular Janus kinase (Jak 2) tyrosine kinase. Both the GHR and Jak 2 are phosphorylated resulting in binding of signal transduction and activators of transcription (STAT) proteins. STAT proteins are themselves phosphorylated and translocated to the nucleus where they initiate transcription of target proteins. Intracellular growth hormone signalling is suppressed by several proteins, especially the suppressors of cytokine signaling (SOCS).

One of the major proteins induced by growth hormone is insulin-like growth factor-1 (IGF-1) (Figure 2). Although classical endocrinology states that it is hepatic derived IGF-1 acting in an endocrine manner that is responsible for most, if not all, of the effects of growth hormone, it is becoming increasing clear that local production of IGF-1 acting either in a paracrine (nearby cells) or autocrine (on the same cell) manner also has important biological effects, predominant of which is stimulating cell proliferation and inhibiting apoptosis (7). Elegant gene 'knock-out' experiments have demonstrated that animals with selective hepatic IGF-1 loss have a normal phenotype and growth, despite marked reduction in serum IGF-1 levels (8). Furthermore, patients with severe GH deficiency, perhaps as a result of pituitary surgery, usually have serum IGF-1 levels just below or at the lower end of the normal range. Thus, rather than being the sole effector of growth hormone, serum IGF-1 should perhaps be more accurately regarded as a marker of serum growth hormone concentrations. Circulating IGF-1 does however have important effects in regulating pulsatile growth hormone secretion with IGF-1 acting in a negative feedback fashion suppressing growth hormone release.

Image acromegaly_neuroendo5e_image004_0004.jpg

Figure 2. The growth hormone molecule binding to the membrane surface growth hormone receptor. Signalling and transduction only occur when adjacent receptors bind the two specific binding sites on the growth hormone moiety to form a dimer.

Central regulation of GH secretion

GHRH consists of 44 amino acids, the first 27 from the N-terminus being essential for physiological activity (9). GHRH containing neurons are located in the arcuate nucleus and surrounding the venteromedial nucleus which is considered the major site of GHRH activity. Somatostatin is widely distributed throughout the hypothalamus. The growth hormone control area is thought to be in the anterior hypothalamus and the anterior periventricular nucleus. The main feedback loop mechanism controlling growth hormone secretion is comprised of GHRH, somatostatin, GH and IGF-1. Indirect evidence suggests that GHRH and somatostatin neurons reciprocally regulate each other's activity via direct synaptic connections. A burst of growth hormone secretion exerts a short feedback inhibitory effect on GHRH secretion and a stimulatory effect on somatostatin release.

A long negative feedback also exists and growth hormone induces hepatic secretion of IGF-1, which in turn inhibits growth hormone release both directly and via stimulating somatostatin activity. The synthesis of IGF-1 also exerts a negative feedback influence on local GH release.

Ghrelin and Growth Hormone secretion

The existence of a growth hormone secretagogue receptor, distinct from the GHRH receptor has been recognized for several decades. The natural ligand was identified in 1999 and designated “ghrelin” (10). It is now known that the gene encoding preproghrelin, a 117 amino acid peptide, is conserved between species (11). Expression of ghrelin is found in many tissues including both the gastrointestinal tract and the CNS, with the strongest concentrations located in the stomach. Ghrelin is a potent growth hormone secretagogue resulting in a greater growth hormone response than either GHRH or any of the tested synthetic secretagogues. Gastric expression of ghrelin is reduced following feeding and increased by fasting and hypoglycaemia, making it probable that the increased growth hormone levels seen overnight and during fasting are at least in part mediated by ghrelin. However the relative contributions of ghrelin from specific tissues to regulation of the growth hormone/ IGF-1 axis has yet to be fully established. In addition to acting as a potent growth hormone secretagogue, ghrelin has orexigenic effects (promotes feeding) and may act to regulate energy utilization (12).

Image acromegaly_neuroendo5e_image006_0004.jpg

Figure 3. The growth hormone/ insulin-like growth factor-I axis.

Peripheral regulation of GH secretion

Several other hormone systems have regulatory effects on growth hormone secretion. Hypothyroidism is associated with low levels of both growth hormone and IGF-1, and in children, short stature. Thyroxine replacement has been shown to reverse these deficits. Further evidence from studies in rodents indicates that growth hormone gene expression is regulated by thyroid hormone acting through a thyroid hormone responsive element in the promoter region of the growth hormone gene. Glucocorticoids are inhibitors of somatic growth both in humans and experimental animals although the precise mechanisms are not yet understood. Human subjects with either Cushing’s syndrome or taking exogenous corticosteroids have been shown to have reduced growth hormone secretion.

Gonadal hormones also play a role in the neuroregulation of growth hormone secretion. In both sexes spontaneous growth hormone secretion is increased during puberty, and reduced in those with delayed puberty (13), suggesting that both oestrogen and testosterone influence growth hormone secretion. Hypoglycaemia is a potent inducer of growth hormone secretion, and insulin induced hypoglycaemia remains the best provocative test of growth hormone reserve in humans. Hypoglycaemia reduces hypothalamic somatostatin secretion facilitating growth hormone release. In contrast, hyperglycaemia suppresses growth hormone secretion from the healthy pituitary. The availability of amino acids as in the post-prandial state stimulates growth hormone secretion whilst elevated non-esterified fatty acid levels suppress growth hormone release.

IGF-1 - STRUCTURE AND FUNCTION

IGF-1 is a single chain polypeptide of 70 amino acids with three intrachain disulphide bridges, coded by a gene situated on the long arm of chromosome (12). It has a 48% amino acid sequence homology to pro-insulin, the A and B domains of IGF-1 have 60-70% homology but there is no homology with the C domain. IGF-1 has a specific receptor, which is structurally and functionally very similar to the insulin receptor. It consists of two extracellular α-subunits which are the hormone binding sites and two transmembrane β-subunits which are involved in initiating intracellular signaling. Post-receptor signaling mechanisms are also similar for IGF-1 and insulin receptors, both activating the tyrosine kinase and IRS-1 cascades. IGF-1 can bind to the insulin receptor but with only 1-5% affinity compared to insulin. Under normal physiological conditions it is thought that IGF-1 acts via the specific IGF-1 receptor, but in the presence of high concentrations of IGF-1 there is likely to be cross activation with the insulin receptor. IGF-1 receptors are found on most tissues with the notable exceptions of liver and adipose tissue. Hybrid IGF-1/insulin receptors have now been well documented and sequenced but their role is unclear.

The majority of circulating IGF-1 is produced by the liver with bone, adipose tissue, kidney, muscle and many other tissues producing a smaller quantity. Plasma concentrations of IGF-1 in the human are regulated by growth hormone, insulin, age and nutritional state. Bioavailabilty of IGF-1 is determined by its binding proteins (see below). Growth hormone and insulin are the main regulators of hepatic IGF-1 production. The precise regulation of local IGF-1 synthesis is uncertain, but it is influenced by many other trophic hormones such as ACTH, fibroblast growth factor and TSH.

Image acromegaly_neuroendo5e_image008_0004.jpg

Figure 4. The regulation of growth hormone secretion.

IGF BINDING PROTEINS (IGFBPS)

Unlike insulin the majority of IGF-1 circulates in plasma bound to a variety of binding proteins which determine its bioavailability and modulate its biological action (14). To date seven binding proteins have been fully characterised and sequenced, although evidence suggests that there may in fact be as many as ten specific binding proteins. The majority of IGF-1 is bound in a 150 KDa complex with IGFBP-3 and an acid labile subunit (ALS, 15). This large molecule (termed the ternary complex) is unable to pass through endothelium and acts as an intravascular reservoir of inactive IGF-1. The half-life of IGF-1 in the complex with IGFBP-3 and ALS is 12-15 hours compared with 10-12 minutes for free IGF-1. The exact mechanisms by which IGF-1 is released from the ternary complex to allow access into the tissues is not known; however IGFBP degrading protease activity has been well documented in many biological fluids and clinical states.

Current knowledge suggests that IGFBP-1 and IGFBP-3/ALS are the binding proteins which have the major effects on the bioavailability of IGF-1. IGFBP-1 is inversely related to insulin levels, has a circadian variation with the highest levels being found overnight when insulin levels are lowest and inhibits the hypoglycaemic action of IGF-1. Growth hormone secretory status is the main regulator of plasma levels of ALS.

CLINICAL FEATURES OF ACROMEGALY

Symptoms and Signs

Growth hormone secreting pituitary adenomas are frequently (more than 70%) large tumors (macroadenoma, ≥ 10 mm in diameter) which may present with local mass effects such as headache (often severe and out of proportion to the size of the pituitary tumour), hydrocephalus, visual field defects, ophthalmoplegia, or other cranial nerve palsies. As the lesion increases in size deficiencies of other anterior pituitary hormones may also occur. Microadenomas (< 10 mm in diameter) are conventionally thought to be less common. However patients presenting with pituitary tumours, without clear features of acromegaly may have elevated IGF-1, and GH +ve immunohistochemistry on the resected tumor specimen. Recognition of such presentations should prompt the endocrine specialist to consider GH secreting tumours in all presenations, but specially in the younger patient with pituitary tumour. Hypogonadism, presenting as decreased libido, infertility or oligo/amenorrhoea is a common finding at presentation; it may be due to both gonadotrophin deficiency as well as hyperprolactinaemia, either from coexistent excessive secretion of prolactin (in about 25% of growth hormone secreting adenomas) or from stalk compression. The occurrence of diabetes insipidus in relation to a pituitary adenoma is extremely rare and almost always suggests an alternative pathology.

The systemic effects of acromegaly relate to the elevated levels of circulating growth hormone either through direct actions, or more probably from the systemic and local production of IGF-1 (Table 2). However, the insidious nature of onset of symptoms from growth hormone excess means that there is usually a considerable delay, typically in the region of 6-8 years, before the diagnosis of acromegaly is established. Affected patients frequently complain of generalised weakness and lethargy. The most characteristic feature and one that usually precipitates the diagnosis is a change in appearance, comprising coarsening of the facial features and broadening of the nose. Thickening of the lips and prominence of the supraorbital ridges occurs simultaneously. Increase in soft tissues results in the other classical clinical manifestations. There is enlargement of the hands resulting in their characteristic 'spade-like' appearance and soft dough-like consistency of the palms. Ring size increases - a sensitive objective assessment of disease activity and response to treatment. Similar changes occur in the feet which become wider with increase in shoe size. There is often marked increase in the size of the tongue. Elongation of the jaw results in prognathism which contributes to dental malocclusion, interdental separation, and temporomandibular joint pain. Greasiness of the skin is a frequent finding with excessive sweating, one of the most sensitive signs of growth hormone excess. Skin tags are a frequent finding, likely related to epithelial cell hyperproliferation in response to IGF-1. Musculoskeletal changes are a common cause of morbidity; excessive growth hormone secretion before fusion of the bony epiphyses results in gigantism, although nowadays this is a rare event due to earlier diagnosis and treatment. Accelerated degenerative changes particularly of the weight-bearing joints – spine, hips and knees, are a common occurrence leading to degenerative arthropathy. Growth of the vertebral cartilage may result in kyphoscoliosis. Carpal tunnel syndrome is present in approximately 60% of patients at diagnosis but about 80% will have electrophysiological evidence of median nerve neuropathy. Interestingly, it appears that the pathophysiology is due to swelling of the median nerve itself within the carpal tunnel rather than extrinsic compression from increased volume of the carpal tunnel contents (16). There is increased total lean body mass and muscle hypertrophy, although the muscles themselves are weaker (17). Hypertrophy of the soft tissues of the upper airway results in deepening of the voice and often obstructive sleep apnoea, although a third of patients with sleep apnoea have a central contribution. Whilst generalised organomegaly is commonly stated to occur in acromegaly, careful analysis of the data leaves it questionable. However, there is no doubt that goiter is common and these tend to become nodular with time. Cardiomegaly has also been well documented, as has enlargement of the colon (18).

Table 2. Clinical Symptoms and Signs of Acromegaly

Facial change, acral enlargement, and soft-tissue swelling100
Excessive sweating83
Acroparesthesiae/ carpal tunnel syndrome68
Tiredness and lethargy53
Headaches53
Oligo- or amenorrhea, infertility55*
Erectile dysfunction and/or decreased libido42#
Arthropathy37
Impaired glucose tolerance/ diabetes37
Goitre35
Ear, nose throat and dental problems32
Congestive cardiac failure/ arrhythmia25
Hypertension23
Visual field defects17
* percentage of female patients # percentage of male patients
Image acromegaly_neuroendo5e_image010_0004.jpg

Figure 5. The typical facial appearance of acromegaly. Evolution of the appearances over 2 decades.

Morbidity and mortality in acromegaly

It is established that uncontrolled acromegaly results in a considerable increase in morbidity with an overall mortality at least two-fold that of the general population (19). In early epidemiological reviews more than 50% of patients had died by the age of 60 years, usually as a result of diabetes, cardiovascular, respiratory or cerebrovascular disease (20, 21). With improved treatment of both the underlying disease and these complications, patients are now surviving longer although may then be susceptible to other complications such as malignancy (22, Table 3).

Complications of acromegaly

Growth hormone is a potent insulin antagonist and acromegaly results in abnormal glucose tolerance in many patients with frank diabetes mellitus seen in up to a third. Lipid abnormalities, in particular elevation of serum triglycerides may be an accompanying feature of insulin resistance. Cardiovascular complications are common and account for as much as 60% of the mortality in acromegaly (23). Left ventricular hypertrophy with increased wall thickness and stroke volume are thought to occur early in the condition (24). When left untreated t his may progress to biventricular cardiomyopathy with both diastolic (25) and systolic dysfunction leading to cardiac failure with signs of dilative cardiomyopathy (23) . The cardiac changes seen in acromegaly increase the likelihood of cardiac rhythm disturbance (26) and valvular disease (27). Hypertension frequently occurs in acromegaly and is related to sodium retention, volume expansion and sympathetic nervous system overactivity. It often persists despite treatment of the underlying growth hormone excess. The metabolic abnormalities and hypertension are thought to contribute to the increased cerebrovascular morbidity, although contrary to earlier reports it now seems that the prevalence of ischaemic heart disease is not increased in acromegaly.

Table 3. Complications of acromegaly

COMPLICATIONS OF ACROMEGALY
Local
1. headache
2. visual field loss
3. cranial nerve lesions4. hydrocephalus5. temporal lobe epilepsy
6. Hypopituitarism
Systemic
Cardiovascular
1. Left ventricular hypertrophy
2. Cardiomyopathy
3. Congestive cardiac failure
4. Arrythymias
5. Hypertension
Respiratory
1. Kyphosis
2. sleep apnoea (obstructive and central)
CNS
1. cerebrovascular disease
Endocrine and Metabolic
1. Diabetes mellitus,
2. Impaired glucose tolerance (insulin resistance)
3. Hyperlipidaemia (triglycerides)
4. Hypogonadism – decreased libido and fertility5. Polycystic ovary syndrome6. Multiple endocrine neoplasia type 1
7. Hyperparathyroidism
8. Pancreatic islet cell tumours
Neoplastic
1. Colorectal adenomas and cancer
2. (breast and prostate – uncertain)
Skeletal
1. Degenerative arthropathy
2. Calcific discopathy, pyrophosphate arthropathy

Pulmonary complications are common in acromegaly. Total lung capacity is commonly reduced and narrowing of both large upper airways and small airways occurs (28). Macroglossia, increased thickness of laryngeal structures and vocal cord enlargement increases the risk of anesthesia and makes intubation difficult. Obstructive sleep apnoea is common with men more likely to be affected (29), but central sleep apnoea is also a well recognised feature of acromegaly (30).

In addition to these established complications, in recent years it has become increasingly apparent that patients with acromegaly are also at increased risk of developing neoplasia, particularly colorectal tubular adenomas and carcinoma (22, 31). Although some of these studies are hampered by a lack of matched control groups, the increased risk for colorectal cancer appears to be at least threefold and may be as high as 14-fold. It is related to disease activity with patients with elevated serum growth hormone and IGF-1 levels being particularly prone to developing colonic adenomas (32). Although the exact pathogenesis of these tumours remains uncertain it is likely to involve altered homeostasis of cell numbers within the colonic epithelial crypts; increased proliferation and decreased apoptosis within the crypts of patients with acromegaly have both been documented (33). In addition to its overall increased incidence, colorectal neoplasia in acromegaly has different characteristics compared to the general population, in that the adenomas are more likely to be located in the right side of the colon, tend to be bigger and are more often multiple as well as demonstrating increased dysplasia. Given these findings, it is now generally accepted that patients with acromegaly should be regarded as a high-risk group for colorectal cancer and regular colonoscopic screening should be offered to all patients. Current evidence suggests that this should begin at the age of 40 years with the subsequent interval depending both on disease activity and the findings at the original colonoscopic screening (34). In the presence of a polyp (hyperplastic or adenoma) or elevated serum IGF-1 levels screening should be repeated after five years, whilst a normal colonoscopic screening, or serum IGF-1 level within the normal range suggests screening every 10 years may be appropriate. As approximately 30% of lesions occur at the caecum or in the ascending colon, total full-length colonoscopy is required. This should be performed by an experienced colonoscopist, as the caecum is reached in only about 70% of patients in inexperienced hands. Due to their slow bowel transit time and elongated colon, patients with acromegaly require rigorous bowel preparation, often twice that necessary for the non-acromegalic patient. Failure to visualise the caecum necessities a repeat colonoscopy or failing this examination using CT virtual colonoscopy.

Whether patients with acromegaly are also prone to other malignancies remains controversial. Certainly there is epidemiological evidence in the general population that serum IGF-1 levels in the upper part of the normal range are associated with an increased risk of breast and prostate cancer and some reviews have shown the former to be increased in acromegaly (35, 36). However, to date these findings have not generally been confirmed in other large series, although it may be that, as with colorectal cancer, the demonstration of an increased prevalence of these tumours will only now become apparent as patients are surviving longer from other causes of morbidity.

More recently, it has also become apparent that patients with acromegaly often have severe impairment in their quality of life, as evidenced by both generic and specific questionnaires (37, 38). The most affected dimension is appearance and least affected is personal relations. Reported exacerbating factors include female gender, ageing, disease duration, presence of joint symptoms and prior pituitary irradiation. Whether there is a correlation between the impaired quality of life and circulating IGF-1 levels remains uncertain.

Familial and genetic inheritance

There is increasing understanding of the role of specific genes and mechanisms responsible for development of pituitary tumours. The most exciting developments relate to recent recognition that aryl hydrocarbon receptor interacting protein (AIP) mutations may account for familial pituitary adenomas. Such cases may present in younger patients with more aggressive tumours, including somatotroph adenomas. On-going studies and International Collaborative Studies are now providing further information on the importance of AIP mutations in clinical practice (39,40). Testing for AIP mutations (FIPA) should be considered for any patient with a family history of pituitary tumour, especially GH and/or Prolactin secreting tumours. This is particularly so, in those presenting at younger age (<30 years) with aggressive pituitary adenoma. There is some evidence that the response to somatostatin analogue treatment is reduced in acromegaly associated with with AIP mutation. Data from the German Pituitary Registry suggest that even in younger patients with acromegaly that the prevalence of AIP mutations is low (<5%) (76). GH secreting adenoma is reported to occur in approximately 6% of patients with MEN1 (77). In practice patients presenting at a young age with acromegaly, and certainly those with a family history of pituitary tumours should be considered for AIP and MEN1 gene sequencing.

INVESTIGATIONS IN THE PATIENT WITH ACROMEGALY

Confirmation of diagnosis and biochemical assessment

The diagnosis is made using a combination of clinical examination and biochemical assessment. Serum growth hormone concentrations are typically elevated, and although pulsatility may be reduced, levels may fluctuate widely in acromegaly. Failure of normal suppression of serum growth hormone following administration of oral glucose remains the ‘gold-standard’ biochemical test (5). 75 g of oral glucose is given at 9 am to the fasting patient and plasma glucose and serum growth hormone levels are measured at baseline, 30, 60, 90, 120 and 150 minutes thereafter. In normal subjects, growth hormone levels suppress to undetectable values (typically <0.2 ng/ml), whilst in acromegaly serum growth hormone remains detectable, and in approximately 30% of cases there is a paradoxical increase. In conventional practice failure to suppress serum growth hormone to a level < 0.4 ng/ml following ingestion of glucose supports the diagnosis of acromegaly. The use of this test also detects those patients with impaired glucose tolerance or diabetes mellitus. Due to the pulsatile nature of growth hormone secretion, a single growth hormone measurement is of little use in either monitoring or confirming the diagnosis of acromegaly. The assessment of growth hormone hypersecretion requires the mean value of serial samples taken throughout the day (e.g. 5 samples over a 12 hour period). The samples should be taken through an indwelling venous cannula to avoid the stress effects of repeated venepuncture. In normal subjects, the majority of values throughout the day are undetectable, but in acromegaly typically each value is measurable, often with a fixed rate of secretion. Basal serum prolactin should also be measured as prolactin may be co-secreted with growth hormone in up to a third of patients with acromegaly, which often indicates therapeutic responsiveness to the use of dopamine agonists. In those with hyperprolactinaemia the presence of macroprolactin should be excluded (41).

A single serum IGF-1 level has been advocated as being an alternative test for the diagnosis of acromegaly as it is elevated in the majority of subjects. However, as previously indicated, it is an indirect assessment of growth hormone secretion with approximately 25% of patients having a discrepancy between the mean value of a growth hormone day curve and an IGF-1 level. IGF-1 secretion is subject to several influences including liver and renal dysfunction, nutrition and diabetes mellitus and the presence of a statistical correlation between its levels and those of growth hormone should not be used as proof that they are interchangeable. However, despite these limitations, from a practical point of view, an elevated serum IGF-1 measurement may be useful as confirmatory evidence, assuming that age and sex matched normal ranges are used, and for monitoring treatment.

In cases of remaining doubt about the diagnosis of acromegaly, a TRH test can be used (200 mg of thyrotrophin releasing hormone given intravenously with serum measurement at 0, 20 and 60 minutes). In normal subjects TRH inhibits growth hormone secretion with a fall in serum concentration, whilst approximately 60% of patients with acromegaly demonstrate a paradoxical rise in growth hormone levels (42).

In the rare patient in whom a non-pituitary aetiology is suspected, measurement of serum GHRH may be performed, typically with very elevated levels occurring in ectopic GHRH syndromes such as neuroendocrine tumours.

The Endocrine Society guideline on Acromegaly, advocates measurement of IGF-1 and use of the glucose suppression test in the diagnosis of acromegaly (78).

Radiological Assessment

A skull x-ray remains a quick and easy preliminary assessment which can offer useful information, providing it is taken correctly with alignment of the posterior clinoid processes. Enlargement or ballooning of the pituitary fossa is seen, in addition to increased size of the frontal air sinuses and increased bony thickness of the skull vault. More detailed information regarding the presence and size of a pituitary mass requires either a CT or MRI contrast enhanced scan with the latter generally being preferable. The advantages of MRI are no ionising radiation, the ability to image in any desired plane and demonstration of the inherent contrast between tissues. Not only is it able to accurately determine the shape and dimensions of the anterior and posterior pituitary lobes; the latter has a high signal on T1 weighted images in over 90% of normal subjects, but also delineates clearly the hypothalamic region and optic chiasm. MRI allows accurate assessment of the size of the pituitary adenoma, detecting lesions as small as 2mm. At diagnosis, more than 70% of patients with acromegaly have a macroadenoma (≥10 mm in diameter) which often extends laterally to the cavernous sinus or dorsally to the suprasellar region. Younger patients often present with more aggressive disease, with more invasive tumours which often extend inferiorly. MRI will determine the extent of any invasion. On T1 weighted images the pituitary adenoma tends to be of lower signal intensity than the surrounding normal gland and enhances less briskly than the normal gland after injection with intravenous gadolinium contrast.

Image acromegaly_neuroendo5e_image012_0004.jpg

Figure 6 Enlargement of pituitary fossae on lateral skull xray.

Image acromegaly_neuroendo5e_image014_0004.jpg

Figure 7. A MRI demonstrating a somatotroph macroadenoma of the pituitary gland.

There is considerable interest in the use of functional imaging, using PET-MRI with 11c-Methionine currently the most promising tracer (79). Developments in PET technology will likely lead to effective imaging of pituitary adenoma. This may guide planning of surgery, and possibly radiotherapy in the near future.

Neuro-opthalmological Testing

Neuro-ophthalmological assessment is mandatory in all cases of acromegaly. At the initial consultation visual acuity should be assessed with the use of Snellen charts and fundoscopy performed to exclude optic atrophy, retinal vein engorgement or papilloedema from pressure on the visual pathways. Visual fields may be assessed by confrontation using a red pin. Patients with any clinical symptoms or evidence of optic chiasmal compression from imaging studies require formal assessment of visual fields with formal perimetry or visual evoked responses, stimulating each half field in turn.

Although permanent loss of vision and/or visual field defects usually result from long standing optic chiasmal compression, the shorter the time of compression the easier and more complete is the reversal of any visual field deficit. Surgical decompression may result in rapid improvement in visual fields within hours or days, although the presence of optic atrophy reduces the likelihood of this occurring. Because onset is often insidious, patients may be unaware of any alteration in their vision, although once documented its presence requires them to inform the vehicle licensing authority as driving ability may be impaired. An exception to this usual gradual deterioration is pituitary haemorrhage when visual loss may be sudden with a loss of central vision and development of bitemporal field defects and possible opthalmoplegia often accompanied by changes in mental function.

Assessment of pituitary function

Assessment of the integrity of the other pituitary hormones needs to be performed by a combination of the appropriate basal and dynamic tests. These are mentioned in Chapters 1 & 12 in this section. Prior to and following pituitary surgery, both residual pituitary function and the growth hormone secretory status should be evaluated. Basal endocrine testing for early morning cortisol, thyroxine, thyroid stimulating hormone, follicle stimulating hormone, luteinizing hormone, testosterone/oestrogen, prolactin, and serum & urinary osmolality, should be performed. Where there is doubt, a provocative test should be made of ACTH reserve.

Growth hormone status can be assessed using a 5-point day curve. In acromegaly, growth hormone secretion partially loses its normal pulsatile pattern, and values tend not to vary widely throughout the day. Serum IGF-1 is a marker of hepatic growth hormone responsiveness and usually but not always correlates well with growth hormone levels (43), but age- and sex-normalised ranges are required. Both growth hormone and IGF-1 measurements are also confounded by technical differences between different assays and lack of uniformity in reference standards. These lead to poor reproducibility with often marked inter-assay variations.

MANAGEMENT OF ACROMEGALY

Given the chronic nature and associated significant increased morbidity and mortality of acromegaly, treatment is required for almost all patients. Three modalities of treatment are available: surgery, pituitary irradiation and medical therapy. All of these have advantages and disadvantages and more than one modality is frequently needed, often all three. The decision as to whether to treat and the modality employed must be based on a number of factors, including patient age and general health, wish for fertility, severity of disease and any associated complications, and the risk/benefit ratio of the proposed treatment modality. The goals of treatment are summarised in Table 4.

Consensus guidelines define goals for treatment of acromegaly. These include achieving an age-matched normal range IGF-1 and GH <0.4 mcg/L (80).

Table 4. Acromegaly- aims of treatment

1. Removal of the pituitary tumour and resolution of mass effects

2. Relief of the symptoms and signs of acromegaly

3. Restoration of normal rates of secretion of growth hormone and IGF-1

4. Maintenance of normal anterior pituitary function

5. Prevention of recurrence6. Assessment and treatment of chronic complications

Whilst the general principles of these aims are accepted by all endocrinologists, there remains considerable controversy as to the degree of growth hormone reduction that should be the target and what level should be regarded as normal. The use of sensitive growth hormone assays has demonstrated that abnormal patterns of growth hormone secretion can remain despite reduction in mean circulating concentrations to extremely low levels, and thus complete restoration to normality is often not achieved. Early epidemiological reviews, particularly those documenting the results of surgery, tended to regard a mean level of less than 5 ng/ml as being satisfactory. It has become clear in recent years that the excess mortality associated with acromegaly can be significantly reduced and indeed restored to that of the normal population by aggressive treatment and reduction of serum growth hormone concentrations to a mean level of less than 1 ng/ml and/or a serum IGF-1 within the aged-matched reference range. Thus, rather than using the word cure, it is may be more appropriate to consider an average growth hormone concentration of ≤ 1 ng/ml as representing a "safe" level. An alternative target suggested at a consensus conference is a nadir level of less than 0.4 ng/ml after a standard 75g glucose tolerance test (44) (Figure 2).

Surgery for Acromegaly

Trans-sphenoidal surgery is the initial treatment of choice for most patients. Originally performed by Harvey Cushing in 1910, the lack of adequate visualisation prevented it’s reintroduction for routine use until the mid-1970's. With modern equipment and in experienced hands, it is a safe procedure with a low complication rate and mortality of less than 0.5%. The most commonly used approach is with the patient in a semi-reclining position via a mid-line nasal route. Using a sub-labial or direct nasal approach, the mucosa is cleaved off the nasal septum providing access to the sphenoid sinus and subsequent removal of the fossa floor. A less satisfactory alternative approach is via the ethmoidal sinus. Pituitary adenomas are usually soft and easily removed with curettes although firmer and larger tumours may require piecemeal removal. Using this technique, even tumours with a significant suprasellar extension can be removed via the trans-sphenoidal route, although massive tumours may require a craniotomy. Such transcranial surgery is however associated with increased morbidity and mortality. More recent surgical techniques include the use of intra-operative MRI (45) and intra-operative growth hormone measurement (46). The development of endoscopic trans-sphenoidal surgery has been reported to offer several advantages over the conventional technique, and is becoming the method of choice. Reported advantages over the microscopic technique include superior tumour clearance, especially suprasellar extension, less surgical morbidity, fewer complications, and reduced post-operative discomfort (47).

A key recent development in the management of acromegaly internationally is the formalization of a team approach, with endocrinologist, neurosurgeon, specialist nurses, oncologists, radiologists and histopathologists increasingly working as a single-team, making consensus decisions in a timely and co-ordinated fashion. There is general acknowledgement that functioning pituitary tumours are best managed in centres with larger volume and experience of rarer conditions. Certainly this is increasingly the case in Europe and the USA.

The success rate of trans-sphenoidal surgery depends on several factors: (i) the size of the tumour, (ii) pre-operative growth hormone values and (iii) the skill and experience of the surgeon (48, 49). Although different series have often used different criteria to determine success rates, in experienced hands post-operative mean growth hormone levels of less than 1 ng/ml should be achieved in 70%-90% of microadenomas and 30%-50% of macroadenomas (50, 51). Pre-treatment of patients with somatostatin analogues before trans-sphenoidal surgery is increasingly becoming standard practice, even if early surgery is being planned, as it results in significant shrinkage (approximately 50%) of the adenoma and may improve the subsequent surgical cure rates (52, 53).

Complications of trans-sphenoidal surgery include diabetes insipidus; this is usually transient but may be permanent in approximately 5% of cases depending on the criteria for its diagnosis. A serum osmolality of greater than 295 mosmols/l with a simultaneous urine osmolality of less than 150 mosm/l is confirmatory. It responds well to desmopressin (DDAVP, subcutaneous, oral or intranasal). Other complications include CSF rhinorrhoea and subsequent risk of meningitis, although this can be minimised by the use of early antibiotics. The syndrome of inappropriate ADH (SIADH) may occur around one week post-operatively and needs to be considered in the context of decreased urine output – such a clinical scenario must be distinguished from hypovolaemia due to insufficient fluids; increasing intravenous fluids for the latter erroneous diagnosis will obviously dramatically worsen SIADH which almost always spontaneously resolves after a short period of fluid restriction.

The major long-term complication associated with trans-sphenoidal surgery is worsening of anterior pituitary function and hypopituitarism. In a series of 100 patients with acromegaly operated on at St Bartholomew’s Hospital, UK, new hypopituitarism occurred in 21% of patients following surgery, but with 35% having hypopituitarism pre-operatively (54).

Pituitary Irradiation in Acromegaly

A subsequent Chapter in this section is a comprehensive review of the place of radiotherapy in the management of pituitary disorders including acromegaly. Pituitary irradiation is usually used as an adjunct to pituitary surgery when growth hormone levels remain elevated. In elderly patients or those unfit for surgery, it may be used as first-line therapy. There are several techniques that have been used: conventional mega-voltage external irradiation, stereotactic single high dose irradiation, interstitial implantation of yttrium 90 seeds, and whole particle proton beam therapy. Only the first two will be discussed here as the others are only employed in one or two centres. Conventional mega-voltage irradiation has been in routine use for over 30 years and consequently there is a wealth of experience about it, principally relating to it being both safe and effective. A linear accelerator is used as the source; less satisfactory is a cobalt source. Irradiation is focused onto the pituitary fossa using modern CT/MRI imaging and planning, which allows for accurate dosimetry and minimal variation in the daily dosage to surrounding structures. This is particularly so for the optic chiasm, damage to which is avoided by the use of daily fractions of less than 200 cGy. The majority of centres advocate a total dose of 4500 cGy given in 25 fractions of 180 cGy over 5-6 weeks via a minimum of three fields (one frontal and two temporal). Numerous studies have confirmed the efficacy of such mega-voltage irradiation with a 50% fall in growth hormone values occurring in the first two years, regardless of basal levels, followed by a continuing exponential decline thereafter (55). The majority of patients therefore do eventually achieve a level of less than 2 ng/ml, although the interval to reach this depends on the baseline levels. A similar response is seen with IGF-1 with approximately 60% of patients eventually achieving a normal serum level after 10 years. Although it is recognized that pituitary irradiation is associated with several potential adverse consequences, these are rare when irradiation is delivered properly, other than an increased prevalence of hypopituitarism. At ten years after irradiation, approximately 60% of patients are hypogonadal, 50% ACTH deficient and 40% requiring thyroxine replacement. However, the prevalence prior to irradiation, either due to the pituitary tumor itself or previous surgery should be taken into account, with baseline figures being 40% hypogonadal, 35% ACTH and 15% TSH deficient (55). In a large combined series of over 750 patients, a second tumor developed in 1%-2%. However, not only were there no adequate control groups for comparison, but it is also possible that these patients have an inherent predisposition to both their pituitary tumor and also other intracranial neoplasms (56). Furthermore, the increased imaging surveillance of these patients will result in an increased reported incidence of tumor formation. Adverse effects of irradiation on psychological and cognitive function are similarly unproven especially as more recent studies have suggested that any abnormalities detected may be related more to the disease itself and previous surgery rather than the irradiation.

Stereotactic single high dose pituitary irradiation using either the gamma knife (radiosurgery) or stereotactic multiple arc radiotherapy (SMART) has received increasing attention in recent years as an alternative to conventional irradiation, although long term efficacy and safety data is not yet available. These techniques permit the delivery of a single high dose of irradiation to a previously mapped area whilst also ensuring a rapid reduction in radiation exposure to surrounding structures. Care needs to be taken with tumours close to the optic chiasm. Initial impressions suggest that growth hormone levels fall to normal earlier than after conventional radiotherapy, but that hypopituitarism occurs just as often (57). Although the stereotactic technique has clear advantages over conventional external irradiation in terms of precise mapping to a specified tumour volume, it may not encompass tumour tissue that is not visualised radiologically. This is in contrast to conventional irradiation which is usually configured to encompass the whole of the pre-operative tumour volume, and thus will treat tumour beyond the resolution of imaging techniques. It is for this reason that stereotactic irradiation should be seen as complementary to conventional irradiation. In our institutions, it is currently reserved as a second-line therapy for patients who have persisting active disease despite surgery and conventional irradiation.

Medical therapy of Acromegaly

Three different types of medical therapy are currently used in the treatment of acromegaly - dopamine agonists, somatostatin analogs growth hormone antagonists.

Dopamine agonists in the treatment of Acromegaly

From their discovery and synthesis in 1971 until the introduction of somatostatin analogs in the mid- 1980’s, dopamine agonists, such as bromocriptine, were the sole medical therapy for acromegaly. However, they are relatively ineffective and whilst approximately 80% of patients will show a reduction in growth hormone levels, only about 10-15% achieved a mean level of less than 2 ng/ml (58). Furthermore, the doses required, often 20 - 30 mg of bromocriptine per day, are much higher than those needed for prolactin-secreting pituitary adenoma. Consequently, the side effects of nausea, headache, dizziness, postural hypotension, and nasal stuffiness tend to be worse, although can be minimised by taking the drug in the middle of a main meal to slow absorption and most patients will demonstrate tachyphylaxis. Unlike in patients with prolactinomas (where an excellent treatment response is expected), there may be only a modest reduction in tumour size but this is usually insignificant. Cessation of treatment results in rebound growth hormone hypersecretion. The development of the long-acting dopamine agonists such as cabergoline offered greater convenience and reduced side effects, although again high doses of up to 1 mg per day may be needed (59). A meta-analysis has demonstrated that its use can achieve normalization of IGF-1 levels in 34% of patients (60). There are no accurate predictive tests as to which patients will respond to dopamine agonists, but mixed growth hormone and prolactin secreting tumours with elevated serum prolactin levels tend to respond the most favourably.

Image acromegaly_neuroendo5e_image015_0004.jpg

Fig 8: Plasma IGF-1 and GH responses to dopamine agonist suppressive therapy in patients with pure GH secreting tumours. The upper squares indicate the pretreatment levels and lower squares correspond to the concentrations obtained by progressively increasing the weekly dose of cabergoline i.e. 1.0, 1.75, and 3.5 mg, respectively. Note the log scale for GH. Reproduced from JCEM.

Somatostatin analog treatment of acromegaly

The development of octreotide (Sandostatin, Novartis, Basel, Switzerland) a synthetic somatostatin analog, represented a major advance in the treatment of acromegaly. In contrast to the short half-life of native somatostatin (approximately 90-seconds), the 8 amino acid octreotide has a half-life of about two hours. Following a single 100 mcg dose, there is prolonged suppression of growth hormone which lasts for several hours, and indeed this response to a single dose can be used to predict the long-term efficacy of octreotide. It is administered by subcutaneous injection and thus a thrice-daily regimen results in stable drug concentrations and maximal effect. More than 90% of patients show a reduction in growth hormone levels, with approximately 50-60% achieving levels of less than 2 ng/ml and a normal serum IGF-1 level. The usual doses are between 100-200 mg three times daily although occasional patients may require higher doses. This biochemical improvement is matched by rapid clinical improvement. The efficiency of octreotide and other somatostatin analogs (SSAs) such as lanreotide is linked to their preferential binding of the human somatostatin receptor type 2 (SSTR2) with reduced or absent binding of SSTR1, SSTR3, SSTR4 or SSTR5. Somatostatin analogs also have additional and independent, but poorly understood, analgesic properties on the headache associated with acromegaly.

In recent years, depot formulations of somatostatin analogs have become available. These consist of the active drug incorporated with microspheres of biodegradable polylactide and polyglycolide polymers which allow the slow release of analog after intramuscular injection. There are currently three such preparations available, octreotide LAR (Sandostatin LAR, Novartis) which is given at a variable dose of 10 mg, 20 mg or 30 mg at recommended four weekly intervals, lanreotide (Somatuline Autogel, Ipsen Biotech, Paris, France), which is given as a single dose of 60-120 mg every 28 days as a sub-cutaneous depot formulation, and the recently licensed pasireotide LAR. Pasireotide has increased affinity for SSTR5, and this has lead to a license for the treatment of Cushing’s disease in addition to acromegaly. The SSA medications are also used in the treatment of neuroendocrine tumours arising outside the pituitary gland, in particular small bowel carcinoid tumours and pancreatic neuroendocrine tumours. Sandostatin and Lanreotide Autogel are of similar efficacy in suppression of growth hormone and IGF-1 with safe growth hormone levels (<2 ng/ml) occurring in approximately 60-70% of patients (61, 62). Direct comparisons between octreotide LAR and lanreotide Autogel suggest they are of similar efficacy (63, 64), although a meta-analysis of patients unselected for somatostatin responsiveness indicated that normalised IGF-1 levels and safe growth hormone levels occurred in a higher proportion of LAR treated than lanreotide treated patients (65).

Regardless, of the comparative effects, there is variability in individual patient’s sensitivity to these analogs and more than 90% of patients who achieve adequate control with 4 weekly octreotide LAR injections will also do so with 6 weekly injections (66). Consequently, careful dose titration needs to be performed on each patient. This is particularly important given the cost of these depot formulations; in the UK, the approximate annual cost of octreotide LAR given 4-weekly is £8000 for 10 mg injections, £11000 for 20 mg and £14000 for 30 mg, whilst the cost for lanreotide Autogel 90 mg is approximately £10000 per annum.

Pasireotide (SOM 230) is a novel cyclohexapeptide somatostatin analogue which is selective for SSTR2, 3 and 5, but also shows increased binding to SSTR1 compared to octreotide (67). The extended receptor affinity of pasireotide has led to it being referred to as a “second generation somatostatin analogue” with the original depot formulations being termed “first generation” analogues. Novel compounds with combined affinity for SSTR2, SSTR5 and the dopamine D2 receptor are also being developed and in vitro show enhanced inhibition of growth hormone release (68). The ongoing development of these chimeric analogs may increase the efficiency of currently available analogs.

The side effects of somatostatin analogs are related to the widespread distribution of somatostatin and include effects on the gastrointestinal system, comprising colicky abdominal pain, diarrhoea, flatulence and nausea, although these tend to resolve with time. In the long-term gastritis occurs in a significant proportion of patients and perhaps most significantly gallstones form in approximately 50% of patients after two years of use. This is due to both an inhibition of gall bladder contraction and alterations in the composition of bile with cholesterol supersaturation (69). However, perhaps due to the gall bladder paresis, the majority of these remain asymptomatic. The effects of SSAs on glucose metabolism are multifactorial. While they improve insulin sensitivity by reducing growth hormone levels, they also exert direct inhibitory actions on insulin secretion by the pancreatic cells. The net result is normal glucose tolerance in the majority of patients. With their improved patient convenience, there have been suggestions that these depot formulations should be used as first-line treatment for acromegaly. However, their increased cost and the need for continuing treatment should be borne in mind. At present, there remains general consensus that whilst they may have a role prior to surgery to try and decrease tumor size, their major place is post-operatively as an adjunct to irradiation whilst waiting for growth hormone levels to fall. Provisional evidence suggests that treatment of acromegaly with somatostatin analogs prior to surgery improves the cardiovascular risk and respiratory status and may therefore have a place in some patients (70). Patients who remain uncontrolled despite the use of these somatostatin analogs may gain additional benefit with the addition of a dopamine agonist, but this is the exception rather than the rule.

Clinical trial data relating to Pasireotide in acromegaly indicates that this agent is modestly more potent than Sandostatin LAR in achieving control of GH and IGF-1. The incidence of hyperglycaemia or diabetes is higher when patients are treated with pasireotide. This and the cost of the drug have thus far limited its use in the UK, though other health care economies have more readily incorporated pasireotide into the acromegaly treatment algorithm. A recently published Phase III study indicates that in new presentations of acromegaly that achievement of control of GH and IGF-1 is superior with pasreotide (over octreoide) suggesting that pasireotide may replace the earlier SSAs in treatment strategies in the future (81).

Growth Hormone Antagonists in Acromegaly

The development of Pegvisomant, the novel growth hormone receptor antagonist, is a major advance in the treatment of acromegaly. The development of this molecule utilizes the knowledge that the growth hormone molecule contains two distinct sites which bind to two corresponding unique sites on the respective growth hormone receptor dimer. Pegvisomant is a modified recombinant growth hormone molecule which has increased affinity to the first growth hormone receptor binding site but with decreased affinity to the second binding site. Thus, receptor dimerisation and subsequent signal transduction is prevented. Its conjugation with polyethylene glycol (PEG) increases its molecular size, prolongs its half-life and reduces its antigenicity. Several studies have demonstrated pegvisomant to be most effective medical therapy to date and have established its long-term efficacy in the treatment of acromegaly (71, 72). In a study of 152 patients treated for up to 18 months, normalisation of IGF-1 occurred in 90% of patients, although doses of up to 40 mg a day were required (73). Growth hormone levels cannot be measured in routine assays as the drug itself interferes with growth hormone assays and pituitary-derived growth hormone increases modestly. Pegvisomant is currently administered as a daily subcutaneous injection of approximately 1 ml in volume. Theoretical concerns exist regarding the increase in circulating growth hormone levels due to the loss of any negative feedback effects on the tumor, but although experience is still limited there is no evidence to date of risk of pituitary tumor growth (73). Pegvisomant is generally well tolerated although abnormalities of liver function occur in some patients. Whilst there is no doubt that this drug represents a major advance, its role as first line therapy remains to be determined. Its major use is for patients who are resistant to SSAs, either as a sole agent or as an additive agent. A study observed that the combination of 4-weekly octreotide LAR and weekly pegvisomant normalised IGF-1 in more than 90% of patients with active disease who were not controlled with octreotide alone (74). Other suggestions for its use have been in patients with diabetes or impaired glucose tolerance, in whom SSAs might worsen glycaemic control. However, the change in dosing frequency and additional cost needs to be weighed against the use, if required, of simple oral hypoglycaemic agents. The major drawback of pegvisomant other than its usual requirement for daily injection, as opposed to the 4-6 weekly administration of SSAs, is its cost of approximately £1000 per mg per year, which can amount to £50000 per annum for patients resistant to SSAs.

A recent study has demonstrated improved IGF-1control with Pegvisomant and cabergoline in combination, an approach which might enable a lower dose of the Pegvisomant to be used with reduced costs (75). Emerging data suggest that pegvisomant may be an effective long-term treatment for acromegaly (82). Several European countries have registries providing regular outcome related to pegvisomant treatment in acromegaly. However cost and approval restrictions mean that pegvisomant is not yet universally available.

PRACTICAL APPROACH TO MANAGEMENT OF THE PATIENT WITH ACROMEGALY

Following confirmation of the diagnosis of acromegaly surgical treatment should be considered for all patients with a confirmed somatotroph adenoma (80). Current evidence suggests that in cases of growth hormone secreting microadenoma, surgery alone will result in achievement of ‘safe’ growth hormone levels in approximately 70-90% of patients. This figure falls when a macroadenoma (<50%) or a giant adenoma (<20%) is present. Those with the highest pre-operative growth hormone concentrations are least likely to be ‘cured’ by surgery alone. In those post-operative patients with continuing growth hormone excess, further treatment is indicated, and the majority of patients should undergo conventional fractionated external beam irradiation. A second surgical procedure will result in ‘safe’ growth hormone levels in only 20% of patients. Recognising that radiotherapy does not result in an instant lowering of growth hormone levels, medical treatment is commonly required, especially in the short-term. On average, two years following external beam irradiation growth hormone levels have decreased by approximately 50% with a further fall resulting in 75% reduction at 5 years. Newer stereotactic radiotherapy techniques, when used appropriately, may effect a more rapid reduction in growth hormone levels. However, since the tumor in such cases is usually a macroadenoma, we would only use radiosurgery as “salvage therapy” in the face of poor control of tumor secretion or regrowth following conventional radiotherapy. Available adjunctive medical options include the use of dopamine agonists, somatostatin analogs (first and second generation) and pegvisomant. Bromocriptine will normalize growth hormone levels in only 10% of patients, although this may rise to 30% with cabergoline. Octreotide and lanreotide, particularly in their depot formulations which last 4-6 weeks, will normalize mean growth hormone levels in 70-80% of patients, and are therefore highly effective, albeit expensive. It will become clear in coming years whether pasireotide is a more effective (and cost-effective) agent. The growth hormone receptor antagonist, pegvisomant, is now well established and may be used in patients resistant to these agents. Periodic assessment with IGF-1 measurement and growth hormone profile testing should be performed at regular intervals to facilitate titration of doses and determine response to radiotherapy. Following irradiation it is reasonable to assess growth hormone status after appropriate discontinuation of medical therapies at 6-monthly intervals for 2 years and thereafter yearly. In all patients with acromegaly efforts should be made to optimize lung and cardiac function and particular attention be made to the management of cardiovascular risk factors including smoking, dyslipidaemia and abnormalities of carbohydrate metabolism.

Suggested medical management after surgery (with persistent disease, 83).

Image acromegaly_neuroendo5e_image016_0004.JPG.jpg

Treatment of refractory disease

Acromegaly with invasive non-responsive adenoma, with either persistent GH excess or invasive adenoma is a rare and difficult management problem often needing multi-modal therapy. The alkylating agent temozolamide is used in the management of glioblastoma multiforme and this agent has been used to treat a variety of pituitary tumours. The most reported efficacy is in aggressive prolactinoma (84) but temozolamide has also been used with varying results in GH-secreting tumours resistant to standard treatment (85). Other cytotoxic agents have been used but there is no recognized systemic chemotherapeutic strategy that has been consistently effective.

NOVEL AGENTS IN THE TREATMENT OF ACROMEGALY

A number of novel agents are in advanced stages of development for the medical treatment of acromegaly. These include agents that continue to work by the somatostatin mechanism as well as new mechanisms of action. Developments in the understanding of the molecular pathogenesis of growth hormone excess and pituitary tumour development have led to the identification of novel targets for drug development. New treatments need to be safe and well tolerated, as well as effective and importantly cost effective.

Oral octreotide as an agent coupled to a transient gut absorption enhancer has been investigated. Early evidence suggests that using this technology the drug as well absorbed and clinically effective in suppressing growth hormone and IGF-1 (86). The most commonly reported adverse effects include headache nausea and arthralgia. In addition a new formulation of subcutaneous octreotide depot has been trialed in healthy volunteers, demonstrating superior efficacy to intramuscular octreotide (87).

An anti-sense oligonucleotide has been developed directed against the growth hormone receptor. Early clinical trial data suggests that this strategy may prove effective in reducing growth hormone signalling and IGF-1 generation in patients with acromegaly (88). The drug was well tolerated in an early clinical trial with injection site reactions the most common adverse event reported.

Somatoprim is in novel somatostatin analogue. This agent has affinity for the SST2, 4 and 5 receptors. A phase II study to investigate the efficacy of this agent in acromegaly is underway. STAT3 signalling is an important mechanism in the regulation of growth on dependent gene expression. GH-secreting adenomas overexpress STAT3. Recently a STAT3 inhibitor has been shown to suppress growth action. Thus there is early evidence that this novel strategy may have a role in the treatment of acromegaly in the future (89).

In summary, continuing advances in the understanding of the mechanisms responsible for pituitary tumour development and the regulation of GH secretion, are aiding the further development of existing therapeutic agents and enabling the creation of new promising treatment for patients with acromegaly.

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