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 invalid 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 curve5. Assessment of urinary growth hormone secretion is inaccurate. Secretion of growth hormone is governed by both secretory and inhibitory hypothalamic factors. GHRH and the recently identified 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 conditions6. These are summarised in Table 1.

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

Growth hormone circulates in blood bound to a specific binding protein, termed 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-I (IGF-I) (Figure 2). Although classical endocrinology states that it is hepatic derived IGF-I 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-I 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 apoptosis7. Elegant gene 'knock-out' experiments have demonstrated that animals with selective hepatic IGF-I loss have a normal phenotype and growth, despite marked reduction in serum IGF-I levels8. Thus, rather than being the sole effector of growth hormone, serum IGF-I should perhaps be more accurately regarded as a marker of serum growth hormone concentrations. Circulating IGF-I does however have an important effect in regulating pulsatile growth hormone secretion with IGF-I acting in a negative feedback fashion suppressing growth hormone release.

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.

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-I. 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-I, which in turn inhibits growth hormone release both directly and via stimulating somatostatin activity. The synthesis of IGF-I also exerts a negative feedback influence on local GH release.

Ghrelin & 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 species11. 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-I 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 utilization12.

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

Several other hormone systems have regulatory effects on growth hormone secretion. Hypothyroidism is associated with low levels of both growth hormone and IGF-I, 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 steroids, have been shown to have blunted 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 puberty13, 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-I 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-I have 60-70% homology but there is no homology with the C domain. IGF-I has a specific receptor, which is structurally and functionally very similar to the insulin receptor. It consists of two extracellular a-subunits which are the hormone binding sites and two transmembrane b-subunits which are involved in initiating intracellular signaling. Post receptor signaling mechanisms are also similar for IGF-I and insulin receptors, both activating the tyrosine kinase and IRS-1 cascades. IGF-I can bind to the insulin receptor but with only 1-5% affinity compared to insulin. Under normal physiological conditions it is thought that IGF-I acts via the specific IGF-I receptor, but in the presence of high concentrations of IGF-I there is likely to be cross activation with the insulin receptor. IGF-I receptors are found on most tissues with the notable exceptions of liver and adipose tissue. Hybrid IGF-I/insulin receptors have now been well documented and sequenced but their role is unclear.

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

Figure 4. The regulation of growth hormone secretion.

Unlike insulin the majority of IGF-I circulates in plasma bound to a variety of binding proteins which determine its bioavailability and modulate its biological action14. 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-I 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-I. The half-life of IGF-I in the complex with IGFBP-3 and ALS is 12-15 hours compared with 10-12 minutes for free IGF-I. The exact mechanisms by which IGF-I 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-I. 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-I. Growth hormone secretory status is the main regulator of plasma levels of ALS.

Growth hormone secreting pituitary adenomas are frequently (more than 70%) large tumors (macroadenoma, larger than 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 less common. 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-I (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-I. 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 contents16. There is increased total lean body mass and muscle hypertrophy, although the muscles themselves are weaker17. 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 colon18.

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

Figure 6. Acral enlargement in acromegaly. Comparison with a normal subject.

Figure 7. Intradental separation and prognathism in a patient with 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 population19. 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 disease20;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).

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 test5. 75 g of oral glucose (eg. ~394 mls of ‘Lucozade’) 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 or in approximately 30% of cases there is a paradoxical increase. In conventional practice failure to suppress serum growth hormone to a level < 1 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. In those with hyperprolactinaemia the presence of macroprolactin should be excluded39. A single serum IGF-I 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-I level. IGF-I 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-I 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 levels40.

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.

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 Chapter 4 in this section provides a detailed summary of the radiological investigation of the pituitary.

Figure 8. A lateral skull X -Ray demonstrating ballooning of the pituitary fossa in a patient with a somatotroph macroadenoma of the pituitary gland.

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 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 insulin-like growth factor-I (IGF-I) is a marker of hepatic growth hormone responsiveness and usually but not always correlates well with growth hormone levels41, but age- and sex-normalised ranges are required. Both growth hormone and IGF-I 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.

Transsphenoidal surgery is the initial treatment of choice for most patients. Originally performed by Harvey Cushing in 1910, the lack of adequate visualisation prevented its 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 transsphenoidal 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 MRI43 and intra-operative growth hormone measurement44. The development of endoscopic transsphenoidal surgery has been reported to offer several advantages over the conventional technique, although is used by only a few surgeons. These include superior tumour clearance, especially suprasellar extension, less surgical morbidity, fewer complications, and reduced post-operative discomfort 45.

The success rate of transsphenoidal 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 surgeon46;47. Although different series have often used different criteria to determine success rates, in experienced hands post-operative mean growth hormone levels of less than 2 ng/ml should be achieved in 70%-90% of microadenomas and 30%-50% of macroadenomas48,49. Pre-treatment of patients with somatostatin analogues before transsphenoidal surgery results in significant shrinkage (approximately 50%) of the adenoma and may improve the subsequent surgical cure rates50;51. Complications of transsphenoidal 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 prophylactic 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 transsphenoidal 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-operatively52.

Chapter 14 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 yttrium90 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 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 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 thereafter53. 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-I with approximately 60% of patients eventually achieving a normal serum level after 10 years. Although it is claimed, especially in the USA, that pituitary irradiation is associated with several side effects none of these have been proved 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 53. The claim that pituitary irradiation results in second tumour formation in the irradiation fields is unproven. 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 neoplasms54. 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.

Figure 9. A perspex radiotherapy mask individually manufactured to facilitate positioning in an acromegalic.

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 often55. 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 institution, it is currently reserved as a second-line therapy for patients who have persisting active disease despite surgery and conventional irradiation.

Three different types of medical therapy are currently used in the treatment of acromegaly - dopamine agonists, somatostatin analogs and more recently 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% achieve a mean level of less than 2 ng/ml56. Furthermore, the doses required, often 20 - 30 mg of bromocriptine per day, are much higher than those needed for prolactinomas. 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, there may be a slight reduction in tumour size but this is usually insignificant. Cessation of treatment results in rebound growth hormone hypersecretion. Other dopamine agonists have a similar effect, but with the long-acting cabergoline tending to be the most preferred due to its reduced side effects, although again high doses of up to 1 mg per day may be needed 57. 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.

Figure 10. Serum growth hormone responses to dopamine agonist suppressive therapy in 11 patients with acromegaly. Comparison of the responses to bromocriptine and pergolide. Note GH, 1 mU/l º 0.3 ng/ml

Somatostatin analog treatment of acromegaly

The development of octreotide (SandostatinÒ, 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 mg 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-I 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 two 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, and 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. Both compounds are of similar efficacy in suppression of growth hormone and IGF-I with safe growth hormone levels (<2 ng/ml) occurring in approximately 60-70% of patients58;59. Direct comparisons between octreotide LAR and lanreotide Autogel suggest they are of similar efficacy60;61, although a recent meta-analysis of patients unselected for somatostatin responsiveness indicated that normalised IGF-I levels and safe growth hormone levels occurred in a higher proportion of LAR treated than lanreotide treated patients62.

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 injections63. 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.

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 octrotide 64. In vivo studies suggest it has a longer duration of action than octreotide but direct efficacy comparisons are awaited. 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 release65. 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 supersaturation66. 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 patients67. Patients who remain uncontrolled despite the use of these somatostatin analogs may gain occasional additional benefit with the addition of a dopamine agonist, but this is the exception rather than the rule.

Figure 11. Changes in serum growth hormone levels in patients with acromegaly (n=15) during treatment with the somatostatin analogue Octreotide. Note GH, 1 mU/l º 0.3 ng/ml

Following confirmation of the diagnosis of acromegaly surgical treatment should be considered for all patients with a confirmed somatotroph adenoma. 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 3-field 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 and somatostatin analogs. Bromocriptine will normalize growth hormone levels in only 10% of patients, although this may rise to 30% with the newer agent 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. The recently developed growth hormone receptor antagonist, pegvisomant, may be used in patients resistant to these agents, when it becomes available. Periodic assessment with IGF-I measurement and growth hormone day curve 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.