Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 555574

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Best Practice & Research Clinical Endocrinology & Metabolism

journal homepage: www.elsevier.com/locate/beem

Acromegaly
Philippe Chanson, MD, Professor and Head *, Sylvie Salenave, MD, Hospital Practitionner, Peter Kamenicky, MD, PhD, Associate Professor, Laure Cazabat, MD, Associate Professor, Jacques Young, MD, PhD, Professor
Assistance Publique-Hopitaux de Paris, Hopital de Bicetre, Service dEndocrinologie et des Maladies de la Reproduction and Centre de Reference des Maladies Endocriniennes Rares de la Croissance, and Faculte de Medecine, Universite Paris-Sud 11, INSERM U693, Le Kremlin-Bicetre, France

Keywords: acromegaly pituitary growth hormone insulin-like growth factor-I somatostatin analogues pegvisomant

Excessive production of the growth hormone (GH) is responsible for acromegaly. It is related to a pituitary GH-secreting adenoma in most cases. Prevalence is estimated 40130 per million inhabitants. It is characterised by slowly progressive acquired somatic disgurement (mainly involving the face and extremities) and systemic manifestations. The rheumatologic, cardiovascular, respiratory and metabolic consequences determine its prognosis. The diagnosis is conrmed by an increased serum GH concentration, unsuppressible by an oral glucose load and by detection of increased levels of insulin-like growth factor-I (IGF-I). Treatment is aimed at correcting (or preventing) tumour compression by excising the disease-causing lesion, and at reducing GH and IGF-I levels to normal values. When surgery, the usual rst-line treatment, fails to correct GH/IGF-I hypersecretion, medical treatment with somatostatin analogues and/or radiotherapy can be used. The GH-receptor antagonist (pegvisomant) is helpful in patients who are resistant to somatostatin analogues. Thanks to this multistep therapeutic strategy, adequate hormonal disease control is achieved in most cases, allowing a normal life expectancy. 2009 Elsevier Ltd. All rights reserved.

* Corresponding author. Assistance Publique-Ho pitaux de Paris, Service dEndocrinologie et des Maladies de la Reproduction, pital de Bicetre, 78 rue du General Leclerc, F-94275 Le Kremlin-Bicetre, France. Tel.: 33 1 45213705; Fax: 33 1 45212212. Ho E-mail address: philippe.chanson@bct.aphp.fr (P. Chanson). 1521-690X/$ see front matter 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.beem.2009.05.010

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Acromegaly is a rare disease characterised by a progressive somatic disgurement, mainly involving the face and extremities, that is associated with systemic manifestations related to organ overgrowth. This condition is associated with severe co-morbidity and premature mortality if not adequately treated. It is related to the excessive secretion of growth hormone (GH), originating in the vast majority of cases from a pituitary adenoma. Epidemiology Prevalence of acromegaly has long been estimated to be 4070 cases per million inhabitants, with an annual incidence of three to four new cases per million inhabitants.1 However, two recent studies have suggested that the prevalence of acromegaly would be much higher: around 100130 cases per million in a study performed in Belgium2 and also approximately 1000 per million inhabitants in a German study.3 These new data need to be conrmed. Owing to its insidious clinical manifestations, diagnosis of acromegaly is often delayed. Older series, in the 1980s, reported a mean time of delay in diagnosis of 610 years after onset, at an average age of about 40 years.46 Currently, according to a recent retrospective study, the interval seems to have decreased to about 23 years.7 Pathophysiology8,9 Acromegaly related to a pituitary tumour In more than 95% of cases, acromegaly is secondary to GH hypersecretion from a benign monoclonal pituitary adenoma, which develops from the somatotroph cells. Somatotroph pituitary adenomas Pure somatotroph pituitary adenomas (60%) contain either cells rich in secretory granules that show diffuse immunostaining or cells poor in secretory granules with scattered immunolabelling.8 Some of these pure somatotroph adenomas also express free alpha-subunit, which is common to the glycoprotein hormones such as follicle-stimulating hormone (FSH), luteinising hormone (LH), thyroid-stimulating hormone (TSH) and chorionic gonadotropin hormone (CG) and which may be, co-localised in the same cells or even in the same granules as GH.10 Mixed GH- and prolactin (PRL)-secreting adenomas are frequent (25%). Some adenomas contain both cell types, while others develop from a mammosomatotrophic stem cell and consist of more mature monomorphic cells that express both GH and PRL.8 Mixed GH- and TSHsecreting adenomas are rare. They are responsible for acromegaly combined with hyperthyroidism and inappropriate secretion of TSH.11,12 Very rarely, corticotrophin (ACTH) hypersecretion may also be found. The pituitary/hypothalamic origin of pituitary somatotroph adenomas is controversial.13 Some lines of evidence point to a hypothalamic origin. In this case, the main actor would be the growth-hormonereleasing hormone (GHRH), which can cause not only hyperplasia of somatotroph cells but also, as demonstrated in some animal models, true adenomas. In contrast, the monoclonal nature of the tumours and the absence of relapse after total adenoma removal points instead to a pituitary origin.6 In fact, the initiation and/or progression of neoplastic transformation of normal somatotrophs could be due to a polyclonal hyperplastic response of these cells secondary to hypothalamic dysregulation. The prerequisite for an abnormal response to pathological GHRH secretion may be the existence of a mutation in the somatotroph cell. Most human somatotroph adenomas seem to be associated with clonal expansion14 of cells bearing a somatic mutation. However, as for the other types of pituitary adenomas, isolation of a single causative factor in sporadic pituitary tumourigenesis has proved difcult. A mutated Gsa protein has been identied in up to 40% of somatotroph adenomas. Mutations at two critical sites (gsp mutations) inhibit GTPase activity and lead to constitutive adenyl-cyclase activation .15 In the pituitary, loss of heterozygosity on chromosomes 11, 13 and 9 (particularly in invasive macroadenomas), and an activating gene (PTTG, pituitary tumour transforming gene), also play a role. This latter gene (a securin homologue) is over-expressed in functional pituitary tumours, which could lead to aneuploidy16; the degree of overexpression correlates with tumour size and invasiveness.17 Finally, even if it is clear that somatotroph cells are altered in somatotroph adenomas, the sequence of events leading to their clonal expansion seems to be multifactorial. An activated oncogene may be necessary to initiate tumourigenesis, while promotion of

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cell growth may require GHRH or other growth factors, such as bFGF (basic broblast growth factor).18,19 (review the chapter The pathophysiology of pituitary adenomas in this issue). GH-secreting carcinomas In the large majority of cases adenomas are benign. Exceptional pituitary carcinomas (less than 20 cases published) may be observed and the presence of distant metastases is generally required to support the diagnosis of malignancy.20 Genetic syndromes with acromegaly Genetic syndromes with acromegaly (review the chapter The epidemiology and genetics of pituitary adenomas in this issue, and in the work by Chanson et al.20). McCuneAlbright syndrome, which is associated with multiple brous bone dysplasia, precocious puberty and cafe-au-lait spots, can be accompanied by acromegaly. This syndrome is related to a somatic mutation that activates the alpha subunit of Gs protein. Acromegaly can also be associated with hyperparathyroidism, neuroendocrine tumours (e.g., gastrinoma, insulinoma or a non-functional pancreatic tumour), adrenal and other endocrine and nonendocrine tumours in patients with multiple endocrine neoplasia type 1 (MEN1), which is related to a germ-line mutation of the menin gene in many cases. When acromegaly is associated with bilateral pigmented micronodular adrenal hyperplasia (causing ACTH-independent hypercorticism) and with cutaneous lesions or cardiac myxomas, the patient should be screened for the Carney complex, which is often related to a germ-line mutation of the regulatory 1-a subunit of protein kinase A (PRKAR1A). Very recently, familial acromegaly related to germ-line mutations of the AIP (aryl hydrocarbon receptor interacting protein) gene has been described. These mutations may also, albeit rarely, be found in some apparently sporadic cases of acromegaly, in particular, in young patients. Extrapituitary acromegaly Extrapituitary acromegaly (reviewed in Chanson et al.20) Acromegaly can be due to eutopic hypothalamic GHRH hypersecretion (gangliocytoma, hamartoma, choristoma, glioma, etc.) or, more often, to ectopic, peripheral GHRH hypersecretion (pancreatic or bronchial carcinoid tumour) that stimulates the normal somatotrophs to become hyperplastic and to hypersecrete GH. The diagnosis is based on plasma GHRH assay (revealing excess secretion) and on identication of the GHRH-secreting endocrine tumour. GH can also be hypersecreted by an ectopic pituitary adenoma (sphenoidal sinus, petrous temporal bone, nasopharyngeal cavity) or, in exceptional cases, by a peripheral tumour (pancreatic islet tumour or lymphoma). Signs and symptoms6,7,2124 The dysmorphic syndrome6,7,25 The extremities (hands and feet) are broadened; the ngers are widened, thickened and stubby; and the soft tissue is thickened (Fig. 1). The patient may have had to enlarge his or her ring in recent years, or to change shoe size. The facial aspect is characteristic, and patients with established acromegaly are generally alike in this respect: the nose is widened and thickened, the cheekbones are obvious, the forehead bulges, the lips are thick and the facial lines are marked (Fig.1). The forehead and overlying skin is thickened, sometimes leading to frontal bossing. There is a tendency towards mandibular overgrowth with prognathism, maxillary widening, teeth separation and jaw malocclusion. Photographs show a slow, insidious transformation over several years (Fig. 2). The diagnosis is often raised by a doctor who has never seen the patient before. The deformations can also affect the rest of the skeleton and, in severe chronic forms, dorsal kyphosis with deformation of rib cage may be observed, leading to the classical punchinello aspect, especially when GH hypersecretion begins prior to closure of the epiphyses. Acral changes are the most common problem leading to the diagnosis (Table 1), which is made by a general

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Fig. 1. As compared with the hand of a normal person (left), the hand of a patient with acromegaly (right) is enlarged, the ngers are widened, thickened and stubby, and the soft tissue is thickened (A). Facial aspect of a patient with acromegaly. The nose is widened and thickened, the cheekbones are obvious, the forehead bulges, the lips are thick and the facial lines are marked (B and C). Please refer to printed version for actual gure.

practitioner in the majority of cases.7 However, the majority of patients complain of the delay in diagnosis, despite clear signs and symptoms: this is related to the ignorance of many physicians about this disease because they never encountered one of these patients during their training or their practice.26 Symptoms Acromegaly can cause a variety of symptoms, such as headache (whether the pituitary adenoma is large or small), which is the second initial complaint leading to the diagnosis of acromegaly;

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Fig. 2. Series of photographs of the patient of Fig. 1 showing the progressive changes in facial appearance. It is possible to assume that the disease began in 2003, 6 years before the diagnosis. Please refer to printed version for actual gure.

Table 1 Initial complaints at the time of diagnosis of the disease in a large series of patients with acromegaly. Comparison between two decades, 19851994 and 19952004. Values are number and number (%). Adapted from7 with permission. Initial complaint at diagnosis Acral changes Incidentala Headache Amenorrhea Dental Carpal tunnel Visual Sexual dysfunction Galactorrhea Arthralgia Chest pain Hypertensive crisis Dizziness Increased weight Gynecomastia Weakness Diabetes mellitus Sleep apnea Total
a

Total (n 100) 24 18 20 6 4 4 3 3 2 2 2 2 1 1 1 1 5 1 100

Period 19851994 (n 25) 8 (32) 4 (16) 6 (18) 1 (4) 1 (4) 1 (4) 1 (4) 0 (0) 1 (4) 0 (0) 0 (0) 1 (4) 0 (0) 0 (0) 0 (0) 0 (0) 1 (0) 0 (0) 25

Period 19952004 (n 75) 16 14 14 5 3 3 2 3 1 2 2 1 1 1 1 1 4 1 75 (21) (19) (19) (6) (4) (4) (3) (4) (1) (3) (3) (1) (1) (1) (1) (1) (6) (1)

A patient in whom acromegaly was diagnosed independently of symptoms related to acromegaly.

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malodorous sweating (especially at night); acroparesthesia (carpal tunnel syndrome); and joint pain. A progressive deepening of the voice is also observed. Skin changes Nearly 70% of patients have sweaty, oily skin. Skin thickening is due to glycosaminoglycan deposition and to increased collagen production by connective tissue. Skin tags are frequent and may be a marker of colonic polyps. Raynauds disease is present in one-third of cases. Bone changes Craniofacial In response to both GH and IGF-I, periosteal new bone formation leads to an increase in skeletal growth, especially at the level of the mandible (prognathism); jaw thickening, teeth separation, frontal bossing, malocclusion and nasal bone hypertrophy are the usual facial bony deformities seen in acromegaly (Fig. 1). Radiography shows a thickening of the cranial vault and protuberances, frontal internal hyperostosis, and condensation of the walls of the sella turcica with clinoid hypertrophy. Hypertrophy of the sinuses, especially the frontal sinuses, is also clearly visible. This, along with laryngeal hypertrophy, explains why the voice in acromegaly tends to become deeper and has a sonorous resonance. Extremities These changes are not only due to soft-tissue hypertrophy and excess growth of bone and cartilage but also due to bone deformation. Indeed, radiography is abnormal in half of the cases, showing distal tufting of the phalanges, widening of the base of phalanges with osteophyte formation, enthesopathy (mineralisation of ligamentous insertion), widening of diaphysis in cortical bone and widening of joint spaces due to cartilage hypertrophy. Trunk Bony deformation also affects the spine, with upper dorsal kyphosis and compensatory lumbar hyperlordosis. Vertebral enlargement, widened intervertebral spaces and osteophyte formation are also observed. The thorax is deformed due to protuberance of the lower portion of the sternum and by elongation and divergence of the ribs (due to overgrowth of the chondrocostal joints). Limbs Imaging studies show diaphyseal cortical thickening of the long bones and widened joint spaces, sometimes with osteophytes. Bone mineral density Bone remodelling is stimulated in acromegaly. Cortical bone thickens (as measured by the metacarpal index and histomorphometric parameters) and its porosity is diminished. The trabecular bone mass may be decreased, normal or increased. Measurement of spinal bone mass can give contradictory results, probably because acromegaly is often associated with other endocrine disorders that interfere with bone mass. In general, bone mass is normal in the lumbar spine in patients with isolated acromegaly, but is decreased in patients with associated hypogonadism, as it is generally the case for hypogonadism whatever its cause. According to a recent study27, although bone mineral density (BMD) was not signicantly different between acromegalic patients and control subjects, the prevalence of vertebral fractures was higher in acromegalic patients (57.5% vs. 22.6%). Fractures were associated with higher serum IGF-I values and duration of active disease and longer untreated hypogonadism.

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Rheumatologic complications Peripheral arthropathy Peripheral joint symptoms are very frequent. Arthralgia and myalgia occur in 3070% of patients. All the joints can be affected (typically the large joints: knees, shoulders, hands, wrists and hips). Acromegalic arthropathy develops within an average of 10 years after diagnosis. The arthralgia is mainly mechanical, degenerative and non-inammatory in origin but features of osteoarthritis may develop in some patients. Joint mobility (especially of the shoulders) can be limited in the later stages of the disease. Joint effusion is rare and the synovial aspirate shows a generally degenerative picture without the evidence of inammation, but may also point to the presence of calcium microcrystals (associated chrondrocalcinosis). Physical examination of joints often provides little information. The abnormalities are generally minor as compared to the subjective functional discomfort. The shoulders and hips may show a loss of mobility and function. In contrast, some patients have joint hyperlaxity. There is no correlation between the presence (or severity) of arthropathy and the age of onset of acromegaly, or the mean GH or IGF-I concentration at baseline or during follow-up. Arthropathy appears to be more frequent after age of 45 years. Radiological studies show a widening of the joint spaces, reecting hypertrophy of the hyaline cartilage, the presence of osteophytes, bone proliferation at the attachment sites of tendons and ligaments, periarticular calcium deposit and exostosis of the bone surface. The joint space subsequently diminishes due to destructive arthropathy. Sonography shows a thickening of the cartilage in the shoulder, wrist and knee joints, which improves during treatment for acromegaly. The arthropathy progresses inexorably in advanced stages and unpredictably in minor forms. It is not inuenced by successful treatment of acromegaly, with the exception of diffuse articular symptoms and some sites of pain. It considerably impairs the quality of life of the patients.28 Spinal involvement The estimated prevalence of spinal involvement is about 4050%. Backache is more frequent at the level of the lumbar spine than cervical or dorsal spine. The pain is mainly mechanical in nature, but inammatory features can occur (16%). Spinal involvement may be accompanied by nerve compression. Occasionally, bilateral intermittent claudication reveals lumbar spinal stenosis. Radiological examination shows typical features: ossication of the anterior and lateral surface of the vertebral bodies contributing to enlarging their anteroposterior diameter; a biconcave vertebral appearance and scalloping of the vertebral bodies (exaggerated concavity of the posterior vertebral wall). The mechanism is poorly understood and may involve hypertrophy of the intraspinal soft tissues (ligamentous hypertrophy and epidural lipomatosis) or of the bone. In more severe cases, the process of ossication of the anterior surface of the vertebral bodies can bridge the disc space and give the aspect of diffuse idiopathic skeletal hyperostosis. Neuropathies Symptomatic carpal tunnel syndrome is frequent. Nerve conduction studies have documented that the vast majority of acromegalic patients have subclinical abnormalities of nerve conduction. Magnetic resonance imaging (MRI) shows an increase in the amplitude and intensity of the median nerve signal in the patients with symptomatic carpal tunnel syndrome compared to asymptomatic patients.29 The mechanism appears to involve median nerve oedema more than extrinsic compression, due to an excess of connective tissue, bony or synovial hypertrophy, or an increase in extracellular uid within the carpal tunnel itself with Schwann cell demyelination. The nerve oedema improves when GH and IGF-I levels fall, suggesting that hormonal control is a key prerequisite for improving neurological status. Sometimes, however, the carpal tunnel syndrome persists. Ulnar nerve neuropathy at the cubital tunnel is also frequent in patients with acromegaly30 and improves with treatment of acromegaly. Ultrasonography, which can also be used to visualize the nerve, demonstrates a paralel decrease of the nerve diameter.

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Cardiovascular manifestations Arterial hypertension Hypertension occurs in 2050% of patients. Its prevalence increases with time after the onset of acromegaly, the GH level and age. It is at least partly due to chronic hypervolaemia (the plasma volume is 1040% above normal due to increased renal sodium re-absorption at the distal tubule level).31,32 Hypertension can also result from endothelial dysfunction.33 Neither renin angiotensin aldosterone nor sympathetic systems seem to be involved in the pathogenesis of hypertension. Insulin resistance and diabetes may also play a role in the onset of hypertension.34,35 Sleep apnoea syndrome is likely to contribute also to the pathogenesis of hypertension. Specic cardiomyopathy Cardiac involvement is a consistent feature of acromegaly. Many lines of evidence, especially from experimental studies, point to the existence of specic cardiac disorders in acromegaly, independently of coronary involvement (presently found in a minority of patients) and valve disorders.22,36,37 Initially, the cardiac involvement is asymptomatic (at least at rest) and consists mainly of myocardial hypertrophy (of the interventricular septum and left ventricular posterior wall), as assessed by echocardiography, but the dimensions of the left ventricle are normal (concentric hypertrophy). It can occur in the absence of hypertension and even in young patients (<30 years), reecting the role of GH itself on the myocardium. Hypertension further aggravates cardiac hypertrophy. Echocardiography and isotope studies show altered diastolic function (abnormal left and right ventricle lling) related to abnormal relaxation (parietal stiffness is, at least in part, probably linked to oedematous inltration of the ventricular wall38 and perhaps also to a certain degree of brosis). Clinical symptoms such as dyspnoea during exercise may be observed while the patient is asymptomatic at rest. Systolic function is normal at this stage (again, at least at rest), thanks to increased myocardial contractility. A hyperkinetic syndrome (increased cardiac index) is always present. Systolic function is altered during exercise however. Even at this early stage, arrhythmias and/or conduction disorders may occur. Their prevalence in acromegaly was underestimated for many years. In fact, ventricular premature complexes occur in about 40% of patients with acromegaly, and, in one study, systematic 24-h Holter electrocardiogram (ECG) recordings showed complex ventricular arrhythmias in 48% of patients (compared to only 12% of controls). Most of these arrhythmias are subclinical and persist despite successful treatment of acromegaly. Myocardial remodelling, hypertrophy and brosis all are likely to play a role in their onset. Congestive heart failure can occur if the cardiac disorders progress (if GH hypersecretion persists and, probably, if other risk factors such as diabetes, hypertension and sleep apnoea are also present); functional signs appear on effort at rst, before becoming permanent. At this stage, echocardiography shows variable degrees of cavity dilation. Fortunately, these severe forms are now far less frequent (prevalence 3%).39 A number of cardiovascular parameters improve during effective treatment of acromegaly, even if some lesions may appear to be irreversible in certain patients. In general, younger patients and those with a relatively short history of acromegaly show better recovery (from diastolic disorders, myocardial hypertrophy or systolic dysfunction). In contrast, when dilated congestive heart failure occurs, cardiac function (especially systolic function) may show a short-term improvement, allowing some patients to survive or to avoid heart transplantation, but the longer-term prognosis is worse than that of patients with heart failure due to other causes (5-year mortality rate: 37%). Valve disease The increased prevalence of valve disorders can also contribute to the onset or aggravation of the heart disease in patients with acromegaly.40 The risk of valve disease increases with time from onset41, and these abnormalities often persist after effective treatment of acromegaly. They may be related to brotic changes. Metabolic complications Physiologically, GH increases blood glucose levels, exerts a lipolytic effect and promotes triglyceride hydrolysis into free fatty acids and glycerol.

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GH excess leads to insulin resistance at the level of the liver or in the periphery, which leads to hyperinsulinaemia. The prevalence of diabetes in acromegalic patients ranges from 20% to 56% and that of glucose intolerance ranges from 16% to 46%, depending on the series.22 As long as the compensatory increase in insulin secretion by pancreatic b cells counterbalances the reduction in insulin sensitivity, glucose tolerance remains normal. Impaired glucose tolerance occurs when insulin secretion is altered and is followed by diabetes. Acromegaly is associated with decrease in fat mass (both visceral and subcutaneous), but increase in intermuscular fat mass (which may contribute to insulin resistance) and increase in lean body mass.42,43 Respiratory complications Sleep apnoea affects 6080% of all patients with acromegaly (more often men) and 93% of patients with signs of this disorder. Sleep apnoea is more likely to be sought in patients who snore (reported by 78% of patients with acromegaly) and those with daytime sleepiness (51%), or morning fatigue and morning headache (16%). Sleep apnoea may be a contributory factor in hypertension and cardiovascular disease. In most cases, apnoea is obstructive, but one-third of patients have central apnoea. Obstructive apnoea is linked to anatomical changes due to mandibular and maxillary growth, soft-tissue thickening (especially of the palate and uvula) and changes in the angles of the different bone segments, leading to hypercollapsibility of the posterior and lateral hypopharyngeal walls. Hypertrophy of the tongue also plays a role44, as does hypertrophy of the submaxillary glands. Changes in respiratory function are frequent but less well documented. Anatomical modications of thoracic bones and cartilage (leading to profound changes in the geometry of the rib cage) and mechanical changes in thoracic elasticity and inspiratory muscles can lead to ventilatory disorders. Respiratory muscle strength is also abnormal. Altered mechanical and energetic properties of some upper airway dilator muscle have been recently demonstrated.45 The inspiratory time is shorter and the breathing frequency may increase. Patients with acromegaly often have an increase in their total lung capacity (81% of men and 56% of women), owing to an increase in alveolar volume. An obstruction is found in 2030% of patients (small airway or upper airway narrowing). Subclinical hypoxaemia may be present. No ventilationperfusion mismatching has been demonstrated. The apnoeahypopnea index improves during effective treatment of acromegaly, along with the obstructive apnoea index and oximetry values.44,46 However, while apnoea can disappear in some patients whose acromegaly is cured, they other require nocturnal positive-end expiratory pressure for persistent sleep apnoea. Neoplasia and acromegaly Gastrointestinal tumours The issue of colon cancer risk in acromegaly is controversial.47 The relative risk of colon cancer, compared with the general population, has been widely overestimated at 10 to 20, whereas it is, in reality, probably only 2 to 3.48,49 As colon cancer may be the consequence of colon polyps degeneration, many studies have been conducted to assess the prevalence of colon polyps in patients with acromegaly. Prospective studies show that up to 45% of patients with acromegaly have colonic polyps, which are adenomatous in 24% of cases50 and can arise from all the sites of the colon. There is no clear correlation between GH and IGF-I concentrations and the incidence of colonic polyps. Recommendations concerning colonoscopy in acromegaly are a matter of controversy. It seems reasonable to propose that, unless intestinal symptoms occur earlier, colonoscopy has only to be done rst at age 50 years, whatever the progressive status and duration of acromegaly, or the history of colonic disease. As always, colonoscopy must be preceded by careful bowel preparation and be done by a skilled operator because it is often difcult in this setting (patients with acromegaly have a longer colon). When an adenomatous colonic polyp is discovered, an interval of 3 years before repeating the examination seems reasonable.

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Thyroid nodules Goiter is found in 2590% of patients with acromegaly. The risk of developing thyroid nodules increases with the time since the onset of acromegaly. Multinodular goitre is autonomous in 1020% of patients, sometimes causing patent thyrotoxicosis. Thyroid nodules are generally harmless, and the risk of thyroid cancer does not seem to be higher than in the general population. Other cancers (lung, breast, prostate, etc.) are not over-represented in patients with acromegaly.47

Practice points - Acromegaly is associated with numerous systemic complications: hypertension, cardiomyopathy, sleep apnoea syndrome, arthropathy, carpal tunnel syndrome, diabetes mellitus, colon cancer, goitre, etc. - A regular work-up of these potential complications needs to be performed. - In parallel to control of GH/IG-I excess, specic treatment of each of the co-morbidity greatly improves the general prognosis of the patients Diagnosis of acromegaly The diagnosis of acromegaly is clinical and needs to be conrmed biochemically. Clinical diagnosis is suggested by the typical disgurement of the patient related to progressive acral enlargement and modication of facial appearance, as assessed by serial photographs (Fig. 2). Diagnosis is made biochemically by the ndings of increased serum GH concentrations that are not suppressed following an oral glucose load (oral glucose tolerance test, OGTT). An increase (with reference to the age-adjusted normal range) in the serum concentration of IGF-I, the main GH-dependent growth factor, conrms the diagnosis. GH assays The rst GH assays, used since past 35 years, were polyclonal competitive radio-immunoassays (RIAs); their sensitivity was poor. Thereafter, over the last 25 years, non-competitive two-site antibody radio-immunometric assays (IRMAs) have been introduced allowing for enhanced sensitivity. Fifteen years ago, non-isotopic two-site antibody assays were rst available, with the major practical advantage being that some were automated. This last type of assays is the most frequently used today, at least in Europe. The differences in analytical methodologies (RIA, IRMA, immunochemiluminescent assay (ICMA), enzyme-linked immunosorbent assay (ELISA)) are an explanation for the variability in GH results. GH circulates in plasma as a mixture of different molecular forms: 22-kDa GH, 20-kDa GH, a GHbinding protein (GH-BP) linked form, dimers and polymers. Use of polyclonal or monoclonal antibodies specic for the predominant 22 kDa or for several of these different isoforms contributes to bias. Many standard GH preparations were used previously to calibrate GH. In Europe, manufacturers were recently advised to calibrate their GH assay kits with the international standard (IS) 98/574, which was established with recombinant GH. According to a recent European consensus statement on the standardisation of GH assays51, the availability of the second International Standard (IS) for GH (WHO IS 98/574), a recombinant material consisting of 22 kDa GH of more than 95% purity, provides the opportunity for adoption of a single calibrant for GH immunoassays. IS 98/574s well-dened chemical and physical properties allow it to meet European Union legislation calls for all laboratory results to be traceable to a dened material (In vitro Diagnostics Medical Devices Directive, 98/79/EC). As a rst step to standardising GH measurement, they recommend the reporting of GH concentrations in mg/l of IS 98/574 (1 mg corresponding to 3 IU somatropin). Which GH cutoff use for the diagnosis? The basal plasma GH level (in the morning, for example, or at randomly selected times) is elevated in acromegaly. However, high GH concentrations can also be found in healthy subjects, owing to the

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episodic nature of GH secretion, that can uctuate between undetectable levels (most of the time) and peaks of up to 30 mg l1 (90 mIU l1). According to a 2000 Consensus statement52, basal GH and IGF-I measurement must be done when acromegaly is suspected. A GH concentration below 0.4 mg l1 (1.2 mIU l1) plus a normal IGF-I level rules out acromegaly. If the GH is above 0.4 mg l1 (1.2 mIU l1) and/or if the IGF-I is elevated (as compared with age-adjusted normal range), an oral 75 g glucose load (oral glucose tolerance test, OGTT) must be performed. If the lowest GH value (nadir) during OGGT is below 1 mg l1 (3 mIU l1), acromegaly can be ruled out. If it remains above 1 mg l1 (3 mIU l1), acromegaly is conrmed. As detailed below, with the generalised use of very sensitive assays nowadays53, it has recently been considered that this cutoff should be decreased to 0.3 mg/l (0.9 mIU/l). Paradoxically, the OGTT can stimulate GH secretion in about 10% of patients with acromegaly.

IGF-I measurement The IGF-I level increases in parallel to the log of the GH concentration. It must be determined using age-adjusted norms (levels fall with age). Pregnancy, puberty and the post-pubertal period are accompanied by high IGF-I concentrations. The concentration of IGFBP3, the main IGF carrier protein, is usually increased in patients with acromegaly, but this marker offers little further diagnostic information.

Stimulation tests Some patients (up to 50%) have an increase in their GH concentration after thyrotropin-releasing hormone (TRH) and/or gonadotropin-releasing hormone (GnRH) stimulation. These tests have no diagnostic value, however, nor does the response to GHRH.

Difcult and borderline clinical situations A few patients with clear clinical signs of acromegaly and a high IGF-I level have a GH nadir of <1 mg l1 (3 mIU l1) during OGTT.54 Thus, some authors have suggested that when chemiluminescence or uorometric assays with very low detection limits are used (0.100.30 mg l1, i.e., 0.3 0.9 mIU l1), the OGTT positivity cutoff should not be 1 mg l1 (3 mIU l1) but rather 0.30 mg l1 (1 mIU l1).55 Forthcoming guidelines should ratify the choice of this new 0.30 mg l1cutoff (1 mIU l1) when using very sensitive GH assays. Other difcult problems include a typical clinical picture of acromegaly in a patient with normal IGF-I and GH concentrations. This situation probably corresponds to cases in which acromegaly has resolved spontaneously, probably through necrosis of a pituitary adenoma. In some conditions such as diabetes mellitus, chronic renal failure, pregnancy or at the time of puberty, GH and/or IGF-I measurement cannot be used either for the diagnosis or for the assessment of treatment efcacy. Some somatotroph adenomas are not associated with systemic GH hypersecretion or GH hypersecretion is very mild (silent somatotroph adenomas). In such cases, clinical acromegaly is not observed or is very mild, but GH immunolabelling of the excised adenoma (generally resected because of local tumour symptoms) is positive.56 However, subtle abnormalities in GH/IGF-I hypersecretion are frequently observed in these cases.54,57

Differential diagnosis Lastly, some patients have acromegaloid features with normal GH and IGF-I levels; in some cases, severe insulin resistance is the proposed mechanism.

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Practice points - International Standard 98/574, established with recombinant GH, must be used for calibration of GH assay (1 mg corresponding to 3 IU somatropin). - Diagnosis of acromegaly is classically made by the demonstration of increased serum GH levels unsuppressible by OGTT to less than 1 mg l1 (3 mIU l1) and increased IGF-I above the age-adjusted normal range. - In fact, with the generalised use of very sensitive assays presently, it has recently been considered that the cutoff of GH nadir during OGTT should be decreased to 0.3 mg l1 (0.9 mIU l1).

Tumour and functional pituitary assessment Once the diagnosis has been established, and before initiating treatment for acromegaly, patients must undergo a dual work-up focussing on both the tumour mass effects (headaches, visual eld and acuity, MRI) and pituitary function. MRI determines if the pituitary tumour is a micro- or a macroadenoma, if it expands upwards, downwards or laterally, in the cavernous sinus and if there is evidence of invasiveness (Fig. 3). Conversely, the lack of clear signs of an adenoma on MRI, or an appearance showing a bulging, hyperplastic pituitary, suggests that the acromegaly is secondary to ectopic GHRH secretion.20 Evaluation of other pituitary hormones determines if these are decient or secreted in excess: PRL hypersecretion is present in 30% of cases, either functional (secondary to impairment of hypothalamic production of dopamine or compression of the pituitary stalk by the tumour that impairs dopamine transport to the pituitary), or due to a mixed adenoma (see above). Prognosis and outcome Acromegaly is associated with increased mortality.58 According to series published in the 1980s to 1990s, about 60% of patients die from cardiovascular disease, 25% from respiratory complications and

Fig. 3. Pituitary macroadenoma with suprasellar extension, compressing the optic chiasm, and invading cavernous right sinus, responsible for acromegaly in the patient of Figs. 1 and 2.

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567

Physiology GHRH Somatostatin

+ -

Surgery Radiotherapy Dopamine agonists Somatostatin analogues

GPCR

Pituitary adenoma

GH-receptor antagonist

GH
12 12

12 12 12 12 12

12

GH-R Other tissues Liver

IGF-I

Cell proliferation and differentiation Linear growth Glucose metabolism

Fig. 4. Site of action of the different therapeutic tools in acromegaly. Surgery, radiotherapy, somatostatin analogues and dopamine agonists act at the level of the pituitary adenoma, while GH-receptor antagonists act in periphery by blocking the GH receptor and thus impairing the effects of GH on the different tissues.

15% from cancer. If left untreated, patients with acromegaly would die about 10 years earlier than healthy subjects.1 Several studies have shown that cerebrovascular disorders are a frequent cause of death, especially among women, but they involved patients treated in various ways and many years ago (craniotomy, radiotherapy), and a deleterious effect of these treatments (especially radiotherapy) cannot be ruled out.59,60 In two recent meta-analysis58,61, the standardised mortality ratio (the ratio of observed mortality in the acromegalic population to expected mortality in the general population) was 1.72 (95% condence interval (CI): 1.621.83) but survival improved in the more recent studies. The post-treatment GH concentration is probably the best predictor of survival, for all causes of death, independently of the types of complication. Thus, life-expectancy outcomes can be stratied according to the post-treatment GH concentration: if GH secretion is controlled (<2 mg l1, or <5 mIU l1, or IGF-I normalisation), life expectancy merges with that of the matched general population.59,62 It is interesting to note that the recent meta-analysis by Holdaway et al. that investigated the relationship between mortality and levels of GH and IGF-I in patients with acromegaly has conrmed that the current criteria proposed almost a decade ago, that is, achieve serum growth hormone (GH) levels <2.5 mg l1 and age-adjusted normal levels of IGF-I, are adequate in terms of mortality. The metaanalysis also shows that the prognosis of acromegaly has improved in the last 20 years. This improvement may be related to a more aggressive treatment of the disease and management of comorbidities.63 High GH/IGF-I concentrations, arterial hypertension and cardiomyopathy are factors of poor prognosis, while the duration of symptoms and other factors (diabetes, lipid disorders and cancer) are less important.47 Quality of life is also altered in acromegaly and is partially improved by effective treatment.64 Finally, it must be stressed that, with the current therapeutic strategy (Fig. 4), a vast majority of acromegalic patients have very good control of GH/IGF-I secretion and no problems relating to tumour growth. Adverse effects are infrequent and minor, even in the very long term; this picture is very different from the situation only 20 years ago, before the somatostatin analogues era. In addition, the use of more stringent criteria to dene cure, together with aggressive treatment of co-morbidity, has signicantly improved the outlook for patients with acromegaly.65 However, even if

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patients are cured or well controlled, sequelae (joint pain, deformities and altered quality of life) often remain.

Practice points - Current criteria of control of acromegaly, that is, achieving serum GH levels less than 2 mg l1 (5 mIU l1) levels and age-adjusted normal levels of insulin-like growth factor I (IGF-I) are adequate in terms of mortality. - Prognosis of acromegaly has improved in the recent years, thanks to a more aggressive treatment of the disease and management of co-morbidities, as proposed by statements of the Experts Consensus.

Management and treatment Treatment aims66 The clinical aims are to relieve symptoms, to reduce the volume of the pituitary tumour, to avoid tumour relapse and to improve long-term morbidity and mortality. Recent epidemiological studies helped to rene the denitions of cure and good disease control, which are now far more precise: the GH concentration (the mean of several samples, or the nadir in the OGTT) must return to less than 2 mg l1 or 6 mIU l1 (or even 1 mg l1 or 3 mIU l1) when RIA is used and the IGF-I level must return to normal.52 A stepwise therapeutic strategy using surgery and/or radiotherapy and/or medical treatment (Fig. 5) allows to achieve these goals.

GH-secreting pituitary adenoma Surgery

In the majority of patients In selected patients

SA Good control

Persisting disease

(DA trial?)

SA Inadequate response or intolerance Follow-up

In selected patients consider surgical debulking of the tumor remnant

Yes

Concern for tumor mass or location (particularly for optic chiasm) ?

No

Continue SA add GHRA

Good control

Switch to GHRA

Tumor growth? Surgery and/or radiotherapy

Fig. 5. Strategy proposed by the Authors for the current management of acromegaly. SA: somatostatin analogues; DA: dopamine agonists, GHRA: GH-receptor antagonist (pegvisomant).

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569

Surgery is generally the rst-line treatment Tumour excision, usually by the trans-sphenoidal route, is the most rapid way of reducing GH and IGF-I concentrations in patients with acromegaly. Nevertheless, these levels normalise in only 4070% of cases6770, depending on the size of the tumour (microadenomas are more amenable to cure), preoperative GH concentrations (the success rate is higher when GH concentrations are low, i.e., <10 mg l1 or 30 mIU l1) and the surgeons experience. Endoscopic techniques are now currently used in the majority of expert centres.71 Surgical outcome is carefully assessed at 3 months. When surgery fails to achieve good disease control, or when surgery is impossible or contraindicated, patients are offered radiotherapy and/or pharmacological treatments. Radiotherapy Radiotherapy in this setting is external and centred on the tumour; an average total dose of 50 Gy is delivered in about 25 daily sessions. Highly focussed irradiation (radiosurgery, stereotactic radiotherapy, gamma-knife, etc.) is now available in some centres and causes less damage to neighbouring tissues. Fractioned irradiation yields GH concentrations below 2 mg l1 (6 mIU l1) and normal IGF-I levels in 560% of patients, depending on the series, after a median follow-up of about 7 years.7274 In studies with longer follow-up, fractionated radiotherapy normalises the IGF-I level in more than 70% of patients after 10 years. Here again, the baseline GH concentration seems to be predictive of treatment outcome. Radiotherapy leads to variable degrees of anterior pituitary insufciency in 80100% of patients after 1015 years. Complications such as radionecrosis and optic neuropathy are now very rare. In contrast, the risk of stroke may be increased, sometimes many years after irradiation.75 The precise role of stereotactic irradiation in this setting (e.g., with a gamma-knife) is becoming clearer76,77, but long-term studies with strict end-points are needed to tell whether this approach is as effective and safer than the existing alternatives. Results of a French series of 82 patients indicate that efcacy is similar to that of fractionated radiotherapy78: an average of 4 years after the procedure, less than 20% of patients have normal IGF-I levels and GH <2 mg l1 (<6 mIU l1). In any event, this radiosurgery is reserved for patients with small lesions located at least 5 mm from the optic chiasma. Medical treatment Dopamine agonists Bromocriptine attenuates moderately the symptoms of acromegaly and reduces GH concentrations, but it normalises IGF-I levels in only 10% of patients. However, cabergoline appears to be more effective.79,80 Somatostatin analogues (SAs)  SAs suppress GH secretion by binding to somatostatin receptors, of which there are ve subtypes (SST), on somatotrope adenoma cells. These drugs exert their anti-secretory and anti-tumoural effects by acting on SST 2 and 5.  Octreotide (Sandostatin) can be injected subcutaneously (SC), generally by the patient him/ herself, at a dose of 100200 mg twice or thrice times a day. This was the rst such analogue to be marketed, in the 1980s, and represented a real therapeutic advance.81 Sustained-release lanreotide (Somatuline LP 30 mg) was the rst slow-release preparation to be marketed. It was injected intramuscularly every 1014 days (the frequency of injections depends on the impact on the GH concentration). Lanreotide is now available for deep SC injection every 28 days, at doses of 60, 90 and 120 mg (Somatuline Autogel 60, 90 or 120 mg). Octreotide LAR (Sandostatin LAR 10, 20 or 30 mg) is the sustained-release version of octreotide and is administered intramuscularly, once

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a month. Treatment is usually started at the median dose and is then adjusted (decreased or increased) according to the GH concentration. Alternatively, it is possible to increase or decrease the frequency of injections.  These drugs achieve GH concentrations below 2 mg l1 (5 mIU l1) in 6070% of patients and normalise IGF-1 levels in 5080% of patients.8289 Besides their anti-secretory effect, SAs also reduce the tumour volume (generally the suprasellar portion) in 2070% of patients.87,90 The reduction in tumour volume is larger when an SA is the rst-line treatment.87  In selected cases (contraindications to surgery, patients with severe co-morbidities who need to be prepared by medical treatment before surgery91, invasive tumours for which total removal is unlikely {Freda, 2002 #308). SAs may be given as a rst-line therapy. If their effect is incomplete, de-bulking surgery may be proposed before another trial of SA.  These treatments must be continued indenitely because SAs only suppress GH hypersecretion. They have gastrointestinal adverse effects, which are generally transient, and cause gallstones in 1020% of patients. In a meta-analysis, they were found to induce statistically signicant decrease in fasting plasma insulin, without any signicant change of fasting blood glucose and HbA1c. Serum glucose values during OGTT were shown to signicantly increase, although with high inconsistency among trials.92 These data suggest that modications of glucose homeostasis induced by SAs may have an overall minor clinical impact in acromegaly. Finally, they are also expensive.

The GH receptor antagonist, pegvisomant (Somavert) Pegvisomant has a different mechanism of action. It acts in the periphery, blocking the effects of GH on its target organs by binding to GH receptors and preventing their dimerisation; this blocks GH signal transduction and inhibits GH activity, including IGF-I production.93 As pegvisomant inhibits the action of GH but not its secretion, GH concentrations cannot be used to evaluate treatment efcacy. IGF-I is used as a surrogate marker, together with clinical parameters. Pegvisomant is administered subcutaneously at a daily dose of 10, 15 or 20 mg (sometimes more), the dose being adapted to the hormone response (IGF-I normalisation). Pegvisomant is highly effective, as IGF-I levels normalise in more than 90% of patients.94,95 Presently, this treatment is reserved for patients in whom SAs fail. A small increase in tumour volume is observed in a few patients. In a series of 304 patients in whom tumour volume was monitored for at least 3 years, an increase in tumour volume occurred in nine patients, within 8 months after commencing pegvisomant. This is likely related to rebound expansions after discontinuation of SAs and/or the natural history of aggressively growing pituitary tumours96; in this latter case, this may justify combination with an SA to reduce tumour volume.97 Tumour volume must therefore be monitored (by MRI) during this treatment. Available clinical data on pegvisomant concern a relatively small number of patients and relatively short treatment periods. The adverse effects are limited to rare cases of increased transaminases that generally normalise either after interruption of the treatment or spontaneously. Exceptional cases of true hepatitis were reported.98 Current therapeutic strategy The advantages, disadvantages and costs of treatment must be taken into account. A therapeutic strategy is proposed by the authors on Fig. 5. Currently, if surgical treatment fails to cure acromegaly, medical treatment with SAs is recommended rather than radiotherapy. If SAe therapy fails, it may be interesting to propose a re-operation in case of important tumour remnant, before another trial of SA. Otherwise, one can propose pegvisomant before resorting to radiotherapy. The cost of these medical treatments, which may be required indenitely, must be weighed up against the risks of radiotherapy. In any event, medical treatment will be necessary while waiting for the effects of radiotherapy to appear. If surgery and radiotherapy are contraindicated, rst-line somatostatin therapy may be proposed. All these treatments must be re-assessed on a yearly basis.

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Practice points - Surgery is generally the rst-line treatment of acromegaly. - When surgery has failed to achieve control of GH/IGF-I hypersecretion, medical treatment with SAs is generally preferred nowadays to radiotherapy. - GH-receptor antagonists are used as third-line treatment. - Radiotherapy has the advantage of achieving denitive control of acromegaly in some patients, but its effect is delayed (many years), requiring the use of medical treatment in the interval and side effects (pituitary insufciency, cerebrovascular risk, etc.) are important.

Research agenda - Pathophysiology of pituitary adenomas (particularly somatotroph adenomas) remains largely unknown and is the matter of intense research. - Not only to help the understanding of the pathophysiology of complications but also to prepare new effective drugs, progress in the comprehension of mechanisms of action of GH is needed. - Research also focusses on the development of new SAs, more potent, not only for the control of GH/IGF-I excess but also of tumour volume.

To summarise, acromegaly is a rare disease usually caused by growth hormone (GH) hypersecretion, due to a pituitary adenoma. Pathophysiology of pituitary adenomas (particularly somatotroph adenomas) remains largely unknown and is the matter of intense research. Conclusion Because of its insidious onset and progressive course, acromegaly is often diagnosed late (3 to >10 years after onset), at an average age of about 40 years, ahead of an acquired, slowly progressing disgurement mainly involving the face and extremities. Indeed, besides dysmorphic syndrome, acromegaly has cardiovascular, respiratory, rheumatologic and metabolic consequences and is associated with risk of neoplastia. A detailed work-up of the various organs potentially involved in these complications is recommended. Progress needs to be done in detecting acromegaly sooner in order to decrease its consequences, their reversibility largely depending on importance and duration of GH/IGFI excess. The diagnosis is based on an increased serum GH concentration unsuppressed following an oral glucose load and an increased insulin-like growth factor-I (IGF-I). If the lowest GH value (nadir) during OGTT remains above 1 mg l1 (3 mIU l1), acromegaly is conrmed. With the generalised use of very sensitive assays presently, it has recently been considered that this cutoff should be decreased to 0.3 mg l1 (0.9 mIU l1). Treatment is aimed at correcting (or preventing) tumour compression by excising the culprit lesion and at reducing GH and IGF-I levels to normal values (or at least to a safe GH level of <2 mg l1 or <6 mIU l1). A stepwise therapeutic strategy is used: trans-sphenoidal surgery is often the rst-line treatment; when surgery fails to correct GH/IGF-I hypersecretion, medical treatment with somatostatin analogues and/or radiotherapy can be used, SAs being generally preferred; the GH receptor antagonist (pegvisomant) is used in patients who are resistant or intolerant to SAs. New SAs, more potent, that we hope will allow a better control of GH/IGF-I hypersecretion and tumour volume, are currently in clinical development. Prognosis of acromegaly has improved in the recent years; adequate hormonal disease control is achieved in most cases, allowing life expectancy similar to that of the general population. It remains to

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know whether the criteria used for dening control of the disease in terms of mortality also apply for optimal management of co-morbidities. Conict of interest The Service dEndocrinologie et des Maladies de la Reproduction, Universite Paris-Sud 11, receives unrestricted educational and research grants from Novartis, Ipsen and Pzer. PC received consulting and lecture fees from Novartis, Ipsen and Pzer. SS, PK, LC and JY have nothing to declare.

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