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Acromegaly

Philippe Chanson, MD, Professor and Head *, Sylvie Salenave, MD, HospitalPractitionner, Peter Kamenicky, MD, PhD, Associate Professor,

Laure Cazabat, MD, Associate Professor, Jacques Young, MD, PhD, ProfessorAssistance 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 analoguespegvisomant

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 inhabi-

tants. It is characterised by slowly progressive acquired somatic

disfigurement (mainly involving the face and extremities) and

systemic manifestations. The rheumatologic, cardiovascular,respiratory and metabolic consequences determine its prognosis.

The diagnosis is confirmed by an increased serum GH concentra-

tion, 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 first-line treat-

ment, 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 ach-ieved in most cases, allowing a normal life expectancy.

2009 Elsevier Ltd. All rights reserved.

* Corresponding author. Assistance Publique-Hopitaux de Paris, Service dEndocrinologie et des Maladies de la Reproduction,

Hopital de Bicetre, 78 rue du General Leclerc, F-94275 Le Kremlin-Bicetre, France. Tel.: 33 1 45213705; Fax: 33 1 45212212.

E-mail address: [email protected] (P. Chanson).

Contents lists available at ScienceDirect

Best Practice & Research Clinical

Endocrinology & Metabolismj o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / b e e m

1521-690X/$ see front matter 2009 Elsevier Ltd. All rights reserved.

doi:10.1016/j.beem.2009.05.010

Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 555574
mailto:[email protected]://www.sciencedirect.com/science/journal/1521690Xhttp://www.elsevier.com/locate/beemhttp://www.elsevier.com/locate/beemhttp://www.sciencedirect.com/science/journal/1521690Xmailto:[email protected]


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Acromegaly is a rare disease characterised by a progressive somatic disfigurement, 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 confirmed. 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 immunostainingor cells poor in secretory granules withscatteredimmunolabelling.8 Someof these

pure somatotroph adenomas also express free alpha-subunit, which is common to the glycoproteinhormones such as follicle-stimulating hormone (FSH), luteinising hormone (LH), thyroid-stimulating

hormone (TSH)andchorionic 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 TSH-

secreting 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-hormone-

releasing 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 tumoursand 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 prereq-

uisite 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 difficult. A mutated Gsa protein

has been identified 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) isover-expressed in functional pituitary tumours, which could lead to aneuploidy16; the degree of over-

expression 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

P. Chanson et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 555574556


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cell growth may require GHRH or other growth factors, such as bFGF (basic fibroblast 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 tosupport the diagnosis of malignancy.20

Genetic syndromes with acromegaly

Genetic syndromes with acromegaly (review the chapter The epidemiology and genetics of pitu-

itary adenomas in this issue, and in the work by Chanson et al.20).

McCuneAlbright syndrome, which is associated with multiple fibrous 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., gas-

trinoma, insulinoma or a non-functional pancreatic tumour), adrenal and other endocrine and non-

endocrine tumours in patients with multiple endocrine neoplasia type 1 (MEN1), which is related toa 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

identification 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 fingers 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, thelips are thick and thefacial linesaremarked(Fig.1). The forehead andoverlying 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 whohas 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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practitioner in the majority of cases.7 However, the majority of patients complain of the delay in diag-

nosis, 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;

Fig.1. As compared with the hand of a normal person (left), the hand of a patient with acromegaly (right) is enlarged, the fingers 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 figure.



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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 assumethat the disease began in 2003, 6 years before the diagnosis. Please refer to printed version for actual figure.

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 Total (n 100) Period 19851994 (n 25) Period 19952004 (n 75)

Acral changes 24 8 (32) 16 (21)

Incidentala 18 4 (16) 14 (19)

Headache 20 6 (18) 14 (19)

Amenorrhea 6 1 (4) 5 (6)

Dental 4 1 (4) 3 (4)

Carpal tunnel 4 1 (4) 3 (4)

Visual 3 1 (4) 2 (3)

Sexual dysfunction 3 0 (0) 3 (4)

Galactorrhea 2 1 (4) 1 (1)

Arthralgia 2 0 (0) 2 (3)

Chest pain 2 0 (0) 2 (3)

Hypertensive crisis 2 1 (4) 1 (1)

Dizziness 1 0 (0) 1 (1)

Increased weight 1 0 (0) 1 (1)

Gynecomastia 1 0 (0) 1 (1)

Weakness 1 0 (0) 1 (1)

Diabetes mellitus 5 1 (0) 4 (6)Sleep apnea 1 0 (0) 1 (1)

Total 100 25 75

a 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 depo-

sition 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 hyper-

ostosis, 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 hyper-

trophy, 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).

LimbsImaging 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 meta-

carpal 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 acro-

megaly, but is decreased in patients with associated hypogonadism, as it is generally the case for

hypogonadism whatever its cause. According to a recent study

27

, although bone mineral density(BMD) was not significantly different between acromegalic patients and control subjects, the preva-

lence 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). Acro-

megalic arthropathy develops within an average of 10 years after diagnosis. The arthralgia is mainlymechanical, degenerative and non-inflammatory 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 inflammation, 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, reflecting 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 influenced 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 thelevel of the lumbar spine than cervical or dorsal spine. The pain is mainly mechanical in nature, but

inflammatory features can occur (16%). Spinal involvement may be accompanied by nerve compres-

sion. Occasionally, bilateral intermittent claudication reveals lumbar spinal stenosis.

Radiological examination shows typical features: ossification 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

ossification 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 fluid 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 neurologicalstatus. Sometimes, however, the carpal tunnel syndrome persists.

Ulnar nerve neuropathy at the cubital tunnel is also frequent in patients with acromegaly 30 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.

Specific cardiomyopathy

Cardiac involvement is a consistent feature of acromegaly. Many lines of evidence, especially from

experimental studies, point to the existence of specific 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 echo-cardiography, but the dimensions of the left ventricle are normal (concentric hypertrophy). It can occur

in the absence of hypertension and even inyoung patients (


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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 havecentral 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 modifications 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 degener-

ation, 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. Recommenda-

tions 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 first at age 50

years, whatever the progressive status and duration of acromegaly, or the history of colonic disease. Asalways, colonoscopy must be preceded by careful bowel preparation and be done by a skilled operator

because it is often difficult 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

Diagnosis of acromegaly

The diagnosis of acromegaly is clinical and needs to be confirmed biochemically. Clinical diagnosis is

suggested by the typical disfigurement of the patient related to progressive acral enlargement and

modification of facial appearance, as assessed by serial photographs (Fig. 2). Diagnosis is made bio-

chemically by thefindings of increased serum GH concentrations that arenotsuppressed followingan oral

glucose load (oral glucose tolerance test, OGTT). An increase (with reference to the age-adjusted normal

range)in the serum concentrationof IGF-I, themain GH-dependent growth factor, confirms the diagnosis.

GH assays

The first 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 first 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 GH-

binding protein (GH-BP) linked form, dimers and polymers. Use of polyclonal or monoclonal antibodies

specific 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-defined

chemical and physical properties allow it to meet European Union legislation calls for all laboratory

results to be traceable to a defined material (In vitro Diagnostics Medical Devices Directive, 98/79/EC).

As a first 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

Practice points

- Acromegaly is associated with numerous systemic complications: hypertension, cardiomy-

opathy, 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, specific treatment of each of the co-morbidity greatly

improves the general prognosis of the patients



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episodic nature of GH secretion, that can fluctuate 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) duringOGGT 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 confirmed. 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 areaccompanied 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.

Difficult and borderline clinical situations

A few patients with clear clinical signs of acromegaly and a high IGF-I level have a GH nadir of


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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 field andacuity, 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 deficient 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.

Practice points

- International Standard 98/574, established with recombinant GH, must be used for calibra-

tion of GH assay (1 mg corresponding to 3 IU somatropin).

- Diagnosis of acromegaly is classically made by the demonstration of increased serum GHlevels 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).



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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% confidence 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 stratified according

to the post-treatment GH concentration: if GH secretion is controlled (


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

remain.

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 refine the definitions 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 SAIn the majority

of patients

In selected patients consider surgicaldebulking of the tumor remnant

Good

control

Persisting disease(DA trial?)

SA

Inadequate response

or intolerance

Concern for tumor mass or location

(particularly for optic chiasm) ?

Switch to

GHRA

Continue SA

add GHRA

Tumor growth?

Surgery and/or radiotherapy

Follow-up

In selectedpatients

Yes No

Good

control

Fig. 5. Strategy proposed by the Authors for the current management of acromegaly. SA: somatostatin analogues; DA: dopamine

agonists, GHRA: GH-receptor antagonist (pegvisomant).

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.



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Surgery is generally the first-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.,


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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 Thereduction in tumour volume is larger when an SA is the first-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 first-line therapy. If their effect is incomplete,

de-bulking surgery may be proposed before another trial of SA.

These treatments must be continued indefinitely 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 significant decrease

in fasting plasma insulin, without any significant change of fasting blood glucose and HbA1c.

Serum glucose values during OGTT were shown to significantly increase, although with high

inconsistency among trials.92 These data suggest that modifications of glucose homeostasisinduced 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

efficacy. 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 beingadapted 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 oftrue 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 indefinitely, must be weighed up against the risks

of radiotherapy. In any event, medical treatment will be necessary while waiting for the effects ofradiotherapy to appear.

If surgery and radiotherapy are contraindicated, first-line somatostatin therapy may be proposed.

All these treatments must be re-assessed on a yearly basis.



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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

disfigurement mainly involving the face and extremities. Indeed, besides dysmorphic syndrome,

acromegaly has cardiovascular, respiratory, rheumatologic and metabolic consequences and is asso-

ciated 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/IGF-

I 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 confirmed. 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


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know whether the criteria used for defining control of the disease in terms of mortality also apply for

optimal management of co-morbidities.

Conflict 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 Pfizer. PC received consulting

and lecture fees from Novartis, Ipsen and Pfizer. SS, PK, LC and JY have nothing to declare.

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