acro best rnp
TRANSCRIPT
-
8/4/2019 Acro Best Rnp
1/20
3
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] -
8/4/2019 Acro Best Rnp
2/20
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
-
8/4/2019 Acro Best Rnp
3/20
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
P. Chanson et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 555574 557
-
8/4/2019 Acro Best Rnp
4/20
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.
P. Chanson et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 555574558
-
8/4/2019 Acro Best Rnp
5/20
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.
P. Chanson et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 555574 559
http://-/?-http://-/?- -
8/4/2019 Acro Best Rnp
6/20
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.
P. Chanson et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 555574560
-
8/4/2019 Acro Best Rnp
7/20
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.
P. Chanson et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 555574 561
-
8/4/2019 Acro Best Rnp
8/20
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 (
-
8/4/2019 Acro Best Rnp
9/20
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.
P. Chanson et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 555574 563
-
8/4/2019 Acro Best Rnp
10/20
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
P. Chanson et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 555574564
-
8/4/2019 Acro Best Rnp
11/20
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
-
8/4/2019 Acro Best Rnp
12/20
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).
P. Chanson et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 555574566
-
8/4/2019 Acro Best Rnp
13/20
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 (
-
8/4/2019 Acro Best Rnp
14/20
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.
P. Chanson et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 555574568
-
8/4/2019 Acro Best Rnp
15/20
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.,
-
8/4/2019 Acro Best Rnp
16/20
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.
P. Chanson et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 555574570
-
8/4/2019 Acro Best Rnp
17/20
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
-
8/4/2019 Acro Best Rnp
18/20
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.
References
1. Holdaway IM & Rajasoorya C. Epidemiology of acromegaly. Pituitary 1999; 2: 2941.2. Daly AF, Rixhon M, Adam C et al. High prevalence of pituitary adenomas: a cross-sectional study in the province of Liege,
Belgium. The Journal of Clinical Endocrinology and Metabolism 2006; 91: 47694775.3. Schneider HJ, Sievers C, Saller B et al. High prevalence of biochemical acromegaly in primary care patients with elevated
IGF-1 levels. Clinical Endocrinology 2008; 69: 432435.
4. Nabarro JD. Acromegaly. Clinical Endocrinology 1987; 26: 481512.5. Ezzat S, Forster MJ, Berchtold P et al. Acromegaly. Clinical and biochemical features in 500 patients. Medicine (Baltimore)1994; 73: 233240.
6. Melmed S. Acromegaly. In Melmed S (ed.). The pituitary. Malden, Mas, USA: Blackwell Science Inc., 2002, pp. 419454.7. Nachtigall L, Delgado A, Swearingen B et al. Changing patterns in diagnosis and therapy of acromegaly over two decades.
The Journal of Clinical Endocrinology and Metabolism 2008; 93: 20352041.8. Asa SL, Kovacs KT & Melmed S. Functional anatomy of the hypothalamic pituitary axis. In Melmed S (ed.). The pituitary. 2nd
edn. Malden, Mas, USA: Blackwell Science Inc., 2002, pp. 344.9. Heaney AP & Melmed S. Molecular targets in pituitary tumours. Nature Reviews Cancer 2004; 4: 285295.
10. Beck-Peccoz P, Bassetti M, Spada A et al. Glycoprotein hormone alpha-subunit response to growth hormone (GH)-releasinghormone in patients with active acromegaly. Evidence for alpha-subunit and GH coexistence in the same tumoral cell. The
Journal of Clinical Endocrinology and Metabolism 1985; 61: 541546.11. Beck-Peccoz P, Brucker-Davis F, Persani L et al. Thyrotropin-secreting pituitary adenomas. Endocrine Reviews 1996; 17: 610
638.12. Socin HV, Chanson P, Delemer B et al. The changing spectrum of TSH-secreting pituitary adenomas: diagnosis and
management in 43 patients. European Journal of Endocrinology 2003; 148: 433442.*13. Melmed S. Medical progress: acromegaly. The New England Journal of Medicine 2006; 355: 25582573.
14. Herman V, Fagin J, Gonski R et al. Clonal origin of pituitary adenomas. The Journal of Clinical Endocrinology and Metabolism1990; 71: 14271430.
15. Vallar L, Spada A & Giannattasio G. Altered Gs and adenylate cyclase activity in human GH-secreting pituitary adenomas.Nature 1987; 330: 566568.
16. Vlotides G, Eigler T & Melmed S. Pituitary tumor-transforming gene: physiology and implications for tumorigenesis.Endocrine Reviews 2007; 28: 165186.
17. Filippella M, Galland F, Kujas M et al. Pituitary tumour transforming gene (PTTG) expression correlates with the prolif-erative activity and recurrence status of pituitary adenomas: a clinical and immunohistochemical study. Clinical Endo-crinology 2006; 65: 536543.
18. Melmed S. Mechanisms for pituitary tumorigenesis: the plastic pituitary. The Journal of Clinical Investigation 2003; 112:16031618.
*19. Asa SL & Ezzat S. The pathogenesis of pituitary tumours. Nature Reviews Cancer 2002; 2: 836849.20. Chanson P, Salenave S, Droumaguet C et al. Rare causes of acromegaly. In Wass JA (ed.). Acromegaly: a handbook of history,
current therapy and future prospects. Bristol, UK: Bioscientifica Ltd, 2009, pp. 7098.21. Chanson P & Salenave S. Acromegaly. Orphanet Journal of Rare Diseases 2008; 3: 17.
*22. Colao A, Ferone D, Marzullo P et al. Systemic complications of acromegaly: epidemiology, pathogenesis, and management.Endocrine Reviews 2004; 25: 102152.
23. Giustina A, Casanueva FF, Cavagnini F et al. Diagnosis and treatment of acromegaly complications. Journal of Endocrino-logical Investigation 2003; 26: 12421247.
24. Melmed S, Colao A, Barkan A et al. Guidelines for acromegaly management: an update. The Journal of Clinical Endocrinologyand Metabolism 2009; 94: 15091517.
25. Molitch ME. Clinical manifestations of acromegaly. Endocrinology and Metabolism Clinics of North America 1992; 21: 597614.26. Danzig J. Acromegaly. BMJ 2007; 335: 824825.27. Mazziotti G, Bianchi A, Bonadonna S et al. Prevalence of vertebral fractures in men with acromegaly. The Journal of Clinical
Endocrinology and Metabolism 2008; 93: 46494655.28. Miller A, Doll H, David J et al. Impact of musculoskeletal disease on quality of life in long-standing acromegaly. European
Journal of Endocrinology 2008; 158: 587593.
29. Jenkins PJ, Sohaib SA, Akker S et al. The pathology of median neuropathy in acromegaly. Annals of Internal Medicine 2000;133: 197201.
30. Tagliafico A, Resmini E, Nizzo R et al. The pathology of the ulnar nerve in acromegaly. European Journal of Endocrinology2008; 159: 369373.
31. Chanson P, Timsit J, Masquet C et al. Cardiovascular effects of the somatostatin analog octreotide in acromegaly. Annals ofInternal Medicine 1990; 113: 921925.
P. Chanson et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 555574572
-
8/4/2019 Acro Best Rnp
19/20
32. Kamenicky P, Viengchareun S, Blanchard A et al. Epithelial sodium channel is a key mediator of growth hormone-inducedsodium retention in acromegaly. Endocrinology 2008; 149: 32943305.
33. Maison P, Demolis P, Young J et al. Vascular reactivity in acromegalic patients: preliminary evidence for regional endo-thelial dysfunction and increased sympathetic vasoconstriction. Clinical Endocrinology 2000; 53: 445451.
34. Colao A, Baldelli R, Marzullo P et al. Systemic hypertension and impaired glucose tolerance are independently correlatedto the severity of the acromegalic cardiomyopathy. The Journal of Clinical Endocrinology and Metabolism 2000; 85: 193199.
35. Jaffrain-Rea ML, Moroni C, Baldelli R et al. Relationship between blood pressure and glucose tolerance in acromegaly.Clinical Endocrinology 2001; 54: 189195.36. Sacca L, Cittadini A & Fazio S. Growth hormone and the heart. Endocrine Reviews 1994; 15: 555573.37. Clayton RN. Cardiovascular function in acromegaly. Endocrine Reviews 2003; 24: 272277.38. Gouya H, Vignaux O, Le Roux P et al. Rapidly reversible myocardial edema in patients with acromegaly: assessment with
ultrafast T2 mapping in a single-breath-hold MRI sequence. AJR American Journal of Roentgenology 2008; 190: 15761582.39. Bihan H, Espinosa C, Valdes-Socin H et al. Long-term outcome of patients with acromegaly and congestive heart failure.
The Journal of Clinical Endocrinology and Metabolism 2004; 89: 53085313.40. Colao A, Spinelli L, Marzullo P et al. High prevalence of cardiac valve disease in acromegaly: an observational, analytical,
case-control study. The Journal of Clinical Endocrinology and Metabolism 2003; 88: 31963201.41. Pereira AM, van Thiel SW, Lindner JR et al. Increased prevalence of regurgitant valvular heart disease in acromegaly. The
Journal of Clinical Endocrinology and Metabolism 2004; 89: 7175.42. Freda PU, Shen W, Heymsfield SB et al. Lower visceral and subcutaneous but higher intermuscular adipose tissue depots in
patients with growth hormone and insulin-like growth factor I excess due to acromegaly. The Journal of Clinical Endo-crinology and Metabolism 2008; 93: 23342343.
43. Katznelson L. Alterations in body composition in acromegaly. Pituitary 2009; 12: 136142.44. Herrmann BL, Wessendorf TE, Ajaj W et al. Effects of octreotide on sleep apnoea and tongue volume (magnetic resonance
imaging) in patients with acromegaly. European Journal of Endocrinology 2004; 151: 309315.45. Attal P, Claes V, Bobin S, et al. Growth hormone excess and sternohyoid muscle mechanics in rats. The European Respiratory
Journal, (in press, available on line).46. Ip MSM, Tan KCB, Peh WCG et al. Effect of Sandostatin LAR on sleep apneoa in acromegaly: correlation with
computerized tomographic cephalometry and hormonal activity. Clinical Endocrinology 2001; 55: 477483.47. Melmed S. Acromegaly and cancer: not a problem? The Journal of Clinical Endocrinology and Metabolism 2001; 86:
29292934.48. Jenkins PJ & Besser M. Clinical perspective: acromegaly and cancer: a problem. The Journal of Clinical Endocrinology and
Metabolism 2001; 86: 29352941.49. Renehan AG, OConnell J, OHalloran D et al. Acromegaly and colorectal cancer: a comprehensive review of epidemiology,
biological mechanisms, and clinical implications. Hormone and Metabolic Research 2003; 35: 712725.50. Delhougne B, Deneux C, Abs R et al. The prevalence of colonic polyps in acromegaly: a prospective colonoscopic and
pathological study in 103 patients. The Journal of Clinical Endocrinology and Metabolism 1995; 80: 32233226.51. Trainer PJ, Barth J, Sturgeon C et al. Consensus statement on the standardisation of GH assays. European Journal of
Endocrinology 2006; 155: 12.*52. Giustina A, Barkan A, Casanueva FF et al. Criteria for cure of acromegaly: a consensus statement. The Journal of Clinical
Endocrinology and Metabolism 2000; 85: 526529.53. Cazabat L, Souberbielle JC & Chanson P. Dynamic tests for the diagnosis and assesment of treatment efficacy in acromegaly.
Pituitary 2008; 11: 129139.54. Dimaraki EV, Jaffe CA, DeMott-Friberg R et al. Acromegaly with apparently normal GH secretion: implications for diagnosis
and follow-up. The Journal of Clinical Endocrinology and Metabolism 2002; 87: 35373542.55. Trainer PJ. Editorial: acromegalyconsensus, what consensus? The Journal of Clinical Endocrinology and Metabolism 2002;
87: 35343536.56. Kovacs K, Lloyd R, Horvath E et al. Silent somatotroph adenomas of the human pituitary. A morphologic study of three
cases including immunocytochemistry, electron microscopy, in vitro examination, and in situ hybridization. American Journal of Pathology 1989; 134: 345353.
57. Sakharova AA, Dimaraki EV, Chandler WF et al. Clinically silent somatotropinomas may be biochemically active. The
Journal of Clinical Endocrinology and Metabolism 2005; 90: 21172121.58. Dekkers OM, Biermasz NR, Pereira AM et al. Mortality in acromegaly: a metaanalysis. The Journal of Clinical Endocrinologyand Metabolism 2008; 93: 6167.
59. Ayuk J, Clayton RN, Holder G et al. Growth hormone and pituitary radiotherapy, but not serum insulin-like growth factor-Iconcentrations, predict excess mortality in patients with acromegaly. The Journal of Clinical Endocrinology and Metabolism2004; 89: 16131617.
60. Kauppinen-Makelin R, Sane T, Reunanen A et al. A nationwide survey of mortality in acromegaly. The Journal of ClinicalEndocrinology and Metabolism 2005; 90: 40814086.
*61. Holdaway IM, Bolland MJ & Gamble GD. A meta-analysis of the effect of lowering serum levels of GH and IGF-I on mortalityin acromegaly. European Journal of Endocrinology 2008; 159: 8995.
62. Holdaway IM, Rajasoorya RC & Gamble GD. Factors influencing mortality in acromegaly. The Journal of Clinical Endocri-nology and Metabolism 2004; 89: 667674.
63. Chanson P & Maison P. Does attainment of target levels of growth hormone and insulin-like growth factor I improveacromegaly prognosis? Nature Clinical Practice in Endocrinology and Metabolism 2009; 5: 7071.
64. Biermasz NR, van Thiel SW, Pereira AM et al. Decreased quality of life in patients with acromegaly despite long-term cure
of growth hormone excess. The Journal of Clinical Endocrinology and Metabolism 2004; 89: 53695376.65. Maison P & Chanson P. Less is more risky? Growth hormone and insulin-like growth factor 1 levels and cardiovascular risk.
Nature Clinical Practice in Endocrinology and Metabolism 2006; 2: 650651.66. Melmed S, Casanueva FF, Cavagnini F et al. Guidelines for acromegaly management. The Journal of Clinical Endocrinology
and Metabolism 2002; 87: 40544058.
P. Chanson et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 555574 573
-
8/4/2019 Acro Best Rnp
20/20
67. Fahlbusch R, Honegger J & Buchfelder M. Surgical management of acromegaly. Endocrinology and Metabolism Clinics ofNorth America 1992; 21: 669692.
68. Swearingen B, Barker FG II, Katznelson L et al. Long-term mortality after transsphenoidal surgery and adjunctive therapyfor acromegaly. The Journal of Clinical Endocrinology and Metabolism 1998; 83: 34193426.
69. Biermasz NR, van Dulken H & Roelfsema F. Ten-year follow-up results of transsphenoidal microsurgery in acromegaly. The Journal of Clinical Endocrinology and Metabolism 2000; 85: 45964602.
*70. Nomikos P, Buchfelder M & Fahlbusch R. The outcome of surgery in 668 patients with acromegaly using current criteria ofbiochemical cure. European Journal of Endocrinology 2005; 152: 379387.71. Cappabianca P, Cavallo LM & de Divitiis E. Endoscopic endonasal transsphenoidal surgery. Neurosurgery 2004; 55: 933
940. discussion 940931.72. Barkan AL, Halasz I, Dornfeld KJ et al. Pituitary irradiation is ineffective in normalizing plasma insulin-like growth factor I
in patients with acromegaly [see comments]. The Journal of Clinical Endocrinology and Metabolism 1997; 82: 31873191.73. Biermasz NR, van Dulken H & Roelfsema F. Long-term follow-up results of postoperative radiotherapy in 36 patients with
acromegaly. The Journal of Clinical Endocrinology and Metabolism 2000; 85: 24762482.*74. Barrande G, Pittino-Lungo M, Coste J et al. Hormonal and metabolic effects of radiotherapy in acromegaly: long-term
results in 128 patients followed in a single center [In Process Citation]. The Journal of Clinical Endocrinology and Metabolism2000; 85: 37793785.
75. Brada M, Burchell L, Ashley S et al. The incidence of cerebrovascular accidents in patients with pituitary adenoma.International Journal of Radiation Oncology Biology Physics 1999; 45: 693698.
76. Mahmoud-Ahmed AS, Suh JH & Mayberg MR. Gamma knife radiosurgery in the management of patients with acromegaly:a review. Pituitary 2001; 4: 223230.
77. Attanasio R, Epaminonda P, Motti E et al. Gamma-knife radiosurgery in acromegaly: a 4-year follow-up study. The Journalof Clinical Endocrinology and Metabolism 2003; 88: 31053112.
78. Castinetti F, Taieb D, Kuhn JM et al. Outcome of gamma knife radiosurgery in 82 patients with acromegaly: correlationwith initial hypersecretion. The Journal of Clinical Endocrinology and Metabolism 2005; 90: 44834488.
79. Newman CB. Medical therapy for acromegaly. Endocrinology and Metabolism Clinics of North America 1999; 28: 171190.80. Abs R, Verhelst J, Maiter D et al. Cabergoline in the treatment of acromegaly: a study in 64 patients. The Journal of Clinical
Endocrinology and Metabolism 1998; 83: 374378.*81. Lamberts SW, van der Lely AJ, de Herder WW et al. Octreotide. The New England Journal of Medicine 1996; 334: 246254.
82. Sassolas G, Harris AG & James-Deidier A. Long term effect of incremental doses of the somatostatin analog SMS 201-995 in58 acromegalic patients. French SMS 201-995-Acromegaly Study Group. The Journal of Clinical Endocrinology andMetabolism 1990; 71: 391397.
83. Chanson P, Timsit J & Harris AG. Clinical pharmacokinetics of octreotide. Therapeutic applications in patients with pitu-itary tumours. Clinical Pharmacokinetics 1993; 25: 375391.
84. Newman CB, Melmed S, George A et al. Octreotide as primary therapy for acromegaly [see comments]. The Journal ofClinical Endocrinology and Metabolism 1998; 83: 30343040.
85. Gillis JC, Noble S & Goa KL. Octreotide long-acting release (LAR). A review of its pharmacological properties and thera-peutic use in the management of acromegaly. Drugs 1997; 53: 681699.
*86. Freda PU, Katznelson L, van der Lely AJ et al. Long-acting somatostatin analog therapy of acromegaly: a meta-analysis. Journal of Clinical Endocrinology and Metabolism 2005; 90: 44654473.
87. Colao A, Ferone D, Marzullo P et al. Long-term effects of depot long-acting somatostatin analog octreotide on hormonelevels and tumor mass in acromegaly. The Journal of Clinical Endocrinology and Metabolism 2001; 86: 27792786.
88. Chanson P, Boerlin V, Ajzenberg C et al. Comparison of octreotide acetate LAR and lanreotide SR in patients with acro-megaly. Clinical Endocrinology 2000; 53: 577586.
89. Caron P, Beckers A, Cullen DR et al. Efficacy of the new long-acting formulation of lanreotide (lanreotide Autogel) in themanagement of acromegaly. The Journal of Clinical Endocrinology and Metabolism 2002; 87: 99104.
90. Bevan JS, Atkin SL, Atkinson AB et al. Primary medical therapy for acromegaly: an open, prospective, multicenter study ofthe effects of subcutaneous and intramuscular slow- release octreotide on growth hormone, insulin-like growth factor-I,and tumor size. The Journal of Clinical Endocrinology and Metabolism 2002; 87: 45544563.
91. Colao A, Ferone D, Cappabianca P et al. Effect of octreotide pretreatment on surgical outcome in acromegaly. JThe Journal of
Clinical Endocrinology and Metabolism 1997; 82: 33083314.92. Mazziotti G, Floriani I, Bonadonna S et al. Effects of somatostatin analogs on glucose homeostasis: a meta- analysis ofacromegaly studies. The Journal of Clinical Endocrinology and Metabolism 2009.
93. Kopchick JJ, Parkinson C, Stevens EC et al. Growth hormone receptor antagonists: discovery, development, and use inpatients with acromegaly. Endocrine Reviews 2002; 23: 623646.
*94. Trainer PJ, Drake WM, Katznelson L et al. Treatment of acromegaly with the growth hormone-receptor antagonist peg-visomant [see comments]. The New England Journal of Medicine 2000; 342: 11711177.
95. van der Lely AJ, Hutson RK, Trainer PJ et al. Long-term treatment of acromegaly with pegvisomant, a growth hormonereceptor antagonist. Lancet 2001; 358: 17541759.
96. Jimenez C, Burman P, Abs R et al. Follow-up of pituitary tumor volume in patients with acromegaly treated with peg-visomant in clinical trials. European Journal of Endocrinology 2008; 159: 517523.
97. van der Lely AJ, Muller A, Janssen JA et al. Control of tumor size and disease activity during cotreatment with octreotideand the growth hormone receptor antagonist pegvisomant in an acromegalic patient. The Journal of Clinical Endocrinologyand Metabolism 2001; 86: 478481.
98. Schreiber I, Buchfelder M, Droste M et al. Treatment of acromegaly with the GH receptor antagonist pegvisomant in
clinical practice: safety and efficacy evaluation from the German Pegvisomant Observational Study. European Journal ofEndocrinology 2007; 156: 7582.
P. Chanson et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 555574574