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Systemic Complications of Acromegaly: Epidemiology, Pathogenesis, and Management

Department of Molecular and Clinical Endocrinology and Oncology (A.C., P.M., G.L.), "Federico II" University of Naples, 80131 Naples, Italy; and Department of Endocrinological and Metabolic Sciences and Center for Excellence for Biological Research (D.F.), University of Genova, 16132 Genova, Italy

Correspondence: Address all correspondence and requests for reprints to: Annamaria Colao, M.D., Department of Molecular and Clinical Endocrinology and Oncology, "Federico II" University, via S. Pansini 5, 80131 Napoli, Italy. E-mail: colao{at}unina.it.

	Abstract

Top Abstract I. Introduction II. The Complications at... III. The Metabolic Complications IV. The Complications at... V. The Neoplastic Complications VI. The Complications at... VII. Summary VIII. Conclusions References

 
This review focuses on the systemic complications of acromegaly. Mortality in this disease is increased mostly because of cardiovascular and respiratory diseases, although currently neoplastic complications have been questioned as a relevant cause of increased risk of death. Biventricular hypertrophy, occurring independently of hypertension and metabolic complications, is the most frequent cardiac complication. Diastolic and systolic dysfunction develops along with disease duration; and other cardiac disorders, such as arrhythmias, valve disease, hypertension, atherosclerosis, and endothelial dysfunction, are also common in acromegaly. Control of acromegaly by surgery or pharmacotherapy, especially somatostatin analogs, improves cardiovascular morbidity. Respiratory disorders, sleep apnea, and ventilatory dysfunction are also important contributors in increasing mortality and are beneficially advantaged by controlling GH and IGF-I hypersecretion. An increased risk of colonic polyps, which more frequently recur in patients not controlled after treatment, has been reported by several independent investigations, although malignancies in other organs have also been described, but less convincingly than at the gastrointestinal level. Finally, the most important cause of morbidity and functional disability of the disease is arthropathy, which can be reversed at an initial stage, but not if the disease is left untreated for several years.

I. Introduction

A. Epidemiology and causes of mortality in acromegaly

B. The clinical basis of increased mortality in acromegaly

C. The experimental basis for the GH/IGF-I effects at different body organs

D. Management of acromegaly

II. The Complications at the Cardiovascular System

A. Epidemiology

B. Pathogenesis

C. The acromegalic cardiomyopathy

D. Arrhythmias

E. Hypertension

F. Atherosclerosis and endothelial dysfunction

G. Effect of GH and IGF-I control on cardiovascular disease

III. The Metabolic Complications

A. Epidemiology

B. Pathogenesis

C. Effect of GH and IGF-I control on metabolic complications

IV. The Complications at the Respiratory System

A. Epidemiology

B. Pathogenesis

C. The sleep apnea syndrome

D. The respiratory dysfunction

E. Effect of GH and IGF-I control on respiratory disease

V. The Neoplastic Complications

A. Epidemiology

B. Pathogenesis

C. The gastrointestinal tract

D. Neck and lung tumors

E. Tumors of the reproductive system

F. Other tumors

VI. The Complications at the Skeletal System

A. Epidemiology

B. Pathogenesis

C. The acromegalic arthropathy

D. The carpal tunnel syndrome

E. Bone mass alterations

F. Effect of GH and IGF-I control on the skeletal system

VII. Summary

VIII. Conclusions

	I. Introduction

Top Abstract I. Introduction II. The Complications at... III. The Metabolic Complications IV. The Complications at... V. The Neoplastic Complications VI. The Complications at... VII. Summary VIII. Conclusions References

 
IN 1864, THE skull of a woman affected by prosopectasia (derived from the Greek words prosopon, face, and ektasis, stretching) was described by Verga (1) and added to the collection of the Anatomical Museum of Modena, Italy. During her lifetime, this patient suffered from typical somatic disfigurement, arrhythmias, and osteoarthropathy, although a postmortem examination revealed a giant pituitary (1). In 1881, Brigidi reported a description clinically consistent with acromegaly from the autopsy of the Italian actor Ghirlenzoni (2). This man had visceromegaly and enlarged hypertrophic pituitary. However, both Verga and Brigidi misinterpreted the pathogenesis of the syndrome, which was attributed to early menopause in the former and to primary bone disease in the latter case. Five years after Brigidi’s description, Pierre Marie (3) indicated with acromegaly his observation of two patients he had treated at the Salpetrière Hospital in Paris. At autopsy, Marie observed visceromegaly and enlarged pituitaries but was uncertain whether pituitary overgrowth was the cause etiology of such syndrome or whether it reflected the general process of organomegaly observed in these patients (3). Afterward, a progressively increasing number of similar descriptions were provided. Massalongo in 1892 and Benda in 1900 both indicated the cause of the disease as originating in the pituitary (2). However, it was only in 1909 that Harvey Cushing (4) reported the remission of clinical symptoms of acromegaly after partial hypophysectomy, thus indicating the etiology of the disease and its potential treatment as well. Acromegaly is known to be characterized by progressive somatic disfigurement and a wide range of systemic manifestations (5, 6). At diagnosis, patients generally exhibit coarsened facial features, exaggerated growth of hands and feet, and soft tissue hypertrophy (Table 1). Other characteristics may include hyperhidrosis, goiter, osteoarthritis, carpal tunnel syndrome, fatigue, visual abnormalities, increased number of skin tags, colon polyps, sleep apnea and daytime somnolence, reproductive disorders, and cardiovascular disease, which most commonly includes cardiac hypertrophy, hypertension, and moderate arrhythmias, although congestive heart failure occurs more rarely (5, 6, 7). Improvement of surgical procedures, radiotherapy tools, and the availability of pharmacological compounds active on somatotroph pituitary cells greatly changed the approach to this disease that is an extraordinary model to investigate the pathophysiology of GH and IGF-I actions on virtually all body organs and systems; several systemic consequences developing in the course of undiagnosed GH and IGF-I excess may remain undiagnosed for a long time.

A. Epidemiology and causes of mortality in acromegaly
Acromegaly has an estimated annual incidence of three to four cases per million population and a current estimated prevalence of 40 cases per million population, which can be reportedly as high as 90 cases per million population (8, 9, 10). In most cases, chronic GH hypersecretion is caused by a benign pituitary adenoma (5). Due to its indolent and insidious nature, the diagnosis of acromegaly is usually delayed for a variable number of years (7). Retrospective epidemiological studies showed that diagnosis can be preceded by approximately four to 10 or more years of active disease, and it is likely that today the diagnosis is made earlier than before because patients present much less with visual field defects (11). Analysis of determinants of mortality outcome indicates that approximately 60% of acromegalic patients die from cardiovascular disease, 25% from respiratory disease, and 15% from malignancies (12, 13, 14, 15, 16, 17, 18, 19). The nadir GH value likely constitutes the most predictive survival index, regardless of the death cause (13, 15, 16, 17, 18). There is compelling evidence indicating that control of GH levels and/or IGF-I levels normalized for age is associated with improvement of adverse mortality rates, independent of the type of associated complications (17). Suppression of GH below 5 mU/liter (<2.5 µg/liter) had been shown already to portend a favorable mortality outcome (19, 20). In fact, it has been suggested that overall mortality in patients with acromegaly is correlated with the degree of GH control (18); mortality rates for cancer can be stratified according to posttreatment GH levels (18); and, if GH secretion is controlled, mortality rates become similar to those recorded in the nonacromegalic population (13, 18). However, mortality in patients with cardiac disease at the time of diagnosis occurs within 15 yr in almost 100% of cases, and only 20% of patients with diabetes and acromegaly will survive 20 yr (16). High GH levels, hypertension, and heart disease constitute the major negative survival determinants in acromegaly (19), whereas symptoms duration and other factors, including uncontrolled diabetes and/or dyslipidemia and cancer, account less for mortality (Fig. 1). Thus, control of GH hypersecretion, hypertension, and heart disease is relevant to improve the ultimate mortality rates.

View larger version (21K): [in this window] [in a new window]   FIG. 1. Depiction of mortality determinants in patients with acromegaly. The x-axis reflects the P value (log) as calculated from published retrospective reports. [From S. Melmed: J Clin Endocrinol Metab 86:2929–2934, 2001 (19 ). Permission granted by The Endocrine Society.]

C. The experimental basis for the GH/IGF-I effects at different body organs
Nearly one century after Verga’s original documentation (1), Salmon and Daughaday’s findings (26) set the basis for the somatomedin hypothesis with the identification of liver-derived serum factor-mediating GH actions on peripheral tissues. The same serum factor was sequentially termed sulfation factor, nonsuppressible insulin-like activity, multiplication-stimulation activity, and eventually IGF-I in independent investigations (reviewed in Refs. 27 and 28). The concept that GH operated on peripheral tissues through endocrine IGF-I was successively revised in the early 1980s, when IGF-I was shown to be expressed ubiquitously in several body tissues and its local expression could be modulated by exogenous GH administration to animals (27, 28). Subsequent studies in preadipocytes and chondrocytes attempted at discriminating between GH and IGF-I effects in the periphery and demonstrated that GH promoted cellular differentiation, whereas IGF-I preferentially induced clonal expansion, thus introducing the dual effector theory (29). However, the congruity of the aforementioned theories has been recently questioned. GH has been found also to modulate the expression of various growth factors and their receptors in several tissues, in addition to IGF-I. GH can stimulate directly the proliferation of chondrocytes in the germinal zone of the growth plate (30), and it promotes the activation of immediate early gene (i.e., transcription of early growth response factor-1) in 3T3-F442A preadipocytes (31). A demonstration that endocrine GH had local effects on cells originated from studies in mice carrying null mutations for the IGF-I gene that showed a normal proliferation of growth plate chondrocytes despite a 35% decrease in longitudinal bone growth (32). To explain this finding, the authors speculated that the lack of IGF-I stimulus had likely been replaced by endogenous GH or, alternatively, by local IGF-II (32). Recent investigations are now questioning whether liver IGF-I production actually plays an essential role in postnatal growth and development. Studies in conditional IGF-I knockout mouse models obtained with the Cre/loxP recombination system have, in fact, demonstrated that abrogation of liver IGF-I expression blunts 75% of endocrine IGF-I secretion, increases GH levels in serum likely due to feedback mechanisms, and preserves postnatal growth and development; as a result, autocrine/paracrine IGF-I production seems to be sufficient for normal growth and development, although a direct effect of GH on nonhepatic tissues cannot be excluded (33, 34).

GH action is achieved via its interaction on the cell surface with its receptor (GH-R) belonging to the family of the cytokine receptors (35), whereas IGF-I belongs to a system of proteins encompassing IGF-II, the type-I and -II IGF receptors (IGF-IR and -IIR), six IGF binding proteins (IGFBPs), three families of IGFBP proteases, and nine growth-mediating factors that share structural similarities in the N-terminus of the IGFBPs and have therefore also been termed IGFBP-related proteins (Fig. 2) (28). IGF-I circulates in serum bound to IGFBP-3 and the acid-labile subunit (ALS) in a 150-kDa ternary complex, which works both as a reservoir and regulator of IGF-I biodistribution to peripheral tissues/organs. Due to the molecular weight of ALS, IGF-I is unable to cross the endothelium unless it is released from the ternary complex after the proteolysis of IGFBP-3. IGFBP-3 proteolysis generates fragments with a lower IGF-I binding affinity, and this is key in the regulation of local IGF-I bioavailability. Studies in hypophysectomized rats have clearly demonstrated that all three peptides of the ternary complex are synthesized in the liver in a GH-dependent fashion, although a GH-responsive element has only been identified in the ALS promoter (36). In the liver, hepatocytes are the primary source for IGF-I and ALS production, whereas IGFBP-3 is synthesized preferentially in the portal venous and sinusoidal endothelium, as determined by the expression of mRNA by in situ hybridization histochemistry (37). Due to their GH dependence, the impairment of total and free IGF-I, IGFBP-3, and ALS secretion is used for diagnostic purposes in acromegaly and GH deficiency (38, 39). Although it has been shown that both IGF-I and IGFBP-3 elicit multiple cellular effects both dependently and independently of each other, ALS does not seem to possess intrinsic biological activity. The IGF-I cellular effects are achieved through the interaction of IGF-I with the IGF-IR, a heterotetrameric protein that is evolutionarily and structurally similar to the insulin receptor in its - and ß-subunits (40). The intracellular domains of the ß-subunits of IGF-IR possess tyrosine kinase activity and tyrosine residues that are phosphorylated upon receptor activation. The consequence of receptor phosphorylation is the downstream recruitment of signaling proteins including the IRS and Shc families of proteins, which in turn activate the MAPK and phosphatidylinositol 3-kinase pathways, as well as additional downstream signaling proteins leading to gene transcription (27). Depending on the preponderance of intracellular IRS or Shc proteins, IGF-I will promote either cellular proliferation/transformation or differentiation (41). Noteworthy, the primary role of IGF-I is the regulation of postnatal growth and the mediation of the growth-promoting effects of GH. The overexpression of bovine, murine, or rat GH stimulates body growth and increases IGF-I levels in transgenic mice (42). Similar body growth promoting effects are produced by human IGF-I overexpression in the mice liver (43). In contrast, IGF-I null mice suffer from impairment of fetal growth and development, whereas perinatal viability is markedly decreased (44). The physiological actions of IGF-I also encompass increased muscle protein synthesis (45), in vivo and in vitro stimulation of muscle cell differentiation (40), enhanced glucose uptake in peripheral tissues (45), bone growth and maturation (46), oligodendrocyte survival, and neuronal differentiation (47). These effects require a functionally active IGF-IR, which is essential for normal embryonic and fetal growth, modulation of cellular apoptosis, and the growth, proliferation, and migration of normal and tumoral cells (48).

View larger version (18K): [in this window] [in a new window]   FIG. 2. Representation of the IGF system comprising IGFs, IGFBP-1 through 6, IGFBP-related proteins, IGF and IGFBP cell membrane receptors, and additional translocation mechanisms for IGFBP-3 to the nucleus.

D. Management of acromegaly
An extensive discussion on the current approaches for an integrated and modern management of acromegaly lies beyond the scope of this review. However, because most of the subsequent parts will refer to the partial or total recovery of systemic complications of acromegaly after controlling GH/IGF-I hypersecretion, the most recent advances in the management of acromegaly will be summarized here.

The optimal treatment for acromegaly should be able to remove the tumor with resolution of its mass effects, preserve the normal residual pituitary function, prevent recurrences, restore normal GH and IGF-I secretion, relieve symptoms directly caused by GH excess, and, possibly, prevent progressive disfigurement, bone expansion, osteoarthritis, cardiomyopathy, hypertension, insulin resistance, diabetes mellitus, and lipid abnormalities, thus reversing the unfavorable long-term outcome (6). The treatment options currently available for such ambitious goals include surgery, irradiation, and pharmacological suppression of GH levels by somatostatin analogs or dopamine agonists, and/or by functional blockade of the GH-R by modified GH analog (53), which has provided promising results (54, 55). Cure criteria to evaluate the efficacy of all treatment approaches, except for the GH-antagonist, are mean integrated 24-h GH levels less than 2.5 µg/liter or no more than 1 µg/liter after glucose load, together with circulating IGF-I levels normalized for age and gender (20). Clearly, other pituitary hormone deficiencies that may be caused by the tumor and/or by its treatment must be treated as in other types of pituitary tumors.

Transsphenoidal adenomectomy remains a milestone treatment for GH-secreting tumors, but should be performed only in experienced centers. Moreover, it has been reported recently that the outcome of surgery when only one surgeon operates on patients is higher than that observed when more than one surgeon operates (56, 57). The outcome of surgery is successful in most microadenomas and enclosed macroadenomas, but it remains disappointing in larger adenomas and negligible in invasive tumors (6, 16, 56, 58). Among 224 consecutive patients, endocrine remission occurred in 72% of microadenomas, 50% of macroadenomas, and only 17% of giant adenomas (59). Normalized IGF-I levels with GH levels below 3 µg/liter (60), or 2.5 µg/liter (61), were achieved in 59% and 42% of unselected patients, respectively. In microadenomas, success of surgery was obtained in 61% of patients (61). Surgery relieves the compression on adjacent structures such as optic chiasm and ventricles, and it only rarely causes complications. In fact, in a study including questionnaires regarding 14 specific complications of transsphenoidal surgery mailed to 3172 neurosurgeons, it was reported that the mean operative mortality rate was low (0.9%), anterior pituitary insufficiency and diabetes insipidus were the most common complications (19.4% and 17.8%, respectively), whereas cerebrospinal fluid fistulas were found in a low number of cases (3.9%) and other complications, such as carotid artery injuries, hypothalamic injuries, loss of vision, and meningitis, occurred in 1–2% of cases (62). In another study (63), pituitary failure after surgery was confirmed to be the most frequent complication occurring in up to 30% of patients with macroadenomas. A controversy exists on the usefulness of a short preoperative drug treatment to improve surgical outcome (for review, see Refs. 6 and 64); we observed that a 6-month treatment with octreotide preoperatively improved metabolic and hemodynamic parameters and reduced the duration of hospital stay in acromegalic patients (65). Recently, to provide a technical refinement in pituitary surgery, a one-nostril endoscopic endonasal transsphenoidal procedure has been proposed to reduce the damage to nose and sphenoid sinus and to improve the management of the pituitary region (66). Interestingly, postsurgical complications using this technique are likely to be low compared with classical microscopical approach (67). In fact, among 146 consecutively treated patients who underwent an endoscopic endonasal transsphenoidal approach to the sellar region for resection of pituitary adenomas between January 1997 and July 2001, complications (divided into groups, i.e., nasofacial, sphenoid sinus, sella turcica, supra or parasellar, and endocrine) were decreased in their incidence compared with large historical series of the traditional microsurgical transsphenoidal approach (67). The overview inside the anatomy facilitated by the endoscope and the consequent decreased surgical trauma can be taken as explanation for such positive findings.

Irradiation of GH-secreting pituitary tumor should be reserved to patients in whom surgery is contraindicated or unsuccessful and medical treatment fails to control persistent hormone hypersecretion due to a remnant tumor (68). Multiple methods for delivery of radiation are currently used, including external radiation, proton beam, -particles, and interstitial radiotherapy. All seem to induce similar cure rates. The greatest fall in GH levels occurs within the first 2 yr, followed by a gradual decline thereafter for 10 yr (69). Earlier observations that pituitary irradiation normalized IGF-I concentrations only in a minority of patients (70, 71) have not been confirmed by later studies reporting higher cure rates (72, 73). Furthermore, the occurrence of severe complications, such as cranial nerve palsies, optic neuritis, impaired memory, lethargy, and tissue necrosis has decreased with modern techniques. However, damage of the normal hypothalamic-pituitary region results in hypopituitarism in more than half of patients within 10 yr (6, 63, 68, 69). Gamma-knife radiosurgery has been used as adjuvant treatment for pituitary adenomas in selected cases with promising results (74), but definitive data are still lacking.

Bromocriptine, the first and likely still the most widely used dopamine agonist in acromegaly, lowered GH levels below 10 µg/liter and 5 µg/liter in 50% and 10–20%, respectively, of over 500 patients with acromegaly included in a metaanalysis from 28 published series (75). It produced improvement of symptoms of acromegaly in up to 70% of the patients, but tumor shrinkage was rare; very high doses (10–20 mg/d) are generally required, and side effects are common (76). Variable results have been reported recently using cabergoline, a selective D₂ receptor agonist more potent than bromocriptine (77, 78, 79). Disease control is more likely achieved in patients with mixed prolactin (PRL)/GH-secreting adenomas than in the pure GH-secreting ones, and in patients with lower GH and IGF-I levels before treatment than in those with more aggressive disease (6).

Somatostatin analogs are, at present, the most widely used drugs to control acromegaly. Octreotide is an octapeptide, displaying a high affinity for somatostatin receptor subtypes 2 and 5 and a faint affinity for subtype 3, which has been largely used in acromegaly with excellent results (80). Octreotide given sc at a dose of 100–250 µg every 8 h for 6 months reduced GH levels below 5 µg/liter in 53% and normalized IGF-I levels in 68% of 115 patients enrolled in a multicenter placebo-controlled study (81). A metaanalysis of 466 patients treated worldwide showed that octreotide suppressed GH levels below 2.5 µg/liter in 29.2%, normalized IGF-I levels in 39.9%, and reduced tumor size (>20% of reduction in maximal diameter) in 38.6% of patients; the GH-lowering effect was related to initial GH values (6). Most clinical signs and symptoms of acromegaly, such as sweating, soft tissue swelling, fatigue, and headache, are generally relieved after the administration of the first doses of octreotide. Twenty percent of patients develop gallbladder abnormalities (biliary sediment/sludge, microlithiasis, or gallstones), but morbidity is negligible, and treatment with ursodehoxicolic acid can be performed in those patients with symptomatic gallstones (80). Lanreotide is another analog, showing a binding profile comparable to octreotide, and has a similar efficacy in suppressing GH and IGF-I levels (6, 68). Depot preparation of lanreotide and octreotide long-acting repeatable (LAR) have further improved the therapeutic success of sc octreotide (68). In particular, we showed tumor shrinkage, graded from mild to notable, in 80% of 15 newly diagnosed patients treated for 12 months with octreotide-LAR, suggesting its potential application as primary therapy in invasive adenomas (82). Our data have been subsequently confirmed by the results of a multicenter prospective study showing tumor shrinkage in all 27 newly diagnosed patients with acromegaly with median tumor volume reduction of 49% in microadenomas and 43% in macroadenomas (83). However, because a large variability in tumor shrinkage has been reported, it is still hard to estimate tumor size response to slow-release somatostatin analogs. Both depot formulations are well tolerated; the mild-to-moderate side effects experienced by up to 50% of the patients have short duration and often subside with treatment continuation (6, 68, 80).

As anticipated, the newest drug for treating acromegaly bases its efficacy on blocking the activity of the GH-R, thereby inhibiting the synthesis of IGF-I (53). In a placebo-controlled study, there was a significant dose-dependent fall in serum IGF-I in three groups treated with the GH-antagonist compared with placebo-treated patients, and 90% of patients treated with the highest dose (20 mg) achieved normal IGF-I levels for age (54). In line with IGF-I decrease, IGFBP-3 similarly decreased, and patients experienced an improvement of physical well-being and clinical signs. These results persisted until 24 months (55). Even if data on this new drug are still scant, the GH-antagonist seems to be well tolerated, except for rare cases of increased hepatic transaminase levels; two of 133 patients had increased tumor mass (54, 55), one of them being stabilized after a combined treatment with the GH-antagonist plus octreotide (84). Currently, the use of GH-antagonist is permitted in the United States and is still experimental in the rest of the world, but the drug should be available for treatment of acromegaly by the beginning of 2004.

	II. The Complications at the Cardiovascular System

Top Abstract I. Introduction II. The Complications at... III. The Metabolic Complications IV. The Complications at... V. The Neoplastic Complications VI. The Complications at... VII. Summary VIII. Conclusions References

 
A. Epidemiology
GH and IGF-I elicit primary regulatory activities both in developing heart growth and in maintaining its structure (21). In the theoretical absence of other cardiac diseases, the involvement of the heart in acromegaly defines the acromegalic cardiomyopathy, which was first described at the end of the 19th century (85). Although the prevalence of the acromegalic cardiomyopathy has not been investigated in detail, its most common feature is considered to be a concentric biventricular hypertrophy (21, 86, 87, 88, 89, 90). Cardiac walls are generally thickened, but cardiac chambers are rarely enlarged due to the relative increase of cardiac myocyte width for the parallel assembling of new contractile-protein units (91). Aging and long duration of GH/IGF-I excess are main determinants of cardiac derangement; results collected in vivo and postmortem showed a prevalence of cardiac hypertrophy higher than 90% in patients with long disease duration (92, 93). However, more recent surveys demonstrated that structural changes of the heart can even occur in patients shortly exposed to GH hypersecretion (94, 95, 96), and 20% of normotensive patients younger than 30 yr develop cardiac hypertrophy (96). In particular, we recently reported that the left ventricular mass index was approximately 30% higher in 25 acromegalic patients below age 40 yr than in 25 age-matched control subjects (Fig. 3); 60% of the patients had clear-cut left ventricular hypertrophy (97). Characteristically, the cardiac hypertrophy of acromegaly occurs in the absence of hypertension that is present in approximately one third of patients (see Section II.C) and is further aggravated by hypertension and glucose abnormalities. In our analysis (22), 100% of patients with hypertension and diabetes had cardiac abnormalities at echocardiography (Fig. 4). The acromegalic cardiomyopathy develops after three steps: 1) in the early phase, and thus mainly in young patients with a short disease duration, there is initial cardiac hypertrophy, high heart rate, and increased systolic output altogether configuring the hyperkinetic syndrome (98); 2) in the middle phase, hypertrophy becomes more evident, signs of diastolic dysfunction appear, and insufficient systolic function on effort can be documented; and 3) in the end-stage of untreated disease, cardiac abnormalities may include systolic dysfunction at rest and heart failure with signs of dilative cardiomyopathy (21, 99). It should be considered, however, that longer acromegaly duration is generally accompanied by an older age, and it is well known that aging is accompanied by significant cardiovascular modifications, both structural and functional (100). In the nonacromegalic population, aging is associated with a slight degree of left ventricular hypertrophy and decrease, even modest, of resting heart rate and early filling rate, whereas end-diastolic and end-systolic dimensions, stroke volume, and ejection fraction are largely unchanged. It should be noted that in acromegaly the prevalence of left ventricular hypertrophy is predominant but, besides hypertrophy, the majority of the patients at diagnosis have a normal (55–78%) left ventricular ejection fraction in resting conditions (23).

View larger version (21K): [in this window] [in a new window]   FIG. 3. Effect of age on the left ventricular mass index (LVMi, left) and response of left ejection fraction at peak exercise (LVEF, right) in our series. Acromegalic patients and controls were grouped according to age [<40 yr (n = 32), 40–60 yr (n = 33), and >60 yr (n = 22)]. Data are derived from our own experience and include data reported in Refs. 97 , 191 , and 199 . *, P < 0.001 vs. controls; **, P < 0.001 vs. before treatment that consisted of octreotide-LAR at a dose of 20–40 mg/month.

View larger version (47K): [in this window] [in a new window]   FIG. 4. Prevalence of left ventricular hypertrophy, impaired diastolic filling, and inadequate ejection fraction at rest in 130 patients with acromegaly studied at their diagnosis and grouped on the basis of the absence of hypertension and glucose tolerance abnormalities, absence of hypertension and IGT, absence of hypertension and diabetes mellitus, hypertension and glucose tolerance abnormalities, hypertension and IGT, hypertension and diabetes mellitus. [From A. Colao et al.: J Clin Endocrinol Metab 85:193–199, 2000 (23 ). Permission granted by The Endocrine Society.]

B. Pathogenesis
The mechanisms of GH and IGF-I action on the heart have been reviewed recently (21, 107). The effects of GH, IGF, and their binding peptides on the cardiovascular system are both direct, via endocrine, autocrine, and paracrine mechanisms, and indirect because they cause increased cardiovascular risk and hypertension. GH and IGF-I receptors are expressed in cardiomyocytes (108, 109), and IGF-I mRNA is present in the epicardium and the coronary vessel of the human fetus (110). Neonatal rat ventricle tissue preferentially expresses IGF-II mRNA transcripts and contains both IGF-IR and IGR-IIR (111), although cardiac IGF-IR expression is partly blunted in the adult rat (109, 112). Interestingly, IGF-I immunoreactivity is reportedly increased in the inner layers of the left ventricle (113), where both tension and wall stress are high, and gradually decreases toward the epicardial surface (114). IGF-I expression accompanies the development of left ventricular hypertrophy (113, 115); in rat myocardium, IGF-I mRNA is increased after pressure overload secondary to banding of ascending aorta, aorto-caval shunt, myocardial infarction, experimental renal, or pulmonary hypertension (113, 116, 117, 118). However, the role of IGF-I in heart development during the prenatal life is still unclear. In fact, newborns of mice knocked-out for the IGF-I gene show a reduced body size compared with control littermates, but heart size is generally unaffected (119). Similarly, when the IGF-I synthesis in the liver is abolished by the Cre/loxP recombination system, no negative effect on the postnatal cardiac size is found (34). In the GH-R knockout mouse, there was no change in heart weight (120), although GH secretion rate has a prominent role in the postnatal cardiac development. Hypophysectomy in rats induces a decreased cardiac expression of IGF-I mRNA, which can be restored by exogenous GH administration (121). GH administration in hypophysectomized rats with moderate myocardial infarction does not improve ventricular function (122), whereas GH-secreting tumors implanted in rats determine cardiac hypertrophy, enhance the contractile performance, and produce the elongation of the action potential of cardiac fibers (91, 123). Exogenous GH and IGF-I administration in normal adult rats induces a hypertrophic response of the heart without developing significant fibrosis (124). Furthermore, IGF-I increases the intracellular calcium content and enhances the calcium sensitivity of myofilaments in cardiomyocytes (125). Cardiomyocyte stimulation induced by GH and IGF-I is associated with a low-energy conformational status, mediated by myosin pheno-conversion from the isoform V3 to a low ATPase activity isoform (126). GH, either directly (127) or via IGF-I, increases myocardial hypertrophy (127) and increases myocardial contractility in animal models of chronic GH excess (128) and in cardiomyocytes from neonatal rats (129), likely via an increased calcium responsiveness of myofilaments (130).

C. The acromegalic cardiomyopathy
Although new sophisticated methods are currently available to study the acromegalic cardiomyopathy, echocardiography still remains the most used method (131). Clear-cut left ventricular hypertrophy is found in most patients at diagnosis, overall in those with long disease history (21), and interstitial fibrosis constitutes the main abnormality at histology (91, 93, 123). Subsequently, gradual impairment of heart architecture by increased extracellular collagen deposition, myofibrillar derangement, areas of monocyte necrosis, and lympho-mononuclear infiltration occurs, thus configuring a pattern of myocarditis (92, 93). Increase of apoptosis in cardiomyocytes and interstitial fibroblasts, inversely correlated to the output rate, was found in biopsied cardiac tissue obtained during heart catheterization in acromegalic patients (132). In a survey performed in our department including 200 patients undergoing echocardiography at diagnosis, left ventricular hypertrophy was found in 120 patients (60%); the left ventricular mass index significantly increased from young (<30 yr) to elderly (>60 yr) patients (Fig. 5). Accordingly, the prevalence of left ventricular hypertrophy was higher in patients older than 50 yr (74.3%) than in younger patients (57% in patients aged 31–50 yr and 35% in those aged <30 yr; our unpublished data). As already mentioned, left ventricular hypertrophy is not negligible in young patients with a presumed short duration of acromegaly, confirming previous data of other groups (95, 96) as well as from ours (97). This suggests that cardiac hypertrophy is an early event in acromegaly, which worsens proportionately with the duration of disease activity. It is known that arterial hypertension is likely the most important factor aggravating cardiac hypertrophy and has higher prevalence in aged patients (see Section II.E). In another study including a large series of patients (23), we observed that hypertension significantly increased the impact of cardiac hypertrophy, therein documented in 51% of cases. The prevalence of hypertrophy was higher in hypertensive patients (Fig. 4), and the multistep regression analysis showed that the diastolic blood pressure was the best predictive factor of cardiac hypertrophy (23). It should be mentioned that patients with hypertension and diabetes had an older age than those with uncomplicated acromegaly. Because aging in nonacromegalic subjects is characterized by a slight increase in left ventricular hypertrophy (100), it is likely that in acromegaly this phenomenon is emphasized. It should be stated, however, that it is currently unknown whether aging has independent negative effects on the heart in acromegaly, because there are no controlled studies in the elderly patients population. In our series, however, patients older than 60 yr had a significantly higher left ventricular mass than age- and sex-matched controls, who indeed had an increased mass compared with young controls (Fig. 3). It is also unknown whether there are gender differences in the prevalence and severity of the acromegalic cardiomyopathy. Gender difference is well known to occur in GH and IGF-I secretion both in healthy subjects (133) and in acromegaly (134, 135). Reviewing our experience in 200 patients with acromegaly, we did not find any difference in the prevalence of left ventricular hypertrophy between women (63.6%) and men (58%); similarly, the prevalence of hypertension and diabetes was similar in both sexes (our unpublished data). A minor but relevant complication that, similar to hypertension and diabetes, may further complicate acromegalic cardiomyopathy is thyrotoxicosis (136), which appeared to primarily affect systolic function.

View larger version (51K): [in this window] [in a new window]   FIG. 5. Results of the echocardiography study performed at diagnosis in 200 patients with acromegaly studied at the Department of Molecular and Clinical Endocrinology and Oncology, University "Federico II" of Naples. Data are shown according with patients’ age divided into decades. The left ventricular mass index (LVMi, top left) significantly increases with aging, whereas diastolic filling, measured as early to late mitral flow velocity (E/A, top right), and left ventricular ejection fraction at rest (LVEF, bottom left) significantly decrease with aging. As a consequence, the prevalence of left ventricular hypertrophy (LVH), inadequate diastolic filling, and systolic performance increases with aging.

View larger version (21K): [in this window] [in a new window]   FIG. 6. Linear correlation analysis in patients (•) and controls () between age and left ventricular ejection fraction at rest (top) and at peak exercise (bottom). [From A. Colao et al.: J Clin Endocrinol Metab 84:1518–1523, 1999 (137 ). Permission granted by The Endocrine Society.]

View larger version (13K): [in this window] [in a new window]   FIG. 7. Linear correlation analysis between the estimated disease duration and the diastolic filling, measured as the ratio between the peak filling rate and the peak ejection rate. [Data were modified from A. Colao et al.: J Clin Endocrinol Metab 84:1518–1523, 1999 (137 ). Permission granted by The Endocrine Society.]

E. Hypertension
Arterial hypertension is considered one of the most relevant negative prognostic factors for mortality in acromegaly. However, both epidemiology and pathophysiological mechanisms are far from totally clear. Hypertension is reported to affect approximately one third of patients with acromegaly, but only a few studies have estimated the prevalence of hypertension using the 24-h pressure Holter recording (147, 148, 149, 150), and no control populations were included in these studies. The only study including a control group (151) revealed an increased prevalence of hypertension only in patients with familiarity for hypertension. In a survey study of 200 patients with acromegaly studied at diagnosis, we have found hypertension (based on a diastolic blood pressure > 90 mm Hg) in 40%, compared with 8% of controls; there was no gender difference in the patients or in controls (our unpublished data).

One mechanism likely contributing to inducing hypertension in acromegaly is represented by the increased plasma volume (152, 153). The evidence of an increase in the total exchangeable sodium pool in normotensive (154, 155, 156, 157) and hypertensive acromegalic patients (151) further supports this hypothesis, because a direct relationship was demonstrated between total exchangeable sodium and blood pressure values (156, 157). Whether the sodium exchange pump is also involved is unclear, because either a reduction (158) or an increase (159) of its activity has been reported. Plasma volume and total exchangeable sodium were initially supposed to follow variations of aldosterone secretion. However, the levels of aldosterone, and its precursors corticosterone and 11-deoxy-corticosterone as well, were found to be normal in patients with acromegaly without (152, 157, 160, 161) or with (151) hypertension. Aldosterone levels were not correlated with disease activity unless overt heart failure was present (152). Similarly the aldosterone response to stimuli, such as posture or saline infusion, gave contradictory responses (152, 160, 162). Both the atrial natriuretic peptide (ANP) and the renin-angiotensin system have been claimed as potential causes to explain hypertension in acromegaly without success. In fact, basal ANP levels were found to be normal (160), not correlated with disease activity (152), not increased after saline infusion (160) or increased as in controls (152). Similarly, basal PRA was normal in most studies (152, 157, 160, 161), not correlated with disease activity (152) or hypertension (151), and reduced (155, 161) or inappropriately reduced to hypernatremia (155, 156); the response of the renin activity to stimuli was also unclear (152, 153, 157, 160, 161). The adrenergic system has also been investigated, but no clear evidence for its involvement emerged from different studies. Plasma epinephrine and/or norepinephrine levels were normal (157, 163, 164) or increased (165), and urinary catecholamines were also normal (157, 163, 166) or increased (167). Bondanelli et al. (162) reported that plasma catecholamines were normal but without the physiological circadian rhythm (Fig. 8) that reappeared after successful surgery (Fig. 8). No difference between patients with acromegaly and controls was found in catecholamine levels both basally and after hyperinsulinemic clamp (168). No change of catecholamine levels was found after bromocriptine or lysuride treatment (164), whereas norepinephrine levels were reduced in another study (167).

View larger version (34K): [in this window] [in a new window]   FIG. 8. Plasma norepinephrin (NE) and epinephrin (E) concentrations in blood obtained at 1-h intervals for 24 h from normal subjects and acromegalic patients before transsphenoidal surgery (A) and from acromegalic patients in remission or active disease after transsphenoidal surgery (B). [From M. Bondanelli et al.: J Clin Endocrinol Metab 84:2458–2467, 1999 (162 ). Permission granted by The Endocrine Society.]

View larger version (21K): [in this window] [in a new window]   FIG. 9. Linear correlation analysis between fasting insulin levels and diastolic blood pressure in 200 patients with acromegaly () and 100 controls () studied at the Department of Molecular and Clinical Endocrinology and Oncology, University "Federico II" of Naples.

View larger version (46K): [in this window] [in a new window]   FIG. 10. Capillaroscopy in one control (A) and one patient with acromegaly (B). Note the remarkable meandering of several capillaries. [From F. Schiavon et al.: J Clin Endocrinol Metab 84:3151–3155, 1999 (175 ). Permission granted by The Endocrine Society.]

F. Atherosclerosis and endothelial dysfunction
Few data are currently available on the vascular involvement in acromegaly. Cardiac output was shown to be heterogeneously distributed with lower regional brachial artery blood flow and increased local resistance (172). The study of the peripheral microcirculation (Fig. 10) showed a significantly lower capillary number and length and a significantly higher number of tortuous loops and meandering capillaries in patients with acromegaly than in controls (175). The capillaroscopic alterations were still observed in a smaller group of patients not bearing diabetes and hypertension (175). Increase of the carotid intima-media thickness (IMT) was observed in active as well as cured patients with acromegaly, but the prevalence of well-defined atherosclerotic plaques was not higher than in control subjects (177). It should be noted that in the group of cured acromegalic patients insulin, cholesterol, and fibrinogen levels were still slightly higher than in controls (177). The presence of still elevated insulin levels in patients cured from acromegaly can be the underlying factor able to maintain an increased IMT, because insulin levels are known to be directly correlated with IMT (178). In another series of patients with acromegaly, prospectively studied before and after 6 months of treatment with lanreotide, an increase of IMT at the level of common carotid arteries was similarly observed, and 29 of them had abnormal IMT levels (179). Only a mild increase of carotid IMT was conversely reported by Kasayama et al. (180); however, because plasma IGF-I concentration was significantly higher and the prevalence of hypertension was significantly lower in patients without than in those with atherosclerotic changes, the authors concluded that increased concentration of IGF-I might be involved in the lack of susceptibility to atherosclerosis in some acromegalic patients (180). We could not find, however, any correlation between IGF-I levels and carotid IMT (177, 179).

Laser Doppler flowmetry has also confirmed endothelial dysfunction at the hand cutaneous circulation. Vascular smooth cell ability to produce skin vasodilatation was normal, but endothelium-dependent vasodilatation was impaired and sympathetic-mediated vasoconstrictive response was increased in normotensive acromegalic patients (181). Very recently, we demonstrated that the increased IMT in patients with acromegaly mainly depends on concomitant risk factors, because there was no difference between patients with active or cured acromegaly and their controls matched for hypertension, diabetes, or dyslipidemia (182). Interestingly, the endothelium-dependent vasodilatation, measured at the brachial artery level, was impaired in patients with active acromegaly more than that expected on the basis of classical risk factors (Fig. 11); this allowed us to hypothesize a direct negative effect of GH and IGF-I hypersecretion on endothelial function (182). Clearly, the existence of other negative factors, such as glucose intolerance, dyslipidemia, and smoking habitus, further impairs vascular relaxation.

View larger version (9K): [in this window] [in a new window]   FIG. 11. Boxes showing median values () and interquartile ranges of flow-mediated dilatation (FMD) in the study population. Active, Active acromegalics; Active MC, active acromegalic-matched controls; Cured, cured acromegalics; Cured MC, cured acromegalic-matched controls. *, Lower than in healthy subjects (P < 0.01); , lower than in active MC (P < 0.01); #, lower than in cured (P < 0.01); , lower than in healthy subjects (P < 0.05); lower than in cured MC (P < 0.05). [From G. Brevetti et al.: J Clin Endocrinol Metab 87:3174–3179, 2002 (182 ). Permission granted by The Endocrine Society.]

	III. The Metabolic Complications

Top Abstract I. Introduction II. The Complications at... III. The Metabolic Complications IV. The Complications at... V. The Neoplastic Complications VI. The Complications at... VII. Summary VIII. Conclusions References

 
A. Epidemiology
GH has long been known to be associated with changes in human metabolism. It is well established that GH counteracts the effects of insulin on glucose as well as on lipid metabolism, although it shares anabolic properties on protein metabolism with insulin. Moreover, GH modulates tissue response to insulin; indeed GH excess may cause insulin resistance, whereas GH deficiency may increase the sensitivity to insulin (203). GH exerts an overall lipolytic effect, inducing the hydrolysis of triglycerides to FFA and glycerol. However, the influence of GH on lipolysis has long been debated, and either direct or indirect effects on lipolysis have been described. Conversely, GH has been shown to elicit some degree of antilipolytic activity in different species depending strictly on other lipolytic factors. Moreover, there is clear evidence that GH can influence the sensitivity and or the responsiveness of adipose tissue to agents that influence lipolysis.

Impaired glucose tolerance (IGT) and overt diabetes mellitus are frequently associated with acromegaly (9, 63, 204, 205). Patients with acromegaly are insulin resistant either in the liver or in the periphery, displaying hyperinsulinemia and increased glucose turnover in the basal postabsorptive states (206). The prevalence of diabetes mellitus in acromegaly is unknown but ranges from 19–56% in different series (207). Alternatively, the most well-known intermediate form of altered glucose metabolism, referred to as IGT, has been assessed only recently in three different studies: the prevalence was 31% in a study by Biering et al. (208), 46% in the study by Kasayama et al. (209), and 16% in the analysis by Kreze et al. (207). Impaired fasting glycemia has recently been recognized as a second intermediate form of glucose intolerance (210). This intermediate disorder of glucose metabolism has not been detected in acromegaly in the only study where it has been investigated so far (207). Because impaired fasting glycemia occurs less frequently than IGT in the general population, the analysis of this entity appears to require a larger series of patients and alternative approaches. In fact, insulin sensitivity is reduced to a similar extent in acromegalic patients with normal glucose tolerance and those with IGT or diabetes, suggesting that a compensatory hyperfunction of pancreatic ß-cells might counterbalance the reduced insulin sensitivity in the patients with normal glucose tolerance, but not in those with IGT or diabetes (207). The presence of impaired fasting glycemia was not assessed in this latter study. This new category warrants further investigation because it could predict the risk and/or the progression of developmental alterations of glucose metabolism in acromegaly.

As already mentioned, as well as suggested in even earlier investigations, the prevalence of overt diabetes mellitus in acromegaly largely differs among studies, likely due to different patient series and ethnicity (211). In the study by Nabarro (9), the analysis of risk factors promoting the development of glucose intolerance revealed that higher GH levels, higher age, and longer disease duration significantly predicted the tendency of developing symptomatic diabetes (9). In the study by Biering et al. (208), aging was the only variable that significantly predisposed patients to an increase in the severity of this complication. Results from a study by Kreze et al. (207), suggested that the development of glucose intolerance appeared to be associated with a family history of diabetes and with the concomitant presence of arterial hypertension. The importance of family history had already been suggested in previous analyses, although the supporting data was quantitatively insufficient. Systemic hypertension and IGT were also found to correlate independently to the severity of acromegalic cardiomyopathy in our patients (23). Compared with patients with uncomplicated acromegaly, those with hypertension but without abnormalities of glucose tolerance had an increased prevalence of left ventricular hypertrophy associated with impaired systolic and diastolic function, whereas patients with glucose tolerance abnormalities lacking hypertension had only an increased prevalence of impaired diastolic and systolic function (23). In our survey study, including 200 patients studied at their diagnosis, we found impaired fasting glycemia in 13%, IGT in 25.5%, and diabetes in 15.5% (Table 2), giving an overall prevalence of different alteration of glucose metabolism in 54% of the patients compared with 23% of controls, and in our series the prevalence was similar in men and women. Among other variables, the concomitance of hyperprolactinemia and pituitary tumor size are unlikely to predispose acromegalic patients to impairments of glucose metabolism. A positive association was found with female gender when the data of two studies were pooled, although in each single study the analysis was not significant (9, 207). It should be emphasized, however, that epidemiological data on the prevalence of glucose tolerance alterations in acromegaly should be reviewed after the currently accepted criteria for the diagnosis and classification of diabetes mellitus (210).

Besides the increased prevalence of glucose abnormalities, acromegaly is also associated with abnormalities of lipid metabolism. Already in the early 1970s, patients with active acromegaly were shown to have lower cholesterol levels and higher triglyceride levels than in an age-matched control population. The incidence of hypercholesterolemia was similar to that in the general population, whereas the incidence of type IV hypertriglyceridemia was almost three times higher than in controls (212). Serum triglyceride levels were not related to relative body weight, basal serum GH, or insulin concentrations, nor did they correlate with glucose tolerance or with plasma insulin response to oral glucose load. However, patients with a higher insulin response had significantly higher serum triglycerides than the remaining acromegalic population. The endogenous serum triglycerides turnover rate was apparently unaltered, but the increased serum triglyceride levels were associated with an increase in production rate (212). In a small cohort of patients with active acromegaly, hyperlipidemia occurred in 63%, type V hyperlipoproteinemia in 13%, and type III hyperlipoproteinemia in 6% (213). In these latter cases, the activity of hepatic triglyceride lipase of lipoprotein lipase (LPL) was decreased (213). GH stimulates Apo E secretion, and Apo E as well as Apo A-I concentrations are significantly elevated in acromegalics (214); a correlation between GH, IGF-I, and changes in fibrinolysis has been observed in acromegalics, and disturbances in fibrinolysis may be a major cardiovascular risk factor for these patients. Plasma levels of Lp-a, Apo A-I, and Apo E are similarly increased, and 30% of patients have increased plasminogen activator inhibitor activity, whereas 66% have increased tissue plasminogen activator concentration levels compared with controls (214). A study of low-density lipoprotein (LDL) subfraction distribution in 24 patients with active acromegaly showed significantly higher LDL-III levels when compared with controls, with a concomitant reduction in the intermediate subfraction LDL-II (215). In this study, acromegalic patients were found to have lower hepatic lipase and LPL activities and higher plasma cholesteryl ester transfer protein (CETP) activity than controls (215). Univariate analyses showed that both GH and IGF-I correlated directly with LDL-III and inversely with LDL-II (215). Maffei et al. (216) reported an abnormal lipid pattern in 57% of 42 patients compared with 51% of controls; Lp-a was, however, the only parameter abnormal in 31% of patients and 7% of controls, whereas both triglyceride and cholesterol levels were closer to the upper limit of the normal range compared with controls. The prevalence of an altered lipoprotein pattern was addressed by Maldonado Castro et al. (217) in a relatively small series consisting of 20 patients (12 with active disease and eight cured); the highest Lp-a levels were observed in patients with active acromegaly, followed by patients with controlled acromegaly, whose Lp-a concentrations were still significantly higher than levels recorded in the normal subjects. There were no differences in other lipid and lipoprotein values among the groups. This study suggests that the currently used biochemical criteria for the cure of acromegaly may not be strict enough to cause the normalization of all the undesirable metabolic changes found in this disease. As an indirect consequence, the cardiovascular risk may persist significantly despite the successful treatment of acromegaly (217). Lower levels of HDL cholesterol and Apo A-I and higher Lp-a concentrations were confirmed by another study which demonstrated that patients with acromegaly have smaller and/or more dense LDL particles compared with controls (218); these alterations might contribute to the development of atherosclerosis, increasing the cardiovascular risk of these patients. Total cholesterol levels have been reported to be increased, normal, or even decreased in acromegaly (211, 212, 215). Lp-a, small dense LPL, and triglycerides were most likely to be increased (211, 212, 215, 216, 217, 218), whereas HDL-cholesterol levels were unchanged or low (215, 219). Decreased levels of lecithin/cholesterol acyl transferase, CETP, phospholipid transfer protein activity levels, plasma cholesterol esterification, and cholesteryl ester transfer have also recently been reported compared with controls (220). At multistep regression analysis, plasma IGF-I was demonstrated to be negatively correlated with plasma lecithin/cholesterol acyl transferase, CETP, and phospholipid transfer protein activity (220). Postprandial lipoprotein remnant levels, which are commonly associated with premature atherosclerosis, have also been found to be significantly elevated at baseline and in the postprandial period in acromegalic patients (221). The altered postprandial response of lipoprotein remnant may increase the susceptibility for premature atherosclerosis, as observed in patients with acromegaly.

Abnormalities of protein metabolism in acromegaly have not been investigated as deeply as glucose and lipid metabolism thus far. GH increases muscle weight and nitrogen retention; these effects are partially indirect, via hepatic and locally produced IGF-I, and partially direct. However, most changes in protein metabolism are derived from the influence of GH and IGF-I on renal function. Glomerular hyperfiltration is a characteristic feature of acromegaly; overnight urinary albumin excretion rate and creatinine clearance are higher in patients than in controls, suggesting an influence of GH and IGF-I levels on albuminuria (222). This phenomenon is emphasized during submaximal exercise, where increased microalbuminuria is likely to be due to functional glomerular involvement (223).

B. Pathogenesis
1. Glucose metabolism.
The mechanisms responsible for the GH action on carbohydrate metabolism have been investigated at different levels. Pharmacological doses of GH decrease glucose utilization; therefore, GH excess has been shown to induce insulin resistance by impairing the ability of insulin to suppress glucose production and stimulate glucose utilization. Numerous authors investigated how GH and IGF-I modulate insulin actions by altering insulin receptor binding or postreceptor events. Earlier studies suggested that impairment of glucose metabolism develops only in the so-called prediabetic patients, such as those with a decreased insulin response to hyperglycemia and thus unable to overcome the diabetogenic effect of GH by compensatory hyperinsulinism (224). In fact, the plasma insulin response to glucose is notably increased in patients with active acromegaly and with a normal glucose tolerance. Moreover, the insulin response to glucose is more pronounced in patients with highly active acromegaly than in those with moderately active disease (224). Sonksen et al. (204) confirmed the presence of hyperinsulinism in a number of patients with acromegaly, delineating two intermediate stages in the development of diabetes in acromegaly: 1) a hyperinsulinemic stage, characterized by a normal or borderline glucose tolerance with a more rapid and higher insulin peak after glucose load, returning to normal later than controls; and 2) a stage characterized by a delayed insulin response to glucose in the presence of normal or slightly impaired glucose tolerance, which is likely reversible after adequate treatment. These authors (204) described an additional third stage characterized by a maximal pancreatic response in the fasting state with no further rise in insulin concentrations after glucose administration, which is likely irreversible after treatment. Therefore, GH excess is likely to induce a state of insulin resistance, initially manifested as a rise in fasting insulin concentration and an exaggerated insulin response to the glucose load. If GH excess remains untreated, fasting hyperglycemia may develop with a fall in fasting insulin, but a more dramatic loss of insulin response to the glucose load.

The number of insulin receptors, their affinity, and/or postreceptor defects may play a role in the development of glucose metabolism alterations in acromegaly as well. Muggeo et al. (225) demonstrated the abnormal binding of insulin to its receptor on circulating monocytes, which correlated with the severity of GH excess as well as with abnormal carbohydrate metabolism and insulin secretion. Moreover, in patients with euglycemia or hyperglycemia, the total receptor concentration per cell was decreased proportionately to hyperinsulinemia (226). In diseases involving the GH/IGF-I axis, the decrease in insulin sensitivity cannot be attributed exclusively to an alteration of insulin binding, but postreceptor defects must also be considered (227). In acromegaly, suppression of glucose production was impaired at insulin concentrations in the physiological but not in the supraphysiological range, whereas stimulation of glucose utilization was decreased at insulin concentrations in both the physiological and supraphysiological ranges (228). The decreased glucose utilization at supraphysiological insulin concentrations, together with normal monocyte and erythrocyte insulin binding, suggests that there is a postreceptor alteration in insulin action in acromegaly (228).

New insight in the pathogenesis of insulin resistance in acromegaly is derived from the prospective analysis of patients studied before and after cure. Cure is generally accompanied with the remission of diabetes and recovery of the normal pattern of insulin secretion, although this latter may be delayed. In fact, in a controlled study, acromegalic patients with normalized GH levels still had increased insulin secretion after glucose ingestion, suggesting either a persistently increased pancreatic islet ß-cell mass or peripheral insulin resistance (229).

Insulin resistance in chronic GH excess might be accompanied by impaired muscle glucose uptake and nonoxidative glucose metabolism, which are considered early derangements, as observed in patients with normal glucose tolerance (230). Patients with acromegaly have indeed impaired peripheral muscle glucose uptake despite high insulin levels. Increased activity of the hepatic glucose-glucose 6-phosphate cycle is unlikely to contribute to the hepatic insulin resistance induced by GH, whereas changes in fatty acid metabolism may be partially responsible (231). On the other hand, in the early 1990s it was also demonstrated that lipids constitute the major fuel substrate in acromegalic patients (232). Subsequent data from glucose clamp studies showed definitively that the striated muscle is the primary site of peripheral insulin resistance (232). An improvement of the intermediate metabolism was reported after successful surgery (232). As already stated (see Section II.E), there is a close correlation between blood pressure values and plasma insulin levels in acromegaly. Recent studies have critically clarified that insulin sensitivity is clearly reduced to a similar extent in acromegalic patients with normal glucose tolerance as well as in those with IGT or diabetes (209). In patients with normal glucose tolerance, but not in those with impaired glucose metabolism, a compensatory hyperactivity of ß-cells counteracts the reduced insulin sensitivity (209). Recently, two new actors entered the scene: glucose-dependent insulinotropic polypeptide and ghrelin. Hypersecretion of fasting and postprandial glucose-dependent insulinotropic polypeptide was recently found to be involved in determining the occurrence of hyperinsulinemia in acromegaly (233). Moreover, patients with active acromegaly show low levels of circulating ghrelin that did not change after the oral glucose tolerance test (234). This may depend on both GH-induced insulin resistance and the putative GH/IGF-I negative feedback control on ghrelin secretion. Further studies should investigate the potential role of ghrelin on metabolic pathways in acromegaly, because this recently discovered peptide has a wide range of metabolic functions. Insulin resistance in acromegaly involves protein metabolism as well, because both insulin and GH promote protein accretion. In fact, acromegalic patients recently have been shown to be severely insulin resistant for both glucose and protein metabolism (235). Although 6 months after successful surgery insulin resistance for glucose metabolism is completely reversed, a marked antagonism with the insulin effect on proteolysis and on leucine oxidation seems still to persist, demonstrating that the effects of GH on protein metabolism are not reversed by surgery, at least in the short term (235).

2. Lipid metabolisms.
Alterations in lipid profile are more evident in patients with concomitant abnormalities in glucose metabolism, although the influence of genetic, dietary, ethnic as well as geographical aspects cannot be ruled out. Although the underlying mechanism of increased Lp-a concentrations in acromegalic patients is still poorly understood, the positive correlation between GH and Lp-a levels, as well as the decrease of Lp-a after either medical or surgical treatment, not only indicated a close link between these two parameters but also suggested that Lp-a synthesis may be GH-regulated (214, 236). However, it should be considered that other authors did not find any correlation between Lp-a and IGF-I (217, 237), suggesting that the GH stimulatory effect on Lp-a may be independent from IGF-I. Similarly, findings of increased HDL-cholesterol levels after treatment of acromegaly may be a consequence of GH decrease (214). GH excess can directly induce the reduction in LPL activity in acromegaly; a stimulatory GH effect on liver LDL-receptor expression has also been proven to be independent of IGF-I levels (238, 239). The GH effect is probably displayed in the catabolism of LDL subfractions, because GH has been reported to induce hepatic LDL receptors, which will selectively lower LDL-II more than LDL-III (240).

Of particular interest is the recent data on LDL physical characteristics in acromegaly (205), because increased risk of vascular complications is associated with the presence of small and/or dense LDL particles in both diabetic and nondiabetic patients. In acromegaly, both hyperinsulinemia and reduced postheparin lipase activity, already known to influence the development of hyperlipidemia in these patients, are among the factors involved in modifying the LDL physical properties, which might also be modified by the hepatic lipase activity that is low in acromegaly (241). Therefore, small and/or dense LDL particles in acromegalic patients are likely due to factors other than hepatic lipase. Arosio et al. (218) found a correlation between Lp-a and GH, but not IGF-I. This confirms that GH and IGF-I have different, and probably contrasting, effects on Lp-a (242) and supports a major role for GH in the physiological regulation of Lp-a expression. Several abnormalities in HDL lipid composition in patients with acromegaly are consistent with an impaired plasma lecithin/cholesterol acyl transferase action and a decreased phospholipid transfer protein (220). Decreases in plasma cholesterol esterification and cholesteryl ester transfer and decreases in plasma phospholipid transfer protein activity in acromegaly may impair reverse cholesterol transport, thereby contributing to the increased cardiovascular risk. Finally, what remains to be clarified is the significance of changes in leptin release in acromegaly that are related to differences in body fat content and mass as well as insulin resistance (243). However, leptin in acromegaly does not seem to be influenced directly by GH or IGF-I secretion, because the acute effect of somatostatin analogs on leptin levels differs from the effect of a radical cure after pituitary surgery (243).

C. Effect of GH and IGF-I control on metabolic complications
Since the late 1960s, it was already recognized that surgical removal of GH-secreting pituitary tumors improved both glucose tolerance and diabetes (204). Successively, with the development of more accurate methods for assessing insulin immunoreactivity and glucose measurement, increased insulin secretion after glucose load failed to recover in some patients despite normalization of GH levels (229). Ongoing abnormalities were suggested to be due to persistently increased pancreatic islet ß-cell mass and/or peripheral insulin resistance (229). However, it should be mentioned that cure criteria of acromegaly at that time were significantly different from those currently accepted. When stricter criteria for the control of the disease were considered, together with more sophisticated methods for assessing glucose and lipid metabolism, reversibility of metabolic abnormalities was demonstrated in a small series of patients that were surgically cured (232). Somatostatin analogs significantly improve GH and IGF-I control, especially in those patients in which surgery was unsuccessful, but they were initially suspected to aggravate glucose tolerance in acromegaly by suppressing plasma insulin concentrations (244). Later results, however, demonstrated that glucose tolerance and insulin resistance were only modestly altered by octreotide therapy (245). Additionally, improvement of insulin resistance by octreotide may likely counterbalance its inhibitory effect on insulin secretion (245). During octreotide treatment, the early insulin response to glucose load is reduced and is followed by a delayed normal increase. However, due to the concomitant GH suppression, peripheral insulin resistance is reduced, and glucose tolerance remains generally normal in most patients (246). Basically, both of the most widely used somatostatin analogs, octreotide and lanreotide, decrease insulin resistance in acromegalic patients. Interestingly, octreotide-LAR seems to be more detrimental to glucose metabolism than lanreotide SR, despite being more effective in reducing GH and IGF-I levels (247). The mechanism behind this phenomenon is still unclear. We observed, however, that the negative effect of somatostatin analogs on insulin levels appears to be more evident at the beginning of treatment, whereas glucose tolerance usually improves during long-term treatment with these drugs (68, 82). The newly discovered GH antagonist pegvisomant proved to be effective in improving insulin sensitivity and carbohydrate metabolism in acromegalics, an effect apparently independent of weight loss (248), and suggesting a potential role for this compound in the treatment of insulin-resistant states other than acromegaly (248).

The first study assessing changes in the altered lipid profile after treatment with octreotide in acromegaly reported a significant decrease in triglyceride levels despite reducing insulin levels, probably due to direct GH suppression (249). Several studies reported on the effectiveness of surgery and somatostatin analogs in lowering Lp-a levels in acromegaly (205, 206, 236, 249), but negative findings have also been described (217). Treatment with octreotide is associated with a general amelioration of lipid profile without any impact on small and/or dense LDL particles (218). In our cohort of patients, lipid profile abnormalities were also generally improved by treatment with somatostatin analogs, in either the short or the slow-acting formulation (64, 68, 97, 179).

Only limited data are currently available on lipid profile after GH-antagonist treatment. Very recently, van der Lely et al. (55) reported the results of a multicenter trial that confirmed the normalization of IGF-I levels previously shown. The majority of cases also showed a decrease of insulin and glucose levels without any change in cholesterol levels, which were elevated at study entry, nor were there changes of triglycerides and urea nitrogen. It should be noted that although 152 patients were included in the study, only data from 39 of them were available at the 18-month follow-up analysis (55). In another study including 48 patients receiving the GH-antagonist for 18 months, total cholesterol levels increased as well as the total/HDL-cholesterol ratio and triglyceride levels (250). Lp-a decreased, whereas glucose, insulin, homocysteine, and IL-6 did not change (250). Interestingly, C-reactive protein levels that were low at study entry significantly increased during treatment (250), leading the authors to hypothesize a direct GH effect on this cardiovascular risk parameter. Parkinson et al. (251) recently confirmed that successful treatment with pegvisomant in acromegaly increases low baseline serum total cholesterol and LDL levels, restoring the distribution of values to that of the general population and improving insulin resistance as well.

In conclusion, successful control of GH and IGF-I excess improves glucose and lipid metabolism, although at the beginning of treatment with somatostatin analogs an impairment of insulin secretion leading to further increase of glucose may be observed. Generally, this effect subsides with treatment continuation, but rarely, mostly in elderly patients, overt diabetes mellitus may develop, inducing treatment discontinuation. The effect of treatment of acromegaly on protein metabolism is largely unknown. As far as the new therapeutic approach to acromegaly is concerned, i.e., the GH-antagonist, further data are required to establish its impact on metabolic parameters.

	IV. The Complications at the Respiratory System

Top Abstract I. Introduction II. The Complications at... III. The Metabolic Complications IV. The Complications at... V. The Neoplastic Complications VI. The Complications at... VII. Summary VIII. Conclusions References

 
A. Epidemiology
Respiratory disorders constitute a relevant cause of illness and impaired physical performance in patients with acromegaly, contributing to 25% of all deaths recorded in this condition, where respiratory mortality appears to be three-fold higher than in normal subjects (19). The pathophysiology and clinic of respiratory disorders occurring in acromegaly will be more extensively analyzed in the following two sections. Patients with acromegaly develop several respiratory alterations, as a consequence of anatomical changes affecting craniofacial bones and soft tissues, respiratory mucosa/cartilages, lung volumes, rib cage geometry, as well as activity of respiratory muscles (Table 4). This range of abnormalities results in two main respiratory dysfunctions, namely sleep apnea and impaired respiratory function. Sleep apnea, the phenomenon of recurrent cessation or decrease of airflow to the lungs during sleep, is a common cause of snoring and daytime sleepiness in acromegaly. It may affect as many as 60% of unselected acromegalic patients and 93% of patients with suspected sleep apnea (25), the vast majority of cases being due to anatomical narrowing of the upper respiratory airways causing obstructive sleep apnea (see Sections IV.B and IV.C). Impaired respiratory function is an alteration less frequently investigated in acromegaly and originates from multiple alterations involving the bone and muscle structure of the chest as well as the lung elasticity. Lung volumes become increased in as much as 81% of men and 56% of women with acromegaly (252, 253, 254), whereas up to 80% of patients may develop subclinical hypoxemia (255).

B. Pathogenesis
Experimentally, the expression and the activity of GH and IGF-I have been investigated in several respiratory cell types. Both in rodents and humans, GH and IGF-I exert proliferative effects on lung and smooth muscle cells through interaction with their cognate receptors. This has been confirmed in Northern blot studies revealing the presence of GH-R mRNA in lung epithelium, smooth muscle cells, and pneumocytes of rodents (256), whereas the expression of mRNA transcripts for GH-R has been found subsequently in human fetal lung tissue by RT-PCR followed by Southern hybridization assays (257). Despite this observation, however, immunocytochemical analysis of GH-R failed to detect protein expression in human fetal lung tissue (258). Also, activated alveolar macrophages in human airway express gene transcripts encoding for GH and GH-R, IGF-I and IGF-IR, and several IGFBPs (259). On lung tissue, GH was shown to enhance the synthesis of type I collagen fibers and mucopolysaccharides (260) and to increase compensatory postpneumonectomy lung growth in rats (261). Similar effects have been subsequently shown for IGFs. In fact, IGF-I and IGF-II were shown to promote cell proliferation in cultured rabbit airway smooth muscle cells expressing IGF-IR and IGF-IIR (262). Inversely, IGF-I treatment was unable to induce the elastogenic response in rat pulmonary fibroblasts, as evaluated by expression of tropoelastin mRNA and soluble elastin levels (263).

C. The sleep apnea syndrome
Excessive nocturnal snoring and sleep apnea are disturbances about which acromegalic patients frequently complain. The first report of daytime sleepiness and obstructive apnea in patients with acromegaly appeared in 1896 (264, 265). It is now evident that between 20 and 80% of patients may suffer from sleep apnea (25, 266, 267, 268). In their detailed investigation, Grunstein et al. (25) reported the occurrence of sleep apnea in 60% of unselected patients and 81% of their entire series, encompassing patients preselected for sleep disorders. Weiss et al. (266) documented sleep apnea in 75% of patients, snoring in 78%, fragmented sleep in 60%, daytime somnolence in 51%, and morning sleepiness and morning headache in 16% of cases. Similar figures were reported by Dostalova et al. (267). As expected, these rates notably outnumber those observed in normal middle-aged men (2–4% prevalence) and women (1–2% prevalence) (269), where sleep apnea is a common cause of daytime sleepiness, impaired cognitive performance, and road traffic accidents. In the general population, sleep apnea also has been shown to predispose to ischemic heart disease, arrhythmias, arterial hypertension, and cerebrovascular accidents (269), which are also relevant sequelae of acromegaly. Sleep apnea, considered to be at least 10 (270) or at least five (271) episodes of apnea/hypopnea lasting at least 10 sec of every sleep hour, is classified as either central, due to cessation of respiratory movements, or obstructive, due to narrowing of upper respiratory airways. A combination of these two conditions leads to mixed sleep apnea. Central sleep apnea is known to depend on alterations of the nonbehavioral system controlling ventilation, as seen in several neurological and cardiovascular disorders. It is characterized by repeated apneic events occurring during the sleep without associated ventilatory effort. Grunstein et al. (25) noted that as many as one third of patients with acromegaly developed central sleep apnea in association with the obstructive type. This observation was speculatively related to direct effects on the breathing center exerted by either high GH/IGF-I levels or an enhanced somatostatin tone, because somatostatin is able to reduce animal breathing and decrease chemosensitivity to hypoxia in humans (25). In addition, acromegalic patients with central sleep apnea had a greater ventilatory response to hypercapnic hypoxia, compared with patients with obstructive sleep apnea (272). Despite this finding, however, acromegaly is predominantly associated with obstructive sleep apnea, a disorder ordinarily caused by anatomical abnormalities of the pharynx lumen. Under normal conditions, the pharyngeal potency depends on the balance between the negative intraluminal pressure on inspiration and the dilating activity of muscles acting on the tongue and the soft palate (i.e., the genioglossus and the palatoglossus muscles) (269). As shown in Table 4, acromegaly causes several anatomical alterations, which may contribute to impairing the intrapharyngeal balance during inspiration and thus increase pharynx collapsibility during the sleep. By studying cephalometric geometry, Dostalova et al. (267) observed that acromegaly causes mandible protrusion, increases the mandibular length, and decreases the angle of sagittal maxillomandibular relations. The facial height of acromegalic patients is frequently elongated, and the mandible may undergo dorsocaudal rotation, thus causing a dolichofacial aspect (269). Compared with nonacromegalic patients suffering from sleep apnea, acromegalic patients with sleep breathing disorders have a narrower pharyngeal airway both at the level of the uvula tip and at the mandibular plane (267, 273). There is a similar degree of mandible/maxillary overgrowth and soft palate lengthening between patients with and without sleep apnea, but the uvular-tip plane is significantly narrower in those with sleep apnea (267). Other relevant pharyngeal abnormalities include swelling of soft tissues and mucosa hypertrophy. These alterations contribute to increasing the collapsibility of lateral/posterior hypopharyngeal walls on inspiration, which may then become invaginated into the laryngeal vestibule during sleep apneic episodes (274). Descriptions also exist of tongue hypertrophy causing fatal asphyxia (9), voluminous bilateral laryngocele (271), and increased volume of submandibular salivary glands (276). Remarkably, studies on static pharyngeal mechanics have identified the edge of the soft palate and the tongue base as the narrowest sites in the passive pharynx (277), whereas Morewood et al. (278) documented obstruction of the upper airways in 23% of their patients due to the thickening of both true and false vocal cords. Like ordinary sleep apnea, however, the reduction of upper airway muscle activity at sleep onset appears to be an initial key event for the development of apnea in patients with acromegaly, because disordered breathing does not usually occur during active contraction of upper airway muscles in the awake state (277). Several studies have also reviewed the correlation between the severity of sleep apnea and both disease activity and GH/IGF-I levels. In a series of 11 patients, Perks et al. (279) diagnosed sleep apnea in five patients whose GH levels were significantly higher than in unaffected patients. Similarly, four of 10 acromegalic patients with active disease studied by Hart et al. (280) had obstructive sleep apnea, whereas none of 11 patients with inactive disease was affected. In the Grunstein et al. study (25), patients with central sleep apnea had higher GH and IGF-I levels than did patients with obstructive apnea. At variance with other reports, these authors failed to demonstrate any relationship between GH/IGF-I levels and either the severity or the frequency of apneas, whereas aging and disease duration were positively associated with the rate of apneic episodes (25). The role played by gender has been addressed by Pekkarinen et al. (281) using polysomnography; they reported a higher number of apneic episodes during non-rapid eye movement sleep in five of six active men and in none of five women. In the Weiss et al. study (266), the degree of sleep apnea was positively associated with male gender (3-fold higher prevalence compared with women), active disease (82% of active vs. 62% of inactive patients), and aging. Although the positive correlation between central sleep apnea and activity of acromegaly implies that control of disease activity may lead to the disappearance of central sleep apnea, previous studies reported the persistence of sleep apnea after pituitary surgery, presumably because of the persistence of obstructive causes. Pekkarinen et al. (281) recorded reversal of sleep apnea in only one of five patients treated with pituitary surgery, whereas Pelttari et al. (282) found persistence of periodic breathing in 10 of 11 patients previously treated by adenomectomy and/or radiotherapy, nine of whom were inactive at the time of the study.

D. The respiratory dysfunction
Acromegaly alters the structure, elasticity, and function of the entire respiratory apparatus (Table 4). Patients with acromegaly develop a barrel chest due to changes in vertebral and costal morphology. Vertebral bodies become enlarged and elongated due to periosteal bony apposition, whereas the intervertebral discs thicken at the cervical and lumbar levels and become thin in the thoracic region, thus resulting in development of kyphosis (283, 284). The epiphyses of the osteochondral junctions fail to close, and the ribs become elongated and diverged. The costochondral junctions may even become prominent and enlarged, thus giving a typical rosary-like aspect (285). These anatomical rearrangements alter the elastic chest mechanics and markedly impair the inspiratory muscle activation, which is further aggrieved by muscle weakness/wasting associated with acromegaly. In fact, muscle biopsy studies have shown segmental fiber degeneration, foci of small cell infiltration, thickening of capillary basement membranes, and variable derangement of type I or type II fibers (286). Both bone and muscle alterations may deteriorate the contraction of sternal intercostals, scalene, and diaphragm muscles and thus impair the physiological breathing act. Indirect proof of respiratory muscle dysfunction originates from the study by Iandelli et al. (287), showing that most patients with acromegaly achieve subnormal respiratory muscle force, during either inspiratory or expiratory breathing. The inspiratory time is usually shorter and, consequently, the breathing frequency may increase. As in several neuromuscular disorders, nonvagal afferent information originating from either weak respiratory muscles or stiffened rib cage may act centrally to terminate respiration and accelerate the respiratory pattern. The authors’ observation of a normal chemoresponsiveness of respiratory muscles is consistent with the normal role of central factors and the prevalent effect of reduced muscle force in the setting of the respiratory responses observed (287). The relevance of lung volumes and ventilation/perfusion relationship is similarly crucial in the pathogenesis of respiratory disorders. Patients with acromegaly develop increased total lung capacity. This abnormality was originally observed by chest radiographs and subsequently confirmed in spirometry and pletismography studies. Brody et al. (288) found lung volume to be twice the normal in five of six men with acromegaly, and suggested that this increase was mostly due to hypertrophied interstitial tissue. Total lung capacity is increased in 81% of men and 56% of women, 36% have small airway narrowing, and 26% have upper airway narrowing (252, 253, 254, 255). Eighty per cent of patients examined by Luboshitzky et al. (255) had subclinical hypoxemia; partial pressure of oxygen in arterial blood ranged between 58 and 90 mm Hg, whereas four of five patients subjected to lung perfusion scans showed defects in perfusion, indicative of ventilation-perfusion derangement. Increased vital capacity was reported in 34% of patients, upper airflow obstruction in 50%, and nocturnal hypoxemia in 23% of cases (255).

It has been shown that the increased lung volume is unrelated to hyperinflation or muscle strength. Rather, lung compliance is generally increased, whereas elastic recoil, diffusing capacity, and diffusing capacity per unit of alveolar volume are unchanged. Based on these evidences, many authors have attributed lung overgrowth to an increase in the size of alveoli (25, 252, 289). In line with these findings, studies of gas exchange across the alveolar capillary membrane failed to demonstrate ventilation/perfusion mismatching in patients with acromegaly. Donnelly et al. (290) reported values of pulmonary distensibility and diffusing capacity similar to those observed in control subjects. At significant variance with previous reports, however, they observed that the diffusing capacity per unit of alveolar volume was significantly lower than in controls, and thus interpreted these results as the consequence of an increased number of alveoli rather than their overgrowth (290). The role of disease duration and activity on lung disorders has been similarly analyzed. Lung volumes and the narrowing of intrathoracic and extrathoracic airways were correlated with the duration of acromegaly, and longer disease duration significantly increased the risk of developing respiratory abnormalities (252). Other authors failed to reproduce these correlations (254, 289).

For the aforementioned reasons, patients with acromegaly often achieve an inadequate response to ventilatory and skeletal muscle demand on effort. The workload at the cycloergometer is significantly reduced in acromegaly compared with controls, both at anaerobic threshold and at maximal exercise (97, 137, 198). Studies of aerobic fitness by self-paced walk test resulted in significantly higher heart rate and perceived fatigue in patients, whereas maximum oxygen uptake and ventilation threshold at the maximal exercise were significantly lower than the predicted values (291). Despite this body of evidence, however, the causes leading to respiratory deaths are still largely unknown. Nabarro (9) documented kyphoscoliosis in 13 cases, chronic bronchitis and emphysema in five, and bronchiectasis in three other patients out of a total of 256 cases reviewed. In this series, two patients with kyphoscoliosis and muscle weakness died from chest infections. In the largest series currently available, Orme et al. (18) identified 43 cases of cancer-independent respiratory deaths; the majority (31 cases) were caused by bronchopneumonia/pneumonia, which may have been smoking-related, whereas only a minority (11 cases) were attributable to smoking, chronic bronchitis, emphysema, and chronic airway obstruction. Despite these indications, however, more accurate ascertainment of specific mortality causes still awaits further clarification.

E. Effect of GH and IGF-I control on respiratory disease
Reports published in the early 1980s postulated that tracheostomy and/or tongue plasty needed to be included in the treatment plans for sleep apnea in acromegaly (274). Subsequent studies provided convincing evidence that control of acromegaly, either by pituitary surgery or somatostatin analogs, improved sleep breathing disorders in acromegaly. The likelihood of developing sleep apnea reportedly decreases to 25% in the case of posttreatment GH levels of 5 mU/liter or less (2.5 µg/liter) (292). As previously mentioned, nocturnal breathing abnormalities may paradoxically persist several years after adenomectomy. Initial studies by Pekkarinen et al. (281) indicated that only one of five patients cured by pituitary adenomectomy achieved reversal of sleep apnea. Based on these findings, the authors hypothesized that anatomical abnormalities occurring in acromegaly were irreversible or, alternatively, took a longer follow-up time to improve significantly. Analysis of their results by modern cure criteria (20), however, revealed that only two of their patients achieved a reduction of GH levels into the therapeutic range. Pelttari et al. (282) studied the occurrence of periodic sleep breathing through analysis of body and respiratory movements in 11 patients previously treated by adenomectomy and/or radiotherapy, nine of whom were inactive at the time of the study. The authors found that periodic breathing persisted in 10 of their 11 acromegalic patients (282). Part of the occurrence of sleeping disturbances was explained by age and body mass index, but not by gender or by the duration of disease activity/inactivity (282). The introduction of somatostatin analogs in the clinical practice dramatically influenced the cure rate of sleep apnea. Chanson et al. (293) reported the significant improvement of sleep apnea in three patients treated with sc octreotide. Grunstein et al. (25) showed that octreotide treatment decreased the frequency of apneic and hypopneic episodes by 50% of baseline values, regardless of whether apnea was central or obstructive. Of note, these authors documented that patients with mixed or central sleep apnea achieved the predominant improvement of the central component of sleep breathing control. In the study by Ip et al. (268), the severity of obstructive apneas was significantly improved by octreotide-LAR treatment, whereas mixed and/or central sleep apnea was only modestly changed. In the case of persisting sleep breathing disorders, the use of continuous positive airway pressure devices should be recommended to prevent the long-term cardiovascular consequences of sleep apnea. GH and IGF-I suppression is also expected to produce similar beneficial effects on other ventilatory dysfunctions. Lung volumes and lung distensibility decrease after 3–11 months of octreotide treatment, whereas diffusion capacity remains unaltered (289). The change in lung elastic properties after therapy seems to suggest either changes in surface forces or increases in the strength of tissues tethering. Thus, changes in elasticity are reflected by a significantly improved response to physical exercise. Giustina et al. (198) observed that both workload and oxygen consumption at anaerobic threshold increased significantly after octreotide treatment, which abrogated the difference in exercise capacity recorded at baseline between acromegalics and controls. A 6-month treatment with octreotide-LAR did not determine a significant increase in the maximal oxygen uptake during a progressive treadmill test, but patients achieved an increase in ventilation threshold and in vigor score, as well as a decrease in perceived fatigue (291).

From the analysis of the above-mentioned studies, respiratory disorders of acromegaly appear to be complex in both their origin and development. The hypertrophic action of GH and IGF-I causes structural changes at the level of the upper as well as the lower airways. Thus, acromegaly leads potentially to several types of ventilatory dysfunction. In upper airways, remodeling of bones and soft tissues results in the impairment of the normal pharyngeal patency during sleep and is key to the onset of obstructive sleep apnea, the prominent type of sleep breathing disorder in acromegaly. Sleep apnea may affect as much as around 80% of patients and is apparently more frequent and severe in case of persistently active disease, elevated GH/IGF-I levels, and male gender. In up to one third of patients, obstructive sleep apnea can coexist with the central type likely due to concomitant neuronal stimuli to the respiratory center mediated by the somatostatin tone and triggered by an altered sensitivity threshold to carbon dioxide. Successful treatment of acromegaly dramatically improves sleep breathing disorders. However, the persistence of sleep apnea after surgical cure of acromegaly may be attributable to an irreversible process of remodeling of upper airways and should prompt the use of continuous positive airway pressure devices to prevent further cardiovascular complications associated with sleep apnea. In the lungs, the proliferation of pneumocytes and smooth muscle cells is reflected in the overgrowth of pulmonary epithelium and thickening of interstitial tissue. This alteration decreases pulmonary elasticity, whereas lung volumes are increased due to alveoli overgrowth. Clinically, this process leads to respiratory dysfunction; the ventilatory response on effort is frequently inadequate in the face of a greater effort as well as the sense of physical exhaustion. Ventilatory dysfunctions are well correlated with both the activity and the duration of acromegaly, so that successful therapy of acromegaly improves significantly the ventilatory response to effort and the personal sense of weakness. From the studies reviewed, some questions remain: 1) can successful treatment of acromegaly also be reflected in a significant improvement of respiratory failure; 2) can respiratory dysfunctions consistently contribute to the impact/progression of cardiovascular complications in acromegaly; and 3) should researchers look into more specific causes to explain the enhanced respiratory mortality seen in this condition? Additional investigations are required to fully answer these questions.

	V. The Neoplastic Complications

Top Abstract I. Introduction II. The Complications at... III. The Metabolic Complications IV. The Complications at... V. The Neoplastic Complications VI. The Complications at... VII. Summary VIII. Conclusions References

 
A. Epidemiology
Over the years, epidemiology studies have provided increasingly debated evidence that acromegaly may enhance the neoplastic risk, and that cancers constitute the third leading cause of mortality in this condition (8, 9, 10, 12, 13, 14, 15, 16, 17, 18). The recently identified relationship between the IGF system and human cancers has further persuaded many researchers that neoplasms of acromegaly may constitute an informative model to legitimize this link. From a teleological point of view, understanding of the GH/IGF-I role in tumorigenesis may depend upon reconciling this association with the neoplastic phenomena of acromegaly.

The first study exploring the cancer risk in acromegaly was performed in 1956 by Mustacchi and Shimkin (294) on 223 patients referred to 16 cooperating institutions, yielding 2981.5 person-years at risk. These authors found five patients with malignancy among 128 men, three of whom had developed lung carcinomas, and eight cancers among 95 women, two of whom had breast cancer and two had endometrial adenocarcinoma. No colon cancer was recorded, although a man with leukemia and a woman with sphenoidal angiosarcoma had received pituitary irradiation 15–20 yr earlier. Compared with the incidence rates recorded in North American metropolitan areas, they reported a nonsignificant increase in standardized incidence ratio (SIR) by 1.3 in the group as a whole (294) (Table 5). Data subsequently published by other groups added strength to the argument that acromegaly may increase both the cancer risk and cancer-related deaths. In 1982, Klein et al. (295) studied a group of 44 patients to explore the possible association between colon tumors and skin tags, an occurrence previously noted in the normal population. They reported four cases of colon adenocarcinoma among 26 acromegalic patients reviewed retrospectively, with no cancer among 17 patients consecutively studied by colonoscopy. Although the observed rates were not compared with those obtained in a control population, the authors speculated that acromegaly increased remarkably the risk of colon tumors. Two subsequent studies by Ituarte et al. (296) and Pines et al. (297) drew similar conclusions. The first investigation documented three cases of colon cancer among 12 patients, yielding a prevalence of 25% in the group as a whole and a 3-fold greater risk of colon cancer than in age-matched controls (296). In the second study on 48 patients, malignancies occurred in seven patients who all turned out to be Ashkenazic Jews, five of whom had gastrointestinal cancers and two had breast adenocarcinoma (297). Comparison with expected rates derived from age-sex-ethnic cancer rates yielded a SIR of 4.6 for gastrointestinal cancers and 3.5 for breast adenocarcinoma (297). In his personal series, Nabarro (9) reported evidence of malignancies in 26 of 256 cases, of whom nine were men and 17 were women. Cancer incidence rates were similar between men with acromegaly and men from the general population, whereas acromegalic women had 87% greater prevalence of cancer than the control population, mainly due to a greater prevalence of breast cancer (11 observed vs. 2.6 expected) (9). In 1991, Barzilay et al. (298) examined 120 clinical records of acromegalic patients; from an analysis of 87 of these charts, the authors found seven cases of cancer, which yielded a total standardized incidence rate of 2.45 compared with sex- and age-adjusted rates. Taken separately, the incidence rate in women with acromegaly was twice as high as in men (3.5 vs. 1.7). The existence of a causal link between acromegaly and cancer became even more suggestive after the publication of a 16-yr follow-up study by Ron et al. (299), who drew records on 1,041 acromegalic males hospitalized between 1969 and 1985 in United States Veterans Affairs (VA) hospitals, documenting a total of 116 cases of cancers. These included 27 digestive, 22 respiratory, and 15 genitourinary malignancies, as well as 27 cases of pituitary cancers. After a comparison with rates obtained from 3.7 million first admissions to VA hospitals among white and Afro-American nonacromegalic patients, acromegalic patients showed a 3-fold greater incidence of both esophageal and colon cancers and a 2.5-fold higher rate of gastric cancers. The overall standard incidence ratio calculated for cancers was 1.6 (299). Although remarkable, these latter results have raised a few criticisms: 1) inclusion of 27 cases of pituitary tumors may have originated from miscoded diagnoses of pituitary adenoma; 2) the prevalence of acromegaly emerging from the study outnumbers that observed in the general population (1 in 4000 vs. 4–6 per million population) (8); 3) because acromegaly is equally distributed between genders, results obtained in gender-restricted populations should be interpreted carefully; 4) inclusion of nonacromegalic hospital patients as control population may have led to ascertainment bias (19); and 5) analysis of databases collected in different centers may mask significant differences in management practice. Between then and 1998, two other studies have been published. The study by Rajasoorya et al. (15) analyzed the clinical determinants of acromegaly outcome from the medical records of 151 patients, followed up during a 26-yr period. These authors documented five cases of malignancies in their series, which caused overall 9% of the deaths recorded (15). Tumors were highly variable with regard to tumor type and gender distribution. A subsequent study by Cheung and Boyages (300) recorded seven malignant events in 50 patients; five cancers were diagnosed in women and contributed to a 4.3-fold higher cancer risk in this subgroup. Although breast and kidney cancers predominated in this series (two cases each), two other subjects developed dual malignancies (300). A deeper insight into this alleged acromegaly-cancer network has been provided by the key study published by Orme et al. (18), who investigated the incidence and mortality for cancer in a cohort of 1,239 patients, yielding 16,778 person-years at risk. Besides the study cohort, other strengths of this investigation resided in the exclusion of all malignancies prediagnosed with regard to the diagnosis of acromegaly and the cross-examination of reliable national cancer registers. The most striking finding of this study was the lack of difference in cancer incidence between acromegalic patients and the normal population (79 vs. 104 malignancies, respectively). Nevertheless, analysis of SIRs in acromegalic patients revealed a slight increase in colon cancers (SIR, 1.68) and a lower incidence of bronchial neoplasms (SIR, 0.33). Accordingly, this study partly confirmed previous reports of a higher incidence of colon cancers and a lower incidence of rectum and bronchial neoplasms (299), but it failed to record any significant increase in breast cancer incidence (9). One drawback emerging from the Orme et al. study (18) is the lack of a gender-related analysis, which would serve for comparative purposes with the prevalence rates reported in the other large study by Ron et al. (299). However, if we assume that acromegalic men constituted approximately one half of Orme’s population, this study showed a lower prevalence of colon and, significantly, of bronchial cancers and a slight increase in the number of rectum cancers. In a successive study, Popovic et al. (301) observed a 3.4-fold higher rate of cancer incidence in patients with acromegaly, but the conclusions drawn by this study have been questioned (302).

B. Pathogenesis
The effect of GH and IGF-I on different cell systems has been discussed in more detail in Section I.C. The first evidence linking the GH/IGF system to cancer originates from experimental in vitro and in vivo studies. Although the effects produced by impure extracts of GH should be viewed with caution due to the potential action of natural contaminants, Moon et al. (303) recognized in 1950 that chronic high-dose treatment with extracted GH caused the development of tumors in lungs, adrenals, ovaries, and breast in female rats. Administration of bovine GH to Balb/c mice also induced lymphopoietic tumors, whereas hypophysectomy was found to modulate the growth of rat liver tumors induced by benzenic compounds and to decrease the growth of breast cancers xenografted in mice (304, 305). The role of GH in animal tumorigenesis was further confirmed in studies in which transgenic mice expressing human GH developed mammary tumors (306), although transgene expression of bovine GH did not appear to be carcinogenetic (307). GH was then found to stimulate the proliferation of several cancer cell lines in vitro, including human leukemic lymphocytes and murine erythroleukemic cells (308). Evidence for GH synthesis in a number of extrapituitary organs, including the lateral hypothalamus, lymphocytes, thymocytes, neutrophils, the placenta, and both normal and neoplastic mammary tissues, suggests that GH may have local paracrine/autocrine effects independent of or additional to endocrine-mediated IGF-I action (27). In mammary carcinoma cell lines, autocrine GH functions as a direct proliferative stimulus and decreases apoptotic activity, with marked synergism with trophic agents such as IGF-I (309). In prostate cancer cell lines, GH stimulation increases the rate of cell proliferation, and the coexpression of both pituitary and placental GH as well as GH-R mRNA isoforms has been shown in ALVA41, PC3, DU145, and LNCaP prostate cancer cells, where it can enable an autocrine-paracrine pathway to stimulate prostate growth (310). All of the effects of autocrine GH are mediated by GH-R. GH-R and its signal transductional mechanisms stimulate several genes involved with tumorigenesis, such as c-myc mRNA expression in liver and kidney (311). Nevertheless, the significance of GH-R activation in experimental animal models of tumorigenesis remains largely unknown.

Unlike GH, the IGF system modulates the tumorigenic process at different levels. Most human tumors develop by a multistep process in which cells acquire growth advantage by genetic damage, involving an accumulation of mutations. Gene mutations are usually prevented by host defense mechanisms including apoptosis, but several survival factors, such as IGF-I, may override these internal signals (312). Once quiescent cells are made competent, stimulation with IGF-I alone is sufficient to complete the cell cycle, promote cell proliferation, and arrest apoptosis, both in normal and cancer cell lines (48, 313). The efficiency of IGF-I stimulation requires an adequate density and functionality of the IGF-IR on the cell surface, and this prerequisite is also essential for the IGF-I-mediated proliferation of cells previously transformed by viral, cellular, and/or chemical oncogenes (48). IGF-I/IGF-IR involvement in cancer cell proliferation has been demonstrated in experiments where knockout of IGF-IR gene, either by antisense oligodeoxynucleotides, dominant negative mutants, or triple-helix formation, was capable of decreasing cell proliferation and increasing apoptosis. The IGF-I/IGF-IR system appears to further influence cancer progression by promoting adhesion and migration of cells, as well as angiogenesis within tumoral tissues and in the surrounding areas (48, 314). Conversely, activation of tumor suppressor genes, such as p53, BRCA-1, or WT-1, results in a reduction of IGF-IR gene transcription and, hence, of cell proliferation (48). In vitro, IGF-I does not seem to promote cellular transformation, rather it stimulates proliferation of transformed cell clones and the growth of preexisting tumor tissues. These effects have been confirmed in studies on liver-specific IGF-I-deficient mice, in which chronic IGF-I treatment was able to promote growth and metastatic proliferation of colon adenocarcinomas transplanted on the caecum surface of the animals (315). In addition to its endocrine functions, IGF-I is widely synthesized locally and exerts autocrine/paracrine effects in a number of tissues and cell systems. Modulation of IGF-I gene transcription, usage of either of the two IGF-I promoters, alternative RNA splicing, and changes in RNA stability allow IGF-I gene expression to be cell- or tissue-specific, ontogeny-determined, or regulated by several factors (for review, see Refs. 49 and 316). Regulation of cancer growth through an IGF-I/IGF-IR-mediated autocrine/paracrine loop emerges from the demonstration of IGF-IR mRNA expression in colon carcinoma samples, which is significantly more abundant than IGF-I mRNA expression (317), and predominates in samples from colon tumor vs. the adjacent normal mucosa, a circumstance that is suggestive of paracrine and autocrine modulation of tumor growth (318). In breast cancer, IGF-I is expressed in the stromal cells and very rarely in the breast epithelium, as determined by in situ hybridization, whereas IGF-IR has been found on the surface of malignant breast epithelial cells, an event that suggests the existence of a paracrine interaction (for review, see Ref. 319). More recently, increasing attention has been paid to the biological activity of several IGFBPs, independently of their binding to IGF-I and/or IGF-II (44). IGFBP-3 has been extensively shown to promote apoptosis and arrest the proliferation of numerous tumoral cell lines, a process that involves intracellular modulation of cyclins and caspases (320). Initial studies demonstrated that mouse IGFBP-3 could inhibit the fibroblast growth factor-stimulated proliferation of mouse and chick embryo fibroblasts (321), whereas exogenous IGFBP-3 addition to HS578T human breast cancer cells inhibited proliferation, independently of IGF-I (322). In other investigations, transfection of IGFBP-3 cDNA in mouse embryo fibroblasts previously disrupted for the IGF-IR gene inhibited cell growth and promoted apoptosis (323, 324). Furthermore, IGFBP-3 mediates the antiproliferative activity of TGF-ß, retinoic acid, vitamin D, TNF-, tamoxifen, and histone deacetylase inhibitors (320). The biological activity of IGFBP-3 seems to be mediated by specific receptors present on the cell surface, although nuclear translocation mechanisms have been documented also.

The second clue relating the GH/IGF system to cancer originates from clinical studies performed in the normal population. In humans, it has been hypothesized that the pattern of IGF-I and IGFBP-3 secretion may predict cancer risk during the lifetime. IGF-I levels are significantly higher in women diagnosed with breast cancer (325) and in men harboring prostate tumors (326), compared with their normal counterparts. An 18-yr follow-up study found a positive association between the risk of developing malignant tumors and GH levels measured during an oral glucose tolerance test performed at the baseline visit (327), whereas an even tighter association emerged in large nested case-control studies between serum IGF-I levels and the risk of prostate, breast, and colon cancers (50, 51, 52). In a survey on 152 cases of prostate cancers, among nearly 15,000 men subjected to blood sampling for an average of 7 yr before diagnosis, Chan et al. (50) provided evidence of a 2.4-fold greater cancer risk associated with IGF-I levels in the upper quartile of the normal range, compared with patients whose IGF-I values were in the lower quartile. By inclusion of IGFBP-3 levels, the relative cancer risk lifted up to 4.3 and was nearly eight times above normal in men older than 60 yr. A similar study was conducted by Hankinson et al. (51) reporting that the relative risk of breast cancer in premenopausal women with IGF-I levels in the upper tertile of the normal range was 2.3 times higher than in patients with IGF-I in the lower tertile. In women below age 50 yr, the highest IGF-I tertile was associated with an increase in breast cancer risk to 4.6 and, after inclusion of IGFBP-3 levels in the multivariate analysis, to 7.3 (51). Ma et al. (52) analyzed IGF-I and IGFBP-3 levels in 193 men diagnosed with colorectal cancer over a 12-yr follow-up, and reported that the relative risk in men having IGF-I levels in the top quintile was 2.5 times greater than in those whose IGF-I was at the bottom quintile. Inversely, the relative risk calculated by IGFBP-3 quintiles was 0.28 for top vs. bottom quintile. In the Nurses’ Health Study, IGF-I levels did not predict colon cancer risk unless a combination of high IGF-I and low IGFBP-3 tertiles was used; patients stratified by the highest IGF-I and the lowest IGFBP-3 had an increased risk of colon tumors (328). However, the relationship between IGF-I and cancer has been recently questioned (329).

The third corollary linking the GH/IGF system to human cancers arises from the demonstration that GHRH-antagonists, GH-antagonist, and somatostatin analogs elicit antineoplastic activity by altering the GH/IGF-I axis at the pituitary level or by inhibiting autocrine/paracrine activity of GHRH, GH, and IGFs. Ablative hypophysectomy has long been shown to reduce the neoplastic progression of disseminated breast and prostate cancers (330). Splicing variants of GHRH receptors have been found in many cancer cell lines, and GHRH-antagonists have proven to be able to inhibit tumor growth in mice xenografted with colorectal, prostate, breast, and lung cancers (331). Other studies have demonstrated that somatostatin analogs powerfully suppress tumor growth in experimental models of pancreatic, prostate, colorectal, breast, and lung carcinoma and elicit marked antineoplastic effects in several types of neuroendocrine tumors; however, their clinical efficacy in cases of prostate, breast, and lung cancers is largely disappointing (332, 333). Preliminary findings have indicated that the GH-antagonist decreased proliferation, stimulated apoptosis, and reduced metastatic spreading of MCF-7 breast cancer cells (309).

C. The gastrointestinal tract
Digestive tumors constitute the most frequent malignancies recorded in acromegaly (Table 5). Experimental studies have demonstrated that both normal and tumoral colorectal cell lines express large amounts of IGF-IR, and IGF-I induces the proliferation and antiapoptotic activity in colorectal cancer cells lines (330, 334). The role of serum IGF-I levels in stimulating tumor growth and metastasis has been further confirmed in mice carrying liver-specific deficiency of IGF-I, where both the growth and the metastatic spreading of adenocarcinomas transplanted on the caecum surface were significantly increased by a 6-wk ip treatment with IGF-I (315). In patients with acromegaly, the length of the colon and sigma is generally greater than in controls, and epithelial cells of sigmoid crypts present an enhanced pattern of proliferation, which is positively correlated with circulating IGF-I levels (335, 336). This finding is consistent with the observation of a decreased apoptotic activity, independent of Bcl-2 and Bcl-x_L proapoptotic proteins (337). It can thus be speculated that GH/IGF-I excess in acromegaly increases epithelial cell proliferation and decreases the apoptotic rate, which then may predispose to a greater accumulation of genetic defects leading to colon cancer. Many researchers have intriguingly claimed that one mechanism compensating for these growth-promoting effects of IGF-I on colon mucosa may depend upon the concomitant increase in IGFBP-3 levels, because IGFBP-3 has shown intrinsic antiproliferative effects in vitro and its serum levels are negatively correlated with cancer risk (50, 51, 52). IGFBP-3 may either promote apoptosis through specific receptors or bind IGF-I in small binary aggregates, thus inhibiting IGF-I activity. However, this unresolved issue awaits further clarification. Several other humoral and mechanical factors may play a crucial role in modulating colon cell proliferation in acromegaly. Abnormalities in lymphocyte subset pattern, consistent with a decrease in the number of B lymphocytes and Natural Killers and an increase in T lymphocytes, have been described by our group in the colon mucosa of acromegalic patients and appeared to be correlated with disease activity (338). The decrease in helper-inducer lymphocytes may imply an impairment of local Ig pattern and, hence, of immune surveillance mechanisms in the colon mucosa. Another potential tumor-promoting mechanism resides in the pattern of bile acid secretion. Unconjugated deoxycolic acids are able to stimulate the transformation and proliferation of colorectal cells in vitro, and it has been shown that in the general population subjects with higher levels of serum and intracolonic unconjugated deoxycolic acids are at increased risk of developing colorectal cancer (339). Patients with acromegaly harbor increased serum and intracolonic levels of secondary bile acids, especially if affected with colorectal cancer, and the coexistence of this event with a greater colon/sigmoid loop length and an increased colonic transit has been suggested to enhance the susceptibility to the development of colon tumors in acromegaly (340, 341).

The issue of whether acromegaly enhances the risk of colorectal cancer has attracted great attention, thus generating a heated debate. Cancers arising in the digestive tract constitute nearly 27% of all tumors developing in acromegaly, 18% of them being due to colorectal carcinomas (Table 5). The relative importance of esophageal and gastric cancers has been delineated in the study by Pines et al. (297) reporting a 7-fold higher risk of gastric cancer in their patient population. Upper digestive cancers constituted 60% of all gastrointestinal malignancies reported by Ron et al. (299), and the standard incidence ratios for esophagus, stomach, and small intestine cancers were 3.1, 2.5, and 6.2, respectively. As previously discussed in Section IV.A, however, many of the conclusions drawn by this study constitute a matter of concern. Remarkably, other studies failed to demonstrate similar data (10, 12, 342, 343). On the other hand, the past two decades have provided overwhelming evidence that acromegaly especially stimulates the development of colon adenomatous polyps. Colon adenomas are regarded as benign glandular dysplastic lesions carrying a high cellular proliferation rate, enlarged and hyperchromatic nuclei, and reduced cytoplasmic mucin (344). The cellular architecture identifies tubular, villous, or tubulovillous adenomas, with tubular and tubulovillous being the predominant types found in acromegaly. The existence of similarities between colon adenomas and carcinomas indicates a temporal link between these lesions; minute carcinomas are adenomatous in origin; adenomas and carcinomas share homologies in morphology, clonality, genetic mutations, and chromosomal deletions; familial adenomatous polyposis predisposes to colon cancer; adenomas and carcinomas often arise from the same area; and adenomas may swap into cancer within 10–15 yr of their onset (344). Mutation in tumor suppressor genes, such as adenomatous polyposis coli and p53, DDC (deleted in colon cancer), and DNA mismatch repair genes have been additionally isolated in colon adenomas and carcinomas (345). Very recently, a reduced expression of peroxisome proliferator-activated receptor- was found in the colonic mucosa of patients with active acromegaly (346); the expression of peroxisome proliferator-activated receptor- was inversely correlated with IGF-I levels, suggesting a direct role of this factor in the increased prevalence of colonic polyps. As in the general population, colon adenomas identify individuals at increased risk for colorectal cancer in patients with acromegaly. The first demonstration of an increased occurrence of premalignant colon polyps in acromegaly was provided almost two decades ago by Klein et al. (295), documenting nearly a 30% prevalence of colon adenomatous polyps in a prospective colonoscopy analysis in 17 patients with acromegaly. By retrospective review of this patient group as well as charts from 26 further patients, a total of four colon cancers were accounted (295). Several reports that followed have provided evidence that acromegalic patients are more prone to develop colon adenomas; on average, 24% of patients screened for colon disorders harbor colon adenomas (19). This estimate is representative of rates fluctuating between 9 and 38% across different studies, a wide range that may reflect dissimilarities in the selection of patients and/or controls, as well as in the gender prevalence, age, and adequate colon visualization. Terzolo et al. (347) studied 113 patients with acromegaly and compared colonoscopic results to those obtained in a control population undergoing colonoscopy because of hematochezia. Patients with acromegaly exhibited a greater prevalence of colon adenomas (38% vs. 14%; P < 0.001), hyperplastic polyps (26% vs. 10%; P < 0.001), as well as multiple adenomas (57% vs. 29%). The difference between the two groups remained significant at ages below 50 yr (46% vs. 7% of controls; P < 0.001). GH/IGF-I levels as well as activity or duration of acromegaly appeared not to play any role in colonoscopic findings. Similar results were obtained by Delhougne et al. (348), recording a greater prevalence of adenomatous (22.3% vs. 8%; P < 0.01) and hyperplastic polyps (24.3% vs. 4.4%; P < 0.001) in acromegaly than in their control group. Like Terzolo’s study, the finding of a higher prevalence of polyps in patients under the age of 55 yr (20% vs. 3% of controls) appeared to suggest an anticipated occurrence of adenomas in acromegaly, although both the duration and the activity of acromegaly did not influence the prevalence observed (348). In the Jenkins’ series (349), tubulovillous adenomas were detected in 34 patients (29%), 53% of whom had multiple adenomas. Expectedly, aging predicted the occurrence of colon adenomas, because the proportion of patients with one or more adenomas increased with each decade, so that 39% of patients aged over 70 yr harbored at least one adenoma. Compared with a screening study on left-sided adenomas in asymptomatic subjects, the prevalence of left-sided adenomas reported by Jenkins et al. (349) was significantly higher in acromegalic patients at ages above 49 yr, providing an odds ratio of 4.2. A study performed by our group (338) located two thirds of adenomas in the proximal colon; the prevalence (22% vs. 5.7%; P < 0.01), synchronicity, and dysplasia of adenomas was significantly greater in acromegaly than in the control group, although the number of polyps was unrelated to disease duration and GH/IGF-I levels. The selection of our control group included subjects referred to colonoscopy because of irritable bowel syndrome. As in the studies of others in which control subjects were subjected to colonoscopy because of various bowel disturbances, the absence of a perfectly matched healthy population in our study may constitute a significant caveat in the interpretation of results. At variance with previous studies, the prevalence of colon adenomas reported by Renehan et al. (335) in their series of 115 patients recruited from two different centers was strikingly lower than in previous reports. The observed prevalence summed up to 9.5% and increased proportionately with patients’ age; no adenoma was diagnosed under 40 yr (17 patients), whereas progressively increasing rates of 8, 12, 20, and 21% were recorded for decades of 40–49, 50–59, 60–69 and more than 70 yr. Five of 11 patients with adenomas (45% of this subgroup) had multiple polyps, whereas 18 subjects (16% of the whole series) had hyperplastic polyps. Interestingly, the significance of these findings was tested against a binary control model: eight autopsy studies encompassing 3559 exams of bowels from noncancerous patients, and four colonoscopy screening studies performed on 810 asymptomatic subjects with no family history of colorectal cancer (335). Such a comparison failed to demonstrate differences in adenoma prevalence between these control models and acromegaly, where adenomas exhibited a less advanced degree of dysplasia than in the control models. Of note, acromegalic patients with neoplasia were, on average, 10 yr older and had received colonoscopy 4 yr later than patients without neoplasia. Nevertheless, it has been noted that the observed 20% prevalence of adenomas reported by Renehan et al. (335) in patients older than 50 yr is similar to the rates reported in previous studies and outnumbers the generally accepted control prevalence of 9% (24). On the basis of the above-mentioned studies, indication emerges that acromegaly increases the risk of developing colon adenomas after the age of 50 yr and that colon adenomas developing in acromegaly share several clinical-pathological features: 1) although adenomatous polyps may virtually arise from any colon site, the involvement of ascending colon in acromegaly is variably predominant and is estimated to account for 5% (343), 21% (338, 349), 25% (347), 35% (348), 45% (350), and 68% (335) of cases; 2) polyp size is usually larger in acromegaly than in controls from a normal population: 3–15 mm vs. 4–10 mm (mean, 9 mm vs. 6 mm) in the study by Vasen et al. (350) and 7–28 mm vs. 5–14 mm (mean, 18.4 mm vs. 9 mm) in the study published by our group (338); in line with these observations, Jenkins et al. (349) reported evidence of polyps ranging from 5 to 35 mm in their series, whereas Renehan et al. (335) indicated a significantly higher prevalence (P < 0.01) of adenomas sized greater than 10 mm in acromegaly compared with control models; 3) colon adenomas in acromegaly occur more frequently after the age of 50 yr, and they predominate in males, in patients with disease duration longer than 5 yr, in those with three or more skin tags, as well as in the case of a family history of colon polyps; 4) conversely, disease activity, GH and IGF-I levels, years of exposure to high GH and IGF-I levels as well as familiarity for colon cancer do not predict the occurrence of colon adenomas (Table 5) (295, 296, 297, 335, 342, 343, 347, 348, 349, 350, 351, 352, 353, 354).

The issue of whether the enhanced frequency of premalignant colon lesions implies a higher prevalence of colon cancers is, however, still a matter of debate, due to divergent conclusions reached in diverse epidemiology studies. The findings of a high cancer mortality in acromegaly reported in the retrospective studies published by Wright et al. in 1970 (12) and Alexander et al. in 1980 (8) were instrumental in the publication of four retrospective/prospective studies between 1982 and 1990, reporting 11 cases of colon cancer among 156 acromegalic patients (295, 296, 297, 352). This association was later supported by the findings of Ron et al. (299) of a 3-fold higher incidence of colon cancers in acromegalic men compared with in-hospital nonacromegalic patients. Despite its caveats, this latter study convinced many researchers of an enhanced colon cancer risk in acromegaly, thus endorsing further prospective research. Prospective series of colonoscopy screening studies in patients with acromegaly have revealed 25 cases of cancer out of 681 examinations (24), and colorectal cancers have been calculated to affect 2.5% to 3.7% of acromegalic patients (19, 24). In their series, Jenkins et al. (349) found six cases of colon adenocarcinomas in 129 patients, yielding a 5% prevalence in the group as a whole. Carcinomas were diagnosed at an average age of 66 yr and did not show any colon site preference, with two cancers located at the caecum, one at the splenic flexure, and the remaining three at the rectosigmoid area. None of the patients fulfilled criteria for either hereditary nonpolyposis colonic rectal cancer or familial adenomatous polyposis. By comparing multiple control models, the authors recorded a 13.5-fold greater prevalence of colon cancer compared with a published series of 621 asymptomatic subjects and a rate 92.6-fold higher than age-matched Southeast England incidence rates (349). Such findings have been subsequently extended by the observation of four additional malignancies in a total of 155 patients, giving a combined prevalence of 6.5%. The results achieved in our concomitant prospective study (338) were somewhat in line with Jenkins’ findings. Our observed prevalence rate of colon cancer in acromegaly was not significantly greater (2% vs. 1.2%) than that in our control population of subjects with irritable bowel syndrome (338), although another patient was diagnosed with a caecum adenocarcinoma soon after the publication of our study. More intriguing observations originated, however, from Renehan’s study (335), which found three cases of colon cancer in 115 acromegalic patients, giving an overall prevalence of 2.6%. This rate proved to be similar to that recorded in autopsy (2.3%) and in vivo screening (0.9%) control models. Although adenomas tended to be right-sided, all neoplasms were detected in the recto-sigmoid area. Of note, two of three patients with carcinoma were 79 and 81 yr old, an age significantly older than the average age of 66 yr recorded in neoplastic patients by Jenkins et al. (349). On the basis of their findings, Renehan et al. (351) have indicated that acromegaly does not enhance the risk of colon malignancy and have thus questioned the policy of an aggressive diagnostic approach for colon disorders in acromegaly (Fig. 12). However, the control models used in this study by Renehan et al. have drawn a number of criticisms. Autopsy bowel examinations involve optimized visualization conditions, i.e., detailed and magnified visualization of uncontaminated tissues, a circumstance that allows detection and excision of even minute lesions. Conversely, colonoscopy is associated with a significant miss rate for polyps sized less than 1 cm (355), and vigorous bowel preparation is additionally required in patients with acromegaly to compensate for the increased colon length (335). It is also significant that the control colonoscopy studies used in Renehan’s study showed a nearly 3-fold greater prevalence of males, which may have overestimated the general cancer prevalence because colon adenomas/cancers are more frequent in males. A series of colonoscopy screening programs including nearly 6,000 asymptomatic subjects have reported colon cancer prevalence rates between 0.3 and 0.4% (356, 357) and 0.9% (358), but this latter study was biased by a tendency to select male subjects exposed to colon disorders and with a family history of colon cancer. Taking these circumstances into account, Renehan’s results may be partly viewed in support of a positive association between acromegaly and colon cancer risk. In a recent retrospective study, Baris et al. (359) have collected 1634 cases of acromegaly in Sweden and Denmark and documented a value of SIR of digestive cancers 2.1-fold greater than in the control population. The incidence rate of colon and rectal cancers was 2.6- and 2.5-fold higher than normal, respectively, but risks were also enhanced for cancers of the brain, thyroid, kidney, and bones (standardized incidence rates equal to 2.7, 3.7, 3.2, and 13.8%, respectively). Another relevant issue is constituted by the influence of age and disease activity on colon cancer risk. Most prospective studies have indicated that colon carcinomas arise especially after the age of 50 yr, but up to one third of reported cancers have been diagnosed before age 55 yr (247, 296, 297, 298, 300, 301, 335, 352, 354). As noted by Atkin (360), colon cancer risk is highest just before the diagnosis of acromegaly, suggesting that the risk may increase in untreated disease. The Orme et al. study (18) showed that acromegaly quasi-significantly increased the incidence rates of colon cancer (P > 0.06 at one-sided Poisson probability). The finding of a 2.5-fold greater colon cancer mortality was speculatively attributed to the finding of higher posttreatment values of GH in patients with cancer (18). Consistent with this interpretation, colon cancer mortality was increased by three times in case of posttreatment GH levels between 2.5 and 9.9 µg/liter and by nearly five times for GH levels above 10 µg/liter. Renehan et al. (335) reported a nonsignificant increase in the prevalence of colonic lesions between active and inactive patients (18% vs. 6%), but they did not find any association between IGF-I or IGFBP-3 and the presence of adenomatous polyps. These findings would be in agreement with the observation that persistent elevation of GH/IGF-I levels increases the residual risk of developing colon tumors in the short term, as indicated in a follow-up study performed by Jenkins et al. (361). The authors recorded a recurrence of colon polyps in 14% of patients examined within 3–36 months after initial colonoscopy, and IGF-I was used as a surrogate to predict tumor recurrence rate: in fact, the relative risk of a new adenoma increased to 10.3 in case of elevated IGF-I levels (Fig. 13) (361). Colonoscopy studies have also provided information that carcinomas developing in acromegaly can potentially arise from any colon site and that patients can be asymptomatic for years; therefore, the finding of different degrees of colon wall infiltration, reportedly ranging from Dukes stage A through D at diagnosis, is not surprising (296, 335, 347, 354), although disseminated cancers are definitely rare (296, 352). Significantly, no information exists at the moment on clinical evolution and chemotherapeutic responsiveness of colon cancers in acromegaly.

View larger version (19K): [in this window] [in a new window]   FIG. 12. Cumulative incidence of colorectal cancer by age in groups with hereditary predisposition and acromegaly compared with the general population. [Adapted from A. G. Renehan et al.: Clin Endocrinol (Oxf) 55:731–733, 2001 (351 ). Permission granted by Blackwell Science.]

View larger version (24K): [in this window] [in a new window]   FIG. 13. The mean (±SEM) serum IGF-I at the second colonoscopy in 66 patients with acromegaly with colorectal adenomas, hyperplastic polyps, or normal colon. [From P. J. Jenkins et al.: J Clin Endocrinol Metab 85:3218–3221, 2000 (361 ). Permission granted by The Endocrine Society.]

D. Neck and lung tumors
1. Thyroid tumors.
GH and IGF-I excess causes thyroid overgrowth, which is usually considered one typical aspect of the visceromegaly developing in acromegaly. Experimental work has demonstrated not only that IGF-I increases proliferation of porcine thyroid cells and FRTL-5 rat thyroid cells, but also that it potentiates TSH-mediated thyroid cell proliferation (365). Indirect evidence of a positive role for GH and IGF-I in thyroid growth is based on the antiproliferative effect exerted by hypophysectomy on TSH-mediated thyroid growth in rats (366) and, oppositely, by the stimulatory action elicited by incubation of FRTL-5 cells with serum from acromegalic patients (367). The existence of a local IGF-I-mediated autocrine loop is suggested by the detection of IGF-I production in follicular thyroid cells (368), papillary cell lines (369), and surgical thyroid specimens in which IGF-I synthesis is greater in tumoral than in normal tissue (370). Affinity cross-linking studies have shown the presence of IGF-I receptor in follicular and papillary cancer cells, as well as in tumoral tissue specimens.

Although benign thyroid overgrowth is a common phenomenon in acromegaly, the occurrence of thyroid tumors constitutes a relatively rare event in this condition (Table 5). Neck palpation and ultrasonography reveal goiter in 25–92% of cases, independent of TSH levels, whereas a positive relationship between GH/IGF-I levels and thyroid volume has been debatably documented (371, 372, 373, 374, 375). Multinodular goiter is detected in 65% of patients, and the chance of developing thyroid nodules increases with increasing disease duration (371, 374). Nodular goiter is toxic in 14% of patients (375), but the prevalence of hyperthyroidism reportedly ranges between 3.5 and 26% in unselected patients from different investigations (9, 136, 372, 375). In a study performed by our group, seven of eight patients who developed thyrotoxicosis were undergoing octreotide treatment at the time of onset of the disease (136). Unlike the general population, the influence of gender on the prevalence in thyroid disorders is seemingly null in acromegaly (375). Thyroid nodules are usually benign. At histology, colloidal, hyperplastic, or adenomatous aspects of thyroid tissue have been described (9, 295). In the study by Gasperi et al. (375) thyroid biopsy was performed in seven cases and showed histological patterns of microfollicular architecture (n = 2), Hurthle cells (n = 2), cellular dysplasia (n = 2), and papillary thyroid carcinoma in one patient, whereas two others were found to harbor papillary thyroid cancers. Overall, thyroid cancers constitute 3.1% of malignant events in acromegaly (9, 10, 297, 298, 376); the incidence of this cancer significantly increased by 3.3%-fold only in the study by Baris et al. (359). Thyroid tumors are predominantly papillary and occasionally aggressive, as confirmed by the rare occurrence of multifocal tumors (377) and by low mortality rates (9, 297, 298). The studies reviewed and our experience indicate that acromegaly enhances the risk of developing goiter, although the prevalence of thyroid cancers is not different from normal. Thyroid enlargement seems to occur independently of endemic, nutritional, and hereditary factors, but it is reportedly associated with aging, years of exposure to GH/IGF-I hypersecretion, as well as IGF-I levels. In the setting of a multinodular goiter, prudence should be used when starting thyroid suppressive therapy with L-T₄ due to an apparently enhanced risk of thyrotoxicosis. Because the rate of benign and malignant thyroid tumors appears to be similar to that recorded in the general population, acromegalic patients should undergo standard periodical examinations of thyroid morphology and function.

2. Lung tumors.
The relationship between lung cancers and the IGF system has been suggested by experimental studies, demonstrating that IGF-IR expression occurs in small cell lung cancer (SCLC) and non-SCLC, as well as in normal and tumoral lung tissue (313). Autocrine IGF-I synthesis has been detected in lung cancer specimens and SCLC lines (378). IGI-I/IGF-IR stimulation and IGF-IR overexpression cause lung cancer cell proliferation and increase the metastatic activity of lung cancer cells; conversely, tumor growth progression is abolished by blockade of IGF-IR by IR3 antibody (379, 380). An ongoing hospital-based case-control study detected a dose-dependent association between circulating IGF-I levels and lung cancer risk (odds ratio, 2.06) and a negative association with IGFBP-3 levels (381). The relationship between acromegaly and lung tumors emerged in the study of Mustacchi and Shimkin (294), where three cases of lung cancer were mentioned. In the study published by Wright et al. in 1970 (12), lung cancer mortality accounted for three of 10 cancer deaths. Similar records were obtained by Nabarro (9) and Bengtsson et al. (10), each reporting two deaths from this malignancy. In the general population, lung cancer affects the male gender more frequently, and the finding of 22 bronchial and seven oropharyngeal tumors in the Ron et al. study (299) on acromegalic men is, therefore, not surprising. These authors failed to record any significant difference in the lung cancer prevalence compared with nonacromegalic hospital controls. Similar observations were reported in the study by Orme et al. (18) in which both the incidence and the mortality from lung cancer were even lower than the expected rates.

E. Tumors of the reproductive system
1. Breast and female reproductive system.
There is a tight link between the growth regulatory pathways of IGFs, and estrogen-receptor positive breast cancer cells in an in vivo study suggest a role of IGF-I and IGF-IR in breast cancer development (383). The relevance of GH/IGF-I involvement in breast tumors emerged in studies where extracted GH given chronically to female rats induced breast tumors over the long term (303). Mammary tissue expresses both GH-R and PRL-R, but only human GH is able to activate either receptor in primates and nonprimates, whereas nonprimate GH acts only through the GH-R and PRL acts only through the PRL-R (382). In mutant lit/lit mice carrying a mutation of the GHRH receptor, which thus blunts GH secretion, the growth of mammary tumor transplants is dramatically reduced (305), whereas mice transgenic for human GH were shown to develop pregnancy-independent metastatic mammary tumors through activation of the PRL-R (307). Experiments in other mammals appear to suggest that this tumor-promoting effect may be species-related. In fact, a 7-wk treatment with GH and/or IGF-I in rhesus monkeys caused the nontumoral proliferation of both stromal and epithelial mammary cells (384). Interestingly, GH-treated animals showed a greater rate of mammary lobule number and size than IGF-I-treated counterparts, suggesting a direct GH effect additional to that mediated by IGF-I. In humans, the GH-R is expressed in mammary tumors and cell lines, and although the expression of GH-R and PRL-R is primarily localized in epithelial cells, some expression is also evident in stromal cells (385). The additional finding of GH and PRL protein expression in mammary tumors as well as normal tissue appears to suggest a possible autocrine/paracrine role of these hormones on tumor development and growth (382). In line with this hypothesis, studies in MCF-7 mammary cancer cell lines have shown that blockade of GH-R by the specific GH-antagonist B2036 was capable of abrogating tyrosine phosphorylation of JAK2, cellular proliferation, and apoptosis mediated by autocrine GH (309). Similarly, the relevance of the IGF system in breast cancer has been suggested by studies demonstrating the existence of a polarized IGF-I/IGF-IR loop, where stromal cells can stimulate epithelial cells to grow via paracrine mechanisms. IGF-I is secreted in the conditioned medium of human breast cancer cell lines (386), whereas Rnase protection assays and in situ hybridization studies have identified the stromal tissue of breast cancer specimens as the source of IGF-I (387, 388). As in other cancer cell lines, exogenous addition of IGF-I to breast cancer cells promotes cell proliferation, and this effect can be prevented by stimulation with anti-IGF-IR antibody IR3 (389). Conversely, IGF-IR mRNA is expressed on the surface of primary cultures of malignant breast epithelial cells (390) as well as in several estrogen-dependent and, at lower amounts, in estrogen-independent cell lines, where the expression of IGF-IR is positively correlated with that of estrogen (ER), progesterone (PR), and PRL receptors (391). The correlation between IGF-IR expression and the ER status in breast cancer specimens has been further confirmed in studies in which IGF-IR expression was significantly higher in specimens from ER/PR positive tumors at lower degree of risk than in ER/PR negative tumor at higher risk, thus suggesting a predictive role for IGF-IR as a good prognostic factor (392). From a clinical perspective, sex steroids can modulate the GH/IGF-I axis at many levels, including pituitary GH secretion, secretion of liver IGF-I as well as production of IGFBPs, which is ultimately reflected in IGF-I clearance rate (312). No consensus estrogen-responsive element has been identified in IGF-I promoters, but studies in chicken IGF-I gene P1 promoter have identified the AP-1 enhancer as a mediator of estrogen responsiveness, whereas time- and dose-dependent induction of IGF-I gene expression by estradiol treatment has been observed in human fetal osteoblasts (316). Because the concentrations of ovarian steroids are higher in the premenopausal stage, a greater effect of estrogen steroids on IGF-I levels may explain the results of studies exploring the relationship between IGF-I levels and breast cancer risk in premenopausal women. As discussed above, breast cancer risk developing in premenopausal women has been suggested to be directly related to serum IGF-I and inversely related to serum IGFBP-3. Hankinson et al. (51) found that stratification of breast cancer-bearing patients by progressively increasing tertiles of IGF-I levels allowed them to identify a 2.6-fold greater risk of breast cancer in the group with the highest IGF-I levels; in premenopausal women less than 50 yr old, high IGF-I tertiles alone predicted a 4.6-fold higher risk and, in combination with low IGFBP-3, a 7.3-fold higher risk than in unaffected women. On the other hand, analysis of reports on breast cancers in acromegaly reveals an average prevalence of 1.7% for this type of tumor. As a whole, breast cancers represent 13% of all malignancies developing in acromegaly and cause nearly 11% of cancer-related deaths in acromegaly (Table 5). Despite these figures, reports focusing on mammary tumors are predominantly epidemiological and fail to provide an accurate insight into the problem. Nabarro’s findings (9) attracted attention on a 4-fold higher incidence of breast cancer in acromegalic women, although the strong association between acromegaly and breast cancer was in apparent conflict with the low mortality from breast cancer observed in this study. Conversely, Orme et al. (18) did not find any increase in either the incidence or mortality from mammary tumors compared with the general rates, although the mortality from breast cancer was 60% higher than in normal women and increased by 3-fold in the case of posttreatment GH values above 10 µg/liter. Several studies have noted that a short interval (on average, 5 yr) generally separates the diagnosis of acromegaly from that of breast cancer, thus suggesting that risk may increase in the short term and/or in the presence of untreated disease (298, 301).

On the other hand, only a few reports have been published on the occurrence of cancers at the level of the female reproductive system, thus suggesting indirectly that uterine and ovarian tumors are much less common. Remarkably, a significant increase in the occurrence of uterine leiomyomata has been documented in nearly 80% of women in a small study (393). Oppositely, ovarian and uterine carcinomas are rare (Table 5); indirect evidence exists that uterine cancers may develop earlier in life and with shorter disease duration than ovarian carcinomas (9, 295, 298, 301, 352).

2. Prostate and the male reproductive system.
As in breast tumors, the link between IGF-I and prostate tumorigenesis has experimental and clinical bases. Both normal and tumoral prostate cells express negligible amounts of IGF-I mRNA, which is increased in prostate tumors from transgenic adenocarcinoma of mouse prostate models, in which the severity of cancer progression seems to be directly correlated with IGF-I expression (394, 395). PC-3, DU-45, and LNCaP cancer cell lines do not produce IGF-I, whereas the elevated expression of IGF-IR mRNA constitutes a prerequisite for IGF-I to stimulate proliferation in these prostate cancer cell lines, which is, as a consequence, abrogated by transfection with antisense oligonucleotides complementary to IGF-IR mRNA (for review, see Refs. 313 , 396 , and 397). Conversely, the loss in IGF-IR mRNA expression documented in tumors from castrated transgenic adenocarcinoma of mouse prostate mice has been interpreted as a mechanism leading to dedifferentiation and greater tumorigenicity. Androgen sensitivity may similarly drive the proliferative response under IGF-I stimulation. In androgen-independent prostate cancer cells, such as PC-3 and DU-45, IGF-I causes cell proliferation regardless of the presence of androgens in culture media, whereas cultures of androgen-dependent cells, such as LNCaP, become responsive to IGF-I only in the presence of dihydrotestosterone (396). Transfection of rat PA-III prostate adenocarcinoma cells with an IGF-IR antisense construct reduced IGF-I mRNA levels in these cells, whereas injection with transfected PA-III cells induced tumors that were approximately 90% smaller than controls (398). One relevant phenomenon, which may explain some of the prostate alterations seen in acromegaly, is constituted by the observation that stromal cells derived from benign prostatic hyperplasia express IGF-IR mRNA and that IGF-I stimulation increases stromal cell density by 80%, an effect that is abrogated by coincubation with the IGF-IR-neutralizing antibody IR3 (399). In humans, serum IGF-I levels appear to predict both risk and growth rate of prostate cancers, and the aforementioned study by Chan et al. (50) attributed to IGF-I the role of predictor of prostate cancer. In a subsequent nested case-control study on 530 patients with prostate cancer, IGF-I and IGFBP-3 levels appeared to predict the progression of advanced-stage prostate cancers, the relative risks being 5.1 for the highest vs. the lowest IGF-I quartiles and 0.2 for the highest vs. the lowest IGFBP-3 quartiles; combination of high IGF-I and low IGFBP-3 increased the relative risk to 9.5, whereas the combination of IGF-I and IGFBP-3 with values of prostate-specific antigen (PSA) increased the specificity from 91 to 93% but decreased sensitivity from 40 to 36% (400). The role of PSA remains, however, significantly more predictive than IGF-I in men with prostate cancers and elevated levels of PSA; the analysis of ratios of IGF-I, IGFBP-3, and free and total PSA does not seem to further improve the accuracy of PSA measurements alone (401, 402).

Acromegaly predisposes to benign prostate hypertrophy, the condition of stromal proliferation of the prostate. A pilot transrectal ultrasonography study revealed a marked increase of prostate volume and of the transitional zone in untreated acromegalic males, regardless of gonadal status and age of patients (403). In fact, all patients screened by transrectal ultrasonography study were found to be hypogonadal and were aged below 40 yr. In a larger series, including patients with active or cured acromegaly and postsurgical hypopituitarism, benign prostate enlargement (that is, volume exceeding 30 ml by ellipsoidal formula) occurred in 80% of active patients, 30% of cured acromegalic patients, none of the GH-deficient patients, and 26% of controls (404). At multiple regression analysis, prostate volume correlated significantly more with disease duration than with patients’ age. Additional findings were represented by the development of calcifications in 61%, cysts in 26%, vesicle inflammation in 8%, and biopsy-proven benign nodules in 13% of acromegalic patients (404). On the other hand, and at variance with the indication that IGF-I links to prostate cancer risk in the normal population, acromegalic patients harbor a decreased risk of prostate cancers. This inference emerges mostly from epidemiology studies in which the number of prostate cancers constitutes a minority of malignancies and are significantly less prevalent that in the normal population (Table 5). In 1970, Campbell and Harrison suggested that acromegaly did not predispose to prostate enlargement (405), and Krawitt’s description, 3 yr later, of a 75-yr-old acromegalic man deceased after unsuccessful removal of a giant invasive prostate cancer remains anecdotal (406). In the largest study published on acromegalic men, 15 tumors arising from the genitourinary tract accounted for a 17% prevalence among all nonpituitary cancers, a rate nonsignificantly different from that recorded in the nonacromegalic control population enrolled in VA hospitals (299). Although unique among all epidemiology studies, however, the relevance of this observation is blunted by a pooled presentation of genitourinary tumors. Intriguingly, the absence of prostate cancers in any of the patients screened in our studies constitutes a relevant caveat in the theory linking IGF-I levels to prostate cancer in the general population. In this regard, Cohen et al. (407) have indicated a series of hypotheses to explain the observed relationship between IGF-I and prostate/breast cancer risk that are worth considering: 1) the observation may have originated from an ascertainment bias or a methodological error; 2) other cancer-controlling factors, such as nutrition, may have modulated IGF-I concentrations, which then act as a confounding factor rather than as cause of cancer; 3) tumors may work as a source of IGF-I, which can thus be considered as a tumor marker; 4) it is possible that autocrine IGF-I production is involved in the pathogenesis of a number of tumors, including those linked to increased circulating IGF-I levels; and 5) it is possible that IGF-I elevation reflects GH action on some types of cancer. It is interesting to note, however, that acromegaly also increases liver synthesis of IGFBP-3, which has shown IGF-independent proapoptotic and antitumoral effects at the local level, as discussed above. Although IGFBP-3 levels appear to predict a less aggressive behavior of breast, prostate, and colon cancers (50, 51, 52), it has been shown that a number of tumors are associated with increased IGFBP-3 proteolysis in the serum (49), which normally acts to release IGF-I locally. Because PSA also functions as a major IGFBP-3 protease, thus serum PSA elevation in prostate cancer-bearing patients may indirectly promote free IGF-I release locally. This possible mechanism is not applicable in acromegaly where IGFBP-3 proteolysis is not increased; speculatively, this circumstance may even protect acromegalic patients against the development of prostate cancers. However, this issue awaits further clarification. Of note, the return of GH and IGF-I levels to normal has beneficial effects on the prostate in acromegaly. Two years of treatment with lanreotide, together with a GH, IGF-I, and IGFBP-3 level decrease, induced a decrease of prostate volume in 16 patients well controlled by the treatment (408). Prostate volume decreased after treatment only in the eight controlled patients younger than 50 yr, but not in those controlled with age above 50 yr, despite a similar decrease in GH, IGF-I, and IGFBP3 levels. Taken together, these data appear to indicate that chronic elevation of GH and IGF-I levels constitutes a proliferative stimulus for stromal cells of the prostate independent of the androgen status. Thus, prostate epithelial cells appear not to be targeted by GH/IGF-I excess, although more extensive follow-ups are necessary to fully understand this observation.

F. Other tumors
At the level of the genitourinary tract, GH excess affects renal function and kidney size and increases glomerular filtration rate and renal plasma flow in GH-deficient as well as normal adults. IGF-I is implicated in compensatory renal hypertrophy, whereas markedly elevated serum GH levels accelerate glomerular sclerosis in rodents. Measurement of absolute glomerular size using a semiautomatic image analyzer revealed heavier kidneys in acromegalic patients than in controls (409). Histological comparison between acromegalic patients and subjects with single kidneys showed more global glomerulosclerosis and segmental lesions in single kidneys, a finding that likely implies different mechanisms for the renal enlargement seen in acromegaly. Functionally, submaximal exercise induces abnormal increases in microalbuminuria in patients with acromegaly, although 1-microglobulinuria levels, a marker of renal tubular damage, were normal both at rest and at peak exercise (410). Unlike these disorders, kidney cancers play an irrelevant role in tumoral phenomena of acromegaly (Table 5). Similarly, scattered reports have been published on brain tumors (299), meningiomas (410), osseous tumors (294, 411), ocular melanocytic nevi and melanoma (412), skin epidermoid cancers or melanomas (294, 299), as well as adrenal tumors (10). Description of lymphohematopoietic neoplasms includes lymphoma, multiple myeloma, chronic myelogenic or lymphocytic leukemia, and polycythemia vera (9, 294, 298, 299, 301, 352, 413). Among 106 patients treated for over 15 yr, Au et al. (414) found two cases of acute lymphoblastic leukemia and one patient with acute myeloid leukemia. Two of these patients had received radiotherapy as part of their treatment. At variance with other reports, the incidence of leukemia adjusted for age and follow-up years was significantly higher in this cohort than in the general population (414). The occurrence of lymphopoietic tumors in the late course of acromegaly suggests, however, that these two conditions are likely unrelated.

	VI. The Complications at the Skeletal System

Top Abstract I. Introduction II. The Complications at... III. The Metabolic Complications IV. The Complications at... V. The Neoplastic Complications VI. The Complications at... VII. Summary VIII. Conclusions References

 
A. Epidemiology
As already stated, the osteoarticular manifestations feature the disease; symptoms or signs referable to articular joint disorders occur in the great majority of patients with acromegaly at their diagnosis (415, 416, 417). The delay between the estimated onset of acromegaly and the appearance of joint disease is approximately 10 yr, but the range is wide and oscillates between 0 and 27.5 yr, according to the report by Detenbeck et al. (418). Early signs of joint involvement were also noted in patients with short disease duration (419). The duration of acromegaly does not seem to be correlated with the presence and/or the severity of arthropathy (415, 420, 421), although the patients with arthropathy included in the study of Bluestone et al. (420) had severe and long-standing acromegaly. Articular manifestations include articular involvement and enthesopathy and are a leading cause of morbidity and functional disability in these patients (418, 420, 422). Crepitus on clinical examination is the most common sign (416, 418, 420, 423), whereas pain is the most common symptom, usually intermittent and exacerbated by activity (420).

The acromegalic arthropathy affects both axial and peripheral sites. The appendicular skeleton is involved in up to 74% of patients with moderate-to-severe involvement in one third of cases (9, 418, 420); neck or back pain is also common, occurring in more than half the patients, but abnormalities could be detected in 20–25% of cases (417, 421). The knee is the most commonly involved peripheral joint, followed by the shoulder, hip, ankle, elbow, and joints of the hand (417, 418, 420). Joint stiffness and swelling are also common; in 1952 Kellgren et al. (416) reported joint swelling in 52% and effusions in 40%, whereas prevalence rates reported 20 yr later by Bluestone et al. (420) accounted for 21% and 5% of patients, respectively. Acromegalic arthropathy is generally noninflammatory (418, 423), although features of osteoarthritis frequently develop in later stages of the disease (416, 418, 420, 422, 423, 424). Sinovial aspirates showed that effusions are degenerative without evidence of inflammation or crystal deposition (416, 418, 420). As noted by Lieberman et al. (425), the occurrence of hypermobility (15–30% of cases) or limitation of joint movement (16–27% of cases) likely depends on disease duration. The unusual bone disease that is occasionally associated with acromegaly, the McCune-Albright syndrome, has not been considered in this paper for its peculiar bone aspects.

B. Pathogenesis
The pathogenesis of arthropathy is complex, involving both GH/IGF-I excess and secondary degenerative changes. Most in vitro studies have focused on the effect of GH and IGF-I in chondrocytes derived from the epiphysial growth plate, which is metabolically active and whose function and degree of differentiation follow a topographical organization (425). However, the chondrocytes in adult articular cartilage are consistently less active than their epiphysial plate counterparts. These cells are found alone or in pairs in isolated lacunae within the cartilage matrix and rarely divide (426). They maintain the extracellular matrix through degradation and replacement of collagen proteoglycans, glycosaminoglycans, and other macromolecules (426), but their ability to repair damaged cartilage is very limited (427). Of historical note, the lack of in vitro response of cartilage to GH was the cause leading Salmon and Daughaday (26) to propose the existence of a secondary mediator later named IGF-I. Subsequent studies in suspension chondrocytes cultures demonstrated that GH preferentially stimulated growth and differentiation of prechondrocytes from the resting cell layers and increased their sensitivity to IGF-I (428, 429). Like other cells, chondrocytes are able to synthesize and release IGF-I locally (430). GH is an important stimulus for chondrocytes IGF-I mRNA and peptide expression. Other cytokines, such as TGF-ß, basic fibroblast growth factor, and insulin, also stimulate chondrocyte growth (425). IGF-I binds specifically to chondrocytes with a greater binding affinity for proliferative than for resting zone cells (431). IGF-I stimulates DNA synthesis, cell replication, proteoglycan and glycosaminoglycan synthesis in chondrocytes or explants from a variety of animals and under a variety of culture conditions (425). IGF-I is a relevant regulator of collagen synthesis, because it can reverse the abnormalities in collagen synthesis based on experimental models of ascorbate deficiency (432). The role of GH and IGF-I in bone metabolism parallels their effects on the articular cartilage. Stimulation of DNA synthesis and cell proliferation by GH depends on the degree of cell differentiation (433), but GH also stimulates production of alkaline phosphatase (433) and collagen (434). As in the cartilage, GH effects on osteoblasts are likely to be mediated through paracrine IGF-I production, although circulating IGF-I also influences osteoblast metabolism (435). Additional effects of IGF-I include increased mRNA levels of ₁(I)-procollagen (435, 436), increased noncollagen protein mRNA and peptide synthesis (435, 436, 437), inhibition of protein degradation (438), and increased bone production in organ culture (437). However, in analogy with other body tissues, IGF-I action on the bone comprises interactions among IGF-I, IGF-I receptors, and IGFBPs. At least four distinct IGFBPs (IGFBP-1, -2, -3, and -4) are produced by various bone cells in culture, and distinct studies have intriguingly suggested that IGFBP-3 may enhance (439), whereas IGFBP-4 may inhibit, IGF-I action (440). Additionally, many osteotrophic factors including PTH, TGF-ß, platelet-derived growth factor, estrogens, and cortisol, contribute in regulating GH and IGF-I production by osteoblasts (425). Although this complex system still needs to be fully elucidated, it seems conceivable that IGF-I may act to integrate multiple trophic signals controlling bone metabolism.

Based on experimental evidence, the pathophysiology of the acromegalic arthropathy may be hypothesized. At the initial stage, GH excess stimulates local production of IGF-I in cartilage which, combined with increased levels of circulating IGF-I, results in replication and hyperfunction of articular chondrocytes and increased matrix synthesis. The cartilage begins to thicken, leading to widening of the joint space, alteration of the normal geometry of the joint, and hypermobility of joints (Fig. 14). At radiology, widening of the joint spaces and periarticular soft tissue hypertrophy can be documented. GH also stimulates connective cell hyperfunction, resulting in growth of periarticular structures; sinovial hypertrophy further exacerbates the abnormal mechanical loading of the joint. At this stage arthropathy may be reversed by control of GH and IGF-I hypersecretion (see Section VI.C). Along with disease progression, fissures develop onto the cartilage surface and gradually enlarge, whereas regenerative fibrocartilage proliferates disproportionately more than in osteoarthritis, presumably as a result of GH stimulation (425, 432). The regenerative fibrocartilage frequently becomes calcified, resulting in osteophyte formation. In more advanced cases, fissures may extend to the subchondral bone, widen, and become undercut, producing ulceration of the articular cartilage. The underlying bone shows accelerated turnover, eburnation, and subchondral cyst formation. Ultimately, the articular cartilage becomes thinned with narrowing of the joint space, a process that shares many features with osteoarthritis. At this stage, the acromegalic arthropathy cannot be any further improved by GH and IGF-I suppression (Fig. 14).

View larger version (59K): [in this window] [in a new window]   FIG. 14. Scheme of the potential progression of the acromegalic arthropathy during the different stages of the disease.

View larger version (77K): [in this window] [in a new window]   FIG. 15. Radiographic features of abnormalities of the hand and wrist in a female patient aged 48 yr with an estimated disease duration of 8–10 yr. At the hand, note at terminal phalanges the enlargement of tuft and bases. At metacarpophalangeal joints, it is worth noting the widening of some articular spaces, whereas at the proximal interphalangeal joints there is narrowing of others. Note the width of some proximal phalanges resembling the presence of "beak-like" osteophytes at the level of distal interphalangeal joints and at proximal interphalangeal joints. Periarticular calcific deposits are also present. At the wrist, note the enlargement of distal radius and ulna as well as at ulnar styloid. Lateral to the radius, some "beak-like" osteophytes can be appreciated.

View larger version (95K): [in this window] [in a new window]   FIG. 16. Radiographic features of bone proliferation at sites of tendon and ligament attachment to bone (enthesopathy) in a female patient aged 48 yr with an estimated disease duration of 8–10 yr. Note the proliferation along the posterior margin of the calcaneus. This is a proliferative enthesopathy different from the common enthesopathy occurring in other rheumatic diseases. This latter spondyloarthopathy is characterized by a primary erosive, due to local release of cytokines, and a secondary proliferative process.

E. Bone mass alterations
Until the end of the 1960s, acromegaly was considered as a relevant cause of secondary osteoporosis (456), a theory that paradoxically contradicts the observed stimulatory effect of GH and IGF-I on osteoblast function. In the 1970s, several studies contributed to changing this inference by indicating a potential anabolic effect of GH, at least on the cortical bone (457, 458). Successively, Seeman et al. (459) demonstrated that osteoporosis occurs rarely in acromegaly and thus hypothesized that it could be a consequence of hypogonadism in a variable number of patients. Characteristically, acromegaly causes an increase in both bone apposition and resorption (460), but data on bone mass are controversial (457, 459, 461, 462, 463, 464, 465, 466, 467, 468). This discordance of results depends mainly on differences in skeletal sites investigated, diagnostic equipment used, and grouping of patients regardless of gender and gonadal status. Data on cortical bone generally show a normal or even increased bone mineral density (regardless of the gonadal status), although discrepant data are available on the trabecular bone (460). Riggs et al. (457) first reported increased cortical bone density in the forearm at a distal site, which is almost entirely composed of cortical tissue. Increased cortical, but not trabecular, bone density in the forearm was also reported by Diamond et al. (461). At the spine and femur, both cortical and trabecular bone density has been reported to be increased in series including both hypogonadal and eugonadal patients (464), as well as only eugonadal patients (468). Differently, bone density at the spine levels was reported to be normal in other series including either eugonadal patients (461, 463) or hypo- and eugonadal patients (461, 465). Indeed, the impact of hypogonadism should be considered of the utmost importance in patients with acromegaly when evaluating bone density. Scillitani et al. (466) reported normal bone density in the forearm regardless of the gonadal status of patients, while bone density was increased in the femur in their entire series of patients. The authors also documented an increased trabecular bone mass in the spine, but not in the femur or the forearm, in the series as a whole as well as in the subset of eugonadal patients. In contrast, at each site examined, hypogonadal patients had values of trabecular bone mass similar to those detected in the matched controls (466). Altogether, these data suggest that GH and IGF-I excess induces an increase of the cortical bone density, independently of gonadal function, whereas hypogonadism seems to counteract the anabolic effect of GH on the trabecular bone.

F. Effect of GH and IGF-I control on the skeletal system
Whether acromegalic arthropathy can be reversed by controlling GH and IGF-I levels is still questioned. The extensive structural changes occurring at the joints and the limited reparative ability of chondrocytes appear to prevent the significant improvement of acromegalic arthropathy. However, surgery or treatment with somatostatin analogs was shown to be associated with improved symptoms and signs of acromegalic arthropathy (6, 417, 441, 469, 470). Mild to moderate improvement in pain, crepitus, and range of motion has been reported in the majority of patients treated with octreotide (6). The possibility exists that some of the milder early changes, such as cartilage thickening and joint space widening, may resolve with successful early treatment. Nonetheless, several reports indicate that symptomatic and functional improvement may occur, although the arthropathic process itself is irreversible. Podgorski et al. (421) noted that arthropathy was milder in patients responder than in nonresponder to octreotide, and Layton et al. (417) reported improvement of symptoms after octreotide treatment, but objective improvement was observed only in one of nine patients. Conversely, Dons et al. (415) reported decreased joint pain in 12 patients and pain worsening in 29 of 47 patients 5 yr after radiotherapy. We recently demonstrated that cartilage thickness measured by ultrasonography at the shoulder, wrist, and left knee was significantly decreased after 6 months of octreotide treatment in a small group of previously untreated acromegalic patients (419). However, in neither patients cured for acromegaly nor those receiving octreotide treatment did cartilage thickness return to values comparable to healthy subjects (419). In a subsequent study, we found that thickening of shoulder, wrist, and knee cartilages and of heel tendons significantly decreased in all patients after 12 months of treatment with lanreotide (471). We also found that the reduction of right shoulder cartilage thickness by 37% was significantly greater than that observed at the level of right and left knee cartilages and heel tendons, ranging in these sites from 14 to 19% (471). More recently, in a prospective evaluation of joint thickness after 12 months of octreotide-LAR treatment, we demonstrated that there was a decrease in the thickness of the shoulder (15.1 ± 3.2%), wrist (20.5 ± 3.1%), right (22.2 ± 3.4%) and left knee (18.2 ± 2.8%) in all patients; however, the reduction in joint thickness at all sites was significantly greater in the patients with controlled disease after octreotide-LAR treatment than in the uncontrolled ones (Fig. 17) (472). Moreover, values compared with controls of shoulder and right knee thickening were found in as high as 61% and 89%, respectively, in well-controlled patients (472). We did not find any gender difference (472). Carpal tunnel syndrome is also significantly improved in most patients after control of GH and IGF-I level hypersecretion (186, 445, 447, 453), but the underlying pathogenic mechanisms are unknown (452, 454). Jenkins et al. (448) showed that the increased nerve size and signal intensity at MRI improved with treatment of acromegaly in symptomatic patients, whereas asymptomatic patients experienced no change or worsening. Because the prevalent pathological mechanism of median neuropathy in acromegaly is edema of the perineural sheathes, rather than increased volume of the carpal tunnel contents, the rapid resolution of edema after suppression of GH and IGF-I levels is associated with resolution of neuropathic symptoms (448). However, when all findings on acromegalic arthropathy are considered together, it appears that some early alterations, such as joint thickness or osteopenia, can be reversed by suppressing GH and IGF-I levels, whereas later bone complications, such as osteoarthritis and bone deformities, should be considered definitive features of the disease.

View larger version (23K): [in this window] [in a new window]   FIG. 17. Ultrasonographic evaluation of joint thickness before and during octreotide-LAR therapy for 12 months in 30 de novo patients with active acromegaly. A, Left shoulder; B, left wrist; C, right knee; D, left knee. •, Patients with controlled disease; , patients with uncontrolled disease. Data were modified by Ref. 272 . Data are shown as mean ± SD and were analyzed by the two-way ANOVA.

	VII. Summary

Top Abstract I. Introduction II. The Complications at... III. The Metabolic Complications IV. The Complications at... V. The Neoplastic Complications VI. The Complications at... VII. Summary VIII. Conclusions References

	VIII. Conclusions

Top Abstract I. Introduction II. The Complications at... III. The Metabolic Complications IV. The Complications at... V. The Neoplastic Complications VI. The Complications at... VII. Summary VIII. Conclusions References

 
Early and modern studies agree on identifying cardiovascular and respiratory complications as the most relevant causes of the increased risk of mortality in acromegaly. Doubts have been raised on the relevance of neoplastic complications, and future elucidation of local IGF-I and IGFBP-3 action will contribute to clarifying this issue more adequately. There is enough good evidence to infer that acromegaly is currently diagnosed earlier than, for instance, in the 1930s because patients only rarely present visual field defects. Indeed, early detection prevents the development of irreversible complications of the disease, including cardiomyopathy, respiratory dysfunction, and arthropathy. Clear evidence also exists that, in the early stage, all of these disorders can be totally reversed. Whether improvement in morbidity will correspond to a similar improvement in mortality, although highly likely, still awaits further demonstration by large prospective studies.

	Acknowledgments

 
The authors thank Dr. Gillian Elisabeth Walker (Department of Pediatrics, Oregon Health & Sciences University) for critically reviewing this manuscript. We are grateful to Dr. Letizia Spinelli and Dr. Maurizio Galderisi for kindly providing the echocardiography studies described in Fig. 5. We are also indebted to R. Scarpa, M.D. (Department of Clinical and Experimental Medicine, Section of Rheumatology, University "Federico II" of Naples), for kindly providing the radiographic pictures in Figs. 15 and 16 and for his comment about bone involvement of acromegaly.

	Footnotes

 
This study was partially supported by a grant of the Italian Minister of Reseach and University in Rome (no. 2003068735).

Abbreviations: ALS, Acid-labile subunit; ANP, atrial natriuretic peptide; Apo, apolipoprotein; CETP, cholesteryl ester transfer protein; DISH, diffuse idiopathic skeletal hyperostosis; ECG, electrocardiogram; ER, estrogen receptor; GH-R, GH receptor; HDL, high-density lipoprotein; IGFBP, IGF binding protein; IGF-IR, IGF type I receptor; IGT, impaired glucose tolerance; IMT, intima-media thickness; LAR, long-acting repeatable; LDL, low-density lipoprotein; Lp-a, lipoprotein-a; LPL, lipoprotein lipase; MRI, magnetic resonance imaging; PR, progesterone receptor; PRL, prolactin; PSA, prostate-specific antigen; SCLC, small cell lung cancer; SIR, standardized incidence ratio; TGHM, transgenic for the GH gene.

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Top Abstract I. Introduction II. The Complications at... III. The Metabolic Complications IV. The Complications at... V. The Neoplastic Complications VI. The Complications at... VII. Summary VIII. Conclusions References

 

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