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Mônica R Gadelha, Neuroendocrinology Research Center/Endocrine Section and Medical School, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil Neuroendocrine Section, Instituto Estadual do Cérebro Paulo Niemeyer, Secretaria Estadual de Saúde do Rio de Janeiro, Rio de Janeiro, Brazil Neuropathology and Molecular Genetics Laboratory, Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, Brazil Correspondence and Reprint Requests: Mônica R. Gadelha, MD, PhD, Rua Professor Rodolpho Paulo Rocco, 255, 9° andar, Setor 9F, Centro de Pesquisa em Neuroendocrinologia, Ilha do Fundão, Rio de Janeiro 21941-913, Brazil. E-mail: . Search for other works by this author on: Leandro Kasuki,Neuroendocrinology Research Center/Endocrine Section and Medical School, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil Neuroendocrine Section, Instituto Estadual do Cérebro Paulo Niemeyer, Secretaria Estadual de Saúde do Rio de Janeiro, Rio de Janeiro, Brazil Endocrine Unit, Hospital Federal de Bonsucesso, Rio de Janeiro, Brazil Search for other works by this author on: Dawn S T Lim,Department of Endocrinology, Singapore General Hospital, Singapore, Singapore Search for other works by this author on: Maria FleseriuDepartment of Endocrinology, Diabetes and Metabolism, Oregon Health and Science University, Portland, Oregon Department of Neurological Surgery, Oregon Health and Science University, Portland, Oregon Northwest Pituitary Center, Oregon Health and Science University, Portland, Oregon Search for other works by this author on: (*M.R.G and M.F. contributed equally to this study). Author Notes Published: 31 August 2018
Close Navbar Search Filter Microsite Search Term Search AbstractAcromegaly is a chronic systemic disease with many complications and is associated with increased mortality when not adequately treated. Substantial advances in acromegaly treatment, as well as in the treatment of many of its complications, mainly diabetes mellitus, heart failure, and arterial hypertension, were achieved in the last decades. These developments allowed change in both prevalence and severity of some acromegaly complications and furthermore resulted in a reduction of mortality. Currently, mortality seems to be similar to the general population in adequately treated patients with acromegaly. In this review, we update the knowledge in complications of acromegaly and detail the effects of different acromegaly treatment options on these complications. Incidence of mortality, its correlation with GH (cumulative exposure vs last value), and IGF-I levels and the shift in the main cause of mortality in patients with acromegaly are also addressed. Essential Points
Acromegaly is a chronic systemic disease resulting from excess levels of GH and consequently IGF-I that is caused by a GH-secreting pituitary adenoma (somatotropinoma) in ~98% of cases (1, 2). It affects both sexes equally and is usually diagnosed in the fourth or fifth decade of life, although a delay of 5 to 10 years from symptom initiation to diagnosis has been reported and seems to have remained unchanged for the last few decades (3, 4). Annual incidence of acromegaly is approximately three to four cases per million in most studies, including those published in the last decade (4, 5). However, in a recent nationwide study from Iceland, the incidence was 1.16 cases per million/y from 1955 to 1964 and progressively increased, reaching 7.7 cases per million/y from 2005 to 2013 (6). It is not known whether there was a true increase in the incidence of acromegaly or whether there was an increase in the awareness of the disease per se, with more patients thus being diagnosed with acromegaly. The prevalence has also increased over time, as it was previously reported to be ~40 cases per million (7), but in more recent studies, it ranges from 85 to 133 cases per million (4–6, 8, 9). Acromegaly is associated with many systemic complications secondary to chronic excess GH levels and to tumoral mass effect, including cardiovascular disease, osteoarthropathy, metabolic complications [insulin resistance (IR), hyperglycemia, and hyperlipidemia], respiratory disease, possible increased risks of some neoplasias, hypopituitarism, and more recently described complications, such as vertebral fractures (VFs) and decreased quality of life (QoL) (7, 10, 11). Cardiovascular disease was considered the main cause of death for many years (7). However, this perspective has changed in more recent studies as the severity of cardiac involvement in acromegaly has changed (12–14). Active acromegaly is still associated with increased mortality, but disease control has reduced the mortality risk to an equivalent level to the normal population in more recent studies, using previously unavailable treatment modalities (14–16). Acromegaly treatment has evolved substantially in the last few decades, with new options available (17). Surgery remains the first choice of treatment for most patients, as it is the only treatment that results in immediate disease control (remission) (18). The exceptions are patients with a high surgical risk or who refuse surgery, and patients whose tumors are almost completely located in the cavernous sinus (18). A surgical remission is defined as a random or a nadir GH level in an oral glucose tolerance test (OGTT) <1.0 μg/L and a normal age-matched IGF-I level 3 months after surgery and is achieved in ~50% of patients, with total tumor resection being more common in microadenomas (up to 85%) and the experience of the neurosurgeon having great impact in surgical success rates (18, 19). Thus, in general, half of the patients will require adjuvant treatment. Adjuvant medical treatment is based on three drug classes: somatostatin receptor ligands (SRLs), dopamine agonists (DAs), and GH receptor (GHR) antagonists (17, 18). The SRLs (octreotide LAR and lanreotide Autogel) have been considered the first-choice medical treatment and are recommended for most patients who are not cured by surgery and patients with contraindications to surgical treatment (18). In prospective studies with no selection bias, disease control is achieved in ~40% of patients (20). For patients receiving medical treatment, disease control is defined as a random GH level <1.0 μg/L and a normal age-matched IGF-I level (18). The GH nadir in the OGTT has a low accuracy and should not be used, as SRLs interfere with the feedback of glucose and GH secretion (21). The multireceptor targeted SRL, pasireotide, differs from the other SRLs owing to its higher affinity for somatostatin receptors (SSTRs) 3 and 5 (22). It was shown to be more effective than other SRLs in a randomized prospective study (23), and in another randomized prospective study, disease control was achieved in 20% of the patients whose disease was uncontrolled after treatment with octreotide LAR or lanreotide Autogel (24). The DA cabergoline acts by binding to dopamine receptor type 2 that is expressed at high levels in somatotropinomas; this agonist has been used as a monotherapy or in combination with SRLs in patients who are resistant to the latter treatment (25, 26). Cabergoline is not licensed for acromegaly treatment (off-label use) and there are no prospective randomized trials to evaluate its efficacy in acromegaly. Additionally, in some of the studies there was preselection of patients, and efficacy was assessed only considering IGF-I normalization and not GH or composite GH/IGF-I as well (25). Nevertheless, it seems to have a lower efficacy than other drug classes (~20% to 30% as a monotherapy and 30% to 35% in combination therapy), and some patients present treatment escape during long-term treatment (25, 27). Cabergoline can be used as an adjuvant treatment, particularly for patients with mild disease [IGF-I levels up to 1.5-fold the upper limit of the normal range (ULNR)] (17, 18). The GHR antagonist pegvisomant (PEG) binds to the receptor without activating the intracellular signaling pathways (28). As it acts in the periphery, PEG has no action on the somatotropinoma (28). It is the drug with the highest efficacy in controlling acromegaly, with control rates ranging from 63% to 97%, depending on the study type (29–31). PEG has been used as a monotherapy, increasingly used as first-line therapy (32), and Food and Drug Administration approved in the United States, mainly when the tumor is not a concern or in combination with SRLs or cabergoline (33–35). Radiotherapy is effective at controlling tumor volume in >90% of cases and leads to biochemical control in ~60% of cases, but GH normalization can take several years (36). Although highly effective, radiotherapy is associated with many side effects, including hypopituitarism, cerebrovascular disease, cranial nerve damage, and, possibly, secondary malignancies (37, 38). Additionally, it is associated with increased mortality (16, 39, 40) (data are discussed in “Mortality in Patients With Acromegaly: The Changing Face of the Disease in Recent Decades” below). These data are mainly derived from studies using conventional radiotherapy (CRT), and perhaps complications are not as frequent with stereotactic radiotherapy, although follow-up of series may not be long enough to evaluate all long-term complications with more modern techniques (41). Therefore, radiotherapy is considered a third-line therapy and reserved for patients with aggressive tumors that are resistant to surgical and medical treatment (18). In the last two decades, acromegaly treatment has evolved in many centers with less frequent use of radiotherapy and more frequent use of surgery and medical therapy (14, 16). This strategy resulted in a normalized mortality rate and a change in the prognosis of different acromegaly complications, as disease control is essential to reduce the excess acromegaly-associated morbidity and mortality (12, 18). Systemic complications of acromegaly have been extensively reviewed in a previous publication (7), but more recent data on disease complications and the effects of new treatments on acromegaly complications and disease mortality have been published since that review was published. The present review focuses on novel data from studies examining well-known complications and provides a detailed description of newly described complications, such as VFs and decreased QoL. The review also discusses the effects of current acromegaly treatment modalities on all these complications and makes recommendations for the diagnosis and follow-up of these complications. Systemic Complications of AcromegalyCardiovascular and cerebrovascular diseaseThe effects of GH on the cardiovascular system have been considered the main cause of mortality in patients with acromegaly (7, 42, 43). Autopsy studies described a high frequency of left ventricular (LV) hypertrophy (LVH), fibrosis, and myocardial infarction (MI) (44, 45). Furthermore, clinical studies that included echocardiography (ECHO) also reported increased frequencies of LVH and diastolic dysfunction, and some authors have suggested that in cases of uncontrolled acromegaly, patients could develop systolic dysfunction (7, 46, 47). Additionally, valvular disease and arrhythmias have been described (7), as well as cerebrovascular disease in patients with acromegaly (37, 48). However, recent advances in acromegaly treatment and in the treatment of some comorbidities that influence the cardiovascular system, such as arterial hypertension (AH), hyperlipidemia, and diabetes mellitus (DM), have occurred during the last few decades (17, 18, 49–51). We review findings from the most recent studies below, as different methods to evaluate cardiovascular disease are available and new studies have addressed the effects of different acromegaly treatments on cardiovascular disease (13, 14, 42, 48, 52–58). GH/IGF-I and the cardiovascular systemPathophysiology: animal models and in vitro studies.The effects of GH and IGF-I on the cardiovascular system have been examined in animal models and human myocardial tissue. The GHR is expressed at high levels in both myocardium and vessels, as is the IGF-I receptor (59–61). Importantly, note that most of data presented in this section are derived from animal studies and do not necessarily reflect the physiopathology in the human heart. Most GH effects on the heart are mediated by IGF-I (59, 62). The addition of IGF-I to cultured neonatal rat cardiomyocytes induces cell hypertrophy without affecting the number of cells and induces the expression of myosin light chain 2, troponin I, and skeletal α-actin, without affecting the expression of cardiac muscle α-actin (63, 64). Treatment of long-term cultures of adult rat cardiomyocytes with IGF-I increases the numbers of newly built sarcomeres and myofibrils; however, this treatment reduces the expression of smooth muscle α-actin (65). In the same study, GH treatment had no effect on cardiomyocyte morphology (65). Treatment of hypophysectomized rats with GH or IGF-I also induces the expression of skeletal muscle α-actin, but not cardiac muscle α-actin, and it does not cause a shift in myosin heavy chains (66). The influence of these alterations in the human myocardium is not known. Interestingly, the effects of GH/IGF-I–induced cardiac hypertrophy and hypertrophy induced by mechanical forces, such as pressure or volume overload, differ (67). In rats treated with a combination of GH and IGF-I, LV weight increased by 35%; however, significant changes in levels of the atrial natriuretic factor, α-actin, and collagen III mRNAs were not observed. This finding differed from the results obtained in rats with cardiac hypertrophy induced by pressure or volume overload (67). Additionally, a 34% increase in myocardial contractility was observed in GH/IGF-I–treated rats, suggesting that the hypertrophy induced by excess GH/IGF-I levels may be a more physiological type than hypertrophy induced by mechanical overload (67). Although GH and IGF-I can induce myocardial hypertrophy in cell culture and rats, interstitial fibrosis is reduced and muscular trophism is preserved (68, 69). In a study of rat hearts, the positive inotropic effect of IGF-I was shown to be due to increased Ca2+ sensitivity of myofilaments and was not secondary to increased intracellular Ca2+ content (70). The same mechanism was not observed in response to GH treatment, indicating that the effect is secondary to increased IGF-I production (70). In contrast, in the human myocardium, the activation of IGF-I receptors exerts a concentration-dependent positive inotropic effect due to elevated intracellular Ca2+ concentrations, which are a consequence of both enhanced l-type Ca2+ currents and enhanced Na+–H+ exchange (71). GH, in contrast, does not seem to influence Ca2+ currents in acute settings (70, 72); however, it may increase peak intracellular Ca2+ concentrations after long-term treatment in vitro (73, 74). In addition to its positive inotropic effects, IGF-I seems to exert another beneficial effect on the heart through its antiapoptotic properties (75, 76). As shown in the study by Buerke et al. (75) of a murine model of myocardial ischemia/reperfusion, IGF-I administration 1 hour prior to ischemia attenuates myocardial injury, reduces cardiac myeloperoxidase activity (an index of neutrophil accumulation), and reduces the incidence of myocyte apoptosis in histopathological analyses. According to Li et al. (76), transgenic mice overexpressing human IGF-I exhibit reduced apoptosis, ventricular dilatation, and myocardial loading after coronary ligation compared with wild-type littermates. GH and IGF-I also have indirect effects on the cardiovascular system by regulating peripheral resistance (62). In experimental models, IGF-I–induced vascular resistance is reduced through a tyrosine kinase–dependent mechanism mediated by the stimulation of nitric oxide release from the endothelium (77). This finding was observed in cultured vascular smooth muscle cells (78), aortic preparations (79), and endothelial cells (77). Additionally, eicosanoids mediate the IGF-I–induced reduction in vascular resistance (80, 81), as well as changes in potassium channels (82). The vasodilatory effects of IGF-I have also been observed after administration to patients with chronic heart failure, who showed decreased systemic vascular resistance and diminished right atrial pressure (83). In healthy subjects, GH administration is also associated with an acute reduction in peripheral vascular resistance and activation of the nitric oxide pathway, effects that were independent of IGF-I (84). Figure 1 summarizes the main effects of GH and IGF-I on the cardiovascular system. Figure 1.  Effects of GH and IGF-I on the cardiovascular function. Both GH and IGF-I have direct actions on the kidney, whereas IGF-I has direct actions on the myocardium and the vessels. ENaC, epithelial sodium channel.[© 2019 Illustration Presentation ENDOCRINE SOCIETY]. CardiomyopathyCardiac structure—ECHO.One of the first studies to report a high frequency of LVH in patients with acromegaly was the study published by Lie (45), who showed a LVH frequency of 93% in autopsy studies of 27 patients with acromegaly. Moreover, 83% of the patients presented myocardial fibrosis. Many studies using ECHO have subsequently shown an increased frequency of cardiac enlargement, mainly LVH, with a highly variable percentage, depending on the study population (13, 46, 58, 65, 66, 85–91). Since the last Endocrine Reviews update in 2004 on comorbidities in acromegaly by Colao et al. (7), various studies have reported a frequency of LVH ranging from 11% to 78% when analyzed by ECHO (12, 13, 54, 58, 86–89, 91–99) (Table 1). The dissimilarities in LVH frequency may be a consequence of the use of different methodologies to define LVH, different study designs (retrospective, prospective, or cross-sectional), and/or different study populations. Additionally, factors that may be associated with LVH development are variable and include age, disease duration, IGF-I levels, and presence of AH, none of which has been consistently associated with LVH in acromegaly. Table 1. Studies Published After 2004 Evaluating LVH and Diastolic Dysfunction in Acromegaly
Abbreviation: N/A, not available. Table 1. Studies Published After 2004 Evaluating LVH and Diastolic Dysfunction in Acromegaly
Abbreviation: N/A, not available. Cardiac structure—cardiac MRI.More recently, presence of LVH has been analyzed by cardiac MRI (CMRI), which is the gold standard for evaluating LVH and fibrosis (13, 87, 100, 101). Bogazzi et al. (87) performed a transverse analysis of 14 patients with acromegaly and determined that LVH frequency (measured using CMRI) was 72%, which was higher than the one observed in the same sample using ECHO (i.e., 36%). Presence of LVH was not associated with disease duration, AH, or IGF-I levels. In the same study, the authors did not observe cardiac fibrosis, as analyzed by delayed contrast enhancement after gadolinium injection (late gadolinium enhancement) (87). In the largest prospective study using CMRI in patients with acromegaly (published by our group), which included 40 patients with medical treatment-naive active acromegaly, LVH was observed in only two patients (5%) at baseline (13). Myocardial fibrosis was present in 13.5% of patients when analyzed by late gadolinium enhancement and was similar to the prevalence reported in a multiethnic healthy population (9.2%) (102). Using myocardial T1 mapping and extracellular volume quantification, techniques that had not been used previously in patients with acromegaly and allow the acquisition of quantitative measurements of myocardial fibrosis, only 3.5% of patients presented some degree of fibrosis (13). In the same population sample, frequency of LVH was 31% when analyzed by ECHO, indicating that this methodology may overestimate LVH presence in patients with acromegaly (13). No difference in LVH frequency or fibrosis was observed using CMRI 1 year after treatment with SRLs.
The results of our study (13) differed from the findings reported by Bogazzi et al. (87); however, the application of the same cut-off used in our study to define a normal LV mass (LVM) index to the patients examined by Bogazzi et al. results in a LVH frequency measured by CMRI of only 14%. The cut-off of 48 to 78 g/m2 for females and of 57 to 91 g/m2 for males was selected because it was validated in an asymptomatic Brazilian population (103) and was similar to a previous study in an asymptomatic English population (104). Because these studies included a limited number of patients, we were not able to determine whether LVH frequency in contemporary cohorts of patients with acromegaly is indeed lower than the frequency observed in previous studies. However, CMRI is a more precise methodology that enables a geometric assumption-free quantification and a higher accuracy than ECHO, displaying an excellent correlation with LVM quantified by autopsy (105, 106). ECHO has also been shown to overestimate LVH, particularly in patients with AH and cardiomyopathy (107, 108). Therefore, in more recently studied cohorts, the severity of acromegaly-induced cardiomyopathy may have changed as the treatments for acromegaly have evolved, as well as the treatments for comorbidities associated with heart disease, such as AH, DM, and dyslipidemia. LV function.Diastolic dysfunction has been observed in 11% to 58% of patients when analyzed by ECHO (13, 87, 88, 92, 94–98) (Table 1). Diastolic dysfunction is characterized by an inadequate filling capacity (7, 109), is generally mild, and can be reversed by medical treatment and LVM reduction (88, 92). Akdeniz et al. (95) specifically evaluated diastolic dysfunction in patients with acromegaly and found a frequency of 35.7%; however, no difference was observed between patients with active and controlled diseases. Only older age and presence of DM were associated with an increased risk of diastolic dysfunction (95). Although diastolic dysfunction is frequently observed, systolic dysfunction is uncommon (14, 110), not seen or observed in <3% of the patients in most recent studies that used ECHO (Fig. 2). Conversely, in a study by Colao et al. (88), systolic dysfunction was defined as an ejection fraction (EF) of <50% on ECHO and was observed in 26.3% of patients at their baseline evaluation. The authors did not clearly determine whether these patients presented with clinical manifestations of heart failure or whether the systolic dysfunction was only an ECHO finding. In a recent multicenter French study that included 943 patients, heart failure was present in only 1.9% of patients at diagnosis (evaluated by ECHO), and incident heart failure occurred in only two patients (0.2%) (14). Additionally, CMRI studies did not report systolic dysfunction in the patients evaluated (13, 87, 111). In contrast, in a Danish national study, heart failure was increased in acromegaly patients [hazard ratio (HR), 2.5 (1.4 to 4.5)] (4). Figure 2. Frequency of systolic dysfunction (%) in acromegaly patients in different studies published since 2004. [© 2019 Illustration Presentation ENDOCRINE SOCIETY]. As overt systolic dysfunction is not common, some studies sought to evaluate the presence of incipient myocardial damage (56, 112). This evaluation is possible through the analysis of myocardial strain, which evaluates the deformation of the myocardial fibers during systole (calculated as the percentage change in the myocardial fiber length between the end-diastole and the end-systole) (113). The impairment in global longitudinal strain has been used as a marker of subclinical systolic dysfunction in patients with many conditions (114, 115). In a study including 22 patients with active acromegaly, Di Bello et al. (112) evaluated the presence of myocardial strain using color Doppler myocardial imaging. Although patients and controls presented a similar mean LV ejection fraction (LVEF), patients presented lower values for systolic heart deformation, which may indicate subclinical systolic dysfunction. More recently, our group evaluated the presence of myocardial strain in a larger sample of patients with active acromegaly (40 patients) using a speckle tracking ECHO technique that is a more accurate method because it quantifies regional and global strains, regardless of the insonation angle (56, 116). No difference in global longitudinal strain was observed between patients and controls (matched for sex, age, AH, and DM), indicating that patients with acromegaly lack subclinical and overt systolic dysfunction (56). Therefore, although diastolic dysfunction is frequently observed in ECHO studies, it is usually mild and with no clinical consequence, and the progression to systolic dysfunction has generally not been described in more recent studies, although it has been previously described in the literature (59, 117). This finding is consistent with cell culture and animal studies showing that although GH and IGF-I induce the hypertrophy of myocardial cells, they exert a positive inotropic effect and do not change myocardial energetics or mechanics and are not associated with gene reprograming (a characteristic of pathological cardiac hypertrophy) (65, 67, 70, 72, 77). Ischemic cardiac diseaseAcromegaly is associated with many known risk factors for coronary heart disease (CHD), such as AH, DM, and dyslipidemia (88, 99, 118, 119). Some studies have evaluated the presence of coronary calcification or obstruction, markers of early atherosclerosis and inflammation in patients with acromegaly (119–125). Bogazzi et al. (121) evaluated the coronary artery calcium content (CAC) using the Agatston score in 52 consecutively enrolled patients and stratified them according to the Framingham scoring system. The CHD risk was considered low in 71% of patients, intermediate in 27%, and high in 2% and was unrelated to disease activity or duration. In all patients with a positive Agatston score, a myocardial exercise stress single photon emission CT scan was performed to evaluate ischemia, which was negative in all patients. No major cardiovascular events occurred in patients in the 5-year follow-up period (121). In another study by Akutsu et al. (120), a lower CAC was observed in patients with acromegaly compared with a control group, and no cardiovascular events were recorded in their series after a mean follow-up of 4.6 years. Our group has also evaluated Framingham scores and CAC in the largest series published in the literature (122), which included 56 patients with acromegaly and 56 control patients matched for age, sex, smoking habit, and presence of AH, DM, and hypercholesterolemia. Interestingly, a similar Framingham score and median risk of cardiovascular events was observed during 10 years in the acromegaly and control groups. Additionally, the CAC did not differ between patients and controls or between patients with active acromegaly or controlled disease (122). A recent multicenter German study that included 479 patients reported a standardized incidence ratio (SIR) of MI in patients with acromegaly that was similar to the normal population [0.89 (0.47 to 1.52), P = 0.80] (48). Interestingly, prevalence of AH was higher in patients who suffered an MI or stroke than in patients who did not (94% vs 43%, respectively; P < 0.001), indicating that AH was probably the main contributor to vascular complications. Corroborating these data, MI was not increased in patients with acromegaly in comparison with a normal population in a national Danish study [HR, 1.0 (0.5 to 1.9)] (4). Intriguingly, although patients with acromegaly display decreased flow-mediated dilatation and increased carotid intima thickness, they present lower levels of highly sensitive C-reactive protein (hsCRP) and oxidative stress parameters, indicating that inflammation and oxidative stress are not increased in these patients (124). Also, hsCRPs were higher in controlled acromegaly patients than in those with active disease (124). Therefore, in summary, current knowledge indicates that CHD does not seem to be increased in patients with acromegaly. ArrhythmiaA previous autopsy study reported a high frequency of fibrosis in patients with acromegaly (45); additionally, IGF-I alters myocardial calcium channels. Therefore, a proarrhythmogenic scenario is possible, although recent studies with CMRI have not observed the presence of myocardial fibrosis (45, 72). The occurrence of complex ventricular arrhythmias was reported in a series of 32 patients with a high frequency of structural disease (65% of the patients presented LVH) (126). In more recent cohort studies, some possible markers of increased arrhythmia risk have been described, including a longer QT duration or dispersion (127–129), higher frequency of late potentials (130), and reduced normal-to-normal heart period (53), whereas another study did not observe alterations in the atrial electromechanical intervals or in P wave dispersion (131). However, in some studies, the final end point of arrhythmia was not examined (127–129, 131), and in studies that evaluated the presence of arrhythmia (evaluated through 12- or 24-hour Holter monitoring), clinically significant arrhythmias were not observed (53, 130). Likewise, Comunello et al. (132), evaluated 47 patients with acromegaly and found an increased mean heart rate (HeR) and increased HeR variability, but did not observe clinically significant arrhythmias in 24-hour Holter monitoring. Consistent with these findings, our group studied 36 patients with active acromegaly using 24-hour Holter monitoring and correlated the findings with the presence of structural disease as analyzed by CMRI (55). No sustained or clinically significant arrhythmias were detected in our contemporary sample, consistent with a low frequency of LVH and fibrosis (55). Valvular cardiac diseaseActive acromegaly has been associated with cardiac valvular abnormalities. Colao et al. (133) described a frequency of mild to moderate aortic regurgitation of 31% in patients with active acromegaly, 18% in patients with controlled acromegaly, and 7% in a matched control cohort. Furthermore, mild mitral regurgitation was observed in 26% of patients with active acromegaly and in 7% of controls. Notably, this series exhibited a high frequency of LVH: 81% in patients with active acromegaly and 41% in patients with cured acromegaly (133). In another study, Pereira et al. (134) observed an increased frequency of significant regurgitation (mild or greater aortic regurgitation or mitral regurgitation equal to or greater than moderate severity) in patients with acromegaly compared with controls (20% vs 4%, P = 0.002 and 5% vs 0%, P = 0.014, respectively). LV systolic function and mean LVM were within the normal ranges in patients with acromegaly in this study, although 25% of the patients presented with LVH. The only risk factor for valvular disease was acromegaly duration, with no effect of either GH or IGF-I levels, presence of AH, or disease activity. The authors observed a 19% annual increase in the risk of valvular disease (134). Although GH and IGF-I levels were not risk factors for valvular disease in a previously cited study, progression of valvular disease was associated with excess GH and IGF-I levels in a prospective study (135). The authors observed an increase in the degree of valvular regurgitation from 46% at baseline to 67% after 24 months of follow-up. This increase was due to an increase in mitral regurgitation (32% to 60%), which was only observed in patients with active disease; notably, frequency of aortic regurgitation was not altered (136). Another factor that may contribute to the increased frequency of aortic regurgitation is the occurrence of aortic root ectasia, which has been reported in up to 26% of patients (136, 137). As there are only a few small studies evaluating risk factors for valvular disease, more studies are needed to better understand valvular disease in acromegaly. Arterial hypertensionThe increased prevalence of AH observed in patients with acromegaly probably has a multifactorial etiology. One of the most accepted mechanisms is the increase in plasma volume, secondary to sodium and water retention in the kidney (138, 139). This mechanism was observed in animal models, as well as in normal subjects who used GH recreationally (amateur athletes) (140, 141). The antinatriuretic effect of GH may be mediated by the activation of the renin–angiotensin–aldosterone system, as suggested by some studies showing an increase in the levels of renin and aldosterone after a GH infusion (142–144). Elevated aldosterone levels may be observed in the absence of elevated renin levels and is an IGF-I–independent effect of GH (145). However, the antinatriuretic effects of GH have also been shown to be more likely mediated by a direct effect of GH on the kidney (139). Data supporting this hypothesis are found in studies showing that GH-induced sodium retention is observed even in the absence of the adrenal glands (146, 147) and in studies that show a renin–angiotensin–aldosterone system -independent antinatriuretic effect (148–150). GH directly stimulates the epithelial sodium channel subunit in the cortical collecting ducts (151, 152). Additionally, IGF-I also exerts a direct effect on stimulating transcellular sodium transport through IGF-I receptor (IGF-IR), which is blocked by amiloride, suggesting involvement of the epithelial sodium channel (139). In contrast, the role of the activation of the adrenergic system and the reduction in atrial natriuretic peptide production in patients with acromegaly is more controversial (153–156). Contrary to the deleterious effects of sodium and water retention, IGF-I can promote reduction of vascular resistance, as previously mentioned in “GH/IGF-I and the cardiovascular system” above. Therefore, determination of which patient will have AH or not depends probably on the balance between these two opposite effects, but also on the individual predisposition to develop this complication. Prevalence of AH in patients with acromegaly has been observed in 29.4% of 6531 patients included in four recent multicenter national/international databank studies (14, 99, 157, 158). Most data are derived from retrospective studies with only an ambulatory evaluation of blood pressure (BP), but in some studies, 24-hour ambulatory BP monitoring (ABPM) has been performed (159–162). Minniti et al. (160) observed a AH frequency of 42.5% in 40 patients with acromegaly who were assessed using clinical measurements, and was reduced to 17.5% when measured using ABPM. Thus, the authors concluded that prevalence is probably overestimated by clinical measurements. Likewise, Costenaro et al. (159) observed an AH rate of 32.4% evaluated using clinical measurement, but the rate was reduced to 22.9% when ABPM was used. Therefore, the true prevalence of AH in patients with acromegaly may have been overestimated in studies that used only a clinical outpatient BP evaluation. Factors associated with an elevated risk of AH are controversial, with IGF-I levels showing a positive correlation with prevalence in some studies, but not in others (163, 164). In a study by Vitale et al. (163) including 200 patients with acromegaly and 200 controls, the AH prevalence was higher in patients with acromegaly and only positively correlated with age. Another study (165) observed positive correlations between body mass index (BMI), AH, and age. A family history of AH and IGF-I levels was not associated with a higher frequency of AH (163). Moreover, patients with acromegaly have a higher diastolic BP and lower systolic BP than do nonacromegaly hypertensive controls (163), consistent with the results from a previous study (161). Cerebrovascular disease and strokeAcromegaly is associated with an increased frequency of AH, DM, and IR, all of which are risk factors for cerebrovascular disease. Thus, stroke prevalence is expected to be elevated in patients with acromegaly. However, in a multicenter German study that included 479 patients, the SIR of stroke in patients with acromegaly was similar to the normal population [1.17 (0.66 to 1.93), P = 0.61] (48). A higher prevalence of AH was observed in patients who suffered a stroke than in patients who did not (94% vs 43%, respectively, P < 0.001), indicating a greater contribution of this comorbidity to the cerebrovascular complications than acromegaly per se. Also, stroke was not increased in acromegaly patients in a Danish national study [HR, 1.1 (0.6 to 2.0)] (4). However, in patients with acromegaly who have undergone radiotherapy, stroke incidence seems to be clearly elevated, as well as mortality from stroke, with a standardized mortality ratio (SMR) of 4.42 (range, 2.71 to 7.22) for cerebrovascular disease (39). Nevertheless, this increased incidence seems to be an effect of radiotherapy, rather than a consequence of acromegaly, as an increased incidence of cerebrovascular disease has been described in patients with all types of pituitary adenomas who are undergoing radiotherapy (37). Effect of treatments for acromegaly on cardiovascular and cerebrovascular diseaseGH and IGF-I normalization achieved by different treatment modalities can impact the cardiovascular abnormalities in patients with acromegaly. Surgery enables rapid normalization of GH and IGF-I levels and has been previously shown to reduce LVM and improve diastolic function (166–168). Jaffrain-Rea et al. (168) evaluated 31 patients before and after surgical treatment and observed a reversion of LVH in 12 of the 14 patients who presented this abnormality on ECHO. Additionally, BP normalized, with decreases in both systolic and diastolic BP, as evaluated by 24-hour monitoring. Colao et al. (166) studied 18 patients followed for 5 years after surgery and observed a reduction in HeR and an increase in LVEF at peak exercise. Most studied impacts of medical treatment on the cardiovascular system are derived from studies with SRLs. Both lanreotide and octreotide have been shown to reduce LVM and improve diastolic function when disease control is achieved. Maison et al. (169) performed a meta-analysis of published studies through 2007, including a total of 11 studies encompassing 290 patients. The authors concluded that SRL treatment significantly reduced the HeR and LVM and improved the ratio of E-wave and A-wave peak velocities of the mitral flow profile (with the latter indicating an improvement in diastolic function). An increase in exercise tolerance was also observed. The median LVEF improved by 3.3%, without reaching statistical significance. Improvements in BP were not observed. Subsequent studies performed after this meta-analysis analyzed the long-term effects of SRLs on cardiovascular changes. Colao et al. (170) evaluated 45 patients with treatment-naive acromegaly who were treated with octreotide LAR (n = 28), lanreotide SR (slow release), or Autogel (n = 17) and observed a high frequency of disease control (IGF-I normalization in 98% and GH levels <2.5 μg/L in 100%). These patients were followed for 5 years and exhibited improvements in the frequency of AH, LVH, and diastolic and systolic dysfunction. A comparison of surgical remission and disease control with SRLs by the same group showed that both treatments decreased LVM, diastolic BP, and HeR, whereas only the SRL treatment was associated with an increase in LVEF, although this value was normal at baseline (baseline 55.3% and after treatment 58.0%) (171). In contrast, Annamalai et al. (89), in a prospective study of 30 patients treated with lanreotide Autogel therapy for 24 weeks, did not observe a reduction in either systolic or diastolic BP, and a reduction in LVM was only observed in men. However, improvements in arterial stiffness and endothelial function (aortic flow–mediated dilatation) were noted (89). In addition to the known effect on reduction of HeR, SRLs can have an effect on corrected QT (QTc) interval. In a study by Fatti et al. (129), acromegaly patients were shown to have longer QTc intervals than did matched controls (which may predispose to arrhythmias). After treatment with SRLs for a median of 18 months, there was a reduction of the QTc interval that became similar to that of the control group. Studies that analyzed cardiac parameters by CMRI have reported conflicting results (13, 100, 101). Bogazzi et al. (100) showed a reversion of LVH in 6 of 10 patients after a 6-month treatment with lanreotide Autogel. Our group evaluated 30 patients at baseline and after 1 year of octreotide LAR treatment and did not observe any differences in the LVM or the LVEF (13). Andreassen et al. (101) did not observe a difference in LVM in eight patients after 3 months of treatment (four receiving SRL monotherapy, two receiving PEG therapy, and two receiving combination therapy with SRLs and PEG), although the authors observed an increase in the end-diastolic volume index. One of the probable reasons for discordance between studies is the different frequency of LVH at baseline between studies. PEG treatment has also been shown to exert cardiovascular effects. Pivonello et al. (92) examined 12 patients after 18 months of PEG treatment and identified a reduction in LVM and improvements in both diastolic and systolic function. Conversely, Kuhn et al. (54) did not observe a change in the LVEF or the LVM in 42 patients treated with PEG alone (45%) or in combination with SRLs or cabergoline (55%). However, when the authors only analyzed the patients with an EF ≤60%, a significant increase of the EF from 56% ± 4% to 61% ± 8% was observed (although it was normal in the baseline evaluation). Furthermore, by analyzing only patients with LVH, a significant reduction in LVM from 123 ± 25 to 101 ± 21 g/m2 was detected. In another study evaluating 36 patients treated with a combination of PEG and SRLs, a reduction in LVM and an improvement of diastolic function (early to late ventricular filling velocity) were observed after 60 months of treatment (57). In conclusion, studies analyzing the impact of different treatment modalities have shown reductions in LVM and improvements in diastolic function that constitute the main cardiac abnormalities described in patients with acromegaly. Although slight EF improvements were observed in some studies, EF was normal at baseline and, furthermore, systolic dysfunction does not appear to be a common condition in patients with acromegaly. There are no studies describing the effects of cabergoline on cardiovascular end points in acromegaly. In 2007, it was described that cabergoline in high doses (>3 mg/d) was associated with valvular lesion in Parkinson disease patients (172). However, after that, many studies with doses used to treat pituitary adenomas were undertaken without clear evidence of valvular lesion in these patients (173). To date, no study has reported an effect of medical treatment on other cardiovascular and cerebrovascular end points, such as cardiac failure, MI, stroke, or cardiovascular mortality. RecommendationsBP measurements are recommended for all patients with acromegaly at diagnosis in the outpatient clinic. In patients with AH, a 24-hour ABPM might be advisable, as some patients who are identified based solely on the ambulatory measurement will not display AH on ABPM (160). If BP is normal at the first consultation, subsequent ambulatory measurements should be performed, particularly in patients with active acromegaly. Treatment and follow-up of patients diagnosed with AH should follow current guidelines (174). An ECHO is also recommended at diagnosis for all patients with acromegaly to evaluate valvular disease, diastolic and systolic function, and the presence of LVH. If the ECHO is normal at diagnosis, no additional screening evaluation is needed in patients whose disease is controlled with treatment. The examination may be repeated after 1 year in patients with a normal ECHO at diagnosis who continue to have active disease. Similarly, a repeat ECHO after 1 year is recommended for patients with ECHO abnormalities at the acromegaly diagnosis. Evaluation of arrhythmias is more complex and should include a search for suggestive symptoms and a careful physical examination. If cardiac rhythm abnormalities are detected at clinical examination, an ECG should be considered, as well as 24-hour Holter monitoring, depending on clinical circumstances. Referral to a cardiologist is needed in most cases. Although CHD prevalence per se does not seem to be increased in patients with acromegaly based on recent data, patients have many CHD risk factors. Therefore, an evaluation of risk factors (AH, glucose abnormalities, and hyperlipidemia) and aggressive treatment to achieve clinical goals are required. Evaluations and treatments should be performed according to the recommended guidelines for the normal population (175). Respiratory diseaseRespiratory complications in acromegaly arise from both structural and functional changes in the entire respiratory system, resulting in sleep apnea syndrome (SAS) and/or respiratory insufficiency (7, 10). Anatomical changes include bone and soft tissues of the craniofacial region, respiratory mucosa/cartilages, lung volumes, and rib cage geometry, all detailed in Table 2. Table 2. Anatomical Changes Detailed by Site, Pathological Findings, and Clinical Disorder
[Adapted with permission from Colao A, Ferone D Marzullo P, Lombardi G. Systemic complications of acromegaly: epidemiology, pathogenesis, and management. Endocrine Rev 2004;25(1):102–152.] Table 2. Anatomical Changes Detailed by Site, Pathological Findings, and Clinical Disorder
[Adapted with permission from Colao A, Ferone D Marzullo P, Lombardi G. Systemic complications of acromegaly: epidemiology, pathogenesis, and management. Endocrine Rev 2004;25(1):102–152.] Studies published up to the 1990s, all extensively reviewed in Colao et al. (7), suggested that respiratory mortality accounted for 12% to 25% of mortality cases in acromegaly (7, 176–178). Surprisingly, recently published national registry data showed respiratory complications remaining prevalent, accounting for 10% to 20% of mortality in acromegaly (14, 179, 180). SASSAS is defined as recurrent episodes of apnea (cessation of airflow for >10 s) or hypopnea (a reduction in airflow to <50% of normal) and is caused by total or partial pharyngeal collapse and temporary upper airway obstruction [obstructive sleep apnea (OSA)] and/or central depression of respiratory drive (central sleep apnea), resulting in repeated hypoxic and hypercapnic episodes (181, 182). Anatomical changes in the craniofacial region and upper respiratory tract resulting from GH/IGF-I excess (including macroglossia, soft palate, pharyngeal and laryngeal swelling, vocal cord thickening, and mandible and maxilla overgrowth) account for the obstructive component (OSA), a key feature in SAS associated with acromegaly (7, 181). The key event that initiates apnea seems to be a reduction in upper airway muscle activity at sleep onset. The structural changes detailed above (Table 2) result in an altered intrapharyngeal balance during inspiration, increasing pharynx collapsibility during sleep (7, 183). Up to a third of patients have an additional central component of SAS, characterized by repeated apneic episodes without any associated ventilatory efforts. It has been postulated that this may be directly related to high GH or IGF-I levels resulting in modulation of central respiratory center function and an increased ventilatory threshold for carbon dioxide (184, 185).
SAS is a common cause of nocturnal snoring, fragmenting sleep and resulting in poor sleep quality and daytime sleepiness. The latter is commonly evaluated with the Epworth sleepiness scale, which, although not specifically validated in an acromegaly population, when combined with other clinical parameters such as snoring, BMI, and neck circumference may be useful in predicting presence or absence of sleep hypoxemia (186). The severity of SAS, graded by the apnea–hypopnea index (AHI) that is the mean episodes of apnea and hypopnea per hour of sleep on polysomnography, is defined as mild (5 to15 per hour), moderate (>15 to 30 per hour), or severe (>30 per hour) (187). There is strong evidence that undiagnosed SAS, with or without clinical symptoms, is independently associated with AH, cardiovascular disease, stroke, daytime sleepiness, motor vehicle accidents, and diminished QoL (188–190). Likewise, it has also been linked in some studies to the development of IR, DM, and dyslipidemia (191, 192). Recent population-based studies in acromegaly suggest SAS prevalence of 14% to 26% (14, 158, 180), but this is likely an underestimate and dependent on the frequency of screening polysomnography. Documented SAS in cross-sectional studies is more prevalent, but also variable, ranging from 27% to 88% of patients with acromegaly (7, 185, 190–201). Approximately 70% of patients with active acromegaly (181) have SAS, representing a significantly higher prevalence than the estimated one in the general population at 5% to 10% (182, 188, 189, 202). A new Danish national registry found an HR of 11.7 (95% CI, 7.0 to 19.4) in acromegaly compared with the general population (4). The correlation between acromegaly activity and SAS severity is complex. Initial case series suggested a positive correlation (193, 198), but this was not confirmed in subsequent and larger studies and remains debatable (185, 190, 192, 196). A reduction in tongue volume with acromegaly treatment is described in almost all patients (194, 203, 204); it is generally accepted that SAS improvement with disease control is mediated through a decrease in upper airway obstruction via reduction in soft tissue bulk or collapsibility and improvement in upper airway muscle function. Effect of treatments for acromegaly on SASTreatment of acromegaly improves SAS in a substantial number of patients (54, 196, 197, 199, 205–207), but biochemical control does not reliably predict SAS complete reversal (53, 89, 192, 205, 208, 209). Furthermore, no correlation between an absolute GH/IGF-I decrease and AHI changes has been documented (89, 194, 203). Although many patients will demonstrate improved respiratory symptoms, prospective studies suggest that 40% of those with controlled acromegaly continue to have persistent SAS (Table 3) (181, 192, 197, 199, 205). Table 3. Prevalence of Sleep Apnea in Patients with Acromegaly and Effects of Treatment
[Adapted with permission from Attal P, Chanson P. Endocrine aspects of obstructive sleep apnea. J Clin Endocrinol Metab 2010;95(2):483–495.] Abbreviations: GHRA, GHR antagonist; N/A, not available; RT, radiotherapy; S, surgery. a In the study by Pekkarinen et al. (197), only apneas were considered for the evaluation of OSA and calculation of index (apnea index). Table 3. Prevalence of Sleep Apnea in Patients with Acromegaly and Effects of Treatment
[Adapted with permission from Attal P, Chanson P. Endocrine aspects of obstructive sleep apnea. J Clin Endocrinol Metab 2010;95(2):483–495.] Abbreviations: GHRA, GHR antagonist; N/A, not available; RT, radiotherapy; S, surgery. a In the study by Pekkarinen et al. (197), only apneas were considered for the evaluation of OSA and calculation of index (apnea index). In a study of newly diagnosed acromegaly (16 patients) who achieved biochemical control after surgery, with or without adjuvant SRLs (2 patients), PEG (9 patients), or cabergoline (2 patients), 7 of 16 (44%) had SAS at baseline. No significant improvement in mean AHI was observed after IGF-I normalization (mean treatment duration, 10 ± 6 months). However, polysomnographic indices normalized in four of seven (57%) patients with OSA at baseline, and there was clear reduction of soft tissue in individual patients (Fig. 3); small sample size may account for the lack of a statistically significant improvement in mean AHI. Of note, there was also a relatively short interval between IGF-I normalization and repeat sleep studies (2 to 8 months); longer follow-up may be needed to detect subsequent OSA improvements after normalization. Interestingly, de novo OSA occurred in 22% of patients (53), confirming the multifaceted OSA in acromegaly (181). Figure 3. (a and b) Sagittal T1-weighted MRI sequences of the neck before (a) and after treatment (b) of acromegaly in a male patient with OSA. Treatment of acromegaly resulted in a decrease in tongue (black star), soft palate (white star), and pharyngeal wall thickness, and widening of both the oropharynx space (solid arrow) between the tongue and soft palate and of the posterior nasopharynx (dashed arrow). Resolution of OSA was seen in this patient after treatment of GH excess. [Reproduced with permission from Attal P, Chanson P. Endocrine aspects of obstructive sleep apnea. J Clin Endocrinol Metab 2010;95(2):483–495. © 2019 Illustration Presentation ENDOCRINE SOCIETY.] Another prospective study in patients with newly diagnosed acromegaly (48 patients) showed SAS (a majority with OSA) present in 87.5% at baseline. Biochemical remission within 1 month after surgery was achieved in 70% of patients (204); at 6 months 55% showed OSA improvement, and the proportion of severe OSA decreased from 45.8% to 28%. Mean AHI also dropped dramatically at 1 month and further declined at 3 months with stabilization thereafter. However, no patients had complete OSA resolution. Several studies have demonstrated OSA improvements with SRLs (192–194, 196, 205–207). In a more recent prospective study (within-subject comparison) of 30 newly diagnosed acromegaly patients undergoing primary treatment with lanreotide Autogel, the authors showed variable AHI responses after 24 weeks. At baseline, OSA was documented in 79% of patients. Despite reductions in GH and IGF-I levels in 93% of patients, 14 of 29 (61%) had AHI improvements, 8.7% remained stable, but OSA deterioration was observed in almost one-third (30.4%) (89). Interestingly, AHI change was independent of the change in GH/IGF-I levels with treatment. Of note, however, is that in this primary medical treatment study, only 60% of patients achieved GH mean <2.5 μg/L and just 40% achieved normal IGF-I levels. With the introduction of the GHR antagonist PEG into the medical treatment armamentarium, its impact on SAS has been of interest. Twelve acromegaly patients (failed surgery and SRLs) were studied prospectively; 10 of 12 (83%) had OSA at baseline, 8 with moderate-severe apnea (203). After 6 months of PEG, a significant AHI reduction (24% ± 28%) was observed (23.4 vs 17.5, P = 0.007), but no correlation was seen between the drop in IGF-I levels and AHI changes. Additionally, although overall tongue volume reduced significantly (105 vs 83 mL, P = 0.007), no correlation was seen between AHI and BMI-adjusted tongue volume. Although AHI decreased in 9 of 12 (75%) patients, complete resolution was not observed in any of the patients. More recently, Kuhn et al. (54) also examined, in a retrospective study, a subgroup of 12 patients who underwent polysomnography before and while on PEG alone or in combination; most patients had undergone prior pituitary surgery and had failure or intolerance to SRLs or DAs. IGF-I normalized in 10 of 12 (83%) of patients. At baseline, OSA was present in 9 of 12 (75%) patients and was severe, moderate, and mild in 3, 2, and 4 patients, respectively. After treatment duration of 16 ± 17 months, overall AHI showed significant improvement (P < 0.05). OSA improved in six of eight patients, of whom resolution occurred in four patients (54). Although these studies do not allow any definite conclusions to be drawn regarding the impact of specific treatments on sleep apnea, it is clear that disease activity, although an important determinant, is not the only factor impacting SAS in acromegaly. Other risk factors for OSA in the general population include increasing age, obesity, sex, and smoking (188, 189). Although several studies (albeit several with conflicting results) have suggested a relationship between age, male sex, obesity, and smoking and OSA severity (190, 191, 194, 200), their relative contribution in the acromegaly population needs further study. With regard to obesity, some, but not all, studies demonstrate a correlation between BMI and SAS (89, 190, 191, 194). Hermann et al. (194) demonstrated a positive correlation between BMI and AHI (r = 0.58, P = 0.001). A trend toward higher BMI values was also observed in patients with SAS in an Italian cross-sectional study (190). Interestingly, AHI responses seems to be independent of the GH and IGF-I decreases with treatment, but are instead moderately and positively correlated with changes in weight (r2 = 0.43, P = 0.0001), with most patients whose OSA deteriorated having gained weight (≥4.5 kg in five of seven patients) (89). As the only OSA intervention strategy (supported with adequate evidence) so far in the general population is weight loss (188), it would therefore be reasonable to also address weight in the overall management of acromegaly patients. Hypopituitarism impact on OSA in patients with acromegaly is also notable. Hypothyroidism increases OSA prevalence, albeit replacement therapy improves OSA, at least in nonobese patients (210–213). Conversely, several, but not all, studies demonstrated OSA exacerbation of sleep apnea in eugonadal or hypogonadal men treated with androgens (214–220). Therefore, caution is needed when commencing androgen replacement in patients with acromegaly with severe untreated OSA (214, 221). Respiratory insufficiency and lung involvementRespiratory insufficiency in acromegaly is less well studied compared with SAS, but it has been reported in 30% to 80% of patients (10), with the wide range reflecting differing criteria in definition of respiratory insufficiency. In animal models and humans, GH and IGF-I, via interaction with their cognate receptors on lung epithelium, smooth muscle cells, pneumocytes, and activated alveolar macrophages in the airway, exert proliferative effects on lung parenchyma, respiratory airways, and muscles (222–227). Interstitial tissue hypertrophy, increase in alveolar size, and possibly number, and air trapping ensue, and lung volumes and distensibility are increased, but lung elasticity is reduced (228–230). Furthermore, patients with acromegaly have reduced inspiratory and expiratory muscle force (204, 231, 232). Increased lung volumes were first observed on chest radiographs of acromegaly patients and subsequently confirmed by several spirometry and body pletismography studies (228, 233–235). The reproducibility of these results is, however, limited by the small study sample size. Several recent studies confirm both increased lung volumes and air trapping, as well as small airway resistance and obstruction (236, 237). Furthermore, there is increasing evidence for a loss of homogeneity of the respiratory system, with increase of both nonaerated or poorly aerated areas, despite the increase in lung volume (236–238). Forced vital capacity (FVC), total lung capacity (TLC), and residual volume (RV) have been shown to be greater in acromegaly patients (n = 20) vs age-and height-matched controls (236). Airway resistance was also increased, reflecting small airway involvement that may be explained by a loss of elastic tissue. Interestingly, the TLC–alveolar volume was higher in acromegaly patients vs controls, likely reflecting nonuniform gas distribution in a poorly ventilated lung, a result of large areas of gas trapping. Furthermore, corroborative findings were seen on high-resolution CT in these patients; air trapping, airway calcification, and bronchiectasis were observed in 60%, 40%, and 35%, respectively, although no control group was available (236). In the largest cohort to date, 109 acromegaly patients in a German single-center, cross-sectional study underwent prospectively pulmonary function tests (including spirometry, body plethysmography, and blood gas analysis). FVC, TLC, and RV were increased compared with age-, sex-, weight-, and height-matched normative data, confirming greater lung volumes (237). The RV increase was clinically relevant (>120% predicted value) in 40% of patients. Small airway obstruction was also evident, based on a reduced maximum expiratory flow after 75% of FVC had been exhaled. Moreover, a significant proportion of patients (56.5%) had clinically important reductions (<80% predicted value) in maximum expiratory flow after 75% of FVC had been exhaled. Interestingly, this study revealed sex differences, with females having significantly more subclinical airway obstruction. Although blood gas analysis showed significant hypoxemia (mean partial pressure of oxygen, 93% of predicted value; mean partial pressure of carbon dioxide, 102% of predicted value), this was only clinically relevant in a minority (5%) of patients, most notably in the obese patients. This confirms other studies where hypoxemia caused by ventilation–perfusion mismatch was seen in 80% of patients, but remained subclinical (234). In a large German population-based study (>1300 subjects), IGF-I and IGF-I/IGF–binding protein ratios were positively associated with lung volumes in healthy men across all ages, and in women >50 years of age (possibly indicating the influence of estrogen in modulating the effects of GH), even after adjustment for major confounders such as age, BMI, physical activity, smoking, and respiratory conditions (239). These changes were not associated with increased respiratory muscle strength measured as maximal respiratory pressures, suggesting that the increase in forced lung volumes is not explained by IGF-I anabolic effects on respiratory muscle. However, no significant difference in lung volumes or airway obstruction has been observed in studies comparing patients with active disease and those with controlled disease, or when patients were classified based on disease severity using IGF-I tertiles (237). In conclusion, no significant correlation between GH/IGF-I levels and lung volume/lung function, respiratory dysfunction, or air trapping in patients with acromegaly has been consistently proven (230, 233, 236, 240, 241). Meanwhile, the impact of GH/IGF-I excess on alveolar function remains controversial. Diffusing capacity for carbon monoxide (TLCO) was significantly lower in acromegaly patients compared with controls (TLCO percentage predicted, 78.1% vs 90%, P = 0.04; carbon monoxide transfer coefficient percentage predicted, 77% vs 93% P = 0.02), despite similar pulmonary function [forced expiratory volume in 1 second (FEV1), FVC, FEV1/FVC, TLC] (240). Of note, in this study of 10 patients, with a relatively short disease duration (estimated mean, 5.5 years), high-resolution CT did not reveal structural abnormalities. Although this may indicate early involvement of lung parenchyma, including alveolar membrane or microvascular damage, these findings are in contrast to two other studies in which TLCO was similar in acromegaly and healthy subjects (235, 236). Newer assessment techniques.Recently, the use of newer techniques in the assessment of lung function and quantification of lung volume in acromegaly has been of interest. The forced oscillation technique (FOT) characterizes respiratory impedance and its two components, respiratory system resistance and reactance (compliance). The FOT technique has several advantages over spirometry: it is effort-independent, requiring less patient cooperation (performed during spontaneous breathing), and it is time saving (242). This technique allows early detection of pulmonary function abnormalities (243, 244). Imaging processing for quantification of lung volume using multidetector CT has been found to be accurate in assessing lung (including regional) volumes, predicting lung function, assessing the distribution of pulmonary aeration, and correlating with other classical methods of volumetric analysis (245–247). Camilo et al. (238) compared the inspiratory and expiratory multidetector CT findings between acromegaly patients and control subjects. Acromegaly patients had a greater volume of poor aerated areas (135 vs 83 mL, P = 0.0001) in the inspiratory phase, as well as higher percentages of total lung volume of nonaerated or poorly aerated areas (0.42% vs 0.25%, P = 0.039 and 3.25% vs 1.70%, P = 0.001, respectively). Similarly in the expiratory phase, patients had a greater volume of nonaerated areas (47.3 vs 10.2 mL, P = 0.0006) and a higher percentage of total lung volume of nonaerated areas (2.15% vs 0.52%, P = 0.007). These findings reflect an overall increased amount of nonaerated areas in the lung parenchyma in acromegaly. The FOT, reflecting lung elastic and inertial properties of the respiratory system, shows heterogeneity of the respiratory system in acromegaly patients. This may be a result of increased pulmonary distensibility and transpulmonary pressure. Importantly, significant correlations were found between FOT parameters and densitovolumetric values, suggesting an important correlation between the functional and structural components of the respiratory dysfunction seen in patients with acromegaly (238). These techniques and findings warrant further investigation. Less is known about tracheal and large airway changes in acromegaly. Preliminary cross-sectional studies comparing acromegaly patients with matched controls suggest that structural abnormalities in these airways, detected using CT airway lumen volumetry analysis, are associated with functional indicators of large airway obstruction (241, 248). Compared with controls, acromegaly patients had higher tracheal diameters, as well as right and left main bronchus diameters, indicating tracheobronchomegaly (241). Higher tracheal sinuosity indices (an indication of tracheal tortuosity) were also observed, and tracheal stenosis was present in 25%. A positive, albeit moderate, correlation was observed between tracheal area and GH and IGF-I levels (r = 0.45, P = 0.02 and r = 0.38, P = 0.04, respectively) (241), which may reflect the increase in pulmonary compliance seen in active acromegaly previously documented (230). Spirometry revealed that the ratio between the forced expiratory flow and forced inspiratory flow at 50% of the FVC was increased in acromegaly patients vs controls (2.05 vs 1.06, P = 0.0001), correlating positively with mean airway resistance (r = 0.95, P = 0.0001), and therefore reflecting large airway obstruction in these patients (248). Furthermore, the forced expiratory flow and forced inspiratory flow at 50% of the FVC correlated with tracheal area (241); with tracheal dilatation, airflow changes from laminar to turbulent in the airways, increasing airway resistance thereby reducing airflow (249). The associations observed between tracheobronchomegaly noted on CT airway lumen volumetry, serum GH/IGF-I levels, and functional parameters of large airway obstruction need to be further investigated in larger studies. Bronchoscopy studies may also be needed to confirm findings detected on CT imaging. Effect of treatments for acromegaly on respiratory functionFew studies have examined this impact. In a recent prospective study (204), respiratory function did not appear to improve in the first year after pituitary surgery despite biochemical remission in most patients. Although the TLC percentage predicted was elevated (116% ± 28%) at baseline, alterations in lung volumes and ventilation function did not change at 6 months. Similarly, respiratory muscle hypofunction, as reflected by decreased maximum inspiratory pressure (percentage) predicted and maximum expiratory pressure (percentage) predicted, did not improve after treatment (204). Alternatively, although no significant difference in lung volumes or airway obstruction has been observed when comparing patients with active disease and those with disease control, or when classified based on disease severity using IGF-I tertiles, Störmann et al. (237) demonstrated that VC and forced expiratory flow at 25% were increased in patients with longer duration of disease control compared with those with <4 years of disease control. The potential benefit of long-term disease control on improvement in respiratory function needs further evaluation in larger studies. In this particular cohort, 42% of patients were on medical treatment. Interestingly, although no direct correlation was demonstrated, airflow obstruction parameters (FEV1, PEF, and forced expiratory flow at 25%) normalized in patients treated with SRLs for >4 years (range, 4 to 26 years). SSTR subtypes 1 to 5 are expressed in bronchial glands and interstitial lung tissue (250). In fact, SRLs are currently being investigated for their potential utility in the treatment of pulmonary fibrosis (251). In a proof-of-concept study, bleomycin-induced lung fibrosis in a rat model (resulting in increased lung volumes and reduced compliance) improved with administration of an SRL. Reduction in lung volumes following SRLs resulted from a decrease in extracellular matrix deposition (251). Whether these findings are GH or IGF-I related or to a specific SRL effect also warrants further investigation.
The clinical impact of respiratory dysfunction is significant, decreasing overall physical performance and exercise capacity. In particular, patients with acromegaly have inadequate responses to exercised-induced ventilatory demand. Maximum oxygen uptake and ventilation threshold at maximal exercise are reduced compared with predicted values in acromegaly, contributing to significant fatigue and inability to sustain similar workloads compared with controls (252, 253). Furthermore, expiratory muscle strength (based on maximum expiratory pressure), along with peripheral muscle tiredness and fat-free mass, is an independent predictor of exercise capacity, as assessed by the distance covered in a 6-minute walk test (232). RecommendationsRespiratory complications contribute to significant comorbidity and impaired physical performance in patients with acromegaly. However, both optimal assessment and individualized management of respiratory dysfunction in acromegaly remain unclear. Current guidelines recommend that all patients be evaluated for SAS at diagnosis (18, 254), the gold standard for which is polysomnography. In patients with severe SAS, preoperative treatment with SRLs may be considered, which can potentially reduce upper airway soft tissue swelling, thereby minimizing the risk of intubation-related complications (18, 254–258). Notably, although normalization of GH/IGF-I remains a key goal, and improves the severity of SAS, a significant proportion of patients continue to have SAS despite disease control. Furthermore, patients without SAS at baseline may develop it de novo. Longitudinal follow-up is therefore critical, although the optimal timing and frequency have not been exactly established. Although not specifically validated in the acromegaly population, the Epworth Sleepiness Scale is a useful screening tool (259) to determine the need for more specialized investigations, and it may be a simple outpatient clinic means of monitoring progression. Close collaboration with respiratory physicians is needed, with the view to initiation and titration of continuous positive airway pressure treatment as needed during follow-up. This is especially pertinent given the potential impact of untreated SAS on cardiovascular and other comorbidities, including QoL. As SAS pathophysiology is likely to be multifactorial, attention should be paid to other factors such as weight management and smoking cessation, as well as appropriate management of other pituitary deficiencies. Although newer assessment techniques for SAS are validated and the exact impact of disease control and medications remains unknown, it may be prudent to incorporate yearly clinic assessment of physical function using validated patient questionnaires, such as the Epworth Sleepiness Scale, for example, into the routine management (259). Multidisciplinary care involving respiratory physicians and pulmonary function testing may be also necessary in selected cases. Suitable candidates should be offered participation in specialized cardiopulmonary rehabilitation programs that focus on optimizing respiratory and peripheral muscle function, along with cardiovascular function and nutritional status. Bone complicationsGH and IGF-I are important regulators of bone metabolism and growth, although the exact mechanisms of bone disease in acromegaly are poorly understood. The first evidence that excess GH may influence calcium homeostasis and bone remodeling emerged in 1948 (260); since then, several studies have confirmed increased bone turnover in acromegaly. However, it has only been during the last decade that additional data on the long-term consequences of GH excess on skeletal fragility have emerged. Up to 60% prevalence of radiological VFs has been reported in cross-sectional studies (261–267), and prospective studies demonstrate a substantial risk of incident fractures despite biochemical disease control (267, 268), which may result in significant pain, morbidity, and poor QoL (269–272). Bone remodelingIt is widely accepted that GH, both directly and via systemic and local IGF-I production, mediates the effects of PTH and has an anabolic effect on bone, stimulating osteoblastogenesis, osteoblast differentiation and function, and increasing osteoprotegerin and its accumulation in bone matrix (273–278). IGF-I also upregulates type 1 collagen transcription and decreases collagen-degrading proteases (279), maintaining both bone matrix and bone mass. The mechanisms behind increased bone resorption are, however, less well established: GH- and IGF-I–induced cytokine production (e.g., IL-6, TNF-α), the WnT signaling pathway, and receptor activator of nuclear factor κB ligand/osteoprotegerin system have been hypothesized to play important roles (280, 281). Indeed, evidence for increased bone turnover has been demonstrated in multiple studies based on biochemical markers and histomorphometry (282–288). Several studies reported disproportionately elevated markers of bone resorption compared with bone formation markers in patients with acromegaly (289–291). However, increased bone resorption in acromegaly seems to be coupled to bone formation (292), highlighting that other factors are implicated in the skeletal fragility observed in acromegaly. More recently, transgenic mouse studies demonstrate that overexpression of GH/IGF-I transiently increases trabecular bone volume, but with a negative impact on bone microstructure (293, 294). The exact role and clinical relevance of IGF-binding proteins (IGFBPs) in bone turnover remains, however, to be elucidated (295). In vitro studies show that IGFBP-2 stimulates osteoblastogenesis whereas IGFBP-4 exerts an opposite effect. Details of these mechanisms have recently been reviewed by Mazziotti et al. (278). Calcium phosphate and vitamin D metabolismHypercalcemia and hypercalciuria have been reported in 5% to 10% and 47% to 68% of acromegaly cases, respectively (296, 297), owing, in several case reports, to either concomitant primary hyperparathyroidism or elevated 1,25-dihyroxyvitamin D from renal activation of 1-α-hydroxylase by GH, resulting in increased intestinal absorption of calcium (298–300). However, hypovitaminosis D has also been reported in acromegaly (301), and preliminary evidence suggests reduced bioavailability of vitamin D due to increased vitamin D binding protein in active acromegaly (302), which may further confound the clinical picture. Recently, a prospective pilot study demonstrated PTH-independent alterations in calcium phosphate metabolism in acromegaly patients. Compared with controls who had nonfunctioning pituitary adenomas (NFPAs), patients with active acromegaly had higher phosphate and lower PTH, but similar 25-hydroxyvitamin D and 1,25-dihyroxyvitamin D levels. In this study, hypercalcemia and hypercalciuria were present in 13% and 22% of the patients, respectively, and IGF-I levels positively correlated with serum calcium levels (292). The hypercalciuria frequently observed has been attributed to increased bone turnover by GH excess, and therefore may also be considered a marker of skeletal fragility (139). Methods to evaluate bone qualityBone mineral density.Bone mineral density (BMD) measurement is the mainstay in diagnosis of skeletal fragility in the general population; however, BMD interpretation in the context of acromegaly remains challenging for several reasons: (i) overestimation of BMD at the lumbar spine due to osteophyte formation and facet joint hypertrophy, (ii) the effect of bony enlargement on two-dimensional areal dual-energy x-ray absorptiometry (DXA) measurement, and (iii) differential effects of GH on cortical and trabecular bone (increased periosteal ossification vs weakened trabecular microarchitecture), which are variably distributed at different skeletal sites, but are not distinguishable by DXA. Furthermore, use of a T-score of −2.5 SD or lower in the definition of osteoporosis and its impact on management decisions only applies to postmenopausal women and men >50 years of age; a large proportion of patients who are diagnosed with acromegaly are premenopausal women or men at a younger age than 50 years. Although z scores may be used to define low bone mass in this population, the therapeutic implications of the T-score cannot be applied (303). Indeed, data on BMD in patients with acromegaly are mixed, with some studies demonstrating reduced BMD (286, 304), some increased BMD (305–307), and yet others reporting no BMD differences in acromegaly compared with controls (287, 308, 309). A 2015 meta-analysis of 1935 patients demonstrated higher femoral neck BMD, but similar lumbar spine BMD, in acromegaly patients compared with controls (310). Furthermore, currently available diagnostic tools do not adequately identify acromegaly patients at high risk of VFs. Increased fracture risk appears to be independent of BMD (261, 262, 264), and the fracture risk assessment score has not been shown to be predictive of fractures (265). Evidence for the link between abnormal bone microarchitecture and fragility fractures is, however, beginning to emerge (detailed in “Fragility fractures” below). In recent years, alternative methods of assessing bone microarchitecture, quality, and strength, and in particular that of different bone compartments, have been studied. These include high-resolution peripheral quantitative CT, trabecular bone score (TBS), and impact microindentation. High-resolution peripheral quantitative CT.This technique allows three-dimensional, volumetric BMD (vBMD) assessment and better spatial resolution and delineation of the cortical and trabecular compartments of bone. Cross-sectional studies consistently demonstrate reductions in trabecular framework, architecture, and vBMD in acromegaly patients compared with age-, sex-, and BMI-matched controls (311–313). These changes in bone microarchitecture have been observed regardless of current disease activity, although duration of active disease has been inversely associated with trabecular vBMD (313). Data on cortical bone remain conflicting, with some studies showing no difference in cortical thickness or porosity compared with controls (311, 312) and others showing reduction in cortical vBMD alongside reductions in trabecular vBMD. Most recently, however, despite similar areal BMDs, cortical area, thickness, and volume were demonstrated to be increased, but trabecular bone density was reduced in the radius of patients vs controls, at least in men (314). Concomitant untreated hypogonadism and older age are likely to have additional deleterious effects on bone microarchitecture (311, 312), although this has not been consistently shown (313). TBS.TBS is a novel technique that utilizes gray-level textural metric extraction from lumbar spine DXA images. It correlates with direct microarchitecture measurements of bone volume fraction, trabecular number, trabecular separation, and with vertebral mechanical behavior, using micro-CT, which is another form of high-resolution CT (315). Whereas higher scores reflect more intact bone microarchitecture, lower scores have been reported to predict fracture risk in postmenopausal osteoporosis (316). TBS has also been shown to be of value in the evaluation of secondary osteoporosis and of greater utility than BMD in several circumstances, including DM2 and glucocorticoid (GC)-induced osteoporosis, where BMD readings are often misleading (317, 318). More recently, it has been evaluated as a potential skeletal fragility index in acromegaly; despite similar BMD values, lower lumbar spine TBS was demonstrated in acromegaly patients compared with controls, especially in hypogonadal patients and women (319). Reliability in predicting fragility fractures, however, remains unknown. Impact microindentation.Impact microindentation is another novel technique used to acquire bone material strength index measurements in vivo and is used as a surrogate to assess tissue-level properties of cortical bone. This technique involves insertion of a test probe/indentation tool into the midshaft of the tibia and measurement of the indentation distance increase as compared with that for a fixed calibrator. Greater indentation distance increases were first demonstrated in postmenopausal women with osteoporotic fractures or atypical femoral fractures compared with controls without fractures (320–323). In a recent cross-sectional study (324), despite having similar BMD, the bone material strength index was significantly lower in acromegaly patients in remission compared with controls, even after adjusting for age. No differences were noted, however, in patients with and without a VF, suggesting that other factors, including trabecular bone strength, highlighted above, are likely to play an important role. Fragility fracturesRadiological VFs are classified based on the Genant method that grades severity based on visual semiquantitative assessment of vertebral height and area reduction, with grade 1 (mild) defined as a 20% to 25%, grade 2 (moderate) as 25% to 40%, and grade 3 (severe) as >40% reduction in anterior, middle, and/or posterior vertebral height (325). Although x-rays remain an important diagnostic tool for the diagnosis of VFs, VF assessment on DXA may slowly surpass it due to low cost, high practicability, and a lower radiation dose (326). The prevalence of radiological VFs in acromegaly, regardless of BMD, has been reported to be between 11% and 60% in cross-sectional studies (261–267, 326). Similarly, an increased incidence of VFs was reported in two prospective studies published in 2013, occurring in more than a third of all acromegaly patients (267), and in 20% to 25% of patients in biochemical control (267, 268). Fractures were most frequent in the thoracic spine and occurred as early as 2 to 3 years after diagnosis (267, 268). Analysis of pooled data from these studies in the aforementioned meta-analysis by Mazziotti et al. (310) confirmed the significantly higher frequency of VFs (OR, 8.26; 95% CI, 2.91 to 23.39; P < 0.0001) among acromegaly patients compared with controls. Furthermore, the risk was three times greater in patients with active disease (62%) compared with those in biochemical control (25%), as well as in those with active disease, correlating also with total duration of disease activity (267). The association between VF risk and disease duration/severity has also been replicated in recently published studies (327, 328). As expected, hypogonadism was also associated with a higher prevalence of VFs (267). Examples of vertebral deformities in a controlled acromegaly patient are depicted in Fig. 4. Figure 4. (a and b) Thoracic and lumbar radiography. Exaggerated thoracic kyphosis and moderate multilevel disc space narrowing with degenerative spurring in a 58-y-old patient with long-standing acromegaly, biochemically controlled, are shown. Chronic, multilevel compression deformities of the thoracic and lumbar spine, T8 vertebra plana are visible. Height loss: T6 (30%), T10 (25%), T11 (30%), T12 (45%), L1 (45%) and L3 (30%). [© 2019 Illustration Presentation ENDOCRINE SOCIETY]. The risk of osteoporotic fractures is also increased in patients with DM in the general population (329–334), a result of altered bone metabolism and strength that is largely independent of BMD (335–337). Furthermore, certain DM treatments are known to affect bone metabolism, and several DM complications increase the risk of falls and fractures (338). Although VF prevalence appears to be independent of the presence of DM in active acromegaly, in controlled acromegaly, the prevalence of VFs has been reported to be higher in patients with DM (63%) compared with patients without (28%) (339). Although the degree to which coexisting hypogonadism and DM individually contribute to VF risk remains uncertain (312), these risk factors for bone loss need to be addressed in the overall treatment of patients with acromegaly.
As highlighted above, increased fracture risk appears to be independent of BMD (261, 262, 264). Despite similar BMDs, acromegaly patients with VFs were found to have significantly lower trabecular bone (bone volume ratios, greater mean trabecular separation, and higher cortical porosity) as measured by high-resolution cone beam CT analysis at the distal radius, compared with patients without fractures (312). High-resolution cone beam CT is a multitask tomography technique characterized by low radiation dose and cost, reduced scanning time, and three-dimensional modalities with the ability to define independently trabecular and cortical microstructures (340). Interestingly, GHR polymorphism may also play a role in VF risk (341). Exon 3–deleted GHR carriers appear to have an increased prevalence of VFs compared with patients expressing a full-length GHR (63% vs 22%); the incidence of new VFs was also significantly higher in these patients (52%) compared with those with the full-length gene (19%) (342). Effects of treatments for acromegaly on bone complicationsDespite a decline in bone turnover markers and BMD increases seen within 6 to 12 months of treatment (292, 343), the risk of VFs persists in patients in biochemical control. VF progression (incident fractures and/or a significant reduction in pre-existing fractured vertebral height) has been observed in 20% to 25% of patients, despite biochemical control of acromegaly during 2 to 3 years (267, 268). This is significantly higher than the 3.8% seen in age- and sex-matched controls (267), and higher than the rate of VF progression in untreated postmenopausal women (5% to 7% during 4 to 5 years) reported in randomized controlled trials of bisphosphonate use (344–346). Persistent alteration in bone architecture has been postulated as a potential mechanism. In one study, following either surgical or primary therapy with SRLs, a reduction in TBS was observed in men, despite IGF-I normalization, improvement in bone turnover markers, and BMD increases (343). A recent small histomorphometric study demonstrated that whereas patients with active disease with fractured bones despite normal BMDs showed histomorphometric features of increased bone turnover, those with controlled disease had normal bone turnover, but significantly lower osteoblastic activity (lower osteoblast number, active osteoblasts, and reduced osteocytes) (347). Furthermore, prevalent VFs (especially if two or more) appear to be consistently correlated with the risk of fracture progression (267, 268, 328), highlighting the impact of baseline skeletal fragility on incident fracture risk. Untreated hypogonadism further increases the risk (267), although this has not been consistently reported (likely due to baseline differences in the prevalence of hypogonadism in different study populations). Interestingly, the effects of prevalent fractures or untreated hypogonadism were not observed in patients with active acromegaly, suggesting that disease activity remains the primary determinant of fracture risk (267, 327, 328). Although comparisons are limited by study size, different treatment modalities do not appear to influence fracture progression (268, 328). Patients treated with higher doses of PEG had higher rates of fractures, but this is probably related to severity of disease, rather than treatment per se (327). In a multivariate analysis, incident radiological VFs were independently predicted by pre-existing VFs, duration of active acromegaly, and mean serum IGF-I during follow-up, regardless of the treatment regimen with SRLs alone, PEG alone, or in combination (328), although this study is limited by the small number of patients in the PEG group. The effects of sex, baseline BMD, and BMD changes over time are unclear. The exact role of antiosteoporosis drugs in patients with acromegaly remains to be elucidated; there are, to date, no published data on the effects of antiosteoporosis drugs in the setting of acromegaly (278). However, in general in patients with uncontrolled disease, antireabsorptives drugs (bisphosphonates and denosumab) are preferred owing to high bone turnover, resulting from excess GH and IGF-I, especially in the presence of reduced BMD. Teriparatide might be preferred in patients with VFs and progression of skeletal fragility despite controlled acromegaly (and lower bone turnover overall) (278). RecommendationsThe management of bone disease in patients with acromegaly remains complex. Although recent data confirm the effects of disease activity and duration on bone microarchitecture, skeletal fragility, and fractures, further studies are needed to clarify the role of various tools in the assessment of bone quality and to determine other predictors of fracture. Notwithstanding, the impact of prevalent VFs on predicting new fractures, the long-term implications of radiological VFs on long-term survival and QoL remain to be seen. Current Endocrine Society guidelines do not address bone complications in patients with acromegaly (18). However, given that VFs are associated with decreased survival, increased risk of future vertebral, hip, and other nonspinal fractures, chronic back pain, limitations of activities of daily living, and QoL in the general population (269–272), it would seem reasonable to extrapolate that the impact in patients with acromegaly, in conjunction with other comorbidities, is likely to be similar, if not worse. Clinicians should therefore be aware of the risk of fragility fractures in these patients. We recommend that screening x-rays or VF assessment for thoracic and lumbar spine fractures be undertaken at diagnosis, as patients with prevalent fractures are likely to be at highest risk for further fractures. Repeat imaging is needed although the exact interval is not clear; recommendations suggest every 2 to 3 years when osteoporosis risk factors, kyphosis, or symptoms are present (259). However, based on new findings that fracture progression can be observed in 20% to 30% of patients despite acromegaly biochemical control, repeat imaging at 18 months to 2 years after diagnosis in all patients is warranted. The correlation between disease activity and duration with fracture incidence suggests that early and effective biochemical control of GH excess takes priority in the management algorithm. The impacts of different treatment modalities, however, need further studies. Although medical therapy has pleiotrophic properties, there is no known clear advantage vs surgery on bone effects. Beyond GH and IGF-I normalization, attention should be paid to early treatment of hypogonadism, appropriate physiologic GC replacement in hypocortisolic patients (348), and treatment of DM. A multidisciplinary approach with orthopedics is also paramount for optimal care in selected cases. Similarly, patient education on bone health, adequate calcium and vitamin D supplementation, and clinical monitoring for signs and symptoms of incident fractures (such as height loss) are adjunctive measures that should be part of the holistic management of acromegaly patients. Joint complicationsArthropathyArthropathy, affecting both weight-bearing and non–weight-bearing joints (including shoulders, wrists, spine, hips, and knees), is one acromegaly presenting condition in 50% to 70% of patients (349). Registry-based studies suggest a 20% to 69% prevalence in acromegaly patients (14, 180, 350–352), which is double that of the general population (14). The most commonly affected joints are shoulder, knee, and hip (349), impacting physical function and QoL (353, 354). Furthermore, radiological manifestations of osteoarthritis (OA) in at least one joint site are present in almost all patients, particularly the spine and hip (355). Acromegaly joint disease shares several similarities with primary OA and is therefore generally considered to be a degenerative joint disease. However, one unique difference is the presence of cartilage hypertrophy with severe osteophytosis in acromegalic arthropathy (AA), resulting in joint space widening, rather than the narrowing observed in OA due to cartilage loss (356). There are two distinct phases in AA development. First, elevated GH stimulates both hepatic IGF-I and, via a locally expressed GHR, chondrocyte IGF-I synthesis (357, 358). IGF-I is an important anabolic factor for bone and cartilage metabolism, stimulating cell proliferation (359, 360) and synthesis of both proteoglycan and type II collagen in chondrocytes from the articular cartilage or the epiphyseal cartilage (361–363). Through these mechanisms, cartilage hypertrophy, periarticular ligament laxity, and limitation of overall range of motion ensue. Widening of joint spaces and periarticular soft tissue hypertrophy are detected on radiographic images. Notably, this phase is thought to be at least partially reversible with GH and IGF-I normalization (364–366). In the second, irreversible phase, persistent GH/IGF-I excess results in further deterioration in joint architecture, leading to repeat intra-articular trauma, ultimately leading to disproportionate proliferation of regenerative fibrocartilage, scar, cyst, and osteophyte formation (367). IGF-I regulates osteophyte formation in an autocrine and/or paracrine fashion, as demonstrated in animal models (368). During this later stage, reduction in GH/IGF-I has a limited effect on improving joint symptoms (369). The exact pathophysiology of joint destruction, however, remains to be fully elucidated. Predictors for AA include well-known risk factors for primary OA, such as age at diagnosis, female sex, and higher BMI (370). Disease-specific risk factors have been studied, with some, but not all, studies demonstrating an association between higher baseline GH and IGF-I levels at diagnosis (371–373), duration of uncontrolled disease (374), and the common exon 3–deleted GHR polymorphism (375) with both prevalence and severity of AA. Clinical evaluation and imaging.The evaluation of AA is largely dependent on clinical symptoms and radiographic abnormalities. Several clinical instruments to measure pain, joint function, stiffness, and QoL have been used to quantify and monitor functional outcomes, but these have only been validated in patients with primary OA (376–378). Whereas conventional radiography has long been the most common modality used to assess qualitative structural abnormalities, such as osteophytes and joint space, newer imaging techniques have recently been developed, allowing semiautomated image quantitative analysis of joint space width using hand radiographs. Using this method, an increase in joint space width was seen in acromegaly patients despite long-term disease control compared with controls and was correlated with disease severity at diagnosis (379). Ultrasonography studies confirm the presence of cartilage thickening in acromegaly patients compared with age-, sex-, and BMI-matched controls (364–366, 380), although the exact relationship between cartilage thickness and disease activity remains controversial. Observed discrepancies may, in part, relate to differences in study population and design (e.g., disease duration, activity, assessment of weight-bearing vs non–weight-bearing joints). The use of MRI may provide further insight into the observed cartilage and bone abnormalities. In a recent cross-sectional study, the prevalence of severe osteophytosis was higher in patients with acromegaly compared with controls (literature) with primary OA. Additionally, knee cartilage thickening and higher cartilage T2 relaxation times (indicating unhealthy cartilage with increased water content) were observed in acromegaly patients, especially in those with active disease (381), highlighting the effect of GH excess on both structural joint abnormalities and cartilage quality. The authors (381) hypothesized that cartilage thickening in active acromegaly results from both edema as well as structural cartilage hypertrophy, with the former being reversible with GH/IGF-I normalization, and the latter being (partially) irreversible despite disease control; this needs confirmation in larger, prospective studies. Effect of treatments for acromegaly on joint complicationsSeveral ultrasonography studies show partial reversibility of cartilage hypertrophy (and thereby joint space widening) after treatment of acromegaly with SRLs, especially in non–weight-bearing joints (364–366). After a year of taking octreotide LAR, a 15% to 20% decrease in shoulder, wrist, and knee joint thickening has been seen in all patients; joint thickening normalized in the shoulder and knee in 60% and 90%, respectively, of patients with biochemical control (366). However, although joint pain and mobility improve partially (365), arthropathy persists in the large majority of patients, despite long-term biochemical acromegaly control (378). In the aforementioned study, overall joint thickness was still greater in the cured patients vs controls (366). In case-control studies, the prevalence of clinical arthropathy has also been reported to be 4- to 12-fold higher in these patients vs controls, and already present at a younger age, with persistent pain or stiffness at one or more joints in >70% of patients and radiographic OA in >90% of patients, especially in the spine and hip (355). As a result, despite long-term cure (up to 15 years), QoL is decreased significantly in patients with acromegaly (353–356, 379, 382). There appears to be joint site–specific effects on QoL scores; clinical OA of the spine seems to have the greatest impact, not only on physical and general well-being, but also on psychological well-being, including anxiety and depression (353). Interestingly, worsening of joint pain has been reported after radiotherapy for acromegaly in a retrospective analysis of longitudinally collected data (372); 61.7% of patients followed for at least 5 years were found to have subjectively worsening joint pain scores, of whom 40% developed severe arthropathy. However, there is currently no clear evidence to suggest that this is any different from that experienced by patients with surgery or medical therapy alone and is most likely related to delay of diagnosis and duration of uncontrolled acromegaly. Joint space narrowing may be observed in a subset of patients, and this correlates with more severe symptoms, more active disease at diagnosis, and longer duration of GH exposure, at least in the hip (383). In fact, progressive joint space narrowing and/or osteophytosis have been reported in >70% of patients despite long-term biochemical control for >15 years (384). Interestingly, progression rates were highest in patients treated medically with SRLs, compared with those who achieved surgical remission in this study. It has been suggested that discordant results (subtle GH elevations despite normal IGF-I levels) may play a role in ongoing AA (369, 384), but this needs to be further confirmed in larger prospective studies. Apart from controlling GH excess, the treatment of acromegaly joint disease is similar to that of primary OA, with analgesia (using simple analgesics or nonsteroidal anti-inflammatories) and improving mobility as main goals in management (369). RecommendationsThe impact of AA on patients’ physical functioning and QoL cannot be understated. Although biochemical control of GH excess remains the cornerstone of management, clinicians need to be aware of the persistence and progression of arthropathy despite IGF-I normalization. Yearly clinical assessment of joint pain and function should be routinely incorporated into clinical follow-up of acromegaly patients, with targeted radiographic imaging when necessary, as well as appropriate pain control and joint mobilization. Attention should be paid to older individuals, especially women, who are at greatest risk of primary OA, and on addressing modifiable risk factors, such as weight gain, which might be exacerbated by biochemical control. Although the optimal management strategy is unknown, a multidisciplinary approach, involving rheumatologists, orthopedic surgeons, physiotherapists, and the pain management team, is recommended. Neoplastic complicationsThe GH/IGF-I system is intricately involved in growth and metabolism control (385). Its role in carcinogenesis and promoting tumor progression has been of concern (386–389). Uncontrolled acromegaly has been in the past associated with an increased risk of several malignancies (7). Based on retrospective mortality studies, 15% to 24% of acromegaly deaths were previously attributable to cancer, most commonly colorectal cancer, and to a lesser extent, breast, thyroid, prostate, and other cancers (7). Although vascular and respiratory diseases have long been thought to be the leading causes of death, emerging data suggest that cancer may be the most common cause of mortality in acromegaly (12, 14, 15, 179). As cancer risk is age-dependent, whether this represents a result of better disease control and management of comorbidities, and increased life expectancy in patients with acromegaly, remains to be confirmed (178, 390). In the evaluation of such risk, ascertainment bias needs to be considered, and there remains considerable debate surrounding the direct link between acromegaly and cancer risk (178, 386, 387, 390, 391). In a large recent study (392), performed on a nationwide cohort study in Denmark (1978 to 2010) including 529 acromegaly cases, cancer incidence rates were slightly elevated in patients with acromegaly compared with national rates estimating SIRs (SIR, 1.1; 95% CI, 0.9 to 1.4). Interestingly, in this study, cancer-specific mortality was not elevated. A meta-analysis of 23 studies compiled by the authors also confirmed a slight increase in cancer incidence and suggested a possible selection bias in some of the earlier reports. GH/IGF-I and tumor developmentGH and IGF-I promote cellular proliferation and differentiation, protein synthesis, and angiogenesis and inhibit apoptosis. Although this theoretically favors tumor development, opposing mechanisms, involving IGFBP-3 (also GH regulated), proteases, and IGF receptors, modulate IGF-I actions to limit tumor growth (386–389, 393). Limited knowledge on this question derives from in vitro studies, animal models, epidemiological data from nonacromegaly populations, and cross-sectional and prospective studies on patients with acromegaly and GH deficiency (GHD), discussed below. Pathophysiology: in vitro and animal model studies.In vitro studies demonstrate expression of GH/IGF-I and their cognate receptors in colorectal, breast, prostate, brain, thyroid, renal, pancreas, endometrial, and ovarian cancer cells (394–397). Overexpression of GH (via autocrine and/or paracrine mechanisms) increases cell proliferation and promotes survival in normal human mammary cells and breast carcinoma, promoting metastasis via cell migration, invasion, and secretion of metalloproteinases such as matrix metalloproteinase-2 and matrix metalloproteinase-9 (398). IGF-I and IGF-II also directly stimulate migration, differentiation, and survival of endothelial cells, inducing hypoxia-inducible factor 1α, and thereby vascular endothelial growth factor expression, driving angiogenesis (399, 400). IGF-I and IGF-IR signaling may also promote metastasis via expression of metalloproteinases (401, 402).
Much of this in vitro evidence has been corroborated in vivo; overexpression or constitutive activation of human GH, IGF-I, IGF-II, or IGF-IR promotes carcinogenesis, with increased incidence or rate of mammary, skin, kidney, salivary, pancreatic, and prostate growth in transgenic animal models (403–408). In contrast, overexpression of IGFBPs in vivo leads to marked reduction or attenuation of tumor growth in several tissues (409–412). Animal models of GH/IGF-I deficiency (inactivating mutations in the GH gene, missense mutations in the GH-releasing hormone (GHRH)R gene, GHR gene disruption or antagonism, and IGF-I gene deletion) also show an overall protection from tumor development/burden and increased longevity (413–419). The specific mechanisms by which IGFBPs modulate tumor growth are more complex, with variable in vitro results, depending on the type of malignancy and the experimental conditions (393). However, in animal models, overexpression of IGFBPs resulted in marked reduction or attenuation of tumor growth at different tissues, inducing apoptosis and inhibiting angiogenesis by decreasing the mitogenic activity of IGFs (386, 388, 393). Recently, several studies have provided new insights into the initiating, promoting, and permissive actions of GH on cancer development, discussed below. Our understanding of the role of GH in oncogenic transformation derives mainly from studies involving mammary epithelial cells. Via autocrine (but not exogenous) activation of oncogenic signaling pathways by GH, oncogenic transformation has been seen in immortalized mammary epithelial cells in vitro (420–422). Local GH secretion by progesterone-stimulated normal mammary epithelial cells results in proliferation of a subset of cells that express GHRs and have functional properties of stem and early progenitor cells. Expansion of the cell population that expressed GHRs was observed in 72% of ductal carcinoma in situ lesions (423). In xenograft studies, autocrine GH also increased the tumor-initiating capacity of estrogen receptor–negative mammary carcinoma cells (424). Alternatively, insights into the role of GH as a molecular component of the milieu permissive for neoplastic growth derive from in vitro and in vivo studies of colon cells. Tumor protein p53 (a tumor suppressor gene) levels are suppressed by both circulating GH and local GH (release in response to DNA damage or inflammation), leading to downregulation of tumor suppressor adenomatous polyposis coli, increased nuclear β-catenin accumulation, and epithelial–mesenchymal transition factors, ultimately leading to increased cell survival and motility. Conversely, PEG, by blocking the GHR, induces colon p53 expression in patients with acromegaly. Furthermore, cross-breeding GH-deficient mice (Prop1)−/− with ApcMin+/− mice that normally develop colon tumors results in double-mutant progenies with reduced tumor growth (425). This suggests that, at least in colon cancer, GH may act within the tumor microenvironment to reduce tumor suppressor proteins and thereby sustain neoplastic growth (422). Beyond this, the role of GH in promoting further cancer growth and metastasis has been studied in several in vitro and in vivo studies. Both autocrine and exogenous GH has been demonstrated to increase tumor growth, angiogenesis and vascularization, and cell migration and thereby promote metastasis (422, 424, 426–428). As an example, intracellular GH has been shown to promote breast cancer cell invasiveness in vitro, by upregulating epithelial–mesenchymal transition transcription factors, and also metastasis in vivo (424, 429). Furthermore, several studies demonstrate GH-induced chemoresistance and radioresistance in breast and endometrial cancer cell lines (430–433). Recently, GH signal prolongation due to a GHR SNP was also shown to promote lung cancer (434). However, the extent to which tumor GH expression correlates with clinical outcome needs further evaluation. GH expression has been associated with human epidermal growth factor receptor 2 positivity and lymph node metastasis in breast cancer, as well as with myometrial invasion in endometrial cancer, predicting a significant difference in survival outcome for patients with these tumors (435). Figure 5 summarizes the endocrine and paracrine effects of GH on cancer cells. Figure 5. Endocrine (systemic), autocrine and paracrine effects of GH on cancer cells. GH is secreted from somatotroph cells of the anterior pituitary, stimulating hepatic IGF-I production. GH release is positively regulated by hypothalamic GHRH, and negatively by somatostatin (SST). GH and IGF-I are also secreted locally by tumor cells (blue) and other cells in the tumor microenvironment, including endothelial cells (red), and potentially immune cells (yellow) and fibroblasts (green). GH acts in an autocrine/paracrine fashion to upregulate IGF-I, trefoil factors 1 and 3 (TFF1 and TFF3), IL-27, vascular endothelial growth factor-A (VEGF-A), osteomodulin (OMD), bone morphogenetic protein 7 (BMP7), and laminin-3 secretion, contributing to oncogenic transformation, providing a milieu permissive for neoplastic growth and promoting further metastasis. [Reproduced with permission from Perry JK, Wu Z-S, Mertani HC, et al. Tumor-derived human growth hormone as a therapeutic target in oncology. Trends Endocrinol Metab 2017; 28 (8):587-596. © 2019 Illustration Presentation ENDOCRINE SOCIETY.] The GH/IGF-I pathway as a target in anticancer therapy.As the role of GH in cancer development and progression continues to become more clearly defined, the GHR has become a prime target in experimental therapeutic strategies. Currently available as a treatment of acromegaly, PEG, a GHR antagonist, addresses both systemic GH as well as autocrine/paracrine GH. In in vitro and animal studies, cancer inhibition through GH antagonism was demonstrated in some colorectal carcinoma cell lines, breast cancer, and meningiomas (436–438). More recent in vitro studies demonstrate the efficacy of GH antagonism with PEG in reduction of human mammary carcinoma cell and endometrial cancer cell proliferation, reduction in vascularity, and in enhancing tumor chemosensitivity and radiosensitivity (430, 439, 440). Functional antagonism of GH, used in conjunction with radiotherapy, may therefore enhance treatment efficacy and improve the prognosis of patients with breast and endometrial cancer (430). GHR knockdown also reduced growth, cell migration, and invasion in vitro in pancreatic adenocarcinoma and melanoma cell lines (441, 442). Novel cancer therapies targeting GHRH and other IGF-IR–mediated pathways are also under investigation (443). GHRH antagonists have been shown to inhibit tumor in various cell lines in vitro (444). Neutralizing IGF-I and IGF-II antibodies inhibit their respective IGF subtype signaling and suppress tumor cell growth (445, 446). Tumor load reduction has also been observed with IGF-IR–targeted therapy in animal models of prostate cancer (447). Phase 1 clinical trials have also demonstrated an anticancer efficacy of anti–IGF-IR monoclonal antibodies in patients with sarcomas (448, 449). It is acknowledged, however, that complexity of the IGF system and its interaction with other pathways are likely to limit the efficacy of these therapies as monotherapies, with a combined approach likely to be more promising (393, 443). Human studies on GH/IGF-I: cancer link in patients without acromegaly.Epidemiologic studies suggest a link between adult height and cancer risk across numerous cancer sites. A systematic review and several meta-analyses found a significant increase in the incidence of colon, breast, prostate, ovarian, pancreatic, and kidney cancer in taller individuals (450–453). Interestingly, several height-associated genes have also been linked to cancer risk (454), and GH expression was also associated with tumor size and grade, relapse, and overall survival in patients with hepatocellular carcinoma (455). Prospective and nested case-control studies in healthy individuals have also found an association between IGF-I levels in the highest quartiles/quintiles and increased colorectal (456–458), breast (both premenopausal and postmenopausal) (459–461), prostate (462, 463), and, more recently, thyroid cancer (464). Large meta-analyses, including pooled analyses of individual patient data, have confirmed this, albeit weak, association [relative risk (RR), 1.14 to 1.38] (386, 461, 465–467), suggesting that even IGF-I levels in the ULNR may be associated with increased cell division and survival. These associations appear to be unaffected by adjustment for circulating IGFBP-3 levels (386). IGF-I gene polymorphisms have also been associated with varying risks of many cancers; a recent meta-analysis, however, showed that they are unlikely to be a major determinant of cancer susceptibility (468). Conversely, genome-wide association studies have identified the GH signal transduction pathway as one of three key signaling pathways that are highly associated with breast cancer susceptibility (469). The significance of genetic alterations in this pathway with respect to other cancers needs further evaluation. Conversely, the strongest epidemiological evidence for reduced cancer incidence in individuals with IGF-I deficiency derives from studies of subjects with inactivating mutations in the GHR (Laron syndrome), who have a markedly reduced risk of developing cancer compared with unaffected relatives who developed cancer at rates similar to those of the general population, with only 1% having developed malignancy vs 17% in relatives, although lifespan was similar (470). In in vitro studies, reduced IGF-I signaling was seen to protect against DNA damage and to favor apoptosis of damaged cells (470, 471). Overall prevalence, incidence, and risk of malignancy in acromegalyThe true incidence and risk of malignancy in acromegaly remains unknown. A recent review of cancer prevalence and incidence in acromegaly in 17 published series up until 2015 (12, 177, 352, 472–485) showed a mean cancer prevalence of 10.8% (4.8% to 21.3%) (390), significantly higher than in the global population (5-year cancer prevalence estimated at 0.59%). This difference is important, even after accounting for significant heterogeneity observed between developed and less developed regions (486). Evaluating cancer risk in acromegaly, however, is challenging, with risk of ascertainment bias; the estimates commonly used are: (i) SIR, whereby cancer rates in patients with acromegaly observed over a period of time are compared with those of the general population; and (ii) OR/HR, whereby cancer rates are compared with a matched control group in a cross-sectional analysis. As the latter often leads to higher estimates in comparison with the former (482), population-based/registry studies are thought to be more appropriate for assessing cancer risk (487). Of 11 population-based series in which SIRs were documented, cancer risk was increased in five studies (SIR, 1.5 to 3.4) (473, 474, 479, 483, 485), whereas in three studies, cancer incidence was not increased (177, 480, 482). Interestingly, sex differences were noted in the three remaining studies, with an increased risk observed in women only in two studies (475, 481) and in men only in one study (478). Given the overall rarity of acromegaly, conflicting results could be due to the small study size lacking statistical power. However, results differ even among the three largest series (>1000 patients) that compared cancer rate in acromegaly to the general population. Cancer incidence was increased in two studies, a nationwide survey study in the United States and an epidemiological study conducted in Sweden and Denmark (473, 485), and was lower or comparable to the general population in a study conducted in the United Kingdom (177). Several other factors are likely to have influenced these observations: heterogeneity of study and control populations, not just across geographical boundaries with differing genetic and environmental influences, but also arising from differences in study methodology. For example, the US study analyzed a purely hospital-based cohort of males, with a control group that included only hospitalized patients, rather than the general population. Furthermore, nonstandardized data collection methods that rely on national cancer registries or disease databases as compared with medical record review, as well as differences in duration and completeness of follow-up, are likely to result in different outcomes. As the diagnosis of acromegaly is often made many years after the onset of GH/IGF-I excess, exclusion of cancers registered in the preceding years before the diagnosis of acromegaly may result in underestimation of cancer risk; this is a potential limitation of the UK study (177). Beyond study methodology, intrinsic changes in cancer patterns and life expectancy, changes in trends in acromegaly treatment [such as the decline in pituitary irradiation and increasing use of medical treatment (14, 488)], and effectiveness of treatment during the last few decades (14, 488, 489) make comparison of studies conducted during different eras problematic. It has been suggested that “competitive cardiovascular morbidity” may hinder cancer incidence; studies conducted in an era when the goal of IGF-I and/or GH normalization was often unmet may report lower incidence rates due to mortality occurring prior to the age when malignancy usually develops (390, 490). Several recent case-control and European population-based studies showed, again, mixed results; however, they placed an additional focus on risk factor assessment for cancer in the acromegaly population (14, 490, 491). A register-linkage population-based study in Sweden reported among 358 acromegaly patients a 30% prevalence of neoplasms outside the pituitary (158). However, in this study, the proportions of malignant neoplasms and cancer location were not clearly documented; benign neoplasms of the central nervous system and glands were the most common neoplasms. In a small case-control study conducted in Poland, comparing 200 acromegaly patients with 145 controls with prolactinomas or hormonally inactive pituitary lesions, an increased prevalence of cancer was observed in acromegaly patients compared with controls (13.5% vs 4.1%, P = 0.003), and, in particular thyroid cancer (7.0% vs 1.4%, P = 0.02) and breast cancer (5.4% vs 0%, P = 0.02) (492). In contrast, a Danish nationwide population-based cohort study of 405 incident cases (1991 to 2010) did not show a statistically significant increase in cancer risk compared with a general population comparison cohort [HR, 1.4 based on rate per 1000 person-years (95% CI ,0.9 to 2.2)]. No increase was noted specifically for colorectal, breast, or lung cancer (Table 4) (4). Table 4. Population-Based Studies on Cancer Incidence in Acromegaly
Abbreviations: N/A, not available; VA, Veterans Affairs. Table 4. Population-Based Studies on Cancer Incidence in Acromegaly
Abbreviations: N/A, not available; VA, Veterans Affairs. Cancer incidence was 10% in a French acromegaly registry of close to 1000 patients followed up for 6728 patient-years (median, 7 years; range, 0.6 to 34), most commonly breast (20.5%), thyroid (17.6%), and colorectal malignancies (14.7%). A trend toward increased cancer risk was observed: SIR, 1.34 (95% CI, 0.94 to 1.87) in men and 1.24 (0.77 to 1.73) in women, although this, again, did not reach statistical significance. It is unclear whether the relatively shorter duration of follow-up or rate of loss to follow-up (16.5%) could have affected these outcomes. Neither GH nor IGF-I levels were associated with cancer occurrence or with tumor site (14). More recently, in one of the largest nationwide studies to date, cancer risk was found to be significantly increased in an Italian multicenter cohort of 1512 acromegaly patients compared with the general Italian population (SIR, 1.41; 95% CI, 1.18 to 1.68; P < 0.001) (490). In particular, colorectal cancer (SIR, 1.67; P = 0.022), thyroid cancer (SIR, 3.99; P < 0.001), and kidney cancer (SIR, 2.87; P < 0.001) had increased incidence. Of note, this study was conducted in the modern era of widespread medical therapies use; patients had been diagnosed between 1980 and 2002 and followed for a mean of 10 years (12,573 person-years). Although study size and long follow-up duration are strengths of this study, it is possible that the relatively high rate of proactive cancer screening (60% of all acromegaly patients) could have affected incidence rates. Results are, however, comparable to Finnish data that were collected in the same period where SIR for overall cancer incidence was 1.5 (479). In the Italian cohort, age and a family history of cancer were found, in multivariate analysis, to be associated with an increased risk of cancer in this population, with a nonsignificant trend for duration of acromegaly before diagnosis (490). Similar to the French data (14), no direct association was found between GH or IGF-I levels and cancer risk. Overall/cumulative GH exposure may be more important in determining morbidity and mortality in acromegaly (493); absolute levels at specific time points such as diagnosis, after treatment, or at last follow-up are unable to accurately estimate this. Furthermore, other factors such as insulin, IR, IGFBP levels, obesity, and body composition are likely to contribute to cancer risk (390, 456). Interestingly, DM has been linked to increased cancer risk in a Canadian study in which 22.6% of acromegaly patients with diabetes developed malignant tumors vs 9.2% of patients without diabetes (OR, 2.873; 95% CI, 1.572 to 5.250; P < 0.001) (491). IGF-I at diagnosis was, however, higher in patients with diabetes compared with patients without DM. In the aforementioned Italian study, DM was linked to cancer risk only in univariate analysis (490); the relative contribution of GH excess and DM to cancer risk warrants further investigation. Impact of GH excess on cancer mortality.As discussed above, increased tumor GH has been associated with worse relapse-free and overall survival in patients with mammary or endometrial carcinoma (435) and in hepatocellular carcinoma (455). The exact impact of systemic GH on cancer mortality in acromegaly remains to be determined. In the Finnish study, basal GH levels were similar in patients who died from cancer compared with those who did not die from this cause (179). Colonic polyps and colon cancerData on colon cancer remain conflicting. The incidence of colon cancer in patients with acromegaly has been documented to be 0.9% to 2.4% in several population-based studies with varying follow-up durations (14, 177, 473, 479, 483, 490). Similar to cancers overall, SIRs of colon cancer compared with the general population have also been variable, with some (473, 485, 494), but not all (4, 177, 479), studies finding an excess risk of colon cancer in acromegaly (Table 4). Case-control cohorts of at least 100 patients, published up to the beginning of the 2000s, showed increased risk for colon cancer in some, but not in others. In two studies, the ORs were 4.9 (95% CI, 1.1 to 22.4) (495) and 13.5 (3.1 to 75) (496), whereas in two other studies, risk was not increased (497, 498). A 2008 meta-analysis that included nine colonoscopy-based case-control studies (1994 to 2006) with no significant heterogeneity or apparent publication bias showed a significantly increased risk of colon cancer (OR, 4.4; 95% CI, 1.5 to 12.4) in acromegaly patients vs controls (499). The number of patients with acromegaly within each study ranged from 19 to 235. Case-control studies may, however, overestimate risk due to “ascertainment bias” and matching problems within specific groups. The wide CIs documented in these studies also limit the degree to which these results can be interpreted and applied. Although the epidemiological data on colon cancer per se remain controversial, the increased risk of colonic polyposis in acromegaly is well recognized (7). Increased bowel length and colonic diverticula (and hemorrhoids) are also observed in acromegaly (500), and they correlate with GH and IGF-I. Elevated IGF-I levels predispose to increased proliferation of colonic epithelial cells (501). National registry data suggest that the prevalence of colonic polyps is 27% to 55%, most recently reported in the French Registry (14). Even greater variability has been reported by other epidemiological studies, with prevalence as low as 7% and up to 76% (495, 498, 502–508). Alternatively, prevalence of polyps at diagnosis was 13% in the Liege Acromegaly Survey Database, athough only a fourth of patients (n = 820) had a colonoscopy at diagnosis in this international database of >3000 patients from 14 centers across Europe (including Belgium, Bulgaria, Czech Republic, France, Germany, Italy, Netherlands, Portugal, Spain, and Sweden) (99). Differing prevalence of colonoscopies performed, variability in complete colonic examination, or different genetic and environmental backgrounds of various populations studied can explain the wide range observed. Similar findings were noted in a recent Italian single-center study where prevalence of polyps was observed in 32% of the patients who had been subjected to at least one colonoscopy since diagnosis (68% of 146 acromegaly patients) (500). In this study, a polyp was detected in 32% at first colonoscopy, and 60.5% had multiple lesions, with a trend toward an association with increased age. More than half were adenomatous polyps (54%) with low-grade dysplasia and 44% were hyperplastic polyps. No cancerous polyps were detected. Compared with a literature reference control population of individuals living in the same region with no alarming lower gastrointestinal signs or symptoms (509), acromegaly patients had a fourfold higher risk for hyperplastic polyps (500). This is similar to the aforementioned meta-analysis (499), in which a significantly increased risk of hyperplastic polyps (OR, 3.6; 95% CI, 2.6 to 4.9) and colonic adenomas (OR, 2.5; 95% CI, 1.9 to 3.2) was demonstrated. As previously mentioned, the intrinsic biases of case-control studies need to be taken into account in interpretation of these results.
Notably, disease activity has been reported to be the best predictor of new polyp development (390). The association of IGF-I levels with the presence of polyps at first colonoscopy has been a fairly consistently finding among various studies (14, 500, 510), although not all studies demonstrated similar association with GH levels. IGF-I levels above the ULNR, but not GH levels, correlated with the presence of polyps even after adjustment for age, BMI, and smoking in the aforementioned French acromegaly registry (14). No clear correlation has, however, been found between polyp size and IGF-I levels, although polyp size has been reported to be lower in treated vs untreated patients (500). As a reflection of disease burden, duration of active acromegaly is also implicated in polyp development; the interval between symptoms and signs and diagnosis was higher than for those without hyperplastic polyps (16 ± 4 vs 5.5 ± 7.4 years, P = 0.03) in one study (500). Presence of polyps (either adenomatous or hyperplastic) at first colonoscopy is associated with an increased risk of a polyp at subsequent surveillance colonoscopies (500, 503, 510). Polyp size and multiple polyps at first colonoscopy were also associated with recurrence at subsequent colonoscopies in one study (500). Conversely, absence of polyps is a negative predictor of subsequent polyp development. Furthermore, it has also been shown that patients with high IGF-I levels and a polyp (either hyperplastic or adenomatous) found on initial colonoscopy to be at greatest risk of an adenomatous polyp on second colonoscopy (24% vs 2%, P < 0.005) (510), highlighting that the incidence of colonic polyps is dependent on both the occurrence of previous polyps and elevated IGF-I levels. Of note, highly negative predictive values of a normal initial colonoscopy and normal IGF-I levels are associated with a >80% chance of a negative follow-up colonoscopy (510). Recommendations.Most colorectal cancers encountered in the general population derive from oncogene and tumor suppressor gene mutations arising in pre-existing adenomatous polyps during the course of 10 to 20 years (511). Hyperplastic polyps, which were previously thought to be completely benign entities, may also contain dysplastic foci, and they have also been shown to be associated with subsequent malignant transformation (512–514). Randomized trials have also documented an association between screening and reduced colorectal cancer mortality, through early detection of cancer, endoscopic removal of adenomas, and continued surveillance of patients at high risk of further development of neoplasms (515–517). This has led to widespread adoption of screening programs in developed countries (518). This should be an impetus for colonoscopy screening to be a routine part of management of patients with acromegaly who are at higher risk of both adenomatous and hyperplastic polyps. Current guidelines for screening for colorectal cancer in patients with acromegaly suggest that at least one colonoscopy should be done at the time of diagnosis, followed by appropriate surveillance depending on findings from initial colonoscopy and disease activity (18, 259, 519, 520). Given that the exact onset of GH hypersecretion is hard to ascertain and often precedes the diagnosis of acromegaly by several years, such a surveillance regimen would appear to be prudent. However, in younger patients, the age at which screening should start remains controversial (18). Some have proposed that colonoscopy only be offered starting at age 40 years (390, 510, 521), but others suggest that screening at diagnosis be performed regardless of age, as up to a fifth of acromegaly patients <40 years of age have been found to have colonic neoplasia vs 5% of controls in one study (495). It would appear reasonable to consider cancer epidemiology and other personal risk factors for younger individuals, and to also consider availability of technical expertise (390). If initial colonoscopy is normal, then patients should be screened in a similar manner to the general population every 10 years (522), provided acromegaly is biochemically controlled (18, 390, 510). More frequent screening may be required in patients with persistently active disease, but the optimal frequency is yet to be determined (259). Some have recommended colonoscopy every 3 to 5 years in patients with either a polyp or persistently elevated IGF-I (18, 510). Surveillance should also be in accordance with guidelines for the general population, taking into account size, number, and histology of the existing polyp (390) and other risk factors. Owing to the frequent finding of dolichocolon and tortuous bowel loops, colonoscopy can be technically challenging in patients with acromegaly (523); it may be prudent for these procedures to be performed by dedicated endoscopy specialists with vast experience in such patients. Despite these guidelines and real-life studies suggesting a progressive increase in screening for colonic polyps during the last few decades, adherence to guidelines remains incomplete. Results from a single-center study in Italy showed that despite endocrinologists routinely offering colonoscopies to patients at diagnosis, only 68% underwent the procedure, and only 25% at diagnosis. Mean time from diagnosis to first colonoscopy was 9 ± 9 years (500). This highlights the need for further patient educational efforts with regard to the long-term implications of chronic GH excess. Thyroid nodules and cancerNodular thyroid disease is frequently seen in patients with acromegaly (7). Thyroid cell proliferation occurs in response to the direct action of hepatic IGF-I on its receptors on thyroid cells and through autocrine secretion of IGF-I by thyrocytes in response to GH stimulation (524). GH and IGF-I also indirectly promote thyroid growth by potentiating the effect of TSH (7, 494). Conversely, individuals with severe untreated GHD due to a homozygous GHRHR mutation and heterozygous carriers of the same mutation have smaller thyroid volumes than do normal subjects, suggesting that GH has a permissive role in the growth of the thyroid gland (525). Thyroid gland volume and the development of nodules have been linked in several, but not all, studies with disease duration and GH and IGF-I levels (526–531). No definite link has, however, been found between thyroid cancer and disease activity or duration per se (477, 532). Nodular goiter has been reported in 43% to 75.6% of patients with acromegaly in ultrasound-based studies, with a pooled prevalence of 59.2% (7, 533). Interestingly, unlike in the general population, where thyroid nodules are threefold to fourfold more common in women (534), the prevalence is comparable in men and women (530). Data on the use of ultrasound elastography in thyroid cancer risk assessment in the general population are mixed and therefore not used routinely (535). It also does not appear to add value to routine ultrasonography in patients with acromegaly. In one study, acromegaly was associated with a high prevalence of stiff thyroid nodules compared with that seen in nonacromegaly patients (56.7% vs 33.7%); however, this did not correlate with malignancy rate, reflecting that the firmness is likely due to fibrosis (536). Based on a review of 11 series published before 2004, thyroid cancer constituted 3.1% of malignancies in acromegaly (7). Several registry-based studies published during that period suggest an increased incidence of thyroid cancer in patients with acromegaly vs the general population, with SIRs ranging from 2.5 to 4.3, albeit with only one to three cancers diagnosed, and a large 95% CI (Table 4) (177, 473, 485). In the last decade, estimates of thyroid cancer prevalence have been doubled, up to 7% (390, 477, 528, 529, 531, 532, 537–542). Registry-based studies conducted during the same period have reported mixed results on thyroid cancer risk. In 2010, a study based on the Finnish registry reported 6 cases of thyroid cancer among 313 patients with acromegaly (SIR, 13.4; 95% CI, 4.9 to 29.3) (479). This is in contrast to a German study, where an increased risk was not evident, with only 3 of 446 thyroid cancers found (SIR, 2.0; P = not significant; CI, 0.4% to 5.8%), likely due to the low number of observed and expected cases (482). Most recently, in an Italian study, 13 out of 1512 cases were reported (SIR, 3.3; 95% CI, 2.32 to 6.87) (490). Eighteen of 999 patients with acromegaly were diagnosed with thyroid cancer in a French cohort, although no information on SIR was available in this report (14). A 2014 meta-analysis of case-control studies showed an increased risk of nodular thyroid disease (OR, 3.6; 95% CI, 1.8 to 7.4) and thyroid cancer (OR, 7.9; 95% CI, 2.8 to 22.0) in patients with acromegaly, compared with healthy controls or patients with other pituitary tumors (533). Of note, however, are the small number of studies included (three for nodular thyroid disease, and five for thyroid cancer) and the low precision estimate due to the low number of events (1 to 10 cases of thyroid cancer). Recently, an update to this meta-analysis was published that included two more recently published case-control studies (492, 531). Pooled ORs for nodular thyroid disease were similar at 3.3, but with a narrower 95% CI (2.1 to 5.4). The pooled OR for thyroid cancer was reduced at 4.1 (95% CI, 2.0 to 8.3) in the updated analysis (543). For various reasons as previously discussed, case-control studies are likely to overestimate risk. Importantly, in the 2014 analysis, of 10 studies that included data on both thyroid nodules and thyroid cancer frequency, rate of malignancy per patient with thyroid nodules was 8.7% (95% CI, 6.1 to 12.3), which was not significantly higher than that of patients with nodular thyroid disease and without acromegaly (RR, 3.2; 95% CI, 0.5 to 20.1) (533). Therefore, it remains controversial whether the risk of thyroid cancer is indeed increased in patients with acromegaly. Furthermore, thyroid malignancy is frequently asymptomatic in the general population. Routine screening is not advocated, and the true incidence in the general population is therefore unknown. In the context of case series and case-controls studies where all acromegaly patients are routinely subjected to ultrasonography, the absence of a comparative group or the comparison with unmatched controls is likely to result in bias (390). Likewise, heterogeneity of study methodologies, including differing indications for ultrasonography [routine screening in all acromegaly patients (476, 477, 529, 531, 532, 538, 540) vs selected screening in patients with a palpable goiter or nodule (528)], criteria for fine needle aspiration biopsy (FNAB), or surgical resection, make comparison of results between studies difficult. The observed trend toward a higher prevalence of thyroid cancer in acromegaly patients may merely be a reflection of an increased rate of screening and diagnosis, similar to that seen in the general population, the “epidemic of diagnosis” (544). Additionally, although some studies have not provided information on thyroid cancer size (540, 543), several studies, in determining prevalence of thyroid cancer, have taken into account micropapillary carcinomas identified during routine ultrasonography screening and biopsied based on suspicious imaging characteristics (476, 529, 538, 541). In the general population, excellent long-term outcomes seen after surgical management of such microcarcinomas have been attributed to the indolent nature of the disease, rather than treatment effectiveness (535, 545); it is unclear whether screening for, and surgical resection of, such tumors affects long-term morbidity and survival in acromegaly. This is unlikely, as the natural history of thyroid cancer in acromegaly does not appear to differ greatly from that in the general population; multifocal, aggressive, or anaplastic tumors have only rarely been reported (7, 178, 390, 487). The most frequently reported thyroid cancer in acromegaly is differentiated thyroid cancer, most commonly papillary thyroid cancer (PTC) (476, 477, 530, 532, 540, 546), reflecting a similarity to epidemiology in the general population. Whereas BRAF mutations are the most common genetic alterations in the general population (accounting for ~45% of cases) (547), this is not clearly apparent in the acromegaly population. Molecular alterations in thyroid cancer in acromegaly patients have been of interest. A 2014 study reported a 70% prevalence of BRAF V600E mutations in acromegaly patients with PTC (542). In contrast, more recent case-control studies suggest that the frequency of BRAF mutations may be lower in PTC in patients with acromegaly compared with patients without acromegaly (541, 548). In one retrospective study of 60 acromegaly patients who underwent routine thyroid ultrasonography, the BRAF V600E mutation was present in only 1 of 11 (9.1%) patients diagnosed with PTC, as compared with 62.5% of control nonacromegaly patients with PTC (P = 0.007) (541). Another small study reported similarly low BRAF mutations (14.3%), but higher NRAS codon 61 mutations, detected in 21.4% of acromegaly patients with differentiated thyroid cancer (548). No alterations in RET/PTC and PAX8/PPARγ gene arrangements were found. At present, the impact of BRAF status and molecular profiling on PTC extent, prognosis, and management have not been established in the general population (535); findings from the above mentioned studies will need confirmation in larger and longitudinal studies before any clinical application of such molecular profiling in the context of acromegaly can be determined. Recommendations.More recently, there have been increasing calls for routine surveillance for both thyroid nodules and cancer in patients with acromegaly (18). However, in the general population, ultrasound is recommended only in the presence of clinically palpable thyroid nodularity, rather than routinely. In the authors’ view, this approach is reasonable, and given the lack of evidence for improved morbidity and mortality through early and aggressive treatment of small and low-risk thyroid malignancies, it would also be cost-effective. In one study, which employed such a surveillance method, two thirds of acromegaly patients underwent ultrasonography, of which 7.8% were found to have differentiated thyroid cancer. Cancer remission occurred in all patients diagnosed in this manner (528). In the absence of symptoms, or patient-observed goiter, clinical examination for thyroid nodules should be performed yearly, followed by ultrasonography in those with palpable nodules. In general, indications for FNAB should be guided by guidelines for the investigation of thyroid nodules. However, although current guidelines recommend a cut-off of 1.5 cm as an indication for FNAB in low-suspicion nodules (535), based on the above-mentioned studies, most of which employed the older recommended cut-off of 1 cm (549), it may be prudent to consider a 1 cm threshold for FNAB in acromegaly patients. Other cancersWith regard to breast and other cancers, no increase in risk has been conclusively reported (18). One recent single-center case-control study demonstrated an increased risk of breast cancer in acromegaly patients compared with controls (5.4% vs 0%, P = 0.02) (492). However, in registry-based studies, breast cancer does not appear to be more prevalent than in the general population (SIR, 0.9 to 1.3; P = not significant) (4, 177, 473, 479, 482, 490), and insufficient data are available for prostate and kidney cancer. However, assessment for other risk factors and adherence to standard age- and gender-based international, local screening guidelines should be emphasized in patients with acromegaly (18, 259, 390, 519). However, assessment for other risk factors and adherence to standard age- and gender-based international and local guidelines should be emphasized in patients with acromegaly. SummaryAlthough data from in vitro and in vivo studies seem to suggest a strong link between the GH/IGF-I axis and tumorigenesis, it is not possible to conclusively extrapolate these results to patients with acromegaly. Uncontrolled acromegaly theoretically confers a growth advantage to pre-existing neoplasms due to prolonged GH excess inducing both IGF-I and IGFBP3 production; however, the resultant balance and regulation of cell growth and cell death are unpredictable. There is no clear evidence for enhanced de novo tumorigenesis in acromegaly and, as yet, no direct proven causal relationship between acromegaly and malignancy. The true incidence of malignancy and cancer-linked mortality in acromegaly remains inconclusive. Control of GH excess continues to be a key priority, and attention must be paid to timely and appropriate screening, especially witth respect to colorectal cancer. Metabolic complicationsGH and IGF-I have several metabolic functions in humans (550). These growth factors influence glucose, protein, and lipid metabolism through different pathways, depending on the nutrition state (feast or famine) (550). Consequences of excess GH levels on metabolism in patients with acromegaly are addressed below. Effects of GH and IGF-I on glucose and lipid metabolismGH, the major anabolic hormone that functions in states of food restriction, counters the actions of insulin, the major anabolic hormone that functions in states with excess food (550). IGF-I exerts the opposite effects on glucose and lipid metabolism compared with GH (551).
During fasting states, the major effects of GH on normal subjects are the inductions of lipolysis and lipid oxidation, modifying fuel consumption from carbohydrates and protein to lipids (552). The administration of GH to healthy male subjects leads to a dose-dependent elevation of serum free fatty acids (FFAs), 3-hydroxy-butyrate, and glycerol levels and induces lipid oxidation, as assessed by indirect calorimetry (553, 554). It potentiates epinephrine-induced lipolysis in adipocytes (555). GH also inhibits lipoprotein lipase activity in adipose tissues, counteracting the effects of insulin and GCs, and subsequently contributing to increased levels of serum lipids and changes in body fat distribution (556). Lipoprotein lipase is the major enzyme driving the hydrolysis of triacylglycerol in chylomicrons to provide FFAs for tissue storage and utilization (557). The increase in the efflux of FFAs to the liver in combination with the presence of IR increases the synthesis of triglycerides (TGs) and reduces high-density lipoprotein (HDL) levels (550). In contrast, IGF-I promotes FFA uptake into adipocytes and hepatocytes, leading to reduced serum FFA levels (558). IGF-I also induces lipogenesis, although this effect on lipid metabolism appears to be less important (551, 559). GH impacts glucose metabolism by influencing both insulin secretion and action (550, 560). Although GH stimulates insulin secretion, the predominant effect is to induce IR that elevates glucose levels and subsequently increases the prevalence of prediabetes and DM (560). One of the main consequences of excess GH is a reduction in glucose uptake (550, 552, 553) secondary to increased FFA levels and to reduction in the expression of glucose transporters 1 and 4 (560). The increase in FFA production seems to be the main mechanism underlying the development of IR in patients with acromegaly (561). Additionally, GH directly impairs the insulin-induced intracellular signaling pathway by blocking insulin receptor substrate-1 and phosphoinositide 3-kinase in adipose tissues (562). An increase in gluconeogenesis has been observed due to increased glucose synthesis in the liver and/or in the kidney (563, 564). More recently, another mechanism that contributes to IR in patients with acromegaly has been proposed (565). GH increases the expression of genes encoding adipokines, such as visfatin and IL-6, which induce an inflammatory state in the adipose tissue and lead to IR (565–567). Therefore, although patients with acromegaly exhibit a reduced fat mass compared with healthy subjects, the adipose tissue in patients with acromegaly can display an “inflammatory” phenotype that contributes to the elevated lipid levels and IR observed in these patients (565, 566). Additionally, GH stimulates insulin secretion to induce β-cell proliferation, insulin synthesis, and secretion (560, 568). IGF-I exerts the opposite effects to GH on glucose metabolism, as it increases glucose uptake in the tissues, thereby increasing insulin sensitivity (558). In patients with acromegaly, the balance between the beneficial effects of GH on insulin secretion and of IGF-I on insulin action and the negative effect of GH on IR determine the patient’s individual risk of developing glucose intolerance and DM. Figure 6 exhibits the main actions of GH on glucose and lipid metabolism. Figure 6. Effects of GH on glucose and lipid metabolism in acromegaly. GLUT, glucose transporter. [© 2019 Illustration Presentation ENDOCRINE SOCIETY]. Glucose abnormalities in patients with acromegalyAlthough most patients with acromegaly present with hyperinsulinemia and IR, not all patients exhibit abnormal glucose levels (560). Therefore, impairments in β-cell function are probably present in patients who develop abnormalities in glucose metabolism, including those who develop secondary DM that may be present in acromegaly (7, 569). The prevalence of secondary DM in different case series reported in the literature is highly variable; it was previously reported to range from 16% to 56% in two literature reviews (7, 560). Various factors may contribute to this difference, including ethnicity and the methodology used to diagnose DM (fasting glucose level, OGTT, or HbA1c level) (560). Studies evaluating the prevalence of prediabetes [impaired glucose tolerance (IGT) and impaired fasting glucose (IFG)] are rare (560). Recently, single-center studies and large national acromegaly database investigations have reported a prevalence of DM ranging from 11% to 53% (Table 5) (93, 99, 180, 191, 570–578). In larger multicenter series, the prevalence of DM in patients with acromegaly was ~30% (99, 573, 575), a value that was clearly higher than the prevalence observed in the normal population (575, 576). Table 5. Studies Evaluating Glucose Metabolism in Acromegaly
Abbreviation: N/A, not available. a Combined IFG and IGT. b The prevalence of IFG and/or IGT was 26%, but prevalence of each one individually was not provided. Table 5. Studies Evaluating Glucose Metabolism in Acromegaly
Abbreviation: N/A, not available. a Combined IFG and IGT. b The prevalence of IFG and/or IGT was 26%, but prevalence of each one individually was not provided. Niculescu et al. (574) evaluated 114 patients and observed that 38.6% presented some type of glucose abnormality (18.4% had IFG, 9.6% had IGT, and 10.5% had DM). IR indices positively correlated with both GH and IGF-I levels. Ciresi et al. (572) evaluated 24 patients and observed that 45.8% had IFG and 29.2% had IGT, whereas 24.9% presented with normal glucose tolerance and no patient presented with DM. In this study, the authors evaluated the visceral adipose index (VAI) and insulin secretion and resistance with the euglycemic hyperinsulinemic clamp. A positive correlation between VAI and GH levels was observed, and patients with a high VAI showed decreased insulin sensitivity (572). In a larger multicenter study (307 patients), the same authors observed frequencies of 6.2%, 10.7%, 33.3%, and 49.8% for IGT, combined IFG and IGT, DM, and normal glucose levels, respectively (571). Interestingly, in this study, sex affected the frequency of DM, as a greater proportion of female patients had DM (51.3% vs 19.1% for male patients, P < 0.001). Furthermore, women presented higher fasting insulin levels and homeostasis model assessment of the IR index (HOMA-IR) values (571). However, in a larger retrospective series (519 patients), differences in DM prevalence were not observed between sexes (575). Presence of abnormal glucose metabolism is associated with an older age, disease duration, a family history of DM, and higher GH and IGF-I levels (570, 573); these patients also display a higher prevalence of AH (573). Severity of DM in patients with acromegaly varies widely between studies and is probably influenced by genetic predisposition, BMI, GH and IGF-I levels, and age (560). A significant proportion of patients have a mild disease that is treated by modifying the diet; more severe DM and even cases of diabetic ketoacidosis have been observed as the form of the disease at presentation in patients with acromegaly (180, 575, 579). In most patients, good control of glucose levels is achieved through diet alone or in combination with metformin; the addition of other drugs, including insulin therapy, has been successful in other cases (580). Lipid abnormalities in patients with acromegalyAs previously described, GH induces lipolysis and subsequent FFA release into the circulation (558). An “inflammatory” phenotype of the adipose tissue has also been described (565). Therefore, hyperlipidemia is expected at presentation in patients with acromegaly, with a prevalence ranging from 13% to 51%, depending on the series (93, 124, 566, 581, 582). The main abnormalities of lipid metabolism in patients with acromegaly are hypertriglyceridemia and reduced HDL levels (583). The levels of low-density lipoprotein (LDL) are either similar to (584) or greater than normal subjects (88, 583). Additionally, higher levels of oxidized LDL have been described (585). Boero et al. (582) evaluated 18 patients with acromegaly and 18 sex- and age-matched controls and observed higher TG and apolipoprotein B levels and a higher TG/HDL ratio in patients with acromegaly. Vilar et al. (583) evaluated 62 patients and observed higher levels of total cholesterol, LDL, and lipoprotein(a) and lower levels of HDL than in the control group. Effects of treatments for acromegaly on metabolic complicationsAs described above, DM and hyperlipidemia are frequent comorbidities of acromegaly and, therefore, the effect of each treatment option on glucose and lipid metabolism is of great interest. Surgical cure can improve glucose levels and reduce TG levels in most, but not all, patients. Colao et al. (577) prospectively evaluated glucose metabolism in 100 patients with acromegaly for 5 years. Patients were divided into four groups: A, SRL treatment only (n = 34); B, SRLs followed by surgery (n = 20); C, surgery only (cured by surgery, n = 30); and D, surgery followed by SRLs (n = 16). Interestingly, the authors only observed improvements in the fasting glucose levels in patients in group A. During follow-up, new-onset DM was observed in 16% of patients treated with SRLs and in 13% of the patients treated with surgery alone. The same expert group expanded the evaluation to 80 patients treated with surgery and observed reductions in HOMA-IR and VAI, but did not observe changes in HbA1c or fasting insulin levels after surgery (578). However, surgery improved the lipid profile, as hypertriglyceridemia decreased from 23% to 10% and low HDL levels decreased from 46% to 35%, both of which were statistically significant. A similar effect on lipid profile was reported by Reyes-Vidal et al. (586), who showed both reduced TG levels and increased HDL cholesterol levels after surgery. In contrast to previously discussed studies, Kinoshita et al. (587) showed that a normal OGTT was reestablished in 27 of 53 patients (51%) with DM or IGT before surgery. Moreover, patients with impaired β-cell function did not improve after surgery, but IR improved in all patients (587). Consistent with these findings, Tzanela et al. (588) compared patients whose disease was controlled with SRLs alone (n = 20) or cured after surgery (n = 30) and only observed a significant reduction in posttreatment fasting glucose levels in the surgery group. Both groups exhibited a reduction in post-glucose insulin levels and HOMA-IR, but a reduction of HOMA-β was only observed in the SRL group, indicating an impairment in β-cell function (588). Rochette et al. (589) evaluated 130 patients with controlled acromegaly (73 cured by surgery, 34 patients controlled with medical therapy, and 23 patients who were also treated with radiotherapy). A reduction in IGT and/or IFG prevalence was observed after disease control (21.4% vs 5.4%, respectively), without changes in DM prevalence (20.5% and 21.6%, respectively). Interestingly, after excluding patients who had received radiotherapy, 41.2% of the patients whose disease was controlled with SRLs presented glucose abnormalities compared with only 20.5% of patients who were cured by surgery. In the same study, the prevalence of hypertriglyceridemia was reduced from 28% at diagnosis to 15% after disease control (589). The effect of medical treatment on metabolic parameters in patients with acromegaly has been reported for most of the drugs; SRLs are the most studied (560). SSTR ligands act by binding to and activating the SSTR. Five SSTRs have been reported, and SRLs bind to SSTR2 with higher affinity but also activate SSTR5 (590, 591). SSTRs are also expressed in α-cells and β-cells and, thus, SRLs can impact glucagon and insulin secretion (592). The SSTR that is expressed at the highest levels in β-cells is SSTR5, whereas SSTR2 is expressed at the highest levels in α-cells (593). The impact of SRLs has been previously addressed. Mazziotti et al. (594) performed a meta-analysis encompassing 619 patients; no significant effects on fasting plasma glucose levels or HbA1c levels were observed, and similar results were obtained for octreotide and lanreotide. Additionally, a significant decrease in fasting plasma insulin levels was observed following treatment. Notably, the effect of SRLs on glucose metabolism was not influenced by the duration of treatment or the biochemical response to the drugs (594). In a subsequent study, Colao et al. (595) reported the effect of SRL treatment (octreotide LAR or lanreotide SR) on 112 patients who were prospectively evaluated for 12 months, and disease control was achieved in 48% of the patients (normal age-matched IGF-I and GH levels <2.5 μg/L). Glucose levels improved in 10% and were impaired in 15% of the patients. As expected, patients who presented improvements were more likely to be controlled by SRL treatment. More recently, Caron et al. (596) studied 90 patients who were primarily treated with lanreotide Autogel at 120 mg for 48 weeks, and disease control was achieved in 44% (defined as normal age-matched IGF-I and GH levels ≤2.5 μg/L). The authors did not observe effects on fasting plasma glucose or HbA1c levels in the whole cohort. Among the patients who presented with DM at baseline, the HbA1c levels decreased by 1.44% (95% CI, −2.52 to −0.36). In the same study, the authors also reported a significant decrease in TG levels and a significant increase in HDL levels, without modifications of LDL cholesterol levels (596). PEG theoretically can reverse the deleterious effects of GH on glucose and lipid metabolism without affecting insulin secretion (560). Indeed, seven patients with active acromegaly who were treated with PEG for 4 weeks exhibited reduced basal serum glucose and insulin levels and increased suppression of endogenous glucose production, as evaluated using an euglycemic clamp (597). Additionally, five patients who were treated with PEG exhibited reduced overnight FFA concentrations and increased insulin sensitivity, both of which were evaluated using a hyperinsulinemic euglycemic clamp (598). An improved beneficial effect of PEG on glucose metabolism compared with SRLs was noted in two studies where the treatment was switched from an SRL to PEG (599, 600). Barkan et al. (599) observed a reduction in fasting plasma glucose (−30.6 mg/dL) and HbA1c (−0.2%) levels in 53 patients with acromegaly after the treatment change, regardless of the presence of DM. However, in patients with DM, a greater reduction in HbA1c levels was observed: 1.5% after 32 weeks of treatment. Colao et al. (600) studied 16 patients who were previously resistant to SRLs and switched to PEG, and they observed a reduction in plasma glucose (−21.6 mg/dL) and insulin levels (−4.3 mIU/L) and an increase in HDL cholesterol levels (+0.3 mmol/L). Furthermore, the addition of PEG to SRL treatment has been reported to reduce plasma glucose levels compared with SRLs alone; an additional reduction was observed when SRLs were withdrawn (601). Pasireotide binds to SSTR3 and SSTR5 with higher affinity than SRLs (22, 602). Based on the results from studies of healthy volunteers, pasireotide elevates both fasting and postprandial plasma glucose levels. These elevations are a consequence of a marked suppression of insulin secretion, with only a mild inhibition of glucagon secretion, and are also secondary to a suppression of incretin production (glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide) (603, 604). Accordingly, in a large head-to-head clinical trial, hyperglycemia-related events were observed in 57.3% of patients treated with pasireotide LAR compared with 21.7% of patients treated with octreotide LAR. Most patients only exhibited slightly elevated glucose levels, with increases in mean HbA1c levels (from baseline to 12 months) of 0.87%, 0.64%, and 0.75% in patients with DM, prediabetic patients, and patients with normal glucose tolerance at baseline, respectively. However, pasireotide was discontinued in six patients due to hyperglycemia. In the PAOLA study, in which patients whose disease was not controlled with SRLs were randomized to maintain the treatment or to switch to pasireotide LAR (24), hyperglycemia-related adverse events were reported in 67%, 61%, and 30% of the patients in the pasireotide LAR at 40 mg, pasireotide LAR at 60 mg, and SRL groups, respectively, and five patients discontinued the drug due to hyperglycemia. Additionally, 24 (38%) patients in the pasireotide LAR at 40 mg group and 24 patients (39%) in the pasireotide LAR at 60 mg group required a new antidiabetic treatment. Interestingly, the prevalence of hyperglycemia was similar in patients who did or did not exhibit a biochemical response to pasireotide treatment, and hyperglycemia was more frequently observed in patients with baseline fasting plasma glucose levels >100 mg/dL (80% of patients treated with pasireotide in the study) (605). Pasireotide-related hyperglycemia seems to be reversible after drug discontinuation, as fasting plasma glucose and HbA1c levels decreased to near normal levels after switching from pasireotide LAR to octreotide LAR in another study (606). The rates of hyperglycemia have been confirmed in the ACCESS trial, in which patients were treated with pasireotide LAR at 40 mg in a closer to real life setting; mean fasting plasma glucose and HbA1c levels increased from 100.4 mg/dL and 5.9% at baseline to 135.9 mg/dL and 6.8% after 3 months of treatment, respectively (607). Hyperglycemia-related adverse events were reported in 46% of patients (607), and 48% of patients initiated an antidiabetic medication.
The addition of PEG, a drug with a favorable effect on glucose metabolism, could theoretically mitigate the deleterious effect of pasireotide on glucose levels. However, in a recent trial (PAPE study), patients whose disease was controlled with SRLs plus PEG were switched to pasireotide plus PEG and worsening of glucose levels was noted; the percentage of patients with DM increased from 32.8% at baseline to 68.9% after 24 weeks of treatment (608). Of note, however, the PEG dose was reduced by 66% after changing the SRLs to pasireotide owing to improved biochemical efficacy on combination. Recommendations for managing hyperglycemia in patients who are treated with pasireotide have been published (609, 610). Glucose levels usually increase in the first 1 to 3 months of treatment and remain stable thereafter (22, 610). A patient with normal glucose metabolism before pasireotide initiation should self-monitor blood glucose levels once or twice a week in the first 1 to 3 months. However, patients with impaired glucose metabolism at baseline require daily self-monitoring of blood glucose levels (22, 610). If glucose levels remain elevated despite dietary therapy, metformin is a good first-line therapy; if hyperglycemia persists, either a glucagon-like peptide 1 agonist or a dipeptidyl peptidase-4 inhibitor is the more logical choice, considering the effects of pasireotide on incretin secretion (610). Patients with more severe hyperglycemia (fasting glucose levels >250 mg/dL) should discontinue pasireotide or initiate insulin treatment when no other therapies for acromegaly are available (610). In summary, different treatment modalities can exert different effects on glucose metabolism in patients with acromegaly (Fig. 7). Diabetes is not reversible in some patients despite biochemical control of acromegaly. Although surgery and PEG exert neutral or even beneficial effects, the effects of SRLs vary between patients, but are mostly neutral in most cases. Pasireotide, alternatively, exerts a deleterious effect on glucose levels. No studies have evaluated the effect of the DA cabergoline on glucose metabolism in patients with acromegaly. Figure 7. Effects of different treatments on glucose metabolism in acromegaly. All treatments lead to reduction of IR; SRLs and multireceptor-targeted SRL pasireotide cause reduction of insulin (more pronounced with pasireotide) and glucagon (more pronounced with SRLs) secretion; only pasireotide causes a reduction of incretin secretion. The sum of all effects result in beneficial effects for surgery and PEG, neutral effects for SRLs, and detrimental effects on glucose metabolism for pasireotide in most patients. [© 2019 Illustration Presentation ENDOCRINE SOCIETY]. Potentially novel drugs are under development: a new dual SSTR2/SSTR5-specific SRL, AP102, did not induce hyperglycemia compared with pasireotide in a study using a healthy rat model (611), and somatoprim is 10,000-fold more potent in inhibiting GH release than insulin secretion (612). The effects of the therapy on lipids are less well described, but beneficial effects of surgery and SRLs have been reported. RecommendationsAs glucose and lipid abnormalities are frequent in patients with acromegaly, measurements of fasting glucose levels and lipid profiles are advised in all patients at diagnosis. In patients with active disease, annual tests for glucose levels, HbA1c levels, and the lipid panel are recommended. The timeline for screening in patients with a controlled disease is less clear, but it should depend on age, BMI, type of treatment, and the presence of other comorbidities. In cases when the treatment changes or a new treatment is initiated, glucose levels should be measured earlier, particularly in patients who are treated with pasireotide LAR in whom a worsening of glucose levels can occur at the beginning of treatment. Metabolic comorbidities should be aggressively treated according to general guidelines (51, 174, 613, 614). Pituitary hormone alterations in acromegalyHyperprolactinemiaHyperprolactinemia in acromegaly, similar to NFPAs (615–619), may be due to a “stalk effect,” in which there is disruption of the normal dopaminergic inhibition of prolactin (PRL) secretion owing to space-occupying and pressure effects of a macroadenoma. Additionally, ~25% of GH-secreting adenomas co-secrete PRL (2). These include mixed somatotroph/lactotroph adenomas (dimorphous adenomas composed of both somatotrophs and lactotrophs), mammosomatotroph adenomas (monomorphous adenomas that produce both GH and PRL), and the more primitive acidophil stem-cell adenoma (620, 621). These GH-PRL adenomas have been demonstrated to have lower surgical cure rates than do pure somatotroph adenomas (622). However, whether these adenomas have different patient demographics or tumor behavior from pure somatotroph adenomas remains to be investigated (623). Interestingly, patients who secrete GH and PRL unsynchronously have also been reported; some patients initially diagnosed as having prolactinomas may develop acromegaly (624–626). Patients with gigantism often have plurihormonal (especially prolactin) hypersecretion (18). Hyperprolactinemia is an important contributor to hypogonadism in acromegaly (627–629), especially for microadenomas (629), and it has been documented in up to 45% of patients with hypogonadism at diagnosis of acromegaly (629). In females, a higher incidence of menstrual disorders and galactorrhea is seen in patients with concurrent hyperprolactinemia than in patients with pure GH-secreting tumors (630). Dopamine receptor type 2 is expressed on both pure GH-secreting adenomas and GH-PRL adenomas (631); DAs suppress GH secretion in acromegaly (632, 633), both as monotherapy (25, 27) and in combination with SRLs (25, 27, 634–636) or PEG (33, 637). Mechanisms leading to GH suppression are unclear. Whether treatment outcomes depend on the presence of hyperprolactinemia remains controversial. Hyperprolactinemia was found in some studies to be predictive of tumor response to DAs (27, 638); others have demonstrated that neither baseline PRL levels, positive immunohistochemical staining for PRL (634–636, 639–642), nor dopamine receptor type 2 (635) predicts treatment efficacy. Importantly, however, greater efficacy is seen in patients with mild IGF-I elevations, with or without hyperprolactinemia (17, 18, 25). HypopituitarismIt is well known that hypopituitarism (defined as one or more pituitary hormone deficiency) itself leads to excess mortality (40, 643, 644). In a recent meta-analysis of observational studies, hypopituitarism was associated with an overall excess mortality (weighted SMR, 1.99; 95% CI, 1.21 to 2.76) in adults (643). Given previous data on possible excess mortality already associated with acromegaly (see details in “Mortality in Patients With Acromegaly: The Changing Face of the Disease in Recent Decades” below), emphasis needs to be placed on minimizing the development of hypopituitarism (including GHD) and, if present, adequate replacement of pituitary deficiencies. Hypopituitarism in acromegaly is attributable to compression of normal pituitary tissue and/or stalk, usually in the setting of macroadenomas, or a result of treatment. Basal and pulsatile TSH has been found to be diminished also in the absence of other pituitary hormone deficits, suggesting an increased restraint by tumoral GH feedback-driven somatostatin outflow in addition to tumor-compressive effects (645, 646). Adrenal insufficiency (AI) has been reported in up to 20% of the patients and central hypothyroidism in 9% of cases (519, 647–649). Hypogonadism has been described in up to 70% of women of child-bearing age (627, 628) and in up to 50% of men at diagnosis (628). The estimated prevalence of hypopituitarism ranges from 23% to 40% in registry-based studies (14, 180, 352, 650, 651). Most recently, in a Swedish registry, a prevalence of 34% was recorded (650), similar to that documented in the French and Spanish registries (31% and 26%, respectively) (14, 352). Notably, the prevalence of hypopituitarism declined from 41% to 23% during three time periods, that is, 1987 to 1995, 1996 to 2004, and 2005 to 2013 (650). This may be associated with an improvement in surgical techniques, the more widespread use of pharmacotherapy, and the decline in radiation treatment over time (14, 652). Interestingly, there appears to be a relative sparing of anterior pituitary function in patients with acromegaly due to a pituitary macroadenoma at baseline, in comparison with NFPAs. Greenman et al. (653) found that despite similar tumor grade/stage, patients with acromegaly had a lower AI prevalence (7% vs 43%, P = 0.02), hypothyroidism (0% vs 23%, P = 0.06), and secondary hypogonadism (40% vs 78%, P < 0.05) compared with NFPA patients (653). Furthermore, 46% vs 89% had at least one deficiency, and only 8% had deficiencies in more than one axis, compared with 56% in those with NFPAs. Rates were similar to studies documenting the preoperative status of these two diseases separately (616, 654–658). Reasons for these differences are, however, not clear. Effects of treatments for acromegaly on pituitary functionPituitary surgery.Reported rates of new anterior pituitary deficits that occur after surgery for acromegaly differ widely in the literature, ranging from 4% to 39% (622, 659–663). A systemic review and meta-analysis assessed close to 7000 patients and documented a weighted incidence rate of 6.5% (95% CI, 4.1 to 9.4) for central AI, 4.4% (95% CI, 3.0 to 6.0) for central hypothyroidism, 6.7% (95% CI, 3.9 to 10.2) for central hypogonadism, 12.8% (95% CI, 9.9 to 16.0) for hypopituitarism, and 2.5% (95% CI, 1.2 to 4.2) for panhypopituitarism (664). Studies on repeat or aggressive pituitary surgery had conflicting results; some studies suggest a higher rate of hypopituitarism (665, 666), whereas several others report that the overall risk for new pituitary hormone deficiencies is not significantly higher, and that aggressive surgery may be necessary to achieve biochemical control (662, 667–669). However, in the aforementioned study by Carvalho et al. (664), although the incidence of individual pituitary hormone deficiencies was similar, a statistically significant (albeit small) lower incidence of panhypopituitarism was observed in patients who had transsphenoidal selective adenomectomy, compared with those requiring craniotomy or a hypophysectomy (0.50% vs 0.59%). There is, however, no evidence to suggest that patients who achieve biochemical control of GH excess after surgery are at greater risk of developing a new pituitary hormone deficiency (659). Several systematic reviews and meta-analyses of outcomes in endoscopic endonasal vs microsurgical transsphenoidal surgery (TSS) examined the role of different surgical techniques in postoperative hypopituitarism. Thus far, no significant difference in rates of postoperative hypopituitarism, AI, hypothyroidism, hypogonadism, and permanent or temporary diabetes insipidus has been found (670–673). Most recently, Phan et al. (670) examined 950 acromegaly patients who underwent endoscopic TSS, and 2137 patients who underwent microsurgical resection; AI occurred in 13.7% (4.8 to 23.6) vs 15.9% (0.3 to 31.6), hypothyroidism in 4.1% (0.5 to 7.8) vs 16.1% (0.6 to 26), and hypogonadism in 2.0% (0 to 4.8) vs 7.7% (1.9 to 13.5), all statistically not significant. Overall, several studies have confirmed that surgical complications are lower with increasing surgical technical expertise (674, 675). Even though pituitary surgery may induce new pituitary insufficiencies, several studies also demonstrate that improvement in pituitary function has also been shown to improve in both NFPAs (658, 676, 677) and hormone-secreting tumors (678, 679), although different study methodologies, including differing definitions of pituitary hormone recovery, need to be taken into account. Earlier studies showed that a single assessment of cortisol reserve at the beginning of the late postoperative phase, in patients with a sellar mass undergoing surgical resection, is predictive of long-term cortisol sufficiency in the absence of tumor recurrence (676, 680). This has led to the common clinical practice of assessing cortisol reserve 1 to 3 months after surgery, with patients demonstrating AI being left on replacement therapy without repeated testing. However, in the first postoperative year, recovery of some pituitary function has been documented in as many as 50% of patients (658, 679), with recovery of ACTH being the most frequent (679).The ongoing recovery of corticotroph function is thought to be due to re-expansion of the compressed normal pituitary, but the mechanism is likely multifactorial (681). In acromegaly, normalization of adrenal function has been observed within 1 year in half of patients with AI in the early postoperative period (682). Burgers et al. (682) observed AI in 16 of 91 (18%) patients in the early postoperative period, with a lower prevalence, 12%, at 1 year postoperatively. The incidence rate of late, new-onset AI [based on an insulin tolerance test (ITT)] was two per 1000 person-years. Additionally, AI recovery in the first year postoperatively appears to be more apparent in patients with acromegaly undergoing pituitary surgery vs NFPAs; 60% of acromegaly vs 45% NFPA patients, matched for tumor size (P = 0.003), regardless of the need for adjunctive medical therapy to maintain disease control (683). Studies have also documented improvement in gonadal function postoperatively with normalization of testosterone levels in 41% of men and return of regular menses in 83% of women (659). Conversely, no significant changes in TSH deficiency have been observed postoperatively (537, 659, 684). Radiation therapy.The reported incidence of hypopituitarism is higher with radiation therapy than with surgery alone (650). Traditionally, CRT has been used, in which a linear accelerator is used to focus single beams of high-energy radiation onto the treatment zone, with a total dose of 40 to 45 Gy, fractionated in at least 20 sessions. Although it achieves long-term tumor growth control in most patients and GH/IGF-I normalization in 60% to 80% during 5 to 15 years (685–691), several adverse effects related to irradiation of healthy surrounding tissues have been well described, most notably hypopituitarism. Hypopituitarism has been documented in 30% to 80% of patients at 5 to 10 years after CRT (686, 688–690, 692–695). Stereotactic radiation therapy delivers a more precise high radiation dose to a defined target, with a steep dose gradient at the tumor margin, thereby limiting effects on surrounding tissues (695). The most commonly used technique is stereotactic radiosurgery (SRS), with less long-term data being available for fractionated stereotactic radiotherapy. In a recent systematic review and meta-analysis of studies including 2464 patients, followed up between 12 and 240 months (696), the incidence of hypopituitarism was reported to be lower in SRS-treated as compared with CRT-treated patients (32% vs 51%, P = 0.05), largely due to differences in hypogonadism rates. However, noncomparative data, large heterogeneity, and the lack of long-term follow-up in some studies make a direct comparison between these modalities difficult. Hypopituitarism remains highly prevalent despite the utilization of stereotactic techniques, and it increases over time (697, 698), occurring in up to a third of patients with acromegaly at a mean follow-up duration of 5 years (695, 697–699) and nearly 60% at 10 years (695). Varying degrees of deficiencies in each pituitary hormone have been reported, with panhypopituitarism being documented in a small (1.5%) but significant proportion (698). Several predictors of stereotactic radiation therapy–induced hypopituitarism include residual tumor volume, suprasellar extension, cavernous sinus invasion and prior craniotomy (markers of tumor extent and invasion), radiation dose to tumor margins, pretreatment pituitary gland function, and duration of follow-up (697–702). Medical therapy.Limited data on the effect of medical therapy on anterior pituitary function is available. In human fetal pituitary cell cultures, SRLs with high affinity for SSTR2 or SSTR5 decrease TSH (703). Based on manufacturer reports (640, 704, 705), decreases in thyroid function have been reported with the use of the SRLs in acromegaly, with central hypothyroidism documented in 2% for octreotide LAR (706). In a small randomized prospective study that compared primary therapy with octreotide LAR and surgical treatment in 22 newly diagnosed patients with acromegaly, no patients in either group developed hypothyroidism at 1 year follow-up, nor there were any significant TSH changes (707). In another study of treatment-naive patients on lanreotide, FT4 and TSH levels did not change after treatment (89). Although SRLs reduce TSH secretion in patients with TSHomas (708), the effect on normal TSH secretion of the pituitary seems to be overall negligible. In the aforementioned octreotide LAR prospective study, the number of patients with AI was also similar in both groups at 12 months (707). However, although clinical hypothyroidism is rare (<1%) (704), thyroid function tests are recommended where clinically indicated. Pasireotide has higher binding affinity for SSTR5 (631, 709) and thus a higher potential for ACTH and/or TSH suppression. Monitoring pituitary function (e.g., thyroid, adrenal, gonadal) prior to initiation of therapy with pasireotide LAR, as well as periodically during treatment, as clinically appropriate, is recommended (602, 705). GH inhibits the activity of 11β-hydroxysteroid dehydrogenase type 1, the enzyme that is responsible for the conversion of cortisone to cortisol in the liver, adipocytes, and gonads. Conversely, 11β-hydroxysteroid dehydrogenase type 2, which converts cortisol to cortisone, is not influenced by GH (710). Trainer et al. (711), by measuring urinary metabolites of cortisol and cortisone, demonstrated that blockade of GH action with PEG was associated with reversal of the inhibition of 11β-hydroxysteroid dehydrogenase type 1, thereby producing a net increase in cortisone to cortisol conversion. This accelerated clearance of cortisol is reversed by successful treatment (711). Therefore, GH normalization with treatment may potentially influence GC replacement doses; dose reductions of hydrocortisone may be needed to avoid overtreatment after cortisol clearance reduction. GHD in (over)treated acromegaly and the impact of recombinant human GH treatmentThe exact prevalence of GHD in patients treated for acromegaly (acroGHD) is uncertain but has been reported to be 10% to 50% after pituitary surgery (712–714). The variable frequencies reported are likely to be related to differences in methods used in dynamic evaluation of GH reserve, interval after surgical resection, tumor size, and surgical expertise (715). Tumor volume or preoperative GH/IGF-I levels per se do not appear to be independent predictors of GHD (712, 714). In one study of 123 acromegaly patients after TSS and followed up for a mean duration of 5.8 (3 to 12.1) years (712), 72-h postoperative GH levels (OR, 0.079 across decreasing GH levels; 95% CI, 0.006 to 0.967; P = 0.047) and bilaterality of tumor involvement (OR, 10.7; 95% CI, 2.25 to 50.7; P = 0.003) were acroGHD predictors. AcroGHD is even more common after radiation therapy and has been reported in 30% to 75% of acromegaly patients after CRT (686, 716). GH is usually the first hormone affected by radiation therapy to the pituitary (717); the risk appears to be >50% if the radiation dose is >40 Gy (718). Irradiation alters GH dynamics, attenuating hypothalamic drive to somatotropes and diminishing somatotrope mass. There is often discordance between GH and IGF-I after radiotherapy, whereby the combination of elevated IGF-I but normal GH levels is seen, due to flattening of the GH secretory pattern by radiotherapy (719, 720). Alternatively, GHD is not expected in patients receiving medical therapy, which should be adjusted according to GH/IGF-I levels (17). Low IGF-I levels <2 SDs below the age-matched mean are highly suggestive of GHD (721). However, as in other GHD patients, ITT seems to be the gold standard for establishing acroGHD (722, 723). Diminished GH response to insulin-induced hypoglycemia is time-dependent, increasing from 22% after 1 to 5 years to 47% after 11 to 15 years (686). Both ITT and GHRH-arginine tests have been used in treated acromegaly patients, with peak GH responses correlating well (724). However, the GHRH-arginine test has been shown to have false-negative rates and therefore may be unreliable for diagnosing GHD in the first 5 years following CRT in nonacromegaly populations (725). Half of those classified as severely GHD patients by the ITT were classified as normal or only GH insufficient by the GHRH-arginine test, suggesting that hypothalamic dysfunction occurs earlier than somatotroph dysfunction following radiation damage to the hypothalamic–pituitary axis. Late somatotroph dysfunction may reflect either secondary somatotroph atrophy due to hypothalamic GHRH deficiency or delayed direct radiation-induced damage to the pituitary gland. GHD results in altered body composition (decrease in lean mass and increase in fat mass), an unfavorable lipid profile, and altered endothelial function, resulting in high cardiometabolic risk, favoring accelerated atherosclerosis and coronary artery disease, and increasing mortality (726–729). It has also been associated with a high risk of fragility fractures (730) and poorer QoL (731, 732). As highlighted throughout this review, patients with acromegaly already have a considerable burden of complications and comorbidities, including AH, IR/DM, sleep apnea, osteoarthropathy, and fragility VFs, leading to impaired QoL. Clinical and epidemiological data on the impact of GHD on these outcomes is, however, limited. BMI may be slightly increased (733–735) or similar (714, 736, 737) in treated acromegaly patients with GHD. A cross-sectional study demonstrated, using abdominal CT and DXA, that total adipose tissue, abdominal visceral adipose tissue, and total body fat are indeed higher in treated acromegaly patients with GHD compared with cured acromegaly or patients with active disease (P < 0.05), as is hsCRP, an inflammatory biomarker of cardiovascular risk (736). Fasting glucose, post-OGTT glucose, and measures of IR, mean arterial pressure, and lipid profiles were, however, similar in this study, suggesting that GHD does not appear to adversely affect glucose homeostasis, lipids, or other cardiovascular markers. In another cross-sectional study, although LV dimensions, wall thickness, and mass were similar, diastolic function was impaired in patients with GHD when compared with both patients with disease control (6.0 ± 2.1 cm/s vs 8.3 ± 1.5 cm/s, P = 0.005) and healthy controls (8.1 ± 1.9 cm/s, P = 0.006) (735). Systolic function appeared to be decreased (although not statistically significant) compared with controlled patients, but it was higher than in patients with active acromegaly. Several, although not all (738), studies on recombinant human GH (rhGH) treatment in acroGHD patients demonstrate improvement in body composition and lipid profile without a deterioration in glucose homeostasis (734, 737, 739–741). In the first randomized, placebo-controlled trial of 30 patients with acroGHD, patients who received rhGH treatment (mean dose 0.58 ± 0.26 mg/d at 6 months) had significant reductions in total fat mass, visceral adipose tissue (−15.3% ± 18.6% vs 1.3% ± 12.5%, P = 0.01), and total abdominal fat compared with the placebo arm (739). hsCRP levels decreased, but no significant changes in the lipid profile and glucose parameters (glucose before and after OGTT, HbA1c, HOMA-IR) were detected between the two groups (739). Conversely, significant improvements after 12 months in not just body composition, but also in lipid profile, have been demonstrated in a prospective study of rhGH-treated acroGHD patients; findings were confirmed at 36 months (737). Notably, acroGHD patients who did not receive rhGH treatment had lipid profile deterioration (737). As expected, long-term studies found more remarkable effects of rhGH therapy (734, 737, 741), suggesting that long-term (≥3 years) rhGH treatment may be needed to achieve significant improvements in body composition and lipid profile (722).
Concerns have arisen with regard to the cardiovascular safety of rhGH treatment in acroGHD. In 2008, a prospective, open-label study reported an increased risk of cardiovascular events (one MI and two strokes) in a group of 10 patients with acroGHD receiving rhGH treatment, as compared with none among patients with GHD from NFPAs; both groups had similar improvements in body composition and lipid profile without any deterioration in glucose homeostasis (740). Subsequently, in a KIMS (Pfizer International Metabolic Database) database study that compared the outcome of rhGH treatment in acroGHD to individuals with GHD secondary to an NFPA, although all-cause mortality was similar in the acroGHD group compared with the general population (SIR, 1.32; 95% CI, 0.70 to 2.25), an increased risk of cardiovascular mortality was observed (SMR, 3.03, acroGHD vs NFPA, P = 0.02) in acroGHD patients receiving rhGH treatment (median GH dose of 0.3 mg/d at 5 years) (741). Of note, none of these studies included a control group of acroGHD patients who did not receive rhGH replacement. Furthermore, not all studies have consistently demonstrated this increased cardiovascular mortality (734). Recently, the impact of rhGH treatment on cardiac function was addressed in a small prospective study that compared LVM per body surface area and diastolic function in acroGHD patients who were either treated or not with rhGH (742). At 12 months, no significant differences in LVM per body surface area or parameters of diastolic function were observed. Half of the patients in each group had normal diastolic function. Although these data provide some reassurance regarding the short-term cardiovascular safety of rhGH treatment in acromegaly, long-term safety and benefits need to be further evaluated. Alternatively, studies on QoL have consistently documented an impaired QoL in acroGHD (737, 739, 743, 744), based on multiple methods of QoL assessment (including the Quality of Life–Assessment of Growth Hormone Deficiency in Adults, the Symptom Questionnaire, and the Short-Term Health Survey Short Form 36), and after controlling for potential confounders such as sex, radiation therapy, or other hormone deficiencies. Severity of GHD remained an important factor; peak GH levels after GHRH-arginine stimulation were inversely associated with Quality of Life–Assessment of Growth Hormone Deficiency in Adults scale scores (R = −0.53; P = 0.0005) and the Symptom Questionnaire Depression subscale scores (R = −0.35; P = 0.031) and positively associated with most Short-Term Health Survey Short Form 36 subscale scores (744). Importantly, similar to that seen in nonacromegaly patients with GHD treated with rhGH (745), the benefits of rhGH in improving QoL have consistently been demonstrated in several studies (737, 739, 741, 743). RecommendationsBaseline assessment of PRL and pituitary function should be performed in all patients newly diagnosed with acromegaly. Following pituitary surgery, dynamic changes are seen in anterior and posterior pituitary function occurring in the first 12 months postoperatively (recovery of pituitary function in some, but development of hypopituitarism in others); pituitary function should be periodically reassessed in all patients. In particular, ACTH reserve should be routinely assessed at 3, 6, and 12 months following surgery. Guidelines for hormonal replacement in hypopituitarism in adults have been recently published (348). In particular, the avoidance of overreplacement of GCs, which increases metabolic risk and adversely affects bone health, is crucial in this patient population that is already at high risk of these adverse outcomes. As both AI and overreplacement of GCs are independent predictors of mortality in acromegaly (40), low-dose hydrocortisone replacement (15 to 20 mg/d) (746), rather than doses ≥25 mg/d should be used (40, 747). Appropriate levothyroxine replacement and testosterone and estrogen replacement in hypogonadal men and women, respectively, should also be instituted. Postoperative monitoring for central diabetes insipidus, which may be transient, is necessary, and desmopressin should be administered according to individualized therapeutic schedules (348). With regard to acroGHD, all patients with controlled disease should be periodically assessed for clinical features of GHD, such as poor exercise capacity, reduced QoL, adverse lipid profiles, heart failure, and fractures (722). IGF-I values below the reference range are highly suggestive for severe GHD, especially in the presence of multiple pituitary hormone deficiencies. Confirmatory testing should be undertaken on an individualized basis; the ITT remains the gold standard for diagnosis. In patients with confirmed acroGHD, GH replacement can improve QoL, body composition, and lipid profile; studies on long-term cardiovascular effects are awaited. In the absence of known contraindications, low-dose GH replacement can be entertained, and we suggest titrating GH doses to maintain IGF-I levels in the low-normal range. Importantly, the interaction between GH, GC, and thyroid function needs to be considered. As GH suppresses the conversion of cortisone to cortisol, once GH replacement is initiated, patients with low adrenal reserve may develop AI, and those with pre-existing AI on GCs may require higher doses (710, 748). Similarly, as GH replacement most commonly decreases FT4 levels (749–752), euthyroid patients should have thyroid function reassessed 6 weeks after initiation of GH replacement, and those with pre-existing hypothyroidism may require increased levothyroxine doses to maintain FT4 levels within target ranges (348). QoL in patients with acromegalyAssessment of health-related QoLImpaired health-related QoL (HR-QoL) is often reported in acromegaly relative to the normal population, irrespective of disease state, although some overall improvement has been seen with disease control (753–755). As therapeutic options improve, addressing HR-QoL has increasingly become a goal in management of acromegaly in addition to controlling GH excess, treating its associated comorbidities and reducing mortality. HR-QoL describes the functional effect of an illness and its consequent therapy on a patient, based on the patient’s perspective on their physical, emotional, and social health. It refers to how an individual feels, functions, and responds in daily life, and is influenced by the patient’s goals and expectations, concerns, and cultural context (754, 756). Many disease-specific, generic, and domain-specific questionnaires (Table 6) are used to measure HR-QoL in acromegaly. The disease-specific Acromegaly Quality of Life (AcroQoL) questionnaire assesses specific dimensions affected by acromegaly (757, 758). This 22-item questionnaire consists of physical (n = 8) and psychological (n = 14) dimensions, with the latter subdivided into appearance (n = 7) and personal relationships (n = 7) domains, which can be analyzed separately or globally (756). Originally developed in Spanish, it is now available in more than 30 languages (754) and has been validated against other well-authenticated generic measures of QoL such as the Psychological General Well Being Scale and EuroQoL (758, 759). Studies are also underway to map AcroQoL scores to the EuroQoL so as to allow cost-utility analysis (760). Table 6. Commonly Used Questionnaires in Measuring HR-QoL in Acromegaly
Table 6. Commonly Used Questionnaires in Measuring HR-QoL in Acromegaly
Commonly used generic questionnaires include the Nottingham Health Profile, the Psychological General Well Being Scale, EuroQoL (including EQ-5 Dimensions and EQ-Visual Analog Scale), and the Short Form 36 (761–765). Some domain-specific questionnaires relevant to acromegaly include the Arthritis Impact Measurement Scale 2 and the Beck Depression Inventory II. Effects of physical symptoms on QoLClinical arthropathy and physical pain, limiting physical functioning, contribute to the impaired QoL seen in patients with both active disease and in controlled patients (353, 354, 766–769). Joint pain has been reported in up to 90% of patients with disease duration of at least 5 years, despite biochemical control in most (354, 766) (reviewed in detail in “Joint complications” above) In several studies, patients with significant physical pain scored poorer on both generic scales and AcroQoL (global, physical, and psychological scores) (353, 766). Acromegaly patients in long-term disease control (mean of 15 years) had high pain scores of the spine, knee, and hip, which limited physical functioning (mean difference, −27.0; 95% CI, −9.5 to −41.0) and psychological well-being (mean difference, −44.4; 95% CI, −26.1 to −60.9) compared with patients without pain (353). Interestingly, compared with both the normal population, and age- and sex-matched patients with NFPAs or prolactinomas, acromegaly patients had more physical pain, translating to reduced QoL scores in generic questionnaires, particularly in the domains of physical ability and functioning, social functioning, general health perception, and vitality (766, 770, 771). Headache also correlates with worse QoL in acromegaly (767, 772), and neuropathic pain correlates with both impaired QoL and depression (767). Other acromegaly symptoms, including fatigue, excessive sweating, soft tissue swelling, and carpal tunnel symptoms, also impair QoL, with greater symptoms scores correlating with lower generic and disease-specific HR-QoL scores, and even higher economic burden due to factors such as loss of employment (773). Effects of psychological symptoms on QoLIncreased psychopathology is observed in acromegaly, with lifetime rates of affective disorders (predominantly anxiety and depression) reported to be significantly higher compared with patients with chronic somatic disorders [acromegaly vs chronic somatic disorder, 34.6% vs 21.4% (OR, 2.0; 95% CI, 1.2 to 3.2)] (774). Symptoms are evident from the onset of GH excess (774), and a delay in diagnosis has been associated with lower psychological QoL scores (775). Furthermore, negative illness perception, maladaptive personality traits, and less effective coping strategies have been described among acromegaly patients, even in controlled ones (776–779), and when compared with patients with NFPAs (776). Poor body image contributes to the impaired psychological well-being, with “appearance” being identified as one of the most affected subscales in AcroQoL scores (762, 769); significantly lower scores have been reported compared with obese controls (758). Despite long-term biochemical control, close to half of patients are reported to be persistently self-conscious about their facial appearance, resulting in psychological distress and disruption to everyday life; Derriford Appearance Scale 59 scores correlated well with AcroQoL scores (780). Cognitive function (memory and recall, concentration, ability to learn, and mental agility) is also impaired in acromegaly and is seen in both active disease (781–783) and patients controlled (782, 783) with or without medical therapy (784). This is evident not only from studies examining electrophysiological brain activity in active acromegaly (781, 785), but it is also based on patient self-perception, with >50% of patients with either active or controlled acromegaly expressing some degree of cognitive dysfunction (782). Furthermore, there appears to be a link between psychopathology and cognitive dysfunction; anxiety and depression have been found to correlate with poorer memory and impaired decision-making (786). Effects of treatments for acromegaly on QoLAs mentioned before, although surgery remains the first-line treatment in most cases, a significant proportion of acromegaly patients have suboptimal disease control, necessitating adjuvant treatment. Pharmacological therapy improves biochemical control and several comorbidities, but the burden of chronic medication, especially injection of long-acting SRLs, has been found to significantly impact QoL, based on both generic questionnaires and AcroQOL (787, 788). Furthermore, negative medication beliefs (e.g., concerns about adverse effects) have been found to relate to negative illness perceptions (e.g., disease chronicity) and worse disease-specific QoL scores (789). An observational patient-reported outcomes survey demonstrated that chronic long-acting SRL injections negatively affected the daily functioning/physical and emotional well-being of patients with acromegaly, with no significant differences between those biochemically controlled and those with active disease (788). In another recent survey, only half of patients on injectable medications (SRLs or PEG) were satisfied with their treatment, although nonresponder bias may have influenced the results (773). Patients treated with radiotherapy also have lower QoL scores (768, 770, 790–793); impairment in physical functioning and increased psychopathology and social isolation has been documented (791). It is unclear whether this relates to the underlying aggressive nature of the disease or to radiotherapy-induced hypopituitarism (770); etiology is likely to be multifactorial. Interestingly, in a nationwide study in Finland (790), QoL was correlated to nadir GH in OGTT in an inverted U-shaped fashion (overall P = 0.021); patients with the highest QoL were those with normal GH responses to an OGTT after treatment (0.3 to 1 μg/L), whereas those with lower levels or higher values (suggesting active disease) had lower QoL. GHD after (over)treatment of acromegaly (acroGHD) also impairs QoL (737, 739, 743, 744) (see “GHD in (over)treated acromegaly and the impact of recombinant human GH treatment” above). Moreover, rhGH replacement has been demonstrated to improve QoL in several studies (737, 739, 741, 743). Specific interventions influencing QoL.Sixteen intervention studies have been published (Table 7) with QoL measured before and after intervention, including pituitary surgery (n = 3), SRLs (n = 11), and PEG (n = 4). Data on the effects of pituitary surgery in newly diagnosed patients are conflicting, with some, but not all, showing improvement in QoL (707, 794, 795). However, QoL symptoms scores improved as early as 12 weeks after surgery in one study (795). Table 7. Specific Interventions Influencing QoL in Patients With Acromegaly
For therapy effect, the following apply: 0, no significant correlation with QoL; 1+, positive correlation with a subscale of QoL only; 2+, positive correlation with QoL. Abbreviations: CSKSLPP, Cognitive Scale of Kellner’s Screening List for Psychosocial Problems; EQ-5D, European QoL scale; KSQ, Kellner’s Symptom Questionnaire (psychological distress, well-being); NHP, Nottingham Health Profile; OCT-LAR, octreotide LAR; PAS-LAR, pasireotide LAR; PASQ, Patient-Assessed Acromegaly Symptom Questionnaire; SF-36, Short Form 36; SSS, Signs and Symptoms Scale—acromegaly. Table 7. Specific Interventions Influencing QoL in Patients With Acromegaly
For therapy effect, the following apply: 0, no significant correlation with QoL; 1+, positive correlation with a subscale of QoL only; 2+, positive correlation with QoL. Abbreviations: CSKSLPP, Cognitive Scale of Kellner’s Screening List for Psychosocial Problems; EQ-5D, European QoL scale; KSQ, Kellner’s Symptom Questionnaire (psychological distress, well-being); NHP, Nottingham Health Profile; OCT-LAR, octreotide LAR; PAS-LAR, pasireotide LAR; PASQ, Patient-Assessed Acromegaly Symptom Questionnaire; SF-36, Short Form 36; SSS, Signs and Symptoms Scale—acromegaly. With regard to SRLs, three studies demonstrated a significant positive effect of lanreotide (slow-release or Autogel) on QoL of SRL-naive patients with active disease with or without prior surgery (796–798). Similarly, octreotide LAR appears to also have a positive effect on QoL in active disease or mixed cohorts (772, 799, 800). Note, however, that no difference in QoL was documented in patients with disease control, in whom the interval of octreotide LAR was increased from 4 to 6 weeks (801), or when switching from octreotide LAR to lanreotide Autogel (802). No beneficial QoL effect was seen in a crossover trial with patients with persistent disease switching between pasireotide LAR and octreotide LAR and vice versa (606). Interestingly, in a recently published study that examined the effects of SRL dose titration according to IGF-I vs GH nadir after an OGTT, no differences were noted between groups with regard to AcroQoL and Patient-Assessed Acromegaly Symptom Questionnaire scores at baseline and after 12 months (803). Addition of PEG to SRLs both in patients with suboptimal control (804) and to those in biochemical control (805) appears to have significant positive effects on QoL. AcroQoL scores (most notably in the physical domain) improved independent of IGF-I changes, when subcutaneous PEG at 40 mg weekly was added to monthly SRL therapy in patients who already had normal IGF-I on SRL monotherapy (805). Conversely, in a smaller study of patients well controlled on SRLs, no QoL benefit was derived from the addition of PEG; however, dose reductions in SRLs were made concurrently in that study (806). Interestingly, no apparent differences in QoL outcomes were seen in patients randomized to PEG vs octreotide LAR (800). Given the heterogeneity of the above studies, there are insufficient data to suggest that one particular treatment modality is more effective than another in improving QoL in acromegaly. Patient populations, disease status, prior treatments, duration of follow-up, and intervention are important factors that need to be considered in the analysis of these results. Figure 8 summarizes the factors affecting QoL in acromegaly. Figure 8. Factors affecting QoL in patients with acromegaly. [© 2019 Illustration Presentation ENDOCRINE SOCIETY]. Predictors of QoL in acromegalyData regarding the impact of biochemical control of GH excess on QoL remain conflicting. Although some studies suggest that biochemical disease control improves QoL (at least in some subscales) (807, 808), others have demonstrated no correlation between the objective biochemical parameters of disease control and patient-reported subjective senses of well-being (779, 788, 809). Geraedts et al. (810), in a systematic review that included 51 studies, but excluding patients with documented acroGHD, assessed the impact of disease phase (active disease, transition from active to controlled disease, and disease remission) on factors influencing QoL. These included disease-specific factors, general factors, or interventions inherently linked to acromegaly. Disease activity, reflected by biochemical control measures such as GH/IGF-I, change in IGF-I, disease duration, and duration of disease control, yielded mixed and therefore inconclusive results on its impact on QoL (810). Interestingly, in contrast with other studies, hypopituitarism was not significantly correlated with QoL (353, 759, 762, 768, 790, 791, 811). Alternatively, degree of depression (768, 781, 811–814) and higher BMI (790, 815) showed consistently negative association with QoL in cohorts consisting of both patients with active and controlled acromegaly. In fact, psychopathology had been shown in an earlier study to be superior over biochemical and other variables (such as age, sex, disease duration, tumor size, treatment modalities, and comorbidities) in predicting QoL in acromegaly (816). In cohorts with patients with active acromegaly only, age and female sex had a significant negative effect on QoL (793). No consistent results were found with regard to other general factors. In cohorts with acromegaly-controlled patients only, previous radiotherapy had a significant negative effect on QoL subscales, but not hypopituitarism or remission duration or other general factors (354, 757, 791, 793). RecommendationsGoals of management in current acromegaly guidelines focus on achieving biochemical targets of disease control, evaluation, and management of comorbidities, with an overall aim to reduce acromegaly mortality (18). However, as part of the management of this “chronic disease,” emphasis needs to also be placed on HR-QoL, which, although improved, often remains impaired despite control of GH excess. Physical and psychological aspects contribute to poor QoL, and the impact of prior and current treatments need to be considered. In particular, physical pain, anxiety, and depression are closely linked, and the latter also with cognitive function, overall impacting physical and social functioning. The use of validated patient questionnaires (both disease-specific AcroQoL and generic) should be incorporated into routine clinical care; yearly assessment is recommended for timely identification of patients with impaired QoL. Individualized, multidisciplinary management is needed, with involvement of pain management teams, physiotherapists, neuropsychologists, and/or psychiatrists where appropriate. Ongoing patient education and targeted psychosocial interventions such as cognitive behavioral therapy and self-management training may be beneficial (777). Table 8 summarizes the recommendations for acromegaly complication screening at diagnosis. Table 8. Recommended Screening for Acromegaly Complications at Diagnosis
Abbreviations: US, ultrasonography; VFA, VF assessment. a In case of elevated ambulatorial BP (if available). Table 8. Recommended Screening for Acromegaly Complications at Diagnosis
Abbreviations: US, ultrasonography; VFA, VF assessment. a In case of elevated ambulatorial BP (if available). Mortality in Patients With Acromegaly: The Changing Face of the Disease in Recent DecadesAcromegaly has had a long-standing association with increased mortality (7). In a 1966 study, half of the patients died before the age of 50 and 89% died before 60 years of age (817). In a previous review by Colao et al. (7), which included studies published until 2004, the mortality rate in patients with acromegaly was indeed increased and was mainly caused by cardiovascular (60%) and respiratory diseases (25%), with the remaining patients dying of malignancies (15%). However, as emphasized by the authors (7), mortality data from patients undergoing more modern therapies were lacking. Since then, more studies have been published that included more strict criteria for disease control and patients who were treated with modern alternatives. In this section, we discuss the more recent data on mortality risk in patients with acromegaly and causes of death. We will also review in detail the factors associated with increased mortality. Do acromegaly patients still display an increased mortality risk?Acromegaly was associated with a twofold to threefold increase in mortality in studies published before 1995 (818–820). In 2008, two meta-analyses showed a reduction in mortality rates (821, 822). Holdaway et al. (821) analyzed 18 studies encompassing 4806 patients who were followed from 1965 to 2008 and observed an SMR of 1.7 (95% CI, 1.5 to 2.0). Interestingly, the SMR was 2.2 (95% CI, 1.8 to 2.8) in studies published before 1984 and was reduced to 1.3 (95% CI, 1.1 to 1.6) in studies published after 1984 (821). Dekkers et al. (822) reviewed 16 studies including 4947 patients who were followed from 1970 to 2005 and observed a similar SMR (1.72; 95% CI, 1.62 to 1.83). Furthermore, when studies were divided into two time periods, studies published before 1995, in which not all patients with active acromegaly were treated and radiotherapy was often the primary therapy, and studies published after 1995, in which surgery was the primary therapy for most patients (822), the SMR was higher in the “older studies” than in studies published after 1995 (2.11 and 1.62, respectively). Ten single-center or nationwide studies were published after these two meta-analyses (4, 12, 14–16, 40, 179, 493, 823, 824); in nine of them the SMR was calculated (Fig. 9) and in one the HR was provided (4). In half of these studies, the mortality rate was equal to the normal population (12, 14–16, 823), including the largest investigation that studied 1512 patients from multiple centers in Italy and observed an SMR of 1.13 (95% CI, 0.87 to 1.46) (15). Even in some of the studies that still showed an increased mortality rate, the analysis of the patients who were treated with more modern options revealed a similar mortality rate to the normal population (493, 824). Varadhan et al. (493) observed an SMR of 1.6 (95% CI, 1.3 to 2.0) in the whole acromegaly group that was followed at a single center. However, when only patients who were treated from 1994 to 2012 were analyzed, SMR was not increased (1.0; 95% CI, 0.6 to 1.8). In a nationwide Swedish study by Esposito et al. (824) examining 1089 patients, an SMR of 2.79 (95% CI, 2.43 to 3.15) was observed in the whole cohort; however, when only patients who were treated with surgery alone or with surgery and medical therapy were analyzed, the SMR was not elevated (0.45 and 0.98, respectively). The importance of modern treatment in this variability of mortality rates in patients with acromegaly was also highlighted in a study (16) that compared a cohort form Italy (220 patients) and a cohort from Bulgaria (407 patients). An elevated mortality rate was only observed in Bulgarian patients (SMR in Italy, 0.66; 95% CI, 0.27 to 1.36; SMR in Bulgaria, 2.0; 95% CI, 1.54 to 2.47). The main difference between the two cohorts was the treatment modalities. In particular, radiotherapy was used much less frequently in Italy (16% vs 26%, respectively), whereas SRLs were used more frequently in Italy (64% vs 8%, respectively). There are no studies addressing long-term consequences of using pasireotide (either cardiovascular disease or mortality) in patients with acromegaly. However, as there is an increased frequency of DM in patients being treated with this drug, this may have an impact on mortality. However, there are no data on long-term consequences of the drug. Figure 9. SMRs in studies of acromegaly since 2008. Data are in standardized mortality ratio: SMR (95% CI). [© 2019 Illustration Presentation ENDOCRINE SOCIETY]. Causes of deathMortality in patients with acromegaly has been mainly attributed to cardiovascular disease in previous studies (7). Nevertheless, as depicted in “Cardiovascular and cerebrovascular disease” above, the prevalence and severity of cardiovascular disease has changed in more contemporary cohorts, a finding that is also reflected in the changes in causes of mortality in patients with acromegaly in more recent studies (12, 14–16, 179, 823). In four studies published in the last decade encompassing 3391 patients, malignancies were the leading cause of death, with cardiovascular disease as the second cause, but these causes were not different from the general population (12, 14, 15, 823). Three other studies published in the last decade showed different results (4, 40, 824). The study by Sherlock et al. (40) included 501 patients and observed an increased mortality due to cardiovascular, cerebrovascular, and respiratory diseases, but not from malignances. Ritvonen et al. (179) reported cardiovascular disease as the cause of death in 34% of the patients, with CHD being responsible for 23% of the deaths, other cardiovascular diseases for 11% and malignancy for 27%. However, this distribution was not different from the general population. Additionally, as previously reported, in this Finnish study (179), cardiovascular disease was the main cause of death in the first decade, with malignancy being the main cause of death (35%) in the next two decades. In a recently published study (Swedish patients treated from 1987 until 2013), Esposito et al. (824) described the main cause of death as circulatory disease (40.1%), followed by malignancies (21.1%). Interestingly, compared with the normal population, only death from infectious disease was increased in the whole cohort (SMR, 7.91; 95% CI, 1.58 to 14.24), deaths from CHD were increased in female patients (SMR, 2.85; 95% CI, 1.63 to 4.07), and deaths from malignancies were increased in male patients (SMR, 2.26; 95% CI, 1.41 to 3.11). Table 9 describes the main causes of death in patients with acromegaly reported in studies published in the last decade, reiterating that malignancy is the main cause of death in patients with acromegaly, surpassing cardiovascular diseases. Table 9. Studies Published in the Last Decade Assessing Causes of Death in Acromegaly
a Main cause: coronary artery disease. b Mortality changed from cardiovascular in the first decade to cancer deaths (35%) in the next two decades. c Combined cerebrovascular disease and CHD (individual numbers not provided in the article). Table 9. Studies Published in the Last Decade Assessing Causes of Death in Acromegaly
a Main cause: coronary artery disease. b Mortality changed from cardiovascular in the first decade to cancer deaths (35%) in the next two decades. c Combined cerebrovascular disease and CHD (individual numbers not provided in the article). Factors influencing mortalityMany studies have evaluated, with variable success, predictors of mortality in patients with acromegaly (825). In most studies, age and previous radiotherapy are associated with increased mortality (825). The HR associated with radiotherapy is as high as 34.25, as reported by Bogazzi et al. (823). The mortality associated with radiotherapy is mainly due to cerebrovascular disease (16). Notably, survival data for patients who are treated with modern radiation techniques (SRS and fractionated stereotactic radiotherapy) are lacking. Another feature associated with the poor survival of patients with acromegaly is the presence of hypopituitarism (40, 493, 825). Sherlock et al. (40) reported an increased SMR for patients with ACTH (SMR, 2.5; 95% CI, 1.9 to 3.2) and gonadotropin deficiencies (SMR, 2.1; 95% CI, 1.6 to 2.7). However, after an internal analysis with adjustments for other variants, such as age, sex, and radiotherapy, only an ACTH deficiency was associated with increased mortality (RR, 1.7; 1.2 to 2.5). This finding was confirmed for patients receiving high doses of hydrocortisone replacement, with daily doses ranging from 25 to 30 mg associated with an RR of 1.6 (1.1 to 2.4) and doses >30 mg per day associated with an RR of 2.9 (1.4 to 5.9) (see also “Pituitary hormone alterations in acromegaly” above). Presence of active acromegaly has also been consistently associated with increased mortality (15, 493, 821, 822, 825). In a recent large nationwide study including 1512 patients, overall SMR was not increased (15). However, when only patients with active disease were analyzed, an SMR of 1.93 (95% CI, 1.34 to 2.70) was observed (15). Therefore, disease control is essential to improve the survival of patients with acromegaly. The definitions of disease control have also evolved over time. Measurements of GH levels to assess disease control are consistently associated with reduced mortality in the literature (825). In the meta-analysis of studies published until 2008, GH levels >2.5 μg/L were associated with an SMR of 1.9 (95% CI, 1.5 to 2.4), whereas a reduction in GH to levels <2.5 μg/L led to SMR normalization (1.1; 95% CI, 0.9 to 1.4)] (821). Importantly, most studies included in this meta-analysis measured GH levels using an RIA, and lower GH levels measured using more modern assays are probably associated with better survival, as some studies have indicated that a reduction in GH levels to <1.0 μg/L would lead to clinical benefits (15, 16, 39, 350, 493, 821, 823, 825). Consistent with this finding, the last Endocrine Society acromegaly guideline recommends targeting GH levels <1.0 μg/L in patients with acromegaly (18). Interestingly, most studies addressed GH levels at the last follow-up; this strategy may not perfectly quantify the cumulative exposure to excess GH (825). Sherlock et al. (826) analyzed the effects of cumulative exposure with a “time-dependent” method and showed that the last available GH level probably overestimates the mortality risk. The last available GH level value >1.0 μg/L is associated with an increased risk (RR, 1.8), whereas only GH levels >5.0 μg/L are associated with an increased risk (RR, 1.5) using the “time-dependent” method. Thus, estimating the cumulative GH exposure would be a better method for assessing the mortality risk in patients with acromegaly (826), but additional studies are needed. The association of IGF-I levels with mortality is less consistent in the literature (825). In some studies, IGF-I was a predictor of mortality (12, 15, 823), but this association was not observed in other studies (16, 39, 40, 179, 493, 826). In the meta-analysis by Holdaway et al. (821), the normalization of the last available IGF-I levels (expressed as SD) was associated with SMR normalization (1.1; 95% CI, 0.9 to 1.4), whereas patients with elevated IGF-I levels displayed an SMR of 2.5 (95% CI, 1.6 to 4.0). However, in the multivariate analysis, GH level, but not IGF-I level, was an independent predictor of mortality. ConclusionAcromegaly is associated with many complications and with increased mortality when not adequately treated. This has been known since the first descriptions of the disease, but the spectrum of complications has changed in the recent years, with a reduction in prevalence and severity of cardiovascular disease (formerly the main complication and cause of death) and the awareness of new complications, such as VFs and decreased QoL. New treatment modalities of acromegaly and its complications have also contributed to a reduction of mortality that is now similar to that of normal population in controlled patients. Furthermore, the main cause of death has changed from cardiovascular to malignancy in most recent studies. Abbreviations
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McCabe J ,Ayuk J ,Sherlock M .Treatment factors that influence mortality in acromegaly . Neuroendocrinology . 2016 ; 103 ( 1 ): 66 – 74 . 826. Sherlock M ,Reulen RC ,Aragon-Alonso A ,Ayuk J ,Clayton RN ,Sheppard MC ,Hawkins MM ,Bates AS ,Stewart PM .A paradigm shift in the monitoring of patients with acromegaly: last available growth hormone may overestimate risk . J Clin Endocrinol Metab . 2014 ; 99 ( 2 ): 478 – 485 . Author notes(*M.R.G and M.F. contributed equally to this study). Copyright © 2019 Endocrine Society Copyright © 2019 Endocrine Society Which manifestation would a nurse assess for when providing care for a client with acromegaly?Enlarged hands and feet. Enlarged facial features, including the facial bones, lips, nose and tongue. Coarse, oily, thickened skin. Excessive sweating and body odor.
Which symptom would the nurse assess in a patient with acromegaly?A classic sign of acromegaly is enlargement of the hands and feet with joint pain that ranges from mild to crippling. One may also see hypertrophy and thickening of the skin, especially on the top of the feet, making it difficult to wear shoes. Vision changes may occur due to pressure on the optic nerve.
What would the nurse expect the assessment findings to be for a client diagnosed with metabolic syndrome?These conditions include increased blood pressure, high blood sugar, excess body fat around the waist, and abnormal cholesterol or triglyceride levels.
How is diabetic acromegaly diagnosed?Therefore, doctors rely on IGF-1 and OGTT tests to help diagnose acromegaly.. Testing Insulin-like Growth Factor-1 (IGF-1) Insulin-like growth factor-1 (IGF-1) is a hormone that's closely tied to growth hormone. ... . Oral Glucose Tolerance Test (OGTT) ... . Imaging Tests to Confirm Acromegaly.. |
The nurse assesses a 40-year-old client with acromegaly in an outpatient health clinic
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