Abstract
Acromegaly is a rare chronic, systemic disorder caused by excessive growth hormone (GH) secretion from a somatotroph pituitary adenoma. GH hypersecretion leads to overproduction of insulin-like growth factor-1 (IGF-1), which contributes to the somatic overgrowth, physical disfigurement, onset of multiple systemic comorbidities, reduced quality of life (QoL) and premature mortality of uncontrolled patients. Somatostatin receptor ligands, dopamine agonists and a GH receptor antagonist are currently available for medical therapy of acromegaly. The main aim of treatment is biochemical normalisation, defined as age-normalised serum IGF-1 values and random GH levels <1.0 μg/L. However, there is an increasing evidence suggesting that achieving biochemical control does not always decrease the burden of disease-related comorbidities and/or improve patients’ QoL. This lack of correlation between biochemical and clinical control can be due to both disease duration (late diagnosis) or to the peculiarity of a given comorbidity. Herein we conducted ad hoc literature searches in order to find the most recent and relevant reports on biochemical and clinical disease control during medical treatment of acromegaly. Particularly, we analyse and describe the relationship between biochemical, as well as clinical disease control in patients with acromegaly receiving medical therapy, with a focus on comorbidities and QoL. In conclusion, we found that current literature data seem to indicate that clinical disease control (besides biochemical control), encompassing clinical signs and symptoms, comorbidities and QoL, emerge as a primary focus of acromegaly patient management.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
1 Introduction
Acromegaly is a rare chronic disorder caused by excessive growth hormone (GH) secretion, arising predominantly from a benign pituitary adenoma (>95% of cases) [1]. In patients with acromegaly, GH hypersecretion leads to overproduction of insulin-like growth factor-1 (IGF-1) thus resulting in a multitude of clinical manifestations, including somatic overgrowth, physical disfigurement, multisystem comorbidities, reduced quality of life (QoL) and premature mortality (Fig. 1) [2,3,4]. In line with this complex scenario, a recent Statement by the Pituitary Society strongly recommend to refer acromegaly patients to selected Centres of Excellence, identified based on clinicians’ expertise and health care provider facilities [5].
The normalization of mortality risk and the improvement of patients’ quality of life (QoL) represent the final goal of acromegaly treatment. These targets can be achieved only through the control of hormone hypersecretion (primary target of current available medical treatments) and the reduction/prevention of disease related comorbidities. However, biochemical control does not always results in the complete resolution of comorbidities, with an impact on QoL and mortality. Therefore, in such cases, additional treatments, directly directed on specific comorbidities (i.e. anti-hypertensive drugs, anti-diabetic-agents, psychological support, etc.) need to be promptly started in order to pursue a general clinical improvement of patient’s health status
Acromegaly-related comorbidities mainly include cardiovascular, metabolic and respiratory disorders, rheumatological and orthopaedic issues, hypopituitarism and sexual dysfunction, as well as malignancies [3, 6, 7]. Patients without typical features of acromegaly, affected, however, by several of these comorbidities should raise the suspicion of acromegaly in physicians [2]. Measurement of IGF-1 levels is the recommended biochemical screening. However, in patients with elevated or equivocal serum IGF-1 levels, failure of GH to decrease <1 μg/L following an oral glucose load should be used to confirm the diagnosis [2].
Current treatment modalities include surgery, radiotherapy and medical (pharmacological) therapy [2, 8, 9]. The Endocrine Society Clinical Practice Guidelines and the Consensus Statement of 2018 recommend transsphenoidal surgery as the primary therapy in most patients [2, 9]. Medical therapy with first generation somatostatin receptor ligands (SRLs) is recommended as adjuvant therapy in patients with persistent disease following surgery and as first-line treatment for those ineligible for surgery, while its role in a neo-adjuvant setting is still debated [2, 10, 11]. To date three different classes of drugs (alone or in combination) are available for the medical treatment of acromegaly [namely, SRLs, dopamine agonists (DAs) and GH receptor antagonist (GHRA)] (Table 1) [2, 8, 12].
The aim of treatment is the biochemical control, with current treatment targets being age-normalised serum IGF-1 (for all the drugs), and random GH levels <1.0 μg/L for only SRLs and DAs [2, 8]. Biochemical criteria have changed over time, with current recommendations being more rigorous [13, 14]. In a comprehensive meta-analysis, GH or IGF-1 control was achieved in approximately 55% of patients by use of SRLs [13]. In this light, a puzzling discordance in biochemical disease activity has been observed in clinical practice, where patients exhibit normalised GH but elevated IGF-1 levels and vice versa [15,16,17,18]. The exact mechanisms underlying this discordance [15] and its clinical significance remain to be established [9].
Beyond biochemical control, the goals of treatment for acromegaly include reduction of mortality risk, management of comorbidities, minimising clinical signs and symptoms of the disease, as well as control of tumour mass and maintenance of the remaining pituitary function [2]. Another significant consideration in the management of acromegaly is health-related QoL [8], which is significantly impaired by comorbidities [19].
The management of comorbidities and the improvement of patients’ QoL are often considered secondary endpoints in the treatment of acromegaly. Although biochemical control leads to a significant improvement in a number of comorbidities, this is not always the case. Full biochemical control cannot reverse some of the pathological changes associated with acromegaly, while partial control can still produce significant improvements in a patient’s clinical status.
2 Objectives and methodology
The aim of this review is to describe the relationship between biochemical and clinical disease control in patients with acromegaly who are receiving medical therapy (mainly SRLs and GHRA), with a focus on comorbidities and QoL. Discussion of control of tumour burden is beyond the scope of this review.
Ad hoc literature searches were carried out in order to find the most recent and relevant reports on the correlation between pharmacological treatment of acromegaly, normalization of biochemical parameters and clinical disease control.
3 Biochemical control: Targets and treatment efficacy
3.1 Biochemical control targets
The hormone targets currently recommended by the Endocrine Society Clinical Practice Guidelines are: age-normalised serum levels for IGF-1 and random GH levels of <1.0 μg/L [2]. Indeed, mortality can be reduced to the level of the general population when GH levels are <1 μg/L or IGF-1 is normalised [4, 20, 21]. Notably, most clinical trials, including those investigating the efficacy of newly developed drugs (i.e, pasireotide), had used a GH cut-off of 2.5 μg/L until recently [13], while the updated threshold of <1 μg/L was only used in the latest studies [22]. Applying these international guideline criteria at a local level is undermined by many practical issues: there can be as much as a 2-fold variation in GH and IGF-1 values measured between different laboratories, different assay performance and differing interpretation of IGF-1 levels depending on the reference ranges used [23]. For this reason, expert consensus recommend that the same assay is used in the management of a given patient [9]; that clinicians familiarise themselves with appropriate hormone standards, assay specificity and sensitivity; and that GH cut-offs are assay- and method-specific [8].
Routine use of the post-glucose GH nadir levels, obtained during an oral glucose tolerance test (OGTT), is not recommended in patient follow-up during medical treatments [2, 9]. However, results of a recent study dispute the appropriateness of this approach: patients apparently controlled with SRL therapy failed to suppress GH levels in response to OGTT [24]. Due to the complexity of the assessment of the IGF-1 system, in the past some authors speculated about the possible use of the acid-labile subunit (ALS) as a relative GH-independent sign of disease activity [25].
3.2 Does pharmacological treatment reach biochemical targets?
According to meta-analyses, biochemical control of GH levels is achieved by 57–58% of patients treated with octreotide and 48–64% of patients treated with lanreotide [13, 26], while 55–67% of patients who receive octreotide and 47–61% of patients treated with lanreotide reach the normalization (age-adjusted) of IGF-1 levels [13, 26]. Of note, some of the studies included in these meta-analyses preselected patients based on responsiveness to SRL treatment [27]. Therefore, more recent studies conducted in treatment-naïve patients show that the control of both GH and IGF-1 levels is achieved in about 20–30% of patients treated with octreotide and 30–50% of those treated with lanreotide [27].
Of note, patients’ preselection in clinical studies on acromegaly includes variable designs, such as the evaluation of subjects previously treated with different formulations of the same drug (i.e. octreotide s.c. vs octreotide LAR and/or lanreotide SR vs lanreotide Autogel), post-operative SRL treatment in patients who underwent successful pre-surgical treatment, or the inclusion based on the response to an acute octreotide test. Particularly, the role of the acute octreotide test in predicting long-term responsiveness to SRL treatment remains controversial [28]. This is partially due to the heterogeneity of data presentation (GH nadir vs percent GH reduction; lack of standardized GH cut-offs), as well as to the different design of the procedure observed among centres [29,30,31,32,33,34]. To our opinion, taking into account the above mentioned limitations, data from literature suggest that the acute octreotide test can predict long-term responsiveness to SRL treatment with high sensitivity, although counterbalanced by a relatively lower specificity.
According to a meta-analysis of relevant studies including a limited and biased number of patients, cabergoline monotherapy seems associated with control of IGF-1 levels in 34% of patients [35]. Low baseline IGF-1 concentration, longer duration of treatment and high baseline prolactin concentration were identified as factors predictive of successful treatment [35]. In the study with the largest number of patient included in this meta-analysis, the majority of those normalizing IGF-1 had very mild disease activity [36]. The current recommendation is to consider a first-line treatment with cabergoline if IGF-1 levels are <2.5 x ULN [9].
According to the last Consensus Statement, medical therapy options to achieve biochemical control in patients partially responsive or resistant to first-generation SRLs therapy (octreotide and lanreotide) include: increasing the dose of SRL, combination therapy with pegvisomant or cabergoline, switching to pegvisomant monotherapy or to pasireotide depending on glucose metabolism, tumor volume and the response degree to first-line SRLs [9].
The first clinical trials evaluating the efficacy of pegvisomant in acromegaly [37, 38] showed a great efficacy of the drug in the achievement of normal age-adjusted IGF-1 levels (89% and 97% of patients, respectively), at least one time during the study period. Following data from real-world evidences report a significant lower rate of biochemical control (65–70% of treated patients) during long term treatment [22]. On the other hand, pasireotide has been shown to be superior to octreotide long-acting release (LAR) in terms of efficacy in a prospective, randomised, double-blind study conducted in 358 patients [39]. Furthermore, among patients inadequately controlled on first-generation SRL monotherapy, complete biochemical control (GH <2.5 μg/L and normal IGF-1) was achieved with add-on pasireotide (40–60 mg, 1 injection every 4 weeks) in 15% of patients in the 40 mg group and 20% in the 60 mg group, while none of the patients who remained on first-generation SRL monotherapy experienced biochemical control [40].
Combination medical therapy led to biochemical control in 54% of patients in a German registry study and 60–70% of patients included in the French Acromegaly Registry (the majority of recipients of combination therapy received a SRL plus a dopamine agonist) [16, 21]. In a narrative review of studies that evaluated combination therapies in the treatment of acromegaly, the authors concluded that the SRL plus pegvisomant combination allowed the majority of patients to achieve normal IGF-1 levels (58–100%), while SRL plus cabergoline combination was most effective in patients with mildly elevated IGF-1 levels [41].
3.3 Does biochemical control produce clinical disease control?
The insidious nature of acromegaly often means a significant lag time between disease presentation and diagnosis, resulting in long-term exposure to elevated levels of GH and IGF-1 [42]. Some, but not all, of the complications or comorbidities may be reversed or minimised after therapy-induced biochemical control [43, 44]. However, it is interesting to note that some complications of acromegaly are not directly related to circulating GH and IGF-1 levels (i.e., neurocognitive deficits [45]).
This section reviews the effectiveness of acromegaly treatment (focusing on medical therapy) on clinical disease control, and whether biochemical control is associated with clinical disease control.
3.4 Treatment impact on acromegaly signs, symptoms and comorbidities
As discussed, medical therapy achieves biochemical control in a significant proportion of patients. Previous reviews of clinical studies have concluded that the SRLs octreotide [46], lanreotide [47, 48], pasireotide [12, 39] and the GHRA pegvisomant [22, 49] generally improve selected signs and symptoms of acromegaly. It seems, therefore, that biochemical control is associated with an improvement in the clinical signs and symptoms of the disease in most cases.
The correlation between biochemical control and its impact on comorbidities is crucial, moving from the perspective of a holistic approach to the disease. In the recent years a number of studies focused on the description and characterization of acromegaly related comorbidities, together with their impact on patients’ health status and cost-of-illness, by use of national registers (i.e. German, French, Swedish registers) [16, 21, 50] or large international surveys (i.e. Liège Acromegaly Survey (LAS) Database) [51]. Particularly, the LAS database, evaluating the clinical features at diagnosis of >3100 acromegaly patients from 14 different Countries, highlighted a high prevalence of cardiovascular comorbidities (mainly cardiac hypertrophy and hypertension), metabolic disorders (i.e. diabetes mellitus) and respiratory diseases (sleep apnea) in the largest cohort of acromegaly patients published so far. In line with these findings, the analysis of data collected from the French and Swedish registers focused on the outcome of disease related comorbidities after long-term treatment [21] and their economic burden on the whole disease direct and indirect medical costs [50].
This huge amount of data strength the clinical need to consider the recognition, management and follow-up of acromegaly comorbidities as primary goals of disease management, besides to the biochemical control of GH and IGF-1 excess.
3.5 Cardiovascular comorbidities
Cardiovascular complications are the most common comorbidities of acromegaly and significant contributors to the increased mortality [52]. Older age at diagnosis is associated with an increased risk of major cardiovascular events [53].
Cardiac complications characteristically associated with acromegaly are represented by left ventricular hypertrophy (LVH), diastolic dysfunction (LVDD), reduced left ventricular ejection fraction (LVEF), systolic dysfunction (LVSD), arrhythmias, valvulopathy, and endothelial dysfunction (early atherosclerosis) [44, 54].
In this context, a number of studies, including a meta-analysis published in 2007, have shown improvement in cardiovascular complications, primarily LVH and LVDD, following biochemical control achieved by medical treatment [55,56,57,58,59,60,61,62,63,64,65].
However, other authors did not find a direct correlation between GH and/or IGF-1 normalization and improvement in LVH, LVDD as well as left ventricular mass (index) (LVMi), cardiomyopathy and maximum heart rate [53, 66,67,68,69,70,71] (Table 2). In detail, Akdeniz et al. [67] and dos Santos Silva and colleagues [70] showed that, after SRL treatment, LVH and LVEF did not significantly differ in patients achieving biochemical control, compared to those with uncontrolled disease. Likewise, Kuhn and colleagues reported no significant changes in LVEF or LVM in patients treated with pegvisomant alone or in combination with SRLs or cabergoline [69].
Of note, another study even showed a lower prevalence of LVH in uncontrolled patients compared to those achieving normal age-adjusted IGF-1 levels, while (as expected) the presence of cardiomyopathy was higher in patients with active disease. In this latest study, most patients received surgery followed by medical therapy during almost 6 years of follow-up. Interestingly, the authors had no explanation for their finding [71].
Valvulopathy is another common cardiovascular complication [52]. Aortic valve regurgitation occurs in 30% of patients, whereas mitral regurgitation in 5%, with disease duration being a significant risk factor [72]. In this context, a prospective study showed that increased GH and IGF-1 levels are associated with a progression of valvular disease, with a significant increase in valvular regurgitation observed after 24 months follow-up [73]. Of note, the detrimental effect of uncontrolled disease may remain even after long-term biochemical control [72, 74].
Furthermore, the presence of arrhythmias has been also correlated to acromegaly, possibly due to the high prevalence of cardiac fibrosis and to the effect of IGF-1 on calcium channels [44]. However, a real increase of cardiac rhythm disturbances in acromegaly patients is still debated. Indeed, a study conducted using a 24-h ECG Holter monitoring reported more frequent and severe ventricular arrhythmias in acromegaly patients compared to controls [75], while two other studies did not find any clinical significant arrhythmia in the acromegaly subjects evaluated [76, 77]. In this context, other groups focused on the QT interval duration corrected for heart rate (QTc) as a possible marker of increased arrhythmia risk. Some authors demonstrated that QTc was longer in active acromegaly patients compared to control subjects [78, 79], with one report even showing that SRL treatment was associated with shorten (and even normalized) QTc [79]. On the contrary, a study from Orosz and colleagues did not find any differences in QTc between acromegaly patients and controls [80].
In conclusion, an improvement with biochemical control occurs in some, but not all cardiovascular complications, and the risk of cardiovascular events remains high and warrants attention. Indeed, it has been shown that regardless of disease control, a high Framingham risk score is associated with reduced life expectancy [81]. Furthermore, another study showed that the risk of coronary heart disease over a 5-year period was independent of biochemical control and estimated disease duration [82].
3.6 Hypertension
Hypertension is a relatively common comorbidity. Recent data from registries estimate a 23–40% prevalence of hypertension in patients with acromegaly [21, 50, 83]. Disease control is associated with better control of blood pressure in patients with acromegaly and hypertension [62, 84, 85], as well as with a lower incidence of hypertension among acromegaly patients (41.8% vs 58.5%) [71]. Furthermore, biochemical control may also prevent progression to hypertension in normotensive acromegalic patients [86].
However, the increased prevalence of hypertension observed in acromegaly patients needs to be completely elucidated from a pathophysiological perspective, since it involves a balance between the antinatriuretic effect of GH and the potential role of IGF-1 in reducing vascular resistance [87,88,89]. As a consequence, biochemical control shows a positive correlation with the prevalence of hypertension in some studies, but not in others [44]. As an example, a retrospective study evaluated 105 patients with acromegaly receiving antihypertensive drugs. All patients were treated with SRLs in the context of a multimodal approach (monotherapy, neoadjuvant, adjuvant setting). After 24 months only patients reaching normal GH and IGF-1 showed significantly lower diastolic (DBP) and systolic blood pressure (SBP) as compared to baseline, while uncontrolled patients showed only a lowering in DBP levels [85]. In 2008, Colao and colleagues compared the efficacy of first-line SRL treatment vs first-line surgery in 89 patients with active acromegaly (12-month follow-up). The authors found that both treatment modalities resulted in a significant decrease of DBP levels, while SBP was unchanged [60].
On the other hand, a recent study showed that a 24 weeks treatment with lanreotide failed to significantly reduce SBP or DBP in treatment-naïve patients with acromegaly [68].
As far as treatment with the GH-receptor antagonist pegvisomant, an early study including 14 patients treated for 12 months, SBP and DBP were not affected at the end of follow-up. However, when only hypertensive patients were considered, pegvisomant therapy was found to significantly reduce DBP [84]. On the contrary, data from 62 acromegaly patients included in the German pegvisomant observational study demonstrated that after 12 months treatment, both SBP and DBP were significantly lower in controlled (normal IGF-1) than in partially-controlled patients (IGF-1 reduced without normalization) [90]. Moreover, SBP significantly decreased during treatment in controlled patients, while not in partially-controlled ones [90].
3.7 Metabolic complications
Glucose metabolism disorders found in patients with acromegaly mainly include impaired glucose tolerance (IGT), impaired fasting glucose (IFG) and diabetes mellitus [52]. Recent registry studies indicate that diabetes is found in 17–30% of patients with acromegaly [21, 50, 83], and glucose intolerance in about 20% [83]. Since the direct action of GH is diabetogenic (through increasing lipolysis and inducing insulin resistance) [52], biochemical control would be expected to reduce insulin resistance, notwithstanding the small beneficial effect of excess IGF-1 on insulin sensitivity [52]. However, IGF-1 levels seem to show a better correlation than GH with the presence of glycometabolic comorbidities [91].
Biochemical control after transsphenoidal surgery improves glucose tolerance and reduces the prevalence of diabetes mellitus, whereas the effects of medical therapy vary between drug classes and treatment modalities [52] (Table 3). Several studies have shown that conventional SRLs reduce insulin resistance, while simultaneously reducing insulin and glucagon secretion [92, 93]. On the other hand, pegvisomant has been demonstrated to improve insulin sensitivity, increase glucose tolerance as well as decrease fasting glucose and glycosylated hemoglobin levels (HbA1c) [94]. Conflicting findings are often reported on the effect of SRL treatment on glucose tolerance in patients with acromegaly, likely due to the variations in study methodology [52].
A retrospective study conducted on 200 consecutive patients reported a three-fold higher risk of diabetes in patients with acromegaly uncontrolled after SRL treatment as compared with those in remission after surgery (hazard ratio [HR] 3.32, p = 0.006). However, only a 1.4-fold higher risk was recorded in those with biochemical control induced by SRLs compared with neurosurgery recipients (HR 1.43, p = 0.38) [53].
Data from prospective clinical trials suggest that the second-generation SRL pasireotide is associated with a significantly higher incidence and a greater degree of severity of hyperglycaemia-related adverse events than first-generation SRLs [12]. However, a number of recent studies have shown that the hyperglycaemic effect of pasireotide is often predictable, mainly based on baseline fasting plasma glucose and HbA1c, and changes in glucose metabolism are reversible [95]. Moreover, proactive monitoring and treatment results in a rapid and successful control of hyperglycaemia in most patients [95].
A meta-analysis from Mazziotti and colleagues, published in 2009, showed that SRLs treatment does not affect fasting plasma glucose (FPG), HbA1c and glucose response to OGTT, while the authors found a significant reduction of fasting plasma insulin (FPI). However, on a metaregression analysis, the effects of SRLs treatment on these parameters was not significantly correlated with biochemical control (percent of patient achieving safe GH and normal IGF-1 levels) [96]. More recently, another meta-analysis confirmed that SRLs resulted in a significant lowering of FPI, although resulting in a significant improvement of insulin-resistance (HOMA-I) and β-cell function (HOMA-β). Furthermore, no major changes were observed for FPG levels after SRLs. However, differently from the previous report from Mazziotti et al., the authors reported a worsened glucose response to OGTT as well as a mild, but significant, increase in HbA1c. Interestingly, the reduction of both GH and IGF-1 levels was directly correlated with the drop in insulin levels, while IGF-1 levels affected HOMA-I values [97].
On the other hand, pegvisomant monotherapy mainly results in beneficial effect on glucose metabolism in acromegaly [22]. Of note, the majority of studies reporting the effects of pegvisomant treatment on glucose metabolism included patients completely or partially resistant to SRLs. Therefore, it could be speculated that this effect might be due to a better biochemical control of the disease. However, a direct beneficial activity of pegvisomant cannot be ruled out. In this context, a multicentre, open-label, 32-week study evaluated glucose homeostasis in patients converted from SRLs to pegvisomant [98]. The authors showed a significant improvement in glucose-related indices after the switch to pegvisomant, also in the subset of patients who had normal IGF-I concentrations during previous SRL treatment [98].
In summary, despite disease control, disorders of glucose metabolism may persist, particularly in acromegaly patients treated with SRLs compared to those cured after adenomectomy or treated with pegvisomant [99].
3.8 Osteoarticular and musculoskeletal complications
Arthropathy is common in acromegaly: the incidence of acral complications may be as high as 70% at diagnosis [100]. There is evidence that certain signs and symptoms may improve with medical therapy [101], however, arthropathy and established degenerative arthritis may persist despite biochemical control [6, 102]. On the other hand, normalization of GH and IGF-1 levels seems to be associated with improved joint thickness. Indeed, after 12 months of long-acting octreotide, 25–29% of patients with controlled disease experienced a maximum decrease in joint thickness (across all joint sites) as compared with 58% of patients without disease control [103]. However, a prospective follow-up study of patients with controlled acromegaly for a mean of 17.6 years reported joint function deterioration over the long term [104]. Progressive osteophytosis and joint space narrowing have been reported in over 70% of patients with long-term control of IGF-1 levels. In addition, the highest rates of joint disease progression has been reported in patients on medical therapy [105]. This has led some authors to conclude that elevated circulating GH levels despite SRL treatment, are responsible for the persistence of osteoarticular complications in acromegaly [106].
Furthermore, it is known that GH (and IGF-1) excess negatively affects bone status [107, 108].
A wide range in prevalence of vertebral fractures (VFs) has been reported (10–40% of patients) [6] and duration of active disease seems to be the most important determinant of VFs in acromegaly, while an adequate treatment can reduce this risk [100, 109]. In a recent meta-analysis, the risk of VFs was three times higher in uncontrolled patients when compared with controlled ones (odds ratio [OR] 3.35, 95% confidence interval [CI] 1.61–6.96) [107]. Anyway, some patients with controlled acromegaly still maintained high fracture risk, specifically in presence of preexisting VFs, thus reflecting a sort of domino-effect [108]. In this context, the presence of uncontrolled hypogonadism and/or diabetes mellitus has been associated with a higher risk of VFs in acromegaly patients, as well (Fig. 2). Notably, despite biochemical control, skeletal complications may progress in up to 20% of patients [105].
A relevant percentage of acromegaly patients present vertebral fractures (VFs) during their clinical history. Active disease and disease duration correlate with a higher risk of VFs, while biochemical control seems to reduce their prevalence. However, other clinical conditions (i.e. untreated hypogonadism and diabetes mellitus) and the presence of pre-existing VFs have been highlighted as GH and IGF-1 independent risk factors in acromegaly patients
Patients with acromegaly have increased bone turnover, which results in a peculiar bone structure. Particularly, high GH and IGF-I levels mainly affect trabecular microarchitecture, while cortical bone density is often increased [110]. Dual X-ray absorptiometry (DXA) measurement of bone mineral density (BMD) does not distinguish between cortical and trabecular bone in acromegaly, and therefore most patients show normal or even increased BMD at various skeletal sites [107]. According to a study examining bone architecture and BMD at the lumbar spine, fracture risk may persist because of irreversible alterations in trabecular bone architecture [111]. Indeed, biochemical control of acromegaly is associated with a decrease of biochemical markers of bone turnover, accompanied by variable changes in BMD. However, this is generally associated with a persistently abnormal bone structure even after reversal of GH hypersecretion [108].
Finally, carpal tunnel syndrome is another common symptom of acromegaly and represents one of the hallmark of the disease, with much research focus on medial nerve neuropathy at the carpal tunnel level [112]. An ultrasound study in patients with acromegaly sought to examine the effects of biochemical control not only on the median but also the ulnar nerve cross-sectional area [112, 113]. Full or partial biochemical control was associated with smaller nerve cross-sectional area than in patients with uncontrolled hormone levels [112]. However, after 1-year follow-up, it appeared that biochemical control was associated with only partial reversal of nerve enlargement [113].
3.9 Respiratory disorders
Respiratory insufficiency and sleep breathing disorders, mainly sleep apnoea, are the main respiratory complications of acromegaly [52]. Disease activity, older age, and neck circumference have been reported to be independent predictors of sleep apnoea [114].
Biochemical control has been shown to improve sleep breathing disorders and respiratory insufficiency in patients with acromegaly by reducing the number of apnoeic and hypopneic episodes, improving central control of breathing and reducing soft tissue hypertrophy [52]. Interestingly, some authors showed that, following SRLs treatment, lung volume and distensibility decrease, while diffusion capacity remained stable [115].
A registry study reported a lower incidence of sleep apnoea in patients with controlled disease versus uncontrolled ones (20.3% vs 26.8%) [71]. However, sleep apnoea can persist after recovery of acromegaly, although in a multivariate analysis higher IGF-1 levels have been associated with the presence of this complication [116]. Furthermore, the observed improvements of sleep breathing disorders can result in a limited clinical benefit because the indication for positive airway pressure therapy may remain, even in those subjects with improved sleep apnoea due to biochemical control [117].
Because the soft tissue hypertrophy associated with acromegaly is the main factor driving the development of respiratory comorbidities, prompt treatment may allow for these changes to be reversed. Therefore, permanent anatomical changes due to delayed diagnosis or therapeutic inertia are the reason for the persistence of respiratory complications following biochemical remission [52].
3.10 Quality of life
The effect of biochemical control on QoL is unclear. QoL is generally assessed using the disease-specific AcroQoL questionnaire. While several studies have found no improvement in QoL in patients with controlled disease [118,119,120,121], others have reported improved QoL in patients reaching biochemical control [122,123,124,125]. A meta-analysis on the relationship between QoL and disease-activity, as reflected by biochemical control, confirmed the ‘mixed-bag’ of results [19]. The authors concluded that there are currently insufficient published data to confirm a beneficial effect of biochemical control on the QoL of patients with acromegaly [19].
In this context, the results from a recent 5-year prospective study show that QoL remains impaired in patients with acromegaly (n = 58) as compared with matched healthy controls (n = 116), despite long-term biochemically stable disease [121].
QoL is per se multifactorial, and there are several possibilities for the persistence of impaired QoL in patients with acromegaly in “remission”, according to standard definitions. These include persistent physical and psychological limitations due to the irreversible effects of long-term exposure to GH and IGF-1 excess [126], such as irreversible craniofacial changes [127] and persistent joint complaints [128]. Furthermore, QoL may also be affected by depressive symptoms and anxiety [19, 129], negative illness perceptions [130, 131], body mass index and metabolic comorbidities [19], burden of ongoing treatment and follow-up [126], duration of remission [125], impaired physical function and psychosocial wellbeing [121].
4 Clinical disease control with different medical therapy regimens
4.1 Second versus first-generation somatostatin receptor ligands
The first-generation SRLs octreotide and lanreotide preferentially bind somatostatin receptor type 2 (SST2) [48] while the second-generation SRL pasireotide is a ‘panligand’, showing the highest affinity for SST5 and SST2 (namely, SST5 > SST2 > SST3 > SST1) [48]. Pasireotide was more effective than octreotide in improving QoL as first-line medical therapy [39] and improved QoL in patients with poorly-controlled disease after first-generation SRLs [40]. In detail, in a prospective, randomized, double-blind, multicentre, 12-month study of 358 patients with medically-naïve acromegaly [39], pasireotide LAR was associated with a larger increase in AcroQoL score than octreotide LAR (7.0 vs 4.9 points; baseline scores were similar in the two treatment groups). Improvements in symptom severity scores for all symptoms assessed were generally similar in the two treatment groups. Pasireotide LAR resulted in a greater inhibition of IGF-1 levels than octreotide LAR, while the two compounds had a similar impact on GH reduction [39]. However, hyperglycaemia-related adverse events were more frequent in the pasireotide LAR than the octreotide LAR group (57.3% vs 21.7%) [39].
The difference in efficacy and safety profile between pasireotide and a first generation SRLs may be partially explained by the pharmacodynamic differences between these agents, involving their extra-pituitary effects, as well as the differential receptor binding profile [132,133,134].
4.2 Growth hormone receptor antagonist versus first-generation somatostatin receptor ligands
Pegvisomant has been compared with octreotide in a phase III trial in patients with medically-naïve acromegaly (n = 113). The authors found no significant difference in disease signs and symptoms, ring size variation and AcroQoL total scores between the two treatment groups [135]. However, pegvisomant was more effective than octreotide in the achievement of normal IGF-1 in patients with more severe disease (IGF-1 ≥ 2 x ULN), in whom a trend towards greater improvement in AcroQoL scores was also observed [135]. On the other hand, in a cross-sectional study of 133 patients with acromegaly, patients were asked to complete questionnaires on QoL (AcroQoL), symptoms of depression (Beck’s Depression Inventory [BDI]) and satisfaction with their medical therapy. Particularly, the Treatment Satisfaction Questionnaire for Medication (TSQM) evaluates patients’ perceptions of effectiveness, side effects, convenience and global satisfaction. In this context, pegvisomant treatment (alone or in combination with SRLs) was associated with significantly lower convenience scores and a tendency towards a lower score for global satisfaction compared with octreotide and lanreotide monotherapy. Considering the peculiar treatment schedule of the patients included in the study, the authors suggested that this finding might be explained by the requirement for daily pegvisomant injections [136].
4.3 Combination of somatostatin receptor ligands plus growth hormone receptor antagonist
Therapies combining drugs with different mechanisms of action may be a rational choice to increase the likelihood of achieving clinical control and improving patients’ signs, symptoms and QoL. Van der Lely and colleagues have shown that co-administration of lanreotide and pegvisomant decreased mean acromegaly symptom scores, with the greatest reductions observed in arthralgia and soft tissue swelling. Small improvements in global QoL score were also recorded, although considerable data variability was noted. Interestingly, there was no correlation between changes in IGF-1 z-score and change in the QoL score [137].
When low-dose pegvisomant was added to SRL in patients already adequately controlled on SRL monotherapy, QoL improved [122]. However, these results were not confirmed in a study using a different approach (progressive reduction of SRL dosage during pegvisomant treatment) [138]. In the placebo-controlled crossover study by Neggers and colleagues (n = 20), the addition of pegvisomant 40 mg weekly to SRL therapy (lanreotide or octreotide) was associated with significantly greater improvements in AcroQoL total scores (p = 0.008) and physical subscale scores (p = 0.002) compared to SRL monotherapy [122]. This improvement was observed without a significant decrease in IGF-1 levels [122]. Improvement in QoL was correlated with improvement in GH-dependent symptoms such as loss of body weight, perspiration, soft tissue swelling and AcroQoL physical subscale score [122].
The controversial study by Neggers and colleagues introduced the concept of ‘extra-hepatic’ acromegaly [134], which in turn prompted the discussion of whether the current approach to the treatment of patients with acromegaly may need to be re-evaluated. However, confirmation of this hypothesis is still warranted.
As for acromegaly-related metabolic complications, combination therapy with SRLs and pegvisomant has been reported to improve insulin response to OGTT in patients with either controlled [138] or inadequately controlled disease during SRL therapy [139, 140]. In a historical-prospective study of 50 patients, SRL monotherapy was associated with higher glucose compared with the combination treatment (SRL plus pegvisomant) during OGTT [141]. In addition, when SRL was withdrawn, and pegvisomant continued, glycaemic response further improved significantly. This effect was observed in both patients with biochemically controlled and uncontrolled disease [141]. However, SRL plus pegvisomant combination seemed not to improve other measures of glucose metabolism, such as fasting plasma glucose, HbA1c, insulin resistance and beta-cell function, compared to SRL treatment [138, 140].
Finally, no direct comparison of the effects of pasireotide and pegvisomant on disease and symptom control has been published to date.
5 Conclusions
Adequate biochemical control plays a role in reducing the impact of several comorbidities in acromegaly. Current guidelines already suggest longitudinal monitoring and rigorous management of hypertension, cardiovascular disease, diabetes mellitus, osteoarthritis and sleep apnoea [2, 9]. However, in the present review, we aimed to highlight clinical disease control as a primary focus of acromegaly patient management, besides biochemical control based on currently accepted criteria. In this light, it is widely recognised that early diagnosis and timely therapeutic intervention improve clinical outcomes [142]. Moreover, focusing exclusively on the biochemical control of the disease is affected by issues related to timely changing hormone targets, hormone assay [2], discrepancy between GH and IGF-1 levels in SRL-treated patients [16], and, as a consequence, lack of appropriate dose up-titration in the daily clinical practice [16]. Although some aspects of patients’ QoL may be improved with biochemical control, there is some evidence that QoL should be considered a separate treatment target in addition to biochemical control, i.e., as a standalone entity [19]. Acromegaly comorbidities impact QoL [19], and some of them do not improve, even when biochemical control is achieved, suggesting that without an early diagnosis and intervention, long-term exposure to excess GH and IGF-1 levels lead to irreversible effects (i.e., degenerative arthritis, craniofacial abnormalities) [6]. Specific interventions, aimed at targeting factors associated with reduced QoL, such as depression and obesity [19], should be developed, as well as the importance of treating comorbidities to further reduce mortality risk is mandatory [143]. Finally, although data are currently limited, newer drugs with (also) a peripheral action, such as pegvisomant and, via different mechanisms, pasireotide, may lead to a better control of the disease, not only identified as the normalisation of biochemical parameters, but also at the clinical level.
References
Melmed S. Medical progress: acromegaly. N Engl J Med. 2006;355(24):2558–73. https://doi.org/10.1056/NEJMra062453.
Katznelson L, Laws ER Jr, Melmed S, Molitch ME, Murad MH, Utz A, et al. Acromegaly: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(11):3933–51. https://doi.org/10.1210/jc.2014-2700.
Colao A, Ferone D, Marzullo P, Lombardi G. Systemic complications of acromegaly: epidemiology, pathogenesis, and management. Endocr Rev. 2004;25(1):102–52. https://doi.org/10.1210/er.2002-0022.
Holdaway IM, Bolland MJ, Gamble GD. A meta-analysis of the effect of lowering serum levels of GH and IGF-I on mortality in acromegaly. Eur J Endocrinol. 2008;159(2):89–95. https://doi.org/10.1530/EJE-08-0267.
Casanueva FF, Barkan AL, Buchfelder M, Klibanski A, Laws ER, Loeffler JS, et al. Criteria for the definition of pituitary tumor centers of excellence (PTCOE): a pituitary society statement. Pituitary. 2017;20(5):489–98. https://doi.org/10.1007/s11102-017-0838-2.
Abreu A, Tovar AP, Castellanos R, Valenzuela A, Giraldo CM, Pinedo AC, et al. Challenges in the diagnosis and management of acromegaly: a focus on comorbidities. Pituitary. 2016;19(4):448–57. https://doi.org/10.1007/s11102-016-0725-2.
Lotti F, Rochira V, Pivonello R, Santi D, Galdiero M, Maseroli E, et al. Erectile dysfunction is common among men with acromegaly and is associated with morbidities related to the disease. J Sex Med. 2015;12(5):1184–93. https://doi.org/10.1111/jsm.12859.
Giustina A, Chanson P, Kleinberg D, Bronstein MD, Clemmons DR, Klibanski A, et al. Expert consensus document: a consensus on the medical treatment of acromegaly. Nat Rev Endocrinol. 2014;10(4):243–8. https://doi.org/10.1038/nrendo.2014.21.
Melmed S, Bronstein MD, Chanson P, Klibanski A, Casanueva FF, Wass JAH, et al. A consensus statement on acromegaly therapeutic outcomes. Nat Rev Endocrinol. 2018;14(9):552–61. https://doi.org/10.1038/s41574-018-0058-5.
Pita-Gutierrez F, Pertega-Diaz S, Pita-Fernandez S, Pena L, Lugo G, Sangiao-Alvarellos S, et al. Place of preoperative treatment of acromegaly with somatostatin analog on surgical outcome: a systematic review and meta-analysis. PLoS One. 2013;8(4):e61523. https://doi.org/10.1371/journal.pone.0061523.
Bacigaluppi S, Gatto F, Anania P, Bragazzi NL, Rossi DC, Benvegnu G, et al. Impact of pre-treatment with somatostatin analogs on surgical management of acromegalic patients referred to a single center. Endocrine. 2016;51(3):524–33. https://doi.org/10.1007/s12020-015-0619-5.
McKeage K. Pasireotide in acromegaly: a review. Drugs. 2015;75(9):1039–48. https://doi.org/10.1007/s40265-015-0413-y.
Carmichael JD, Bonert VS, Nuno M, Ly D, Melmed S. Acromegaly clinical trial methodology impact on reported biochemical efficacy rates of somatostatin receptor ligand treatments: a meta-analysis. J Clin Endocrinol Metab. 2014;99(5):1825–33. https://doi.org/10.1210/jc.2013-3757.
Schilbach K, Strasburger CJ, Bidlingmaier M. Biochemical investigations in diagnosis and follow up of acromegaly. Pituitary. 2017;20(1):33–45. https://doi.org/10.1007/s11102-017-0792-z.
Alexopoulou O, Bex M, Abs R, T'Sjoen G, Velkeniers B, Maiter D. Divergence between growth hormone and insulin-like growth factor-i concentrations in the follow-up of acromegaly. J Clin Endocrinol Metab. 2008;93(4):1324–30. https://doi.org/10.1210/jc.2007-2104.
Schofl C, Franz H, Grussendorf M, Honegger J, Jaursch-Hancke C, Mayr B, et al. Long-term outcome in patients with acromegaly: analysis of 1344 patients from the German acromegaly register. Eur J Endocrinol. 2013;168(1):39–47. https://doi.org/10.1530/EJE-12-0602.
Machado EO, Taboada GF, Neto LV, van Haute FR, Correa LL, Balarini GA, et al. Prevalence of discordant GH and IGF-I levels in acromegalics at diagnosis, after surgical treatment and during treatment with octreotide LAR. Growth Hormon IGF Res. 2008;18(5):389–93. https://doi.org/10.1016/j.ghir.2008.02.001.
Carmichael JD, Bonert VS, Mirocha JM, Melmed S. The utility of oral glucose tolerance testing for diagnosis and assessment of treatment outcomes in 166 patients with acromegaly. J Clin Endocrinol Metab. 2009;94(2):523–7. https://doi.org/10.1210/jc.2008-1371.
Geraedts VJ, Andela CD, Stalla GK, Pereira AM, van Furth WR, Sievers C et al. Predictors of Quality of Life in Acromegaly: No Consensus on Biochemical Parameters. Front Endocrinol (Lausanne). 2017;8:40. https://doi.org/10.3389/fendo.2017.00040.
Holdaway IM, Rajasoorya RC, Gamble GD. Factors influencing mortality in acromegaly. J Clin Endocrinol Metab. 2004;89(2):667–74. https://doi.org/10.1210/jc.2003-031199.
Maione L, Brue T, Beckers A, Delemer B, Petrossians P, Borson-Chazot F, et al. Changes in the management and comorbidities of acromegaly over three decades: the French acromegaly registry. Eur J Endocrinol. 2017;176(5):645–55. https://doi.org/10.1530/EJE-16-1064.
Giustina A, Arnaldi G, Bogazzi F, Cannavo S, Colao A, De Marinis L, et al. Pegvisomant in acromegaly: an update. J Endocrinol Investig. 2017;40(6):577–89. https://doi.org/10.1007/s40618-017-0614-1.
Pokrajac A, Wark G, Ellis AR, Wear J, Wieringa GE, Trainer PJ. Variation in GH and IGF-I assays limits the applicability of international consensus criteria to local practice. Clin Endocrinol. 2007;67(1):65–70. https://doi.org/10.1111/j.1365-2265.2007.02836.x.
Christiansen Arlien-Soborg M, Trolle C, Alvarson E, Baek A, Dal J. Otto Lunde Jorgensen J. biochemical assessment of disease control in acromegaly: reappraisal of the glucose suppression test in somatostatin analogue (SA) treated patients. Endocrine. 2017;56(3):589–94. https://doi.org/10.1007/s12020-017-1258-9.
Minuto F, Resmini E, Boschetti M, Arvigo M, Sormani MP, Giusti M, et al. Assessment of disease activity in acromegaly by means of a single blood sample: comparison of the 120th minute postglucose value with spontaneous GH secretion and with the IGF system. Clin Endocrinol. 2004;61(1):138–44. https://doi.org/10.1111/j.1365-2265.2004.02064.x.
Freda PU, Katznelson L, van der Lely AJ, Reyes CM, Zhao S, Rabinowitz D. Long-acting somatostatin analog therapy of acromegaly: a meta-analysis. J Clin Endocrinol Metab. 2005;90(8):4465–73. https://doi.org/10.1210/jc.2005-0260.
Colao A, Auriemma RS, Pivonello R, Kasuki L, Gadelha MR. Interpreting biochemical control response rates with first-generation somatostatin analogues in acromegaly. Pituitary. 2016;19(3):235–47. https://doi.org/10.1007/s11102-015-0684-z.
Puig DM. Treatment of acromegaly in the era of personalized and predictive medicine. Clin Endocrinol. 2015;83(1):3–14. https://doi.org/10.1111/cen.12731.
Colao A, Ferone D, Lastoria S, Marzullo P, Cerbone G, Di Sarno A, et al. Prediction of efficacy of octreotide therapy in patients with acromegaly. J Clin Endocrinol Metab. 1996;81(6):2356–62. https://doi.org/10.1210/jcem.81.6.8964877.
Lindsay JR, McConnell EM, Hunter SJ, McCance DR, Sheridan B, Atkinson AB. Poor responses to a test dose of subcutaneous octreotide predict the need for adjuvant therapy to achieve 'safe' growth hormone levels. Pituitary. 2004;7(3):139–44. https://doi.org/10.1007/s11102-005-1756-2.
de Herder WW, Taal HR, Uitterlinden P, Feelders RA, Janssen JA, van der Lely AJ. Limited predictive value of an acute test with subcutaneous octreotide for long-term IGF-I normalization with Sandostatin LAR in acromegaly. Eur J Endocrinol. 2005;153(1):67–71. https://doi.org/10.1530/eje.1.01935.
Biermasz NR, Pereira AM, Smit JW, Romijn JA, Roelfsema F. Intravenous octreotide test predicts the long term outcome of treatment with octreotide-long-acting repeatable in active acromegaly. Growth Hormon IGF Res. 2005;15(3):200–6. https://doi.org/10.1016/j.ghir.2005.02.007.
Karavitaki N, Botusan I, Radian S, Coculescu M, Turner HE, Wass JA. The value of an acute octreotide suppression test in predicting long-term responses to depot somatostatin analogues in patients with active acromegaly. Clin Endocrinol. 2005;62(3):282–8. https://doi.org/10.1111/j.1365-2265.2004.02191.x.
Halperin I, Nicolau J, Casamitjana R, Sesmilo G, Serra-Prat M, Palomera E, et al. A short acute octreotide test for response prediction of long-term treatment with somatostatin analogues in acromegalic patients. Horm Metab Res. 2008;40(6):422–6. https://doi.org/10.1055/s-2008-1065339.
Sandret L, Maison P, Chanson P. Place of cabergoline in acromegaly: a meta-analysis. J Clin Endocrinol Metab. 2011;96(5):1327–35. https://doi.org/10.1210/jc.2010-2443.
Abs R, Verhelst J, Maiter D, Van Acker K, Nobels F, Coolens JL, et al. Cabergoline in the treatment of acromegaly: a study in 64 patients. J Clin Endocrinol Metab. 1998;83(2):374–8. https://doi.org/10.1210/jcem.83.2.4556.
Trainer PJ, Drake WM, Katznelson L, Freda PU, Herman-Bonert V, van der Lely AJ, et al. Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant. N Engl J Med. 2000;342(16):1171–7. https://doi.org/10.1056/NEJM200004203421604.
van der Lely AJ, Hutson RK, Trainer PJ, Besser GM, Barkan AL, Katznelson L, et al. Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist. Lancet. 2001;358(9295):1754–9.
Colao A, Bronstein MD, Freda P, Gu F, Shen CC, Gadelha M, et al. Pasireotide versus octreotide in acromegaly: a head-to-head superiority study. J Clin Endocrinol Metab. 2014;99(3):791–9. https://doi.org/10.1210/jc.2013-2480.
Gadelha MR, Bronstein MD, Brue T, Coculescu M, Fleseriu M, Guitelman M, et al. Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA): a randomised, phase 3 trial. Lancet Diabetes Endocrinol. 2014;2(11):875–84. https://doi.org/10.1016/S2213-8587(14)70169-X.
Lim DS, Fleseriu M. The role of combination medical therapy in the treatment of acromegaly. Pituitary. 2017;20(1):136–48. https://doi.org/10.1007/s11102-016-0737-y.
Christofides EA. Clinical importance of achieving biochemical control with medical therapy in adult patients with acromegaly. Patient Prefer Adherence. 2016;10:1217–25. https://doi.org/10.2147/PPA.S102302.
Tolis G, Angelopoulos NG, Katounda E, Rombopoulos G, Kaltzidou V, Kaltsas D, et al. Medical treatment of acromegaly: comorbidities and their reversibility by somatostatin analogs. Neuroendocrinology. 2006;83(3–4):249–57. https://doi.org/10.1159/000095535.
Gadelha MR, Kasuki L, Lim DST, Fleseriu M. Systemic complications of acromegaly and the impact of the current treatment landscape: an update. Endocr Rev. 2019;40(1):268–332. https://doi.org/10.1210/er.2018-00115.
Yedinak CG, Fleseriu M. Self-perception of cognitive function among patients with active acromegaly, controlled acromegaly, and non-functional pituitary adenoma: a pilot study. Endocrine. 2014;46(3):585–93. https://doi.org/10.1007/s12020-013-0106-9.
Yang LP, Keating GM. Octreotide long-acting release (LAR): a review of its use in the management of acromegaly. Drugs. 2010;70(13):1745–69. https://doi.org/10.2165/11204510-000000000-00000.
Burness CB, Dhillon S, Keam SJ. Lanreotide autogel((R)): a review of its use in the treatment of patients with acromegaly. Drugs. 2014;74(14):1673–91. https://doi.org/10.1007/s40265-014-0283-8.
Gadelha MR, Wildemberg LE, Bronstein MD, Gatto F, Ferone D. Somatostatin receptor ligands in the treatment of acromegaly. Pituitary. 2017;20(1):100–8. https://doi.org/10.1007/s11102-017-0791-0.
Tritos NA, Biller BM. Pegvisomant: a growth hormone receptor antagonist used in the treatment of acromegaly. Pituitary. 2017;20(1):129–35. https://doi.org/10.1007/s11102-016-0753-y.
Lesen E, Granfeldt D, Houchard A, Dinet J, Berthon A, Olsson DS, et al. Comorbidities, treatment patterns and cost-of-illness of acromegaly in Sweden: a register-linkage population-based study. Eur J Endocrinol. 2017;176(2):203–12. https://doi.org/10.1530/EJE-16-0623.
Petrossians P, Daly AF, Natchev E, Maione L, Blijdorp K, Sahnoun-Fathallah M, et al. Acromegaly at diagnosis in 3173 patients from the Liege acromegaly survey (LAS) database. Endocr Relat Cancer. 2017;24(10):505–18. https://doi.org/10.1530/ERC-17-0253.
Pivonello R, Auriemma RS, Grasso LF, Pivonello C, Simeoli C, Patalano R, et al. Complications of acromegaly: cardiovascular, respiratory and metabolic comorbidities. Pituitary. 2017;20(1):46–62. https://doi.org/10.1007/s11102-017-0797-7.
Sardella C, Cappellani D, Urbani C, Manetti L, Marconcini G, Tomisti L, et al. Disease activity and lifestyle influence comorbidities and cardiovascular events in patients with acromegaly. Eur J Endocrinol. 2016;175(5):443–53. https://doi.org/10.1530/EJE-16-0562.
Topaloglu O, Sayki Arslan M, Turak O, Ginis Z, Sahin M, Cebeci M, et al. Three noninvasive methods in the evaluation of subclinical cardiovascular disease in patients with acromegaly: epicardial fat thickness, aortic stiffness and serum cell adhesion molecules. Clin Endocrinol. 2014;80(5):726–34. https://doi.org/10.1111/cen.12356.
Colao A, Marzullo P, Ferone D, Spinelli L, Cuocolo A, Bonaduce D, et al. Cardiovascular effects of depot long-acting somatostatin analog Sandostatin LAR in acromegaly. J Clin Endocrinol Metab. 2000;85(9):3132–40. https://doi.org/10.1210/jcem.85.9.6782.
Lombardi G, Colao A, Marzullo P, Biondi B, Palmieri E, Fazio S, et al. Improvement of left ventricular hypertrophy and arrhythmias after lanreotide-induced GH and IGF-I decrease in acromegaly. A prospective multi-center study. J Endocrinol Investig. 2002;25(11):971–6. https://doi.org/10.1007/BF03344070.
Colao A, Marzullo P, Cuocolo A, Spinelli L, Pivonello R, Bonaduce D, et al. Reversal of acromegalic cardiomyopathy in young but not in middle-aged patients after 12 months of treatment with the depot long-acting somatostatin analogue octreotide. Clin Endocrinol. 2003;58(2):169–76.
Maison P, Tropeano AI, Macquin-Mavier I, Giustina A, Chanson P. Impact of somatostatin analogs on the heart in acromegaly: a metaanalysis. J Clin Endocrinol Metab. 2007;92(5):1743–7. https://doi.org/10.1210/jc.2006-2547.
Pivonello R, Galderisi M, Auriemma RS, De Martino MC, Galdiero M, Ciccarelli A, et al. Treatment with growth hormone receptor antagonist in acromegaly: effect on cardiac structure and performance. J Clin Endocrinol Metab. 2007;92(2):476–82. https://doi.org/10.1210/jc.2006-1587.
Colao A, Pivonello R, Galderisi M, Cappabianca P, Auriemma RS, Galdiero M, et al. Impact of treating acromegaly first with surgery or somatostatin analogs on cardiomyopathy. J Clin Endocrinol Metab. 2008;93(7):2639–46. https://doi.org/10.1210/jc.2008-0299.
De Marinis L, Bianchi A, Mazziotti G, Mettimano M, Milardi D, Fusco A, et al. The long-term cardiovascular outcome of different GH-lowering treatments in acromegaly. Pituitary. 2008;11(1):13–20. https://doi.org/10.1007/s11102-007-0062-6.
Colao A, Auriemma RS, Galdiero M, Lombardi G, Pivonello R. Effects of initial therapy for five years with somatostatin analogs for acromegaly on growth hormone and insulin-like growth factor-I levels, tumor shrinkage, and cardiovascular disease: a prospective study. J Clin Endocrinol Metab. 2009;94(10):3746–56. https://doi.org/10.1210/jc.2009-0941.
Bogazzi F, Lombardi M, Strata E, Aquaro G, Lombardi M, Urbani C, et al. Effects of somatostatin analogues on acromegalic cardiomyopathy: results from a prospective study using cardiac magnetic resonance. J Endocrinol Investig. 2010;33(2):103–8. https://doi.org/10.1007/BF03346562.
Comunello A, Dassie F, Martini C, De Carlo E, Mioni R, Battocchio M, et al. Heart rate variability is reduced in acromegaly patients and improved by treatment with somatostatin analogues. Pituitary. 2015;18(4):525–34. https://doi.org/10.1007/s11102-014-0605-6.
Auriemma RS, Grasso LF, Galdiero M, Galderisi M, Pivonello C, Simeoli C, et al. Effects of long-term combined treatment with somatostatin analogues and pegvisomant on cardiac structure and performance in acromegaly. Endocrine. 2017;55(3):872–84. https://doi.org/10.1007/s12020-016-0995-5.
Jayasena CN, Comninos AN, Clarke H, Donaldson M, Meeran K, Dhillo WS. The effects of long-term growth hormone and insulin-like growth factor-1 exposure on the development of cardiovascular, cerebrovascular and metabolic co-morbidities in treated patients with acromegaly. Clin Endocrinol. 2011;75(2):220–5. https://doi.org/10.1111/j.1365-2265.2011.04019.x.
Akdeniz B, Gedik A, Turan O, Ozpelit E, Ikiz AO, Itil O, et al. Evaluation of left ventricular diastolic function according to new criteria and determinants in acromegaly. Int Heart J. 2012;53(5):299–305.
Annamalai AK, Webb A, Kandasamy N, Elkhawad M, Moir S, Khan F, et al. A comprehensive study of clinical, biochemical, radiological, vascular, cardiac, and sleep parameters in an unselected cohort of patients with acromegaly undergoing presurgical somatostatin receptor ligand therapy. J Clin Endocrinol Metab. 2013;98(3):1040–50. https://doi.org/10.1210/jc.2012-3072.
Kuhn E, Maione L, Bouchachi A, Roziere M, Salenave S, Brailly-Tabard S, et al. Long-term effects of pegvisomant on comorbidities in patients with acromegaly: a retrospective single-center study. Eur J Endocrinol. 2015;173(5):693–702. https://doi.org/10.1530/EJE-15-0500.
dos Santos Silva CM, Gottlieb I, Volschan I, Kasuki L, Warszawski L, Balarini Lima GA, et al. Low frequency of cardiomyopathy using cardiac magnetic resonance imaging in an acromegaly contemporary cohort. J Clin Endocrinol Metab. 2015;100(12):4447–55. https://doi.org/10.1210/jc.2015-2675.
Carmichael JD, Broder MS, Cherepanov D, Chang E, Mamelak A, Said Q, et al. The association between biochemical control and cardiovascular risk factors in acromegaly. BMC Endocr Disord. 2017;17(1):15. https://doi.org/10.1186/s12902-017-0166-6.
Pereira AM, van Thiel SW, Lindner JR, Roelfsema F, van der Wall EE, Morreau H, et al. Increased prevalence of regurgitant valvular heart disease in acromegaly. J Clin Endocrinol Metab. 2004;89(1):71–5. https://doi.org/10.1210/jc.2003-030849.
van der Klaauw AA, Bax JJ, Roelfsema F, Bleeker GB, Holman ER, Corssmit EP, et al. Uncontrolled acromegaly is associated with progressive mitral valvular regurgitation. Growth Hormon IGF Res. 2006;16(2):101–7. https://doi.org/10.1016/j.ghir.2006.02.002.
Colao A, Spinelli L, Marzullo P, Pivonello R, Petretta M, Di Somma C, et al. High prevalence of cardiac valve disease in acromegaly: an observational, analytical, case-control study. J Clin Endocrinol Metab. 2003;88(7):3196–201. https://doi.org/10.1210/jc.2002-021099.
Kahaly G, Olshausen KV, Mohr-Kahaly S, Erbel R, Boor S, Beyer J, et al. Arrhythmia profile in acromegaly. Eur Heart J. 1992;13(1):51–6.
Maffei P, Martini C, Milanesi A, Corfini A, Mioni R, de Carlo E, et al. Late potentials and ventricular arrhythmias in acromegaly. Int J Cardiol. 2005;104(2):197–203. https://doi.org/10.1016/j.ijcard.2004.12.010.
Warszawski L, Kasuki L, Sa R, Dos Santos Silva CM, Volschan I, Gottlieb I, et al. Low frequency of cardniac arrhythmias and lack of structural heart disease in medically-naive acromegaly patients: a prospective study at baseline and after 1 year of somatostatin analogs treatment. Pituitary. 2016;19(6):582–9. https://doi.org/10.1007/s11102-016-0749-7.
Unubol M, Eryilmaz U, Guney E, Ture M, Akgullu C. QT dispersion in patients with acromegaly. Endocrine. 2013;43(2):419–23. https://doi.org/10.1007/s12020-012-9828-3.
Fatti LM, Scacchi M, Lavezzi E, Pecori Giraldi F, De Martin M, Toja P, et al. Effects of treatment with somatostatin analogues on QT interval duration in acromegalic patients. Clin Endocrinol. 2006;65(5):626–30. https://doi.org/10.1111/j.1365-2265.2006.02639.x.
Orosz A, Csajbok E, Czekus C, Gavaller H, Magony S, Valkusz Z, et al. Increased short-term beat-to-beat variability of QT interval in patients with acromegaly. PLoS One. 2015;10(4):e0125639. https://doi.org/10.1371/journal.pone.0125639.
Ragonese M, Alibrandi A, Di Bella G, Salamone I, Puglisi S, Cotta OR, et al. Cardiovascular events in acromegaly: distinct role of Agatston and Framingham score in the 5-year prediction. Endocrine. 2014;47(1):206–12. https://doi.org/10.1007/s12020-013-0115-8.
Bogazzi F, Battolla L, Spinelli C, Rossi G, Gavioli S, Di Bello V, et al. Risk factors for development of coronary heart disease in patients with acromegaly: a five-year prospective study. J Clin Endocrinol Metab. 2007;92(11):4271–7. https://doi.org/10.1210/jc.2007-1213.
Portocarrero-Ortiz LA, Vergara-Lopez A, Vidrio-Velazquez M, Uribe-Diaz AM, Garcia-Dominguez A, Reza-Albarran AA, et al. The Mexican acromegaly registry: clinical and biochemical characteristics at diagnosis and therapeutic outcomes. J Clin Endocrinol Metab. 2016;101(11):3997–4004. https://doi.org/10.1210/jc.2016-1937.
Colao A, Pivonello R, Auriemma RS, De Martino MC, Bidlingmaier M, Briganti F, et al. Efficacy of 12-month treatment with the GH receptor antagonist pegvisomant in patients with acromegaly resistant to long-term, high-dose somatostatin analog treatment: effect on IGF-I levels, tumor mass, hypertension and glucose tolerance. Eur J Endocrinol. 2006;154(3):467–77. https://doi.org/10.1530/eje.1.02112.
Colao A, Terzolo M, Bondanelli M, Galderisi M, Vitale G, Reimondo G, et al. GH and IGF-I excess control contributes to blood pressure control: results of an observational, retrospective, multicentre study in 105 hypertensive acromegalic patients on hypertensive treatment. Clin Endocrinol. 2008;69(4):613–20. https://doi.org/10.1111/j.1365-2265.2008.03258.x.
Sardella C, Urbani C, Lombardi M, Nuzzo A, Manetti L, Lupi I, et al. The beneficial effect of acromegaly control on blood pressure values in normotensive patients. Clin Endocrinol. 2014;81(4):573–81. https://doi.org/10.1111/cen.12455.
Ho KY, Weissberger AJ. The antinatriuretic action of biosynthetic human growth hormone in man involves activation of the renin-angiotensin system. Metabolism. 1990;39(2):133–7.
Muniyappa R, Walsh MF, Rangi JS, Zayas RM, Standley PR, Ram JL, et al. Insulin like growth factor 1 increases vascular smooth muscle nitric oxide production. Life Sci. 1997;61(9):925–31.
Tsukahara H, Gordienko DV, Tonshoff B, Gelato MC, Goligorsky MS. Direct demonstration of insulin-like growth factor-I-induced nitric oxide production by endothelial cells. Kidney Int. 1994;45(2):598–604.
Berg C, Petersenn S, Lahner H, Herrmann BL, Buchfelder M, Droste M, et al. Cardiovascular risk factors in patients with uncontrolled and long-term acromegaly: comparison with matched data from the general population and the effect of disease control. J Clin Endocrinol Metab. 2010;95(8):3648–56. https://doi.org/10.1210/jc.2009-2570.
Puder JJ, Nilavar S, Post KD, Freda PU. Relationship between disease-related morbidity and biochemical markers of activity in patients with acromegaly. J Clin Endocrinol Metab. 2005;90(4):1972–8. https://doi.org/10.1210/jc.2004-2009.
Colao A. Improvement of cardiac parameters in patients with acromegaly treated with medical therapies. Pituitary. 2012;15(1):50–8. https://doi.org/10.1007/s11102-011-0318-z.
Singh V, Brendel MD, Zacharias S, Mergler S, Jahr H, Wiedenmann B, et al. Characterization of somatostatin receptor subtype-specific regulation of insulin and glucagon secretion: an in vitro study on isolated human pancreatic islets. J Clin Endocrinol Metab. 2007;92(2):673–80. https://doi.org/10.1210/jc.2006-1578.
Giustina A, Ambrosio MR, Beck Peccoz P, Bogazzi F, Cannavo S, De Marinis L, et al. Use of Pegvisomant in acromegaly. An Italian Society of Endocrinology guideline. J Endocrinol Investig. 2014;37(10):1017–30. https://doi.org/10.1007/s40618-014-0146-x.
Samson SL. Management of Hyperglycemia in patients with acromegaly treated with Pasireotide LAR. Drugs. 2016;76(13):1235–43. https://doi.org/10.1007/s40265-016-0615-y.
Mazziotti G, Floriani I, Bonadonna S, Torri V, Chanson P, Giustina A. Effects of somatostatin analogs on glucose homeostasis: a metaanalysis of acromegaly studies. J Clin Endocrinol Metab. 2009;94(5):1500–8. https://doi.org/10.1210/jc.2008-2332.
Cozzolino A, Feola T, Simonelli I, Puliani G, Pozza C, Giannetta E, et al. Somatostatin analogs and glucose metabolism in acromegaly: a meta-analysis of prospective interventional studies. J Clin Endocrinol Metab. 2018;103:2089–99. https://doi.org/10.1210/jc.2017-02566.
Barkan AL, Burman P, Clemmons DR, Drake WM, Gagel RF, Harris PE, et al. Glucose homeostasis and safety in patients with acromegaly converted from long-acting octreotide to pegvisomant. J Clin Endocrinol Metab. 2005;90(10):5684–91. https://doi.org/10.1210/jc.2005-0331.
Jonas C, Maiter D, Alexopoulou O. Evolution of glucose tolerance after treatment of acromegaly: a study in 57 patients. Horm Metab Res. 2016;48(5):299–305. https://doi.org/10.1055/s-0035-1569277.
Ben-Shlomo A, Sheppard MC, Stephens JM, Pulgar S, Melmed S. Clinical, quality of life, and economic value of acromegaly disease control. Pituitary. 2011;14(3):284–94. https://doi.org/10.1007/s11102-011-0310-7.
Colao A, Marzullo P, Vallone G, Marino V, Annecchino M, Ferone D, et al. Reversibility of joint thickening in acromegalic patients: an ultrasonography study. J Clin Endocrinol Metab. 1998;83(6):2121–5. https://doi.org/10.1210/jcem.83.6.4865.
Colao A, Marzullo P, Vallone G, Giaccio A, Ferone D, Rossi E, et al. Ultrasonographic evidence of joint thickening reversibility in acromegalic patients treated with lanreotide for 12 months. Clin Endocrinol. 1999;51(5):611–8.
Colao A, Cannavo S, Marzullo P, Pivonello R, Squadrito S, Vallone G, et al. Twelve months of treatment with octreotide-LAR reduces joint thickness in acromegaly. Eur J Endocrinol. 2003;148(1):31–8.
Claessen KM, Ramautar SR, Pereira AM, Romijn JA, Kroon HM, Kloppenburg M, et al. Increased clinical symptoms of acromegalic arthropathy in patients with long-term disease control: a prospective follow-up study. Pituitary. 2014;17(1):44–52. https://doi.org/10.1007/s11102-013-0464-6.
Claessen KM, Ramautar SR, Pereira AM, Smit JW, Roelfsema F, Romijn JA, et al. Progression of acromegalic arthropathy despite long-term biochemical control: a prospective, radiological study. Eur J Endocrinol. 2012;167(2):235–44. https://doi.org/10.1530/EJE-12-0147.
Claessen KM, Mazziotti G, Biermasz NR, Giustina A. Bone and joint disorders in acromegaly. Neuroendocrinology. 2016;103(1):86–95. https://doi.org/10.1159/000375450.
Mazziotti G, Biagioli E, Maffezzoni F, Spinello M, Serra V, Maroldi R, et al. Bone turnover, bone mineral density, and fracture risk in acromegaly: a meta-analysis. J Clin Endocrinol Metab. 2015;100(2):384–94. https://doi.org/10.1210/jc.2014-2937.
Mazziotti G, Frara S, Giustina A. Pituitary diseases and bone. Endocr Rev. 2018;39(4):440–88. https://doi.org/10.1210/er.2018-00005.
Bonadonna S, Mazziotti G, Nuzzo M, Bianchi A, Fusco A, De Marinis L, et al. Increased prevalence of radiological spinal deformities in active acromegaly: a cross-sectional study in postmenopausal women. J Bone Miner Res. 2005;20(10):1837–44. https://doi.org/10.1359/JBMR.050603.
Giustina A, Mazziotti G, Canalis E. Growth hormone, insulin-like growth factors, and the skeleton. Endocr Rev. 2008;29(5):535–59. https://doi.org/10.1210/er.2007-0036.
Godang K, Olarescu NC, Bollerslev J, Heck A. Treatment of acromegaly increases BMD but reduces trabecular bone score: a longitudinal study. Eur J Endocrinol. 2016;175(2):155–64. https://doi.org/10.1530/EJE-16-0340.
Tagliafico A, Resmini E, Nizzo R, Bianchi F, Minuto F, Ferone D, et al. Ultrasound measurement of median and ulnar nerve cross-sectional area in acromegaly. J Clin Endocrinol Metab. 2008;93(3):905–9. https://doi.org/10.1210/jc.2007-1719.
Resmini E, Tagliafico A, Nizzo R, Bianchi F, Minuto F, Derchi L, et al. Ultrasound of peripheral nerves in acromegaly: changes at 1-year follow-up. Clin Endocrinol. 2009;71(2):220–5. https://doi.org/10.1111/j.1365-2265.2008.03468.x.
Weiss V, Sonka K, Pretl M, Dostalova S, Klozar J, Rambousek P, et al. Prevalence of the sleep apnea syndrome in acromegaly population. J Endocrinol Investig. 2000;23(8):515–9. https://doi.org/10.1007/BF03343767.
Garcia-Rio F, Pino JM, Diez JJ, Ruiz A, Villasante C, Villamor J. Reduction of lung distensibility in acromegaly after suppression of growth hormone hypersecretion. Am J Respir Crit Care Med. 2001;164(5):852–7. https://doi.org/10.1164/ajrccm.164.5.2005059.
Davi MV, Dalle Carbonare L, Giustina A, Ferrari M, Frigo A, Lo Cascio V, et al. Sleep apnoea syndrome is highly prevalent in acromegaly and only partially reversible after biochemical control of the disease. Eur J Endocrinol. 2008;159(5):533–40. https://doi.org/10.1530/EJE-08-0442.
Akkoyunlu ME, Ilhan MM, Bayram M, Tasan E, Yakar F, Ozcelik HK, et al. Does hormonal control obviate positive airway pressure therapy in acromegaly with sleep-disordered breathing? Respir Med. 2013;107(11):1803–9. https://doi.org/10.1016/j.rmed.2013.08.043.
Hua SC, Yan YH, Chang TC. Associations of remission status and lanreotide treatment with quality of life in patients with treated acromegaly. Eur J Endocrinol. 2006;155(6):831–7. https://doi.org/10.1530/eje.1.02292.
Matta MP, Couture E, Cazals L, Vezzosi D, Bennet A, Caron P. Impaired quality of life of patients with acromegaly: control of GH/IGF-I excess improves psychological subscale appearance. Eur J Endocrinol. 2008;158(3):305–10. https://doi.org/10.1530/EJE-07-0697.
T'Sjoen G, Bex M, Maiter D, Velkeniers B, Abs R. Health-related quality of life in acromegalic subjects: data from AcroBel, the Belgian registry on acromegaly. Eur J Endocrinol. 2007;157(4):411–7. https://doi.org/10.1530/EJE-07-0356.
Kyriakakis N, Lynch J, Gilbey SG, Webb SM, Murray RD. Impaired quality of life in patients with treated acromegaly despite long-term biochemically stable disease: results from a 5-years prospective study. Clin Endocrinol. 2017;86(6):806–15. https://doi.org/10.1111/cen.13331.
Neggers SJ, van Aken MO, de Herder WW, Feelders RA, Janssen JA, Badia X, et al. Quality of life in acromegalic patients during long-term somatostatin analog treatment with and without pegvisomant. J Clin Endocrinol Metab. 2008;93(10):3853–9. https://doi.org/10.1210/jc.2008-0669.
Paisley AN, Rowles SV, Roberts ME, Webb SM, Badia X, Prieto L, et al. Treatment of acromegaly improves quality of life, measured by AcroQol. Clin Endocrinol. 2007;67(3):358–62. https://doi.org/10.1111/j.1365-2265.2007.02891.x.
Trepp R, Everts R, Stettler C, Fischli S, Allemann S, Webb SM, et al. Assessment of quality of life in patients with uncontrolled vs. controlled acromegaly using the Acromegaly Quality of Life Questionnaire (AcroQoL). Clin Endocrinol (Oxf). 2005;63(1):103–10. https://doi.org/10.1111/j.1365-2265.2005.02307.x.
Vandeva S, Yaneva M, Natchev E, Elenkova A, Kalinov K, Zacharieva S. Disease control and treatment modalities have impact on quality of life in acromegaly evaluated by acromegaly quality of life (AcroQoL) questionnaire. Endocrine. 2015;49(3):774–82. https://doi.org/10.1007/s12020-014-0521-6.
Webb SM, Crespo I, Santos A, Resmini E, Aulinas A, Valassi E. MANAGEMENT OF ENDOCRINE DISEASE: quality of life tools for the management of pituitary disease. Eur J Endocrinol. 2017;177(1):R13–26. https://doi.org/10.1530/EJE-17-0041.
Imran SA, Tiemensma J, Kaiser SM, Vallis M, Doucette S, Abidi E, et al. Morphometric changes correlate with poor psychological outcomes in patients with acromegaly. Eur J Endocrinol. 2016;174(1):41–50. https://doi.org/10.1530/EJE-15-0888.
Biermasz NR, Pereira AM, Smit JW, Romijn JA, Roelfsema F. Morbidity after long-term remission for acromegaly: persisting joint-related complaints cause reduced quality of life. J Clin Endocrinol Metab. 2005;90(5):2731–9. https://doi.org/10.1210/jc.2004-2297.
Geraedts VJ, Dimopoulou C, Auer M, Schopohl J, Stalla GK, Sievers C. Health Outcomes in Acromegaly: Depression and Anxiety are Promising Targets for Improving Reduced Quality of Life. Front Endocrinol (Lausanne). 2014;5:229. https://doi.org/10.3389/fendo.2014.00229.
Tiemensma J, Pereira AM, Romijn JA, Broadbent E, Biermasz NR, Kaptein AA. Persistent negative illness perceptions despite long-term biochemical control of acromegaly: novel application of the drawing test. Eur J Endocrinol. 2015;172(5):583–93. https://doi.org/10.1530/EJE-14-0996.
Tiemensma J, Kaptein AA, Pereira AM, Smit JW, Romijn JA, Biermasz NR. Affected illness perceptions and the association with impaired quality of life in patients with long-term remission of acromegaly. J Clin Endocrinol Metab. 2011;96(11):3550–8. https://doi.org/10.1210/jc.2011-1645.
Murray RD, Kim K, Ren SG, Chelly M, Umehara Y, Melmed S. Central and peripheral actions of somatostatin on the growth hormone-IGF-I axis. J Clin Invest. 2004;114(3):349–56. https://doi.org/10.1172/JCI19933.
Pokrajac A, Frystyk J, Flyvbjerg A, Trainer PJ. Pituitary-independent effect of octreotide on IGF1 generation. Eur J Endocrinol. 2009;160(4):543–8. https://doi.org/10.1530/EJE-08-0822.
Neggers SJ, Kopchick JJ, Jorgensen JO, van der Lely AJ. Hypothesis: extra-hepatic acromegaly: a new paradigm? Eur J Endocrinol. 2011;164(1):11–6. https://doi.org/10.1530/EJE-10-0969.
Ghigo E, Biller BM, Colao A, Kourides IA, Rajicic N, Hutson RK et al. Comparison of pegvisomant and long-acting octreotide in patients with acromegaly naive to radiation and medical therapy. J Endocrinol Invest. 2009;32(11):924–933. https://doi.org/10.3275/6723 10.1007/BF03345774.
Kepicoglu H, Hatipoglu E, Bulut I, Darici E, Hizli N, Kadioglu P. Impact of treatment satisfaction on quality of life of patients with acromegaly. Pituitary. 2014;17(6):557–63. https://doi.org/10.1007/s11102-013-0544-7.
van der Lely AJ, Bernabeu I, Cap J, Caron P, Colao A, Marek J, et al. Coadministration of lanreotide autogel and pegvisomant normalizes IGF1 levels and is well tolerated in patients with acromegaly partially controlled by somatostatin analogs alone. Eur J Endocrinol. 2011;164(3):325–33. https://doi.org/10.1530/EJE-10-0867.
Madsen M, Poulsen PL, Orskov H, Moller N, Jorgensen JO. Cotreatment with pegvisomant and a somatostatin analog (SA) in SA-responsive acromegalic patients. J Clin Endocrinol Metab. 2011;96(8):2405–13. https://doi.org/10.1210/jc.2011-0654.
Jorgensen JO, Feldt-Rasmussen U, Frystyk J, Chen JW, Kristensen LO, Hagen C, et al. Cotreatment of acromegaly with a somatostatin analog and a growth hormone receptor antagonist. J Clin Endocrinol Metab. 2005;90(10):5627–31. https://doi.org/10.1210/jc.2005-0531.
De Marinis L, Bianchi A, Fusco A, Cimino V, Mormando M, Tilaro L, et al. Long-term effects of the combination of pegvisomant with somatostatin analogs (SSA) on glucose homeostasis in non-diabetic patients with active acromegaly partially resistant to SSA. Pituitary. 2007;10(3):227–32. https://doi.org/10.1007/s11102-007-0037-7.
Urbani C, Sardella C, Calevro A, Rossi G, Scattina I, Lombardi M, et al. Effects of medical therapies for acromegaly on glucose metabolism. Eur J Endocrinol. 2013;169(1):99–108. https://doi.org/10.1530/EJE-13-0032.
Brue T, Castinetti F. The risks of overlooking the diagnosis of secreting pituitary adenomas. Orphanet J Rare Dis. 2016;11(1):135. https://doi.org/10.1186/s13023-016-0516-x.
Mercado M, Gonzalez B, Vargas G, Ramirez C. de los Monteros AL, Sosa E et al. successful mortality reduction and control of comorbidities in patients with acromegaly followed at a highly specialized multidisciplinary clinic. J Clin Endocrinol Metab. 2014;99(12):4438–46. https://doi.org/10.1210/jc.2014-2670.
Acknowledgments
Financial support for medical editorial assistance was provided by Novartis Pharma AG. We thank Tracy Harrison and Georgii Filatov, Springer Healthcare Communications for the medical writing assistance.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflicts of interest/financial disclosures
FG has been a speaker for Novartis and has participated on advisory boards of Novartis, AMCo Ltd. and IONIS Pharmaceuticals. DF has been a speaker for and participated on advisory boards and received research grants from Novartis and Ipsen. The other Authors have no conflicts of interest to declare.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Gatto, F., Campana, C., Cocchiara, F. et al. Current perspectives on the impact of clinical disease and biochemical control on comorbidities and quality of life in acromegaly. Rev Endocr Metab Disord 20, 365–381 (2019). https://doi.org/10.1007/s11154-019-09506-y
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11154-019-09506-y