Acromegaly complications: an update.

Acromegaly is associated with growth hormone (GH) hypersecretion, leading to excess circulating insulin-like growth factor 1 (IGF-I) levels, which exert adverse effects on peripheral organs and physiologic processes ( 1 , 2 ). Patients commonly experience abnormal growth of bone and soft tissue, dysregulated glucose and lipid metabolism with increased risk for cardiovascular disease ( 2 , 3 ), and consequent increased mortality risk if not appropriately controlled ( 4 ). The treatment goal is to normalize GH and IGF-I levels, as well as signs and symptoms of the disease that often persist despite achievement of biochemical remission ( 5-8 ). Early diagnosis and patient-centered comorbidities management favors optimal long-term outcomes ( 9-13 ) with superior outcomes reported in Pituitary Tumor Centers of Excellence (PTCOEs) ( 14 , 15 ).

The purpose of our manuscript is to provide the reader with a comprehensive, updated, and critical review of the available literature including novel research findings on acromegaly comorbidities referring to the modern consensus derived practical guidelines for timing of tests at diagnosis and follow-up ( 9-12 ). Management of specific comorbidities is also briefly discussed to complement the available consensus guidelines ( 9-12 ). With this aim we performed a comprehensive literature search for English language papers published between September 2015 and September 2025. Search terms included “acromegaly” AND “comorbidities,” “sleep apnea,” “cardiovascular complications,” “bone disease,” “quality of life,” “metabolic complications,” and “cancer,” as well as other terms associated with each respective topic covered. Moreover, terms such as “growth hormone,” “GH,” “insulin-like growth factor 1,” and “IGF-I” were also included because acromegaly signs and symptoms, as well as comorbidities, are mediated either directly by GH or indirectly by elevated IGF-I levels resulting from excess GH action on the liver ( 16 ). Non-IGF-I-mediated actions of GH are mainly metabolic effects (eg, lipolysis and increased gluconeogenesis and glycogenolysis, together with decreased tissue glucose uptake) ( 17 ) and osteoblast stimulation ( 18 ). Circulating IGF-I is the best marker of GH action, and when measured by a validated assay with robust age-related reference ranges, it is the best biochemical marker of disease activity ( 19 ). Prevalence and severity of disease complications appear to be related to cumulative exposure to high IGF-I ( 20 ).

Cardiorespiratory complications

Cardiovascular and respiratory comorbidities are frequent clinically relevant findings linked to increased mortality risk ( 21 ) ( Fig. 1 ). Cardiomyopathy, arrhythmia, valvular abnormalities, and hypertension occur with varying incidence ( 22 ). Sleep apnea and snoring are also common and potentially severe respiratory comorbidities ( 23 ). Coexistent cardiac and respiratory complications may lead to decreased exercise tolerance ( 24 ).

Cardiomyopathy

Cardiomyopathy, often an early manifestation of acromegaly, is characterized initially by a reversible hyperkinetic left ventricle. This is followed—especially if acromegaly is not controlled (even without hypertension)—by progressive concentric hypertrophy with a prevalence ranging from 15% to 70% and leading to diastolic dysfunction in 10% to 50% of patients. Combined diastolic and systolic dysfunction is seen mostly in the late stages of acromegaly ( 25 , 26 ). Speckle-tracking echocardiography and cardiac magnetic resonance ( 27 , 28 ) showed that treatment partially reversed cardiomyopathy, especially in patients achieving biochemical control. Magnetic resonance imaging is more accurate than echocardiography in detecting ventricular mass, volume, and heart function, and after gadolinium enhancement, it may detect myocardial fibrosis, whereas T1 mapping correlates with myocardial collagen content ( 28 , 29 ).

IGF-I normalization, through either surgery or medical therapy with somatostatin receptor ligands (SRLs) or pegvisomant, reduces left ventricular mass and improves diastolic function ( 30-32 ). Interestingly, SRLs may improve acromegaly cardiomyopathy, including myocardial fibrosis ( 33 ), even in some patients who fail to achieve biochemical control ( 34 ). Cardiovascular risk in patients undergoing surgery for GH excess is not higher than in patients with nonfunctioning pituitary adenomas ( 35 ). Heart failure, although an earlier and severe outcome of acromegaly cardiomyopathy, is fortunately becoming a rare event, occurring in <5% of patients ( 36 ), likely as a result of better control of the disease and concomitant risk factors ( 37 ).

As per current guidelines, all patients should undergo an electrocardiogram and echocardiography at the time of diagnosis and should undergo periodical long-term echocardiographic follow-up, particularly those who either were not normal before treatment, or did not achieve biochemical control during treatment or have persistent arterial hypertension ( 11 ).

Arrhythmias

Up to 40% of patients with acromegaly may be diagnosed with arrhythmias, including atrial fibrillation with cardiomyopathy ( 26-39 ). Patients also may present with prolonged QT interval ( 40 ), elevated beat-to-beat QT interval variability, and a higher prevalence of late potentials ( 41 ). Diagnosis of prolonged QT interval is relevant prior to treatment, in particular for pasireotide, which may be associated with QT interval prolongation ( 42 ).

Valvular abnormalities

Frequent echocardiographic findings ( 43 , 44 ) include tricuspid regurgitation, although mitral and aortic valves also may be involved ( 45 ). Despite the achievement of biochemical control, valvular disorders are rarely reversible ( 26 ). Cabergoline, even at low doses, should be used with caution in patients with acromegaly and severe heart valve regurgitation ( 46 ).

Hypertension

Hypertension has a variable prevalence, ranging from 30% to 60% of patients with acromegaly in different series, particularly in those with active disease ( 47 ). Furthermore, hypertension in acromegaly is more frequent and may occur earlier than in individuals without acromegaly, matched for sex, age, body mass index (BMI), and smoking habits, involving predominantly, although not exclusively diastolic blood pressure. Importantly, hypertension prevalence does not differ by sex and is unfrequently related to family history of hypertension ( 48 ). Hypertension increases mortality risk significantly, especially when associated with cardiomyopathy or other cardiovascular risk factors ( 49 , 50 ).

Persistent hypertension, even after controlling acromegaly, is not uncommon ( 51 ) and may be due, particularly in older patients, to the coexistence of primary hypertension as well as partial reversibility of volume expansion, peripheral vascular resistance, and sleep apnea ( 1 ).

Although not used routinely, 24-hour ambulatory blood pressure monitoring has been recommended ( 52 ), as it is more sensitive and correlates better with ventricular mass than office blood pressure measurement. This can also have higher accuracy for assessing the efficacy of antihypertensive treatment. Nondipper behavior was reported to be significantly associated with the hormonal profile ( 53 ).

Surgery improves blood pressure levels, at least in the short-term, with restored day/night rhythm, particularly in individuals with controlled disease ( 54 ). The impact of SRLs on blood pressure is controversial, being reported either to improve or to have no significant effect. SRLs may have a beneficial antihypertensive effect due to biochemical control and are less likely to have a pleiotropic effect ( 55 ). The observation that pegvisomant may improve hypertension ( 56 ) also confirms the existence of a tight link between hormonal excess and increased blood pressure levels. Controlled studies evaluating or comparing different antihypertensive treatments in acromegaly are not available. Therefore, any recommendations for specific antihypertensive treatment in acromegaly have been so far issued on consensus guidelines, which suggest following general population guidelines ( 11 ). However, since sodium overload may occur, an epithelial sodium channel blocker (eg, amiloride) may be clinically helpful ( 57 ).

Sleep apnea

Sleep apnea is highly prevalent and present in up to 80% of patients at diagnosis ( 23 ). Upper airway obstruction due to soft tissue swelling is the main pathophysiological feature ( 58 ) even if central sleep apnea is present in about 30% of patients. Obstructive sleep apnea is associated with cardiovascular complications ( 59 , 60 ) and with disordered sleep and heavy snoring, which may lead to impaired quality of life (QoL), and mood and cognitive symptoms ( 61 ). Sleep apnea is one of the most underdiagnosed though clinically impactful complications ( 62 ), due in part to reduced access to sleep units ( 63 ). Moreover, assessment of sleep apnea, recommended in all patients with acromegaly at the time of diagnosis ( 11 ), may require polysomnography, which is not a routinely performed test in all countries. Administration of sleep questionnaires, such as the Epworth Sleepiness Scale, may be a viable alternative but is time consuming ( 64 ), and follow-up of changes in polysomnographic sleep apnea scores is logistically challenging. Interestingly, the availability of new technologies and artificial intelligence may transform the approach to the diagnosis of sleep apnea in acromegaly ( 65 , 66 ).

Treatment of acromegaly may improve obstructive sleep apnea by reducing pharyngeal swelling ( 67-69 ). However, even if biochemical control of acromegaly is achieved, sleep apnea does not improve in all patients. Few studies with SRL treatment have shown improvement ( 70 ) in sleep apnea, yet SRLs have, nevertheless, been considered as presurgical treatment for facilitating intubation ( 71 ), though not proven to improve outcomes. Masks for continuous positive airway pressure may be necessary in some patients with the most severe forms ( 11 ).

Inclusion of a sleep specialist in a PTCOE in the future might partially alleviate the difficulties in diagnosis and treatment for sleep disorders in patients with acromegaly.

Cardiopulmonary response to exercise

Impaired cardiopulmonary function may reduce exercise capacity to only 60% to 85% of normal sex- and age-adjusted values ( 72 ). Impaired physical performance may appear early in the disease course, primarily due to diastolic dysfunction despite a resting normal systolic function ( 24 ). Decreased ejection fraction at peak exercise inversely correlates with age and disease duration ( 73 ).

The main feature of impaired cardiopulmonary response to exercise is reduced maximal oxygen consumption ( 74 ). Increased lung volume and distensibility with decreased elasticity ( 75 ), together with altered rib cage geometry, may reduce ventilatory efficiency with inadequate ventilatory response to exercise demand, resulting in low workload capacity ( 76 ). Finally, the recently recognized myopathy in acromegaly, characterized by ectopic lipid deposition and decreased muscle performance, also may contribute to impaired exercise capacity ( 77 , 78 ).

GH and IGF-I may acutely impact cardiorespiratory function ( 24 ); octreotide may have beneficial effects on exercise tolerance ( 79 ) and improve ejection fraction ( 80 ), although increased maximal oxygen consumption is limited ( 81 ). Specific measures to improve exercise capacity include short-term regular exercise programs that may improve cardiopulmonary function and exercise time and capacity ( 82 ), even in patients with controlled disease.

Metabolic complications

Glucose metabolism

Glucose metabolism is frequently altered in acromegaly, with approximatively one-third of patients already living with diabetes mellitus at diagnosis ( 83 , 84 ). GH impairs glucose tolerance by decreasing peripheral sensitivity to insulin and glucose uptake and increasing hepatic gluconeogenesis ( 85 , 86 ). Diabetes mellitus has a significant clinical impact in patients with acromegaly, increasing the risk of morbidity and mortality by up to 60% ( 87 ).

Glucose homeostasis should be evaluated at diagnosis by assessing fasting glucose and glycated hemoglobin levels ( 11 ). Measuring the blood glucose level at 120 minutes of the oral glucose tolerance test (OGTT) may better define the patient's glycemic status. OGTT, used in selected instances to confirm acromegaly diagnosis, is relatively contraindicated in patients with diabetes and/or those receiving antidiabetic treatment ( 88 ).

In fact, acromegaly control is crucial to the management of hyperglycemia, as β-cell function was normalized in ∼20% of patients after successful pituitary surgery if there was normal anterior pituitary function ( 89 , 90 ). In contrast, due to their direct negative impact on insulin secretion, SRLs may adversely impact glucose metabolism. However, octreotide, lanreotide, and paltusotine ( 8 ) have marginal, if any, hyperglycemic actions ( 91 , 92 ). On the other hand, pasireotide binds not only to somatostatin 2 receptor (SST2) but also to SST5, which frequently disrupts glucose metabolism by reducing insulin secretion and glucagon and incretin effects, particularly in patients with preexisting hyperglycemia ( 93 , 94 ), and is not recommended in patients with poorly controlled diabetes ( 7 , 95 ). Therefore, fasting and postprandial glucose should be monitored, particularly in patients taking pasireotide, because hyperlipidemia, hypertension, and older age at diagnosis predispose patients to a higher risk of hyperglycemia ( 85 ). Hyperglycemia can occur rapidly after starting treatment and can be effectively managed with incretin therapy or insulin if needed ( 96-98 ). Conversely, pegvisomant may enhance glucose metabolism in certain patients by mitigating insulin resistance, partly through mechanisms independent of biochemical control. It should be considered as monotherapy or in combination with SRLs for individuals with impaired glucose metabolism ( 99 , 100 ), and should be considered either as monotherapy or with SRLs in patients with impaired glucose metabolism ( 7 ).

Choice of antidiabetic medications is guided by severity of hyperglycemia, undesired effects and patient preference, and cardiovascular and kidney comorbidities. In fact, structural and functional renal alterations found in active acromegaly, such as renal hypertrophy, high glomerular filtration rate, nephrolithiasis due to hypercalciuria, and microalbuminuria, may be only partly reversible after GH and IGF-I normalization ( 101-103 ). Diabetes and hypertension contribute to an increased risk of renal insufficiency ( 104 ).

Initially, nonpharmacologic measures and metformin, unless contraindicated, can be used. Sodium–glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists may have cardiovascular and renal protective effects. However, sodium–glucose cotransporter 2 inhibitors, which may have diuretic effects, should be used with caution in patients with suppressed insulin who are taking pasireotide due to the risk of diabetic ketoacidosis ( 105 ).

Lipid metabolism

Atherogenic dyslipidemia patterns occur in about one-third of patients with acromegaly ( 106 ), with coexistent hyperglycemia and/or metabolic syndrome. The typical lipid profile is characterized by hypertriglyceridemia with reduced high-density lipoprotein cholesterol and increased lipoprotein(a) levels ( 106 ). GH excess may enhance lipolysis with consequent increase of circulating free fatty acids, which may in turn increase insulin resistance ( 107 ).

Treatment of acromegaly may lower serum triglycerides and lipoprotein(a) and increase high-density lipoprotein cholesterol ( 108 ). Lipid-lowering treatments should be used according to guidelines for the general population ( 109 ).

Increased triglycerides with dyslipidemia may be associated with metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatic fibrosis ( 110 , 111 ). Interestingly, MASLD may not be related to acromegaly disease control ( 110 ); on the contrary, it may be even more frequent in patients with GH deficiency after acromegaly treatment ( 112-114 ).

Since patients with acromegaly undergo at least 1 abdominal ultrasound in some countries (particularly before starting SRLs), a preliminary echographic liver evaluation, as well as serum transaminase measurements, could be beneficial at diagnosis because MASLD may be associated with increased cardiovascular risk. Further specific hepatologic assessments should be performed according to guidelines for the general population. In patients with clinically relevant MASLD, caution is necessary when combining SRLs with pegvisomant, which has an increased risk of liver enzyme abnormalities ( 7 ).

Acromegaly is associated with a specific lipodystrophic pattern as evidenced when body composition is evaluated with dual-energy X-ray absorptiometry (DXA), which importantly cannot be captured by simple BMI calculation ( 115 ). It is characterized by reduced visceral and subcutaneous adipose tissue, with ectopic lipid and adipose tissue deposition in the muscles ( 116 ). Increased lean body mass may be due more to expansion of extracellular water rather than increased skeletal muscle which, in fact, is characterized by decreased performance, particularly in uncontrolled disease ( 117 , 118 ). Because DXA is used in all patients to assess bone mineral density (BMD) and morphometric vertebral fractures (VFs), we suggest that body composition be evaluated at the same time when possible.

Paradoxically, surgery or medical GH-lowering treatments may increase central adiposity with either decreased or unchanged lean body mass likely due to subsequent GH deficiency ( 119 ).

Osteopathy

GH is osteoanabolic ( 120-122 ), but hyperactivity of the GH/IGF-I axis causes excess skeletal turnover, assessed by specific biochemical markers ( 121 , 122 ); trabecular bone microarchitecture is mostly damaged ( 122-124 ). This, in turn, increases skeletal fragility, associated with a high prevalence and incidence of sex-independent morphometric VF risk already at diagnosis ( 125 ). In fact, seminal studies published 20 years ago ( 126 , 127 ) have been confirmed worldwide, identifying skeletal fragility as an emerging major complication of acromegaly ( 128-130 ) ( Fig. 1 ). VFs can be predicted based on disease activity, as expressed by random circulating GH levels (especially if >12 ng/mL) ( 131 ) and disease duration due to long diagnostic delay ( 132 ). In fact, biochemical remission of the disease decreases fracture risk ( 133 ); however, it may persist in patients with controlled acromegaly and prior VFs, hypogonadism, vitamin D deficiency, coexisting diabetes mellitus, and hypopituitarism, the latter particularly if glucocorticoid replacement has been supraphysiological ( 134-137 ).

VFs are a common and early event in the natural history of acromegaly affecting around one-third of patients ( 131 ) and one of the most important determinants of refracture risk, mortality, and QOL ( 138 ), vertebral morphometry using spine X-rays, DXA, or even, opportunistically, thoracic X-ray performed for anesthesiology or other diagnostic purposes is necessary ( 131 ). In fact, VFs also may occur in patients with apparently normal or slightly reduced lumbar spine BMD measured by DXA ( 126 , 139 ) since deteriorated bone quality is the main feature of acromegaly osteopathy ( 122 , 140 ). Measures of vertebral bone quality such as trabecular bone score can be provided by DXA and may have a practical role in the assessment of skeletal status ( 141 ), especially in PTCOEs where a bone expert is available ( 142 ). When used in research, high-resolution peripheral quantitative or cone beam computed tomography have shown increased cortical porosity and reduced cortical strength in patients with acromegaly and VFs vs those without VFs ( 140 , 143 ).

Monitoring bone status during follow-up depends on the risk of fracture assessed at diagnosis and the degree of biochemical control after acromegaly treatment, as well as coexisting fracture risk factors ( 139 ). If BMD is low at diagnosis, measurement of femoral neck BMD using DXA every 12 to 18 months may be useful because it can predict incident VF risk ( 139 ). DXA-based vertebral morphometry and bone quality assessments should be repeated at follow-up, particularly in patients with prevalent VFs, decreased BMD, and uncontrolled acromegaly ( 144 ).

Importantly, the frequent presence VFs may impact the choice of GH-lowering treatments, which may have a differential effect on progression ( 135 ) or occurrence of new incident VFs in high-risk patients ( 139 ). Biochemical control is associated with a decreased risk of fractures ( 145 ). However, in a single study, patients with uncontrolled acromegaly who were taking pasireotide but not pegvisomant possibly experienced a protective effect against incident VFs ( 146 ), suggesting that treatment with pasireotide may be preferable in patients with resistant disease ( 144 ) and prevalent VFs ( 138 ).

Hypovitaminosis D is omnipresent in the general population ( 147 ) and in patients with acromegaly and high IGF-I ( 148 ), who have reduced free vitamin D levels due to increased vitamin D binding protein ( 149 ). Low vitamin D levels may increase the risk of incident VFs and in acromegaly, cholecalciferol supplementation may be associated with reduced incidence of VFs ( 150 ). Antiresorptive therapies may be preferable first-line treatments (as in the general population), based on high bone turnover, which characterizes acromegaly osteopathy ( 133 ).

Balance abnormalities also are common in patients with long-term acromegaly and can increase risk of falls with fractures in patients at higher risk of severe osteopathy ( 151 ).

Integration of dentistry into interdisciplinary care is also desirable and collaboration models reduce delays in diagnosis of dental manifestations such as dental diastema, mandibular overgrowth and prognathism, overbite and malocclusion ( 1 ), while also improving the management of craniofacial complications encountered in some patients ( 152 , 153 ).

Arthropathy

The presence of arthropathy in acromegaly is increased 4- to 12-fold vs the general population, with joint cartilage changes due to increased GH and IGF-I levels ( 138 , 154 ), which stimulate chondrocyte synthesis and replication, as well as the production of glycosaminoglycans and proteoglycans that alter cartilage structure ( 155 ). In the initial stages, cartilage and periarticular tissue hypertrophy ( 156 ) are potentially reversible, especially if biochemical control is achieved, underscoring the importance of early diagnosis and treatment for this complication ( 156-158 ). If GH hypersecretion persists, a degenerative process develops, with appearance of cysts, osteophytes, and excessive growth and thickness of cartilage tissue, with unique radiologic findings ( 159 ). At this point, the joint is irreversibly and progressively damaged, with narrowed joint space even if the disease is well controlled ( 159 ), and becomes severely symptomatic ( 156 , 159 ). This clinical picture is not uncommon, affecting 10% to 15% of patients, particularly women and older patients with uncontrolled GH/IGF-I levels ( 160 ). Pain and loss of function characterize arthropathy, leading to deterioration of QoL, disability, and depression ( 161 ).

Although early joint alterations may be reversible after SRL treatment ( 20 ), late stage arthropathy does not improve after long-term medical treatment and management in patients with acromegaly should be similar to that of the general population ( 156 ). Interestingly, a relatively short-term, tailored physical activity program is beneficial even in patients with controlled acromegaly ( 162 ). Since advanced stages of disease are characterized by progressive disability, joint replacement is often necessary and the risk of requiring this procedure on the shoulder, knee, or hip is more than double that of the general population ( 153 ). Notably, patients with acromegaly had a 3.5-fold increased risk of repeat hip surgery.

Carpal tunnel syndrome, a frequent and early complication ( 163 ), often leads to consequent neuropathic manifestations ( 164 ), median nerve enlargement, and edema ( 165 , 166 ). A retrospective cohort study of >500 patients with acromegaly in Sweden reported a 6-fold higher incidence of surgery for carpal tunnel syndrome vs the general population, particularly in females and primarily before an acromegaly diagnosis ( 167 ).

Neoplasms

GH and IGF-I may be mechanistically involved in cancer development and progression ( 168 ). Most studies, although not all, have reported a possible increased risk of malignancies, especially colon cancer, in acromegaly ( 169 ). Importantly, high prevalence of colon polyps, a known precancerous condition, has been consistently reported ( 170 ) ( Fig. 1 ). However, while meta-analyses had high heterogeneity ( 171-173 ), 3 large, longitudinal studies published in 2025 better defined cancer risk in acromegaly ( 174-176 ).

In a longitudinal Korean cohort study of 2382 patients with acromegaly and 11 910 controls with adjustments for age, sex, and metabolic factors, the risk of overall cancer in patients with acromegaly (10.2%) was double that of controls (5.9%) (hazard ratio [HR], 1.90 [95% CI, 1.63-2.22]). Brain cancer had the highest relative risk (HR, 6.80 [2.83-16.38]), followed by lymphoma, multiple myeloma, thyroid, pancreatic, and colorectal cancers ( 174 ).

In a prospective US longitudinal study on 598 patients with acromegaly, cancer prevalence was 22.6%, almost double that of patients with nonfunctioning adenomas from the same referral population (12.7%) (odds ratio [OR], 1.99 [95% CI, 1.34-2.97]). Overall, cancer standardized incidence ratio of 1.78 (95% CI, 1.51-1.81) was almost superimposable to that of the Korean study; furthermore, it was related to a cumulative exposure to IGF-I ( 175 ).

A similar prevalence of solid cancers (21.3%) was reported in a cohort of 470 patients with acromegaly in Israel with a 10-year follow-up ( 176 ). They also had significantly higher risk vs controls for thyroid cancer (OR, 5.1 [95% CI, 2.3-11.0]), but the incidence of colorectal, prostate, and renal cancers was not increased ( 176 ). However, another cohort study reported increased renal cancer risk ( 177 ). Smoking and age >50 years were related to a higher risk of premalignant/colon cancer lesions ( 178 ). While large studies often report increased cancer incidence, increases in malignancy-associated mortality have not been consistently reported ( 21 ). Uncertainty about the real clinical impact of cancer risk in acromegaly also is reflected in the lack of specific guidelines for cancer screening ( 179 ). At this time, recommendations for screening patients with acromegaly follow those for the general population, even for colon cancer, despite the higher prevalence of colon polyps in these patients ( 180 , 181 ). Colonoscopy is recommended at the time of acromegaly diagnosis, but practices differ between countries.

Quality of life

Despite efforts to increase awareness, patients with acromegaly still experience a prolonged diagnostic delay, at times >10 years ( 181 ). This leads to prolonged cumulative exposure to high levels of GH and IGF-I. In turn, this further adds to the disease burden due to the potentially irreversible complications that impact QoL ( 182 ). A recent meta-analysis (8 studies, 1387 patients) showed an increased risk of depression (risk ratio [RR], 1.8 [95% CI, 1.3-2.50]) and anxiety (RR, 1.9 [95% CI, 1.1-3.2]) vs patients with nonfunctioning pituitary adenomas ( 183 ).

Impaired QoL based on disease-specific questionnaires such as the Acromegaly Quality of Life questionnaire (AcroQoL) ( 184 ) shows little correlation with biochemical outcomes in ≥33% of patients. However, effective therapy improves AcroQoL scores after all treatment types ( 185 ), especially surgical adenoma resection. Despite controlling many clinical disease features, frequent SRL injections may reduce patients’ sense of well-being, even in those considered biochemically controlled ( 186 ). Frequent gastrointestinal and local injection site side effects may increase treatment burden ( 187 ). Interestingly, oral octreotide ( 188-190 ) and paltusotine ( 191 , 192 ) could decrease treatment burden and improve QoL ( 193 ). Adding pegvisomant to long-acting SRLs improves the AcroQoL physical domain independent of biochemical control ( 194 ). In addition to arthropathic, muscular, and psychological complications ( 193 ), QoL may be adversely impacted by age of disease onset, female sex, obesity, duration of disease, fatigue, hypopituitarism, and conventional radiotherapy ( 195-197 ).

Poor correlation between patient- and physician-reported outcomes reinforces a communication gap ( 198 ). Tools used by clinicians for improving diagnosis and follow-up such as SAGIT, which was the first evaluation to include symptoms and complications for a holistic physician evaluation ( 199 ), should be integrated with patient-reported outcome measures to include patients’ perception of the journey and disease/treatment burden with shared decision-making ( 200 ).

Mortality

Acromegaly continues to carry an increased risk of mortality, as reported by several recent studies from parts of the world ( 201-203 ), although this risk is now lower than in earlier reports ( 204 , 205 ). Diagnostic delay has been consistently shown to be a key predictor of mortality risk ( 181 , 203 ). Disease control, essential to slow progression, if not reversal of complications, is crucial to reducing adverse mortality rates ( 206 ). Interestingly, in a recent retrospective analysis of >2000 patients from the ACROSTUDY who received pegvisomant and were followed for a median of 4 years, mortality due to cardiovascular, cerebrovascular, cancer, and respiratory causes significantly increased when associated with higher IGF-I levels, with ORs ranging from 1.57 to 1.97 ( 207 ). These results underscore that despite advances in treatment ( 208 ), patients who do not achieve early disease control have an adverse long-term prognosis. Intriguingly, a recent survey of several centers of excellence around the world providing multidisciplinary care ( 209 ) reported that with any medical treatment option, a relevant number of patients with acromegaly still remained uncontrolled ( 15 ). In addition to diagnostic delay, therapeutic inertia seems to be a pillar of poor prognosis ( 210 ). In fact, shortening the time to switch to another treatment ( 7 ) or simply to optimize dose uptitration of the same treatment ( 211-213 ) in patients with uncontrolled acromegaly ( 214 ) should be prioritized, because maintaining patients on an ineffective therapy increases the cumulative exposure to high GH and IGF-I levels.

Conclusion

Acromegaly is a chronic disease still highly burdened by severe cardiorespiratory, metabolic, and oncologic complications that have a significant impact on QOL and lifespan. Since delays in diagnosis are still very long, a thorough assessment of complications present at the time of diagnosis is crucial because the patient may already have been exposed to high GH and IGF-I levels for several years. In addition to reducing diagnostic delay—a modifiable risk factor—rapid and effective biochemical disease control and appropriate treatment of already existing complications should be prioritized to optimize QOL and prognosis. A multimodal management provided by PTCOEs may provide optimal surgical and medical management to counteract therapeutic inertia, as well as enable specialist consultations for follow-up and treatment of systemic complications. These approaches will ideally improve prognosis, and ultimately mortality rates, particularly for truly resistant forms of acromegaly.

Acknowledgments

The authors thank Synchrony Medical Communications for graphical support and editorial support, and Simcoe Consultants, Inc., for administrative assistance.

Funding

Funding for this support was provided by Crinetics Pharmaceuticals, Inc.

Disclosures

A.G. participated in Advisory Board meetings for Alexion, Amolyt, and Crinetics Pharmaceuticals and has occasionally consulted for Abiogen, Ipsen, Pfizer, and Recordati and received research grant funding to University from Recordati.

M.F. reports receiving occasional scientific consulting fees from Alexion, Camurus, Crinetics Pharmaceuticals, Debiopharm, and Recordati; and serves as a principal investigator of research grants to the University from Alexion, Crinetics Pharmaceuticals, and Debiopharm.

Data availability

Data sharing is not applicable to this article, as no datasets were generated or analyzed during the current study.

Supplement sponsorship

This article appears as part of the supplement “Acromegaly: State of the Art and Future Directions,” sponsored by Crinetics Pharmaceuticals. Inc.

References

1 Giustina A , Colao A . Acromegaly . N Engl J Med . 2025 ; 393 ( 19 ): 1926 ‐ 1939 . 41223366 10.1056/NEJMra2409076

2 Fleseriu M , Langlois F , Lim DST , Varlamov EV , Melmed S . Acromegaly: pathogenesis, diagnosis, and management . Lancet Diabetes Endocrinol . 2022 ; 10 ( 11 ): 804 ‐ 826 . 36209758 10.1016/S2213-8587(22)00244-3

3 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 . 30184064 10.1210/er.2018-00115

4 Sherlock M , Ayuk J , Tomlinson JW , et al Mortality in patients with pituitary disease . Endocr Rev . 2010 ; 31 ( 3 ): 301 ‐ 342 . 20086217 10.1210/er.2009-0033

5 Giustina A , Biermasz N , Casanueva FF , et al Consensus on criteria for acromegaly diagnosis and remission . Pituitary . 2024 ; 27 ( 1 ): 7 ‐ 22 . 37923946 10.1007/s11102-023-01360-1 PMC10837217

6 Melmed S , Bronstein MD , Chanson P , et al A consensus statement on acromegaly therapeutic outcomes . Nat Rev Endocrinol . 2018 ; 14 ( 9 ): 552 ‐ 561 . 30050156 10.1038/s41574-018-0058-5 PMC7136157

7 Melmed S , di Filippo L , Fleseriu M , et al Consensus on acromegaly therapeutic outcomes: an update . Nat Rev Endocrinol . 2025 ; 21 ( 11 ): 718 ‐ 737 . 40804505 10.1038/s41574-025-01148-2

8 Gadelha MR , Wildemberg LE , Marques NV , Kasuki L . Medical treatment of acromegaly: navigating the present, shaping the future . Endocr Rev . 2025 ; 46 ( 6 ): 838 ‐ 855 . 40644375 10.1210/endrev/bnaf020

9 Giustina A , Casanueva FF , Cavagnini F , et al Diagnosis and treatment of acromegaly complications . J Endocrinol Invest . 2003 ; 26 ( 12 ): 1242 ‐ 1247 . 15055479 10.1007/BF03349164

10 Melmed S , Casanueva FF , Klibanski A , et al A consensus on the diagnosis and treatment of acromegaly complications . Pituitary . 2013 ; 16 ( 3 ): 294 ‐ 302 . 22903574 10.1007/s11102-012-0420-x PMC3730092

11 Giustina A , Barkan A , Beckers A , et al A consensus on the diagnosis and treatment of acromegaly comorbidities: an update . J Clin Endocrinol Metab . 2020 ; 105 ( 4 ): e937 ‐ e946 .

12 Giustina A , di Filippo L , Fleseriu M , et al Consensus on acromegaly complications: an update . Pituitary 2026 . in press. DOI: 10.1007/s11102-026-01639-z

13 Pennlund A , Esposito D , Bontell TO , et al Long-term clinical outcome of 103 patients with acromegaly after pituitary surgery . Pituitary . 2025 ; 8 ( 2 ): 33 .

14 Giustina A , Uygur MM , Frara S , et al Pilot study to define criteria for pituitary tumors centers of excellence (PTCOE): results of an audit of leading international centers . Pituitary . 2023 ; 26 ( 5 ): 583 ‐ 596 . 37640885 10.1007/s11102-023-01345-0 PMC10539196

15 Giustina A , Uygur MM , Frara S , et al Standards of care for medical management of acromegaly in pituitary tumor centers of excellence (PTCOE) . Pituitary . 2024 ; 27 ( 4 ): 381 ‐ 388 . 38833044 10.1007/s11102-024-01397-w PMC11289172

16 Melmed S . Medical progress: acromegaly . N Engl J Med . 2006 ; 355 ( 24 ): 2558 ‐ 2573 . 17167139 10.1056/NEJMra062453

17 Vila G , Jørgensen JOL , Luger A , Stalla GK . Insulin resistance in patients with acromegaly . Front Endocrinol (Lausanne) . 2019 ; 10 : 509 . 31417493 10.3389/fendo.2019.00509 PMC6683662

18 Bolamperti S , Villa I , di Filippo L . Growth hormone and bone: a basic perspective . Pituitary . 2024 ; 27 ( 6 ): 745 ‐ 751 . 39476263 10.1007/s11102-024-01464-2

19 Melmed S . Pituitary-tumor endocrinopathies . N Engl J Med . 2020 ; 382 ( 10 ): 937 ‐ 950 . 32130815 10.1056/NEJMra1810772

20 Yamamoto N , Urai S , Yamamoto M , et al Body mass index and metabolic complications in individuals with treatment-naïve acromegaly . Endocr J . 2025 ; 72 ( 9 ): 1041 ‐ 1049 . 40484689 10.1507/endocrj.EJ25-0047 PMC12436081

21 Orme S , McNally R , James PW , et al Increased mortality in acromegaly is due to vascular and respiratory disease and is normalised by control of GH levels-A retrospective analysis from the UK Acromegaly Register 1970-2016 . Clin Endocrinol (Oxf) . 2024 ; 100 ( 6 ): 558 ‐ 564 . 38652736 10.1111/cen.15060

22 Iglesias P . Acromegaly and cardiovascular disease: associated cardiovascular risk factors, cardiovascular prognosis, and therapeutic impact . J Clin Med . 2025 ; 14 ( 6 ): 1906 . 40142714 10.3390/jcm14061906 PMC11943432

23 Davì MV , Giustina A . Sleep apnea in acromegaly: a review on prevalence, pathogenetic aspects and treatment . Expert Rev Endocrinol Metab . 2012 ; 7 ( 1 ): 55 ‐ 62 . 30736111 10.1586/eem.11.82

24 Giustina A , Boni E , Romanelli G , Grassi V , Giustina G . Cardiopulmonary performance during exercise in acromegaly, and the effects of acute suppression of growth hormone hypersecretion with octreotide . Am J Cardiol . 1995 ; 75 ( 15 ): 1042 ‐ 1047 . 7747686 10.1016/s0002-9149(99)80721-8

25 Ramos-Leví AM , Marazuela M . Bringing cardiovascular comorbidities in acromegaly to an update. Should we diagnose and manage them? Front Endocrinol (Lausanne) . 2019 ; 10 : 120 . 30930848 10.3389/fendo.2019.00120 PMC6423916

26 Sherin RPV , Vietor NO , Usman A , Hoang TD , Shakir MKM . Cardiovascular disorders associated with acromegaly: an update . Endocr Pract . 2024 ; 30 ( 12 ): 1212 ‐ 1219 . 39332498 10.1016/j.eprac.2024.09.014

27 Huang R , Jin J , Zhang P , et al Use of speckle tracking echocardiography in evaluating cardiac dysfunction in patients with acromegaly: an update . Front Endocrinol (Lausanne) . 2023 ; 14 : 1260842 . 37929035 10.3389/fendo.2023.1260842 PMC10623426

28 De Alcubierre D , Feola T , Cozzolino A , et al The spectrum of cardiac abnormalities in patients with acromegaly: results from a case-control cardiac magnetic resonance study . Pituitary . 2024 ; 27 ( 4 ): 416 ‐ 427 . 38847918 10.1007/s11102-024-01403-1 PMC11289141

29 Chen Y , Li Y , Tang Y , et al Cardiac structure and function recovery in acromegaly after treatment: insights from cardiac magnetic resonance imaging . Front Endocrinol (Lausanne) . 2025 ; 16 : 1630037 . 40822942 10.3389/fendo.2025.1630037 PMC12350105

30 Colao A , Cuocolo A , Marzullo P , et al Is the acromegalic cardiomyopathy reversible? Effect of 5-year normalization of growth hormone and insulin-like growth factor I levels on cardiac performance . J Clin Endocrinol Metab . 2001 ; 86 ( 4 ): 1551 ‐ 1557 . 11297582 10.1210/jcem.86.4.7376

31 Huynh KA , Al-Gully J , Montero-Cabezas JM , et al The effect of first intervention on cardiac parameters in patients with acromegaly: a systematic review . Eur J Endocrinol . 2025 ; 192 ( 2 ): S1 ‐ S14 . 39880368 10.1093/ejendo/lvaf009

32 Kuhn E , Maione L , Bouchachi A , 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 . 26429918 10.1530/EJE-15-0500 PMC4592912

33 Bogazzi F , Di Bello V , Palagi C , et al Improvement of intrinsic myocardial contractility and cardiac fibrosis degree in acromegalic patients treated with somatostatin analogues: a prospective study . Clin Endocrinol (Oxf) . 2005 ; 62 ( 5 ): 590 ‐ 966 . 15853830 10.1111/j.1365-2265.2005.02265.x

34 De Marinis L , Bianchi A , Mazziotti G , et al The long-term cardiovascular outcome of different GH-lowering treatments in acromegaly . Pituitary . 2008 ; 11 ( 1 ): 13 ‐ 20 . 17987389 10.1007/s11102-007-0062-6

35 Stocker M , Zimmermann SE , Laager R , et al Cardiovascular risk in patients with acromegaly vs. non-functioning pituitary adenoma following pituitary surgery: an active-comparator cohort study . Pituitary . 2024 ; 27 ( 5 ): 518 ‐ 526 . 38819619 10.1007/s11102-024-01405-z

36 Hinojosa-Amaya JM , Varlamov EV , Yedinak CG , et al Echocardiographic findings in acromegaly: prevalence of concentric left ventricular remodeling in a large single-center cohort . J Endocrinol Invest . 2021 ; 44 ( 12 ): 2665 ‐ 2674 . 33893617 10.1007/s40618-021-01579-4

37 Wolf P , Maione L , Kamenický P , Chanson P . Cardiomyopathy in patients with acromegaly - not truly a concern anymore? J Clin Endocrinol Metab . 2025 ; 110 ( 10 ): 2718 ‐ 2728 . 40488310 10.1210/clinem/dgaf338

38 Colao A , Ferone D , Marzullo P , Lombardi G . Systemic complications of acromegaly: epidemiology, pathogenesis, and management . Endocr Rev . 2004 ; 25 ( 1 ): 102 ‐ 152 . 14769829 10.1210/er.2002-0022

39 Hong S , Kim K-S , Han K , Park C-Y . Acromegaly and cardiovascular outcomes: a cohort study . Eur Heart J . 2022 ; 43 ( 15 ): 1491 ‐ 1499 . 34864952 10.1093/eurheartj/ehab822

40 Unubol M , Eryilmaz U , Guney E , Ture M , Akgullu C . QT dispersion in patients with acromegaly . Endocrine . 2013 ; 43 ( 2 ): 419 ‐ 423 . 23149908 10.1007/s12020-012-9828-3

41 Maffei P , Martini C , Milanesi A , et al Late potentials and ventricular arrhythmias in acromegaly . Int J Cardiol . 2005 ; 104 ( 2 ): 197 ‐ 203 . 16168814 10.1016/j.ijcard.2004.12.010

42 Breitschaft A , Hu K , Darstein C , et al Effects of subcutaneous pasireotide on cardiac repolarization in healthy volunteers: a single-center, phase I, randomized, four-way crossover study . J Clin Pharmacol . 2014 ; 54 ( 1 ): 75 ‐ 86 . 24242903 10.1002/jcph.213 PMC4272414

43 Pereira AM , van Thiel SW , Lindner JR , et al Increased prevalence of regurgitant valvular heart disease in acromegaly . J Clin Endocrinol Metab . 2004 ; 89 ( 1 ): 71 ‐ 75 . 14715829 10.1210/jc.2003-030849

44 Nemes A , Rácz G , Kormányos Á , et al Three-dimensional speckle-tracking echocardiography-derived tricuspid annular properties in acromegaly-results from the MAGYAR-path study . Biomedicines . 2024 ; 12 ( 7 ): 1464 . 39062037 10.3390/biomedicines12071464 PMC11274697

45 Orihuela Rodríguez O , Valle Nava L , Ferreira-Hermosillo A , et al Echocardiographic findings in cardiomyopathy due to acromegaly . Biomedicines . 2025 ; 13 ( 3 ): 605 . 40149581 10.3390/biomedicines13030605 PMC11940142

46 Izgi C , Feray H , Cevik C , Saltan Y , Mansuroglu D , Nugent K . Severe tricuspid regurgitation in a patient receiving low-dose cabergoline for the treatment of acromegaly . J Heart Valve Dis . 2010 ; 19 ( 6 ): 797 ‐ 800 . 21214109

47 Araujo-Castro M , García-Centeno R , González L , et al Prevalence and evolution of hypertension in a large Iberian cohort of patients with acromegaly . Pituitary . 2025 ; 28 ( 6 ): 119 . 41139153 10.1007/s11102-025-01586-1

48 Vitale G , Pivonello R , Auriemma RS , et al Hypertension in acromegaly and in the normal population: prevalence and determinants . Clin Endocrinol (Oxf) . 2005 ; 63 ( 4 ): 470 ‐ 476 . 16181242 10.1111/j.1365-2265.2005.02370.x

49 Puglisi S , Terzolo M . Hypertension and acromegaly . Endocrinol Metab Clin North Am . 2019 ; 48 ( 4 ): 779 ‐ 793 . 31655776 10.1016/j.ecl.2019.08.008

50 Vila G , Luger A , van der Lely AJ , et al Hypertension in acromegaly in relationship to biochemical control and mortality: global ACROSTUDY outcomes . Front Endocrinol (Lausanne) . 2020 ; 11 : 577173 . 33329385 10.3389/fendo.2020.577173 PMC7734123

51 González B , Vargas G , de Los Monteros ALE , Mendoza V , Mercado M . Persistence of diabetes and hypertension after multimodal treatment of acromegaly . J Clin Endocrinol Metab . 2018 ; 103 ( 6 ): 2369 ‐ 2375 . 29618021 10.1210/jc.2018-00325

52 Rocha P , Barroso J , Carlos F , Muxfeldt E , Gadelha M , Kasuki L . Importance of 24 h ambulatory blood pressure monitoring in patients with acromegaly and correlation with cardiac magnetic resonance findings . Pituitary . 2023 ; 26 ( 4 ): 402 ‐ 410 . 37247075 10.1007/s11102-023-01321-8

53 Costenaro F , Martin A , Horn RF , Czepielewski MA , Rodrigues TC . Role of ambulatory blood pressure monitoring in patients with acromegaly . J Hypertens . 2016 ; 34 ( 7 ): 1357 ‐ 1363 . 27153464 10.1097/HJH.0000000000000962

54 Reyes-Vidal C , Fernandez JC , Bruce JN , et al Prospective study of surgical treatment of acromegaly: effects on ghrelin, weight, adiposity, and markers of CV risk . J Clin Endocrinol Metab . 2014 ; 99 ( 11 ): 4124 ‐ 4132 . 25137427 10.1210/jc.2014-2259 PMC4223431

55 Maison P , Tropeano A-I , 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 ‐ 1747 . 17311857 10.1210/jc.2006-2547

56 Colao A , Pivonello R , Auriemma RS , 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 ‐ 477 . 16498061 10.1530/eje.1.02112

57 Kamenicky P , Blanchard A , Frank M , et al Body fluid expansion in acromegaly is related to enhanced epithelial sodium channel (ENaC) activity . J Clin Endocrinol Metab . 2011 ; 96 ( 7 ): 2127 ‐ 2135 . 21508131 10.1210/jc.2011-0078

58 Pivonello R , Auriemma RS , Grasso LFS , et al Complications of acromegaly: cardiovascular, respiratory and metabolic comorbidities . Pituitary . 2017 ; 20 ( 1 ): 46 ‐ 62 . 28224405 10.1007/s11102-017-0797-7

59 Cao W , Wang X , Luo J , Huang R , Xiao Y . Impact of obstructive sleep apnea on cardiovascular risk in patients with acromegaly . Sleep Med . 2021 ; 80 : 193 ‐ 198 . 33601232 10.1016/j.sleep.2021.01.033

60 Filchenko I , Korostovtseva L , Bochkarev M , Tsoy U , Sviryaev Y . Cardiovascular remodeling in active and controlled acromegaly: association with sleep-disordered breathing . Sleep Breath . 2023 ; 27 ( 6 ): 2305 ‐ 2314 . 37148385 10.1007/s11325-023-02838-9

61 Wennberg A , Lorusso R , Dassie F , et al Sleep disorders and cognitive dysfunction in acromegaly . Endocrine . 2019 ; 66 ( 3 ): 634 ‐ 641 . 31473920 10.1007/s12020-019-02061-1

62 De Menis E , Giustina A , Colao A , et al Assessment of the awareness and management of sleep apnea syndrome in acromegaly. The COM.E.TA (comorbidities evaluation and treatment in acromegaly) Italian study group . J Endocrinol Invest . 2011 ; 34 ( 1 ): 60 ‐ 64 . 21406941 10.1007/BF03346696

63 Schulz H . The history of sleep research and sleep medicine in Europe . J Sleep Res . 2022 ; 31 ( 4 ): e13602 . 35522132 10.1111/jsr.13602

64 Powlson AS , Annamalai AK , Moir S , et al High prevalence of severe sleep cycle disruption in de novo acromegaly and underdiagnosis by common clinical screening tools: a prospective, observational, cross-sectional study . Clin Endocrinol (Oxf) . 2024 ; 100 ( 3 ): 251 ‐ 259 . 38127470 10.1111/cen.14994

65 Bazoukis G , Bollepalli SC , Chung CT , et al Application of artificial intelligence in the diagnosis of sleep apnea . J Clin Sleep Med . 2023 ; 19 ( 7 ): 1337 ‐ 1363 . 36856067 10.5664/jcsm.10532 PMC10315608

66 Giustina A , Giustina A . Artificial intelligence in acromegaly: why, when and how . Pituitary . 2025 ; 28 ( 3 ): 66 . 40442498 10.1007/s11102-025-01534-z

67 Berg C , Wessendorf TE , Mortsch F , et al Influence of disease control with pegvisomant on sleep apnoea and tongue volume in patients with active acromegaly . Eur J Endocrinol . 2009 ; 161 ( 6 ): 829 ‐ 835 . 19773369 10.1530/EJE-09-0694

68 Cho J , Kim JH , Kim YH , Lee J . Obstructive sleep apnea screening and effects of surgery in acromegaly: a prospective study . Endocrinol Metab (Seoul) . 2024 ; 39 ( 4 ): 641 ‐ 652 . 38918903 10.3803/EnM.2024.1933 PMC11375303

69 Wolters TLC , Roerink SHPP , Drenthen LCA , et al The course of obstructive sleep apnea syndrome in patients with acromegaly during treatment . J Clin Endocrinol Metab . 2020 ; 105 ( 1 ): 290 ‐ 304 . 31612224 10.1210/clinem/dgz050 PMC7705224

70 Davi’ MV , Dalle Carbonare L , Giustina A , 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 ‐ 540 . 18765561 10.1530/EJE-08-0442

71 Annamalai AK , Webb A , Kandasamy N , 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 ‐ 1050 . 23393175 10.1210/jc.2012-3072

72 Spinelli L , Petretta M , Verderame G , et al Left ventricular diastolic function and cardiac performance during exercise in patients with acromegaly . J Clin Endocrinol Metab . 2003 ; 88 ( 9 ): 4105 ‐ 4109 . 12970271 10.1210/jc.2003-030462

73 Colao A , Cuocolo A , Marzullo P , et al Impact of patient's age and disease duration on cardiac performance in acromegaly: a radionuclide angiography study . J Clin Endocrinol Metab . 1999 ; 84 ( 5 ): 1518 ‐ 1523 . 10323372 10.1210/jcem.84.5.5674

74 Clayton RN . Cardiovascular function in acromegaly . Endocr Rev . 2003 ; 24 ( 3 ): 272 ‐ 277 . 12788799 10.1210/er.2003-0009

75 Störmann S , Gutt B , Roemmler-Zehrer J , et al Assessment of lung function in a large cohort of patients with acromegaly . Eur J Endocrinol . 2017 ; 177 ( 1 ): 15 ‐ 23 . 28432267 10.1530/EJE-16-1080

76 Dorelli G , Venturelli M , Sartori G , et al Exercise ventilatory inefficiency may be a specific feature of patients with acromegaly . Pituitary . 2025 ; 28 ( 6 ): 114 . 41099943 10.1007/s11102-025-01585-2 PMC12532638

77 Martel-Duguech L , Bascuñana H , Cuartero J , Webb SM , Valassi E . Muscle dysfunction is associated with poor quality of life in long-term controlled patients with acromegaly . Pituitary . 2025 ; 28 ( 3 ): 68 . 40442526 10.1007/s11102-025-01539-8

78 Inojosa AC , Hirt AV , Araújo T , et al Sarcopenic obesity and physical function in acromegaly: impact of disease control and evaluation using dual X-ray absorptiometry and multifrequency bioelectrical impedance analysis . J Endocrinol Invest . 2025 ; 48 ( 9 ): 2027 ‐ 2039 . 40493164 10.1007/s40618-025-02624-2

79 Padayatty SJ , Perrins EJ , Belchetz PE . Octreotide treatment increases exercise capacity in patients with acromegaly . Eur J Endocrinol . 1996 ; 134 ( 5 ): 554 ‐ 559 . 8664974 10.1530/eje.0.1340554

80 Colao A , Marzullo P , Cuocolo A , 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 (Oxf) . 2003 ; 58 ( 2 ): 169 ‐ 176 . 12580932 10.1046/j.1365-2265.2003.01689.x

81 Thomas SG , Woodhouse LJ , Pagura SM , Ezzat S . Ventilation threshold as a measure of impaired physical performance in adults with growth hormone excess . Clin Endocrinol (Oxf) . 2002 ; 56 ( 3 ): 351 ‐ 358 . 11940047 10.1046/j.1365-2265.2002.01476.x

82 Hatipoglu E , Topsakal N , Erkut Atilgan O , et al Physical and cardiovascular performance in cases with acromegaly after regular short-term exercise . Clin Endocrinol (Oxf) . 2015 ; 83 ( 1 ): 91 ‐ 97 . 25523748 10.1111/cen.12708

83 Petrossians P , Daly AF , Natchev E , et al Acromegaly at diagnosis in 3173 patients from the Liège Acromegaly Survey (LAS) database . Endocr Relat Cancer . 2017 ; 24 ( 10 ): 505 ‐ 518 . 28733467 10.1530/ERC-17-0253 PMC5574208

84 Slagboom TNA , van Bunderen CC , De Vries R , Bisschop PH , Drent ML . Prevalence of clinical signs, symptoms and comorbidities at diagnosis of acromegaly: a systematic review in accordance with PRISMA guidelines . Pituitary . 2023 ; 26 ( 4 ): 319 ‐ 332 . 37210433 10.1007/s11102-023-01322-7 PMC10397145

85 Frara S , Maffezzoni F , Mazziotti G , Giustina A . Current and emerging aspects of diabetes mellitus in acromegaly . Trends Endocrinol Metab . 2016 ; 27 ( 7 ): 470 ‐ 483 . 27229934 10.1016/j.tem.2016.04.014

86 Esposito D , Boguszewski CL , Colao A , et al Diabetes mellitus in patients with acromegaly: pathophysiology, clinical challenges and management . Nat Rev Endocrinol . 2024 ; 20 ( 9 ): 541 ‐ 552 . 38844688 10.1038/s41574-024-00993-x

87 Esposito D , Olsson DS , Franzén S , et al Effect of diabetes on morbidity and mortality in patients with acromegaly . J Clin Endocrinol Metab . 2022 ; 107 ( 9 ): 2483 ‐ 2492 . 35779017 10.1210/clinem/dgac400 PMC9387713

88 Mazziotti G , Bonadonna S , Doga M , et al Biochemical evaluation of patients with active acromegaly and type 2 diabetes mellitus: efficacy and safety of the galanin test . Neuroendocrinology . 2008 ; 88 ( 4 ): 299 ‐ 304 . 18617732 10.1159/000144046

89 Cozzolino A , Feola T , Simonelli I , et al Metabolic complications in acromegaly after neurosurgery: a meta-analysis . Eur J Endocrinol . 2020 ; 183 ( 6 ): 597 ‐ 606 . 33075752 10.1530/EJE-20-0497

90 Pascual-Corrales E , Biagetti B , Marazuela M , et al Glucose metabolism outcomes after pituitary surgery in patients with acromegaly . Pituitary . 2024 ; 27 ( 5 ): 497 ‐ 506 . 38940859 10.1007/s11102-024-01415-x

91 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 ‐ 1508 . 19208728 10.1210/jc.2008-2332

92 Mazziotti G , Porcelli T , Bogazzi F , et al Effects of high-dose octreotide LAR on glucose metabolism in patients with acromegaly inadequately controlled by conventional somatostatin analog therapy . Eur J Endocrinol . 2011 ; 164 ( 3 ): 341 ‐ 347 . 21212103 10.1530/EJE-10-0811

93 Schmid HA , Brue T , Colao A , et al Effect of pasireotide on glucose- and growth hormone-related biomarkers in patients with inadequately controlled acromegaly . Endocrine . 2016 ; 53 ( 1 ): 210 ‐ 219 . 26906713 10.1007/s12020-016-0895-8 PMC4901125

94 Biagetti B , Araujo-Castro M , Tebe C , Marazuela M , Puig-Domingo M . Real-world evidence of effectiveness and safety of pasireotide in the treatment of acromegaly: a systematic review and meta-analysis . Rev Endocr Metab Disord . 2025 ; 26 ( 1 ): 97 ‐ 111 . 39527181 10.1007/s11154-024-09928-3 PMC11790789

95 Gadelha M , Marques NV , Fialho C , et al Long-term efficacy and safety of pasireotide in patients with acromegaly: 14 years of single-center real-world experience . J Clin Endocrinol Metab . 2023 ; 108 ( 12 ): e1571 ‐ e1579 . 37357993 10.1210/clinem/dgad378 PMC10655523

96 Samson SL , Gu F , Feldt-Rasmussen U , et al Managing pasireotide-associated hyperglycemia: a randomized, open-label, phase IV study . Pituitary . 2021 ; 24 ( 6 ): 887 ‐ 903 . 34275099 10.1007/s11102-021-01161-4 PMC8550309

97 Gadelha MR , Gu F , Bronstein MD , et al Risk factors and management of pasireotide-associated hyperglycemia in acromegaly . Endocr Connect . 2020 ; 9 ( 12 ): 1178 ‐ 1190 . 33434154 10.1530/EC-20-0361 PMC7774766

98 Feldt-Rasmussen U , Bolanowski M , Zhang S-L , et al Predictive factors and the management of hyperglycemia in patients with acromegaly and Cushing's disease receiving pasireotide treatment: post hoc analyses from the SOM230B2219 study . Front Endocrinol (Lausanne) . 2024 ; 15 : 1250822 . 38577574 10.3389/fendo.2024.1250822 PMC10993249

99 Chiloiro S , Giampietro A , Visconti F , et al Glucose metabolism outcomes in acromegaly patients on treatment with pasireotide-LAR or pasireotide-LAR plus pegvisomant . Endocrine . 2021 ; 73 ( 3 ): 658 ‐ 666 . 33907985 10.1007/s12020-021-02711-3 PMC8325668

100 Feola T , Cozzolino A , Simonelli I , et al Pegvisomant improves glucose metabolism in acromegaly: a meta-analysis of prospective interventional studies . J Clin Endocrinol Metab . 2019 ; 104 ( 7 ): 2892 ‐ 2902 . 30869797 10.1210/jc.2018-02281

101 Bostan H , Kizilgul M , Calapkulu M , et al The prevalence and associated risk factors of detectable renal morphological abnormalities in acromegaly . Pituitary . 2024 ; 27 ( 1 ): 44 ‐ 51 . 38064149 10.1007/s11102-023-01370-z

102 Castagna G , Ippolito S , Cassibba S , et al Kidney function in acromegaly: evidence from a long-term observational study . Pituitary . 2025 ; 28 ( 3 ): 56 . 40329088 10.1007/s11102-025-01520-5 PMC12055623

103 Kamenický P , Mazziotti G , Lombès M , Giustina A , Chanson P . Growth hormone, insulin-like growth factor-1, and the kidney: pathophysiological and clinical implications . Endocr Rev . 2014 ; 35 ( 2 ): 234 ‐ 281 . 24423979 10.1210/er.2013-1071

104 Hong S , Kim K-S , Han K , Park C-Y . A cohort study found a high risk of end-stage kidney disease associated with acromegaly . Kidney Int . 2023 ; 104 ( 4 ): 820 ‐ 827 . 37490954 10.1016/j.kint.2023.06.037

105 Adnan Z . Sodium glucose co-transporter inhibitors in patients with acromegaly and diabetes . Trends Endocrinol Metabol . 2019 ; 30 ( 2 ): 77 ‐ 79 .

106 Wang M , Guo S , He M , et al High-performance liquid chromatography-mass spectrometry-based lipid metabolite profiling of acromegaly . J Clin Endocrinol Metab . 2020 ; 105 ( 4 ): e1075 ‐ e1084 .

107 Møller N , Jørgensen JOL . Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects . Endocr Rev . 2009 ; 30 ( 2 ): 152 ‐ 177 . 19240267 10.1210/er.2008-0027

108 Shao X-Q , Chen Z-Y , Wang M , et al Effects of long-acting somatostatin analogues on lipid metabolism in patients with newly diagnosed acromegaly: a retrospective study of 120 cases . Horm Metab Res . 2022 ; 54 ( 01 ): 25 ‐ 32 . 34986497 10.1055/a-1717-9332

109 Grundy SM , Stone NJ , Bailey AL , et al 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines . Circulation . 2019 ; 139 ( 25 ): e1082 ‐ e1143 . 30586774 10.1161/CIR.0000000000000625 PMC7403606

110 Karadeniz Y , Karakose M . Non-invasive assessment of metabolic dysfunction-associated steatotic liver disease and cardiovascular risk in acromegaly indicates persistence of cardiac risks despite biochemical disease control . J Clin Med . 2025 ; 14 ( 14 ): 4822 . 40725515 10.3390/jcm14144822 PMC12295490

111 Eroğlu İ , Iremli BG , Idilman IS , et al Nonalcoholic fatty liver disease, liver fibrosis, and utility of noninvasive scores in patients with acromegaly . J Clin Endocrinol Metab . 2023 ; 109 ( 1 ): e119 ‐ e129 . 37590020 10.1210/clinem/dgad490 PMC10735300

112 Giustina A , Barkan A , Chanson P , et al Guidelines for the treatment of growth hormone excess and growth hormone deficiency in adults . J Endocrinol Invest . 2008 ; 31 ( 9 ): 820 ‐ 838 . 18997495 10.1007/BF03349263

113 Mazziotti G , Marzullo P , Doga M , Aimaretti G , Giustina A . Growth hormone deficiency in treated acromegaly . Trends Endocrinol Metab . 2015 ; 26 ( 1 ): 11 ‐ 21 . 25434492 10.1016/j.tem.2014.10.005

114 Nishizawa H , Iguchi G , Murawaki A , et al Nonalcoholic fatty liver disease in adult hypopituitary patients with GH deficiency and the impact of GH replacement therapy . Eur J Endocrinol . 2012 ; 167 ( 1 ): 67 ‐ 74 . 22535644 10.1530/EJE-12-0252

115 Reyes-Vidal CM , Mojahed H , Shen W , et al Adipose tissue redistribution and ectopic lipid deposition in active acromegaly and effects of surgical treatment . J Clin Endocrinol Metab . 2015 ; 100 ( 8 ): 2946 ‐ 2955 . 26037515 10.1210/jc.2015-1917 PMC4524994

116 Freda PU . The acromegaly lipodystrophy . Front Endocrinol (Lausanne) . 2022 ; 13 : 933039 . 36176462 10.3389/fendo.2022.933039 PMC9513226

117 Freda PU , Shen W , Reyes-Vidal CM , et al Skeletal muscle mass in acromegaly assessed by magnetic resonance imaging and dual-photon x-ray absorptiometry . J Clin Endocrinol Metab . 2009 ; 94 ( 8 ): 2880 ‐ 2886 . 19491226 10.1210/jc.2009-0026 PMC2730874

118 Milioto A , Corica G , Nista F , et al Skeletal muscle evaluation in patients with acromegaly . J Endocr Soc . 2024 ; 8 ( 4 ): bvae032 . 38434516 10.1210/jendso/bvae032 PMC10907006

119 Kuker AP , Shen W , Jin Z , et al Body composition changes with long-term pegvisomant therapy of acromegaly . J Endocr Soc . 2021 ; 5 ( 3 ): bvab004 . 33553983 10.1210/jendso/bvab004 PMC7853172

120 Canalis E , Giustina A , Bilezikian JP . Mechanisms of anabolic therapies for osteoporosis . N Engl J Med . 2007 ; 357 ( 9 ): 905 ‐ 916 . 17761594 10.1056/NEJMra067395

121 Giustina A , Mazziotti G , Canalis E . Growth hormone, insulin-like growth factors, and the skeleton . Endocr Rev . 2008 ; 29 ( 5 ): 535 ‐ 559 . 18436706 10.1210/er.2007-0036 PMC2726838

122 Mazziotti G , Frara S , Giustina A . Pituitary diseases and bone . Endocr Rev . 2018 ; 39 ( 4 ): 440 ‐ 488 . 29684108 10.1210/er.2018-00005

123 Silva FF , Lima ML , Pedreira CC , Matos MA . Influence of disease activity and gonadal status on bone mineral density and turnover in acromegaly . J Bone Miner Metab . 2025 ; 43 ( 2 ): 123 ‐ 132 . 39508862 10.1007/s00774-024-01561-z

124 Uygur MM , Frara S , di Filippo L , Giustina A . New tools for bone health assessment in secreting pituitary adenomas . Trends Endocrinol Metab . 2023 ; 34 ( 4 ): 231 ‐ 242 . 36869001 10.1016/j.tem.2023.01.006

125 Giustina A . Acromegaly and vertebral fractures: facts and questions . Trends Endocrinol Metab . 2020 ; 31 ( 4 ): 274 ‐ 275 . 32187523 10.1016/j.tem.2020.01.011

126 Bonadonna S , Mazziotti G , Nuzzo M , 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 ‐ 1844 . 16160741 10.1359/JBMR.050603

127 Mazziotti G , Bianchi A , Bonadonna S , et al Prevalence of vertebral fractures in men with acromegaly . J Clin Endocrinol Metab . 2008 ; 93 ( 12 ): 4649 ‐ 4655 . 18827004 10.1210/jc.2008-0791

128 Kužma M , Vaňuga P , Ságová I , et al Vertebral fractures occur despite control of acromegaly and are predicted by cortical volumetric bone mineral density . J Clin Endocrinol Metab . 2021 ; 106 ( 12 ): e5088 ‐ e5096 . 34270719 10.1210/clinem/dgab259

129 Kim J , Hong N , Choi J , et al Increased risk of hip fracture in patients with acromegaly: a nationwide cohort study in Korea . Endocrinol Metab (Seoul) . 2023 ; 38 ( 6 ): 690 ‐ 700 . 37899569 10.3803/EnM.2023.1782 PMC10764994

130 Almalki MH , Almohaya M , Aziz F , et al Prevalence of vertebral fractures in patients with acromegaly: multicenter cross-sectional study . Hormones (Athens) . 2025 ; 24 ( 3 ): 843 ‐ 849 . 40210828 10.1007/s42000-025-00652-4

131 Frara S , Uygur M M , di Filippo L , et al High prevalence of vertebral fractures associated with preoperative GH levels in patients with recent diagnosis of acromegaly . J Clin Endocrinol Metab . 2022 ; 107 ( 7 ): e2843 ‐ e2850 . 35349698 10.1210/clinem/dgac183

132 Chiloiro S , Giampietro A , Gagliardi I , et al Impact of the diagnostic delay of acromegaly on bone health: data from a real life and long term follow-up experience . Pituitary . 2022 ; 25 ( 6 ): 831 ‐ 841 . 35922724 10.1007/s11102-022-01266-4 PMC9362053

133 Mazziotti G , Biagioli E , Maffezzoni F , et al Bone turnover, bone mineral density, and fracture risk in acromegaly: a meta-analysis . J Clin Endocrinol Metab . 2015 ; 100 ( 2 ): 384 ‐ 394 . 25365312 10.1210/jc.2014-2937

134 Chiloiro S , Costanza F , Riccardi E , et al Vitamin D in pituitary driven osteopathies . Pituitary . 2024 ; 27 ( 6 ): 847 ‐ 859 . 39180644 10.1007/s11102-024-01439-3 PMC11632065

135 Pelsma ICM , Biermasz NR , Pereira AM , et al Progression of vertebral fractures in long-term controlled acromegaly: a 9-year follow-up study . Eur J Endocrinol . 2020 ; 183 ( 4 ): 427 ‐ 437 . 32688336 10.1530/EJE-20-0415

136 Mazziotti G , Gola M , Bianchi A , et al Influence of diabetes mellitus on vertebral fractures in men with acromegaly . Endocrine . 2011 ; 40 ( 1 ): 102 ‐ 108 . 21594681 10.1007/s12020-011-9486-x

137 Mazziotti G , Formenti AM , Frara S , et al Management of endocrine disease: risk of overtreatment in patients with adrenal insufficiency: current and emerging aspects . Eur J Endocrinol . 2017 ; 177 ( 5 ): R231 ‐ R248 . 28583942 10.1530/EJE-17-0154

138 Claessen KM , Mazziotti G , Biermasz NR , Giustina A . Bone and joint disorders in acromegaly . Neuroendocrinology . 2016 ; 103 ( 1 ): 86 ‐ 95 . 25633971 10.1159/000375450

139 Mazziotti G , Bianchi A , Porcelli T , et al Vertebral fractures in patients with acromegaly: a 3-year prospective study . J Clin Endocrinol Metab . 2013 ; 98 ( 8 ): 3402 ‐ 3410 . 23771918 10.1210/jc.2013-1460

140 Ornellas PG , Gama E , Mendonça L , et al Evaluation of bone density and microstructure by DXA, TBS and HR-pQCT: an assessment of cortical porosity and its association with vertebral fractures in patients with acromegaly . J Endocrinol Invest . 2025 ; 48 ( 9 ): 2087 ‐ 2095 . 40526264 10.1007/s40618-025-02619-z

141 Bioletto F , Berton AM , Barale M , et al Skeletal fragility in pituitary disease: how can we predict fracture risk? Pituitary . 2024 ; 27 ( 6 ): 789 ‐ 801 . 39240510 10.1007/s11102-024-01447-3 PMC11631825

142 Frara S , Rodriguez-Carnero G , Formenti AM , Martinez-Olmos MA , Giustina A , Casanueva FF . Pituitary tumors centers of excellence . Endocrinol Metab Clin North Am . 2020 ; 49 ( 3 ): 553 ‐ 564 . 32741488 10.1016/j.ecl.2020.05.010

143 Maffezzoni F , Maddalo M , Frara S , et al High-resolution-cone beam tomography analysis of bone microarchitecture in patients with acromegaly and radiological vertebral fractures . Endocrine . 2016 ; 54 ( 2 ): 532 ‐ 542 . 27601020 10.1007/s12020-016-1078-3

144 Frara S , Acanfora M , Franzese V , Brandi ML , Losa M , Giustina A . Novel approach to bone comorbidity in resistant acromegaly . Pituitary . 2024 ; 27 ( 6 ): 813 ‐ 823 . 39570564 10.1007/s11102-024-01468-y

145 Chiloiro S , Mazziotti G , Giampietro A , et al Effects of pegvisomant and somatostatin receptor ligands on incidence of vertebral fractures in patients with acromegaly . Pituitary . 2018 ; 21 ( 3 ): 302 ‐ 308 . 29397538 10.1007/s11102-018-0873-7

146 Chiloiro S , Giampietro A , Frara S , et al Effects of pegvisomant and pasireotide LAR on vertebral fractures in acromegaly resistant to first-generation SRLs . J Clin Endocrinol Metab . 2020 ; 105 ( 3 ): e100 ‐ e107 .

147 Giustina A , Bilezikian JP , Adler RA , et al Consensus statement on vitamin D status assessment and supplementation: whys, whens, and hows . Endocr Rev . 2024 ; 45 ( 5 ): 625 ‐ 654 . 38676447 10.1210/endrev/bnae009 PMC11405507

148 Halupczok-Żyła J , Jawiarczyk-Przybyłowska A , Bolanowski M . Patients with active acromegaly are at high risk of 25(OH)D deficiency . Front Endocrinol (Lausanne) . 2015 ; 6 : 89 . 26082755 10.3389/fendo.2015.00089 PMC4451637

149 Mazziotti G , Maffezzoni F , Giustina A . Vitamin D-binding protein: one more piece in the puzzle of acromegalic osteopathy? Endocrine . 2016 ; 52 ( 2 ): 183 ‐ 186 . 26899438 10.1007/s12020-016-0890-0

150 Chiloiro S , Frara S , Gagliardi I , et al Cholecalciferol use is associated with a decreased risk of incident morphometric vertebral fractures in acromegaly . J Clin Endocrinol Metab . 2023 ; 109 ( 1 ): e58 ‐ e68 . 37606222 10.1210/clinem/dgad493 PMC10735684

151 Rosendal C , Kvist AV , Hirata RP , Vestergaard P , Dal J . Static and dynamic balance is impaired in patients with long-term, well-controlled acromegaly: a cross-sectional study . Clin Endocrinol (Oxf) . 2025 ; 103 ( 5 ): 703 ‐ 710 . 40765123 10.1111/cen.70010 PMC12492776

152 Giustina A , Colao A . Acromegaly. Reply . N Engl J Med . 2026 ; 394 ( 8 ): 829 ‐ 830 . 41707164 10.1056/NEJMc2518017

153 Wiśniewska B , Piekarski K , Spychała S , Golusińska-Kardach E , Stelmachowska-Banaś M , Wyganowska M . Collaboration between endocrinologists and dentists in the care of patients with acromegaly a narrative review . J Clin Med . 2025 ; 14 ( 15 ): 5511 . 40807135 10.3390/jcm14155511 PMC12347475

154 Rosendal C , Arlien-Søborg MC , Nielsen EH , et al Musculoskeletal disease in acromegaly-a population-based registry study . Eur J Endocrinol . 2025 ; 192 ( 3 ): 308 ‐ 317 . 40079357 10.1093/ejendo/lvaf047

155 Barkan A . Acromegalic arthropathy and sleep apnea . J Endocrinol . 1997 ; 155 ( Suppl 1 ): S41 ‐ S44 ; discussion S45 . 9389994

156 Claessen KMJA , Canete AN , de Bruin PW , et al Acromegalic arthropathy in various stages of the disease: an MRI study . Eur J Endocrinol . 2017 ; 176 ( 6 ): 779 ‐ 790 . 28348071 10.1530/EJE-16-1073

157 Pelsma ICM , Kroon HM , Andela CD , et al Approach to the patient with controlled acromegaly and acromegalic arthropathy: clinical diagnosis and management . Pituitary . 2024 ; 27 ( 6 ): 824 ‐ 836 . 39485592 10.1007/s11102-024-01465-1 PMC11632006

158 Colao A , Marzullo P , Vallone G , et al Reversibility of joint thickening in acromegalic patients: an ultrasonography study . J Clin Endocrinol Metab . 1998 ; 83 ( 6 ): 2121 ‐ 2125 . 9626149 10.1210/jcem.83.6.4865

159 Claessen KMJA , Ramautar SR , Pereira AM , et al Progression of acromegalic arthropathy despite long-term biochemical control: a prospective, radiological study . Eur J Endocrinol . 2012 ; 167 ( 2 ): 235 ‐ 244 . 22645199 10.1530/EJE-12-0147

160 Fatti LM , Cangiano B , Vitale G , et al Arthropathy in acromegaly: a questionnaire-based estimation of motor disability and its relation with quality of life and work productivity . Pituitary . 2019 ; 22 ( 5 ): 552 ‐ 560 . 31032537 10.1007/s11102-019-00966-8

161 Cangiano B , Giusti E , Premoli C , et al Psychological complications in patients with acromegaly: relationships with sex, arthropathy, and quality of life . Endocrine . 2022 ; 77 ( 3 ): 510 ‐ 518 . 35779206 10.1007/s12020-022-03106-8 PMC9385810

162 Martel-Duguech L , Bascuñana H , Corredor VP , et al Benefits of a 12 weeks-individually tailored physical activity program in patients with Cushing's disease in remission and controlled acromegaly . Endocrine . 2025 ; 90 ( 1 ): 276 ‐ 289 . 40637819 10.1007/s12020-025-04331-7

163 Caron P , Brue T , Raverot G , et al Signs and symptoms of acromegaly at diagnosis: the physician's and the patient's perspectives in the ACRO-POLIS study . Endocrine . 2019 ; 63 ( 1 ): 120 ‐ 129 . 30269264 10.1007/s12020-018-1764-4 PMC6329724

164 Alibas H , Gogas Yavuz D , Kahraman Koytak P , Uygur M , Tanridag T , Uluc K . Peripheral nervous system assessment in acromegaly patients under somatostatin analogue therapy . J Endocrinol Invest . 2017 ; 40 ( 1 ): 33 ‐ 40 . 27484912 10.1007/s40618-016-0522-9

165 Sasagawa Y , Tachibana O , Doai M , Tonami H , Iizuka H . Median nerve conduction studies and wrist magnetic resonance imaging in acromegalic patients with carpal tunnel syndrome . Pituitary . 2015 ; 18 ( 5 ): 695 ‐ 700 . 25663441 10.1007/s11102-015-0642-9

166 Chanson P . Carpal tunnel syndrome in acromegaly is also related to median nerve oedema . BMJ . 2020 ; 369 : m1701 . 32354842 10.1136/bmj.m1701

167 Vouzouneraki K , Esposito D , Mukka S , et al Carpal tunnel syndrome in acromegaly: a nationwide study . Eur J Endocrinol . 2021 ; 184 ( 2 ): 209 ‐ 216 . 33136549 10.1530/EJE-20-0530

168 Basu R , Boguszewski CL , Kopchick JJ . Growth hormone action as a target in cancer: significance, mechanisms, and possible therapies . Endocr Rev . 2025 ; 46 ( 2 ): 224 ‐ 280 . 39657053 10.1210/endrev/bnae030

169 Boguszewski CL , Ayuk J . Management of endocrine disease: acromegaly and cancer: an old debate revisited . Eur J Endocrinol . 2016 ; 175 ( 4 ): R147 ‐ R156 . 27089890 10.1530/EJE-16-0178

170 Hepşen S , Üçgül E , Menekşe B , et al Prevalence and risk factors of colon polyps and other colonic lesions in acromegaly: from colonoscopy screening . Pituitary . 2025 ; 28 ( 2 ): 44 . 40167828 10.1007/s11102-025-01513-4 PMC11961538

171 Dal J , Leisner MZ , Hermansen K , et al Cancer incidence in patients with acromegaly: a cohort study and meta-analysis of the literature . J Clin Endocrinol Metab . 2018 ; 103 ( 6 ): 2182 ‐ 2188 . 29590449 10.1210/jc.2017-02457

172 Xiao Z , Xiao P , Wang Y , Fang C , Li Y . Risk of cancer in acromegaly patients: updated meta-analysis and systematic review . PLoS One . 2023 ; 18 ( 11 ): e0285335 . 38032888 10.1371/journal.pone.0285335 PMC10688666

173 Petroff D , Tönjes A , Grussendorf M , et al The incidence of cancer among acromegaly patients: results from the acromegaly registry . J Clin Endocrinol Metab . 2015 ; 100 ( 10 ): 3894 ‐ 3902 . 26244491 10.1210/jc.2015-2372

174 Kim YS , Yun J-S , Kim H , et al Acromegaly and the risk of cancer: a nationwide population-based cohort study in Korea . Eur J Endocrinol . 2025 ; 192 ( 3 ): 220 ‐ 227 . 40037898 10.1093/ejendo/lvaf029

175 Freda PU , Bruce JN , Jin Z , et al Prospective, longitudinal study of cancer predictors and rates in a New York city cohort of 598 patients with acromegaly . J Clin Endocrinol Metab . 2025 ; 110 ( 5 ): 1247 ‐ 1257 . 38986012 10.1210/clinem/dgae469 PMC12168067

176 Duskin-Bitan H , Perez A , Netzer D , et al Increased cancer risk in a cohort of patients with acromegaly in Israel . Endocr Relat Cancer . 2025 ; 32 ( 5 ): e240087 . 40062775 10.1530/ERC-24-0087

177 Esposito D , Ragnarsson O , Johannsson G , Olsson DS . Incidence of benign and malignant tumors in patients with acromegaly is increased: a nationwide population-based study . J Clin Endocrinol Metab . 2021 ; 106 ( 12 ): 3487 ‐ 3496 . 34343297 10.1210/clinem/dgab560

178 Maia B , Madeira E , Gadelha MR , Kasuki L . Assessment of the frequency and risk factors for colorectal cancer in acromegaly . Endocrine . 2025 ; 87 ( 3 ): 1162 ‐ 1170 . 39537960 10.1007/s12020-024-04099-2

179 Demarchis L , Chiloiro S , Giampietro A , et al Cancer screening in patients with acromegaly: a plea for a personalized approach and international registries . Rev Endocr Metab Disord . 2025 ; 26 ( 4 ): 525 ‐ 538 . 40088375 10.1007/s11154-025-09957-6 PMC12316805

180 Dal J . Colonoscopy in acromegaly: when and why . Pituitary . 2025 ; 28 ( 3 ): 55 . 40329062 10.1007/s11102-025-01528-x

181 Esposito D , Ragnarsson O , Johannsson G , Olsson DS . Prolonged diagnostic delay in acromegaly is associated with increased morbidity and mortality . Eur J Endocrinol . 2020 ; 182 ( 6 ): 523 ‐ 531 . 32213651 10.1530/EJE-20-0019

182 Siegel S , Streetz-van der Werf C , Schott JS , Nolte K , Karges W , Kreitschmann-Andermahr I . Diagnostic delay is associated with psychosocial impairment in acromegaly . Pituitary . 2013 ; 16 ( 4 ): 507 ‐ 514 . 23179964 10.1007/s11102-012-0447-z

183 Matthesen AT , Rosendal C , Christensen EH , et al Psychiatric morbidity in acromegaly: a cohort study and meta-analysis of the literature . Pituitary . 2025 ; 28 ( 2 ): 42 . 40082297 10.1007/s11102-025-01509-0 PMC11906539

184 Coopmans EC , Andela CD , Claessen KMJA , Biermasz NR . Evaluating the impact of acromegaly on quality of life . Endocrinol Metab Clin North Am . 2022 ; 51 ( 4 ): 709 ‐ 725 . 36244688 10.1016/j.ecl.2022.04.004

185 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 ‐ R26 . 28351913 10.1530/EJE-17-0041

186 Crespo I , Valassi E , Webb SM . Update on quality of life in patients with acromegaly . Pituitary . 2017 ; 20 ( 1 ): 185 ‐ 188 . 27730455 10.1007/s11102-016-0761-y

187 Fleseriu M , Molitch M , Dreval A , et al Disease and treatment-related burden in patients with acromegaly who are biochemically controlled somatostatin receptor ligands . Front Endocrinol (Lausanne) . 2021 ; 12 : 627711 . 33790860 10.3389/fendo.2021.627711 PMC8006928

188 Samson SL , Nachtigall LB , Fleseriu M , et al Maintenance of acromegaly control in patients switching from injectable somatostatin receptor ligands to oral octreotide . J Clin Endocrinol Metab . 2020 ; 105 ( 10 ): e3785 ‐ e3797 . 32882036 10.1210/clinem/dgaa526 PMC7470473

189 Fleseriu M , Dreval A , Bondar I , et al Maintenance of response to oral octreotide compared with injectable somatostatin receptor ligands in patients with acromegaly: a phase 3, multicentre, randomised controlled trial . Lancet Diabetes Endocrinol . 2022 ; 10 ( 2 ): 102 ‐ 111 . 34953531 10.1016/S2213-8587(21)00296-5

190 Fleseriu M , Molitch M , Dreval A , et al MPOWERED open-label extension: long-term efficacy and safety data for oral octreotide capsules in acromegaly . J Clin Endocrinol Metab . 2023 ; 108 ( 12 ): 3214 ‐ 3222 . 37319438 10.1210/clinem/dgad365 PMC10655542

191 Gadelha MR , Casagrande A , Strasburger CJ , et al Acromegaly disease control maintained after switching from injected somatostatin receptor ligands to oral paltusotine . J Clin Endocrinol Metab . 2024 ; 110 ( 1 ): 228 ‐ 237 . 38828555 10.1210/clinem/dgae385 PMC11651685

192 Biller BMK , Casagrande A , Elenkova A , et al Rapid and sustained response of biochemically uncontrolled acromegaly to once-daily oral paltusotine treatment . J Clin Endocrinol Metab . 2026 ; 111 (4) : e1050 ‐ e1063 . 41128642 10.1210/clinem/dgaf579 PMC13016795

193 McLaren DS , Kyriakakis N , Seejore K , Lynch J , Murray RD . Are oral somatostatin receptor ligands moving closer to becoming a reality? Clin Endocrinol (Oxf) . 2025 ; 102 ( 3 ): 288 ‐ 290 . 39737607 10.1111/cen.15193

194 Neggers SJCMM , van Aken MO , de Herder WW , 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 ‐ 3859 . 18647806 10.1210/jc.2008-0669

195 van der Meulen M , Zamanipoor Najafabadi AH , Broersen LHA , et al State of the art of patient-reported outcomes in acromegaly or GH deficiency: a systematic review and meta-analysis . J Clin Endocrinol Metab . 2022 ; 107 ( 5 ): 1225 ‐ 1238 . 34871425 10.1210/clinem/dgab874 PMC9016456

196 Geraedts VJ , Andela CD , Stalla GK , et al Predictors of quality of life in acromegaly: no consensus on biochemical parameters . Front Endocrinol (Lausanne) . 2017 ; 8 : 40 . 28316591 10.3389/fendo.2017.00040 PMC5334635

197 Wang W , Han X , Huang Q . Fatigue in acromegaly patients: a scoping review . Front Endocrinol (Lausanne) . 2025 ; 16 : 1601661 . 40727910 10.3389/fendo.2025.1601661 PMC12301152

198 Geer EB , Sisco J , Adelman DT , et al Observed discordance between outcomes reported by acromegaly patients and their treating endocrinology medical provider . Pituitary . 2020 ; 23 ( 2 ): 140 ‐ 148 . 31808101 10.1007/s11102-019-01013-2 PMC7066283

199 Giustina A , Bevan JS , Bronstein MD , et al SAGIT®: clinician-reported outcome instrument for managing acromegaly in clinical practice–development and results from a pilot study . Pituitary . 2016 ; 19 ( 1 ): 39 ‐ 49 . 26377024 10.1007/s11102-015-0681-2 PMC4710645

200 Shah SN , Yuen KCJ , Bonert V , et al Patient perspectives on acromegaly disease burden: insights from a community meeting . Front Endocrinol (Lausanne) . 2025 ; 16 : 1516131 . 39963277 10.3389/fendo.2025.1516131 PMC11830622

201 Biagetti B , Iglesias P , Villar-Taibo R , et al Mortality in acromegaly diagnosed in older individuals in is higher in women compared to the general population . J Clin Endocrinol Metab . 2023 ; 108 ( 9 ): 2193 ‐ 2202 . 36916151 10.1210/clinem/dgad141

202 Hong S , Han K , Park C-Y . Long-term prognosis and systemic impact of acromegaly: analyses utilizing national health insurance data . Endocrinol Metab (Seoul) . 2025 ; 40 ( 1 ): 1 ‐ 9 . 39901807 10.3803/EnM.2024.2285 PMC11898327

203 Gasco V , Prencipe N , Cuboni D , et al Diagnostic delay, older age, and hormonal levels at diagnosis affect disease burden and mortality in acromegaly . J Endocrinol Invest . 2025 ; 48 ( 4 ): 919 ‐ 929 . 39739300 10.1007/s40618-024-02519-8

204 Bolfi F , Neves AF , Boguszewski CL , Nunes-Nogueira VS . Mortality in acromegaly decreased in the last decade: a systematic review and meta-analysis . Eur J Endocrinol . 2018 ; 179 ( 1 ): 59 ‐ 71 . 29764907 10.1530/EJE-18-0255

205 Rosendal C , Arlien-Søborg MC , Nielsen EH , et al The changing landscape of acromegaly – an epidemiological perspective . Rev Endocr Metab Disord . 2024 ; 25 ( 4 ): 691 ‐ 705 . 38337125 10.1007/s11154-024-09875-z

206 Mercado M , Gonzalez B , Vargas G , 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 ‐ 4446 . 25210882 10.1210/jc.2014-2670

207 Tritos NA , Carlsson MO , Vila G , et al Disease-specific mortality in patients with acromegaly treated with pegvisomant: an ACROSTUDY analysis . Endocr Connect . 2025 ; 14 ( 9 ): e250247 . 40923548 10.1530/EC-25-0247 PMC12464337

208 Giustina A , Arnaldi G , Bogazzi F , et al Pegvisomant in acromegaly: an update . J Endocrinol Invest . 2017 ; 40 ( 6 ): 577 ‐ 589 . 28176221 10.1007/s40618-017-0614-1 PMC5443862

209 Giustina A , Barkhoudarian G , Beckers A , et al Multidisciplinary management of acromegaly: a consensus . Rev Endocr Metab Disord . 2020 ; 21 ( 4 ): 667 ‐ 678 . 32914330 10.1007/s11154-020-09588-z PMC7942783

210 Giustina A , Bronstein MD , Chanson P , et al Staging and managing patients with acromegaly in clinical practice: baseline data from the SAGIT® validation study . Pituitary . 2019 ; 22 ( 5 ): 476 ‐ 487 . 31338660 10.1007/s11102-019-00977-5 PMC6728296

211 Giustina A , Mazziotti G , Cannavò S , et al High-dose and high-frequency lanreotide autogel in acromegaly: a randomized, multicenter study . J Clin Endocrinol Metab . 2017 ; 102 ( 7 ): 2454 ‐ 2464 . 28419317 10.1210/jc.2017-00142

212 Fleseriu M . Clinical efficacy and safety results for dose escalation of somatostatin receptor ligands in patients with acromegaly: a literature review . Pituitary . 2011 ; 14 ( 2 ): 184 ‐ 193 . 21161602 10.1007/s11102-010-0282-z PMC3094533

213 Chiloiro S , Giampietro A , Giambò P , et al IGF-I levels during standard lanreotide dose predicts biochemical outcome of high-frequency regimen in acromegaly . Pituitary . 2024 ; 28 ( 1 ): 7 . 39724447 10.1007/s11102-024-01479-9

214 Gola M , Bonadonna S , Mazziotti G , Amato G , Giustina A . Resistance to somatostatin analogs in acromegaly: an evolving concept? J Endocrinol Invest . 2006 ; 29 ( 1 ): 86 ‐ 93 . 16553040 10.1007/BF03349183

Abbreviations

acromegaly quality of life questionnaire

bone mineral density

dual-energy X-ray absorptiometry

growth hormone

hazard ratio

insulin-like growth factor 1

metabolic dysfunction-associated steatotic liver disease

oral glucose tolerance test

odds ratio

Pituitary Tumor Center of Excellence

quality of life

risk ratio

“signs & symptoms, associated comorbidities, GH levels, IGF-I levels, and tumor profile”

somatostatin receptor ligand

somatostatin receptor type

vertebral fracture