Acromegaly in humans and cats: Pathophysiological, clinical and management resemblances and differences.

OBJECTIVE: Acromegaly is a disorder associated with excessive levels of growth hormone (GH) and insulin-like growth factor-1 (IGF-1). In general, GH/IGF-1 excess leads to morphologic craniofacial and acral changes as well as cardiometabolic complications, but the phenotypic changes and clinical presentation of acromegaly differ across species. Here, we review the pathophysiology, clinical presentation and management of acromegaly in humans and cats, and we provide a systematic comparison between this disease across these different species. DESIGN: A comprehensive literature review of pathophysiology, clinical features, diagnosis and management of acromegaly in humans and in cats was performed. RESULTS: Acromegaly is associated with prominent craniofacial changes in both species: frontal bossing, enlarged nose, ears and lips, and protuberant cheekbones are typically encountered in humans, whereas increased width of the head and skull enlargement are commonly found in cats. Malocclusion, prognathism, dental diastema and upper airway obstruction by soft tissue enlargement are reported in both species, as well as continuous growth and widening of extremities resulting in osteoarticular compromise. Increase of articular joint cartilage thickness, vertebral fractures and spine malalignment is more evident in humans, while arthropathy and spondylosis deformans may also occur in cats. Generalized organomegaly is equally observed in both species. Other similarities between humans and cats with acromegaly include heart failure, ventricular hypertrophy, diabetes mellitus, and an overall increased cardiometabolic risk. In GH-secreting pituitary tumours, local compressive effects and behavioral changes are mostly observed in humans, but also present in cats. Cutis verticis gyrata and skin tags are exclusively found in humans, while palmigrade/plantigrade stance may occur in some acromegalic cats. Serum IGF-1 is used for acromegaly diagnosis in both species, but an oral glucose tolerance test with GH measurement is only useful in humans, as glucose load does not inhibit GH secretion in cats. Imaging studies are regularly performed in both species after biochemical diagnosis of acromegaly. Hypophysectomy is the first line treatment for humans and cats, although not always available in veterinary medicine. CONCLUSION: Acromegaly in humans and cats has substantial similarities, as a result of common pathophysiological mechanisms, however species-specific features may be found.

Assessment of multimodal treatment options in recurrent and persistent acromegaly: a systematic review and meta-analysis.

PURPOSE: In patients with acromegaly, secondary treatment options in cases of hormonal non-remission or tumor progression include repeat transsphenoidal surgery (TSS), radiation-based treatment (RT), or medical therapy (MT). In this study, we aim to evaluate the clinical effectiveness of various second-line treatment options for acromegaly. METHODS: Using the PRISMA guideline, a systematic review was performed by searching MEDLINE (PubMed), Web of Science, Scopus, and Cochrane electronic bibliographic databases from conception to the end of 2022. Outcomes of interest included hormonal remission rate, complications, and mortality associated with each treatment modality for refractory acromegaly. RESULTS: A total of 79 studies including 3,208 refractory acromegaly patients (44.90% males) were analyzed, with a mean patient age of 43.89 years. There was a statistically significant difference between various therapeutic modalities in terms of remission rate, with MT offering the highest remission rate (62.55%), followed by RT (50.15%) and TSS (37.39%). Subgroup analysis of radiotherapeutic and medical modalities did not show a significant difference in remission rate between different kinds of sub-modalities in each treatment approach. Recurrence following secondary treatment was not different in patients treated with reoperation TSS compared to other modalities. CONCLUSIONS: The management of persistent and recurrent acromegaly optimally requires a multimodal approach. In different scenarios of refractory acromegaly based on previous treatment, secondary treatments may vary in terms of remission rate and complications. Medical agents provide considerable effectiveness as a second-line therapy for recurrent or persistent disease. In selected cases, however, reoperation still provides an opportunity for cure or freedom from medications. The findings of this study may help clinicians to prioritize varying options involved in this multifaceted decision-making process.

Changes in acromegaly comorbidities, treatment, and outcome over three decades: a nationwide cohort study.

Objective: To study the time-dependent changes in disease features of Danish patients with acromegaly, including treatment modalities, biochemical outcome, and comorbidities, with a particular focus on cancer and mortality. Methods: Pertinent acromegaly-related variables were collected from 739 patients diagnosed since 1990. Data are presented across three decades (1990-1999, 2000-2009, and 2010-2021) based on the year of diagnosis or treatment initiation. Results: Adenoma size and insulin-like growth factor I (IGF-I) levels at diagnosis did not differ significantly between study periods. The risk of being diagnosed with diabetes, heart disease, sleep apnea, joint disease, and osteoporosis increased from the 1990s to the later decades, while the mortality risk declined to nearly half. The risk of cancer did not significantly change. Treatment changed toward the use of more medical therapy, and fewer patients underwent repeat surgeries or pituitary irradiation. A statistically significant increase in the proportion of patients achieving IGF-I normalization within 3-5 years was observed over time (69%, 83%, and 88%). The proportion of patients with three or more deficient pituitary hormones decreased significantly over time. Conclusion: Modern medical treatment regimens of acromegaly as well as increased awareness and improved diagnostics for its comorbidities have led to better disease control, fewer patients with severe hypopituitarism, and declining mortality in the Danish cohort of acromegaly patients. The risk of cancer did not increase over the study period.

Pregnancy and acromegaly: clinical outcomes of retrospectively analysed data from the German acromegaly registry.

CONTEXT: Acromegaly is a rare disease caused by excessive growth hormone (GH) secretion, mostly induced by pituitary adenomas. The care of pregnant women with acromegaly is challenging, in part due to existing clinical data being limited and not entirely consistent with regard to potential risks for mother and child. OBJECTIVE: To retrospectively examine data on pregnancy and maternal as well as neonatal outcomes in patients with acromegaly. DESIGN & METHODS: Retrospective data analysis from 47 pregnancies of 31 women treated in centers of the German Acromegaly Registry. RESULTS: 87.1% of the studied women underwent transsphenoidal surgery before pregnancy. In 51.1% a combination of dopamine agonists and somatostatin analogs were used before pregnancy. Three women did not receive any therapy for acromegaly. During pregnancy only 6.4% received either somatostatin analogs or dopamine agonists. In total, 70.2% of all documented pregnancies emerged spontaneously. Gestational diabetes was diagnosed in 10.6% and gravid hypertension in 6.4%. Overall, no preterm birth was detected. Indeed, 87% of acromegalic women experienced a delivery without complications. CONCLUSION: Pregnancies in women with acromegaly are possible and the course of pregnancy is in general safe for mother and child both with and without specific treatment for acromegaly. The prevalence of concomitant metabolic diseases such as gestational diabetes is comparable to the prevalence in healthy pregnant women. Nevertheless, larger studies with more data in pregnant patients with acromegaly are needed to provide safe and effective care for pregnant women with this condition.

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.

CONTEXT: Epidemiological studies involving patients with acromegaly have yielded conflicting results regarding cancer incidence and causes of mortality in relation to control of growth hormone (GH) excess. OBJECTIVE: The objective of this retrospective cohort study is to clarify these questions and identify goals for treatment and monitoring patients. METHODS: We studied 1845 subjects from the UK Acromegaly Register (1970-2016), obtaining cancer standardised incidence rates (SIR) and all causes standardised mortality rates (SMR) from UK Office for National Statistics, to determine the relationship between causes of mortality-age at diagnosis, duration of disease, post-treatment and mean GH levels. RESULTS: We found an increased incidence of all cancers (SIR, 1.38; 95% CI: 1.06-1.33, p < .001), but no increase in incidence of female breast, thyroid, colon cancer or any measure of cancer mortality. All-cause mortality rates were increased (SMR, 1.35; 95% CI: 1.24-1.46, p < .001), as were those due to vascular and respiratory diseases. All-cause, all cancer and cardiovascular deaths were highest in the first 5 years following diagnosis. We found a positive association between post-treatment and mean treatment GH levels and all-cause mortality (p < .001 and p < .001), which normalised with posttreatment GH levels of <1.0 µg/L or meantreatment GH levels of <2.5 µg/L. CONCLUSION: Acromegaly is associated with increased incidence of all cancers but not thyroid or colon cancer and no increase in cancer mortality. Excess mortality is due to vascular and respiratory disease. The risk is highest in the first 5 years following diagnosis and is mitigated by normalising GH levels.

Changes in multi-modality management of acromegaly in a tertiary centre over 2 decades.

PURPOSE: Acromegaly is a rare disease associated with chronic multisystem complications. New therapeutic strategies have emerged in the last decades, combining pituitary transsphenoidal surgery (TSS), radiotherapy or radiosurgery (RXT) and medical treatments. METHODS: This retrospective monocentric study focused on presentation, management and outcome of acromegaly patients diagnosed between 2000 and 2020, still followed up in 2020, with a minimum follow-up of 1 year, and comparison of the first vs. second decade of the study. RESULTS: 275 patients were included, 50 diagnosed before 2010 and 225 after 2010. 95% of them had normal IGF-1 levels (with or without treatment) at the last follow-up. Transsphenoidal surgery was more successful after 2010 (75% vs. 54%; p < 0.01), while tumor characteristics remained the same over time. The time from first treatment to biochemical control was shorter after 2010 than before (8 vs. 16 months; p = 0.03). Since 2010, RT was used less frequently (10% vs. 32%; p < 0.01) but more rapidly after surgery (26 vs. 53 months; p = 0.03). In patients requiring anti-secretory drugs after TSS, the time from first therapy to biochemical control was shorter after 2010 (16 vs. 29 months; p < 0.01). Tumor size, tumor invasiveness, baseline IGF-1 levels and Trouillas classification were identified as predictors of remission. CONCLUSION: The vast majority of patients with acromegaly now have successful disease control with a multimodal approach. They reached biochemical control sooner in the most recent half of the study period. Future work should focus on those patients who are still uncontrolled and on the sequelae of the disease.

Real-world experience with 11C-methionine positron emission tomography in the management of acromegaly.

BACKGROUND: L-[methyl-11C]-methionine-positron emission tomography (Met-PET) is a potentially important imaging adjunct in the diagnostic workup of pituitary adenomas, including somatotroph tumors. Met-PET can identify residual or occult disease and make definitive therapies accessible to a subgroup of patients who would otherwise require lifelong medical therapy. However, existing data on its use are still limited to small case series. Here, we report the largest single-center experience (n = 61) in acromegaly. METHODS: A total of 189 cases of acromegaly were referred to our national Met-PET service in the last 12 years. For this analysis, we have reviewed outcomes in those 61 patients managed exclusively by our multidisciplinary team (single center, single surgeon). Referral indications were as follows: indeterminate magnetic resonance imaging (MRI; n = 38, 62.3%), occult residual (n = 14, 23.0%), (radio-)surgical planning (n = 6, 9.8%), and occult de novo tumor (n = 3, 4.9%). RESULTS: A total of 33/61 patients (54.1%) underwent PET-guided surgery. Twenty-four of 33 patients (72.7%) achieved complete biochemical remission following (re-)surgery. Insulin-like growth factor 1 levels were reduced to <2 × upper limit of normal (ULN) in 6 of the remaining 9 cases, 3 of whom achieved levels of <1.1 × ULN compared with mean preoperative levels of 2.4 × ULN (SD 0.8) for n = 9. Only 3 patients developed single new hormonal deficits (gonadotropic/thyrotropic insufficiency). There were no neurovascular complications after surgery. CONCLUSION: In patients with persistent/recurrent acromegaly or occult tumors, Met-PET can facilitate further targeted intervention (surgery/radiosurgery). This led to complete remission in most cases (24/33) or significant improvement with comparatively low risk of complications. L-[methyl-11C]-methionine-positron emission tomography should therefore be considered in all patients who are potential candidates for further surgical intervention but present no clear target on MRI.

Genetic diagnosis in acromegaly and gigantism: From research to clinical practice.

It is usually considered that only 5% of all pituitary neuroendocrine tumours are due to inheritable causes. Since this estimate was reported, however, multiple genetic defects driving syndromic and nonsyndromic somatotrophinomas have been unveiled. This heterogeneous genetic background results in overlapping phenotypes of GH excess. Genetic tests should be part of the approach to patients with acromegaly and gigantism because they can refine the clinical diagnoses, opening the possibility to tailor the clinical conduct to each patient. Even more, genetic testing and clinical screening of at-risk individuals have a positive impact on disease outcomes, by allowing for the timely detection and treatment of somatotrophinomas at early stages. Future research should focus on determining the actual frequency of novel genetic drivers of somatotrophinomas in the general population, developing up-to-date disease-specific multi-gene panels for clinical use, and finding strategies to improve access to modern genetic testing worldwide.

Disease control of acromegaly does not prevent excess mortality in the long term: results of a nationwide survey in Italy.

OBJECTIVE: This study aimed to assess the long-term outcome of patients with acromegaly. DESIGN: This is a multicenter, retrospective, observational study which extends the mean observation period of a previously reported cohort of Italian patients with acromegaly to 15 years of follow-up. METHODS: Only patients from the centers that provided information on the life status of at least 95% of their original cohorts were included. Life status information was collected either from clinical records or from the municipal registry offices. Standardized mortality ratios (SMRs) were computed comparing data with those of the general Italian population. RESULTS: A total of 811 patients were included. There were 153 deaths, with 90 expected and an SMR of 1.7 (95% CI 1.4-2.0, p < 0.001). Death occurred after a median of 15 (women) or 16 (men) years from the diagnosis, without gender differences. Mortality remained elevated in the patients with control of disease (SMR 1.3, 95% CI 1.1-1.6). In the multivariable analysis, only older age and high IGF1 concentrations at last available follow-up visit were predictors of mortality. The oncological causes of death outweighed the cardiovascular ones, bordering on statistical significance with respect to the general population. CONCLUSIONS: Mortality remains significantly high in patients with acromegaly, irrespectively of disease status, as long as the follow-up is sufficiently long with a low rate of patients lost to follow-up. Therapy strategy including radiotherapy does not have an impact on mortality. Oncological causes of death currently outweigh the cardiovascular causes.

New Treatments for Acromegaly in Development.

Acromegaly treatment has greatly evolved in recent decades, but there are still patients whose acromegaly is not controlled with currently available treatments, and there is a need to improve the treatment burden. Fortunately, there are new treatments under development that may increase treatment efficacy and convenience.

Acromegaly presented with acne vulgaris: a retrospective study with 123 cases.

BACKGROUND: Acne vulgaris is a prevalent skin condition. We have found that some acromegaly patients have acne. However, no study has examined the relationship between acromegaly and acne. OBJECTIVE: To explore prevalence and correlation of adult acne in patients with acromegaly. METHODS: For this cross-sectional study, we collected questionnaires, clinical information, and laboratory test results of acromegaly patients from January 2022 to December 2022 at Huashan Hospital. Of the 133 questionnaires returned, 123 had valid responses. RESULTS: Of the 123 patients with acromegaly enrolled in this study, 54.5% had adult acne. No statistically significant difference was found in prevalence between male and female patients. 61.2% of adult acne patients reported late-onset acne. Late-onset acne patients first developed acne years before acromegaly diagnosis (mean of 5.6 years for male and 4.5 years for female patients). Some acne patients have received traditional anti-acne treatment. Moreover, 31% of the patients reported no improvement, and only 3.5% of patients claimed complete resolution of acne after treatment. Before acromegaly treatment, the prevalence of adult acne was 51.2%, with mild acne accounting for 73.0%, moderate acne accounting for 23.8%, and severe acne accounting for 3.2%. After acromegaly treatment, the prevalence of adult acne was significantly decreased to 37.4% (P = 0.007). An overall decrease in acne severity was noted, with 93.5%, 6.5%, and 0% having mild, moderate, and severe acne, respectively. A total of 83.6% of the patients had self-assessed acne remission, and 33.3% of the patients reported complete acne resolution. However, 9.0% of patients reported that their condition had worsened after acromegaly treatment. After treatment, GH, IGF-1, IGF-1 index, insulin levels, and HOMA-IR decreased significantly in all patients with acromegaly (P < 0.05). Acne remission correlated positively with IGF-1 levels, but not with GH levels. The relationship between acromegaly and acne remains to be elucidated. CONCLUSIONS: Our findings provide preliminary evidence of the high prevalence of adult acne in acromegaly patients, and a high rate of late-onset acne as well. Traditional anti-acne treatments are less effective. Acne could be considerably relieved by treating acromegaly. Acne remission positively correlated with IGF-1 decline as well, which revealed the correlation between acne and IGF-1.

Acromegalic Cardiomyopathy: An Entity on its own? The Effects of GH and IGF-I Excess and Treatment on Cardiovascular Risk Factors.

Acromegaly is a chronic disease resulting from constantly elevated concentrations of growth hormone (GH) and insulin-like growth factor I (IGF-I). If not adequately treated, GH and IGF-I excess is associated with various cardiovascular risk factors. These symptoms mainly include hypertension and impaired glucose metabolism, which can be observed in approximately one-third of patients. Other comorbidities are dyslipidemia and the presence of obstructive sleep apnea syndrome. However, even in the absence of conventional cardiovascular risk factors, myocardial hypertrophy can occur, which reflects the impact of GH and IGF-I excess itself on the myocardium and is defined as acromegalic cardiomyopathy. Whereas previous echocardiography-based studies reported a high prevalence of cardiomyopathy, this prevalence is much lower in cardiac magnetic resonance imaging-based studies. Myocardial hypertrophy in acromegaly is due to a homogeneous increase in the intracellular myocardial mass and extracellular myocardial matrix and improves following successful treatment through intracellular changes. Intramyocardial water retention or ectopic lipid accumulation might not be of relevant concern. Successful treatment significantly improves myocardial morphology, as well as cardiovascular risk factors. In addition to GH/IGF-I-lowering therapy, the diagnosis and treatment of cardiovascular complications is crucial for the successful management of acromegaly.

Acromegaly and Cancer: An Update.

Acromegaly is a chronic and rare disease. The diagnosis usually takes several years. Multiple comorbidities are associated with acromegaly. Long-term exposure to growth factors may lead to complications such as the development of benign or malignant tumors. However, the association between acromegaly and cancer remains a matter of debate due to multiple limitations in epidemiological data. There is controversy between acromegaly and mortality, but evidence shows a significant improvement in mortality rates with disease control and careful management of comorbidities. Older age, increased growth hormone levels (GH) at last follow-up, higher insulin-like growth factor-1 (IGF-1) levels at diagnosis, malignancy and radiotherapy were proposed as independent predictors of mortality. In this review we summarize the current state of knowledge in this field. Incidence of different cancer types is described. Rigorous surveillance of endocrine diseases may contribute to increased tumor detection. Personalized screening should probably be recommended.

Interpreting growth hormone and IGF-I results using modern assays and reference ranges for the monitoring of treatment effectiveness in acromegaly.

Standard treatment for acromegaly focuses on the achievement of target absolute levels of growth hormone (GH) and insulin-like growth factor (IGF-I). The appropriateness of these targets when measured using modern assay methods is not well defined. This paper reviews biochemical status assessed using methods available at the time and associated clinical outcomes. GH measurements were shown to provide an indication of changes in tumor size, and failure of GH suppression after glucose stimulation is associated with tumor recurrence. IGF-I levels were more closely associated with changes in symptoms and signs. Reduced GH and IGF-I concentrations were shown to be associated with increased longevity, although the degree of increase has only been analyzed for GH. Lowering of GH and IGF-I has consistently been associated with improved outcomes; however, absolute levels reported in previous studies were based on results from methods and reference ranges that are now obsolete. Applying previously described absolute thresholds as targets (e.g. "normal" IGF-I level) when using current methods is best applied to those with active acromegaly symptoms who could benefit from further lowering of biochemical markers. In asymptomatic individuals with mild IGF-I or GH elevations, targeting biochemical "normalization" would result in the need for combination pharmacotherapy in many patients without proven benefit. Measurement of both GH and IGF-I remains an essential component of diagnosis and monitoring the effectiveness of treatment in acromegaly; however, treatment goals based only on previously identified absolute thresholds are not appropriate without taking into account the assay and reference ranges being employed. Treatment goals should be individualized considering biochemical improvement from an untreated baseline, symptoms of disease, risks, burdens and costs of complex treatment regimens, comorbidities, and quality of life.

Multiomics Approach to Acromegaly: Unveiling Translational Insights for Precision Medicine.

The clinical characteristics and prognoses of acromegaly vary among patients. Assessment of current and novel predictors can lead to multilevel categorization of patients, allowing integration into new clinical guidelines and a reduction in the increased morbidity and mortality associated with acromegaly. Despite advances in the diagnosis and treatment of acromegaly, its pathophysiology remains unclear. Recent advancements in multiomics technologies, including genomics, transcriptomics, proteomics, metabolomics, and radiomics, have offered new opportunities to unravel the complex pathophysiology of acromegaly. This review comprehensively explores the emerging role of multiomics approaches in elucidating the molecular landscape of acromegaly. We discuss the potential implications of multiomics data integration in the development of novel diagnostic tools, identification of therapeutic targets, and the prospects of precision medicine in acromegaly management. By integrating diverse omics datasets, these approaches can provide valuable insights into disease mechanisms, facilitate the identification of diagnostic biomarkers, and identify potential therapeutic targets for precision medicine in the management of acromegaly.

Practical therapeutic approach in the management of diabetes mellitus secondary to Cushing's syndrome, acromegaly and neuroendocrine tumours.

Cushing's syndrome, acromegaly and neuroendocrine disorders are characterized by an excess of counterregulatory hormones, able to induce insulin resistance and glucose metabolism disorders at variable degrees and requiring immediate treatment, until patients are ready to undergo surgery. This review focuses on the management of diabetes mellitus in endocrine disorders related to an excess of counterregulatory hormones. Currently, the landscape of approved agents for treatment of diabetes is dynamic and is mainly patient-centred and not glycaemia-centred. In addition, personalized medicine is more and more required to provide a precise approach to the patient's disease. For this reason, we aimed to define a practical therapeutic algorithm for management of diabetes mellitus in patients with glucagonoma, pheochromocytoma, Cushing's syndrome and acromegaly, based on our practical experience and on the physiopathology of the specific endocrine disease taken into account. This document is addressed to all specialists who approach patients with diabetes mellitus secondary to endocrine disorders characterized by an excess of counterregulatory hormones, in order to take better care of these patients. Care and control of diabetes mellitus should be one of the primary goals in patients with an excess of counterregulatory hormones requiring immediate and aggressive treatment.

Position statement on the diagnosis and management of acromegaly: The French National Diagnosis and Treatment Protocol (NDTP).

Acromegaly is a rare disease with prevalence of approximately 60 cases per million, slight female predominance and peak onset in adults in the fourth decade. Clinical diagnosis is often delayed by several years due to the slowly progressive onset of symptoms. There are multiple clinical criteria that define acromegaly: dysmorphic syndrome of insidious onset, symptoms related to the pituitary tumor (headaches, visual disorders), general signs (sweating, carpal tunnel syndrome, joint pain, etc.), complications of the disease (musculoskeletal, cardiovascular, pneumological, dental, metabolic comorbidities, thyroid nodules, colonic polyps, etc.) or sometimes clinical signs of associated prolactin hypersecretion (erectile dysfunction in men or cycle disorder in women) or concomitant mass-induced hypopituitarism (fatigue and other symptoms related to pituitary hormone deficiencies). Biological confirmation is based initially on elevated IGF-I and lack of GH suppression on oral glucose tolerance test or an elevated mean GH on repeated measurements. In confirmed cases, imaging by pituitary MRI identifies the causal tumor, to best determine management. In a minority of cases, acromegaly can be linked to a genetic predisposition, especially when it occurs at a young age or in a familial context. The first-line treatment is most often surgical removal of the somatotroph pituitary tumor, either immediately or after transient medical treatment. Medical treatments are most often proposed in patients not controlled by surgical removal. Conformal or stereotactic radiotherapy may be discussed on a case-by-case basis, especially in case of drug inefficacy or poor tolerance. Acromegaly should be managed by a multidisciplinary team, preferably within an expert center such as a reference or skill center for rare pituitary diseases.