Acromegaly and gigantism are rare neuroendocrine diseases caused by excessive secretion of growth hormone (GH) and/ or high levels of insulin-like growth factor (IGF-1). Gigantism develops when excess GH or IGF-1 leads to accelerated linear growth before the completion of puberty and the closure of the epiphyses, most commonly caused by a somatotropic pituitary adenoma. The diagnosis of somatotropinoma in childhood is particularly challenging due to its subtle and nonspecific clinical presentation. Somatotropinomas at a young age are more often caused by genetic abnormalities and have a more aggressive course. The article presents a clinical case of acrogigantism in a patient with two identified heterozygous variants in the PRKAR1A and SDHB genes. The scientific interest of the described observation is due to the debut of gigantism in childhood, complex pathogenetic treatment, as well as the experience of using the growth hormone receptor antagonist pegvisomant in a teenager in Russia.

Ghrelin acts via the growth hormone secretagogue receptor (GHSR) and increases both food intake and growth hormone (GH) secretion. Studies in mice with genetic manipulations of GH receptor (GHR) revealed that GH action is required for ghrelin's orexigenic effects. However, the biological basis of this interdependence remains unclear. Here, we studied the mechanisms by which GHR contributes to ghrelin-induced hyperphagia in male mice. Transcriptomic analyses of single-cell datasets revealed that Ghr and Ghsr are co-expressed in a small subset of neurons, particularly within the hypothalamic arcuate nucleus (ARH). Systemic ghrelin administration increased food intake, circulating GH, and glycemia but did not induce GHR activation in the brain, as indicated by the absence of pSTAT5 immunoreactivity. Central GH administration failed to enhance ghrelin-induced food intake or glycemia. To evaluate the role of peripheral GHR signaling, we treated mice with the brain-impermeable GHR antagonist pegvisomant. Systemically injected pegvisomant impaired ghrelin's orexigenic effect without affecting its impact on glycemia or hypothalamic c-Fos activation, indicating that peripheral GHR signaling is required for ghrelin-induced hyperphagia. Pegvisomant did not alter refeeding-induced or AgRP neuron-mediated hyperphagia, suggesting a selective blockade of ghrelin's action. Moreover, ghrelin-induced food intake was preserved in hepatocyte-specific GHR knockout mice, despite disrupted hepatic GH signaling. Thus, peripheral, non-hepatic GHR signaling is selectively required for the orexigenic effects of ghrelin. This work reveals a critical GH-dependent, liver-independent mechanism underlying ghrelin-driven feeding, with potential implications for the neuroendocrine regulation of appetite and for therapeutic strategies targeting the ghrelin-GH axis in metabolic diseases.

The 15th Acromegaly Consensus Conference in September 2023 updated recommendations on therapeutic outcomes for acromegaly. Since the publication of medical management guidelines in 2018, new pharmacological agents and new treatment approaches have been developed. Fifty-two experts in the management of acromegaly reviewed the current literature and assessed changes in drug approvals, clinical practice standards and management. Current outcome goals were considered, with a focus on the effect of current and emerging somatostatin receptor ligands, the growth hormone receptor antagonist pegvisomant and the dopamine agonist cabergoline on biochemical control, clinical control, adenoma mass and surgical outcomes. Participants assessed factors that determine pharmacological choices, as well as the proposed use of each agent. Here, we present consensus recommendations highlighting how an evidence-based acromegaly management algorithm could be optimized in clinical practice.

Pituitary gigantism is a rare manifestation of chronic growth hormone (GH) excess that begins before closure of the growth plates. Nearly half of patients with pituitary gigantism have an identifiable genetic cause. X-linked acrogigantism (X-LAG; 10% of pituitary gigantism) typically begins during infancy and can lead to the tallest individuals described. In the 10 years since its discovery, about 40 patients have been identified. Patients with X-LAG usually develop mixed GH and prolactin macroadenomas with occasional hyperplasia that secrete copious amounts of GH, and frequently prolactin. Circulating GH-releasing hormone is also elevated in a proportion of patients. X-LAG is caused by constitutive or sporadic mosaic duplications at chromosome Xq26.3 that disrupt the normal chromatin architecture of a topologically associating domain (TAD) around the orphan G-protein-coupled receptor, GPR101. This leads to the formation of a neo-TAD in which GPR101 overexpression is driven by ectopic enhancers ("TADopathy"). X-LAG has been seen in 3 families due to transmission of the duplication from affected mothers to sons. GPR101 is a constitutively active receptor with an unknown natural ligand that signals via multiple G proteins and protein kinases A and C to promote GH/prolactin hypersecretion. Treatment of X-LAG is challenging due to the young patient population and resistance to somatostatin analogs; the GH receptor antagonist pegvisomant is often an effective option. GH, insulin-like growth factor 1, and prolactin hypersecretion and physical overgrowth can be controlled before definitive adult gigantism occurs, often at the cost of permanent hypopituitarism.

Fracture rate is increased in patients with active acromegaly and those in remission. Abnormalities of bone microstructure are present in patients with active disease and persist despite biochemical control after surgery. Effects of treatment with the GH receptor antagonist pegvisomant on bone microstructure were unknown. We studied 25 patients with acromegaly (15 men, 10 women). In 20, we evaluated areal bone mineral density (BMD) by dual-energy X-ray absorptiometry and bone turnover markers (BTMs) longitudinally, before and during pegvisomant treatment. After long-term pegvisomant in 17, we cross-sectionally assessed volumetric BMD, microarchitecture, stiffness, and failure load of the distal radius and tibia using high-resolution peripheral quantitative computed tomography (HRpQCT) and compared these results to those of healthy controls and 2 comparison groups of nonpegvisomant-treated acromegaly patients, remission, and active disease, matched for other therapies and characteristics. In the longitudinal study, areal BMD improved at the lumbar spine but decreased at the hip in men after a median ∼7 years of pegvisomant. In the cross-sectional study, patients on a median ∼9 years of pegvisomant had significantly larger bones, lower trabecular and cortical volumetric density, and disrupted trabecular microarchitecture compared to healthy controls. Microstructure was similar in the pegvisomant and acromegaly comparison groups. BTMs were lowered, then stable over time. In this, the first study to examine bone microstructure in pegvisomant-treated acromegaly, we found deficits in volumetric BMD and microarchitecture of the peripheral skeleton. BTM levels remained stable with long-term therapy. Deficits in bone quality identified by HRpQCT may play a role in the pathogenesis of fragility in treated acromegaly.

The term 'fugitive acromegaly' was introduced by the neurosurgeons Bailey and Cushing in 1928 to describe subjects manifesting signs and symptoms of somatotroph hyperfunction with pituitary insufficiency. Currently, it identifies patients with subtle acromegalic dysmorphisms and inconsistent hormonal profile, possibly presenting only with hyperprolactinemia and related clinical symptoms. Patients have rapidly growing, locally invasive, relapsing pituitary macrotumors that can be classified as either acidophil stem cell tumors (ASCTs) or sparsely granulated somatotroph tumors (SGSTs), both of PIT1-lineage. ASCTs also express estrogen receptor (ER)α, show predominant prolactin (PRL) release, and less abundantly, growth hormone (GH). In contrast, SGSTs have moderately increased GH and IGF1 levels, but rarely PRL increase. ASCTs often present resistance to dopamine agonists, and long-acting somatostatin analogs are used. In contrast, SGSTs are often resistant to somatostatin analogues and instead are treated with the GH receptor antagonist pegvisomant. Differential diagnosis includes mammosomatotroph, mixed GH-/PRL-secreting, immature PIT1-lineage, and densely granulated somatotroph tumors. Studies in ER-sensitive rat tumoral mammosomatotroph cells (GH3, GH4C1) suggest that overexpression of chaperones in immature PIT1-/ER-expressing progenitors induces posttranscriptional conformational changes to tumor suppressors of the ERα and aryl hydrocarbon receptor pathways, like AIP, leading to the development of aggressive pituitary tumors like those causing fugitive acromegaly.

The prevalence of diabetes mellitus in acromegaly is significantly higher than that in the general population. Carbohydrate metabolism abnormalities often precede other phenotypic manifestations of acromegaly. The review presents data on the prevalence of carbohydrate metabolism disorders in acromegaly and describes their pathophysiological characteristics and approaches to treatment.
 Growth hormone (GH) excess is recognized as a key factor of glucose homeostasis abnormalities due to decreased insulin sensitivity (resulting from active lipolysis) and direct stimulation of insulin secretion. Insulin-like growth factor 1 (IGF1) improves insulin sensitivity; however, the GH diabetogenic effects prevail over the insulin-sensitizing impact of IGF1. Surgical and radiation treatment for somatotropinoma may indirectly improve carbohydrate metabolism, because they decrease the GH levels. Treatment with first generation somatostatin analogues can both improve glycemic control due to decreased GH levels and worsen it due to deterioration of postprandial insulin release, especially in patients with already manifest carbohydrate metabolism disorders. The GH receptor antagonist pegvisomant blocks the effects of excess GH on the target tissues without suppressing insulin secretion, which results in better glucose control; treatment with this agent can be preferred in patients with acromegaly and diabetes mellitus. Management of carbohydrate metabolism disorders in acromegaly is done in accordance with general treatment principles for type 2 diabetes mellitus.

This post-marketing surveillance is to investigate the long-term safety and effectiveness of the growth hormone receptor antagonist pegvisomant, which is used in patients with acromegaly in routine clinical practice. This surveillance included all cases treated with pegvisomant during the study period from the start of marketing (June 5, 2007) to December 2015. Data for 251 patients with acromegaly treated with pegvisomant were collected from 119 institutions nationwide in Japan. Eighty-five patients received pegvisomant monotherapy throughout their treatment, while 165 patients were treated with somatostatin analogue or dopamine agonist in combination with pegvisomant. Mean dose of pegvisomant was 10.6 ± 6.1 mg/day in the entire treatment period (except for initial loading dose). The incidence of adverse drug reactions was 35.6% (89/250). No new safety concerns related to long-term treatment were observed. The major investigation items of incidence of abnormal liver function and tumor enlargement were 16.0% (40/250), and 5.2% (13/250) respectively. Efficacy at the final evaluation point was 96.4% (217/225) based on the overall clinical judgement of attending physicians, and efficacy in each observation period was over 94%. Improvement in IGF-I levels and clinical symptoms scores were also observed by comparing the data at baseline with each observation point during treatment. IGF-I normalization rate was 68.2% at 5 years. Pegvisomant monotherapy showed similar improvement here as well. These results suggest that long-term treatment with pegvisomant is effective in clinical practice.

Background: ACROSTUDY is an open-label, non-interventional post-authorization safety study that began in 2004 to evaluate safety in at least 1000 acromegaly patients treated with the GH receptor antagonist pegvisomant (PEGV). This commitment was fulfilled in Jan 2013. ACROSTUDY was later amended to enroll an additional 110 patients that were naïve/semi-naive to PEGV treatment. Semi-naïve patients are defined as not having received PEGV therapy for at least 6 months prior to enrollment. Objectives: The primary objectives were to: 1) assess the long-term safety of PEGV in real world practice; 2) assess the effect of IGF-I normalization on treatment outcomes, including safety, glucose control and patient-reported outcomes (PROs). Patients & Methods: 110 patients with Acromegaly 53.6% male, 81.8% Caucasian, median age 42.4 years at diagnosis; median age 48.9 years at PEGV start. Patients were considered ‘IGF-I Controlled’ if the most temporally-related IGF-I measurement was normal for that laboratory. Safety data including adverse events and liver tests were collected. IGF-I and HbA1C were measured; PROs were evaluated using the Acromegaly Quality of Life Questionnaire (AcroQoL) and PatientAssessed Acromegaly Symptom Questionnaire (PASQ), stratified by IGF-I control. Results: No new safety signals were identified in this sub-study. IGF-I SDS >2 decreased from 87% of patients at baseline to 31% at year 2 at a mean dose(±SD) of 10.4(±7.45) mg/day; patients with IGF-I SDS <2 had a mean dose of 14.8(±6.7). Among IGF-I controlled patients, median (range) HbA1C levels were 5.8% (5.4-6.1) at baseline and 5.6% (4.5-7.2) at year 2; in IGF-I uncontrolled patients, HbA1C was 6.1% (4.9-6.6) at baseline and 6.3% (2.9-10.6) at year 2. Among IGF-I controlled patients, median (range) global AcroQoL scores were 54.6 (24-73) at baseline and 61.4 (13-86) at year 2; while in IGF-I uncontrolled patients, median global AcroQoL score was 59.7 (8-92) at baseline and 63.6 (25-76) at year 2. Among IGF-I controlled patients, median (range) total PASQ score was 20 (3-38) at baseline and 17.5 (1-40) at year 2; in IGF-I uncontrolled patients, median total PASQ score was 17 (0-44) at baseline and 14 (3-39) at year 2. A greater number of the six individual symptoms of the PASQ score showed a positive trend for improvement from baseline to year 2 in the IGF-I controlled patients than in the uncontrolled patients. Summary: In this real-life world international study, overall biochemical control (i.e. normal IGF-I) was achieved with pegvisomant in 64.3% patients by year 2. Improved IGF-I control was associated with improved HbA1C, QoL and symptoms of acromegaly. One limitation of the study was that the PEGV dose may not have been adequately titrated to achieve IGF-I normalization. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

ACROSTUDY is an open-label, non-interventional post-authorization safety study (PASS) that began in 2004 to evaluate safety in at least 1000 acromegaly patients treated for 5 years with the GH receptor antagonist pegvisomant (PEGV). This commitment was fulfilled in 2013 but ACROSTUDY was extended as a voluntary PASS, ultimately collecting data on 2221 patients who were followed through Dec 2017. Objectives: To monitor the long-term safety of PEGV including the pituitary tumor volume, as prescribed in clinical practice. Patients & Methods: 50.8% were male, 92.4% Caucasian with median age 41.1 years (1.7-83.7) at diagnosis and median age 49.7 years (3.9-85.6) at start of PEGV. Mean duration of PEGV treatment was 9.3 years (0.0-20.8); 80.8% of patients started PEGV on a daily schedule and patients came from fifteen countries. Safety data included adverse events, change in tumor volume and liver tests. Efficacy was measured by IGF-I control (Patients were considered ‘IGF-I Controlled’ if the most temporally-related IGF-I measurement was normal for the local reference laboratory). Patient-reported outcomes (PROs) were evaluated using the PatientAssessed Acromegaly Symptom Questionnaire (PASQ). Results: No new safety signals were identified in the study. IGF-I SDS >2 decreased progressively from 88.4% of patients at baseline to 34.8% at year 5 at a mean dose(±SD) of 19.2(±12.9) mg/day; 63.3% of patients with a documented normal IGF-I SDS had a mean dose of 16.2(±9.03), while 1.9% had IGF-I SDS < -2 at a mean dose of 16.5(±5.81). 1795 Patients had at least 1 local pituitary imaging result reported: 71.1% of patients reported no change, 17.3% reported a decrease and 7.1% reported an increase in tumor size while 4.5% reported both an increase and a decrease. Scans reported as showing a meaningful change in tumor volume (n=264) were re-evaluated centrally by an independent expert: 54 were corroborated enlarged, 84 were decreased, 12 were read as both increased and decreased, 23 were read as no change and 40 inconclusive; thus the overall incidence of (corroborated) tumor increases was 3.0% and decreases 4.7%. In the overall cohort, AST and/or ALT were >3 × ULN at any time during PEGV treatment in 3.2% of patients. PASQ score was 15 (0-46) at baseline and 10 (0-41) at year 8. Summary: In this real world international study, overall biochemical control (i.e. normal IGF-I) progressively improved with pegvisomant, and was achieved in 63.3% patients by year 5. Improved IGF-I control was associated with improved symptoms of acromegaly. Importantly, in this large cohort of patients the incidence of pituitary tumor increase and liver test elevations were low, and similar to previously reported rates. One limitation of this observational study was that the PEGV dose may not have been adequately titrated to achieve IGF-I normalization. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Acromegaly is characterized by increased release of growth hormone and, consequently, insulin-like growth factor I (IGF1), most often by a pituitary adenoma. Prolonged exposure to excess hormone leads to progressive somatic disfigurement and a wide range of systemic manifestations that are associated with increased mortality. Although considered a rare disease, recent studies have reported an increased incidence of acromegaly owing to better disease awareness, improved diagnostic tools and perhaps a real increase in prevalence. Acromegaly treatment approaches, which include surgery, radiotherapy and medical therapy, have changed considerably over time owing to improved surgical procedures, development of new radiotherapy techniques and availability of new medical therapies. The optimal use of these treatments will reduce mortality in patients with acromegaly to levels in the general population. Medical therapy is currently an important treatment option and can even be the first-line treatment in patients with acromegaly who will not benefit from or are not suitable for first-line neurosurgical treatment. Pharmacological treatments include somatostatin receptor ligands (such as octreotide, lanreotide and pasireotide), dopamine agonists and the growth hormone receptor antagonist pegvisomant. In this Primer, we review the main aspects of acromegaly, including scientific advances that underlie expanding knowledge of disease pathogenesis, improvements in disease management and new medical therapies that are available and in development to improve disease control.

Pasireotide for a Patient with Acromegaly and Chronic Kidney Disease on Hemodialysis

First report on persistent remission of acromegaly after withdrawal of long-term pegvisomant monotherapy

Pegvisomant monotherapy is effective and safe in treatment of acromegaly. However, some clinicians combine pegvisomant with somatostatin analogues (SSA) or dopamine agonist (DA). In this analysis of ACROSTUDY, a long-term non-interventional study, the use of combination regimens was evaluated. Based on their baseline treatment, 2043 patients were retrospectively categorized as: long-acting SSA combined with pegvisomant, ‘Combo SSA’ 768 patients (38%); DA combined with pegvisomant, ‘Combo DA’ 123 (6%); pegvisomant monotherapy, ‘Peg mono’ 1128 (55%). Treatment patterns changed over the 10-year period, with recent patients more likely to receive any combination (20% in 2003 vs 54% in 2012). Combo SSA use varied widely among countries from 22% to 78%. Exposure periods of the three treatment modalities were defined from pegvisomant start until the last visit in ACROSTUDY; patients could switch treatment categories. At year 4, IGF-I was normal in 62% of Combo SSA, 63% of Combo DA and 65% of Peg mono groups. Pegvisomant was initiated as daily injections in 94% of patients in the Peg mono group, 66% of Combo SSA and 91% of Combo DA patients. During 6169 years of treatment exposure, 3424 adverse events (AEs) were reported in 946 (51%) patients, of which 617 (18%) were serious and 401 (12%) were considered treatment related. The reported incidence of serious AEs and treatment-related non-serious AEs were similar among the three treatment modalities. This analysis describes real-world clinical care and shows favorable efficacy and safety for Peg mono and combinations. Novel findings include an increased use of combination therapy over time and variability in treatment modalities between countries.

Prostate cancer (PCa) growth is mainly driven by androgen receptor (AR), and tumors that initially respond to androgen deprivation therapy (ADT) or AR inhibition usually relapse into a more aggressive, castration-resistant PCa (CRPC) stage. Circulating growth hormone (GH) has a permissive role in PCa development in animal models and in human PCa xenograft growth. As GH and GH receptor (GHR) are both expressed in PCa cells, we assessed whether prostatic GH production is linked to AR activity and whether GH contributes to the castration-resistant phenotype. Using online datasets, we found that GH is highly expressed in human CRPC. We observed increased GH expression in castration-resistant C4-2 compared with castration-sensitive LNCaP cells as well as in enzalutamide (MDV3100)-resistant (MDVR) C4-2B (C4-2B MDVR) cells compared with parental C4-2B. We describe a negative regulation of locally produced GH by androgens/AR in PCa cells following treatment with AR agonists (R1881) and antagonists (enzalutamide, bicalutamide). We also show that GH enhances invasive behavior of CRPC 22Rv1 cells, as reflected by increased migration, invasion, and anchorage-independent growth, as well as expression of matrix metalloproteases. Moreover, GH induces expression of the AR splice variant 7, which correlates with antiandrogen resistance, and also induces insulinlike growth factor 1, which is implicated in PCa progression and ligand-independent AR activation. In contrast, blockade of GH action with the GHR antagonist pegvisomant reverses these effects both in vitro and in vivo. GH induction following ADT or AR inhibition may contribute to CRPC progression by bypassing androgen growth requirements.

Acromegaly, a rare disease due to growth hormone (GH) hypersecretion by a pituitary adenoma, is associated with severe comorbidity and premature death if not adequately treated. The usual first-line treatment is surgery. Various drugs, including somatostatin receptor ligands, dopamine agonists and GH receptor antagonists, are now available for use if surgery fails to suppress GH/IGF-I hypersecretion. Cabergoline, now the preferred dopamine agonist for treating hyperprolactinemia, is also used off-label for treating acromegaly. Cabergoline monotherapy is reported to normalize IGF-I levels in more than one-third of patients with acromegaly. When a somatostatin receptor ligand proves ineffective, cabergoline add-on therapy normalizes the IGF-I level in 40-50% of patients. Finally, when combined with the GH receptor antagonist pegvisomant in patients with mild uncontrolled disease, cabergoline helps to achieve normal IGF-I levels while avoiding the need for high-dose pegvisomant. Cabergoline is also inexpensive and well tolerated; in particular, it does not appear to promote heart valve disease.

Background: Growth hormone-secreting pituitary adenomas (somatotroph adenoma) predominantly express somatostatin receptors (SSTRs) subtypes 2 and 5. Higher SSTR2 expression on somatotroph adenomas results in a better response to somatostatin analogues (SSAs), which preferentially bind, but also downregulate, SSTR2. The effect of the combined treatment with SSAs and the GH receptor antagonist pegvisomant (PEGV) on SSTR expression in somatotroph adenomas is currently unknown. Aim of the Study: To assess SSTR2 and SSTR5 expression in three groups of somatotroph adenomas: drug-naive, treated with long-acting (LA) SSA monotherapy, or LA-SSA/PEGV combination therapy before surgery. Additionally, we evaluated the required PEGV dose to achieve insulin-like growth factor I (IGF-I) normalization in relation to the SSTR expression. Materials and Methods: At our Pituitary Center Rotterdam, we selected acromegalic patients who underwent transsphenoidal neurosurgery. All patients were eventually treated with LA-SSA/PEGV combination therapy during their medical history. SSTR2 and SSTR5 expression in somatotroph adenoma tissues was determined using immunohistochemistry. Results: Out of 39 somatotroph adenoma tissue samples, 23 were drug-naive, 9 received pretreatment with LA-SSA and 7 LA-SSA/PEGV combined treatment. SSTR2 expression was significantly higher in treatment-naive compared to combined treatment somatotroph adenomas (p = 0.048), while SSTR5 expression did not differ. Noteworthy, SSTR2 expression in naive somatotroph adenoma tissues was inversely correlated with the required PEGV dose to achieve IGF-I normalization during postsurgical medical treatment (ρ = -0.538, p = 0.024). Conclusion: In our specific cohort, the SSTR2 expression was lower in patients pretreated with LA-SSA/PEGV compared to the drug-naive acromegalic patients. Additionally, the SSTR2 expression in treatment-naive somatotroph adenoma tissues was inversely correlated with the required PEGV dose to achieve IGF-I normalization.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Acromegaly is a rare, chronic, progressive disease characterized by an excess secretion of growth hormone (GH) and increased circulating insulin-like growth factor 1 (IGF-1) concentrations. It is caused by a pituitary adenoma in the vast majority of cases. The clinical diagnosis, based on symptoms related to GH excess, is often delayed due to the insidious nature of the disease. Consequently, patients often have established systemic complications at diagnosis with increased morbidity and premature mortality. Serum IGF-1 measurement is recommended as the initial screen for patients with suspected acromegaly. The gold standard diagnostic test remains the oral glucose tolerance test with concomitant GH measurement. Therapy for acromegaly is targeted at decreasing GH and IGF-1 levels, ameliorating patients' symptoms and decreasing any local compressive effects of the pituitary adenoma. The therapeutic options for acromegaly include surgery, medical therapies (such as dopamine agonists, somatostatin receptor agonists and the GH receptor antagonist pegvisomant) and radiotherapy. A multidisciplinary approach is recommended with often a requirement for combined treatment modalities. With disease control, associated morbidity and mortality can be reduced. The recently published evidence-based guidelines by the Endocrine society addressed important clinical issues regarding the evaluation and management of acromegaly. This review discusses advances in our understanding of the pathophysiology of acromegaly, diagnosis of various forms of the disease and focuses on current treatment modalities, and on future pharmacological therapies for patients with acromegaly.

Efficacy of the GH-receptor antagonist pegvisomant (PEG) has differed between preclinical and observational studies mainly due to dose adjustment and IGF-I normalization criteria. An escape phenomenon has also been described, but its definition and underlying causes have not been fully established. To re-evaluate the outcomes of long-term PEG in a series of previously published patients and analyse the escape phenomenon. We reviewed all patients with acromegaly resistant to SSA in whom PEG was started as monotherapy, who had been included in a previous publication. We prospectively evaluated 64 (56·3% women) from six tertiary care referral hospitals in Spain, for whom data as of June 2014 were available. Escape to PEG was defined as confirmed loss of biochemical control (IGF-I >1·2xULN), after at least 6 months of previous control with a stable dose of PEG. Patients were followed up for 13·0 (5·9-34·8) years since diagnosis, and 9·0 (4·1-10·4) years since the first administration of PEG. Fifty-one (89·5%) patients had an adequate IGF-I control at the last follow-up visit, 9 of them without treatment. Tumour growth was reported in 6 of 64 cases (9·4%), none of whom had received prior radiotherapy (P = 0·011). Seven patients died during follow-up. We found 16 escapes in 10 patients (15·6%). We identified potential underlying causes in 9 cases (tumour regrowth, previous treatment modifications, concomitant menopause and change in testosterone administration). The reason was unknown in 7 escapes, which occurred in 6 patients (9·4%). All patients, except one, achieved subsequent biochemical control after treatment adjustment. We reassure the efficacy and safety of long-term PEG. An escape phenomenon may occur, but it can be overcome by adjusting therapy.