Growth Hormone Receptor Antagonist Pegvisomant Research Articles

The Genetic Pathophysiology and Clinical Management of the TADopathy, X-Linked Acrogigantism.

Pituitary gigantism is a rare manifestation of chronic growth hormone (GH) excess that begins before closure of the growth plates. Nearly half of pituitary gigantism patients 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 (GHRH) 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 (GPCR), GPR101. This leads to the formation of a neoTAD in which GPR101 over-expression is driven by ectopic enhancers ("TADopathy"). X-LAG has been seen in three 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 (IGF-1) and prolactin hypersecretion and physical overgrowth can be controlled before definitive adult gigantism occurs, often at the cost of permanent hypopituitarism.

Long-term Pegvisomant Therapy of Acromegaly: Effects on Bone Density, Turnover and Microstructure Using HRpQCT.

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.

Diabetes mellitus in acromegaly: prevalence, pathophysiological particulars and treatment strategies

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.

Octreotide-Resistant Acromegaly: Challenges and Solutions.

Acromegaly is a rare and severe disease caused by an increased and autonomous secretion of growth hormone (GH), thus resulting in high circulating levels of insulin-like growth factor 1 (IGF-1). Comorbidities and mortality rate are closely related to the disease duration. However, in most cases achieving biochemical control means reducing or even normalizing mortality and restoring normal life expectancy. Current treatment for acromegaly includes neurosurgery, radiotherapy and medical therapy. Transsphenoidal surgery often represents the recommended first-line treatment. First-generation somatostatin receptor ligands (SRLs) are the drug of choice in patients with persistent disease after surgery and are suggested as first-line treatment for those ineligible for surgery. However, only about half of patients treated with octreotide (or lanreotide) achieve biochemical control. Other available drugs approved for clinical use are the second-generation SRL pasireotide, the dopamine agonist cabergoline, and the GH-receptor antagonist pegvisomant. In the present paper, we revised the current literature about the management of acromegaly, aiming to highlight the most relevant and recent therapeutic strategies proposed for patients resistant to first-line medical therapy. Furthermore, we discussed the potential molecular mechanisms involved in the variable response to first-generation SRLs. Due to the availability of different medical therapies, the choice for the most appropriate drug can be currently based also on the peculiar clinical characteristics of each patient.

Long-term safety and treatment outcomes of pegvisomant in Japanese patients with acromegaly: results from the post-marketing surveillance.

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.

SUN-LB080 ACROSTUDY - Safety and Efficacy of a Cohort of 110 Naïve Patients with Acromegaly Treated with Pegvisomant

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.

SUN-LB079 Acrostudy - Safety And Treatment Outcomes In 2221 Patients With Acromegaly Treated With Pegvisomant: Real World Experience

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.

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

Acromegaly is a rare disease. Medical management with somatostatin analogs and the growth hormone receptor antagonist pegvisomant can normalize insulin-like growth factor-1 (IGF1) levels after failed surgery and decrease mortality and comorbidities. We present a case report of a patient with acromegaly on chronic hemodialysis resistant to first-generation, long-acting somatostatin analogs with remarkable response to pasireotide long-acting release (PAS-LAR). A 66-year-old woman with acromegaly and chronic renal failure on hemodialysis resistant to lanreo-tide autogel (at 120 mg) was treated successfully with PAS-LAR. Acromegaly was diagnosed in 1996 and transsphenoidal resection of macroadenoma was performed with normalization of IGF1 levels. Nine years later, recurrence of the tumor led to a second operation. Lanreotide autogel was initiated due to persistently high levels of IGF1, but the patient was resistant to treatment. A positive response was observed with pegvisomant. However, the patient was nonadherent and treatment was discontinued. PAS-LAR was initiated and normalization of IGF1 and growth hormone was achieved. This is the first case report of a patient with acromegaly on chronic hemodialysis who was resistant to first-generation, long-acting somatostatin analogs and successfully treated with PAS-LAR.

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

The GH-receptor antagonist pegvisomant (PEG) reduces peripheral IGF-1 synthesis and is used to treat acromegaly patients resistant or intolerant to somatostatin analogues (SSA). Medical therapy is generally life-long in patients with acromegaly, since disease remission is very uncommon after SSA discontinuation and has never been reported after PEG withdrawal. Here, we report for the first time the cases of two acromegaly patients treated with PEG monotherapy for many years because of resistance to SSA, who persistently maintained normal serum IGF-1 levels after PEG withdrawal. The first patient autonomously discontinued PEG treatment after 8 years, while in the second case we stopped the treatment after 11 years, because slight hypertransaminasemia occurred. After PEG discontinuation, in both cases IGF-1 values remained persistently normal and GH during OGTT regularly suppressed. To date, both patients are still in remission. Therefore, we suggest that PEG could exert unknown antitumoral effects in pituitary tumor cells and that long-term PEG treatment can induce acromegaly remission in some patients.

Increasing frequency of combination medical therapy in the treatment of acromegaly with the GH receptor antagonist pegvisomant.

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.

Androgen Receptor Regulation of Local Growth Hormone in Prostate Cancer Cells.

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.

Cabergoline in acromegaly

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.

Somatostatin Receptor Expression in GH-Secreting Pituitary Adenomas Treated with Long-Acting Somatostatin Analogues in Combination with Pegvisomant

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.

Impact of the GH-receptor antagonist pegvisomant on mammographic breast density in postmenopausal acromegalic women

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

Acromegaly.

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.

Long-term treatment with pegvisomant for acromegaly: a 10-year experience.

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.

Pegvisomant in combination with long-acting somatostatin analogues in acromegaly: the role of the GH receptor deletion of exon 3.

Doses of the GH receptor (GHR) antagonist pegvisomant (PEGV) that normalize insulin-like growth factor 1 (IGF1) levels vary widely among acromegaly patients. Predictors for PEGV response are baseline IGF1 levels, sex, body weight and previous radiotherapy. A GHR polymorphism lacking exon 3 (d3-GHR) is frequent in the general population. The influence of d3-GHR on PEGV responsiveness in acromegaly is unclear. To assess the influence of d3-GHR on IGF1 levels and PEGV responsiveness in acromegaly patients using combined PEGV and long-acting somatostatin receptor ligand (LA-SRIF) treatment. Data were collected at the Rotterdam Pituitary Centre between 2004 and 2013. Patients with elevated IGF1 levels (>1.2 upper limit of normal; n=112) and over 6 months of high-dose LA-SRIF treatment were co-treated with PEGV. GHR genotype was assessed using genomic DNA in 104 patients. D3-GHR was observed in 51 (49.0%) of the patients (7.7% homozygous, 41.3% heterozygous) and was in Hardy-Weinberg equilibrium (P=0.859). Baseline characteristics were similar in d3-GHR and full-length (fl)-GHR genotypes. During PEGV/LA-SRIF treatment IGF1 levels were not different between d3-carriers and non-carriers. Similarly, no difference in PEGV dose required to normalize IGF1 (P=0.337) or PEGV serum levels (P=0.433) was observed between the two groups. However, adenoma size decreased significantly (>20% of largest diameter) in 25.6% of the fl-GHR genotype but only in 7.5% of d3-carriers (P=0.034, OR: 4.6 (CI: 1.1-18.9)). GHR genotype does not predict the IGF1 normalizing dose of PEGV in acromegaly patients using combination PEGV/LA-SRIF treatment. However, fewer d3-carriers showed significant reductions in adenoma size.

Does pegvisomant treatment expertise improve control of resistant acromegaly? The Italian ACROSTUDY experience.

GH receptor antagonist pegvisomant is indicated for treatment of patients with resistant acromegaly. We compared safety and treatment outcomes of pegvisomant therapy in patients managed by Italian centers enrolling less or more than 15 cases in ACROSTUDY, a safety surveillance study of long-term pegvisomant treatment of patients with acromegaly. A noninterventional safety surveillance study in which safety and treatment outcomes of pegvisomant were evaluated on the basis of data collected during a 7-year period. A total of 204 acromegaly patients treated by seven centers enrolling 16-49 patients each (group A) and 137 subjects by 18 centers following 3-14 cases ( group B). Patients of group A and B were treated for 4.4±2.7 and 4.2±2.2years, respectively. IGF-1 ULN normalized in 64.4% (n=56) and 54.4% (n=31) in group A and B, respectively, after 1-year treatment, and in 57.3% (n=106) and 72.5% (n=87) at last visit. Starting doses were significantly higher in group A. They were progressively increased during treatment in both groups, but were higher in uncontrolled patients than in controlled ones only in group A. Reported adverse events were more frequent, and the prevalence of patients with adverse events was higher in group B. On the basis of this original study approach, we could speculate that in the centers in which more patients are treated with pegvisomant, less adverse events are reported, but the long-term effectiveness is lower than in centers with less cases, perhaps because of an inadequate patient's selection.

Diagnosis and Management of Acromegaly in 2014 (Update from 2012)

In this update to the 2012 summary, the current diagnostic and therapeutic approaches to acromegaly are reviewed. The goals of therapy are to control excess growth hormone (GH) secretion and tumor growth, and to limit, if not reverse, the long-term medical consequences and risk for premature mortality associated with acromegaly. Surgery is the preferred primary therapeutic option because it can lead to rapid reductions in GH levels and prevent mass effects from local tumor growth. Use of a somatostatin receptor ligand (SRL) preoperatively to improve surgical outcomes has not been substantiated. Medical therapy, including SRLs, dopamine agonists, and the GH receptor antagonist pegvisomant, is used most often in an adjuvant, secondary role for patients in whom surgery has been unsuccessful. Radiation therapy is most commonly recommended in the setting of failed surgery and lack of adequate control with medical therapy. A role of primary medical therapy forde novopatients has been proposed, particularly with SRLs. Using a multimodality approach, successful management of the disease and associated consequences should be achieved in the majority of subjects.