Acromegaly is a rare disorder caused by chronic growth hormone (GH) hypersecretion. While diagnostic and therapeutic methods have advanced, little information exists on trends in acromegaly characteristics over time. The Liège Acromegaly Survey (LAS) Database, a relational database, is designed to assess the profile of acromegaly patients at diagnosis and during long-term follow-up at multiple treatment centers. The following results were obtained at diagnosis. The study population consisted of 3173 acromegaly patients from ten countries; 54.5% were female. Males were significantly younger at diagnosis than females (43.5 vs 46.4 years; P < 0.001). The median delay from first symptoms to diagnosis was 2 years longer in females (P = 0.015). Ages at diagnosis and first symptoms increased significantly over time (P < 0.001). Tumors were larger in males than females (P < 0.001); tumor size and invasion were inversely related to patient age (P < 0.001). Random GH at diagnosis correlated with nadir GH levels during OGTT (P < 0.001). GH was inversely related to age in both sexes (P < 0.001). Diabetes mellitus was present in 27.5%, hypertension in 28.8%, sleep apnea syndrome in 25.5% and cardiac hypertrophy in 15.5%. Serious cardiovascular outcomes like stroke, heart failure and myocardial infarction were present in <5% at diagnosis. Erythrocyte levels were increased and correlated with IGF-1 values. Thyroid nodules were frequent (34.0%); 820 patients had colonoscopy at diagnosis and 13% had polyps. Osteoporosis was present at diagnosis in 12.3% and 0.6–4.4% had experienced a fracture. In conclusion, this study of >3100 patients is the largest international acromegaly database and shows clinically relevant trends in the characteristics of acromegaly at diagnosis.
Patrick Petrossians, Adrian F Daly, Emil Natchev, Luigi Maione, Karin Blijdorp, Mona Sahnoun-Fathallah, Renata Auriemma, Alpha M Diallo, Anna-Lena Hulting, Diego Ferone, Vaclav Hana Jr, Silvia Filipponi, Caroline Sievers, Claudia Nogueira, Carmen Fajardo-Montañana, Davide Carvalho, Vaclav Hana, Günter K Stalla, Marie-Lise Jaffrain-Réa, Brigitte Delemer, Annamaria Colao, Thierry Brue, Sebastian J C M M Neggers, Sabina Zacharieva, Philippe Chanson, and Albert Beckers
Elina Ritvonen, Eliisa Löyttyniemi, Pia Jaatinen, Tapani Ebeling, Leena Moilanen, Pirjo Nuutila, Ritva Kauppinen-Mäkelin, and Camilla Schalin-Jäntti
It is unclear whether mortality still is increased in acromegaly and whether there are gender-related differences. We dynamically assessed outcome during long-term follow-up in our nationwide cohort.
Patients and methods
We studied standardized mortality ratios (SMRs) relative to the general population and causes of death in acromegaly (n=333) compared with age- and gender-matched controls (n=4995).
During 20 (0–33) years follow-up, 113 (34%) patients (n=333, 52% women) and 1334 (27%) controls (n=4995) died (P=0.004). SMR (1.9, 95% CI: 1.53–2.34, P<0.001) and all-cause mortality (OR 1.6, 95% CI: 1.2–2.2, P<0.001) were increased in acromegaly. Overall distribution of causes of death (P<0.001) differed between patients and controls but not cardiovascular (34% vs 33%) or cancer deaths (27% vs 27%). In acromegaly, but not in controls, causes of deaths shifted from 44% cardiovascular and 28% cancer deaths during the first decade, to 23% cardiovascular and 35% cancer deaths during the next two decades. In acromegaly, cancer deaths were mostly attributed to pancreatic adenocarcinoma (n=5), breast (n=4), lung (n=3) and colon (n=3) carcinoma. In acromegaly, men were younger than women at diagnosis (median 44.5 vs 50 years, P<0.001) and death (67 vs 76 years, P=0.0015). Compared with controls, women (36% vs 25%, P<0.01), but not men (31% vs 28%, P=0.44), had increased mortality.
In acromegaly, men are younger at diagnosis and death than women. Compared with controls, mortality is increased during 20 years of follow-up, especially in women. Causes of deaths shift from predominantly cardiovascular to cancer deaths.
Iulia Potorac, Patrick Petrossians, Adrian F Daly, Orsalia Alexopoulou, Sophie Borot, Mona Sahnoun-Fathallah, Frederic Castinetti, France Devuyst, Marie-Lise Jaffrain-Rea, Claire Briet, Florina Luca, Marion Lapoirie, Flavius Zoicas, Isabelle Simoneau, Alpha M Diallo, Ammar Muhammad, Fahrettin Kelestimur, Elena Nazzari, Rogelio Garcia Centeno, Susan M Webb, Marie-Laure Nunes, Vaclav Hana, Véronique Pascal-Vigneron, Irena Ilovayskaya, Farida Nasybullina, Samia Achir, Diego Ferone, Sebastian J C M M Neggers, Brigitte Delemer, Jean-Michel Petit, Christof Schöfl, Gerald Raverot, Bernard Goichot, Patrice Rodien, Bernard Corvilain, Thierry Brue, Franck Schillo, Luaba Tshibanda, Dominique Maiter, Jean-François Bonneville, and Albert Beckers
GH-secreting pituitary adenomas can be hypo-, iso- or hyper-intense on T2-weighted MRI sequences. We conducted the current multicenter study in a large population of patients with acromegaly to analyze the relationship between T2-weighted signal intensity on diagnostic MRI and hormonal and tumoral responses to somatostatin analogs (SSA) as primary monotherapy. Acromegaly patients receiving primary SSA for at least 3 months were included in the study. Hormonal, clinical and general MRI assessments were performed and assessed centrally. We included 120 patients with acromegaly. At diagnosis, 84, 17 and 19 tumors were T2-hypo-, iso- and hyper-intense, respectively. SSA treatment duration, cumulative and mean monthly doses were similar in the three groups. Patients with T2-hypo-intense adenomas had median SSA-induced decreases in GH and IGF-1 of 88% and 59% respectively, which were significantly greater than the decreases observed in the T2-iso- and hyper-intense groups (P < 0.001). Tumor shrinkage on SSA was also significantly greater in the T2-hypo-intense group (38%) compared with the T2-iso- and hyper-intense groups (8% and 3%, respectively; P < 0.0001). The response to SSA correlated with the calculated T2 intensity: the lower the T2-weighted intensity, the greater the decrease in random GH (P < 0.0001, r = 0.22), IGF-1 (P < 0.0001, r = 0.14) and adenoma volume (P < 0.0001, r = 0.33). The T2-weighted signal intensity of GH-secreting adenomas at diagnosis correlates with hormone reduction and tumor shrinkage in response to primary SSA treatment in acromegaly. This study supports its use as a generally available predictive tool at diagnosis that could help to guide subsequent treatment choices in acromegaly.
Sylvia L Asa, Walter Kucharczyk, and Shereen Ezzat
Acromegaly has traditionally been regarded as a monomorphous disorder resulting from a benign pituitary adenoma. Increasing evidence, however, is highlighting that this disorder is associated with a spectrum of morphologically distinct pituitary tumors with variable clinical, biochemical and radiologic features and differing therapeutic outcomes that are attributed to different genetic and epigenetic changes. These data underscore the need for developing a more refined clinicopathological risk stratification system and implementing personalized targeted therapeutic approaches.
Massimo Terzolo, Giuseppe Reimondo, Paola Berchialla, Emanuele Ferrante, Elena Malchiodi, Laura De Marinis, Rosario Pivonello, Silvia Grottoli, Marco Losa, Salvatore Cannavo, Diego Ferone, Marcella Montini, Marta Bondanelli, Ernesto De Menis, Chiara Martini, Efisio Puxeddu, Antonino Velardo, Alessandro Peri, Marco Faustini-Fustini, Patrizia Tita, Francesca Pigliaru, Giulia Peraga, Giorgio Borretta, Carla Scaroni, Nicoletta Bazzoni, Antonio Bianchi, Alessandro Berton, Andreea Liliana Serban, Roberto Baldelli, Letizia Maria Fatti, Annamaria Colao, Maura Arosio, and for the Italian Study Group of Acromegaly
It is debated if acromegalic patients have an increased risk to develop malignancies. The aim of the present study was to assess the standardized incidence ratios (SIRs) of different types of cancer in acromegaly on a large series of acromegalic patients managed in the somatostatin analogs era. It was evaluated the incidence of cancer in an Italian nationwide multicenter cohort study of 1512 acromegalic patients, 624 men and 888 women, mean age at diagnosis 45 ± 13 years, followed up for a mean of 10 years (12573 person-years) in respect to the general Italian population. Cancer was diagnosed in 124 patients, 72 women and 52 men. The SIRs for all cancers was significantly increased compared to the general Italian population (expected: 88, SIR 1.41; 95% CI, 1.18–1.68, P < 0.001). In the whole series, we found a significantly increased incidence of colorectal cancer (SIR 1.67; 95% CI, 1.07–2.58, P = 0.022), kidney cancer (SIR 2.87; 95% CI, 1.55–5.34, P < 0.001) and thyroid cancer (SIR 3.99; 95% CI, 2.32–6.87, P < 0.001). The exclusion of 11 cancers occurring before diagnosis of acromegaly (all in women) did not change remarkably the study outcome. In multivariate analysis, the factors significantly associated with an increased risk of malignancy were age and family history of cancer, with a non-significant trend for the estimated duration of acromegaly before diagnosis. In conclusion, we found evidence that acromegaly in Italy is associated with a moderate increase in cancer risk.
Albert Beckers, Maya Beth Lodish, Giampaolo Trivellin, Liliya Rostomyan, Misu Lee, Fabio R Faucz, Bo Yuan, Catherine S Choong, Jean-Hubert Caberg, Elisa Verrua, Luciana Ansaneli Naves, Tim D Cheetham, Jacques Young, Philippe A Lysy, Patrick Petrossians, Andrew Cotterill, Nalini Samir Shah, Daniel Metzger, Emilie Castermans, Maria Rosaria Ambrosio, Chiara Villa, Natalia Strebkova, Nadia Mazerkina, Stéphan Gaillard, Gustavo Barcelos Barra, Luis Augusto Casulari, Sebastian J Neggers, Roberto Salvatori, Marie-Lise Jaffrain-Rea, Margaret Zacharin, Beatriz Lecumberri Santamaria, Sabina Zacharieva, Ee Mun Lim, Giovanna Mantovani, Maria Chaira Zatelli, Michael T Collins, Jean-François Bonneville, Martha Quezado, Prashant Chittiboina, Edward H Oldfield, Vincent Bours, Pengfei Liu, Wouter W de Herder, Natalia Pellegata, James R Lupski, Adrian F Daly, and Constantine A Stratakis
X-linked acrogigantism (X-LAG) is a new syndrome of pituitary gigantism, caused by microduplications on chromosome Xq26.3, encompassing the gene GPR101, which is highly upregulated in pituitary tumors. We conducted this study to explore the clinical, radiological, and hormonal phenotype and responses to therapy in patients with X-LAG syndrome. The study included 18 patients (13 sporadic) with X-LAG and microduplication of chromosome Xq26.3. All sporadic cases had unique duplications and the inheritance pattern in two families was dominant, with all Xq26.3 duplication carriers being affected. Patients began to grow rapidly as early as 2–3 months of age (median 12 months). At diagnosis (median delay 27 months), patients had a median height and weight standard deviation scores (SDS) of >+3.9 SDS. Apart from the increased overall body size, the children had acromegalic symptoms including acral enlargement and facial coarsening. More than a third of cases had increased appetite. Patients had marked hypersecretion of GH/IGF1 and usually prolactin, due to a pituitary macroadenoma or hyperplasia. Primary neurosurgical control was achieved with extensive anterior pituitary resection, but postoperative hypopituitarism was frequent. Control with somatostatin analogs was not readily achieved despite moderate to high levels of expression of somatostatin receptor subtype-2 in tumor tissue. Postoperative use of adjuvant pegvisomant resulted in control of IGF1 in all five cases where it was employed. X-LAG is a new infant-onset gigantism syndrome that has a severe clinical phenotype leading to challenging disease management.
Kjell Öberg and Steven W J Lamberts
Acromegaly is a hormonal disorder that arises when the pituitary gland secretes excess growth hormone (GH), which in turn stimulates a concomitant increase in serum insulin-like growth factor 1 (IGF-1) levels. Gastroenteropancreatic neuroendocrine tumours (GEP-NET) constitute a heterogeneous group of tumours that can secrete serotonin and a variety of peptide hormones that may cause characteristic symptoms known as carcinoid syndrome or other symptoms and hormonal hypersecretion syndromes depending on the tumour’s site of origin. Current medical therapy for the treatment of acromegaly and GEP-NET involves the administration of somatostatin analogues that effectively suppress excess hormone secretion. After its discovery in 1979, octreotide became the first synthetic biologically stable somatostatin analogue with a short-acting formulation of octreotide introduced into clinical practice in the late 1980s. Lanreotide, another somatostatin analogue, became available in the mid-1990s initially as a prolonged-release formulation administered every 10 or 14 days. Long-acting release formulations of both octreotide (Sandostatin LAR and Novartis) and lanreotide (Somatuline Autogel, Ipsen), based on microparticle and nanoparticle drug-delivery technologies, respectively, were later developed, which allowed for once-monthly administration and improved convenience. First-generation somatostatin analogues remain one of the cornerstones of medical therapy in the management of pituitary and GEP-NET hormone hypersecretion, with octreotide having the longest established efficacy and safety profile of the somatostatin analogue class. More recently, pasireotide (Signifor), a next-generation multireceptor-targeted somatostatin analogue, has emerged as an alternative therapeutic option for the treatment of acromegaly. This review summarizes the development and clinical success of somatostatin analogues.
Alberto Fernandez, Michael Brada, Lina Zabuliene, Niki Karavitaki, and John A H Wass
The hypothalamic–pituitary unit is a particularly radiosensitive region in the central nervous system. As a consequence, hypopituitarism commonly develops after radiation treatments for sellar and parasellar neoplasms, extrasellar brain tumours, head and neck tumours, and following whole body irradiation for systemic malignancies. Increasing tumour-related survival rates provide an expanding population at risk of developing hypopituitarism. In this population, long-term monitoring tailored to the individual risk profile is required to avoid the sequelae of untreated pituitary hormonal deficiencies and resultant decrease in the quality of life. This review analyses the pathogenesis, prevalence and consequences of radiation-induced hypopituitarism (RIH) in diverse subgroups at risk. Also discussed is the impact of modern radiotherapy techniques in the prevalence of RIH, the spectrum of endocrine disorders and radiation-induced brain conditions that also occur in patients with RIH.
G Minniti, M-L Jaffrain-Rea, V Esposito, A Santoro, G Tamburrano, and G Cantore
Criteria to define the biochemical remission of acromegaly following surgery have changed over the years, and the current use of stringent criteria needs a critical re-evaluation of the surgical results. On the other hand, few data are currently available concerning the possible impact of pituitary surgery on the quality of life of operated acromegalic patients. In this prospective study, we wished to evaluate the initial outcome and long-term recurrence rate in a large series of acromegalic patients operated on by transsphenoidal surgery (TSS), to carefully analyse predictive factors for surgical outcome and to point out possible additional effects of surgery in these patients. Ninety-two out of 98 operated patients could be considered for follow-up. Biochemical remission was strictly defined as plasma GH levels <1 ng/ml during an oral glucose tolerance test (OGTT) and normalisation of age-related IGF-I levels. Hormonal assessment, including an OGTT, was performed 6 months following surgery and then annually to evaluate pituitary function. Fifty-five per cent of patients achieved a biochemical remission of acromegaly. The remission rate at 6 months was 80% for patients with microadenoma and 50% for macroadenoma. Univariate analysis showed that a large extrasellar extension, preoperative high GH levels and dural invasion were correlated with a poor outcome of surgery while, according to multivariate analysis, only invasion of cavernous sinus and preoperative GH levels > 10 ng/ml were independent negative predictors. Mortality was 0% and the overall complication rate was about 10%. Pituitary function worsened in five patients but improved in 16 out of 30 patients with preoperative pituitary defects. No recurrence was observed during a median follow-up of about 8 years. We conclude that TSS is able to achieve a biochemical remission in more than half of acromegalic patients, and that the current criteria for remission seem to indicate a cure in most cases.
Manel Puig-Domingo, Joan Gil, Miguel Sampedro-Nuñez, Mireia Jordà, Susan M Webb, Guillermo Serra, Laura Pons, Isabel Salinas, Alberto Blanco, Montserrat Marques-Pamies, Elena Valassi, Antonio Picó, Araceli García-Martínez, Cristina Carrato, Raquel Buj, Carlos del Pozo, Gabriel Obiols, Carles Villabona, Rosa Cámara, Carmen Fajardo-Montañana, Clara V Alvarez, Ignacio Bernabéu, and Mónica Marazuela
Pharmacologic treatment of acromegaly is currently based upon assay-error strategy, the first-generation somatostatin receptor ligands (SRL) being the first-line treatment. However, about 50% of patients do not respond adequately to SRL. Our objective was to evaluate the potential usefulness of different molecular markers as predictors of response to SRL. We used somatotropinoma tissue obtained after surgery from a national cohort of 100 acromegalic patients. Seventy-one patients were treated with SRL during at least 6 months under maximal therapeutic doses according to IGF1 values. We analyzed the expression of SSTR2, SSTR5, AIP, CDH1 (E-cadherin), MKI67 (Ki-67), KLK10, DRD2, ARRB1, GHRL, In1-Ghrelin, PLAGL1 and PEBP1 (RKIP) by RT-qPCR and mutations in GNAS gene by Sanger sequencing. The response to SRL was categorized as complete response (CR), partial (PR) or non-response (NR) if IGF1 was normal, between >2<3 SDS or >3 SDS IGF1 at 6 months of follow-up, respectively. From the 71 patients treated, there were 27 CR (38%), 18 PR (25%) and 26 NR (37%). SSTR2, Ki-67 and E-cadherin were associated with SRL response (P < 0.03, P < 0.01 and P < 0.003, respectively). E-cadherin was the best discriminator for response prediction (AUC = 0.74, P < 0.02, PPV of 83.7%, NPV of 72.6%), which was validated at protein level. SSTR5 expression was higher in patients pre-treated with SRL before surgery. We conclude that somatotropinomas showed heterogeneity in the expression of genes associated with SRL response. E-cadherin was the best molecular predictor of response to SRL. Thus, the inclusion of E-cadherin in subsequent treatment-decision after surgical failure may be useful in acromegaly.