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.
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
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.
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.
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.
María Andrea Camilletti, Alejandra Abeledo-Machado, Pablo A Perez, Erika Y Faraoni, Fernanda De Fino, Susana B Rulli, Jimena Ferraris, Daniel Pisera, Silvina Gutierrez, Peter Thomas, and Graciela Díaz-Torga
Membrane progesterone receptors are known to mediate rapid nongenomic progesterone effects in different cell types. Recent evidence revealed that mPRα is highly expressed in the rat pituitary, being primarily localized in lactotrophs, acting as an intermediary of P4-inhibitory actions on prolactin secretion. The role of mPRs in prolactinoma development remains unclear. We hypothesize that mPR agonists represent a novel tool for hyperprolactinemia treatment. To this end, pituitary expression of mPRs was studied in three animal models of prolactinoma. Expression of mPRs and nuclear receptor was significantly decreased in tumoral pituitaries compared to normal ones. However, the relative proportion of mPRα and mPRβ was highly increased in prolactinomas. Interestingly, the selective mPR agonist (Org OD 02-0) significantly inhibited PRL release in both normal and tumoral pituitary explants, displaying a more pronounced effect in tumoral tissues. As P4 also regulates PRL secretion indirectly, by acting on dopaminergic neurons, we studied mPR involvement in this effect. We found that the hypothalamus has a high expression of mPRs. Interestingly, both P4 and OrgOD 02-0 increased dopamine release in hypothalamus explants. Moreover, in an in vivo treatment, that allows both, pituitary and hypothalamus actions, the mPR agonist strongly reduced the hyperprolactinemia in transgenic females carrying prolactinoma. Finally, we also found and interesting gender difference: males express higher levels of pituitary mPRα/β, a sex that does not develop prolactinoma in these mice models. Taken together, these findings suggest mPRs activation could represent a novel tool for hyperprolactinemic patients, especially those that present resistance to dopaminergic drugs.
Adrian F Daly, Philippe A Lysy, Céline Desfilles, Liliya Rostomyan, Amira Mohamed, Jean-Hubert Caberg, Veronique Raverot, Emilie Castermans, Etienne Marbaix, Dominique Maiter, Chloe Brunelle, Giampaolo Trivellin, Constantine A Stratakis, Vincent Bours, Christian Raftopoulos, Veronique Beauloye, Anne Barlier, and Albert Beckers
X-linked acrogigantism (X-LAG) syndrome is a newly described form of inheritable pituitary gigantism that begins in early childhood and is usually associated with markedly elevated GH and prolactin secretion by mixed pituitary adenomas/hyperplasia. Microduplications on chromosome Xq26.3 including the GPR101 gene cause X-LAG syndrome. In individual cases random GHRH levels have been elevated. We performed a series of hormonal profiles in a young female sporadic X-LAG syndrome patient and subsequently undertook in vitro studies of primary pituitary tumor culture following neurosurgical resection. The patient demonstrated consistently elevated circulating GHRH levels throughout preoperative testing, which was accompanied by marked GH and prolactin hypersecretion; GH demonstrated a paradoxical increase following TRH administration. In vitro, the pituitary cells showed baseline GH and prolactin release that was further stimulated by GHRH administration. Co-incubation with GHRH and the GHRH receptor antagonist, acetyl-(d-Arg2)-GHRH (1-29) amide, blocked the GHRH-induced GH stimulation; the GHRH receptor antagonist alone significantly reduced GH release. Pasireotide, but not octreotide, inhibited GH secretion. A ghrelin receptor agonist and an inverse agonist led to modest, statistically significant increases and decreases in GH secretion, respectively. GHRH hypersecretion can accompany the pituitary abnormalities seen in X-LAG syndrome. These data suggest that the pathology of X-LAG syndrome may include hypothalamic dysregulation of GHRH secretion, which is in keeping with localization of GPR101 in the hypothalamus. Therapeutic blockade of GHRH secretion could represent a way to target the marked hormonal hypersecretion and overgrowth that characterizes X-LAG syndrome.
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.
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
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.
Fabio R Faucz, Anelia D Horvath, Monalisa F Azevedo, Isaac Levy, Beata Bak, Ying Wang, Paraskevi Xekouki, Eva Szarek, Evgenia Gourgari, Allison D Manning, Rodrigo Bertollo de Alexandre, Emmanouil Saloustros, Giampaolo Trivellin, Maya Lodish, Paul Hofman, Yvonne C Anderson, Ian Holdaway, Edward Oldfield, Prashant Chittiboina, Maria Nesterova, Nienke R Biermasz, Jan M Wit, Daniel J Bernard, and Constantine A Stratakis
IGSF1 is a membrane glycoprotein highly expressed in the anterior pituitary. Pathogenic mutations in the IGSF1 gene (on Xq26.2) are associated with X-linked central hypothyroidism and testicular enlargement in males. In this study, we tested the hypothesis that IGSF1 is involved in the development of pituitary tumors, especially those that produce growth hormone (GH). IGSF1 was sequenced in 21 patients with gigantism or acromegaly and 92 healthy individuals. Expression studies with a candidate pathogenic IGSF1 variant were carried out in transfected cells and immunohistochemistry for IGSF1 was performed in the sections of GH-producing adenomas, familial somatomammotroph hyperplasia, and in normal pituitary. We identified the sequence variant p.N604T, which in silico analysis suggested could affect IGSF1 function, in two male patients and one female with somatomammotroph hyperplasia from the same family. Of 60 female controls, two carried the same variant and seven were heterozygous for other variants. Immunohistochemistry showed increased IGSF1 staining in the GH-producing tumor from the patient with the IGSF1 p.N604T variant compared with a GH-producing adenoma from a patient negative for any IGSF1 variants and with normal control pituitary tissue. The IGSF1 gene appears polymorphic in the general population. A potentially pathogenic variant identified in the germline of three patients with gigantism from the same family (segregating with the disease) was also detected in two healthy female controls. Variations in IGSF1 expression in pituitary tissue in patients with or without IGSF1 germline mutations point to the need for further studies of IGSF1 action in pituitary adenoma formation.
Maria A Tichomirowa, Misu Lee, Anne Barlier, Adrian F Daly, Ilaria Marinoni, Marie-Lise Jaffrain-Rea, Luciana A Naves, Patrice Rodien, Vincent Rohmer, Fabio Rueda Faucz, Philippe Caron, Bruno Estour, Pierre Lecomte, Françoise Borson-Chazot, Alfred Penfornis, Maria Yaneva, Mirtha Guitelman, Emily Castermans, Catherine Verhaege, Jean-Louis Wémeau, Antoine Tabarin, Carmen Fajardo Montañana, Brigitte Delemer, Veronique Kerlan, Jean-Louis Sadoul, Christine Cortet Rudelli, Françoise Archambeaud, Sabine Zacharieva, Marily Theodoropoulou, Thierry Brue, Alain Enjalbert, Vincent Bours, Natalia S Pellegata, and Albert Beckers
Familial isolated pituitary adenoma (FIPA) occurs in families and is unrelated to multiple endocrine neoplasia type 1 and Carney complex. Mutations in AIP account only for 15–25% of FIPA families. CDKN1B mutations cause MEN4 in which affected patients can suffer from pituitary adenomas. With this study, we wanted to assess whether mutations in CDKN1B occur among a large cohort of AIP mutation-negative FIPA kindreds. Eighty-eight AIP mutation-negative FIPA families were studied and 124 affected subjects underwent sequencing of CDKN1B. Functional analysis of putative CDKN1B mutations was performed using in silico and in vitro approaches. Germline CDKN1B analysis revealed two nucleotide changes: c.286A>C (p.K96Q) and c.356T>C (p.I119T). In vitro, the K96Q change decreased p27 affinity for Grb2 but did not segregate with pituitary adenoma in the FIPA kindred. The I119T substitution occurred in a female patient with acromegaly. p27I119T shows an abnormal migration pattern by SDS–PAGE. Three variants (p.S56T, p.T142T, and c.605+36C>T) are likely nonpathogenic because In vitro effects were not seen. In conclusion, two patients had germline sequence changes in CDKN1B, which led to functional alterations in the encoded p27 proteins in vitro. Such rare CDKN1B variants may contribute to the development of pituitary adenomas, but their low incidence and lack of clear segregation with affected patients make CDKN1B sequencing unlikely to be of use in routine genetic investigation of FIPA kindreds. However, further characterization of the role of CDKN1B in pituitary tumorigenesis in these and other cases could help clarify the clinicopathological profile of MEN4.