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Free access

Elina Ritvonen, Eliisa Löyttyniemi, Pia Jaatinen, Tapani Ebeling, Leena Moilanen, Pirjo Nuutila, Ritva Kauppinen-Mäkelin, and Camilla Schalin-Jäntti

Objective

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).

Results

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.

Conclusions

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.

Open access

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.

Free access

Lautaro Zubeldía-Brenner, Catalina De Winne, Sofía Perrone, Santiago A Rodríguez-Seguí, Christophe Willems, Ana María Ornstein, Isabel Lacau-Mengido, Hugo Vankelecom, Carolina Cristina, and Damasia Becu-Villalobos

Preclinical and clinical studies support that Notch signaling may play an important oncogenic role in cancer, but there is scarce information for pituitary tumors. We therefore undertook a functional study to evaluate Notch participation in pituitary adenoma growth. Tumors generated in Nude mice by subcutaneous GH3 somatolactotrope cell injection were treated in vivo with DAPT, a γ-secretase inhibitor, thus inactivating Notch signaling. This treatment led to pituitary tumor reduction, lower prolactin and GH tumor content and a decrease in angiogenesis. Furthermore, in silico transcriptomic and epigenomic analyses uncovered several tumor suppressor genes related to Notch signaling in pituitary tissue, namely Btg2, Nr4a1, Men1, Zfp36 and Cnot1. Gene evaluation suggested that Btg2, Nr4a1 and Cnot1 may be possible players in GH3 xenograft growth. Btg2 mRNA expression was lower in GH3 tumors compared to the parental line, and DAPT increased its expression levels in the tumor in parallel with the inhibition of its volume. Cnot1 mRNA levels were also increased in the pituitary xenografts by DAPT treatment. And the Nr4a1 gene was lower in tumors compared to the parental line, though not modified by DAPT. Finally, because DAPT in vivo may also be acting on tumor microenvironment, we determined the direct effect of DAPT on GH3 cells in vitro. We found that DAPT decreases the proliferative, secretory and migration potential of GH3 cells. These results position selective interruption of Notch signaling as a potential therapeutic tool in adjuvant treatments for aggressive or resistant pituitary tumors.

Free access

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.

Free access

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.

Free access

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.

Free access

Gerard A Tarulli, Lisa M Butler, Wayne D Tilley, and Theresa E Hickey

While it has been known for decades that androgen hormones influence normal breast development and breast carcinogenesis, the underlying mechanisms have only been recently elucidated. To date, most studies have focused on androgen action in breast cancer cell lines, yet these studies represent artificial systems that often do not faithfully replicate/recapitulate the cellular, molecular and hormonal environments of breast tumours in vivo. It is critical to have a better understanding of how androgens act in the normal mammary gland as well as in in vivo systems that maintain a relevant tumour microenvironment to gain insights into the role of androgens in the modulation of breast cancer development. This in turn will facilitate application of androgen-modulation therapy in breast cancer. This is particularly relevant as current clinical trials focus on inhibiting androgen action as breast cancer therapy but, depending on the steroid receptor profile of the tumour, certain individuals may be better served by selectively stimulating androgen action. Androgen receptor (AR) protein is primarily expressed by the hormone-sensing compartment of normal breast epithelium, commonly referred to as oestrogen receptor alpha (ERa (ESR1))-positive breast epithelial cells, which also express progesterone receptors (PRs) and prolactin receptors and exert powerful developmental influences on adjacent breast epithelial cells. Recent lineage-tracing studies, particularly those focussed on NOTCH signalling, and genetic analysis of cancer risk in the normal breast highlight how signalling via the hormone-sensing compartment can influence normal breast development and breast cancer susceptibility. This provides an impetus to focus on the relationship between androgens, AR and NOTCH signalling and the crosstalk between ERa and PR signalling in the hormone-sensing component of breast epithelium in order to unravel the mechanisms behind the ability of androgens to modulate breast cancer initiation and growth.

Free access

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.

Free access

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.

Free access

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.