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Open access

Diego Ferone, Alexandru Saveanu, Michael D Culler, Marica Arvigo, Alberto Rebora, Federico Gatto, Francesco Minuto, and Philippe Jaquet

Dopamine and somatostatin receptor agonists inhibit hormone secretion by normal pituitary cells and pituitary adenomas. Indeed, initially several dopaminergic drugs, and lately somatostatin analogs, have been developed for the treatment of pituitary adenomas. Recently, it has been demonstrated that subtypes of somatostatin and dopamine receptors may form homo- and hetero-dimers at the membrane level, as part of their normal trafficking and function. Interestingly, a specific ligand for a given receptor may influence the activity of an apparently unrelated receptor, and the association between the two different receptors could be induced by addition of either dopamine or somatostatin. The new properties of these families of G-protein coupled receptors (GPCRs) offer a potential explanation for the apparent conflicting results observed both in vivo and in vitro in human cell systems treated with the presently available analogs. Moreover, this observation not only increases the possibilities of modulating the activities of these receptors, but also raises new questions on the role of associations of specific receptors in the control of cell functions. In fact, results from preclinical studies have shown that receptor activation may not only trigger different intracellular signaling pathways, but also induce a distinct response depending upon the specific cell type. Recently, a number of new interesting compounds (subtype selective analogs and antagonists, as well as bi-specific and hybrid somatostatin/dopamine compounds) have been developed. The effects of these new molecules have been explored in few animal and human cell lines and primary cultures from human tumors, revealing a heterogeneous, but broader, profile of activities. Further studies are certainly needed to fully elucidate the complex interplay between the GPCRs and consequent biological effects, to identify suitable therapies for controlling hormonal secretion of pituitary tumors. However, these recent observations form the basis for the application of new interesting strategies for the treatment of not only pituitary tumors but also other human malignancies.

Free access

Federico Gatto, Nienke R Biermasz, Richard A Feelders, Johan M Kros, Fadime Dogan, Aart-Jan van der Lely, Sebastian J C M M Neggers, Steven W J Lamberts, Alberto M Pereira, Diego Ferone, and Leo J Hofland

Abstract

Objective

The high expression of somatostatin receptor subtype 2 (SSTR2 also known as sst2) usually present in growth hormone (GH)-secreting adenomas is the rationale for therapy with somatostatin analogs (SSAs) in acromegaly. Although SSTR2 expression is a good predictor for biochemical response to SSA treatment, we still face tumors resistant to SSAs despite high SSTR2 expression. Recently, beta-arrestins (β-arrestins) have been highlighted as key players in the regulation of SSTR2 function.

Design

To investigate whether β-arrestins might be useful predictors of responsiveness to long-term SSA treatment in acromegaly, we retrospectively evaluated 35 patients with acromegaly who underwent adenomectomy in two referral centers in The Netherlands.

Methods

β-arrestin mRNA levels were evaluated in adenoma samples, together with SSTR2 (and SSTR5) mRNA and protein expression. Biochemical response to long-term SSA treatment (median 12 months) was assessed in 32 patients.

Results

β-arrestin 1 and 2 mRNA was significantly lower in adenoma tissues from patients who achieved insulin-like growth factor 1 normalization (P = 0.024 and P = 0.047) and complete biochemical control (P = 0.047 and P = 0.039). The SSTR2 mRNA was higher in SSA responder patients compared with the resistant ones (P = 0.026). This difference was more evident when analyzing the SSTR2/β-arrestin 1 and SSTR2/β-arrestin 2 ratio (P = 0.011 and P = 0.010). β-arrestin 1 and 2 expression showed a significant trend of higher median values from full responders, partial responders to resistant patients (P = 0.045 and P = 0.021, respectively). Interestingly, SSTR2 protein expression showed a strong inverse correlation with both β-arrestin 1 and 2 mRNA (ρ = –0.69, P = 0.0011 and ρ = –0.67, P = 0.0016).

Conclusions

Low β-arrestin expression and high SSTR2/β-arrestin ratio correlate with the responsiveness to long-term treatment with SSAs in patients with acromegaly.

Restricted access

Salvatore Crisafulli, Nicoletta Luxi, Janet Sultana, Andrea Fontana, Federica Spagnolo, Giuseppe Giuffrida, Francesco Ferrau, Daniele Gianfrilli, Alessia Cozzolino, Maria Cristina De Martino, Federico Gatto, Francesco Barone-Adesi, Salvatore Cannavò, and Gianluca Trifirò

Objective: To date, no systematic reviews and meta-analysis on the global epidemiology of acromegaly are available in literature. The aims of this study are to provide a systematic review and a meta-analysis of the global epidemiology of acromegaly and to evaluate the quality of study reporting for the identified studies.

Methods: MEDLINE, EMBASE and The Cochrane Library databases were searched for studies assessing the epidemiology of acromegaly from inception until 31st January 2020. We included original observational studies written in English, reporting acromegaly prevalence and/or incidence for a well-defined geographic area. Two reviewers independently extracted data and performed quality assessments. Prevalence and incidence pooled estimates were derived performing a random-effects meta-analysis.

Results: A total of 32 studies were included in the systematic review, and 22 of them were included in the meta-analysis. The pooled prevalence of acromegaly was 5.9 (95%CI: 4.4-7.9) per 100,000 persons, while the incidence rate (IR) was 0.38 (95%CI: 0.32-0.44) cases per 100,000 person-years. For both prevalence and IR, a considerable between-study heterogeneity was found (I2= 99.3% and 86.0%, respectively). The quality of study reporting was rated as medium for 20 studies and low for 12 studies.

Conclusions: Although the largest amount of heterogeneity was due to the high precision of the studies’ estimates, data source and geographic area could represent relevant study-levels factors which could explain about 50% of the total between-study variability. Large-scale high quality studies on the epidemiology of acromegaly are warranted to help the public health system in making decisions.