Over the last 5 years, new actors involved in the pathogenesis of combined pituitary hormone deficiency in humans have been reported: they included a member of the immunoglobulin superfamily glycoprotein and ciliary G protein-coupled receptors, as well as new transcription factors and signalling molecules. New modes of inheritance for alterations of genes encoding transcription factors have also been described. Finally, actors known to be involved in a very specific phenotype (hypogonadotroph hypogonadism for instance) have been identified in a wider range of phenotypes. These data thus suggest that new mechanisms could explain the low rate of aetiological identification in this heterogeneous group of diseases. Taking into account the fact that several reviews have been published in recent years on classical aetiologies of CPHD such as mutations of POU1F1 or PROP1, we focused the present overview on the data published in the last 5 years, to provide the reader with an updated review on this rapidly evolving field of knowledge.
Frederic Castinetti, Rachel Reynaud, Alexandru Saveanu, Nicolas Jullien, Marie Helene Quentien, Claire Rochette, Anne Barlier, Alain Enjalbert and Thierry Brue
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.
Alessandra Fusco, Ginette Gunz, Philippe Jaquet, Henry Dufour, Anne Laure Germanetti, Michael D Culler, Anne Barlier and Alexandru Saveanu
Ten percent of patients with prolactinoma fail to respond with normalization of prolactin (PRL) and tumor shrinkage under dopamine agonist (DA) therapy. The resistance to treatment is linked to a loss of dopamine receptor 2 (D2DR). Prolactinomas express somatostatin (SST) receptor subtypes, SSTR1, 2, and 5. The aim of this study was to determine whether different SST compounds could overcome the resistance to DA in prolactinomas.
Design and methods
The efficacy of SSTR1, SSTR2, and SSTR5 ligands; the universal SST ligand, SOM230; and the chimeric SST-DA compound, BIM-23A760, was compared with cabergoline in suppressing PRL secretion from primary cultures of ten prolactinomas (six DA responders and four DA resistant). Receptor mRNAs were assessed by quantitative PCR.
The mean mRNA levels for D2DR, SSTR1, SSTR2, and SSTR5 were 92.3±47.3, 2.2±1.4, 1.1±0.7, and 1.6±0.6 copy/copy β-glucuronidase (β-Gus) respectively. The SSTR1 agonist, BIM-23926, did not suppress PRL in prolactinomas. In a DA-resistant prolactinoma, it did not inhibit [3H]thymidine incorporation. The SSTR5 compound, BIM-23206, produced a dose-dependent inhibition of PRL release similar to that of cabergoline in three DA-sensitive prolactinomas. BIM-23A760 produced a maximal PRL inhibition superimposable to that obtained with cabergoline with a lower EC50 (0.5±0.1 vs 2.5±1.5 pmol/l). In DA-resistant prolactinomas, BIM-23206 and SOM230 were ineffective. Cabergoline and BIM-23A760 produced a partial inhibition of PRL secretion (19±6 and 21±3% respectively).
Although the SSTRs are expressed in prolactinomas, the somatostatinergic ligands analyzed do not appear to be highly effective in suppressing PRL. D2DR remains the primary target for effective treatment of prolactinomas.
Dermot O’Toole, Alexandru Saveanu, Anne Couvelard, Ginette Gunz, Alain Enjalbert, Philippe Jaquet, Philippe Ruszniewski and Anne Barlier
Objective: Somatostatin (sst) are present in the majority of gastro-entero-pancreatic (GEP) tumours. Effects of somatostatin receptor (sst) analogues are partial and of limited duration. Cell lines derived from GEP express dopaminergic receptors D2. New chimeric analogues simultaneously recognising sst2 and sst5 or sst2 and D2 have additive effects in inhibition of GH and prolactin secretion in pituitary adenomas. Our aim was to quantify the expression of sst and D2 mRNA in human GEP tumours.
Design and methods: mRNA expression of sst1, sst2, sst3 and sst5 as well as D2, was analysed using real-time PCR (TaqMan probe) in a series of 35 patients with GEP tumours (pancreas (n = 19) and intestinal (n = 16)). Levels of expression were compared with a group of 13 somatotroph adenomas.
Results: All GEP tumours express sst1, sst2 and D2. Expression of sst3 and sst5 was observed in 89 and 76% of tumours respectively with highly variable levels. sst2 mRNA expression was higher in nonfunctional tumours (P < 0.009) and sst5 was higher in pancreatic than in intestinal tumours (P < 0.02). Whereas sst2 levels were similar between GEP and somatotroph tumours, levels of sst5 and D2 were higher in the former (394.9 ± 156.1 × 10−2 vs 69.7 ± 19.5 × 10−2 copy/copy β-Gus (P < 0.0036) and 519.6 ± 121.2 × 10−2 vs 50.0 ± 21.6 × 10−2 copy/copy β-Gus (P < 0.0001) respectively). In small tumours ( < 30 mm), sst2 density appeared as a crucial parameter in somatostatin receptor scintigraphy results, whereas in big tumours, a consistent bias in SRS results was introduced by the size. In pancreatic GEP, high-level sst3 expression was found in tumours with more active angiogenesis (higher microvessel density and vascular endothelial growth factor expression (P < 0.03)).
Conclusions: GEP tumours co-express sst2 and D2 in 100% of cases and sst5 in 89% thus supporting the testing of bi-specific agonists (sst2/sst5 or sst2/D2) in these tumours.
Julia Vergier, Frederic Castinetti, Alexandru Saveanu, Nadine Girard, Thierry Brue and Rachel Reynaud
Pituitary stalk interruption syndrome (PSIS) is a congenital pituitary anatomical defect. This syndrome is an antenatal developmental defect belonging to the holoprosencephaly phenotype spectrum. It is heterogeneous regarding clinical, biological and radiological presentation and is characterized by the following triad: thin (<1 mm) or interrupted pituitary stalk connecting the hypothalamus to the pituitary gland, no eutopic posterior lobe, and hypoplasia or aplasia of the anterior lobe. This review reports current knowledge about the composite pathogenesis, for which underlying mechanisms remain unclear. Current data suggest genetic origins involving early developmental gene mutations with complex inheritance patterns and environmental influence, placing PSIS at the crossroads between Mendelian and multifactorial diseases. The phenotype associated with PSIS is highly heterogeneous with a high incidence of various combinations of hormonal deficiencies, sometimes associated with extra-pituitary birth defects. The age at onset is variable, but typical presentation is evolutive combined anterior pituitary hormone deficiencies at pediatric age, which progress even during adulthood to panhypopituitarism. Therefore, patients’ follow-up throughout life is essential for adequate management.