RESUMO
Endogenous Cushing's syndrome is rare, with an incidence of 0.7-2.4 per a million people a year. Clinical presentation of Cushing syndrome can be pleomorphic, and establishing diagnosis can be difficult. Early recognition and rapid control of hypercortisolaemia are necessary to decrease morbidity and mortality in these patients. We report a series of 6 endogenous Cushing's syndromes of different etiologies (4 Cushing's disease and 2 adrenal Cushing's syndrome) assessed in our endocrine department over a decade (2009-2019). In order to highlight the diversity of clinical forms, diagnostic tools and specific management of this condition we labelled each case suggestively: the typical Cushing's disease, the Pseudo Cushing's, the elusive Cushing's disease, the mild autonomous cortisol hypersecretion, Cushing's syndrome in pregnancy and Cushing's disease with thromboembolism. We discussed their particularities which were revelatory for the diagnosis, such as dermatologic, cardiovascular, musculoskeletal, neuropsychiatric, or reproductive signs, reviewing literature for each manifestation. We also discuss the commonalities and differences in laboratory and imagistic findings. Therapeutic approach can also differ with respect to the particular condition of each patient and the multiple choices of therapy will be reviewed.
RESUMO
Pituitary tumours have previously been shown to harbour several abnormalities that cause deregulation of the cell cycle, particularly down-regulation of expression of the cyclin-dependent kinase inhibitor p27. However, it has been unclear whether these are the primary initiating events, or are secondary to other more proximate alterations in signalling pathways. In other cellular systems the Akt signalling pathway has been associated with downstream modulation of cell-cycle control. The aim of the present study was to test the hypothesis that Akt signalling is enhanced in pituitary tumours, and to see if changes in Akt expression are related to previous findings on low expression levels of the nuclear cell-cycle inhibitor p27 in pituitary tumours. We examined normal and adenomatous human pituitary tissue for mRNA and protein expression of Akt1, Akt2 and p27, and the activation of Akt, as well the phosphatase involved in the inactivation of Akt, phosphatase and tensin homologue deleted on chromosome 10 (PTEN). In pituitary adenomas Akt1 and Akt2 mRNA were found to be over-expressed compared with normal pituitary, while PTEN transcripts showed similar levels between the two tissue types. Immunohistochemical expression of phospho-Akt was found to be higher in the tumours than normal pituitaries, while the protein expression of nuclear p27 and PTEN was lower in the adenomas. However, the expression of p27 and Akt were not directly correlated. PTEN sequencing revealed no mutation in the coding region of the gene in pituitary adenomas, and thus we did not locate a cause for the increased phosphorylation of Akt. In summary, we have shown over-expression and activation of the Akt pathway in pituitary tumours, and we speculate that cell-cycle changes observed in such tumours are secondary to these more proximate alterations. Since Akt is a major downstream signalling molecule of growth factor-liganded tyrosine kinase receptors, our data are most compatible with an abnormality at this level as the primary driver of pituitary tumorigenesis.
