Sexual Dimorphism in Cellular and Molecular Features in Human ACTH-Secreting Pituitary Adenomas

Giraldi, Francesca Pecori; Cassarino, Maria Francesca; Sesta, Antonella; Terreni, Mariarosa; Lasio, Giovanni; Losa, Marco

doi:10.3390/cancers12030669

Cited by 14 publications

(9 citation statements)

References 98 publications

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“…Such reduction of the "gender-gap" in the prevalence of pituitary-dependent CS in the elderly may be due to the lack of estrogen in postmenopausal women, and resembles that reported in prepubertal individuals [11]. Indeed, estrogens enhance corticotrope proliferation in vitro, and the expression of the estrogen receptor beta (ERβ) has been detected in the majority of the ACTH-secreting adenomas, suggesting that estrogens may promote the development of CD in premenopausal women [12].…”

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confidence: 67%

Cushing's Syndrome in the Elderly

Zdrojowy-Wełna,

Valassi

2024

Exp Clin Endocrinol Diabetes

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Management of Cushing’s syndrome (CS) can be particularly challenging in older patients, due to the lack of several clinical features associated with cortisol excess along with a greater burden of comorbidities in them, as compared with the younger. Moreover, interpretation of diagnostic tests could be influenced by age-related physiological changes of cortisol secretion. While mortality is higher and quality of life is more impaired in the elderly with CS as compared with the younger, there is currently no agreement on the most effective therapeutic options in aged individuals, and safety data concerning medical treatment are scanty. In this review, we summarize the current knowledge about age-related differences in etiology, clinical presentation, treatment and outcomes of CS, and describe the potential underlying mechanisms.

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confidence: 67%

Cushing's Syndrome in the Elderly

Zdrojowy-Wełna,

Valassi

2024

Exp Clin Endocrinol Diabetes

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“…Both USP8 variant specimens were responsive to silibinin, whereas wildtype adenomas exhibited both responsive and non-responsive patterns. No difference as regards sensitivity to silibinin was observed between adenomas from male (#1, #2, #5, and #7) and female (#3, #4, and #6) patients, in keeping with comparable responsivity to other corticotroph modulators, e.g., corticotrophin-releasing hormone, steroids, in vitro [ 22 ].…”

Section: Resultsmentioning

confidence: 99%

Silibinin, an HSP90 Inhibitor, on Human ACTH-Secreting Adenomas

Giraldi¹,

Cassarino²,

Sesta³

et al. 2023

Neuroendocrinology

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Introduction. The glucocorticoid receptor is pivotal to control corticotrophin (ACTH) secretion and its function is closely linked to the heat shock protein 90 (HSP90) chaperone complex. Impaired sensitivity to glucocorticoid feedback is a hallmark of human corticotroph adenomas, i.e., Cushing’s disease, a disorder with few medical treatment options. Silibinin, a HSP90 inhibitor, has been studied in tumoral corticotroph cells and its use proposed in Cushing’s disease. Aim of the present study was to further investigate the effect of silibinin on human corticotroph adenomas in vitro. Methods. Seven human ACTH-secreting pituitary adenomas were established in culture and treated with 10 – 50 µM silibinin with/without dexamethasone for up to 72 hours. ACTH medium levels were measured and POMC and glucocorticoid receptor, i.e., NR3C1, gene expression assessed. Results. Silibinin reduced spontaneous ACTH secretion and restored sensitivity to steroid negative feedback to a different extent in individual adenomas. POMC expression was decreased both in control and dexamethasone-treated wells in specimens sensitive to silibinin. Interestingly, silibinin reduced constitutive NR3C1 expression and reversed the dexamethasone-induced inhibition. Conclusions. Our findings indicate that silibinin can inhibit ACTH synthesis and secretion in individual human corticotroph adenomas and directly affects NR3C1 gene expression. These results reveal promising effects of this HSP90 inhibitor on human corticotroph adenomas and support an innovative target treatment for patients with Cushing’s disease.

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“…ACTH-secreting tumours in men are less likely to harbour somatic USP8 mutations that are linked to smaller and less invasive tumours ( 14 , 15 ). In addition, the transcriptomic analysis revealed enrichment of genes involved in tumour development in corticotroph tumours from men ( 16 ). The finding of enrichment for Cushing’s disease is in line with other cohorts of APT/PC ( 17 , 18 ).…”

Section: Discussionmentioning

confidence: 99%

Aggressive pituitary tumours and carcinomas, characteristics and management of 171 patients

Burman

Trouillas

Losa

et al. 2022

European Journal of Endocrinology

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Objective: To describe clinical and pathological characteristics and treatment outcome in a large cohort of aggressive pituitary tumours (APT)/carcinomas (PC). Design: Electronic survey August 2020–May 2021. Results: 96% of 171 (121 APT, 50 PC) initially presented as macro/giant tumours, 6 were microadenomas (5 corticotroph). Ninety-seven tumours, initially considered clinically benign, demonstrated an aggressive behavior after 5.5 years (IQR 2.8-12). 63% of patients were men. ACTH-secreting tumours constituted 30% of the APT/PC, the gonadotroph subtypes were underrepresented.5/13 silent corticotroph tumours and 2/6 silent somatotroph tumours became secreting. Metastases were observed after median 6.3 years (IQR 3.7-12.1) from diagnosis. At the first surgery, Ki67 index was ≥3% in 74/93 (80%), ≥10% in 38/93 (41%) tumours. An absolute increase of Ki67 ≥10% after median 6 years from the first surgery occurred in 18/49 examined tumours. Tumours with an aggressive course from outset had higher Ki67, mitotic counts, and p53. Temozolomide treatment in 156/171 patients resulted in complete response in 9.6%, partial response in 30.1%, stable disease in 28.1%, and progressive disease in 32.2% of the patients. Treatment with bevacizumab, immune checkpoint inhibitors, and peptide receptor radionuclide therapy resulted in partial regression in 1/10, 1/6, and 3/11, respectively. Median survival in APT and PC was 17.2 and 11.3 years, respectively. Tumours with Ki67≥10% and ACTH-secretion were associated with worse prognosis. Conclusion: APT/PCs exhibit a wide and challenging spectrum of behavior. Temozolomide is the first line chemotherapy, other oncological therapies are emerging. Treatment response continues to be difficult to predict with currently studied biomarkers.

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Sexual Dimorphism in Cellular and Molecular Features in Human ACTH-Secreting Pituitary Adenomas

Cited by 14 publications

References 98 publications

Cushing's Syndrome in the Elderly

Cushing's Syndrome in the Elderly

Silibinin, an HSP90 Inhibitor, on Human ACTH-Secreting Adenomas

Aggressive pituitary tumours and carcinomas, characteristics and management of 171 patients

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