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Objective: Activating mutation in Ubiquitin-specific peptidase (USP8) is identified to enhance cell proliferation and adrenocorticotropic hormone (ACTH) secretion from corticotroph pituitary adenoma. We investigated the USP8 variant status in a population of Iranian people with functional corticotroph pituitary adenoma (FCPA). Moreover, a systematic review was conducted to thoroughly explore the role of USP8 variants and the related pathways in corticotroph adenomas, genotype-phenotype correlation in USP8-mutated individuals with FCPA, and the potential role of USP8 and epidermal growth factor receptor (EGFR) as targeted therapies in PFCAs. Methods: Genetic analysis of 20 tissue samples from 19 patients with PFCAs was performed using Sanger sequencing. Moreover, a systematic literature review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Scopus, web of Sciences, and Cochrane databases were searched. The last search was performed on 20 September 2023 for all databases. Results: In our series, we found two somatic mutations including a 7-bp deletion variant: c.2151_2157delCTCCTCC, p. Ser718GlnfsTer3, and a missense variant: c.2159 C > G, p. Pro720Arg (rs672601311) in exon 14. The Systematic review indicated USP8 variant in 35% of corticotroph adenomas, with the highest frequency (25%) in 720 code regions, p. Pro720Arg. Data regarding the impact of USP8 mutational status on clinical characteristics and outcomes in FCPAs are inconsistent. Moreover, Pasireotide as well as inhibitors of EGFR such as Gefitinib and Lapatinib, as well as USP8 inhibitors including -ehtyloxyimino9H-indeno (1, 2-b) pyrazine-2, 3-dicarbonitrile, DUBs-IN-2, and RA-9 indicated promising results in treatment of corticotroph adenomas. Conclusion: Although the USP8-EGFR system has been identified as the main trigger and target of corticotroph tumorigenesis, more precise multicenter studies are required to yield more consistent information regarding the phenotype-genotype correlation and to develop effective targeted therapies. [ABSTRACT FROM AUTHOR]

Background: Cushing's disease is the most prevalent cause of endogenous adrenocorticotrophic hormone hypersecretion. The aim of this study was to document the current clinical practice pattern in the management of Cushing's disease by Iranian Endocrinologists to determine their opinions and compare them with the current clinical practice guidelines. Methods: An eight-item questionnaire dealing with diagnosis, treatment and follow up of patients with Cushing's disease was developed, piloted, and sent to the members of Iranian Endocrinology Society. Results: Among 90 endocrinologists invited to participate in the survey, 76 replied. Most respondents selected overnight dexamethasone suppression test (ONDST) and assessment of 24-hour urinary free cortisol (UFC) as the best screening tests followed by midnight serum cortisol and midnight salivary cortisol. Classic high dose dexamethasone suppression test and measurement of serum ACTH were selected for localization of the primary lesion by 64.5%. The primary choice of treatment was trans-sphenoidal pituitary surgery (86.8%). For the recurrence of Cushing's disease, the preferred treatment modality was medical therapy followed by bilateral adrenalectomy, and pituitary re-surgery. In case of treatment failure after the first pituitary surgery and ketoconazole treatment, 51% chose bilateral adrenalectomy, while36.8% selected pasireotide only. Conclusion: ONDST and UFC are two most common tests used to screen an index case with signs and symptoms of hypercortisolism. The primary choice of treatment in Cushing's disease is pituitary surgery. However, medical treatment by ketokonazol is preferred for the recurrences. Pasireotide is the second alternative after bilateral adrenalectomy in case of treatment failure after pituitary surgery and ketoconazole. [ABSTRACT FROM AUTHOR]