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The Mechanisms Underlying Autonomous Adrenocorticotropic Hormone Secretion in Cushing’s Disease

1
Division of Diabetes and Endocrinology, Kobe University Hospital, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan
2
Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan
3
Department of Diabetes and Endocrinology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(23), 9132; https://doi.org/10.3390/ijms21239132
Received: 20 October 2020 / Revised: 21 November 2020 / Accepted: 29 November 2020 / Published: 30 November 2020
(This article belongs to the Special Issue Molecular Biology of the Pituitary)
Cushing’s disease caused due to adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (ACTHomas) leads to hypercortisolemia, resulting in increased morbidity and mortality. Autonomous ACTH secretion is attributed to the impaired glucocorticoid negative feedback (glucocorticoid resistance) response. Interestingly, other conditions, such as ectopic ACTH syndrome (EAS) and non-neoplastic hypercortisolemia (NNH, also known as pseudo-Cushing’s syndrome) also exhibit glucocorticoid resistance. Therefore, to differentiate between these conditions, several dynamic tests, including those with desmopressin (DDAVP), corticotrophin-releasing hormone (CRH), and Dex/CRH have been developed. In normal pituitary corticotrophs, ACTH synthesis and secretion are regulated mainly by CRH and glucocorticoids, which are the ACTH secretion-stimulating and -suppressing factors, respectively. These factors regulate ACTH synthesis and secretion through genomic and non-genomic mechanisms. Conversely, glucocorticoid negative feedback is impaired in ACTHomas, which could be due to the overexpression of 11β-HSD2, HSP90, or TR4, or loss of expression of CABLES1 or nuclear BRG1 proteins. Genetic analysis has indicated the involvement of several genes in the etiology of ACTHomas, including USP8, USP48, BRAF, and TP53. However, the association between glucocorticoid resistance and these genes remains unclear. Here, we review the clinical aspects and molecular mechanisms of ACTHomas and compare them to those of other related conditions. View Full-Text
Keywords: adrenocorticotrophic hormone; Cushing’s disease; glucocorticoid resistance; ectopic ACTH syndrome adrenocorticotrophic hormone; Cushing’s disease; glucocorticoid resistance; ectopic ACTH syndrome
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MDPI and ACS Style

Fukuoka, H.; Shichi, H.; Yamamoto, M.; Takahashi, Y. The Mechanisms Underlying Autonomous Adrenocorticotropic Hormone Secretion in Cushing’s Disease. Int. J. Mol. Sci. 2020, 21, 9132. https://doi.org/10.3390/ijms21239132

AMA Style

Fukuoka H, Shichi H, Yamamoto M, Takahashi Y. The Mechanisms Underlying Autonomous Adrenocorticotropic Hormone Secretion in Cushing’s Disease. International Journal of Molecular Sciences. 2020; 21(23):9132. https://doi.org/10.3390/ijms21239132

Chicago/Turabian Style

Fukuoka, Hidenori; Shichi, Hiroki; Yamamoto, Masaaki; Takahashi, Yutaka. 2020. "The Mechanisms Underlying Autonomous Adrenocorticotropic Hormone Secretion in Cushing’s Disease" Int. J. Mol. Sci. 21, no. 23: 9132. https://doi.org/10.3390/ijms21239132

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