ACTH-Dependent Cyclic Cushing Syndrome Triggered by Glucocorticoid Excess Through a Positive-Feedback Mechanism

Abstract

Context Cyclic Cushing syndrome is a rare variant of Cushing syndrome that demonstrates periodic cortisol excess. It has been thought that inhibition of a glucocorticoid positive-feedback loop is associated with remission of hypercortisolism in ACTH-dependent cyclic Cushing syndrome. However, the underlying mechanism that triggers the development of the hypercortisolism is still unknown. We observed a case of ACTH-dependent cyclic Cushing syndrome that was developed by exogenous glucocorticoids, possibly through a glucocorticoid positive-feedback loop. Case Description A 75-year-old woman had experienced cyclic ACTH and cortisol elevations six times in the previous 4 years. Her diagnosis was cyclic Cushing syndrome. During the hypercortisolemic phase, neither low-dose nor high-dose dexamethasone suppressed her plasma ACTH and cortisol levels. Daily metyrapone therapy decreased her plasma cortisol and ACTH levels during every hypercortisolemic phase. After the sixth remission of a hypercortisolemic phase, she took 25 mg of hydrocortisone for 4 weeks and developed ACTH-dependent hypercortisolemia. Treatment with 1 mg of dexamethasone gradually increased both plasma ACTH and cortisol levels over 2 weeks, resulting in the eighth hypercortisolemic phase. Treatment using a combination of dexamethasone and metyrapone did not increase plasma ACTH or cortisol level and successfully prevented development of ACTH-dependent hypercortisolism. Conclusion We present an interesting case of cyclic Cushing syndrome in which ACTH-dependent hypercortisolemic phases relapsed during exogenous glucocorticoid treatment. A glucocorticoid positive-feedback loop and endogenous glucocorticoid synthesis may play key roles in the periodicity of hypercortisolism in cyclic Cushing syndrome.

Somatostatin Receptor-negative and Fluorodeoxyglucose-positron Emission Tomography-positive Lung Neuroendocrine Tumor G1 Exhibiting Cyclic Cushing's Syndrome

“…To this end, we searched a PubMed database (https://pubmed.ncbi.nlm.nih.gov/) using the following keywords 'ACTH,' 'ectopic,' 'cyclic,' 'periodic,' and/ or 'intermittent.' Furthermore, we manually checked the reference lists to find relevant articles (6,7,(16)(17)(18)(19)(20)(21)(22)(23)(24). We ultimately found 12 cases of cyclic ectopic Cushing's syndrome (Table 5).…”

“…Some previous patients with cyclic ectopic ACTH-producing tumors were unable to receive radical resection because their responsible tumors were not identified ( 6 , 7 ) ( Table 5 ). Therefore, a sequential analysis of these radioisotope imaging modalities is important for the localization of cyclic ectopic ACTH-production tumors and radical resection.…”

“…Furthermore, no report has included the complete radiological findings and immunohistolochemistry findings, including the SSTR expression. Some cases could not receive radical resection because their responsible tumors were unable to be localized ( 6 , 7 ).…”

Cyclic Cushing’s Syndrome – A Diagnostic Challenge

“…The low-dose overnight DST and two-day LDDST are generally contraindicated during remission since subjects can achieve full suppression. Importantly, hormonal suppression tests during relapses may generate paradoxical responses resulting in peaks of serum cortisol ( 15 , 29 ).…”

Paradoxical cortisol response to dexamethasone in corticotroph microadenoma: A useful feature of underlying cyclic hormonogenesis

“…The presence of a GC positive feedback loop on corticotrophs and simultaneous endogenous hypercortisolemia has been suggested as the underlying cause of such paradoxical response. [ 4 ] A period of low endogenous cortisol, as seen during the trough of cyclic CD, probably changes the character of pituitary corticotroph adenoma, that eventually develops a positive feedback response to GC only during subsequent hypercortisolemia in the peak phase of cyclic CS. Exogenous GC administration thus results in paradoxical ACTH-dependent rise in cortisol secretion only during endogenous hypercortisolemia (as noticed during initial visit and second FU visit) and preceding episode of hypocortisolemia is an essential prerequisite to trigger ACTH hypersecretion through a positive feedback loop.…”