Cushing\'s syndrome (CS) is a complex disorder characterized by the excessive secretion of cortisol, with Cushing\'s disease (CD), particularly associated with pituitary tumors, exhibiting heightened morbidity and mortality. Although transsphenoidal pituitary surgery (TSS) stands as the primary treatment for CD, there is a crucial need to optimize patient prognosis. Current medical therapy serves as an adjunctive measure due to its unsatisfactory efficacy and unpredictable side effects. In this comprehensive review, we delve into recent advances in understanding the pathogenesis of CS and explore therapeutic options by conducting a critical analysis of potential drug targets and candidates. Additionally, we provide an overview of the design strategy employed in previously reported candidates, along with a summary of structure-activity relationship (SAR) analyses and their biological efficacy. This review aims to contribute valuable insights to the evolving landscape of CS research, shedding light on potential avenues for therapeutic development.

OBJECTIVE: To present a case series of Cushing\'s syndrome (CS) during pregnancy caused by adrenocortical adenomas, highlighting clinical features, hormonal assessments and outcomes.
METHODS: We describe five pregnant women with CS, detailing clinical presentations and laboratory findings.
RESULTS: Common clinical features included a full moon face, buffalo back and severe hypertension. Elevated blood cortisol levels with circadian rhythm disruption and suppressed adrenocorticotrophic hormone (ACTH) levels were observed. Imaging revealed unilateral adrenal tumours. Two cases underwent laparoscopic adrenalectomies during the second trimester, while three had postpartum surgery. All required hormone replacement therapy, with postoperative pathological confirmation of adrenocortical adenomas.
CONCLUSIONS: Diagnosis of CS during pregnancy is challenging due to overlapping features with normal pregnancy: elevated blood cortisol levels and abnormal diurnal rhythm of blood cortisol, suppressed aid diagnosis. Treatment should be individualised due to a lack of explicit optimum therapeutic approaches. Laparoscopic adrenalectomy may be an optimal choice, along with multidisciplinary management including hormone replacement therapy.

Adrenal cortical eosinophilic adenoma usually presents as non-functional adrenal tumor but may lead to Cushing\'s syndrome in patients. The present article reports a patient with Cushing\'s syndrome caused by right adrenocortical oncocytoma. The patient was treated in Urology Department of Wuchuan People\'s Hospital (Zunyi, China) in November 2022 because of hirsutism, weight gain and hypertension. A laparoscopic right adrenal tumor resection was performed using an abdominal approach. Following surgery, blood pressure and heart rate of the patient fluctuated within a healthy range and menstruation returned to normal. Laparoscopic adrenalectomy has obvious advantages over open adrenalectomy, such as less trauma, shorter recovery time and fewer complications. Thus, this treatment for this rare disease is safe and feasible.

BACKGROUND: The occurrence of hypercortisolism resulting from adrenocorticotropic hormone (ACTH)-secreting pheochromocytoma is exceedingly uncommon, with limited documented instances thus far.
METHODS: We present a case of ectopic ACTH-secreting pheochromocytoma in a patient who suffered from severe metabolic disorders. Our clinical case outlines the diagnostic history, preoperative correction of the patient\'s metabolic disturbances and surgical strategy for management of a rare ectopic ACTH producing pheochromocytoma.
CONCLUSIONS: Ectopic adrenocorticotropic hormone-secreting pheochromocytoma displays multifaceted clinical features and requires prompt diagnosis and multidisciplinary management in order to overcome the related severe clinical derangements.
CONCLUSIONS: The combination of biochemical and hormonal testing and imaging procedures is mandatory for the diagnosis of ectopic ACTH secretion, and in the presence of an adrenal mass, the possibility of an ACTH-secreting pheochromocytoma should be taken into account.

Cushing\'s syndrome is a rare cause of myocardial infarction and heart failure. Herein, we report a female patient who presented acute myocardial infarction and heart failure with reduced ejection fraction. The patient was found to have hypercortisolism secondary to adrenocortical adenoma and responded well to therapy. This case underlines the effects of hypercortisolism on the cardiovascular system. The clinical presentation of this patient is unique because non-atherosclerotic myocardial infarction is rarely reported in Cushing\'s syndrome patients.

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UNASSIGNED: The most common etiologies of Cushing\'s syndrome (CS) are adrenocorticotropic hormone (ACTH)-producing pituitary adenoma (pitCS) and primary adrenal gland disease (adrCS), both of which burden patients with metabolic disturbance. The aim of this study was to compare the metabolic features of pitCS and adrCS patients.
UNASSIGNED: A retrospective review including 114 patients (64 adrCS and 50 pitCS) diagnosed with CS in 2009-2019 was performed. Metabolic factors were then compared between pitCS and adrCS groups.
UNASSIGNED: Regarding sex, females suffered both adrCs (92.2%) and pitCS (88.0%) more frequently than males. Regarding age, patients with pitCS were diagnosed at a younger age (35.40 ± 11.94 vs. 39.65 ± 11.37 years, p = 0.056) than those with adrCS, although the difference was not statistically significant. Moreover, pitCS patients had much higher ACTH levels and more serious occurrences of hypercortisolemia at all time points (8 AM, 4 PM, 12 AM) than that in adrCS patients. Conversely, indexes, including body weight, BMI, blood pressure, serum total cholesterol, low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), triglycerides, fasting plasma glucose, and uric acid, showed no differences between adrCS and pitCS patients. Furthermore, diabetes prevalence was higher in pitCS patients than in adrCS patients; however, there were no significant differences in hypertension or dyslipidemia prevalence between the two.
UNASSIGNED: Although adrCS and pitCS had different pathogenetic mechanisms, different severities of hypercortisolemia, and different diabetes prevalences, both etiologies had similar metabolic characteristics.

BACKGROUND: Adrenocorticotropic hormone (ACTH)-independent Cushing\'s syndrome (CS) with right adrenal adenoma combined with HIV infection has rarely been reported.
METHODS: A 39-year-old Chinese male patient with HIV infection was admitted to our hospital due to increased blood pressure in the previous 2 years and weight gain in the previous 6 months. Endocrinological examinations showed that blood cortisol (8 a.m.) was 22.23 μg/dl, the level of ACTH (8 a.m.) was less than 1pg/ml and twenty-four-hour urinary cortisol was 1429 μg/24h. ACTH-independent CS was diagnosed based on low ACTH levels (<1.00 pg/ml), a lack of cortisol circadian rhythms, and unsuppressed cortisol levels by dexamethasone. The ultrasonography and multislice spiral computed tomography scan revealed a right adrenal mass. Due to the HIV status of the patient, we measured the count of CD4+ T helper cells. Laparoscopic right adrenal resection was performed after the CD4+ T helper cell count was > 200 cells/μl. Subsequent immunohistochemical staining confirmed right adrenal adenoma.
RESULTS: The postoperative recovery was good, and wound healing was possible. After surgical treatment, endocrinological examinations indicated that the level of ACTH increased and the levels of serum cortisol and twenty-four-hour urinary cortisol decreased, which indicated that CS was controlled. CD4/CD8 was 0.47 at reexamination, and the patient\'s immunity was improved.
CONCLUSIONS: Due to the potential side effects of steroid drugs, clinicians should use these medications with caution and closely monitor the development of adrenal deficiency.

Background: Endogenous Cushing\'s syndrome (CS), also called hypercortisolism, leads to a significant increase in mortality due to excessive cortisol production, which is mainly due to cardiovascular disease. CS complicated with cardiomyopathies, which is a rare and severe condition, has rarely been reported in the literature. Objective: To investigate the clinical characteristics of CS complicated with cardiomyopathies, we retrospectively reviewed the clinical manifestations, laboratory results, cardiac imaging results and prognosis to further understand the diagnosis, treatment, and management of these cases. Methods: The clinical data of patients diagnosed with CS complicated with cardiomyopathies obtained from discharge sheets from Peking Union Medical College Hospital from January 1986 to August 2021 were collected. Case reports of CS complicated with cardiomyopathies were retrieved from PubMed. In addition, Cushing\'s disease (CD) patients without cardiomyopathies were collected as controls to compare the clinical features. Results: A total of 19 cases of CS complicated with cardiomyopathies and cases of CD without cardiomyopathies (n = 242) were collected. The causes of CS included pituitary adenoma (n = 8, 42.11%), adrenal adenoma (n = 7, 36.84%), ectopic adrenocorticotropic hormone (ACTH) tumor (n = 2, 10.53%) and unclear causes (n = 2, 10.53%) in the CS complicated with cardiomyopathies group. The types of cardiomyopathies were dilated cardiomyopathies (n = 15, 78.94%) and hypertrophic cardiomyopathies (n = 4, 21.05%). The serum sodium concentration was significantly higher [145.50 (140.50-148.00) mmol/L vs. 141.00 (140.00-143.00) mmol/L], while the serum potassium concentration was significantly lower [2.70 (2.40-3.60) mmol/L] vs. 3.90 (3.50-4.20 mmol/L)] in the CS complicated with cardiomyopathies group compared to the CD patients without cardiomyopathies. There were no significant differences between the CS complicated with cardiomyopathies group and the CD patients without cardiomyopathies in the serum cortisol concentration and 24-h urine free cortisol, but a significant difference in the adrenocorticotropic hormone level [109.00 (91.78-170.30) pg/ml vs. 68.60 (47.85-110.00) pg/ml]. Twelve/16 (75.0%) patients showed significant improvement or even a complete healing of the heart structure and function after remission of hypercortisolemia after treatment with CS. Conclusions: CS complicated with cardiomyopathies is a very rare clinical entity, in which cortisol plays an important role and it can be greatly improved after remission of hypercortisolemia.

Somatic mutations in the PRKACA gene encoding the catalytic α subunit of protein kinase A (PKA-C) are responsible for cortisol-producing adrenocortical adenomas. These benign neoplasms contribute to the development of Cushing\'s syndrome. The majority of these mutations occur at the interface between the two lobes of PKA-C and interfere with the enzyme\'s ability to recognize substrates and regulatory (R) subunits, leading to aberrant phosphorylation patterns and activation. Rarely, patients with similar phenotypes carry an allosteric mutation, E31V, located at the C-terminal end of the αA-helix and adjacent to the αC-helix, but structurally distinct from the PKA-C/R subunit interface mutations. Using a combination of solution NMR, thermodynamics, kinetic assays, and molecular dynamics simulations, we show that the E31V allosteric mutation disrupts central communication nodes between the N- and C- lobes of the enzyme as well as nucleotide-substrate binding cooperativity, a hallmark for kinases\' substrate fidelity and regulation. For both orthosteric (L205R and W196R) and allosteric (E31V) Cushing\'s syndrome mutants, the loss of binding cooperativity is proportional to the density of the intramolecular allosteric network. This structure-activity relationship suggests a possible common mechanism for Cushing\'s syndrome driving mutations in which decreased nucleotide/substrate binding cooperativity is linked to loss in substrate fidelity and dysfunctional regulation.