RARE DISEASE
Endogenous Cushing syndrome
Endogenous Cushing syndrome
Endogenous Cushing syndrome
Synonyms: Endogenous CS
Synonyms: Endogenous CS
Synonyms: Endogenous CS
Drug discovery
19
drugs
With orphan designations
Overview
Endogenous Cushing syndrome is a rare endocrine disorder caused by chronic cortisol excess due to ACTH-secreting pituitary tumors (Cushing disease, 70-80% of cases), ectopic ACTH production, or adrenal tumors. Clinical features include central obesity, muscle weakness, hypertension, metabolic disturbances, and neuropsychiatric symptoms. Diagnosis relies on biochemical testing (e.g., late-night salivary cortisol, dexamethasone suppression) and imaging. First-line treatment involves tumor resection, but persistent/recurrent disease often requires multimodal therapy (radiation, medical management). Despite treatment, patients often experience persistent comorbidities and reduced quality of life [1][3][9][11][13].
Burden
Morbidity: Persistent symptoms (fatigue, anxiety, weight gain) and comorbidities (cardiovascular disease, osteoporosis, diabetes) despite treatment [1][4][6][14].
Mortality: 3.5–5× higher risk vs. general population, driven by cardiovascular/thromboembolic events [9][19].
Quality of life: Moderate-to-severe impairment, ~25 missed workdays/year, frequent healthcare utilization [1][4][14].
Therapies
Second-line: Radiation, repeat surgery, or medical therapy (steroidogenesis inhibitors [ketoconazole, osilodrostat], pituitary-directed agents [pasireotide, cabergoline], glucocorticoid receptor antagonists [mifepristone]) [3][8][13].
Emerging: Combination therapies to improve efficacy and tolerability [10][13].
Categories: rare endocrine diseases
Research Papers
348 drug discovery papers about Endogenous Cushing syndrome, with 2 first-in-class and 8 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
348 drug discovery papers about Endogenous Cushing syndrome, with 2 first-in-class and 8 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2025-09-13 | Growth hormone deficiency in Cushing's syndrome: an update on diagnosis and management.
Endogenous Cushing's syndrome (CS) is associated with substantial morbidity and mortality. Patients in remission may experience many comorbidities, including growth hormone deficiency (GHD). Electronic searches (PubMed) were conducted through July 2025. The published data largely pertain to patients with Cushing's disease (CS caused by a pituitary tumor). This article reviews the epidemiology of GHD in patients with CS in remission, underlying mechanisms, and clinical manifestations. The diagnosis of GHD is discussed along with data on the effectiveness and safety of growth hormone replacement. GHD is common in patients with active CS and may persist among patients in remission. In children, decreased linear growth is prevalent. In adults in remission, GHD has been associated with a higher prevalence of cardiometabolic burden (hypertension, diabetes mellitus, cardiovascular and cerebrovascular disease), decreased muscle strength, lower bone mineral density and increased prevalence of fractures. The diagnosis of GHD generally requires stimulation testing and should only be undertaken in patients in remission. In children with CS in remission, growth hormone replacement improves adult height. In adults, growth hormone replacement may improve quality of life, bone mineral density, muscle strength and dyslipidemia but requires careful monitoring for the possible development of hyperglycemia.
2022-03-03 | Cushing syndrome and glucocorticoids: T-cell lymphopenia, apoptosis, and rescue by IL-21.
Pediatric endogenous Cushing syndrome (eCs) is mainly caused by pituitary corticotropin-producing adenomas, and most glucocorticoid-dependent effects progressively regress upon tumor removal. eCs reproduces long-term, high-dose glucocorticoid therapy, representing a clean, natural, and unbiased model in which to study glucocorticoid bona fide effects on immunity. We performed extensive immunologic studies in otherwise healthy pediatric patients with eCs before and 6 to 13 months after tumor resection, as well as in in vitro glucocorticoid-treated control cells. Flow cytometry, immunoblotting, enzyme-linked immunosorbent assay, real-time quantitative PCR, and RNA-Seq techniques were used to characterize patients' and in vitro glucocorticoid treated cells. Reduced thymic output, decreased naive T cells, diminished proliferation, and increased T-cell apoptosis were detected before surgery; all these defects eventually normalized after tumor removal in patients. In vitro studies also showed increased T-cell apoptosis, with correspondingly diminished NF-κB signaling and IL-21 levels. In this setting, IL-21 addition upregulated antiapoptotic BCL2 expression and rescued T-cell apoptosis in a PI3K pathway-dependent manner. Similar and reproducible findings were confirmed in eCs patient cells as well. We identified decreased thymic output and lymphocyte proliferation, together with increased apoptosis, as the underlying causes to T-cell lymphopenia in eCs patients. IL-21 was decreased in both natural and in vitro long-term, high-dose glucocorticoid environments, and in vitro addition of IL-21 counteracted the proapoptotic effects of glucocorticoid therapy. Thus, our results suggest that administration of IL-21 in patients receiving long-term, high-dose glucocorticoid therapy may contribute to ameliorate lymphopenia and the complications associated to it.
2021-06-18 | Cushing Syndrome Associated Myopathy: It Is Time for a Change
Cushing syndrome is the result of excessive levels of glucocorticoids. Endogenous Cushing syndrome is rare with an incidence of two to three cases per million per year. Clinically, the presentation consists of a characteristic phenotype including skin symptoms and metabolic manifestations. A frequent co-morbidity with high impact on quality of life is Cushing syndrome associated myopathy. It characteristically affects the proximal myopathy, impairing stair climbing and straightening up. The pathophysiology is complex and involves protein degradation via the forkhead box O3 (FOXO3) pathway, intramuscular fat accumulation, and inactivity-associated muscle atrophy. Surgical remission of Cushing syndrome is the most important step for recovery of muscle function. Restoration depends on age, co-morbidities and postoperative insulin-like growth factor concentrations. At average, functionality remains impaired during the long-term compared to age and sex matched control persons. Growth hormone therapy in individuals with impaired growth hormone secretion could be an option but has not been proved in a randomized trial. Keywords: Glucocorticoids; Quality of life; Cushing syndrome; Growth hormone; Stair climbing; Muscular atrophy; Somatomedins; Phenotype; Bodily secretions; Muscles
2019-12-23 | Discovery of Melanocortin Ligands via a Double Simultaneous Substitution Strategy Based on the Ac-His-dPhe-Arg-Trp-NH2 Template.
The melanocortin system regulates an array of diverse physiological functions including pigmentation, feeding behavior, energy homeostasis, cardiovascular regulation, sexual function, and steroidogenesis. Endogenous melanocortin agonist ligands all possess the minimal messaging tetrapeptide sequence His-Phe-Arg-Trp. Based on this endogenous sequence, the Ac-His1-dPhe2-Arg3-Trp4-NH2 tetrapeptide has previously been shown to be a useful scaffold when utilizing traditional positional scanning approaches to modify activity at the various melanocortin receptors (MC1-5R). The study reported herein was undertaken to evaluate a double simultaneous substitution strategy as an approach to further diversify the Ac-His1-dPhe2-Arg3-Trp4-NH2 tetrapeptide with concurrent introduction of natural and unnatural amino acids at positions 1, 2, or 4, as well as an octanoyl residue at the N-terminus. The designed library includes the following combinations: (A) double simultaneous substitution at capping group position (Ac) together with position 1, 2, or 4, (B) double simultaneous substitution at positions 1 and 2, (C) double simultaneous substitution at positions 1 and 4, and (D) double simultaneous substitution at positions 2 and 4. Several lead ligands with unique pharmacologies were discovered in the current study including antagonists targeting the neuronal mMC3R with minimal agonist activity and ligands with selective profiles for the various melanocortin subtypes. The results suggest that the double simultaneous substitution strategy is a suitable approach in altering melanocortin receptor potency or selectivity or converting agonists into antagonists and vice versa.
2011-01-31 | Solid-phase peptide head-to-side chain cyclodimerization: discovery of C(2)-symmetric cyclic lactam hybrid α-melanocyte-stimulating hormone (MSH)/agouti-signaling protein (ASIP) analogues with potent activities at the human melanocortin receptors.
A novel hybrid melanocortin pharmacophore was designed based on the pharmacophores of the agouti-signaling protein (ASIP), an endogenous melanocortin antagonist, and α-melanocyte-stimulating hormone (α-MSH), an endogenous melanocortin agonist. The designed hybrid ASIP/MSH pharmacophore was explored in monomeric cyclic, and cyclodimeric templates. The monomeric cyclic disulfide series yielded peptides with hMC3R-selective non-competitive binding affinities. The direct on-resin peptide lactam cyclodimerization yielded nanomolar range (25-120 nM) hMC1R-selective full and partial agonists in the cyclodimeric lactam series which demonstrates an improvement over the previous attempts at hybridization of MSH and agouti protein sequences. The secondary structure-oriented pharmacophore hybridization strategy will prove useful in development of unique allosteric and orthosteric melanocortin receptor modulators. This report also illustrates the utility of peptide cyclodimerization for the development of novel GPCR peptide ligands.
cell therapies
2024-02-15 | Gut microbiota dysbiosis and decreased levels of acetic and propionic acid participate in glucocorticoid-induced glycolipid metabolism disorder.
Long-term/high-dose glucocorticoid (GC) use results in glycolipid metabolism disorder, which severely limits its clinical application. The role of the gut microbiota and its metabolites in GC-induced glycolipid metabolism disorder remains unclear. Our previous human study found that obvious gut microbiota dysbiosis characterized by an increasing abundance of Proteobacteria and a decreased abundance of Lachnospiraceae and Faecalibacterium were observed in patients with endogenous hypercortisolism. In this study, we established a mouse model of GC-induced glycolipid metabolism disorder (Dex group) and found that the relative abundances of Proteobacteria and Parasuttrerella were increased, while the abundances of Lachnospiraceae, Faecalibacterium, and Lachnospiraceae_NK4A136_group were decreased significantly in the Dex group. Compared with the control group, serum total short-chain fatty acids (SCFAs), acetic acid, propionic acid, and GLP-1 levels were all decreased in the Dex group. The mRNA expression of the GPR41 receptor and Pcsk1 in the colon was significantly decreased in the Dex group. Furthermore, GC-induced glycolipid metabolism disorder could be alleviated by depletion of the gut microbiota or fecal bacteria transplantation with control bacteria. The abundances of Lachnospiraceae_NK4A136_group and the serum GLP-1 levels were significantly increased, while the abundances of Proteobacteria and Parasutterella were significantly decreased after fecal bacteria transplantation with control bacteria. Our work indicates that gut microbiota dysbiosis and decreased levels of serum acetic acid and propionic acid may participate in GC-induced glycolipid metabolism disorder. These findings may provide novel insights into the prevention and treatment of GC-induced metabolic disorders.IMPORTANCEThe role of the gut microbiota in glucocorticoid (GC)-induced glycolipid metabolism disorder remains unclear. In our study, gut microbiota dysbiosis characterized by an increased abundance of Proteobacteria/Parasuttrerella and a decreased abundance of Lachnospiraceae_NK4A136_group was observed in mice with GC-induced glycolipid metabolism disorder. Some bacteria were shared in our previous study in patients with endogenous hypercortisolism and the mouse model used in the study. Furthermore, the depletion of the gut microbiota and fecal bacteria transplantation with control bacteria could alleviate GC-induced glycolipid metabolism disorder. Plasma acetic acid, propionic acid, and GLP-1 and the mRNA expression of the GPR41 receptor and Pcsk1 in the colon were decreased significantly in mice with GC-induced glycolipid metabolism disorder, which indicated that the gut microbiota/SCFA/GPR41/GLP-1 axis may participate in GC-induced glycolipid metabolism disorder. Our findings indicate that the gut microbiota may serve as a novel therapeutic target for GC-related metabolic disorders.
2019-10-09 | Cushing Syndrome: The Role of MSCs in Wound Healing, Immunosuppression, Comorbidities, and Antioxidant Imbalance
Cushing syndrome (CS), caused by glucocorticoid (GCs) excess, is strictly connected to onset of different metabolic diseases and impaired wound healing. The source of excessively high levels of GCs allows the identification of endogenous and exogenous (iatrogenic) CS. Iatrogenic patients usually receive also anti-metabolites serving as the foundation to modern steroid-sparing immunosuppressive therapy. Tissues mainly targeted by CS are bone and fat, both derived from progenitor cells named mesenchymal stem cells (MSCs). In addition, the pathogenic role of MSCs in other diseases sharing common properties with CS, such as an altered inflammatory profile and increased oxidative stress, has been identified. In this light, MSCs isolated from skin of control healthy subjects (C-MSCs), patients affected by endogenous CS (ENDO-MSCs), patients affected by iatrogenic CS (IATRO-MSCs) and patients affected by exogenous CS receiving steroid-sparing drugs (SS-MSCs), respectively, have been isolated and analyzed. ENDO- and IATRO-MSCs showed a reduced differentiative potential toward osteogenic and adipogenic lineages compared to C-MSCs, whereas SS-MSCs re-acquired the ability to differentiate, with a trend similar to control cells. In addition, MSCs from CS groups, compared to control MSCs, displayed a reduction in the secretion of cytokines (immune-suppression), a decreased expression of genes related to wound healing and a dysregulation of the enzymes/genes related to antioxidant capacity. In conclusion, our results suggest that the hallmarks of CS, such as wound healing impairment and immunosuppression, are already detectable in undifferentiated cells, which could be considered a potential therapeutic early target for control of CS.
2006-12-16 | Aberrant GPCR expression is a sufficient genetic event to trigger adrenocortical tumorigenesis
Aberrant expression of G protein-coupled receptors (GPCR) in the adrenal cortex is observed in some cases of ACTH-independent macronodular adrenal hyperplasias and adenomas associated with Cushing syndrome (CS). Although there is clinical evidence for the implication of these receptors in abnormal regulation of cortisol secretion, whether this aberrant expression also directly causes the development of a benign adrenocortical tumor is an open question. Cell transplantation provides a way to study genes that may be important in human tumor development. The system we developed uses genetically modified adrenocortical cells transplanted into adrenalectomized immunodeficient mice, which form a functional tissue structure. We observed that enforcing expression of the gastric inhibitory polypeptide (GIP) receptor or the luteinizing hormone (LH) receptor genes (taken as canonical examples of aberrantly expressed GPCRs) in adrenocortical cells resulted in the formation of hyperplastic tissues and the development of Cushing syndrome features in transplanted mice.
small molecules
2026-08-11 | Pituitary tumour shrinkage and diabetic remission in two cats with Cushing syndrome treated with cabergoline.
We describe two cats with diabetes mellitus and Cushing's syndrome. Diabetes mellitus was initially managed with insulin glargine (Lantus; Sanofi-Aventis, Paris, France), nutritional therapy and continuous glucose monitoring. Hypercortisolism was suspected based on severe hypertension (Case 1), and insulin resistance in combination with typical clinical features of Cushing's syndrome (Case 2). Endocrine testing revealed non-suppressible cortisol concentrations on low-dose-dexamethasone suppression test, elevated endogenous adenocorticotrophic hormone (ACTH) concentration and pituitary enlargement on computed tomography. Cabergoline (Holiday®, Holliday-Scott S.A., Buenos Aires, Argentina) was initiated at a dose of 10 μg/kg po every 48 hours targeting both the pituitary tumour and hypercortisolism. In Case 2, the cabergoline dosage was gradually increased to a final dose of 10 μg/kg po every 12 hours. Both cats achieved diabetic remission within 1 and 6 months of treatment, respectively. Serial monitoring demonstrated a decrease in endogenous ACTH concentrations and a reduction in pituitary volume of 29% of baseline (Case 1) and of 52% of baseline (Case 2) after 8 months of treatment. These findings suggest that cabergoline may be a potential medical treatment option in cats with pituitary-dependent hypercortisolism.
2026-07-03 | Importance of Hypercortisolism in BP Control, Cardiovascular Risk and in Patients With Difficult-to-Control Hypertension: An Overview for Primary Care Physicians.
Hypertension remains one of the most prevalent and consequential modifiable cardiovascular risk factors worldwide, affecting approximately 1.28 billion adults globally and nearly half of the United States population. Despite the availability of effective therapies, optimal blood pressure control is achieved in fewer than one in four patients, contributing substantially to the burden of myocardial infarction, stroke, heart failure, chronic kidney disease and cognitive decline. Resistant hypertension, defined as blood pressure remaining above goal despite three maximally tolerated antihypertensive agents including a diuretic or requiring four or more agents to achieve control, affects a meaningful proportion of hypertensive patients and carries a disproportionately elevated risk of end-organ damage and adverse cardiovascular events. In this review, we sought to describe how hypercortisolism has historically been underrecognized and under screened as a secondary cause of resistant hypertension, in part due to the perception that overt Cushing's syndrome is rare. However, emerging evidence is challenging this assumption. The CATALYST study demonstrated a 24% prevalence of endogenous hypercortisolism amongst patients with difficult-to-control type 2 diabetes and a 37% prevalence in those requiring three or more antihypertensive medications. Treatment with the glucocorticoid receptor antagonist mifepristone resulted in improvements in glycemic control and body weight, providing hypothesis generating evidence that hypercortisolism may be a relevant, as opposed to an incidental, contributor to cardiometabolic dysregulation. The MOMENTUM registry prospectively evaluated the prevalence of endogenous hypercortisolism specifically in patients with resistant hypertension and found that hypercortisolism was present in 27.3% of this cohort of patients. Primary care providers occupy a central role in the recognition, initial workup and coordinated management of hypertension, including appropriate screening for secondary causes. Awareness of hypercortisolism as an underdiagnosed driver of treatment-resistant hypertension represents an important and potentially treatable opportunity to improve outcomes at the primary care level.
2026-04-24 | Deterioration Of Blood Lipids During Early Postoperative Remission Of Cushing's Syndrome: A Longitudinal Cohort Study.
Cushing´s syndrome (CS) is associated with an unfavorable lipid profile. However, data on lipid alterations during early postoperative remission, a particularly cardiovascular vulnerable period, are lacking. Evaluation of lipid profiles during active CS and the early postoperative period. In this single-center cohort study at LMU Hospital Munich, we analyzed lipid profiles (Total cholesterol, LDL, HDL, ApoA1, ApoB, Lipoprotein (a), Triglycerides and Non-esterified fatty acids) and metabolic markers in 26 patients with endogenous CS before surgery and 1, 3, 6, 12 and 24 months (n=23) after curative surgery, and compared them with 26 age-, BMI-, and sex-matched controls without hypercortisolism at baseline. Paradoxically most lipid parameters postoperatively worsened. One month postoperatively, HDL (1mo postoperative 38 mg/dL [35-46] vs. active CS 49.5 mg/dL [45-61.3], p<0.0001) and ApoA1 concentrations (1mo postoperative 160 mg/dL [147-168] vs. active CS 193 mg/dL [169-211], p<0.0001) were significantly lower compared to preoperative levels. Similarly one month following surgery triglycerides concentrations (1mo postoperative 185 mg/dL [154-218] vs. active CS 129 mg/dL [89.3-186] preoperatively, p<0.0001) were higher. These changes remained evident until 6 months post-surgery. The triglyceride-glucose index increased during early remission and showed a positive correlation with inflammatory markers CRP and IL-6. Non-esterified fatty acids displayed three distinct postoperative trajectories depending on BMI at baseline. During the early remission phase following curative surgery, we observed a further deterioration in lipid parameters. This can affect cardiovascular health and provides the basis for targeted therapy.
2026-04-09 | "Glucocorticoids, Cushing syndrome and cellular senescence: a mechanistic link to metabolic ageing".
Glucocorticoids are key regulators of immune, stress and inflammatory responses, as well as of multiple metabolic pathways throughout life, and they play an anabolic role in tissue and organ development. Chronic glucocorticoid excess, whether due to endogenous Cushing syndrome, long-term pharmacological treatment or persistent stress, induces tissue-specific alterations that closely resemble those seen during physiological ageing. These shared changes include loss of tissue regenerative capacity, altered body composition, impaired glucose and lipid homeostasis and increased cardiovascular and neuropsychiatric vulnerability. Emerging evidence indicates that glucocorticoid excess can promote cellular senescence, amplify proinflammatory signalling and disrupt interorgan communication, thereby accelerating a state of metabolic ageing. This review synthesises current clinical and experimental data linking glucocorticoid excess with cellular senescence in key metabolic organs and systems, including adipose tissue, skeletal muscle, liver, bone, the cardiovascular system and the brain. Particular emphasis is placed on chronic neoplastic hypercortisolism as a human model, while also considering prolonged pharmacological glucocorticoid exposure and sustained stress as more prevalent, subclinical sources of hormonal overload. By integrating these lines of evidence, we outline the emerging concept of glucocorticoid-driven metabolic ageing and highlight potential mechanistic targets along the glucocorticoid axis and within senescence pathways. A better understanding of these mechanisms may inform strategies to prevent or mitigate age-related metabolic and cardiovascular complications in patients with Cushing syndrome, in individuals exposed to long-term glucocorticoid therapy and in the broader ageing population.
2026-04-03 | Small-cell carcinoma of the cervix with acute-onset psychotic symptoms associated with clinically diagnosed ectopic ACTH production: a case report.
Small-cell carcinoma of the cervix (SCCC) is a rare and highly aggressive histological subtype of cervical cancer, associated with poor prognosis. SCCC is histologically classified as a neuroendocrine tumor and has the potential to produce ectopic hormones, leading to various paraneoplastic syndromes. This report is a rare case of recurrent SCCC presenting with psychiatric symptoms due to endogenous Cushing's syndrome caused by ectopic adrenocorticotropic hormone (ACTH) production. The patient initially developed mood and behavioral disturbances as the disease progressed, leading to hospitalization under the suspicion of a primary psychiatric disorder. However, further evaluation, prompted by the discovery of severe hypokalemia, revealed Cushing's syndrome associated with clinically diagnosed ectopic ACTH production in the setting of recurrent disease. Her psychiatric symptoms rapidly remitted following the administration of a cortisol synthesis inhibitor. This case highlights the importance of considering endocrine disorders as potential causes of psychiatric manifestations in patients with cancer, particularly those with neuroendocrine tumors such as SCCC. Acute and marked elevation of endogenous cortisol can induce distinct psychiatric symptoms, such as manic features and grandiose delusions, that often respond better to endocrine treatment aimed at normalizing cortisol levels rather than to antipsychotic therapy alone. Clinicians should be aware of this rare but important clinical presentation as timely diagnosis and management can improve patient outcomes.
gene therapies
2023-05-03 | Glucocorticoid receptor polymorphism BclI with increased glucocorticoid sensitivity has a positive influence on quality of life in endogenous Cushing's syndrome in remission.
Patients with endogenous Cushing's syndrome (CS) may suffer from a wide range of neuropsychiatric symptoms leading to impaired quality of life (QoL). Glucocorticoid receptor (GR) polymorphisms are associated with increased (BclI and N363S) or decreased (A3669G and ER22/23EK) GR sensitivity. GR genotypes may modulate and affect QoL and recovery after remission differently via GR sensitivity. 295 patients with endogenous CS (81 active, 214 in remission) from 3 centers of the German Cushing's Registry were included for the cross-sectional analysis. All subjects were assessed with three questionnaires (CushingQoL, Tuebingen CD-25, SF-36). For the longitudinal part, 120 patients of them were analyzed at baseline and after 1.5 ± 0.9 yrs of follow-up. DNA samples were obtained from peripheral blood leukocytes for GR genotyping. Patients in remission scored significantly better than patients with active CS in the CushingQoL questionnaire and in the SF-36 sub-categories physical and social functioning, role-physical, bodily pain, and vitality. In cross-sectional analysis, no differences in QoL between minor allele and wildtype carriers were detected for all polymorphisms in active or cured CS. In longitudinal analysis, however, carriers with BclI minor allele showed significant improvement in SF-36 sub-categories vitality (P = .038) and mental health (P = .013) compared to wildtype carriers (active CS at baseline vs. CS in remission at follow-up). The outcome of the two questionnaires CushingQoL and Tuebingen CD-25 improved significantly in both wildtype and minor allele carriers. BclI minor allele carriers initially had the lowest QoL but recovered better from impaired QoL than wildtype carriers.
2011-11-03 | Association of glucocorticoid receptor polymorphism A3669G with decreased risk of developing diabetes in patients with Cushing's syndrome
Objective Glucocorticoid receptor ( GR ) polymorphisms alter glucocorticoid (GC) sensitivity and have been associated with altered metabolic profiles. We evaluate the prevalence of the four GR ( NR3C1 ) polymorphisms BclI, N363S, ER22/23EK, and A3669G in patients with Cushing's syndrome (CS) compared with healthy controls (HC) and we investigate their role in the development of metabolic abnormalities in patients with CS according to their hormonal profile. Patients and methods Sixty-one patients with CS and 71 sex- and age-matched HC were genotyped. Results BclI variant was markedly higher in patients with CS compared with HC (62 vs 41%, P <0.05) while no significant differences were found among other polymorphisms. A very low frequency of N363S and the ER22/23EK was observed. In CS patients, despite the significantly increased levels of morning serum cortisol in BclI carriers compared with wild type no clinical or metabolic differences were found. In contrast, A3669G GR carriers showed a significantly reduced prevalence of type 2 diabetes mellitus compared with wild type (19 vs 68%, P =0.001) despite the higher levels of both serum morning (21.7±6 vs 27.3±8.6 μg/dl, P =0.009) and midnight cortisol (18.8±5.8 vs 24.0±8.0 μg/dl, P =0.01). The negative association between diabetes and A3669G GR polymorphism remained significant when data were adjusted for potential confounding factors. Conclusions The A3669G polymorphism of the GR gene plays a protective role in patients with CS, attenuating the effects of GC excess on glucose metabolism as shown by their reduced risk of diabetes.
other
2026-01-29 | Reversal of Cushing syndrome by antibody-mediated neutralization of ACBP/DBI.
Cushing syndrome (CS) is caused by an increase in endogenous or exogenous glucocorticoids, leading to major alterations in body composition, including visceral obesity, sarcopenia, osteoporosis, type 2 diabetes, and dyslipidemia. Cardiovascular complications resulting from CS are often lethal. We previously demonstrated that CS induced by oral corticosterone (CORT) supplementation in mice can be prevented by inhibition of the peptide hormone acyl-CoA binding protein (ACBP), encoded by the gene diazepam binding inhibitor (DBI). Here, we investigated whether ACBP/DBI inhibition could be used to treat, rather than prevent, CS. To this end, we initiated treatment with anti-ACBP/DBI monoclonal antibodies (mAbs) in mice three weeks after the start of CORT supplementation, when hyperphagia and body weight gain were already established. Two anti-ACBP/DBI mAbs, 7G4a (specific for mouse ACBP/DBI only) and 82 (which recognizes both mouse and human ACBP/DBI), were able to normalize food intake and halt weight gain in mice under continuous CORT treatment. In addition, both mAbs attenuated CORT-induced sarcopenia, adiposity in inguinal, perigonadal, and visceral fat depots, and fully restored metabolic parameters, including type-2 diabetes, insulinemia, free fatty acids, triglycerides, and liver transaminases. In conclusion, neutralization of ACBP/DBI may serve as an effective therapeutic strategy for the treatment of established CS.
2022-06-22 | Successful Immunomodulatory Treatment of COVID-19 in a Patient With Severe ACTH-Dependent Cushing’s Syndrome: A Case Report and Review of Literature
Introduction Patients with Cushing’s syndrome (CS) represent a highly sensitive group during corona virus disease 2019 (COVID-19) pandemic. The effect of multiple comorbidities and immune system supression make the clinical picture complicated and treatment challenging. Case report A 70-year-old female was admitted to a covid hospital with a severe form of COVID-19 pneumonia that required oxygen supplementation. Prior to her admission to the hospital she was diagnosed with adrenocorticotropic hormone (ACTH)-dependent CS, and the treatment of hypercortisolism had not been started yet. Since the patient’s condition was quickly deteriorating, and with presumend immmune system supression due to CS, we decided on treatement with intraveonus immunoglobulins (IVIg) that enabled quick onset of immunomodulatory effect. All comorbidities were treated with standard of care. The patient’s condition quickly stabilized with no direct side effects of a given treatment. Conclusion Treatment of COVID-19 in patients with CS faces many challenges due to the complexity of comorbidity effects, immunosupression and potential interactions of available medications both for treatment of COVID-19 and CS. So far, there are no guidelines for treatment of COVID-19 in patients with active CS. It is our opinion that immunomodulating therapies like IVIg might be an effective and safe treatment modality in this particularly fragile group of patients.
proteins
2025-09-13 | Growth hormone deficiency in Cushing's syndrome: an update on diagnosis and management.
Endogenous Cushing's syndrome (CS) is associated with substantial morbidity and mortality. Patients in remission may experience many comorbidities, including growth hormone deficiency (GHD). Electronic searches (PubMed) were conducted through July 2025. The published data largely pertain to patients with Cushing's disease (CS caused by a pituitary tumor). This article reviews the epidemiology of GHD in patients with CS in remission, underlying mechanisms, and clinical manifestations. The diagnosis of GHD is discussed along with data on the effectiveness and safety of growth hormone replacement. GHD is common in patients with active CS and may persist among patients in remission. In children, decreased linear growth is prevalent. In adults in remission, GHD has been associated with a higher prevalence of cardiometabolic burden (hypertension, diabetes mellitus, cardiovascular and cerebrovascular disease), decreased muscle strength, lower bone mineral density and increased prevalence of fractures. The diagnosis of GHD generally requires stimulation testing and should only be undertaken in patients in remission. In children with CS in remission, growth hormone replacement improves adult height. In adults, growth hormone replacement may improve quality of life, bone mineral density, muscle strength and dyslipidemia but requires careful monitoring for the possible development of hyperglycemia.
2022-03-03 | Cushing syndrome and glucocorticoids: T-cell lymphopenia, apoptosis, and rescue by IL-21.
Pediatric endogenous Cushing syndrome (eCs) is mainly caused by pituitary corticotropin-producing adenomas, and most glucocorticoid-dependent effects progressively regress upon tumor removal. eCs reproduces long-term, high-dose glucocorticoid therapy, representing a clean, natural, and unbiased model in which to study glucocorticoid bona fide effects on immunity. We performed extensive immunologic studies in otherwise healthy pediatric patients with eCs before and 6 to 13 months after tumor resection, as well as in in vitro glucocorticoid-treated control cells. Flow cytometry, immunoblotting, enzyme-linked immunosorbent assay, real-time quantitative PCR, and RNA-Seq techniques were used to characterize patients' and in vitro glucocorticoid treated cells. Reduced thymic output, decreased naive T cells, diminished proliferation, and increased T-cell apoptosis were detected before surgery; all these defects eventually normalized after tumor removal in patients. In vitro studies also showed increased T-cell apoptosis, with correspondingly diminished NF-κB signaling and IL-21 levels. In this setting, IL-21 addition upregulated antiapoptotic BCL2 expression and rescued T-cell apoptosis in a PI3K pathway-dependent manner. Similar and reproducible findings were confirmed in eCs patient cells as well. We identified decreased thymic output and lymphocyte proliferation, together with increased apoptosis, as the underlying causes to T-cell lymphopenia in eCs patients. IL-21 was decreased in both natural and in vitro long-term, high-dose glucocorticoid environments, and in vitro addition of IL-21 counteracted the proapoptotic effects of glucocorticoid therapy. Thus, our results suggest that administration of IL-21 in patients receiving long-term, high-dose glucocorticoid therapy may contribute to ameliorate lymphopenia and the complications associated to it.
2021-06-18 | Cushing Syndrome Associated Myopathy: It Is Time for a Change
Cushing syndrome is the result of excessive levels of glucocorticoids. Endogenous Cushing syndrome is rare with an incidence of two to three cases per million per year. Clinically, the presentation consists of a characteristic phenotype including skin symptoms and metabolic manifestations. A frequent co-morbidity with high impact on quality of life is Cushing syndrome associated myopathy. It characteristically affects the proximal myopathy, impairing stair climbing and straightening up. The pathophysiology is complex and involves protein degradation via the forkhead box O3 (FOXO3) pathway, intramuscular fat accumulation, and inactivity-associated muscle atrophy. Surgical remission of Cushing syndrome is the most important step for recovery of muscle function. Restoration depends on age, co-morbidities and postoperative insulin-like growth factor concentrations. At average, functionality remains impaired during the long-term compared to age and sex matched control persons. Growth hormone therapy in individuals with impaired growth hormone secretion could be an option but has not been proved in a randomized trial. Keywords: Glucocorticoids; Quality of life; Cushing syndrome; Growth hormone; Stair climbing; Muscular atrophy; Somatomedins; Phenotype; Bodily secretions; Muscles
2019-12-23 | Discovery of Melanocortin Ligands via a Double Simultaneous Substitution Strategy Based on the Ac-His-dPhe-Arg-Trp-NH2 Template.
The melanocortin system regulates an array of diverse physiological functions including pigmentation, feeding behavior, energy homeostasis, cardiovascular regulation, sexual function, and steroidogenesis. Endogenous melanocortin agonist ligands all possess the minimal messaging tetrapeptide sequence His-Phe-Arg-Trp. Based on this endogenous sequence, the Ac-His1-dPhe2-Arg3-Trp4-NH2 tetrapeptide has previously been shown to be a useful scaffold when utilizing traditional positional scanning approaches to modify activity at the various melanocortin receptors (MC1-5R). The study reported herein was undertaken to evaluate a double simultaneous substitution strategy as an approach to further diversify the Ac-His1-dPhe2-Arg3-Trp4-NH2 tetrapeptide with concurrent introduction of natural and unnatural amino acids at positions 1, 2, or 4, as well as an octanoyl residue at the N-terminus. The designed library includes the following combinations: (A) double simultaneous substitution at capping group position (Ac) together with position 1, 2, or 4, (B) double simultaneous substitution at positions 1 and 2, (C) double simultaneous substitution at positions 1 and 4, and (D) double simultaneous substitution at positions 2 and 4. Several lead ligands with unique pharmacologies were discovered in the current study including antagonists targeting the neuronal mMC3R with minimal agonist activity and ligands with selective profiles for the various melanocortin subtypes. The results suggest that the double simultaneous substitution strategy is a suitable approach in altering melanocortin receptor potency or selectivity or converting agonists into antagonists and vice versa.
2011-01-31 | Solid-phase peptide head-to-side chain cyclodimerization: discovery of C(2)-symmetric cyclic lactam hybrid α-melanocyte-stimulating hormone (MSH)/agouti-signaling protein (ASIP) analogues with potent activities at the human melanocortin receptors.
A novel hybrid melanocortin pharmacophore was designed based on the pharmacophores of the agouti-signaling protein (ASIP), an endogenous melanocortin antagonist, and α-melanocyte-stimulating hormone (α-MSH), an endogenous melanocortin agonist. The designed hybrid ASIP/MSH pharmacophore was explored in monomeric cyclic, and cyclodimeric templates. The monomeric cyclic disulfide series yielded peptides with hMC3R-selective non-competitive binding affinities. The direct on-resin peptide lactam cyclodimerization yielded nanomolar range (25-120 nM) hMC1R-selective full and partial agonists in the cyclodimeric lactam series which demonstrates an improvement over the previous attempts at hybridization of MSH and agouti protein sequences. The secondary structure-oriented pharmacophore hybridization strategy will prove useful in development of unique allosteric and orthosteric melanocortin receptor modulators. This report also illustrates the utility of peptide cyclodimerization for the development of novel GPCR peptide ligands.
cell therapies
2024-02-15 | Gut microbiota dysbiosis and decreased levels of acetic and propionic acid participate in glucocorticoid-induced glycolipid metabolism disorder.
Long-term/high-dose glucocorticoid (GC) use results in glycolipid metabolism disorder, which severely limits its clinical application. The role of the gut microbiota and its metabolites in GC-induced glycolipid metabolism disorder remains unclear. Our previous human study found that obvious gut microbiota dysbiosis characterized by an increasing abundance of Proteobacteria and a decreased abundance of Lachnospiraceae and Faecalibacterium were observed in patients with endogenous hypercortisolism. In this study, we established a mouse model of GC-induced glycolipid metabolism disorder (Dex group) and found that the relative abundances of Proteobacteria and Parasuttrerella were increased, while the abundances of Lachnospiraceae, Faecalibacterium, and Lachnospiraceae_NK4A136_group were decreased significantly in the Dex group. Compared with the control group, serum total short-chain fatty acids (SCFAs), acetic acid, propionic acid, and GLP-1 levels were all decreased in the Dex group. The mRNA expression of the GPR41 receptor and Pcsk1 in the colon was significantly decreased in the Dex group. Furthermore, GC-induced glycolipid metabolism disorder could be alleviated by depletion of the gut microbiota or fecal bacteria transplantation with control bacteria. The abundances of Lachnospiraceae_NK4A136_group and the serum GLP-1 levels were significantly increased, while the abundances of Proteobacteria and Parasutterella were significantly decreased after fecal bacteria transplantation with control bacteria. Our work indicates that gut microbiota dysbiosis and decreased levels of serum acetic acid and propionic acid may participate in GC-induced glycolipid metabolism disorder. These findings may provide novel insights into the prevention and treatment of GC-induced metabolic disorders.IMPORTANCEThe role of the gut microbiota in glucocorticoid (GC)-induced glycolipid metabolism disorder remains unclear. In our study, gut microbiota dysbiosis characterized by an increased abundance of Proteobacteria/Parasuttrerella and a decreased abundance of Lachnospiraceae_NK4A136_group was observed in mice with GC-induced glycolipid metabolism disorder. Some bacteria were shared in our previous study in patients with endogenous hypercortisolism and the mouse model used in the study. Furthermore, the depletion of the gut microbiota and fecal bacteria transplantation with control bacteria could alleviate GC-induced glycolipid metabolism disorder. Plasma acetic acid, propionic acid, and GLP-1 and the mRNA expression of the GPR41 receptor and Pcsk1 in the colon were decreased significantly in mice with GC-induced glycolipid metabolism disorder, which indicated that the gut microbiota/SCFA/GPR41/GLP-1 axis may participate in GC-induced glycolipid metabolism disorder. Our findings indicate that the gut microbiota may serve as a novel therapeutic target for GC-related metabolic disorders.
2019-10-09 | Cushing Syndrome: The Role of MSCs in Wound Healing, Immunosuppression, Comorbidities, and Antioxidant Imbalance
Cushing syndrome (CS), caused by glucocorticoid (GCs) excess, is strictly connected to onset of different metabolic diseases and impaired wound healing. The source of excessively high levels of GCs allows the identification of endogenous and exogenous (iatrogenic) CS. Iatrogenic patients usually receive also anti-metabolites serving as the foundation to modern steroid-sparing immunosuppressive therapy. Tissues mainly targeted by CS are bone and fat, both derived from progenitor cells named mesenchymal stem cells (MSCs). In addition, the pathogenic role of MSCs in other diseases sharing common properties with CS, such as an altered inflammatory profile and increased oxidative stress, has been identified. In this light, MSCs isolated from skin of control healthy subjects (C-MSCs), patients affected by endogenous CS (ENDO-MSCs), patients affected by iatrogenic CS (IATRO-MSCs) and patients affected by exogenous CS receiving steroid-sparing drugs (SS-MSCs), respectively, have been isolated and analyzed. ENDO- and IATRO-MSCs showed a reduced differentiative potential toward osteogenic and adipogenic lineages compared to C-MSCs, whereas SS-MSCs re-acquired the ability to differentiate, with a trend similar to control cells. In addition, MSCs from CS groups, compared to control MSCs, displayed a reduction in the secretion of cytokines (immune-suppression), a decreased expression of genes related to wound healing and a dysregulation of the enzymes/genes related to antioxidant capacity. In conclusion, our results suggest that the hallmarks of CS, such as wound healing impairment and immunosuppression, are already detectable in undifferentiated cells, which could be considered a potential therapeutic early target for control of CS.
2006-12-16 | Aberrant GPCR expression is a sufficient genetic event to trigger adrenocortical tumorigenesis
Aberrant expression of G protein-coupled receptors (GPCR) in the adrenal cortex is observed in some cases of ACTH-independent macronodular adrenal hyperplasias and adenomas associated with Cushing syndrome (CS). Although there is clinical evidence for the implication of these receptors in abnormal regulation of cortisol secretion, whether this aberrant expression also directly causes the development of a benign adrenocortical tumor is an open question. Cell transplantation provides a way to study genes that may be important in human tumor development. The system we developed uses genetically modified adrenocortical cells transplanted into adrenalectomized immunodeficient mice, which form a functional tissue structure. We observed that enforcing expression of the gastric inhibitory polypeptide (GIP) receptor or the luteinizing hormone (LH) receptor genes (taken as canonical examples of aberrantly expressed GPCRs) in adrenocortical cells resulted in the formation of hyperplastic tissues and the development of Cushing syndrome features in transplanted mice.
small molecules
2026-08-11 | Pituitary tumour shrinkage and diabetic remission in two cats with Cushing syndrome treated with cabergoline.
We describe two cats with diabetes mellitus and Cushing's syndrome. Diabetes mellitus was initially managed with insulin glargine (Lantus; Sanofi-Aventis, Paris, France), nutritional therapy and continuous glucose monitoring. Hypercortisolism was suspected based on severe hypertension (Case 1), and insulin resistance in combination with typical clinical features of Cushing's syndrome (Case 2). Endocrine testing revealed non-suppressible cortisol concentrations on low-dose-dexamethasone suppression test, elevated endogenous adenocorticotrophic hormone (ACTH) concentration and pituitary enlargement on computed tomography. Cabergoline (Holiday®, Holliday-Scott S.A., Buenos Aires, Argentina) was initiated at a dose of 10 μg/kg po every 48 hours targeting both the pituitary tumour and hypercortisolism. In Case 2, the cabergoline dosage was gradually increased to a final dose of 10 μg/kg po every 12 hours. Both cats achieved diabetic remission within 1 and 6 months of treatment, respectively. Serial monitoring demonstrated a decrease in endogenous ACTH concentrations and a reduction in pituitary volume of 29% of baseline (Case 1) and of 52% of baseline (Case 2) after 8 months of treatment. These findings suggest that cabergoline may be a potential medical treatment option in cats with pituitary-dependent hypercortisolism.
2026-07-03 | Importance of Hypercortisolism in BP Control, Cardiovascular Risk and in Patients With Difficult-to-Control Hypertension: An Overview for Primary Care Physicians.
Hypertension remains one of the most prevalent and consequential modifiable cardiovascular risk factors worldwide, affecting approximately 1.28 billion adults globally and nearly half of the United States population. Despite the availability of effective therapies, optimal blood pressure control is achieved in fewer than one in four patients, contributing substantially to the burden of myocardial infarction, stroke, heart failure, chronic kidney disease and cognitive decline. Resistant hypertension, defined as blood pressure remaining above goal despite three maximally tolerated antihypertensive agents including a diuretic or requiring four or more agents to achieve control, affects a meaningful proportion of hypertensive patients and carries a disproportionately elevated risk of end-organ damage and adverse cardiovascular events. In this review, we sought to describe how hypercortisolism has historically been underrecognized and under screened as a secondary cause of resistant hypertension, in part due to the perception that overt Cushing's syndrome is rare. However, emerging evidence is challenging this assumption. The CATALYST study demonstrated a 24% prevalence of endogenous hypercortisolism amongst patients with difficult-to-control type 2 diabetes and a 37% prevalence in those requiring three or more antihypertensive medications. Treatment with the glucocorticoid receptor antagonist mifepristone resulted in improvements in glycemic control and body weight, providing hypothesis generating evidence that hypercortisolism may be a relevant, as opposed to an incidental, contributor to cardiometabolic dysregulation. The MOMENTUM registry prospectively evaluated the prevalence of endogenous hypercortisolism specifically in patients with resistant hypertension and found that hypercortisolism was present in 27.3% of this cohort of patients. Primary care providers occupy a central role in the recognition, initial workup and coordinated management of hypertension, including appropriate screening for secondary causes. Awareness of hypercortisolism as an underdiagnosed driver of treatment-resistant hypertension represents an important and potentially treatable opportunity to improve outcomes at the primary care level.
2026-04-24 | Deterioration Of Blood Lipids During Early Postoperative Remission Of Cushing's Syndrome: A Longitudinal Cohort Study.
Cushing´s syndrome (CS) is associated with an unfavorable lipid profile. However, data on lipid alterations during early postoperative remission, a particularly cardiovascular vulnerable period, are lacking. Evaluation of lipid profiles during active CS and the early postoperative period. In this single-center cohort study at LMU Hospital Munich, we analyzed lipid profiles (Total cholesterol, LDL, HDL, ApoA1, ApoB, Lipoprotein (a), Triglycerides and Non-esterified fatty acids) and metabolic markers in 26 patients with endogenous CS before surgery and 1, 3, 6, 12 and 24 months (n=23) after curative surgery, and compared them with 26 age-, BMI-, and sex-matched controls without hypercortisolism at baseline. Paradoxically most lipid parameters postoperatively worsened. One month postoperatively, HDL (1mo postoperative 38 mg/dL [35-46] vs. active CS 49.5 mg/dL [45-61.3], p<0.0001) and ApoA1 concentrations (1mo postoperative 160 mg/dL [147-168] vs. active CS 193 mg/dL [169-211], p<0.0001) were significantly lower compared to preoperative levels. Similarly one month following surgery triglycerides concentrations (1mo postoperative 185 mg/dL [154-218] vs. active CS 129 mg/dL [89.3-186] preoperatively, p<0.0001) were higher. These changes remained evident until 6 months post-surgery. The triglyceride-glucose index increased during early remission and showed a positive correlation with inflammatory markers CRP and IL-6. Non-esterified fatty acids displayed three distinct postoperative trajectories depending on BMI at baseline. During the early remission phase following curative surgery, we observed a further deterioration in lipid parameters. This can affect cardiovascular health and provides the basis for targeted therapy.
2026-04-09 | "Glucocorticoids, Cushing syndrome and cellular senescence: a mechanistic link to metabolic ageing".
Glucocorticoids are key regulators of immune, stress and inflammatory responses, as well as of multiple metabolic pathways throughout life, and they play an anabolic role in tissue and organ development. Chronic glucocorticoid excess, whether due to endogenous Cushing syndrome, long-term pharmacological treatment or persistent stress, induces tissue-specific alterations that closely resemble those seen during physiological ageing. These shared changes include loss of tissue regenerative capacity, altered body composition, impaired glucose and lipid homeostasis and increased cardiovascular and neuropsychiatric vulnerability. Emerging evidence indicates that glucocorticoid excess can promote cellular senescence, amplify proinflammatory signalling and disrupt interorgan communication, thereby accelerating a state of metabolic ageing. This review synthesises current clinical and experimental data linking glucocorticoid excess with cellular senescence in key metabolic organs and systems, including adipose tissue, skeletal muscle, liver, bone, the cardiovascular system and the brain. Particular emphasis is placed on chronic neoplastic hypercortisolism as a human model, while also considering prolonged pharmacological glucocorticoid exposure and sustained stress as more prevalent, subclinical sources of hormonal overload. By integrating these lines of evidence, we outline the emerging concept of glucocorticoid-driven metabolic ageing and highlight potential mechanistic targets along the glucocorticoid axis and within senescence pathways. A better understanding of these mechanisms may inform strategies to prevent or mitigate age-related metabolic and cardiovascular complications in patients with Cushing syndrome, in individuals exposed to long-term glucocorticoid therapy and in the broader ageing population.
2026-04-03 | Small-cell carcinoma of the cervix with acute-onset psychotic symptoms associated with clinically diagnosed ectopic ACTH production: a case report.
Small-cell carcinoma of the cervix (SCCC) is a rare and highly aggressive histological subtype of cervical cancer, associated with poor prognosis. SCCC is histologically classified as a neuroendocrine tumor and has the potential to produce ectopic hormones, leading to various paraneoplastic syndromes. This report is a rare case of recurrent SCCC presenting with psychiatric symptoms due to endogenous Cushing's syndrome caused by ectopic adrenocorticotropic hormone (ACTH) production. The patient initially developed mood and behavioral disturbances as the disease progressed, leading to hospitalization under the suspicion of a primary psychiatric disorder. However, further evaluation, prompted by the discovery of severe hypokalemia, revealed Cushing's syndrome associated with clinically diagnosed ectopic ACTH production in the setting of recurrent disease. Her psychiatric symptoms rapidly remitted following the administration of a cortisol synthesis inhibitor. This case highlights the importance of considering endocrine disorders as potential causes of psychiatric manifestations in patients with cancer, particularly those with neuroendocrine tumors such as SCCC. Acute and marked elevation of endogenous cortisol can induce distinct psychiatric symptoms, such as manic features and grandiose delusions, that often respond better to endocrine treatment aimed at normalizing cortisol levels rather than to antipsychotic therapy alone. Clinicians should be aware of this rare but important clinical presentation as timely diagnosis and management can improve patient outcomes.
gene therapies
2023-05-03 | Glucocorticoid receptor polymorphism BclI with increased glucocorticoid sensitivity has a positive influence on quality of life in endogenous Cushing's syndrome in remission.
Patients with endogenous Cushing's syndrome (CS) may suffer from a wide range of neuropsychiatric symptoms leading to impaired quality of life (QoL). Glucocorticoid receptor (GR) polymorphisms are associated with increased (BclI and N363S) or decreased (A3669G and ER22/23EK) GR sensitivity. GR genotypes may modulate and affect QoL and recovery after remission differently via GR sensitivity. 295 patients with endogenous CS (81 active, 214 in remission) from 3 centers of the German Cushing's Registry were included for the cross-sectional analysis. All subjects were assessed with three questionnaires (CushingQoL, Tuebingen CD-25, SF-36). For the longitudinal part, 120 patients of them were analyzed at baseline and after 1.5 ± 0.9 yrs of follow-up. DNA samples were obtained from peripheral blood leukocytes for GR genotyping. Patients in remission scored significantly better than patients with active CS in the CushingQoL questionnaire and in the SF-36 sub-categories physical and social functioning, role-physical, bodily pain, and vitality. In cross-sectional analysis, no differences in QoL between minor allele and wildtype carriers were detected for all polymorphisms in active or cured CS. In longitudinal analysis, however, carriers with BclI minor allele showed significant improvement in SF-36 sub-categories vitality (P = .038) and mental health (P = .013) compared to wildtype carriers (active CS at baseline vs. CS in remission at follow-up). The outcome of the two questionnaires CushingQoL and Tuebingen CD-25 improved significantly in both wildtype and minor allele carriers. BclI minor allele carriers initially had the lowest QoL but recovered better from impaired QoL than wildtype carriers.
2011-11-03 | Association of glucocorticoid receptor polymorphism A3669G with decreased risk of developing diabetes in patients with Cushing's syndrome
Objective Glucocorticoid receptor ( GR ) polymorphisms alter glucocorticoid (GC) sensitivity and have been associated with altered metabolic profiles. We evaluate the prevalence of the four GR ( NR3C1 ) polymorphisms BclI, N363S, ER22/23EK, and A3669G in patients with Cushing's syndrome (CS) compared with healthy controls (HC) and we investigate their role in the development of metabolic abnormalities in patients with CS according to their hormonal profile. Patients and methods Sixty-one patients with CS and 71 sex- and age-matched HC were genotyped. Results BclI variant was markedly higher in patients with CS compared with HC (62 vs 41%, P <0.05) while no significant differences were found among other polymorphisms. A very low frequency of N363S and the ER22/23EK was observed. In CS patients, despite the significantly increased levels of morning serum cortisol in BclI carriers compared with wild type no clinical or metabolic differences were found. In contrast, A3669G GR carriers showed a significantly reduced prevalence of type 2 diabetes mellitus compared with wild type (19 vs 68%, P =0.001) despite the higher levels of both serum morning (21.7±6 vs 27.3±8.6 μg/dl, P =0.009) and midnight cortisol (18.8±5.8 vs 24.0±8.0 μg/dl, P =0.01). The negative association between diabetes and A3669G GR polymorphism remained significant when data were adjusted for potential confounding factors. Conclusions The A3669G polymorphism of the GR gene plays a protective role in patients with CS, attenuating the effects of GC excess on glucose metabolism as shown by their reduced risk of diabetes.
other
2026-01-29 | Reversal of Cushing syndrome by antibody-mediated neutralization of ACBP/DBI.
Cushing syndrome (CS) is caused by an increase in endogenous or exogenous glucocorticoids, leading to major alterations in body composition, including visceral obesity, sarcopenia, osteoporosis, type 2 diabetes, and dyslipidemia. Cardiovascular complications resulting from CS are often lethal. We previously demonstrated that CS induced by oral corticosterone (CORT) supplementation in mice can be prevented by inhibition of the peptide hormone acyl-CoA binding protein (ACBP), encoded by the gene diazepam binding inhibitor (DBI). Here, we investigated whether ACBP/DBI inhibition could be used to treat, rather than prevent, CS. To this end, we initiated treatment with anti-ACBP/DBI monoclonal antibodies (mAbs) in mice three weeks after the start of CORT supplementation, when hyperphagia and body weight gain were already established. Two anti-ACBP/DBI mAbs, 7G4a (specific for mouse ACBP/DBI only) and 82 (which recognizes both mouse and human ACBP/DBI), were able to normalize food intake and halt weight gain in mice under continuous CORT treatment. In addition, both mAbs attenuated CORT-induced sarcopenia, adiposity in inguinal, perigonadal, and visceral fat depots, and fully restored metabolic parameters, including type-2 diabetes, insulinemia, free fatty acids, triglycerides, and liver transaminases. In conclusion, neutralization of ACBP/DBI may serve as an effective therapeutic strategy for the treatment of established CS.
2022-06-22 | Successful Immunomodulatory Treatment of COVID-19 in a Patient With Severe ACTH-Dependent Cushing’s Syndrome: A Case Report and Review of Literature
Introduction Patients with Cushing’s syndrome (CS) represent a highly sensitive group during corona virus disease 2019 (COVID-19) pandemic. The effect of multiple comorbidities and immune system supression make the clinical picture complicated and treatment challenging. Case report A 70-year-old female was admitted to a covid hospital with a severe form of COVID-19 pneumonia that required oxygen supplementation. Prior to her admission to the hospital she was diagnosed with adrenocorticotropic hormone (ACTH)-dependent CS, and the treatment of hypercortisolism had not been started yet. Since the patient’s condition was quickly deteriorating, and with presumend immmune system supression due to CS, we decided on treatement with intraveonus immunoglobulins (IVIg) that enabled quick onset of immunomodulatory effect. All comorbidities were treated with standard of care. The patient’s condition quickly stabilized with no direct side effects of a given treatment. Conclusion Treatment of COVID-19 in patients with CS faces many challenges due to the complexity of comorbidity effects, immunosupression and potential interactions of available medications both for treatment of COVID-19 and CS. So far, there are no guidelines for treatment of COVID-19 in patients with active CS. It is our opinion that immunomodulating therapies like IVIg might be an effective and safe treatment modality in this particularly fragile group of patients.
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Drug Discovery Landscape
19 orphan drug designations for Endogenous Cushing syndrome, including 5 approved therapies.
19 orphan drug designations for Endogenous Cushing syndrome, including 5 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Asedebart | antibodies | EMA | 2026-08-20 | — | H. Lundbeck A/S |
Clofutriben | small molecules | EMA | 2025-01-16 | — | Scendea (NL) B.V. |
clofutriben | small molecules | FDA | 2024-10-16 | — | Sparrow Pharmaceuticals, Inc. |
osilodrostat [Isturisa] | small molecules | FDA | 2024-04-29 | 2025-04-15 | Recordati Rare Diseases Inc. |
Relacorilant | small molecules | EMA | 2019-05-29 | — | Corcept Therapeutics Netherlands B.V. |
relacorilant | small molecules | FDA | 2018-10-15 | — | Corcept Therapeutics, Inc. |
fluasterone | small molecules | FDA | 2018-03-28 | — | Sterotherapeutics, LLC |
N-[2,6-bis(1-methylethyl)phenyl]-N'-[[1-[4-(dimethylamino)phenyl]cyclopentyl]methyl]urea, hydrochloride salt | small molecules | FDA | 2015-01-07 | — | Millendo Therapeutics, Inc. |
Osilodrostat [Isturisa] | small molecules | EMA | 2014-10-15 | 2020-01-13 | Recordati Rare Diseases |
metyrapone | small molecules | FDA | 2012-09-25 | — | HRA Pharma Rare Diseases |
Ketoconazole | small molecules | EMA | 2012-08-09 | — | Agenzia Industrie Difesa-Stabilimento Chimico Farmaceutico Militare |
2S, 4R ketoconazole | small molecules | EMA | 2012-07-04 | — | S-cubed Pharmaceutical Services ApS |
Ketoconazole [Ketoconazole HRA] | small molecules | EMA | 2012-04-23 | 2014-11-21 | [INACTIVE] Esteve RD France S.A.S. |
levoketoconazole [Recorlev] | small molecules | FDA | 2012-03-09 | 2021-12-30 | Strongbridge Dublin Limited |
Mifepristone | small molecules | EMA | 2011-10-27 | — | Granzer Regulatory Consulting & Services GmbH |
Pasireotide [Signifor] | small molecules | EMA | 2009-10-08 | — | Recordati Rare Diseases |
Mifepristone | small molecules | EMA | 2009-02-27 | — | EXELGYN |
mifepristone [Korlym] | small molecules | FDA | 2007-07-05 | 2012-02-17 | Corcept Therapeutics, Inc. |
Mifepristone [Mifedren and/or Mifadren] | small molecules | EMA | 2005-07-27 | — | [INACTIVE] Laboratoire Hra Pharma |
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