RARE DISEASE
ACTH-dependent Cushing syndrome
ACTH-dependent Cushing syndrome
ACTH-dependent Cushing syndrome
Synonyms: ACTH-dependent CS, Adrenocorticotropic hormone-dependent Cushing syndrome, Corticotropin-dependent Cushing syndrome
Synonyms: ACTH-dependent CS, Adrenocorticotropic hormone-dependent Cushing syndrome, Corticotropin-dependent Cushing syndrome
Synonyms: ACTH-dependent CS, Adrenocorticotropic hormone-dependent Cushing syndrome, Corticotropin-dependent Cushing syndrome
Drug discovery
2
drugs
With orphan designations
Overview
ACTH-dependent Cushing syndrome results from excessive adrenocorticotropic hormone (ACTH) production, primarily due to pituitary adenomas (Cushing’s disease, ~70-80% of cases) or ectopic ACTH-secreting tumors (e.g., neuroendocrine tumors) [1][6][19]. Chronic hypercortisolism drives multisystem morbidity, including metabolic, cardiovascular, and psychiatric complications. Diagnosis requires dynamic hormonal testing (e.g., dexamethasone suppression, CRH stimulation) and imaging, with inferior petrosal sinus sampling to distinguish pituitary from ectopic sources [7][13].
Burden
Mortality risk 3.5–5× higher than general population, primarily due to cardiovascular/thromboembolic events [5][11][19].
≥42% develop infections; 60% have hypertension/diabetes; osteoporosis occurs in 50–80% [5][7][15].
Prolonged hypercortisolism (>18 months) correlates with irreversible comorbidities [11][16][19].
Therapies
First-line: Transsphenoidal adenoma resection (curative in ~70% of pituitary cases) [3][8][12].
Second-line: Medical therapy (pasireotide, osilodrostat, ketoconazole) or radiation (stereotactic radiosurgery) for persistent/recurrent disease [1][8][14].
Ectopic ACTH: Tumor resection (if localized) or bilateral adrenalectomy for refractory cases [3][8][12].
Categories: rare endocrine diseases, rare infertility disorders
Research Papers
826 drug discovery papers about ACTH-dependent Cushing syndrome, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
826 drug discovery papers about ACTH-dependent Cushing syndrome, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-13 | Ectopic ACTH-dependent Cushing syndrome in 3 hospitalized patients: lessons learned from management with osilodrostat.
Severe Cushing syndrome (CS) is a rare diagnosis with high mortality, which limits the ability of endocrinologists to gain experience delivering care. Here we describe our experience treating 3 cases of ectopic ACTH-dependent CS presenting in a single year. The initial diagnosis of each case was made during hospitalization resulting from complications of CS, implicating severe disease and delayed diagnosis. Our experience suggests that rapid initiation and titration of osilodrostat effectively treats hypercortisolism and improves outcomes.
2026-07-16 | Consensus on Biomarker Utility for ACTH-Dependent Cushing's Syndrome: A Pituitary Society Modified Delphi Panel.
Biochemical test results are central to clinical decision-making for the diagnosis and management of Cushing's syndrome (CS). With emerging research and increasing availability of different tests, updated consensus on the utility of these biomarkers is warranted. To establish an updated consensus on the role of biomarkers in the diagnosis and monitoring of adrenocorticotropic hormone-dependent CS, address novel therapeutic approaches, and identify areas for future research. A modified two-round Delphi panel was conducted. Consensus was defined as ≥70% agreement/disagreement for Likert-scale statements or ≥70% selection of the same option for single-choice questions. Participants represented a range of international expertise. Forty-one participants took part in the Delphi panel, with no attrition between rounds (one non-clinician was not required to complete the second round). An eight-member Steering Committee guided statement development. Of statements designed to reach consensus, 45% (14/31) and 44% (11/25) statements reached consensus in Rounds 1 and 2, respectively. Notably, most panelists reported the use of late-night salivary cortisol for diagnosis of mild CS and for monitoring following pituitary surgery or medical or radiation therapy. Most panelists responded that block-and-replace therapies can be considered in patients with cyclical or severe CS, and consensus was reached that restoration of circadian rhythm is a treatment goal for patients with CS. Areas of alignment among experts on the diagnosis and monitoring of CS are presented. The findings from this study are intended to support clinicians in their clinical decision-making and highlight priority areas for future research.
2026-07-10 | Individualized osilodrostat treatment for patients with ACTH-dependent Cushing’s syndrome: real-world evidence
Context Osilodrostat is an 11β-hydroxylase inhibitor that has demonstrated high efficacy in Cushing’s syndrome (CS) in clinical trials; however, real-world data remain limited. Objective To evaluate dosing patterns, effectiveness, and safety of osilodrostat in patients with adrenocorticotropic hormone (ACTH)–dependent CS. Design This retrospective analysis included 26 adults with ACTH-dependent CS (15 with Cushing’s disease [CD] and 11 with ectopic CS [ECS]) treated with osilodrostat between 2020 and 2025. Results Osilodrostat was introduced as first-line therapy in 12 of 26 patients. A titration regimen was used in 21 patients, and a block-and-replace approach in five. A therapeutic effect was achieved in 92% at a median dose of 5 mg/day (4.5 mg/day in CD and 6.5 mg/day in ECS) within 14 days. Morning cortisol normalized in 92% of cases, and urinary free cortisol in 75%. The median clinical score decreased from 9 to 4, and muscle strength increased from 50% to 75% of normal. All 22 patients requiring potassium supplementation showed improvement, with a median time to dose reduction of 10 days. Systolic/diastolic blood pressure decreased from 142/87 to 124/70 mmHg, enabling reduction of antihypertensive therapy in 22 of 23 patients. Among 20 patients with diabetes, 18 reduced the number or dose of antidiabetic medications, including insulin. Adverse events were mild to moderate and included fatigue and nausea (34.6% each), adrenal insufficiency (30.8%), and dizziness (23.1%). Conclusions In real-world clinical practice, osilodrostat provided rapid and effective biochemical control and clinical improvement in ACTH-dependent CS, with a manageable safety profile and effective doses in the low-to-moderate range.
2026-06-11 | Alternating Therapy With Osilodrostat and Etomidate in Severe Ectopic Cushing's Syndrome Complicated by Silent Bowel Perforation.
Ectopic adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome (CS), ectopic ACTH secretion (EAS) is a rare condition caused by ACTH-secreting neuroendocrine tumors (NETs), such as bronchial carcinoids. We report a 65-year-old woman with severe EAS complicated by bowel perforation. She presented with hypokalemia (K+ 2.3 mmol/L), metabolic alkalosis, resistant hypertension (180/110 mmHg), worsening diabetes (HbA1c 6.7%-9.1%), proximal muscle weakness, and 14 kg weight gain over 3 months. A silent sigmoid colon perforation required emergency resection and colostomy. Biochemical tests confirmed hypercortisolism (urine free cortisol [UFC], 1256 µg/24 h, plasma ACTH 175 pg/mL, and cortisol >40 µg/dL post-dexamethasone). Imaging identified a 2.3 cm pulmonary nodule with mild uptake on Ga-68 DOTATATE PET/CT. Bronchoscopic biopsy confirmed an ACTH-positive low-grade bronchial carcinoid tumor. Initial treatment with osilodrostat was interrupted due to acute illness and oral medication intolerance. Intravenous etomidate was employed in the ICU for rapid cortisol suppression, followed by resumption of osilodrostat after stabilization. Thoracoscopic lobectomy confirmed a low-grade carcinoid tumor (Ki-67 < 2%). Postoperatively, cortisol normalized, electrolytes stabilized, and HbA1c improved to 6.5%. This case highlights bowel perforation as a severe complication of EAS and underscores the importance of dynamic, alternating therapy with osilodrostat and etomidate, along with individualized surgical and medical management strategies.
2026-06-04 | Molecular profile of Cushing's syndrome.
Cushing's syndrome comprises a heterogeneous group of disorders characterized by chronic excess of glucocorticoid release from adrenal glands, caused by altered adrenal function or by ACTH hypersecretion from pituitary or ectopic sources. Advances in high-throughput molecular profiling have substantially refined our understanding of the mechanisms underlying endogenous hypercortisolism. This chapter provides an integrated overview of the genetic, transcriptomic, and epigenetic alterations driving both ACTH-dependent and ACTH-independent forms of the disease. Hypothalamic-pituitary-adrenal axis regulation of cortisol homeostasis is controlled by complex feedback circuits involving glucocorticoid receptor signaling, transcriptional POMC regulation, and multilayered neuroendocrine inputs. Disruption of these regulatory networks represents a central event in disease pathogenesis. In corticotroph adenomas, recurrent somatic mutations in USP8, USP48, and BRAF converge on enhanced POMC transcription and ACTH secretion, while aggressive tumors frequently harbor alterations in TP53 and ATRX. Transcriptomic and spatial profiling reveal lineage-defined tumor identities alongside significant intratumoral heterogeneity, whereas epigenetic mechanisms-including DNA methylation, miRNA dysregulation, and chromatin remodeling-fine-tune hormone secretion and glucocorticoid feedback resistance. Ectopic ACTH-secreting neuroendocrine tumors exhibit a distinct molecular profile characterized by epigenetic reactivation of POMC through promoter hypomethylation and context-dependent transcriptional reprogramming, independent of canonical pituitary lineage factors. In contrast, ACTH-independent Cushing's syndrome is predominantly driven by constitutive activation of the cAMP/PKA pathway in adrenal lesions, most commonly through activating PRKACA mutations, with additional contributions from GNAS and CTNNB1. Adrenocortical carcinoma displays a more complex genomic landscape involving IGF2 overexpression, Wnt/β-catenin activation, and tumor suppressor alterations, reflecting its malignant phenotype. These molecular insights have direct clinical implications, enabling refined disease classification, improved prognostic stratification, and the identification of actionable therapeutic targets, including EGFR, MAPK, PKA, and glucocorticoid receptor-associated pathways. Collectively, the integration of multi-omics approaches is redefining the conceptual framework of Cushing's syndrome and paving the way toward precision medicine strategies in endocrine oncology.
cell therapies
2026-06-12 | ACTH-dependent Cushing's syndrome in MEN1: When multiple tumors complicate the diagnosis.
ACTH-dependent Cushing's syndrome (CS) is a rare manifestation of multiple endocrine neoplasia type 1 (MEN1). Identifying the ACTH source is challenging in MEN1 due to the frequent coexistence of multiple synchronous neuroendocrine tumors (NETs) in these patients. We describe the diagnostic dilemma in a 51-year-old male with MEN1 and severe ACTH-dependent CS. To analyze the specific diagnostic pitfalls in this population, we conducted a systematic literature review focusing exclusively on documented cases of ectopic Cushing syndrome (ECS) in MEN1 patients. The patient presented severe CS, with urinary free cortisol (UFC) at 3,188μg/24h (exceeding 25 times the upper limit of normal). Rapid biochemical control was achieved within 10 days using a high-dose (60mg/day) osilodrostat "block-and-replace" regimen. Imaging identified 3 potential sources: a 7×8mm pituitary microadenoma, a small pancreatic NET, and a large thymic NET (48×62×67mm). Despite a desmopressin stimulation test falsely suggesting a pituitary source (+118% ACTH increase), clinical severity and imaging indicated total thymectomy. Pathology confirmed a typical carcinoid tumor with ACTH expression. Postoperatively, the patient achieved complete remission. Our review of ectopic Cushing's syndrome (ECS) in MEN1 identified a total of 18 cases to date. Thymic NETs were the most frequent source (61%), followed by pancreatic NETs (28%). Notably, ectopic secretion of corticotropin-releasing hormone (CRH) was identified in 4 cases (22%), constituting a major diagnostic pitfall that led to unnecessary transsphenoidal surgery in 3 cases. ACTH-dependent CS in MEN1 is a diagnostic "perfect storm", where pituitary incidentalomas frequently mislead clinicians. Based on our review, ectopic CRH or ACTH secretion from thoracic or abdominal NETs must be systematically considered. We advocate a strategy prioritizing resection of the most suspicious lesion identified on imaging, thereby avoiding unnecessary transsphenoidal surgery.
2023-10-01 | THU014 Post-surgical Remission After Resection Of Solitary Mediastinal Lymph Node In A Metastatic Occult Ectopic ACTH Syndrome Patient
Abstract Disclosure: I.P. de Magalhães: None. C.P. Oliveira: None. L.P. Lins: None. N.X. Andrade: None. M.S. Lima: None. S.A. Siqueira: None. J.S. Fonini: None. E.C. Assis Filho: None. A.W. Mariani: None. M.C. Machado: None. BACKGROUND: The prevalence of occult cases has been increasing in the most recent series of Ectopic ACTH syndrome (EAS) maybe due to the small size of pulmonary neuroendocrine tumors. We present an atypical and very rare case of EAS with initial presentation of a single metastatic mediastinal lymph node that evolved with remission after your resection with no defined primary tumor. CASE REPORT: A 15-year-old female patient presented a clinical feature of Cushing’s syndrome (CS) with a 1-year evolution. Hormonal evaluation confirmed ACTH-dependent CS: urinary free cortisol of 819 µg/24h (3-43), late night salivary cortisol of 409 ng/dL (<274) and ACTH of 105 pg/mL (<63.3). Noninvasive methods for differential diagnosis of ACTH-dependent CS did not clarify the etiology (conflicting results): pituitary MRI negative, suppression of 59.6% of cortisol after high dose dexamethasone suppression test, positive response of ACTH and cortisol at desmopressin test, suppression of 81% of ACTH at acute octreotide SC test, negative serum tumor markers (gastrin, calcitonin, CEA, CA125, alpha-fetoprotein, CA19.9 and bhCG), negative cervical and pelvic ultrasound, negative computed tomography of thorax and negative abdominal MRI. Bilateral and simultaneous petrosal inferior sinus sampling with desmopressin confirmed EAS due to negative central to peripheral ACTH gradient, even after normalized PRL/ACTH gradients. Finally, PET/CT with Ga68-DOTATATE revealed a single infracarinal nodule of 1.5x0.6 cm with high capture of radioligand, SUVmax of 23.2, suggestive of affected mediastinal lymph node. The patient was submitted to thoracic surgery and the infracarinal lymph node was dissected and removed. Anatomopathological and immunohistochemical analyses disclosed a lymph node metastatic of a well-differentiated grade neuroendocrine tumor ACTH positive, Ki-67 2%. After surgery, the patient exhibited CS improvement and impressive drop of hormones at 5th postsurgical day (serum cortisol <1.0 µg/dL and ACTH of 2.2 pg/mL) confirming remission of CS. CONCLUSION: To our knowledge, approximately 36 cases of EAS due to neuroendocrine tumor of unknown primary origin were reported. However, previous cases commonly exhibited no remission after only removal of metastasis. Our case presented initial remission even with no primary tumor identified (occult primary tumor non-functioning?). Follow up with clinical, hormonal and imaging methods are necessary due to recurrence risk. Presentation: Thursday, June 15, 2023
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.
2011-06-28 | Moving toward personalized cell-based interventions for adrenal cortical disorders: Part 2 — Human diseases and tissue engineering
Transdifferentiation of an individual's own cells into functional differentiated cells to replace an organ's lost function would be a personalized approach to therapeutics. In this two part series, we will describe the progress toward establishing functional transdifferentiated adrenal cortical cells. In this article (Part 2), we describe the disorders of the adrenal cortex, therefore establishing why there is the need for personalized cell-based therapy for individuals with these disorders. We then present our pilot studies of cell transdifferentiation toward an adrenal cortical fate using genes described in the first article of this pair (Part 1).
1987-11-17 | Cushing's syndrome caused by an ectopic pituitary adenoma.
A 49-year old woman with a 5-year history of Cushing's syndrome was evaluated. Biochemical measurements revealed high cortisol and adrenocorticotropic hormone (ACTH) levels consistent with the ACTH-dependent type of Cushing's syndrome. However, the source of ACTH seemed to be autonomous as she demonstrated abnormal feedback control, with lack of response to metyrapone and high coses of dexamethasone. A search for an ectopic ACTH-secreting nonpituitary neoplasm was unsuccessful. Transsphenoidal pituitary exploration revealed a normal pituitary gland, but an ectopic pituitary adenoma was found incidentally in the mucosa of the sphenoid sinus. This adenoma stained strongly positive for ACTH on immunocytochemical studies. Resection of this lesion led to remission of the Cushing's syndrome. This variant of ACTH-dependent Cushing's syndrome can mimic the ectopic ACTH-dependent type and should be looked for in patients who fail to respond to pituitary operation.
proteins
2026-07-23 | Fourteen-year bridge to cure in occult ectopic ACTH syndrome: resection of a 3-mm pulmonary carcinoid.
Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) often involves occult microtumors, making localization challenging. We report a 68-year-old woman with severe ACTH-dependent hypercortisolism in whom the primary tumor remained occult despite extensive imaging, including 68Ga-tetraazacyclododecanetetraacetic acid-D-Phe(1)-Tyr(3)-octreotide positron emission tomography/computed tomography. Based on a positive octreotide challenge test, she received long-acting release octreotide for over a decade, achieving sustained biochemical stability. In 2020, she developed breast cancer, with the tumor being ACTH-negative on immunohistochemistry. In 2023, during resection of pulmonary metastases of the breast cancer, a 3-mm nodule was incidentally discovered in the adjacent lung tissue. Through close interdisciplinary coordination, the nodule was removed and was confirmed as an ACTH- and somatostatin receptor (SSTR) 2-positive pulmonary carcinoid. Thereafter, the EAS resolved completely with prompt recovery of adrenal function. In this case, intensive medical stabilization in occult EAS probably served as a strategic "bridge to surgery." Importantly, long-term biochemical control using somatostatin analogs facilitated prompt recovery of the hypothalamic-pituitary-adrenal axis immediately after tumor resection. This may also have preserved SSTR2 expression, potentially by mitigating cortisol-induced receptor downregulation, facilitating its eventual localization. This report shows that meticulous multidisciplinary communication during unrelated surgical procedures is indispensable for identifying radiologically occult lesions.
2025-05-26 | A case series of bilateral inferior petrosal sinus sampling using desmopressin for evaluation of ACTH-dependent cushing's syndrome in pediatric patients: insights from Iran.
Pediatric Cushing Syndrome (CS) is rare and difficult to diagnose, especially when distinguishing ACTH-dependent subtypes. Bilateral inferior petrosal sinus sampling (BIPSS) is an essential but technically challenging procedure for this purpose. Because corticotropin-releasing hormone (CRH), the standard stimulant, has limitations, desmopressin is being explored as an alternative. This study assesses desmopressin-stimulated BIPSS for its diagnostic accuracy and tumor localization in pediatric CS within an Iranian cohort, addressing a gap in pediatric-specific diagnostic strategies and offering insights into the applicability of desmopressin in this context. Four pediatric patients with inconclusive pituitary imaging and suspected Cushing's disease (CD) underwent BIPSS with desmopressin at Taleghani Hospital, Tehran, Iran, between August 2015 and March 2019. Sensitivity of BIPSS for CD diagnosis was assessed, and tumor localization accuracy was evaluated during surgery. Bilateral IPSS demonstrated a sensitivity of 100% for diagnosing CD in pediatric patients. However, accuracy for tumor lateralization was moderate, with only 50% concordance between BIPSS lateralization and surgical findings. Specifically, two out of four patients had correct lateralization confirmed during surgery, while one patient with left lateralization was consistent with hypophysectomy findings. These discrepancies highlight challenges such as anatomical and drainage variations that can lead to mislocalization. Desmopressin enhances the sensitivity of BIPSS for diagnosing pediatric CD, presenting as a viable alternative to CRH stimulation. Despite high sensitivity, caution is advised when interpreting BIPSS results for tumor localization. Further research is needed to optimize diagnostic strategies for pediatric CS management.
2025-03-27 | Sex-dependent effects of FGF21 on HPA axis regulation and adrenal regeneration after Cushing syndrome in mice
BACKGROUND: Cushing's syndrome (CS) results from prolonged exposure to excessive glucocorticoids (GCs), leading to metabolic disturbances and adrenal insufficiency (AI). Fibroblast growth factor 21 (FGF21) has shown promise as a potential therapeutic target for metabolic disorders. This study explores the effects of FGF21 on adrenal gland function in a mouse model of AI following chronic hypercortisolism and investigates sex-dependent differences in the hypothalamic-pituitary-adrenal (HPA) axis response. METHODS: We employed a mouse model of AI after chronic corticosterone (CORT) treatment. The effects of recombinant human FGF21 (hFGF21) administration on adrenal function were evaluated in AI mice. Male and female wild-type (WT) and FGF21-overexpressing transgenic (Tg) mice were subjected to 5 weeks of CORT treatment, reaching CS phenotype, followed by immediate analysis or a 10-week recovery period. Metabolic parameters, HPA axis function, and adrenal gland morphology and gene expression were assessed. RESULTS: Prolonged CORT exposure resulted in metabolic disturbances and HPA axis dysregulation. hFGF21 treatment increased CORT and ACTH secretion in AI mice. FGF21 overexpression influenced glucose homeostasis and insulin regulation during CORT treatment and recovery, with sex-specific effects. Tissue-specific regulation of Klb expression was observed across the HPA axis, with distinct patterns between males and females. Tg mice displayed altered adrenal progenitor cell activation and steroidogenic gene expression. Sex-specific differences were observed in adrenal capsule remodeling and gene expression patterns during recovery. CONCLUSIONS: This study reveals the complex interplay between FGF21 signaling and GC-induced metabolic and endocrine changes, suggesting a potential sex-specific role of FGF21 in metabolic regulation and HPA axis recovery following after CS.
2025-01-30 | Performance of Vasopressin Stimulated Bilateral Inferior Petrosal Sinus Sampling in Corticotropin Dependent Cushing's Syndrome with Negative or Equivocal 3 Tesla Contrast Enhanced Magnetic Resonance Imaging of Pituitary.
Corticotropin releasing hormone (CRH)-stimulated bilateral inferior petrosal sinus sampling (BIPSS) is the most accurate procedure in the differential diagnosis of adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome (CS) with a sensitivity of 88-100% and a specificity of 67-100%. However, CRH is not available globally currently. We undertook this study of BIPSS using lysine vasopressin (LVP) as an agent to stimulate the release of ACTH from corticotrophs. Our objective was to assess the accuracy of LVP-stimulated BIPSS in differentiating Cushing's disease (CD) from ectopic ACTH syndrome (EAS) with negative or equivocal 3T contrast-enhanced MRI (CEMRI). Seventeen patients with clinically and biochemically confirmed ACTH-dependent CS with equivocal or negative CEMRI pituitary underwent BIPSS using LVP as a stimulating agent. Of seventeen patients who underwent BIPSS, nine patients had a raised central-to-peripheral ACTH ratio and were classified as having CD that was confirmed on histopathology following transsphenoidal sinus surgery. Remaining eight patients, who did not show a raised central-to-peripheral ACTH ratio, were classified to have EAS. All patients with EAS underwent contrast-enhanced computerised tomography of the neck, chest, and abdomen and/or Gallium 68 DOTANOC positron emission tomography/computerised tomography. Seven out of eight patients demonstrated solitary pulmonary nodule in the lung (bronchial carcinoid), and one patient had a mass in the thymus (thymic carcinoid). BIPSS using LVP confirmed the source of ACTH excess correctly in all the patients with ACTH-dependent CS without the loss of specificity.
2024-12-16 | Lateralization outcomes of bilateral inferior petrosal sinus sampling: desmopressin vs CRH.
Bilateral inferior petrosal sinus sampling (BIPSS) is the gold standard for localizing ACTH-dependent Cushing's syndrome (CS). While corticotropin-releasing hormone (CRH) was initially used for stimulation, desmopressin has become a common alternative. This research evaluates desmopressin's effectiveness in lateralizing Cushing's disease (CD) during BIPSS compared to CRH stimulation. The study included 33 individuals with ACTH-dependent CS who underwent BIPSS and had diagnoses confirmed by endoscopic endonasal transsphenoidal pituitary surgery (EETPS). Fourteen participants underwent BIPSS with CRH and 19 with desmopressin. A comparative analysis was conducted. BIPSS accurately lateralized 76% of cases, specifically, 71% with CRH and 79% with desmopressin (p = 0.2). For tumors < 6 mm on MRI, overall accuracy was 82%, namely, 75% with CRH and 90% with desmopressin (p = 0.4). IPSS achieved 100% accuracy in the four cases with no lesion on preoperative MRI. This study demonstrates no significant difference in lateralization accuracy between desmopressin and CRH for IPSS. In challenging cases, especially those with microadenomas or non-lesional CD, desmopressin with IPSS aids in preoperative lateralization.
antibodies
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.
2019-06-05 | A Long-Acting Neutralizing Monoclonal ACTH Antibody Blocks Corticosterone and Adrenal Gene Responses in Neonatal Rats
The control of steroidogenesis in the neonatal adrenal gland is of great clinical interest. We have previously demonstrated that the postnatal day (PD) 2 rat exhibits a large plasma corticosterone response to hypoxia in the absence of an increase in plasma ACTH measured by RIA, whereas the corticosterone response to exogenous ACTH is intact. By PD8, the corticosterone response to hypoxia is clearly ACTH-dependent. We hypothesized that this apparently ACTH-independent response to hypoxia in the newborn rat is due to an increase in a bioactive, nonimmunoassayable form of ACTH. To evaluate this phenomenon, we pretreated neonatal rats with a novel, specific, neutralizing anti-ACTH antibody (ALD1611) (20 mg/kg or 1 mg/kg IP) on the morning of PD1, PD7, and PD14. Twenty-four hours later, we measured hypoxia- or ACTH-stimulated plasma ACTH and corticosterone. For long-term effects, ALD1611 was given on PD1 and pups were studied on PD8 and PD15. Pretreatment with ALD1611 significantly decreased baseline corticosterone and completely blocked the corticosterone response to hypoxia and exogenous ACTH stimulation at all ages. The effect of 1 mg/kg ALD1611 on PD1 had dissipated by PD15. The decrease in corticosterone in ALD1611-treated pups was associated with decreases in baseline and hypoxia- and ACTH-stimulated adrenal Ldlr, Mrap, and Star mRNA expression at all ages. The adrenal response to hypoxia in the newborn rat is ACTH-dependent, suggesting the release of nonimmunoassayable, biologically active forms of ACTH. ALD1611 is useful as a tool to attenuate stress-induced, ACTH-dependent adrenal steroidogenesis in vivo.
2018-08-23 | Glucocorticoid-induced insulin resistance is related to macrophage visceral adipose tissue infiltration
Insulin resistance is frequently present in patients with glucocorticoid (GC) excess (Cushing’s syndrome) or treated with high doses of GCs. Furthermore, others similarities between metabolic syndrome (visceral obesity, elevated blood glucose levels, dyslipidemia) and Cushing’s syndrome suggest that GCs could play a role in obesity-linked complications. Here we reported that long-term corticosterone (CORT) exposure in mice induced weight gain, dyslipidemia as well as hyperglycaemia and systemic insulin resistance. CORT-treated mice exhibited an increased 11β-Hsd1 expression and corticosterone levels in fat depots but a specific upregulation of glucocorticoid receptor (Gr) and hexose-6-phosphate dehydrogenase only in gonadal adipose tissue, suggesting that GC could act differentially on various fat depots. Despite fat accumulation in all depots, an increased expression of adipogenic (Pparγ, C/ebpα) and lipogenic (Acc, Fas) key genes was restricted to gonadal adipose tissue. Hypertrophied adipocytes observed in both visceral and subcutaneous depots also resulted from reduced lipolytic activity due to CORT treatment. Surprisingly, GC treatment promoted macrophage infiltration (F4/80, Cd68) within all adipose tissues along with predominant M2-like macrophage phenotype, and can directly act on macrophages to induce this phenotype. Moreover, macrophage infiltration preceded mass gain and adipocyte hypertrophy. Of note, specific macrophage depletion in gonadal fat preferentially reduced the M2-like macrophage content, and partially restored insulin sensitivity in mice with GC-induced obesity and insulin resistance. These data provide evidence that GCs act on adipose tissue in a depot-dependent manner and that gonadal adipose macrophages are key effectors of GC-associated insulin resistance.
2017-02-20 | Interleukin-1 Antagonism Decreases Cortisol Levels in Obese Individuals
Increased cortisol levels in obesity may contribute to the associated metabolic syndrome. In obesity, the activated innate immune system leads to increased interleukin (IL)-1β, which is known to stimulate the release of adrenocorticotropin hormone (ACTH). We hypothesized that in obesity IL-1 antagonism would result in downregulation of the hypothalamo-pituitary-adrenal axis, leading to decreased cortisol levels. In this prospective intervention study, we included 73 patients with obesity (body mass index [BMI] ≥30 kg/m2) and at least one additional feature of the metabolic syndrome. The primary end point was change in morning cortisol from baseline to after the administration of the IL-1 receptor antagonist (anakinra/Kineret®, total dose 3 × 100 mg). Secondary end points were effects on salivary cortisol and ACTH. Median age was 56 years, 50.7% of patients were female, and median BMI was 36.3 kg/m2. Median morning serum cortisol levels (nmol/L) decreased significantly after IL-1 antagonism [from baseline, 452 to 423; absolute difference, −38.7; 95% confidence interval (CI), −64 to −13.4; P = 0.0019]. Similar effects were found for salivary cortisol levels (−2.8; 95% CI, −4.4 to −1.3; P = 0.0007), ACTH levels (−2.2; 95% CI; −4.2 to −0.1; P = 0.038), systolic blood pressure (−5.2, 95% CI, −8.5 to −1.8; P = 0.0006), and heart rate (−2.9; 95% CI, −4.7 to −1.0; P = 0.0029). IL-1 antagonism in obese individuals with features of the metabolic syndrome leads to a decrease in serum cortisol, salivary cortisol, and ACTH levels along with a reduction in systolic blood pressure and heart rate.
1994-04-01 | The value of inferior petrosal sinus sampling in diagnosis and treatment of Cushing's disease
Summary OBJECTIVE While microsurgical selective adenomectomy is the best method available at present for the treatment of Cushing's disease, its success depends to a large degree on precise preoperative intrapituitary microadenoma localization. This study compares the results of intrapituitary adenoma localization obtained with inferior petrosal sampling, computerized tomography and magnetic resonance imaging with the adenoma localization as found at surgery. DESIGN The results of inferior petrosal sampling for intrapituitary localization of ACTH‐producing pituitary adenomas were compared in a retrospective study with the results of computerized tomography, magnetic resonance imaging, surgical and pathological findings. Special attention was paid to the intersinus ACTH relation. PATIENTS Thirty‐eight patients (33 women and 5 men) of 11‐68 years of age suffering from pituitary‐dependent Cushing's disease were studied. Patients with ectopic ACTH‐secreting tumours and and recurrent pituitary adenomas were excluded. MEASUREMENTS Blood samples were obtained simultaneously from both inferior petrosal sinuses and a peripheral vein before and 5, 10, 15 and 20 minutes after stimulation with 60 /μg/m 2 human corticotrophin‐releasing hormone (hCRH). RESULTS of the adenomas in our series, 42% had a diameter of 3 mm or less. Only 6 of 20 adenomas examined by computerized tomography and 11 of 29 examined by magnetic resonance imaging were identified correctly. Inferior petrosal sinus sampling produced significantly better results, particularly when combined with a stimulation test with hCRH: for 29 of 38 adenomas examined, the location was predicted correctly with these techniques. Analysis of the intersinus adrenocorticotrophin concentration ratio showed that the best right‐central‐left discrimination was obtained with values of 1.3 and 1.4. CONCLUSIONS We conclude that inferior petrosal sinus ACTH sampling after hCRH stimulation is the best method available for the intrapituitary localization of microadenomas causing Cushing's disease provided that the appropriate technique of blood sampling is used meticulously.
small molecules
2026-08-13 | Ectopic ACTH-dependent Cushing syndrome in 3 hospitalized patients: lessons learned from management with osilodrostat.
Severe Cushing syndrome (CS) is a rare diagnosis with high mortality, which limits the ability of endocrinologists to gain experience delivering care. Here we describe our experience treating 3 cases of ectopic ACTH-dependent CS presenting in a single year. The initial diagnosis of each case was made during hospitalization resulting from complications of CS, implicating severe disease and delayed diagnosis. Our experience suggests that rapid initiation and titration of osilodrostat effectively treats hypercortisolism and improves outcomes.
2026-07-16 | Consensus on Biomarker Utility for ACTH-Dependent Cushing's Syndrome: A Pituitary Society Modified Delphi Panel.
Biochemical test results are central to clinical decision-making for the diagnosis and management of Cushing's syndrome (CS). With emerging research and increasing availability of different tests, updated consensus on the utility of these biomarkers is warranted. To establish an updated consensus on the role of biomarkers in the diagnosis and monitoring of adrenocorticotropic hormone-dependent CS, address novel therapeutic approaches, and identify areas for future research. A modified two-round Delphi panel was conducted. Consensus was defined as ≥70% agreement/disagreement for Likert-scale statements or ≥70% selection of the same option for single-choice questions. Participants represented a range of international expertise. Forty-one participants took part in the Delphi panel, with no attrition between rounds (one non-clinician was not required to complete the second round). An eight-member Steering Committee guided statement development. Of statements designed to reach consensus, 45% (14/31) and 44% (11/25) statements reached consensus in Rounds 1 and 2, respectively. Notably, most panelists reported the use of late-night salivary cortisol for diagnosis of mild CS and for monitoring following pituitary surgery or medical or radiation therapy. Most panelists responded that block-and-replace therapies can be considered in patients with cyclical or severe CS, and consensus was reached that restoration of circadian rhythm is a treatment goal for patients with CS. Areas of alignment among experts on the diagnosis and monitoring of CS are presented. The findings from this study are intended to support clinicians in their clinical decision-making and highlight priority areas for future research.
2026-07-10 | Individualized osilodrostat treatment for patients with ACTH-dependent Cushing’s syndrome: real-world evidence
Context Osilodrostat is an 11β-hydroxylase inhibitor that has demonstrated high efficacy in Cushing’s syndrome (CS) in clinical trials; however, real-world data remain limited. Objective To evaluate dosing patterns, effectiveness, and safety of osilodrostat in patients with adrenocorticotropic hormone (ACTH)–dependent CS. Design This retrospective analysis included 26 adults with ACTH-dependent CS (15 with Cushing’s disease [CD] and 11 with ectopic CS [ECS]) treated with osilodrostat between 2020 and 2025. Results Osilodrostat was introduced as first-line therapy in 12 of 26 patients. A titration regimen was used in 21 patients, and a block-and-replace approach in five. A therapeutic effect was achieved in 92% at a median dose of 5 mg/day (4.5 mg/day in CD and 6.5 mg/day in ECS) within 14 days. Morning cortisol normalized in 92% of cases, and urinary free cortisol in 75%. The median clinical score decreased from 9 to 4, and muscle strength increased from 50% to 75% of normal. All 22 patients requiring potassium supplementation showed improvement, with a median time to dose reduction of 10 days. Systolic/diastolic blood pressure decreased from 142/87 to 124/70 mmHg, enabling reduction of antihypertensive therapy in 22 of 23 patients. Among 20 patients with diabetes, 18 reduced the number or dose of antidiabetic medications, including insulin. Adverse events were mild to moderate and included fatigue and nausea (34.6% each), adrenal insufficiency (30.8%), and dizziness (23.1%). Conclusions In real-world clinical practice, osilodrostat provided rapid and effective biochemical control and clinical improvement in ACTH-dependent CS, with a manageable safety profile and effective doses in the low-to-moderate range.
2026-06-11 | Alternating Therapy With Osilodrostat and Etomidate in Severe Ectopic Cushing's Syndrome Complicated by Silent Bowel Perforation.
Ectopic adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome (CS), ectopic ACTH secretion (EAS) is a rare condition caused by ACTH-secreting neuroendocrine tumors (NETs), such as bronchial carcinoids. We report a 65-year-old woman with severe EAS complicated by bowel perforation. She presented with hypokalemia (K+ 2.3 mmol/L), metabolic alkalosis, resistant hypertension (180/110 mmHg), worsening diabetes (HbA1c 6.7%-9.1%), proximal muscle weakness, and 14 kg weight gain over 3 months. A silent sigmoid colon perforation required emergency resection and colostomy. Biochemical tests confirmed hypercortisolism (urine free cortisol [UFC], 1256 µg/24 h, plasma ACTH 175 pg/mL, and cortisol >40 µg/dL post-dexamethasone). Imaging identified a 2.3 cm pulmonary nodule with mild uptake on Ga-68 DOTATATE PET/CT. Bronchoscopic biopsy confirmed an ACTH-positive low-grade bronchial carcinoid tumor. Initial treatment with osilodrostat was interrupted due to acute illness and oral medication intolerance. Intravenous etomidate was employed in the ICU for rapid cortisol suppression, followed by resumption of osilodrostat after stabilization. Thoracoscopic lobectomy confirmed a low-grade carcinoid tumor (Ki-67 < 2%). Postoperatively, cortisol normalized, electrolytes stabilized, and HbA1c improved to 6.5%. This case highlights bowel perforation as a severe complication of EAS and underscores the importance of dynamic, alternating therapy with osilodrostat and etomidate, along with individualized surgical and medical management strategies.
2026-06-04 | Molecular profile of Cushing's syndrome.
Cushing's syndrome comprises a heterogeneous group of disorders characterized by chronic excess of glucocorticoid release from adrenal glands, caused by altered adrenal function or by ACTH hypersecretion from pituitary or ectopic sources. Advances in high-throughput molecular profiling have substantially refined our understanding of the mechanisms underlying endogenous hypercortisolism. This chapter provides an integrated overview of the genetic, transcriptomic, and epigenetic alterations driving both ACTH-dependent and ACTH-independent forms of the disease. Hypothalamic-pituitary-adrenal axis regulation of cortisol homeostasis is controlled by complex feedback circuits involving glucocorticoid receptor signaling, transcriptional POMC regulation, and multilayered neuroendocrine inputs. Disruption of these regulatory networks represents a central event in disease pathogenesis. In corticotroph adenomas, recurrent somatic mutations in USP8, USP48, and BRAF converge on enhanced POMC transcription and ACTH secretion, while aggressive tumors frequently harbor alterations in TP53 and ATRX. Transcriptomic and spatial profiling reveal lineage-defined tumor identities alongside significant intratumoral heterogeneity, whereas epigenetic mechanisms-including DNA methylation, miRNA dysregulation, and chromatin remodeling-fine-tune hormone secretion and glucocorticoid feedback resistance. Ectopic ACTH-secreting neuroendocrine tumors exhibit a distinct molecular profile characterized by epigenetic reactivation of POMC through promoter hypomethylation and context-dependent transcriptional reprogramming, independent of canonical pituitary lineage factors. In contrast, ACTH-independent Cushing's syndrome is predominantly driven by constitutive activation of the cAMP/PKA pathway in adrenal lesions, most commonly through activating PRKACA mutations, with additional contributions from GNAS and CTNNB1. Adrenocortical carcinoma displays a more complex genomic landscape involving IGF2 overexpression, Wnt/β-catenin activation, and tumor suppressor alterations, reflecting its malignant phenotype. These molecular insights have direct clinical implications, enabling refined disease classification, improved prognostic stratification, and the identification of actionable therapeutic targets, including EGFR, MAPK, PKA, and glucocorticoid receptor-associated pathways. Collectively, the integration of multi-omics approaches is redefining the conceptual framework of Cushing's syndrome and paving the way toward precision medicine strategies in endocrine oncology.
cell therapies
2026-06-12 | ACTH-dependent Cushing's syndrome in MEN1: When multiple tumors complicate the diagnosis.
ACTH-dependent Cushing's syndrome (CS) is a rare manifestation of multiple endocrine neoplasia type 1 (MEN1). Identifying the ACTH source is challenging in MEN1 due to the frequent coexistence of multiple synchronous neuroendocrine tumors (NETs) in these patients. We describe the diagnostic dilemma in a 51-year-old male with MEN1 and severe ACTH-dependent CS. To analyze the specific diagnostic pitfalls in this population, we conducted a systematic literature review focusing exclusively on documented cases of ectopic Cushing syndrome (ECS) in MEN1 patients. The patient presented severe CS, with urinary free cortisol (UFC) at 3,188μg/24h (exceeding 25 times the upper limit of normal). Rapid biochemical control was achieved within 10 days using a high-dose (60mg/day) osilodrostat "block-and-replace" regimen. Imaging identified 3 potential sources: a 7×8mm pituitary microadenoma, a small pancreatic NET, and a large thymic NET (48×62×67mm). Despite a desmopressin stimulation test falsely suggesting a pituitary source (+118% ACTH increase), clinical severity and imaging indicated total thymectomy. Pathology confirmed a typical carcinoid tumor with ACTH expression. Postoperatively, the patient achieved complete remission. Our review of ectopic Cushing's syndrome (ECS) in MEN1 identified a total of 18 cases to date. Thymic NETs were the most frequent source (61%), followed by pancreatic NETs (28%). Notably, ectopic secretion of corticotropin-releasing hormone (CRH) was identified in 4 cases (22%), constituting a major diagnostic pitfall that led to unnecessary transsphenoidal surgery in 3 cases. ACTH-dependent CS in MEN1 is a diagnostic "perfect storm", where pituitary incidentalomas frequently mislead clinicians. Based on our review, ectopic CRH or ACTH secretion from thoracic or abdominal NETs must be systematically considered. We advocate a strategy prioritizing resection of the most suspicious lesion identified on imaging, thereby avoiding unnecessary transsphenoidal surgery.
2023-10-01 | THU014 Post-surgical Remission After Resection Of Solitary Mediastinal Lymph Node In A Metastatic Occult Ectopic ACTH Syndrome Patient
Abstract Disclosure: I.P. de Magalhães: None. C.P. Oliveira: None. L.P. Lins: None. N.X. Andrade: None. M.S. Lima: None. S.A. Siqueira: None. J.S. Fonini: None. E.C. Assis Filho: None. A.W. Mariani: None. M.C. Machado: None. BACKGROUND: The prevalence of occult cases has been increasing in the most recent series of Ectopic ACTH syndrome (EAS) maybe due to the small size of pulmonary neuroendocrine tumors. We present an atypical and very rare case of EAS with initial presentation of a single metastatic mediastinal lymph node that evolved with remission after your resection with no defined primary tumor. CASE REPORT: A 15-year-old female patient presented a clinical feature of Cushing’s syndrome (CS) with a 1-year evolution. Hormonal evaluation confirmed ACTH-dependent CS: urinary free cortisol of 819 µg/24h (3-43), late night salivary cortisol of 409 ng/dL (<274) and ACTH of 105 pg/mL (<63.3). Noninvasive methods for differential diagnosis of ACTH-dependent CS did not clarify the etiology (conflicting results): pituitary MRI negative, suppression of 59.6% of cortisol after high dose dexamethasone suppression test, positive response of ACTH and cortisol at desmopressin test, suppression of 81% of ACTH at acute octreotide SC test, negative serum tumor markers (gastrin, calcitonin, CEA, CA125, alpha-fetoprotein, CA19.9 and bhCG), negative cervical and pelvic ultrasound, negative computed tomography of thorax and negative abdominal MRI. Bilateral and simultaneous petrosal inferior sinus sampling with desmopressin confirmed EAS due to negative central to peripheral ACTH gradient, even after normalized PRL/ACTH gradients. Finally, PET/CT with Ga68-DOTATATE revealed a single infracarinal nodule of 1.5x0.6 cm with high capture of radioligand, SUVmax of 23.2, suggestive of affected mediastinal lymph node. The patient was submitted to thoracic surgery and the infracarinal lymph node was dissected and removed. Anatomopathological and immunohistochemical analyses disclosed a lymph node metastatic of a well-differentiated grade neuroendocrine tumor ACTH positive, Ki-67 2%. After surgery, the patient exhibited CS improvement and impressive drop of hormones at 5th postsurgical day (serum cortisol <1.0 µg/dL and ACTH of 2.2 pg/mL) confirming remission of CS. CONCLUSION: To our knowledge, approximately 36 cases of EAS due to neuroendocrine tumor of unknown primary origin were reported. However, previous cases commonly exhibited no remission after only removal of metastasis. Our case presented initial remission even with no primary tumor identified (occult primary tumor non-functioning?). Follow up with clinical, hormonal and imaging methods are necessary due to recurrence risk. Presentation: Thursday, June 15, 2023
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.
2011-06-28 | Moving toward personalized cell-based interventions for adrenal cortical disorders: Part 2 — Human diseases and tissue engineering
Transdifferentiation of an individual's own cells into functional differentiated cells to replace an organ's lost function would be a personalized approach to therapeutics. In this two part series, we will describe the progress toward establishing functional transdifferentiated adrenal cortical cells. In this article (Part 2), we describe the disorders of the adrenal cortex, therefore establishing why there is the need for personalized cell-based therapy for individuals with these disorders. We then present our pilot studies of cell transdifferentiation toward an adrenal cortical fate using genes described in the first article of this pair (Part 1).
1987-11-17 | Cushing's syndrome caused by an ectopic pituitary adenoma.
A 49-year old woman with a 5-year history of Cushing's syndrome was evaluated. Biochemical measurements revealed high cortisol and adrenocorticotropic hormone (ACTH) levels consistent with the ACTH-dependent type of Cushing's syndrome. However, the source of ACTH seemed to be autonomous as she demonstrated abnormal feedback control, with lack of response to metyrapone and high coses of dexamethasone. A search for an ectopic ACTH-secreting nonpituitary neoplasm was unsuccessful. Transsphenoidal pituitary exploration revealed a normal pituitary gland, but an ectopic pituitary adenoma was found incidentally in the mucosa of the sphenoid sinus. This adenoma stained strongly positive for ACTH on immunocytochemical studies. Resection of this lesion led to remission of the Cushing's syndrome. This variant of ACTH-dependent Cushing's syndrome can mimic the ectopic ACTH-dependent type and should be looked for in patients who fail to respond to pituitary operation.
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2026-07-23 | Fourteen-year bridge to cure in occult ectopic ACTH syndrome: resection of a 3-mm pulmonary carcinoid.
Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) often involves occult microtumors, making localization challenging. We report a 68-year-old woman with severe ACTH-dependent hypercortisolism in whom the primary tumor remained occult despite extensive imaging, including 68Ga-tetraazacyclododecanetetraacetic acid-D-Phe(1)-Tyr(3)-octreotide positron emission tomography/computed tomography. Based on a positive octreotide challenge test, she received long-acting release octreotide for over a decade, achieving sustained biochemical stability. In 2020, she developed breast cancer, with the tumor being ACTH-negative on immunohistochemistry. In 2023, during resection of pulmonary metastases of the breast cancer, a 3-mm nodule was incidentally discovered in the adjacent lung tissue. Through close interdisciplinary coordination, the nodule was removed and was confirmed as an ACTH- and somatostatin receptor (SSTR) 2-positive pulmonary carcinoid. Thereafter, the EAS resolved completely with prompt recovery of adrenal function. In this case, intensive medical stabilization in occult EAS probably served as a strategic "bridge to surgery." Importantly, long-term biochemical control using somatostatin analogs facilitated prompt recovery of the hypothalamic-pituitary-adrenal axis immediately after tumor resection. This may also have preserved SSTR2 expression, potentially by mitigating cortisol-induced receptor downregulation, facilitating its eventual localization. This report shows that meticulous multidisciplinary communication during unrelated surgical procedures is indispensable for identifying radiologically occult lesions.
2025-05-26 | A case series of bilateral inferior petrosal sinus sampling using desmopressin for evaluation of ACTH-dependent cushing's syndrome in pediatric patients: insights from Iran.
Pediatric Cushing Syndrome (CS) is rare and difficult to diagnose, especially when distinguishing ACTH-dependent subtypes. Bilateral inferior petrosal sinus sampling (BIPSS) is an essential but technically challenging procedure for this purpose. Because corticotropin-releasing hormone (CRH), the standard stimulant, has limitations, desmopressin is being explored as an alternative. This study assesses desmopressin-stimulated BIPSS for its diagnostic accuracy and tumor localization in pediatric CS within an Iranian cohort, addressing a gap in pediatric-specific diagnostic strategies and offering insights into the applicability of desmopressin in this context. Four pediatric patients with inconclusive pituitary imaging and suspected Cushing's disease (CD) underwent BIPSS with desmopressin at Taleghani Hospital, Tehran, Iran, between August 2015 and March 2019. Sensitivity of BIPSS for CD diagnosis was assessed, and tumor localization accuracy was evaluated during surgery. Bilateral IPSS demonstrated a sensitivity of 100% for diagnosing CD in pediatric patients. However, accuracy for tumor lateralization was moderate, with only 50% concordance between BIPSS lateralization and surgical findings. Specifically, two out of four patients had correct lateralization confirmed during surgery, while one patient with left lateralization was consistent with hypophysectomy findings. These discrepancies highlight challenges such as anatomical and drainage variations that can lead to mislocalization. Desmopressin enhances the sensitivity of BIPSS for diagnosing pediatric CD, presenting as a viable alternative to CRH stimulation. Despite high sensitivity, caution is advised when interpreting BIPSS results for tumor localization. Further research is needed to optimize diagnostic strategies for pediatric CS management.
2025-03-27 | Sex-dependent effects of FGF21 on HPA axis regulation and adrenal regeneration after Cushing syndrome in mice
BACKGROUND: Cushing's syndrome (CS) results from prolonged exposure to excessive glucocorticoids (GCs), leading to metabolic disturbances and adrenal insufficiency (AI). Fibroblast growth factor 21 (FGF21) has shown promise as a potential therapeutic target for metabolic disorders. This study explores the effects of FGF21 on adrenal gland function in a mouse model of AI following chronic hypercortisolism and investigates sex-dependent differences in the hypothalamic-pituitary-adrenal (HPA) axis response. METHODS: We employed a mouse model of AI after chronic corticosterone (CORT) treatment. The effects of recombinant human FGF21 (hFGF21) administration on adrenal function were evaluated in AI mice. Male and female wild-type (WT) and FGF21-overexpressing transgenic (Tg) mice were subjected to 5 weeks of CORT treatment, reaching CS phenotype, followed by immediate analysis or a 10-week recovery period. Metabolic parameters, HPA axis function, and adrenal gland morphology and gene expression were assessed. RESULTS: Prolonged CORT exposure resulted in metabolic disturbances and HPA axis dysregulation. hFGF21 treatment increased CORT and ACTH secretion in AI mice. FGF21 overexpression influenced glucose homeostasis and insulin regulation during CORT treatment and recovery, with sex-specific effects. Tissue-specific regulation of Klb expression was observed across the HPA axis, with distinct patterns between males and females. Tg mice displayed altered adrenal progenitor cell activation and steroidogenic gene expression. Sex-specific differences were observed in adrenal capsule remodeling and gene expression patterns during recovery. CONCLUSIONS: This study reveals the complex interplay between FGF21 signaling and GC-induced metabolic and endocrine changes, suggesting a potential sex-specific role of FGF21 in metabolic regulation and HPA axis recovery following after CS.
2025-01-30 | Performance of Vasopressin Stimulated Bilateral Inferior Petrosal Sinus Sampling in Corticotropin Dependent Cushing's Syndrome with Negative or Equivocal 3 Tesla Contrast Enhanced Magnetic Resonance Imaging of Pituitary.
Corticotropin releasing hormone (CRH)-stimulated bilateral inferior petrosal sinus sampling (BIPSS) is the most accurate procedure in the differential diagnosis of adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome (CS) with a sensitivity of 88-100% and a specificity of 67-100%. However, CRH is not available globally currently. We undertook this study of BIPSS using lysine vasopressin (LVP) as an agent to stimulate the release of ACTH from corticotrophs. Our objective was to assess the accuracy of LVP-stimulated BIPSS in differentiating Cushing's disease (CD) from ectopic ACTH syndrome (EAS) with negative or equivocal 3T contrast-enhanced MRI (CEMRI). Seventeen patients with clinically and biochemically confirmed ACTH-dependent CS with equivocal or negative CEMRI pituitary underwent BIPSS using LVP as a stimulating agent. Of seventeen patients who underwent BIPSS, nine patients had a raised central-to-peripheral ACTH ratio and were classified as having CD that was confirmed on histopathology following transsphenoidal sinus surgery. Remaining eight patients, who did not show a raised central-to-peripheral ACTH ratio, were classified to have EAS. All patients with EAS underwent contrast-enhanced computerised tomography of the neck, chest, and abdomen and/or Gallium 68 DOTANOC positron emission tomography/computerised tomography. Seven out of eight patients demonstrated solitary pulmonary nodule in the lung (bronchial carcinoid), and one patient had a mass in the thymus (thymic carcinoid). BIPSS using LVP confirmed the source of ACTH excess correctly in all the patients with ACTH-dependent CS without the loss of specificity.
2024-12-16 | Lateralization outcomes of bilateral inferior petrosal sinus sampling: desmopressin vs CRH.
Bilateral inferior petrosal sinus sampling (BIPSS) is the gold standard for localizing ACTH-dependent Cushing's syndrome (CS). While corticotropin-releasing hormone (CRH) was initially used for stimulation, desmopressin has become a common alternative. This research evaluates desmopressin's effectiveness in lateralizing Cushing's disease (CD) during BIPSS compared to CRH stimulation. The study included 33 individuals with ACTH-dependent CS who underwent BIPSS and had diagnoses confirmed by endoscopic endonasal transsphenoidal pituitary surgery (EETPS). Fourteen participants underwent BIPSS with CRH and 19 with desmopressin. A comparative analysis was conducted. BIPSS accurately lateralized 76% of cases, specifically, 71% with CRH and 79% with desmopressin (p = 0.2). For tumors < 6 mm on MRI, overall accuracy was 82%, namely, 75% with CRH and 90% with desmopressin (p = 0.4). IPSS achieved 100% accuracy in the four cases with no lesion on preoperative MRI. This study demonstrates no significant difference in lateralization accuracy between desmopressin and CRH for IPSS. In challenging cases, especially those with microadenomas or non-lesional CD, desmopressin with IPSS aids in preoperative lateralization.
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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.
2019-06-05 | A Long-Acting Neutralizing Monoclonal ACTH Antibody Blocks Corticosterone and Adrenal Gene Responses in Neonatal Rats
The control of steroidogenesis in the neonatal adrenal gland is of great clinical interest. We have previously demonstrated that the postnatal day (PD) 2 rat exhibits a large plasma corticosterone response to hypoxia in the absence of an increase in plasma ACTH measured by RIA, whereas the corticosterone response to exogenous ACTH is intact. By PD8, the corticosterone response to hypoxia is clearly ACTH-dependent. We hypothesized that this apparently ACTH-independent response to hypoxia in the newborn rat is due to an increase in a bioactive, nonimmunoassayable form of ACTH. To evaluate this phenomenon, we pretreated neonatal rats with a novel, specific, neutralizing anti-ACTH antibody (ALD1611) (20 mg/kg or 1 mg/kg IP) on the morning of PD1, PD7, and PD14. Twenty-four hours later, we measured hypoxia- or ACTH-stimulated plasma ACTH and corticosterone. For long-term effects, ALD1611 was given on PD1 and pups were studied on PD8 and PD15. Pretreatment with ALD1611 significantly decreased baseline corticosterone and completely blocked the corticosterone response to hypoxia and exogenous ACTH stimulation at all ages. The effect of 1 mg/kg ALD1611 on PD1 had dissipated by PD15. The decrease in corticosterone in ALD1611-treated pups was associated with decreases in baseline and hypoxia- and ACTH-stimulated adrenal Ldlr, Mrap, and Star mRNA expression at all ages. The adrenal response to hypoxia in the newborn rat is ACTH-dependent, suggesting the release of nonimmunoassayable, biologically active forms of ACTH. ALD1611 is useful as a tool to attenuate stress-induced, ACTH-dependent adrenal steroidogenesis in vivo.
2018-08-23 | Glucocorticoid-induced insulin resistance is related to macrophage visceral adipose tissue infiltration
Insulin resistance is frequently present in patients with glucocorticoid (GC) excess (Cushing’s syndrome) or treated with high doses of GCs. Furthermore, others similarities between metabolic syndrome (visceral obesity, elevated blood glucose levels, dyslipidemia) and Cushing’s syndrome suggest that GCs could play a role in obesity-linked complications. Here we reported that long-term corticosterone (CORT) exposure in mice induced weight gain, dyslipidemia as well as hyperglycaemia and systemic insulin resistance. CORT-treated mice exhibited an increased 11β-Hsd1 expression and corticosterone levels in fat depots but a specific upregulation of glucocorticoid receptor (Gr) and hexose-6-phosphate dehydrogenase only in gonadal adipose tissue, suggesting that GC could act differentially on various fat depots. Despite fat accumulation in all depots, an increased expression of adipogenic (Pparγ, C/ebpα) and lipogenic (Acc, Fas) key genes was restricted to gonadal adipose tissue. Hypertrophied adipocytes observed in both visceral and subcutaneous depots also resulted from reduced lipolytic activity due to CORT treatment. Surprisingly, GC treatment promoted macrophage infiltration (F4/80, Cd68) within all adipose tissues along with predominant M2-like macrophage phenotype, and can directly act on macrophages to induce this phenotype. Moreover, macrophage infiltration preceded mass gain and adipocyte hypertrophy. Of note, specific macrophage depletion in gonadal fat preferentially reduced the M2-like macrophage content, and partially restored insulin sensitivity in mice with GC-induced obesity and insulin resistance. These data provide evidence that GCs act on adipose tissue in a depot-dependent manner and that gonadal adipose macrophages are key effectors of GC-associated insulin resistance.
2017-02-20 | Interleukin-1 Antagonism Decreases Cortisol Levels in Obese Individuals
Increased cortisol levels in obesity may contribute to the associated metabolic syndrome. In obesity, the activated innate immune system leads to increased interleukin (IL)-1β, which is known to stimulate the release of adrenocorticotropin hormone (ACTH). We hypothesized that in obesity IL-1 antagonism would result in downregulation of the hypothalamo-pituitary-adrenal axis, leading to decreased cortisol levels. In this prospective intervention study, we included 73 patients with obesity (body mass index [BMI] ≥30 kg/m2) and at least one additional feature of the metabolic syndrome. The primary end point was change in morning cortisol from baseline to after the administration of the IL-1 receptor antagonist (anakinra/Kineret®, total dose 3 × 100 mg). Secondary end points were effects on salivary cortisol and ACTH. Median age was 56 years, 50.7% of patients were female, and median BMI was 36.3 kg/m2. Median morning serum cortisol levels (nmol/L) decreased significantly after IL-1 antagonism [from baseline, 452 to 423; absolute difference, −38.7; 95% confidence interval (CI), −64 to −13.4; P = 0.0019]. Similar effects were found for salivary cortisol levels (−2.8; 95% CI, −4.4 to −1.3; P = 0.0007), ACTH levels (−2.2; 95% CI; −4.2 to −0.1; P = 0.038), systolic blood pressure (−5.2, 95% CI, −8.5 to −1.8; P = 0.0006), and heart rate (−2.9; 95% CI, −4.7 to −1.0; P = 0.0029). IL-1 antagonism in obese individuals with features of the metabolic syndrome leads to a decrease in serum cortisol, salivary cortisol, and ACTH levels along with a reduction in systolic blood pressure and heart rate.
1994-04-01 | The value of inferior petrosal sinus sampling in diagnosis and treatment of Cushing's disease
Summary OBJECTIVE While microsurgical selective adenomectomy is the best method available at present for the treatment of Cushing's disease, its success depends to a large degree on precise preoperative intrapituitary microadenoma localization. This study compares the results of intrapituitary adenoma localization obtained with inferior petrosal sampling, computerized tomography and magnetic resonance imaging with the adenoma localization as found at surgery. DESIGN The results of inferior petrosal sampling for intrapituitary localization of ACTH‐producing pituitary adenomas were compared in a retrospective study with the results of computerized tomography, magnetic resonance imaging, surgical and pathological findings. Special attention was paid to the intersinus ACTH relation. PATIENTS Thirty‐eight patients (33 women and 5 men) of 11‐68 years of age suffering from pituitary‐dependent Cushing's disease were studied. Patients with ectopic ACTH‐secreting tumours and and recurrent pituitary adenomas were excluded. MEASUREMENTS Blood samples were obtained simultaneously from both inferior petrosal sinuses and a peripheral vein before and 5, 10, 15 and 20 minutes after stimulation with 60 /μg/m 2 human corticotrophin‐releasing hormone (hCRH). RESULTS of the adenomas in our series, 42% had a diameter of 3 mm or less. Only 6 of 20 adenomas examined by computerized tomography and 11 of 29 examined by magnetic resonance imaging were identified correctly. Inferior petrosal sinus sampling produced significantly better results, particularly when combined with a stimulation test with hCRH: for 29 of 38 adenomas examined, the location was predicted correctly with these techniques. Analysis of the intersinus adrenocorticotrophin concentration ratio showed that the best right‐central‐left discrimination was obtained with values of 1.3 and 1.4. CONCLUSIONS We conclude that inferior petrosal sinus ACTH sampling after hCRH stimulation is the best method available for the intrapituitary localization of microadenomas causing Cushing's disease provided that the appropriate technique of blood sampling is used meticulously.
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Drug Discovery Landscape
2 orphan drug designations for ACTH-dependent Cushing syndrome, including 1 approved therapy.
2 orphan drug designations for ACTH-dependent Cushing syndrome, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Synthetic double-stranded short interfering RNA oligonucleotide directed against proopiomelanocortin | oligonucleotides | EMA | 2010-10-01 | — | Neurocrine Netherlands B.V. |
Corticorelin ovine triflutate [Acthrel] | proteins | FDA | 1989-11-24 | 1996-05-23 | Ferring Laboratories, Inc. |
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