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
823 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:
823 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:
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.
2026-06-12 | 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.
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.
2026-07-10 | 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.
2026-06-12 | 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.
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.
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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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