RARE DISEASE
Cushing syndrome due to ectopic ACTH secretion
Cushing syndrome due to ectopic ACTH secretion
Cushing syndrome due to ectopic ACTH secretion
Synonyms: Adrenocorticotropic hormone secretion syndrome, Ectopic ACTH secreting tumor, Ectopic Cushing syndrome, Occult ectopic ACTH secretion, Paraneoplastic Cushing syndrome
Synonyms: Adrenocorticotropic hormone secretion syndrome, Ectopic ACTH secreting tumor, Ectopic Cushing syndrome, Occult ectopic ACTH secretion, Paraneoplastic Cushing syndrome
Synonyms: Adrenocorticotropic hormone secretion syndrome, Ectopic ACTH secreting tumor, Ectopic Cushing syndrome, Occult ectopic ACTH secretion, Paraneoplastic Cushing syndrome
Drug discovery
1
drug
With orphan designation
Overview
Cushing syndrome due to ectopic ACTH secretion (EAS) is a rare, ACTH-dependent hypercortisolism caused by neuroendocrine tumors (NETs) outside the pituitary gland. Common sources include bronchial carcinoids (40%) and small cell lung cancer. Diagnosis requires biochemical confirmation of hypercortisolism, elevated ACTH levels (>20 pg/mL), and localization via imaging (CT/MRI) or functional studies (e.g., CRH tests, petrosal sinus sampling). Severe hypokalemia, infections, and metabolic derangements are frequent, necessitating urgent treatment [1][4][6][16].
Therapies
Primary: Surgical resection of ACTH-secreting tumors (curative if localized) [3][18].
Medical: Adrenal enzyme inhibitors (metyrapone, osilodrostat, ketoconazole) or somatostatin analogs to control hypercortisolism [3][8][10].
Adjunctive: Chemotherapy/radiotherapy for malignancies; bilateral adrenalectomy for refractory cases [4][18][20].
Categories: rare endocrine diseases, rare gastroenterological diseases, rare infertility disorders, rare neoplastic diseases
Research Papers
784 drug discovery papers about Cushing syndrome due to ectopic ACTH secretion, with 4 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
784 drug discovery papers about Cushing syndrome due to ectopic ACTH secretion, with 4 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
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.
2026-07-28 | Real-World Effectiveness and Safety of Osilodrostat in Cushing's Syndrome: A Retrospective Phase IV Study.
Osilodrostat has demonstrated efficacy in clinical trials for Cushing's syndrome (CS). Real-world data remain limited. To assess real-world effectiveness and safety of osilodrostat in a large cohort of CS patients. Multicenter, retrospective, phase IV-study across 11 Italian endocrine referral centers. 100 CS patients [74% pituitary, 16% adrenal, 10% ectopic]. Primary endpoint was the percentage of patients with UFC≤ULN at their last observation. Secondary endpoints included biochemical and hormonal control, clinical outcomes, QoL, AEs. 81% of patients had normal UFC levels at last observation, 92% at least once within study period. Excluding 12 patients with normal baseline UFC levels, 78.4% of patients had normal UFC levels at their last observation, whereas 90.9% at least once within the study period.The mean±SD (median,range) time to the first normalization of UFC levels, in the 80 patients who achieved normalization, was 92.1±86.3 (67.5,8-455) days, at a mean± SD (median,range) osilodrostat dose of 7.2±6.8 (5,1-40) mg/day.Significant reductions in late-night salivary cortisol and morning serum cortisol levels were observed. Improvements were noted in anthropometric parameters, blood pressure, glucose metabolism, clinical signs, and QoL. AEs occurred in 29% of patients, mostly mild-to-moderate; adrenal insufficiency was the most common AE reported in 20% of patients. Hormonal control and safety profiles were consistent across CS etiologies. Osilodrostat is effective, generally well tolerated in routine clinical practice, representing a valuable therapy for CS management, able to achieve rapid and sustained hormonal control, significant metabolic, cardiovascular, clinical and QoL improvements with a well-tolerated safety profile.
2026-07-25 | Individualized osilodrostat treatment for patients with ACTH-dependent Cushing's syndrome: real-world evidence.
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. To evaluate dosing patterns, effectiveness, and safety of osilodrostat in patients with adrenocorticotropic hormone (ACTH)-dependent CS. 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. 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%). 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.
2026-07-24 | Protracted osilodrostat-induced pan-adrenal steroidogenic suppression and adrenal size reduction in Cushing disease.
Osilodrostat, a potent 11β-hydroxylase inhibitor, is used for Cushing syndrome. Transient adrenal insufficiency during dose titration is common and usually reversible, whereas prolonged adrenal insufficiency after treatment discontinuation appears uncommon. A man with treatment-resistant Cushing disease was treated with osilodrostat after prior transsphenoidal surgeries and stereotactic radiosurgery. He initially demonstrated the expected biochemical profile of 11β-hydroxylase inhibition, with elevated adrenocorticotropic hormone (ACTH) and 11-deoxycortisol concentrations. After 18 months of therapy, he developed adrenal insufficiency with morning cortisol 1.27 μg/dL (SI: 35 nmol/L) [reference 5-22.6 μg/dL; 145-619 nmol/L], ACTH 989 pg/mL (SI: 217.6 pmol/L) [reference 4-46 pg/mL; 1.0-10.1 pmol/L], suppressed aldosterone 1.2 ng/dL (SI: 33.2 pmol/L) [reference 2-35 ng/dL; 55.4-970 pmol/L], markedly elevated direct renin 288.5 mIU/mL [reference 4.4-46.1 mIU/mL], and suppression of adrenal androgen production. Osilodrostat was discontinued and glucocorticoid replacement initiated, with later introduction of mineralocorticoid replacement. At 2.5 years, glucocorticoid and androgen suppression persist, together with prolonged mineralocorticoid dysfunction and adrenal size reduction. Review of 10 previous reports suggests prolonged adrenal insufficiency is uncommon and mineralocorticoid deficiency rarely documented, while persistent androgen suppression has not previously been reported. This case highlights prolonged pan-adrenal steroidogenic suppression with adrenal shrinkage and suggests recovery of adrenal function may take years.
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.
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.
2026-07-28 | Real-World Effectiveness and Safety of Osilodrostat in Cushing's Syndrome: A Retrospective Phase IV Study.
Osilodrostat has demonstrated efficacy in clinical trials for Cushing's syndrome (CS). Real-world data remain limited. To assess real-world effectiveness and safety of osilodrostat in a large cohort of CS patients. Multicenter, retrospective, phase IV-study across 11 Italian endocrine referral centers. 100 CS patients [74% pituitary, 16% adrenal, 10% ectopic]. Primary endpoint was the percentage of patients with UFC≤ULN at their last observation. Secondary endpoints included biochemical and hormonal control, clinical outcomes, QoL, AEs. 81% of patients had normal UFC levels at last observation, 92% at least once within study period. Excluding 12 patients with normal baseline UFC levels, 78.4% of patients had normal UFC levels at their last observation, whereas 90.9% at least once within the study period.The mean±SD (median,range) time to the first normalization of UFC levels, in the 80 patients who achieved normalization, was 92.1±86.3 (67.5,8-455) days, at a mean± SD (median,range) osilodrostat dose of 7.2±6.8 (5,1-40) mg/day.Significant reductions in late-night salivary cortisol and morning serum cortisol levels were observed. Improvements were noted in anthropometric parameters, blood pressure, glucose metabolism, clinical signs, and QoL. AEs occurred in 29% of patients, mostly mild-to-moderate; adrenal insufficiency was the most common AE reported in 20% of patients. Hormonal control and safety profiles were consistent across CS etiologies. Osilodrostat is effective, generally well tolerated in routine clinical practice, representing a valuable therapy for CS management, able to achieve rapid and sustained hormonal control, significant metabolic, cardiovascular, clinical and QoL improvements with a well-tolerated safety profile.
2026-07-25 | Individualized osilodrostat treatment for patients with ACTH-dependent Cushing's syndrome: real-world evidence.
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. To evaluate dosing patterns, effectiveness, and safety of osilodrostat in patients with adrenocorticotropic hormone (ACTH)-dependent CS. 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. 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%). 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.
2026-07-24 | Protracted osilodrostat-induced pan-adrenal steroidogenic suppression and adrenal size reduction in Cushing disease.
Osilodrostat, a potent 11β-hydroxylase inhibitor, is used for Cushing syndrome. Transient adrenal insufficiency during dose titration is common and usually reversible, whereas prolonged adrenal insufficiency after treatment discontinuation appears uncommon. A man with treatment-resistant Cushing disease was treated with osilodrostat after prior transsphenoidal surgeries and stereotactic radiosurgery. He initially demonstrated the expected biochemical profile of 11β-hydroxylase inhibition, with elevated adrenocorticotropic hormone (ACTH) and 11-deoxycortisol concentrations. After 18 months of therapy, he developed adrenal insufficiency with morning cortisol 1.27 μg/dL (SI: 35 nmol/L) [reference 5-22.6 μg/dL; 145-619 nmol/L], ACTH 989 pg/mL (SI: 217.6 pmol/L) [reference 4-46 pg/mL; 1.0-10.1 pmol/L], suppressed aldosterone 1.2 ng/dL (SI: 33.2 pmol/L) [reference 2-35 ng/dL; 55.4-970 pmol/L], markedly elevated direct renin 288.5 mIU/mL [reference 4.4-46.1 mIU/mL], and suppression of adrenal androgen production. Osilodrostat was discontinued and glucocorticoid replacement initiated, with later introduction of mineralocorticoid replacement. At 2.5 years, glucocorticoid and androgen suppression persist, together with prolonged mineralocorticoid dysfunction and adrenal size reduction. Review of 10 previous reports suggests prolonged adrenal insufficiency is uncommon and mineralocorticoid deficiency rarely documented, while persistent androgen suppression has not previously been reported. This case highlights prolonged pan-adrenal steroidogenic suppression with adrenal shrinkage and suggests recovery of adrenal function may take years.
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.
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Drug Discovery Landscape
1 orphan drug designation for Cushing syndrome due to ectopic ACTH secretion.
1 orphan drug designation for Cushing syndrome due to ectopic ACTH secretion.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Mifepristone | small molecules | FDA | 2005-02-07 | — | HRA Pharma |
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