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:
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.
2026-07-23 | 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.
2026-07-16 | 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.
2026-06-12 | 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.
2026-08-13 | 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.
2026-07-23 | 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.
2026-07-16 | 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.
2026-06-12 | 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.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
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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