RARE DISEASE
Cushing disease
Cushing disease
Cushing disease
Synonyms: Corticotroph pituitary adenoma, Pituitary corticotroph micro-adenoma, Pituitary-dependent Cushing syndrome
Synonyms: Corticotroph pituitary adenoma, Pituitary corticotroph micro-adenoma, Pituitary-dependent Cushing syndrome
Synonyms: Corticotroph pituitary adenoma, Pituitary corticotroph micro-adenoma, Pituitary-dependent Cushing syndrome
Drug discovery
2
drugs
With orphan designations
Overview
Cushing disease is an ACTH-dependent form of Cushing syndrome caused by a pituitary corticotroph adenoma, resulting in chronic hypercortisolism. It presents with central obesity, moon face, hypertension, glucose intolerance, proximal muscle weakness, and neuropsychiatric symptoms [4][5][14]. Diagnosis requires biochemical confirmation of hypercortisolism and pituitary MRI/ACTH testing [1][5]. First-line treatment involves transsphenoidal adenomectomy, with adjuvant therapies for persistent cases [1][4][15].
Categories: rare endocrine diseases, rare infertility disorders, rare neoplastic diseases
Research Papers
1,180 drug discovery papers about Cushing disease, with 4 first-in-class and 19 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,180 drug discovery papers about Cushing disease, with 4 first-in-class and 19 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-03 | A case report of osilodrostat treatment in primary bilateral macronodular adrenal hyperplasia associated with bilateral adrenal mass reduction
Abstract Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing syndrome (CS), characterized by bilateral adrenal nodules larger than 1 cm. Cortisol hypersecretion in PBMAH is driven by intra-adrenal rather than pituitary adrenocorticotropic hormone (ACTH), with its pathogenesis mediated by aberrant hormone receptor expression in the adrenal cortex. This article reports a case of a 60-year-old woman with PBMAH in whom a marked reduction in bilateral adrenal masses was observed following treatment with osilodrostat. The patient presented with typical Cushingoid features, accompanied by hypertension, diabetes mellitus, osteoporosis, and severe restrictive lung disease. Genetic testing identified a pathogenic mutation in the ARMC5 gene, confirming the diagnosis. Because she was intolerant of surgical treatment, left adrenal artery embolization (AAE) was performed but failed to control hypercortisolism. Osilodrostat therapy was subsequently initiated—this potent 11β-hydroxylase inhibitor was recently approved in China for the treatment of Cushing syndrome. Notably, after 23 weeks of treatment, the patient's 24-hour urinary free cortisol (24 hours-UFC, CLIA) level returned to normal. Treatment was then discontinued, and during 11 months of follow-up the patient’s 24 hours-UFC remained within the normal range. Moreover, imaging performed during the period of osilodrostat therapy demonstrated significant shrinkage of both adrenal glands. To our knowledge, this is the first reported case of bilateral adrenal mass reduction observed in temporal association with osilodrostat treatment in a PBMAH patient. However, prior AAE confounds the attribution of tumor shrinkage to osilodrostat alone. These findings highlight an observed association between the drug and mass reduction, warranting further investigation to clarify its potential role beyond symptomatic control.
2026-07-31 | Determining Medical Versus Surgical Management for Cushing’s Syndrome: A Case Series
Cushing’s Syndrome is a rare disorder resulting from prolonged exposure to elevated levels of glucocorticoids. While Cushing’s disease, associated with a pituitary corticotroph adenoma, is the most prevalent cause, endogenous Cushing’s Syndrome may also arise from adrenal lesions, including cortisol-producing adenomas, adrenocortical carcinoma, and other forms of hyperplasia.
2026-07-31 | Evaluation of desmopressin stimulation test specificity in healthy volunteers.
The desmopressin stimulation test (DesST) is used to identify Cushing disease (CD). Reportedly, most healthy people and patients with non-neoplastic hypercortisolism lack a significant response. We aimed to evaluate and improve DesST specificity (Sp). Prospective evaluation of four DesST protocols in healthy volunteers. Twenty healthy volunteers underwent four DesST protocols in a randomized order. Protocols involved fluid restriction with desmopressin 10 µg (10NPO; 'standard'), 4 µg (4NPO), and 10 µg preceded by dexamethasone 1 mg (10+DexNPO); and desmopressin 10 µg without fluid restriction (10H2O). We evaluated Sp for each protocol, using established response criteria. Previous criteria of relative increases of 35% and/or 20% for ACTH and cortisol, respectively, had low Sp: 50% (95% CI: 28-72%; 10NPO) to 85% (95% CI: 69-100%; 10+DexNPO). Using absolute ACTH increase >8.1 pmol/L (37 pg/mL) improved Sp to 100% across all protocols. Compared with 10NPO, median ACTH and cortisol were lower throughout during 10+DexNPO and also at +15 min during 4NPO (ACTH: 4.4 vs 4.9 pmol/L (19.9 vs 22.1 pg/mL), P = 0.06; cortisol: 248 vs 284 nmol/L (9.0 vs 10.3 µg/dL), P = 0.01). 10H2O and 10NPO results were similar. Adverse events were mild; hyponatremia occurred after 5/80 tests. After desmopressin, healthy volunteers have small absolute increases in ACTH and cortisol that equate to large relative changes from baseline. Optimized response criteria should likely incorporate absolute values. Fluid restriction did not impact Sp, but using a lower desmopressin dose and dexamethasone pre-treatment are promising ways to improve diagnostic accuracy, if sensitivity is maintained in CD. Half of healthy volunteers had a response consistent with Cushing disease (CD) during a commonly used 10 µg desmopressin stimulation test, interpreted using relative ACTH and/or cortisol increases. This puts the test's reliability for excluding CD in question, particularly in settings of mild hypercortisolism. These situations include differentiating CD from non-neoplastic hypercortisolism, identifying cyclic ectopic ACTH-producing tumors during nadir phases, and establishing early CD recurrence. Optimized response criteria likely require absolute ACTH and/or cortisol cutoffs. Using a reduced 4 µg dose of desmopressin or pre-treatment with 1 mg dexamethasone improved test specificity, offering promising ways to improve test performance if sensitivity is maintained in CD. NCT06635629.
2026-07-28 | An unusually small pituitary microadenoma causing severe Cushing disease in a male patient: lessons from early Radiosurgical management.
Cushing disease is a rare endocrine disorder caused by an ACTH-secreting pituitary adenoma. We report a 27-year-old male with severe hypercortisolism due to a 1.2-mm pituitary microadenoma. He presented with facial plethora, centripetal obesity, violaceous striae, hypertension, diabetes, dyslipidemia, and fatigue. Biochemical testing confirmed ACTH-dependent hypercortisolism, and 3 T MRI identified the lesion. Owing to its minute size and the anticipated difficulty of surgical localization, transsphenoidal surgery was deferred and Gamma Knife radiosurgery (GKRS) was performed as first-line therapy. After 5 months, biochemical hypercortisolism persisted, with elevated cortisol and ACTH levels. Ketoconazole 200 mg daily was subsequently initiated, resulting in normalization of serum cortisol within four weeks, ACTH levels remained elevated. Mild transient ALT elevation was observed during treatment. This case highlights that very small adenomas can cause severe disease and underscores the delayed response to GKRS, necessitating early adjunctive medical therapy to control hypercortisolism and reduce morbidity.
2026-07-17 | Steroid alterations in Cushing's disease persist after remission: ACTH-driven steroid changes dissociate from mood-regulatory neurosteroids.
Cushing's disease (CD) is associated with high rates of depression and anxiety that often persist despite biochemical remission, yet the underlying mechanisms remain unclear. This study aims to characterize circulating neurosteroid (NS) profiles in CD and examine their associations with psychological symptoms. This is a cross-sectional study of 37 patients with CD (22 active, 15 remission) and 21 nonfunctioning pituitary adenoma (NFA) controls. NS levels were quantified by mass spectrometry; psychological symptoms were assessed using the 21-item Depression Anxiety Stress Scale (DASS-21). Discriminatory NS were identified by partial least squares discriminant analysis (PLS-DA), with a variable importance in projection (VIP) score > 1.0 used as the selection threshold. Patients with CD exhibited higher depression (14 vs. 7.5, p = 0.03) and stress scores (17 vs. 8.5, p = 0.03) than NFA. PLS-DA identified five discriminatory NS: 4-androstenedione (VIP = 2.0), 11-deoxycorticosterone (DOC) (VIP = 1.8), 7-OH-pregnenolone (VIP = 1.8), corticosterone (VIP = 1.7), and androsterone (VIP = 1.1); the first four were elevated, and androsterone decreased in CD. Despite biochemical remission, most NS alterations persisted, with 7-OH-pregnenolone paradoxically increasing further (121 vs. 22.5 ng/mL, p = 0.008). Mood symptoms did not correlate with cortisol, adrenocorticotropic hormone (ACTH), or urinary free cortisol (UFC). However, dehydroepiandrosterone (DHEA) correlated positively with depression (r = 0.4, p = 0.02) and stress (r = 0.4, p = 0.02), whereas allopregnanolone correlated negatively with depression (r = -0.4, p = 0.03) and stress (r = -0.4, p = 0.04). Among discriminatory NS, only 7-OH-pregnenolone correlated with stress (r = 0.3, p = 0.04). These NS-mood associations were absent in NFA. CD is characterized by a distinct and persistent steroid signature that persists beyond biochemical remission, reflecting hypercortisolism-driven epigenetic remodeling of steroidogenic pathways. The dissociation between ACTH-driven steroid alterations and mood-associated NS suggests that cortisol reduction alone may inadequately address psychiatric symptoms, warranting investigation of NS-targeted therapies.
2026-08-03 | A case report of osilodrostat treatment in primary bilateral macronodular adrenal hyperplasia associated with bilateral adrenal mass reduction
Abstract Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing syndrome (CS), characterized by bilateral adrenal nodules larger than 1 cm. Cortisol hypersecretion in PBMAH is driven by intra-adrenal rather than pituitary adrenocorticotropic hormone (ACTH), with its pathogenesis mediated by aberrant hormone receptor expression in the adrenal cortex. This article reports a case of a 60-year-old woman with PBMAH in whom a marked reduction in bilateral adrenal masses was observed following treatment with osilodrostat. The patient presented with typical Cushingoid features, accompanied by hypertension, diabetes mellitus, osteoporosis, and severe restrictive lung disease. Genetic testing identified a pathogenic mutation in the ARMC5 gene, confirming the diagnosis. Because she was intolerant of surgical treatment, left adrenal artery embolization (AAE) was performed but failed to control hypercortisolism. Osilodrostat therapy was subsequently initiated—this potent 11β-hydroxylase inhibitor was recently approved in China for the treatment of Cushing syndrome. Notably, after 23 weeks of treatment, the patient's 24-hour urinary free cortisol (24 hours-UFC, CLIA) level returned to normal. Treatment was then discontinued, and during 11 months of follow-up the patient’s 24 hours-UFC remained within the normal range. Moreover, imaging performed during the period of osilodrostat therapy demonstrated significant shrinkage of both adrenal glands. To our knowledge, this is the first reported case of bilateral adrenal mass reduction observed in temporal association with osilodrostat treatment in a PBMAH patient. However, prior AAE confounds the attribution of tumor shrinkage to osilodrostat alone. These findings highlight an observed association between the drug and mass reduction, warranting further investigation to clarify its potential role beyond symptomatic control.
2026-07-31 | Determining Medical Versus Surgical Management for Cushing’s Syndrome: A Case Series
Cushing’s Syndrome is a rare disorder resulting from prolonged exposure to elevated levels of glucocorticoids. While Cushing’s disease, associated with a pituitary corticotroph adenoma, is the most prevalent cause, endogenous Cushing’s Syndrome may also arise from adrenal lesions, including cortisol-producing adenomas, adrenocortical carcinoma, and other forms of hyperplasia.
2026-07-31 | Evaluation of desmopressin stimulation test specificity in healthy volunteers.
The desmopressin stimulation test (DesST) is used to identify Cushing disease (CD). Reportedly, most healthy people and patients with non-neoplastic hypercortisolism lack a significant response. We aimed to evaluate and improve DesST specificity (Sp). Prospective evaluation of four DesST protocols in healthy volunteers. Twenty healthy volunteers underwent four DesST protocols in a randomized order. Protocols involved fluid restriction with desmopressin 10 µg (10NPO; 'standard'), 4 µg (4NPO), and 10 µg preceded by dexamethasone 1 mg (10+DexNPO); and desmopressin 10 µg without fluid restriction (10H2O). We evaluated Sp for each protocol, using established response criteria. Previous criteria of relative increases of 35% and/or 20% for ACTH and cortisol, respectively, had low Sp: 50% (95% CI: 28-72%; 10NPO) to 85% (95% CI: 69-100%; 10+DexNPO). Using absolute ACTH increase >8.1 pmol/L (37 pg/mL) improved Sp to 100% across all protocols. Compared with 10NPO, median ACTH and cortisol were lower throughout during 10+DexNPO and also at +15 min during 4NPO (ACTH: 4.4 vs 4.9 pmol/L (19.9 vs 22.1 pg/mL), P = 0.06; cortisol: 248 vs 284 nmol/L (9.0 vs 10.3 µg/dL), P = 0.01). 10H2O and 10NPO results were similar. Adverse events were mild; hyponatremia occurred after 5/80 tests. After desmopressin, healthy volunteers have small absolute increases in ACTH and cortisol that equate to large relative changes from baseline. Optimized response criteria should likely incorporate absolute values. Fluid restriction did not impact Sp, but using a lower desmopressin dose and dexamethasone pre-treatment are promising ways to improve diagnostic accuracy, if sensitivity is maintained in CD. Half of healthy volunteers had a response consistent with Cushing disease (CD) during a commonly used 10 µg desmopressin stimulation test, interpreted using relative ACTH and/or cortisol increases. This puts the test's reliability for excluding CD in question, particularly in settings of mild hypercortisolism. These situations include differentiating CD from non-neoplastic hypercortisolism, identifying cyclic ectopic ACTH-producing tumors during nadir phases, and establishing early CD recurrence. Optimized response criteria likely require absolute ACTH and/or cortisol cutoffs. Using a reduced 4 µg dose of desmopressin or pre-treatment with 1 mg dexamethasone improved test specificity, offering promising ways to improve test performance if sensitivity is maintained in CD. NCT06635629.
2026-07-28 | An unusually small pituitary microadenoma causing severe Cushing disease in a male patient: lessons from early Radiosurgical management.
Cushing disease is a rare endocrine disorder caused by an ACTH-secreting pituitary adenoma. We report a 27-year-old male with severe hypercortisolism due to a 1.2-mm pituitary microadenoma. He presented with facial plethora, centripetal obesity, violaceous striae, hypertension, diabetes, dyslipidemia, and fatigue. Biochemical testing confirmed ACTH-dependent hypercortisolism, and 3 T MRI identified the lesion. Owing to its minute size and the anticipated difficulty of surgical localization, transsphenoidal surgery was deferred and Gamma Knife radiosurgery (GKRS) was performed as first-line therapy. After 5 months, biochemical hypercortisolism persisted, with elevated cortisol and ACTH levels. Ketoconazole 200 mg daily was subsequently initiated, resulting in normalization of serum cortisol within four weeks, ACTH levels remained elevated. Mild transient ALT elevation was observed during treatment. This case highlights that very small adenomas can cause severe disease and underscores the delayed response to GKRS, necessitating early adjunctive medical therapy to control hypercortisolism and reduce morbidity.
2026-07-17 | Steroid alterations in Cushing's disease persist after remission: ACTH-driven steroid changes dissociate from mood-regulatory neurosteroids.
Cushing's disease (CD) is associated with high rates of depression and anxiety that often persist despite biochemical remission, yet the underlying mechanisms remain unclear. This study aims to characterize circulating neurosteroid (NS) profiles in CD and examine their associations with psychological symptoms. This is a cross-sectional study of 37 patients with CD (22 active, 15 remission) and 21 nonfunctioning pituitary adenoma (NFA) controls. NS levels were quantified by mass spectrometry; psychological symptoms were assessed using the 21-item Depression Anxiety Stress Scale (DASS-21). Discriminatory NS were identified by partial least squares discriminant analysis (PLS-DA), with a variable importance in projection (VIP) score > 1.0 used as the selection threshold. Patients with CD exhibited higher depression (14 vs. 7.5, p = 0.03) and stress scores (17 vs. 8.5, p = 0.03) than NFA. PLS-DA identified five discriminatory NS: 4-androstenedione (VIP = 2.0), 11-deoxycorticosterone (DOC) (VIP = 1.8), 7-OH-pregnenolone (VIP = 1.8), corticosterone (VIP = 1.7), and androsterone (VIP = 1.1); the first four were elevated, and androsterone decreased in CD. Despite biochemical remission, most NS alterations persisted, with 7-OH-pregnenolone paradoxically increasing further (121 vs. 22.5 ng/mL, p = 0.008). Mood symptoms did not correlate with cortisol, adrenocorticotropic hormone (ACTH), or urinary free cortisol (UFC). However, dehydroepiandrosterone (DHEA) correlated positively with depression (r = 0.4, p = 0.02) and stress (r = 0.4, p = 0.02), whereas allopregnanolone correlated negatively with depression (r = -0.4, p = 0.03) and stress (r = -0.4, p = 0.04). Among discriminatory NS, only 7-OH-pregnenolone correlated with stress (r = 0.3, p = 0.04). These NS-mood associations were absent in NFA. CD is characterized by a distinct and persistent steroid signature that persists beyond biochemical remission, reflecting hypercortisolism-driven epigenetic remodeling of steroidogenic pathways. The dissociation between ACTH-driven steroid alterations and mood-associated NS suggests that cortisol reduction alone may inadequately address psychiatric symptoms, warranting investigation of NS-targeted therapies.
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Drug Discovery Landscape
2 orphan drug designations for Cushing disease, including 2 approved therapies.
2 orphan drug designations for Cushing disease, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
osilodrostat [Isturisa] | small molecules | FDA | 2013-09-13 | 2020-03-06 | Recordati Rare Diseases, Inc |
pasireotide [Signifor] | small molecules | FDA | 2009-07-24 | 2012-12-14 | Novartis Pharmaceuticals Corporation |
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