RARE DISEASE
Chronic primary adrenal insufficiency
Chronic primary adrenal insufficiency
Chronic primary adrenal insufficiency
Synonyms: CPAI, Chronic adrenocorticoid insufficiency
Synonyms: CPAI, Chronic adrenocorticoid insufficiency
Synonyms: CPAI, Chronic adrenocorticoid insufficiency
Drug discovery
4
drugs
With orphan designations
Overview
Chronic primary adrenal insufficiency (CPAI) is a rare endocrine disorder caused by inadequate cortisol and aldosterone production due to adrenal cortex dysfunction. Autoimmune adrenalitis (Addison's disease) accounts for 70-90% of cases in developed countries, while infections (e.g., tuberculosis) and genetic factors are less common etiologies [1][2][6]. Key manifestations include fatigue, weight loss, hyperpigmentation, and hypotension, with life-threatening adrenal crises during physiological stress [1][6][12]. Diagnosis requires ACTH stimulation testing and elevated plasma ACTH levels [6][14]. Lifelong glucocorticoid/mineralocorticoid replacement forms the cornerstone of management [3][12][15].
Burden
Healthcare costs: 3-7x higher annual expenditures vs matched controls ($10,714-$32,456) [4][9]
Morbidity: 40% experience ≥1 adrenal crisis; doubled mortality risk vs general population [2][9][13]
Comorbidities: Increased rates of cardiovascular disease, infections, and autoimmune conditions (e.g., thyroid disorders) [4][5][9]
Therapies
Glucocorticoid replacement: Hydrocortisone (15-25 mg/day) in 2-3 divided doses; prednisolone or dexamethasone alternatives in select cases [3][12][15]
Mineralocorticoid replacement: Fludrocortisone (0.05-0.2 mg/day) with sodium supplementation as needed [1][3][18]
Stress-dose protocols: 2-3x maintenance hydrocortisone during illness/surgery; emergency injectable kits for crisis prevention [3][10][12]
Categories: rare endocrine diseases
Research Papers
298 drug discovery papers about Chronic primary adrenal insufficiency, with 1 first-in-class and 10 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
298 drug discovery papers about Chronic primary adrenal insufficiency, with 1 first-in-class and 10 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-09 | IFNG-producing self-reactive CD4+ T cells induce autoimmune adrenalitis in a mouse model of Addison's disease.
Autoimmune Addison's disease (AD) is a rare but life-threatening disorder caused by immune-mediated destruction of the adrenal cortex, and progress in therapy has been limited by insufficient mechanistic insight. Here, we establish a model of Experimental Autoimmune Adrenalitis (EAA) that recapitulates key features of AD and reveals sex-dependent differences in disease manifestation within the model. Immunization with peptides derived from the adrenal self-antigen CYP11A1 induces corticosterone insufficiency. We show that autoimmune adrenalitis is driven by IFNG produced by self-reactive CD4+ T cells, promoting granulomatous inflammation in the adrenal cortex. Together, these findings identify IFNG as a central effector of autoimmune adrenalitis and suggest that targeting the IFNG pathway may represent a potential therapeutic strategy for AD.
2026-06-24 | Unilateral phaeochromocytoma in a dog with pre-existing, long-standing primary hypoadrenocorticism: a case report.
This is a rare occurrence of a phaeochromocytoma in a dog with pre-existing, long-standing primary hypoadrenocorticism that underwent successful surgical intervention with a favourable outcome. The objective of this case report is to describe the diagnosis, management and outcome for unilateral phaeochromocytoma in a dog with pre-existing chronic adrenal insufficiency and atrophy. A 14-year-old neutered female Jack Russell Terrier had a 1-week history of hyporexia, lethargy and progressive weight loss of 1.4 kg in 5 months. Computed tomography identified a left adrenal gland nodule of 5.3 mm diameter, several 1 to 2 mm soft tissue attenuating pulmonary nodules, and a large 65 mm diameter intraparenchymal right renal mass. A left adrenalectomy and right nephroureterectomy were performed. Histopathology with immunohistochemistry confirmed the diagnosis of phaeochromocytoma and renal cell carcinoma. The dog continued treatment for hypoadrenocorticism and was in good clinical condition at 3, 7, and 11 weeks postoperative follow-up. This report details a unique finding of phaeochromocytoma in a dog with long-standing adrenocortical insufficiency and highlights the need for consideration of this as a differential for adrenal nodules, even in dogs with known cortical insufficiency and adrenal gland atrophy.
2026-03-14 | GDF15 in Patients with Autoimmune Primary Adrenal Insufficiency.
Growth differentiation factor 15 (GDF15) is a stress-response protein that conveys cellular distress signals to the brain and activates neural pathways leading to weight loss. GDF15 levels are increased in glucocorticoid deficiency; however, multiple factors may influence its levels in patients with primary adrenal insufficiency (PAI). The objective of this study was to determine circulating GDF15 levels in patients with PAI compared with a control group and to assess their associations with other clinical parameters. We included 37 patients (22 females) with autoimmune PAI and 47 healthy controls. Serum GDF15 levels, together with anthropometrical, hormonal and biochemical parameters, were assessed. Patients with PAI had significantly higher circulating GDF15 levels than controls did (1276.8 ± 952.1 vs. 682.8 ± 270.2 pg/mL, p < 0.001). In both groups, GDF15 levels were positively correlated with age (p < 0.001). In patients with PAI, GDF15 showed positive correlations with disease duration and duration of autoimmune thyroid disease, gonadotropin levels, waist-to-hip ratio, and body fat percentage, and negative correlations with DHEAS and sex hormone levels. In conclusion, GDF15 levels are increased in patients with PAI compared with healthy controls and correlate with age and the duration of autoimmune disease.
2026-02-26 | Pharmacokinetics and pharmacodynamics of desoxycorticosterone pivalate in dogs with hypoadrenocorticism.
Desoxycorticosterone pivalate (DOCP) is commonly used to treat mineralocorticoid deficiency in dogs with hypoadrenocorticism (HA). To determine the pharmacokinetics and pharmacodynamics of DOCP. Twenty-one dogs with newly diagnosed HA. Prospective clinical trial. Dogs were randomly assigned to treatment with an SC injection of either 1.1 mg/kg (low-dose) or 2.2 mg/kg (label-dose) DOCP. Blood samples were collected at set time points for measurement of serum drug concentrations, serum electrolyte concentrations, and plasma renin activities (PRAs). A one-compartment model was used to determine pharmacokinetics variables. Pharmacodynamics variables including duration of DOCP action and duration of overtreatment were estimated from serum electrolyte concentrations and PRA. Pharmacokinetics and pharmacodynamics variables were compared between low-dose and label-dose groups. Maximum drug concentrations and overall drug exposures were higher in label-dose dogs (1.22 ± 0.46 ng/mL and 32.1 ± 12.3 day × ng/mL) than in low-dose dogs (0.69 ± 0.32 ng/mL and 19.6 ± 5.3 day × ng/mL; P = .008 for both comparisons). However, duration of DOCP action as determined by PRA in label-dose (55 ± 16 days) and low-dose (45 ± 12 days) dogs was not different (P = .2). Serum electrolyte concentrations overestimated the duration of action in the combined group by a mean of 10 days when compared with PRA (P < .001). Pharmacokinetics and pharmacodynamics data suggest that low-dose DOCP administered every 5-7 weeks is a reasonable treatment strategy for most dogs with HA. Prolonging dosing intervals > 7-8 weeks based solely on electrolyte concentrations should be avoided.
2026-01-21 | Clinical case of primary chronic adrenal cortex insufficiency (Addison’s disease)
Adrenal insufficiency is a relatively rare but serious disease characterized by decreased production of glucocorticoids and/or mineralocorticoids and adrenal androgens due to adrenal destruction or lack of its stimulation. This condition is characterized with subtle and rather nonspecific signs and symptoms that develop over weeks to months, and often go unnoticed, leading to delays in diagnosis [1]. A high level of clinical suspicion and diagnostic knowledge are required for diagnosis. The article presents a clinical case of primary chronic adrenal cortex insufficiency in a middle-aged patient. An analysis of literary sources, clinical data, and laboratory test results was performed.
2026-08-09 | IFNG-producing self-reactive CD4+ T cells induce autoimmune adrenalitis in a mouse model of Addison's disease.
Autoimmune Addison's disease (AD) is a rare but life-threatening disorder caused by immune-mediated destruction of the adrenal cortex, and progress in therapy has been limited by insufficient mechanistic insight. Here, we establish a model of Experimental Autoimmune Adrenalitis (EAA) that recapitulates key features of AD and reveals sex-dependent differences in disease manifestation within the model. Immunization with peptides derived from the adrenal self-antigen CYP11A1 induces corticosterone insufficiency. We show that autoimmune adrenalitis is driven by IFNG produced by self-reactive CD4+ T cells, promoting granulomatous inflammation in the adrenal cortex. Together, these findings identify IFNG as a central effector of autoimmune adrenalitis and suggest that targeting the IFNG pathway may represent a potential therapeutic strategy for AD.
2026-06-24 | Unilateral phaeochromocytoma in a dog with pre-existing, long-standing primary hypoadrenocorticism: a case report.
This is a rare occurrence of a phaeochromocytoma in a dog with pre-existing, long-standing primary hypoadrenocorticism that underwent successful surgical intervention with a favourable outcome. The objective of this case report is to describe the diagnosis, management and outcome for unilateral phaeochromocytoma in a dog with pre-existing chronic adrenal insufficiency and atrophy. A 14-year-old neutered female Jack Russell Terrier had a 1-week history of hyporexia, lethargy and progressive weight loss of 1.4 kg in 5 months. Computed tomography identified a left adrenal gland nodule of 5.3 mm diameter, several 1 to 2 mm soft tissue attenuating pulmonary nodules, and a large 65 mm diameter intraparenchymal right renal mass. A left adrenalectomy and right nephroureterectomy were performed. Histopathology with immunohistochemistry confirmed the diagnosis of phaeochromocytoma and renal cell carcinoma. The dog continued treatment for hypoadrenocorticism and was in good clinical condition at 3, 7, and 11 weeks postoperative follow-up. This report details a unique finding of phaeochromocytoma in a dog with long-standing adrenocortical insufficiency and highlights the need for consideration of this as a differential for adrenal nodules, even in dogs with known cortical insufficiency and adrenal gland atrophy.
2026-03-14 | GDF15 in Patients with Autoimmune Primary Adrenal Insufficiency.
Growth differentiation factor 15 (GDF15) is a stress-response protein that conveys cellular distress signals to the brain and activates neural pathways leading to weight loss. GDF15 levels are increased in glucocorticoid deficiency; however, multiple factors may influence its levels in patients with primary adrenal insufficiency (PAI). The objective of this study was to determine circulating GDF15 levels in patients with PAI compared with a control group and to assess their associations with other clinical parameters. We included 37 patients (22 females) with autoimmune PAI and 47 healthy controls. Serum GDF15 levels, together with anthropometrical, hormonal and biochemical parameters, were assessed. Patients with PAI had significantly higher circulating GDF15 levels than controls did (1276.8 ± 952.1 vs. 682.8 ± 270.2 pg/mL, p < 0.001). In both groups, GDF15 levels were positively correlated with age (p < 0.001). In patients with PAI, GDF15 showed positive correlations with disease duration and duration of autoimmune thyroid disease, gonadotropin levels, waist-to-hip ratio, and body fat percentage, and negative correlations with DHEAS and sex hormone levels. In conclusion, GDF15 levels are increased in patients with PAI compared with healthy controls and correlate with age and the duration of autoimmune disease.
2026-02-26 | Pharmacokinetics and pharmacodynamics of desoxycorticosterone pivalate in dogs with hypoadrenocorticism.
Desoxycorticosterone pivalate (DOCP) is commonly used to treat mineralocorticoid deficiency in dogs with hypoadrenocorticism (HA). To determine the pharmacokinetics and pharmacodynamics of DOCP. Twenty-one dogs with newly diagnosed HA. Prospective clinical trial. Dogs were randomly assigned to treatment with an SC injection of either 1.1 mg/kg (low-dose) or 2.2 mg/kg (label-dose) DOCP. Blood samples were collected at set time points for measurement of serum drug concentrations, serum electrolyte concentrations, and plasma renin activities (PRAs). A one-compartment model was used to determine pharmacokinetics variables. Pharmacodynamics variables including duration of DOCP action and duration of overtreatment were estimated from serum electrolyte concentrations and PRA. Pharmacokinetics and pharmacodynamics variables were compared between low-dose and label-dose groups. Maximum drug concentrations and overall drug exposures were higher in label-dose dogs (1.22 ± 0.46 ng/mL and 32.1 ± 12.3 day × ng/mL) than in low-dose dogs (0.69 ± 0.32 ng/mL and 19.6 ± 5.3 day × ng/mL; P = .008 for both comparisons). However, duration of DOCP action as determined by PRA in label-dose (55 ± 16 days) and low-dose (45 ± 12 days) dogs was not different (P = .2). Serum electrolyte concentrations overestimated the duration of action in the combined group by a mean of 10 days when compared with PRA (P < .001). Pharmacokinetics and pharmacodynamics data suggest that low-dose DOCP administered every 5-7 weeks is a reasonable treatment strategy for most dogs with HA. Prolonging dosing intervals > 7-8 weeks based solely on electrolyte concentrations should be avoided.
2026-01-21 | Clinical case of primary chronic adrenal cortex insufficiency (Addison’s disease)
Adrenal insufficiency is a relatively rare but serious disease characterized by decreased production of glucocorticoids and/or mineralocorticoids and adrenal androgens due to adrenal destruction or lack of its stimulation. This condition is characterized with subtle and rather nonspecific signs and symptoms that develop over weeks to months, and often go unnoticed, leading to delays in diagnosis [1]. A high level of clinical suspicion and diagnostic knowledge are required for diagnosis. The article presents a clinical case of primary chronic adrenal cortex insufficiency in a middle-aged patient. An analysis of literary sources, clinical data, and laboratory test results was performed.
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
4 orphan drug designations for Chronic primary adrenal insufficiency, including 2 approved therapies.
4 orphan drug designations for Chronic primary adrenal insufficiency, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
methylprednisolone oral suspension | small molecules | FDA | 2016-09-19 | — | Generic Specialty Pharma |
hydrocortisone [Khindivi] | small molecules | FDA | 2015-05-13 | 2025-05-28 | Eton Pharmaceuticals, Inc. |
Hydrocortisone [ALKINDI® SPRINKLE] | small molecules | FDA | 2015-05-13 | 2020-09-29 | Eton Pharmaceuticals, Inc. |
Hydrocortisone [Plenadren] | small molecules | EMA | 2006-05-22 | — | Shire Services |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI's forecasts to outperform average preclinical success rates. Whether you're expanding your R&D pipeline, evaluating a partnership, or simply have a question — we'd love to hear from you.