RARE DISEASE
Primary adrenal insufficiency
Primary adrenal insufficiency
Primary adrenal insufficiency
Drug discovery
5
drugs
With orphan designations
Overview
Primary adrenal insufficiency (PAI) is a rare, life-threatening disorder caused by inadequate cortisol and aldosterone production, most commonly due to autoimmune adrenalitis [1][3][9]. Diagnosis involves low morning cortisol with elevated ACTH and requires lifelong glucocorticoid (hydrocortisone/prednisone) and mineralocorticoid (fludrocortisone) replacement [1][7][14]. Delayed diagnosis increases mortality risk from adrenal crises [1][4][6]. Patient education on medication adherence and stress-dose adjustments is critical [1][5][14].
Burden
Mortality: 2× higher than general population, driven by adrenal crises/infections [2][4][17]
Adrenal crises: Incidence 6–8/100 patient-years requiring hospitalization [4][6][17]
Chronic morbidity: Reduced quality of life, frequent healthcare visits, comorbidities (autoimmune thyroid disease) [4][6][10]
Therapies
Hormone replacement:
Hydrocortisone (10–25 mg/day divided) + fludrocortisone (0.05–0.2 mg/day) [1][7][14]
Emergency protocols: Stress-dose steroids (IV hydrocortisone) during illness/surgery [1][5][14]
Patient education: Sick-day rules, steroid emergency cards, injectable hydrocortisone kits [1][5][14]
Categories: rare endocrine diseases
Research Papers
765 drug discovery papers related to Primary adrenal insufficiency, with 3 first-in-class and 22 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
765 drug discovery papers related to Primary adrenal insufficiency, with 3 first-in-class and 22 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-08 | Confounding-aware disproportionality analysis reveals disease-inherent versus drug-attributable endocrine safety signals of immune checkpoint inhibitors.
Conventional disproportionality analysis assumes comparable background event rates between case and control cohorts. In patients with primary endocrine malignancies treated with immune checkpoint inhibitors (ICIs), this assumption fails: disease-inherent hormonal dysregulation and therapy-related sequelae inflate background event rates and may produce signals misattributed to ICI exposure. No prior study has used tumor-type-specific reference populations to separate drug-attributable from disease-inherent signals in this setting. Forty quarterly FAERS cycles (Q1 2015 to Q4 2024) were analyzed after deduplication of 2,264,070 reports. In a pooled analysis, 329 ICI-treated endocrine cancer cases were compared with 80,191 ICI-treated non-endocrine cancer controls across six pre-specified endocrine immune-related adverse event categories, with false discovery rate (FDR) correction. The central step was a confounding-aware reanalysis comparing ICI-exposed patients of a given tumor type against a reference cohort with the same malignancy but no ICI exposure, using logistic regression adjusted for age and sex. The thyroid carcinoma association was tested using reporter type, Firth penalized regression, multiple imputation, and a tipping-point analysis. Pooled adrenal insufficiency did not reach the signal threshold after FDR correction (ROR = 1.922; 95% CI 1.051-3.513; q = 0.143). This non-significance concealed two opposing patterns. In ACC, adrenal insufficiency was the strongest uncorrected subgroup signal yet was not associated with ICI exposure after adjustment (OR = 0.58; 95% CI 0.09-1.95); with four exposed events and 12.6% power, this subgroup cannot confirm or exclude an association. In thyroid carcinoma, ICI exposure showed markedly higher adrenal insufficiency reporting odds (OR = 13.33; 95% CI 4.81-31.85), remaining positive under reporter adjustment, Firth regression, and multiple imputation, with a tipping-point analysis indicating only implausibly extreme confounding could nullify it. Pooled pharmacovigilance can misclassify drug-attributable and disease-inherent events. Tumor-type-specific reference modeling separates them: ACC data are most consistent with disease-inherent pathophysiology, whereas thyroid carcinoma shows a robust adrenal insufficiency signal. We interpret the thyroid signal as hypothesis-generating, since differential endocrine surveillance may contribute to its magnitude, and prospective validation is warranted.
2026-07-01 | Bilateral adrenal histoplasmosis incidentally detected on 18F-FDG PET/CT in an immunocompetent man with primary adrenal insufficiency: A case report
Adrenal histoplasmosis is an uncommon manifestation of Histoplasma capsulatum infection and may closely mimic malignancy or granulomatous diseases on imaging. We describe an immunocompetent 51 year old man with 5 months of constitutional symptoms who underwent 18F-FDG PET/CT for evaluation of occult disease. The scan revealed intensely FDG avid bilateral adrenal masses with necrotic components, with no other abnormal sites. Biochemical testing confirmed primary adrenal insufficiency. CT guided adrenal biopsy, targeted to the most FDG-avid viable component, demonstrated necrotizing granulomatous inflammation with intracellular yeast forms consistent with Histoplasma capsulatum. Antifungal therapy with itraconazole plus glucocorticoid replacement led to clinical improvement and interval regression of adrenal lesions on follow-up. This case highlights the value of 18F-FDG PET/CT for detecting unsuspected adrenal histoplasmosis, localizing optimal biopsy targets, and facilitating timely treatment even in immunocompetent patients presenting with nonspecific symptoms.
2026-06-26 | NR0B1 Gene Variants as Rare Forms of Primary Adrenal Insufficiency in Children: Case Report and Narrative Review.
Primary adrenal insufficiency (PAI) is a severe and potentially life-threatening condition characterised by the inability of the adrenal cortex to produce enough glucocorticoids and/or mineralocorticoids. The clinical signs of PAI are primarily due to deficient steroid hormone synthesis and include weight loss, orthostatic hypotension secondary to dehydration, hyponatremia, hyperkalaemia, and hypoglycaemia. In the paediatric population, PAI is most commonly associated with inherited monogenic disorders, particularly enzyme deficiencies. X-linked adrenal hypoplasia congenita (AHC) is a rare condition caused by deletions or single-nucleotide variants in the NR0B1 (DAX1) gene, which encodes the DAX1 protein expressed in the adrenal cortex, gonads, hypothalamus and pituitary gland. Although molecular genetics has significantly expanded our understanding of the aetiology of PAI, clinical diagnosis remains challenging when the initial hormonal findings are atypical, often delaying recognition and treatment. Pathogenic variants of DAX1 can lead to a spectrum of phenotypes, ranging from isolated adrenal insufficiency (AI) to complex syndromic presentations combining AI with hypogonadotropic hypogonadism and impaired spermatogenesis. Here, we report a case of a male patient with AI due to a de novo pathogenic variant in the NR0B1 gene. Furthermore, we provide a non-systematic review of the available literature on the diagnostic challenges facing and clinical variability in AHC, with a particular focus on the paediatric population. This case highlights the importance of a stepwise, comprehensive diagnostic approach to suspected PAI, particularly when initial biochemical and genetic testing is inconclusive. Considering rare causes-such as NR0B1 pathogenic variants in men-can be crucial for establishing a definitive diagnosis, with significant implications for the management of patients and their families.
2026-07-08 | Confounding-aware disproportionality analysis reveals disease-inherent versus drug-attributable endocrine safety signals of immune checkpoint inhibitors.
Conventional disproportionality analysis assumes comparable background event rates between case and control cohorts. In patients with primary endocrine malignancies treated with immune checkpoint inhibitors (ICIs), this assumption fails: disease-inherent hormonal dysregulation and therapy-related sequelae inflate background event rates and may produce signals misattributed to ICI exposure. No prior study has used tumor-type-specific reference populations to separate drug-attributable from disease-inherent signals in this setting. Forty quarterly FAERS cycles (Q1 2015 to Q4 2024) were analyzed after deduplication of 2,264,070 reports. In a pooled analysis, 329 ICI-treated endocrine cancer cases were compared with 80,191 ICI-treated non-endocrine cancer controls across six pre-specified endocrine immune-related adverse event categories, with false discovery rate (FDR) correction. The central step was a confounding-aware reanalysis comparing ICI-exposed patients of a given tumor type against a reference cohort with the same malignancy but no ICI exposure, using logistic regression adjusted for age and sex. The thyroid carcinoma association was tested using reporter type, Firth penalized regression, multiple imputation, and a tipping-point analysis. Pooled adrenal insufficiency did not reach the signal threshold after FDR correction (ROR = 1.922; 95% CI 1.051-3.513; q = 0.143). This non-significance concealed two opposing patterns. In ACC, adrenal insufficiency was the strongest uncorrected subgroup signal yet was not associated with ICI exposure after adjustment (OR = 0.58; 95% CI 0.09-1.95); with four exposed events and 12.6% power, this subgroup cannot confirm or exclude an association. In thyroid carcinoma, ICI exposure showed markedly higher adrenal insufficiency reporting odds (OR = 13.33; 95% CI 4.81-31.85), remaining positive under reporter adjustment, Firth regression, and multiple imputation, with a tipping-point analysis indicating only implausibly extreme confounding could nullify it. Pooled pharmacovigilance can misclassify drug-attributable and disease-inherent events. Tumor-type-specific reference modeling separates them: ACC data are most consistent with disease-inherent pathophysiology, whereas thyroid carcinoma shows a robust adrenal insufficiency signal. We interpret the thyroid signal as hypothesis-generating, since differential endocrine surveillance may contribute to its magnitude, and prospective validation is warranted.
2026-07-01 | Bilateral adrenal histoplasmosis incidentally detected on 18F-FDG PET/CT in an immunocompetent man with primary adrenal insufficiency: A case report
Adrenal histoplasmosis is an uncommon manifestation of Histoplasma capsulatum infection and may closely mimic malignancy or granulomatous diseases on imaging. We describe an immunocompetent 51 year old man with 5 months of constitutional symptoms who underwent 18F-FDG PET/CT for evaluation of occult disease. The scan revealed intensely FDG avid bilateral adrenal masses with necrotic components, with no other abnormal sites. Biochemical testing confirmed primary adrenal insufficiency. CT guided adrenal biopsy, targeted to the most FDG-avid viable component, demonstrated necrotizing granulomatous inflammation with intracellular yeast forms consistent with Histoplasma capsulatum. Antifungal therapy with itraconazole plus glucocorticoid replacement led to clinical improvement and interval regression of adrenal lesions on follow-up. This case highlights the value of 18F-FDG PET/CT for detecting unsuspected adrenal histoplasmosis, localizing optimal biopsy targets, and facilitating timely treatment even in immunocompetent patients presenting with nonspecific symptoms.
2026-06-26 | NR0B1 Gene Variants as Rare Forms of Primary Adrenal Insufficiency in Children: Case Report and Narrative Review.
Primary adrenal insufficiency (PAI) is a severe and potentially life-threatening condition characterised by the inability of the adrenal cortex to produce enough glucocorticoids and/or mineralocorticoids. The clinical signs of PAI are primarily due to deficient steroid hormone synthesis and include weight loss, orthostatic hypotension secondary to dehydration, hyponatremia, hyperkalaemia, and hypoglycaemia. In the paediatric population, PAI is most commonly associated with inherited monogenic disorders, particularly enzyme deficiencies. X-linked adrenal hypoplasia congenita (AHC) is a rare condition caused by deletions or single-nucleotide variants in the NR0B1 (DAX1) gene, which encodes the DAX1 protein expressed in the adrenal cortex, gonads, hypothalamus and pituitary gland. Although molecular genetics has significantly expanded our understanding of the aetiology of PAI, clinical diagnosis remains challenging when the initial hormonal findings are atypical, often delaying recognition and treatment. Pathogenic variants of DAX1 can lead to a spectrum of phenotypes, ranging from isolated adrenal insufficiency (AI) to complex syndromic presentations combining AI with hypogonadotropic hypogonadism and impaired spermatogenesis. Here, we report a case of a male patient with AI due to a de novo pathogenic variant in the NR0B1 gene. Furthermore, we provide a non-systematic review of the available literature on the diagnostic challenges facing and clinical variability in AHC, with a particular focus on the paediatric population. This case highlights the importance of a stepwise, comprehensive diagnostic approach to suspected PAI, particularly when initial biochemical and genetic testing is inconclusive. Considering rare causes-such as NR0B1 pathogenic variants in men-can be crucial for establishing a definitive diagnosis, with significant implications for the management of patients and their families.
Access all drug discovery articles and probability of success in trials forecasts:
Access all drug discovery articles and probability of success in trials forecasts:
Drug Discovery Landscape
5 orphan drug designations for Primary adrenal insufficiency.
5 orphan drug designations for Primary adrenal insufficiency.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
hydrocortisone modified release capsules | small molecules | FDA | 2015-09-03 | — | Diurnal Limited |
hydrocortisone modified release tabs | small molecules | FDA | 2008-06-18 | — | Takeda Development Center Americas, Inc. |
Hydrocortisone [Chronocort] | small molecules | EMA | 2007-03-20 | — | Immedica Netherlands B.V. |
Dehydroepiandrosterone (DHEA) | small molecules | FDA | 2003-08-19 | — | Paladin Labs, Inc. |
Prasterone | small molecules | EMA | 2003-07-28 | — | Medicom Healthcare BV |
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