RARE DISEASE
Addison disease
Addison disease
Addison disease
Synonyms: Autoimmune Addison disease, Autoimmune adrenalitis, Classic Addison disease, Primary Addison disease
Synonyms: Autoimmune Addison disease, Autoimmune adrenalitis, Classic Addison disease, Primary Addison disease
Synonyms: Autoimmune Addison disease, Autoimmune adrenalitis, Classic Addison disease, Primary Addison disease
Drug discovery
0
drugs
With orphan designations
Overview
Addison disease is a primary adrenal insufficiency typically caused by autoimmune adrenal destruction, leading to cortisol and aldosterone deficiency. Key features include progressive fatigue, hyperpigmentation, hypotension, and gastrointestinal symptoms. Diagnosis requires elevated ACTH with low cortisol and abnormal ACTH stimulation testing. Treatment involves lifelong glucocorticoid (hydrocortisone) and mineralocorticoid (fludrocortisone) replacement, stress-dose adjustments during physiologic stress, and prompt IV hydrocortisone/fluids for adrenal crises [1][2][3].
Burden
40% experience ≥1 adrenal crisis (5–10 episodes/100 patient-years), with 8% requiring emergency treatment [11][17]
Mortality risk 2–4× higher than general population, driven by cardiovascular events and infections [6][17]
Chronic complications include osteoporosis, diabetes from over-replacement, and reduced quality of life [5][6][17]
Therapies
Glucocorticoids: Hydrocortisone (15–25 mg/day in divided doses) or prednisone (3–5 mg/day) [2][3][16]
Mineralocorticoids: Fludrocortisone (0.05–0.2 mg/day), titrated to normalize plasma renin activity [2][3][16]
Emergency protocols: Stress-dose steroid adjustments during illness/surgery; mandatory emergency hydrocortisone injection kits [2][16][19]
Categories: rare endocrine diseases
Research Papers
466 drug discovery papers about Addison disease, with 4 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
466 drug discovery papers about Addison disease, with 4 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
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.
2026-06-01 | Successful Therapeutic Approach to Facial Hyperpigmentation Secondary to Addison's Disease: A Case Report and Literature Review.
Addison's disease, or primary adrenal insufficiency, is a rare endocrine disorder characterized by deficient glucocorticoid and mineralocorticoid production, frequently associated with cutaneous hyperpigmentation due to chronic elevation of adrenocorticotropic hormone. Facial hyperpigmentation may persist despite adequate hormonal replacement, representing a therapeutic challenge with limited evidence to guide dermatologic management. We report the case of a 41-year-old female patient with an eight-year history of progressive hyperpigmentation affecting the face, hands, and oral mucosa. Physical examination revealed severe facial involvement with brown-violaceous macules and associated telangiectasias. The patient had a prior diagnosis of autoimmune ovarian failure in 2017 and was diagnosed with Addison's disease in 2020, receiving stable glucocorticoid replacement therapy. Histopathological evaluation demonstrated basal layer hyperpigmentation without interface dermatitis, consistent with endocrine-related pigmentation and overlapping melasma features. A multimodal therapeutic approach was implemented, including picosecond Nd:YAG laser therapy (approximately seven sessions at six- to eight-week intervals), oral tranexamic acid (250 mg twice daily), and a topical depigmenting regimen containing tranexamic acid, niacinamide, retinoids, and antioxidants. The patient demonstrated a significant reduction in modified Melasma Area and Severity Index score from 19.8 to 7.8 (60.6% reduction), along with a marked improvement in quality of life, as evidenced by a posttreatment Melasma Quality of Life Scale score of 20/70. This case highlights that persistent hyperpigmentation in Addison's disease may not fully resolve with endocrine treatment alone and may require adjunctive dermatologic interventions. A personalized, multimodal strategy targeting multiple pathogenic pathways, including melanogenesis, plasmin-mediated signaling, vascular factors, and dermal pigment deposition, can achieve significant improvement, even in patients with darker phototypes and long-standing disease. These findings underscore the importance of a multidisciplinary approach and suggest a potential role for combination therapies, including laser-based modalities, in managing complex pigmentary disorders associated with systemic conditions. Further studies are needed to establish standardized treatment protocols and evaluate long-term outcomes.
2026-03-24 | Prednisolone Once Daily vs Hydrocortisone Thrice Daily in Hypoadrenalism: A Randomized Clinical Trial.
Adrenal insufficiency is conventionally treated with daily multiple-dose hydrocortisone, and once-daily low-dose prednisolone is an alternative for glucocorticoid replacement. Clinical trials comparing once-daily low-dose prednisolone with thrice-daily hydrocortisone are lacking. To examine the differences in metabolism and bone turnover in patients receiving hydrocortisone vs prednisolone for adrenal insufficiency. This double-blind, crossover randomized clinical trial of multiple-daily standard-dose hydrocortisone vs once-daily low-dose prednisolone (2-5 mg), performed from September 3, 2019, to December 14, 2023, involved adults with adrenal insufficiency. Anthropometrics, biochemical data for cardiometabolic and bone health, and subjective health survey data were collected at days 1, 30, and 120 of each study period for both medications. Individuals were randomized to receive 4 months of once-daily prednisolone in the morning (with placebos at noon and afternoon) or hydrocortisone at the same times. All participants were crossed over to the alternative treatment for an additional 4 months. The primary outcome was assessment of bone turnover, detected by change in carboxylated and undercarboxylated osteocalcin between days 1 and 120 in each treatment period. Secondary outcomes included change in weight, body mass index, waist circumference, glycated hemoglobin, and subjective heath survey responses. Forty-seven participants were randomized, with 46 participants included in the analysis (median [IQR] age, 55.0 [46.5-62.8] years; 24 [52.2%] male). Twenty-four received prednisolone first and 22 received hydrocortisone first. Bone turnover was significantly slowed with prednisolone compared with hydrocortisone as evidenced by a significantly lower level of multiple bone markers, including carboxylated osteocalcin (mean treatment difference, -1.22 ng/mL; 95% CI, -2.35 to -0.10 ng/mL; P = .04), undercarboxylated osteocalcin (mean treatment difference, -1.38 ng/mL; 95% CI, -2.32 to -0.44 ng/mL; P = .005) (to convert osteocalcin to micrograms per liter, multiply by 1), urinary N-terminal telopeptide (mean treatment difference, -9.34 nmol/mmol; 95% CI, -15.4 to -3.29 nmol/mmol; P = .002), and procollagen type 1 N-terminal propeptide (mean treatment difference, -13.8 ng/mL; 95% CI, -22.2 to -5.49 ng/mL; P < .001). The mean treatment group difference in weight reduction from baseline was -1.87 kg (95% CI, -3.02 to -0.72 kg; P = .002) for prednisolone treatment compared with hydrocortisone, and this was associated with concordant significantly greater reductions in body mass index (BMI; calculated as weight in kilograms divided by the square of height in meters; treatment difference, -0.522; 95% CI, -1.01 to -0.04; P = .04), waist circumference (treatment difference, -2.26 cm; 95% CI, -3.97 to -0.56 cm; P = .01), and HbA1c (treatment difference, -0.12% [-1.23 mmol/mol; 95% CI, -1.95 to -0.51 mmol/mol]; P = .001). There were no differences in safety measures or subjective health outcomes, including all 36-Item Short-Form Health Survey domains and Addison's Disease-Specific Quality of Life Questionnaire. In this randomized clinical trial, once-daily low-dose prednisolone was associated with slower bone turnover and improvements in cardiometabolic health markers compared with multiple-dose hydrocortisone without compromising well-being. Studies assessing longer-term mortality and morbidity outcomes are needed. ClinicalTrials.gov Identifier: NCT03936517.
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.
2026-02-13 | Different metabolic pathways associated with total cortisol exposure and the cortisol time profile: a randomized crossover trial.
Excess cortisol exposure and disruption of its circadian pattern have both been linked to adverse health outcomes; however, whether distinct metabolic signatures differentiate total cortisol exposure from cortisol secretion dynamics remains unclear. This study aimed to identify metabolites and metabolic pathways uniquely associated with total cortisol exposure and/or variation of the cortisol time profile. In a randomized, 12-week, cross-over trial 18 adults with primary adrenal insufficiency (AI) received the same total daily dose of hydrocortisone (HC) administered as a once-daily (OD) dual-release tablet and conventional HC tablets 3 times daily (TID). Serum and urine samples were collected during 24h in-house standardized pharmacokinetic sampling days and metabolites were detected using liquid and gas chromatography-mass spectrometry (LC-MS and GC-MS). Total cortisol exposure was quantified as the area under the serum cortisol concentration-time curve and variability in the cortisol time profile was assessed by calculating the lag–1 autocorrelation from serum cortisol concentrations over 24 hours. Compared with OD dosing, TID administration resulted in a 20% higher total cortisol exposure and a greater variability in the cortisol time profile. In total, 2406 metabolites were detected. Pathway analysis of serum metabolites uniquely correlated with total cortisol exposure were involved in amino acid metabolism - including arginine, tryptophan and glutamate pathways - as well as glycerolipid metabolism. In contrast, metabolites uniquely associated with variability of the cortisol time profile were mapped to primary bile acid biosynthesis and cysteine-methionine metabolism. We identified distinct groups of metabolites and metabolic pathways that specifically correlate with either overall serum cortisol exposure or variability in its time profile, indicating that cortisol dose exposure and the circadian dynamics may exert independent metabolic and regulatory effects in humans, with potential implications for personalized hydrocortisone therapy.
cell therapies
2026-01-05 | Anti-aging effects of the adrenal androgens dehydroepiandrosterone and dehydroepiandrosterone sulfate: mechanisms of action and beneficial effects in older people.
We review the recent remarkable progress of the molecular mechanisms of action of the adrenal androgens dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) regarding their beneficial effects on older people and adrenal regenerative therapy by looking back on our research extending over 50 years since 1971. DHEAS is the most abundant circulating steroid hormone in humans and apes. DHEAS is essential for brain development in adrenarche and for anti-aging in adrenopause as shown by the evolutionary process in primates. The molecular mechanisms of action of DHEA and DHEAS have been clarified by the discovery of many membrane receptors and by the concept of intracrinological action, which is especially important in menopausal women. The genes associated with serum DHEAS concentrations were identified by genome-wide association study meta-analysis of cohort studies. Recent advances in aging research have shown that DHEA and DHEAS have anti-aging action via antioxidants, anti-inflammation, telomere protection, p38MAPK inhibition, anti-cortisol effects, and chaperone induction. DHEA has beneficial effects on the prevention of atherosclerosis based on visceral obesity-induced metabolic syndrome in middle-aged people. DHEA also prevents infection, frailty via reverse metabolism, sarcopenia, and osteoporosis in older people, with a marked decrease in serum DHEAS concentrations. This review discusses adrenal regenerative therapy using steroid-producing cell replacement by overexpressing Ad4BP/steroidogenic factor 1 in mouse or human bone marrow mesenchymal stem cells. This therapy replaces cortisol and DHEAS treatment for the prevention of sudden death by adrenal crisis and severe infection in primary adrenal insufficiency (Addison's disease).
2023-05-18 | Future Directions for Adrenal Insufficiency: Cellular Transplantation and Genetic Therapies.
Primary adrenal insufficiency (PAI) occurs in 1 in 5 to 7000 adults. Leading etiologies are autoimmune adrenalitis in adults and congenital adrenal hyperplasia (CAH) in children. Oral replacement of cortisol is lifesaving, but poor quality of life, repeated adrenal crises, and dosing uncertainty related to lack of a validated biomarker for glucocorticoid sufficiency persists. Adrenocortical cell therapy and gene therapy may obviate many of the shortcomings of adrenal hormone replacement. Physiological cortisol secretion regulated by pituitary adrenocorticotropin could be achieved through allogeneic adrenocortical cell transplantation, production of adrenal-like steroidogenic cells from either stem cells or lineage conversion of differentiated cells, or for CAH, gene therapy to replace or repair a defective gene. The adrenal cortex is a high-turnover organ and thus failure to incorporate progenitor cells within a transplant will ultimately result in graft exhaustion. Identification of adrenocortical progenitor cells is equally important in gene therapy, for which new genetic material must be specifically integrated into the genome of progenitors to ensure a durable effect. Delivery of gene-editing machinery and a donor template, allowing targeted correction of the 21-hydroxylase gene, has the potential to achieve this. This review describes advances in adrenal cell transplants and gene therapy that may allow physiological cortisol production for children and adults with PAI.
2021-09-15 | New Horizons: Novel adrenal regenerative therapies
In this narrative review, the authors discuss the potential role of novel regenerative therapies for the treatment of adrenal insufficiency, including gene therapy and cell replacement strategies. More specifically, the authors discuss the heterogeneity in adrenal function in patients with Addison disease, including numerous case reports of spontaneous remission. The authors cite recent studies showing that, shortly after the onset of Addison disease, residual adrenal function might be restored using B-lymphocyte-depleting immunotherapy and ACTH treatment. The rationale is that ACTH stimulates the differentiation of the persisting progenitor or stem cells, while B-cell depletion prevents destruction of the newly differentiated cells (1). Furthermore, the cell turnover of the adrenal cortex limits the time-span of the effectiveness of gene therapy (2). A more promising strategy is adrenal cell transplantation, which is potentially curative. Research foci in this strategy include alternative cell sources, novel biomaterials that have been developed to improve cell viability of engineered cells upon implantation, and cellular therapies based on pluripotent stem cells (3).
2021-03-02 | MANAGEMENT OF ENDOCRINE DISEASE: Residual adrenal function in Addison's disease.
Over the last 10 years, evidence has accumulated that autoimmune Addison's disease (AAD) is a heterogeneous disease. Residual adrenal function, characterised by persistent secretion of cortisol, other glucocorticoids and mineralocorticoids is present in around 30% of patients with established AAD, and appears commoner in men. This persistent steroidogenesis is present in some patients with AAD for more than 20 years, but it is commoner in people with shorter disease duration. The clinical significance of residual adrenal function is not fully clear at the moment, but as it signifies an intact adrenocortical stem cell population, it opens up the possibility of regeneration of adrenal steroidogenesis and improvement in adrenal failure for some patients.
2014-12-09 | High frequency of cytolytic 21-hydroxylase-specific CD8+ T cells in autoimmune Addison's disease patients.
The mechanisms behind destruction of the adrenal glands in autoimmune Addison's disease remain unclear. Autoantibodies against steroid 21-hydroxylase, an intracellular key enzyme of the adrenal cortex, are found in >90% of patients, but these autoantibodies are not thought to mediate the disease. In this article, we demonstrate highly frequent 21-hydroxylase-specific T cells detectable in 20 patients with Addison's disease. Using overlapping 18-aa peptides spanning the full length of 21-hydroxylase, we identified immunodominant CD8(+) and CD4(+) T cell responses in a large proportion of Addison's patients both ex vivo and after in vitro culture of PBLs ≤20 y after diagnosis. In a large proportion of patients, CD8(+) and CD4(+) 21-hydroxylase-specific T cells were very abundant and detectable in ex vivo assays. HLA class I tetramer-guided isolation of 21-hydroxylase-specific CD8(+) T cells showed their ability to lyse 21-hydroxylase-positive target cells, consistent with a potential mechanism for disease pathogenesis. These data indicate that strong CTL responses to 21-hydroxylase often occur in vivo, and that reactive CTLs have substantial proliferative and cytolytic potential. These results have implications for earlier diagnosis of adrenal failure and ultimately a potential target for therapeutic intervention and induction of immunity against adrenal cortex cancer.
proteins
2026-01-05 | [Hormones and skin pigmentation: fundamentals and clinical relevance].
Skin pigmentation by the endogenous pigment melanin is a highly coordinated process in which hormones play a crucial role. They are synthesized not only in classical endocrine organs but also in the skin itself, which acts as an independent endocrine organ. Among the endocrine target structures of the skin, the melanocortin 1 receptor (MC1R) is of particular importance. Via its high expression and tonic activity in melanocytes, as well as by binding to natural melanocortins such as α‑melanocyte-stimulating hormone (α-MSH), being generated in the skin following ultraviolet (UV) light irradiation, MC1R crucially contributes to the different skin phototypes. Gene mutations of MC1R resulting in defective cyclic adenosine monophosphate (cAMP)-mediated signalling can lead to a shift of the eumelanin/pheomelanin ratio towards the pro-oxidant, yellowish-orange pheomelanin. In patients with Addison's disease and associated syndromes, ectopic proopiomelanocortin syndrome and primary adrenal cortex insufficiency elevated melanocortin levels result in increased melanin content of the skin. Two synthetic melanocortins, afamelanotide (NDP-α-MSH) and setmelanotide, are currently approved in Germany. By targeting MC1R directly (afamelanotide) or as a bystander effect (setmelanotide), both agents increase the skin melanin content. Non-licenced synthetic melanocortins, on the other hand, are used as lifestyle products in an unregulated manner. Additional hormones regulating melanogenesis and skin pigmentation include estrogens, thyroid hormones, insulin, insulin-like growth-factor‑1 and melatonin. They are of physiological and clinical relevance during pregnancy and in patients with melasma and vitiligo. Autoimmune thyroid disorders and diabetes are associated with non-segmental vitiligo. Melatonin appears to have a lightening effect on skin pigmentation by melanin.
2025-12-24 | Pathogenesis of acute adrenal crisis in children: current concepts and emerging mechanisms
Aim. The aim of this article is to provide a comprehensive review of the pathogenetic mechanisms underlying the development of acute adrenal crisis (AAC) in children, with an emphasis on recent experimental and clinical findings. Materials and Methods. A comprehensive literature search was conducted using MEDLINE, Embase, Scopus, Cochrane, PubMed, Google Scholar and Elibrary databases, as well as through citation tracking of studies published between 2019 and June 2025. A total of 40 national and international publications were analyzed, including clinical, experimental, and genomic studies, as well as systematic reviews and meta-analyses focused on the pathogenesis of adrenal insufficiency and adrenal crisis in pediatric populations. Results. The classical pathogenesis of AAC is associated with cortisol and aldosterone deficiency, leading to severe metabolic and hemodynamic disturbances. However, in recent years, a new concept of the multifactorial nature of this syndrome has emerged, encompassing systemic, molecular, immune, and microbiota-related components. Key etiological forms have been analyzed, including congenital adrenal hyperplasia, glucocorticoid-induced adrenal insufficiency, and autoimmune adrenalitis. Data are presented on the involvement of pro-inflammatory cytokines (IL-6, TNF-α), mitochondrial dysfunction, altered expression of ACTH receptors (MC2R, MRAP), and epigenetic modifications (NR0B1, CYP21A2). Particular attention is given to sepsis-induced adrenal dysfunction, endothelial impairment, and the influence of the gut–adrenal axis on crisis development. Conclusion. The current understanding of AAC pathogenesis extends beyond the classical hormonal deficiency model and includes complex interactions among inflammatory, mitochondrial, immune, genetic, and microbiota-related mechanisms. The importance of early diagnosis, molecular stratification, and personalized treatment strategies is emphasized. These findings highlight the need to revise current approaches to prevention and management in pediatric practice, with a focus on targeted and multidisciplinary therapeutic interventions.
2022-04-19 | Effect of Recombinant Gonadotropin on Testicular Function and Testicular Sperm Extraction in Five Cases of NR0B1 (DAX1) Pathogenic Variants.
NR0B1 pathogenic variants can cause congenital adrenal hypoplasia or primary adrenal insufficiency in early childhood usually associated with hypogonadotropic hypogonadism. NR0B1 is necessary for organogenesis of the adrenal cortex and to maintain normal spermatogenesis. In humans, restoration of fertility in patients carrying NR0B1 pathogenic variants is challenging. The aim of the study was to investigate the clinical, hormonal, histological, spermiological, and molecular genetic characteristics of a cohort of patients with NR0B1 pathogenic variants, monitored for fertility preservation. We included five patients, including four teenagers, with NR0B1 pathogenic or likely pathogenic variants. They all had primary adrenal insufficiency and were receiving replacement therapy with glucocorticoids and mineralocorticoids. Patients received recombinant follicle-stimulating hormone and recombinant human chorionic gonadotropin in order to induce spermatogenesis. Combined gonadotropin treatment was initiated between 13 years and 15 years and 6 months for the four teenagers and at 31 years and 2 months for the only adult. Physical and hormonal assessments were performed just before starting gonadotropin treatment. After 12 months of gonadotropin treatment, physical examination and hormonal assessments were repeated, and semen analyses were performed. If no sperm cells were observed in at least 2 semen collections at 3-month interval, testicular biopsy for testicular sperm extraction was proposed. Bilateral testicular volume increased from 8 ml (interquartile range, 6-9) to 12 ml (10-16) after gonadotropin treatment. Inhibin B levels were relatively stable: 110 ng/L (46-139) before and 91 ng/L (20-120) at the end of gonadotropin treatment. Azoospermia was observed in all semen analyses for all cases during gonadotropin treatment. Three patients agreed to testicular biopsy; no mature sperm cells could be retrieved in any. We characterized a cohort of patients with NR0B1 pathogenic or likely pathogenic variants for fertility preservation by recombinant gonadotropin treatment, which began either at puberty or in adulthood. No sperm cells could be retrieved in semen samples or testicular biopsy even after gonadotropin treatment, indicating that gonadotropin treatment, even when started at puberty, is ineffective for restoring fertility.
2018-09-27 | Acute adrenal crisis and mortality in adrenal insufficiency: Still a concern in 2018!
Despite established replacement therapy, mortality in patients suffering from chronic adrenal insufficiency is increasing. This may be partly explained by the fact that lack of adrenal stress hormones impairs the body's capacity to deal adequately with stress situations, resulting in life-threatening adrenal crises. Since many such situations are of rapid onset, concepts that allow for quick response to emergencies are particularly important. Optimal education for patients and relatives, improved awareness on the part of health professionals and the development of new easy-to-use drugs for acute therapy are of prime importance.
2016-12-13 | Spontaneous and tetracosactide-induced anti-ACTH antibodies in man.
During a clinical trial of regular tetracosactide depot injections, four of 13 patients with autoimmune Addison's disease (AAD) developed adverse reactions immediately following tetracosactide injections. We wished to investigate whether these adverse effects could be due to the production of circulating antitetracosactide (ACTH1-24 ) antibodies. Anti-ACTH binding activity was investigated using immunoblotting and ELISA on sera from participants in the trial (n = 13; baseline and after tetracosactide exposure), 131 unrelated patients with AAD, 92 patients with Graves' disease (GD), 15 patients with isolated ACTH deficiency and 102 controls. Immunohistochemistry of human pituitary tissue sections was also performed using pooled sera. Bands at approximately 4 and 6 kDa, corresponding to ACTH1-24 and full-length ACTH1-39, respectively, were found in 10 of 13 (77%) of sera from trial patients exposed to tetracosactide, including all those who had an adverse reaction. This is in contrast with healthy control sera, which showed no binding. The same 10 subjects also showed high levels of binding to tetracosactide by ELISA, along with 21% of patients with AAD, 14% of patients with GD (both P < 0·001 compared to controls) and 1 isolated ACTH deficiency patient (7% of 15). These sera also recognized native ACTH in human pituitary sections. Our study demonstrates that repeated administration of depot tetracosactide can lead to anti-ACTH1-24 autoreactivity. In addition, a significant number of patients with AAD and GD also had similar, spontaneous, anti-ACTH reactivity. The presence of these antibodies could mediate some of the adverse effects or explain the well-described phenomenon of resistance to chronic ACTH therapy.
antibodies
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.
2025-08-11 | IFNG-producing self-reactive CD4 + T cells drive autoimmune adrenalitis in a mouse model of Addison’s disease
Abstract Autoimmune Addison’s disease (AD) is a rare, life-threatening endocrine disorder caused by immune-mediated destruction of the adrenal cortex. AD frequently occurs in patients with autoimmune polyglandular syndrome type 1, a monogenic autoimmune syndrome caused by AIRE deficiency. The pathogenesis of AD remains poorly understood due to the lack of suitable animal models. Here, we established a mouse model of Experimental Autoimmune Adrenalitis by targeting the adrenal self-antigen CYP11A1. Immunization with CYP11A1-derived peptides elicited clonal expansion of CYP11A1-specific T-cell clones and the adrenal infiltration of CD4 + and CD8 + T cells and myeloid cells. Inflammation progressed to granulomatous lesions and culminated in adrenal insufficiency in AIRE-deficient mice with impaired central tolerance. A modification of the model based an adoptive transfer of polyclonal CYP11A1-stimulated CD4 + T cells into T-cell deficient hosts accelerated adrenal dysfunction. In contrast, IFNG-deficient CD4 + T cells induced only mild granulomatous inflammation and failed to cause overt adrenal insufficiency. These findings established a tractable mouse model for dissecting AD pathogenesis and identified CD4 + T cell-derived IFNG as a key effector of adrenal autoimmunity, providing a preclinical platform for testing targeted immunotherapies.
2025-02-20 | Anti-perilipin-1 autoantibodies in autoimmune Addison's disease and related endocrine disorders.
Immune-mediated lipodystrophy syndromes are rare autoimmune disorders characterized by complete or partial destruction of adipocytes in the body. Recently, autoantibodies against perilipin-1 (PLIN1-autoAbs) have been linked to lipodystrophy. Since various perilipins are expressed in the adrenal cortex and ovaries, we asked whether PLIN1-autoAbs were present in patients with adrenal dysfunction and other autoimmune endocrinopathies. Using a sensitive radiobinding immune assay we analyzed anti-PLIN1-autoAbs in 521 patients with endocrinopathies including Sjögren's syndrome. We identified 22 (4.2%) PLIN1-autoAbs positive patients, of whom 15% had autoimmune polyendocrine syndrome type 1 (4/27), 4% autoimmune Addison's disease and/or autoimmune polyendocrine syndrome type 2 (11/274), 8% type 1 diabetes patients (4/53), and 2% Sjögren's syndrome patients (1/50). However, none of them had known lipodystrophy. In conclusion, PLIN1-autoAbs are found in subgroups of autoimmune endocrinopathies and indicate autoimmunity against adipose tissue, but their pathogenic role if any, remains to be defined. Investigating their role in disease progression and their potential as therapeutic targets could pave the way for novel interventions in autoimmune endocrine diseases.
2023-12-05 | Major immunophenotypic abnormalities in patients with primary adrenal insufficiency of different etiology.
Patients with primary adrenal insufficiency (PAI) suffer from increased risk of infection, adrenal crises and have a higher mortality rate. Such dismal outcomes have been inferred to immune cell dysregulation because of unphysiological cortisol replacement. As the immune landscape of patients with different types of PAI has not been systematically explored, we set out to immunophenotype PAI patients with different causes of glucocorticoid (GC) deficiency. This cross-sectional single center study includes 28 patients with congenital adrenal hyperplasia (CAH), 27 after bilateral adrenalectomy due to Cushing's syndrome (BADx), 21 with Addison's disease (AD) and 52 healthy controls. All patients with PAI were on a stable GC replacement regimen with a median dose of 25 mg hydrocortisone per day. Peripheral blood mononuclear cells were isolated from heparinized blood samples. Immune cell subsets were analyzed using multicolor flow cytometry after four-hour stimulation with phorbol myristate acetate and ionomycin. Natural killer (NK-) cell cytotoxicity and clock gene expression were investigated. The percentage of T helper cell subsets was downregulated in AD patients (Th1 p = 0.0024, Th2 p = 0.0157, Th17 p < 0.0001) compared to controls. Cytotoxic T cell subsets were reduced in AD (Tc1 p = 0.0075, Tc2 p = 0.0154) and CAH patients (Tc1 p = 0.0055, Tc2 p = 0.0012) compared to controls. NKCC was reduced in all subsets of PAI patients, with smallest changes in CAH. Degranulation marker CD107a expression was upregulated in BADx and AD, not in CAH patients compared to controls (BADx p < 0.0001; AD p = 0.0002). In contrast to NK cell activating receptors, NK cell inhibiting receptor CD94 was upregulated in BADx and AD, but not in CAH patients (p < 0.0001). Although modulation in clock gene expression could be confirmed in our patient subgroups, major interindividual-intergroup dissimilarities were not detected. In patients with different etiologies of PAI, distinct differences in T and NK cell-phenotypes became apparent despite the use of same GC preparation and dose. Our results highlight unsuspected differences in immune cell composition and function in PAI patients of different causes and suggest disease-specific alterations that might necessitate disease-specific treatment.
2004-08-10 | Polymorphisms in the cytotoxic T lymphocyte antigen-4 gene region confer susceptibility to Addison's disease.
The cytotoxic T lymphocyte antigen-4 (CTLA4) gene on chromosome 2q33 encodes a key regulator in the adaptive immune system. The CTLA4 surface molecule is expressed on activated T lymphocytes and involved in down-regulation of the immune response. Previous studies on a possible association between autoimmune Addison's disease and CTLA4 polymorphisms have shown conflicting results. A recent study identified new candidate polymorphisms in the CTLA4 region, influencing gene splicing and thereby the relative abundance of soluble CTLA4. We genotyped 134 patients with Addison's disease and 413 healthy controls from Norway and United Kingdom for these newly identified polymorphisms. Our data demonstrate that the same polymorphisms that have recently been demonstrated to confer susceptibility to autoimmune thyroid disease and type 1 diabetes also confer susceptibility to Addison's disease. This finding suggests that polymorphisms in CTLA4 confer general risk to develop autoimmunity and identifies a potential therapeutic target in the prevention of autoimmune endocrine disorders.
small molecules
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.
2026-06-01 | Successful Therapeutic Approach to Facial Hyperpigmentation Secondary to Addison's Disease: A Case Report and Literature Review.
Addison's disease, or primary adrenal insufficiency, is a rare endocrine disorder characterized by deficient glucocorticoid and mineralocorticoid production, frequently associated with cutaneous hyperpigmentation due to chronic elevation of adrenocorticotropic hormone. Facial hyperpigmentation may persist despite adequate hormonal replacement, representing a therapeutic challenge with limited evidence to guide dermatologic management. We report the case of a 41-year-old female patient with an eight-year history of progressive hyperpigmentation affecting the face, hands, and oral mucosa. Physical examination revealed severe facial involvement with brown-violaceous macules and associated telangiectasias. The patient had a prior diagnosis of autoimmune ovarian failure in 2017 and was diagnosed with Addison's disease in 2020, receiving stable glucocorticoid replacement therapy. Histopathological evaluation demonstrated basal layer hyperpigmentation without interface dermatitis, consistent with endocrine-related pigmentation and overlapping melasma features. A multimodal therapeutic approach was implemented, including picosecond Nd:YAG laser therapy (approximately seven sessions at six- to eight-week intervals), oral tranexamic acid (250 mg twice daily), and a topical depigmenting regimen containing tranexamic acid, niacinamide, retinoids, and antioxidants. The patient demonstrated a significant reduction in modified Melasma Area and Severity Index score from 19.8 to 7.8 (60.6% reduction), along with a marked improvement in quality of life, as evidenced by a posttreatment Melasma Quality of Life Scale score of 20/70. This case highlights that persistent hyperpigmentation in Addison's disease may not fully resolve with endocrine treatment alone and may require adjunctive dermatologic interventions. A personalized, multimodal strategy targeting multiple pathogenic pathways, including melanogenesis, plasmin-mediated signaling, vascular factors, and dermal pigment deposition, can achieve significant improvement, even in patients with darker phototypes and long-standing disease. These findings underscore the importance of a multidisciplinary approach and suggest a potential role for combination therapies, including laser-based modalities, in managing complex pigmentary disorders associated with systemic conditions. Further studies are needed to establish standardized treatment protocols and evaluate long-term outcomes.
2026-03-24 | Prednisolone Once Daily vs Hydrocortisone Thrice Daily in Hypoadrenalism: A Randomized Clinical Trial.
Adrenal insufficiency is conventionally treated with daily multiple-dose hydrocortisone, and once-daily low-dose prednisolone is an alternative for glucocorticoid replacement. Clinical trials comparing once-daily low-dose prednisolone with thrice-daily hydrocortisone are lacking. To examine the differences in metabolism and bone turnover in patients receiving hydrocortisone vs prednisolone for adrenal insufficiency. This double-blind, crossover randomized clinical trial of multiple-daily standard-dose hydrocortisone vs once-daily low-dose prednisolone (2-5 mg), performed from September 3, 2019, to December 14, 2023, involved adults with adrenal insufficiency. Anthropometrics, biochemical data for cardiometabolic and bone health, and subjective health survey data were collected at days 1, 30, and 120 of each study period for both medications. Individuals were randomized to receive 4 months of once-daily prednisolone in the morning (with placebos at noon and afternoon) or hydrocortisone at the same times. All participants were crossed over to the alternative treatment for an additional 4 months. The primary outcome was assessment of bone turnover, detected by change in carboxylated and undercarboxylated osteocalcin between days 1 and 120 in each treatment period. Secondary outcomes included change in weight, body mass index, waist circumference, glycated hemoglobin, and subjective heath survey responses. Forty-seven participants were randomized, with 46 participants included in the analysis (median [IQR] age, 55.0 [46.5-62.8] years; 24 [52.2%] male). Twenty-four received prednisolone first and 22 received hydrocortisone first. Bone turnover was significantly slowed with prednisolone compared with hydrocortisone as evidenced by a significantly lower level of multiple bone markers, including carboxylated osteocalcin (mean treatment difference, -1.22 ng/mL; 95% CI, -2.35 to -0.10 ng/mL; P = .04), undercarboxylated osteocalcin (mean treatment difference, -1.38 ng/mL; 95% CI, -2.32 to -0.44 ng/mL; P = .005) (to convert osteocalcin to micrograms per liter, multiply by 1), urinary N-terminal telopeptide (mean treatment difference, -9.34 nmol/mmol; 95% CI, -15.4 to -3.29 nmol/mmol; P = .002), and procollagen type 1 N-terminal propeptide (mean treatment difference, -13.8 ng/mL; 95% CI, -22.2 to -5.49 ng/mL; P < .001). The mean treatment group difference in weight reduction from baseline was -1.87 kg (95% CI, -3.02 to -0.72 kg; P = .002) for prednisolone treatment compared with hydrocortisone, and this was associated with concordant significantly greater reductions in body mass index (BMI; calculated as weight in kilograms divided by the square of height in meters; treatment difference, -0.522; 95% CI, -1.01 to -0.04; P = .04), waist circumference (treatment difference, -2.26 cm; 95% CI, -3.97 to -0.56 cm; P = .01), and HbA1c (treatment difference, -0.12% [-1.23 mmol/mol; 95% CI, -1.95 to -0.51 mmol/mol]; P = .001). There were no differences in safety measures or subjective health outcomes, including all 36-Item Short-Form Health Survey domains and Addison's Disease-Specific Quality of Life Questionnaire. In this randomized clinical trial, once-daily low-dose prednisolone was associated with slower bone turnover and improvements in cardiometabolic health markers compared with multiple-dose hydrocortisone without compromising well-being. Studies assessing longer-term mortality and morbidity outcomes are needed. ClinicalTrials.gov Identifier: NCT03936517.
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.
2026-02-13 | Different metabolic pathways associated with total cortisol exposure and the cortisol time profile: a randomized crossover trial.
Excess cortisol exposure and disruption of its circadian pattern have both been linked to adverse health outcomes; however, whether distinct metabolic signatures differentiate total cortisol exposure from cortisol secretion dynamics remains unclear. This study aimed to identify metabolites and metabolic pathways uniquely associated with total cortisol exposure and/or variation of the cortisol time profile. In a randomized, 12-week, cross-over trial 18 adults with primary adrenal insufficiency (AI) received the same total daily dose of hydrocortisone (HC) administered as a once-daily (OD) dual-release tablet and conventional HC tablets 3 times daily (TID). Serum and urine samples were collected during 24h in-house standardized pharmacokinetic sampling days and metabolites were detected using liquid and gas chromatography-mass spectrometry (LC-MS and GC-MS). Total cortisol exposure was quantified as the area under the serum cortisol concentration-time curve and variability in the cortisol time profile was assessed by calculating the lag–1 autocorrelation from serum cortisol concentrations over 24 hours. Compared with OD dosing, TID administration resulted in a 20% higher total cortisol exposure and a greater variability in the cortisol time profile. In total, 2406 metabolites were detected. Pathway analysis of serum metabolites uniquely correlated with total cortisol exposure were involved in amino acid metabolism - including arginine, tryptophan and glutamate pathways - as well as glycerolipid metabolism. In contrast, metabolites uniquely associated with variability of the cortisol time profile were mapped to primary bile acid biosynthesis and cysteine-methionine metabolism. We identified distinct groups of metabolites and metabolic pathways that specifically correlate with either overall serum cortisol exposure or variability in its time profile, indicating that cortisol dose exposure and the circadian dynamics may exert independent metabolic and regulatory effects in humans, with potential implications for personalized hydrocortisone therapy.
cell therapies
2026-01-05 | Anti-aging effects of the adrenal androgens dehydroepiandrosterone and dehydroepiandrosterone sulfate: mechanisms of action and beneficial effects in older people.
We review the recent remarkable progress of the molecular mechanisms of action of the adrenal androgens dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) regarding their beneficial effects on older people and adrenal regenerative therapy by looking back on our research extending over 50 years since 1971. DHEAS is the most abundant circulating steroid hormone in humans and apes. DHEAS is essential for brain development in adrenarche and for anti-aging in adrenopause as shown by the evolutionary process in primates. The molecular mechanisms of action of DHEA and DHEAS have been clarified by the discovery of many membrane receptors and by the concept of intracrinological action, which is especially important in menopausal women. The genes associated with serum DHEAS concentrations were identified by genome-wide association study meta-analysis of cohort studies. Recent advances in aging research have shown that DHEA and DHEAS have anti-aging action via antioxidants, anti-inflammation, telomere protection, p38MAPK inhibition, anti-cortisol effects, and chaperone induction. DHEA has beneficial effects on the prevention of atherosclerosis based on visceral obesity-induced metabolic syndrome in middle-aged people. DHEA also prevents infection, frailty via reverse metabolism, sarcopenia, and osteoporosis in older people, with a marked decrease in serum DHEAS concentrations. This review discusses adrenal regenerative therapy using steroid-producing cell replacement by overexpressing Ad4BP/steroidogenic factor 1 in mouse or human bone marrow mesenchymal stem cells. This therapy replaces cortisol and DHEAS treatment for the prevention of sudden death by adrenal crisis and severe infection in primary adrenal insufficiency (Addison's disease).
2023-05-18 | Future Directions for Adrenal Insufficiency: Cellular Transplantation and Genetic Therapies.
Primary adrenal insufficiency (PAI) occurs in 1 in 5 to 7000 adults. Leading etiologies are autoimmune adrenalitis in adults and congenital adrenal hyperplasia (CAH) in children. Oral replacement of cortisol is lifesaving, but poor quality of life, repeated adrenal crises, and dosing uncertainty related to lack of a validated biomarker for glucocorticoid sufficiency persists. Adrenocortical cell therapy and gene therapy may obviate many of the shortcomings of adrenal hormone replacement. Physiological cortisol secretion regulated by pituitary adrenocorticotropin could be achieved through allogeneic adrenocortical cell transplantation, production of adrenal-like steroidogenic cells from either stem cells or lineage conversion of differentiated cells, or for CAH, gene therapy to replace or repair a defective gene. The adrenal cortex is a high-turnover organ and thus failure to incorporate progenitor cells within a transplant will ultimately result in graft exhaustion. Identification of adrenocortical progenitor cells is equally important in gene therapy, for which new genetic material must be specifically integrated into the genome of progenitors to ensure a durable effect. Delivery of gene-editing machinery and a donor template, allowing targeted correction of the 21-hydroxylase gene, has the potential to achieve this. This review describes advances in adrenal cell transplants and gene therapy that may allow physiological cortisol production for children and adults with PAI.
2021-09-15 | New Horizons: Novel adrenal regenerative therapies
In this narrative review, the authors discuss the potential role of novel regenerative therapies for the treatment of adrenal insufficiency, including gene therapy and cell replacement strategies. More specifically, the authors discuss the heterogeneity in adrenal function in patients with Addison disease, including numerous case reports of spontaneous remission. The authors cite recent studies showing that, shortly after the onset of Addison disease, residual adrenal function might be restored using B-lymphocyte-depleting immunotherapy and ACTH treatment. The rationale is that ACTH stimulates the differentiation of the persisting progenitor or stem cells, while B-cell depletion prevents destruction of the newly differentiated cells (1). Furthermore, the cell turnover of the adrenal cortex limits the time-span of the effectiveness of gene therapy (2). A more promising strategy is adrenal cell transplantation, which is potentially curative. Research foci in this strategy include alternative cell sources, novel biomaterials that have been developed to improve cell viability of engineered cells upon implantation, and cellular therapies based on pluripotent stem cells (3).
2021-03-02 | MANAGEMENT OF ENDOCRINE DISEASE: Residual adrenal function in Addison's disease.
Over the last 10 years, evidence has accumulated that autoimmune Addison's disease (AAD) is a heterogeneous disease. Residual adrenal function, characterised by persistent secretion of cortisol, other glucocorticoids and mineralocorticoids is present in around 30% of patients with established AAD, and appears commoner in men. This persistent steroidogenesis is present in some patients with AAD for more than 20 years, but it is commoner in people with shorter disease duration. The clinical significance of residual adrenal function is not fully clear at the moment, but as it signifies an intact adrenocortical stem cell population, it opens up the possibility of regeneration of adrenal steroidogenesis and improvement in adrenal failure for some patients.
2014-12-09 | High frequency of cytolytic 21-hydroxylase-specific CD8+ T cells in autoimmune Addison's disease patients.
The mechanisms behind destruction of the adrenal glands in autoimmune Addison's disease remain unclear. Autoantibodies against steroid 21-hydroxylase, an intracellular key enzyme of the adrenal cortex, are found in >90% of patients, but these autoantibodies are not thought to mediate the disease. In this article, we demonstrate highly frequent 21-hydroxylase-specific T cells detectable in 20 patients with Addison's disease. Using overlapping 18-aa peptides spanning the full length of 21-hydroxylase, we identified immunodominant CD8(+) and CD4(+) T cell responses in a large proportion of Addison's patients both ex vivo and after in vitro culture of PBLs ≤20 y after diagnosis. In a large proportion of patients, CD8(+) and CD4(+) 21-hydroxylase-specific T cells were very abundant and detectable in ex vivo assays. HLA class I tetramer-guided isolation of 21-hydroxylase-specific CD8(+) T cells showed their ability to lyse 21-hydroxylase-positive target cells, consistent with a potential mechanism for disease pathogenesis. These data indicate that strong CTL responses to 21-hydroxylase often occur in vivo, and that reactive CTLs have substantial proliferative and cytolytic potential. These results have implications for earlier diagnosis of adrenal failure and ultimately a potential target for therapeutic intervention and induction of immunity against adrenal cortex cancer.
proteins
2026-01-05 | [Hormones and skin pigmentation: fundamentals and clinical relevance].
Skin pigmentation by the endogenous pigment melanin is a highly coordinated process in which hormones play a crucial role. They are synthesized not only in classical endocrine organs but also in the skin itself, which acts as an independent endocrine organ. Among the endocrine target structures of the skin, the melanocortin 1 receptor (MC1R) is of particular importance. Via its high expression and tonic activity in melanocytes, as well as by binding to natural melanocortins such as α‑melanocyte-stimulating hormone (α-MSH), being generated in the skin following ultraviolet (UV) light irradiation, MC1R crucially contributes to the different skin phototypes. Gene mutations of MC1R resulting in defective cyclic adenosine monophosphate (cAMP)-mediated signalling can lead to a shift of the eumelanin/pheomelanin ratio towards the pro-oxidant, yellowish-orange pheomelanin. In patients with Addison's disease and associated syndromes, ectopic proopiomelanocortin syndrome and primary adrenal cortex insufficiency elevated melanocortin levels result in increased melanin content of the skin. Two synthetic melanocortins, afamelanotide (NDP-α-MSH) and setmelanotide, are currently approved in Germany. By targeting MC1R directly (afamelanotide) or as a bystander effect (setmelanotide), both agents increase the skin melanin content. Non-licenced synthetic melanocortins, on the other hand, are used as lifestyle products in an unregulated manner. Additional hormones regulating melanogenesis and skin pigmentation include estrogens, thyroid hormones, insulin, insulin-like growth-factor‑1 and melatonin. They are of physiological and clinical relevance during pregnancy and in patients with melasma and vitiligo. Autoimmune thyroid disorders and diabetes are associated with non-segmental vitiligo. Melatonin appears to have a lightening effect on skin pigmentation by melanin.
2025-12-24 | Pathogenesis of acute adrenal crisis in children: current concepts and emerging mechanisms
Aim. The aim of this article is to provide a comprehensive review of the pathogenetic mechanisms underlying the development of acute adrenal crisis (AAC) in children, with an emphasis on recent experimental and clinical findings. Materials and Methods. A comprehensive literature search was conducted using MEDLINE, Embase, Scopus, Cochrane, PubMed, Google Scholar and Elibrary databases, as well as through citation tracking of studies published between 2019 and June 2025. A total of 40 national and international publications were analyzed, including clinical, experimental, and genomic studies, as well as systematic reviews and meta-analyses focused on the pathogenesis of adrenal insufficiency and adrenal crisis in pediatric populations. Results. The classical pathogenesis of AAC is associated with cortisol and aldosterone deficiency, leading to severe metabolic and hemodynamic disturbances. However, in recent years, a new concept of the multifactorial nature of this syndrome has emerged, encompassing systemic, molecular, immune, and microbiota-related components. Key etiological forms have been analyzed, including congenital adrenal hyperplasia, glucocorticoid-induced adrenal insufficiency, and autoimmune adrenalitis. Data are presented on the involvement of pro-inflammatory cytokines (IL-6, TNF-α), mitochondrial dysfunction, altered expression of ACTH receptors (MC2R, MRAP), and epigenetic modifications (NR0B1, CYP21A2). Particular attention is given to sepsis-induced adrenal dysfunction, endothelial impairment, and the influence of the gut–adrenal axis on crisis development. Conclusion. The current understanding of AAC pathogenesis extends beyond the classical hormonal deficiency model and includes complex interactions among inflammatory, mitochondrial, immune, genetic, and microbiota-related mechanisms. The importance of early diagnosis, molecular stratification, and personalized treatment strategies is emphasized. These findings highlight the need to revise current approaches to prevention and management in pediatric practice, with a focus on targeted and multidisciplinary therapeutic interventions.
2022-04-19 | Effect of Recombinant Gonadotropin on Testicular Function and Testicular Sperm Extraction in Five Cases of NR0B1 (DAX1) Pathogenic Variants.
NR0B1 pathogenic variants can cause congenital adrenal hypoplasia or primary adrenal insufficiency in early childhood usually associated with hypogonadotropic hypogonadism. NR0B1 is necessary for organogenesis of the adrenal cortex and to maintain normal spermatogenesis. In humans, restoration of fertility in patients carrying NR0B1 pathogenic variants is challenging. The aim of the study was to investigate the clinical, hormonal, histological, spermiological, and molecular genetic characteristics of a cohort of patients with NR0B1 pathogenic variants, monitored for fertility preservation. We included five patients, including four teenagers, with NR0B1 pathogenic or likely pathogenic variants. They all had primary adrenal insufficiency and were receiving replacement therapy with glucocorticoids and mineralocorticoids. Patients received recombinant follicle-stimulating hormone and recombinant human chorionic gonadotropin in order to induce spermatogenesis. Combined gonadotropin treatment was initiated between 13 years and 15 years and 6 months for the four teenagers and at 31 years and 2 months for the only adult. Physical and hormonal assessments were performed just before starting gonadotropin treatment. After 12 months of gonadotropin treatment, physical examination and hormonal assessments were repeated, and semen analyses were performed. If no sperm cells were observed in at least 2 semen collections at 3-month interval, testicular biopsy for testicular sperm extraction was proposed. Bilateral testicular volume increased from 8 ml (interquartile range, 6-9) to 12 ml (10-16) after gonadotropin treatment. Inhibin B levels were relatively stable: 110 ng/L (46-139) before and 91 ng/L (20-120) at the end of gonadotropin treatment. Azoospermia was observed in all semen analyses for all cases during gonadotropin treatment. Three patients agreed to testicular biopsy; no mature sperm cells could be retrieved in any. We characterized a cohort of patients with NR0B1 pathogenic or likely pathogenic variants for fertility preservation by recombinant gonadotropin treatment, which began either at puberty or in adulthood. No sperm cells could be retrieved in semen samples or testicular biopsy even after gonadotropin treatment, indicating that gonadotropin treatment, even when started at puberty, is ineffective for restoring fertility.
2018-09-27 | Acute adrenal crisis and mortality in adrenal insufficiency: Still a concern in 2018!
Despite established replacement therapy, mortality in patients suffering from chronic adrenal insufficiency is increasing. This may be partly explained by the fact that lack of adrenal stress hormones impairs the body's capacity to deal adequately with stress situations, resulting in life-threatening adrenal crises. Since many such situations are of rapid onset, concepts that allow for quick response to emergencies are particularly important. Optimal education for patients and relatives, improved awareness on the part of health professionals and the development of new easy-to-use drugs for acute therapy are of prime importance.
2016-12-13 | Spontaneous and tetracosactide-induced anti-ACTH antibodies in man.
During a clinical trial of regular tetracosactide depot injections, four of 13 patients with autoimmune Addison's disease (AAD) developed adverse reactions immediately following tetracosactide injections. We wished to investigate whether these adverse effects could be due to the production of circulating antitetracosactide (ACTH1-24 ) antibodies. Anti-ACTH binding activity was investigated using immunoblotting and ELISA on sera from participants in the trial (n = 13; baseline and after tetracosactide exposure), 131 unrelated patients with AAD, 92 patients with Graves' disease (GD), 15 patients with isolated ACTH deficiency and 102 controls. Immunohistochemistry of human pituitary tissue sections was also performed using pooled sera. Bands at approximately 4 and 6 kDa, corresponding to ACTH1-24 and full-length ACTH1-39, respectively, were found in 10 of 13 (77%) of sera from trial patients exposed to tetracosactide, including all those who had an adverse reaction. This is in contrast with healthy control sera, which showed no binding. The same 10 subjects also showed high levels of binding to tetracosactide by ELISA, along with 21% of patients with AAD, 14% of patients with GD (both P < 0·001 compared to controls) and 1 isolated ACTH deficiency patient (7% of 15). These sera also recognized native ACTH in human pituitary sections. Our study demonstrates that repeated administration of depot tetracosactide can lead to anti-ACTH1-24 autoreactivity. In addition, a significant number of patients with AAD and GD also had similar, spontaneous, anti-ACTH reactivity. The presence of these antibodies could mediate some of the adverse effects or explain the well-described phenomenon of resistance to chronic ACTH therapy.
antibodies
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.
2025-08-11 | IFNG-producing self-reactive CD4 + T cells drive autoimmune adrenalitis in a mouse model of Addison’s disease
Abstract Autoimmune Addison’s disease (AD) is a rare, life-threatening endocrine disorder caused by immune-mediated destruction of the adrenal cortex. AD frequently occurs in patients with autoimmune polyglandular syndrome type 1, a monogenic autoimmune syndrome caused by AIRE deficiency. The pathogenesis of AD remains poorly understood due to the lack of suitable animal models. Here, we established a mouse model of Experimental Autoimmune Adrenalitis by targeting the adrenal self-antigen CYP11A1. Immunization with CYP11A1-derived peptides elicited clonal expansion of CYP11A1-specific T-cell clones and the adrenal infiltration of CD4 + and CD8 + T cells and myeloid cells. Inflammation progressed to granulomatous lesions and culminated in adrenal insufficiency in AIRE-deficient mice with impaired central tolerance. A modification of the model based an adoptive transfer of polyclonal CYP11A1-stimulated CD4 + T cells into T-cell deficient hosts accelerated adrenal dysfunction. In contrast, IFNG-deficient CD4 + T cells induced only mild granulomatous inflammation and failed to cause overt adrenal insufficiency. These findings established a tractable mouse model for dissecting AD pathogenesis and identified CD4 + T cell-derived IFNG as a key effector of adrenal autoimmunity, providing a preclinical platform for testing targeted immunotherapies.
2025-02-20 | Anti-perilipin-1 autoantibodies in autoimmune Addison's disease and related endocrine disorders.
Immune-mediated lipodystrophy syndromes are rare autoimmune disorders characterized by complete or partial destruction of adipocytes in the body. Recently, autoantibodies against perilipin-1 (PLIN1-autoAbs) have been linked to lipodystrophy. Since various perilipins are expressed in the adrenal cortex and ovaries, we asked whether PLIN1-autoAbs were present in patients with adrenal dysfunction and other autoimmune endocrinopathies. Using a sensitive radiobinding immune assay we analyzed anti-PLIN1-autoAbs in 521 patients with endocrinopathies including Sjögren's syndrome. We identified 22 (4.2%) PLIN1-autoAbs positive patients, of whom 15% had autoimmune polyendocrine syndrome type 1 (4/27), 4% autoimmune Addison's disease and/or autoimmune polyendocrine syndrome type 2 (11/274), 8% type 1 diabetes patients (4/53), and 2% Sjögren's syndrome patients (1/50). However, none of them had known lipodystrophy. In conclusion, PLIN1-autoAbs are found in subgroups of autoimmune endocrinopathies and indicate autoimmunity against adipose tissue, but their pathogenic role if any, remains to be defined. Investigating their role in disease progression and their potential as therapeutic targets could pave the way for novel interventions in autoimmune endocrine diseases.
2023-12-05 | Major immunophenotypic abnormalities in patients with primary adrenal insufficiency of different etiology.
Patients with primary adrenal insufficiency (PAI) suffer from increased risk of infection, adrenal crises and have a higher mortality rate. Such dismal outcomes have been inferred to immune cell dysregulation because of unphysiological cortisol replacement. As the immune landscape of patients with different types of PAI has not been systematically explored, we set out to immunophenotype PAI patients with different causes of glucocorticoid (GC) deficiency. This cross-sectional single center study includes 28 patients with congenital adrenal hyperplasia (CAH), 27 after bilateral adrenalectomy due to Cushing's syndrome (BADx), 21 with Addison's disease (AD) and 52 healthy controls. All patients with PAI were on a stable GC replacement regimen with a median dose of 25 mg hydrocortisone per day. Peripheral blood mononuclear cells were isolated from heparinized blood samples. Immune cell subsets were analyzed using multicolor flow cytometry after four-hour stimulation with phorbol myristate acetate and ionomycin. Natural killer (NK-) cell cytotoxicity and clock gene expression were investigated. The percentage of T helper cell subsets was downregulated in AD patients (Th1 p = 0.0024, Th2 p = 0.0157, Th17 p < 0.0001) compared to controls. Cytotoxic T cell subsets were reduced in AD (Tc1 p = 0.0075, Tc2 p = 0.0154) and CAH patients (Tc1 p = 0.0055, Tc2 p = 0.0012) compared to controls. NKCC was reduced in all subsets of PAI patients, with smallest changes in CAH. Degranulation marker CD107a expression was upregulated in BADx and AD, not in CAH patients compared to controls (BADx p < 0.0001; AD p = 0.0002). In contrast to NK cell activating receptors, NK cell inhibiting receptor CD94 was upregulated in BADx and AD, but not in CAH patients (p < 0.0001). Although modulation in clock gene expression could be confirmed in our patient subgroups, major interindividual-intergroup dissimilarities were not detected. In patients with different etiologies of PAI, distinct differences in T and NK cell-phenotypes became apparent despite the use of same GC preparation and dose. Our results highlight unsuspected differences in immune cell composition and function in PAI patients of different causes and suggest disease-specific alterations that might necessitate disease-specific treatment.
2004-08-10 | Polymorphisms in the cytotoxic T lymphocyte antigen-4 gene region confer susceptibility to Addison's disease.
The cytotoxic T lymphocyte antigen-4 (CTLA4) gene on chromosome 2q33 encodes a key regulator in the adaptive immune system. The CTLA4 surface molecule is expressed on activated T lymphocytes and involved in down-regulation of the immune response. Previous studies on a possible association between autoimmune Addison's disease and CTLA4 polymorphisms have shown conflicting results. A recent study identified new candidate polymorphisms in the CTLA4 region, influencing gene splicing and thereby the relative abundance of soluble CTLA4. We genotyped 134 patients with Addison's disease and 413 healthy controls from Norway and United Kingdom for these newly identified polymorphisms. Our data demonstrate that the same polymorphisms that have recently been demonstrated to confer susceptibility to autoimmune thyroid disease and type 1 diabetes also confer susceptibility to Addison's disease. This finding suggests that polymorphisms in CTLA4 confer general risk to develop autoimmunity and identifies a potential therapeutic target in the prevention of autoimmune endocrine disorders.
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