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:
categories:
Small molecules
small molecules
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.
antibodies
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.
2014-04-10 | Oxytocin projections to the nucleus of the solitary tract contribute to the increased meal-related satiety responses in primary adrenal insufficiency.
Anorexia is a common clinical manifestation of primary adrenal gland failure. Adrenalectomy (ADX)-induced hypophagia is reversed by oxytocin (OT) receptor antagonist and is associated with increased activation of satiety-related responses in the nucleus of the solitary tract (NTS). This study evaluated OT projections from the paraventricular nucleus of the hypothalamus (PVN) to the NTS after ADX and the effect of pretreatment with intracerebroventricular injection of an OT receptor antagonist ([d(CH2)5,Tyr(Me)(2),Orn(8)]-vasotocin; OVT) on the activation of NTS neurons induced by feeding in adrenalectomized rats. Adrenalectomized animals showed higher OT labelling in the NTS than the sham and the ADX with corticosterone replacement (ADX + B) groups. Adrenalectomized animals exhibited co-localization of the anterograde tracer Phaseolus vulgaris leucoagglutinin and OT in axons in the NTS as well as OT fibres apposing NTS neurons activated by refeeding. After vehicle pretreatment, compared with fasting, refeeding increased the numbers of Fos- and Fos + TH-immunoreactive neurons in the NTS in sham, ADX and ADX + B groups, with a higher number of these immunolabelled neurons in adrenalectomized animals. Compared with fasting conditions, refeeding also increased the activation of NTS neurons in OVT-pretreated sham, ADX and ADX + B groups, but there was no difference among the three experimental groups. These data demonstrate that OT is upregulated in projections to the NTS following ADX and that OT receptor antagonist reverses the greater activation of NTS neurons induced by feeding after ADX. The data indicate that OT pathways to the NTS contribute to higher satiety-related responses and, thus, to reduce meal size in primary adrenal insufficiency.
2012-12-18 | Adrenal steroidogenesis after B lymphocyte depletion therapy in new-onset Addison's disease.
A diagnosis of Addison's disease means lifelong dependence on daily glucocorticoid and mineralocorticoid therapy and is associated with increased morbidity and mortality as well as a risk of unexpected adrenal crisis. The objective of the study was to determine whether immunomodulatory therapy at an early stage of autoimmune Addison's disease could lead to preservation or improvement in adrenal steroidogenesis. This was an open-label, pilot study of B lymphocyte depletion therapy in new-onset idiopathic primary adrenal failure. Doses of iv rituximab (1 g) were given on d 1 and 15, after pretreatment with 125 mg iv methylprednisolone. Six patients (aged 17-47 yr; four females) were treated within 4 wk of the first diagnosis of idiopathic primary adrenal failure. Dynamic testing of adrenal function was performed every 3 months for at least 12 months. Serum cortisol levels declined rapidly and were less than 100 nmol/liter (3.6 μg/dl) in all patients by 3 months after B lymphocyte depletion. Serum cortisol and aldosterone concentrations remained low in five of the six patients throughout the follow-up period. However, a single patient had sustained improvement in both serum cortisol [peak 434 nmol/liter (15.7 μg/dl)] and aldosterone [peak 434 pmol/liter (15.7 ng/dl)] secretion. This patient was able to discontinue steroid medications 15 months after therapy and remains well, with improving serum cortisol levels 27 months after therapy. New-onset autoimmune Addison's disease should be considered as a potentially reversible condition in some patients. Future studies of immunomodulation in autoimmune Addison's disease may be warranted.
2011-06-22 | Cellular immunity and immunopathology in autoimmune Addison's disease.
Autoimmune adrenocortical failure, or Addison's disease, is a prototypical organ-specific autoimmune disorder. In common with related autoimmune endocrinopathies, Addison's disease is only manageable to a certain extent with replacement therapy being the only treatment option. Unfortunately, the available therapy does not restore the physiological hormone levels and biorhythm. The key to progress in treating and preventing autoimmune Addison's disease lies in improving our understanding of the predisposing factors, the mechanisms responsible for the progression of the disease, and the interactions between adrenal antigens and effector cells and molecules of the immune system. The aim of the present review is to summarize the current knowledge on the role of T cells and cellular immunity in the pathogenesis of autoimmune Addison's disease.
2006-02-09 | Analysis of the interaction between human steroid 21-hydroxylase and various monoclonal antibodies using comparative structural modelling.
To study the interaction between human steroid 21-hydroxylase (21-OH) and monoclonal antibodies (MAbs) to 21-OH directed to 3 different epitopes recognised by 21-OH autoantibodies characteristic of autoimmune Addison's disease. Build comparative structural models of 21-OH, 21-OH MAbs and complexes of 21-OH-21-OH MAbs and study the effects of 21-OH MAbs on 21-OH enzyme activity. Then, analyse the relationship between sites important for binding of 21-OH MAbs and 21-OH autoantibodies and sites important for 21-OH enzyme activity. Variable (V) regions of 21-OH MAbs (M21-OH1, M21-OH3, M21-OH5) were sequenced and models of the MAbs built using structures of antibodies in the database as templates. A comparative model of 21-OH was built using the crystal structure of rabbit cytochrome p450 2c5/3LVdH as template. 21-OH enzyme activity was measured in terms of conversion of [3H]progesterone to deoxycorticosterone and the effect of purified MAb IgGs on 21-OH enzyme activity was assessed. M21-OH1, M21-OH3 and control MAb had no effect on 21-OH enzyme activity with 88.8% +/- 24% (n = 6), 86.7% +/- 7.6% (n = 6) and 86.5% +/- 10.6% (n = 6) of activity remaining in the presence of the respective IgGs. This was consistent with the epitopes for M21-OH1 and M21-OH3 being located distant from 21-OH enzyme active sites in our 21-OH model. The epitope for M21-OH5 which inhibited 21-OH enzyme activity (48.5 +/- 8.3% activity remaining; P < 0.001 compared with control MAb IgG) was found close to the redox protein binding site in our 21-OH model. A comparative model of 21-OH has been produced. Analysis of experimental data in the context of the model suggests that M21-OH5 inhibits 21-OH enzyme activity through interference with redox protein binding.
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).
2025-10-01 | MON-500 Adrenal Bioprinted Tissue Therapeutics Restore Function in Murine Models of Primary Adrenal Insufficiency
Abstract Disclosure: H. Soliman: None. Z.A. Bazzi: None. O. Nemirovsky: None. S. Keshvani: None. C. Song: None. N.A. Chan: None. S. Gicole: None. R.B. Jalili: None. S. Wadsworth: None. C.T. Dickman: None. Primary adrenal insufficiency, caused by either autoimmune Addison’s disease or congenital adrenal hyperplasia, is a life-threatening condition that requires lifelong adrenal hormone replacement. Current hormone replacement therapies have a high treatment burden and fail to mimic the natural circadian rhythms of hormone secretion. Transplanting functional adrenal cells has the potential to restore the natural hypothalamic-pituitary-adrenal (HPA) axis feedback loop, enabling dynamic hormonal regulation that mimics physiological function rather than relying on fixed-dose steroid replacement. An allogeneic cell therapy that achieves this without the need for chronic immune suppression could be a breakthrough in the treatment of primary adrenal insufficiency. Adrenal Bioprinted Tissue Therapeutics (BTTs) were developed using primary human adrenocortical cells with Aspect Biosystems’ full-stack tissue therapeutic platform, which incorporates proprietary bioprinting technology. These cells were encapsulated in a cell-supporting biomaterial with an immunoprotective outer shell. In vitro assessment of these BTTs indicated that the encapsulated adrenal cells were viable for extended durations and able to sense exogenously administered adrenocorticotrophic hormone (ACTH) and respond by releasing cortisol. Implantation of these xenogeneic adrenal BTTs in adrenalectomized mice led to a dose-dependent, rapid, marked, and sustained responsive elevation of plasma cortisol and reduction in plasma ACTH, as well as an increase in survival. There was a robust response to exogenously administered ACTH resulting in a significant increase in plasma cortisol in mice implanted with adrenal BTTs. ACTH responsive cortisol secretion was observed through study end at six months. To assess whether implanted adrenal BTTs respond to physiological circadian fluctuations in endogenous mouse ACTH levels, plasma cortisol and ACTH were measured mornings and evenings and showed that plasma cortisol levels followed the same secretion pattern as endogenous ACTH in the adrenalectomized mice, indicating responsiveness of the implanted BTTs to physiological fluctuations in ACTH. Adrenal BTTs retrieved from mice at termination after six months demonstrated high viability and remained responsive to in vitro incubation with ACTH. These results indicate that Aspect Biosystems’ adrenal BTTs can restore precise ACTH responsive adrenal function with appropriate circadian rhythm in in vivo models of primary adrenal insufficiency. Such an approach could revolutionize therapy for patients with primary adrenal insufficiency. Presentation: Monday, July 14, 2025
2025-10-01 | MON-471 Establishment of Adrenal Cortex Like Cells From Human Induced Pluripotent Stem Cells That Produce Adrenal Hormones
Abstract Disclosure: J. Thyagraj: None. M.M. Laronda: None. Adrenal insufficiency (AI) is a rare and chronic condition characterized by the adrenal cortex’s inability to secrete adequate amounts of steroid hormones. Since the adrenal cortex and the gonads originate from a common progenitor cell, adrenal morbidities can occur co-occur with differences in sex development (DSD/intersex), primary ovarian insufficiency or infertility. Disruptions in reproductive functions associated with adrenal co-morbidities can be difficult to diagnose until during or after puberty. Our lab is interested in studying pathways involved in adrenal hormone production within patients with disrupted reproductive functions caused by specific gene variants. We aimed to optimize a culturing system that generates human adrenal cortex like cells (hACLC) from human induced pluripotent stem cells (hiPSCs) and to establish the baseline hormone outputs of functional hACLC aggregates. Using the protocol ligand-based protocol by Sakata et al., hiPSCs were differentiated into adrenogonadal primordium-like cells then hACLCs. 14.06% of cells differentiated hACLC aggregates expressed the adrenal cortex cell surface protein DLK1. We cultured the aggregates in submerged culture (sub) with the published air-liquid interface (ALI) culture to choose a culture that facilitated maximum hormone production. The levels of cortisol were significantly lower in the ALI than in sub across all time intervals (20.442+/-1.84, 26.61+/-3.66), DHEA was significantly reduced over time in Sub (8.007+/-1.05, 7.349+/-1.14) but not ALI (5.380 +/- 0.5, 2.735 +/- 0.38) and there was no significant difference in estradiol production in either condition (217+/-29.7, 118+/-923). Neither culture condition produced detectable levels of aldosterone. As submerged culture system performed better and maintained their aggregate form, we continued experiments with this method and measured their baseline hormone ranges over a week. The hACLC aggregates produced the most DHEA (14.20 ng/ml) on day 22 which significantly decreased by day 25 and 28 (7.930-14.20 ng/ml). The differentiated hACLCs also produced cortisol in the range of 20.44-26.62 ng/ml. Overall, the levels of cortisol remained consistent in all time intervals. Estradiol production also peaks at day 22 (638.2 pg/ml) followed by a significant decline on day 25 and day 28. On average, a hACLC aggregate produced up to 14.20 ng/ml DHEA, 26.62 ng/ml cortisol and 638.2 pg/ml estradiol. Our findings support a previously published protocol for generating hACLCs from hiPSCs with adjustments to increase secretion of cortisol, DHEA and estradiol. Ongoing research is advancing these tools to understand how patient-specific gene variants can influence adrenal cortex development and hormone production and may act as a predictive measure of pubertal-onset adrenal insufficiency. Presentation: Monday, July 14, 2025
2024-07-25 | In Vivo Formation of Adrenal Organoids in a Novel Porcine Model of Adrenocortical Cell Transplantation.
Recognizing the limitations of current therapies for Addison's disease, novel treatments that replicate dynamic physiologic corticosteroid secretion, under control of ACTH, are required. The aim of these experiments was to evaluate the feasibility of adrenocortical cell transplantation (ACT) in a large animal model, adapting methods successfully used for intracutaneous pancreatic islet cell transplantation, using a fully biodegradable temporizing matrix. Autologous porcine ACT was undertaken by bilateral adrenalectomy, cell isolation, culture, and intracutaneous injection into a skin site preprepared using a biodegradable temporizing matrix (BTM) foam. Hydrocortisone support was provided during adrenocortical cell engraftment and weaned as tolerated. Blood adrenocortical hormone concentrations were monitored, and the transplant site was examined at endpoint. Outcome measures included cellular histochemistry, systemic hormone production, and hydrocortisone independence. Transplanted adrenocortical cells showed a capability to survive and proliferate within the intracutaneous site and an ability to self-organize into discrete tissue organoids with features of the normal adrenal histologic architecture. Interpretation of systemic hormone levels was confounded by the identification of accessory adrenals and regenerative cortical tissue within the adrenal bed postmortem. Corticosteroids were unable to be completely ceased. ACT in a large animal model has not previously been attempted, yet it is an important step toward clinical translation. These results demonstrate rhe potential for ACT based on the development of adrenal organoids at the BTM site. However, the inability to achieve clinically relevant systemic hormone production suggests insufficient function, likely attributable to insufficient cells through delivered dose and subsequent proliferation.
2024-06-09 | Effect of resuscitation of cryopreserved porcine adrenal glands at 26 °C on their recovery and functioning under xenotransplantation.
The study is devoted to the effect of lowered resuscitation temperature (26 °C) on cryopreserved porcine adrenal glands functional activity in vitro and in vivo under xenotransplantation. The adrenals were collected from newborn pigs, cryopreserved with 5 % DMSO at a rate of 1 °C/min, resuscitated at 26 or 37 °C for 48 h (5 % CO2, DMEM), embedded into small intestinal submucosa, and transplanted to bilaterally adrenalectomized rats. It has been shown that the glands resuscitated at 26 °C have suppressed free-radical processes and can produce cortisol and aldosterone in vitro, and may lead to elevated blood levels of these hormones. Moreover, the adrenal grafts maintain blood glucose levels and promote the formation of glycogen stores. Thus, the resuscitation at 26 °C can improve the quality of grafts and favor the introduction and application of the cryopreserved organs and tissues for transplantation in clinical and experimental practice.
gene therapies
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.
2018-08-06 | Latest Insights on the Etiology and Management of Primary Adrenal Insufficiency in Children.
Primary adrenal insufficiency (PAI) is a heterogeneous group of disorders characterized by an impaired production of cortisol and other steroid hormones by the adrenal cortex. Most of the causes of PAI in childhood are inherited and monogenic in origin and are associated with significant morbidity and mortality whenever the diagnosis and treatment is delayed. Therefore, early and accurate diagnosis would allow appropriate management for the patients and genetic counselling for the family. Congenital adrenal hyperplasia accounts for most cases of PAI in childhood, followed by abnormalities in the development of the adrenal gland, resistance to adrenocorticotropin hormone action and adrenal destruction. In recent years, the use of genome-wide, next-generation sequencing approaches opened new avenues for identifying novel genetic causes in the PAI spectrum. Understanding the genetic basis of adrenal disorders is key to develop innovative therapies for patients with PAI. The promising progress made in congenital adrenal hyperplasia treatment brings new perspectives for personalized treatment in children with PAI. The aim of this review is to characterize recent advances in the genetics and management of PAI in children.
other
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.
small molecules
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.
antibodies
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.
2014-04-10 | Oxytocin projections to the nucleus of the solitary tract contribute to the increased meal-related satiety responses in primary adrenal insufficiency.
Anorexia is a common clinical manifestation of primary adrenal gland failure. Adrenalectomy (ADX)-induced hypophagia is reversed by oxytocin (OT) receptor antagonist and is associated with increased activation of satiety-related responses in the nucleus of the solitary tract (NTS). This study evaluated OT projections from the paraventricular nucleus of the hypothalamus (PVN) to the NTS after ADX and the effect of pretreatment with intracerebroventricular injection of an OT receptor antagonist ([d(CH2)5,Tyr(Me)(2),Orn(8)]-vasotocin; OVT) on the activation of NTS neurons induced by feeding in adrenalectomized rats. Adrenalectomized animals showed higher OT labelling in the NTS than the sham and the ADX with corticosterone replacement (ADX + B) groups. Adrenalectomized animals exhibited co-localization of the anterograde tracer Phaseolus vulgaris leucoagglutinin and OT in axons in the NTS as well as OT fibres apposing NTS neurons activated by refeeding. After vehicle pretreatment, compared with fasting, refeeding increased the numbers of Fos- and Fos + TH-immunoreactive neurons in the NTS in sham, ADX and ADX + B groups, with a higher number of these immunolabelled neurons in adrenalectomized animals. Compared with fasting conditions, refeeding also increased the activation of NTS neurons in OVT-pretreated sham, ADX and ADX + B groups, but there was no difference among the three experimental groups. These data demonstrate that OT is upregulated in projections to the NTS following ADX and that OT receptor antagonist reverses the greater activation of NTS neurons induced by feeding after ADX. The data indicate that OT pathways to the NTS contribute to higher satiety-related responses and, thus, to reduce meal size in primary adrenal insufficiency.
2012-12-18 | Adrenal steroidogenesis after B lymphocyte depletion therapy in new-onset Addison's disease.
A diagnosis of Addison's disease means lifelong dependence on daily glucocorticoid and mineralocorticoid therapy and is associated with increased morbidity and mortality as well as a risk of unexpected adrenal crisis. The objective of the study was to determine whether immunomodulatory therapy at an early stage of autoimmune Addison's disease could lead to preservation or improvement in adrenal steroidogenesis. This was an open-label, pilot study of B lymphocyte depletion therapy in new-onset idiopathic primary adrenal failure. Doses of iv rituximab (1 g) were given on d 1 and 15, after pretreatment with 125 mg iv methylprednisolone. Six patients (aged 17-47 yr; four females) were treated within 4 wk of the first diagnosis of idiopathic primary adrenal failure. Dynamic testing of adrenal function was performed every 3 months for at least 12 months. Serum cortisol levels declined rapidly and were less than 100 nmol/liter (3.6 μg/dl) in all patients by 3 months after B lymphocyte depletion. Serum cortisol and aldosterone concentrations remained low in five of the six patients throughout the follow-up period. However, a single patient had sustained improvement in both serum cortisol [peak 434 nmol/liter (15.7 μg/dl)] and aldosterone [peak 434 pmol/liter (15.7 ng/dl)] secretion. This patient was able to discontinue steroid medications 15 months after therapy and remains well, with improving serum cortisol levels 27 months after therapy. New-onset autoimmune Addison's disease should be considered as a potentially reversible condition in some patients. Future studies of immunomodulation in autoimmune Addison's disease may be warranted.
2011-06-22 | Cellular immunity and immunopathology in autoimmune Addison's disease.
Autoimmune adrenocortical failure, or Addison's disease, is a prototypical organ-specific autoimmune disorder. In common with related autoimmune endocrinopathies, Addison's disease is only manageable to a certain extent with replacement therapy being the only treatment option. Unfortunately, the available therapy does not restore the physiological hormone levels and biorhythm. The key to progress in treating and preventing autoimmune Addison's disease lies in improving our understanding of the predisposing factors, the mechanisms responsible for the progression of the disease, and the interactions between adrenal antigens and effector cells and molecules of the immune system. The aim of the present review is to summarize the current knowledge on the role of T cells and cellular immunity in the pathogenesis of autoimmune Addison's disease.
2006-02-09 | Analysis of the interaction between human steroid 21-hydroxylase and various monoclonal antibodies using comparative structural modelling.
To study the interaction between human steroid 21-hydroxylase (21-OH) and monoclonal antibodies (MAbs) to 21-OH directed to 3 different epitopes recognised by 21-OH autoantibodies characteristic of autoimmune Addison's disease. Build comparative structural models of 21-OH, 21-OH MAbs and complexes of 21-OH-21-OH MAbs and study the effects of 21-OH MAbs on 21-OH enzyme activity. Then, analyse the relationship between sites important for binding of 21-OH MAbs and 21-OH autoantibodies and sites important for 21-OH enzyme activity. Variable (V) regions of 21-OH MAbs (M21-OH1, M21-OH3, M21-OH5) were sequenced and models of the MAbs built using structures of antibodies in the database as templates. A comparative model of 21-OH was built using the crystal structure of rabbit cytochrome p450 2c5/3LVdH as template. 21-OH enzyme activity was measured in terms of conversion of [3H]progesterone to deoxycorticosterone and the effect of purified MAb IgGs on 21-OH enzyme activity was assessed. M21-OH1, M21-OH3 and control MAb had no effect on 21-OH enzyme activity with 88.8% +/- 24% (n = 6), 86.7% +/- 7.6% (n = 6) and 86.5% +/- 10.6% (n = 6) of activity remaining in the presence of the respective IgGs. This was consistent with the epitopes for M21-OH1 and M21-OH3 being located distant from 21-OH enzyme active sites in our 21-OH model. The epitope for M21-OH5 which inhibited 21-OH enzyme activity (48.5 +/- 8.3% activity remaining; P < 0.001 compared with control MAb IgG) was found close to the redox protein binding site in our 21-OH model. A comparative model of 21-OH has been produced. Analysis of experimental data in the context of the model suggests that M21-OH5 inhibits 21-OH enzyme activity through interference with redox protein binding.
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).
2025-10-01 | MON-500 Adrenal Bioprinted Tissue Therapeutics Restore Function in Murine Models of Primary Adrenal Insufficiency
Abstract Disclosure: H. Soliman: None. Z.A. Bazzi: None. O. Nemirovsky: None. S. Keshvani: None. C. Song: None. N.A. Chan: None. S. Gicole: None. R.B. Jalili: None. S. Wadsworth: None. C.T. Dickman: None. Primary adrenal insufficiency, caused by either autoimmune Addison’s disease or congenital adrenal hyperplasia, is a life-threatening condition that requires lifelong adrenal hormone replacement. Current hormone replacement therapies have a high treatment burden and fail to mimic the natural circadian rhythms of hormone secretion. Transplanting functional adrenal cells has the potential to restore the natural hypothalamic-pituitary-adrenal (HPA) axis feedback loop, enabling dynamic hormonal regulation that mimics physiological function rather than relying on fixed-dose steroid replacement. An allogeneic cell therapy that achieves this without the need for chronic immune suppression could be a breakthrough in the treatment of primary adrenal insufficiency. Adrenal Bioprinted Tissue Therapeutics (BTTs) were developed using primary human adrenocortical cells with Aspect Biosystems’ full-stack tissue therapeutic platform, which incorporates proprietary bioprinting technology. These cells were encapsulated in a cell-supporting biomaterial with an immunoprotective outer shell. In vitro assessment of these BTTs indicated that the encapsulated adrenal cells were viable for extended durations and able to sense exogenously administered adrenocorticotrophic hormone (ACTH) and respond by releasing cortisol. Implantation of these xenogeneic adrenal BTTs in adrenalectomized mice led to a dose-dependent, rapid, marked, and sustained responsive elevation of plasma cortisol and reduction in plasma ACTH, as well as an increase in survival. There was a robust response to exogenously administered ACTH resulting in a significant increase in plasma cortisol in mice implanted with adrenal BTTs. ACTH responsive cortisol secretion was observed through study end at six months. To assess whether implanted adrenal BTTs respond to physiological circadian fluctuations in endogenous mouse ACTH levels, plasma cortisol and ACTH were measured mornings and evenings and showed that plasma cortisol levels followed the same secretion pattern as endogenous ACTH in the adrenalectomized mice, indicating responsiveness of the implanted BTTs to physiological fluctuations in ACTH. Adrenal BTTs retrieved from mice at termination after six months demonstrated high viability and remained responsive to in vitro incubation with ACTH. These results indicate that Aspect Biosystems’ adrenal BTTs can restore precise ACTH responsive adrenal function with appropriate circadian rhythm in in vivo models of primary adrenal insufficiency. Such an approach could revolutionize therapy for patients with primary adrenal insufficiency. Presentation: Monday, July 14, 2025
2025-10-01 | MON-471 Establishment of Adrenal Cortex Like Cells From Human Induced Pluripotent Stem Cells That Produce Adrenal Hormones
Abstract Disclosure: J. Thyagraj: None. M.M. Laronda: None. Adrenal insufficiency (AI) is a rare and chronic condition characterized by the adrenal cortex’s inability to secrete adequate amounts of steroid hormones. Since the adrenal cortex and the gonads originate from a common progenitor cell, adrenal morbidities can occur co-occur with differences in sex development (DSD/intersex), primary ovarian insufficiency or infertility. Disruptions in reproductive functions associated with adrenal co-morbidities can be difficult to diagnose until during or after puberty. Our lab is interested in studying pathways involved in adrenal hormone production within patients with disrupted reproductive functions caused by specific gene variants. We aimed to optimize a culturing system that generates human adrenal cortex like cells (hACLC) from human induced pluripotent stem cells (hiPSCs) and to establish the baseline hormone outputs of functional hACLC aggregates. Using the protocol ligand-based protocol by Sakata et al., hiPSCs were differentiated into adrenogonadal primordium-like cells then hACLCs. 14.06% of cells differentiated hACLC aggregates expressed the adrenal cortex cell surface protein DLK1. We cultured the aggregates in submerged culture (sub) with the published air-liquid interface (ALI) culture to choose a culture that facilitated maximum hormone production. The levels of cortisol were significantly lower in the ALI than in sub across all time intervals (20.442+/-1.84, 26.61+/-3.66), DHEA was significantly reduced over time in Sub (8.007+/-1.05, 7.349+/-1.14) but not ALI (5.380 +/- 0.5, 2.735 +/- 0.38) and there was no significant difference in estradiol production in either condition (217+/-29.7, 118+/-923). Neither culture condition produced detectable levels of aldosterone. As submerged culture system performed better and maintained their aggregate form, we continued experiments with this method and measured their baseline hormone ranges over a week. The hACLC aggregates produced the most DHEA (14.20 ng/ml) on day 22 which significantly decreased by day 25 and 28 (7.930-14.20 ng/ml). The differentiated hACLCs also produced cortisol in the range of 20.44-26.62 ng/ml. Overall, the levels of cortisol remained consistent in all time intervals. Estradiol production also peaks at day 22 (638.2 pg/ml) followed by a significant decline on day 25 and day 28. On average, a hACLC aggregate produced up to 14.20 ng/ml DHEA, 26.62 ng/ml cortisol and 638.2 pg/ml estradiol. Our findings support a previously published protocol for generating hACLCs from hiPSCs with adjustments to increase secretion of cortisol, DHEA and estradiol. Ongoing research is advancing these tools to understand how patient-specific gene variants can influence adrenal cortex development and hormone production and may act as a predictive measure of pubertal-onset adrenal insufficiency. Presentation: Monday, July 14, 2025
2024-07-25 | In Vivo Formation of Adrenal Organoids in a Novel Porcine Model of Adrenocortical Cell Transplantation.
Recognizing the limitations of current therapies for Addison's disease, novel treatments that replicate dynamic physiologic corticosteroid secretion, under control of ACTH, are required. The aim of these experiments was to evaluate the feasibility of adrenocortical cell transplantation (ACT) in a large animal model, adapting methods successfully used for intracutaneous pancreatic islet cell transplantation, using a fully biodegradable temporizing matrix. Autologous porcine ACT was undertaken by bilateral adrenalectomy, cell isolation, culture, and intracutaneous injection into a skin site preprepared using a biodegradable temporizing matrix (BTM) foam. Hydrocortisone support was provided during adrenocortical cell engraftment and weaned as tolerated. Blood adrenocortical hormone concentrations were monitored, and the transplant site was examined at endpoint. Outcome measures included cellular histochemistry, systemic hormone production, and hydrocortisone independence. Transplanted adrenocortical cells showed a capability to survive and proliferate within the intracutaneous site and an ability to self-organize into discrete tissue organoids with features of the normal adrenal histologic architecture. Interpretation of systemic hormone levels was confounded by the identification of accessory adrenals and regenerative cortical tissue within the adrenal bed postmortem. Corticosteroids were unable to be completely ceased. ACT in a large animal model has not previously been attempted, yet it is an important step toward clinical translation. These results demonstrate rhe potential for ACT based on the development of adrenal organoids at the BTM site. However, the inability to achieve clinically relevant systemic hormone production suggests insufficient function, likely attributable to insufficient cells through delivered dose and subsequent proliferation.
2024-06-09 | Effect of resuscitation of cryopreserved porcine adrenal glands at 26 °C on their recovery and functioning under xenotransplantation.
The study is devoted to the effect of lowered resuscitation temperature (26 °C) on cryopreserved porcine adrenal glands functional activity in vitro and in vivo under xenotransplantation. The adrenals were collected from newborn pigs, cryopreserved with 5 % DMSO at a rate of 1 °C/min, resuscitated at 26 or 37 °C for 48 h (5 % CO2, DMEM), embedded into small intestinal submucosa, and transplanted to bilaterally adrenalectomized rats. It has been shown that the glands resuscitated at 26 °C have suppressed free-radical processes and can produce cortisol and aldosterone in vitro, and may lead to elevated blood levels of these hormones. Moreover, the adrenal grafts maintain blood glucose levels and promote the formation of glycogen stores. Thus, the resuscitation at 26 °C can improve the quality of grafts and favor the introduction and application of the cryopreserved organs and tissues for transplantation in clinical and experimental practice.
gene therapies
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.
2018-08-06 | Latest Insights on the Etiology and Management of Primary Adrenal Insufficiency in Children.
Primary adrenal insufficiency (PAI) is a heterogeneous group of disorders characterized by an impaired production of cortisol and other steroid hormones by the adrenal cortex. Most of the causes of PAI in childhood are inherited and monogenic in origin and are associated with significant morbidity and mortality whenever the diagnosis and treatment is delayed. Therefore, early and accurate diagnosis would allow appropriate management for the patients and genetic counselling for the family. Congenital adrenal hyperplasia accounts for most cases of PAI in childhood, followed by abnormalities in the development of the adrenal gland, resistance to adrenocorticotropin hormone action and adrenal destruction. In recent years, the use of genome-wide, next-generation sequencing approaches opened new avenues for identifying novel genetic causes in the PAI spectrum. Understanding the genetic basis of adrenal disorders is key to develop innovative therapies for patients with PAI. The promising progress made in congenital adrenal hyperplasia treatment brings new perspectives for personalized treatment in children with PAI. The aim of this review is to characterize recent advances in the genetics and management of PAI in children.
other
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.
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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 |
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