Hereditary adrenocortical unresponsiveness to adrenocorticotropin (HAUA) is a rare congenital disorder characterized by isolated glucocorticoid deficiency with preserved mineralocorticoid production. HAUA encompasses familial glucocorticoid deficiency (FGD) and triple A syndrome (AAAS) and is caused by autosomal recessive defects in ACTH-signaling-related genes, including MC2R, MRAP, AAAS, NNT, TXNRD2, and MCM4. To clarify the current clinical characteristics of HAUA (including FGD and AAAS) in Japan, we conducted a nationwide questionnaire-based survey. The primary survey identified the number of affected patients, and the secondary survey collected detailed clinical information. Fifteen patients were identified from 12 institutions. Detailed clinical data were obtained from nine patients (mean age, 40.6 years). Most patients developed symptoms during childhood [3.75 (0-8) years]. Seven presented with chronic adrenal insufficiency, and two experienced life-threatening events, hypoglycemia or encephalopathy. Genetic confirmation was obtained in four cases. All patients received glucocorticoid replacement therapy (mean hydrocortisone-equivalent dose, 13.0 mg/m[2]/day). Notably, 50% of adult patients were obese (BMI ≥25 kg/m[2]), although no clear association between glucocorticoid dose and BMI was observed. Despite the limited cohort size, this study provides detailed clinical information on HAUA (including FGD and AAAS) in Japan and suggests a potential risk of obesity in long-term management.

Opioid-induced adrenal insufficiency (OIAI) is a known, but often overlooked complication associated with chronic opioid use. It is important to recognize OIAI as, if untreated, can lead to increased morbidity and mortality.

Pathogenic variants in the autoimmune regulator (AIRE) cause autoimmune polyendocrine syndrome type 1 (APS-1), a rare primary immunodeficiency disease with symptoms including hypoparathyroidism, adrenal insufficiency, and chronic mucocutaneous candidiasis. AIRE increases the expression and presentation of tissue-specific genes expressing "self" antigens in the developing T cell niche, thus triggering the elimination of self-reactive T cells and preventing autoimmunity. Earlier diagnoses can benefit those with APS-1, and APS-1 diagnosis by AIRE sequencing is increasingly common. However, two-thirds of reported clinical variants are missense, and more than half of these are variants of uncertain significance (VUSs). Cell-based variant functional assays can provide strong evidence toward more informative variant classification, but these are carried out reactively, often years after clinical presentation. By contrast, proactively assessing all possible missense variants could provide immediate evidence to guide genetic diagnosis, even for never-before-seen variants. Here, we used an insulin-promoter-driven reporter to proactively assess the function of 9,790 AIRE missense variants. The resulting AIRE variant effect map both validates and extends current biochemical knowledge, concords with pathogenicity annotations, and provides proactive evidence for 70% of previously reported VUSs. Placing our map in the context of both an international APS-1 cohort and the UK Biobank revealed quantitative genotype-phenotype correlations. Moreover, evidence from our variant effect map resolved 32% of current VUSs. Together, our proactive resource of AIRE variant impacts offers the potential to improve outcomes via more rapid and definitive APS-1 diagnosis.

100 years ago in the U.S., tuberculosis was the most common cause of primary adrenal insufficiency (AI) (Addison's disease). Autoimmune adrenalitis is now responsible for 80-90% of AI in this country and Europe; nevertheless today, in the U.S. and certainly abroad, diverse infections can involve the adrenals in both the immunocompetent and immunocompromised and potentially produce AI. Such infections range widely: bacterial (e.g., Mycobacterium tuberculosis, in particular), fungal (e.g., histoplasmosis), viral and even protozoal (e.g., severe Plasmodium falciparum malaria). Suspecting AI, especially if chronic, is not straightforward, delays in AI diagnosis may reach > 6 months in 50%, and 50-75% of patients initially present in overt adrenal crisis. Diagnosing adrenal involvement by an infection may be drawn out, typically requires careful imaging, a thorough infectious disease evaluation, and may require adrenal biopsy.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED/APS-1) is a monogenic autoimmune disorder of impaired central tolerance classically diagnosed by the presence of 2 out of 3 classic triad manifestations: chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency. However, many patients develop non-triad manifestations years earlier, delaying recognition and care. In 2016, we proposed expanded diagnostic criteria incorporating 3 early clinical manifestations - APECED rash, autoimmune enteritis, and enamel hypoplasia - based on observations in 35 North American patients. Here, we provide further support for the clinical utility of these expanded diagnostic criteria in independent cohorts of 57 American and 12 European patients enrolled in a prospective natural history study at the NIH. Across all cohorts, the expanded diagnostic criteria decreased the time to diagnosis by half relative to the classic diagnostic criteria. Patients exhibited an enrichment of early non-endocrine autoimmune manifestations, underscoring disease heterogeneity and the potential for developing organ-specific autoimmunity before endocrine failure. These findings demonstrate the clinical utility of the expanded APECED diagnostic criteria and support the notion that their adoption might enable earlier disease recognition and timely immunomodulatory therapy to improve long-term outcomes.

Immune thrombocytopenia (ITP) is an autoimmune cytopenia that may occur in association with lymphoproliferative disorders. In such cases, treatment of the underlying malignancy may influence platelet recovery. CD20xCD3 bispecific antibodies have become important options for relapsed or refractory diffuse large B-cell lymphoma (DLBCL), but their effect on coexisting autoimmune cytopenias is not well defined. We report the case of an 81-year-old woman with relapsed DLBCL arising from an underlying marginal zone lymphoma and longstanding ITP. She achieved complete metabolic remission with initial rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone (R-CHOP) and again with polatuzumab vedotin, bendamustine, and rituximab (Pola-BR) after the first relapse, but her thrombocytopenia persisted. Following a second relapse, she was treated with epcoritamab, a CD20xCD3 bispecific T-cell engager. Her course was complicated by steroid-induced hyperglycemia, grade 1 cytokine release syndrome, and adrenal insufficiency, but she achieved complete metabolic remission on follow-up positron emission tomography. Her platelet counts also markedly improved, increased to 142 K/mcL (140-450 K/mcL) from a chronically thrombocytopenic baseline. This case highlights the possibility that bispecific therapy may simultaneously control relapsed DLBCL and secondary ITP through depletion of pathogenic CD20-expression B cells, as well as exhaustion and redirection of T-cells. Further study is needed to determine whether this represents a reproducible therapeutic effect.

Premature ovarian insufficiency (POI) is increasingly viewed not merely as an ovarian-centered reproductive disorder but as a systemic neuroendocrine condition characterized by multilevel dysregulation spanning the central nervous system, ovaries, immune system, metabolism, and stress-response networks. Beyond disruption of the hypothalamic-pituitary-ovarian (HPO) axis, POI involves impairment of the KNDy-GnRH network, chronic inflammatory activation, gut-ovary axis-related metabolic disturbances, and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system. Acupuncture has been proposed as a multi-target neuroendocrine intervention whose effects may extend beyond local ovarian regulation toward broader physiological modulation. Available evidence suggests that acupuncture may influence reproductive hormone regulation, including follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2), and may be associated with changes in ovarian reserve-related indicators and menstrual function. Some studies also report effects on stress-related endocrine activity, autonomic function, and emotional symptoms, potentially involving inflammatory and metabolic pathways. Experimental evidence further suggests possible effects on hypothalamic neuropeptide signaling, ovarian oxidative stress and inflammation, and systemic stress-metabolic pathways. However, the current evidence is limited by small sample sizes, short follow-up durations, and methodological variability, and there is insufficient evidence regarding clinically meaningful long-term outcomes. Overall, while acupuncture demonstrates biological plausibility and preliminary therapeutic potential, its clinical efficacy in POI remains inconclusive. Further well-designed, large-scale studies incorporating standardized outcome measures and long-term endpoints are required to evaluate its effectiveness and clarify its mechanisms. This review aims to delineate the systemic neuroendocrine mechanisms and potential clinical roles of acupuncture in POI, providing a conceptual framework to guide future research and integrative therapeutic strategies.

Glucocorticoid-induced adrenal insufficiency (GIAI) can persist for months after discontinuation of chronic corticosteroid therapy, placing patients at risk for life-threatening adrenal crises. This prolonged suppression has been attributed primarily to delayed restoration of hypothalamic-pituitary signaling based on indirect measures of central axis activity. To identify the rate-limiting site of hypothalamic-pituitary-adrenal (HPA) axis recovery, we evaluated the timing of functional and histologic recovery at each node of the axis following 8 weeks of dexamethasone (DEX) treatment in adult, male mice. Dexamethasone administration fully suppressed HPA axis activity. Unexpectedly, within 1 week of DEX withdrawal, hypothalamic Crh mRNA and plasma adrenocorticotropic hormone (ACTH) rebounded above control levels, whereas corticosterone (CORT) remained suppressed for an additional 7 weeks. Dexamethasone-treated adrenals were markedly atrophic and contained large clusters of lipid-filled macrophages. Even after adjusting for macrophage content, CORT secretion was disproportionately low relative to the remaining adrenocortical cell mass despite supraphysiologic ACTH stimulation. The adrenal is thus the principal site of postwithdrawal GIAI, involving adrenocortical cell loss and a superimposed defect in steroidogenesis. We next tested whether preserving adrenal trophic signaling during glucocorticoid exposure could prevent GIAI. Adrenal function recovered more slowly in mice treated with DEX and daily cosyntropin (a synthetic ACTH analog) compared to those treated with DEX alone. In contrast, mice with nonsuppressible endogenous ACTH due to targeted hypothalamic deletion of the glucocorticoid receptor maintained normal adrenal architecture and steroidogenic capacity despite prolonged DEX treatment. Pharmacologic treatments that mimic sustained trophic signaling to the adrenal during chronic glucocorticoid treatment may thus prevent GIAI.

Autoimmune polyendocrine syndrome type 1 (APS-1), also known as Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is a monogenic disorder of impaired central immune tolerance classically inherited in an autosomal recessive manner and caused by biallelic deleterious variants in the autoimmune regulator (AIRE) gene, leading to chronic mucocutaneous candidiasis (CMC) and multiorgan autoimmunity. Although hypoparathyroidism and adrenal insufficiency are among the most common and clinically consequential manifestations, it is increasingly recognized that several non-endocrine features - including autoimmune enteritis, urticarial eruption (termed APECED rash), enamel hypoplasia, autoimmune pneumonitis, and autoimmune hepatitis - often precede classical endocrinopathies, contributing to delayed diagnosis. Endocrinologists are often among the first specialists to encounter these patients and play a central role in early recognition and longitudinal care. Here we present five cases that illustrate the expanding clinical spectrum of APS-1, novel genetic mechanisms, key diagnostic challenges, and emerging therapeutic approaches. These cases highlight the importance of applying expanded clinical criteria and recognizing the limitations of standard genetic testing, including the need to consider deep intronic and dominant-negative AIRE variants. Finally, evolving mechanistic insights have established APS-1 as an interferon-γ (IFN-γ)-driven disease, providing a rationale for emerging targeted immunomodulatory therapies such as Janus kinase (JAK) inhibition with ruxolitinib. Early diagnosis enables proactive surveillance and may allow timely initiation of disease-modifying treatment.

Hypoadrenocorticism in cats is a rare endocrine disorder that should be considered in patients presenting with vague, intermittent, or waxing and waning clinical signs. Chronic gastrointestinal signs, poor growth, or episodes of hypovolemic shock should raise clinical suspicion. British Shorthair cats may be overrepresented among affected cats, and clinicians should be particularly alert when this breed presents with compatible signs. Definitive diagnosis requires an ACTH stimulation test, which should be performed prior to the initiation of any glucocorticoid treatment to avoid diagnostic interference. In clinically stable cats, baseline cortisol measurement may be used as an initial screening tool. However, as no feline-specific thresholds have been validated, the commonly used cut-off of >2 µg/dL (>55 nmol/L) to rule out hypoadrenocorticism should be interpreted with caution, as it may be less reliable than in dogs. Long-term management involves lifelong glucocorticoid replacement, typically using oral prednisolone. Cats generally require higher maintenance doses than dogs to maintain clinical stability. Mineralocorticoid deficiency is managed with subcutaneous administration of an extended-release desoxycorticosterone preparation (Zycortal®) given monthly at a starting dose of 2,2 mg/kg - substantially higher than canine doses. As an alternative, daily oral fludrocortisone acetate (Florinef® or Astonin®H) could be used at 0,01-0,02 mg/kg/day in selected cases. Regular monitoring of sodium and potassium levels is essential to adjust mineralocorticoid dosages and optimize treatment. Because affected cats cannot mount an adequate stress response, additional glucocorticoid supplementation («glucocorticoid boost») is required during stressful situations or concurrent illness. Owners must be educated about the signs of adrenal crisis, which can be more subtle and difficult to recognize in cats compared to dogs. Emphasis should be placed on consistent medication administration and routine veterinary monitoring to ensure long-term disease control and quality of life.

Chronic opioid use disrupts the female endocrine system, affecting the hypothalamic-pituitary-gonadal (HPG), hypothalamic-pituitary-adrenal (HPA), and hypothalamic-pituitary-thyroid (HPT) axes. In women, these disruptions manifest as menstrual irregularity, infertility, early menopause, reduced bone mineral density, adrenal insufficiency, and altered mood and sexual function. Despite the magnitude of the opioid epidemic and its impact on women of reproductive age, the existing evidence base is overwhelmingly male: across the major studies of opioid-induced endocrinopathy reviewed here, 99.5 percent of participants were male. Sex-specific mechanisms, prevalence estimates, and clinical thresholds therefore remain poorly defined, and current guidelines do not adequately address the reproductive, skeletal, and adrenal consequences of chronic opioid exposure in women. This review synthesizes available human and preclinical evidence on opioid-induced endocrine dysfunction in women across the lifespan, distinguishing established findings from hypotheses extrapolated from male or animal data. We propose a practical framework for routine endocrine screening of HPG, HPA, and HPT axis function, bone health, and fertility, and outline the roles of relevant specialties in multidisciplinary care. Available evidence suggests a substantial risk of endocrine dysfunction in women on chronic opioid therapy, but the precise prevalence remains unknown. Sex-sensitive research, guidelines, and routine screening are urgently needed to close this gap.