Glucocorticoid treatment and adrenal suppression in children: current view and open issues.

PURPOSE: Glucocorticoids (GCs) are commonly used for several acute and chronic pediatric diseases. However, chronic treatment may result in hypothalamic-pituitary-adrenal axis (HPA) dysfunction. Glucocorticoid-induced adrenal insufficiency (GI-AI) is indeed the most frequent cause of adrenal insufficiency (AI) in children, possibly resulting in a life-threatening event such as adrenal crisis (AC). It is generally underestimated, especially when using non-systemic glucocorticoid formulations. This review aims at summarizing current evidence on the effects of long-term GC treatment on the HPA axis, management of GC tapering and assessment of the HPA recovery. METHODS: We conducted a narrative review of the relevant literature focusing on pathogenic mechanisms, predictive factors, diagnosis and treatment of GI-AI. RESULTS: All types of GCs, whatever the route of administration, may have suppressive effects on the HPA axis, especially when compounds with higher potency and long half-life are used. Moreover, chronic GC administration is the most common cause of Cushing syndrome in children. In order to overcome the risk of GI-AI, slow withdrawal of GCs is necessary. When approaching the replacement dose, it is recommended to switch to shorter half-life formulations such as hydrocortisone. Assessment of HPA axis recovery with basal and stimulated cortisol levels may help detecting children at risk of AC that may require hydrocortisone supplementation. CONCLUSION: The management of GI-AI in children is challenging and many areas of uncertainty remain. Improving the knowledge on long-term GC effects on HPA in children, the management of steroid discontinuation and emergency dosing may help preventing GI-AI symptoms and acute hospital admission for AC.

Whitaker syndrome: A case report of autoimmune polyendocrine syndrome type 1 with dilated cardiomyopathy.

Key Clinical Message: This case report highlights dilated cardiomyopathy as a cardiovascular complication in autoimmune polyendocrine syndrome type 1 (APS-1), emphasizing the need for early recognition and a multidisciplinary approach. Comprehensive care and regular follow-up are crucial in managing these atypical presentations to optimize patient outcomes. Abstract: APS-1, also known as Whitaker syndrome, is characterized by a triad of mucocutaneous candidiasis, adrenal insufficiency, and hypoparathyroidism. This rare autosomal recessive disorder results from mutations in the autoimmune regulator (AIRE) gene. Cardiovascular and pulmonary manifestations in APS-1 are infrequently reported in the literature. We present a case of a 28-year-old male who presented with shortness of breath and pedal edema. Physical examination revealed alopecia, absence of eyebrows, hyperpigmentation on joints, oral candidiasis, and nail dystrophy. Echocardiography demonstrated dilated cardiomyopathy (DCM) and pericardial effusion. Chest x-ray showed left-sided pleural effusion. Laboratory investigations revealed hypocalcemia, hyperphosphatemia, low parathyroid hormone (PTH), low cortisol, and high adrenocorticotropic hormone (ACTH) levels. The combination of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and adrenal insufficiency confirmed the diagnosis of APS-1. To the best of our knowledge, this is the first Pakistani and second worldwide reported case of APS-1 presenting with such a combination of manifestations. Early recognition and multidisciplinary management are crucial for improving outcomes in these patients.

The multiple faces of autoimmune Addison's disease in children.

Primary adrenal insufficiency (PAI) is a rare medical condition, characterized by a deficiency in adrenal hormones. Although rare, PAI is a life-threatening disease requiring prompt recognition and treatment. However, symptoms of PAI are often non-specific and diagnosis can be challenging, causing frequent diagnostic delays. In adults, autoimmunity is the most common cause of PAI in industrialized countries, whereas in children, the most frequent etiology is represented by congenital defects of steroidogenesis and, in particular, by congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. A few recent case series from different countries have reported that autoimmunity is the second most common etiology of PAI in the pediatric age group. However, data on autoimmune PAI in children are still scant and the exact epidemiology, clinical manifestations, and long-term outcomes of this condition have yet to be defined. The scope of this review is to summarize the current knowledge on the etiology, presentation, and treatment of autoimmune PAI in childhood and to increase physicians' awareness of the signs that should raise an early suspicion of this condition.

Very early and severe presentation of Triple A syndrome - case report and review of the literature.

Triple A syndrome (TAS), also known as Allgrove syndrome (OMIM#231550), is a rare, autosomal recessive disorder characterized by the triad of alacrima, achalasia, and adrenal insufficiency. Additional neurological features may be present in two-thirds of patients, involving central, peripheral, and autonomic nervous system manifestations. TAS is caused by genetic alterations in the AAAS gene on chromosome 12q13, which encodes the nuclear pore complex protein termed ALADIN (ALacrima, Achalasia, aDrenal Insufficiency, and Neurologic disorder). ALADIN plays a crucial role in nucleocytoplasmic transport of specific proteins, including the transport of DNA repair proteins. TAS exhibits significant phenotypic variability in terms of symptom onset, frequency, and severity, often presenting with a progressive clinical course indicative of an underlying degenerative process. In this study, we report the case of an infant with exceptionally early and severe manifestations of triple A syndrome, with a review of the literature. Our patient exhibited the complete classical triad of TAS at six months of age, being among the youngest reported cases of the syndrome. The clinical course was complicated by severe involvement of the autonomic nervous system, neurogenic bladder, and recurrent urinary tract infections. Subsequently, the patient developed acute pancreatitis, leading to multiorgan dysfunction and a fatal outcome at 25 months of age. This case underscores the potential for atypical disease presentations and the need for clinical awareness in diagnosing and managing patients with TAS.

A review of the interplay between Takotsubo cardiomyopathy and adrenal insufficiency: Catecholamine surge and glucocorticoid deficiency.

BACKGROUND: Takotsubo Cardiomyopathy (TCM) is a transient heart condition often precipitated by stress and characterized by atypical ventricular ballooning. The interplay between TCM and Adrenal Insufficiency (AI), particularly the influence of catecholamine excess and glucocorticoid deficiency on TCM's pathogenesis in individuals with AI, warrants comprehensive exploration for a better understanding of TCM pathophysiology and establishment of potential therapeutic strategies. METHODS: We conducted an extensive literature search via PubMed and Google Scholar, targeting reports on AI, heart failure, and cardiomyopathy, supplemented by forward and backward citation tracing. We analyzed 46 cases from 45 reports, assessing the clinical presentation and outcomes in the context of AI categorization. RESULTS: In patients with AI, a glucocorticoid deficit appears to exacerbate the myocardial vulnerability to catecholamine toxicity, precipitating TCM. Most conditions were reversible; however, three pre-1990 cases resulted in irreversible outcomes. CONCLUSIONS: The investigation into the AI and TCM intersection highlights the pathogenic significance of catecholamines in the absence of glucocorticoids. The data consolidates the hypothesis that glucocorticoid scarcity exacerbates the cardiac susceptibility to catecholaminergic toxicity, potentially triggering TCM. The study affirms glucocorticoids' cardioprotective roles and elucidates how catecholamine surges contribute to TCM pathogenesis, suggesting strategic clinical management adjustments for AI patients to reduce TCM incidence.

A pathological complete response and adrenal insufficiency in a patient with advanced renal pelvic cancer treated with pembrolizumab.

Metastatic upper tract urothelial carcinoma (mUTUC) often has poor prognosis. While systemic therapy is the standard care for mUTUC, lymph node dissection (LND) combined with radical nephroureterectomy (RNU) can be considered for patients with only clinical locoregional LN, resulting in a surgical cure. However, since pembrolizumab, an anti-PD-1 monoclonal antibody, was approved for mUTUC patients, prognosis of mUTUC has been improved and some patients with immune-related adverse events have experienced a clinical complete response and a long-lasting therapeutic response without surgery. Thus, clarifying the optimal patient selection and timing for RNU + LND is warranted to avoid unnecessary surgery. We herein report the first unique case with a clinical N + UTUC patient who underwent RNU plus LND and showed a pathological complete response after discontinuation of pembrolizumab due to adrenal insufficiency. We feel that our case may affect the treatment strategy for N + UTUC in the era of ICIs.

Circulatory collapse requiring mechanical circulatory support in a child with autoimmune adrenal insufficiency: a case report.

BACKGROUND: We report a rare case of new onset autoimmune adrenal insufficiency in childhood, presenting with severe shock requiring mechanical circulatory support. In the current era of readily available imaging, laboratory and other diagnostic investigations, medical history and careful physical exam can often provide valuable diagnostic information for timely therapy. CASE PRESENTATION: A 7-year-old boy with a history of mild intermittent asthma, presented with severe cardiogenic shock requiring extracorporeal membrane oxygenation (ECMO). Bronzing of his entire body was noted on physical exam. Stress dose hydrocortisone was given for suspected adrenal insufficiency. After weaning from ECMO and extensive rehabilitation, the patient recovered and was discharged home. CONCLUSION: Primary adrenal insufficiency (PAI) should be considered in the context of physical exam and laboratory findings, even in the presence of circulatory shock.

Adrenal insufficiency - causes and laboratory diagnosis.

Adrenal insufficiency (AI) manifests as a clinical syndrome arising from either the direct impairment of adrenal glands, leading to primary AI characterized by deficiencies in glucocorticoids and mineralocorticoids, or adrenal cortex atrophy due to diminished adrenocorticotropic hormone (ACTH) stimulation, a consequence of hypothalamic and/or pituitary damage, resulting in secondary AI. The diagnosis of AI is based on clinical assessment and biochemical tests, including basal hormone level measurements and stimulation tests. In evaluating the results of laboratory tests, it is necessary to consider factors that may influence both pre-analytical and analytical phases, as well as the chosen methodology. Correct diagnosis of adrenal insufficiency and timely initiation of suitable replacement therapy are paramount. These steps are crucial not only for managing the condition but also to avert potentially life-threatening adrenal crises.

Immunotherapy Induced Adrenal Insufficiency: An Underdiagnosed Cause of Persistent Hypotension in Cancer.

Endocrinopathies following immunotherapy have infrequently been documented in the literature. Adrenal insufficiency is a rare consequence of pembrolizumab immunotherapy, with incidence reported to be between 0.98 and 1.3%. We present the case of a 34-year-old female with triple negative breast cancer on chemotherapy who presented with generalized weakness with tachycardia, tachypnea and hypotension unresponsive to fluids. Despite initial improvement with intravenous hydrocortisone and midodrine, the patient continued to be symptomatically hypotensive following discharge and required re-admission. AM cortisol level was found to be < 0.5 ug/dl and ACTH was <1.5 pg/dL, consistent with secondary adrenal insufficiency. CT abdomen and pelvis was unremarkable for adrenal pathology. Patient had been initiated on pembrolizumab (Keytruda) 4 months prior to presentation as part of neoadjuvant chemotherapy. The patient was provided supportive treatment with discharge on fludrocortisone, prednisone, and midodrine. This case reports an unusual consequence of immune checkpoint inhibitors, in which early diagnostic testing, identification, and management is critical.

C5a Induces Inflammatory Signaling and Apoptosis in PC12 Cells through C5aR-Dependent Signaling: A Potential Mechanism for Adrenal Damage in Sepsis.

The complement system is critically involved in the pathogenesis of sepsis. In particular, complement anaphylatoxin C5a is generated in excess during sepsis, leading to cellular dysfunction. Recent studies have shown that excessive C5a impairs adrenomedullary catecholamine production release and induces apoptosis in adrenomedullary cells. Currently, the mechanisms by which C5a impacts adrenal cell function are poorly understood. The PC12 cell model was used to examine the cellular effects following treatment with recombinant rat C5a. The levels of caspase activation and cell death, protein kinase signaling pathway activation, and changes in inflammatory protein expression were examined following treatment with C5a. There was an increase in apoptosis of PC12 cells following treatment with high-dose C5a. Ten inflammatory proteins, primarily involved in apoptosis, cell survival, and cell proliferation, were upregulated following treatment with high-dose C5a. Five inflammatory proteins, involved primarily in chemotaxis and anti-inflammatory functions, were downregulated. The ERK/MAPK, p38/MAPK, JNK/MAPK, and AKT protein kinase signaling pathways were upregulated in a C5aR-dependent manner. These results demonstrate an apoptotic effect and cellular signaling effect of high-dose C5a. Taken together, the overall data suggest that high levels of C5a may play a role in C5aR-dependent apoptosis of adrenal medullary cells in sepsis.

The Glucocorticoid Taper: A Primer for the Clinicians.

Glucocorticoid (GC) therapy can ameliorate debilitating and life-threatening symptoms in several inflammatory/immunological disorders. However, it can also cause significant side effects, especially with higher doses and longer duration of use. Therefore, GCs should be used at the lowest effective dose for the shortest possible time to minimise adverse effects. GC therapy may cause suppression of the endogenous hypothalamic-pituitary-adrenal (HPA) axis and abrupt discontinuation predisposes patients to features of GC-induced adrenal insufficiency. The practice of tapering GC therapy allows for recovery of the HPA axis while minimising the risk of a disease flare-up or symptoms of AI. Moderate-to-high dose GC therapy may be tapered rapidly to near-physiological doses while watching for features of disease reactivation. Once close to the physiological dose, tapering is slower and at longer intervals to allow for recovery of the HPA axis. It is important to use short- or intermediate-acting GC preparations such as hydrocortisone or prednisolone in physiological doses, administered in the morning to mimic the endogenous cortisol rhythm. A general principle to follow is that HPA axis recovery takes longer if the period of suppression has been long. In such cases, tapering should be slower over a few months to even a year. In select cases at high risk of AI or if symptoms appear during tapering, the decision to further taper and discontinue steroids may be based on testing of HPA axis function using basal and/or stimulated serum cortisol. All patients on exogenous steroids should be advised about the need for an appropriate increase in GC doses during acute medical or surgical illness and should carry a steroid alert card to avoid adrenal crisis.

NEW-ONSET PRIMARY ADRENAL INSUFFICIENCY AFTER COVID-19: CASE REPORT.

COVID-19 primarily affects the respiratory system. What comes after the disease is now a greater concern for the scientific world. It is remarkable for causing endocrine organ involvement, particularly in the adrenal glands. However, its effect on the adrenal gland has not been fully elucidated. A case of primary adrenal insufficiency after COVID-19. A 31-year-old female patient who presented with complaints of weakness, anorexia, nausea, recent onset of vomiting, dizziness, and low blood pressure for two months was admitted to the outpatient Department of Endocrinology and Metabolism. After discharge, the patient had routine follow-ups, and here we present the information on the first and seventh month after discharge. The patient was diagnosed with primary adrenal insufficiency with cortisol <0.054 µg/dL and adrenocorticotropic hormone >1200 pg/mL in the laboratory. In the non-contrast computed tomography taken in the adrenal protocol, the stem and leaves of both adrenal glands are significantly thinned and appear atrophic, the right adrenal gland is hardly distinguished. Hydrocortisone was started. All complaints were resolved within a week, except hyperpigmentation, which was resolved six months later after treatment. Our study support adrenal gland involvement due to COVID-19, further research is needed to obtain data on damage mechanisms.

Cognitive Impairment Caused by Isolated Adrenocorticotropic Hormone Deficiency Mimicking Dementia with Lewy Bodies.

A 73-year-old man who presented with nonspecific general symptoms and cognitive impairment was initially diagnosed with mild cognitive impairment due to dementia with Lewy bodies (DLB) based on a reduced blood flow in the parietal and occipital lobes on single-photon emission computed tomography (SPECT) imaging. However, the patient later presented with hyponatremia and hypoglycemia, leading to impaired consciousness, and was diagnosed with isolated adrenocorticotropic hormone deficiency (IAD). Hydrocortisone treatment improved the blood test scores and general symptoms, including cognitive impairment. IAD may show a DLB-like presentation on cerebral blood flow SPECT; therefore, caution is required for the correct diagnosis of IAD.

Factors influencing survival in sphingosine phosphate lyase insufficiency syndrome: a retrospective cross-sectional natural history study of 76 patients.

BACKGROUND: Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is a recently recognized inborn error of metabolism associated with steroid-resistant nephrotic syndrome as well as adrenal insufficiency and immunological, neurological, and skin manifestations. SPLIS is caused by inactivating mutations in SGPL1, encoding the pyridoxal 5'phosphate-dependent enzyme sphingosine-1-phosphate lyase, which catalyzes the final step of sphingolipid metabolism. Some SPLIS patients have undergone kidney transplantation, and others have been treated with vitamin B6 supplementation. In addition, targeted therapies including gene therapy are in preclinical development. In anticipation of clinical trials, it will be essential to characterize the full spectrum and natural history of SPLIS. We performed a retrospective analysis of 76 patients in whom the diagnosis of SPLIS was established in a proband with at least one suggestive finding and biallelic SGPL1 variants identified by molecular genetic testing. The main objective of the study was to identify factors influencing survival in SPLIS subjects. RESULTS: Overall survival at last report was 50%. Major influences on survival included: (1) age and organ involvement at first presentation; (2) receiving a kidney transplant, and (3) SGPL1 genotype. Among 48 SPLIS patients with nephropathy who had not received a kidney transplant, two clinical subgroups were distinguished. Of children diagnosed with SPLIS nephropathy before age one (n = 30), less than 30% were alive 2 years after diagnosis, and 17% were living at last report. Among those diagnosed at or after age one (n = 18), ~ 70% were alive 2 years after diagnosis, and 72% were living at time of last report. SPLIS patients homozygous for the SPL R222Q variant survived longer compared to patients with other genotypes. Kidney transplantation significantly extended survival outcomes. CONCLUSION: Our results demonstrate that SPLIS is a phenotypically heterogeneous condition. We find that patients diagnosed with SPLIS nephropathy in the first year of life and patients presenting with prenatal findings represent two high-risk subgroups, whereas patients harboring the R222Q SGPL1 variant fare better than the rest. Time to progression from onset of proteinuria to end stage kidney disease varies from less than one month to five years, and kidney transplantation may be lifesaving.

Adrenal Insufficiency following Stereotactic Ablative Radiotherapy (SAbR) of Adrenal Gland Metastases.

BACKGROUND: Adrenal metastases are often treated with stereotactic ablative radiation (SAbR). We aimed to assess the incidence, timing, and factors associated with the development of primary adrenal insufficiency (PAI) following SAbR. METHODS: A retrospective cohort study comprised 66 consecutive patients (73% men, median age 61 years) who underwent SAbR for adrenal metastasis. RESULTS: The series encompassed metastases from renal cell carcinoma (41%), lung tumors (38%), colorectal adenocarcinoma (9%), melanoma (5%), and others (7%). Median follow-up was 17 months from SAbR. Nine (14%) patients developed PAI at a median of 4.3 months (range, 0.7-20.2). The incidence of PAI was 44% in patients with prior adrenalectomy receiving unilateral SAbR, 44% with bilateral SAbR, 2% with unaffected contralateral gland, and 0% with bilateral metastases treated with unilateral SAbR. PAI was associated with prior adrenalectomy (odds ratio [OR] 32) and bilateral SAbR (OR 8.2), but not age, sex, metastasis size, or biological effective dose. Post-SAbR 6-month and 1-year local control rates were 82% and 75%, respectively. CONCLUSIONS: Patients undergoing SAbR for adrenal metastasis are at high risk of developing PAI. PAI is associated with bilateral SAbR and contralateral adrenalectomy. PAI is unlikely with a remaining unaffected adrenal gland or in the setting of bilateral adrenal metastases with unilateral SAbR.

Gabapentin-Induced Adrenal Insufficiency: The Hypothalamic-Pituitary-Adrenal Axis Stress Misresponse and Risk of Infection: A Case Report and Literature Review.

This literature review, in light of the presented case report, explores the complex interplay between gabapentin (GBP), a gamma-aminobutyric acid (GABA) analog, and the hypothalamic-pituitary-adrenal (HPA) axis in patients undergoing major surgical procedures. It specifically investigates the potential impact of GBP on cortisol levels, stress responses, and infection risk, illustrated by a detailed clinical case. This review combines a comprehensive literature search with a case report of a 17-year-old male with osteosarcoma who experienced transient adrenal insufficiency and infections while receiving GBP. The case is analyzed in the context of the existing literature on GBP and the HPA axis. The findings highlight the intricate relationship between GBP use, adrenal insufficiency, and infection susceptibility. It underscores the need for further research and clinical vigilance when prescribing GBP to patients with underlying medical conditions, particularly in the context of major surgical procedures. The review underscores the need for further research and clinical vigilance when prescribing GBP, particularly in perioperative settings. In conclusion, GBP's effects on the HPA axis and immune responses are complex and multifaceted. Clinicians should exercise caution when prescribing GBP, especially for patients with underlying conditions undergoing major surgery. Further research is needed to elucidate the mechanisms of GBP's influence on cortisol levels and stress responses.

Effectiveness and safety of continuous subcutaneous hydrocortisone infusion in managing adrenocortical insufficiency in adult patients: a systematic review.

Oral hormone replacement therapy has been and continues to be the cornerstone of adrenocortical insufficiency management. However, the introduction of continuous subcutaneous hydrocortisone infusion (CSHI) shows great potential for advancing the management of adrenocortical insufficiency. It resembles the circadian rhythm of physiological cortisol secretion and was shown to have a promising outcome in terms of quality of life (QOL) and clinical outcomes in the literature. We conducted a systematic search strategy including MEDLINE, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), and the online trials registers at ClinicalTrials.gov without geographic restrictions. Research investigations where self-reported quality of life (QOL) was assessed as a variable in adult individuals with confirmed adrenal disease, treated by CSHI, and results were presented in English. All articles included were published between 2014 and 2023, even though we had no timeframe limitations in our inclusion criteria. A total of six studies were included, with 63 subjects enrolled, and the average age was 40 years, a study showed a significant reduction in the average total daily dose of HC from 47.5 mg to 31.4 mg on CSHI, while other two studies estimated a reduction in the hospitalization rate due to adrenal crisis from 2.6 to 1.3 admissions per year on CSHI. Most of the studies on subjective well-being and quality of life have shown significant improvement. Overall, CSHI shows great potential as a treatment method for Adrenal insufficiency. It improves the quality of life and lowers hospitalization rates, resulting in increased patient satisfaction and acceptance. Additional comprehensive research is necessary to strengthen these discoveries, gain a deeper understanding of the effectiveness and safety of this treatment approach, and provide guidance for medical practitioners.

Successful laparotomic ethanol ablation for an adrenal tumour in a dog.

Adrenalectomy is the gold standard for canine adrenal tumours, but not always recommended due to patient age, underlying conditions and perioperative mortality. Ethanol ablation is an alternative in human medicine for poor surgical candidates. A 13-year-old neutered female toy-poodle with hypercortisolism presented with severe haematuria. Ultrasonography revealed left adrenal and right kidney tumours. Due to high surgical risk, simultaneous laparotomic right nephroureterectomy and ethanol ablation of the left adrenal tumour were performed. Post-ethanol injection complications included transient hypertension and arrhythmia, which resolved spontaneously. The adrenal tumour size decreased within 2.5 months, and cortisol levels normalised within 8 days, remaining stable for 12 months. No hypercortisolism signs were observed without trilostane until death from renal insufficiency. Autopsy showed that the ablated left adrenal gland was an adrenocortical tumour and had shrunk. Ethanol ablation may be a feasible alternative to adrenalectomy for high-risk canine patients.

Sheehan Syndrome Unmasked by Adrenal Crisis Secondary to Severe Dengue Fever.

Background: Sheehan syndrome is the infarction of a pituitary gland that has been physiologically enlarged as a result of postpartum bleeding. Agalactorrhea and amenorrhea are classic symptoms, but a constellation of manifestations occurs in both the acute and chronic forms. These manifestations can remain largely nonemergent unless Sheehan syndrome is complicated by severe adrenal dysfunction secondary to an inciting event such as dengue. We present a case of Sheehan syndrome that was uncovered in a patient with a dengue infection presenting as adrenal crisis. Case Report: A 45-year-old female presented with symptoms of acute gastroenteritis and severe dehydration. Her medical history was significant for secondary amenorrhea for 14 years after her last delivery followed by symptoms of endocrine dysfunction. At presentation, the patient was in adrenal crisis with hypotension, hypoglycemia, and hyperthermia. Dengue nonstructural protein 1 antigen was positive, along with signs of plasma leakage. Bloodwork showed bicytopenia with abnormal liver enzymes. Ultrasonography and computed tomography of the abdomen were suggestive of serositis with acalculous cholecystitis. Magnetic resonance imaging of the brain revealed an empty sella. Anterior pituitary hormone levels were significantly decreased with low serum cortisol, and the patient's thyroid profile analysis suggested secondary hypothyroidism. The final diagnosis was Sheehan syndrome presenting as adrenal crisis precipitated by severe dengue fever. The patient was managed conservatively and discharged on hormone supplement therapy. Conclusion: Sheehan syndrome is an important cause of panhypopituitarism in the developing world. Knowledge of Sheehan syndrome is important to help prevent its occurrence and reduce its resultant multifactorial effects.

Long COVID and pituitary dysfunctions: a bidirectional relationship?

Long COVID is a novel emerging syndrome known to affect multiple health areas in patients previously infected by SARS-CoV-2 markedly impairing their quality of life. The pathophysiology of Long COVID is still largely poorly understood and multiple mechanisms were proposed to underlie its occurrence, including alterations in the hormonal hypothalamic-pituitary axes. Aim of this review is to present and discuss the potential negative implications of these hormonal dysfunctions in promoting and influencing the Long COVID syndrome. To date, the hypothalamic-pituitary-adrenal axis is the mostly investigated and several studies have reported a prolonged impairment leading to mild and subclinical forms of central adrenal insufficiency. Few data are also available regarding central hypogonadism, central hypothyroidism and growth hormone (GH) deficiency. A high prevalence of central hypogonadism in COVID-19 survivors several months after recovery was consistently reported in different cohorts. Conversely, very few data are available on the hypothalamic-pituitary-thyroid axis function that was mainly shown to be preserved in COVID-19 survivors. Finally, a potential impairment of the hypothalamic-GH axis in Long COVID has also been reported. These data altogether may suggest a novel possible pituitary-centred pathophysiological view of Long COVID syndrome which if confirmed by large clinical studies may have relevant implication for the diagnostic and therapeutic approach at least in a subset of patients with the syndrome.