An update on the endocrine manifestations of antiphospholipid syndrome.

Antiphospholipid Syndrome (APS), characterized by hypercoagulability and pregnancy morbidity, poses a significant clinical challenge when involving organ systems, such as the endocrine system. APS can directly and indirectly influence the anterior and posterior lobes of the pituitary gland. The thyroid gland exhibits involvement, especially in patients with positive anticardiolipin antibodies, yet the clinical significance of the relationship with APS remains elusive. The pancreas, often overlooked, manifests in diverse ways, from pancreatitis to implications in diabetes. Adrenal insufficiency emerges as a common endocrine manifestation of APS, with adrenal hemorrhage or infarction being a presenting manifestation. Adrenal gland involvement has also been reported in the context of catastrophic APS. Pregnancy complications and infertility might be effects of APS on the female ovaries, while testicular torsion and decreased sperm concentration and total sperm count have been reported as rare effects of APS on male testes.

Should we routinely assess hypothalamic-pituitary-adrenal axis in pediatric patients with Prader-Willi syndrome?

Background: It has been reported that central adrenal insufficiency (CAI) in pediatric patients (pts) with Prader-Willi syndrome (PWS) may be a potential cause of their sudden death. In addition, the risk of CAI may increase during treatment with recombinant human growth hormone (rhGH). Objective: To prevent both over- and undertreatment with hydrocortisone, we evaluated the prevalence of CAI in a large multicenter cohort of pediatric pts with PWS analyzing adrenal response in the low-dose ACTH test (LDAT) and/or the glucagon stimulation test (GST) and reviewing the literature. Methods: A total of 46 pts with PWS were enrolled to the study, including 34 treated with rhGH with a median dose of 0.21 mg/kg/week. LDAT was performed in 46 pts, and GST was carried out in 13 pts. Both tests were conducted in 11 pts. The tests began at 8:00 a.m. Hormones were measured by radioimmunoassays. Serum cortisol response >181.2 ng/mL (500 nmol/L) in LDAT and >199.3 ng/mL (550 nmol/L) in GST was considered a normal response. Additionally, cortisol response delta (the difference between baseline and baseline) >90 ng/mL and doubling/tripling of baseline cortisol were considered indicators of normal adrenal reserve. Results: Three GSTs were not diagnostic (no hypoglycemia obtained). LDAT results suggested CAI in four pts, but in two out of four pts, and CAI was excluded in GST. GST results suggested CAI in only one patient, but it was excluded in LDAT. Therefore, CAI was diagnosed in 2/46 pts (4.3%), 1 treated and 1 untreated with rhGH, with the highest cortisol values of 162 and 175 ng/dL, but only in one test. However, in one of them, the cortisol delta response was >90 ng/mL and peak cortisol was more than tripled from baseline. Finally, CAI was diagnosed in one patient treated with rhGH (2.2%). Conclusion: We present low prevalence of CAI in pediatric pts with PWS according to the latest literature. Therefore, we do not recommend to routinely screen the function of the hypothalamic-pituitary-adrenal axis (HPAA) in all pts with PWS, both treated and untreated with rhGH. According to a review of the literature, signs and symptoms or low morning ACTH levels suggestive of CAI require urgent and appropriate diagnosis of HPAA by stimulation test. Our data indicate that the diagnosis of CAI should be confirmed by at least two tests to prevent overtreatment with hydrocortisone.

Pituitary Complications of Checkpoint Inhibitor Use.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy but are associated with a risk of endocrine immune-related adverse events (irAEs), including pituitary complications. Autoimmune hypophysitis, traditionally a rare diagnosis, has become a more frequently encountered clinical entity with the emergence of antitumor immunotherapy. This mini-review aims to consolidate current knowledge, encompassing the epidemiology, pathophysiology, clinical presentation, diagnosis, and management of pituitary complications of ICI use.

The existence of adrenal insufficiency in patients with COVID-19 pneumonia.

Introduction: Infection with SARS-CoV-2 virus may result in long COVID, a syndrome characterized by symptoms such as dyspnea, cardiac abnormalities, cognitive impairment, and fatigue. One potential explanation for these symptoms is hypocortisolism. Objective: To evaluate the prevalence of hypocortisolism in patients with a history of COVID-19 pneumonia. Methods: Cross-sectional study of patients who were aged ≥18 years and had a 3-month history of radiography-confirmed COVID-19 pneumonia. Exclusion criteria included current or previous treatment with glucocorticoids and use of an oral contraceptive. Adrenal function was evaluated using a low dose (1ug) corticotropin stimulation test (CST). Serum cortisol levels were measured at 0, 30, and 60 minutes, and baseline plasma ACTH was also measured. Results: Of the 41 patients enrolled, the median age was 62 years, 17 (42%) were female, and all 41 (100%) had severe pneumonia at baseline. Eleven patients (27%) had hypocortisolism, as evidenced by peak cortisol of less than 402.81 nmol/l after low dose (1 µg) CST. Of these 11 patients, 10 (91%) had secondary hypocortisolism (median ACTH 6.27 pmol/L, range 4.98-9.95 pmol/L) and one had primary hypocortisolism (mean ACTH 32.78 pmol/L). Six of the 11 patients with hypocortisolism (54.5%) reported symptoms of persistent fatigue and 5 (45.5%) required regular glucocorticoid replacement. Conclusions: Our results suggest that hypocortisolism, predominantly caused by pituitary disruption, may emerge after SARS-CoV-2 infection and should be considered in patients with a history of COVID-19 pneumonia with or without clinical hypocortisolism.

Late-onset Schmidt's Syndrome Presenting with Severe Hyponatremia: A Case Report.

BACKGROUND: Schmidt's syndrome (SS) is a subtype of polyglandular autoimmune syndrome type-2 combining autoimmune thyroiditis (AIT) and autoimmune Addison's disease (aAD). It occurs most frequently in young adult females, and aAD is the most common initial manifestation [1]. We present a rare case of SS with late-onset aAD and severe hyponatremia as the first sign. CASE REPORT: A 73-year-old woman presented to the emergency department (ED) with a 10-day history of vomiting, diarrhea, and altered mental status. Her past medical history was remarkable for AIT and hypokinetic cardiomyopathy. Moreover, she had recently undergone a 2-week course of corticosteroid therapy for vertiginous symptoms, reporting subjective well-being. In ED, she appeared confused and hypotensive. Blood tests revealed a sodium level of 99 mEq/l with normal potassium. Initial treatment with saline infusions were started, followed by ex juvantibus intravenous hydrocortisone awaiting hormone results, which proved consistent with primary adrenal insufficiency (ACTH 1314 pg/ml, cortisol 4.72 ug/dL). Replacement therapy with both hydrocortisone and fludrocortisone was then implemented, with substantial clinical improvement and normalization of sodium levels. However, the patient later developed right heart failure and hypokalemia, which were likely caused by overreplacement and resolved after adjusting the treatment regimen. The final diagnosis of aAD was confirmed by positive adrenal autoantibodies. CONCLUSIONS: aAD should be suspected in each case of severe hyponatremia [2], especially in patients with AIT independent of age. Furthermore, caution is needed in managing high-dose glucocorticoids along with fludrocortisone in elderly patients with cardiac disease to limit the risk of excessive mineralocorticoid activity and heart failure [3].

Is endocrine surveillance important in the care of Duchenne Muscular Dystrophy? Results from a national survey to patients and families on endocrine complications.

Glucocorticoids are standard of care for patients with Duchenne muscular dystrophy (DMD). Although prolonged exposure is associated with multiple endocrine side effects, current guidelines related to monitoring and management of endocrinopathies are suboptimal. We aim to explore community perceptions of endocrine related complications in patients with DMD, assess current level of understanding, and desire for further education. A 31-item online survey was sent through Parent Project to Muscular Dystrophy (PPMD) to Duchenne Registry members to be completed by patients or their caretakers. Response rate was 55% (n = 75). Steroids were taken by 93%, but only 50% were followed by endocrinology and 21% report never been seen by endocrinology. Bone health was discussed with 87% of patients and 60% were diagnosed with osteoporosis. Delayed puberty was discussed with 41% of patients with 23% receiving testosterone therapy. About half the patients reported a diagnosis of slowed growth. Only 51% of the participants recalled discussing adrenal insufficiency. Obesity was discussed with 59% of participants. Families felt education about steroid-induced endocrinopathies to be very or extremely important and prefer to discuss about this at the beginning of their steroid therapy. This demonstrates significant gaps in education and access to endocrine care in patients with DMD.

Utility of salivary cortisol and cortisone in the diagnostics of adrenal insufficiency.

BACKGROUND: Salivary cortisol (sa-cortisol) and salivary cortisone (sa-cortisone) correlate well with serum cortisol (s-cortisol) but validated reference ranges for healthy individuals are lacking. OBJECTIVE: To establish cutoff levels for sa-cortisol and cortisone following cosyntropin testing, and assess their diagnostic utility in adrenal insufficiency (AI). METHODS: Steroids in saliva were assayed using liquid-chromatography tandem-mass-spectrometry (LCMS/MS) before and after administration of 250µg cosyntropin test in 128 healthy subjects (16 on oral estrogens) and 59 patients with suspected AI, of whom 26 were diagnosed with AI with conventional serum cortisol criteria. The cutoff level for AI was defined as the 2.5th centile in healthy subjects not receiving estrogens. Performance was evaluated by calculating diagnostic accuracy and analyzing receiver operating characteristic-curves. RESULTS: The sa-cortisol cutoff 60 minutes after cosyntropin stimulation was 12.6 nmol/L (accuracy 89%, sensitivity 85%, and specificity 90%). Sa-cortisone and the sum of sa-cortisol and cortisone exhibited poorer diagnostic performance than sa-cortisol. The correlation between sa-cortisol and s-cortisol was best described by a model incorporating two regression lines (R2 = 0.80). Segmented regression analysis identified a breakpoint at sa-cortisol 9.7 nmol/L and s-cortisol 482 nmol/L, likely corresponding to saturation of cortisol binding globulin (CBG). Healthy subjects on oral estrogens demonstrated a linear agreement between s- and sa-cortisol through all measurements. Seventeen healthy subjects repeated the test, with similar outcome, but reproducibility in terms of intraclass coefficient and correlation was poor. CONCLUSIONS: Sa-cortisol in cosyntropin-test has high diagnostic accuracy in detecting adrenal insufficiency, and is particularly useful in women on oral estrogens. A sa-cortisol > 12.6 nmol/L assayed with LCMS/MS 60 min after 250µg cosyntropin is normal.

Impact of Glucocorticoid Replacement Therapy on Nocturnal Hypoglycemia in Adrenal Insufficiency: An Analysis of Multiple Case Studies.

BACKGROUND AND AIM: Adrenal insufficiency (AI) is a hormonal disorder characterized by insufficient glucocorticoid production. Nocturnal hypoglycemia (NH) occurs in patients with AI. However, the effect of glucocorticoid replacement therapy (GCRT) on AI and NH remains unclear. This study aimed to investigate the relationship between AI and NH by evaluating the impact of GCRT on NH in patients newly diagnosed with AI. METHODS: The present study was conducted between October 2018 and December 2022 at the Department of Diabetes, Metabolism and Endocrinology of the Tokyo Rosai Hospital, Japan. In total, 15 patients aged ≥18 years with newly diagnosed AI or NH were included in this study. The NH frequency was measured using continuous glucose monitoring (CGM). The primary outcome was the change in NH frequency before and after the GCRT intervention. RESULTS: GCRT significantly decreased NH frequency. Severe NH frequency and minimum nocturnal glucose levels changed significantly while fasting blood glucose and glycated hemoglobin levels did not change significantly. GCRT intervention improved CGM profiles' time below range, time in range, and average daily risk range. CONCLUSIONS:  The present study suggests that GCRT can help newly diagnosed patients with AI manage NH. These findings show that CGM can detect NH in patients with newly diagnosed AI, determine the optimal GCRT dosage, and hence prevent an impaired quality of life and even serious adverse effects in these patients. Further large multicenter studies should validate these findings and delve deeper into the mechanistic link between AI and NH.

A Rare Case Report of Hypoketotic Hypoglycemia Induced Seizures Due to Secondary Carnitine Deficiency in a 44-year-old Female.

Carnitine deficiency is a rare metabolic condition that can result in fasting hypoglycemia. Carnitine deficiency could be primary or secondary to other conditions. Among secondary causes, antiepileptics such as valproic acid have been incriminated. Valproic acid is known to deplete carnitine stores and inhibit the process of ß-oxidation. Herein we report the case of a 44-year-old female with epilepsy that presented with breakthrough seizures associated with hypoglycemia despite being on appropriate antiepileptic therapy. The patient was later found to have carnitine deficiency. Discontinuation of valproic acid and supplementation with l-carnitine resolved the patient's hypoglycemia and breakthrough seizures. With this case report, we hope to encourage clinicians to include carnitine deficiency in the differential diagnosis of unexplained hypoglycemia.

Adrenal Insufficiency and Thyrotoxicosis Following Combined Immune Checkpoint Inhibitor Use: A Case Report and Literature Review.

Destructive thyroiditis and secondary adrenal insufficiency are major endocrinological immune-related adverse events of immune checkpoint inhibitors (ICIs). However, the timing at which each event occurs most frequently after drug administration varies, and cases where multiple events occur simultaneously are rare. We encountered a patient who concurrently suffered from thyrotoxicosis and adrenal insufficiency. An 80-year-old woman with a history of type 2 diabetes mellitus (DM) was diagnosed with stage IVA squamous cell carcinoma of the lungs. Treatment with a combination of nivolumab and ipilimumab was initiated. Although she tested positive for thyroglobulin antibody and transient subclinical hyperthyroidism was observed after two courses, treatment with ICIs was continued. Four months later, treatment was discontinued due to drug-induced lung disease. One month after the last administration, the patient became unconscious and was admitted to another hospital, diagnosed with diabetic ketoacidosis, urinary tract infection, and sepsis. After acute-phase treatment, she was transferred to our hospital due to persistent fever and tachycardia. Thyrotoxicosis and adrenal insufficiency were observed, with high levels of free thyroxine, low thyroid-stimulating hormone (TSH), and cortisol levels. Treatment with extracellular fluids, potassium iodide, beta-blockers, and hydrocortisone was initiated, and the patient's condition improved. No other pituitary hormone deficiencies were observed. She was diagnosed with painless thyroiditis and secondary adrenal insufficiency based on the positive thyroglobulin antibody, negative TSH receptor antibody, decreased Doppler flow in thyroid ultrasonography, low adrenocorticotrophic hormone (ACTH), and low response of ACTH and cortisol to corticotropin-releasing hormone loading test. MRI revealed no abnormalities. We report a case of thyrotoxicosis and secondary adrenal insufficiency five months after the first administration of nivolumab and ipilimumab. Careful follow-up and early detection of endocrine disorders are critical in patients treated with a combination of ICIs.

A Silent Cause of Shock: Autoimmune Polyglandular Syndromes.

Addison's disease is a rare, autoimmune condition leading to destruction of the adrenal gland. Autoimmune conditions are known to commonly co-occur. When Addison's disease presents in the setting of autoimmune thyroid disease and/or type 1 diabetes, this condition is termed autoimmune polyendocrine syndrome type II, a rare endocrinopathy found in roughly 1.4-4.5 per 100,000 individuals. Here, we describe a clinical case presenting with hypotension refractory to fluid resuscitation and electrolyte derangements later diagnosed as autoimmune polyendocrine syndrome type II. LEARNING POINTS: Primary adrenal insufficiency may present clinically as shock refractory to fluid resuscitation.Autoimmune polyglandular syndrome type 2 is a rare autoimmune condition occurring in 1.5-4.5 per 100,000 individuals.The presence of an underlying autoimmune condition should raise suspicion for multiple concurrent autoimmune conditions.

What is the materno-fetal prognosis of adrenal insufficiency and pregnancy in low-resource setting? a case report.

Introduction and importance: Adrenal insufficiency is a rare chronic disease with a prevalence of 39 to 60 cases per million peoples in Europe. However, the prevalence is higher in sub-saharian Africa. The occurrence of pregnancy in adrenal insufficiency is rare but associated with high maternal and perinatal morbidity and mortality. For this reason, the management of pregnancy in adrenal insufficiency patient must be provided by a multidisciplinary team. Case presentation: The authors report the case of a 34-year-old pregnant woman followed for adrenal insufficiency secondary to prolonged corticosteroid therapy. Treatment consisted to an obstetrical and endocrinological follow-up and corticosteroid replacement therapy with hydrocortisone. A prophylactic cesarean section at 38 weeks resulted in the birth of a newborn male weighing 3395 g. Maternal and perinatal prognosis was good. Clinical discussion: Pregnancy in adrenal insufficiency is a therepeutic challenge in developing countries. Through this case, the authors discuss the therapeutic and prognostic aspects of adrenal insufficiency in our setting. Conclusion: With the introduction of gluco-corticosteroid replacement therapy, pregnancy in adrenal insufficiency can progress normally.

Current Advances in the Management of Congenital Adrenal Hyperplasia.

Congenital adrenal hyperplasia (CAH) is an autosomal recessive genetic condition caused by various enzyme deficiencies that result in disruptions of pathways of adrenal steroidogenesis. 21-hydroxylase deficiency is the most common form of CAH and has a variable phenotype which ranges a spectrum, from the most severe salt-wasting type to the simple-virilizing type and the least severe nonclassical form. Patients with CAH are at risk for various comorbidities due to the underlying adrenal hormone production imbalance as well as the treatment of the condition, which typically includes supraphysiologic glucocorticoid dosing. Children and adults require frequent monitoring and careful medication dosing adjustment. However, there are multiple novel therapies on the horizon that offer promise to patients with CAH in optimizing their treatment regimens and reducing the risk of comorbidities.

Too Dry for Primary Adrenal Insufficiency (PAI): PAI Masked by Volume Depletion.

Adrenal insufficiency (AI) is a rare but potentially life-threatening endocrine disorder characterized by inadequate production or impaired response to adrenal hormones. Symptoms may range from acute emergent crisis presenting as hemodynamic shock or may be more chronic in presentation with a gradual onset of nonspecific symptoms. These vague symptoms are often accompanied by typical laboratory findings, such as hyponatremia, hypotension, and hyperkalemia, and point toward a diagnosis of chronic AI. In this case presentation, we demonstrate chronic AI presenting with severe hyponatremia, which was revealed after return to an euvolemic baseline. Because of an insidious presentation, AI can be both an incidental finding and easily missed. This case highlights the importance of evaluating suspected cases of AI at a baseline metabolic and hemodynamic state, including volume status. High clinical suspicion is warranted in these patients to avoid potential emergent adrenal crisis and to provide appropriate replacement therapy once etiology is established.

STAR gene mutation in a patient with congenital lipoid adrenal hyperplasia.

Not required for Clinical Vignette.

Comparison of modified-release hydrocortisone capsules versus prednisolone in the treatment of congenital adrenal hyperplasia.

Background: Prednisolone and prednisone are recommended treatment options for adults with congenital adrenal hyperplasia (CAH); however, there is no randomised comparison of prednis(ol)one with hydrocortisone. Design: Six-month open-label randomised phase 3 study and interim analysis of a single-arm extension study was the design of the study. Methods: The method of the study was hydrocortisone dose equivalent and 09:00-h 17-hydroxyprogesterone (17OHP) from 48 patients taking prednis(ol)one at baseline. Results: At baseline, the median hydrocortisone dose equivalent was 30 mg/day and 17OHP was < 36 nmol/L (3× upper limit of normal) in 56% of patients. Patients were randomised to continue prednis(ol)one or switch to modified-release hydrocortisone capsule (MRHC) at the same hydrocortisone-equivalent dose. At 4 weeks, 94% on MRHC and 71% on prednis(ol)one had 17OHP < 36 nmol/L. At 18 months in the extension study of MRHC, the median MRHC dose was 20 mg/day and 82% had 17OHP < 36 nmol/L. The per cent of patients with 17OHP < 36 nmol/L on a hydrocortisone dose equivalent ≤ 25 mg/day was greater at 18 months in the extension study on MRHC than while on prednis(ol)one at baseline: 57% vs 27%, P = 0.04. In the randomised study, no patients had an adrenal crisis on MRHC and one on prednisolone. In the extension study (221 patient years), there were 12 adrenal crises in 5 patients (5.4/100 patient years). Conclusion: MRHC reduces 17OHP at 09:00 h compared to prednis(ol)one and the dose of MRHC can be down-titrated over time in the majority of patients.

Clinical spectrum of human STAR variants and their genotype-phenotype correlation.

Biallelic variants of steroidogenic acute regulatory protein (STAR/STARD1) may cause primary adrenal insufficiency and 46,XY disorder of sex development. STAR plays a pivotal role in transporting cholesterol into mitochondria where cholesterol serves as an essential substrate for initiating steroid biosynthesis by its conversion to pregnenolone. Generally, loss-of-function mutations of STAR cause the classic form of lipoid congenital adrenal hyperplasia (LCAH) where steroidogenesis of the adrenal cortex and the gonads is severely affected. By contrast, partial activity of STAR causes a less severe phenotype, the non-classic LCAH, which is characterized by later onset and initial manifestation with isolated adrenal insufficiency only. Disease-causing STAR variants are very rare. Numerous variants of all types have been described worldwide. Prevailing variants have been reported from Japan and Korea and in some population clusters where STAR is more common. Genotype-phenotype correlation is pretty good for STAR variants. While the exact mechanisms of cholesterol transport into mitochondria for steroidogenesis are still under investigation, the important role of STAR in this process is evident by inactivating STAR variants causing LCAH. The mechanism of disease with STAR deficiency is best described by a two-hit model: the first hit relates to impaired cholesterol import into mitochondria and thus lack of substrate for all steroid hormone biosynthesis; the second hit then relates to massive cytoplasmic lipid overload (evidenced by typically enlarged and fatty adrenal glands) leading to cell death and organ destruction. This review summarizes phenotype and genotype characteristics of human STAR variants found through the ClinVar database.

Infections and gender: clues for diagnosis of adrenal insufficiency-a case report and a review of the literature.

The clinical presentation of adrenal insufficiency, a condition causing adrenal hormone deficiency, is characterised by non-specific symptoms and signs: consequently, an important diagnostic delay is often evident which correlates with an increased mortality. This case report shows how the clustering of some symptoms and signs may hamper the diagnostic suspicion for this condition: serum electrolyte alterations and weight loss, when associated to recurrent infections and, in female patients, an empty sella may further guide the clinician towards a diagnosis of adrenal insufficiency. Accordingly, a clinical approach taking into account gender medicine could improve the diagnostic workup.

Childhood Cerebral Adrenoleukodystrophy: Case Report and Literature Review Advocating for Newborn Screening.

Background: X-linked adrenoleukodystrophy (ALD) is a rare genetic disorder caused by a pathogenic variant of the ABCD1 gene, leading to impaired peroxisomal function and the accumulation of very long-chain fatty acids (VLCFAs). ALD presents a wide range of neurological and adrenal symptoms, ranging from childhood cerebral adrenoleukodystrophy to adrenomyeloneuropathy and adrenal insufficiency. Newborn screening (NBS) for ALD is available in some regions but remains lacking in others, such as India. Case Presentation: We present a case of a 10-year-old boy with ALD who presented with seizures, progressive weakness, visual impairment, and adrenal insufficiency. Despite symptomatic management and dietary adjustments, the disease progressed rapidly, leading to respiratory failure and eventual demise. The diagnosis was confirmed through molecular analysis and elevated VLCFA levels. Neuroimaging revealed characteristic white matter changes consistent with ALD. Conclusion: ALD is a devastating disease with no cure, emphasizing the importance of early detection through newborn screening and genetic testing. Management strategies include adrenal hormone therapy, gene therapy, and allogenic stem cell transplantation, as well as investigational treatments such as VLCFA normalization. Our case advocates the need for worldwide NBS and pediatric neurologic follow-up to enable early intervention and improve patient outcomes. Additionally, the association between ALD, recurrent febrile seizures, and unexplained developmental delay warrants further investigation to better understand disease progression and potential therapeutic targets.