Pituitary and adrenal disorders induced by immune checkpoint inhibitors.

Over the past decade, the development of ICI (immune checkpoint inhibitors) has constituted a revolution in the treatment of many cancers, but with a specific toxicity profile including endocrine IRAEs (immune-related adverse events). As the indications for these molecules are constantly increasing due to their efficacy, it is important that endocrinologists and oncologists know how to detect, manage and monitor this type of toxicity. Many guidelines and recommendations have been proposed in the last few years for the management of endocrinopathies. French guidelines on immunotherapy-related endocrine IRAEs were published in 2018, with a specific algorithm for hypophysitis and primary adrenal insufficiency (PAI), based on clinical suspicion followed by biochemical and imaging evaluation, and are still relevant today. Here we present the general pathophysiological mechanisms of these toxicities, and discuss the incidence, diagnosis, treatment, progression, management and monitoring of pituitary and adrenal disorders in patients treated by immunotherapy, with emphasis on hypophysitis, which is much more frequent than PAI with this type of molecule. We also highlight several key points, such as the need for emergency treatment by hydrocortisone with the possibility of continuing immunotherapy in these endocrinopathies, and the long-term persistence of corticotropin or adrenal deficiency in most cases, requiring specific "hydrocortisone education". These points should be kept in mind by oncologists and endocrinologists who treat and monitor patients treated by immunotherapy.

Adrenal Hemorrhage: A Review.

Importance: Adrenal hemorrhage in pregnancy is rare. The prevalence of pregnant patients whose pregnancies are complicated by preeclampsia or eclampsia is hypothesized to be slightly higher than the 0.4% to 1.1% occurrence rate in the nonpregnant population. However, the mortality rate of adrenal hemorrhage is reportedly as high as 15%. Therefore, it is critical for obstetric providers to have basic knowledge on the presentation, diagnosis, and management of adrenal hemorrhage in the pregnant population so that prompt diagnosis can be made. Objective: This review highlights incidence, pathophysiology, risk factors, diagnosis, management, and complications of adrenal hemorrhage in the peripartum period. Evidence Acquisition: A literature search was undertaken by our research university librarian using the search engines of PubMed, CINAHL, and EMBASE (Medline items removed). The search terms used included "adrenal hemorrhage" OR "adrenal gland hemorrhage" AND "pregnancy" OR "maternal." The search was limited to articles in English, and the years searched were from January 1, 2015 to December 31, 2021. Results: There were 130 abstracts identified, and 30 of the articles were ultimately used as the basis for this review. Presenting signs and symptoms of adrenal hemorrhage were typically abdominal, back, and flank pain. Diagnosis was typically made with ultrasound and computed tomography or magnetic resonance imaging without contrast for confirmation. Management options include conservative management versus surgical management with adrenalectomy or interventional radiology embolization in the unstable patient. For patients with evidence of adrenal insufficiency, steroid replacement was used. Most patients with adrenal hemorrhage in the literature had unilateral adrenal hemorrhage; however, several cases of bilateral adrenal hemorrhage have been reported. Patients with bilateral adrenal hemorrhage were more likely to require steroids for adrenal insufficiency. There are no known contraindications to vaginal delivery in this group of patients, and patients who were managed conservatively were often able to continue the pregnancy to term. Conclusions: Early recognition and management are integral in decreasing the morbidity and mortality associated with adrenal hemorrhage. Relevance Statement: This is an evidence-based review of adrenal hemorrhage in pregnancy and how to diagnose and manage a pregnancy complicated by adrenal hemorrhage.

History of Adrenal Research: From Ancient Anatomy to Contemporary Molecular Biology.

The adrenal is a small, anatomically unimposing structure that escaped scientific notice until 1564 and whose existence was doubted by many until the 18th century. Adrenal functions were inferred from the adrenal insufficiency syndrome described by Addison and from the obesity and virilization that accompanied many adrenal malignancies, but early physiologists sometimes confused the roles of the cortex and medulla. Medullary epinephrine was the first hormone to be isolated (in 1901), and numerous cortical steroids were isolated between 1930 and 1949. The treatment of arthritis, Addison's disease, and congenital adrenal hyperplasia (CAH) with cortisone in the 1950s revolutionized clinical endocrinology and steroid research. Cases of CAH had been reported in the 19th century, but a defect in 21-hydroxylation in CAH was not identified until 1957. Other forms of CAH, including deficiencies of 3ß-hydroxysteroid dehydrogenase, 11ß-hydroxylase, and 17α-hydroxylase were defined hormonally in the 1960s. Cytochrome P450 enzymes were described in 1962-1964, and steroid 21-hydroxylation was the first biosynthetic activity associated with a P450. Understanding of the genetic and biochemical bases of these disorders advanced rapidly from 1984 to 2004. The cloning of genes for steroidogenic enzymes and related factors revealed many mutations causing known diseases and facilitated the discovery of new disorders. Genetics and cell biology have replaced steroid chemistry as the key disciplines for understanding and teaching steroidogenesis and its disorders.

[Adrenal gland diseases: Addison's Disease]. / Nebennieren-Erkrankungen: Morbus Addison.

Addison's disease typically results from the autoimmune destruction of the adrenal cortex and requires lifelong replacement with glucocorticoids and mineralocorticoids. Main symptoms are non-specific and, therefore, often overlooked or misleading. Patients are frequently not diagnosed until experiencing a life-threatening adrenal crisis. This article highlights the essential clinical characteristics, diagnostic aspects and principles of management of adrenal insufficiency.

[Spontaneous adrenal hematomas. Retrospective analysis of 20 cases from a tertiary center]. / Hématomes surrénaliens non traumatiques : série rétrospective de 20 cas.

INTRODUCTION: Spontaneous adrenal hemorrhages (AH) are a rare condition with no consensus about their management. METHODS: Patients were identified using the Medicalization of the Information System Program database, imaging software and a call for observations to internists, intensivists and obsetricians working at our institution. Adult patients whose medical records were complete and whose diagnosis was confirmed by medical imaging were included. RESULTS: From 2000 to 2007, 20 patients were identified, including 15 were women. The clinical onset of AH was non-specific. In five cases, AH occurred during pregnancy; four of them were unilateral and right sided. The etiology of the other fifteen (bilateral adrenal hemorrhage in 11) were as follows: antiphospholipid syndrome (n=8), heparin-induced thrombocytopenia (n=4), essential thrombocythemia (n=3), spontaneous AH due to oral anticoagulants (n=1), complication of a surgical act (n=3), and sepsis (n=3). In seven cases, two causes were concomitant. The diagnosis of AH was often confirmed by abdominal CT. An anticoagulant treatment was initiated in 16 cases. Ten of the eleven patients presenting with bilateral adrenal hematomas were treated using a long-term substitute opotherapy. One patient died because of a catastrophic antiphospholipid syndrome. CONCLUSION: The clinical onset of HS is heterogeneous and non-specific. The confirmatory diagnosis is often based on abdominal CT. The search for an underlying acquired thrombophilia is essential and we found in this study etiological data comparable to the main series in the literature. Adrenal insufficiency is most of the time definitive in cases of bilateral involvement.

Chronic kidney disease in adrenal disorders.

PURPOSE OF REVIEW: This review will focus on hypertension due to underlying adrenal disorders in chronic kidney disease (CKD). Diagnosis of adrenal hypertension and particularly primary aldosteronism (PA) in CKD is frequently not pursued. We outline limitations that advanced kidney disease poses on the diagnostic work up of these disorders and provide a framework for approaching CKD patients suspected of having an adrenal disorder. Recognition of these disorders is important as they are often underdiagnosed which leads to poorer outcomes. RECENT FINDINGS: Adrenal disease associated with hypertension in CKD is most commonly due to PA whereas pheochromocytoma and Cushing's disease are important but less common. Diagnosis of these diseases is important as their identification leads to better blood pressure control and can possibly mitigate the risk of progression of CKD. Work up and treatment of PA has been shown to be safe and is associated with less antihypertensive medication requirement for the associated hypertension and slower progression of CKD. SUMMARY: This chapter summarizes the importance of recognizing adrenal hypertension in CKD and reinforces the need for physicians to pursue these diagnoses in CKD patients as this is safe and improves both BP control and delays progression of CKD.

Adrenal extramedullary haematopoiesis: an unusual incidentaloma.

We report a case of adrenal extramedullary haematopoiesis in a 24-year-old women who presented with pallor and weakness. Ultrasonography of the abdomen detected moderate hepatosplenomegaly with multiple lesions in the spleen and an incidental right adrenal mass. There was no ascites or lymphadenopathy. CT scan revealed a heterogeneous right adrenal mass with multiple non-enhancing lesions in the spleen. Ultrasound guided trucut biopsy was performed after excluding a functioning tumour, which confirmed the diagnosis. Later, she was diagnosed to have haemoglobin E/beta thalassaemia and was put on hydroxyurea trial.

Towards novel treatments for adrenal diseases: Cell- and gene therapy-based approaches.

Adrenal insufficiency, the inability to produce adequate levels of corticosteroids, is a multi-causal disease that requires lifelong daily hormone replacement. Nevertheless, this cannot replace the physiological demand for steroids which are secreted following a circadian rhythm and vary in periods of stress; the consequences of under- or over-replacement include adrenal crisis and metabolic disturbances, respectively. Although clinical research has focused on enhancing the effectiveness/reducing side effects of current treatment modalities, only small improvements are deemed possible; thus, alternative solutions are urgently needed. Gene and cell therapy strategies have opened new possibilities for the cure of many diseases in a way that has never been possible before and could offer a viable option for the cure of adrenal diseases. The current state of cell- and gene-based approaches to restore adrenocortical function is discussed in this review.

Fixing the broken clock in adrenal disorders: focus on glucocorticoids and chronotherapy.

The circadian rhythm derives from the integration of many signals that shape the expression of clock-related genes in a 24-h cycle. Biological tasks, including cell proliferation, differentiation, energy storage, and immune regulation, are preferentially confined to specific periods. A gating system, supervised by the central and peripheral clocks, coordinates the endogenous and exogenous signals and prepares for transition to activities confined to periods of light or darkness. The fluctuations of cortisol and its receptor are crucial in modulating these signals. Glucocorticoids and the autonomous nervous system act as a bridge between the suprachiasmatic master clock and almost all peripheral clocks. Additional peripheral synchronizing mechanisms including metabolic fluxes and cytokines stabilize the network. The pacemaker is amplified by peaks and troughs in cortisol and their response to food, activity, and inflammation. However, when the glucocorticoid exposure pattern becomes chronically flattened at high- (as in Cushing's syndrome) or low (as in adrenal insufficiency) levels, the system fails. While endocrinologists are well aware of cortisol rhythm, too little attention has been given to interventions aimed at restoring physiological cortisol fluctuations in adrenal disorders. However, acting on glucocorticoid levels may not be the only way to restore clock-related activities. First, a counterregulatory mechanism on the glucocorticoid receptor itself controls signal transduction, and second, melatonin and/or metabolically active drugs and nutrients could also be used to modulate the clock. All these aspects are described herein, providing some insights into the emerging role of chronopharmacology, focusing on glucocorticoid excess and deficiency disorders.

Bilateral adrenal haemorrhage after a high energetic trauma: a case report and review of current literature.

Most adrenal injuries are asymptomatic. In traumatic events, adrenal haemorrhage is very likely to be accompanied by injuries to other organs. Isolated adrenal injury after trauma is very rare and mostly unilateral. We report a case of a 44-year-old male who suffered a major traffic accident with multiple trauma, including a bilateral adrenal haemorrhage. This caused a primary adrenal insufficiency, as proven with a cortisol stimulation test with synthetic corticotrophin. Bilateral adrenal haemorrhage is a very rare but potentially fatal disorder and should not be missed. This case illustrates that early diagnosis and prompt treatment with hydrocortisone may contribute to a beneficial outcome.

Management of incidental adrenal masses: an update.

OBJECTIVE: To review the current evidence and guidelines for diagnosis and management of incidental adrenal masses with a focus on the recent changes made by the American College of Radiology (ACR) Incidental Findings Committee. CONCLUSION: Incidentally detected adrenal nodules are a commonly encountered finding estimated to occur in 5-7% of the adult population. By following current recommendations, radiologists can improve patient care by efficiently determining which masses require further diagnostic testing and which masses can be considered benign and not require further follow-up.

Adrenal disorders in pregnancy, labour and postpartum - an overview.

Adrenal disorders may manifest during pregnancy for the first time, or present from before pregnancy as either undiagnosed or diagnosed and treated. They may present as hormonal hypofunction or hyperfunction, or with mass effects or other non-endocrine effects. Adrenal disorders such as Cushing's syndrome, Addison's disease, pheochromocytoma, primary hyper-aldosteronism and adreno-cortical carcinoma are rare in pregnancy. Pregnancy presents special problems in the evaluation of the hypothalamic-pituitary-adrenal and renin-angiotensin-aldosterone axis as these undergoe major changes during pregnancy. Diagnosis is challenging as symptoms associated with pregnancy are also seen in adrenal diseases. A timely diagnosis and treatment is critical as these disorders can cause maternal and foetal morbidity and mortality. A high index of suspicion must be maintained as they can go unrecognised and untreated. An early diagnosis and treatment often improves outcomes. The aim of this article is to review the patho-physiology, clinical manifestation, diagnosis and management of various adrenal disorders during pregnancy.

Abnormal linear growth in paediatric adrenal diseases: Pathogenesis, prevalence and management.

Abnormal adrenal function can interfere with linear growth, potentially causing either acceleration or impairment of growth in paediatric patients. These abnormalities can be caused by direct effects of adrenal hormones, particularly glucocorticoids and sex steroids, or be mediated by indirect mechanisms such as the disturbance of the growth hormone-insulin-like growth factor-1 axis and aromatization of androgens to oestrogens. The early diagnosis and optimal treatment of adrenal disorders can prevent or minimize growth disturbance and facilitate improved height gain. Mechanisms of growth disturbance in the following abnormal states will be discussed; hypercortisolaemia, hyperandrogenaemia and obesity. Prevalence and features of growth disturbance will be discussed in ACTH-dependent and ACTH-independent Cushing's syndrome, adrenocortical tumours, premature adrenarche, congenital adrenal hyperplasia and adrenal insufficiency disorders. Recommendations for management have been included.

Management of immune-related adverse events in endocrine organs induced by immune checkpoint inhibitors: clinical guidelines of the Japan Endocrine Society.

Immune checkpoint inhibitors (ICIs) have become a promising treatment for advanced malignancies. However, these drugs can induce immune-related adverse events (irAEs) in several organs, including skin, gastrointestinal tract, liver, muscle, nerve, and endocrine organs. Endocrine irAEs comprise hypopituitarism, primary adrenal insufficiency, thyroid dysfunction, hypoparathyroidism, and type 1 diabetes mellitus. These conditions have the potential to lead to life-threatening consequences, such as adrenal crisis, thyroid storm, severe hypocalcemia, and diabetic ketoacidosis. It is therefore important that both endocrinologists and oncologists understand the clinical features of each endocrine irAE to manage them appropriately. This opinion paper provides the guidelines of the Japan Endocrine Society and in part the Japan Diabetes Society for the management of endocrine irAEs induced by ICIs.

Evaluation and Treatment of Adrenal Dysfunction in the Primary Care Environment.

Adrenal insufficiency (Addison's disease) and Cushing's syndrome are rare disorders characterized by abnormal secretion of adrenal hormones. All patients with adrenal insufficiency and many with Cushing's syndrome require life-long therapy with the potential to impact the quality of life. Management requires gain of a significant amount of knowledge related to treatment, self-care, and how to react quickly in critical situations. Knowledge deficits related to management may cause patients to become critically ill and may even cause death. Ongoing patient/family teaching is crucial for proper disease management and sustaining the quality of life.

Monogenic Disorders of Adrenal Steroidogenesis.

Disorders of adrenal steroidogenesis comprise autosomal recessive conditions affecting steroidogenic enzymes of the adrenal cortex. Those are located within the 3 major branches of the steroidogenic machinery involved in the production of mineralocorticoids, glucocorticoids, and androgens. This mini review describes the principles of adrenal steroidogenesis, including the newly appreciated 11-oxygenated androgen pathway. This is followed by a description of pathophysiology, biochemistry, and clinical implications of steroidogenic disorders, including mutations affecting cholesterol import and steroid synthesis, the latter comprising both mutations affecting steroidogenic enzymes and co-factors required for efficient catalysis. A good understanding of adrenal steroidogenic pathways and their regulation is crucial as the basis for sound management of these disorders, which in the majority present in early childhood.

Intermittent hypoxia improves behavioral and adrenal gland dysfunction induced by posttraumatic stress disorder in rats.

Nonpharmacological treatments of stress-induced disorders are promising, since they enhance endogenous stress defense systems, are free of side effects, and have few contraindications. The present study tested the hypothesis that intermittent hypoxia conditioning (IHC) ameliorates behavioral, biochemical, and morphological signs of experimental posttraumatic stress disorder (PTSD) induced in rats with a model of predator stress (10-day exposure to cat urine scent, 15 min daily followed by 14 days of stress-free rest). After the last day of stress exposure, rats were conditioned in an altitude chamber for 14 days at a 1,000-m simulated altitude for 30 min on day 1 with altitude and duration progressively increasing to 4,000 m for 4 h on day 5. PTSD was associated with decreased time spent in open arms and increased time spent in closed arms of the elevated X-maze, increased anxiety index, and increased rate of freezing responses. Functional and structural signs of adrenal cortex degeneration were also observed, including decreased plasma concentration of corticosterone, decreased weight of adrenal glands, reduced thickness of the fasciculate zone, and hydropic degeneration of adrenal gland cells. The thickness of the adrenal fasciculate zone negatively correlated with the anxiety index. IHC alleviated both behavioral signs of PTSD and morphological evidence of adrenal cortex dystrophy. Also, IHC alone exerted an antistress effect, which was evident from the increased time spent in open arms of the elevated X-maze and a lower number of rats displaying freezing responses. Therefore, IHC of rats with experimental PTSD reduced behavioral signs of the condition and damage to the adrenal glands. NEW & NOTEWORTHY Intermittent hypoxia conditioning (IHC) has been shown to be cardio-, vaso-, and neuroprotective. For the first time, in a model of posttraumatic stress disorder (PTSD), this study showed that IHC alleviated both PTSD-induced behavioral disorders and functional and morphological damage to the adrenal glands. Also, IHC alone exerted an antistress effect. These results suggest that IHC may be a promising complementary treatment for PTSD-associated disorders.

The difficulties of pseudo-Cushing's syndrome (or "non-neoplastic hypercortisolism").

Pseudo-Cushing's syndrome covers different pathological conditions responsible for mild-to-moderate ACTH-dependent hypercortisolism, related not to an ACTH-secreting tumor but rather to CRH and/or AVP hypothalamic secretion through activation of various neural pathways, in patients generally displaying excess central adiposity. It is better termed "non-neoplastic hypercortisolism" (NNH). The main conditions implicated in NNH comprise: neuropsychiatric disorder, alcohol abuse, insulin-resistant obesity, polycystic ovary syndrome, and end-stage kidney disease. Glucocorticoid resistance is one differential diagnosis, as are some cases of primary adrenal disease with incompletely suppressed ACTH. Differentiating between NNH and mild-to-moderate Cushing's disease can be a real challenge. Clinical analysis, based on thorough history taking and screening for catabolic signs is essential; useful explorations include midnight serum or salivary cortisol and Dex/CRH and ddAVP stimulation response. Pituitary MRI suffers from limitations regarding both sensitivity and specificity, while bilateral inferior petrosal sinus sampling cannot distinguish between pituitary ACTH secretion by a tumor or by normal cells stimulated by endogenous CRH. Definitive diagnosis of functional etiology requires demonstrating that treatment of the underlying condition restores normal secretion of ACTH and cortisol, but this is not always possible. Lingering diagnostic uncertainty has to be accepted in certain patients, who will have to be followed up for some time before diagnosis can be considered more or less definitive.