Central adrenal insufficiency: who, when, and how? From the evidence to the controversies - an exploratory review

ABSTRACT Central adrenal insufficiency (CAI) is a life-threatening disorder. This occurs when ACTH production is insufficient, leading to low cortisol levels. Since corticosteroids are crucial to many metabolic responses under organic stress and inflammatory conditions, CAI recognition and prompt treatment are vital. However, the diagnosis of CAI is challenging. This is not only because its clinical presentation is usually oligosymptomatic, but also because the CAI laboratory investigation presents many pitfalls. Thus, the clarification of when to use each test could be helpful in many contexts. The CAI challenge is also involved in treatment: Several formulations of synthetic steroids exist, followed by the lack of a biomarker for glucocorticoid replacement. This review aims to access all available literature to synthesize important topics about who should investigate CAI, when it should be suspected, and how CAI must be treated.

Management of hypopituitarism: a perspective from the Brazilian Society of Endocrinology and Metabolism

ABSTRACT Hypopituitarism is a disorder characterized by insufficient secretion of one or more pituitary hormones. New etiologies of hypopituitarism have been recently described, including head trauma, cerebral hemorrhage, and drug-induced hypophysitis. The investigation of patients with these new disorders, in addition to advances in diagnosis and treatment of hypopituitarism, has increased the prevalence of this condition. Pituitary hormone deficiencies can induce significant clinical changes with consequent increased morbidity and mortality rates, while hormone replacement based on current guidelines protects these patients. In this review, we will first discuss the different etiologies of hypopituitarism and then address one by one the clinical aspects, diagnostic evaluation, and therapeutic options for deficiencies of TSH, ACTH, gonadotropin, and GH. Finally, we will detail the hormonal interactions that occur during replacement of pituitary hormones.

The clinical reports on adrenal insufficiency of patients with advanced solid tumors accepting anti-PD-1 antibody, SHR-1210 therapy / 中华肿瘤杂志

Objective@#To investigate the adrenocortical function changes of patients with advanced solid tumors who received the anti- programmed cell death protein-1 (PD-1) antibody, SHR-1210 therapy.@*Methods@#The clinical data of 98 patients with advanced solid tumors who were enrolled in a prospective phase I trial of SHR-1210 therapy at our institution between April 27, 2016 and June 8, 2017 were collected. The levels of plasma adrenocorticotropic hormone (ACTH) and cortisol were evaluated in 96 patients. The clinical manifestations, laboratory tests and radiologic data were collected to define the immune-related adrenal insufficiency.@*Results@#Until December 14th, 2018, no SHR-1210 related primary adrenal insufficiency occurred, and the incidence of immune-related secondary adrenal insufficiency was 1.0% among the 96 patients, which was identified as grade 2. No patient developed grade 3-4 adrenal insufficiency. The main clinical manifestations of the patient who was diagnosed as secondary adrenal insufficiency were grade 2 fatigue, anorexia and headache.The patient developed fatigue and anorexia at the 267th day after receiving the first dose of SHR-1210, the hypocortisolism occurred on the 279th day, and the headache emerged on the 291th day. The anorexia of patient who treated by physiological replacement doses of glucocorticoid since the 457th day was attenuated.The patient whose cortisol level was still below the normal limit continued to accept the hormone replacement therapy up to 776 days after the initial administration of SHR-1210.@*Conclusions@#The incidence of SHR-1210 related adrenal insufficiency of patients with advanced solid tumors is low, and the symptoms can be effectively ameliorated by hormone replacement therapy. The potential adverse outcome of adrenal insufficiency following immunotherapy should be noticed by clinicians to avoid the occurrence of adrenal crisis.

A Case of Pituitary Macroadenoma Accompanied with CRH Deficiency / 대한내분비학회지

Pituitary tumor can be accompanied with various pituitary hormone abnormalities. Pituitary tumors can be divided into functioning or nonfunctioning tumors. A functioning pituitary tumor, via the oversecretion of pituitary hormones, causes diverse clinical features. A nonfunctioning pituitary tumor can be accompanied with pituitary dysfunction and this may be due to compression or destruction of normal pituitary tissue, suppression of the pituitary portal system or direct damage to the hypothalamus. Corticotropin-releasing hormone (CRH) deficiency, which is caused by defects in the synthesis or release of CRH, is a cause of secondary adrenocortical insufficiency. The clinical presentations are hypoglycemia, weight loss, anemia, weakness, nausea, vomiting and hyponatremia. Acquired CRH deficiency has also been suggested to occur based on a lack of adrenocorticotropic hormone (ACTH) response to insulin-induced hypoglycemia, but there is a normal ACTH response to exogenous CRH. We experienced a case of a woman with pituitary macroadenoma accompanied with CRH deficiency. We report here on this case with the review of the literature.

Determination of Glucocorticoid Replacement Therapy and Adequate Maintenance Dose in Patients with Secondary Adrenal Insufficiency / 대한내분비학회지

BACKGROUND: Determination of the adequate dose of glucocorticoid replacement therapy, in patients with secondary adrenal insufficiency, is of great importance to avoid the consequences of under or over treatment. The aims of this study were: 1) to assess the value of adrenal cortical function tests in determining whether glucocorticoid replacement should be given, and 2) to investigate the adequate maintenance dose of glucocorticoid in patients with secondary adrenal insufficiency. METHODS: Forty patients, with secondary adrenal insufficiency, confirmed by the insulin-induced hypoglycemia test (IHT), were studied. All subjects underwent basal serum cortisol measurement, IHT and 250 g rapid ACTH stimulation tests (AST). The clinical usefulness of these tests, for the determination of glucocorticoid replacement therapy, was evaluated in patients with secondary adrenal insufficiency. 26 of the 40 patients had received prednisolone (Pd) (5 mg per day) replacement due to symptoms from adrenal insufficiency. The dose of Pd was serially changed from 5 to 3.75, and then to 6.25 mg per day, every 3 month. The measured lipid parameters, serum osteocalcin and urinary N-telopeptide were measured and the quality of life evaluated by the administration of an Addisonian questionnaire, both before and after the dose changes. RESULTS: 1) For all tests, cut-offs were selected that would provide adequate specificity and sensitivity. When the cut-offs were set to provide 95% specificity, the corresponding sensitivitycut-off values, obtained with basal serum cortisol, peak serum cortisol in IHT and AST were: 88.4% <5 microgram/dL, 80.7% <11 microgram/dL and 76.9% <16 microgram/dL. 2) The urinary type I collagen N-telopeptide, total cholesterol, HDL- and LDL-cholesterol levels were significantly increased, and the serum osteocalcin levels significantly decreased when the daily dose of Pd was increased to 6.25 from 3.75 or 5 mg. The LDL-cholesterol levels especially, were significantly increased, even though the change in the Pd from 3.75 to 5 mg per day was subtle. CONCLUSION: The basal cortisol levels, HPA axis tests and the symptoms of patients may be helpful to determine whether prednisolone replacement therapy should be given. It is suggest that an adequate dose of glucocorticoid replacement therapy should be not exceed Pd 5mg per day, so as not to have adverse effects on the bone and lipid metabolisms.

Usefullness of Urinary Free Cortisol Measurement in Diagnosis of Iatrogenic Cushing Syndrome / 대한내분비학회지

BACKGROUND: Although insulin induced hypoglycemia test is a standard diagnostic method in assessment of hypothalamo-pituitary-adrenal axis, rapid ACTH stimulation test using 250microgram has been used as a first line diagnostic test especially in secondary adrenal insufficiency due to iatrogenic Cushing syndrome because it is easy and safe. However, it was suggested that a maximal cortisol response can be achieved with a much lower ACTH dose and 1microgram ACTH enhances the sensitivity without decreasing specificity of test. Also recently, there was a report that midnight to morning urine cortisol increment is more accurate, noninvasive method can be used for measurement of hypothalmo-pituitary-adrenal axis. In this study, we compared the 1microgram ACTH stimulation test with midnight to morning urinary free cortisol increment in secondary adrenal insufficiency due to iatrogenic Cushing syndrome to study the agreement of two test and accuracy of increment of urinary free cortisol in diagnosis of adrenal insufficiency. METHODS: Double voided urine sample were collected at midnight and 8 A.M. in 12 patients who have Cushing-like feature and history of taking glucocorticoids and in 12 normal controls. Urinary free cortisol was measured and cortisol increment was defined as the morning urine free cortisol minus the midnight urine free cortisol. The 1microgram ACTH stimulation test was performed in 12 iatrogenic Cushing syndrome patients at the same day and compard with the result of cortisol increment. RESULTS: Using the results of 12 controls, normal urine free cortisol increment was defined as greater than 165.5nmol/L(6.0microgram/dL). Subnormal cortisol response in 1microgram ACTH stimulation test was noted in 8 out of 12 patients group and urinary free cortisol increment was not observed in 7 out of 8 subnormal response group. Normal cortisol response in 1microgram ACTH stimulation test was noted in 4 out of 12 patients group and urinary free cortisol increment was observed in 3 out of 4 normal response group. So 83% of concordance rate between 1microgram ACTH stimulation test and urine free cortisol increment was recorded. CONCLUSION: Urinary free cortisol increment has high concordance rate with 1microgram ACTH stimulation test and simple, easy test in diagnosing secondary adrenal insufficiency due to iatrogenic Cushing syndrome. Further study including more patients will be helpful to know the adequacy and reliability of test in evaluation of hypothalamo-pituitary-adrenal axis.