Investigation of the Hypothalamo-pituitary-adrenal (HPA) axis: a contemporary synthesis.

The hypothalamo-pituitary-adrenal (HPA) axis is one of the main components of the stress system. Maintenance of normal physiological events, which include stress responses to internal or external stimuli in the body, depends on appropriate HPA axis function. In the case of severe cortisol deficiency, especially when there is a triggering factor, the patient may develop a life-threatening adrenal crisis which may result in death unless early diagnosis and adequate treatment are carried out. The maintenance of normal physiology and survival depend upon a sufficient level of cortisol in the circulation. Life-long glucocorticoid replacement therapy, in most cases meeting but not exceeding the need of the patient, is essential for normal life expectancy and maintenance of the quality of life. To enable this, the initial step should be the correct diagnosis of adrenal insufficiency (AI) which requires careful evaluation of the HPA axis, a highly dynamic endocrine system. The diagnosis of AI in patients with frank manifestations is not challenging. These patients do not need dynamic tests, and basal cortisol is usually enough to give a correct diagnosis. However, most cases of secondary adrenal insufficiency (SAI) take place in a gray zone when clinical manifestations are mild. In this situation, more complicated methods that can simulate the response of the HPA axis to a major stress are required. Numerous studies in the assessment of HPA axis have been published in the world literature. In this review, the tests used in the diagnosis of secondary AI or in the investigation of suspected HPA axis insufficiency are discussed in detail, and in the light of this, various recommendations are made.

Evaluation of plasma ACTH in the metyrapone test is insufficient for the diagnosis of secondary adrenal insufficiency.

Objective: To determine whether a single measurement of ACTH instead of less available in daily practice 11-deoxycortisol assay is sufficient to rule out or confirm secondary adrenal insufficiency (SAI) in the short Metyrapone test. Design: A retrospective analysis of diagnostic tests (Metyrapone and Synacthen tests) performed at our Center between 2016 and 2018 in patients with suspicion of secondary adrenal insufficiency. Material and methods: In 103 patients short metyrapone test was performed with assessment of 11-deoxycortisol and ACTH concentration after Metyrapone administered at midnight. In 89 of them short Synacthen (SST) test was also done (1 or/and 250 mcg 1-24ACTH). ROC curves have been performed to evaluate the diagnostic performance of ACTH level in metyrapone test as the predictor of secondary adrenal insufficiency (SAI) analysing sensitivity and specificity for various possible thresholds proposed in literature. Results: 40 (39%) of examined subjects were diagnosed as SAI, basing on post-Metyrapone 11-deoxycortisol concentration below 70 µg/l. In this group ACTH concentration was 128.1 ng/l (95% CI 96.8-159.4) versus 289.9 ng/l (95% CI 249.1-330.9) in patients with proper adrenal response. There was only a moderate positive correlation between ACTH and 11-deoxycortisol concentrations (r=0.5; p<0.05). The best cut off value of ACTH in relation to 11-deoxycortisol serum concentrations was 147 ng/l - with sensitivity of 73.2% and specificity 83.9%. However, plasma ACTH was>200ng/ml (the highest threshold proposed in literature) in 8 cases (20%) with positive diagnosis of SAI made on the basis of low 11-deoxycortisole and confirmed in short Synacthen test. Conclusion: Our results indicate that for a valuable evaluation of the results of the metyrapone test, the more readily available plasma ACTH assay cannot replace the measurement of 11-deoxycortisol concentrations.

Central Adrenal Insufficiency Is Rare in Adults With Prader-Willi Syndrome.

CONTEXT: Prader-Willi syndrome (PWS) is associated with several hypothalamic-pituitary hormone deficiencies. There is no agreement on the prevalence of central adrenal insufficiency (CAI) in adults with PWS. In some countries, it is general practice to prescribe stress-dose hydrocortisone during physical or psychological stress in patients with PWS. Side effects of frequent hydrocortisone use are weight gain, osteoporosis, diabetes mellitus, and hypertension-already major problems in adults with PWS. However, undertreatment of CAI can cause significant morbidity-or even mortality. OBJECTIVE: To prevent both over- and undertreatment with hydrocortisone, we assessed the prevalence of CAI in a large international cohort of adults with PWS. As the synacthen test shows variable results in PWS, we only use the metyrapone test (MTP) and insulin tolerance test (ITT). DESIGN: Metyrapone test or ITT in adults with PWS (N = 82) and review of medical files for symptoms of hypocortisolism related to surgery (N = 645). SETTING: Outpatient clinic. PATIENTS OR OTHER PARTICIPANTS: Eighty-two adults with genetically confirmed PWS. MAIN OUTCOME MEASURE: For MTP, 11-deoxycortisol > 230 nmol/L was considered sufficient. For ITT, cortisol > 500 nmol/L (Dutch, French, and Swedish patients) or > 450 nmol/L (British patients) was considered sufficient. RESULTS: Central adrenal insufficiency was excluded in 81 of 82 patients. Among the 645 patients whose medical files were reviewed, 200 had undergone surgery without perioperative hydrocortisone treatment. None of them had displayed any features of hypocortisolism. CONCLUSIONS: Central adrenal insufficiency is rare (1.2%) in adults with PWS. Based on these results, we recommend against routinely prescribing hydrocortisone stress-doses in adults with PWS.

No central adrenal insufficiency found in patients with Prader-Willi syndrome with an overnight metyrapone test.

Background Individuals with Prader-Willi syndrome (PWS) have hypothalamic dysfunction and may have central adrenal insufficiency (CAI). The prevalence of CAI in PWS remains unknown. Methods Twenty-one subjects with PWS aged 4-53 years underwent a low dose adrenocorticotropic hormone (ACTH) stimulation test (LDAST) (1 µg/m2, maximum 1 µg) followed by an overnight metyrapone test (OMT). Metyrapone (30 mg/kg, maximum 3 g) was administered at 2400 h. Cortisol, 11-deoxycortisol (11-DOC) and ACTH levels were collected the following morning at 0800 h. OMT was the standard test for comparison. Peak cortisol ≥15.5 µg/dL (427.6 nmol/L) on LDAST and 0800 h 11-DOC ≥7 µg/dL (200 nmol/L) on OMT were classified as adrenal sufficiency. Results Twenty subjects had 0800 h 11-DOC values ≥7 µg/dL on OMT indicating adrenal sufficiency. One subject had an inconclusive OMT result. Six of the 21 (29%) subjects had peak cortisol <15.5 µg/dL on LDAST. Conclusions We found no evidence of CAI based on OMT, yet 29% of our PWS population failed the LDAST. This suggests that the LDAST may have a high false positive rate in diagnosing CAI in individuals with PWS. OMT may be the preferred method of assessment for CAI in patients with PWS.