Cortisol Deficiency in Lenvatinib Treatment of Thyroid Cancer: An Underestimated Common Adverse Event.

Background: Lenvatinib treatment has shown a significant improvement in progression-free survival in patients with metastatic, progressive, radioiodine-refractory differentiated thyroid cancer, although its use is associated with considerable toxicity. Fatigue is one of the most frequent adverse events (AEs). It has been reported that adrenal insufficiency (AI) may be involved in lenvatinib-related fatigue. In our study, we assessed the pituitary/adrenal axis before and during treatment, and the possible involvement of AI in lenvatinib-related fatigue. This was done to clarify the incidence, development, and time course of AI during lenvatinib treatment. Methods: We studied 13 patients who were selected for lenvatinib therapy. Adrenal function was evaluated by measuring cortisol and adrenocorticotropic hormone (ACTH) levels and through the ACTH (250 µg) stimulation test. Results: During treatment, seven patients (54%) developed AI. High levels of ACTH were observed in accordance with the diagnosis of primary AI (PAI). By evaluating the first ACTH test, before starting lenvatinib treatment, we found that patients with <646.6 nmol/L cortisol peak had an increased risk of developing PAI during lenvatinib treatment. Fatigue was observed in 11 patients (84.6%) during lenvatinib treatment. Cortisone acetate treatment induced an improvement in fatigue in six of seven patients (85.7%) in the PAI group, without the need to change the lenvatinib dosage. Conclusions: PAI may be considered one of the most common AEs associated with lenvatinib. Our data strongly suggest that PAI could be involved in lenvatinib-associated fatigue, particularly in patients with extreme fatigue. In this context, early diagnosis of PAI is essential, especially since glucocorticoid replacement therapy can induce a significant improvement in fatigue, without the need to reduce the dosage of lenvatinib. However, further studies are required to confirm these preliminary findings.

The broad phenotypic spectrum of 17α-hydroxylase/17,20-lyase (CYP17A1) deficiency: a case series.

CONTEXT: 17α-Hydroxylase/17,20-lyase deficiency (17OHD) caused by mutations in the CYP17A1 gene is a rare form of congenital adrenal hyperplasia typically characterised by cortisol deficiency, mineralocorticoid excess and sex steroid deficiency. OBJECTIVE: To examine the phenotypic spectrum of 17OHD by clinical and biochemical assessment and corresponding in silico and in vitro functional analysis. DESIGN: Case series. PATIENTS AND RESULTS: We assessed eight patients with 17OHD, including four with extreme 17OHD phenotypes: two siblings presented with failure to thrive in early infancy and two with isolated sex steroid deficiency and normal cortisol reserve. Diagnosis was established by mass spectrometry-based urinary steroid profiling and confirmed by genetic CYP17A1 analysis, revealing homozygous and compound heterozygous sequence variants. We found novel (p.Gly111Val, p.Ala398Glu, p.Ile371Thr) and previously described sequence variants (p.Pro409Leu, p.Arg347His, p.Gly436Arg, p.Phe53/54del, p.Tyr60IlefsLys88X). In vitro functional studies employing an overexpression system in HEK293 cells showed that 17,20-lyase activity was invariably decreased while mutant 17α-hydroxylase activity retained up to 14% of WT activity in the two patients with intact cortisol reserve. A ratio of urinary corticosterone over cortisol metabolites reflective of 17α-hydroxylase activity correlated well with clinical phenotype severity. CONCLUSION: Our findings illustrate the broad phenotypic spectrum of 17OHD. Isolated sex steroid deficiency with normal stimulated cortisol has not been reported before. Attenuation of 17α-hydroxylase activity is readily detected by urinary steroid profiling and predicts phenotype severity. SIGNIFICANCE STATEMENT: Here we report, supported by careful phenotyping, genotyping and functional analysis, a prismatic case series of patients with congenital adrenal hyperplasia due to 17α-hydroxylase (CYP17A1) deficiency (17OHD). These range in severity from the abolition of function, presenting in early infancy, and unusually mild with isolated sex steroid deficiency but normal ACTH-stimulated cortisol in adult patients. These findings will guide improved diagnostic detection of CYP17A1 deficiency.

Occurrence of Hypopituitarism in Tunisian Turner Syndrome patients: familial versus sporadic cases.

OBJECTIVE: To explore unusual association between Turner Syndrome (TS) and Hypopituitarism in a Tunisian cohort. METHODS: We reported 6 patients with TS associated to Hypopituitarism, including three familial cases except the fourth sister who showed only a TS phenotype. Biochemical analysis, resonance magnetic imaging and cytogenetic analyses were performed. RESULTS: The average age of our patients was 17.2 years (11-31 years). They were all referred for short stature and pubertal delay, except for the fourth sister who presented spontaneous puberty with the integrity of the pituitary axis and the presence of an X ring chromosome. Karyotype analysis showed monosomy in 3 cases and a mosaic TS in the 3 remaining cases, including one patient with abnormal X chromosome structure. Somatotropic and corticotropic deficiencies were confirmed in 2 sporadic cases while the gonadotropic and thyrotropic axes were spared. In contrast; familial cases were consistently affected by the integrity of the corticotropic axis. MRI showed pituitary hypoplasia in all familial cases and pituitary stalk interruption syndrome in only one sporadic case. No correlation was found between the chromosome formula and the anterior pituitary involvement. CONCLUSION: Co-segregation of congenital Hypopituitarism with pituitary hypoplasia and X chromosome aberrations could imply a molecular anomaly of transcription factors responsible for the differentiation and development of pituitary cells such as PROP1, POUF1, Hesx1, Lhx3, Lhx4. The etiopathogenic link between X chromosome abnormalities and the occurrence of Hypopituitarism remains unclear; however, the progress of molecular biology may clarify the interrelation between transcription factors and sex chromosome segregation abnormalities.

Immune checkpoint inhibitor combination therapies very frequently induce secondary adrenal insufficiency.

Immune checkpoint inhibitors (ICIs) are potent therapeutic options for many types of advanced cancer. The expansion of ICIs use however has led to an increase in immune-related adverse events (irAEs). Secondary adrenal insufficiency (AI) can be life-threatening especially in patients with delayed diagnosis. We retrospectively investigated secondary AI in ICI-treated patients. A total of 373 cancer patients treated with ICIs were included and evaluated. An adrenocorticotropic hormone (ACTH) deficiency was described in 13 patients. Among 24 patients with a combination of nivolumab and ipilimumab therapy, 7 patients (29%) developed secondary AI in a median time of 8 weeks during the combination therapy and 2 of 15 patients (13%) developed isolated ACTH deficiency during maintenance nivolumab monotherapy following the combination therapy. More than half of the patients (4/7) with a combination therapy-induced multiple anterior hormone deficiencies was diagnosed as secondary AI based on regular ACTH and cortisol tests with slight subjective symptoms. Secondary AI can arise frequently and rapidly in cancer patients receiving a combination ICI therapy, and thus we speculate active surveillance of AI using regular ACTH and cortisol tests during the combination therapy might be useful for avoiding life-threatening conditions due to secondary AI.

Minimally invasive partial versus total adrenalectomy for unilateral primary hyperaldosteronism-a retrospective, multicenter matched-pair analysis using the new international consensus on outcome measures.

BACKGROUND: Primary hyperaldosteronism is a recognized risk factor for myocardial infarction, stroke, and atrial fibrillation. Minimally invasive adrenalectomy is the first-line treatment for localized primary hyperaldosteronism. Whether minimally invasive adrenalectomy should be performed using a cortex-sparing technique (partial minimally invasive adrenalectomy) or not (total minimally invasive adrenalectomy) remains a subject of debate. The aim of our study was to evaluate the clinical and biochemical efficacy of both procedures and to examine the morbidity associated with partial minimally invasive adrenalectomy versus total minimally invasive adrenalectomy in a multicenter study. METHODS: Using a retrospective study design, we determined the efficacy, morbidity, and mortality of partial minimally invasive adrenalectomy and total minimally invasive adrenalectomy. The Primary Aldosteronism Surgical Outcome Study classification was used to explore clinical and biochemical success. Matched-pair analysis was used in order to address possible bias. RESULTS: We evaluated 234 matched patients with unilateral primary hyperaldosteronism: 78 (33.3%) underwent partial minimally invasive adrenalectomy, and 156 (66.7%) were treated with total minimally invasive adrenalectomy. Complete clinical success was achieved in 40.6%, and partial clinical success in an additional 52.6% of patients in the entire cohort. Complete biochemical success was seen in 94.0% of patients. Success rates and the incidence of perioperative complications were comparable between groups. Both postoperative hypocortisolism (11.5% vs 25.0% after partial minimally invasive adrenalectomy and total minimally invasive adrenalectomy, respectively; P < .001) and postoperative hypoglycemia (2.6% vs 7.1% after partial minimally invasive adrenalectomy and total minimally invasive adrenalectomy; P = .039) occurred more frequently after total minimally invasive adrenalectomy. CONCLUSION: Our study provides evidence that patients with unilateral primary hyperaldosteronism are good surgical candidates for partial minimally invasive adrenalectomy. Not only is the surgical outcome comparable to that of total minimally invasive adrenalectomy, but also postsurgical morbidity, particularly in terms of hypocortisolism and hypoglycemia, may be reduced.

Pituitary stalk interruption syndrome: A rare case report and literature review.

RATIONALE: Pituitary stalk interruption syndrome (PSIS) is a congenital pituitary anatomical defect. It is characterized by the triad of thin or interrupted pituitary stalk, absent or ectopic posterior lobe, and hypoplastic or aplastic anterior lobe. Moreover, this condition is considered rare. PATIENT CONCERNS: A 23-year-old male patient presented with a history of short stature and hypogonadism. Laboratory assessment revealed low thyroxine, cortisol, and adrenocorticotropic hormone levels, which are consistent with adrenal insufficiency without hypoglycemia. The insulin-induced hypoglycemia tolerance test finding indicated growth hormone (GH) deficiency. Moreover, magnetic resonance imaging revealed an interrupted pituitary stalk, ectopic posterior pituitary, and hypoplastic anterior pituitary. This triad of symptoms was indicative of PSIS. DIAGNOSIS: INTERVENTIONS:: The patient was deficient in adrenaline, thyroxine, gonadal steroid, and GH. Thus, glucocorticoid replacement therapy was initiated, followed by euthyrox, androgen, and human chorionic gonadotropin treatment. Calcium tablets, calcitriol, and alendronate sodium were used for the management of osteoporosis. The patient was 164 cm tall, and his bone age was approximately 15 years old. However, owing to a poor economic condition, the family did not proceed with GH therapy. OUTCOMES: The patient did not present with adrenal or hypothyroidism crisis after receiving poly-hormonal replacement therapy. His secondary sexual characteristics began to develop. However, owing to a short treatment window period, the patient could not receive the required treatment. Hence, whether the patient would have a normal fertility function needs to be confirmed. LESSONS: PSIS is a rare disease with various clinical characteristics. During the neonatal period and infancy, the signs and symptoms of PSIS are often not evident. Therefore, diagnosis is delayed. The early detection of hormone deficiency and treatment initiation can affect both the quality of life and the prognosis of patients with PSIS. Thus, the diagnosis and treatment of this disease must be improved to help patients achieve a better quality of life and to prevent reproductive health problems.

Selective perioperative steroid supplementation protocol in patients undergoing endoscopic transsphenoidal surgery for pituitary adenomas.

BACKGROUND: There is no consensus regarding the use of perioperative steroids for transsphenoidal pituitary surgery. We audited the effectiveness and safety of our selective perioperative steroid supplementation protocol in patients with pituitary adenomas. METHODS: Two hundred ninety-seven patients underwent 306 endoscopic transsphenoidal surgeries for removal of their pituitary tumors. Steroids were given to those with an impaired hypothalamic-pituitary-adrenal (HPA) axis, age ≥ 60 years, clinical apoplexy, hyponatremia, or if the pituitary gland was not preserved at surgery. We excluded 111 patients in whom the integrity of the HPA axis could not be determined. We compared the incidence of early postoperative adrenal insufficiency and complications in 135 patients with intact HPA axes who underwent surgery without steroids (group A) with 60 patients who had compromised preoperative HPA axes and received perioperative steroids (group B). In addition, we audited the total number of protocol violations during this period. RESULTS: Five patients (3.7%) in group A developed postoperative hypocortisolemia. There was no significant difference in the incidence of cerebrospinal fluid leak, diabetes insipidus, or hyponatremia between both groups. There were protocol deviations in 47 (15.4%) patients. Twenty one of these patients did not receive perioperative steroids in violation of the protocol, of whom 4 (19%) developed postoperative hypocortisolemia. CONCLUSIONS: Our steroid sparing protocol was both safe and effective. The 15% incidence of protocol deviations is a reminder that the rigorous usage of checklists is mandatory for successful clinical practice.

GDF15 Is Elevated in Conditions of Glucocorticoid Deficiency and Is Modulated by Glucocorticoid Replacement.

CONTEXT: GDF15 is a stress-induced hormone acting in the hindbrain that activates neural circuitry involved in establishing aversive responses and reducing food intake and body weight in animal models. Anorexia, weight loss, nausea and vomiting are common manifestations of glucocorticoid deficiency, and we hypothesized that glucocorticoid deficiency may be associated with elevated levels of GDF15. OBJECTIVE: To determine the impact of primary adrenal insufficiency (PAI) and glucocorticoid replacement on circulating GDF15 levels. METHODS AND RESULTS: We measured circulating concentrations of GDF15 in a cohort of healthy volunteers and Addison's disease patients following steroid withdrawal. Significantly higher GDF15 (mean ± standard deviation [SD]) was observed in the Addison's cohort, 739.1 ± 225.8 pg/mL compared to healthy controls, 497.9 ± 167.7 pg/mL (P = 0.01). The effect of hydrocortisone replacement on GDF15 was assessed in 3 independent PAI cohorts with classical congenital adrenal hyperplasia or Addison's disease; intravenous hydrocortisone replacement reduced GDF15 in all groups. We examined the response of GDF15 to increasing doses of glucocorticoid replacement in healthy volunteers with pharmacologically mediated cortisol deficiency. A dose-dependent difference in GDF15 (mean ± SD) was observed between the groups with values of 491.0 ± 157.7 pg/mL, 427.0 ± 152.1 pg/mL and 360 ± 143.1 pg/mL, in the low, medium and high glucocorticoid replacement groups, respectively, P < .0001. CONCLUSIONS: GDF15 is increased in states of glucocorticoid deficiency and restored by glucocorticoid replacement. Given the site of action of GDF15 in the hindbrain and its effects on appetite, further study is required to determine the effect of GDF15 in mediating the anorexia and nausea that is a common feature of glucocorticoid deficiency.

The prevalence and clinical profile of adrenocortical deficiency among HIV infected persons in Northern Nigeria.

BACKGROUND: Infection with the human immune deficiency virus (HIV) is still a prevalent problem in Africa. OBJECTIVES: The aim of this study was to determine the prevalence of hypocortisolism among patients with HIV and their clinical profile at Aminu Kano Teaching Hospital (AKTH), Kano, Nigeria. METHOD: Three hundred and fifty adult patients with HIV infection were recruited from the HIV clinic of AKTH, Kano. Blood samples for serum electrolytes, and cortisol both before and after the short Synacthen test were taken for estimation. Data were analyzed using the SPSS version 20.0 software. RESULTS: One hundred and eight (30.9%) of participants had low baseline serum cortisol levels, while 57 (16.3%) had a low serum cortisol after short synacthen test. There was no significant relationship between the cortisol levels and clinical features of hypocortisolism, WHO clinical stage of HIV, hypernatremia or HAART regimen. There was a negative correlation between the stimulated serum cortisol and duration of diagnosis of HIV, participants BMI and CD4 counts. CONCLUSION: The biochemical evidence of hypocortisolism was common among patients infected with HIV, associated with a longer duration of HIV infection. However, none of CD4 counts, clinical features or HAART regimen were associated with hypocortisolism.

Predictive Factors for Rathke's Cleft Cyst Consistency.

OBJECTIVE: Rathke's cleft cysts (RCCs) may have various anatomic, clinical, and radiologic characteristics, which may be related to their differences in texture or consistency. The purpose of the study was to investigate RCCs based on consistency. METHODS: We retrospectively reviewed 25 cases of patients with RCCs who underwent endoscopic endonasal transsphenoidal surgery between 2008 and 2018. Cases were divided into 3 types based on cyst consistency: fluid (serous) or type A (n = 4); semi-fluid (mucoid) or type B (n = 17); and non-fluid (caseous) or type C (n = 4). Demographic, clinical, radiologic, and surgical characteristics for each group were analyzed. RESULTS: All type A RCCs (100%) had visual impairment. The mean age (42.8 ± 13 years) and cyst volume (2442.5 ± 533.6 mm3) were higher in these patients. T1-weighted images were hypointense and T2-weighted images were hyperintense on magnetic resonance imaging. Type B RCCs were more frequently encountered (68%). Although headache was the most common (82.3%) symptom, endocrine disorders were also prevalent (52.9%). T1-weighted images were typically isointense or hyperintense on magnetic resonance imaging. Type C RCCs had the youngest patient population (30.3 ± 10.2 years) and T2-weighted images were predominantly hypointense in this group. CONCLUSIONS: The proposed novel consistency classification of RCCs will provide a practical tool for more accurately estimating the nature of the pathology, because each type has its own specific characteristics. Furthermore, the new classification of RCCs may aid in planning a consistency-specific surgery.

Glucocorticoid Activity of Adrenal Steroid Precursors in Untreated Patients With Congenital Adrenal Hyperplasia.

CONTEXT AND OBJECTIVE: We describe the clinical features and biochemical characteristics of a unique population of severely affected untreated patients with congenital adrenal hyperplasia (CAH) from an Indonesian population with proven cortisol deficiency but without clinical signs of cortisol deficiency. We evaluated the in vitro glucocorticoid activity of all relevant adrenal steroid precursors occurring in patients with CAH. DESIGN: Cross-sectional cohort study and translational research. INTERVENTION/MAIN OUTCOME MEASURES: Adrenal steroid precursor concentrations before and 60 minutes after ACTH administration to 24 untreated patients with CAH (3 to 46 years) with proven cortisol deficiency (<500 nmol/L post-ACTH) measured by liquid chromatography-tandem mass spectrometry were compared with six control patients (Mann-Whitney U test). Glucocorticoid receptor (GR) activation was determined by dual-luciferase assays in human embryonic kidney cells transfected with the GR and exposed to increasing amounts of adrenal steroid precursors for 24 hours. RESULTS: Blood concentrations of the steroid precursors 11-deoxycortisol (457 nmol/L, P = 0.003), 11-deoxycorticosterone (55 nmol/L, P = 0.003), 17-hydroxyprogesterone (610 nmol/L, P < 0.001), progesterone (29 nmol/L, P < 0.001), and 21-deoxycortisol (73 nmol/L) were strongly elevated compared with control subjects. The GR was activated with comparable potency to cortisol by corticosterone and 21-deoxycortisol or with 4 to 100 times lower potency by 11-hydroxyprogesterone, 11-deoxycortisol, aldosterone, 11-deoxycorticosterone, progesterone, and 17-hydroxyprogesterone. CONCLUSIONS: We identified strongly elevated adrenal steroid precursor concentrations in blood from untreated patients with CAH and demonstrated glucocorticoid activity of these adrenal precursors in vitro, suggesting a possible role of these precursors in the clinical phenotype of these patients. Further studies are necessary to evaluate the role of these precursors in more detail.

Hypophysitis and other autoimmune complications related to immune checkpoints inhibitors´ treatment: Spectrum of imaging appearances.

OBJECTIVES: Immune checkpoints inhibitors (ICI) represent a new therapy option for the treatment of several advanced tumors. However, this therapy has been linked to a spectrum of ICI related autoimmune (AI) adverse events. Some may be life threatening and their diagnosis is tricky. The aim of our study was to describe various imaging appearances of ICI related secondary hypophysitis and other coincidental AI diseases. MATERIAL AND METHODS: We included 28 patients (19 females, 9 men, mean aged 58±13 years), who were consecutively treated mostly for advanced stage melanoma by different ICI. All their CT/MRI records and clinical data were reviewed. RESULTS: We found 5 (18%) cases of endocrinology proven secondary hypophysitis; 2 cases of panhypopituitarism and 3 cases of central hypocortisolism. Four cases were MRI positive, 1 case was MRI negative. Three cases were accompanied by other AI diseases: 1 by hemorrhagic colitis and mesenterial lymphadenitis, 1 by AI pancreatitis and 1 by pneumonitis. On MRI pituitary gland was swollen in 3 cases, twice enhanced non-homogenously, once homogenously; infundibular enlargement was present in 2 cases. Those 3 cases reacted to glucocorticoid therapy by hypophyseal shrinkage. In 1 case of MRI positive hypophysitis, the pituitary gland was not enlarged, slightly nonhomogeneous with peripheral contour enhancement; no reaction to glucocorticoids was mentioned. CONCLUSION: Secondary hypophysitis is probably more common ICI related adverse event than reported in the literature. Its MRI appearance is variable. Most of our cases were in coincidence with other AI ICI related events that affected their clinical manifestations.

MECHANISMS OF ENDOCRINOLOGY: Endocrinology of opioids

The use of opioids has grown substantially over the past two decades reaching the dimensions of a global epidemic. These drugs have effects on multiple levels of the endocrine system through mechanisms which are still not fully elucidated, and awareness of their endocrine sequelae is vital for all specialists prescribing or managing patients on them. Hypogonadism is the most well-recognised consequence of opioid use (prevalence 21­86%) which, however, may remain undiagnosed with potential adverse outcomes for the patients. Although less frequent, cortisol deficiency can also be found. Furthermore, there is a negative impact on bone health (with reduced bone mineral density and increased fracture risk) and occasionally hyperprolactinaemia, whereas the clinical significance of alterations in other hormones remains to be clarified. Discontinuation or reduction of the opioid and, in cases of chronic pain, consideration of alternative therapies for pain relief are potential management options. Hormonal replacement, especially when the above measures are not practically feasible, needs to be considered. Further studies are needed to clearly establish the prevalence of hormonal abnormalities with various regimes, doses and routes of opioids and to address reliably the long-term benefits and risks of hormonal treatment in patients on opioids. Until evidence-based, safe and cost-effective clinical guidelines become available, periodical assessment of the gonadal and adrenal function (particularly when relevant clinical manifestations are present) and evaluation of the bone health status are advised.

Cortisol deficiency as a rare cause of neonatal cholestasis.

Cortisol deficiency constitutes a rare cause of neonatal cholestasis. The aim of this manuscript was to present the pathogenesis of cortisol deficiency in neonatal cholestasis. The authors also present the characteristics of selected disorders resulting in cortisol deficiency.

Congenital Adrenal Hyperplasia (CAH) due to 21-Hydroxylase Deficiency: A Comprehensive Focus on 233 Pathogenic Variants of CYP21A2 Gene.

Congenital adrenal hyperplasia (CAH) comprises a group of autosomal recessive disorders caused by complete or partial defects in one of the several steroidogenic enzymes involved in the synthesis of cortisol from cholesterol in the adrenal glands. More than 95-99% of all cases of CAH are caused by deficiency of steroid 21-hydroxylase, an enzyme encoded by the CYP21A2 gene. Currently, CYP21A2 genotyping is considered a valuable complement to biochemical investigations in the diagnosis of 21-hydroxylase deficiency. More than 200 mutations have been described in literature reports, and much energy is still focused on the clinical classification of new variants. In this review, we focus on molecular genetic features of 21-hydroxylase deficiency, performing an extensive survey of all clinical pathogenic variants modifying the whole sequence of the CYP21A2 gene. Our aim is to offer a very useful tool for clinical and genetic specialists in order to ease clinical diagnosis and genetic counseling.

Suboptimal rise in awakening-induced cortisol is an accurate marker of cortisol insufficiency in patients with normal renal function (eGFR >60 mL/min).

Background The insulin tolerance test is the gold standard for diagnosis of cortisol insufficiency. However, it is cumbersome, invasive, requires supervised hospital facilities and has unpleasant side-effects. A non-invasive outpatient-based test will be useful. We hypothesized that free cortisol concentrations in multiple spot urine samples can be used to diagnose cortisol insufficiency in patients with normal renal function (eGFR > 60 mL/min). Method Patients and controls provided urine samples at bedtime (S1), and first (S2) and second (S3) void the next day. Cortisol and creatinine were measured in all three samples, and cortisol:creatinine ratio (S1, S2 and S3) was used for further analysis. The sum of S1 + S2 + S3 was used to calculate total cortisol secretion (T). Variation (V) in cortisol secretion in response to circadian rhythm was calculated as the modulus of the difference between S1 and S2 and S2 and S3. Results Samples were collected from 96 controls and 11 patients. S1 was significantly lower vs . S2 and S3 in controls ( P < 0.0001) but not in patients. S2, S3, T and V were significantly lower in patients vs . controls ( P < 0.0001). ROC curve analysis using insulin tolerance test as gold standard showed that S2, S3, T and V were all equally accurate diagnostic markers for cortisol insufficiency (AUC: 0.87, NPV: 100%). The best balance of sensitivity and specificity was achieved using T (sensitivity: 100%, specificity: 58%). Conclusion Multiple spot urine samples test is an accurate, relatively inexpensive, non-invasive, convenient outpatient-based screening test for exclusion of cortisol insufficiency.

Human studies on hypothalamo-pituitary-adrenal (HPA) axis.

The daily rhythm of the hypothalamo-pituitary-adrenal (HPA) axis is regulated by the central clock in the suprachiasmatic nucleus. Cortisol, a glucocorticoid, acts as a secondary messenger between the central clock and the peripheral tissues. Changes in clock time, as seen in shift workers, alters the HPA axis and results in metabolic disturbances associated with ill health. Depression, anorexia nervosa and obstructive sleep apnoea, are associated with cortisol rhythm phase shifts and increased cortisol exposure. Higher nocturnal cortisol exposure is observed in patients with Cushing's syndrome and adrenal incidentalomas with autonomous cortisol secretion and is associated with insulin resistance, and increased cardiovascular risk and mortality. A decrease in cortisol rhythm amplitude is seen in adrenal insufficiency, and despite replacement, patients have an impaired quality of life and increased mortality. Research on cortisol replacement has focused on replacing the cortisol daily rhythm by subcutaneous hydrocortisone infusions and oral modified release hydrocortisone formulations with the aim of improving disease control and quality of life.