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. OBJECTIVE: To assess 17-hydroxyprogesterone (17OHP) levels and glucocorticoid dose in CAH comparing prednis(ol)one versus modified-release hydrocortisone (MRHC). DESIGN: Six-month open-label randomised phase 3 study and interim analysis of a single-arm extension study. METHODS: Hydrocortisone dose equivalent and 09:00h 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 <36nmol/l (3X upper limit of normal) in 56% of patients. Patients were randomised to continue prednis(ol)one or switch to MRHC at the same hydrocortisone equivalent dose. At 4 weeks, 94% on MRHC and 71% on prednis(ol)one had 17OHP <36nmol/l. At 18 months in the extension study of MRHC, the median MRHC dose was 20 mg /day and 82% had 17OHP <36nmol/l. The percent of patients with 17OHP <36nmol/l on a hydrocortisone dose equivalent ≤25mg /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). CONCLUSIONS: MRHC reduces 17OHP at 09:00h compared to prednis(ol)one and the dose of MRHC can be down-titrated over time in the majority of patients.

Current utility of first-line FT4 and TSH in screening for central hypothyroidism.

BACKGROUND: Thyroid testing strategies vary across laboratories. First-line combined thyroid stimulating hormone (TSH) and freeT4 (FT4) have historically been preferred by many laboratories as this detects individuals with undiagnosed central hypothyroidism who can be missed with a first-line TSH-only strategy. However, an up-to-date evaluation of the utility of this approach is lacking. OBJECTIVES: We investigated the clinical utility of first-line TSH and FT4 in the detection of central hypothyroidism in current day practice. DESIGN, PATIENTS, AND MEASUREMENTS: The All-Wales laboratory information system was queried to identify thyroid function tests in patients aged ≥16 years with decreased FT4 and inappropriate TSH (low-FT4). The 1-year incidence of low-FT4 was determined using mid-year population data. Clinical information of patients with low-FT4 was reviewed to determine causes of low-FT4 and the incidence of central hypothyroidism. RESULTS: The incidence of low-FT4 varied according to FT4 assay method (range: 98-301 cases/100,000 population/year). Fifteen new cases of central hypothyroidism were detected in two health boards, equivalent to 2 cases/100,000 population/year. Positive predictive value of low-FT4 for central hypothyroidism was 2%-4%. In a cross-section of primary care patients, low-FT4 was detected in 0.5% of all thyroid tests with assay-related differences in detection rates. CONCLUSIONS: Although low-FT4 is a common laboratory finding, the incidence of central hypothyroidism remains rare. With the currently increased rates of thyroid testing and increased use of medications that decrease FT4, low-FT4 has a much lower predictive value for central hypothyroidism than previously reported. Thyroid screening strategies will need to balance the yield from first line TSH and FT4 testing with the cost of investigating individuals with non-pathological laboratory abnormalities.

Hormonal control during infancy and testicular adrenal rest tumor development in males with congenital adrenal hyperplasia: a retrospective multicenter cohort study.

IMPORTANCE: Testicular adrenal rest tumors (TARTs), often found in male patients with congenital adrenal hyperplasia (CAH), are benign lesions causing testicular damage and infertility. We hypothesize that chronically elevated adrenocorticotropic hormone exposure during early life may promote TART development. OBJECTIVE: This study aimed to examine the association between commencing adequate glucocorticoid treatment early after birth and TART development. DESIGN AND PARTICIPANTS: This retrospective multicenter (n = 22) open cohort study collected longitudinal clinical and biochemical data of the first 4 years of life using the I-CAH registry and included 188 male patients (median age 13 years; interquartile range: 10-17) with 21-hydroxylase deficiency (n = 181) or 11-hydroxylase deficiency (n = 7). All patients underwent at least 1 testicular ultrasound. RESULTS: TART was detected in 72 (38%) of the patients. Prevalence varied between centers. When adjusted for CAH phenotype, a delayed CAH diagnosis of >1 year, compared with a diagnosis within 1 month of life, was associated with a 2.6 times higher risk of TART diagnosis. TART onset was not predicted by biochemical disease control or bone age advancement in the first 4 years of life, but increased height standard deviation scores at the end of the 4-year study period were associated with a 27% higher risk of TART diagnosis. CONCLUSIONS AND RELEVANCE: A delayed CAH diagnosis of >1 year vs CAH diagnosis within 1 month after birth was associated with a higher risk of TART development, which may be attributed to poor disease control in early life.

Age-related variation in thyroid function - a narrative review highlighting important implications for research and clinical practice.

BACKGROUND: Thyroid hormones are key determinants of health and well-being. Normal thyroid function is defined according to the standard 95% confidence interval of the disease-free population. Such standard laboratory reference intervals are widely applied in research and clinical practice, irrespective of age. However, thyroid hormones vary with age and current reference intervals may not be appropriate across all age groups. In this review, we summarize the recent literature on age-related variation in thyroid function and discuss important implications of such variation for research and clinical practice. MAIN TEXT: There is now substantial evidence that normal thyroid status changes with age throughout the course of life. Thyroid stimulating hormone (TSH) concentrations are higher at the extremes of life and show a U-shaped longitudinal trend in iodine sufficient Caucasian populations. Free triiodothyronine (FT3) levels fall with age and appear to play a role in pubertal development, during which it shows a strong relationship with fat mass. Furthermore, the aging process exerts differential effects on the health consequences of thyroid hormone variations. Older individuals with declining thyroid function appear to have survival advantages compared to individuals with normal or high-normal thyroid function. In contrast younger or middle-aged individuals with low-normal thyroid function suffer an increased risk of adverse cardiovascular and metabolic outcomes while those with high-normal function have adverse bone outcomes including osteoporosis and fractures. CONCLUSION: Thyroid hormone reference intervals have differential effects across age groups. Current reference ranges could potentially lead to inappropriate treatment in older individuals but on the other hand could result in missed opportunities for risk factor modification in the younger and middle-aged groups. Further studies are now needed to determine the validity of age-appropriate reference intervals and to understand the impact of thyroid hormone variations in younger individuals.

Postradioiodine Graves' management: The PRAGMA study.

OBJECTIVE: Thyroid status in the months following radioiodine (RI) treatment for Graves' disease can be unstable. Our objective was to quantify frequency of abnormal thyroid function post-RI and compare effectiveness of common management strategies. DESIGN: Retrospective, multicentre and observational study. PATIENTS: Adult patients with Graves' disease treated with RI with 12 months' follow-up. MEASUREMENTS: Euthyroidism was defined as both serum thyrotropin (thyroid-stimulating hormone [TSH]) and free thyroxine (FT4) within their reference ranges or, when only one was available, it was within its reference range; hypothyroidism as TSH ≥ 10 mU/L, or subnormal FT4 regardless of TSH; hyperthyroidism as TSH below and FT4 above their reference ranges; dysthyroidism as the sum of hypo- and hyperthyroidism; subclinical hypothyroidism as normal FT4 and TSH between the upper limit of normal and <10 mU/L; and subclinical hyperthyroidism as low TSH and normal FT4. RESULTS: Of 812 patients studied post-RI, hypothyroidism occurred in 80.7% and hyperthyroidism in 48.6% of patients. Three principal post-RI management strategies were employed: (a) antithyroid drugs alone, (b) levothyroxine alone, and (c) combination of the two. Differences among these were small. Adherence to national guidelines regarding monitoring thyroid function in the first 6 months was low (21.4%-28.7%). No negative outcomes (new-onset/exacerbation of Graves' orbitopathy, weight gain, and cardiovascular events) were associated with dysthyroidism. There were significant differences in demographics, clinical practice, and thyroid status postradioiodine between centres. CONCLUSIONS: Dysthyroidism in the 12 months post-RI was common. Differences between post-RI strategies were small, suggesting these interventions alone are unlikely to address the high frequency of dysthyroidism.

The impact of endoscopic transsphenoidal pituitary adenoma surgery on endocrine function: a single-centre study.

INTRODUCTION: The outcome for pituitary endocrine function following endoscopic transsphenoidal surgery remains unclear. This study aims to evaluate endocrine outcomes following endoscopic surgery in order to provide a benchmark to assist in the counselling of patients perioperatively. METHODS: A prospectively held pituitary database was retrospectively analysed for all adult pituitary adenoma patients undergoing endoscopic surgery from May 2011 to May 2017. All operations were performed by a single neurosurgeon at a regional centre for pituitary surgery. Functioning and non-functioning adenomas were included. Hormonal status was assessed at most recent follow-up. RESULTS: One hundred forty-five patients (69 M, 76 F) were included in the study with a median age of 52 years. Median follow-up was 52 months. Eighty-eight patients (61%) were not taking any hormone replacement medications, whilst 57 patients (39%) required hormone replacement therapy (HRT) preoperatively. Preoperatively, 29 patients (20%) had hypothalamo-pituitary-adrenal (HPA) axis dysfunction, 39 patients (27%) had thyroid axis dysfunction, 11 males (16%) and 7 females (9%) had gonadal axis dysfunction, and one patient had preoperative diabetes insipidus. Postoperatively, 26 patients (18%) had a new deficiency in pituitary function, whilst 6 patients (11%) were able to cease HRT. Nineteen patients (13%) had new HPA axis deterioration, 12 (8%) had new thyroid axis dysfunction, 8 males (11%) and 4 females (5%) had gonadal axis deterioration, and 6 patients (4%) had new diabetes insipidus (DI). CONCLUSIONS: The ability to restore pituitary function following endoscopic surgery remains limited, whilst new deficits still occur. It is essential that patients are counselled accordingly as hormonal replacement therapy can have a significant impact on quality of life. Larger longer-term collaborative studies of endocrine outcome in endoscopic pituitary surgery are needed.

Spinal epidural lipomatosis: a rare association of Cushing's disease.

SUMMARY: Excess cortisol is associated with hypertrophy and redistribution of adipose tissue leading to central obesity which is classically seen in Cushing's syndrome. Abnormal accumulation of fatty tissue in the spinal canal is most commonly associated with chronic steroid therapy and rarely reported with endogenous Cushing's syndrome. Herein, we describe a case of spinal epidural lipomatosis (SEL) associated with Cushing's disease. A 17-year-old man was referred with lower limb weakness, weight gain, multiple stretch marks, back pain and loss of height. He had clinical and biochemical features of Cushing's syndrome. MRI and Inferior Petrosal Sinus Sampling (IPSS) confirmed a pituitary adenoma as the source. On day 1 post trans-sphenoidal adenectomy he developed spastic paraparesis with a sensory deficit to the level of T5. MRI spine showed increased fat deposition in the spinal canal from T2 to T9 consistent with a diagnosis of SEL. He was managed conservatively and made a good recovery following restoration of eucortisolism and a period of rehabilitation. LEARNING POINTS: SEL is a serious complication of glucocorticoid excess and should be considered in any patient presenting with new lower limb neurological symptoms associated with hypercortisolism. It is important to distinguish symptomatic SEL from cortisol-induced proximal myopathy by good history and clinical examination. MRI of the spine is the gold standard investigation for making a diagnosis of SEL. Restoration of eucortisolism can lead to resolution of fat accumulation and good neurological outcome.

Oxytocin therapy in hypopituitarism: Challenges and opportunities.

Patients with hypopituitarism display impaired quality of life and excess morbidity and mortality, despite apparently optimal pituitary hormone replacement. Oxytocin is a neuropeptide synthesized in the anterior hypothalamus which plays an important role in controlling social and emotional behaviour, body weight and metabolism. Recent studies have suggested that a deficiency of oxytocin may be evident in patients with hypopituitarism and craniopharyngioma, and that this may be associated with deficits in cognitive empathy. Preliminary data hint at potential benefits of oxytocin therapy in improving these deficits and the accompanying metabolic disturbances that are common in these conditions. However, several challenges remain, including an incomplete understanding of the regulation and mechanisms of action of oxytocin, difficulties in accurately measuring oxytocin levels and in establishing a diagnosis of oxytocin deficiency, and a need to determine both the optimal mode of administration for oxytocin therapy and an acceptable safety profile with long-term use. This review considers the data linking oxytocin to the neuropsychological and metabolic disturbances evident in patients with craniopharyngioma and hypopituitarism, and describes the challenges that need to be overcome before replacement therapy can be considered as a therapeutic option in clinical practice.

A randomised, open-label, parallel group phase 2 study of antisense oligonucleotide therapy in acromegaly.

OBJECTIVE: ATL1103 is a second-generation antisense oligomer targeting the human growth hormone (GH) receptor. This phase 2 randomised, open-label, parallel-group study assessed the potential of ATL1103 as a treatment for acromegaly. DESIGN: Twenty-six patients with active acromegaly (IGF-I >130% upper limit of normal) were randomised to subcutaneous ATL1103 200 mg either once or twice weekly for 13 weeks and monitored for a further 8-week washout period. METHODS: The primary efficacy measures were change in IGF-I at week 14, compared to baseline and between cohorts. For secondary endpoints (IGFBP3, acid labile subunit (ALS), GH, growth hormone-binding protein (GHBP)), comparison was between baseline and week 14. Safety was assessed by reported adverse events. RESULTS AND CONCLUSIONS: Baseline median IGF-I was 447 and 649 ng/mL in the once- and twice-weekly groups respectively. Compared to baseline, at week 14, twice-weekly ATL1103 resulted in a median fall in IGF-I of 27.8% (P = 0.0002). Between cohort comparison at week 14 demonstrated the median fall in IGF-I to be 25.8% (P = 0.0012) greater with twice-weekly dosing. In the twice-weekly cohort, IGF-I was still declining at week 14, and remained lower at week 21 than at baseline by a median of 18.7% (P = 0.0005). Compared to baseline, by week 14, IGFBP3 and ALS had declined by a median of 8.9% (P = 0.027) and 16.7% (P = 0.017) with twice-weekly ATL1103; GH had increased by a median of 46% at week 14 (P = 0.001). IGFBP3, ALS and GH did not change with weekly ATL1103. GHBP fell by a median of 23.6% and 48.8% in the once- and twice-weekly cohorts (P = 0.027 and P = 0.005) respectively. ATL1103 was well tolerated, although 84.6% of patients experienced mild-to-moderate injection-site reactions. This study provides proof of concept that ATL1103 is able to significantly lower IGF-I in patients with acromegaly.

Bariatric Surgery Is Accompanied by Changes in Extracellular Vesicle-Associated and Plasma Fatty Acid Binding Protein 4.

BACKGROUND: Bariatric surgery markedly reduces fat mass with beneficial effects on cardiometabolic health but the mechanisms involved are not fully understood. Extracellular vesicles (EVs) are secreted by a variety of cells, including adipocytes, and may mediate some of these benefits. However, the effects of bariatric surgery on circulating EVs are unclear. METHODS: Concentration of plasma EVs isolated by ultracentrifugation at baseline, 1 and 6 months post-bariatric surgery (n = 20) was established using Nanoparticle Tracking Analysis. EV origin (CD9: exosome; CD41: platelet; CD235a: erythrocyte; CD11b: leukocyte; CD144: endothelial), cytokine (interferon γ, interleukin-6, TNF-α) and adipocyte marker (adiponectin, FABP4, PPARγ) expression was measured by time-resolved fluorescence immunoassay. RESULTS: EV concentration and cell-of-origin markers (CD41, CD235a, CD11b, CD144) did not alter in response to surgery, neither did EV-expressed interferon γ, IL-6, TNF-α, adiponectin, PPARγ or CD9. EV-derived fatty acid binding protein 4 (FABP4) increased at 1 month (+ 49%) before returning to baseline by 6 months (- 51%, p < 0.05), corresponding to similar changes in circulating plasma FABP4 (+ 22 and - 24% at 1 and 6 months, respectively; p < 0.001). Patients who underwent biliopancreatic diversion had lower FABP4-expressing EVs at 6 months compared to those who underwent sleeve gastrectomy/gastric banding (p < 0.05), despite similar percentage weight reduction (- 19 vs - 20%, respectively). CD9 expression correlated with EV-expressed FABP4, adiponectin, TNF-α and interferon γ (r = 0.5, r = 0.59, r = 0.53, r = 0.41, respectively, p < 0.005), suggesting transport by an EV population of exosomal rather than microvesicular origin. CONCLUSIONS: Bariatric surgery leads to a transient change in circulating EV- and plasma-derived FABP4, reflecting alterations in adipose tissue homeostasis.

Oxytocin increases attention to the eyes and selectively enhances self-reported affective empathy for fear.

Oxytocin (OXT) has previously been implicated in a range of prosocial behaviors such as trust and emotion recognition. Nevertheless, recent studies have questioned the evidence for this link. In addition, there has been relatively little conclusive research on the effect of OXT on empathic ability and such studies as there are have not examined the mechanisms through which OXT might affect empathy, or whether OXT selectively facilitates empathy for specific emotions. In the current study, we used eye-tracking to assess attention to socially relevant information while participants viewed dynamic, empathy-inducing video clips, in which protagonists expressed sadness, happiness, pain or fear. In a double-blind, within-subjects, randomized control trial, 40 healthy male participants received 24 IU intranasal OXT or placebo in two identical experimental sessions, separated by a 2-week interval. OXT led to an increase in time spent fixating upon the eye-region of the protagonist's face across emotions. OXT also selectively enhanced self-reported affective empathy for fear, but did not affect cognitive or affective empathy for other emotions. Nevertheless, there was no positive relationship between eye-gaze patterns and affective empathy, suggesting that although OXT influences eye-gaze and may enhance affective empathy for fear, these two systems are independent. Future studies need to further examine the effect of OXT on eye-gaze to fully ascertain whether this can explain the improvements in emotional behavior.

Maturation in Serum Thyroid Function Parameters Over Childhood and Puberty: Results of a Longitudinal Study.

Context: Serum thyroid hormone levels differ between children and adults, but have not been studied longitudinally through childhood. Objective: To assess changes in thyroid-stimulating hormone (TSH) and thyroid hormone levels over childhood and their interrelationships. Design: Cohort study. Setting: The Avon Longitudinal Study of Parents and Children, a population-based birth cohort. Participants: A total of 4442 children who had thyroid function measured at age 7, and 1263 children who had thyroid function measured at age 15. Eight hundred eighty-four children had measurements at both ages. Main Outcome Measures: Reference ranges for TSH, free tri-iodothyronine (FT3), free thyroxine (FT4), their longitudinal stability, and interrelationships. Results: Children at age 7 years had a higher FT3 [6.17 pmol/L, standard deviation (SD) 0.62] than children at age 15 (5.83 pmol/L, SD 0.74); P < 0.0001 with 23.2% of children at age 7 having FT3 above the adult reference range. Higher FT3 levels at age 7 in boys (P = 0.0001) and girls (P = 0.04) were associated with attainment of a more advanced pubertal stage at age 13. TSH was positively associated with FT3 at age 7 and age 15 even after adjusting for confounders. In contrast, TSH was negatively associated with FT4. Conclusions: There are substantial changes in TSH and thyroid hormone levels over childhood, in particular for FT3, which appear to relate to pubertal readiness. Our data provide increased insight into the evolution of the pituitary-thyroid axis over childhood and may have implications for determining optimal ranges for thyroid hormone replacement in children.

Cerebral salt wasting following traumatic brain injury.

SUMMARY: Hyponatraemia is the most commonly encountered electrolyte disturbance in neurological high dependency and intensive care units. Cerebral salt wasting (CSW) is the most elusive and challenging of the causes of hyponatraemia, and it is vital to distinguish it from the more familiar syndrome of inappropriate antidiuretic hormone (SIADH). Managing CSW requires correction of the intravascular volume depletion and hyponatraemia, as well as mitigation of on-going substantial sodium losses. Herein we describe a challenging case of CSW requiring large doses of hypertonic saline and the subsequent substantial benefit with the addition of fludrocortisone. LEARNING POINTS: The diagnosis of CSW requires a high index of suspicion. Distinguishing it from SIADH is essential to enable prompt treatment in order to prevent severe hyponatraemia.The hallmarks of substantial CSW are hyponatraemia, reduced volume status and inappropriately high renal sodium loss.Substantial volumes of hypertonic saline may be required for a prolonged period of time to correct volume and sodium deficits.Fludrocortisone has a role in the management of CSW. It likely reduces the doses of hypertonic saline required and can maintain serum sodium levels of hypertonic saline.

Oxytocin Reduces Face Processing Time but Leaves Recognition Accuracy and Eye-Gaze Unaffected.

OBJECTIVES: Previous studies have found that oxytocin (OXT) can improve the recognition of emotional facial expressions; it has been proposed that this effect is mediated by an increase in attention to the eye-region of faces. Nevertheless, evidence in support of this claim is inconsistent, and few studies have directly tested the effect of oxytocin on emotion recognition via altered eye-gaze Methods: In a double-blind, within-subjects, randomized control experiment, 40 healthy male participants received 24 IU intranasal OXT and placebo in two identical experimental sessions separated by a 2-week interval. Visual attention to the eye-region was assessed on both occasions while participants completed a static facial emotion recognition task using medium intensity facial expressions. RESULTS: Although OXT had no effect on emotion recognition accuracy, recognition performance was improved because face processing was faster across emotions under the influence of OXT. This effect was marginally significant (p<.06). Consistent with a previous study using dynamic stimuli, OXT had no effect on eye-gaze patterns when viewing static emotional faces and this was not related to recognition accuracy or face processing time. CONCLUSIONS: These findings suggest that OXT-induced enhanced facial emotion recognition is not necessarily mediated by an increase in attention to the eye-region of faces, as previously assumed. We discuss several methodological issues which may explain discrepant findings and suggest the effect of OXT on visual attention may differ depending on task requirements. (JINS, 2017, 23, 23-33).

Paradoxical Relationship Between Body Mass Index and Thyroid Hormone Levels: A Study Using Mendelian Randomization.

CONTEXT: Free T3 (FT3) has been positively associated with body mass index (BMI) in cross-sectional studies in healthy individuals. This is difficult to reconcile with clinical findings in pathological thyroid dysfunction. OBJECTIVE: We aimed to investigate whether childhood adiposity influences FT3 levels. DESIGN: Mendelian randomization using genetic variants robustly associated with BMI. SETTING: Avon Longitudinal Study of Parents and Children, a population-based birth cohort. PARTICIPANTS: A total of 3014 children who had thyroid function measured at age 7, who also underwent dual x-ray absorptiometry scans at ages 9.9 and 15.5 years and have genetic data available. MAIN OUTCOME MEASURES: FT3. RESULTS: Observationally at age 7 years, BMI was positively associated with FT3: ß-standardized (ß-[std]) = 0.12 (95% confidence interval [CI]: 0.08, 0.16), P = 4.02 × 10(-10); whereas FT4 was negatively associated with BMI: ß-(std) = -0.08 (95% CI: -0.12, -0.04), P = 3.00 × 10(-5). These differences persisted after adjustment for age, sex, and early life environment. Genetic analysis indicated 1 allele change in BMI allelic score was associated with a 0.04 (95% CI: 0.03, 0.04) SD increase in BMI (P = 6.41 × 10(-17)). At age 7, a genetically determined increase in BMI of 1.89 kg/m(2) was associated with a 0.22 pmol/L (95% CI: 0.07, 0.36) increase in FT3 (P = .004) but no substantial change in FT4 0.01 mmol/L, (95% CI: -0.37, 0.40), P = .96. CONCLUSION: Our analysis shows that children with a genetically higher BMI had higher FT3 but not FT4 levels, indicating that higher BMI/fat mass has a causal role in increasing FT3 levels. This may explain the paradoxical associations observed in observational analyses. Given rising childhood obesity levels, this relationship merits closer scrutiny.

Salivary Oxytocin Concentrations in Males following Intranasal Administration of Oxytocin: A Double-Blind, Cross-Over Study.

The use of intranasal oxytocin (OT) in research has become increasingly important over the past decade. Although researchers have acknowledged a need for further investigation of the physiological effects of intranasal administration, few studies have actually done so. In the present double-blind cross-over study we investigated the longevity of a single 24 IU dose of intranasal OT measured in saliva in 40 healthy adult males. Salivary OT concentrations were significantly higher in the OT condition, compared to placebo. This significant difference lasted until the end of testing, approximately 108 minutes after administration, and peaked at 30 minutes. Results showed significant individual differences in response to intranasal OT administration. To our knowledge this is the largest and first all-male within-subjects design study to demonstrate the impact of intranasal OT on salivary OT concentrations. The results are consistent with previous research in suggesting that salivary OT is a valid matrix for OT measurement. The results also suggest that the post-administration 'wait-time' prior to starting experimental tasks could be reduced to 30 minutes, from the 45 minutes typically used, thereby enabling testing during peak OT concentrations. Further research is needed to ascertain whether OT concentrations after intranasal administration follow similar patterns in females, and different age groups.

Effectiveness of Metyrapone in Treating Cushing's Syndrome: A Retrospective Multicenter Study in 195 Patients.

BACKGROUND: Cushing's syndrome (CS) is a severe condition with excess mortality and significant morbidity necessitating control of hypercortisolemia. There are few data documenting use of the steroidogenesis inhibitor metyrapone for this purpose. OBJECTIVE: The objective was to assess the effectiveness of metyrapone in controlling cortisol excess in a contemporary series of patients with CS. DESIGN: This was designed as a retrospective, multicenter study. SETTING: Thirteen University hospitals were studied. PATIENTS: We studied a total of 195 patients with proven CS: 115 Cushing's disease, 37 ectopic ACTH syndrome, 43 ACTH-independent disease (adrenocortical carcinoma 10, adrenal adenoma 30, and ACTH-independent adrenal hyperplasia 3). MEASUREMENTS: Measurements included biochemical parameters of activity of CS: mean serum cortisol "day-curve" (CDC) (target 150-300 nmol/L); 9 am serum cortisol; 24-hour urinary free cortisol (UFC). RESULTS: A total of 164/195 received metyrapone monotherapy. Mean age was 49.6 ± 15.7 years; mean duration of therapy 8 months (median 3 mo, range 3 d to 11.6 y). There were significant improvements on metyrapone, first evaluation to last review: CDC (91 patients, 722.9 nmol/L [26.2 µg/dL] vs 348.6 nmol/L [12.6 µg/dL]; P < .0001); 9 am cortisol (123 patients, 882.9 nmol/L [32.0 µg/dL] vs 491.1 nmol/L [17.8 µg/dL]; P < .0001); and UFC (37 patients, 1483 nmol/24 h [537 µg/24 h] vs 452.6 nmol/24 h [164 µg/24 h]; P = .003). Overall, control at last review: 55%, 43%, 46%, and 76% of patients who had CDCs, UFCs, 9 am cortisol less than 331 nmol/L (12.0 µg/dL), and 9 am cortisol less than upper limit of normal/600 nmol/L (21.7 µg/dL). Median final dose: Cushing's disease 1375 mg; ectopic ACTH syndrome 1500 mg; benign adrenal disease 750 mg; and adrenocortical carcinoma 1250 mg. Adverse events occurred in 25% of patients, mostly mild gastrointestinal upset and dizziness, usually within 2 weeks of initiation or dose increase, all reversible. CONCLUSIONS: Metyrapone is effective therapy for short- and long-term control of hypercortisolemia in CS.

The diagnosis and management of inpatient hyponatraemia and SIADH.

BACKGROUND: Hyponatraemia is a very common medical condition that is associated with multiple poor clinical outcomes and is often managed suboptimally because of inadequate assessment and investigation. Previously published guidelines for its management are often complex and impractical to follow in a hospital environment, where patients may present to divergent specialists, as well as to generalists. DESIGN: A group of senior, experienced UK clinicians, met to develop a practical algorithm for the assessment and management of hyponatraemia in a hospital setting. The latest evidence was discussed and reviewed in the light of current clinical practicalities to ensure an up-to-date perspective. An algorithm was largely developed following consensus opinion, followed up with subsequent additions and amendments that were agreed by all authors during several rounds of review. RESULTS: We present a practical algorithm which includes a breakdown of the best methods to evaluate volume status, simple assessments for the diagnosis of the various causes and a straightforward approach to treatment to minimise complexity and maximise patient safety. CONCLUSION: The algorithm we have developed reflects the best available evidence and extensive clinical experience and provides practical, useable guidance to improve patient care.