Copeptin is increased by nausea and vomiting during hypertonic saline infusion in healthy individuals.

OBJECTIVE: Measurement of hypertonic saline-stimulated copeptin has recently been described for the differentiation of polyuria-polydipsia syndrome. This study aims to determine the copeptin response to intravenous 3% hypertonic saline, including evaluation of adverse effects, in a local cohort of healthy adults >18 years in Australia. DESIGN: Prospective clinical study. METHODS: Twenty healthy volunteers (10 males and 10 females) were recruited. Participants underwent infusion of 3% hypertonic saline via a previously described standardized protocol, until the plasma sodium was ≥150 mmol/L, with measurement of plasma copeptin. RESULTS: Mean peak sodium was 152 mmol/L ± SD 1.4 with osmolality 315 mmol/kg ± SD 3.9. Median volume of hypertonic saline infused to reach target sodium ≥ 150 mmol/L was 1536 mL (IQR 1362, 1992). Mean rate of plasma sodium rise was 5.9 mmol/L/hour ± SD 1.5. Hypertonic saline-stimulated copeptin had non-parametrical distribution with median of 33.8 pmol/L (IQR 27.6, 63.6). Overall median symptom burden was 6/10 (range 3/10-9/10). Copeptin was significantly higher for those who experienced nausea and/or vomiting (n = 13) (median 39.0 pmol/L; IQR 32.5, 90), compared to those participants who did not experience either (median 20.0 pmol/L; IQR 13.0, 31.0) (P = 0.003). There were no serious adverse events. CONCLUSION: Hypertonic saline-stimulated copeptin measurements were similar in our population compared with previously reported reference intervals in healthy volunteers. There is a wide range of stimulated copeptin measurements in the healthy population. Nausea and vomiting are common adverse effects which enhance the copeptin response.

The effect of glucocorticoids on Thrombospondin-1, Osteocalcin and the Thrombospondin-1:Osteocalcin ratio in humans.

OBJECTIVE: Thrombospondin-1 (TSP1), a matricellular protein, and Osteocalcin (OCN), a noncollagenous protein secreted by osteoblasts, are known to be up- and down-regulated, respectively, by glucocorticoids. The aim of this study was to determine whether a ratio between TSP1:OCN was altered by changes in glucocorticoid activity in humans. DESIGN: Prospective observational study. SETTING: Tertiary university hospital in Queensland, Australia. PATIENTS AND MEASUREMENTS: Patients with Cushing's syndrome (CS, n = 19), asthma or giant cell arteritis on chronic prednisolone treatment (PRED, n = 13), adrenal insufficiency (AI, n = 16) and healthy volunteers (HV, n = 20). Plasma TSP1 and serum total OCN were measured by immunoassay at 0800h, 1200h and 1600h in patients with CS, patients with AI taking replacement glucocorticoids, HV before and after 4 mg dexamethasone and PRED patients predose at 800 and 4 hours post-dose at 1200 hours. RESULTS: Plasma TSP1 in CS was higher (P < .0001), and serum OCN was lower (P < .0001) than HV. The TSP1:OCN ratio in HV increased significantly after 4 mg dexamethasone (P < .0001) and in AI after taking their hydrocortisone replacement therapy (P < .001). PRED patients had a higher TSP1:OCN ratio compared with HV at both 800 and 1200 hours (both P < .001), but no significant change occurred from pre- to post-dose. A TSP1:OCN ratio of >73 at 800 hours differentiated CS from HV with a sensitivity of 95% and a specificity of 100%. CONCLUSIONS: The TSP1:OCN ratio is elevated in patients on prednisolone and in patients with CS compared with healthy volunteers. It may be a useful biomarker of total body glucocorticoid activity in humans.

Prospective evaluation of a week one overnight metyrapone test with subsequent dynamic assessments of hypothalamic-pituitary-adrenal axis function after pituitary surgery.

OBJECTIVE: To determine whether an overnight metyrapone test (OMT) within the first week postpituitary surgery can definitively assess the hypothalamic-pituitary-adrenal (HPA) axis, compared with subsequent dynamic tests and glucocorticoid requirement at 6 months. DESIGN: Prospective study measuring morning cortisol levels on days 3 and 4 post-operatively, OMT day 5-7 and week 6, week 6 250 µg short Synacthen test (SST) and week 7 insulin tolerance test (ITT). PATIENTS AND MEASUREMENTS: Forty participants who underwent pituitary surgery at a single centre (Cushing's disease excluded) were followed for at least 6 months. 46% had pre-operative adrenal insufficiency. PRIMARY OUTCOME: week 1 OMT compared to glucocorticoid requirement at 6 months. SECONDARY OUTCOMES: the performance of ITT as a "definitive" test and all tests compared to glucocorticoid requirement at 6 months. RESULTS: Week 1 OMT showed concordance with ITT at week 7 of 78% and glucocorticoid requirement at 6 months of 81% respectively which was not significantly different from post-operative morning cortisol levels; 37% of participants with an abnormal OMT on day 6 had a normal OMT at week 6. All HPA axis tests showed similar concordance with glucocorticoid requirement at 6 months of 80%-85%. CONCLUSIONS: Overnight metyrapone test within the first week after pituitary surgery was no better than an early morning cortisol level at predicting glucocorticoid requirement at 6 months. OMT at week 6 demonstrated recovery of HPA axis in a substantial proportion of participants who failed earlier assessments; thus, definitive testing should be delayed until 6 weeks post-operatively.

Impulse Control Disorders in Dopamine Agonist-Treated Hyperprolactinemia: Prevalence and Risk Factors.

CONTEXT: There are growing reports of dopamine agonist (DA)-induced impulse control disorders (ICDs) in hyperprolactinemic patients. However, the magnitude of this risk and predictive factors remain uncertain. OBJECTIVE: To determine ICD prevalence and risk factors in DA-treated hyperprolactinemic patients compared to community controls. DESIGN, SETTING AND PARTICIPANTS: Multicenter cross-sectional analysis of 113 patients and 99 healthy controls. MAIN OUTCOME MEASURES: Participants completed a neuropsychological questionnaire consisting of the Depression Anxiety Stress Scale (DASS21), Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP-S), Hypersexual Behavior Inventory (HBI), Hypersexual Behavior Consequences Scale and Social Desirability Response Set Scale. Demographic and clinical data were collated to determine ICD risk factors. Patients testing positive for an ICD were offered a semistructured psychological interview. RESULTS: Patients were more likely than controls to test positive by QUIP-S for any ICD (61.1 vs 42.4%, P = .01), hypersexuality (22.1 vs 8.1%, P = .009), compulsive buying (15.9 vs 6.1%, P = .041) and punding (18.6 vs 6.1%, P = 0.012), and by HBI for hypersexuality (8.0 vs 0.0%, P = 0.004). Independent risk factors were male sex (odds ratio [OR] 13.85), eugonadism (OR 7.85), Hardy's tumor score and psychiatric comorbidity (OR 6.86) for hypersexuality, and age (OR 0.95) for compulsive buying. DASS21 subset scores were higher in patients vs controls and in patients with vs without different ICDs. Only 19/51 (37.3%) interviewed patients were aware of the relationship between DAs and ICDs before the study. CONCLUSIONS: DA therapy poses a high, previously underestimated risk of ICDs, especially in the form of hypersexuality in eugonadal men.

Secondary adrenal insufficiency and pituitary dysfunction in oral/transdermal opioid users with non-cancer pain.

Objective To evaluate pituitary function, sexual function and quality of life (QoL) in patients on oral or transdermal opioids. Design and methods Cross-sectional study comparing pituitary function, QoL and sexual function in people on long-term opioid therapy (n = 40) vs an age- and sex-matched control group (n = 25). Baseline pituitary function was assessed on blood samples collected prior to 0900 h. Further testing with corticotropin (250 µg IV) and metyrapone (30 mg/kg) stimulation tests was undertaken on participants with serum cortisol <250 nmol/L. Validated questionnaires completed to assess QoL, fatigue and sexual function. Results Secondary adrenal insufficiency (SAI) was identified on the basis of a failed stimulation test in 22.5% of opioid users vs no controls (P = 0.01). Opioid users with SAI had a higher median morphine-equivalent daily dose (MEDD), P = 0.037 - 50% with MEDD >200 mg and 0% with MEDD <60 mg had SAI. Among male participants, testosterone was inversely associated with BMI (P = 0.001) but not opioid use. A non-significant trend to low testosterone <8 nmol/L in male opioid users (11/24 opioid users vs 2/14 control, P = 0.08) suggests a small subgroup with opioid-induced androgen deficiency. Opioid users had greater fatigue, reduced quality of life in all subsections of the SF-36 and impaired sexual function in both males and females (all scores P < 0.001 compared to controls). Conclusion Long-term opioid therapy was associated with dose-related SAI in over 20% of chronic pain patients and is associated with poor quality of life, fatigue and sexual dysfunction. Obesity confounds the interpretation of opioid-induced male androgen deficiency.

Characterization of the serum and salivary cortisol response to the intravenous 250 µg ACTH1-24 stimulation test.

PURPOSE: The ACTH1-24 stimulation test is commonly used to assess the hypothalamic-pituitary-adrenal (HPA) axis. Given variations in CBG concentration and binding affinity, serum total cortisol may misclassify some patients. Salivary cortisol correlates well with serum free cortisol but is easier to measure and widely available in commercial laboratories. The aim of this study was to investigate the utility of measuring salivary cortisol during the ACTH1-24 stimulation test. DESIGN AND METHODS: Case-control study in a clinical research facility. Eighty-seven patients with suspected cortisol deficiency, twenty-four healthy controls, and ten healthy women on the oral contraceptive (OC) underwent an intravenous 250 µg ACTH1-24 stimulation test. Concordance of ACTH1-24 stimulated serum and salivary cortisol was evaluated. RESULTS: There was a significant difference in serum cortisol between the healthy volunteers and the women on the OC (P < 0.001) but no difference in salivary cortisol. The lower limit of the reference interval for salivary cortisol at 60 min was 26 nmol/L. 27/89 (30%) of tests with suspected HPA axis disorder failed the 60 min serum cortisol cut-off of 500 nmol/L. Of these, 24/27 (89%) had a salivary cortisol of <26 nmol/L. In contrast, 12/19 (63%) tests and 5/43 (12%) tests where the 60 min serum cortisol was 500-599 and ≥600 nmol/L, respectively had a salivary cortisol of <26 nmol/L. CONCLUSIONS: Salivary cortisol provides additional diagnostic value during the 250 µg ACTH1-24 stimulation test in patients with proven or suspected alterations in CBG and potentially those with a borderline 60 min serum cortisol 500-599 nmol/L.

Thrombospondin-1 is a glucocorticoid responsive protein in humans.

OBJECTIVE: Thrombospondin-1 (TSP1) is a matricellular protein whose gene expression has previously been shown to increase acutely after exposure to dexamethasone in vitro. The aim of this study was to determine if TSP1 is altered by acute and chronic states of glucocorticoid excess in human subjects. DESIGN AND METHODS: Three studies have been undertaken to assess the difference or change in TSP1 in response to altered glucocorticoid activity: i) an acute interventional study assessed the effects of a single 4 mg dose of dexamethasone in 20 healthy volunteers; ii) a cross-sectional study compared plasma TSP1 in 20 healthy volunteers and eight patients with Cushing's syndrome; iii) an interventional study assessed the effect on plasma TSP1 of an increase in hydrocortisone dose from ≤20 mg/day to 30 mg/day for 7 days in 16 patients with secondary adrenal insufficiency. RESULTS: In healthy volunteers, 4 mg dexamethasone significantly increased peripheral blood mononuclear cell (PBMC) TSP1 mRNA levels (P<0.0001) and plasma TSP1 concentrations (P<0.0001), peaking at 12 h. Median (interquartile range) plasma TSP1 was higher in Cushing's, 638 (535-756) ng/ml, than in healthy volunteers, 272 (237-336) ng/ml (P<0.0001). Plasma TSP1 >400 ng/ml diagnosed Cushing's syndrome with sensitivity of 100% and specificity of 85%. The higher hydrocortisone dose increased plasma TSP1 from 139 (86-199) to 256 (133-516) ng/ml, (P<0.01) in patients with secondary adrenal insufficiency. CONCLUSIONS: TSP1 is a glucocorticoid responsive protein in humans. Further research is required to determine if plasma TSP1 has a role as a glucocorticoid biomarker.

Continuous subcutaneous hydrocortisone infusion therapy in Addison's disease: a randomized, placebo-controlled clinical trial.

CONTEXT: Patients with Addison's disease (AD) report impaired subjective health status (SHS). Since cortisol exhibits a robust circadian cycle that entrains other biological clocks, impaired SHS may be due to the noncircadian cortisol profile achieved with conventional glucocorticoid replacement. Continuous subcutaneous hydrocortisone infusion (CSHI) reproduces a circadian cortisol profile, but its effects on SHS have not been objectively evaluated. OBJECTIVE: The aim of this study was to determine the effect of CSHI on SHS in AD. SETTING AND DESIGN: This was a multicentre, double-blind, placebo-controlled trial of CSHI vs oral glucocorticoid therapy. Participants received in random order 4 weeks of: CSHI and oral placebo, and subcutaneous placebo and oral hydrocortisone, separated by a 2-week washout period. SHS was assessed using the Short-Form 36 (SF-36), General Health Questionnaire (GHQ-28), Fatigue Scale (FS), Gastrointestinal Symptom Rating Scale (GSRS); and Addison's Quality of Life Questionnaire (AddiQoL). Participants were asked their (blinded) treatment preference. Twenty-four hour urine free cortisol (UFC) and diurnal salivary cortisol collections compared cortisol exposure during each treatment. RESULTS: Ten participants completed the study. Baseline SHS scores (mean ± SE) were consistent with mild impairment: SF-36 physical component summary 48.4 (± 2.4), mental component summary 53.3 (± 3.0); GHQ-28 18.1 (± 3.3); GSRS 3.7 (± 1.6), and AddiQoL 94.7 (± 3.7). FS was similar to other AD cohorts 13.5 (± 1.0) (P = 0.82). UFC between treatments was not different (P = 0.87). The salivary cortisol at 0800 h was higher during CSHI (P = 0.03), but not at any other time points measured. There was no difference between the treatments in the SHS assessments. Five participants preferred CSHI, four oral hydrocortisone, and one was uncertain. CONCLUSIONS: Biochemical measurements indicate similar cortisol exposure during each treatment period, although a more circadian pattern was evident during CSHI. CSHI does not improve SHS in AD with good baseline SHS. This casts some doubt on the potential benefit of circadian cortisol delivery on SHS in AD.