Warrick J. Inder

Exercise-induced right ventricular dysfunction and structural remodelling in endurance athletes

AIMSnEndurance training may be associated with arrhythmogenic cardiac remodelling of the right ventricle (RV). We examined whether myocardial dysfunction following intense endurance exercise affects the RV more than the left ventricle (LV) and whether cumulative exposure to endurance competition influences cardiac remodelling (including fibrosis) in well-trained athletes.nnnMETHODS AND RESULTSnForty athletes were studied at baseline, immediately following an endurance race (3-11 h duration) and 1-week post-race. Evaluation included cardiac troponin (cTnI), B-type natriuretic peptide, and echocardiography [including three-dimensional volumes, ejection fraction (EF), and systolic strain rate]. Delayed gadolinium enhancement (DGE) on cardiac magnetic resonance imaging (CMR) was assessed as a marker of myocardial fibrosis. Relative to baseline, RV volumes increased and all functional measures decreased post-race, whereas LV volumes reduced and function was preserved. B-type natriuretic peptide (13.1 ± 14.0 vs. 25.4 ± 21.4 ng/L, P = 0.003) and cTnI (0.01 ± .03 vs. 0.14 ± .17 μg/L, P < 0.0001) increased post-race and correlated with reductions in RVEF (r = 0.52, P = 0.001 and r = 0.49, P = 0.002, respectively), but not LVEF. Right ventricular ejection fraction decreased with increasing race duration (r = -0.501, P < 0.0001) and VO(2)max (r = -0.359, P = 0.011). Right ventricular function mostly recovered by 1 week. On CMR, DGE localized to the interventricular septum was identified in 5 of 39 athletes who had greater cumulative exercise exposure and lower RVEF (47.1 ± 5.9 vs. 51.1 ± 3.7%, P = 0.042) than those with normal CMR.nnnCONCLUSIONnIntense endurance exercise causes acute dysfunction of the RV, but not the LV. Although short-term recovery appears complete, chronic structural changes and reduced RV function are evident in some of the most practiced athletes, the long-term clinical significance of which warrants further study.

Antipsychotic-induced hyperprolactinaemia

Background and objectives: Antipsychotic medications are a potential cause of hyperprolactinaemia and may be implicated in the development of pituitary adenomas. This review examines the effect of different antipsychotic medications on prolactin and sexual function, and provides practical guidelines for investigation and management of antipsychotic-induced hyperprolactinaemia. Method: Literature review. Results and conclusions: Antipsychotic-induced hyperprolactinaemia occurs overall in up to 70% of patients with schizophrenia, depending on the medications used. It is associated with significant levels of hypogonadism and sexual dysfunction, which in general relates to the degree of prolactin elevation. A consequence of the hypogonadism is clinically significant bone loss which may lead to osteoporosis and increased risk of minimal trauma fracture. Where the potentially offending drug cannot be safely withdrawn to document a normal prolactin, imaging with MRI should be undertaken to exclude a structural pituitary lesion. The management strategy of choice is switching to a prolactin-sparing antipsychotic. Sex steroid replacement can reverse many of the adverse effects including the hypogonadal symptoms and bone loss. Low dose dopamine agonist therapy should be used with caution as a third line treatment, since there have been cases of dopamine agonist-induced exacerbation of psychosis. There is a need for a randomised controlled trial of low dose dopamine agonist therapy versus sex steroid replacement to establish the relative safety and efficacy of each approach.

Adiponectin, skeletal muscle adiponectin receptor expression and insulin resistance following dexamethasone

Objectiveu2002 Skeletal muscle is a major site of adiponectin action and of glucocorticoid‐induced insulin resistance. Little human data exist however, regarding the impact of exogenous glucocorticoids on adiponectin receptors in skeletal muscle.

Prandial regulation of ghrelin secretion in humans: does glucagon contribute to the preprandial increase in circulating ghrelin?

Objectiveu2002 Glucagon secretion is stimulated by fasting and inhibited postprandially, a pattern that mimics the secretory profiles of both ghrelin and GH. We thus hypothesized that glucagon may be a determinant of the changes in circulating ghrelin and GH that occur in relation to meals. The objective of the study was to explore this hypothesis by determining the ghrelin and GH response to a bolus of glucagon or saline in healthy subjects.

Free and Total Plasma Cortisol Measured by Immunoassay and Mass Spectrometry Following ACTH1–24 Stimulation in the Assessment of Pituitary Patients

CONTEXTnMeasurement of plasma cortisol by immunoassay after ACTH₁₋₂₄ stimulation is used to assess the hypothalamic-pituitary-adrenal (HPA) axis. Liquid chromatography-tandem mass spectrometry (LCMS) has greater analytical specificity than immunoassay and equilibrium dialysis allows measurement of free plasma cortisol.nnnOBJECTIVEnWe investigated the use of measuring total and free plasma cortisol by LCMS and total cortisol by immunoassay during an ACTH₁₋₂₄ stimulation test to define HPA status in pituitary patients.nnnDESIGN AND SETTINGnThis was a case control study conducted in a clinical research facility.nnnPARTICIPANTSnWe studied 60 controls and 21 patients with pituitary disease in whom HPA sufficiency (n = 8) or deficiency (n = 13) had been previously defined.nnnINTERVENTIONnParticipants underwent 1 μg ACTH(1-24) intravenous and 250 μg ACTH₁₋₂₄ intramuscular ACTH₁₋₂₄ stimulation tests.nnnMAIN OUTCOME MEASURESnConcordance of ACTH₁₋₂₄-stimulated total and free plasma cortisol with previous HPA assessment.nnnRESULTSnTotal cortisol was 12% lower when measured by immunoassay than by LCMS. Female sex and older age were positively correlated with ACTH₁₋₂₄-stimulated total and free cortisol, respectively. Measurements of total cortisol by immunoassay and LCMS and free cortisol 30 minutes after 1 μg and 30 and 60 minutes after 250 μg ACTH₁₋₂₄ were concordant with previous HPA axis assessment in most pituitary patients. However, free cortisol had greater separation from the diagnostic cutoff than total cortisol.nnnCONCLUSIONSnCategorization of HPA status by immunoassay and LCMS after ACTH₁₋₂₄ stimulation was concordant with previous assessment in most pituitary patients. Free cortisol may have greater clinical use in patients near the diagnostic threshold.

Evidence for transcript-specific epigenetic regulation of glucocorticoid-stimulated skeletal muscle 11β-hydroxysteroid dehydrogenase-1 activity in type 2 diabetes

BackgroundThe enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) converts inactive cortisone into active cortisol in insulin target tissues. In people with type 2 diabetes, skeletal muscle (SkM) 11βHSD1 is upregulated by the potent glucocorticoid dexamethasone. The HSD11B1 gene has two promoters designated P1 and P2. CCAAT/enhancer-binding protein beta (C/EBPβ) is known to regulate expression of 11βHSD1 via the P2 promoter. In this study, we investigated the potential role of altered DNA methylation of the P1 and P2 promoters in the observed dexamethasone-induced upregulation of SkM 11βHSD1 oxoreductase activity in human diabetic subjects. SkM biopsies from 15 people with type 2 diabetes were collected before and after treatment with oral dexamethasone 4 mg/day for 4 days and SkM 11βHSD1, C/EBPβ and P1 and P2 promoter region mRNA levels were measured by quantitative RT-PCR. 11βHSD1 oxoreductase activity was quantified by measuring the conversion of radiolabeled 3H-cortisone to cortisol by thin layer chromatography. Analysis of HSD11B1 promoter methylation (P1 and P2) was performed using Sequenom MassARRAY EpiTYPER analysis.ResultsDexamethasone treatment resulted in a significant increase in 11βHSD1 mRNA levels (P = 0.003), oxoreductase activity (P = 0.017) and C/EBPβ mRNA (P = 0.015), and increased expression of both the P1 (P = 0.008) and P2 (P = 0.016) promoter regions . The distal P1 promoter region showed a significant reduction in methylation following dexamethasone (P = 0.026). There was a significant negative correlation between the change in methylation at this site and the increment in 11βHSD1 oxoreductase activity (r = −0.62, P = 0.014).ConclusionsOur findings of reduced methylation in the HSD11B1 P1 promoter in association with increased 11βHSD1 oxoreductase activity implicate complex multi-promoter epigenetic mechanisms in the regulation of 11βHSD1 levels in SkM.

Investigation of cushing’s syndrome

In the biochemical investigation of suspected Cushing’s syndrome, screening tests are used to identify potential cases and should have high sensitivity, be inexpensive and easy to perform. Appropriate screening tests are a midnight salivary cortisol and/or the 1xa0mg dexamethasone suppression test (DST). Normal screening tests indicate the patient is unlikely to have Cushing’s syndrome. An abnormal screening test should be followed up by diagnostic testing using 24 hour urinary free cortisol levels and either a low dose oral or iv DST. After the diagnosis of Cushing’s syndrome is confirmed, differential diagnostic testing should be undertaken. A suppressed plasma ACTH suggests adrenal disease. Those with ACTH-dependent Cushing’s require further localising investigation to distinguish between pituitary and ectopic sources of ACTH. The current gold standard is bilateral inferior petrosal sinus sampling (IPSS). The relative sensitivity and specificity of other biochemical tests in the differential diagnosis of ACTH-dependent Cushing’s will be discussed. The majority of cases will have Cushing’s disease, where the treatment of choice is trans-sphenoidal pituitary surgery. There is no clear consensus of what constitutes biochemical remission post-operatively; the strictest definition requires a plasma cortisol of