Cognition and testosterone replacement therapy

Testosterone replacement therapy in postmenopausal women might preserve cognitive function according to results of a single-centre, double-blind, randomised, placebo-controlled trial presented by Susan Davis (Monash University, Melbourne, VIC, Australia). Women participating in the study were aged 55—65 years, not receiving other hormone replacement therapy, and had normal cognitive function. 92 participants were randomly assigned to receive 220 μg per day of transdermal testosterone gel or placebo for 26 weeks, and were assessed for cognitive function at 0, 12, and 26 weeks. Results of intention-to-treat analyses showed women receiving testosterone treatment scored 1·57 points higher on a 48-point scale for verbal learning and memory than did women in the placebo group, a change roughly equal to the cognitive decline reported over 1 year in a patient with Alzheimer’s disease. Other cognitive measures did not differ between treatment groups. These results suggest that normalising testosterone in postmenopausal women to concentrations found in younger women might help to preserve visual learning and memory abilities with age.

Sleep irregularities or restriction are increasingly associated with metabolic dysfunction. Blind individuals unable to perceive light frequently have sleep disorders, such as non-24-h sleep-wake disorder, due to dysregulation of light-regulated circadian rhythms. Steven Lockely (Harvard Medical School, Boston, MA, USA) presented the results of two phase 3 randomised, multicentre, double-blind, placebo-controlled trials that tested tasimelteon to treat individuals that have non-24-h sleep-wake disorder. Tasimelteon is a selective agonist for melatonin receptors MT1 and MT2 hypothesised to entrain the sleep cycles of blind individuals with non-24-h sleep-wake disorder. In the Safety and Efficacy of Tasimelteon (SET) study, 84 patients were randomly assigned to receive tasimelteon or placebo for up to 6 months. Significantly more patients receiving tasimelteon than those receiving placebo were entrained after 6 months of treatment (20% vs 3%, p=0·0171). In the Randomised-withdrawal Study of the Efficacy and Safety of Tasimelteon (RESET), 20 blind individuals with non-24-h sleep-wake disorder who had been entrained with tasimelteon treatment were randomly assigned to continue taking the drug, or switch to placebo, for 2 months. 90% taking the drug maintained entrainment versus 20% taking placebo (p=0·0026), suggesting that continuous treatment with tasimelteon is needed to maintain benefit. Tasimelteon was safe and well tolerated and caused a low incidence of minor adverse events such as nausea, headache, and sleepiness. This drug might also have a role for other indications such as delayed sleep phase disorder or jetlag.

Preliminary results of a randomised controlled trial, presented by J Atilio Canas (Nemours Children’s Clinic, Jacksonville, FL, USA), showed that atorvastatin is safe and effective for reducing LDL cholesterol and other atherogenic lipoprotein particles in children with type 1 diabetes. Children with type 1 diabetes have a high risk of cardiometabolic complications later in life and thus early management of lipoprotein might prove beneficial. After a 3 month run-in period, 42 children with type 1 diabetes were randomly assigned to receive atorvastatin (n=21) or placebo (n=21) for 6 months. At baseline, all randomly assigned children had significantly higher concentrations of lipoprotein subfractions than a control group of healthy children. After 6 months, concentrations of atherogenic lipoproteins had decreased significantly in type 1 diabetic children receiving atorvastatin, whereas those in the placebo group stayed the same or increased. HbA1c concentrations remained the same in both groups. No severe adverse events related to atorvastatin were reported.

In some countries, adolescents with gender dysphoria can be treated with gonadotropic-releasing hormone analogues (GnRHa) to reversibly suppress puberty, lessening psychological difficulties. Whether such treatment affects the development of other systems, particularly bone, has been unclear. Henriette Delemarre-van de Waal (Leiden University Medical Center, Leiden, Netherlands) presented the results of a study done in the Netherlands in which 126 adolescents aged 12—14 years received GnRHa for up to 4 years, after which they began receiving cross-sex hormones involved in gender reassignment. GnRHa treatment for up to 4 years did not affect insulin sensitivity, or amounts of cholesterol, HDL, or LDL. Normal accumulation of bone mass was slowed with GnRHa treatment, but rapidly recovered to amounts seen in untreated individuals once treatment with cross-sex hormones was started. Studies in progress will address the effects of GnRH treatment on brain development and function.

Pancreatic neuroendocrine tumours (pNETs) are the second most common tumour in patients with multiple endocrine neoplasia type 1 (MEN1), and the leading cause of MEN1-related death. Sophie van Asselt (University of Groningen, Groningen, Netherlands) presented results showing that endoscopic ultrasound (EUS) is better than CT or MRI for pNET yearly screening in patients with MEN1. In a prospective, multicentre, cross-sectional study, 41 patients with genetically confirmed MEN1 were screened by CT or MRI, EUS, and 11C-5-hydroxytryptophan PET (11C-5-HTP PET). 102 pancreatic lesions were reported in 35 patients. EUS was more sensitive than CT or MRI, both at the patient level (tumours detected in 97% vs51% of patients) and the lesion level (94% vs 30% of lesions detected). Screening by 11C-5-HTP PET contributed no added value. A limitation of the study was the absence of histological confirmation of the pNETs; follow-up studies will assess clinical outcomes.

Bart Clarke (Mayo Clinic, Rochester, MN, USA) presented results of the PARADOX study, which aimed to characterise in detail the symptoms of individuals with hypoparathyroidism. 374 patients from the USA participated in an internet-based survey that included questions about clinical symptoms and quality of life. The results showed many patients had symptoms not previously thought to be associated with low calcium concentrations, such as mental confusion and exercise and heat intolerance. Despite supplementation with vitamin D and calcium, almost all patients that responded to the survey continued to have symptoms, and 69% had cormorbid disorders including arrhythmias (66%) and kidney stones (35%). Limitations of this study will be addressed in a long-term follow-up, the PARADIGM study, which will involve creating a registry of several thousand patients, not limited to the USA. Trials investigating a new drug for hypoparathyroidism, PTH(1—84), are in progress.

US hospital readmissions for paediatric diabetic ketoacidosis (DKA) are frequent, despite being preventable. A retrospective study presented by Faisal Malik (University of Washington, Seattle, WA, USA) assessed data from 42 children’s hospitals: 12 488 patients aged 2—18 years were admitted between 2004 and 2007 and followed up for 5 years. 28·3% of children were readmitted for DKA one or more times within 1 year of a previous admission. Characteristics associated with risk of readmission were age 12 years or older, female sex, mental health disorder, non-hispanic black ethnicity, or having public health insurance. Because each readmission for paediatric DKA costs an average of US$7162, and DKA can be reduced by better education and disease management, scope exists to reduce the number of readmissions.

Low-dose androgen improves quality of life in Klinefelter syndrome (47, XXY) according to Judith Ross (Alfred I duPont Hospital for Children, Philadelphia, PA, USA) who presented a subset of results from a randomised clinical trial. In addition to hypogonadism and reduced fertility, Klinefelter syndrome is associated with a range of cognitive, behavioural, and motor deficits, some of which might be due to androgen deficiency in childhood. 93 prepubertal boys aged 4—12 years were randomly assigned to receive oxandrolone (n=46) or placebo (n=47) for 2 years. Children were tested at baseline, 1 year, and 2 years with standard questionnaires to assess anxiety and depression; at the same timepoints, parents responded to questionnaires that assessed child behaviour. After 2 years, children that had received oxandrolone had more positive scores for anxiety and depression than at baseline, whereas those in the placebo group scored the same as at baseline. Parents of children in the oxandrolone group documented improvements in several child behavioural measures, whereas parents of children in the placebo group did not report changes. No major adverse events were noted.

Kathryn Hackman (The Alfred Hospital, Melbourne, VIC, Australia) presented results of a single-centre retrospective study showing that diabetes is a major contributor to mortality in patients who have had a lung transplant. In 367 patients that received a lung transplant between 2001 and 2010, diabetes increased the risk of mortality by five times—more than any other risk factor. Surprisingly, the commonest cause of death was chronic graft rejection rather than diabetic complications. Whether patients had diabetes before or after transplant did not affect outcomes. These results call for more focused efforts to screen and prevent diabetes in patients who have received a lung transplant. Outstanding questions are whether glycaemic control affects graft function, and whether tight glycaemic control might improve outcomes in transplant recipients.

Source: Lancet