Are the adverse effects of glitazones linked to induced testosterone deficiency?

BACKGROUND: Adverse side-effects of the glitazones have been frequently reported in both clinical and animal studies, especially with rosiglitazone (RGZ) and pioglitazone (PGZ), including congestive heart failure, osteoporosis, weight gain, oedema and anaemia. These led to consideration of an evidence-based hypothesis which would explain these diverse effects, and further suggested novel approaches by which this hypothesis could be tested. PRESENTATION OF HYPOTHESIS: The literature on the clinical, metabolic and endocrine effects of glitazones in relation to the reported actions of testosterone in diabetes, metabolic syndrome, and cardiovascular disease is reviewed, and the following unifying hypothesis advanced: "Glitazones induce androgen deficiency in patients with Type 2 Diabetes Mellitus resulting in pathophysiological changes in multiple tissues and organs which may explain their observed clinical adverse effects." This also provides further evidence for the lipocentric concept of diabetes and its clinical implications. TESTING OF THE HYPOTHESIS: Clinical studies to investigate the endocrine profiles, including measurements of TT, DHT, SHBG, FT and estradiol, together with LH and FSH, in both men and women with T2DM before and after RGZ and PGZ treatment in placebo controlled groups, are necessary to provide data to substantiate this hypothesis. Also, studies on T treatment in diabetic men would further establish if the adverse effects of glitazones could be reversed or ameliorated by androgen therapy. Basic sciences investigations on the inhibition of androgen biosynthesis by glitazones are also warranted. IMPLICATIONS OF THE HYPOTHESIS: Glitazones reduce androgen biosynthesis, increase their binding to SHBG, and attenuate androgen receptor activation, thus reducing the physiological actions of testosterone, causing relative and absolute androgen deficiency. This hypothesis explains the adverse effects of glitazones on the heart and other organs resulting from reversal of the action of androgens in directing the maturation of stem cells towards muscle, vascular endothelium, erythroid stem cells and osteoblasts, and away from adipocyte differentiation. The higher incidence of side-effects with RGZ than PGZ, may be explained by a detailed study of the mechanism by which glitazones down-regulate androgen biosynthesis and action, resulting in a state of androgen deficiency.

Androgens, andropause and neurodegeneration: exploring the link between steroidogenesis, androgens and Alzheimer's disease.

The relationship between menopause and cognitive decline has been the subject of intense research since a number of studies have shown that hormone replacement therapy could reduce the risk of developing Alzheimer's disease in women. In contrast, research into andropause has only recently begun. Furthermore, evidence now suggests that steroidogenesis is not restricted to the gonads and adrenals, and that the brain is capable of producing its own steroid hormones, including testosterone and estrogen. Sex hormones have been demonstrated to be of critical importance in the embryonic development of the central nervous system (CNS); however, we are only just beginning to understand the role that these hormones may play in the normal functioning and repair of the adult mammalian CNS. This review will summarize current research into the role of androgens and andropause on cognition and the possible mechanisms of action of androgens, with particular reference to Alzheimer's disease.

Propofol intravenous conscious sedation for anxious children in a specialist paediatric dentistry unit.

OBJECTIVES: To report on both the use and dosage of propofol, as a new intravenous (IV) conscious sedative agent, for anxious children referred to a specialist paediatric dentistry service. SETTING: Paediatric Dentistry Unit, Glasgow Dental Hospital and School. SAMPLE: Thirty-four children, 25 females and 9 males, mean age 12 years 10 months, with a mean weight of 54.6 kg (range 30-110 kg). METHODS: Report from 34 patients receiving intravenous sedation for the first time in respect of weight dose and amount of treatment completed. RESULTS: Thirty-two children successfully accepted operative dental care on their first visit, they received a mean total dose of 146.25 mg of propofol (range 10 mg to 356 mg); in relation to body weight, the mean was 2.5 mg/kg (range 0.2-5.4 mg/kg). The treatment that they received included fissure sealants, amalgam and adhesive restorations, root canal therapy and single and multiple extractions. Their sedation and recovery were uneventful. CONCLUSIONS: Sub-anaesthetic doses of propofol used for IV conscious sedation infusion facilitated operative dental treatment in anxious children.

Polymorphisms in PNLIP, encoding pancreatic lipase, and associations with metabolic traits.

Pancreatic lipase (EC 3.1.1.3) is an exocrine secretion that hydrolyzes dietary triglycerides in the small intestine. We developed genomic amplification primers to sequence the 13 exons of PNLIP, which encodes pancreatic lipase, in order to screen for possible mutations in cell lines of four children with pancreatic lipase deficiency (OMIM 246600). We found no missense or nonsense mutations in these samples, but we found three silent single-nucleotide polymorphisms (SNPs), namely, 96A/C in exon 3, 486C/T in exon 6, and 1359C/T in exon 13. In 50 normolipidemic Caucasians, the PNLIP 96C and 486T alleles had frequencies of 0.083 and 0.150, respectively. The PNLIP 1359T allele was absent from Caucasian, Chinese, South Asian, and North American aboriginal samples, but had a frequency of 0.085 in an African sample, suggesting that it is a population-specific variant. In an association analysis of 185 African neonates, the PNLIP 1359C/T SNP genotype was significantly associated with concentrations of plasma lipoproteins. These associations were most likely due to linkage disequilibrium with another functional variant at or near PNLIP. Thus, we report three new SNPs for the PNLIP, which may serve as markers for association analyses and for pharmacogenetic studies of pancreatic lipase inhibitors.

Study of the effect of time availability on the consultation.

This study looked at the effect of different appointment time intervals on process and outcome measures in the consultation. Over a five-month period patients attending a two-partner surgery were non-systematically allocated to appointments at five, 10 or 15 minute intervals. Consultations were audiotaped and analysed. When appointments were scheduled at longer intervals, doctors asked significantly more questions and made significantly more statements explaining the problem and its management, while patients asked significantly more questions and made significantly more statements of their own ideas about the problem. In consultations booked at shorter intervals patients were significantly more likely to report in satisfaction questionnaires that they had little or far too little time available. The implications of the results for future planning are discussed.

Stress/catecholamine-induced cardiac necrosis. Reduction by beta 1-selective blockade.

Catecholamine-induced cardiac necrosis is a well-described phenomenon. Patients with severe head injury are known to be in a marked hyperadrenergic state and can experience cardiac morbidity; this was confirmed in a pilot study. A further study was then undertaken to examine a possible relationship between plasma catecholamine concentration and cardiac morbidity in patients with severe head injury and to assess the effect of intervention with the beta 1-selective agent atenolol. The study involved 114 hemodynamically stable patients with acute head injury who were randomized, double blind, to either placebo or atenolol given intravenously (10 mg every six hours) for three days and then orally (100 mg once a day) for four days. Both groups were equally stressed in terms of raised arterial norepinephrine levels. In patients receiving placebo, but not in those given atenolol, there was a significant (P less than 0.01) positive correlation between arterial level of norepinephrine and plasma level of cardiac-specific isoenzyme CK-MB. Thirty percent of the placebo group, in contrast to 7.4% of the atenolol group (P less than 0.05), had pathologically elevated CK-MB levels (ie, greater than 3% of total CK, a value compatible with acute myocardial infarction). Atenolol appeared to significantly reduce the likelihood of supraventricular tachycardia and ST-segment and T-wave changes and prevented cardiac necrosis (as determined post mortem). The finding that beta 1-selective blockade significantly inhibits catecholamine-induced necrosis has possible broad clinical implications.

Reduction of stress/catecholamine-induced cardiac necrosis by beta 1-selective blockade.

114 haemodynamically stable patients with acute head injury were randomised, double-blind, to either placebo or atenolol given intravenously (10 mg every 6 h) for 3 days then orally (100 mg daily) for a further 4 days. Both groups were equally stressed as shown by raised arterial noradrenaline levels. In patients receiving placebo, but not in those receiving atenolol, there was a significant (p less than 0.01) positive correlation between arterial noradrenaline and levels of the myocardial isoenzyme of creatine kinase (CKMB). 30% of the placebo group compared with 7.4% of the atenolol group (p less than 0.05) showed CKMB levels greater than 3% of total creatine kinase (compatible with myocardial damage). CKMB levels greater than 6% of total creatine kinase (compatible with acute myocardial infarction) were present in 16.7% of patients receiving placebo but in no patients receiving atenolol (p = 0.053). Atenolol appeared to reduce significantly the likelihood of supraventricular tachycardia and ST-segment and T-wave changes and prevented cardiac necrosis seen at necropsy.

Trial of relaxation in reducing coronary risk: four year follow up.

On screening 192 men and women aged 35-64 were identified as having two or more of the following risk factors: blood pressure greater than or equal to 140/90 mm Hg, plasma cholesterol concentration greater than or equal to 6.3 mmol/l (243.6 mg/100 ml), and current smoking habit greater than or equal to 10 cigarettes a day. They were randomly allocated to a group for modification of behaviour or to serve as controls. Both groups were given health education leaflets containing advice to stop smoking, to reduce animal fats in the diet, and on the importance of reducing blood pressure. In addition, the treatment group had group sessions of one hour a week for eight weeks in which they were taught breathing exercises, relaxation, and meditation and about managing stress. It had previously been found that after eight weeks and eight months there was a significantly greater reduction in both systolic and diastolic blood pressures in the group taught to relax compared with the control group. After four years of follow up these differences in blood pressure were maintained. Plasma cholesterol concentration and the number of cigarettes smoked were lower in the treatment group at eight weeks and eight months but not at the four year follow up. At four years more subjects in the control group reported having had angina and treatment for hypertension and its complications. Incidence of ischaemic heart disease, fatal myocardial infarction, or electrocardiographic evidence of ischaemia was significantly greater in the control group. If the results of this study could be obtained in a larger study the financial and health care implications would be enormous.

Detection of antibody to staphylococcal lipoteichoic acid with a microenzyme-linked immunosorbent assay.

Sera from individuals with Staphylococcus aureus endocarditis and osteomyelitis and from some individuals with other forms of gram-positive endocarditis yielded higher readings in a microenzyme-linked immunosorbent assay against lipoteichoic acid from S. aureus than did sera from individuals with other types of serious staphylococcal infection or non-staphylococcal osteomyelitis, or from unselected inpatients.

Mediation of staphylococcal adherence to mucosal cells by lipoteichoic acid.

Staphylococcal lipoteichoic acid markedly reduced adherence by Staphylococcus aureus to buccal cells in vitro, suggesting that lipoteichoic acid mediates adherence by that bacterium. Adherence inhibition by lipoteichoic acid was lost after deacylation of the preparation, suggesting that fatty acids on the molecule are essential to binding.

Some effects of emotion on the normal and abnormal heart.

Increased heart rate and catecholamine secretion are induced by certain emotions. Automobile driving in busy city traffic, racing driving, speaking before an audience, and parachute jumping are associated with sinus tachycardia 120-180 per minute, and increase in the plasma levels of adrenaline and/or noradrenaline. Electrocardiographic changes, chiefly ST depression, may occur in a small proportion of persons without ischemic symptoms and with normal resting tracings. Patients with clinical coronary disease, angina, and ischemic ST changes and arrhythmias may be induced by the emotional stimuli associated with car driving and public speaking; plasma catecholamine levels are increased in proportion to the intensity of the stimulus. beta-blockade reduces the tachycardia, and prevents in whole or in part the ST changes, arrhythmia and symptoms associated with emotional challenge to the heart. We would like to leave the reader with a final morsel of food for thought. Emotion may parallel exercise in its ability to accelerate the heart rate up to 180 per minute in healthy subjects, comparable to the maximum reached during physical exertion. Thus, there are good grounds to advise persons at risk not only against violent exercise but also against exposing themselves to intense emotion. At the same time, we would not advocate emotional overprotection, and we believe our ideas would be misinterpreted if healthy persons were to be deterred on the grounds of apprehension or nervousness from facing up to reasonable everyday professional or social challenges.

Psychosomatic aspects in idiopathic infertility: effects of treatment with autogenic training.

It has long been recognised that there is a relationship between emotional stress and some forms of infertility. We have endeavoured to estimate "stress' levels before and after Autogenic Training in 15 couples with infertility of at least two years' duration. Potential stress markers were: plasma prolactin, total urinary free cortisol and catecholamines, and four psychological tests: Spielberger State-Trait anxiety scale, Taylor Manifest Anxiety Scale, the Cattell 16 personality factor questionnaire, and the Eysenck Personality Questionnaire. A control group of ten normal couples was included for comparison. The biochemical finding of higher mean prolactin levels in the female patients vs their controls was of particular interest. The significant reduction of the prolactin level, in parallel with decreased anxiety scores following treatment, supports the hypothesis that the elevated prolactin levels in these patients are indeed linked with emotional stress.

Measurement of catecholamines in biological fluids by high-performance liquid chromatography: a comparison of fluorimetric with electrochemical detection.

An improved method for the determination of catecholamines in biological fluids, by reversed-phase high-performance liquid chromatography (HPLC) with fluorimetric detection is presented. The pH titration previously employed in the alumina extraction was abandoned in favour of the use of a molar excess of PH 8.5 Tris--HCl buffer. A novel lyophilisation step serves to concentrate the catechols and by reconstituting in mobile phase, chromatography disturbances are minimised. The addition of 2 mM octanesulphonic acid to citrate--phosphate mobile phase at pH 6.0 gave optimal resolution and sensitivity. That HPLC separation can improve the specificity of the trihydroxyindole reaction, to the extent of providing a reliable analytical method, has been demonstrated and validated by the technique of HPLC with electrochemical detection. A correlation coefficient of 0.98 was obtained between the two techniques as applied to the measurement of urinary catecholamines. The HPLC--fluorimetric method was sensitive enough to measure 0.1 ng/ml of noradrenaline or adrenaline at a signal-to-noise ratio of 2.0. Application of the method to the quantitative determination of catecholamines in human urine, plasma and rat brain homogenates is demonstrated.