A recent study has revealed a link between levels of the hormone thyrotropin, also know as thyroid stimulating hormone (TSH), and risk of Alzheimer’s disease in older women. It was previously known that hyperthyroidism and hypothyroidism are linked to cognitive impairments, for example difficulties in learning, thinking and memory. However, the results from the Framington study show that high or low levels of TSH within the boundaries currently set for euthyroid (normal functioning thyroid) TSH levels are associated with an increased risk of Alzheimer’s onset by up to two-times.
“Low and high thyrotropin levels were associated with an increased risk of Alzheimer’s disease in women but not in men,” the authors wrote. “These findings should be considered hypothesis generating and should be validated in other populations before clinical conclusions are drawn.” Indeed, these findings could lead to the need for re-evaluation, with a view to narrowing the range of TSH levels considered acceptable for a normal functioning thyroid.
The study, conducted by Dr Tan and colleagues at Hebrew Senior Life, Beth Israel Deaconess Medical Center and Harvard Medical School in Boston, MA, USA involved almost 2000 euthyroid individuals, 59% of whom were women and the mean age of whom was 71 years. Subjects were followed over an average period of 13 years and their serum TSH concentrations measured. Of those in the study, 209 individuals developed Alzheimer’s disease, a degenerative disease of the brain that results in dementia. In the men studied, no link between TSH levels and Alzheimer’s onset was observed. In women, those with TSH levels near to the top and bottom of the normal 0.5–5.0 mIU/l range were at higher risk of Alzheimer’s than those with more moderate TSH levels in the middle of the range.
One interesting finding was that thyroid treatment had no observed effect on risk of Alzheimer’s in this study, suggesting that TSH level was the bottom line in relation to probability of Alzheimer’s onset. This contradicts the established view that thyroid treatment for hyperthyroidism and hypothyroidism may reverse any developing cognitive damage.
Further studies are needed to corroborate these findings and, furthermore, to try to establish whether maintaining moderate TSH levels can protect against Alzheimer’s or fluctuating TSH levels that actually cause Alzheimer’s, or whether deviations in TSH levels are observed as a result of Alzheimer’s. However, given the relationship recorded by Tan and colleagues, these results may open up a promising new area of research for the development of prophylactics or therapeutics for Alzheimer’s.
This study may provide the evidence needed to reduce the range of TSH levels considered normal. In the past, experts have recommended that TSH values considered euthyroid should only range from 0.3 to 3.0 mIU/l and, currently, the ‘normal’ range that is adopted may vary from one clinician to the next. These results support arguments to standardize the target range for TSH levels to a much narrower window, which some believe should be between 1.0 and 2.0 mIU/l.
Dr Tan remains cautious, however, highlighting the limitations of the results with respect to a possible cure for Alzheimer’s stating that, “…whether maintaining hormone levels within limits will actually prevent dementia I think might be a big jump…that will have to be proven in clinical trials.”
Source: Zaldy S Tan, Alexa Beiser, Ramachandran S Vasant et al. Thyroid Function and the Risk of Alzheimer Disease The Framingham Study. Arch. Intern. Med. 168(14), 1514–1520 (2008).
Increased risk of gallbladder disease due to HRT can be cut by transdermal versus oral application
Orally administered hormone replacement therapy puts women at a greater risk of gallbladder disease.
The Million Women Study, conducted by researchers led by Bette Liu of Oxford University, has found that orally administered hormone replacement therapy (HRT) puts women at a greater risk of gallbladder disease compared with transdermal HRT. The authors report that the “use of transdermal therapy rather than oral therapy over a 5-year period could avoid one cholecystectomy in every 140 users.”
Hormone replacement therapy involves the delivery of estrogen to women to relieve the symptoms of the menopause. When estrogen is given orally it is first metabolized before uptake from the bloodstream. Transdermal administration of estrogen avoids this initial metabolism by the liver and this could be the basis of the difference in risk of gallbladder disease associated with each treatment.
The study followed 1,001,391 postmenopausal women recruited between 1996 and 2001, with a mean age at commencement of 56 years. Subjects were selected from National Health Service (NHS) breast cancer screening centres and identified as sufferers of gallbladder disease from NHS hospital admission data, which was routinely collected throughout the study.
The data was used to calculate relative risk (RR) and standardized incidence rates of hospital admission for gallbladder disease; incidences per 100 women for each category of HRT use (e.g., nonusers and HRT, both oral and transdermal, at various doses).
Of those studied, 19,889 women developed gallbladder disease. The RR for women using HRT compared with those who had never used it was 1.64. However, out of these, the RR of those using transdermal HRT was just 1.17, whereas the RR of those using oral HRT was 1.74. It was also found that different types of oral HRT carried varying risks, with equine estrogens presenting a higher risk than estradiol. Furthermore, dosage affected RR, with those taking higher doses being most at risk. Over 5 years, for every 100 women studied, the incidence of cholecystectomy was increased from 1.1 in those never having used HRT to 1.3 and 2.0 for transdermal and oral HRT, respectively.
The study concluded that “gallbladder disease is common in postmenopausal women and use of HRT increases the risk.” This may be worrying for postmenopausal women, although the study shows that by taking HRT transdermally, a large proportion of HRT-associated risk may be avoided.
Source: Liu B, Beral V, Balkwill A et al. Gallbladder disease and use of transdermal versus oral hormone replacement therapy in postmenopausal women: prospective cohort study. BMJ (2008) DOI: 10.1136/bmj.a386 (Epub ahead of print).
Blood sugar levels may be an important indication of future health
New Zealand researcher Naomi Brewer has found that haemoglobin AC1 level, a measure of blood sugar, was linked to a greater probability of mortality in 47,904 subjects who were part of a screening program for hepatitis B between 1999 and 2004. This relationship even applied to subjects not classed as diabetic.
Brewer, of Massey University in Wellington, stated that “in future, people will need to know their hemoglobin A1C level, just as they may currently know their blood pressure or their cholesterol levels.”
Elevated blood sugar levels are strongly linked to major diseases, such as diabetes, heart disease and cystic fibrosis, the study found, with equal implications in men and women. These findings support arguments that blood sugar levels should be evaluated as part of a continuous scale, rather than as levels for diabetics and levels for nondiabetics. As Ms Brewer postulates, “people might have thought of those with diabetes as being in one corner and themselves in another. This suggests there might be more to it than that.”
Women with schizophrenia may benefit from estrogen treatment
Estradiol has been found to reduce psychotic symptoms of schizophrenia in women.
Published in the August issue of Archives of General Psychiatry, researchers from Monash University (Melbourne, Australia) have demonstrated beneficial effects of transdermal estradiol on women with schizophrenia.
A total of 102 women of childbearing age with schizophrenia were randomized to either 100 µg transdermal estradiol (n = 56) or placebo (n = 46) as an adjunct to their usual antipsychotic medication for 28 days. Psychological symptoms were assessed weekly using the Positive and Negative Syndrome Scale.
Those treated with transdermal estradiol experienced an improvement in psychotic symptoms and a reduction in positive symptoms of schizophrenia. There was no change in negative symptoms between those receiving estradiol and schizophrenia.
“Estrogen treatment is a promising new area for future treatment of schizophrenia and potentially for other severe mental illnesses” commented first author Jayashri Kulkarni. “There is a lot to be done, but I believe that we have opened up a new and promising area of treatment for a debilitating illness in both women and men.”
Source: Kulkarni J, de Castella A, Fitzgerald PB et al. Estrogen in severe mental illness: a potential new treatment approach. Arch. Gen. Psychiatry 65(8), 955–960 (2008)
Study shows obesity risk FTO gene variant may work by affecting satiety
Genetic variation in the FTO gene has long been linked to incidence of obesity. However, this influence on weight was unknown until now. In a recent study of over 3000 British children between the ages of 8 and 1, it was found that those with either both or one copy of the A allele of the FTO gene had significantly reduced Satiety Responsivness scores. Results show that obesity linked to the FTO polymorphism is caused by overintake of food as a result of individuals not being able to recognize when they are full, rather than FTO having a diminishing effect on energy expenditure.
The study, funded by the Medical Research Council, was conducted by researchers from Kings College London (KCL) and University College London (UCL). Professor Jane Wardle, lead author from the department of Epidemiology and Public Health UCL, summarized that “while recent research has shown that the FTO gene is strongly linked with children’s body weight and food intake, this study tells us more about how the gene could be exerting its effect. What we have shown is that children with the ‘risky’ variants of the gene have weaker satiety responses – meaning they don’t just overeat, but they struggle to recognize when they are full.”
Certain alleles of the FTO gene are associated with a greater risk of obesity. A total of 3337 UK children were genotyped for the A allele of FTO, FTO SNP (rs9939609). Psychometric tests, part of the Child Eating Behaviour Questionnaire, were used to glean information about ‘satiety responsiveness’ and ‘enjoyment of food’ in subjects. It was found that the A allele was linked to obesity but also that AA children, those with both copies of the high risk allele, could not recognize when they were full.
Obviously, individuals carrying the A allele do not automatically become obese, but as Professor Wardle explains, “they are more susceptible to overeating. This makes them significantly more vulnerable to the modern environment which, confronts all of us with large portion sizes and limitless opportunities to eat.” She also noted that, “…the effect of FTO on appetite is the same regardless of the age, sex, socioeconomic background or BMI of the children.”
Claire Howarth of KCL believes that the study provides important information about the genetic basis of obesity and how this genotype translates to the phenotype so that future therapeutics may be developed. “It is exciting to come closer to understanding how the FTO gene might affect obesity,” she remarked. “This research suggests that the genetic risk comes from not recognizing signs of being full after eating (satiety), which is also exciting because it suggests ways in which this research can be translated into treatment and prevention.”
Source: Wardle J, Carnell S, Haworth CMA, Farooqi IS, O’Rahilly S, Plomin R. Obesity-associated genetic variation in FTO is associated with diminished satiety. J. Clin, Endocrinol. Metab. (2008) DOI: 10.1210/jc.2008–0472 (Epub ahead of print).
AMPK and PPARd pathways targeted to mimic exercise and enhance endurance
Researchers at the Salk Institute for Biological Sciences in California, USA, have recently published data on two drugs that have been found to increase the physical endurance of mice. The research team, led by Ronald Evans, found that when regularly exercised mice were fed the drug GW1516 for a period of 4 weeks, their endurance increased by 77%. The endurance increase was only found in regularly exercising mice. It is thought that an AMP signaling pathway must first be activated by high-energy demands created by exercise.
This led to the trialing of a second compound, AICAR, a synthetic form of AMP. After 4 weeks of treatment with AICAR and no regular exercise, the test group of mice was found to have an increase in running endurance of 44% when compared with mice that received no drug and had a similarly sedentary lifestyle. It was concluded that the AMP signaling pathway affected could “be targeted by orally active drugs to enhance training adaptation or even to increase endurance without exercise.”
Evans is now working with the World Anti-Doping Association to develop blood and urine tests that detect the two drugs and their metabolites.
Source: Narkar VA, Downes M, Yu RT et al. AMPK and PPARd agonists are exercise mimetics. Cell 134, 405–415 (2008).