Eef Hogervorst

The nature of the effect of female gonadal hormone replacement therapy on cognitive function in post-menopausal women : A meta-analysis

We reviewed epidemiological and experimental studies of female gonadal hormone replacement therapy (HRT) on cognitive function in post-menopausal women and carried out meta-analyses. In healthy ageing women, HRT has small and inconsistent effects that include enhancement of verbal memory, abstract reasoning and information processing. Epidemiological studies show larger effects than experimental studies, which is not related to sample size. Important confounds may be that women who start using HRT are healthier than women who do not. Also, controlling for socio-economic status diminishes the effect of HRT. The effects of HRT may depend on the age and type of menopause and the therapeutic intervention used, with the most widely used drug, Premarin, having least effect. However, the effects are independent of mood and climacteric symptom alleviation. There is a paucity of experimental studies that include healthy elderly women. The evidence for an estrogen deficiency in women with dementia and cognitive dysfunction is inconsistent. Nevertheless, epidemiological studies suggest that HRT protects against the development of clinically diagnosed Alzheimers disease. However, poor recall of HRT use by patients and altered physician behaviour may have confounded the effects. Surprisingly, both healthy and demented women with low education seem to benefit most from HRT. Three recent controlled experimental studies using Premarin showed no effects of HRT in preventing further cognitive decline in women who already have Alzheimers disease. Duration of treatment seems to play an important role, with beneficial effects declining-and even reversing-with longer treatment in women with Alzheimers disease.Future research should further investigate the cognitive effect of different HRT preparations, serum estrogen levels, and the interactions of HRT with age, menopausal status and existing protective (e.g. education) and risk factors (e.g. smoking and apolipoprotein E genotype) for cognitive decline and Alzheimers disease.

Tryptophan depletion impairs memory consolidation but improves focussed attention in healthy young volunteers

Animal and human studies have provided evidence for serotonergic modulation of cognitive processes. However, the exact nature of this relationship is not clear. We used the acute tryptophan depletion (ATD) method to investigate the effects of lowered serotonin synthesis on cognitive functions in 17 healthy young volunteers. The study was conducted according to a placebo-controlled, double-blind, crossover design. Cognitive performance and mood were assessed at baseline and 5 and 9 h after administration of ATD. A specific impairment of word recognition, without effects on short-term memory, occurred during ATD. No memory deficits were seen if ATD was induced after acquisition of new words. The Stroop Test and dichotic listening task demonstrated a modality independent improvement of focussed attention after ATD. Fluency was also improved after ATD. ATD did not alter speed of information processing, divided attention or planning functions. These results indicate that serotonin is essential in the process of long-term memory consolidation, primarily in the first 30 min after acquisition. Improvement of specific cognitive processes by lowered 5-HT function may be linked to the removal of inhibitory actions of 5-HT in the cortex.

Cognitive performance after strenuous physical exercise

Stimulating as well as detrimental effects of exercise on cognitive functioning have been reported. In the present study, 15 endurance-trained athletes (aged 18 to 42 years) performed a bicycle ergometer endurance test at 75% of their maximal work capacity (Wmax). Psychomotor and cognitive tests were administered before and immediately after exercise. These consisted of simple reaction time (RT), 3-choice RT and Stimulus-Response (S-R) incompatible RT tasks, a finger-tapping task, and the Stroop test. Simple RT tasks, but also the more complex S-R in compatible RT, and Color Word Interference in the Stroop test showed an increase in speed of performance after exercise relative to baseline. An enhanced activation was probably responsible for this better performance on psychomotor and cognitive tests. Since performance on the most complex task, the Interference subtest of the Stroop, was especially improved after exercise, the expectancy of the subjects of a potential positive effect of exercise was thought to have been responsible.

Low free testosterone is an independent risk factor for Alzheimer's disease

The purpose of this study was to assess pituitary gonadotropins and free testosterone levels in a larger cohort of men with Alzheimers disease (AD, n=112) and age-matched controls (n=98) from the Oxford Project to Investigate Memory and Ageing (OPTIMA). We measured gonadotropins (follicle stimulating hormone, FSH, and luteinizing hormone, LH), sex hormone binding globulin (SHBG, which determines the amount of free testosterone) and total testosterone (TT) using enzyme immunoassays. AD cases had significantly higher LH and FSH and lower free testosterone levels. LH, FSH and SHBG all increased with age, while free testosterone decreased. Low free testosterone was an independent predictor for AD. Its variance was overall explained by high SHBG, low TT, high LH, an older age and low body mass index (BMI). In controls, low thyroid stimulating hormone levels were also associated with low free testosterone. Elderly AD cases had raised levels of gonadotropins. This response may be an attempt to normalize low free testosterone levels. In non-demented participants, subclinical hyperthyroid disease (a risk factor for AD) which can result in higher SHBG levels, was associated with low free testosterone. Lowering SHBG and/or screening for subclinical thyroid disease may prevent cognitive decline and/or wasting in men at risk for AD.

Testosterone levels and cognition in elderly men: A review

Average testosterone levels and many cognitive functions show a decline with age. There is evidence to suggest that this association is not just age related. Results from cell culture and animal studies provide convincing evidence that testosterone could have protective effects on brain function. Alzheimers disease (AD) is characterised by brain pathology affecting cognitive function and AD prevalence increases with age. Testosterone levels are lower in AD cases compared to controls, and some studies have suggested that low free testosterone (FT) may precede AD onset. Men with AD may show accelerated endocrinological ageing, characterised by an earlier lowering of thyroid stimulating hormone, an earlier increase in sex hormone binding globulin (SHBG), a subsequent earlier decrease in FT and an earlier increase in gonadotropin levels in response to this. Positive associations have been found between testosterone levels and global cognition, memory, executive functions and spatial performance in observational studies. However, non-significant associations were also reported. It may be that an optimal level of testosterone exists at which some cognitive functions are improved. This may be modified with an older age, with a shifting of the optimal testosterone curve to maintain cognition to the left and a lower optimal level thus needed to be beneficial for the brain. Genetic factors, such as APOE and CAG polymorphisms may further interact with testosterone levels in their effects on cognition. The roles of SHBG, gonadotropins, thyroid hormones and estrogens in maintaining cognitive function and preventing dementia in men are also not completely understood and should be investigated further. Hypogonadal men do not seem to benefit from testosterone supplementation but small scale, short term intervention studies in eugonadal men with and without cognitive impairments have shown promising results. Larger randomised, controlled trials are needed to further investigate testosterone treatment in protecting against cognitive decline and/or dementia.

Caffeine Improves Physical and Cognitive Performance during Exhaustive Exercise

UNLABELLED Caffeine is thought to act as a central stimulant and to have effects on physical, cognitive, and psychomotor functioning. PURPOSE To examine the effects of ingesting a performance bar, containing caffeine, before and during cycling exercise on physical and cognitive performance. METHODS Twenty-four well-trained cyclists consumed the products [a performance bar containing 45 g of carbohydrate and 100 mg of caffeine (CAF), an isocaloric noncaffeine performance bar (CHO), or 300 mL of placebo beverage (BEV)] immediately before performing a 2.5-h exercise at 60% VO2max followed by a time to exhaustion trial (T2EX) at 75% VO2max. Additional products were taken after 55 and 115 min of exercise. Cognitive function measures (computerized Stroop and Rapid Visual Information Processing tests) were performed before exercise and while cycling after 70 and 140 min of exercise and again 5 min after completing the T2EX ride. RESULTS Participants were significantly faster after CAF when compared with CHO on both the computerized complex information processing tests, particularly after 140 min and after the T2EX ride (P < 0.001). On the BEV trial, performance was significantly slower than after both other treatments (P < 0.0001). There were no speed-accuracy tradeoffs (P > 0.10). T2EX was longer after CAF consumption compared with both CHO and BEV trials (P < 0.05), and T2EX was longer after CHO than after BEV (P < 0.05). No differences were found in the ratings of perceived exertion, mean heart rate, and relative exercise intensity (% VO2max; P > 0.05). CONCLUSION Caffeine in a performance bar can significantly improve endurance performance and complex cognitive ability during and after exercise. These effects may be salient for sports performance in which concentration plays a major role.

Plasma Total Homocysteine and Cognitive Performance in a Volunteer Elderly Population

Case-control studies have demonstrated associations between moderately elevated blood levels of total homocysteine (tHcy) and cerebrovascular disease,1 vascular dementia,2–4 and Alzheimer’s disease.3–5 Clarke et al.3 showed an association between elevated tHcy, low levels of folate and vitamin B12, and histopathologically confirmed Alzheimer’s disease. However, the influence of elevated tHcy levels or its biologic determinants on cognitive performance in the normal elderly and on the development of cognitive impairment or its progression to dementia is not well established. Riggs et al.6 and La Rue et al.7 have suggested that levels of plasma homocysteine, vitamin B12, and folate may exert differential effects on cognitive abilities. Recently, Jensen et al.8 reported negative relationships between elevated tHcy levels (>15 μmol/L) and a broad range of cognitive, quality of life, and psychologic variables in 80-year-old subjects. However, these studies could not assess whether these associations were independent of differences in age, gender, IQ, and depression. Furthermore, it is important to explore the relationship between tHcy and cognitive performance as continuous variables, rather than as dichotomous variables. The aim of this study was to examine the influence of plasma tHcy levels on global cognitive performance in 156 elderly community volunteers.

ESHRE Guideline: management of women with premature ovarian insufficiency

STUDY QUESTION What is the optimal management of women with premature ovarian insufficiency (POI) based on the best available evidence in the literature? SUMMARY ANSWER The guideline development group (GDG) formulated 99 recommendations answering 31 key questions on the diagnosis and treatment of women with POI. WHAT IS KNOWN ALREADY NA. STUDY DESIGN, SIZE, DURATION This guideline was produced by a multidisciplinary group of experts in the field using the methodology of the Manual for ESHRE Guideline Development, including a thorough systematic search of the literature, quality assessment of the included papers up to September 2014 and consensus within the guideline group on all recommendations. The GDG included a patient representative to ensure input from women with POI. After finalization of the draft, the European Society for Human Reproduction and Embryology (ESHRE) members and professional organizations were asked to review the guideline. PARTICIPANTS/MATERIALS, SETTING, METHODS NA. MAIN RESULTS AND THE ROLE OF CHANCE The guideline provides 17 recommendations on diagnosis and assessment of POI and 46 recommendations on the different sequelae of POI and their consequences for monitoring and treatment. Furthermore, 24 recommendations were formulated on hormone replacement therapy in women with POI, and two on alternative and complementary treatment. A chapter on puberty induction resulted in five recommendations. LIMITATIONS, REASONS FOR CAUTION The main limitation of the guideline is that, due to the lack of data, many of the recommendations are based on expert opinion or indirect evidence from studies on post-menopausal women or women with Turner Syndrome. WIDER IMPLICATIONS OF THE FINDINGS Despite the limitations, the guideline group is confident that this document will be able to guide health care professionals in providing the best practice for managing women with POI given current evidence. Furthermore, the guideline group has formulated research recommendations on the gaps in knowledge identified in the literature searches, in an attempt to stimulate research on the key issues in POI. STUDY FUNDING/COMPETING INTERESTS The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the implementation of the guideline. The guideline group members did not receive payment. Dr Davies reports non-financial support from Novo Nordisk, outside the submitted work; the other authors had nothing to disclose. TRIAL REGISTRATION NUMBER NA.

The effect of hormone replacement therapy on cognitive function in elderly women

Although evidence seems to indicate favorable effects of hormone replacement therapy (HRT) on cognitive functions and mood in elderly healthy and demented women, some questions remain. For instance, the nature of the long term effect of HRT, e.g. in preventing cognitive decline is still unclear. In this respect, the addition of progestagens in combined HRT has been mentioned to oppose some of the beneficial effects of estrogens. The present paper aims to illuminate these questions and presents two studies. In the first study, the long term effects of combined HRT in healthy postmenopausal women was investigated using a parallel groups (HRT-users vs. controls) design. HRT subjects were always tested during the estrogen-progestagen phase. Results indicated that after 6 and 12 months, women in the HRT-treatment group had higher scores on several indicators of the subjective feeling of well being (sleep, physical and psychological complaints) than matched controls, although at baseline both groups were not severely impaired. Effects of HRT on memory functions were seen when HRT treated subjects were compared with their own baseline functioning, but not when compared with controls. Hence, the addition of progestagen did not oppose the effects of estrogens on subjective feelings of well being or on memory. Our second (case-control) study involved women of middle-age who were unaware of the purpose of the experiment. No positive effects of HRT use on subjective scales of well being or on memory were found. However, women with HRT were faster on basic sensorimotor speed tasks as compared with controls. It should be kept in mind that double blind testing in an experimental study is difficult due to withdrawal bleeding and the reduction of flushes. Expectancy effects may have confounded the results of the first study. However, our findings indicate that the use of a particular design and type of memory test can explain the controversial results of studies into the effect of HRT on cognitive function. Furthermore, it was concluded that HRT has a global activating, instead of specific direct effect on cognitive functions.

Thyroid function and cognitive decline in the MRC Cognitive Function and Ageing Study

Hypothyroidism and subclinical hyperthyroidism have both been associated with cognitive impairment and dementia. The association between thyroid stimulating hormone (TSH), free thyroid hormone or thyroxine (FT4) levels and cognition was investigated at baseline and after a 2 year follow-up in 1047 participants over 64 years of age, without physical frailty or severe cognitive impairment at baseline. Results indicated that high log transformed TSH levels were associated with lower MMSE performance (B=-0.24 (S.E.=0.09), 95% CI=-0.41 to -0.07) at baseline, independent of FT4, age, sex, education and mood, and, in separate analyses, cardiovascular (risk) factors. Importantly, half of all hypothyroid cases were untreated and unaware of having this disorder. In analyses which excluded cases with thyroid disorders, stroke and those suspected of possible dementia/cognitive impairment (MMSE less than 25) or psychiatric mood disorders at baseline, high-normal FT4 levels were associated with worse MMSE performance and a greater risk for a drop of at least 4 points on the MMSE after 2 years (per pmol/l O.R.=1.13, 95% C.I.=1.03-1.22). In conclusion, elderly patients with cognitive impairment should always be assessed for hypothyroidism. It is unclear why high normal FT4 levels were independently associated with accelerated cognitive decline in those without overt thyroid disease. Other studies found that thyroxine can generate oxidative stress and damage neurons. Treatment with thyroxine in those without thyroid disease (as is sometimes done in anti-ageing clinics) is thus not recommended on the basis of these data and the optimal therapeutic level in the elderly may be lower than is assumed.