Eero Kajantie

The effects of sex and hormonal status on the physiological response to acute psychosocial stress.

Whether one is male or female is one of the most important determinants of human health. While males are more susceptible to cardiovascular and infectious disease, they are outnumbered by women for many autoimmune disorders, fibromyalgia and chronic pain. Recently, individual differences in the physiological response to stress have emerged as a potentially important risk factor for these disorders. This raises the possibility that sex differences in prevalence of disease could at least in part be explained by sex differences in the nature of the physiological response to stress. In a psychophysiological laboratory, the autonomic nervous system response can be provoked by many different stressors including physical, mental and psychosocial tasks, while the hypothalamic-pituitary-adrenal axis (HPAA) response seems to be more specific to a psychosocial challenge incorporating ego involvement. The responses of both systems to different psychosocial challenges have been subject to extensive research, although in respect of sex differences the HPAA response has probably been more systematically studied. In this review, we focus on sex differences in HPAA and autonomic nervous system responses to acute psychosocial stress. Although some differences are dependent on the stressor used, the responses of both systems show marked and consistent differences according to sex, with the phase of the menstrual cycle, menopausal status and pregnancy having marked effects. Between puberty and menopause, adult women usually show lower HPAA and autonomic responses than men of same age. However, the HPAA response is higher in the luteal phase, when for example post stress free cortisol levels approach those of men. After menopause, there is an increase in sympathoadrenal responsiveness, which is attenuated during oral hormone replacement therapy, with most evidence suggesting that HPAA activity shows the same trends. Interestingly, pregnancy is associated with an attenuated response of the sympathoadrenal and HPAA systems at least as assessed by biochemical stimulation. It is likely that these sex differences in autonomic function are a result of estrogen exposure which attenuates sympathoadrenal responsiveness. The HPAA is however somewhat more complex and evidence now suggests the influence of other modifiers such as arginine vasopressin (AVP) and the regulation of circulating cortisol bioavailability by corticosteroid-binding globulin (CBG). The pronounced and multi-faceted sex differences in stress responsiveness suggest that they are a product of a strong evolutionary pressure. We hypothesise that this has to a great deal been driven by the need to protect the fetus from the adverse effects of maternal stress responses, in particular excess glucocorticoid exposure. Studying this hypothesis may have a fundamental impact on our understanding about how adult health is set during early life and how adult disease could be prevented in men and women.

Pre-Eclampsia Is Associated With Increased Risk of Stroke in the Adult Offspring: The Helsinki Birth Cohort Study

Background and Purpose— Women who develop pre-eclampsia in pregnancy are at increased risk of cardiovascular disease. The offspring from pregnancies complicated by pre-eclampsia have higher blood pressures during childhood, but little is known about their long-term health. We hypothesized that pre-eclampsia would lead to an increased risk of cardiovascular disease in the offspring. Methods— We traced 6410 babies born in Helsinki, Finland, from 1934 to 1944. We used the mothers’ blood pressure levels and the presence of proteinuria during pregnancy to define pre-eclampsia and gestational hypertension without proteinuria according to modern criteria. Results— Two hundred eighty-four of the pregnancies were complicated by pre-eclampsia (120 with nonsevere and 164 with severe disease) and 1592 by gestational hypertension. The crude hazard ratio for all forms of stroke among people whose mothers had pre-eclampsia was 1.9 (1.2 to 3.0; P=0.01); among people whose mothers had gestational hypertension, it was 1.4 (1.0 to 1.8; P=0.03). There was no evidence that these pregnancy disorders were associated with coronary heart disease in the offspring. Pre-eclampsia, in particular severe disease, was associated with a reduced mean head circumference at birth, whereas gestational hypertension was associated with an increased head circumference in relation to body length. Conclusions— People born after pregnancies complicated by pre-eclampsia or gestational hypertension are at increased risk of stroke. The underlying processes may include a local disorder of the blood vessels of the brain as a consequence of either reduced brain growth or impaired brain growth leading to “brain-sparing” responses in utero.

Growth and chronic disease: findings in the Helsinki Birth Cohort.

There is now clear evidence that the pace and pathway of early growth is a major risk factor for the development of a group of chronic diseases that include coronary heart disease, stroke, type 2 diabetes and hypertension. This has led to a new ‘developmental’ model for these disorders. The so-called ‘fetal origins hypothesis’ proposes that the disorders originate through developmental plasticity, whereby malnutrition during fetal life, infancy and early childhood permanently change the structure and function of the body, a phenomenon known as ‘programming’. This paper reviews recent findings in the Helsinki Birth Cohort, which comprises 13 345 men and women born in the city during 1934–1944. There is also an older cohort comprising 7086 people born during 1924–1933. We review the paths of pre- and postnatal growth that lead to later disease. Children who later develop coronary heart disease and type 2 diabetes grow slowly during fetal life and infancy but thereafter increase their body mass indices rapidly. Those who later develop stroke grow slowly in fetal life, infancy and during childhood. We also review how the growth of girls during infancy, childhood and at puberty influences chronic disease in the next generation.

Birthweight and mortality in adulthood: a systematic review and meta-analysis

BACKGROUND Small birth size may be associated with increased risk of cardiovascular diseases (CVD), whereas large birth size may predict increased risk of obesity and some cancers. The net effect of birth size on long-term mortality has only been assessed in individual studies, with conflicting results. METHODS The Meta-analyses of Observational Studies in Epidemiology (MOOSE) guidelines for conducting and reporting meta-analysis of observational studies were followed. We retrieved 22 studies that assessed the association between birthweight and adult mortality from all causes, CVD or cancer. The studies were systematically reviewed and those reporting hazard ratios (HRs) and 95% confidence intervals (95% CIs) per kilogram (kg) increase in birthweight were included in generic inverse variance meta-analyses. RESULTS For all-cause mortality, 36,834 deaths were included and the results showed a 6% lower risk (adjusted HR = 0.94, 95% CI: 0.92-0.97) per kg higher birthweight for men and women combined. For cardiovascular mortality, the corresponding inverse association was stronger (HR = 0.88, 95% CI: 0.85-0.91). For cancer mortality, HR per kg higher birthweight was 1.13 (95% CI: 1.07-1.19) for men and 1.04 (95% CI: 0.98-1.10) for women (P(interaction) = 0.03). Residual confounding could not be eliminated, but is unlikely to account for the main findings. CONCLUSION These results show an inverse but moderate association of birthweight with adult mortality from all-causes and a stronger inverse association with cardiovascular mortality. For men, higher birthweight was strongly associated with increased risk of cancer deaths. The findings suggest that birthweight can be a useful indicator of processes that influence long-term health.

Childhood growth and hypertension in later life.

Few studies have examined the effects of both prenatal and postnatal growth on hypertension. We report on hypertension in 2003 people aged 62 years who were randomly selected from the Helsinki birth cohort and examined in a clinic. Their heights and weights had been recorded serially up to age 11 years. A total of 644 had already been diagnosed with hypertension. Compared with normotensive people, they were obese and insulin resistant. At birth they were thin and short, and they gained weight slowly up to age 2 years; thereafter they grew rapidly so that at age 11 years their body size was around the average. The odds ratio associated with each kilogram of birthweight was 0.42 (95% CI: 0.32 to 0.56); with each 10 kg of current weight it was 1.85 (95% CI: 1.66 to 2.05). The blood pressures of another 802 people were classified as hypertensive under current definitions. They were overweight and had an atherogenic lipid profile. At birth they were short, and after birth they grew slowly so that at age 11 years they were short and thin. The odds ratio associated with each kilogram of weight at age 2 years was 0.75 (95% CI: 0.68 to 0.84); with each 10 kg of current weight it was 1.42 (95% CI: 1.28 to 1.57). We conclude that 2 different paths of childhood growth precede the development of hypertension. We suggest that they lead to hypertension through different biological mechanisms and may respond differently to medication.

Birth size, adult body composition and muscle strength in later life.

Objective:Low birth weight has been linked to lower lean body mass and abdominal obesity later in life, whereas high birth weight has been suggested to predict later obesity as indicated by high body mass index (BMI). We examined how birth weight was related to adult body size, body composition and grip strength.Design/subjects:Cross-sectional study on 928 men and 1075 women born in 1934–1944, with measurements at birth recorded.Measurements:Height, weight, waist and hip circumference and isometric grip strength were measured. Lean and fat body mass were estimated by bioelectrical impedance with an eight-polar tactile electrode system.Results:A 1 kg increase in birth weight corresponded in men to a 4.1 kg (95% CI: 3.1, 5.1) and in women to a 2.9 kg (2.1, 3.6) increase in adult lean mass. This association remained significant after adjustment for age, adult body size, physical activity, smoking status, social class and maternal size. Grip strength was positively related to birth weight through its association with lean mass. The positive association of birth weight with adult BMI was explained by its association with lean mass. Low birth weight was related to higher body fat percentage only after adjustment for adult BMI. Abdominal obesity was not predicted by low birth weight.Conclusions:Low birth weight is associated with lower lean mass in adult life and thus contributes to the risk of relative sarcopenia and the related functional inability at the other end of the lifespan. At a given level of adult BMI, low birth weight predicts higher body fat percentage.

Infant Growth and Stroke in Adult Life The Helsinki Birth Cohort Study

Background and Purpose— People who had low birth weight are at increased risk of stroke. Little is known about the effects of early postnatal growth on stroke risk. Methods— We followed-up 12 439 people born in Helsinki during 1934 to 1944. Their body size was measured at birth and, on average, 9 times between birth and age 2 years; 507 of them were hospitalized with stroke or died from the disease. Results— Hazard ratios for stroke declined progressively with increasing gain in weight between birth and age 2 years. The hazard ratio was 0.85 (95% CI, 0.78 to 0.93; P=0.0004) per standard deviation increase in the difference between the weight attained at age 2 years and that predicted from birth weight. A 1-standard deviation increase in body mass index at 2 years of age was associated with a hazard ratio for stroke of 0.84 (95% CI, 0.77 to 0.92; P=0.0002). This association was little changed by adjustment for measures of socio-economic status. Change in body size after the age of 2 years had little effect on the risk of later stroke. People whose mothers had a small external conjugate diameter of the pelvis had an increased risk of stroke. The hazard ratio associated with a diameter of ≤18 cm was 1.62 (95% CI, 1.30 to 2.02; P<0.0001). Conclusion— Thinness during infancy is associated with an increased risk of stroke in later life. This association may be the result of maternal influences which originated in the mothers infancy when her pelvic shape was established.

Genome-Wide Screen for Metabolic Syndrome Susceptibility Loci Reveals Strong Lipid Gene Contribution But No Evidence for Common Genetic Basis for Clustering of Metabolic Syndrome Traits

Background— Genome-wide association (GWA) studies have identified several susceptibility loci for metabolic syndrome (MetS) component traits, but have had variable success in identifying susceptibility loci to the syndrome as an entity. We conducted a GWA study on MetS and its component traits in 4 Finnish cohorts consisting of 2637 MetS cases and 7927 controls, both free of diabetes, and followed the top loci in an independent sample with transcriptome and nuclear magnetic resonance-based metabonomics data. Furthermore, we tested for loci associated with multiple MetS component traits using factor analysis, and built a genetic risk score for MetS. Methods and Results— A previously known lipid locus, APOA1/C3/A4/A5 gene cluster region (SNP rs964184), was associated with MetS in all 4 study samples (P=7.23×10−9 in meta-analysis). The association was further supported by serum metabolite analysis, where rs964184 was associated with various very low density lipoprotein, triglyceride, and high-density lipoprotein metabolites (P=0.024–1.88×10−5). Twenty-two previously identified susceptibility loci for individual MetS component traits were replicated in our GWA and factor analysis. Most of these were associated with lipid phenotypes, and none with 2 or more uncorrelated MetS components. A genetic risk score, calculated as the number of risk alleles in loci associated with individual MetS traits, was strongly associated with MetS status. Conclusions— Our findings suggest that genes from lipid metabolism pathways have the key role in the genetic background of MetS. We found little evidence for pleiotropy linking dyslipidemia and obesity to the other MetS component traits, such as hypertension and glucose intolerance.

Short Sleep Duration and Behavioral Symptoms of Attention-Deficit/Hyperactivity Disorder in Healthy 7- to 8-Year-Old Children

OBJECTIVE. It has been hypothesized that sleep deprivation may manifest in children as behavioral symptoms rather than as tiredness, but only a few studies have investigated this hypothesis. The objective of our study was to evaluate whether short sleep is associated with behavioral symptoms of attention-deficit/hyperactivity disorder in 7- to 8-year-old children. METHODS. We performed a cross-sectional study of children born in 1998 in Helsinki, Finland. The participants included 280 (146 girls, 134 boys) children with a mean age of 8.1 years (SD: 0.3; range: 7.4–8.8). Sleep quality was measured by using actigraphs. The Sleep Disturbance Scale for Children and the Attention-Deficit/Hyperactivity Disorder Rating Scale IV were administered to parents. RESULTS. Children whose average sleep duration as measured by actigraphs was short (<10th percentile, ie, <7.7 hours) and had a higher hyperactivity/impulsivity score (9.7 vs 7.8 or 7.5) and a higher attention-deficit/hyperactivity disorder total score (17.3 vs 14.5 or 13.1) but a similar inattention score (7.6 vs 6.7 or 5.6) compared with children sleeping 7.7 to 9.4 hours or >9.4 hours. In multivariate statistical models, short sleep duration remained a statistically significant predictor of hyperactivity/impulsivity, and sleeping difficulties were associated with hyperactivity/impulsivity, inattention, and the total score. There were no significant interactions between short sleep and sleeping difficulties. CONCLUSIONS. Childrens short sleep duration and sleeping difficulties increase the risk for behavioral symptoms of attention-deficit/hyperactivity disorder.

The surface area of the placenta and hypertension in the offspring in later life

Hypertension is more common among people who had low birthweight. Birthweight depends on the mothers body size and on the growth of the placenta. We studied a group of 2003 subjects, of whom 644 were being treated for hypertension. They were born during 1934-44 in a hospital that kept detailed records of maternal and placental size. Hypertension was associated with reduced placental weight and surface area. These associations were strongest in the offspring of mothers with below average height or low socioeconomic status. In people whose mothers had below average height (160 cm) the prevalence of hypertension fell from 38% if the placental area was 200 cm(2) or less to 21% if the area was more than 320 cm(2) (p=0.0007). In the offspring of tall, middle class mothers, who were likely to have been the best nourished, hypertension was predicted by large placental weight in relation to birthweight. The odds ratio rose from 1.0 if the ratio of placental weight to birthweight was 0.17 or less to 1.9 (95% confidence interval 0.8 to 5.0) if the ratio was more than 0.21 (p for trend =0.03). We conclude that the effects of placental area on hypertension depend on the mothers nutritional state. Poor maternal nutrition may compound the adverse effects of small placental size. In better-nourished mothers the placental surface may expand to compensate for fetal undernutrition. Growth along the minor axis of the surface may be more nutritionally sensitive than growth along the major axis.