Early life stress in women with autoimmune thyroid disorders.

Autoimmune thyroid disorders (AITD) represent the most frequent of all autoimmune disorders. Their aetiopathogenesis is incompletely understood, but most likely multifactorial. Early life stress can have long-lasting effects on the immune system. The aim of the present study was to investigate, for the first time, whether patients with AITD are more frequently affected by early life stress. A total of N = 208 women were recruited into a case-control study. Of these, n = 78 (median age: 53, interquartile range: 15) were patients recruited from a thyroid outpatient clinic with confirmed Hashimoto's thyroiditis, Graves' disease, or AITD not otherwise specified. The remaining n = 130 age- and BMI-matched women (median age: 53, interquartile range: 12) were recruited from the general population. Early life stress was measured with the Childhood Trauma Questionnaire. Patients with AITD did not differ from controls regarding sexual abuse, physical abuse, and physical neglect. However, a greater number of patients reported emotional neglect (29.7% vs. 19.5%) and emotional abuse (41.3% vs. 32%). This study provides initial evidence for emotional neglect and abuse as potential risk factors for the development of AITD. Prospective confirmation of these findings could pave the way for the development of interventions to prevent AITD in predisposed individuals.

Hormone sensitivity predicts the beneficial effects of transdermal estradiol on reward-seeking behaviors in perimenopausal women: A randomized controlled trial.

Depression is highly prevalent during the menopause transition (perimenopause), and often presents with anxious and anhedonic features. This increased vulnerability for mood symptoms is likely driven in part by the dramatic hormonal changes that are characteristic of the menopause transition, as prior research has linked fluctuations in estradiol (E2) to emergence of depressed mood in at risk perimenopausal women. Transdermal estradiol (TE2) has been shown to reduce the severity of depression in clinically symptomatic women, particularly in those with recent stressful life events. This research extends prior work by examining the relation between E2 and reward seeking behaviors, a precise behavioral indicator of depression. Specifically, the current study utilizes a randomized, double blind, placebo-controlled design to investigate whether mood sensitivity to E2 flux ("hormone sensitivity") predicts the beneficial effects of TE2 interventions on reward seeking behaviors in perimenopausal women, and whether recent stressful life events moderate any observed associations. METHOD: Participants were 66 women who met standardized criteria for being early or late perimenopausal based on bleeding patterns. Participants were recruited from a community sample; therefore, mood symptoms varied across the continuum and the majority of participants did not meet diagnostic criteria for a depressive or anxiety disorder at the time of enrollment. Hormone sensitivity was quantified over an 8-week baseline period, using within-subjects correlations between repeated weekly measures of E2 serum concentrations and weekly anxiety (State Trait Anxiety Inventory) and anhedonia ratings (Snaith-Hamilton Pleasure Scale). Women were then randomized to receive 8 weeks of TE2 (0.1 mg) or transdermal placebo, and reward-seeking behaviors were assessed using the Effort-Expenditure for Rewards Task (EEfRT). RESULTS: Participants who were randomized to receive transdermal estradiol and who demonstrated greater anxiety sensitivity to E2 fluctuations at baseline, demonstrated more reward seeking behaviors on the EEfRT task. Notably, the strength of the association between E2-anxiety sensitivity and post-randomization EEfRT for TE2 participants increased when women experienced more recent stressful life events and rated those events as more stressful. E2-anhedonia sensitivity was not associated with reward-seeking behaviors. CONCLUSION: Perimenopausal women who are more sensitive to E2 fluctuations and experienced more recent life stress may experience a greater benefit of TE2 as evidenced by an increase in reward seeking behaviors.

Positive body perception and its link to sexual satisfaction in aging women - findings from the Women 40+ Healthy Aging Study.

Research on the relation between physical appearance and sexual satisfaction in aging women is scarce. This study uniquely links attractiveness, body perception, and sexual satisfaction in 124 healthy aging women. Two-thirds reported being highly sexually satisfied. BMI and fat mass correlated significantly with sexual satisfaction. Weight and shape concerns moderated this relationship, affecting sexual satisfaction beyond the effect of body size and composition. Given the "unattractive stereotype" of older women related to the enduring social beauty ideal of a youthful and thin body, positive body perceptions in light of age-associated bodily changes should be promoted.

Strategies to cope with stress and anxiety during the menopausal transition.

The menopausal transition is often accompanied by psycho-vegetative symptoms, including stress and anxiety symptoms. Identifying stress and anxiety and intervening early can have an enormous public health impact. Health care practitioners like obstetrician-gynecologists or family doctors play a critical role in the diagnosis, prevention and treatment of stress and anxiety symptoms or disorders, as they often represent women's primary medical contact during the menopausal transition. However, they frequently do not feel confident in identifying and treating mental health problems. The aim of this review was to summarize current (since 2010) knowledge from randomized controlled trials, systematic reviews, and meta-analyses on diagnostics and treatment options, and to provide clinical decision-making algorithms. The recent literature suggests pharmacological, (cognitive) behavioral, and complementary treatments. The choice about which one to use should be discussed with the patient.

Baseline anxiety-sensitivity to estradiol fluctuations predicts anxiety symptom response to transdermal estradiol treatment in perimenopausal women - A randomized clinical trial.

BACKGROUND: The menopausal transition (perimenopause) is associated with an increased risk of major depression, characterized by anxiety and anhedonia phenotypes. Greater estradiol (E2) variability predicts the development of perimenopausal depression, especially within the context of stressful life events (SLEs). While transdermal E2 (TE2) reduces perimenopausal depressive symptoms, the mechanisms underlying TE2 efficacy and predictors of TE2 treatment response remain unknown. This study aimed at determining relationships between E2 fluctuations, mood symptoms, and physiologic stress-reactivity (cortisol and interleukin-6) and whether differences in mood-sensitivity to E2 fluctuations predict mood responses to TE2 treatment. METHODS: This randomized, double-blind, placebo-controlled trial investigated medically healthy women (46-60 years) in the early or late menopause transition. Baseline E2-sensitivity strength was calculated from eight weekly individual correlations between week-to-week E2 change and index week anxiety (State-Trait Anxiety Inventory) and anhedonia (Snaith-Hamilton Pleasure Scale). Women then received eight weeks of TE2 or transdermal placebo. RESULTS: Analyses included 73 women (active TE2 n = 35). Greater baseline E2 fluctuations predicted greater anhedonia (p = .002), particularly in women with more SLEs. Greater E2 fluctuations also predicted higher cortisol (p = .012) and blunted interleukin-6 (p = .02) stress-responses. Controlling for baseline symptoms, TE2 was associated with lower post-treatment anxiety (p < .001) and anhedonia (p < .001) versus placebo. However, the efficacy of TE2 for anxiety (p = .007) and also for somatic complaints (p = .05) was strongest in women with greater baseline E2 sensitivity strength. CONCLUSIONS: TE2 treatment reduced perimenopausal anxiety and anhedonia. The ability of baseline mood-sensitivity to E2 fluctuations to predict greater TE2 efficacy has implications for individualized treatment of perimenopausal anxiety disorders.

HPA axis activity across the menstrual cycle - a systematic review and meta-analysis of longitudinal studies.

Differential HPA axis function has been proposed to underlie sex-differences in mental disorders; however, the impact of fluctuating sex hormones across the menstrual cycle on HPA axis activity is still unclear. This meta-analysis investigated basal cortisol concentrations as a marker for HPA axis activity across the menstrual cycle. Through a systematic literature search of five databases, 121 longitudinal studies were included, summarizing data of 2641 healthy, cycling participants between the ages of 18 and 45. The meta-analysis showed higher cortisol concentrations in the follicular vs. luteal phase (dSMC = 0.12, p =.004, [0.04 - 0.20]). Comparisons between more precise cycle phases were mostly insignificant, aside from higher concentrations in the menstrual vs. premenstrual phase (dSMC = 0.17, [0.02 - 0.33], p =.03). In all included studies, nine samples used established cortisol parameters to indicate HPA axis function, specifically diurnal profiles (k = 4) and the cortisol awakening response (CAR) (k = 5). Therefore, the meta-analysis highlights the need for more rigorous investigation of HPA axis activity and menstrual cycle phase.

Methods for characterizing ovarian and adrenal hormone variability and mood relationships in peripubertal females.

Peripubertal females are at elevated risk for developing affective illness compared to males, yet biological mechanisms underlying this sex disparity are poorly understood. Female risk for depression remains elevated across a woman's reproductive lifespan, implicating reproductive hormones. A sensitivity to normal hormone variability during reproductive transition events (e.g., perimenopause) precipitates affective disturbances in susceptible women; however, the extent of hormone variability during the female pubertal transition and whether vulnerability to peripubertal hormone flux impacts affective state change in peripubertal females has not been studied. 52 healthy peripubertal females (ages 11-14) provided 8 weekly salivary samples and mood ratings. 10 salivary ovarian and adrenal hormones (e.g., estrone, testosterone, dehydroepiandrosterone (DHEA)) were analyzed weekly for 8 weeks using an ultrasensitive assay to characterize the female peripubertal hormone environment and its association with affective state. Hormone variability indices, including standard deviation, mean squared and absolute successive differences of the 8 weekly measurements were analyzed by menarche status. Within-person partial correlations were computed to determine the strength of the relationship between weekly change in hormone level and corresponding mood rating for each participant. As expected, results indicated that hormone variability was greater for post- relative to pre-menarchal females and with advancing pubertal development, yet pregnenolone-sulfate and aldosterone did not differ by menarche status. Mood sensitivity to changes in estrone was exhibited by 57% of participants, whereas 37% were sensitive to testosterone and 6% were sensitive to DHEA changes. The present results offer novel evidence that a substantial proportion of peripubertal females appear to be mood sensitive to hormone changes and may inform future investigations on the biological mechanisms underlying hormone-induced affect dysregulation in peripubertal females.

Female Intrasexual Competition and Its Link to Menopausal Stage, Sex Hormone Levels, and Personality Characteristics.

Background: Female intrasexual competition (ISC) represents a unique form of social interaction. It describes behaviors primarily applied to enhance a woman's ability to outcompete other women. Previous research suggests that female ISC is influenced by personality characteristics and sex hormones. Although these factors most likely interact to predict female ISC, no previous study has investigated those factors in parallel in order to link theories from social psychology and biology. Women at the end of the reproductive lifespan represent the ideal study population, as they allow for a controlled hormonal environment. Materials and Methods: Healthy pre- (N = 53) and postmenopausal (N = 56) women were classified according to the Stages of Reproductive Aging Workshop (STRAW+10) criteria. In the follicular phase (for premenopausal women) or on a random day (for postmenopausal women), questionnaires were administered to assess the general tendency to compete intrasexually and the tendency to compete on appearance, attention/interpersonal success, and competence. Additionally, personality characteristics (neuroticism, extraversion, openness, agreeableness, conscientiousness, and self-esteem) were assessed. On the same day, each subject provided an 8 a.m. saliva sample for estradiol, testosterone, progesterone, and dehydroepiandrosterone sulfate. T-tests tested for between-group differences and separate multiple linear regression models tested for an effect of continuous hormone levels and personality characteristics on ISC. Further models were run, testing for an interaction with menopausal stage. Results: No group differences in ISC were evident (all p > 0.05). In premenopausal women, estradiol levels positively predicted the competition for attention (ß = 2.103, p = 0.022). In postmenopausal women, self-esteem predicted the tendency to compete overall (ß = -0.208, p < 0.001), on appearance (ß = -0.061, p = 0.01), on competence (ß = -0.087, p < 0.001), and on attention/interpersonal success (ß = -0.060, p = 0.01). Discussion: These results, though cross-sectional, suggest that women continue to compete intrasexually in postmenopause, giving rise to new questions about the function of female ISC. If confirmed, the findings will indicate that hormones guide competitiveness in fertile women, whereas self-esteem accounts for individual differences in competitiveness post-reproduction. Particularly the function of postmenopausal ISC warrants further investigation.

Sleep and Methylation of Estrogen Receptor Genes, ESR1 and GPER, in Healthy Middle-Aged and Older Women: Findings from the Women 40+ Healthy Aging Study.

PURPOSE: Sleep problems in middle-aged and older women are very common and have been associated with menopause-related changes in estrogen levels. However, not all women experience sleep problems as they enter perimenopause, and epigenetic mechanisms might contribute to the differences in sleep quality within this population. In this study, we hypothesized that increased methylation of two estrogen receptor (ER) genes (ESR1 and GPER) would be associated with increased sleep problems in healthy pre-, peri-, and postmenopausal women, either directly or indirectly through the experience of vasomotor symptoms (VMS). MATERIALS AND METHODS: In 130 healthy women aged 40-73 years, we assessed DNA methylation from dried blood spots (DBS). Women rated their sleep quality using the Pittsburgh Sleep Quality Index (PSQI), and VMS using the Menopause Rating Scale (MRS). RESULTS: Higher percentage methylation of ESR1 was associated with increased sleep problems, mediated by VMS, even after controlling for age, menopausal status, body mass index, estradiol levels, depressive symptoms, and caffeine consumption. There was no significant association between GPER methylation and either sleep problems or VMS. CONCLUSION: The study findings support an association between increased ESR1 methylation and sleep problems through increased VMS among healthy women aged 40-73 years.

Differential ESR1 Promoter Methylation in the Peripheral Blood-Findings from the Women 40+ Healthy Aging Study.

Background Estrogen receptor α (ERα) contributes to maintaining biological processes preserving health during aging. DNA methylation changes of ERα gene (ESR1) were established as playing a direct role in the regulation of ERα levels. In this study, we hypothesized decreased DNA methylation of ESR1 associated with postmenopause, lower estradiol (E2) levels, and increased age among healthy middle-aged and older women. Methods We assessed DNA methylation of ESR1 promoter region from dried blood spots (DBSs) and E2 from saliva samples in 130 healthy women aged 40-73 years. Results We found that postmenopause and lower E2 levels were associated with lower DNA methylation of a distal regulatory region, but not with DNA methylation of proximal promoters. Conclusion Our results indicate that decreased methylation of ESR1 cytosine-phosphate-guanine island (CpGI) shore may be associated with conditions of lower E2 in older healthy women.

The Relation Between Steroid Secretion Patterns and the Androgen Receptor Gene Polymorphism on Physical Health and Psychological Well-Being-Longitudinal Findings From the Men's Health 40+ Study.

Research is increasingly focusing on promoting healthy aging and the related extension of the health span by targeting crucial biological processes responsible for age-related conditions. While age-related gradual changes in steroid hormones such as testosterone, estradiol, or cortisol are well described in men, their interactions among each other or with genetic markers have not been sufficiently investigated with regard to physical health or psychological well-being. More specifically, the examination of age-related alterations in hormone interactions and the androgen receptor polymorphism, which modulates androgen action on target cells, in relation to physical health and psychological well-being represents a promising avenue for research on healthy aging in men. A total of 97 healthy aging men provided complete data on psychometric health measures as well as hormonal and genetic parameters at baseline and a 4-year follow-up assessment. Fasting saliva samples were taken at 8:00 am under standardized laboratory conditions, while the androgen receptor gene polymorphism was analyzed from dried blood spots. Longitudinal analyses revealed that psychological well-being and physical health remained stable over time. Analyses indicated that E2 moderated the course of psychological well-being, while the androgen receptor gene polymorphism moderated the course of physical health. Further, T was a strong predictor of physical health. These results suggest that the hypothalamic-pituitary-gonadal (HPG) axis might be important for the maintenance of psychological well-being in men, while physical health depends more on interindividual differences in the androgen receptor gene and T.

Psychobiological indicators of the subjectively experienced health status - findings from the Women 40+ Healthy Aging Study.

BACKGROUND: Healthy aging is particularly important in women, as their life-span is generally longer than men's, leaving women at higher risk for age-related diseases. Understanding determinants of women's healthy aging is therefore a major public health interest. Clinical utility of previous research is limited, through its focus on either single psychosocial or biological predictors. The present study investigated psychobiological predictors of women's healthy aging, for the first time including positive psychological traits and biomarkers of healthy aging. METHODS: Totally, 121 generally healthy women aged 40 to 75 were investigated cross-sectionally. Healthy aging was operationalized via self-rated health (SRH). To gain a nuanced view of the particularities at the upper end of the illness-wellness continuum, women with excellent SRH and those with good SRH were analyzed as distinct groups. Socioeconomic and sociodemographic variables, health behavior, resilience, optimism, and self-worth as well as menopausal symptoms, and levels of steroid hormones and gonadotropins were considered as predictors of SRH. Binary logistic regression analyses using the forward conditional method were performed with the two health status groups as dependent variable. RESULTS: Women with a lower body mass index (BMI; OR = .59, 95% CI = .33-1.03), higher intensive physical activity (OR = 2.27, 95% CI = 1.06-4.86), and higher resilience (OR = 2.37, 95% CI = 1.34-4.18) were more likely to rate their health as excellent compared to good. No clinically significant differences could be found regarding endocrine levels. CONCLUSION: Psychobiological indicators (lower BMI, intensive physical activity, higher resilience) discriminated SRH at the top level of the health spectrum. In healthy women, the predictive value of endocrine markers seems to be secondary. Interventions targeting these indicators could promote women's healthy aging.

DNA Methylation in Healthy Older Adults With a History of Childhood Adversity-Findings From the Women 40+ Healthy Aging Study.

Background: Adversity in early development seems to increase the risk of stress-related somatic disorders later in life. Physiologically, functioning of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes is often discussed as long-term mediators of risk. In particular, DNA methylation in the glucocorticoid receptor gene promoter (NR3C1) has been associated with type and strength of early life adversity and subsequent effects on HPA axis signaling in humans. Animal studies, moreover, suggest changes in DNA methylation in the estrogen receptor gene (ERα) upon early life adversity. We investigated the association of type and severity of childhood adversity with methylation in NR3C1 and ERα and additionally considered associations between methylation and steroid hormone secretion. Methods: The percentage of methylation within the NR3C1 promoter and the ERα shore was investigated using dried blood spot samples of 103 healthy women aged 40-73 years. Childhood adversity was examined with the Childhood Trauma Questionnaire. Linear regression analyses were performed with methylation as dependent variable and the experience of emotional abuse and neglect, physical abuse and neglect, and sexual abuse (compared to non-experience) as independent variables. All analyses were controlled for age, BMI, annual household income, and smoking status and were adjusted for multiple testing. Results: Overall, over 70% of the sample reported having experienced any kind of abuse or neglect of at least low intensity. There were no significant associations between childhood adversity and methylation in the NR3C1 promoter (all p > .10). Participants reporting emotional abuse showed significantly higher methylation in the ERα shore than those who did not (p = .001). Additionally, higher levels of adversity were associated with higher levels of ERα shore methylation (p = .001). Conclusion: In healthy women, early life adversity does not seem to result in NR3C1 promoter hypermethylation in midlife and older age. This is the first study in humans to suggest that childhood adversity might, however, epigenetically modify the ERα shore. Further studies are needed to gain a better understanding of why some individuals remain healthy and others develop psychopathologies in the face of childhood adversity.

Psychobiological Factors of Sexual Functioning in Aging Women - Findings From the Women 40+ Healthy Aging Study.

Background: A variety of biological and psychosocial factors are associated with women's sexual health in midlife and older age. Evidence suggests a decline in sexual functioning in the context of aging and the menopausal transition, including changes in sexual desire, arousal, lubrication, orgasm, pain, and/or contentment. However, not all women in midlife and older age experience such a decline, and it remains unclear how the endocrine environment and psychosocial aspects contribute to the maintenance of healthy sexual functioning. Therefore, the aim of this study was to examine psychobiological predictors of sexual functioning in healthy middle-aged and elderly females. Methods: A total of 93 healthy, sexually active women aged 40-73 years completed a battery of validated psychosocial questionnaires, including measures of sexual functioning (Female Sexual Function Index) and of protective psychological traits and interpersonal variables. The steroid hormones estrogen, testosterone, progesterone and dehydroepiandrosterone sulfate were determined in saliva samples, while follicle-stimulating hormone, luteinizing hormone and sex hormone-binding globulin were determined in dried blood spots. The findings were statistically adjusted for multiple testing. Results: Age and postmenopausal status were negatively associated with overall sexual functioning, arousal, and lubrication. Regression analyses revealed that relationship satisfaction, emotional support, self-esteem, optimism, and life satisfaction each significantly predicted overall sexual functioning or specific aspects of sexual functioning, including arousal, contentment, orgasm, and pain (all p < 0.029). For desire and lubrication, no associations were found with the tested psychosocial factors. In terms of steroid hormones, testosterone was positively linked to orgasm (p = 0.012). In this sample, 79.6% reported to have healthy sexual functioning according to the questionnaires' cutoff. Younger age (OR = 0.911, 95% CI 0.854-0.970, p = 0.004) and a higher level of emotional support (OR = 1.376, 95% CI 1.033-1.833, p = 0.029) were associated with the presence of healthy sexual functioning. Discussion: Although aging and menopause negatively affected aspects of sexual functioning, the accompanying endocrine correlates were not predictive for sexual functioning in this healthy sample of middle-aged and older females. Instead, our findings suggest that sexual functioning is highly dependent on psychosocial aspects related to well-being. Accordingly, personality traits such as optimism, and interpersonal aspects such as emotional support and relationship satisfaction were identified as important predictors of sexual functioning.

Steroid secretion in healthy aging.

Nowadays, people spend a considerable amount of their lives as older adults, but this longer lifespan is often accompanied by an increase in chronic conditions and disease, resulting in reduced quality of life and unprecedented societal and economic burden. Healthy aging is therefore increasingly recognized as a healthcare priority. Physical and mental adaptations to changes over the life course, and the maintenance of well-being, represent pivotal challenges in healthy aging. To capture the complexity of healthy aging, we propose a specific phenotype based on body composition, cognition, mood, and sexual function as indicators of different dimensions of healthy aging. With increasing age, sex hormones as well as glucocorticoids undergo significant alterations, and different patterns emerge for women and men. This review describes age-related patterns of change for women and men, and sheds light on the underlying mechanisms. Furthermore, an overview is provided of the challenges for healthy aging resulting from these age-related steroid alterations. While clinical practice guidelines recommend hormonal treatment only in the case of consistently low hormone levels and symptoms of hormone deficiency, physical exercise and a healthy lifestyle emerge as preventive strategies which can counter age-related hormonal changes and at best prevent chronic conditions.

Measuring female intrasexual competition by the scale for intrasexual competition: a validation of the German version.

Competitive behaviour amongst members of the same sex is termed intrasexual competition. The tendency to engage in such competition appears to be strongly related to stable individual characteristics such as personality traits. Additionally, recent studies have revealed transient fluctuations in competitiveness according to the female menstrual cycle. To date, no German questionnaire exists to measure intrasexual competition. Our first study aimed to translate and validate the Intrasexual Competition Scale (ICS) by Buunk and Fisher (J Evol Psychol 7:37-48, 2009) in a population of healthy Swiss females (n = 241). Our second study applied the validated German ICS in a group of healthy, regularly cycling females (n = 49) in order to examine possible associations between the menstrual cycle phase and ICS scores. The psychometric properties suggest that the German ICS is a reliable and valid tool to assess individual differences in female intrasexual competition. Furthermore, our second study demonstrated that on average, women showed higher intrasexual competition scores when tested in the late follicular phase (M = 35.77 ± SD = 12.03) compared to the mid-luteal phase (M = 30.93 ± SD = 10.20). Our studies support previous findings of an association between ICS scores and relatively stable individual characteristics such as personality traits. Furthermore, our research endorses the assumption of cycle-dependent fluctuations in intrasexual competition. Future research should clarify the precise mechanisms underlying these findings and include biomarkers such as oestrogen and testosterone.