Ovarian hormones reduce the negative association between worry and cognitive control: A combined neural and behavioral investigation.

BACKGROUND: Increased reactivity to response conflict and errors, processes governed by the dorsal anterior cingulate cortex (dACC), have both been implicated in anxiety. Anxiety is also more common in females than males. Importantly, natural changes in ovarian hormones levels are related to fluctuations in anxiety symptoms in healthy and clinical populations, and ovarian hormones likely modulate prefrontal cortex structure and function. No studies, however, have examined the role of fluctuating ovarian hormones in the association between anxiety and cognitive control across the menstrual cycle. METHODS: In this multimodal proof-of-concept study, naturally cycling females (N = 30 twins from 14 complete twin pairs and 2 participants whose co-twin was not in the final sample; age 18-29) provided saliva samples to assay for estradiol and progesterone and completed the Penn State Worry Questionnaire for 35 consecutive days. At two time points, during projected pre-ovulatory and post-ovulatory phases, they also completed the Flanker task while undergoing functional magnetic resonance imaging to probe cognitive control-related dACC activity. Multilevel modeling was used to examine within- and between-person effects of hormones and worry on cognitive-control indices. RESULTS: On days when estradiol and progesterone were low relative to a female's own average (i.e., within-subjects effect), worry was associated with greater flanker interference. In females with higher estradiol and progesterone levels compared to other females (i.e., between-subject effects), worry was associated with less error-related dACC activity, irrespective of the day that dACC activity was assessed. CONCLUSION: Findings suggest a protective effect of ovarian hormones on the link between worry and cognitive control. Associations between worry and conflict-monitoring were sensitive to daily hormonal fluctuations (within-person states), whereas associations between worry and error-monitoring were sensitive to mean hormone levels (between-person traits), suggesting that ovarian hormones are critical to consider in studies examining associations between anxiety and cognitive control in females.

Determining menstrual cycle phase: An empirical examination of methodologies and recommendations for improvement in behavioral and brain sciences.

The recent decade has brought an exciting proliferation of behavioral, psychological and neuroscientific research involving the menstrual cycle. However, the reliability and validity of many popular methodologies for determining menstrual cycle phase lack empirical examination. These under-investigated methods include: (1) predicting menstrual cycle phase using self-report information only (e.g., "count" methods), (2) utilizing ovarian hormone ranges to determine menstrual cycle phase, and (3) using ovarian hormone changes from limited measurements (e.g., two time points) to determine menstrual cycle phase. In the current study, we examine the accuracy of these methods for menstrual cycle phase determination using 35-day within-person assessments of circulating ovarian hormones from 96 females across the menstrual cycle. Findings indicate that all three common methods are error-prone, resulting in phases being incorrectly determined for many participants, with Cohen's kappa estimates ranging from -0.13 to 0.53 indicating disagreement to only moderate agreement depending on the comparison. Such methodological challenges are surmountable through careful study design, more frequent hormone assays (when possible), and utilization of sophisticated statistical methods. With increased methodological rigor in behavioral, psychological and neuroscientific research, the field will be poised to detect biobehavioral correlates of ovarian hormone fluctuations for the betterment of the mental health and wellbeing of millions of females.

Estrogen moderation of genetic influences on eating disorder symptoms during gonadarche in girls: Specific effects on binge eating.

The heritability of eating disorder (ED) symptoms increases dramatically across gonadarche in girls. Past studies suggest these developmental differences could be due to pubertal activation of estrogen, but findings have been limited to only one ED symptom (i.e., binge eating). The current study examined whether estrogen contributes to gonadarcheal differences in genetic influences on overall levels of ED symptoms as well as key cognitive symptoms (i.e., weight/shape concerns) that are present across all EDs and are early risk factors for eating pathology. Given that binge eating frequently co-occurs with all of these symptoms, analyses also examined whether estrogen effects exist for overall levels of ED symptoms and body weight/shape concerns after accounting for the known effects of estrogen on genetic risk for binge eating. Participants included 964 female twins (ages 8-16) from the Michigan State University Twin Registry. Overall levels of ED symptoms were assessed with the Minnesota Eating Behavior Survey (MEBS) total score. Weight/shape concerns were assessed with a latent factor modeled using subscales from the MEBS and the Eating Disorder Examination Questionnaire. Estradiol levels were assessed with saliva samples. Twin moderation models were used to examine whether genetic influences on overall levels of ED symptoms and weight/shape concerns differed significantly across estradiol levels. Although initial models suggested modest differences in genetic influences on overall levels of ED symptoms across estradiol levels, these effects were eliminated when binge eating was accounted for in the models. In addition, weight/shape concerns did not show significant moderation of genetic influences by estradiol in models with or without binge eating. Taken together, results are significant in suggesting that individual differences in estradiol levels during gonadarche have a unique and specific impact on genetic risk for binge eating, while other etiologic factors must contribute to increased heritability of cognitive ED symptoms during this key developmental period in girls.

The organizational role of ovarian hormones during puberty on risk for binge-like eating in rats.

Puberty is a high-risk period for the development of dysregulated eating, including binge eating. While risk for binge eating in animals and humans increases in both males and females during puberty, the increased prevalence is significantly greater in females. Emerging data suggest that the organizational effects of gonadal hormones may contribute to the female preponderance of binge eating. In this narrative review, we discuss studies conducted in animals that have examined these organizational effects as well as the neural systems that may serve as intermediary mechanisms. Relatively few studies have been conducted, but data thus far suggest that pubertal estrogens may organize risk for binge eating, potentially by altering key circuits in brain reward pathways. These promising results highlight the need for future studies to directly test organizational effects of pubertal hormones using hormone replacement techniques and circuit-level manipulations that can identify pathways contributing to binge eating across development.

Binge Eating Risk During Midlife and the Menopausal Transition: Sensitivity to Ovarian Hormones as Potential Mechanisms of Risk.

PURPOSE OF REVIEW: Recent research suggests that binge eating may be more prevalent among women in midlife than previously believed. The menopausal transition, an important developmental stage during midlife, is characterized by substantial fluctuations and eventual decreases in ovarian hormones that may contribute to increased risk. This narrative review summarizes findings from studies of binge eating during midlife and menopause and discusses the potential role of ovarian hormones in binge eating risk. RECENT FINDINGS: Studies are few in number and findings are mixed, with only some studies showing increased binge eating during midlife and the menopausal transition. Sensitivity to ovarian hormones, potentially through gene x hormone interactions, may influence who experiences increased binge eating risk and could help explain mixed findings in the field. Future studies of hormone sensitivity and gene x hormone interactions are needed to further elucidate midlife and menopausal risk for binge eating in women.

Examining a window of vulnerability for affective symptoms in the mid-luteal phase of the menstrual cycle.

Particular phases of the menstrual cycle may exacerbate affective symptoms for females with a diagnosed mental health disorder. However, there are mixed findings regarding whether affective symptoms change across the menstrual cycle in females without a clinical diagnosis. The window of vulnerability model proposes that natural increases in ovarian hormones in the mid-luteal phase of the menstrual cycle lead to systematic changes in brain networks associated with affective processing. Consequently, the model posits that females may experience stress more intensely and remember negative events more readily in the mid-luteal phase, increasing their risk for higher affective symptoms. Using a 35-day longitudinal study design, we tested the window of vulnerability model in a non-clinical sample. We tracked naturally cycling females' daily stress and three types of affective symptoms: anxious apprehension, anxious arousal, and anhedonic depression. Using multilevel modeling, we simultaneously modeled within- and between-person associations among stress and menstrual phase for each affective symptom. We found increased anhedonic depression in the mid-luteal phase but not anxious apprehension or anxious arousal. Moreover, we detected a positive association between within- and between-person stress and anxious apprehension and anhedonic depression, but not anxious arousal. These associations were not stronger in the mid-luteal phase. Overall, we provide weak evidence for a window of vulnerability for affective symptoms in the mid-luteal phase of the menstrual cycle. Our findings suggest that stress is a better predictor of fluctuations in affective symptoms than the menstrual cycle. Moreover, our findings highlight the importance of measuring multiple negative affective symptoms because they may be differentially related to stress and the menstrual cycle.

Combined oral contraceptive use and risk for binge eating in women: Potential gene × hormone interactions.

Extant animal and human data suggest endogenous ovarian hormones increase risk for binge eating in females, possibly via gene × hormone interactions and hormonally induced increases in genetic influences. Approximately 85 % of women will take combined oral contraceptives (COCs) that mimic the riskiest hormonal milieu for binge eating (i.e., post-ovulation when both estrogen and progesterone are present). The purpose of this narrative review is to synthesize findings of binge eating risk in COC users. Few studies have been conducted, but results suggest that COCs may increase risk for binge eating and related phenotypes (e.g., craving for sweets), particularly in genetically vulnerable women. Larger, more systematic human and animal studies of COCs and binge eating are needed. The goal of this work should be to advance personalized medicine by identifying the extent of COC risk as well as the role of gene × hormone interactions in susceptibility.

Risk for midlife psychosis in women: critical gaps and opportunities in exploring perimenopause and ovarian hormones as mechanisms of risk.

Women show a heightened risk for psychosis in midlife that is not observed in men. The menopausal transition (i.e. perimenopause) and accompanying changes in ovarian hormones are theorized to account for this midlife increase in risk. This narrative review aims to empirically examine these theories by reviewing studies of midlife and perimenopausal psychosis risk in women and potential ovarian hormone mechanisms of effects. Clinical and pre-clinical studies examining the effects of midlife age, menopausal stage, and ovarian hormones across adulthood on psychosis risk were identified. Synthesis of this body of work revealed that the peak ages of midlife psychosis risk in women overlap with the age range of key menopausal stages (especially the perimenopausal transition), although studies directly assessing menopausal stage are lacking. Studies examining ovarian hormone effects have almost exclusively focused on earlier developmental stages and events (e.g. pregnancy, the menstrual cycle) and show increases in psychotic symptoms in women and female rats during periods of lower estradiol levels. Estrogen treatment also tends to enhance the effects of neuroleptics in females across species at various reproductive phases. Initial data are promising in suggesting a role for menopausal stage and ovarian hormones in psychosis risk. However, critical gaps in our knowledge base remain, as there is a tendency to rely on indirect and proxy measures of menopausal status and hormones. Opportunities for future research are discussed with the goal of increasing research in this critical area of women's health.

Examining the role of ovarian hormones in the association between worry and working memory across the menstrual cycle.

Previous research indicates that worry is associated with poorer working memory performance. Moreover, prior work demonstrates that estradiol relates to both worry and working memory performance. In the present study, we sought to further examine interrelations between worry, estradiol and working memory by testing whether estradiol moderates the association between worry and working memory in females. We hypothesized that worry would be associated with poorer working memory performance at higher levels of estradiol. We also conducted exploratory analyses to examine the role of progesterone as a moderator of the association between worry and working memory. Participants were 97 naturally-cycling females who attended four lab sessions across their menstrual cycles. Consistent with predictions, higher average levels of worry were associated with lower working memory accuracy on particularly difficult trials when average levels of estradiol were also high. The same association between higher worry and lower working memory accuracy emerged when average levels of progesterone were high. Findings highlight the importance of considering ovarian hormones in future studies and current theories of anxiety and cognition.

Ovarian Hormones and Reward Processes in Palatable Food Intake and Binge Eating.

Ovarian hormones are associated with risk for binge eating in women. Recent animal and human studies suggest that food-related reward processing may be one set of neurobiological factors that contribute to these relationships, but additional studies are needed to confirm and extend findings.

The Role of Puberty and Ovarian Hormones in the Genetic Diathesis of Eating Disorders in Females.

Puberty is a critical risk period for eating disorders (EDs). ED incidence increases across the pubertal period and becomes female predominant, and genetic influences on disordered eating significantly increase. Surges of ovarian hormones, particularly estrogen, may drive this increasing genetic effect for EDs in pubertal girls and contribute to differential phenotypic presentations beyond puberty. In this article, we explain phenotypic associations between puberty and disordered eating and present evidence showing underlying genetic and hormonal influence. Potential benefits of communicating roles of genetic influence to people with or at risk for EDs are also discussed.

Associations between ovarian hormones and emotional eating across the menstrual cycle: Do ovulatory shifts in hormones matter?

OBJECTIVE: Elevated ovarian hormone levels are associated with increased risk for binge eating (BE) and emotional eating (EE) during the midluteal phase of the menstrual cycle. However, past studies have not examined whether pronounced hormonal changes that precede the midluteal phase (i.e., the dramatic decrease in estradiol and increase in progesterone during/after ovulation) also influence midluteal increases in binge-related symptoms. Past theories and studies of phenotypes strongly related to BE (e.g., depression) suggest that these pronounced hormonal changes may also contribute. This study examined this possibility in 375 female twins (aged 15-25 years) from the Michigan State University Twin Registry. METHODS: Daily ratings of EE (assessed with the Dutch Eating Behavior Questionnaire) and daily saliva samples of estradiol and progesterone were collected for 45 consecutive days. RESULTS: No significant associations were found between pronounced changes in estradiol or progesterone across ovulation and changes in EE scores in the midluteal phase. Results remained unchanged after controlling for body mass index and negative affect and examining participants with clinical BE episodes or more extreme hormonal fluctuations. DISCUSSION: In aggregate, the current findings and past data suggest that hormone levels are more significant predictors of EE than pronounced hormonal changes across the menstrual cycle.

Interaction of hormonal and social environments in understanding body image concerns in adolescent girls.

During adolescence, peer approval becomes increasingly important and may be perceived as contingent upon appearance in girls. Concurrently, girls experience hormonal changes, including an increase in progesterone. Progesterone has been implicated in affiliative behavior but inconsistently associated with body image concerns. The current study sought to examine whether progesterone may moderate the association between perceived social pressures to conform to the thin ideal and body image concerns. Secondary analyses were conducted in cross-sectional data from 813 girls in early puberty and beyond (ages 8-16) who completed assessments of the peer environment, body image concerns, and progesterone. Models for mediation and moderation were examined with BMI, age, and menarcheal status as covariates. Belief that popularity was linked to appearance and the experience of weight-related teasing were both positively associated with greater body image concerns, but neither was associated with progesterone once adjusting for covariates. Progesterone significantly interacted with perceived social pressures in predicting body image concerns. At higher progesterone levels, appearance-popularity beliefs and weight-related teasing were more strongly related to body image concerns than they were at lower progesterone levels. Findings support a moderating role for progesterone in the link between social pressures and body image concerns in girls. This study adds to a growing literature examining how girls' hormonal environments may modulate responses to their social environments. Longitudinal and experimental work is needed to understand temporal relations and mechanisms behind these associations.

Using person-specific neural networks to characterize heterogeneity in eating disorders: Illustrative links between emotional eating and ovarian hormones.

OBJECTIVE: Emotional eating has been linked to ovarian hormone functioning, but no studies to-date have considered the role of brain function. This knowledge gap may stem from methodological challenges: Data are heterogeneous, violating assumptions of homogeneity made by between-subjects analyses. The primary aim of this paper is to describe an innovative within-subjects analysis that models heterogeneity and has potential for filling knowledge gaps in eating disorder research. We illustrate its utility in an application to pilot neuroimaging, hormone, and emotional eating data across the menstrual cycle. METHOD: Group iterative multiple model estimation (GIMME) is a person-specific network approach for estimating sample-, subgroup-, and individual-level connections between brain regions. To illustrate its potential for eating disorder research, we apply it to pilot data from 10 female twins (N = 5 pairs) discordant for emotional eating and/or anxiety, who provided two resting state fMRI scans and hormone assays. We then demonstrate how the multimodal data can be linked in multilevel models. RESULTS: GIMME generated person-specific neural networks that contained connections common across the sample, shared between co-twins, and unique to individuals. Illustrative analyses revealed positive relations between hormones and default mode connectivity strength for control twins, but no relations for their co-twins who engage in emotional eating or who had anxiety. DISCUSSION: This paper showcases the value of person-specific neuroimaging network analysis and its multimodal associations in the study of heterogeneous biopsychosocial phenomena, such as eating behavior.

Estrogen moderates genetic influences on binge eating during puberty: Disruption of normative processes?

Puberty is a critical period for changes in genetic effects for binge eating in girls. Previous twin studies show increases in genetic influences on binge eating from prepuberty (∼0%) to midpuberty and beyond (∼50%). However, little is known about the factors that drive these shifts in genetic effects. A small pilot study showed that pubertal activation of estrogen may contribute to increases in genetic influences, possibly via hormonally induced changes in gene expression. However, large-scale studies investigating hormone effects on genetic risk are lacking. Thus, the purpose of the present study was to examine the effects of estrogen on genetic influences for binge eating in 964 female twins (ages 8-16 years) from the Michigan State University Twin Registry. Binge eating was assessed with the Minnesota Eating Behaviors Survey, whereas afternoon saliva samples were assayed for estradiol levels using standard enzyme immunoassays. Twin moderation models showed substantial differences in genetic influences on binge eating across estradiol levels. Stronger genetic effects were observed at lower (rather than higher) estradiol levels, even when controlling for the effects of age, body mass index, the physical changes of puberty, and the onset of menses. Overall, findings suggest that comparatively lower levels of estradiol during this critical period may disrupt normative developmental processes and enhance genetic influences on binge eating. (PsycINFO Database Record

Preliminary evidence of sex differences in behavioral and neural responses to palatable food reward in rats.

The female bias in eating disorder prevalence is the largest in all of psychiatry. Binge eating on palatable food (PF) is a core, maladaptive symptom that cuts across all major types of eating disorders and can be studied via animal models. Using an individual differences rat model of binge eating that identifies binge eating prone (BEP) and binge eating resistant (BER) phenotypes, we previously showed that, compared with males, females consume more PF and are more likely to be classified as BEP. One potential explanation for this sex difference is that PF is inherently more rewarding to females, leading to higher rates of binge eating. Here we tested the hypothesis that females have more robust behavioral and neural responses to PF reward than males. Adult male (N=18) and female (N=17) Sprague-Dawley rats were exposed to the Conditioned Place Preference paradigm using PF as the unconditioned stimulus. Select males (N=9) and females (N=9) were video-recorded during three of the PF-paired conditioning sessions to score feeding behavior. Following CPP, 13 male and 12 female rats were exposed to PF just prior to sacrifice to induce expression of the neural activation marker Fos, and Fos expression was quantified in mesocorticolimbic, hypothalamic, and amygdalar circuits. In the CPP paradigm, females displayed a more robust shift in preference for the chamber paired with PF compared with males, and behavioral analyses revealed that average duration of individual feeding bouts during pairing sessions was longer in females than in males. Fos expression was significantly higher in females vs. males in select regions of the mesocorticolimbic reward circuit, with no sex differences in hypothalamic or amygdalar regions. These results provide initial evidence that PF may be more rewarding to females than to males, possibly due to heightened responsiveness of neural substrates that mediate the hedonic and motivational responses to PF, which in part, may underlie sex differences in binge eating proneness.

Differential mesocorticolimbic responses to palatable food in binge eating prone and binge eating resistant female rats.

Binge eating is a key symptom of many eating disorders (e.g. binge eating disorder, bulimia nervosa, anorexia nervosa binge/purge type), yet the neurobiological underpinnings of binge eating are poorly understood. The mesocorticolimbic reward circuit, including the nucleus accumbens and the medial prefrontal cortex, is likely involved because this circuit mediates the hedonic value and incentive salience of palatable foods (PF). Here we tested the hypothesis that higher propensity for binge eating is associated with a heightened response (i.e., Fos induction) of the nucleus accumbens and medial prefrontal cortex to PF, using an animal model that identifies binge eating prone (BEP) and binge eating resistant (BER) rats. Forty adult female Sprague-Dawley rats were given intermittent access to PF (high fat pellets) 3×/week for 3 weeks. Based on a pattern of either consistently high or consistently low PF consumption across these feeding tests, 8 rats met criteria for categorization as BEP, and 11 rats met criteria for categorization as BER. One week after the final feeding test, BEP and BER rats were either exposed to PF in their home cages or were given no PF in their home cages for 1h prior to perfusion, leading to three experimental groups for the Fos analysis: BEPs given PF, BERs given PF, and a No PF control group. The total number of Fos-immunoreactive (Fos-ir) cells in the nucleus accumbens core and shell, and the cingulate, prelimbic, and infralimbic regions of the medial prefrontal cortex was estimated by stereological analysis. PF induced higher Fos expression in the nucleus accumbens shell and core and in the prelimbic and infralimbic cortex of BEP rats compared to No PF controls. Throughout the nucleus accumbens and medial prefrontal cortex, PF induced higher Fos expression in BEP than in BER rats, even after adjusting for differences in PF intake. Differences in the neural activation pattern between BEP and BER rats were more robust in prefrontal cortex than in nucleus accumbens. These data confirm that PF activates brain regions responsible for encoding the incentive salience and hedonic properties of PF, and suggest that binge eating proneness is associated with enhanced responses to PF in brain regions that exert executive control over food reward.

The CODATwins Project: The Cohort Description of Collaborative Project of Development of Anthropometrical Measures in Twins to Study Macro-Environmental Variation in Genetic and Environmental Effects on Anthropometric Traits.

For over 100 years, the genetics of human anthropometric traits has attracted scientific interest. In particular, height and body mass index (BMI, calculated as kg/m2) have been under intensive genetic research. However, it is still largely unknown whether and how heritability estimates vary between human populations. Opportunities to address this question have increased recently because of the establishment of many new twin cohorts and the increasing accumulation of data in established twin cohorts. We started a new research project to analyze systematically (1) the variation of heritability estimates of height, BMI and their trajectories over the life course between birth cohorts, ethnicities and countries, and (2) to study the effects of birth-related factors, education and smoking on these anthropometric traits and whether these effects vary between twin cohorts. We identified 67 twin projects, including both monozygotic (MZ) and dizygotic (DZ) twins, using various sources. We asked for individual level data on height and weight including repeated measurements, birth related traits, background variables, education and smoking. By the end of 2014, 48 projects participated. Together, we have 893,458 height and weight measures (52% females) from 434,723 twin individuals, including 201,192 complete twin pairs (40% monozygotic, 40% same-sex dizygotic and 20% opposite-sex dizygotic) representing 22 countries. This project demonstrates that large-scale international twin studies are feasible and can promote the use of existing data for novel research purposes.

The effects of ovarian hormones and emotional eating on changes in weight preoccupation across the menstrual cycle.

OBJECTIVE: Previous research has shown that fluctuations in ovarian hormones (i.e., estradiol and progesterone) predict the changes in binge eating and emotional eating across the menstrual cycle. However, the extent to which other eating disorder symptoms fluctuate across the menstrual cycle and are influenced by ovarian hormones remains largely unknown. This study sought to examine whether the levels of weight preoccupation vary across the menstrual cycle and whether the changes in ovarian hormones and/or other factors (i.e., emotional eating and negative affect) account for menstrual cycle fluctuations in this eating disorder phenotype. METHOD: For 45 consecutive days, 352 women (age, 15-25 years) provided daily ratings of weight preoccupation, negative affect, and emotional eating. Saliva samples were also collected on a daily basis and assayed for levels of estradiol and progesterone using enzyme immunoassay techniques. RESULTS: Weight preoccupation varied significantly across the menstrual cycle, with the highest levels in the premenstrual and menstrual phases. However, ovarian hormones did not account for within-person changes in weight preoccupation across the menstrual cycle. Instead, the most significant predictor of menstrual cycle changes in weight preoccupation was the change in emotional eating. DISCUSSION: Fluctuations in weight preoccupation across the menstrual cycle appear to be influenced primarily by emotional eating rather than ovarian hormones. Future research should continue to examine the relationships among ovarian hormones, weight preoccupation, emotional eating, and other core eating disorder symptoms (e.g., body dissatisfaction, compensatory behaviors) in an effort to more fully understand the role of these biological and behavioral factors for the full spectrum of eating pathology.

Coupled latent differential equation with moderators: simulation and application.

Latent differential equations (LDE) use differential equations to analyze time series data. Because of the recent development of this technique, some issues critical to running an LDE model remain. In this article, the authors provide solutions to some of these issues and recommend a step-by-step procedure demonstrated on a set of empirical data, which models the interaction between ovarian hormone cycles and emotional eating. Results indicated that emotional eating is self-regulated. For instance, when people do more emotional eating than normal, they will subsequently tend to decrease their emotional eating behavior. In addition, a sudden increase will produce a stronger tendency to decrease than will a slow increase. We also found that emotional eating is coupled with the cycle of the ovarian hormone estradiol, and the peak of emotional eating occurs after the peak of estradiol. The self-reported average level of negative affect moderates the frequency of eating regulation and the coupling strength between eating and estradiol. Thus, people with a higher average level of negative affect tend to fluctuate faster in emotional eating, and their eating behavior is more strongly coupled with the hormone estradiol. Permutation tests on these empirical data supported the reliability of using LDE models to detect self-regulation and a coupling effect between two regulatory behaviors.