Ovarian hormones: a long overlooked but critical contributor to cognitive brain structures and function

Cognitive neuroscience research has traditionally overlooked half of the population. Arguing that variability in ovarian hormones confounds empirical findings, girls and women have been excluded from research for decades. But times are changing. This review summarizes historical trends that have led to a knowledge gap in the role of ovarian hormones in neuroscience, synthesizes recent findings on ovarian hormone contributions to cognitive brain structures and function, and highlights areas ripe for future work. This is accomplished by reviewing research that has leveraged natural experiments in humans across the life span that focus on puberty, the menstrual cycle, hormonal contraceptive use, menopause, and menopausal hormone therapy. Although findings must be considered in light of study designs (e.g., sample characteristics and group comparisons versus randomized crossover trials), across natural experiments there is consistent evidence for associations of estradiol with cortical thickness, especially in frontal regions, and hippocampal volumes, as well as with frontal regions during cognitive processing. There are also emerging investigations of resting state connectivity and progesterone along with exciting opportunities for future work, particularly concerning biopsychosocial moderators of and individual differences in effects in novel natural experiments. Thus, delineating complex ovarian hormone contributions to cognitive brain structures and function will advance neuroscience.This review summarizes historical trends that have led to a knowledge gap in the role of ovarian hormones in neuroscience, synthesizes recent findings on ovarian hormone contributions to cognitive brain structures and function, and highlights areas ripe for future work.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154624/1/nyas14255_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154624/2/nyas14255.pd

Sex differences and menstrual cycle effects in cognitive and sensory resting state networks

It has not yet been established if resting state (RS) connectivity reflects stable characteristics of the brain, or if it is modulated by the psychological and/or physiological state of the participant. Based on research demonstrating sex hormonal effects in task-related brain activity, the present study aimed to investigate corresponding differences in RS networks. RS functional Magnetic Resonance Imaging (RS fMRI) was conducted in women during three different menstrual cycle phases, while men underwent three repeated RS fMRI testing sessions. Independent component analysis was used to identify the default mode network (DMN) and an auditory RS network. For the DMN, RS connectivity was stable across testing sessions in men, but varied across the menstrual cycle in women. For the auditory network (AN), retest reliable sex difference was found. Although RS activity in the DMN has been interpreted as trait characteristic of functional brain organization, these findings suggest that RS activity in networks involving frontal areas might be less stable than in sensory-based networks and can dynamically fluctuate. This also implies that some of the previously reported effects of sex hormones on task-related activity might to some extent be mediated by cycle-related fluctuations in RS activity, especially when frontal areas are involve

Oral Contraception and Cognition

Oral contraception is currently used by over 100 million women worldwide. Women utilize contraception not only to prevent pregnancy but also to manage a wide range of health concerns, such as acne and polycystic ovarian syndrome. Although this medication has granted women bodily autonomy, helped them attain higher levels of education, and helped them enter the workforce in greater numbers, little is known about the consequences outside of the intended contraceptive effects, specifically the cognitive and behavioral consequences. Moreover, because doctors can prescribe contraception after the first menstrual cycle and during puberty, it’s possible that this critical window of development could be altered longitudinally as a synthetic form could change the naturally occurring hormonal levels that are in flux during this time. The present research sought to determine the effects of synthetic and naturally occurring estrogen and progesterone on behavior and cognition at a critical developmental period. To determine these effects, we used a mouse model of oral contraception and based the concentration on a commonly used contraceptive. After 31 days of administration with a combination levonorgestrel and ethinyl estradiol solution, we conducted two behavioral tests. First, we used the elevated plus maze to determine anxiety-like behaviors. We then explored fear conditioning and extinction by utilizing a three-day contextual fear extinction protocol with an additional cued fear recall day. Based on the existing literature, we hypothesized (1) animals treated with a combination OC would demonstrate decreased anxiety and fear conditioning and extinction compared to control animals. (2) Naturally cycling mice in diestrus would experience increased anxiety and fear conditioning and extinction compared to mice in estrus. (3) Animals treated in the potentially critical window during puberty would demonstrate significantly different anxiety and fear conditioning and extinction behaviors

Spectral dynamic causal modelling in healthy women reveals brain connectivity changes along the menstrual cycle

Longitudinal menstrual cycle studies allow to investigate the effects of ovarian hormones on brain organization. Here, we use spectral dynamic causal modelling (spDCM) in a triple network model to assess effective connectivity changes along the menstrual cycle within and between the default mode, salience and executive control networks (DMN, SN, and ECN). Sixty healthy young women were scanned three times along their menstrual cycle, during early follicular, pre-ovulatory and mid-luteal phase. Related to estradiol, right before ovulation the left insula recruits the ECN, while the right middle frontal gyrus decreases its connectivity to the precuneus and the DMN decouples into anterior/posterior parts. Related to progesterone during the mid-luteal phase, the insulae (SN) engage to each other, while decreasing their connectivity to parietal ECN, which in turn engages the posterior DMN. When including the most confident connections in a leave-one out cross-validation, we find an above-chance prediction of the left-out subjects’ cycle phase. These findings corroborate the plasticity of the female brain in response to acute hormone fluctuations and may help to further understand the neuroendocrine interactions underlying cognitive changes along the menstrual cycle

Hormonal contraceptive exposure relates to changes in resting state functional connectivity of anterior cingulate cortex and amygdala

IntroductionHormonal contraceptives (HCs), nowadays one of the most used contraceptive methods, downregulate endogenous ovarian hormones, which have multiple plastic effects in the adult brain. HCs usually contain a synthetic estrogen, ethinyl-estradiol, and a synthetic progestin, which can be classified as androgenic or anti-androgenic, depending on their interaction with androgen receptors. Both the anterior cingulate cortex (ACC) and the amygdala express steroid receptors and have shown differential functionality depending on the hormonal status of the participant and the use of HC. In this work, we investigated for the first time the relationship between ACC and amygdala resting state functional connectivity (rs-FC) and HC use duration, while controlling for progestin androgenicity.MethodsA total of 231 healthy young women participated in five different magnetic resonance imaging studies and were included in the final analysis. The relation between HC use duration and (i) gray matter volume, (ii) fractional amplitude of low-frequency fluctuations, and (iii) seed-based connectivity during resting state in the amygdalae and ACC was investigated in this large sample of women.ResultsIn general, rs-FC of the amygdalae with frontal areas, and between the ACC and temporoparietal areas, decreased the longer the HC exposure and independently of the progestin’s androgenicity. The type of HC’s progestin did show a differential effect in the gray matter volume of left ACC and the connectivity between bilateral ACC and the right inferior frontal gyrus

Ovarian steroid hormones: A long overlooked but critical contributor to brain aging and Alzheimer’s disease

Ovarian hormones, particularly 17β-estradiol, are involved in numerous neurophysiological and neurochemical processes, including those subserving cognitive function. Estradiol plays a key role in the neurobiology of aging, in part due to extensive interconnectivity of the neural and endocrine system. This aspect of aging is fundamental for women’s brains as all women experience a drop in circulating estradiol levels in midlife, after menopause. Given the importance of estradiol for brain function, it is not surprising that up to 80% of peri-menopausal and post-menopausal women report neurological symptoms including changes in thermoregulation (vasomotor symptoms), mood, sleep, and cognitive performance. Preclinical evidence for neuroprotective effects of 17β-estradiol also indicate associations between menopause, cognitive aging, and Alzheimer’s disease (AD), the most common cause of dementia affecting nearly twice more women than men. Brain imaging studies demonstrated that middle-aged women exhibit increased indicators of AD endophenotype as compared to men of the same age, with onset in perimenopause. Herein, we take a translational approach to illustrate the contribution of ovarian hormones in maintaining cognition in women, with evidence implicating menopause-related declines in 17β-estradiol in cognitive aging and AD risk. We will review research focused on the role of endogenous and exogenous estrogen exposure as a key underlying mechanism to neuropathological aging in women, with a focus on whether brain structure, function and neurochemistry respond to hormone treatment. While still in development, this research area offers a new sex-based perspective on brain aging and risk of AD, while also highlighting an urgent need for better integration between neurology, psychiatry, and women’s health practices

Ovarian hormones shape brain structure, function, and chemistry: A neuropsychiatric framework for female brain health

There are robust sex differences in brain anatomy, function, as well as neuropsychiatric and neurodegenerative disease risk (1-6), with women approximately twice as likely to suffer from a depressive illness as well as Alzheimer’s Disease. Disruptions in ovarian hormones likely play a role in such disproportionate disease prevalence, given that ovarian hormones serve as key regulators of brain functional and structural plasticity and undergo major fluctuations across the female lifespan (7-9). From a clinical perspective, there is a wellreported increase in depression susceptibility and initial evidence for cognitive impairment or decline during hormonal transition states, such as the postpartum period and perimenopause (9-14). What remains unknown, however, is the underlying mechanism of how fluctuations in ovarian hormones interact with other biological factors to influence brain structure, function, and chemistry. While this line of research has translational relevance for over half the population, neuroscience is notably guilty of female participant exclusion in research studies, with the male brain implicitly treated as the default model and only a minority of basic and clinical neuroscience studies including a female sample (15-18). Female underrepresentation in neuroscience directly limits opportunities for basic scientific discovery; and without basic knowledge of the biological underpinnings of sex differences, we cannot address critical sexdriven differences in pathology. Thus, my doctoral thesis aims to deliberately investigate the influence of sex and ovarian hormones on brain states in health as well as in vulnerability to depression and cognitive impairment:Table of Contents List of Abbreviations ..................................................................................................................... i List of Figures .............................................................................................................................. ii Acknowledgements .....................................................................................................................iii 1 INTRODUCTION .....................................................................................................................1 1.1 Lifespan approach: Sex, hormones, and metabolic risk factors for cognitive health .......3 1.2 Reproductive years: Healthy models of ovarian hormones, serotonin, and the brain ......4 1.2.1 Ovarian hormones and brain structure across the menstrual cycle ........................4 1.2.2 Serotonergic modulation and brain function in oral contraceptive users .................6 1.3 Neuropsychiatric risk models: Reproductive subtypes of depression ...............................8 1.3.1 Hormonal transition states and brain chemistry measured by PET imaging ...........8 1.3.2 Serotonin transporter binding across the menstrual cycle in PMDD patients .......10 2 PUBLICATIONS ....................................................................................................................12 2.1 Publication 1: Association of estradiol and visceral fat with structural brain networks and memory performance in adults .................................................................................13 2.2 Publication 2: Longitudinal 7T MRI reveals volumetric changes in subregions of human medial temporal lobe to sex hormone fluctuations ..............................................28 2.3 Publication 3: One-week escitalopram intake alters the excitation-inhibition balance in the healthy female brain ...............................................................................................51 2.4 Publication 4: Using positron emission tomography to investigate hormone-mediated neurochemical changes across the female lifespan: implications for depression ..........65 2.5 Publication 5: Increase in serotonin transporter binding across the menstrual cycle in patients with premenstrual dysphoric disorder: a case-control longitudinal neuro- receptor ligand PET imaging study ..................................................................................82 3 SUMMARY ...........................................................................................................................100 References ..............................................................................................................................107 Supplementary Publications ...................................................................................................114 Author Contributions to Publication 1 .....................................................................................184 Author Contributions to Publication 2 .....................................................................................186 Author Contributions to Publication 3 .....................................................................................188 Author Contributions to Publication 4 .....................................................................................190 Author Contributions to Publication 5 .....................................................................................191 Declaration of Authenticity ......................................................................................................193 Curriculum Vitae ......................................................................................................................194 List of Publications ................................................................................................................195 List of Talks and Posters ......................................................................................................19

The Neuromodulatory Effects of Sex Hormones on Functional Cerebral Asymmetries and Cognitive Control

Nearly 20 years ago, Hausmann and Güntürkün (2000a, 2000b) published a review article in the Journal of Neuropsychology/Zeitschrift für Neuropsychologie on the influences of sex hormones on functional cerebral asymmetries (FCAs). They further presented a neuroendocrinological model (Hausmann & Güntürkün, 2000c) that could potentially explain how sex hormones modulate FCAs. Their model proposed that high levels of progesterone reduce the synaptic efficiency of cortico-cortical transmission, leading to a reduction of FCAs. However, empirical data testing their hypothesis directly were missing. Using various approaches, we have now gathered behavioral, electrophysiological, and neuroimaging data that partly support the original idea, while also pointing toward estradiol-modulating FCAs. The current review provides an update on this fascinating topic and briefly explores clinical applications