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Beyond Birth Control: The Neuroscience of Hormonal Contraceptives
Abstract
Hormonal contraceptives (HCs) are one of the most highly prescribed classes of drugs in the world used for both contraceptive and noncontraceptive purposes. Despite their prevalent use, the impact of HCs on the brain remains inadequately explored. This review synthesizes recent findings on the neuroscience of HCs, with a focus on human structural neuroimaging as well as translational, nonhuman animal studies investigating the cellular, molecular, and behavioral effects of HCs. Additionally, we consider data linking HCs to mood disorders and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and stress response as a potential mediator. The review also addresses the unique sensitivity of the adolescent brain to HCs, noting significant changes in brain structure and function when HCs are used during this developmental period. Finally, we discuss potential effects of HCs in combination with smoking-derived nicotine on outcomes of ischemic brain damage. Methodological challenges, such as the variability in HC formulations and user-specific factors, are acknowledged, emphasizing the need for precise and individualized research approaches. Overall, this review underscores the necessity for continued interdisciplinary research to elucidate the neurobiological mechanisms of HCs, aiming to optimize their use and improve women's health.
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Irregular menstrual cycles, affecting approximately 30% of women in their reproductive years, are often overlooked in research, limiting our insights into the broader spectrum of hormonal interactions. Understanding the relationship between endogenous hormone fluctuations and brain function across the menstrual cycle, particularly beyond regular menstrual cycles, is essential for comprehending mental disorders prevalent in women. To this aim, a healthy female with an irregular menstrual cycle underwent dense sampling for 5 consecutive weeks, primarily covering the follicular phase and ovulation. Blood draws provided measurements of estradiol, estrone, and progesterone. T 1-weighted MRI scans assessed bilateral hippocampal volumes. Positive and negative affect were collected at each session. Statistical analyses included cubic regression curves, Spearman correlations, and mediation regression models to explore hormonal associations with hippocampal morphology and affect. Significant fluctuations in hormonal concentrations, hippocampal volume, and affect were observed across the 25 testing days. Estradiol and estrone significantly correlated with hippocampal volume, while progesterone showed no significant association. Increasing concentrations of estrogens were linked to decreasing positive affect, mediated by hippocampal volume fluctuations. Increasing concentrations of estrogens were further associated with increasing negative affect, however, independently of hippocampal changes. Our findings suggest potential roles of estrogens in affect regulation and brain function in a participant with an irregular menstrual cycle. This research serves as a blueprint for future investigations into the complex interplay between sex hormones and structural brain dynamics beyond regular menstrual cycles and establishes a fundamental framework for the advancement of sex-specific precision medicine.
Most of mammalian physiology is under the control of biological rhythms, including the endocrine system with time-varying hormone secretion. Precision neuroimaging studies provide unique insights into how the endocrine system dynamically regulates aspects of the human brain. Recently, we established estrogen's ability to drive widespread patterns of connectivity and enhance the global efficiency of large-scale brain networks in a woman sampled every 24 h across 30 consecutive days, capturing a complete menstrual cycle. Steroid hormone production also follows a pronounced sinusoidal pattern, with a peak in testosterone between 6 and 7 A.M. and nadir between 7 and 8 P.M. To capture the brain's response to diurnal changes in hormone production, we carried out a companion precision imaging study of a healthy adult man who completed MRI and venipuncture every 12–24 h across 30 consecutive days. Results confirmed robust diurnal fluctuations in testosterone, 17β-estradiol—the primary form of estrogen—and cortisol. Standardized regression analyses revealed widespread associations between testosterone, estradiol, and cortisol concentrations and whole-brain patterns of coherence. In particular, functional connectivity in the Dorsal Attention Network was coupled with diurnally fluctuating hormones. Further, comparing dense-sampling datasets between a man and a naturally cycling woman revealed that fluctuations in sex hormones are tied to patterns of whole-brain coherence in both sexes and to a heightened degree in the male. Together, these findings enhance our understanding of steroid hormones as rapid neuromodulators and provide evidence that diurnal changes in steroid hormones are associated with patterns of whole-brain functional connectivity.
Introduction
Women are significantly more likely to develop Alzheimer's disease and related dementias (ADRD) than men. Suggestions to explain the sex differences in dementia incidence have included the influence of sex hormones with little attention paid to date as to the effect of hormonal contraception on brain health. The aim of this scoping review is to evaluate the current evidence base for associations between hormonal contraceptive use by women and non-binary people in early adulthood and brain health outcomes.
Methods
A literature search was conducted using EMBASE, Medline and Google Scholar, using the keywords “hormonal contraception” OR “contraception” OR “contraceptive” AND “Alzheimer*” OR “Brain Health” OR “Dementia”.
Results
Eleven papers were identified for inclusion in the narrative synthesis. Studies recruited participants from the UK, USA, China, South Korea and Indonesia. Studies included data from women who were post-menopausal with retrospective data collection, with only one study contemporaneously collecting data from participants during the period of hormonal contraceptive use. Studies reported associations between hormonal contraceptive use and a lower risk of ADRD, particularly Alzheimer's disease (AD), better cognition and larger grey matter volume. Some studies reported stronger associations with longer duration of hormonal contraceptive use, however, results were inconsistent. Four studies reported no significant associations between hormonal contraceptive use and measures of brain health, including brain age on MRI scans and risk of AD diagnosis.
Discussion
Further research is needed on young adults taking hormonal contraceptives, on different types of hormonal contraceptives (other than oral) and to explore intersections between sex, gender, race and ethnicity.
Systematic Review Registration
https://doi.org/10.17605/OSF.IO/MVX63 , identifier: OSF.io: 10.17605/OSF.IO/MVX63
Aim:
Research on the effect of oral contraceptive (OC) use on the risk of depression shows inconsistent findings, especially in adult OC users. One possible reason for this inconsistency is the omission of women who discontinue OCs due to adverse mood effects, leading to healthy user bias. To address this issue, we aim to estimate the risk of depression that is associated with the initiation of OCs as well as the effect of OC use on lifetime risk of depression.
Methods:
This is a population-based cohort study based on data from 264,557 women from the UK Biobank. Incidence of depression was addressed via interviews, inpatient hospital or primary care data. The hazard ratio (HR) between OC use and incident depression was estimated by multivariable Cox regression with OC use as a time-varying exposure. To validate causality, we examined familial confounding in 7,354 sibling pairs.
Results:
We observed that the first 2 years of OC use were associated with a higher rate of depression compared to never users (HR = 1.71, 95% confidence interval [CI]: 1.55-1.88). Although the risk was not as pronounced beyond the first 2 years, ever OC use was still associated with an increased lifetime risk of depression (HR = 1.05, 95% CI: 1.01-1.09). Previous OC use were associated with a higher rate of depression compared to never users, with adolescent OC users driving the increased hazard (HR = 1.18, 95% CI: 1.12-1.25). No significant association were observed among adult OC users who had previously used OCs (HR = 1.00, 95% CI: 0.95-1.04). Notably, the sibling analysis provided further evidence for a causal effect of OC use on the risk of depression.
Conclusions:
Our findings suggest that the use of OCs, particularly during the first 2 years, increases the risk of depression. Additionally, OC use during adolescence might increase the risk of depression later in life. Our results are consistent with a causal relationship between OC use and depression, as supported by the sibling analysis. This study highlights the importance of considering the healthy user bias as well as family-level confounding in studies of OC use and mental health outcomes. Physicians and patients should be aware of this potential risk when considering OCs, and individualized risk-benefit assessments should be conducted.
Smoking-derived nicotine (N) and oral contraceptive (OC) synergistically exacerbate ischemic brain damage in females, and the underlying mechanisms remain elusive. In a previous study, we showed that N + OC exposure altered brain glucose metabolism in females. Since lipid metabolism complements glycolysis, the current study aims to examine the metabolic fingerprint of fatty acids in the brain of female rats exposed to N+/−OC. Adolescent and adult Sprague–Dawley female rats were randomly (n = 8 per group) exposed to either saline or N (4.5 mg/kg) +/−OC (combined OC or placebo delivered via oral gavage) for 16–21 days. Following exposure, brain tissue was harvested for unbiased metabolomic analysis (performed by Metabolon Inc., Morrisville, NC, USA) and the metabolomic profile changes were complemented with Western blot analysis of key enzymes in the lipid pathway. Metabolomic data showed significant accumulation of fatty acids and phosphatidylcholine (PC) metabolites in the brain. Adolescent, more so than adult females, exposed to N + OC showed significant increases in carnitine-conjugated fatty acid metabolites compared to saline control animals. These changes in fatty acyl carnitines were accompanied by an increase in a subset of free fatty acids, suggesting elevated fatty acid β-oxidation in the mitochondria to meet energy demand. In support, β-hydroxybutyrate was significantly lower in N + OC exposure groups in adolescent animals, implying a complete shunting of acetyl CoA for energy production via the TCA cycle. The reported changes in fatty acids and PC metabolism due to N + OC could inhibit post-translational palmitoylation of membrane proteins and synaptic vesicle formation, respectively, thus exacerbating ischemic brain damage in female rats.
The central nervous system effects of oral contraceptives (OCs) are not well-documented. In a set of 3 studies, we investigated a specific cognitive function, mental rotation, in healthy women currently using OCs for contraceptive purposes (n = 201) and in medication-free controls not using OCs (n = 44). Mental rotation was measured using a well-standardized and extensively validated psychometric test, the Vandenberg Mental Rotations Test (MRT). In an initial study (Study 1), current OC users (n = 63) were tested during the active or inactive phases of the contraceptive cycle in a parallel-groups design. Studies 2 and 3 were based on an archival dataset (n = 201 current OC users) that consisted of data on the MRT collected in real-time over a 30-year period and compiled for purposes of the present work. The OCs were combined formulations containing ethinyl estradiol (10-35 ug/day) plus a synthetic progestin. All 4 families of synthetic progestins historically used in OCs were represented in the dataset. Cognitive performance was evaluated during either active OC use (‘active phase’) or during the washout week of the contraceptive cycle (‘inactive phase’) when OC steroids are not used. The results showed a significant phase-of-cycle (POC) effect. Accuracy on the MRT was mildly diminished during the active phase of OC use, while scores on verbal fluency and speeded motor tasks were modestly improved. The POC effect was most evident in women using OCs that contained first- or second-generation progestins (the estrane family of progestins or OCs containing levonorgestrel), but not in women using OCs containing recently developed progestins and lower doses of ethinyl estradiol. Using independently established ratings of the estrogenic, androgenic, and progestogenic intensities of the different OC formulations, each brand of OC was classified according to its distinct endocrine profile. Multiple regression revealed that the effects of OC use on the MRT could be predicted based on the estrogenic strength of the contraceptives used. Estrogenic potency, not androgenic or anti-androgenic effects of the OC pill, may underlie the effects of OC usage on spatial cognition.
Hormonal contraceptives (HCs) containing synthetic ovarian hormones are commonly used among reproductive aged women; HCs alter the physiological state of the user by interfering with endogenous hormone concentrations and their actions on the reproductive tract. As ovarian hormones modulate the incidence of substance abuse disorders in women, this experiment explores how modulating female rat ovarian hormonal states with an HC containing the synthetic progestin levonorgestrel influences measures of drug preference and responsivity. First, rats underwent food-light Pavlovian conditioning to measure conditioned orienting, a known predictor of amphetamine (AMP) place preference. Then, rats were conditioned and tested for AMP place preference with either an HC implant or during estrous cycle stages associated with opposing ovarian hormone levels, that is, proestrus (P) or metestrus/diestrus (M/D), while recording ultrasonic vocalizations (USVs) as an index of he donic drug responsivity. Because of dopamine's (DA's) role in reward learning and memory, DA cell number and activity were examined using tyrosine hydroxylase and FOS immunohistochemistry after a final AMP challenge. Conditioned orienting did not differ between cycling and HC-implanted rats. HC rats emitted fewer USVs in response to AMP, showed marginally less AMP place preference, and had lower DA cell activity in the substantia nigra after AMP compared to P rats. M/D rats showed a similar behavioral profile and neural response as HC rats. This experiment suggests ovarian hormones affect drug preference and responsivity, while providing novel insight into how hormone-altering contraceptives may reduce these measures. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
Many factors must be considered and discussed with women when initiating a contraceptive method and the risk of venous thromboembolism (VTE) is one of them. In this review, we discuss the numerous strategies that have been implemented to reduce the thrombotic risk associated with combined oral contraceptives (COCs) from their arrival on the market until today. Evidences suggesting that COCs were associated with an increased risk of VTE appeared rapidly after their marketing. Identified as the main contributor of this risk, the dosage of the estrogen, i.e., ethinylestradiol (EE), was significantly reduced. New progestins were also synthetized (e.g., desogestrel or gestodene) but their weak androgenic activity did not permit to counterbalance the effect of EE as did the initial progestins such as levonorgestrel. Numerous studies assessed the impact of estroprogestative combinations on hemostasis and demonstrated that women under COC suffered from resistance towards activated protein C (APC). Subsequently, the European Medicines Agency updated its guidelines on clinical investigation of steroid contraceptives in which they recommended to assess this biological marker. In 2009, estradiol-containing COCs were marketed and the use of this natural form of estrogen was found to exert a weaker effect on the synthesis of hepatic proteins compared to EE. In this year 2021, a novel COC based on a native estrogen, i.e., estetrol, will be introduced on the market. Associated with drospirenone, this preparation demonstrated minor effects on coagulation proteins as compared with other drospirenone-containing COCs. At the present time, the standard of care when starting a contraception, consists of identifying the presence of hereditary thrombophilia solely on the basis of familial history of VTE. This strategy has however been reported as poorly predictive of hereditary thrombophilia. One rationale and affordable perspective which has already been considered in the past could be the implementation of a baseline screening of the prothrombotic state to provide health care professionals with objective data to support the prescription of the more appropriate contraceptive method. While this strategy was judged too expensive due to limited laboratory solutions, the endogenous thrombin potential-based APC resistance assay could now represent an interesting alternative.
Objective:
To investigate if users of hormonal contraceptives (HCs) are at increased risk of depression compared to non-users.
Design:
Register-based cohort study.
Setting:
Sweden.
Sample:
Women aged 15-25 between 2010-2017 with no prior antidepressant treatment, psychiatric diagnose or contraindication for HCs (n = 739 585).
Methods:
Women with a prescription of HC were identified via the Swedish Prescribed Drug Register (SPDR). Rate ratios (RRs) for first depression diagnosis in current HC-users compared to non-users were modeled by Poisson regression. Adjustments included e.g. age, medical indication for HC-use and parental history of mental disorders.
Main outcome measures:
Depression, captured by a redeemed prescription of antidepressant treatment, or a first depression diagnosis in the SPDR and the National Patient Register.
Results:
Compared to non-users, women on combined oral contraceptives (COCs) and oral progestogen-only products had lower or no increased risk of depression, RRs 0.89 (95% CI 0.87-0.91) and 1.03 (95% CI 0.99-1.06) after adjustments, respectively. Age-stratified analyses demonstrated that COC use in adolescents conferred no risk increase, RR 0.96 (95% CI 0.93-0.98), whereas use of progestogen-only pills (RR 1.13 (95% CI 1.07-1.19), contraceptive patch/vaginal ring (RR 1.43, 95% CI 1.30-1.58), implant (RR 1.38, 95% CI 1.30-1.45) or a levonorgestrel intrauterine device (RR 1.59, 95% CI 1.46-1.73) was associated with increased risks.
Conclusions:
This study did not find any association between use of COCs, which is the dominating HC in first time users, and depression. Non-oral products were associated with increased risks. Residual confounding must be addressed in the interpretation of the results.
Background
Because of the widespread use of oral contraceptives (OCs) and the devastating effects of depression both on an individual and a societal level, it is crucial to understand the nature of the previously reported relationship between OC use and depression risk. Insight into the impact of analytical choices on the association is important when interpreting available evidence. Hence, we examined the association between adolescent OC use and subsequent depression risk in early adulthood analyzing all theoretically justifiable models.
Methods
Data from the prospective cohort study TRacking Adolescents’ Individual Lives Survey, among women aged 13–25 years were used. Adolescent OC use (ages 16–19 years) was used as a predictor and major depressive disorder (MDD) in early adulthood (ages 20–25 years), as assessed by the Diagnostic and Statistical Manual of Mental Disorders‐IV oriented Lifetime Depression Assessment Self‐Report and the Composite International Diagnostic Interview, was used as an outcome. A total of 818 analytical models were analyzed using Specification Curve Analysis in 534 adolescent OC users and 191 nonusers.
Results
Overall, there was an association of adolescent OC use and an episode of MDD in early adulthood [median odds ratio (OR)median = 1.41; ORmin = 1.08; ORmax = 2.18, p < .001], which was driven by the group of young women with no history of MDD (ORmedian = 1.72; ORmin = 1.21; ORmax = 2.18, p < .001).
Conclusions
In summary, adolescent OC use was associated with a small but robust increased risk for experiencing an episode of MDD, especially among women with no history of MDD in adolescence. Understanding the potential side effects of OCs will help women and their doctors to make informed choices when deciding among possible methods of birth control.
Background
Despite the widespread use of oral contraceptives (OCs), and the well-documented influence of estrogens, notably 17β-estradiol (E2), on cognition, research relating OCs to working memory is limited and mixed. Two factors may contribute to these mixed findings: 1) pharmacokinetics of oral contraceptives, which drive fluctuations in synthetic hormone levels; and 2) genetic polymorphisms related to dopamine degradation and working memory, which interact with E2. This research investigated whether the pharmacokinetics of oral contraceptives, in concert with the single nucleotide polymorphism (Val¹⁵⁸Met; rs4680) of the catechol-o-methyltransferase gene (COMT), influence working memory performance.
Methods
University-age women taking and not taking OCs were tested for working memory and genotyped for COMT. If they were not taking OCs (n = 62), sessions occurred in the early follicular (low E2) and late follicular (high E2) phase. If they were taking OCs (n = 52), sessions occurred 1–2 hours after (high ethinyl estradiol, EE) and ~24 hours after (low EE) pill ingestion. Working memory was tested using the N-back, AX-CPT, Digit Span, and Digit Ordering Tasks. Data were analyzed using multilevel models with estrogen condition, COMT, and group as predictors, controlling for mood and practice effects.
Results
For women taking OCs, time of pill ingestion did not influence performance. However, the subgroup with COMT val/val (low dopamine) were less accurate on 2-back lure trials than those with COMT met/met (high dopamine). For women not taking OCs, cycle phase moderated COMT’s influence on lure accuracy. When compared, women taking OCs had higher AX-CPT proactive control indices than those not taking OCs.
Conclusion
These findings suggest that oral contraceptives are not detrimental for young women’s working memory and that they may increase proactive control. The more pronounced effects of COMT in women taking OCs suggests that, in women taking OCs, suppressed endogenous E2–not fluctuating EE levels–may be more relevant for working memory. Future studies are needed to differentiate effects of endogenous versus synthetic estrogens on working memory.
Across species, adolescence is a period of growing independence that is associated with the maturation of cognitive, social, and affective processing. Reorganization of neural circuits within the frontal cortex is believed to contribute to the emergence of adolescent changes in cognition and behavior. While puberty coincides with adolescence, relatively little is known about which aspects of frontal cortex maturation are driven by pubertal development and gonadal hormones. In this review, we highlight existing work that suggests puberty plays a role in the maturation of specific cell types in the medial prefrontal cortex (mPFC) of rodents, and highlight possible routes by which gonadal hormones influence frontal cortical circuit development.
Smoking-derived nicotine (N) and oral contraceptives (OCs) synergistically exacerbate ischemic brain damage in the female, and the underlying mechanisms remain elusive. Our published study showed that N toxicity is exacerbated by OC via altered mitochondrial electron transport chain function. Because mitochondria play an important role in cellular metabolism, we investigated the global metabolomic profile of brains of adolescent and adult female Sprague-Dawley rats exposed to N with or without OC (N+/−OC). Rats were randomly exposed to saline or N+/−OC for 16–21 days followed by random allocation into two cohorts. The first cohort was used to characterize the cortical metabolome. Pathway enrichment analysis showed a significant increase in several histamine metabolites including 1-methylhistamine, 1-methyl-4-imidazoleacetate, and 1-ribosyl-imidazleacetate, along with carnosine and homocarnosine in adolescent and adult animals treated with N and N+OC in relation to respective saline controls, which may be reflective of altered histamine metabolism with nicotine treatment. We also observed reduced levels of the neurotransmitters N-acetyl-aspartyl-glutamate (NAAG), gamma-aminobutyrate (GABA), and N-methyl-GABA in N+OC treatment in adolescent animals. The second cohort underwent bilateral carotid artery occlusion and hypotension followed by cerebral blood flow (CBF) assessment a day later. Autoradiographic images of the brain 24 h after ischemic episodes showed severe reduction in cortical and hippocampal local CBF in N+/−OC-exposed rats compared with saline treated. Because GABA and histamine are critical for CBF maintenance, altered metabolism of these neurotransmitters may be responsible for observed severe post-ischemic hypoperfusion, which in turn exacerbates ischemic brain damage.
The role of the prefrontal cortex (PFC) takes center stage among unanswered questions in modern neuroscience. The PFC has a Janus-faced nature: it enables sophisticated cognitive and social abilities that reach their maximum expression in humans, yet it underlies some of the devastating symptoms of psychiatric disorders. Accordingly, appropriate prefrontal development is crucial for many high-order cognitive abilities and dysregulation of this process has been linked to various neuropsychiatric diseases. Reviewing recent advances in the field, with a primary focus on rodents and humans, we highlight why, despite differences across species, a cross-species approach is a fruitful strategy for understanding prefrontal development. We briefly review the developmental contribution of molecules and extensively discuss how electrical activity controls the early maturation and wiring of prefrontal areas, as well as the emergence and refinement of input–output circuitry involved in cognitive processing. Finally, we highlight the mechanisms of developmental dysfunction and their relevance for psychiatric disorders.
Background: Hormonal contraceptive drugs are being used by adult and adolescent women all over the world. Convergent evidence from animal research indicates that contraceptive substances can alter both structure and function of the brain, yet such effects are not part of the public discourse or clinical decision-making concerning these drugs. We thus conducted a systematic review of the neuroimaging literature to assess the current evidence of hormonal contraceptive influence on the human brain.
Methods: The review was registered in PROSPERO and conducted in accordance with the PRISMA criteria for systematic reviews. Structural and functional neuroimaging studies concerning the use of hormonal contraceptives, indexed in Embase, PubMed and/or PsycINFO until February 2020 were included, following a comprehensive and systematic search based on predetermined selection criteria.
Results: A total of 33 articles met the inclusion criteria. Ten of these were structural studies, while 23 were functional investigations. Only one study investigated effects on an adolescent sample. The quality of the articles varied as many had methodological challenges as well as partially unfounded theoretical claims. However, most of the included neuroimaging studies found functional and/or structural brain changes associated with the use of hormonal contraceptives.
Conclusion: The included studies identified structural and functional changes in areas involved in affective and cognitive processing, such as the amygdala, hippocampus, prefrontal cortex and cingulate gyrus. However, only one study reported primary research on a purely adolescent sample. Thus, there is a need for further investigation of the implications of these findings, especially with regard to adolescent girls.
The biophysical modeling efforts in diffusion MRI have grown considerably over the past 25 years. In this review, we dwell on the various challenges along the journey of bringing a biophysical model from initial design to clinical implementation, identifying both hurdles that have been already overcome and outstanding issues. First, we describe the critical initial task of selecting which features of tissue microstructure can be estimated using a model and which acquisition protocol needs to be implemented to make the estimation possible. The model performance should necessarily be tested in realistic numerical simulations and in experimental data – adapting the fitting strategy accordingly, and parameter estimates should be validated against complementary techniques, when/if available. Secondly, the model performance and validity should be explored in pathological conditions, and, if appropriate, dedicated models for pathology should be developed. We build on examples from tumors, ischemia and demyelinating diseases. We then discuss the challenges associated with clinical translation and added value. Finally, we single out four major unresolved challenges that are related to: the availability of a microstructural ground truth, the validation of model parameters which cannot be accessed with complementary techniques, the development of a generalized standard model for any brain region and pathology, and the seamless communication between different parties involved in the development and application of biophysical models of diffusion.
Estrone and estradiol differentially modulate neuroplasticity and cognition. How they influence the maturation of new neurons in the adult hippocampus, however, is not known. The present study assessed the effects of estrone and estradiol on the maturation timeline of neurogenesis in the dentate gyrus (DG) of ovariectomized (a model of surgical menopause) young adult Sprague–Dawley rats using daily subcutaneous injections of 17β‐estradiol, estrone or vehicle. Rats were injected with a DNA synthesis marker, 5‐bromo‐2‐deoxyuridine (BrdU), and were perfused 1, 2, or 3 weeks after BrdU injection and daily hormone treatment. Brains were sectioned and processed for various markers including: sex‐determining region Y‐box 2 (Sox2), glial fibrillary acidic protein (GFAP), antigen kiel 67 (Ki67), doublecortin (DCX), and neuronal nuclei (NeuN). Immunofluorescent labeling or co‐labelling of BrdU with Sox2 (progenitor cells), Sox2/GFAP (neural progenitor cells), Ki67 (cell proliferation), DCX (immature neurons), NeuN (mature neurons) was used to examine the trajectory and maturation of adult‐born neurons over time. Estrogens had early (1 week of exposure) effects on different stages of neurogenesis (neural progenitor cells, cell proliferation and early maturation of new cells into neurons) but these effects were less pronounced after prolonged treatment. Estradiol enhanced, whereas estrone reduced cell proliferation after 1 week but not after longer exposure to either estrogen. Both estrogens increased the density of immature neurons (BrdU/DCX‐ir) after 1 week of exposure compared to vehicle treatment but this increased density was not sustained over longer durations of treatments to estrogens, suggesting that the enhancing effects of estrogens on neurogenesis were short‐lived. Longer duration post‐ovariectomy, without treatments with either of the estrogens, was associated with reduced neural progenitor cells in the DG. These results demonstrate that estrogens modulate several aspects of adult hippocampal neurogenesis differently in the short term, but may lose their ability to influence neurogenesis after long‐term exposure. These findings have potential implications for treatments involving estrogens after surgical menopause.
Millions of women around the world use combined oral contraceptives (OCs), yet surprisingly little is known about their central nervous system (CNS) effects. This article provides a short overview of the basic pharmacology of OCs, emphasizing features that may be relevant to understanding their effects in the CNS. Historical and recent findings from studies of cognitive function, mood, and negative affect (depressive changes under OC use) are then reviewed. We also present data from an archival dataset from our own laboratory in which we explore dysphoric changes in women using four generations of contraceptive progestins. Current data in the field are consistent with a modest effect of OC use on CNS variables, but conclusions based on current findings must be made very cautiously because of multiple methodological issues in many published studies to date, and inconsistencies in the findings. Directions for future research over the next 10 years are suggested. (150 words)
Women using hormonal contraceptives (HCs) exhibit numerous signs of chronic inflammation, including elevated C-reactive protein levels and greater risk of developing mood and autoimmune disorders. However, users and non-users of HCs often have similar circulating proinflammatory cytokine levels, making the mechanism of association unclear. One possible explanation for this paradox is that HC users exhibit differences in their inflammatory responses to psychosocial stress that, over time, could contribute to chronic inflammation and its pathologies. Here, we tested this possibility by examining women’s glucocorticoid, inflammatory, and psychological responses to the Trier Social Stress Test (TSST) in 67 naturally cycling (NC) and 60 oral HC-using women (Mage = 19.31, SDage = 1.95). As hypothesized, HC users and NC women exhibited different glucocorticoid and proinflammatory cytokine responses to the TSST. For NC women, TSST-induced increases in glucocorticoids were uncommon, and increases in glucocorticoids were accompanied by elevations in IL-6. In contrast, for women using HCs, increases in glucocorticoids in response to the TSST were common, and increases in glucocorticoids were accompanied by increases in TNF-α. HC users and NC women also differed in their psychological responses to the TSST, with HC users reporting elevated stress levels compared to NC women. Together, these results suggest that HC use impacts women’s glucocorticoid, inflammatory, and psychological responses to psychosocial stress, potentially contributing to observed differences in these women’s mental and physical health.
Adult neurogenesis in the dentate gyrus plays an important role for pattern separation, the process of separating similar inputs and forming distinct neural representations. Estradiol modulates neurogenesis and hippocampus function, but to date no examination of estradiol's effects on pattern separation have been conducted. Here, we examined estrogenic regulation of adult neurogenesis and functional connectivity in the hippocampus after the spatial pattern separation task in female rats. Ovariectomized Sprague-Dawley rats received daily injections of vehicle, 0.32 μg (Low) or 5 μg (High) of estradiol benzoate until the end of experiment. A single bromodeoxyuridine (BrdU) was injected one day after initiation of hormone or vehicle treatment and rats were tested in the delayed nonmatching to position spatial pattern separation task in the 8-arm radial maze for 12 days beginning two weeks after BrdU injection. Rats were perfused 90 min after the final trial and brain sections were immunohistochemically stained for BrdU/neuronal nuclei (NeuN) (new neurons), Ki67 (cell proliferation), and the immediate early gene, zif268 (activation). Results showed that high, but not low, estradiol reduced the density of BrdU/NeuN-ir cells and had significant inter-regional correlations of zif268-ir cell density in the hippocampus following pattern separation. Estradiol treatment did not influence pattern separation performance or strategy use. These results show that higher doses of estradiol can reduce neurogenesis but at the same time increases correlations of activity of neurons within the hippocampus during spatial pattern separation.
The neuroscience of hormonal contraceptives is a vital but relatively new field. Existing studies are limited in size and scope, but they nonetheless highlight that the effects of hormonal contraceptives on the nervous system are complex and can vary because of individual differences, contraceptive type and formulation, and timing of use, among other factors. Neuroscientists can empower individuals with information about the biopsychological effects of hormonal contraceptives by delving more deeply into these effects in rigorous randomized controlled trials, large-scale studies that examine population-level trends, and dense imaging or intensive longitudinal studies that examine individual-level effects.
In this review we systematically summarize the effects of progesterone and synthetic progestins on neurogenesis, synaptogenesis, myelination and six neurotransmitter systems. Several parallels between progesterone and older generation progestin actions emerged, suggesting actions via progesterone receptors. However, existing results suggest a general lack of knowledge regarding the effects of currently used progestins in hormonal contraception regarding these cellular and molecular brain parameters. Human neuroimaging studies were reviewed with a focus on randomized placebo-controlled trials and cross-sectional studies controlling for progestin type. The prefrontal cortex, amygdala, salience network and hippocampus were identified as regions of interest for future preclinical studies. This review proposes a series of experiments to elucidate the cellular and molecular actions of contraceptive progestins in these areas and link these actions to behavioral markers of emotional and cognitive functioning. Emotional effects of contraceptive progestins appear to be related to 1) alterations in the serotonergic system, 2) direct/indirect modulations of inhibitory GABA-ergic signalling via effects on the allopregnanolone content of the brain, which differ between androgenic and anti-androgenic progestins. Cognitive effects of combined oral contraceptives appear to depend on the ethinylestradiol dose.
Oral contraceptives (OCs) are widely used . While the physical impacts of OCs have been well researched, there is increasing interest on potential impacts of OCs on brain, behaviour and cognition. We systematically reviewed the literature to determine the influence of OCs on cognition, including neurocognition, social cognition and emotional processing. Inclusionary criteria were: (a) premenopausal females taking OCs;(b) a control group of naturally cycling women or OCs users in their inactive (i.e. 'sugar pill') phase; and (c) at least one measure of performance on a neurocognitive or social cognitive task. The systematic review found that OC use was associated with some differences in performance on all cognitive domains examined (with the exception of basic auditory attention and psychomotor performance). Several factors were identified that are likely to modulate the way OCs influence cognition, including task related factors, OC type and control group characteristics. Directions for future research are highlighted.
Hormonal contraception has been widely prescribed for decades. Although safety and efficacy are well-established, much uncertainty remains regarding brain effects of hormonal contraception. We systematically review human and animal studies on the brain effects of hormonal contraception which employed neuroimaging techniques such as MRI, PET and EEG, as well as animal studies which reported on neurotransmitter and other brain biochemical effects. We screened 1001 articles and ultimately extracted data from 70, comprising 51 human and 19 animal studies. Of note, there were no animal studies which employed structural or functional MRI, MRS or PET. In summary, our review shows hormonal contraceptive associations with changes in the brain have been documented. Many questions remain and more studies are needed to describe the effects of hormonal contraception on the brain.
During maze navigation rats can rely on hippocampus-mediated place memory or striatum-mediated response memory. Ovarian hormones bias whether females use place or response memory to reach a reward. Here, we investigated the impact of the contraceptive hormones, ethinyl estradiol (EE) and levonorgestrel (LNG), on memory bias. A total of 63 gonadally-intact female rats were treated with either 10 μg/kg of EE alone, 20 μg/kg of LNG alone, both 10 μg/kg of EE and 20 μg/kg of LNG together, or a sesame oil injection with 5% ethanol as a vehicle control. Rats in the control condition were tested during the diestrus phase of the estrous cycle in order to control for the low circulating levels of gonadotropin and ovarian hormones that occur with oral contraceptive administration. Rats treated with LNG alone had a bias towards the use of place memory compared to diestrus phase control rats. This bias was not observed if LNG was administered in combination with EE. Rats treated with EE or EE+LNG did not have a statistically significant difference in memory bias compared to rats in the control group. These data show that synthetic hormones contained in oral contraceptives administered to females influence which cognitive strategy is predominantly used during navigation.
Women’s psychological and behavioral responses to hormonal contraceptive (HC) treatment can be highly variable. One of the great challenges to researchers seeking to improve the experiences of women who use HCs is to identify the sources of this variability to minimize unpleasant psychobehavioral side-effects. In the following, we provide recommendations for programs of research aimed at identifying sources of heterogeneity in women’s experiences with HC. First, we review research demonstrating person- and prescription- based heterogeneity in women’s psychobehavioral responses to HCs. Next, we identify several promising person- and prescription- based sources of this heterogeneity that warrant future research. We close with a discussion of research approaches that are particularly well-suited to address the research questions raised in article. Together, this review provides researchers with several promising research pathways to help support the development of a precision medicine approach to HC treatment.
Combined oral contraceptives (containing synthetic forms of estradiol and progestins) are one of the most commonly used drugs among females. However, their effects on the gut-brain axis have not been investigated to a great extent despite clear evidence that suggest bi-directional interactions between the gut microbiome and endogenous sex hormones. Moreover, oral contraceptives are prescribed during adolescence, a critical period of development during which several brain structures and systems, such as hypothalamic-pituitary-gonadal axis, undergo maturation. Considering that oral contraceptives could impact the developing adolescent brain and that these effects may be mediated by the gut-brain axis, further research investigating the effects of oral contraceptives on the gut-brain axis is imperative. This article briefly reviews evidence from animal and human studies on the effects of combined oral contraceptives on the brain and the gut microbiota particularly during adolescence.
Extant animal and human data suggest endogenous ovarian hormones increase risk for binge eating in females, possibly via gene x 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 x hormone interactions in susceptibility.
In the last decade, there has been a remarkable surge in research on the neural and behavioral correlates of hormonal contraceptive use, particularly oral contraceptive use. Questions have evolved swiftly and notably, with studies no longer revealing if hormonal contraceptives matter for the brain and behavior, but rather how, when, and for whom they matter most. Paralleling this shift, the goal of this review is to move beyond an average synthesis of hormonal contraceptive influences on human cognition and psychopathology (and their neural substrates) in order to consider the nature and specificity of effects. Accompanied by an evaluation of study methods and informed by findings from animal models, this consideration uncovers promising areas of research in the next ten years, including potential activational and organizational effects of hormonal contraceptive use, individual differences in effects that matter for the wellbeing of unique individuals, and correlates of intrauterine device use.
Hormonal contraceptives are among the most important health and economic developments in the 20th Century, providing unprecedented reproductive control and a range of health benefits including decreased premenstrual symptoms and protections against various cancers. Hormonal contraceptives modulate neural function and stress responsivity. These changes are usually innocuous or even beneficial, including their effects on mood. However, in approximately 4-10% of users, or up to 30 million people at any given time, hormonal contraceptives trigger depression or anxiety symptoms. How hormonal contraceptives contribute to these responses, and who is at risk for adverse outcomes remain unknown. In this paper, we discuss studies of hormonal contraceptive use in humans and describe the ways in which laboratory animal models of contraceptive hormone exposure will be an essential tool for expanding findings to understand the precise mechanisms by which hormonal contraceptives influence the brain, stress responses, and depression risk.
Worldwide over 150 million women use oral contraceptives (OCs), which are the most prescribed form of contraception in both the United States and in European countries. Sex hormones, such as estradiol and progesterone, are important endogenous hormones known for shaping the brain across the life span. Synthetic hormones, which are present in OCs, interfere with the natural hormonal balance by reducing the endogenous hormone levels. Little is known how this affects the brain, especially during the most vulnerable times of brain maturation. Here, we review studies that investigate differences in brain gray and white matter in women using OCs in comparison to naturally cycling women. We focus on two neuroimaging methods used to quantify structural gray and white matter changes, namely structural MRI and diffusion MRI. Finally, we discuss the potential of these imaging techniques to advance knowledge about the effects of OCs on the brain and wellbeing in women.
Research on hormonal contraceptives (HC) in animal models is lacking, and as a result, so is our understanding of the impact of HC on the brain and behavior. Here, we provide a review of the pharmacology of HC, as well as the methodology and best practices for designing a model of HC in female rats. We outline specific methodological considerations regarding dosing, route of administration, exposure time/timing, and selecting a control group. We also provide a framework outlining important levels of analysis for thinking about the impact of HC on behavioral and neurobiological outcomes. The purpose of this review is to equip researchers with foundational knowledge, and some basic elements of experimental design for future studies investigating the impact of HC on the brain and behavior of female rats.
Incidents of strokes are increased in young women relative to young men, suggesting that oral contraceptive (OC) use is one of the causes of stroke among young women. Long-term exposures to the varying combinations of estrogen and progestogen found in OCs affect blood clotting, lipid and lipoprotein metabolism, endothelial function, and de novo synthesis of neurosteroids, especially brain-derived 17β-estradiol. The latter is essential for neuroprotection, memory, sexual differentiation, synaptic transmission, and behavior. Deleterious effects of OCs may be exacerbated due to comorbidities like polycystic ovary syndrome, sickle cell anemia, COVID-19, exposures to endocrine disrupting chemicals, and conventional or electronic cigarette smoking. The goal of the current review is to revisit the available literature regarding the impact of OC use on stroke, to explain possible underlying mechanisms, and to identify gaps in our understanding to promote future research to reduce and cure stroke in OC users.
Steroid hormones influence different aspects of brain function, including development, neurogenesis, neuronal excitability, and plasticity, thus affecting emotional states, cognition, sociality, and reward. In women, their levels fluctuate across the lifespan and through the reproductive stages but are also altered by exogenous administration of hormonal contraceptives (HC). HC are widely used by women throughout their fertile life both for contraceptive and therapeutic benefits. However, awareness of their effects on brain function and behavior is still poorly appreciated, despite the emerging evidence of their action at the level of the central nervous system. Here, we summarize results obtained in preclinical studies, mostly conducted in intact female rodents, aimed at investigating the neurobiological effects of HC. HC can alter neuroactive hormones, neurotransmitters, neuropeptides, as well as emotional states, cognition, social and sexual behaviors. Animal studies provide insights into the neurobiological effects of HC with the aim to improve women’s health and well-being.
Hormonal contraceptives prevent ovulation with subsequent reduction in endogenous levels of estradiol, progesterone and its neuroactive metabolite allopregnanolone. These neurosteroids modulate several brain functions, including neuronal plasticity, cognition and memory. We hypothesized that hormonal contraceptives might affect synaptic plasticity, learning and memory, as a consequence of suppressed endogenous hormones levels. Female rats were orally treated with a combination of ethinyl estradiol (EE, 0.020 mg) and levonorgestrel (LNG, 0.060 mg) once daily for four weeks. Decreased hippocampal brain-derived neurotrophic factor (BDNF) levels and altered histone H3 post-translational modifications (PTMs) were observed 14 days after discontinuation from chronic EE-LNG treatment. These effects were not accompanied by alterations in long-term plasticity at glutamatergic synapses, recognition memory in the novel object and novel place location tests, or spatial learning, memory, and behavioral flexibility in the Morris water maze test. Thus, decreased BDNF content does not affect synaptic plasticity and cognitive performance; rather it might be relevant for the occurrence of certain psychiatric symptoms, reported by some women using hormonal contraceptives. These results provide the first evidence of hippocampal epigenetic changes induced by hormonal contraceptives and complement previous studies on the neurobiological actions of hormonal contraceptives; the finding that effects of chronic EE-LNG treatment on BDNF content and histone PTMs are observed 14 days after drug discontinuation warrants further investigation to better understand the implications of such long-term consequences for women's health.
Hormonal contraceptives (HCs), prescribed to millions of women around the world, alter the ovarian hormonal cycle resulting in neurobehavioral changes in HC users. Human epidemiological and experimental data has characterized some of these effects with oftentimes conflicting or irreproducible results, reflecting a dearth of research considering different compositions, routes of administration, or time-courses of HC use. Non-human animal research can model these effects and help elucidate the underlying mechanisms by which different HCs modulate neurobehavioral outcomes. Still, animal models using HCs are not well-established. This may be because the pharmacological profile of HCs - including the metabolism, receptor binding affinity, and neuromodulatory effects - is dynamic and not always clearly translatable between animals and humans. The current review addresses these issues and provides basic methods and considerations for the use of HCs in animal models of neurobehavior to help advance the field of behavioral neuroendocrinology and inform decisions regarding to women's health.
Background:
Millions of women worldwide use exogenous hormones as oral contraceptives or hormone replacement therapy. Still, time-dependent and long-term consequences of exogenous hormones on stroke risk remains unclear.
Methods:
We examined the association between self-reported oral contraceptive and hormone replacement therapy use and stroke risk in 257 194 women from the UK Biobank, born between 1939 and 1970. Outcomes included any type of stroke, ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. Exposures were analyzed as time-varying variables in Cox regression models.
Results:
During first year of oral contraceptive use, an increased event rate of any stroke was observed (hazard ratio [HR], 2.49 [95% CI, 1.44-4.30]), while the hazards were found to be comparable during remaining years of use (HR, 1.00 [95% CI, 0.86-1.14]), compared with nonusers. Similarly, first year of hormone replacement therapy use was associated with higher hazard rates of any stroke (HR, 2.12 [95% CI, 1.66-2.70]), as well as cause-specific stroke, including ischemic stroke (HR, 1.93 [95% CI, 1.05-3.57]) and subarachnoid hemorrhage (HR, 2.17 [95% CI, 1.25-3.78]), which remained increased for any stroke during remaining years of use (HR, 1.18 [95% CI, 1.05-1.31]), and after discontinuation (HR, 1.16 [95% CI, 1.02-1.32]).
Conclusions:
Oral contraceptive use and hormone replacement therapy were associated with an increased risk of stroke, especially during the first year of use, possibly due to immediate changes in hemostatic balance. This study provides new insights on the effects of hormone exposure on stroke risk and provide evidence of not only an overall risk but also a pronounced effects seen in the beginning of treatment.
Hippocampal neurogenesis persists across the lifespan in many species, including rodents and humans, and is associated with cognitive performance and the pathogenesis of neurodegenerative disease and psychiatric disorders. Neurogenesis is modulated by steroid hormones that change across development and differ between the sexes in rodents and humans. Here, we discuss the effects of stress and glucocorticoid exposure from gestation to adulthood as well as the effects of androgens and estrogens in adulthood on neurogenesis in the hippocampus. Throughout the review we highlight sex differences in the effects of steroid hormones on neurogenesis and how they may relate to hippocampal function and disease. These data highlight the importance of examining age and sex when evaluating the effects of steroid hormones on hippocampal neurogenesis.
Importance
Many women spend a substantial proportion of their lives preventing or planning for pregnancy, and approximately 87% of US women use contraception during their lifetime.
Observations
Contraceptive effectiveness is determined by a combination of drug or device efficacy, individual fecundability, coital frequency, and user adherence and continuation. In the US, oral contraceptive pills are the most commonly used reversible method of contraception and comprise 21.9% of all contraception in current use. Pregnancy rates of women using oral contraceptives are 4% to 7% per year. Use of long-acting methods, such as intrauterine devices and subdermal implants, has increased substantially, from 6% of all contraceptive users in 2008 to 17.8% in 2016; these methods have failure rates of less than 1% per year. Estrogen-containing methods, such as combined oral contraceptive pills, increase the risk of venous thrombosis from 2 to 10 venous thrombotic events per 10 000 women-years to 7 to 10 venous thrombotic events per 10 000 women-years, whereas progestin-only and nonhormonal methods, such as implants and condoms, are associated with rare serious risks. Hormonal contraceptives can improve medical conditions associated with hormonal changes related to the menstrual cycle, such as acne, endometriosis, and premenstrual dysphoric disorder. Optimal contraceptive selection requires patient and clinician discussion of the patient’s tolerance for risk of pregnancy, menstrual bleeding changes, other risks, and personal values and preferences.
Conclusions and Relevance
Oral contraceptive pills are the most commonly used reversible contraceptives, intrauterine devices and subdermal implants have the highest effectiveness, and progestin-only and nonhormonal methods have the lowest risks. Optimal contraceptive selection incorporates patient values and preferences.
Background
Some research suggests that oral contraceptive pills (OCPs) blunt the cortisol stress response, thus OCP users are often excluded from stress research. The current study examined changes in salivary cortisol among females taking OCPs and naturally cycling (NC) females after exposure to the Trier Social Stress Test (TSST).
Methods
The literature search included the terms “oral contraceptives” OR “oral contraception” OR “birth control” OR “birth control pill” AND “Trier Social Stress Test” OR “TSST” AND “cortisol” OR “salivary cortisol.” A total of 14 studies with 36 independent samples were included in the meta-analysis. Participant information, including pre- and post- TSST measures of salivary cortisol, and subgroup (i.e., OCP or menstrual cycle phase), were extracted. Additional study characteristics including age, length of stressor, type of OCP, time of day the cortisol samples were collected, and type of cortisol assay used were also considered.
Results
Findings from the current meta-analysis indicated that changes in salivary cortisol in NC participants following the TSST, D = 4.31, SE = 0.53, 95% CI = 3.27, 5.35, were greater than the changes observed in participants on OCPs D = 1.50, SE = 0.30, 95% CI = 0.91, 2.09. Study effects were heterogeneous, Fisher’s Z = 10.87, Q = 620.57, p = <0.001. Between-phase analyses were also conducted.
Conclusions
Results demonstrate that OCPs blunt cortisol reactivity relative to NC females. There was significant heterogeneity, except between OCP and follicular phase groups. Implications for research design and methodology are discussed.
Levonorgestrel-intrauterine-devices (LNG-IUD) are one of the most used contraceptive methods worldwide. While several reviews exist on how LNG-IUDs impact physiology and gynaecological functions, this systematic review focuses on stress, mental health, quality of life, sexual functioning, and effects on brain architecture.
While data on stress is scarce, results on mental health are ambiguous. More consistently, LNG-IUD use seems to improve quality of life and sexual functioning. No studies highlighting the consequences of LNG-IUD use on the brain were found.
The reviewed studies are characterized by a substantial variation in approaches, participant groups, and study quality. More high-quality research assessing the effects of LNG-IUD on mental health, including response to stressors and brain function and structure, is needed to identify women vulnerable to adverse effects of LNG-IUD, also in comparison to oral contraceptives, and to empower women to make more informed choices concerning hormonal contraception.
Depression is associated with blunted reactivity to acute stress, as well as blunted responsivity to rewards. However, the extent to which responses to stress are associated with responses to reward in individuals meeting criteria for a depressive disorder is unknown. The goal of this study was to examine the relation of responses to stress and reward, and to determine if this relation is moderated by depression diagnosis, anhedonia, and sex. Participants included 114 adults (68 depressed, 46 non-depressed; 75% women) recruited from the community. Stress reactivity was operationalized as the total salivary cortisol output to the Trier Social Stress Test (TSST; Kirschbaum et al., 1993). Response bias to monetary reward was assessed following the TSST recovery period with a probabilistic reward task (PRT; Pizzagalli et al., 2005). In men only, total cortisol output during the TSST was more strongly positively associated with response bias to reward across the three blocks of the PRT. In addition, among depressed participants with high levels of anhedonia, higher cortisol output during the TSST was significantly associated with higher overall response bias to reward. We suggest that in men, the stress and reward systems may both respond quickly, and resolve rapidly, in the face of acute stress. Further, in depression, our findings suggest that anhedonia may represent a specific phenotype in which the stress and reward systems are particularly tuned together.
The brain is an endocrine organ whose day-to-day function is tied to the rhythmic production of neuromodulatory hormones. Yet, traditional approaches to studying brain–hormone relationships in humans are often coarse in scope. By contrast, dense-sampling neuroimaging offers the unique ability to probe dynamic interactions between the nervous and endocrine systems. This review summarizes recent evidence of sex hormones’ influence on structural and functional properties of the human brain. In particular, findings from the ‘28andMe’ project suggest that estradiol modulates the topology of large-scale functional brain networks and progesterone rapidly shapes medial temporal lobe morphology across the menstrual cycle. This nascent body of work sets the stage for additional studies in larger cohorts. We end by discussing the potential of dense-sampling designs to further elucidate endocrine modulation of the brain, with implications for personalized medicine.
Women constitute half of the world’s population, yet neuroscience research does not serve the sexes equally. Fifty years of preclinical animal evidence documents the tightly-coupled relationship between our endocrine and nervous systems, yet human neuroimaging studies rarely consider how endocrine factors shape the structural and functional architecture of the human brain. Here, we quantify several blind spots in neuroimaging research, which overlooks aspects of the human condition that impact women’s health (e.g. the menstrual cycle, hormonal contraceptives, pregnancy, menopause). Next, we illuminate potential consequences of this oversight: today over 100 million women use oral hormonal contraceptives, yet relatively few investigations have systematically examined whether disrupting endogenous hormone production impacts the brain. We close by presenting a roadmap for progress, highlighting the University of California Women’s Brain Initiative which is addressing unmet needs in women’s health research.
Millions of women worldwide use oral contraceptives (OCs), often starting during puberty/adolescence. It is, however, unknown how OC use during this critical period of development affects the brain. The objective of the current study was to examine resting state functional connectivity (FC) in the default mode network (DMN), central executive network (CEN), salience network (SN), reward network (RN), and subcortical limbic network of the brain using independent component analysis (ICA) between pubertal- and adult-onset OC users (n = 27) and naturally cycling women (n = 48). It was hypothesized that OC use would result in network-specific increases and decreases in FC and that pubertal-onset OC use would result in differences to the aforementioned networks compared to adult-onset OC use. Pubertal-onset OC use is related to heightened FC in the SN compared to adult-onset OC users. In general, OC use also increases connectivity in the SN, CEN, RN, and subcortical limbic network compared to NC women. No significant differences in connectivity were observed in the DMN between OC users and NC women. These findings provide a mechanistic insight for the altered executive functioning and emotion/reward processing previously seen in OC users, which may then increase their vulnerability to mental health conditions.
Background and purpose:
Cardiovascular risk factors, which are overall more prevalent in men, are considered the major risk factors for strokes among young adults. However, recent European data found the incidence of strokes to be higher in young women. Using a large US claims sample, we examined sex differences in the index stroke rate of young adults.
Methods:
We performed a retrospective cohort study of enrollees in a 10% random sample of PharMetrics, a nationally representative claims database of insured Americans from 2001 to 2014. Outcomes were index ischemic stroke events, based on inpatient admissions using International Classification of Diseases-Ninth Revision codes. The index stroke rate was estimated from Poisson rate models with time varying covariates for 2-year periods, stratified by sex and age groups.
Results:
We identified 20 554 index strokes (50.4% women; mean age 63) including 5198 in young adults ages 15 to 54. There was no difference by sex in the index stroke rate in the extremes of age groups 15 to 24 and ≥75 years old. However, in the 25 to 34 and 35 to 44 year age groups, more women had strokes than men (incidence rate ratio: men:women, 0.70 [95% CI, 0.57-0.86]; 0.87 [95% CI, 0.78-0.98], respectively). In contrast, in the 45 to 54, 55 to 64, and 65 to 74 year age groups, more men had strokes (incidence rate ratio, 1.25 [95% CI, 1.16-1.33]; 1.41 [95% CI, 1.18-1.34]; 1.18 [95% CI, 1.12-125], respectively).
Conclusions:
More young women than men have strokes, suggesting possible importance of sex-mediated etiologies of stroke. Understanding these drivers is critical to stroke treatment and prevention efforts in young adults.