Reproducible stability of verbal and spatial functions along the menstrual cycle.

Recent studies have reported brain changes in response to ovarian hormonal fluctuations along the menstrual cycle. However, it remains unclear, whether these brain changes are of an adaptive nature or whether they are linked to changes in behavior along the menstrual cycle, particularly with respect to cognitive performance. To address this knowledge gap, we report results from 3 well-powered behavioral studies with different task designs, leveraging the advantages of each design type. In all three studies we assessed whether verbal or spatial performance (i) differed between cycle phases, (ii) were related to estradiol and / or progesterone levels and (iii) were moderated by individual hormone sensitivity as estimated by premenstrual symptoms. Overall, results of all three studies point towards a null effect of menstrual cycle phase and - to a lesser extent - ovarian hormones on verbal and spatial performance and provided no evidence for a moderation of this effect by individual hormone sensitivity. We conclude that there is substantial consistency in verbal and spatial performance across the menstrual cycle, and that future studies of intra-individual variation are needed.

Mental Health Symptoms in Oral Contraceptive Users During Short-Term Hormone Withdrawal.

Importance: Hormonal contraception has been linked to mood symptoms and the ability to recognize emotions after short periods of treatment, whereas the mental health of users of long-term hormonal contraceptives has had limited investigation. Objective: To evaluate whether short-term hormonal withdrawal, which users of combined oral contraceptives (COCs) undergo once a month (pill pause), was associated with altered mood and emotional recognition in long-term users of COCs. Design, Setting, and Participants: This case-control study included a community sample of individuals assigned female sex at birth who identified as women and used COC for 6 months or longer. The control group included women with natural menstrual cycles who otherwise fulfilled the same inclusion criteria. The study was conducted between April 2021 and June 2022 in Salzburg, Austria. Exposure: COC users and women with natural menstrual cycles were tested twice within a month, once during their active pill phase or luteal phase and once during their pill pause or menses. Main Outcomes and Measures: Negative affect, anxiety, and mental health problems were assessed during each session. The percentage increase in mental health symptoms was calculated during the pill pause compared with that during the active intake phase in COC users. How this change compared with mood fluctuations along the menstrual cycle in women with natural menstrual cycles was assessed. Results: A total of 181 women aged 18 to 35 years (mean [SD] age, 22.7 [3.5] years) were included in the analysis (61 women with androgenic COC use, 59 with antiandrogenic COC use, 60 women with a menstrual cycle not taking COCs). COC users showed a 12.67% increase in negative affect (95% CI, 6.94%-18.39%), 7.42% increase in anxiety (95% CI, 3.43%-11.40%), and 23.61% increase in mental health symptoms (95% CI, 16.49%-30.73%; P < .001) during the pill pause compared with the active intake phase. The effect size of this change did not differ depending on progestin type (negative affect: F1,117 = 0.30, P = .59; state anxiety: F1,117 = 2.15, P = .15; mental health: F1,117 = .16, P = .69) or ethinylestradiol dose (negative affect: F1,57 = .99, P = .32; state anxiety: F1,57 = 2.30, P = .13; mental health: F1,57 = .14, P = .71) was comparable with mood changes along the menstrual cycle in women with natural cycles (negative affect: F2,175 = 0.13, P = .87; state anxiety: F2,175 = 0.14, P = .32; mental health: F2,175 = 0.65, P = .52). Mood worsening during the pill pause was more pronounced in women with higher baseline depression scores (negative affect increase of 17.95% [95% CI, 7.80%-28.10%] in COC users with higher trait depression [BDI >8]). Emotion recognition performance did not differ between active pill phase and pill pause. Conclusions and Relevance: In this case-control study of long-term COC users, withdrawal from contraceptive steroids during the pill pause was associated with adverse mental health symptoms similar to those experienced by women during menses with withdrawal from endogenous steroids. These results question the use of the pill pause from a mental health perspective. Long-term COC users may benefit more from the mood-stabilizing effects of COCs in cases of continuous intake.

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

Introduction: Hormonal 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. Methods: A 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. Results: In 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.

Emotion recognition and mood along the menstrual cycle.

Previous studies have demonstrated menstrual cycle dependent changes in the recognition of facial emotional expressions, specifically the expression of fear, anger, sadness or disgust. While some studies demonstrate an improvement of emotion recognition performance during the peri-ovulatory phase, when estradiol levels peak, other studies demonstrate a deterioration of emotion recognition performance during the mid-luteal phase, when progesterone levels peak. It has been hypothesized, that these changes in emotion recognition performance mirror mood changes along the menstrual cycle. In the present study, we investigate, whether changes in emotion recognition performance along the menstrual cycle are mediated by mood changes along the menstrual cycle. In a combined cross-sectional and longitudinal study design, two large samples of women completed an emotion recognition task, as well as several mood questionnaires during their menses, peri-ovulatory or mid-luteal cycle phase. 65 women completed the task thrice, once during each cycle phase, order counterbalanced. In order to control for potential learning effects, a sample of 153 women completed the task only once in one of the three cycle phases. In both samples, results demonstrated no significant changes in emotion recognition performance along the menstrual cycle, irrespective of the performance measure investigated (accuracy, reaction time, frequency of emotion classifications) and irrespective of the emotion displayed. Bayesian statistics provided very strong evidence for the null hypothesis, that emotion recognition does not change along the menstrual cycle. There was also no moderation of emotion recognition changes along the menstrual cycle by mood changes along the menstrual cycle. Mood changes along the menstrual cycle followed the expected pattern with highest positive affect and least premenstrual symptoms around ovulation and lowest positive affect, but strongest premenstrual symptoms during menses. Interestingly, premenstrual symptoms were negatively related to estradiol, suggesting a protective effect of estrogen during the luteal cycle phase against mood worsening during the premenstrual phase.

Hormonal contraception & face processing: Examining face gender, androgenicity & treatment duration.

Previous cross-sectional studies observed differences between users and non-users of combined oral contraceptives (COCs) in both the structure and function of the fusiform face area (FFA) related to face processing. For the present study 120 female participants performed high-resolution structural, as well as functional scans at rest, during face encoding and face recognition. Participants were either never-users of COCs (26), current first-time users of androgenic (29) or anti-androgenic COCs (23) or previous users of androgenic (21) or anti-androgenic COCs (21). Results suggest that associations between COC-use and face processing are modulated by androgenicity, but do not persist beyond the duration of COC use. The majority of findings concern the connectivity of the left FFA to the left supramarginal gyrus (SMG), which is a key region in cognitive empathy. While connectivity in anti-androgenic COC users differs from never users irrespective of the duration of COC use already at rest, connectivity in androgenic COC users decreases with longer duration of use during face recognition. Furthermore, longer duration of androgenic COC use was related to reduced identification accuracy, as well as increased connectivity of the left FFA to the right orbitofrontal cortex. Accordingly, the FFA and SMG emerge as promising ROIs for future randomized controlled trials on the effects of COC use on face processing.

Duration of oral contraceptive use relates to cognitive performance and brain activation in current and past users.

Previous studies indicate effects of oral contraceptive (OC) use on spatial and verbal cognition. However, a better understanding of the OC effects is still needed, including the differential effects of androgenic or anti-androgenic OC use and whether the possible impact persists beyond the OC use. We aim to investigate the associations of OC use duration with spatial and verbal cognition, differentiating between androgenic and anti-androgenic OC. Using functional magnetic resonance imaging (MRI), we scanned a group of 94 past and current OC-users in a single session. We grouped current OC users (N=53) and past OC users with a natural cycle (N=41) into androgenic and anti-androgenic user. Effects of OC use duration were observed for current use and after discontinuation. Duration of OC use was reflected only in verbal fluency performance but not navigation: The longer the current OC use, the less words were produced in the verbal fluency task. During navigation, deactivation in the caudate and postcentral gyrus was duration-dependent in current androgenic OC users. Only during the verbal fluency task, duration of previous OC use affects several brain parameters, including activation of the left putamen and connectivity between right-hemispheric language areas (i.e., right inferior frontal gyrus and right angular gyrus). The results regarding performance and brain activation point towards stronger organizational effects of OCs on verbal rather than spatial processing. Irrespective of the task, a duration-dependent connectivity between the hippocampus and various occipital areas was observed. This could suggest a shift in strategy or processing style with long-term contraceptive use during navigation/verbal fluency. The current findings suggest a key role of the progestogenic component of OCs in both tasks. The influence of OC use on verbal fluency remains even after discontinuation which further points out the importance of future studies on OC effects and their reversibility.

Sex and strategy effects on brain activation during a 3D-navigation task.

Sex differences in navigation have often been attributed to the use of different navigation strategies in men and women. However, no study so far has investigated sex differences in the brain networks supporting different navigation strategies. To address this issue, we employed a 3D-navigation task during functional MRI in 36 men and 36 women, all scanned thrice, and modeled navigation strategies by instructions requiring an allocentric vs. egocentric reference frame on the one hand, as well as landmark-based vs. Euclidian strategies on the other hand. We found distinct brain networks supporting different perspectives/strategies. Men showed stronger activation of frontal areas, whereas women showed stronger activation of posterior brain regions. The left inferior frontal gyrus was more strongly recruited during landmark-based navigation in men. The hippocampus showed stronger connectivity with left-lateralized frontal areas in women and stronger connectivity with superior parietal areas in men. We discuss these findings in the light of a stronger recruitment of verbal networks supporting a more verbal strategy in women compared to a stronger recruitment of spatial networks supporting a more spatial strategy use in men. In summary, this study provides evidence that different navigation strategies activate different brain areas in men and women.