Naturally-cycling Women Research Articles

P-426 Comprehensive study of the endometrial early/mid secretory phase during natural cycles reveals conserved molecular dynamics involved in the window of implantation

Abstract Study question Is there a common transcriptomic signature in the endometrial early/mid secretory phase of healthy women in natural cycles? Summary answer We observed a conserved transcriptomic regulation of the endometrium around the window of implantation (WOI), consistent across donors, and not influenced by the biopsy procedure. What is known already Extensive research has been conducted on the gene expression changes that characterize the WOI, aiming to identify signals that indicate its onset. However, much of this work has utilized whole-transcriptome techniques and has involved IVF patients, who require luteal phase support. The few studies performed in natural cycles often relied on restricted methods, such as qPCR that examines only a few targets simultaneously. As such, an extensive transcriptomics study in volunteer donors in true natural cycles is lacking. This may provide deeper insights into the physiological changes during the WOI in young women driven by the endogenous effects of progesterone. Study design, size, duration 34 healthy donors were enrolled. Each donor provided one endometrial sample, on a day between LH + 2 and LH + 9 during their natural cycle. A minimum of two and a maximum of five donors were allocated to each day. Ovulation was detected via ecographic inspection and hormonal determination of LH/E2/P4. LH + 0 was established when the LH peak was detected (>2.8 times basal levels), together with a subsequenc decrease in E2 (-30%) and increase in P4 (>1.6ng/ml) Participants/materials, setting, methods When the biopsy was of sufficient size, we separated it in two parts and extracted RNA separately to assess concordance between different areas of the same biopsy. RNAseq libraries were prepared with NEBNextUltraII Directional RNA LibraryPrep and sequenced on a NovaSeq6000. Fastq files were aligned with STAR to GRCh38. Principal component analyses (PCA) were created with plotPCA, gene expression time course analysis was performed with DEseq2, and pseudotime analysis was performed using the slingshot package. Main results and the role of chance Of the 34 donors, we obtained good quality RNAseq data (minimum 20 million reads) from 41 samples, with 27 donors having one sample sequenced, while 2 independent samples from the same biopsy were obtained from 7 volunteers. Analysing same-biopsy concordance via PCA revealed a great degree of similarity between all the pairs, which clustered close to each other. Samples from different donors collected on the same day also showed a good clustering, apart from a single day LH + 4 sample. Pseudotime analysis revealed a distinct trajectory in transcriptomic profiles changing progressively from day LH + 2 to LH + 9. This analysis clearly delineated three phases: LH + 2 to LH + 5, LH + 6 to LH + 7, and LH + 8 to LH + 9. Accordingly, we categorized these into pre-receptive, receptive and post receptive groups, and conducted a time course experiment. We identified a total of 3,311 genes with varying expression across these three timepoints, primarily associated with progesterone signalling, metabolism and cell-to-cell communication. Based on their expression patterns, we isolated a subset of 538 genes which increased their expression during the receptive phase only. These genes could represent novel markers for a more in-depth characterization of the WOI. Limitations, reasons for caution The samples analysed are in bulk, and the genes identified could be expressed either in the stroma or in the epithelial compartment. These findings are not applicable to artificial cycles, as the absence of the corpus luteum and varying levels of exogenous progesterone administered may change the transcriptomic signatures. Wider implications of the findings Our study revealed good concordance of whole transcriptome profiles of donor’s endometria according to cycle progression. This may lead to the identification of novel markers involved in the regulation of the WOI that may not have been found in previous studies performed on artificial cycles. Trial registration number not applicable

470. [15O]-Water PET Regional Cerebral Blood Flow During Rest in Men, Naturally-Cycling Women, and Women Using Oral Contraceptives

470. [15O]-Water PET Regional Cerebral Blood Flow During Rest in Men, Naturally-Cycling Women, and Women Using Oral Contraceptives

Whole-brain dynamics across the menstrual cycle: the role of hormonal fluctuations and age in healthy women

Recent neuroimaging research suggests that female sex hormone fluctuations modulate brain activity. Nevertheless, how brain network dynamics change across the female menstrual cycle remains largely unknown. Here, we investigated the dynamical complexity underlying three menstrual cycle phases (i.e., early follicular, pre-ovulatory, and mid-luteal) in 60 healthy naturally-cycling women scanned using resting-state fMRI. Our results revealed that the pre-ovulatory phase exhibited the highest dynamical complexity (variability over time) across the whole-brain functional network compared to the early follicular and mid-luteal phases, while the early follicular showed the lowest. Furthermore, we found that large-scale resting-state networks reconfigure along menstrual cycle phases. Multilevel mixed-effects models revealed age-related changes in the whole-brain, control, and dorsal attention networks, while estradiol and progesterone influenced the whole-brain, DMN, limbic, dorsal attention, somatomotor, and subcortical networks. Overall, these findings evidence that age and ovarian hormones modulate brain network dynamics along the menstrual cycle.

Differences in anxiety, worry, and perceived stress among naturally cycling women and oral contraceptives users: a cross-sectional study investigating the role of contraceptive types

The goal of our study was to test whether the types of OC affect the link between anxiety and its main maintenance factors: worry and perceived stress. Women are particularly at risk of being affected by excessive worrying, a core component of generalized anxiety disorder (GAD), and they are twice as likely as men to suffer from GAD. The literature suggests that gonadal hormones and types of oral contraceptives (OC) should be taken into account when exploring anxiety disorders in women, but the precise mechanism of this link remains understudied. We performed an observational cross-sectional study on a sample of 908 women, including 499 women naturally cycling (NC) and 409 taking OC (277 in the anti-androgenic group, 132 in the androgenic group). The participants filled in a battery of online questionnaires. Anxiety positively correlated with worry and perceived stress in the whole sample and in the three groups: androgenic OC, anti-androgenic OC, and NC. There was no significant difference between the groups on all the variables apart from the age of the participants. However, we found that women taking anti-androgenic OC had significantly higher levels of worry than NC women (after controlling for stress and age). The differences in OC types should be taken into account in future studies which might also lead to a better choice of OC based on women’s individual needs.

Hormonal contraceptive use is associated with differences in women’s inflammatory and psychological reactivity to an acute social stressor

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.

Adrenocorticotropic hormone secretion in response to anticipatory stress and venepuncture: The role of menstrual phase and oral contraceptive use

IntroductionOral contraceptives (OCs) are primarily known for their effects on the reproductive system, but they can also impact the hypothalamic–pituitary–adrenal (HPA) axis. The present study aimed to compare plasma adrenocorticotropic hormone (ACTH) responses to the anticipatory stress of participating in a scientific experiment and venepuncture in OC users versus naturally cycling (NC) women, with a focus on variations throughout the menstrual cycle. MethodsWe recruited 131 young women (average age 20.5) and obtained blood samples to measure plasma ACTH concentrations immediately after venepuncture and again after 15 min of group activities designed to facilitate interpersonal attachment and stress-buffering. ResultsACTH levels decreased in 70% of all participants throughout the group activities. A two-way repeated measures ANOVA highlighted a significant interaction between time and OC use, indicating differential changes in ACTH levels during social interaction between OC users and NC women. Further, the post-hoc analysis revealed that a period of stress-buffering group activities significantly decreased ACTH levels in NC women during menstrual and secretory phases, but not during the proliferative phase. In contrast, OC users did not display a decrease during group activities, regardless of the phase. ConclusionThis study underscores the influence of OC use on stress regulation, demonstrating that OCs not only modulate reproductive functions but also impact ACTH stress reactivity. Additionally, it emphasizes the importance of considering hormonal contraceptive use and menstrual cycle phases when assessing female stress responses.

Investigating the effect of hormonal contraceptive use on salivary cortisol response to a CO2 challenge

Hormonal contraceptive (HC) use has been associated with many physiological effects, such as blunted cortisol stress responses, when compared to naturally cycling (NC) women. However, no previous studies comparing these groups have utilized a CO2 challenge to induce stress. Therefore, the aim of the current study was to use a CO2 challenge to compare cortisol stress reactivity in women using HC relative to NC women. While this task has been previously used to induce panic, few studies have assessed its effects on cortisol, especially as it relates to HC use. Thirty-five women (19 current HC users,16 self-reported NC women) were assessed in the lab. Participants had a mean age of 25.2 years and were 74.3% White. A 35% CO2 challenge was used to provoke a stress response. Saliva samples were collected to measure cortisol (1 pre-stress baseline sample, 5 post-stress samples). Linear mixed effects modeling was used to examine whether there was a significant increase in cortisol following the challenge. There were no group differences in baseline cortisol (b = -.0117, p =.801), however, there was a significant difference in cortisol responses from baseline, with NC women having a more robust cortisol response (linear effect, b=.0065, p=.001; quadratic effect, b=-.0001, p<.001). Results are consistent with previous research demonstrating a more blunted cortisol response to a laboratory-based stressor among individuals using HC. In contrast, participants in the NC group displayed greater post-stress peak cortisol levels and a clear down-regulatory response.

The Association Between Women’s Self-Promotion and the Androgenic Effects of Hormonal Contraceptives

Women promote their accomplishments and competencies less than men and this difference may be underpinned by androgenic endocrinological processes. Many women use hormonal contraceptives (HCs) which, in addition to allowing women to delay reproduction, alter women’s hormonal profiles and bind to androgen receptors in the brain. We conducted an online survey using a convenience sample of women (N=741, Mage=20.81) to test the hypothesis that HC users would report higher self-promotion than naturally cycling (NC) women. We additionally explored whether different methods of administration (oral contraceptives [OCs], IUD, implant)] and different progestins (which vary in androgenicity) differentially affected women’s self-promotion. Self-promotion was assessed using the Impression Management Scale (e.g., “How often do you make people aware of your accomplishments?”). HC users reported higher self-promotion than NC women, p=.014. Furthermore, women using hormonal IUDs reported higher self-promotion than NC women (p< 001), as well as women taking OCs with first-generation progestins (p=.005) and third-generation progestins (p<,001). IUDs contain the progestin levonogestrel, which is highly androgenic and bioavailable. We did not find similar patterns for the contraceptive implant which contains a third-generation progestin. Finally, a small sample of women taking OCs containing levonogestrel (n=27) reported descriptively higher self-promotion than women using first and third generation OCs. These findings suggest some women may be experiencing progestin-driven effects contributing to increases in self-promotional attitudes and behaviors. The discussion of results also considers possible self-selection effects and routes for future research to clarify the relationship between HCs and self-promotion.

(100) The Effect of Oral Contraceptive Pill Type on Vulvovaginal Atrophy

Abstract Introduction Oral contraceptive pills (OCPs), which are used by over a quarter of reproductive-age women in the United States (Daniels et al., 2015; Jones et al., 2013), contain either both ethinylestradiol and a synthetic progestin, or solely a synthetic progestin. Through progestin-induced hepatic increases in sex hormone binding globulin (SHBG), OCPs have been found to reduce the number of bioavailable androgens within women’s bodies (Zimmerman et al., 2014). Given that androgens are essential for the maintenance of healthy vaginal tissue (I. Goldstein, 2009), reduced androgen levels may adversely impact the vaginal epithelium in OCP users. While OCPs are indeed associated with symptoms of vulvovaginal atrophy (VVA), such as vaginal pain and vaginal dryness (Battaglia et al., 2012), little is known about how these symptoms may vary based on the androgenicity of OCPs. Objective The aim of the present study was to compare rates of VVA among three groups of women: (1) women using OCPs containing low doses (i.e., ≤25 μg) of ethinylestradiol coupled with an androgenic progestin, (2) women using OCPs containing low doses (i.e., ≤25 μg) of ethinylestradiol coupled with an antiandrogenic progestin, and (3) naturally-cycling women (i.e., women with no history of oral contraceptive pill use). Methods Participants rated the severity of the following symptoms of VVA on a 4-point Likert-type scale ranging from 0 (mild) to 3 (severe): vaginal dryness, vaginal and/or vulvar irritation/itching, dysuria, and vaginal pain associated with sexual activity. Participants also dichotomously rated the presence or absence of vaginal bleeding associated with sexual activity. Results Women taking androgenic OCPs (n = 50) were significantly more likely to report vaginal bleeding associated with sexual activity than were women in the control group (n = 59), χ2(2, 130) = 9.759, p = .007. One participant (1.69%) in the control reported vaginal bleeding, compared to ten women (20%) in the androgenic group. Three participants (14.28%) in the antiandrogenic group endorsed vaginal bleeding, however this result was not significant. A MANOVA indicated no significant between-group differences for any of the remaining VVA items (i.e., dryness, itching/irritation, dysuria, or pain), F(2, 250) = 1.098, p = .365, and an ANOVA confirmed there were no differences between groups in the total VVA score, F(2) = 2.093, p = .127. Conclusions There were elevated rates of vaginal bleeding among OCP users compared to non-OCP users in this sample. This finding could be attributable a range of factors which have previously linked OCP use to vaginal bleeding, such as thinning of the vaginal tissue (Kagan &amp; Rivera, 2018), cervical ectopy (Patil &amp; Sharma, 2017), and thinning of the endometrium (Bright et al., 2011). Disclosure No

Hormonal status effects on the electrophysiological correlates of performance monitoring in women

Fluctuations in ovarian hormones are thought to play a role in the increased prevalence of mood and anxiety disorders in women. Error-related negativity (ERN) and error positivity (Pe) are two putative electrophysiological biomarkers for these internalizing disorders. We investigated whether female hormonal status, specifically menstrual cycle phase and oral contraceptive (OC) use, impact ERN and Pe. Additionally, we examined whether the relationship between the ERN and negative affect (NA) was moderated by hormonal status and tested whether the ERN mediated the relation between ovarian hormones and NA. Participants were healthy, pre-menopausal women who were naturally cycling (NC) or using OCs. Using a counterbalanced within-subject design, all participants performed a speeded-choice reaction-time task twice while undergoing electroencephalography measurements. NC women (N = 42) performed this task during the early follicular and midluteal phase (when estrogen and progesterone are both low and both high, respectively), while OC users (N = 42) performed the task during active OC use and during their pill-free week. Estradiol and progesterone levels were assessed in saliva. Comparing the two cycle phases within NC women revealed no differences in the (Δ)ERN, (Δ)Pe or NA. We did observe a negative relation between phase-related changes in the ΔERN and changes in NA. Mediation analysis additionally showed that phase-related changes in estradiol were indirectly and negatively related to NA through a reduction of ΔERN amplitudes. When comparing active OC users with NC women, we observed increased ΔPe- but not (Δ)ERN amplitudes in the former group. No evidence was found for moderating effects of menstrual cycle phase or OC use on the relation between the ERN and NA. These findings suggest that hormonal status may impact the neural correlates of performance monitoring and error sensitivity, and that this could be a potential mechanism through which ovarian hormones influence mood.

Increased HIV-1 infection in PBMCs treated in vitro with menstrual cycle phase hormones or medroxyprogesterone acetate likely occurs via different mechanisms.

Both luteal phase progesterone (P4) levels and use of the intramuscular (IM) injectable progestin-only contraceptive depo-medroxyprogesterone acetate (DMPA-IM) have been linked to increased S/HIV acquisition in animal, clinical and in vitro models. Several plausible mechanisms could explain MPA-induced HIV-1 acquisition while those for the luteal phase are underexplored. Peripheral blood mononuclear cells (PBMCs) were treated with P4 and estrogen at concentrations mimicking the luteal phase, follicular phase or with levels of MPA mimicking peak serum levels in DMPA-IM users. Cells were infected with an R5-tropic infectious molecular clone and HIV-1 infection was measured. A role for the glucocorticoid receptor (GR) was investigated using the GR/PR antagonist RU486. CCR5 protein levels and activation status, assessed by levels of the activation marker CD69, were measured by flow cytometry after treatment in vitro and in PBMCs from naturally-cycling women or DMPA-IM users. Both MPA and luteal phase hormones significantly increased HIV-1 infection in vitro. However, MPA but not luteal phase hormones increased the CD4+/CD8+ T cell ratio, CCR5 protein expression on CD4+ T cells and increased expression of the activation marker CD69. The GR is involved in MPA-induced, but not luteal phase hormone-induced increased HIV-1 infection. In DMPA-IM users, the frequency of CCR5-expressing CD3+ and CD8+ cells was higher than for women in the luteal phase. MPA increases HIV-1 infection in a manner different from that of luteal phase hormones, most likely involving the GR and at least in part changes in the frequency and/or expression of CCR5 and CD69.

Hormonal contraceptives as disruptors of competitive behavior: Theoretical framing and review

Emerging evidence suggests that hormonal contraceptives (HCs) impact psychological outcomes through alterations in neurophysiology. In this review, we first introduce a theoretical framework for HCs as disruptors of steroid hormone modulation of socially competitive attitudes and behaviors. Then, we comprehensively examine prior research comparing HC users and non-users in outcomes related to competition for reproductive, social, and financial resources. Synthesis of 46 studies (n = 16,290) led to several key conclusions: HC users do not show the same menstrual cycle-related fluctuations in self-perceived attractiveness and some intrasexual competition seen in naturally-cycling women and, further, may show relatively reduced status- or achievement-oriented competitive motivation. However, there a lack of consistent or compelling evidence that HC users and non-users differ in competitive behavior or attitudes for mates or financial resources. These conclusions are tentative given the notable methodological limitations of the studies reviewed. Implications and recommendations for future research are discussed.

The Link Between Masculinity and Spatial Skills Is Moderated by the Estrogenic and Progestational Activity of Oral Contraceptives.

Conversations about gender and spatial skills frequently dissolve into a hackneyed debate over nature and nurture. This is particularly true for conversations concerning three-dimensional (3D) mental rotations skill, which shows the largest gender difference of all aspects of cognition, with men—on average—outperforming women. To advance this empirical area of inquiry, biopsychosocial influences on spatial skills should be considered, and a unique opportunity do to that is provided by combined oral contraceptives (OCs). OCs with relatively low estradiol doses and with highly androgenic progestins have been positively related to spatial skills. Gender self-concepts, including masculine and feminine self-perceptions, have also been positively related to spatial skills. It is wholly unknown, however, whether the exogenous sex hormones contained in OCs moderate the link between self-perceived masculinity and 3D mental rotations. This study filled that knowledge gap by utilizing a sample of 141 naturally cycling (NC) women and 229 OC users who completed a computerized survey and cognitive tests. A series of moderation analyses examined whether the link between masculinity and 3D mental rotations depended on pill use or on the estrogenic, progestational, or androgenic activity in OCs, which were operationalized using a novel coding scheme. Results showed that the positive masculinity-3D mental rotations link was only present for NC women, presumably because it was altered by the exogenous hormones in OCs. Indeed, the link was accentuated in users of OCs with relatively low estrogenic and high progestational activity. Future research on menstrual cycle and pill phase is needed, but these findings importantly delineate ways in which biological and psychosocial factors combine to explain variation in spatial skills among women. They also suggest that focus should be placed on the under-investigated progestational activity of OCs, which is facilitated by the novel quantification of OC action used in this study. Thus, this research increases understanding of the neurocognitive and behavioral correlates of ovarian hormones and has implications for the betterment of women’s health.

Event-Related Potentials in Women on the Pill: Neural Correlates of Positive and Erotic Stimulus Processing in Oral Contraceptive Users.

Background/Aims: Exposure toward positive emotional cues with – and without – reproductive significance plays a crucial role in daily life and regarding well-being as well as mental health. While possible adverse effects of oral contraceptive (OC) use on female mental and sexual health are widely discussed, neural processing of positive emotional stimuli has not been systematically investigated in association with OC use. Considering reported effects on mood, well-being and sexual function, and proposed associations with depression, it was hypothesized that OC users showed reduced neural reactivity toward positive and erotic emotional stimuli during early as well as later stages of emotional processing and also rated these stimuli as less pleasant and less arousing compared to naturally cycling (NC) women.Method: Sixty-two female subjects (29 NC and 33 OC) were assessed at three time points across the natural menstrual cycle and corresponding time points of the OC regimen. Early (early posterior negativity, EPN) and late (late positive potential, LPP) event-related potentials in reaction to positive, erotic and neutral stimuli were collected during an Emotional Picture Stroop Paradigm (EPSP). At each appointment, subjects provided saliva samples for analysis of gonadal steroid concentration. Valence and arousal ratings were collected at the last appointment.Results: Oral contraceptive users had significantly lower endogenous estradiol and progesterone concentrations compared to NC women. No significant group differences in either subjective stimulus evaluations or neural reactivity toward positive and erotic emotional stimuli were observed. For the OC group, LPP amplitudes in reaction to erotic vs. neutral pictures differed significantly between measurement times across the OC regimen.Discussion: In this study, no evidence regarding alterations of neural reactivity toward positive and erotic stimuli in OC users compared to NC was found. Possible confounding factors and lines for future research are elaborated and discussed.

Oral contraceptives, depressive and insomnia symptoms in adult women with and without depression

BackgroundWorldwide, oral contraceptive (OC) use is a very common form of birth control, although it has been associated with symptoms of depression and insomnia. Insomnia is a risk factor for major depressive disorder (MDD) but may also be a symptom of the disorder. Despite the large number of women who use OC, it is yet unknown whether women with previous or current diagnosis of depression are more likely to experience more severe depressive and insomnia symptoms during concurrent OC use than women without diagnosis of depression. AimThis study examined associations between OC use and concurrent symptoms of depression (including atypical depression) and insomnia as well as between OC and prevalences of concurrent dysthymia and MDD. Participants were adult women with and without a history of MDD or dysthymia. We hypothesized that OC use is associated with concurrent increased severity of depressive symptoms and insomnia symptoms, as well as with an increased prevalence of concurrent diagnoses of dysthymia and MDD. We also hypothesized that a history of MDD or dysthymia moderates the relationship between OC use and depressive and insomnia symptoms. MethodsMeasurements from premenopausal adult women from the Netherlands Study of Depression and Anxiety (NESDA) were grouped, based on whether participants were using OC or naturally cycling (NC). OC use, timing and regularity of the menstrual cycle were assessed with a structured interview, self-reported symptoms of depression (including atypical depression), insomnia with validated questionnaires, and MDD and dysthymia with structured diagnostic interviews. ResultsWe included a total of 1301 measurements in women who reported OC use and 1913 measurements in NC women (mean age 35.6, 49.8% and 28.9% of measurements in women with a previous depression or current depression, respectively). Linear mixed models showed that overall, OC use was neither associated with more severe depressive symptoms (including atypical depressive symptoms), nor with higher prevalence of diagnoses of MDD or dysthymia. However, by disentangling the amalgamated overall effect, within-person estimates indicated increased depressive symptoms and depressive disorder prevalence during OC use, whereas between-person estimated indicated lower depressive symptoms and prevalence of depressive disorders. OC use was consistently associated with more severe concurrent insomnia symptoms, in the overall estimates as well as in the within-person and between-person estimates. Presence of current or previous MDD or dysthymia did not moderate the associations between OC use and depressive or insomnia symptoms. DiscussionThe study findings showed consistent associations between OC use and more severe insomnia symptoms, but no consistent associations between OC and depressive symptoms or diagnoses. Instead, post-hoc analyses showed that associations between OC and depression differed between within- and between person-estimates. This indicates that, although OC shows no associations on the overall level, some individuals might experience OC-associated mood symptoms. Our findings underscore the importance of accounting for individual differences in experiences during OC use. Furthermore, it raises new questions about mechanisms underlying associations between OC, depression and insomnia.

Friend vs. Foe: Cognitive and Affective Empathy in Women With Different Hormonal States.

Empathy is crucial for social functioning as well as social coherence. It can be influenced by modulatory factors such as familiarity and liking (i.e., emotional closeness). Furthermore, there are first hints that hormonal status may modulate affective but not cognitive empathy in women. The aim of this study was to investigate potential separate as well as combined modulatory effects of emotional closeness and hormonal status on female cognitive and affective empathy. Three hormonal status groups of women (n = 62) were studied: (1) naturally-cycling (NC) women in the early follicular phase (fNC), (2) NC women during periovulatory phase (oNC), and (3) oral contraceptive (OC) users. All women underwent a newly developed empathy task (i.e., Tübinger Empathy Test, TET) presenting textual descriptions of positive and negative emotional scenes relating to three different perspectives (i.e., self vs. friend vs. enemy/disliked person). Regardless of hormonal status, empathic responses were higher for the friend compared to the enemy perspective for both empathy components. However, cognitive empathy was less affected by varying emotional closeness toward the target person than affective empathy. Hormonal status modulated only affective empathy. OC users showed significantly less affective empathy toward the enemy compared to the fNC women. Overall, affective empathy seems more sensitive to modulatory effects of emotional closeness and hormonal status than cognitive empathy. Possible implications of this current investigation for future research on empathy and OC use, contraceptive education as well as for other clinical applications are discussed.

Effects of oral contraceptive pills on mood and magnetic resonance imaging measures of prefrontal cortical thickness.

Gonadal hormones influence neuronal organization and plasticity. Yet the consequences of altering their concentrations by administering contraceptive agents, which are used by most reproductive-age women in the United States, are unclear. Cross-sectional studies have found both larger and smaller cortical regions alongside a variety of mood alterations in women who use oral contraceptive pills (OCPs) compared to naturally-cycling women. The goal of this study, therefore, was to determine whether there is an effect of OCPs on MRI measures of prefrontal cortical brain structure that may influence regulation of mood. We performed a double-blind, placebo-controlled, randomized crossover study comparing effects of OCPs (0.15 mg levonorgestrel + 0.30 μg ethinyl estradiol) vs placebo (N = 26) on MRI measures of prefrontal cortical thickness and on mood, as indicated by self-report on the Daily Record of Severity of Problems, which also includes one item related to somatic symptoms. MRI measures that reflect cortical thickness were smaller bilaterally in the pars triangularis and in the pars opercularis and frontal pole of the right hemisphere during the OCP arm vs. placebo. Only the effect in the right pars triangularis survived multiple comparisons correction. Right pars triangularis MRI measures of cortical thickness were not related to mood symptoms, but negatively correlated across conditions with severity of somatic symptoms on the DSRP. The somatic symptoms and MRI measures may be independently related to the actions of steroid hormones in OCPs, with OCPs simultaneously inducing both more effects on MRI measures of cortical thickness and somatic symptoms.

Endogenous variation in estradiol in women affects the weighting of metric and categorical information in spatial location memory

Recent work has suggested that sex differences may exist in the strategies or types of cues that are utilized by men and women to remember discrete spatial locations or routes through a visual environment. The current study investigated the effects of circulating estradiol levels in women on the relative weighting of categorical versus fine-grained ‘metric’ information in a test of short-term memory for spatial locations, either presented within a simple geometric surround (a circular enclosure) or within more visually complex landscape scenes. Patterns of displacement error in the point location estimates made by men and women were analyzed. Results confirmed a sex difference in the weighting of metric versus categorical cues. Relative to men, women's estimates of locations were more strongly biased toward the center of the surrounding category (i.e., toward the category ‘prototype’). Furthermore, objective measures of estradiol via saliva collected at the time of memory testing showed that, among naturally-cycling women, estradiol concentrations correlated in a positive, graded, fashion with the degree of emphasis that women placed on categorical information when estimating point locations. No associations were found for progesterone. These findings are consistent with a wider body of research showing that biological sex and reproductive hormone levels, including 17β-estradiol, can subtly influence performance on certain spatial tasks. This is the first study to show that circulating estradiol levels may influence the relative emphasis placed on categorical versus metric cues when remembering simple point locations.

Relationships between ovarian hormone concentrations and mental rotations performance in naturally-cycling women

Circulating gonadal hormones have been linked to variation in the structure and function of the adult human brain, raising the question of how cognition is affected by sex hormones in adulthood. The impacts of progestogens and estrogens are of special interest due to the widespread use of hormone supplementation. Multiple studies have analyzed relationships between ovarian hormones and mental rotation performance, one of the largest known cognitive sex differences; however, results are conflicting. These discrepancies are likely due in part to modest sample sizes and reliance on self-report measures to assess menstrual cycle phase. The present study aimed to clarify the impact of progestogens and estrogens on visuospatial cognition by relating mental rotation task performance to salivary hormone concentrations. Across two studies totaling 528 naturally-cycling premenopausal women, an internal meta-analysis suggested a small, positive effect of within-subjects changes in progesterone on MRT performance (estimate = 0.44, p = 0.014), though this result should be interpreted with caution given multiple statistical analyses. Between-subjects differences and within-subject changes in estradiol did not significantly predict MRT. These results shed light on the potential cognitive effects of endogenous and exogenous hormone action, and the proximate mechanisms modulating spatial cognition.

Hormonal contraceptive use predicts decreased perseverance and therefore performance on some simple and challenging cognitive tasks

A growing body of research suggests that hormonal contraceptive (HC) use may be associated with lower self-control, as well as structural and functional differences in women's brains that could contribute to differences in perseverance on tasks requiring cognitive control. Here, we sought to extend this research by examining the relationship between HC use and college-aged women's perseverance (i.e., time spent) and performance on tasks requiring cognitive control. Across two studies, we find that, compared to naturally-cycling women, women using HCs display less perseverance on both simple (i.e., a spot-the-difference game) and challenging (i.e., Graduate Record Examination quantitative problems) tasks. Moreover, these differences in perseverance were found to predict performance decrements across tasks, with women taking HCs performing worse because they spent less time on the tasks. By demonstrating how HC use may influence perseverance and thereby performance, these results contribute to a growing body of research examining the unintended implications of HC use on cognition, learning, and memory.