The role of sex hormones, oral contraceptive use, and its parameters on visuospatial abilities, verbal fluency, and verbal memory.

Sex hormones can cross the blood-brain barrier and access brain regions underlying higher-order cognition. Containing synthetic sex hormones, oral contraceptives (OC) have been found to modulate visuospatial and verbal abilities, though inconsistencies have been found in the literature. Among possible explanations, certain OC use parameters (progestin androgenicity, synthetic hormone levels, duration of use) have not received consistent consideration. Thus, the objectives were to (1) examine group differences between men, combined OC users, and naturally cycling women (NC women; not using OC) in visuospatial abilities, verbal fluency, and verbal memory and (2) investigate the contribution of endogenous and exogenous sex hormones on these effects. We also aimed to (3) identify OC use parameters relevant to cognitive outcomes. In total, 70 combined OC users, 53 early follicular (EF) women, 43 pre-ovulatory (PO) women, and 47 men underwent cognitive tests. Performance was compared based on hormonal milieus (OC, EF, PO, men) and OC users' contraceptive androgenicity (anti, low, high). Correlations between performance, hormone levels and OC use duration were also conducted. OC use dampened the sex difference that typically favors men in 3D visuospatial abilities, whereas its duration of use positively predicted verbal fluency. Androgenicity and hormone levels did not predict performance in any task. These results highlight the importance of considering OC use duration. Results also did not support a role for androgenicity in cognition. Importantly, combined OC use (including prolonged use) does not impair visuospatial, verbal, and memory functions in a healthy young sample.

Morphologic alterations of the fear circuitry: the role of sex hormones and oral contraceptives.

Background: Endogenous sex hormones and oral contraceptives (OCs) have been shown to influence key regions implicated in fear processing. While OC use has been found to impact brain morphology, methodological challenges remain to be addressed, such as avoiding selection bias between OC users and non-users, as well as examining potential lasting effects of OC intake. Objective: We investigated the current and lasting effects of OC use, as well as the interplay between the current hormonal milieu and history of hormonal contraception use on structural correlates of the fear circuitry. We also examined the role of endogenous and exogenous sex hormones within this network. Methods: We recruited healthy adults aged 23-35 who identified as women currently using (n = 62) or having used (n = 37) solely combined OCs, women who never used any hormonal contraceptives (n = 40), or men (n = 41). Salivary endogenous sex hormones and current users' salivary ethinyl estradiol (EE) were assessed using liquid chromatography - tandem mass spectrometry. Using structural magnetic resonance imaging, we extracted surface-based gray matter volumes (GMVs) and cortical thickness (CT) for regions of interest of the fear circuitry. Exploratory whole-brain analyses were conducted with surface-based and voxel-based morphometry methods. Results: Compared to men, all three groups of women exhibited a larger GMV of the dorsal anterior cingulate cortex, while only current users showed a thinner ventromedial prefrontal cortex. Irrespective of the menstrual cycle phase, never users exhibited a thicker right anterior insular cortex than past users. While associations with endogenous sex hormones remain unclear, we showed that EE dosage in current users had a greater influence on brain anatomy compared to salivary EE levels and progestin androgenicity, with lower doses being associated with smaller cortical GMVs. Discussion: Our results highlight a sex difference for the dorsal anterior cingulate cortex GMV (a fear-promoting region), as well as a reduced CT of the ventromedial prefrontal cortex (a fear-inhibiting region) specific to current OC use. Precisely, this finding was driven by lower EE doses. These findings may represent structural vulnerabilities to anxiety and stress-related disorders. We showed little evidence of durable anatomical effects, suggesting that OC intake can (reversibly) affect fear-related brain morphology.

A Year Through the COVID-19 Pandemic: Deleterious Impact of Hormonal Contraception on Psychological Distress in Women.

Background: Women are more at risk than men of suffering from psychological distress during disease outbreaks. Interestingly, no biological factors have been studied to explain this disparity in such contexts. Sex hormone variations induced by hormonal contraceptives (HC) have been associated with mental health vulnerabilities. However, most studies have examined current effects of HC without considering whether a chronic modulation of sex hormone levels could induce long-lasting effects that persist after HC cessation. Objectives: To date, the role of HC on psychological health in women during a disease outbreak is still unknown. We aimed to investigate both current and long-term effects of HC on psychological distress throughout the COVID-19 pandemic. Method: At four time points during the COVID-19 pandemic (June 2020, September 2020, December 2020, March 2021), we collected self-reported data on psychological distress, assessing symptoms of post-traumatic stress [via the Impact of Event Scale-Revised (IES-R)], symptoms of depression, anxiety, and stress [via the Depression Anxiety Stress Scales (DASS-21)]. Linear mixed models were first used to compare men (n = 49), naturally cycling women (n = 73), and women using HC (n = 32) across time. To examine long-lasting effects of HC, exploratory analyses were restricted to women, comparing current HC users (n = 32), past users (n = 56), and never users (n = 17). Results: The first model revealed that women taking HC reported stable post-traumatic stress symptoms across time, compared to naturally cycling women and men who showed a significant decrease from T1 to T2. HC users also reported greater DASS-21 total scores over time. Moreover, HC users reported higher stress and anxiety symptoms than men. In the second model, results showed that past HC users had similar anxiety levels as current HC users. These two groups reported significantly more anxiety symptoms than never users. Conclusion: HC users report increased distress during the pandemic relative to naturally cycling women and men. Our results also suggest a long-lasting effect of HC intake, highlighting the importance of considering both the current use of HC and its history. This could provide some insight into potential avenues for explaining why some women are prone to higher psychological distress than men.

Exploring the sex and gender correlates of cognitive sex differences.

The correlates of cognitive sex differences are yet to be fully understood. Many biological and psychosocial factors modulate these cognitive abilities leading to mixed results in the scientific literature. The current study aims to explore the different parameters potentially influencing cognitive abilities acting in synergy. Sex and gender correlates of cognitive functioning were assessed in a sample of individuals ages 18 to 45 years (N = 87) from diverse sexual orientations. Sex hormones were assessed via saliva samples at four timepoints throughout the testing. Gender roles, sexual orientation and socio-demographics were measured via self-report questionnaires. Participants completed mental rotation and verbal fluency tasks. Men performed better than women at mental rotation, while no significant difference was found for verbal fluency. Significant positive associations were observed between estradiol and word fluency for the naturally cycling women compared to the women using oral contraception. While controlling for sex hormones, a significant interaction effect of sex by gender roles was identified for mental rotation among masculine women. These exploratory results suggest an effect principally driven by sex and sex hormones on cognitive performance that will need to be furthered with larger studies.

Vicarious conditioned fear acquisition and extinction in child-parent dyads.

The biological mechanisms involved in fear transmission within families have been scarcely investigated in humans. Here we studied (1) how children acquired conditioned fear from observing their parent, or a stranger, being exposed to a fear conditioning paradigm, and (2) the subsequent fear extinction process in these children. Eighty-three child-parent dyads were recruited. The parent was filmed while undergoing a conditioning procedure where one cue was paired with a shock (CS + Parent) and one was not (CS -). Children (8 to 12 years old) watched this video and a video of an adult stranger who underwent conditioning with a different cue reinforced (CS + Stranger). Children were then exposed to all cues (no shocks were delivered) while skin conductance responses (SCR) were recorded. Children exhibited higher SCR to the CS + Parent and CS + Stranger relative to the CS -. Physiological synchronization between the child's SCR during observational learning and the parent's SCR during the actual process of fear conditioning predicted higher SCR for the child to the CS + Parent. Our data suggest that children acquire fear vicariously and this can be measured physiologically. These data lay the foundation to examine observational fear learning mechanisms that might contribute to fear and anxiety disorders transmission in clinically affected families.

A review on how stress modulates fear conditioning: Let's not forget the role of sex and sex hormones.

Stress and fear are two fields of research that have evolved simultaneously. It was not until the eighties that these domains converged in order to better characterize the impact of stress on fear memory formation. Here, we reviewed the effects of stress occurring before fear acquisition on the main phases of fear conditioning protocols (acquisition training, extinction training, extinction retention test), with a specific focus on sex and sex hormones. We also paid close attention to methodological aspects in order to better understand and characterize discrepant findings across studies. In men, stress appears to potentiate fear acquisition at a physiological level but induces lower activations of fear-related brain regions. In women, results are inconsistent. Although some studies have shown that stress lowers physiological fear responses and heightens brain activations in women during fear acquisition, many studies report no significant effects. Irrespective of sex, pre-acquisition stress seems to induce fear extinction learning resistance. Overall, few studies have taken into account sex hormones, despite their impact on both the fear and stress brain networks. As methodological variability makes it complex to draw strong conclusions, several methodological aspects are discussed with the aim of orienting future research.