Studies with animals of both sexes show that the adrenal glands release progesterone in addition to cortisol in response to stress. However, little is known about the progesterone response to stress in naturally cycling women. We investigated the effect of stress on estradiol, progesterone, and cortisol levels in women during the follicular phase of the menstrual cycle. We found that physical stress (the cold pressor test) had no effect on estradiol levels, but increased progesterone and cortisol. We also found positive correlations between baseline progesterone and cortisol levels, as well as between the change in progesterone and cortisol before and after water exposure in both the stress and control sessions. Mediation analyses revealed during the stress session, the change in progesterone from baseline to 42-min post-stress onset was mediated by the magnitude of change in cortisol levels across the same time span. Overall, these findings reveal that progesterone released in response to stress as observed in animals and men extends to women during the low ovarian output follicular phase of the menstrual cycle, and that the mechanism of release may be similar to the mechanism of cortisol release.

We present evidence suggesting ET may protect certain types of cognition in the presence of stress. Such estrogenic protection against stress hormone exposure may prove beneficial to both cognition and the neural circuitry that maintains and propagates cognitive faculties.

Menopause involves dramatic declines in estradiol production and levels. Importantly, estradiol and the class of stress hormones known as glucocorticoids exert countervailing effects throughout the body, with estradiol exerting positive effects on the brain and cognition, glucocorticoids exerting negative effects on the brain and cognition, and estradiol able to mitigate negative effects of glucocorticoids. Although the effects of these hormones in isolation have been extensively studied, the effects of estradiol on the stress response and the neuroprotection offered against glucocorticoid exposure in humans are less well known. Here we review evidence suggesting that estradiol-related protection against glucocorticoids mitigates stress-induced interference with cognitive processes. Animal and human research indicates that estradiol-related mitigation of glucocorticoid damage and interference is one benefit of estradiol supplementation during peri-menopause or soon after menopause. The evidence for estradiol-related protection against glucocorticoids suggests that maintaining estradiol levels in post-menopausal women could protect them from stress-induced declines in neural and cognitive integrity.

Across three different domains, there are similar sex differences in how men and women process information. There tends to be a male advantage in attending to and remembering the gist (essential central information of a scene or situation), but a female advantage in attending to and remembering the details (non-essential peripheral information of a scene or situation). This is seen in emotional memory, where emotion enhances gist memory more for males than for females, but enhances detail memory more for females than for males. It also occurs in spatial memory, where men tend to notice and remember the gist of where they or objects are in space, allowing them to more flexibly manipulate themselves or objects within that space, whereas women tend to recall the details of the space around them, allowing them to accurately remember the locations of objects. Finally, such sex differences have also been noted in perception of stimuli such that men attend to global aspects of stimuli (such as a large letter E) more than women, whereas women attend more to the local aspects (such as the many smaller letter Ts making up the E). We review the parallel sex differences seen across these domains in this paper and how they relate to the different brain systems involved in each of these task domains. In addition, we discuss how sex differences in evolutionary pressures and in the locus coeruleus and norepinephrine system may account for why parallel sex differences occur across these different task domains.

Background: The current pilot study was designed to examine the association between hippocampal γ-aminobutyric acid (GABA) concentration and episodic memory in older individuals, as well as the impact of two major risk factors for Alzheimer’s disease (AD)—female sex and Apolipoprotein ε4 (ApoE ε4) genotype—on this relationship.Methods: Twenty healthy, community-dwelling individuals aged 50–71 (11 women) took part in the study. Episodic memory was evaluated using a Directed Forgetting task, and GABA+ was measured in the right hippocampus using a Mescher-Garwood point-resolved magnetic resonance spectroscopy (MRS) sequence. Multiple linear regression models were used to quantify the relationship between episodic memory, GABA+, ApoE ɛ4, and sex, controlling for age and education.Results: While GABA+ did not interact with ApoE ɛ4 carrier status to influence episodic memory (p = 0.757), the relationship between GABA+ and episodic memory was moderated by sex: lower GABA+ predicted worse memory in women such that, for each standard deviation decrease in GABA+ concentration, memory scores were reduced by 11% (p = 0.001).Conclusions: This pilot study suggests that sex, but not ApoE ɛ4 genotype, moderates the relationship between hippocampal GABA+ and episodic memory, such that women with lower GABA+ concentration show worse memory performance. These findings, which must be interpreted with caution given the small sample size, may serve as a starting point for larger studies using multimodal neuroimaging to understand the contributions of GABA metabolism to age-related memory decline.