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The Influence of Menstrual Cycle and Androstadienone on Female Stress Reactions: An fMRI Study


The Influence of Menstrual Cycle and Androstadienone on Female Stress Reactions: An fMRI Study

Ka Chun Chung et al. Front Hum Neurosci.

Erratum in


Communicating threats and stress via biological signaling is common in animals. In humans, androstadienone (ANDR), a synthetic male steroid, is a socially relevant chemosignal exhibited to increase positive mood and cortisol levels specifically in (periovulatory) females in positively arousing contexts. In a negative context, we expected that such effects of ANDR could amplify social evaluative threat depending on the stress sensitivity, which differs between menstrual cycle phases. Therefore, this fMRI study aimed to examine psychosocial stress reactions on behavioral, hormonal and neural levels in 31 naturally cycling females, between 15 early follicular (EF) and 16 mid-luteal (ML) females tested with ANDR and placebo treatment in a repeated-measures design. Regardless of odor stimulation, psychosocial stress (i.e., mental arithmetic task with social evaluative threat) led to elevated negative mood and anxiety in all females. A negative association of social threat related amygdala activation and competence ratings appeared in ML-females, indicating enhanced threat processing by ANDR, particularly in ML-females who felt less competent early in the stress experience. Further, ML-females showed reduced performance and stronger stress-related hippocampus activation compared to EF-females under ANDR. Hippocampal activation in ML-females also correlated positively with post-stress subjective stress. Contrarily, such patterns were not observed in EF-females or under placebo in either group. Strikingly, unlike passive emotional processing, ANDR in a stressful context decreased cortisol concentration in all females. This points to a more complex interaction of ovarian/gonadal hormones in social threat processing and stress reactivity. Our findings suggest that ANDR enhanced initial evaluation of self-related social threat in ML-females. Female stress reactions are related to stress sensitivity through enhanced awareness and processing of social cues in a stressful context, with menstrual cycle phase being a critical factor.

Keywords: amygdala; cortisol; hippocampus; menstrual cycle; social threat; stress.


Timeline of the paradigm of each testing day: patch application order of androstadienone (ANDR) and placebo (PLAC) were randomized for all females. To ensure ANDR to take effect, a 7 min resting state was performed before the stress task. There were two blocks of the stress paradigm, and experimenters gave negative feedback between the two blocks. Between each condition in each block, a 6–8 s jittered fixation cross was presented.
Mean and standard error of (A) total responses of all participants (n = 31) illustrating the treatment-by-feedback interaction and (B) correct performance of early follicular (EF, n = 15) and mid-luteal (ML; n = 16) group depicting the treatment-by-group interaction. ∗∗Significant difference at p ≤ 0.01; ∗∗∗Significant difference at p ≤ 0.001.
(A) Peak activation coordinate of amygdala left (–19, –6, –17), right (24, 3, –21); (B) Mean parameter estimates extracted from the peak voxel of left and right amygdala depicting the main effect of condition, and (C) Main effect of feedback; (D) Scatterplot of the correlation of activation of right amygdala during stress experience in the pre-FB block and competence rating at T1 in ML-females treated with ANDR. Data represents mean and standard error. ∗∗Significant difference at p ≤ 0.01; ∗∗∗Significant difference at p ≤ 0.001.
(A) Peak activation coordinate of left (–22, –38, –4) and right (21, –38, –4) hippocampus; (B) Mean parameter estimates extracted from the peak voxel of left and right hippocampus depicting the laterality-by-feedback interaction, and (C) Treatment-by-group interaction; (D) Positive correlation between increase in negative mood (T2-T1) and activation of the hippocampus during post-FB stress experience in ML-females treated with ANDR. Data represents mean and standard error. Significant difference at p ≤ 0.05.

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