Menstrual cycle phase modulates reward-related neural function in women

Abstract

There is considerable evidence from animal studies that the mesolimbic and mesocortical dopamine systems are sensitive to circulating gonadal steroid hormones. Less is known about the influence of estrogen and progesterone on the human reward system. To investigate this directly, we used functional MRI and an event-related monetary reward paradigm to study women with a repeated-measures, counterbalanced design across the menstrual cycle. Here we show that during the midfollicular phase (days 4-8 after onset of menses) women anticipating uncertain rewards activated the orbitofrontal cortex and amygdala more than during the luteal phase (6-10 days after luteinizing hormone surge). At the time of reward delivery, women in the follicular phase activated the midbrain, striatum, and left fronto-polar cortex more than during the luteal phase. These data demonstrate augmented reactivity of the reward system in women during the midfollicular phase when estrogen is unopposed by progesterone. Moreover, investigation of between-sex differences revealed that men activated ventral putamen more than women during anticipation of uncertain rewards, whereas women more strongly activated the anterior medial prefrontal cortex at the time of reward delivery. Correlation between brain activity and gonadal steroid levels also revealed that the amygdalo-hippocampal complex was positively correlated with estradiol level, regardless of menstrual cycle phase. Together, our findings provide evidence of neurofunctional modulation of the reward system by gonadal steroid hormones in humans and establish a neurobiological foundation for understanding their impact on vulnerability to drug abuse, neuropsychiatric diseases with differential expression across males and females, and hormonally mediated mood disorders.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Serum steroid hormone levels. Shown are mean estradiol (Left; in pg/ml) and progesterone (Right; in ng/ml) levels during the follicular and luteal phases. Estradiol and progesterone levels were both higher during the luteal phase than during the follicular phase.

Fig. 2.

Cross-menstrual cycle phase differences in BOLD response during anticipation of uncertain rewards. (A) Statistical maps overlaid onto structural MRI showing BOLD fMRI responses greater in follicular phase than in luteal phase in the right amygdala (Upper) and orbitofrontal cortex (Lower). To the right of each map is shown distributions of BOLD signal response for each woman. (B) Greater right dorsolateral prefrontal cortex activity in the luteal phase compared with the follicular phase.

Fig. 3.

Cross-menstrual cycle phase differences in BOLD response at the time of reward outcome. (Left) Greater BOLD response during follicular phase than during luteal phase in midbrain, left amygdala, heads of the caudate nuclei, left inferior frontal gyrus, and left fronto-polar cortex. (Right) Greater BOLD response during luteal phase than during follicular phase was observed in the left intraparietal region and the inferior-temporal cortex.

Fig. 4.

Between-sex differences in brain activity. (Upper) During anticipation of uncertain rewards. Statistical maps showing greater right hippocampal and left middle frontal gyrus activity in women than in men (Left) whereas men showed greater activation (Right) in bilateral ventral striatum. (Lower) At the time of reward delivery. Women showed more activation in anterior medial prefrontal cortex and subgenual gyrus compared with men (Left), who, in turn, showed more activation in a bilateral fronto-parietal network, the right inferior temporal cortex, and the supplementary motor area (Right).

Fig. 5.

Statistical maps of regression analyses between brain activity and estradiol level during the follicular phase of the menstrual cycle. (Left) During anticipation of uncertain rewards. Estradiol level correlated positively with activity of the bilateral amygdalo-hippocampal complex (a) and negatively with activity of the hypothalamus (b). (Right) At the time of rewarded outcome relative to no reward. Estradiol level correlated positively with activity of the bilateral dorsolateral (a) and fronto-polar (b) cortices.

Fig. 6.

Regression analysis between brain activity and estradiol/progesterone levels during the luteal phase of the menstrual cycle. (Upper) During anticipation of uncertain rewards, progesterone level correlated positively with activity of the bilateral amygdalo-hippocampal complex and putamen. (Lower) Interactions between the effects of estradiol and progesterone levels on brain activity in the posterior orbitofrontal, anterior cingulate, and fronto-polar cortices, and amygdala at the time of the rewarded outcome. The graphs show such interactions in the right amygdala.