Hormonal treatment increases the response of the reward system at the menopause transition: A counterbalanced randomized placebo-controlled fMRI study

Preclinical research using rodent models demonstrated that estrogens play neuroprotective effects if they are administered during a critical period near the time of cessation of ovarian function. In women, a number of controversial epidemiological studies reported that a neuroprotective effect of estradiol may be obtained on cognition and mood-related disorders if hormone therapy (HT) begins early at the beginning of menopause. Yet, little is known about the modulatory effects of early HT administration on brain activation near menopause. Here, we investigated whether HT, initiated early during the menopause transition, increases the response of the reward system, a key brain circuit involved in motivation and hedonic behavior. We used fMRI and a counterbalanced, double-blind, randomized and crossover placebo-controlled design to investigate whether sequential 17β-estradiol plus oral progesterone modulate reward-related brain activity. Each woman was scanned twice while presented with images of slot machines, once after receiving HT and once under placebo. The fMRI results demonstrate that HT, relative to placebo, increased the response of the striatum and ventromedial prefrontal cortex, two areas that have been shown to be respectively involved during reward anticipation and at the time of reward delivery. Our neuroimaging results bridge the gap between animal studies and human epidemiological studies of HT on cognition. These findings establish a neurobiological foundation for understanding the neurofunctional impact of early HT initiation on reward processing at the menopause transition.