Sex differences precipitating anorexia nervosa in females: The estrogen paradox and a novel framework for targeting sex-specific neurocircuits and behavior

In anorexia nervosa (AN), reward contamination likely plays a significant role in maintenance of the illness. Reward contamination is a context in which patients' behaviors of self-starvation and excessive exercise, while initially rewarding, become aversive, even punishing; but patients may not recognize the punishing and conflicted/contaminated behaviors. An emerging neurocircuit encompassing the anterior cingulate cortex (ACC) has been functionally linked to symptoms including reward contamination and body dysmorphic processing. Owing to the significantly greater prevalence of AN in females, evidence from clinical literature and preclinical models is spearheaded to provide a novel rationale for estrogen triggering sensitivity to the experience of stress and reward, precipitating AN disproportionately in females at the time of puberty. Paradoxically, however, estrogen may facilitate response to pharmacological interventions and (desensitization of the identified neurocircuits) via its contribution to serotonin modulation, hypothalamo-pituitary adrenal (HPA)-axis attenuation, and effects on dopamine