PPD occurs up to 4 weeks following parturition according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria and follows a dramatic drop in the circulating levels of estradiol (E2) and progesterone (P4). Although depression risk is not predicted by serum levels of gonadal hormones in humans,9 rapid withdrawal from these hormones appears to be an important factor in establishing PPD. In an important experiment, women with a previous history of PPD subjected to supraphysiological doses of E2 and P4 experienced significantly depressed mood symptoms relative to controls upon hormone withdrawal,10,11 suggesting that the at-risk population exhibits a predisposition to PPD through unknown mechanisms that is triggered by gonadal hormone withdrawal. DNA methylation may represent the link between estrogen and its effects on mood. Indeed, it has previously been demonstrated that E2 administration in vitro can modify DNA methylation at multiple locations downstream of an estrogen-response element.12
