Effects of Sex Steroid Manipulation on Irritability in Women with a History of Postpartum Depression

Sex steroid changes interact with antecedent vulnerability to trigger irritability in women. Here we present data from three pharmaco-fMRI studies investigating the effects of experimentally controlled reproductive steroid exposure on irritability. In Study 1, the hormone states of pregnancy and parturition were simulated in women with a history of postpartum depression (PPD; n=15) and controls (n=15) by inducing hypogonadism, adding back supraphysiologic doses of estradiol (E2) and progesterone (P4) for 8 weeks, and then withdrawing both steroids. fMRI was conducted during baseline and withdrawal. In Study 2, the same hormone protocol was employed in PPD (n=10) and controls (n=12) with a truncated addback period of 2 weeks. In Study 3, women who participated in Study 1 were treated with E2 and P4 for 1 week in double-blind, placebo-controlled crossover design. In Study 1, 11/15 of PPD participants were “hormone sensitive” (HS+) (i.e., showed 30% increased mood symptoms during addback or withdrawal). HS+ experienced irritability within one week of starting addback (p<.001). During withdrawal, irritability was associated with reduced activity in supramarginal gyrus (r=-.536, p<.005). In Study 2, 8/10 of PPD participants were HS+, which was characterized by increased irritability during hormone addback (p<.05). In Study 3, the 1-week hormone protocol provoked irritability in the same individuals as the extended protocol used in Study 1 (p<.001). Findings support the role of sex steroids in perinatal-onset irritability, which may be mediated by reduced activity in the supramarginal gyrus.