These hormones, in addition to their reproductive functions, have been shown to exhibit potent neuroregulatory effects on a range of nonreproductive behaviors including mood and cognition.37 With the discovery of the estrogen receptor in 1962 by Jensen and Jacobson, a roadmap emerged for the cellular actions of steroid hormones.37,38 Moreover, beginning with the

work of Phoenix et al in 1959, there has been evidence to suggest that perinatal manipulation of reproductive steroids may have long-term consequences on brain sensitivity to these to steroids postpuberty.37,39 Inhibitors,research,lifescience,medical These two pieces of animal model evidence laid the early framework which implicated hormonal dysregulation in vulnerable or susceptible women as part of the underlying pathogenesis of perinatal depression. More recent work by Block

et al demonstrates that, despite normal CHIR99021 FDA levels of reproductive hormones, women with PPD have an abnormal response to changes in reproductive Inhibitors,research,lifescience,medical steroid levels (estrogen and progesterone).40 Additionally, there is increasing evidence that abnormalities in HPA axis activity play a key role in the etiology of both MDD as well as PPD.41-45 Estrogen and progesterone have profound interactions with the HPA Inhibitors,research,lifescience,medical axis and may therefore trigger the HPA axis abnormalities in susceptible women. Striking hormonal changes take place in the transition from pregnancy to the postpartum period.46 The third trimester of pregnancy is characterized by high estrogen and progesterone levels and a hyperactive HPA axis (normal during pregnancy) with Inhibitors,research,lifescience,medical high plasma cortisol47 which is stimulated in part by the high levels of estrogen and progesterone.44 At the time of childbirth and during the transition

to the postpartum period, estrogen and progesterone rapidly decline, and there is blunted HPA axis activity due to suppressed hypothalamic corticotrophin-releasing hormone (CRH) secretion.43 Inhibitors,research,lifescience,medical The suppression may be due to the length of time it takes for the hypertropic adrenal cortexes (due to the hyperstimulated state during pregnancy), to progressively downsize and gradually return to normal.43 As in nonpuerperal MDD, the HPA axis appears disturbed in women with PPD. Furthermore, although the trigger for PPD is likely heritable, Drug_discovery the human and animal literature suggest that the onset of PPD is determined by the contributions of both genetics and life events.48,49 Thus, it is important to briefly review the normal functioning of the HPA axis and how this differs in depressed (non-PPD) patients as compared with women with PPD. In a normal HPA axis, the delivery of CRH from the paraventricular nucleus of the hypothalamus triggers the stimulation of adrenocorticotropic hormone (ACTH) from the anterior pituitary and, sellekchem consequently, cortisol from the adrenal cortex.