اکسی توسین و واکنش پذیری HPA استرس محور در زنان پس از زایمان

Summary Background Lactation is thought to buffer stress reactivity via oxytocin (OT). Dysregulation of the HPA axis has been reported in women with postpartum depression (PPD). The co-occurrence of PPD and lactation failure suggests that abnormalities in OT signaling may play a role in PPD. We hypothesized that abnormal OT signaling is implicated in dysregulated HPA axis reactivity among postpartum women with mood symptoms. In a prospective perinatal cohort, we tested associations between OT levels during breastfeeding and stress reactivity. Methods We recruited 52 pregnant women who intended to breastfeed, among whom 47 underwent a standardized stressor, the Trier Social Stress Test (TSST), at 8 weeks postpartum. 39 were breastfeeding at time of TSST. We assessed mood symptoms using validated instruments and defined as symptomatic women with EPDS ≥ 10 and/or Spielberger ≥ 34. Following IV placement for blood draws, women breastfed their infants and then underwent the TSST. Mothers’ hormone responses were quantified. Results Among symptomatic breastfeeding women (N = 11; asymptomatic N = 28), we found lower OT levels during breastfeeding (p < 0.05) and higher CORT levels (p < 0.05) both during breastfeeding and the TSST, as compared to asymptomatic breastfeeding women. In a mixed effects model examining CORT reactivity by symptom group and OT AUC, we observed a paradoxical response in symptomatic breastfeeding women during the TSST (group × time × OT AUC p < 0.05); higher OT AUC was associated with higher CORT. Conclusions In all breastfeeding women, the surge of OT during feeding appears to buffer subsequent stress-induced CORT secretion. However, in symptomatic breastfeeding women, we found a positive correlation between OT AUC and CORT, instead of the expected negative correlation, which we found among asymptomatic women.

Introduction Postpartum depression (PPD) and early, undesired weaning attributed to lactation dysfunction (disrupted lactation) are two common public health problems following childbirth. PPD is defined by the DSM-5 as a major depressive episode with onset beginning during pregnancy or within the first 4 weeks postpartum (American Psychiatric Association, 2013). PPD affects between 10 and 15% of all mothers and is the greatest risk factor for maternal suicide and infanticide (Lindahl et al., 2005). PPD is often accompanied by severe anxiety or ruminating thoughts (Bernstein et al., 2008 and Putnam et al., in press). It has also been shown to significantly compromise mother-infant attachment and impairs maternal implementation of recommended parenting practices that provide a safe and stimulating environment for appropriate child growth and development (Flynn et al., 2004). Breastfeeding is recommended by all major medical groups for the first year of the child's life to protect the infant from infection and development of chronic diseases; however, early, undesired weaning attributed to problems with lactation physiology remains very common in the US and has been estimated to occur in one out of eight women (Stuebe et al., 2014). In addition to increased child morbidity, early weaning also impacts maternal health, as curtailed breastfeeding is associated with higher maternal rates of ovarian and breast cancers, type 2 diabetes, hypertension and myocardial infarction (AHRQ, 2007). PPD has been associated with undesired weaning including reduced breastfeeding duration and alterations in lactation physiology (Groer and Davis, 2006, Dennis and McQueen, 2009, Figueiredo et al., 2013, Kendall-Tackett et al., 2013 and Paul et al., 2013). In a recent report that examined data from the Infant Feeding Practices II Study, early, undesired weaning was more common among women with symptoms of PPD, affecting 56% of women with depressive symptoms at 2 months postpartum, compared with 44% of women without depressive symptoms (Stuebe et al., 2014). Oxytocin (OT) is a neuroendocrine hormone that is essential for normal breastfeeding physiology, as it stimulates breast myoepithelial cell contraction, which transfers milk to the areola for the infant (Pang and Hartmann, 2007). OT has been implicated in maternal behavior and in forming and maintaining social bonds, particularly in its interaction with dopamine (Pedersen et al., 1994, Pedersen, 1997, Numan et al., 2005 and Aragona et al., 2006). In an investigation of lactating rats and maternal behavior, Shahrokh et al. demonstrated a direct effect of OT on dopamine release within the mesocorticolimibic dopamine system; OT neurons in the medial preoptic area (mPOA) were shown to regulate dopamine function in the ventral tegmental area (VTA), thereby determining the rewarding properties of a pup (Shahrokh et al., 2010). It is possible that with improper OT signaling, reward properties are altered, which could lead to changes in maternal behavior and mood. The literature is small and conflicted regarding OT abnormalities in major depression, with studies showing that OT has different effects on different individuals (Meinlschmidt and Heim, 2007, Cyranowski et al., 2008, Parker et al., 2010, Chen et al., 2011, Mah et al., 2013 and Thombs et al., 2014). Genetic variations in the OT receptor have been implicated in PPD and decreased breastfeeding duration (Jonas et al., 2013). Disruption of normal OT physiology has been linked to a dysregulated stress response and poor feeding outcomes in animal models (Lonstein and Stern, 1998). Recent work by our research group suggests that there is a relationship between symptoms of depression and anxiety and differences in OT response and effect during breastfeeding, thereby also implicating possible abnormalities in OT signaling in PPD (Stuebe et al., 2013). In addition to the possible abnormalities in OT signaling, dysregulation of the hypothalamic pituitary adrenal (HPA) stress axis, including insufficient glucocorticoid signaling and impaired feedback regulation of relevant stress response systems, has been demonstrated in women with PPD (Greenwood and Parker, 1984, Magiakou et al., 1996, Wisner and Stowe, 1997, Bloch et al., 2003, Bloch et al., 2005, Groer and Davis, 2006 and Jolley et al., 2007). For example, Jolley et al. studied postpartum women who underwent a physical stressor (maximal treadmill test) and measured mood, ACTH and cortisol (CORT) responses to the stressor. They reported a significant difference in within-subject ACTH levels predicting CORT regression slopes in postpartum women with and without depression at both 6 and 12 weeks postpartum; non-depressed postpartum patients exhibited a normal regulated feedback relationship of the HPA axis, with CORT levels rising in response to increasing levels of ACTH, while depressed postpartum patients exhibited an atypical and dysregulated pattern whereby higher levels of ACTH did not result in increased levels of CORT (Jolley et al., 2007). Prior work suggests that breastfeeding immediately before a social stressor buffers CORT response (Heinrichs et al., 2001). In male subjects, both OT and social support blunt HPA axis activation (Heinrichs et al., 2003). To date, no studies to our knowledge have quantified the relationship between the HPA axis, OT, and PPD symptoms. Thus, in the present study, we sought to assess the relationship between OT and HPA reactivity in breastfeeding women with and without postpartum depression symptoms. A well validated measurement of HPA stress reactivity is the Trier Social Stress Test (TSST), introduced by Kirschbaum et al. (1993) as a standardized protocol for inducing and studying the psychosocial stress response and dysregulation of the HPA axis in the laboratory setting (Kirschbaum et al., 1993). The TSST has been shown to reliably induce a well-characterized HPA axis response (Kudielka et al., 2007). Therefore, we administered the TSST to symptomatic and asymptomatic lactating mothers. We hypothesized that the TSST would induce a differential stress response in mothers with symptoms of depression and anxiety versus euthymic mothers. We further hypothesized that the dysregulation of HPA stress reactivity in women with PPD may reflect deficient OT signaling, which could be assessed under breast feeding-induced stimulation and which might be reflected by the loss of expected associations between OT and CORT in women with PPD symptoms.

4. Conclusions In a longitudinal, perinatal prospective cohort study, we found that both infant feeding method and maternal mood symptoms were associated with differences in response to a standardized social stressor. Compared with women who had bottle-fed their infants, women who had breastfed had lower CORT secretion and lower HR during a standardized social stressor. Of those women who breastfed, those with symptoms of anxiety and depression had significantly higher levels of CORT and higher HR during stress when compared to the asymptomatic women. Our results confirm and extend earlier work demonstrating HPA axis dysregulation in both major depressive disorder (MDD) outside of the perinatal period as well as PPD (Jolley et al., 2007). Furthermore, our results confirm earlier work indicating dysregulated patterns of OT release in men and women with MDD, with higher levels of OT associated with higher levels of CORT (Cyranowski et al., 2008 and Parker et al., 2010). Chen et al. (2011) have found that men with different OT receptor genotypes (OXTR) have a differential stress response following social support, with a particular polymorphism serving a protective effect, seen as a decrease in CORT levels. Clinical studies similarly suggest that OT may not improve mood among women with affective symptoms. In a cohort of women with symptoms of PPD, Mah et al. (2013) found that administration of intranasal OT made mothers sadder; however, these mothers described their relationship with their infant more positively. In contrast, Zelkowitz et al. (2014) found that OT was protective in women with high psychosocial stress levels; higher endogenous OT levels were associated with fewer depressive symptoms and more sensitive maternal behavior in a small cohort. These studies suggest that OT plays a critical role in maternal behavior. Further, it is possible that OT plays a role in buffering the stress response in breastfeeding women; however, this relationship appears to be disturbed in women with PPD, suggesting that dysregulation of OT secretion and/or response to OT may play a role in the pathogenesis of PPD (Heinrichs et al., 2001 and Heinrichs et al., 2003). Our results demonstrate that although breastfeeding was associated with buffering of stress-induced CORT, symptomatic breastfeeding women experienced a positive correlation between OT AUC and CORT, instead of the expected negative correlation, seen among asymptomatic women. Our findings must be interpreted within the context of our study design. We did not measure ACTH and therefore cannot determine whether OT affects CORT secretion via ACTH or via direct effects on the adrenal. In addition, because a small number of women did not breastfeed during the study visit, we were not able to analyze differences in TSST response among non-breastfeeding women by symptom group. However, the proportion of symptomatic women in the breastfeeding and non-breastfeeding groups were similar (Bottle: 3/8, 38% vs. breast 11/39, 28%, Fisher's Exact p = 0.68). Our non-breastfeeding group included women who were still lactating, although the intensity of lactation among these women was low. Prior work among euthymic, exclusively breastfeeding women found that breastfeeding immediately before the TSST has a greater impact on the HPA axis than infant contact alone ( Heinrichs et al., 2001). Further studies are needed to explore how both overall lactation intensity and affective symptoms moderate acute associations between infant contact, breastfeeding, and HPA axis response. Moreover, our sample size is relatively small, and participants had mild symptoms of depression and anxiety, limiting our power to detect differences in neuroendocrine markers. Specifically, due to the lower EPDS scores in our population, we were unable to adequately examine the effect of EPDS ≥ 10 on measures, because only two of the breastfeeding participants scored in this range. Nevertheless, we detected differences in the relationship between OT and CORT among women with higher vs. lower state anxiety. Furthermore, we did not detect any significant association between history of previous episodes of depression or anxiety and greater risk for HPA axis dysregulation, thereby decreasing the likelihood that prior histories of depression confound our results and supporting our hypothesis that current anxiety and depressive symptoms are the driving factor. Given the role of stress reactivity in the pathogenesis of depression, our data suggest that dysregulation of OT modulation of CORT response to stressors may play a role in the pathogenesis of PPD. However, we cannot determine the direction of this association in an observational study; it is also possible that PPD may lead to dysregulation of OT. We believe our study is the first to examine this relationship between lactation, OT and the HPA axis in postpartum women with depression and anxiety symptoms. In conclusion, we found that mild symptoms of depression and anxiety modify the relationship between OT and CORT response to stress during the peripartum period. While breastfeeding buffered the stress response, irrespective of mood and anxiety symptoms, the association between OT and CORT was altered in symptomatic women. Increased OT was associated with an increase – instead of the expected decrease – in CORT levels in women with mild depression and anxiety. Our findings suggest that dysregulation of OT and the HPA axis may contribute to postpartum symptoms of depression and anxiety among breastfeeding women.