**5. Oxytocin in female humans**

## **5.1. OXT and female human affiliation**

OXT levels in females rise during massage, genital stimulation, copulation, and orgasm [11, 100] which parallels the association between OXT and physical contact in men. In a study of intrapersonal couple conflict, intranasal OXT increases positive communication and decreases plasma cortisol [101]. It is suggested that OXT may facilitate pair bonding in humans, as in voles. Women with more supportive partners have increased OXT before, during, and after a 10 minute period of physical contact [75]. In contrast, OXT is positively correlated with interpersonal conflict [102, 103], but the relevance of these changes in OXT is debated [104]. This increase in OXT may be in response to the conflict and not a causal factor. Some have speculated that plasma OXT may be a reliable biomarker of distressed relationships in female humans [105]. Intranasal OXT alters the neural response to emotional faces in women, and these effects differ from the effects in males (Domes 2010). One hypothesis is that OXT increases as a mechanism to ameliorate the negative effect of the conflict on the social bond, but further manipulative studies are needed in this area.

Behavioral Roles of Oxytocin and Vasopressin 57

neural responses in brain regions association with reward, such as the ventral striatum [115]. Most notably, it has recently been reported that low plasma OXT concentrations during pregnancy are associated with an increased risk for postpartum depression. Plasma OXT concentrations in mid pregnancy significantly predicted PPD symptoms at 2 weeks postpartum [116]. Taken together, the data on OXT and maternal behavior strongly support the targeting of central OXT in the development of new treatments for maternal mood

Although plasma OXT is difficult to measure and has a high degree of variability, reduced plasma OXT has been documented in both males and females suffering from depression [117]. Changes in the variability of OXT pulses have also been reported in women with major depression [118]. Given the gender differences reported for the roles of AVP and OXT in animal studies, it is likely that there are neuroendocrine differences in the role of OXT and AVP in human depression as well. Studies of maternal humans suggest that OXT may be specifically involved in the development of postpartum mood disorders. Women with lower plasma OXT while interacting with their own infants are at an increased risk for depression due to low attachment ratings as adults and low attachment ratings for their children [115]. Cocaine addicted mothers, who are at an increased risk for postpartum mood disorders which result in impaired maternal infant attachment also have depressed plasma OXT levels [114]. Childhood trauma, which is a reliable predictor of adult depression, has been associated with decreased CSF OXT and high levels of anxiety [119, 120]. Both prior stressful events and current exposure to stress are significant predictors of postpartum depression, so the association between stress and OXT may be involved in a common mechanism for the development of postpartum mood disorders. As mentioned previously, low plasma OXT during pregnancy predicts an increased risk for postpartum depression [116] and elevated OXT in postpartum women is associated with low levels of anxiety [111]. The advantage of targeting clinical studies of OXT and depression at postpartum depression is that improvements in these patients is also beneficial to the rest of the family, and may represent a preventative target for the offspring of depressed mothers. Furthermore, there has been recent speculation that failed lactation and perinatal depression have related neuroendocrine mechanisms [121]. Failed lactation is common in depressed mothers, and in

**5.3. OXT and female human depression and anxiety** 

many cases can exacerbate symptoms of depression in mothers.

The strongest support for a role of OXT in human memory is found in studies of affiliation. Social bonds require memory related components of social recognition. It is postulated that OXT's role in bonding involves social recognition and memory mechanisms [122]. Studies from male subjects suggest that despite a potential amnesiac function of OXT in certain paradigms, central OXT may enhance social memory [123]. It is unknown whether OXT has

**5.4. OXT and female human learning and memory** 

similar effects in women.

disorders.

#### **5.2. OXT and human maternal behavior**

OXT is an important mediator of maternal-infant bonding in humans [106]. Increasing OXT during pregnancy is associated with enhanced maternal bonding [107]. Maternal behaviors such as gazing at the infant, touching, and attachment related thoughts are associated with OXT levels in both early pregnancy and postpartum periods [108]. Mothers who display high levels of affectionate contact exhibit an increase in plasma and salivary OXT, while similar increases are not exhibited by mothers displaying low levels of contact [86]. The primary importance of OXT in human maternal behavior appears to be in enhancing bonding during the first few weeks of lactation [71, 109]. Furthermore, mothers viewing images of their own infants increase brain activity in reward nuclei that contain high levels of OXT and AVP receptors [110]. In breastfeeding women, basal OXT levels are negatively correlated with anxiety and guilt [111], and plasma OXT in mothers is also associated with affectionate touch between mothers, fathers, and offspring [88]. It is concluded that OXT is an important mediator of the formation and maintenance of the family unit. Mothers that may have less efficient OXT systems display lower levels of sensitive responsiveness to their 2 year old toddlers [112]. Intranasal OXT treated mothers use less handgrip force in response to infant cry sounds, but this effect is only present in mothers who were not harshly disciplined as children [113]. One explanation for these effects is that high levels of early life discipline have developmental effects on central OXT circuits which make these individuals less responsive to exogenous OXT. In mothers who used cocaine during pregnancy, decreased OXT levels were associated with greater hostility and depressed mood, results consistent with animal studies reporting inhibitory effects of OXT on aggression. These mothers were also less likely to hold their babies, suggesting impaired bonding [114]. In a fMRI study, securely attached mothers exhibited a more robust OXT response to images of their own infants when crying and smiling, and also had increased neural responses in brain regions association with reward, such as the ventral striatum [115]. Most notably, it has recently been reported that low plasma OXT concentrations during pregnancy are associated with an increased risk for postpartum depression. Plasma OXT concentrations in mid pregnancy significantly predicted PPD symptoms at 2 weeks postpartum [116]. Taken together, the data on OXT and maternal behavior strongly support the targeting of central OXT in the development of new treatments for maternal mood disorders.

## **5.3. OXT and female human depression and anxiety**

56 Neuroendocrinology and Behavior

**5. Oxytocin in female humans** 

**5.1. OXT and female human affiliation** 

**5.2. OXT and human maternal behavior** 

OXT levels in females rise during massage, genital stimulation, copulation, and orgasm [11, 100] which parallels the association between OXT and physical contact in men. In a study of intrapersonal couple conflict, intranasal OXT increases positive communication and decreases plasma cortisol [101]. It is suggested that OXT may facilitate pair bonding in humans, as in voles. Women with more supportive partners have increased OXT before, during, and after a 10 minute period of physical contact [75]. In contrast, OXT is positively correlated with interpersonal conflict [102, 103], but the relevance of these changes in OXT is debated [104]. This increase in OXT may be in response to the conflict and not a causal factor. Some have speculated that plasma OXT may be a reliable biomarker of distressed relationships in female humans [105]. Intranasal OXT alters the neural response to emotional faces in women, and these effects differ from the effects in males (Domes 2010). One hypothesis is that OXT increases as a mechanism to ameliorate the negative effect of the

conflict on the social bond, but further manipulative studies are needed in this area.

OXT is an important mediator of maternal-infant bonding in humans [106]. Increasing OXT during pregnancy is associated with enhanced maternal bonding [107]. Maternal behaviors such as gazing at the infant, touching, and attachment related thoughts are associated with OXT levels in both early pregnancy and postpartum periods [108]. Mothers who display high levels of affectionate contact exhibit an increase in plasma and salivary OXT, while similar increases are not exhibited by mothers displaying low levels of contact [86]. The primary importance of OXT in human maternal behavior appears to be in enhancing bonding during the first few weeks of lactation [71, 109]. Furthermore, mothers viewing images of their own infants increase brain activity in reward nuclei that contain high levels of OXT and AVP receptors [110]. In breastfeeding women, basal OXT levels are negatively correlated with anxiety and guilt [111], and plasma OXT in mothers is also associated with affectionate touch between mothers, fathers, and offspring [88]. It is concluded that OXT is an important mediator of the formation and maintenance of the family unit. Mothers that may have less efficient OXT systems display lower levels of sensitive responsiveness to their 2 year old toddlers [112]. Intranasal OXT treated mothers use less handgrip force in response to infant cry sounds, but this effect is only present in mothers who were not harshly disciplined as children [113]. One explanation for these effects is that high levels of early life discipline have developmental effects on central OXT circuits which make these individuals less responsive to exogenous OXT. In mothers who used cocaine during pregnancy, decreased OXT levels were associated with greater hostility and depressed mood, results consistent with animal studies reporting inhibitory effects of OXT on aggression. These mothers were also less likely to hold their babies, suggesting impaired bonding [114]. In a fMRI study, securely attached mothers exhibited a more robust OXT response to images of their own infants when crying and smiling, and also had increased Although plasma OXT is difficult to measure and has a high degree of variability, reduced plasma OXT has been documented in both males and females suffering from depression [117]. Changes in the variability of OXT pulses have also been reported in women with major depression [118]. Given the gender differences reported for the roles of AVP and OXT in animal studies, it is likely that there are neuroendocrine differences in the role of OXT and AVP in human depression as well. Studies of maternal humans suggest that OXT may be specifically involved in the development of postpartum mood disorders. Women with lower plasma OXT while interacting with their own infants are at an increased risk for depression due to low attachment ratings as adults and low attachment ratings for their children [115]. Cocaine addicted mothers, who are at an increased risk for postpartum mood disorders which result in impaired maternal infant attachment also have depressed plasma OXT levels [114]. Childhood trauma, which is a reliable predictor of adult depression, has been associated with decreased CSF OXT and high levels of anxiety [119, 120]. Both prior stressful events and current exposure to stress are significant predictors of postpartum depression, so the association between stress and OXT may be involved in a common mechanism for the development of postpartum mood disorders. As mentioned previously, low plasma OXT during pregnancy predicts an increased risk for postpartum depression [116] and elevated OXT in postpartum women is associated with low levels of anxiety [111]. The advantage of targeting clinical studies of OXT and depression at postpartum depression is that improvements in these patients is also beneficial to the rest of the family, and may represent a preventative target for the offspring of depressed mothers. Furthermore, there has been recent speculation that failed lactation and perinatal depression have related neuroendocrine mechanisms [121]. Failed lactation is common in depressed mothers, and in many cases can exacerbate symptoms of depression in mothers.

#### **5.4. OXT and female human learning and memory**

The strongest support for a role of OXT in human memory is found in studies of affiliation. Social bonds require memory related components of social recognition. It is postulated that OXT's role in bonding involves social recognition and memory mechanisms [122]. Studies from male subjects suggest that despite a potential amnesiac function of OXT in certain paradigms, central OXT may enhance social memory [123]. It is unknown whether OXT has similar effects in women.
