Biological Aspects of Postpartum Depression
Biological Aspects of Postpartum Depression
A normal pregnancy and postpartum period bring about large endocrine alterations, which represent adaptive changes in preparation for childbirth and nursing, but would be considered pathological in a nonpregnant woman. The physiological effects of these changes obviously include the suspension of ovulation and the development and growth of the uterus, the placenta and the fetus. In order to achieve this, readjustments of the maternal stress systems, immunology and metabolism are required. The changes involve hormones and neurotransmitters, which are known to have important roles in mental health and disease. Several of the hormonal alterations have been, perhaps rightfully, held responsible for impairing women's mental health during the postpartum period. However, it is important to bear in mind that this complex pattern of change obviously includes balancing elements, which do keep the majority of childbearing women in good health at a turbulent time in their lives.
A number of the endocrine changes follow a common pattern: a continuous increase in hormone plasma concentration through the 40 weeks of pregnancy, followed by a drastic drop at parturition. Estrogens, progesterone, testosterone, corticotropin-releasing hormone (CRH) and cortisol all essentially adhere to this temporal plasma profile.
The long-term continuous increase of steroid hormones requires an uncoupling of the regular negative feedback systems. This is achieved by the feto–placental unit, which produces large amounts of estrogens, progesterone and CRH – among numerous other substances – to ultimately cause its own expulsion. Instead of the negative feedback cortisol has on hypothalamic CRH production, cortisol has a positive feedback on placental CRH production. Importantly, a substantial amount of cortisol is produced by the fetal adrenal gland during the very last weeks of gestation, probably as a signal for the maturation of fetal organs, as well as for the timing of parturition. Elevated levels of placental CRH are thought to correlate with premature delivery, but also the start of labor in full-term pregnancies.
During the third trimester, maternal cortisol levels reach approximately three-times that of nonpregnant levels. While the basal levels of CRH, adrenocorticotropic hormone and cortisol are high, the acute hypothalamic–pituitary–adrenal (HPA) axis reactivity to stressful stimuli is dampened in late pregnancy. Furthermore, while the baseline cortisol levels return to normal within a couple of days after parturition, the HPA axis' hyporesponsiveness lingers in breastfeeding women.
Besides the HPA axis, the hormonal changes of pregnancy and childbirth also affects the other major stress system – the sympathetic nervous system (SNS) – in a similar manner. In the third trimester, the basal skin conductance activity is increased, while the reactivity to stress is dampened. This is further emphasized by the finding that the SNS reactivity to cold stress is lower in women with fewer days left to their actual delivery date. In the postpartum period, SNS basal activity and reactivity seem to be continuously dampened. The sympathetic tone and the sympathetic response to stress are lower in breastfeeding women compared with bottle feeding women and nonpostpartum controls.
Another approach to study psychophysiological effects of the endocrine changes during pregnancy and postpartum is measurement of the startle response, an innate reflexive twitch to sudden stimuli. In humans, the acoustic startle response is often measured by the eyeblink response to a sudden sound pulse, and can be enhanced or reduced by aversive and pleasant states, respectively, for example during viewing of emotional pictures. Studies in the present authors' laboratory have indicated a lack of effect of positively and negatively valenced pictures during both late pregnancy and 5 weeks into the postpartum period. They also detected a significant postpartum reduction in startle modulation during the anticipation of viewing emotional pictures compared with late pregnancy, which may be indicative of decreased responsivity of the autonomous defense system postpartum.
Studies on neurotransmitter adaptations inside the CNS during pregnancy are rare, primarily due to a precautionary approach to the effects of imaging techniques on the fetus. However, women undergoing elective cesarian section have lower cerebrospinal fluid (CSF) levels of GABA, as well as the norepinephrine metabolite 3-methoxy-4-phenyl glycol compared with nonpregnant women. A few imaging studies have been made at different stages of the postpartum period. For example, decreased cortical GABA concentrations in healthy women several months into the postpartum period have been demonstrated by magnetic resonance spectroscopy. PET studies have revealed significantly increased monoamine oxidase A activity (i.e., increased breakdown of serotonin, norepinephrine and dopamine) throughout all analyzed brain regions in the early postpartum period of healthy women. Studies on serum indicators of serotonergic activity in healthy women a few days after delivery strengthen the notion that the early postpartum is a state of serotonin deficiency, although the serotonergic indices seem to be restored to late pregnancy values at 6-weeks postpartum. Indirect evidence of central nervous changes also include markedly decreased maternal serum levels of BDNF, both before and after delivery, and at both time points BDNF is correlated with decreased serotonin levels.
Allopregnanolone is another neuroactive substance, which increases approximately 40-fold in serum during pregnancy. This progesterone metabolite enhances GABAA receptor signaling, and thereby has a general inhibitory effect in the brain, as evidenced by its anxiolytic and sedative properties. Based on rodent studies, it has been suggested that allopregnanolone, through upregulation of opioid signaling in the brainstem, is responsible for the reduced HPA axis activity during pregnancy. After delivery, when allopregnanolone has fallen to very low levels, the increase in brain prolactin during lactation is thought to be responsible for the withheld HPA axis suppression.
Finally, the preparation of the mammary gland for lactation is an important goal for the endocrine changes during pregnancy. Prolactin, the key lactogen, starts increasing during early pregnancy, and at term, CSF and plasma levels of prolactin in pregnant women are approximately ten-times higher than in nonpregnant women. When progesterone is withdrawn at parturition, the build-up of prolactin can induce milk production. Furthermore, plasma prolactin crosses the blood–brain barrier, is involved in the inhibition of ovulation, and is responsible for decreasing postpartum stress increases, not only in the HPA-axis activity, but also in the oxytocin system.
The posterior pituitary peptide oxytocin is responsible for the ejection of milk in response to suckling. Oxytocin levels are higher in plasma, but not in the CSF of pregnant women compared with nonpregnant women. Average plasma oxytocin does not increase from pregnancy levels in the postpartum period, although it transiently rises at nursing. On the other hand, a study on lactating rhesus macaques showed that oxytocin levels in the CSF seem to be independent of suckling, and that CSF levels and plasma levels are independent of each other. There is also evidence that oxytocin does not cross the human blood–brain barrier.
Neuropsychoendocrinology of Normal Pregnancy & the Postpartum Period
A normal pregnancy and postpartum period bring about large endocrine alterations, which represent adaptive changes in preparation for childbirth and nursing, but would be considered pathological in a nonpregnant woman. The physiological effects of these changes obviously include the suspension of ovulation and the development and growth of the uterus, the placenta and the fetus. In order to achieve this, readjustments of the maternal stress systems, immunology and metabolism are required. The changes involve hormones and neurotransmitters, which are known to have important roles in mental health and disease. Several of the hormonal alterations have been, perhaps rightfully, held responsible for impairing women's mental health during the postpartum period. However, it is important to bear in mind that this complex pattern of change obviously includes balancing elements, which do keep the majority of childbearing women in good health at a turbulent time in their lives.
A number of the endocrine changes follow a common pattern: a continuous increase in hormone plasma concentration through the 40 weeks of pregnancy, followed by a drastic drop at parturition. Estrogens, progesterone, testosterone, corticotropin-releasing hormone (CRH) and cortisol all essentially adhere to this temporal plasma profile.
The long-term continuous increase of steroid hormones requires an uncoupling of the regular negative feedback systems. This is achieved by the feto–placental unit, which produces large amounts of estrogens, progesterone and CRH – among numerous other substances – to ultimately cause its own expulsion. Instead of the negative feedback cortisol has on hypothalamic CRH production, cortisol has a positive feedback on placental CRH production. Importantly, a substantial amount of cortisol is produced by the fetal adrenal gland during the very last weeks of gestation, probably as a signal for the maturation of fetal organs, as well as for the timing of parturition. Elevated levels of placental CRH are thought to correlate with premature delivery, but also the start of labor in full-term pregnancies.
During the third trimester, maternal cortisol levels reach approximately three-times that of nonpregnant levels. While the basal levels of CRH, adrenocorticotropic hormone and cortisol are high, the acute hypothalamic–pituitary–adrenal (HPA) axis reactivity to stressful stimuli is dampened in late pregnancy. Furthermore, while the baseline cortisol levels return to normal within a couple of days after parturition, the HPA axis' hyporesponsiveness lingers in breastfeeding women.
Besides the HPA axis, the hormonal changes of pregnancy and childbirth also affects the other major stress system – the sympathetic nervous system (SNS) – in a similar manner. In the third trimester, the basal skin conductance activity is increased, while the reactivity to stress is dampened. This is further emphasized by the finding that the SNS reactivity to cold stress is lower in women with fewer days left to their actual delivery date. In the postpartum period, SNS basal activity and reactivity seem to be continuously dampened. The sympathetic tone and the sympathetic response to stress are lower in breastfeeding women compared with bottle feeding women and nonpostpartum controls.
Another approach to study psychophysiological effects of the endocrine changes during pregnancy and postpartum is measurement of the startle response, an innate reflexive twitch to sudden stimuli. In humans, the acoustic startle response is often measured by the eyeblink response to a sudden sound pulse, and can be enhanced or reduced by aversive and pleasant states, respectively, for example during viewing of emotional pictures. Studies in the present authors' laboratory have indicated a lack of effect of positively and negatively valenced pictures during both late pregnancy and 5 weeks into the postpartum period. They also detected a significant postpartum reduction in startle modulation during the anticipation of viewing emotional pictures compared with late pregnancy, which may be indicative of decreased responsivity of the autonomous defense system postpartum.
Studies on neurotransmitter adaptations inside the CNS during pregnancy are rare, primarily due to a precautionary approach to the effects of imaging techniques on the fetus. However, women undergoing elective cesarian section have lower cerebrospinal fluid (CSF) levels of GABA, as well as the norepinephrine metabolite 3-methoxy-4-phenyl glycol compared with nonpregnant women. A few imaging studies have been made at different stages of the postpartum period. For example, decreased cortical GABA concentrations in healthy women several months into the postpartum period have been demonstrated by magnetic resonance spectroscopy. PET studies have revealed significantly increased monoamine oxidase A activity (i.e., increased breakdown of serotonin, norepinephrine and dopamine) throughout all analyzed brain regions in the early postpartum period of healthy women. Studies on serum indicators of serotonergic activity in healthy women a few days after delivery strengthen the notion that the early postpartum is a state of serotonin deficiency, although the serotonergic indices seem to be restored to late pregnancy values at 6-weeks postpartum. Indirect evidence of central nervous changes also include markedly decreased maternal serum levels of BDNF, both before and after delivery, and at both time points BDNF is correlated with decreased serotonin levels.
Allopregnanolone is another neuroactive substance, which increases approximately 40-fold in serum during pregnancy. This progesterone metabolite enhances GABAA receptor signaling, and thereby has a general inhibitory effect in the brain, as evidenced by its anxiolytic and sedative properties. Based on rodent studies, it has been suggested that allopregnanolone, through upregulation of opioid signaling in the brainstem, is responsible for the reduced HPA axis activity during pregnancy. After delivery, when allopregnanolone has fallen to very low levels, the increase in brain prolactin during lactation is thought to be responsible for the withheld HPA axis suppression.
Finally, the preparation of the mammary gland for lactation is an important goal for the endocrine changes during pregnancy. Prolactin, the key lactogen, starts increasing during early pregnancy, and at term, CSF and plasma levels of prolactin in pregnant women are approximately ten-times higher than in nonpregnant women. When progesterone is withdrawn at parturition, the build-up of prolactin can induce milk production. Furthermore, plasma prolactin crosses the blood–brain barrier, is involved in the inhibition of ovulation, and is responsible for decreasing postpartum stress increases, not only in the HPA-axis activity, but also in the oxytocin system.
The posterior pituitary peptide oxytocin is responsible for the ejection of milk in response to suckling. Oxytocin levels are higher in plasma, but not in the CSF of pregnant women compared with nonpregnant women. Average plasma oxytocin does not increase from pregnancy levels in the postpartum period, although it transiently rises at nursing. On the other hand, a study on lactating rhesus macaques showed that oxytocin levels in the CSF seem to be independent of suckling, and that CSF levels and plasma levels are independent of each other. There is also evidence that oxytocin does not cross the human blood–brain barrier.
Source...