Abstract
In response to stress corticotropin releasing hormone (CRH) is secreted from the hypothalamus and travels to the anterior pituitary where it stimulates the release of proteins derived from the precursor protein, proopiomelanocortin (POMC), including adrenocorticotropic hormone (ACTH) and β-endorphin. β-endorphin interacts with opioid receptors and relieves stress while ACTH travels through the blood stream to the adrenal cortex where it stimulates the release of cortisol. Cortisols actions include releasing glucose from stored glycogen and stimulating breakdown of fat from adipose tissue, induction of gluconeogenesis and modulation of the immune system. As a negative feedback control, cortisol inhibits CRH release from the hypothalamus and ACTH from the anterior pituitary. During pregnancy the placenta synthesizes and secretes CRH into the systemic circulation causing a dramatic increase in the circulating levels of CRH throughout pregnancy that peaks at delivery and unlike the situation in the hypothalamus, cortisol has a positive effect on placental CRH production. While the CRH binding protein (CRH-BP) may attenuate the action of placental CRH on the pregnant womans pituitary, there is evidence that the CRH-BP does not completely cut off access of placental CRH to the pituitary. For example, CRH-BP levels decrease in late pregnancy lowering the ability to decrease CRH activity. In late pregnancy when circulating CRH levels rise dramatically and superimpose over falling levels of the CRH-BP, the anterior pituitary may desensitize to placental CRH so that ACTH and cortisol levels do not become pathologically elevated. In non-pregnant individuals, disturbances in the hypothalamic CRH - pituitary ACTH axis are associated with mood disturbances and in pregnant women who have elevated CRH levels during pregnancy an association with prenatal depression has been shown. More work needs to be done to investigate the possible roles of CRH in pregnancy related depression. Besides effects on the pituitary, placental CRH may exert physiological regulation on the uterus. Higher than normal levels of CRH in mid-pregnancy are associated with preterm pregnancy suggesting a role for CRH in the timing of parturition. In preterm pregnancy when the uterus has to be kept quiescent, CRH receptors are coupled to various cell signaling systems including the cyclic AMP system that inhibits myosin light chain phosphorylation in smooth muscle thereby dampening uterine contraction. As the time for labour approaches, CRH receptors may alter coupling to cellular signaling systems that phosphorylate myosin light chain and initiate rhythmic contraction of the uterus. The possibility of using modulators of CRH action such as CRH receptor agonists to correct pathological conditions in the expectant mother provides a powerful motivation for future studies to fully elucidate the roles of CRH in pregnancy.
Keywords: Corticotrophin releasing hormone (CRH), CRH binding protein (CRH-BP), CRH receptors, placenta, uterus, pregnancy, depression
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