Reproductive placental corticotropin-releasing hormone and its clinical implications

Abstract

The hypothalamic-pituitary-adrenal axis and the reproductive system exhibit a complex relationship in both nonpregnant and pregnant women.1,2 The hypothalamic-pituitary-adrenal axis exerts profound, mostly inhibitory, effects on the reproductive axis, with corticotropin-releasing hormone and corticotropin-releasing hormone–induced pro-opiomelanocortin peptides inhibiting hypothalamic gonadotropin-releasing hormone secretion and with glucocorticoids inhibiting pituitary luteinizing hormone and ovarian estrogen and progesterone secretion and rendering estrogen-target tissues, such as the endometrium, resistant to the gonadal steroid. Conversely, estrogen directly stimulates the hypothalamic corticotropin-releasing hormone gene, which may explain the slight hypercortisolism seen in women and the preponderance of depression, anxiety disorders, and anorexia nervosa among women.3 Interestingly, several components of the hypothalamicpituitary-adrenal axis and their receptors are present in reproductive tissues as autacoid regulators of their various functions2, 4-7 (Table I). These include ovarian and endometrial corticotropin-releasing hormone, which may participate in the regulation of steroidogenesis and the inflammatory processes of the ovary (ovulation and luteolysis) and of the endometrium (blastocyst implantation and menstruation), and placental corticotropin-releasing hormone, which is secreted mostly in the latter half of pregnancy and is responsible for the physiologic hypercortisolism seen during this period (Fig 1). Most circulating corticotropin-releasing hormone is neutralized by corticotropin-releasing hormone binding protein produced by the liver. Between weeks 34 and 35 of gestation, however, the concentrations of this protein fall by about 60%, leading to elevations of free corticotropin-releasing hormone. Subsequently plasma free corticotropin-releasing hormone concentrations rise further, to peak at labor and delivery. In addition to the hypercortisolism of pregnancy, placental corticotropin-releasing hormone causes vasodilation of the fetoplacental circulation by activating nitric oxide synthase and participates in labor by stimulating secretion of prostaglandin F2α and prostaglandin E2 by the fetal membranes and by promoting constriction of myometrial cells. Placental corticotropin-releasing hormone secretion is stimulated by glucocorticoids, inflammatory cytokines, and anoxic conditions and therefore by noninflammatory or inflammatory stress, including the stress of preeclampsia or eclampsia.2,6 Premature elevation of placental corticotropin-releasing hormone level has been associated with premature labor and birth. Potent corticotropin-releasing hormone antagonists are in the making and could be tested as labor retardants. The hypercortisolism of pregnancy is followed by a transient suppression of hypothalamic corticotropin-releasing hormone secretion in the postpartum period, which may explain the blues or depression and autoimmune phenomena seen during this period.2,7 Estrogen administration has been shown to ameliorate postpartum depression, probably by returning to normal the secretion of the suppressed corticotropin-releasing hormone neuron. From Section on Pediatric Endocrinology, Developmental Endocrinology Branch, National Institute of Child Health and Development, National Institutes of Health. Reprint requests: G. P. Chrousos, MD, Section on Pediatric Endocrinology, National Institutes of Health, Bethesda, MD 20892-1862. Am J Obstet Gynecol 1999;180:S249-50. 0002-9378/99 $8.00 + 0 6/0/90865 Table I. Reproductive corticotropin-releasing hormone and its potential physiologic functions