Alterations in the hypothalamic pituitary adrenal axis during pregnancy and the placental clock that determines the length of parturition1

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Abstract

Although corticotrophin releasing hormone (CRH) was initially identified as a hypothalamic peptide it is also synthesised in the placenta and secreted into both the maternal and fetal circulation. The presence of large molecular weight forms in the placenta suggest that secretion may be constitutive rather that regulated. Placental CRH is bioactive but causes only modest increases in ACTH and cortisol in the pregnant woman because of agonist induced desensitisation of pituitary CRH receptors. CRH concentrations increase exponentially in maternal plasma as gestation advances. Elevated concentrations, compared with gestational age matched controls, occur in patients in preterm labour. The exponential curve describing the CRH increase is shifted to the left in women who will subsequently deliver preterm and to the right in women who will deliver post dates indicating that CRH is linked to a placental clock which determines the length of gestation. Maternal plasma CRH concentrations may be useful in identifying women at high risk of preterm delivery and CRH antagonists may prevent preterm labour. As significant CRH production by the placenta is restricted to primates future research must take into account the species specificity of the mechanisms regulating parturition.

Section snippets

Placental secretion of corticotrophin releasing hormone

Corticotrophin releasing hormone (CRH) was first identified by Wylie Vale's group in 1981 (Vale et al., 1981). The peptide was localised to the hypothalamus and identified through its ability to stimulate ACTH released from the anterior pituitary. However, in 1982 CRH was identified within the human placenta and 2 years later high concentrations were reported in the plasma of women in the third trimester of pregnancy (Sasaki et al., 1987). Initial studies performed in our laboratory on extracts

The effect of placental CRH on the maternal pituitary

Early studies on CRH within the pregnant woman focused on whether the peptide would influence the maternal hypothalamic pituitary adrenal axis. Several groups have played a part in these investigations, including those of Robin Goland of Columbia Medical School in New York, Felice Petraglia from the University of Moderna, and several others. Our own studies demonstrated that a significant increase in plasma β-endorphin occurs as pregnancy advances but the increase, although statistically

Maternal CRH linkage to a biological clock determines the length of pregnancy

The dramatic increase in CRH concentrations in the pregnant woman's plasma during gestation prompted several groups to explore clinical correlates. Phil Lowry's group in Reading, UK, and their collaborators demonstrated that women in preterm labour had high concentrations of maternal plasma CRH compared to gestational aged matched controls (Wolfe et al., 1988). Similar results were reported by Robin Goland's group. At about the same time, Stalla's group in Germany reported that women with high

The action of placental CRH in both mother and fetus

How might CRH exert its actions to initiate parturition? CRH is secreted both into the maternal and the fetal circulations. In the maternal circulation CRH has potential access to the myometrium. CRH receptors have been identified within the myometrium and several groups have reported that CRH is able to potentiate the action of uterotonics (PGF2α and oxytocin) (Quartero et al., 1989, Benedetto et al., 1994). More recently Hillhouse's group in Warwick, UK, have demonstrated that late in

Regulation of placental CRH production

Glucocorticoids are not the only factors which have been shown to regulate CRH release, the gas nitric oxide has also been shown to have potent inhibitory actions on CRH release on syncytiotrophoblasts in vitro. Sun Kang of the Secondary Military Medical College, Shanghai, Peoples Republic of China, working within our own unit has demonstrated that sodium nitro-prusside inhibits CRH release from cultured placental cells and that this effect is mediated by inhibition of guanylate cyclase (Sun et

Animal models for studying placental CRH

Our more recent studies have focused on identifying a suitable animal model to explore the physiological roles of CRH during primate pregnancy. Our laboratory and that of Dr Golands have described the changes in CRH during baboon pregnancy and have found intriguing similarities and differences between baboons and humans (Smith et al., 1993). Whilst CRH production increases during the baboon pregnancy, it peaks during the second trimester and then falls in contrast to the pure exponential

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1

Paper presented at the workshop on Paracrine Mechanisms in Female Reproduction, Seville, Spain, June 1997.

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