A central theory of preterm and term labor: Putative role for corticotropin-releasing hormone☆,☆☆

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Abstract

Near the end of human pregnancy the concentration of placental corticotropin-releasing hormone in maternal blood rises exponentially. The rate of elevation of corticotropin-releasing hormone and its duration through time have been linked to the time of onset of labor. Paradoxically, although glucocorticoids are known to inhibit corticotropin-releasing hormone production within the hypothalamic-pituitary-adrenal axis, cortisol actually increases corticotropin-releasing hormone levels in several areas outside the hypothalamus, including the placenta. Placental corticotropin-releasing hormone may be an important component of a system that controls the normal maturation of the fetus and signals the initiation of labor. Abnormal elevations in corticotropin-releasing hormone, which may be a hormonal response to stressors arising in either the mother, placenta, or fetus, may prove to participate in the premature onset of parturition. (Am J Obstet Gynecol 1999;180:S232-41.)

Section snippets

Discovery of corticotropin-releasing hormone in human placenta

Corticotropin-releasing hormone was first isolated from the sheep hypothalamus by Vale et al16 in 1981. A major regulator of the hypothalamic-pituitary-adrenal axis, it was named for its ability to stimulate the release of adrenocorticotropic hormone (ACTH) by the pituitary gland. Corticotropin-releasing hormone was subsequently discovered in extrahypothalamic sites, including the human placenta,5, 6, 7, 8, 9 where it was found to have the same structure and bioactivity as hypothalamic

Role of corticotropin-releasing hormone in normal gestation

In the human placenta, corticotropin-releasing hormone is produced exclusively in synchiotrophoblasts29 ; it is only after cytothrophoblasts fuse into synchiotrophoblasts that corticotropin-releasing hormone is expressed and secreted into both maternal and fetal circulations. Levels climb much higher in the maternal than in the fetal circulation, in which the upper limit of concentration is in the 300 pg/mL range. One model that explains the simultaneous rise in corticotropin-releasing hormone

Corticotropin-releasing hormone and the timing of parturition

The human fetal pituitary system develops early in gestation and begins to monitor levels of fetal cortisol at 7 to 8 weeks’ gestation, responding to low cortisol levels by secreting ACTH. This is best demonstrated in fetuses with enzymatic blocks in cortisol synthesis (congenital adrenal hyperplasia); their systems compensate by increasing the synthesis of all steroids, including androgens, proximal to the enzymatic block, resulting in the virilization of female fetuses by 8 to 10 weeks’

Role of corticotropin-releasing hormone in preterm labor

From this hypothetic framework of corticotropin-releasing hormone’s role in normal parturition, it is relatively easy to conjecture its involvement in preterm delivery. Much of the groundwork has already been laid, in the sense that several clinical researchers have demonstrated an association between abnormal or early elevation in corticotropin-releasing hormone levels and preterm labor.40, 50, 51, 52, 53, 54 Maternal plasma corticotropin-releasing hormone concentrations are also elevated in

The mind-body link

Corticotropin-releasing hormone is the molecule of adversity in both the brain and the placenta, and corticotropin-releasing hormone and glucocorticoids are the primary hormones implicated in an arousal pathology involving the chronic and exaggerated anticipation of negative events.67, 68 Corticotropin-releasing hormone production is stimulated rather than inhibited by cortisol in the central region of the central nucleus of the amygdala and the lateral bed nucleus of the stria terminalis.19, 20

Concept of a placental clock

A prospective longitudinal study involving nearly 500 women showed that corticotropin-releasing hormone concentrations measured at 16 to 20 weeks’ gestation could predict term, preterm, or postterm birth.40 Another study, although failing to demonstrate a correlation between abnormal corticotropin-releasing hormone elevations and preterm delivery, did show a negative correlation between corticotropin-releasing hormone binding protein values and gestational age in patients who eventually were

Comment

Without a precursor for estradiol synthesis, the human placenta could not produce the large amounts of this steroid necessary to maintain pregnancy and ultimately signal parturition. It is therefore hypothesized that the presence and differential regulation of corticotropin-releasing hormone in the placenta constitute a positive feedback loop involving the placenta and the fetal adrenal, the purpose of which is to produce estradiol through another route (by stimulating steroidogenesis in the

References (71)

  • WB Warren et al.

    Elevated maternal plasma corticotropin-releasing hormone levels in pregnancies complicated by preterm labor

    Am J Obstet Gynecol

    (1992)
  • RS Goland et al.

    The effect of pre-eclampsia on human placental corticotropin-releasing hormone content and processing

    Placenta

    (1995)
  • WB Warren et al.

    Corticotropin-releasing hormone and pituitary-adrenal hormones in pregnancies complicated by chronic hypertension

    Am J Obstet Gynecol

    (1995)
  • CA Van Meir et al.

    Immunoreactive 15-hydroxyprostaglandin dehydrogenase (PDGH) is reduced in fetal membranes from patients at preterm delivery in the presence of infection

    Placenta

    (1996)
  • DJ Dudley

    Immunoendocrinology of preterm labor: the link between corticotropin-releasing hormone and inflammation

    Am J Obstet Gynecol

    (1999)
  • SA Jones et al.

    Local stimulation of prostaglandin production by corticotropin-releasing hormone in human fetal membranes and placenta

    Biochem Biophys Res Comm

    (1989)
  • J Schulkin et al.

    Allostasis, amygdala, and anticipatory angst

    Neurosci Biobehav Rev

    (1994)
  • GS Berkowitz et al.

    Corticotropin-releasing factor and its binding protein: maternal serum levels in term and preterm deliveries

    Am J Obstet Gynecol

    (1996)
  • MJ Novy et al.

    New perspectives on the prevention of extreme prematurity

    Clin Obstet Gynecol

    (1995)
  • CJ Lockwood

    Recent advances in elucidating the pathogenesis of preterm delivery, the detection of patients at risk, and preventative therapies

    Curr Opin Obstet Gynecol

    (1994)
  • NC Vamvakopoulos et al.

    Hormonal regulation of human corticotropin-releasing hormone gene expression: implications for the stress response and immune/inflammatory reaction

    Endocr Rev

    (1994)
  • GP Chrousos et al.

    The concepts of stress and stress system disorders: overview of physical and behaviorial homeostasis

    JAMA

    (1992)
  • T Shibasaki et al.

    Corticotropin-releasing factor–like activity in human placental extracts

    J Clin Endocrinol Metab

    (1982)
  • A Sasaki et al.

    Immunoreactive corticotropin-releasing factor is present in human maternal plasma during the third trimester of pregnancy

    J Clin Endocrinol Metab

    (1984)
  • RS Goland et al.

    High levels of corticotropin-releasing hormone immunoactivity in maternal and fetal plasma during pregnancy

    J Clin Endocrinol Metab

    (1986)
  • A Sasaki et al.

    Immunoreactive corticotropin-releasing hormone in human plasma during pregnancy, labor, and delivery

    J Clin Endocrinol Metab

    (1987)
  • EA Campbell et al.

    Plasma corticotropin-releasing hormone concentrations during pregnancy and parturition

    J Clin Endocrinol Metab

    (1987)
  • A Sasaki et al.

    Isolation and characterization of a corticotropin-releasing hormone-like peptide from human placenta

    J Clin Endocrinol Metab

    (1988)
  • ME Bowman et al.

    Corticotrophin-releasing hormone in ape pregnancy [abstract OR35-4]

  • RL Emanuel et al.

    Corticotropin-releasing hormone levels in human plasma and amniotic fluid during gestation

    Clin Endocrinol

    (1994)
  • W Vale et al.

    Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin

    Science

    (1981)
  • BG Robinson et al.

    Glucocorticoid stimulates expression of corticotropin-releasing hormone gene in human placenta

    Proc Natl Acad Sci U S A

    (1988)
  • SA Jones et al.

    Steroids modulate corticotropin-releasing hormone production in human fetal membranes and placenta

    J Clin Endocrinol Metab

    (1989)
  • LW Swanson et al.

    Differential steroid hormones and neural influences on peptide mRNA levels in CRH cells of the paraventricular nucleus: a hybridization histochemical study in the rat

    J Comp Neurol

    (1989)
  • AG Watts et al.

    Region specific regulation of neuropeptide mRNAs in rat limbic forebrain neurons by aldo-sterone and corticosterone

    J Physiol

    (1995)

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    ☆

    Reprint requests: Joseph Majzoub, MD, Division of Endocrinology, Children’s Hospital, Harvard Medical School, 300 Longwood Ave, Boston, MA 02115.

    ☆☆

    0002-9378/99 $8.00 + 0 6/0/91057

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