It comes as no surprise to Roger Smith, M.B.B.S., Ph.D., that birth timing would be under hormonal control.
“I’m a hormone specialist,” says the director of the Mothers and Babies Research Centre Endocrine Unit at John Hunter Hospital in Newcastle, Australia. “I think everything has to do with hormones.”
Smith and his colleagues have been tailing reproductive hormones for more than two decades. In 1995, they reported in Nature Medicine that corticotropin-releasing hormone (CRH) is produced by a “placental clock” that controls the length of human pregnancy.
CRH was originally characterized as part of the body’s stress-response system. It is secreted in the brain to stimulate the release of corticotropin (ACTH) from the pituitary in the brain. That ACTH, in turn, prompts the adrenal gland to produce the “stress hormone” cortisol and other steroids.
But during pregnancy, the placenta also produces CRH and releases it into the maternal and fetal circulation.
Smith and his colleagues measured concentrations of CRH and CRH-binding protein in serial blood samples obtained from 485 pregnant women during the second and third trimesters. CRH, they found, was detectable in the maternal circulation from early in the second trimester; it rose exponentially (the concentration increased faster and faster) as pregnancy progressed; and its pattern of increase tracked with birth timing.
“If CRH goes up more rapidly than usual, then the woman is likely to deliver prematurely,” Smith explains. “If it goes up more slowly than usual, she’s likely to deliver late.”
This kind of rapid increase in CRH concentrations requires what’s called a “feed-forward system,” Smith says. CRH acts on the pituitary to prompt the release of ACTH, which stimulates cortisol production by the adrenal glands. The cortisol stimulates more CRH production by the placenta. And so on.
For births that occur at term, the investigators believe that the exponential increase is a function of normal placental growth: more placental cells make more CRH and push the feed-forward system into action. A stressor to the mother or baby – such as nutritional status, infection and social stressors – would increase production of the stress hormone cortisol and ramp up CRH production too early, resulting in premature birth.
Other investigators have confirmed the changes in CRH that track with birth timing. But a lingering question, Smith says, has been “how does CRH lead to the onset of labor?” Now he thinks his team has an answer.
The investigators followed 500 pregnant women from the first prenatal visit to birth, obtaining maternal blood samples at approximately monthly intervals. They measured levels of CRH, progesterone, and two estrogens – estradiol and estriol.
They reported a strong correlation between CRH and estriol levels in the last month of pregnancy in the June 2009 issue of the Journal of Clinical Endocrinology and Metabolism. The idea, Smith says, is that placental CRH stimulates the fetal adrenal gland to make a steroid hormone called DHEAS, which is the precursor for the placental production of estriol.
Interestingly, the ratios of the hormones – and the pattern of change in the ratios – mattered more than the absolute levels of the hormones.
They found that the ratio of estriol to estradiol increases dramatically as birth nears, which allows estriol to work (at lower ratios, estradiol blocks estriol’s actions). Estriol action turns on proteins in the uterine muscle, including cyclooxgenase-2, which produces prostaglandins that prompt muscle cell contraction, and connexin-43, a protein that allows the individual muscle cells to link together in order to generate contractile “waves.”
“With the turning up of these two proteins, you have the two critical events you need: a stimulus for the muscle cells to fire and a system for linking them together to create high contractile pressure,” Smith says.
“I think we’ve uncovered the trigger to the onset of labor – the rising level of estriol at the end of pregnancy. It’s pretty exciting.”
The findings open the possibility of new interventions – such as estriol to bring on labor, or estradiol to delay it.
“Such a thing would have been unthinkable before,” Smith says.
Ultimately, Smith and his colleagues would like to develop computational tools that can predict preterm birth based on patterns of blood hormone levels.
It’s also critical “to understand more about what stresses babies” and could speed up the CRH-triggered clock, he says. Here, it’s important to educate women – for example about proper nutrition at the time of conception, pregnancy spacing and risks like smoking.
“I think the education of women is the most important way of reducing perinatal mortality and improving the health not only of women themselves, but of their children,” Smith says. “I can’t think of anything more important.”