Neurobehavioral Risk Is Associated With Gestational Exposure to Stress Hormones

Curt A Sandman; Elysia Pogg Davis

Expert Rev Endocrinol Metab. 2012;7(4):445-459.

Endocrine Risk

The human placenta integrates numerous sources of maternal stress signals, including cortisol, and responds with a dose-dependent release of placental CRH. The surge in placental CRH is produced by syncytial cells (which can be created in vitro by fusion of purified cytotrophoblast cells).^[49] As described above, there is a positive or feed-forward loop between maternal cortisol and placental CRH, in contrast to the negative-feedback system controlling hypothalamic CRH synthesis and release. The positive relationship between cortisol and CRH release from the placenta is similar to the stimulating effect of cortisol on the amygdala release of CRH.^[56] In placental tissue, glucocorticoids stimulate CRH gene expression by interacting with proteins that bind to the cAMP response site of the CRH promoter.^[57]

Evidence suggests that the normal trajectory of placental CRH production over the course of gestation may be accelerated by an adverse intrauterine environment characterized by physiological stress. For example, elevated placental CRH has been observed in pregnancies complicated by preeclampsia, reduced utero–placental perfusion, intrauterine infection and in cases where fetal distress has led to elective preterm delivery.^[58] A series of in vitro studies have shown that CRH is released from cultured human placental cells in a dose-response manner in response to all the major biological effectors of stress, including cortisol, catecholamines and proinflammatory cytokines.^[49,59,60] The authors have in vivo evidence in humans that elevated levels of maternal cortisol early in gestation are associated with a more rapid rise in placental CRH concentrations.^[15] Not only is placental CRH responsive to stress-related increases in maternal cortisol, but the administration of synthetic glucocorticoids for fetal lung maturation in pregnant women at risk for preterm delivery is similarly associated with significant increases in circulating placental CRH. Placental CRH concentrations increase by 1.5-fold within 12 h in response to the administration of synthetic glucocorticoids, such as betamethasone.^[61,62]

The placental detection of stress or adversity results in a rapid rise in CRH and primes or advances the 'placental clock' and begins the cascade of events influencing myometria^[54] and in extreme cases, precipitating preterm birth. Moreover, placental CRH has been shown to increase the placental production of estrogens and to inhibit the synthesis of progesterone.^[63,64] Placental CRH is additionally released into the fetal compartment, where it stimulates the fetal adrenal to release dehydroepiandrosterone sulfate, an obligate precursor for placental estriol production.^[65] Alterations in the production of progesterone and estriol may be one pathway by which placental CRH regulates the timing of delivery.^[66]

There is evidence that it is the trajectory of placental CRH and other hormone production over gestation, rather than their absolute concentrations, that best predicts preterm delivery, suggesting that target cells are highly responsive to relative changes in circulating concentrations. The effects of HPA and placental axis hormones on gestational length are modulated further by the activities of binding proteins and enzymes. For example, concurrent with increases in circulating levels of placental CRH, a CRH-binding protein (CRH-BP) is produced in the liver and also in the trophoblast and intrauterine tissues during pregnancy, and binds to circulating CRH, reducing its biological action.^[67–69] In contrast to the increasing levels of circulating placental CRH over the course of gestation, CRH-BP levels are constant in the first, second and early third trimester (and are not significantly different from nonpregnant levels), but fall by approximately 30% as birth approaches.^[70] The consequence of these changes in the levels of CRH and CRH-BP is a large increase of free and bioactive CRH during the last part of gestation. Maternal plasma cortisol-binding globulin (CBG) levels also increase progressively with advancing gestation until the end of gestation, when there is a significant decline in CBG leading to an increase in bioactive cortisol.^[71] Moreover, levels of placental 11β-HSD2 (which oxidizes cortisol into its inactive form, cortisone) also increase as gestation progresses before falling abruptly near term (Figure 3).^[72] The decrease in CBG and the decrease in the activity of placental 11β-HSD2 toward the end of gestation increase fetal exposure to maternal cortisol, ensuring maturation of the fetal lungs, CNS and other organ systems in full-term births.^[73,74] These exposures to elevated cortisol toward the end of gestation are normative and necessary for fetal maturation. Excessive exposures such as in the case of maternal stress or synthetic glucocorticoid treatment, however, are detrimental. Maternal stress may result in fetal exposure to excess cortisol both by increasing cortisol production and downregulating the activity of 11β-HSD2.^[75]

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Figure 3.

The regulation of the hypothalamic–pituitary–adrenal axis changes dramatically over the course of gestation. Uniquely during primate pregnancy, cortisol stimulates the synthesis and release of placental corticotrophin-releasing hormone. These two hormones are important stress signals that can influence the timing of birth and alter the neurological development of the fetus.A: Adrenal gland; ACTH: Adrenocorticotropic hormone;CRH: Corticotrophin-releasing hormone; H: Hypothalamus;P: Pituitary gland; pCRH: Placental corticotrophin-releasing hormone.

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Box 1. Changes in the body associated with the fight or flight response.
Heart rate and blood pressure increase. The heart pump rate increases from 1 to 5 gallons per minute, arteries constrict to maximize pressure and veins open out to ease return of blood to the heart Veins in skin constrict to send more blood to major muscle groups. Pupils dilate to take in as much light as possible to improve vision Hairs stand on end, making us more sensitive to the environment Fat from fatty cells and glucose from the liver are metabolized to create instant energy Muscles tense up, energized by adrenaline and glucose Smooth muscles relax to allow more oxygen into the lungs Lungs, throat and nostrils open up and breathing speeds up to get more air into the system, so blood flow can be reoxygenated. The blood carries oxygen to the muscles, allowing them to work harder Blood vessels to the kidney and digestive system are constricted, effectively shutting down systems that are not essential. Shunted blood is directed to muscles and limbs to provide energy for fight or flight Reduction of saliva in the mouth The bowels and bladder may open to reduce the need for other internal actions Blood vessels to the skin are constricted to reduce potential blood loss Sweat glands are opened to provide an external cooling Stress hormones are released

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Key issues

The developmental origins of disease or fetal programming model predict that early exposures to threat or adverse conditions have lifelong consequences that result in poor health outcomes.
The basic premise of the fetal programming model of disease is that developing organisms play an active role in their own construction.
A remarkable surveillance and response system has evolved so that the human fetus can detect threats to survival and adjust its developmental trajectory.
The adaptive 'fight or flight' system is dramatically altered during pregnancy, including the massive changes in the endocrine system characterized by the doubling in size of the pituitary gland and the growth and development of the placenta, which becomes an active endocrine organ.
Stress hormones increase adaptively over the course of human pregnancy; however, abnormal elevations can increase the risk for adverse birth outcomes and other health risks.
The consequences of exposure to stress hormones for the developing fetus are determined by the timetable for fetal organogenesis, vast changes in maternal stress physiology across gestation and changes in placental physiology.
A prospective, longitudinal research program has provided evidence that exposures to stress hormones have neurological consequences for the fetus, neonate, infant and child. The effects are observed in emotional and cognitive regulation and in distinctive patterns of brain structure.
Male and female fetuses respond differently to gestational stress exposures. Female fetuses are more likely to alter their developmental trajectory in response to moderate stressors and thus are better able to survive subsequent stress.
The fetal period in the life cycle is unmatched by any other in growth and development, and it is the period in the human lifespan that is most vulnerable to both organizing and disorganizing influences. It is anticipated that studies of the human fetus and the health consequences of exposures to markers of stress will become an area of intense research.
The predictive adaptive response is an alternative to the programming model. The premise is that health risk is associated with the match between fetal and infant/child exposures rather than just exposures to adversity. It is assumed that developing organisms accurately preparing for future environments will thrive even if the future is hostile.

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Neurobehavioral Risk Is Associated With Gestational Exposure to Stress Hormones

Endocrine Risk

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Authors and Disclosures

Authors and Disclosures

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Key issues

Figure 3.

Figure 3.

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