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The potential influence of maternal stress hormones on development and mental health of the offspring

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Abstract

Recent studies in humans suggest that alterations in the activity of the neuroendocrine system mediate the effects of psychosocial stress on fetal development and birth outcome. Chronic maternal distress compromises the normal regulation of hormonal activity during pregnancy and elevates free circulating corticotrophin-releasing hormone (CRH), probably of placental origin, before the normal increase occurs at term. Excess CRH, and other hormones like cortisol and met-enkephalin that pass through the placenta, could precipitate preterm labor, reduce birth weight and slow growth rate in prenatally stressed infants. CRH and/or cortisol have also been associated with impaired fetal habituation to stimuli and temperamental difficulties in infants. These changes may result from actions of the hormones on their receptors in the fetal limbic system. In the rat, gestational stress and excess maternal and fetal plasma corticosterone cause downregulation of fetal glucocorticoid (GR) and mineralocorticoid (MR) receptors and impair the feedback regulation of the hypothalamic–pituitary adrenal (HPA) axis in infancy and adulthood. The impairment in HPA axis activity can be prevented by maternal adrenalectomy and mimicked by administration of glucocorticoids. Gestational stress also increases CRH activity in the amygdala and the incidence of anxiogenic and depressive-like behavior in rats and non-human primates, which can be ameliorated by CRH antagonists. Excess amounts of CRH and cortisol reaching the human fetal brain during periods of chronic maternal stress could alter personality and predispose to attention deficits and depressive illness through changes in neurotransmitter activity.

Introduction

It is becoming increasingly clear that an interaction between genes and environment determines the functional development of an organism. Because of its rapid growth, the fetus is particularly vulnerable to insults and the attendant changes in its hormonal milieu. The rate of growth is in turn a predictor of developmental outcome. This has led to the suggestion that adverse life situations experienced by the pregnant mother and her reactions to them can induce alterations in the fetal environment and result in deleterious effects on the rate of development, mental and physical health of the child (Maccari et al., 2003, Wadhwa et al., 2001, Weinstock, 2001). The incidence of preterm birth (before 37th week) is increased together with lower birth weight (less than 2.5 kg) (Hedegaard et al., 1993, Hedegaard et al., 1996, Rondo et al., 2003, Ruiz et al., 2002, Stein et al., 1987, Wadhwa et al., 1993). There is also a slower rate of development of walking, speech, toilet training, and attainment of other milestones (Meijer, 1986, Stott, 1973). In turn, low birth weight and preterm delivery have been associated with long-term developmental impairments and motor disabilities (Knoches and Doyle, 1993).

There have also been a number of reports linking maternal stress or antenatal anxiety to the appearance of emotional problems, hyperactivity, and attention deficits (Clements, 1992, Linnet et al., 2003, Minde et al., 1968, O’Connor et al., 2003) and Tourette’s syndrome (Leckman et al., 1990) in children. In the adult, antenatal stress particularly during mid-gestation has been associated with a higher incidence of schizophrenia (Hultman et al., 1999, Imamura et al., 1999, Van Os and Selten, 1998), depression and drug abuse (Huttunen and Niskanen, 1978, Watson et al., 1999). In these retrospective studies, a causal role of prenatal stress was inferred from interviews with the mothers or answers to questionnaires filled in by them. It was not possible to relate the outcome in the offspring directly to maternal stress since most studies did not control for attendant confounding factors such as concomitant illness, smoking or drug intake (Lobel, 1994). Thus, any direct support for a detrimental effect of prenatal stress on offspring development and behavior has come from experiments in rodents and non-human primates, in which it is easier to control for genetic factors, timing of stress, parity, and the maternal pre- and postnatal environment (Maccari et al., 2003, Weinstock, 1997, Weinstock, 2001). These experimental data have provided a possible hormonal basis for the behavioral alterations induced by maternal stress and have led to the measurement of circulating hormones in pregnant women with high levels of perceived stress during the second and early third trimester. At the same time, more attention has been paid to confounding factors in experimental design and their role in the overall effect on offspring development (Hobel et al., 1999, Wadhwa et al., 1998).

Detailed descriptions of the neuroanatomical and behavioral changes induced by prenatal stress in humans and experimental animals have appeared in previous reviews (Weinstock, 1997, Weinstock, 2001). These have included the factors other than alterations in hormone levels in both the mother and fetus, like autonomic nervous system activity and its influence on placental blood flow that also contribute to changes in the offspring. Evidence in support of a role of glucocorticoids in the development of schizophrenia has been reviewed recently (Koenig et al., 2002). The purpose of the current review is to focus on the similarities and differences in the hormonal changes induced in humans and rodents by gestational stress. It will also discuss critically the evidence that maternal stress hormones influence the regulation of the hypothalamic–pituitary adrenal (HPA) axis and hormone production in the fetus and ultimately, the mental and physical development of the offspring.

Section snippets

Organization of the stress response in the adult organism

Stress is defined as a state that threatens or is perceived by the individual to threaten his physiological equilibrium. Such a state results in activation of appropriate central nervous and peripheral systems to prepare the individual for the appropriate responses. In general, the stress response is designed to be of a limited duration and the resulting changes in hormone and neurotransmitter activity are rapidly restored to pre-stress levels within minutes or a few hours. However, when stress

Hormonal regulation during gestation (human and experimental animals)

During gestation in primates and rodents, several changes occur in the regulation of the neuroendocrine system designed to protect the developing fetus and ensure successful delivery. These include mechanisms for suppressing the response to stress of the HPA axis, which have so far only been demonstrated in rodents (Neumann, 2003), and plasma binding proteins that prevent the activity of circulating CRH and of glucocorticoids. In humans and some species of apes the placenta releases CRH and

Hormonal responses to acute stress in pregnant mother and fetus

Relatively few studies in human subjects have measured changes in both maternal and fetal hormone levels in response to acute stress. The invasive stress of piercing the fetal abdomen was found to increase levels of cortisol, β-endorphin and NA in the fetal but not in the maternal blood (Giannakoulopoulos et al., 1994, Gitau et al., 2001). Circulating β-endorphin was also increased in the fetus by anoxia (Ruth et al., 1986). This showed that the hormonal changes in the fetus probably do not

Hormonal response to stress in pregnant animals and their fetuses

The placenta of humans and some species of apes are unique in their ability to synthesize CRH which could mediate some of the effects of maternal stress on fetal growth and neuronal development. That may be the reason why significant reductions in the length of gestation and birth weight in rats were only seen in relatively few studies in rats, and those were usually associated with reduced maternal food intake (Weinstock, 1997, Weinstock, 2001). Severe maternal stress was even reported to

Effect of prenatal stress or excess steroid exposure on programming of fetal HPA axis

The pioneering work of Thompson (1957) showed that maternal psychological stress in rats could affect the behavior of the offspring and prompted several authors to relate these changes to increases in circulating maternal stress hormones. This was accomplished by manipulating the output from the adrenal gland of the stressed rat by adrenalectomy (Smith et al., 1975) and hormone replacement, or by the administration of stress hormones during gestation and comparing their effects with those that

Alterations in activity of CRH in developing brain as a result of maternal or early life stress (human)

A number of anecdotal reports have linked an increased incidence of anxiety and depressive disorders in young adults to high levels of stress experienced by their mothers during pregnancy (Watson et al., 1999). These alterations in behavior could have resulted from increased activity of CRH in the neocortex and central nucleus of the amygdala, two areas that are involved in emotional processing (Owens and Nemeroff, 1991), and/or as a result of impaired regulation of the HPA axis induced by

Conclusions

During pregnancy in rats the response of the HPA axis to acute stress is of a smaller magnitude than that in non-pregnant animals, probably because of an increased feedback through higher circulating cortisol. Even if there is no increased inhibitory activity on the HPA axis in human pregnancy, glucocorticoids arising in the maternal blood are largely prevented from reaching the fetus through inactivation by placental 11βHSD or by binding to CBG. However, as a result of chronic maternal stress,

Uncited reference

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