The neuroendocrine system in pregnancy involves highly complex maternal, fetal, and placental mechanisms, which are critical for the maintenance of pregnancy, the timing of parturition, fetal growth, and protection from adverse fetal programming. The brain and placenta are both central organs in the responses to stress, and the maternal, fetal, and placental hypothalamus-pituitary-adrenal (HPA) axes play a significant role in controlling some of the adaptive mechanisms during pregnancy. The secretion of maternal and fetal HPA axis hormones increases throughout pregnancy. Corticotropin-releasing hormone (CRH) represents the main regulator of the axis as, when released from the hypothalamus, it stimulates adrenocorticotropic hormone (ACTH) release from the anterior pituitary and consequently cortisol secretion from the adrenal cortex. However, the major source of maternal circulating CRH in human pregnancy is the placenta. Indeed, the placenta, may be considered a neuroendocrine organ rich in neurohormones, neuropeptides, and neurosteroids. Stress-related hormones, such as CRH, urocortins, oxytocin, and prolactin, are key placental neuroendocrine factors mediating both endocrine (metabolism, immune function, cardiovascular changes) and paracrine (uterine contractility, local hormone production) mechanisms involved in term and pre-term birth. Aberrations in neurohormones secretion, as an adaptive response of the feto-placental unit to adverse environmental conditions, may contribute to the development of gestational disorders, such as hypertensive disorders of pregnancy, intrauterine growth restriction, and gestational diabetes.

The Developmental Origins of Health and Disease (DOHaD), also termed developmental programming, refers to adaptations during development that predispose an individual or a population towards later life noncommunicable disease (NCD) conditions or chronic diseases. The developmental trajectory of an individual is determined broadly by the interaction between that individual’s genes and the environment. “Environment” in this sense may include maternal or paternal factors, influences such as nutritional status before or during pregnancy, stress and exposure to contaminants, drugs or alcohol; and maternal diseases of pregnancy that influence transport of substrates and nutrients across the placenta (e.g., preeclampsia, placental insufficiency); and pre-term birth; factors that occur before or around the time of conception, during gestation or in the period after birth; the so-called First 1,000 Days. The interactions between genes and environment determine not only the developmental processes of the fetus and placenta leading to short term morbidity (low birth weight) and mortality, but also long term morbidity of multiple systems including neurodevelopmental disorders such as learning difficulties, poor developmental trajectories and cognitive development, mental health and behavioral disorders in children, and metabolic disorders such as obesity and diabetes. In later life, developmental programming contributes to heart disease such as hypertension and coronary heart disease, type II diabetes, obesity, immune, behavioral, and neurological disorders.

The mechanisms underlying developmental programming can result from structural changes in tissues or organs, effects on germ cells or stem cells, alterations in the microbiome, or in core inflammatory and immunological processes. There are clear sex differences in these responses, strong intergenerational effects, and variable vulnerability across the life course. Many adjustments occur as adaptive fetal responses to adversity or stress, such as hypoxemia or inappropriate nutrient supply, to ensure survival. The placenta plays a critical role in developmental programming, both in regulating the impact of maternal influences on the fetus, and through its direct impact on fetal development.

Introduction

The human placenta and its accessory membranes (amnion and chorion) actually undertake the role of intermediary barriers and source(s) of active messengers in the maternal—fetal dialog. In the past decades, an accelerated progress in the understanding of physiological roles and of pathological influences of the placenta and other gestational intrauterine tissues (fetal membranes and deciduae) has occurred. These organs and tissues produce brain, pituitary, gonadal and adrenocortical hormones (Petraglia et al., 1990b; 1996d; Petraglia, 1991; Reis et al., 2001; 2002), chemically identical and as biologically active as their hypothalamic/gonadal counterparts and, when added to placental cell cultures, they modulate the release of both pituitary-like peptide hormones and gonadal/adrenal cortex-like steroid hormones. Thus, the intraplacental mechanism of control of hormone secretion resembles in many aspects the organization of hypothalamus—pituitary—target organ axes. Under this perspective, the human placenta may be considered as a neuroendocrine organ, since its secretion of substances analogous to neurohormones, neuropeptides, neurosteroids and monoamines (Table 1.1) have endocrine, paracrine and autocrine function (Petraglia et al., 1996d).

Physiological functions of these placental secretions include:

1. to maintain an equilibrium between the fetus and the mother;

2. to provide a favorable uterine environment at implantation;

3. to regulate fetal growth during pregnancy;

4. to direct the appropriate signals for the timing of parturition.