**9. Cortisol and glucocorticoids; is it just stress in pregnancy?**

The secretion of cortisol levels during pregnancy is regulated by the placenta, which, by secreting the corticotropin-releasing hormone (CRH), produces an exponential increase in cortisol from the eighth week of gestation up to three times above systemic values [5, 36]. It is present in both the maternal and fetal phases but at different levels; under normal conditions, cortisol levels reach 200 ng/ml at the end of pregnancy, while fetal levels range from around 20 ng/ml [37]. These differences are due to the presence of a natural barrier that prevents maternal cortisol, whose molecular composition can cross the placenta, quickly reaches fetal space [38, 39].

This barrier corresponds to the uterus/fetus interface and is mainly composed of maternal decidua and fetal placenta chorion. Here the regulation of cortisol is carried out through placental glycoprotein P, as well as the enzyme 11-β-hydroxysteroid-dehydrogenase (11-β-HSD) type 2 of trophoblastic and fetal cells, which inactivates cortisol by converting it into cortisone to avoid exposure of the fetus to high levels of cortisol [37, 40]. However, because of its role in organ maturation and labor, fetal cortisol increases towards the end of pregnancy by several mechanisms: a) decrease of 11-β-HSD type 2 in fetal tissues, b) increased synthesis of cortisol by the fetal adrenal gland, and c) increased 11-β-HSD type 1 in fetal tissues, which converts cortisone, into active cortisol [41].

As for the functions of cortisol during pregnancy, glucocorticoids (GC) have been described as participating in the processes of implantation and formation of decidua, as well as in fetal development and maturation, and initiation of childbirth [17, 36, 42]. Elevated levels of GC present during pregnancy are involved in the suppression of inflammation of the uterus, placenta, and fetal membranes, which contributes to maintaining the homeostasis necessary for the maintenance of pregnancy [42]. Moreover, recent evidence suggests that significant increases in cortisol levels play a critical role in the baby's growth in the postnatal stage [43]. In this sense, studies have shown that high concentrations of cortisol during the fetal phase positively correlated with weight gain within the first five years of postnatal growth, indicating that the higher increase in placental cortisol levels, the more significant weight gain can be observed in children during this stage, suggesting that hormonal changes within the maternal-fetal environment have repercussions in post-birth stages, a highly relevant endocrinological aspect [43].

Conversely, cortisol is also involved in developing pregnancy complications, being responsible for the so-called "Hypothalamic Stress Amenorrhea," whose consequence is the generation of miscarriages [8, 44]. On the one hand, it has been shown that low maternal cortisol levels compromise the placenta's structure. In contrast, elevated levels can lead to miscarriages, uterine contractions from placental CRH deregulation, the elevation of fetal cortisol levels, and obstetric alterations by activation of the HPA gland axis [14, 36, 38, 45]. In this sense, two main axes, the HPA, and the sympathetic nervous system-adrenal medulla exerts a negative effect on the reproductive system when activated in stressful situations. In this feedback mechanism, the CRH that is produced at the pituitary can act, in a short negative feedback mechanism, directly inhibiting GnRH at the hypothalamus.

Even more, cortisol act at the pituitary to inhibit the release of LH and FSH, and, consequently, inhibits steroidal ovarian hormones, Estrogen, and P4, resulting in abortion. It has been confirmed in preclinical and clinical studies, where exposure to stressors, such as noise, has been verified to induce miscarriages, with a significant decrease in P4 levels [8, 44]. More interesting, stress increases the excitability of the sympathetic nervous system, resulting in a decrease in blood flow supply to the placenta caused placental hypoxia and increased generation of reactive oxygen species, causing damage to trophoblasts; the outer layer of the blastocyst, responsible for providing nourishing to the embryo [44].

Finally, it has also been suggested that high cortisol levels could mediate a disbalance in T helper cells Th 1 and Th 2, with a specific impact in the decrease of adaptative immune system responses that allow the fetus's maintenance. However, more studies are needed to confirm this [44]. So, it is evident that cortisol is not just a "stress hormone"; it has several functions supporting the MPFU.

## **10. Thyroid hormones in pregnancy; regulation by sex hormones?**

During pregnancy, high estrogens and corticosteroids induce an increase in TGB levels in the liver, which is significant from week twenty of gestation, reaching its maximum level from week twenty to twenty-four. The rise in TGB during the first half of pregnancy is related to further deiodination of the inner ring of the hormones T4 (Thyroxine) and T3 (Triiodothyronine) at the placenta, which is responsible for the physiological effect attributed to them [46, 47].

As far as the fetus is concerned, it has been shown that there are at least two mechanisms for it to contribute to thyroid hormones: the development of the fetal thyroid gland and the maternal thyroid gland. More interesting, the increase in concentrations of T4 in the first half of pregnancy and the expression of receptors to thyroid hormones in the brain, suggesting its participation in the development of brain structures of the fetus. Moreover, from weeks twelve-fourteen, in which the fetal thyroid begins to synthesize T4, its levels increase progressively, until reaching its maximum levels between week thirty-four to thirty-six, remaining elevated until the delivery time [46].

About iodine levels begin to be detected from ten to eleven weeks of gestation, a stage in which the fetal thyroid can concentrate. Around the twelfth week, the pituitary starts to produce and synthesize TSH and TRH (Thyrotropin-releasing hormone) by the hypothalamic neurons [46].

Before the fetal thyroid develops, the placenta has a particular involvement in maternal-fetal thyroid regulation. It is responsible for exchanging thyroid hormones to the fetus, suggesting an essential role in early fetal growth. Among the functions

#### *Neuroendocrinology of Pregnancy: Participation of Sex Hormones DOI: http://dx.doi.org/10.5772/intechopen.95774*

attributed to thyroid hormones are the brain's development and the acceleration of fetal pulmonary maturation. The effect has been demonstrated in preclinical and clinical models in which fetal pulmonary growth has been shown to increase after intraamniotic injection of T3 or T4. On the other hand, the effect at the brain level has been demonstrated in intrauterine hypothyroidism conditions. It is related to irreversible damage to the brain and mental disability in children born under these conditions [46, 47].

Interestingly, clinical studies conducted in children whose mothers suffered from hypothyroidism, a condition that occurs in 0.05–0.02% during pregnancy, have shown that these irreversible changes specifically affect neurodevelopment. In this sense, it has been demonstrated that any situation that leads to the development of clinical hypothyroidism (generally associated with Graves' disease) and hypothyroxinemia (associated with overtreatment of antithyroid drugs) that can occur during the first trimester of pregnancy can lead to a cognitive delay in children, learning disorders, maturational delay, encephalopathy, and seizures among other conditions [48].

Significantly, the increase in TSH, T3, and T4 during pregnancy could have protective effects against fetal anemia because it has been suggested that they may have cardiotonic effects by direct activation of the sympathetic-adrenal nervous system, in addition to being shown to stimulate the production of erythropoietin, which is involved in the production of red blood cells and therefore in the release of oxygen to tissues [47].

In this sense, it is fascinating to understand that sex hormones regulate the release of thyroid hormones and the vital functions involved, like brain development, being crucial during pregnancy and childhood.
