**5. Estrogens in pregnancy, an orchestral regulatory mechanism**

Estrogens are a group of four different steroid hormones: Oestrone (E1), 17β-Oestradiol (E2), Oestriol (E3), and Oesterol (E4), cyclically synthesized in response to changes during the ovarian cycle, specifically during the pre-ovulation phase, favoring folliculogenesis. However, estrogens also play a central role in the growth of the uterus and mammary gland. It increases the blood flow indispensable for transporting nutrients between the uterus and the fetus [16]. During pregnancy and up to the time of delivery, significant amounts of estrogens are released by the maternal-fetus-placental unit, formed by the luteal body, placenta, and the fetal adrenal cortex [3], suffering significant adjustments between the weeks seven to nine of pregnancy, reaching its highest levels at the time of delivery [17, 18].

17β-Oestradiol (E2) is the most abundant hormone synthesized during pregnancy. In connection with this, until the third month of pregnancy, significant levels of E2 are released by the luteal body, a period from which the primary site of estrogen production is the placenta [3]. It should be noted that the placenta has no autonomic innervation, so these increases occur in response to close communication between the mother and the fetus, where the hormone acts in an autocrineparacrine form in the development of the mammary gland and uterus, as well as in the development of sexual characteristics in the fetus. This connection allows the placenta and fetus to exchange and share steroid precursors, thus achieving their hormonal self-regulation [18].

Several studies have shown that the increase in estrogen levels is the result of a mutual exchange between the mother and placenta, in which the placenta uses the circulating androgen DHEA produced by the adrenal glands of the MPFU, where it is converted to Testosterone and Androstenedione and then metabolized to E1 and E2 with the help of the cytochrome cyp450 aromatase enzyme [3, 7]. In such a way, both the mother and the fetus contribute to the increase in estrogen synthesis, regulating their production. In addition to this, and due to the high maintenance of this hormone throughout pregnancy, there is sufficient evidence to suggest that regulation in levels of this hormone could also be at the neural level, where E2 could act as a trigger factor of the HPA gland axis. So, the adaptive changes that occur in the mother-fetus are regulated by a positive feedback mechanism, in which the binding of E2 to their receptors at the brain could be sending signals to the adrenal glands for producing a more significant amount of DHEA, thus maintaining their constant levels [19]. Therefore, it seems clear that estrogen levels regulation during pregnancy occurs both locally, by an interaction of the placental-fetal unit and in an autonomic way, with the direct participation of the Central Nervous System.

Concerning its functions, estrogen has been shown to act through binding to nuclear receptors, participating in multiple processes to ensure the maintenance of pregnancy having different roles: in human endometrial explant cultures, they are involved in uterine vascular restructuring by binding to their nuclear receptors present in epithelial and stromal cells of the cervix and endometrium, acting regulating the expression of different genes that control intrauterine growth, maturation of vital organs such as mammary glands for breastfeeding and childbirth [16–18, 20]. Besides, it promotes the processes of angiogenesis and vasodilation that allow the transfer and exchange of nutrients and oxygen between the placenta and

the fetus through uterine and fetal circulation, a process associated with an increase in endothelial production of nitric oxide [3, 21].

On the other hand, in the primary culture of endometrial-epithelial cells (ESC), it has been found that E2 plays an essential role at the beginning of pregnancy by acting in processes such as differentiation and cell proliferation through the secretion of insulin growth factor type 1 (IGF-1) [22]. Also, it increases the rate at which the fertilized egg travels through the fallopian tube, so low estrogen levels promote ectopic pregnancies because the egg stays longer in the fallopian tube [23].

In addition to the above, estrogens E1, E3, and E4, also, play a central role in pregnancy. E1 is the most abundant conjugated estrogen (estrone sulfate) during pregnancy; it increases from the first trimester of pregnancy, reaching its maximum peak in the 35th week of gestation; among its functions, the decrease of estrogenicity has been indicated in the time of delivery [24]. E3 (Oestriol) is also considered a derivative of estradiol, whose primary role during pregnancy is increased uteroplacental blood flow during pregnancy. However, a specific function has also been suggested in the induction of myometrial cells' contractions through the increase of connexin-4, allowing the restructuring of the myometrium that will trigger the initiation of labor [3]. On the other hand, Oesterol (E4) has an uncertain function during pregnancy since it is produced exclusively by the fetal liver starting up from the ninth week of pregnancy, reaching its significantly elevated levels after week 30, with a peak at week 40. Although its function is unclear, preclinical studies have shown that it can bind to estrogen and progesterone receptors at the uterus, producing histological structural changes and biochemical fluctuations, essential during the differentiation of endometrial cells in pregnancy and delivery [25].

Therefore, during pregnancy, the hyperestrogenic state plays a significant role in maternal-fetal development, being a key piece in fetal growth. Hence, all these actions make the estrogen pleiotropic essential hormones in pregnancy.

#### **6. Prolactin in pregnancy, more than a lactation hormone**

Prolactin (PRL) is a protein hormone synthesized by the lactotroph cells of the anterior pituitary gland. Unlike other pituitary hormones, its release is inhibited by Dopamine (DA), a hypothalamic factor produced by dopaminergic neurons located in the arcuate nucleus, which has not only been shown to be able to regulate the release of PRL but can act at the lactotrophic cells, regulating their proliferation [1]. In addition, PRL can control its release, directly stimulating dopaminergic neurons and through direct and indirect mechanisms regulated by E2 [23].

In this sense, a preclinical rat model study showed that in the different reproductive stages, PRL intervenes in a coordinated manner with E2 and Dopamine in regulating the proliferative activity of lactotrophic cells. In this collaborative process, these cells' activity is elevated in the estrus and delivery stages. But it is decreased during the early stages of pregnancy and lactation, even though PRL levels are increased in all these reproductive stages. In this context, it has been suggested that E2 participates in stimulating the release of PRL during the early stages of pregnancy and lactation by acting at the hypothalamic level regulating both the increase in prolactin levels and the activity of the lactotroph cells when DA is not present, play a dual role in the release of this hormone [23, 26].

Evermore, during pregnancy, essential adaptations occur to allow the release of significant amounts of this hormone by the stimulation caused by the mammary gland and the luteal body [27], with substantial elevations from the twentieth week of pregnancy, until after childbirth [26]. Specifically, PRL has been shown to play a vital role in regulating IL-10 and IL-12 interleukins (essential regulators of immune

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

responses during inflammatory processes). On the one hand, IL-12 interleukin has a pro-inflammatory function, activating itself in response to situations such as stress. On the other hand, IL-10 is an anti-inflammatory cytokine, which intervenes in the regulation of the expression of IL-12. In this sense, it has been shown that, during pregnancy, PRL increases the concentration of IL-10, an effect suggested is associated with the proper maintenance of this [28].

At the clinical level, this hormone has been shown to provide luteotropic support to the luteal body by intervening in the biosynthesis of P4 for its maintenance in the first three months of pregnancy, having an indirect function in the implantation of fetus in the uterus, as well as in the induction of vascular factors necessary for the increase in the volume of the luteal body [1, 29]. On the other hand, it acts directly on the mammary gland, determining the growth and development of alveoli, promoting the expression of genes related to milk synthesis and lactopoiesis. It also helps maintain the luteal body's integrity and decidual cell survival [30]. Moreover, it is involved in the synthesis of relaxin, a hormone responsible for dilating the cervix during labor, thus facilitating the fetus's expulsion [27].

PRL, it has been shown to play an essential role in regulating leptins expression in the gestational stage [31]. Leptins are hormones produced mostly by adipocytes, whose central role is related to the regulation of body weight, appetite, and energy homeostasis. The increase in their plasma levels is associated with the rise in the amount of body fat. However, during the gestational stage, vast quantities of leptins are released by the ovary and placenta, remaining constant throughout pregnancy, intervening in the regulation of fetal weight and growth, and with the development of gestational diabetes [32]. In this sense, the increase in PRL levels has been suggested to inhibit the receptor to leptins (LepR), thus blocking the signaling pathways that regulate the development of gestational diabetes [31].

Finally, it has a central role in mother–child recognition by increasing the generation of neurons at the olfactory bulb level, which is essential for such recognition [29]. For that reason, PRL recognizes like a multifaceted hormone, with dual actions during and after delivery.

## **7. Human placental lactogen, an exclusive metabolic hormone in pregnancy**

The human placental lactogen hormone (hPL), known as human Chorionic somatomammotropin, is a polypeptide hormone elevated during pregnancy and is produced exclusively by the placenta [3]. hPL levels are detected between the first and second weeks of placenta gestation. However, it is released into the maternal circulation between the third to sixth week of pregnancy, being possible its detection, which increases until reaching its constant levels with a significant increase at the end of pregnancy with substantial effects after delivery [3].

Although there is controversy regarding its participation during pregnancy, it has been suggested that its primary function is the regulation of maternal metabolism of lipids and carbohydrates, being crucial to maintaining energy homeostasis between mother and fetus. In this sense, at the preclinical level, it has been shown that it stimulates the production of the IGF-1 factor in maternal hepatocytes. It modulates intermediate metabolism by increasing food intake (orexigenic drive), which favors the increase in glucose available for transfer to the fetus and prevents the development of gestational diabetes caused by peripheral resistance, typical at this stage [1, 3].

Moreover, it has been suggested that it has a central role in intrauterine growth because more than 50% of neonates with stunted growth have shown a deficiency in hPL levels. It is also believed that, by stimulating the uptake of glucose, glycerol, and free fatty acids, it could significantly participate in fat deposits, serving as an energy-saving mechanism for the fetus [1, 3].

Furthermore, it is well documented that in a normal state of pregnancy, insulin sensitivity decreases with the advance of the gestational state, which allows the fetus to maintain energy, an effect caused by a joint inhibitory action of peptide hormones (C-reactive protein, leptins, and hPL) on insulin levels causing dysfunction of pancreatic β-cells, named "diabetogenic condition." However, a clinical study conducted by Ngala et al. (2017) showed that, throughout pregnancy, important maternal factors could predict the development of gestational diabetes mellitus (GDM) in addition to the already known factors of obesity and family history. In this sense, the levels of glucose, insulin, glycosylated hemoglobin (GHb), and hPL, among others, are increased in pregestational pregnant women, an effect not observed in non-diabetic pregnant women. Interestingly, under this condition, E2 and P4 levels decreased in pre-diabetic women, while in healthy women, the levels of both hormones are increased. On the other hand, between weeks 24–28 of gestation, an increase in Progesterone, Estradiol, Leptins, GHb, and Fasting blood glucose (FBG) was observed in developing GMD, an effect associated with the increased insulin resistance. Controversially, although there is little information linking hPL with the development of GDM, it is believed that the decrease in the levels of this hormone after delivery is associated with the reduction in glucose resistance and with the increased risk of diabetes-prediabetes in nursing mothers [33, 34].

Interestingly, hPL participates in lactation by stimulating the breast epithelium, facilitating breast development during the gestational stage. In this process, both hormones (hPL and PRL) act in maternal behavior, suppressing stress responses in the last stage of pregnancy and lactation [1]. In this sense, it has been shown that dopaminergic neurons' activity can be maintained by hPL [23].

All these results confirm the metabolic action of hPL in pregnancy and lactation, alone or together to other placental and maternal hormones.

### **8. Human chorionic gonadotropic (hCG), the placental essential hormone**

HCG is considered one of the essential hormones during gestational development, having similarities with other members of the same family of glycoproteic proteins such as LH and pituitary FSH. Its synthesis is regulated by the luteal body and placenta, exercising a pleiotropic role during gestation by autocrine and paracrine mechanisms [3]. It is possible to detect significant levels from day eight after fertilization, reaching its maximum levels around the tenth week of development. After which, it maintains at constant levels when the placenta is fully developed. At this point, the luteal body's secretions are no longer necessary [3].

It participates in the process of steroidogenesis and in the restoration-maintenance of the luteal body, where it acts as a relay system, whose purpose is to prevent menstruation by increasing the synthesis of P4, allowing that the embryo can be implanted in the uterine endometrium, ensuring pregnancy until placental production of Progesterone is well established [3].

The hCG has also been shown to have a structure like Thyroid stimulating hormone (TSH) to bind to the same receptors, having implications for regulating thyrotropic activity. Preclinical studies have shown that maternal TSH decreases at the end of the third trimester of pregnancy. This decrease correlates with increased

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

placental hCG and fetal thyroxine-binding globulin (TGB) [1]. *In vitro* studies have shown that it can have angiogenic effects; it increases vascular-endothelial growth factor (VEGF) and placental microvascular endothelial cells [3].

Moreover, clinical studies have shown that it is also involved in the differentiation of cytotrophoblast in syncytiotrophoblast, constituting an essential factor in the secretion of relaxing decidual production of PRL. On the other hand, it has androgenic properties. It can promote the synthesis of DHEA by the fetal adrenal cortex, regulating both testicular function and fetal male differentiation during the first weeks of gestation [35]. In addition, it has been suggested that it has participated in other functions; in the immune system, stimulates the production of the anti-inflammatory interleukins IL-8 and IL-10, and inhibits lymphocyte response, preventing rejection of the fetus, suggesting an immunosuppressive role of hCG during pregnancy; it stimulates testicular Leydig cells for testosterone production and provides nutrients and hormones for optimal maintenance of intrauterine microenvironment [3, 35]. So, the metabolic implications of this hormone suggested it like a metabolic hormone in pregnancy.
