**2. Gonadotropin-releasing hormone (GnRH), FSH, and LH, primary mediators of sex hormones releasing**

The GnRH is a hormone synthesized by the hypothalamic neurons. It travels through the portal-pituitary-system to bind to its receptors (GnRHR-I) in pituitary cells (gonadotrophs), activating the synthesis of FSH (Follicle-stimulating hormone) and LH (Luteinizing hormone). These hormones are released into the systemic circulation to act on sex organs regulating both oogenesis and spermatogenesis. Interestingly, GnRH isoforms (GnRH-I and GnRH-II) have also been identified in other tissues, including the testicles, prostate, mammary gland, endometrium, and placenta. In these organs, it has been shown that GnRH-II acts by binding to GnRHR-II receptors [5].

The functions associated with these isoforms are the production of the β-human chorionic gonadotropin (β-hCG) by the syncytiotrophoblast in the early stages of pregnancy. Here, β-hCG intervenes in at least two vital functions, avoiding luteolysis and ensuring Progesterone's production (P4) until the placenta is implanted. Thus, specific conditions that interfere with this endocrine axis before weeks seven to nine of gestation would culminate in pregnancy loss [5].

Moreover, recent evidence indicates that GnRH is involved in the maternal-fetal environment's remodeling (milieu) that allows the fetus's correct implantation. This process is accompanied by increased proliferation of trophoblasts, which invade the decidua and form the outer and inner layers of syncytiotrophoblast, directly contacting maternal tissue. In this condition, the expression of specific metalloproteinases (MMP) is affected. Preclinical studies have shown that both isoforms (GnRH-I and GnRH-II) modify cellular matrix metalloproteinases' expression. Two of them, MMP-2 and MMP-9, are the most directly involved in the migration and invasion of trophoblasts [5].

In addition to the above, it has been shown that both isoforms can produce proangiogenic cytokines, playing a central role in the rerouting of immune system cells involved in the restructuring of the arteries in the maternal-fetal interface [5]. Therefore, GnRH's direct participation is vital for all physiological, hormonal, and structural changes that will culminate in the fetus's correct implantation.

On the other hand, GnRH causes the stimulation of the pituitary hormone's LH and FSH to regulate the sexual function. However, preclinical studies showed that both hormones are inhibited because of Progesterone and Estrogen increased production during pregnancy. Moreover, FSH and LH level rises on day ten after birth, which correlates to the decrease in sex hormones. In this sense, it has been established that the reduction of sex hormones after delivery performs negative feedback, which can achieve the complete reestablishment of reproductive function two months later after birth [6].

Interestingly, these data provide information valuable in understanding the positive and negative feedback mechanisms that play the sexual hormones during the pregnancy to maintain the MPFU.

#### **3. Progesterone, the "pregnancy hormone"**

Progesterone (P4) is considered the "pregnancy hormone" because it is critical for gestational maintenance [3]. During this stage, P4 is produced mainly by the ovary's

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

luteal body until the twelfth week of pregnancy. After that, its release is principally maintained by the placenta, reaching levels of up to 3 μg/g, while blood concentrations range from 100 to 500 nM, being four to six times its basal levels [7, 8]. These values rise significantly as gestational age progresses. It is involved in both the maintenance and development of the endometrium and inhibiting the uterus' smooth muscle from preventing premature contractions (spontaneous abortion) [8].

Interestingly, the increase in this hormone's levels seems to be regulated by an independent mechanism that generally restricts the synthesis of this hormone, being produced by the placental trophoblast cells in response to the stimuli produced in the uterine-fetal microenvironment [9]. At this level, its synthesis is carried out by converting the maternal cholesterol to the pro-hormone pregnenolone into the mitochondrial cytochrome P450. After that, by the action of 3-β-hydroxysteroid dehydrogenases (HSD), it is metabolized to Progesterone. Of the total synthesized Progesterone, 90% go into the maternal circulation, and the remaining 10% goes into fetal circulation [10].

Placental P4 plays an essential role in establishing a pregnancy, as it is responsible for inhibiting uterine contractions that occur at the myometrium's smooth muscle. In this context, the deficiency of this hormone during the luteal phase has been widely related to infertility and loss of the pregnancy, presenting abortion, a situation that can occur at any stage of pregnancy [8, 9]. Besides, it is involved in the formation of decidua (a layer that coats the endometrium). In this sense, P4 is involved in the structural changes that the uterus undergoes during this period by increasing blood vessels' permeability and endometrial density. Moreover, it has been suggested that the increase in decidual density is related to a lower likelihood of miscarriage. Also, P4 ensures the integrity of the fetus-maternal interface during the process of trophoblastic invasion and placenta formation [8, 11, 12]. What is more, P4 blocks the early production of T-cell lymphopoiesis protective role intrauterine environment's immune system (milieu). For that reason, it has been suggested that Progesterone acts as an immunosteroid since a satisfactory pregnancy depends on maternal tolerance to the fetal 'semi-allograft' [8].

Similarly, it has been suggested that the increase in P4 levels induces changes in gene expression in the uterine endometrium, indirectly favoring embryo growth [12]. Furthermore, it is a crucial factor between the endocrine and immune system since it has been shown that this hormone is involved in the implantation of tissue, preventing it from being rejected by the mother, a mechanism that appears to be mediated by Th cells (helper T cells), as well as by the interleukins (IL) IL-3, IL-4, IL-5, and IL-10, in such a way, it has been suggested that through inhibition of Th 1 cells and increased production of interleukins, Progesterone is involved in the implantation of the fetus and its maintenance [7, 8].

On the other hand, P4 is involved in regulating the expression of uterine dendritic cells. These are known as antigen-presenting cells (APCs) involved in innate immune response and tolerance maintenance. However, in immature stages, these cells have a tolerogenic phenotype characterized by the low expression of co-stimulating molecules and pro-inflammatory cytokines. Thereby, it has been shown that in the early stages of pregnancy, Progesterone prevents dendritic cells' maturation. All these previous actions contributed to the maintenance of pregnancy [8].

More interesting, it has been shown that P4 is also involved in reducing gestational stress. In this sense, it has been shown that it can over-express the mPRα gene, which encodes for a membrane receptor present in Cytolytic T lymphocytes CD8 + T cells, and whose increase has been linked to a protective effect against stress-induced abortion [7].

Finally, it is known that P4 levels decrease at the end of pregnancy, a phenomenon that is related to the onset of labor. Hence, an excellent regulatory mechanism of P4 (both at the endocrine and immunological level) from the beginning to the culmination of pregnancy, it is necessary to the implantation, maintenance, and completion of this [12, 13].
