Androgen Signaling in the Placenta

*Agata M. Parsons Aubone, River Evans and Gerrit J. Bouma*

#### **Abstract**

The placenta is a multifunctional, transitory organ that mediates transport of nutrients and waste, gas exchange, and endocrine signaling. In fact, placental secretion of hormones is critical for maintenance of pregnancy, as well as growth and development of healthy offspring. In this chapter, the role of androgens in placental development and function is highlighted. First, a brief summary will be provided on the different mammalian placental types followed by an overview of placental steroidogenesis. Next, the chapter will focus on genomic and non-genomic androgen signaling pathways. Finally, an overview will be provided on the current status of androgen signaling in the placenta during normal and abnormal pregnancies.

**Keywords:** pregnancy, placenta, testosterone, dihydrotestosterone, androgen receptor

### **1. Introduction**

Establishing and maintaining pregnancy requires a finely regulated series of physiological events involving mother, fetus, and placenta. The essential role of steroid hormones in the production and maintenance of many of these changes is well characterized. For example, important effects of progesterone include preparation of the endometrium for implantation [1], modulation of the maternal immune response to tolerate the fetal allograft, maintenance of myometrial quiescence [2], and preparation of mammary glands for lactation. Estrogens appear to influence uterine blood flow and neovascularization, increase the expression of critical proteins that are involved in progesterone production and steroid metabolism and participate in preparation of mammary glands for lactation [3, 4]. Throughout pregnancy, levels of maternal circulating androgens, including testosterone (T), dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA) and androstenedione (A4) increase, with concentrations three-fold higher by the third trimester when compared to nonpregnant levels in women [5]. Although T is a well-known precursor for estrogens (E2) synthesis, the placenta can both be a source and a target for androgens. The goal of this chapter is to summarize what is known about androgens and androgen receptor in pregnancy and compare it between species and between different types of placenta.

#### **2. Placenta classification**

The placenta is a multifunctional, transitory organ that mediates transport of nutrients and waste, gas exchange, and endocrine signaling. In fact, placental

#### *Reproductive Hormones*

secretion of hormones is critical for maintenance of pregnancy, as well as growth and development of a healthy offspring. Despite fulfilling similar functions, there is a wide range of diversity in placental anatomo-histology among species.

During early embryogenesis, the first cells to differentiate are trophoblast cells, which form the chorion or fetal portion of the placenta. Villous trophoblast cells have two distinct cell populations; undifferentiated cytotrophoblast cells and differentiated syncytiotrophoblast tissue. The syncytiotrophoblast tissue is a continuous, multinucleated, specialized layer of epithelial cells, which covers the villous surface and is in direct contact with maternal blood. This layer is formed by fusion of cytotrophoblast cells.

Placental gross morphological classification is based on the shape and the area of contact between fetal and maternal tissue [6]. There are four commonly describe placental shapes among mammals:


In addition to the gross morphological classification, placentas are also categorized by histology (**Figure 1**) which is based on the different number of cell layers separating fetal from maternal circulation [7]. Before the placenta is formed, there are a total of six layers of tissue separating maternal and fetal blood. Three of these layers are fetal extraembryonic membranes in the chorioallantoic placenta of all mammals, all of which are components of the mature placenta. These three layers include endothelium lining allantoic capillaries, connective tissue in the form of chorioallantoic mesoderm, and chorionic epithelium, derived from trophoblast cells. There are also three layers on the maternal side, but the number of these layers which are retained after placentation varies greatly among species. The three potential maternal layers in a placenta are endothelium lining endometrial blood vessels, connective tissue of the endometrium, and endometrial epithelial cells.

Based on this degree of separation, or number of layers separating the fetal and maternal tissues, there are four different types of placenta (see **Figure 1**):

1.**Epitheliochorial placenta**, present in pig and horse, consists of all six layers separating maternal from fetal blood throughout gestation. The trophoblast cells make contact with the uterine epithelium forming microcotyledons (horse) or chorionic folds (pig). Microcotyledons contain highly vascularized chorionic villi that extend into elaborate invaginations of the endometrium. Chorionic folds are formed by the lining of the chorionic villi into the wrinkled surface of the uterine epithelium.

*Androgen Signaling in the Placenta DOI: http://dx.doi.org/10.5772/intechopen.94007*

**Figure 1.** *Histological classification of the placenta.*


During implantation, cytotrophoblast cells surround the central third of the chorioallantois and proliferate to form a syncytium called the syncytiotrophoblast layer. The syncytiotrophoblast layer erodes through the endometrial epithelium and grows around maternal capillaries. Initially, the invading fetal cells are in the form of villi, but villi soon coalesce to form a labyrinthine-type placenta. For this reason, only four tissue layers separate the maternal from the fetal blood.

4.**Hemochorial placenta**, present in humans and rodents, is the most invasive form of placentation. Fetal chorionic epithelium is bathed in maternal blood because chorionic villi have invaded through endometrial epithelium and eroded through maternal endothelium. The number of trophoblast layers in contact with the maternal circulation shows variation between species. It is hemomonochorial in humans, with one layer of syncytiotrophoblast, and hemodichorial in primates, with one layer of syncytiotrophoblast upon one layer of cytotrophoblast cells. Finally, it is hemotrichorial in rodents with one layer of cytotrophoblast and two layers of syncytiotrophoblast separating maternal and fetal blood.
