**4. The modulatory hormones in pregnancy; testosterone (T), androstenedione (A4), and dehydroepiandrosterone (DHEA)**

The androgenic hormones T, A4, and DHEA, plays a central role in regulating reproductive processes in many mammalian species. Besides, the presence of androgen receptors has also been demonstrated in different tissues such as the ovary, the myometrium, and placenta, where they are known to participate in implanting the fetus and placentation. In this sense, it has been shown that, once pregnancy occurs, androgen synthesis takes place in the small luteal cells (SLC) of the corpus luteum by stimulation of the human chorionic gonadotrophin (hCG) [3, 14]. In addition to the above, once the placenta has been established, it becomes an independent androgen production source [14]. In this aspect, placental syncytiotrophoblast uses the circulating DHEA, provided by the maternal and fetal adrenal glands, turning it into A4 and T. Which, in turn, as will be discussed later, can be converted to estrogens by different routes to regulate embryonic development [3, 15]. Interestingly, it has been suggested that myometrium could be another important source of androgens during pregnancy; a recent *in vitro* study showed that this tissue could also produce T and A4 [15].

Suppressively, these hormones are coordinated synthesized during pregnancy. Specifically, it has been shown that T levels increase in the first trimester of pregnancy, reaching a plateau in the second trimester, to later decrease slightly, rising considerably in the last month of pregnancy [14, 15]. Concerning A4, the study carried out by Satué et al. (2018) in mares shows that this hormone rises during gestation, from the second month of pregnancy, reaching a peak maximum in the first stage of pregnancy, and, in the second state, it reduces significantly, reaching its lowest levels in the last month of gestation. However, a clinical study conducted by Makieva et al. (2014) showed that A4 remains stable throughout pregnancy without significant fluctuations. About DHEA, it increases progressively from the first to the fifth month of pregnancy, reaches its highest levels, then begins to decrease between months 6 and 7, reaching its lowest levels in the last month of pregnancy in mares, which is agree with the observed in pregnant women, with levels up to 50% lower than those observed in non-pregnant women, an effect associated with negative E2 feedback to the maternal adrenal glands [14, 15].

The fluctuations in these hormones have specific functions during pregnancy. The significant increase observed in the first months of gestation is associated with the function of the corpus luteum, which uses T for estrogens' production (analyzed in the next topic), regulating the implantation and decidualization. Later, the decrease observed in the middle of the gestation is related significantly to the development of the fetal gonads, providing the necessary substrates for the synthesis of placental estrogens. So, the primary site of estrogen synthesis at this stage could be the fetus. Finally, T's elevation in the last stage of pregnancy, but not of A4 and DHEA, could be associated with the restructuring that the cervix must undergo to be prepared for the moment of delivery. At this stage, it has been shown that the cervix can convert T into another metabolite, Dihydrotestosterone (DHT), through the action of 5-alpha-reductase. This androgen is involved in restructuring the cervix's extracellular matrix tissue, including the structural changes that allow the myometrium's contractility [14, 15].

Therefore, these interesting data confirm the surprising interrelation and interdependence between estrogens and androgens produced by MPFU to protect and ensure pregnancy's proper development.
