Volume 27, Issue 1 - Special issue: Hormones in Normal and Pathological Pregnancies / Editors: Adolf E. Schindler and Jorge R. Pasqualini

The hormonal milieu of an early full-term pregnancy induces lobular development, completing the cycle of differentiation of the breast. This process induces a specific genomic signature in the mammary gland that is represented by the stem cell containing a heterochomatin condensed nucleus (HTN). Even though differentiation significantly reduces cell proliferation in the mammary gland, the mammary epithelium remains capable of responding with proliferation to given stimuli, such as a new pregnancy. The stem cell HTN is able to metabolize the carcinogen and repair the induced DNA damage more efficiently than the stem cell containing an euchromatinic structure (EUN), as it has been demonstrated in the rodent experimental system. The basic biological concept is that pregnancy shifts the stem cell EUN to the stem cell HTN that is refractory to carcinogenesis. Data generated by the use of cDNA micro array techniques have allowed to demonstrate that while lobular development regressed after pregnancy and lactation, programmed cell death genes, DNA repair genes, chromatin remodeling, transcription factors and immune-surveillance gene transcripts all of these genes are upregulated and are part of the genomic signature of pregnancy that is associated with the preventive effect of this physiological process.

The fetal endocrine system constitutes the earliest system developing in fetal life and operates during all the steps of gestation. Its regulation is in part dependent on the secretion of placental and/or maternal precursors emanating across the feto-maternal interface. Human fetal and placental compartments possess all the enzymatic systems necessary to produce steroid hormones. However, their activities are different and complementary: the fetus is very active in converting acetate into cholesterol, in transforming pregnanes to androstanes, various hydroxylases, sulfotransferases, while all these transformations are absent or very limited in the placenta. This compartment can transform cholesterol to C21-steroids, convert 5-ene to 4-ene steroids, and has a high capacity to aromatize C19 precursors and to hydrolyze sulfates. Steroid hormone receptors are present at an early stage of gestation and are functional for important physiological activities. The production rate of some steroids greatly increases with fetal evolution (e.g. estriol increases 500–1000 times in relation to non-pregnant women). Other hormones, such as glucocorticoids, in particular the stress hormone cortisol, adipokines (e.g. leptin, adiponectin), insulin-like growth factors, are also a key factor for regulating reproduction, metabolism, appetite and may be significant in programming the fetus and its growth. We can hypothesize that the fetal and placental factors controlling hormonal levels in the fetal compartment can be of capital importance in the normal development of extra-uterine life.

Progesterone and allopregnanolone have crucial and different roles in brain development, function and recovery after injury. Pregnancy is characterized by an increased synthesis of progesterone and its neuro-active metabolites by the placenta, maternal and fetal brain. This supports the critical role of these steroids in maternal brain adaptation during pregnancy and development of the fetal brain. Moreover, allopregnanolone may play a brain-protective role during complications of pregnancy, complications of pregnancy, such as preterm delivery or intrauterine growth restriction (IUGR), by reducing the impact of hypoxia and excitotoxic brain damage or impairment myelination. Behavioral consequences of altered progesterone/allopregnanolone fetal brain programming have also been hypothesized, although further evidence is needed. New potential applications of allopregnanolone as a treatment strategy have also been proposed, addressing unmet clinical needs in perinatal care.

Progesterone is an essential hormone in the process of reproduction. It is involved in the menstrual cycle, implantation and is essential for pregnancy maintenance. It has been proposed and extensively used in the treatment of different gynecological pathologies as well as in assisted reproductive technologies and in the maintenance of pregnancy. Called “the pregnancy hormone”, natural progesterone is essential before pregnancy and has a crucial role in its maintenance based on different mechanisms such as: modulation of maternal immune response and suppression of inflammatory response (the presence of progesterone and its interaction with progesterone receptors at the decidua level appears to play a major role in the maternal defense strategy), reduction of uterine contractility (adequate progesterone concentrations in myometrium are able to counteract prostaglandin stimulatory activity as well as oxytocin), improvement of utero-placental circulation and luteal phase support (it has been demonstrated that progesterone may promote the invasion of extravillous trophoblasts to the decidua by inhibiting apoptosis of extravillous trophoblasts). Once the therapeutic need of progesterone is established, the key factor is the decision of the best route to administer the hormone and the optimal dosage determination. Progesterone can be administered by many different routes, but the most utilized are oral, the vaginal and intramuscular administration. The main uses of progesterone are represented by: threatened miscarriage, recurrent miscarriage and preterm birth (in the prevention strategy, as a tocolytic agent and also in the maintenance of uterine quiescence).