Placental physiology
In the past, it was assumed that the principal function of the organ was transport. While maternofetal exchange through the placenta is undeniably highly important, the definition fails to recognize the organ's other facets.
It is now well established that the placenta provides the fetus with all essential nutrients, water, and oxygen, and a route for clearance of fetal excretory products, but it also produces a vast array of protein and steroid hormones and factors necessary for the maintenance of pregnancy. Furthermore, transport is selective and in general the placenta either excludes or renders inactive maternal hormones and xenobiotics to allow the fetus to develop in a safe and independent milieu (28). The placenta is metabolically highly active. Placental oxygen consumption per unit mass of the tissue is three times higher than that of the developing fetus.The transport pathways change with gestation. In particular, during most of the first trimester, the secondary yolk sac and the extraembryonic coelom play important roles as an additional transport route inside the gestational sac (29, 30). As described previously, the absence of a continuous maternal circulation inside most of the primitive placenta during the first trimester placenta is essential to control the oxygen level inside the gestational sac during organogenesis (Figure 9.6). It also adds to the natural defence of the fetus against parasites and viruses when at its most vulnerable. Once maternal blood flow to the intervillous space begins at around 10 weeks' gestation, exchange across the barrier between the maternal and fetal circulations within the villi will become predominant.
During most of the first trimester, in addition to its absorptive role, the secondary yolk sac synthesizes several essential serum proteins such as alpha-fetoprotein, alpha-1-antitrypsin, albumin, pre-albumin, and transferrin until the fetal liver has reached its full metabolic capacity (30, 31).
With rare exceptions, the secretion of most of these proteins is confined to the embryonic compartments. The uterine glands are also important in the early fetal and placental metabolic activities (24, 26). They are most prolific and active during the early weeks of pregnancy, with their contribution gradually waning during the first trimester. This would be consistent with a progressive switch from histotrophic to haemotrophic nutrition as the maternal arterial circulation to the placenta is established. Thus, the early, primitive human placenta may function physiologically as a choriovitelline placenta, in common with those of many mammalian species, although morphologically it never develops as such.Placental exchanges mechanisms
Many of the transport mechanisms required to effect exchange are present in the primitive placenta and these may be up- or downregulated throughout the rest of pregnancy to meet the requirements of fetal growth and homeostasis. For a molecule to reach the fetal plasma from the maternal plasma, and vice versa, it must cross the syncytiotrophoblast, the villous mesenchyme, and the endothelium of the fetal capillary. There is also some limited transfer between maternal blood in the decidua and the fluid of the amniotic sac.
Exchange across the definitive placenta occurs by one of the four following mechanisms: bulk flow/solvent drag, diffusion, transporter-mediated mechanisms, and endocytosis/exocytosis (32-35). Water, and with it dissolved solutes, is transferred by bulk flow and is driven by differences in hydrostatic and osmotic pressures between the maternal and fetal circulations across the exchange barrier. The dissolved solutes are filtered as they move through the components of the villous barrier. Water movement may also be via paracellular channels or through pores in the plasma membranes.
Diffusion of any molecule occurs in both directions across the villous barrier. When there is a concentration gradient and/or, for charged species, an electrical gradient, one of these unidirectional fluxes (rates of transfer) is greater in one direction than it is in the other, so that there is a net flux in one direction.
The rate of diffusion of an inert molecule is governed by Fick's law, and so is proportional to the surface area for exchange divided by the thickness of the tissue barrier. A large surface area will therefore facilitate exchange, and this is achieved by repeated branching of the villus trees. Small molecules such as oxygen diffuse rapidly whereas hydrophilic molecules such as glucose will not diffuse easily. Rates of diffusion of many molecules are flow limited, and thus may vary over gestation with changes in uteroplacental and fetoplacental blood flow. Changes in concentration and, for charged molecules, electrical gradients between maternal and fetal plasma will also affect rates of transfer.Some amino acids and glucose are transported across the villous membrane at faster rates than they would occur by diffusion and down concentration gradients (35). Transporter proteins are a large and diverse group of molecules which are found most abundantly in the placenta in the microvillous, and basal plasma membranes of the Syncytiotrophoblast. Large proteins such as immunoglobulin cross the placenta via endocytosis. These molecules are entrapped in invaginations of the microvillous plasma membrane of the syncytiotrophoblast which detach and pass across the intracellular compartment. They eventually fuse with the basal plasma membrane and undergo exocytosis, releasing their contents into the fetal circulation.
Placental endocrinology
As pregnancy advances, the relative number of trophoblastic cells increases and fetomaternal exchange begins to be dominated by the secretory function of the placenta (36). The placenta is a major endocrine organ, secreting over 100 peptide and steroid hormones that modulate maternal physiology. Placental hormones have profound effects on maternal metabolism, initially building up her energy reserves and then releasing these to support fetal growth in later pregnancy and lactation postnatally (28).
Human chorionic gonadotropin (hCG) is the major pregnancy glycoprotein hormone (37).
It is mainly secreted by the villous syncytiotrophoblast into the maternal blood, where its concentration peaks around 8-10 weeks of gestation. It is detectable in maternal blood 2 days after implantation and behaves like an agonist of luteinizing hormone, stimulating progesterone secretion by the corpus luteum. hCG has also a role in inducing quiescence of the myometrium and local immune tolerance.One of the essential roles of the human placenta is to produce the steroid hormone progesterone, which is required for the maintenance of pregnancy (15). Placental synthesis of progesterone begins with the conversion of cholesterol to pregnenolone, as in other steroid- secreting tissues. The rate-determining step of placental progesterone synthesis is the conversion of cholesterol to pregnenolone. The principal actions of the hormone are to maintain quiescence of the myometrium, and maintain the secretory activity of the endometrial glands. Progesterone acts as a negative regulator of trophoblast invasion by controlling matrix metalloproteinase activity (36). It may also be part of the compensatory mechanism that limits the inflammation-induced cytotoxic effects associated with an infection process during gestation (38).
Placental lactogens and growth hormone exert anti-insulin effects and promote lipolysis, boosting maternal glucose and free fatty acid concentrations for exchange to the fetus. Placental growth hormone induces maternal insulin resistance and thereby facilitates the mobilization of maternal nutrients for fetal growth. Human placental lactogen and prolactin increase maternal food intake by induction of central leptin resistance and promote maternal beta-cell expansion and insulin production to defend against the development of gestational diabetes (18). Pregnancy-associated protein A, which is mainly produced by the villous trophoblast, is a key regulator of insulin-like growth factor bioavailability essential for normal fetal development.
The transcriptional regulation of the P450arom gene has been shown to be oxygen responsive through a novel pathway involving the basic helix-loop-helix transcription factor Mash-2 (39). Changes in oxygenation that occur at the end of the first trimester when the intervillous circulation begins may modulate the synthesis of various trophoblastic proteins, such as oestrogens (39) and hCG (40). These findings illustrate the impact of the anatomical changes occurring during the transition from the primitive to the definitive placenta on trophoblastic hormonal synthesis.