The role of progesterone in the prevention of preterm labour

Abstract

Hormonal interactions are indispensable to control the establishment of pregnancy, foetal development, and even the process of parturition. The placental progesterone, along with other hormones, act as allocrine factors, being produced by one organ and used by another, to modify the maternal environment and satisfy the needs of the growing foetus. Parturition is divided into different phases depending on the contractile activity of the myometrium. The initial phase is termed “Phase 0” (quiescence), wherein the myometrium is relaxed and relatively insensitive to stimulatory uterotonics (substances that regulate myometrial tone and contractility) such as prostaglandins and oxytocin. Instead relaxatory uterotropins and uterotonics, such as progesterone, β-adrenergic agents, prostacyclin (PGI2), relaxin, CRH, nitric oxide, work to maintain pregnancy. Generally, all these regulatory factors activate adenylyl cyclase and increase intracellular cAMP. Parturition begins at the transition from “Phase 0” to “Phase 1”, when the myometrium gains response to uterotonics and starts to contract forcibly and rhythmically. This is made possible by progesterone withdrawal and an increase in oestrogen drive. Also, the myometrium is transformed by the expression of genes known as contraction-associated proteins (CAPs), which upregulate gap junctions between cells, ion channels, uterotonin receptors and enzymes. The progesterone withdrawal and oestrogen activation are not mediated by changes in the levels of these hormones but rather by the myometrial responsiveness to these hormones. Progesterone responsiveness depends on the activity of nuclear prostaglandin receptors (nPRs). PR-B is a principal ligand-dependant transcriptional modulator of progesterone responsive genes, which mediates relaxatory actions. Conversely, PR-A represses the transcriptional activity mediated by PR-B. In fact, it is the PR-A/PR-B expression ratio, which determines progesterone responsiveness, and it is hypothesised that progesterone withdrawal is mediated by an increase in this ratio. With regard to oestrogen, the two major subtypes of receptors are ERα and ERβ. ERα is drastically increased at term with the onset of labour, and it is directly associated with Cx43 expression (oestrogen-responsive CAP gene), thereby causing the functional oestrogen activation. Conversely, ERβ is not influenced by the onset of labour. “Phase 2” (active labour) is then initiated by the increase in the levels of prostaglandins and the increased sensitivity of the myometrium to the prostaglandins and oxytocin. This is characterised by rhythmic contractions, which become progressively more forceful. These contractions propel the foetus forward toward the birth canal, and eventually dilate the softened cervix so that the foetus and the placenta are both delivered. The main prostaglandins involved are PGE2 and PGF2α, which are produced by intrauterine tissues, mainly the amnion, chorion, decidua and myometrium. The rate limiting step of prostaglandins production is catalysed by cyclooxygenase, COX-1 and COX-2, enzymes. The prostaglandins are metabolised by prostaglandin dehydrogenase (PGDH), which irreversibly converts PGE2 and PGF2α to inactive forms. The actions of prostaglandins are mediated by specific prostanoid receptors. The other important mediator, oxytocin, is the most potent and specific stimulant of uterine contraction and is used to induce labour and treat postpartum haemorrhage. It is produced during pregnancy by the amnion, chorion and decidua. Despite its potency, it is generally not regarded as being involved in the initiation of labour. “Phase 3” begins after the placenta is expelled. The myometrial contractions are sustained in order to constrict the spiral arteries and minimise post-partum haemorrhage. Finally, the uterus returns to menstrual state by myometrial cell apoptosis and atrophy. The cervix also returns to its closed and rigid state. In pregnancy, immunological suppressor activity is carried out by T regulatory (Treg) cells that increase in number when progesterone levels are high. Treg cells influence other cells through cytokines, which may influence the survival and growth of the foetoplacental unit. Cytokines are also produced by the reproductive tract such as the uterine epithelium and trophoblast. Suppression may also be mediated by a soluble factor that is related to transforming growth factor-β (TGF-β) and by Prostaglandin (PGE2) by decidual cells and macrophages. All these cytokines and factors may inactivate lymphocytes. During pregnancy, the maternal immune system must protect the mother against any infections and tumours but at the same time must protect the foetus from any harmful immunological effects. This occurs by an altered T-helper 1 and T-helper 2 (TH1/TH2) cytokine balance. The establishment of pregnancy, successful foetal development and parturition is achieved by hormonal interactions between the mother, placenta and foetus. In addition, it is essential that there must be well-coordinated interactions between the maternal innate immune system and the trophoblast. The trophoblast and maternal immune system protect the foetus and mother against infectious microorganisms by acting in synchrony. Potentially dangerous molecular signatures are first identified by the trophoblast and then the maternal immune system responds in a coordinated way. The success of a pregnancy depends on good communication between the trophoblast and maternal immune system. Cytokines, which can be elaborated with or without the involvement of the immune system, are involved in this communication. The type of cytokines is very important in the success of pregnancy and it varies between implantation, early and late pregnancy and parturition. There are mutual interactions between the closely related endocrine and immune systems. The steroid hormones and cytokines act as mediators and messengers to achieve a successful pregnancy. An imbalance in hormones or cytokines can cause problems in pregnancies such as preterm birth, as well as miscarriage, pre-eclampsia and intrauterine growth retardation (IUGR).