MI-773 The underlying mechanisms of how progesterone prolong
The underlying mechanisms of how progesterone prolongs pregnancy, although not completely understood, are thought to have to do with reduction in uterine contractility, antimicrobial protein up-regulation, immunosuppression, and inflammatory inhibition. Specific to preterm PROM, progesterone has been shown to inhibit the tumor necrosis factor and thrombin-induced mechanisms of membrane weakening. Women with preterm PROM also have been shown to have lower levels of progesterone receptor membrane component 1, which is a protein that is mediated by progesterone to stabilize the membrane. Although progestogens generally are initiated between 16 and 20 weeks gestation, initiation of progestogens up to 27 weeks is associated with a decrease in the risk of preterm birth. Given this benefit in the late second trimester and the mechanisms of pregnancy prolongation in women with a risk of preterm birth, it is reasonable to suspect that the administration of progestogens would result in prolonging pregnancy after preterm PROM.
Introduction Progestogens are compounds that exhibit progestational activity, and include both endogenous progesterone (Prog) and synthetic progestogens designed to mimic its actions. A wide variety of synthetic progestogens is available and their common progestogenic effects are exploited for many therapeutic applications in female reproductive medicine, including their use in contraception and for menopausal therapy. However, these synthetic progestogens also exhibit a range of biological effects that differ not only from each other, but also from that of Prog , , . Choice of progestogen for maximal benefit and minimal side-effects is hampered by a limited understanding of their relative mechanisms of action due to insufficient comparative clinical and molecular studies. Multiple factors such as route of delivery, metabolism and binding to and regulation of serum proteins affect the bioavailability of the active form of progestogens at target MI-773 , , , , . Progestogens mediate their intracellular effects by modulating transcription of target genes in specific cells via binding not only to the progesterone receptor (PR), but also with varying affinities to other steroid receptors (SRs) such as the glucocorticoid, mineralocorticoid and androgen receptors (GR, MR and AR, respectively) , , , . It is generally assumed that their progestational effects are mediated via the PR in female reproductive tissue while the plethora of side-effects occur via the GR, AR and MR. SRs are ligand-activated transcription factors that function by similar genomic mechanisms, but differ in their target genes and tissues . Once the inactive receptor is activated by hormone binding, the hormone receptor–complex translocates to the nucleus where it binds to specific DNA sequences in the promoter regions of target genes to activate (transactivation) gene expression. In contrast, the expression of specific target genes can also be repressed (transrepression) via protein–protein interactions between the receptor and other transcription factors such as nuclear factor-kappa B (NFκB) and activator protein-1 (AP-1) . A number of assays have been developed to elucidate the intracellular mechanisms of action of progestogens via specific receptors. Binding assays are used to determine the affinity of progestogens for a specific receptor in a number of different model systems, including animal or human tissue or cell lines, as well as in vitro systems. In contrast, most of the data on the subsequent relative biological responses via different SRs following binding, including the potency, efficacy, and biocharacter of the progestogens, have been obtained from animal experiments , .
Receptor binding and affinity The affinity of a progestogen for binding to the PR and other SRs is a major determinant of the potency of its biological response since it affects receptor fractional occupancy and hence the percentage maximal response in a dose response curve. However it should be noted that receptor affinity may not reflect biological activity, which is also affected by the particular conformation of the receptor–ligand complex induced by ligand binding. This is well illustrated by the fact that an antagonist can have a higher affinity for a receptor than an agonist, but exhibits a very different biological response due to the induction of a different receptor conformation as compared to the agonist. Consistent with their different structures, reported affinities of different progestogens for SRs other than the PR vary widely. However, affinities reported for a particular progestogen for a specific SR also vary greatly, most likely due to different methods and sources of biological material used to determine affinity. Table 1 shows a range of relative affinities reported in the literature for progestogens binding to SRs, where the same reference agonist is used for a particular SR, while Supplementary Table 1 shows relative affinities reported using different reference agonists, as well as details of methods and model systems used.