Progesterone withdrawal: key to parturition.

Whereas the essential role of progesterone in the maintenance of pregnancy is accepted generally, the mechanisms that suppress progesterone's function near term to allow labor and delivery of the conceptus are still shrouded in uncertainty. In most subprimate placental mammals, the withdrawal of progesterone before the initiation of labor is manifest by a significant drop in circulating progesterone levels, which is due to either luteolysis or changes in placental steroidogenesis, which shunts precursors towards estrogen production. No such events can be demonstrated in human pregnancy. In this review, we shall present a brief historic background of the research that led to the concepts of "progesterone block" and its withdrawal, based on experiments with rabbits and laboratory rodents, and discuss some of the more recent ideas about "functional progesterone withdrawal," in an attempt to bridge the apparent differences between the regulation of parturition in human and subprimate mammals.

Prostaglandins and the myometrium and cervix.

Prostaglandins have long been thought to play important roles in the mechanism of parturition. Here we review the involvement of prostaglandins in myometrial and cervical functions with emphasis on human labor and birth. In addition, the cellular sources of prostaglandins as well as their interactions with various other endocrine, paracrine and physical factors, such as oxytocin, corticotropin releasing hormone, nitric oxide, platelet activating factor, cytokines, endothelin and stretch are also addressed together with their potential role in the molecular reorganization of cervical structure associated with labor and delivery. Finally, the premier role of progesterone in pregnancy maintenance and parturition is juxtaposed with the proposed "fine-tuning", modulatory role of prostaglandins and the above listed factors in the regulation of parturition.

Interferon gamma antagonizes interleukin-1beta-induced cyclooxygenase-2 expression and prostaglandin E(2) production in human myometrial cells.

OBJECTIVE: To evaluate the effect of interferon gamma (IFNgamma) on interleukin-1beta (IL-1) and tumor necrosis factor-alpha (TNFalpha)-promoted prostaglandin E(2) (PGE(2)) production and to investigate the interaction of IFNgamma and IL-1 on cyclooxygenase-2 (COX-2) expression, as well as nuclear factor-kappaB (NF-kappaB) activation in human myometrial cells. METHODS: An immortalized human myometrial cell line was cultured in Dulbecco modified Eagle medium (DMEM) fortified with 10% (v/v) fetal calf serum (FCS) in multiwell plates until near confluency. Twenty-four hours before the start of the experiments, the medium was replaced with FCS-free medium containing 0.5% bovine serum albumin. Prostaglandin E(2) was determined in the medium with a specific radioimmunoassay having a sensitivity of 10 pg. The COX-2 and NF-kappaB inhibitory protein (IkappaB) protein levels were measured in cell extracts by Western blot. RESULTS: Cell cultures primed with IFNgamma produced significantly less (P <.05-.01) PGE(2) in response to cytokines than cells exposed to IL-1, TNF-alpha, or the combination of the two. This result corresponded to a similar inhibition of IkappaB degradation (a prerequisite of NF-kappaB activation) as well as COX-2 protein steady state levels. CONCLUSION: Interferon gamma acts as a partial antagonist of IL-1 signaling in this cell model at a site upstream from the activation of the NF-kappaB pathway, causing a partial inhibition of COX-2 expression and PGE(2) production.