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Circadian clocks and pregnancy

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The identification of circadian clocks in endocrine tissues has added considerable depth and complexity to our understanding of their physiology. A growing body of research reveals circadian clock gene expression in the uterus of non-pregnant and pregnant mammals.
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The identification of circadian clocks in endocrine tissues has added considerable depth and complexity to our understanding of their physiology. A growing body of research reveals circadian clock gene expression in the uterus of non-pregnant and pregnant mammals.

A key study to draw attention to the potential role of the circadian clock and pregnancy was that of Miller et al (2004), who reported that pregnant mice lacking the functional Clock gene (ClockΔ19) had prolonged and non-productive parturition, suggestive of a role for circadian clocks in the parturition event. Nakamura et al. (2010) showed changes in Per2::LUC rhythmic phase and amplitude in uterine explants treated with estrogen and progesterone. These results are consistent with the idea that ovarian steroid levels during the estrous cycle have a modulating influence of clock gene expression in the uterus. Ratajczak et al. (2010) examined expression of circadian clock genes in the mouse uterus in late pregnancy and found significant daily mRNA variations ex vivo for some but not for all clock genes. Using uterine explants from Per1::LUC rats Akiyama et al. (2010) showed clear rhythms of Per1 expression with peaks values near the predicted onset of the dark phase. Notably, the phasing of the rhythms was stable throughout pregnancy. Uterine stromal cells derived from transgenic Per2::LUC rats were shown to be rhythmic before, but not after, induced decidualization (He et al. 2007a; Hirata et al. 2009). Progesterone, but not estradiol, served to synchronize the circadian rhythms in these cells.

Many questions regarding circadian clocks in the mammalian uterus remain unresolved. Most notably is the issue of their physiological significance. Even given the evidence for a molecular clockwork in multiple cells of the uterus and data showing that the expression levels and/or amplitude of cycling clock genes are modulated by circulating steroids, a clear linkage to uterine physiology has yet to be clearly demonstrated. It can be speculated that various rhythmic events in the uterus depend on regulatory genes that are clock-driven, or that are under the control of circulating hormonal cues.

As evidence continues to accumulate for the expression of circadian clocks in the various layers of the mammalian uterus, numerous questions arise as to the identity of the cues for entrainment of these peripheral clocks, the synchronizing mechanisms across the uterus, as well as downstream clock gene targets. Identifying physiologically important downstream targets for circadian clock genes in the uterus has yet to be achieved, but research in this field promises to contribute new and important insights into normal and pathological uterine physiology. These developments will contribute greatly to new diagnostic and therapeutic approaches in obstetrics and gynecology, as well as improving our basic understanding of circadian mechanisms in all endocrine systems.


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