Impact of the Reproductive Cycle on the Timing of the Circadian System.

Abstract

The circadian clock, an autoregulatory transcriptional oscillator, has been implicated in the timing of endocrine physiology and rhythms of clock gene expression have been described in tissues of the hypothalamo-pituitary-gonadal (HPG) axis. It is well known that reproductive physiology depends on the timing of hierarchical control by the central clock in the suprachiasmatic nucleus (SCN), though recent evidence suggests that timing in this system may also depend on peripheral clock function. Limited evidence reveals that gonadal steroid hormones may alter circadian rhythms of locomotor activity and clock gene expression in tissues of the female reproductive tract. It has been suggested that these effects are mediated by the direct action of steroid hormone receptors on clock- and clock-controlled gene expression in target tissues. However, a systematic analysis of the effects of the reproductive cycle on the coordinated timing of peripheral clocks has not yet been reported. We have examined circadian timing in peripheral clocks across the reproductive cycle. Cycling adult (>60 day old) rats expressing the Period1-luciferase (Per1-luc) clock gene reporter were sacrificed across the four-day cycle. The liver, kidney, lung, pituitary, cornea, oviduct, adipose tissue and individual pre-ovulatory follicles were cultured and Per1-luc expression was analyzed for at least 5 days in vitro. We examined phase synchrony among tissues and phase relationship within tissue across animals as a function of cycle day. Though we saw only modest, organ-specific effects in those tissues associated with metabolism (liver, lung, WAT), we did observe a significant effect of the cycle on synchrony and phase relationships in tissues of the HPG axis (follicles, pituitary) as a function of cycle day. These data suggest that fluctuations in ovarian steroid hormones across the cycle can alter the timing of the circadian system, presumably as a means to coordinate the timing of clock-dependent gene expression in target tissues. It remains to be seen if diseases that have substantial effects on steroid hormone secretion, such as polycystic ovarian syndrome, compound their effects by disrupting phase coordination between central and peripheral oscillators of the metabolic system and HPG axis.