Circadian Rhythms Within the Female HPG Axis: From Physiology to Etiology

Abstract

Declining female fertility has become a global health concern. It results partially from an abnormal circadian clock caused by unhealthy diet and sleep habits in modern life. The circadian clock system is a hierarchical network consisting of central and peripheral clocks. It not only controls the sleep-wake and feeding-fasting cycles but also coordinates and maintains the required reproductive activities in the body. Physiologically, the reproductive processes are governed by the hypothalamic-pituitary-gonadal (HPG) axis in a time-dependent manner. The HPG axis releases hormones, generates female characteristics, and achieves fertility. Conversely, an abnormal daily rhythm caused by aberrant clock genes or abnormal environmental stimuli contributes to disorders of the female reproductive system, such as polycystic ovarian syndrome and premature ovarian insufficiency. Therefore, breaking the "time code" of the female reproductive system is crucial. In this paper, we review the interplay between circadian clocks and the female reproductive system and present its regulatory principles, moving from normal physiology regulation to disease etiology.

Keywords: Circadian clock; clock genes; female reproductive disorders; hypothalamic–pituitary–gonadal axis.

Figure 1.

Organization of the circadian clock system within the female hypothalamic–pituitary–gonadal (HPG) axis. The light entrains the central clock in the suprachiasmatic nucleus (SCN), which drives the daily rhythms of the sleep-wake and feeding-fasting cycles, as well as hormone release within the HPG axis. The circadian clock works at the HPG axis by means of transcription and translation feedback loops. In the main loop, the transcriptional activators CLOCK-BMAL1 activate the transcription of PER, CRY, DBP, ROR, and REV-ERB genes. PER and CRY proteins physically interact and suppress the activities of CLOCK-BMAL1. REVERB and ROR compete to bind with the promoter and enhancer regions of the BMAL1 and play an inhibitory and activation role in transcription, respectively. DBP forms another loop, and it competes with the REV-ERB and ROR target gene NFIL3 to regulate the expression of the clock genes. All these loops control the expression of clock-controlled genes (CCGs), which mediate various reproductive processes. (The yellow box shows the CCGs mentioned in this article.)

Figure 2.

Chronodisruption caused by environmental cues within the female HPG axis. (A) Environmental cues that lead to circadian rhythm disruption within the HPG axis. (B) Circadian clock misalignment induces multiple pathophysiological alternations in the female reproductive system.