Shuyi Shao, Huanqiang Zhao, Zhiying Lu, Xiaohong Lei, Ying Zhang, Circadian Rhythms Within the Female HPG Axis: From Physiology to Etiology, Endocrinology, Volume 162, Issue 8, August 2021, bqab117,


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.

Extract only, for the full study

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 PERCRYDBPROR, 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.)

Remaining Questions and Future Direction

The normal routine of working at sunrise and resting at sunset has been gradually eroded in the social development process. Instead, high-intensity working patterns along with consequent eating and sleeping disorders and other “modern diseases” are becoming the main theme of daily life. Therefore, larger population studies are needed to characterize this remolding of the circadian rhythm. On this basis, chronobiology can help reverse poor physical conditions and improve existing treatment methods.

As early as 1994, the United Nations highlighted the importance of reproductive health in human development. The decline in female fertility resulting from abnormal circadian rhythms caused by unhealthy diet and sleep habits in modern life has become a global health concern (124125). Therefore, breaking the “time code” of the female reproductive system is an urgent task. Despite a large number of studies at present, most studies confine the role of a certain clock gene to a specific cell. As the female reproductive system is by no means a simple superposition of cells and tissues, future chronobiology studies are encouraged from a holistic perspective. Furthermore, constructing and improving the circadian clock network of the female reproductive system is needed to help determine biomarkers that could detect and diagnose circadian rhythm disturbances.

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