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.

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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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