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 (PCOS) and premature ovarian insufficiency (POI). 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.

Impact of sleep patterns upon female neuroendocrinology and reproductive outcomes: a comprehensive review

“…Proper SCN rhythmicity, mediated by Clock genes, stimulates Gonadotropin Releasing Hormone (GnRH) pulsatility and pituitary luteinizing hormone (LH) release through two different neural networks: vasoactive intestinal peptide (VIP)-containing neurons and arginine vasopressin (AVP)-containing neurons [ 18 ]. VIP-containing neurons project from the SCN to GnRH neurons directly, whereas AVP-containing neurons project from the SCN to anteroventral periventricular nucleus Kisspeptin neurons and stimulate GnRH and LH secretion indirectly [ 22 – 24 ]. Clock mutant mice exhibit decreased expression of AVP in their SCN and have irregular estrous cycles without an LH surge [ 25 ].…”

“…Female mice lacking Bmal1 also do not exhibit any LH or follicle stimulating hormone (FSH) surge [ 29 ]. Within granulosa cells, periodic fluctuations in estradiol and progesterone have been observed and are mediated via circadian regulation of aromatase [ 24 ]. The Bmal1 - Clock dimer binds to the E-box sites of Cyp19a1 and StAR promoter, regulating their transcription and the synthesis of estrogen and progesterone [ 30 , 31 ].…”

“…In the follicular phase of the menstrual cycle, FSH, LH, estrogen, progesterone, and SHBG display rhythmicity, whereas in the luteal phase, only FSH and SHBG demonstrate rhythmicity [ 21 ]. Disruption of SCN rhythmicity, as may occur with altered sleep, leads to disruption of the hypothalamic-pituitary–gonadal (HPG) axis, and thus loss of synchronized release of reproductive hormones [ 18 ], which may contribute to altered reproductive processes [ 24 , 55 – 57 ].…”

“…POI is defined as the cessation of menses due to ovarian failure before the age 40 years. Premature declining ovarian reserve is replicated in multiple Clock -gene deficient rodent models, such as Per1 and Per2 loss-of-function mutations, suggesting that disruption in circadian rhythmicity may play a role in the pathophysiology of POI [ 24 , 39 ]. In a cross-sectional study of 61 women with POI receiving hormone therapy (HT) compared to 61 age-matched individuals, women with POI receiving HT had poorer sleep quality, took longer to fall asleep, and had higher fatigue index [ 160 ].…”

Identification of Circular RNAs in the Anterior Pituitary in Rats Treated with GnRH

“…This axis produces gonadotropins, mainly FSH and LH [ 25 ], and plays important physiological roles. Recent studies have shown that the HPG axis regulates the reproductive process in a time-dependent manner, and circadian rhythm disorders can lead to diseases, such as polycystic ovarian syndrome (PCOS) and premature ovarian insufficiency (POI) [ 26 ].…”