Table 1.

Summary of clock genes’ location and the proposed mechanisms of the effects on mammalian reproduction.

Clock Genes	Location	Proposed Function	References
PER1	SCN, premature ovarian follicle	Participate in the coordination of GnRH and LH surge.	[46] Zheng et al., 2019
		Melatonin helps in the regulation of the expression of clock genes at neural and peripheral tissue levels.	[47] Coelho et al., 2015;
		Knockdown of Per1 or Per2 hampers fertility by the disruption of the estrus cycle.	[48] Toffol et al., 2016
		Per1 plays a role in sustainable pregnancy by stimulating progesterone secretion.	[46] Zhang et al., 2019
PER2	SCN, ovarian corpora leutium, granulosa cell, and oviduct	Knockdown of PER2 leads to the flattened diurnal oscillation of all the core clock genes and to disorganized human endometrial stromal cells.	[45] Zhang et al., 2019
		Per2 influence granulosa cell functions, including cell proliferation, steroid production, and LH receptor expression, (which are associated with the follicular recruitment and selection of follicles.	[49] Nagao et al., 2019
		Mutations in Per2 genes reduces the number of ovarian follicles and leads to a adecrease in the fertility process.	[50] Pan et al., 2020
CRY1/CRY2	SCN, leutinized granulosa cell	An age-related decreased expression of these clock genes may partially explain the decreased fertility and steroidogenesis of older women.	[37] Brzezinski et al., 2018
BMAL1	SCN, ovary (antral follicles, corpora leutium), oviduct, GnRH neuron	Bmal1 expression in progesterone induction from leuteinized granulosa cells and maintenance of the postovulatory progesterone surge.	[49] Nagao et al., 2019
		Expression of BMAL1 in the GnRH neuron determines the timing of secretion of GnRH.	[51] Sen and Sellix, 2016
		Brain and muscle ARNT-like protein 1 (BMAL1) is necessary for fertility and is essential for follicle growth and steroidogenesis.	[45] Zhang et al., 2016
		Minor changes in Bmal1 can alter the timing of LH surge.	[41] Sen and Hoffmann 2020
		Deletion of BMAL1 in ovarian theca cells disrupts the ovulation.	[52] Mereness et al., 2016
		Bmal1 plays a role in the molecular clock of ovarian steroidogenic cells, the production of progesterone, and other aspects of female reproduction.	[50] Pan et al., 2020
CLOCK	SCN, ovary (late antral follicle)	Knockdown of CLOCK expression in the ovary leads to a significant reduction in litter size and oocyte release.	[50] Pan et al., 2020
		The heterodimer of BMAL1 and CLOCK determines the timing of secretion of the steroid hormone.	[53] Li et al., 2020
		Rhythms of lhcgr expression are directly regulated by the BMAL1:CLOCK enhancer complex binding to E-box motifs in the lhcgr promoter.	[54] Sellix, 2015
		Defective CLOCK protein enhances the rate of anovulation and pregnancy failure.	[55] Sciarra et al., 2020