The ticking clock sets the pace for female fertility

At a time when an increasing number of men and women face fertility issues, it is necessary to understand the basic mechanisms involved in mammalian reproductive activity in order to propose adapted therapeutic tools. This review describes how endogenous circadian clocks take part in the timing of reproductive cycles in female mammals and, consequently, how exposure to circadian disruption may impair female fertility. In female mammals, the master circadian clock, located in the hypothalamic suprachiasmatic nuclei (SCN), uses a vasopressinergic output to knock on preoptic kisspeptin (Kp) neurons each day at the onset of the active period. Kp is a potent activator of neurons producing the gonadotropin-releasing hormone (GnRH) controlling the release of the pituitary gonadotropins luteinizing (LH) and follicle-stimulating (FSH) hormones, which in turn promote ovarian gameto- and steroido-genesis. Estradiol, produced as oocytes mature, exerts positive feedback on Kp neurons. This dual control of Kp neuronal activity by the clock-driven vasopressin output and the elevated circulating estradiol allows a large increase in GnRH-induced LH release at the onset of the waking period, at the end of the follicular phase, triggering the release of mature oocytes. Additionally, different parts of the reproductive axis also host secondary circadian clocks that participate in the daily and ovarian regulation of female reproductive cycles. Different experiments revealed the functional significance of the circadian regulation of female reproduction. Indeed, exposure of female rodents to different protocols of circadian disruption impairs estrous cycle robustness, LH surge timing, and gestational success. Additionally, epidemiological studies indicate that women working non-standard schedules face increased risks of reproductive issues. Therefore, when women seek medical assistance for infertility, lifestyle factors, including work schedule organization, should be assessed. Chronotherapeutic interventions could then be considered to enhance the robustness of female reproductive cycles and, as a result, improve their reproductive health.