Circadian Clock Function in the Mammalian Ovary

Rhythmic events in the female reproductive system depend on the coordinated and synchronized activity of multiple neuroendocrine and endocrine tissues. This coordination is facilitated by the timing of gene expression and cellular physiology at each level of the hypothalamo-pituitary-ovarian (HPO) axis, including the basal hypothalamus and forebrain, the pituitary gland, and the ovary. Central to this pathway is the primary circadian pacemaker in the suprachiasmatic nucleus (SCN) that, through its myriad outputs, provides a temporal framework for gonadotropin release and ovulation. The heart of the timing system, a transcription-based oscillator, imparts SCN pacemaker cells and a company of peripheral tissues with the capacity for daily oscillations of gene expression and cellular physiology. Although the SCN sits comfortably at the helm, peripheral oscillators (such as the ovary) have undefined but potentially critical roles. Each cell type of the ovary, including theca cells, granulosa cells, and oocytes, harbor a molecular clock implicated in the processes of follicular growth, steroid hormone synthesis, and ovulation. The ovarian clock is influenced by the reproductive cycle and diseases that perturb the cycle and/or follicular growth can disrupt the timing of clock gene expression in the ovary. Chronodisruption is known to negatively affect reproductive function and fertility in both rodent models and women exposed to shiftwork schedules. Thus, influencing clock function in the HPO axis with chronobiotics may represent a novel avenue for the treatment of common fertility disorders, particularly those resulting from chronic circadian disruption.