Hormonal Regulation of Circadian Pacemaker in Ovary and Uterus

Ovarian folliculogenesis is characterized by drastic proliferation and differentiation of granulosa cells and theca cells. Although it is well accepted that gonadotropins and ovarian steroids play the central roles in follicular development by controlling follicular microenvironments, intrafollicular substances including growth factors and cytokines are known to function as modulators of ovarian follicular growth and development. Differentiation of granulosa cells involves follicle-stimulating hormone (FSH)-induced maturation of immature cells into mature cells. The expressions of related genes are rigidly controlled until ovulation, and then granulosa and theca cells are finally differentiated into luteal cells, which produce progesterone. On the other hand, the uterus is closely synchronized to the ovary: increasing ovarian steroids regulate the uterus as one of the principal targets to prepare for embryo implantation following fertilization. In the uterus— composed of heterogeneous cell types including luminal and glandular epithelial cells, stroma cells, and muscle layers—estradiol stimulates the proliferation of epithelial cells, whereas progesterone inhibits estradiol-induced hyperplasia of the epithelial compartments (Carson et al., 2000). In rodents, the endometrial stroma cells undergo proliferation and decidualization in response to ovarian steroids and embryo implantation at the early stage of pregnancy (Clarke & Sutherland, 1990; Dey et al., 2004). Thus, cellular functions in the ovary and uterus are accompanied by cyclic changes of cell proliferation, differentiation and apoptosis. The circadian clock system may contribute to the progress of follicular development, luteinization and luteolysis, and steroid hormone-induced proliferation and differentiation of uterine cells through fluctuating hormones. Recently, there is a growing body of evidence that circadian clock genes are expressed in reproductive tissues including the ovary and uterus (Johnson et al., 2005; Nakamura et al., 2005; Fahrenkrug et al., 2006; Dolatshad et al., 2006; Karman & Tischkau, 2006; He et al., 2007a, 2007b, 2007c; Nakao et al., 2007; Hirata et al., 2009; Sellix & Menaker, 2010; Uchikawa et al., 2011). Many regulatory elements are located at the upstream of clock genes, such as steroid hormone response element half-sites and the adenosine 3’,5’-cyclic monophosphate (cAMP) response element site as well as E-box and D-box elements. The mammalian circadian system is composed of three components: input pathways, central pacemaker, and output pathways. The input pathways transmit environmental signals to the central pacemaker, which coordinates the external signals with the central endogenous rhythm of the body by neural, hormonal and behavioural cues (Reppert & Weaver, 2001; Schibler & Sassone-Corsi, 2002; Yamamoto et al.,