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This version published online on June 11, 2009
Endocrinology, doi:10.1210/en.2008-1280
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Submitted on September 2, 2008
Accepted on June 4, 2009

Timing of the ovarian circadian clock is regulated by gonadotrophins

Tomoko Yoshikawa, Michael Sellix, Pinar Pezuk, and Michael Menaker*

Department of Biology, University of Virginia, Charlottesville, VA 22904-4328

* To whom correspondence should be addressed. E-mail: mm7e{at}virginia.edu.

The timing of ovulation is critically important to the success of reproduction. Current thinking attributes the timing of ovulation to luteinizing hormone (LH) secretion by the pituitary, itself timed by signals from the hypothalamus. The discovery of an internal circadian timer in the ovary raises the possibility that ovulation is in fact timed by an interaction between clocks in the hypothalamus/pituitary and those in the ovary. We asked whether ovarian clocks were influenced by signals from the brain and pituitary. Ovaries of Period1-luciferase transgenic rats display circadian rhythms in vitro. To determine whether the phase of these rhythms is set by neural or endocrine signals we surgically denervated or heterotopically transplanted ovaries with or without encapsulation in dialysis membranes. Animals' light-dark cycles were phase advanced or delayed six hours and the resetting of the ovarian clock was tracked by culturing ovaries at intervals over the next 12 days. Resetting trajectories of control, surgically denervated, and encapsulated ovaries were similar, demonstrating that endocrine signals are sufficient to transmit phase information to the ovary. We next evaluated LH and follicle stimulating hormone (FSH) as potential endocrine signals. Using the phase of Per1-luc expression in granulosa cell cultures, we demonstrated that both of these pituitary hormones caused large phase shifts when applied to the cultured cells. We hypothesize that the ovarian circadian clock is entrained by hormonal signals from the pituitary and that ovulation depends, in part, on the phase in the ovarian circadian cycle at which these signals occur.


Key words: period1-luciferase • luteinizing hormone • follicle stimulating hormone • granulosa cells • rat







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