Estrogens and the circadian system

Abstract

Circadian rhythms are ~24 h cycles of behavior and physiology that are generated by a network of molecular clocks located in nearly every tissue in the body. In mammals, the circadian system is organized hierarchically such that the suprachiasmatic nucleus (SCN) is the main circadian clock that receives light information from the eye and entrains to the light-dark cycle. The SCN then coordinates the timing of tissue clocks so internal rhythms are aligned with environmental cycles. Estrogens interact with the circadian system to regulate biological processes. At the molecular level, estrogens and circadian genes interact to regulate gene expression and cell biology. Estrogens also regulate circadian behavior across the estrous cycle. The timing of ovulation during the estrous cycle requires coincident estrogen and SCN signals. Studies using circadian gene reporter mice have also elucidated estrogen regulation of peripheral tissue clocks and metabolic rhythms. This review synthesizes current understanding of the interplay between estrogens and the circadian system, with a focus on female rodents, in regulating molecular, physiological, and behavioral processes.

Keywords: Circadian rhythm; Clock genes; Estradiol; Female; Mouse; Suprachiasmatic nucleus.

Figure 1.. The luteinizing hormone (LH) surge and ovulation are precisely timed during the estrous cycle in female mice.

The estrous cycle is 4–5 days in female mice. A 5-day estrous is shown as female mice often remain in diestrus for >24h when they are housed without a male. Circulating estrogens increase during diestrus and proestrus and peak at the LH surge. The LH surge occurs in the late afternoon/early night (ZT12 in mice) of proestrus and signals the beginning of estrus, or heat. Ovulation occurs ^~12h later, coincident with copulatory behavior.

Figure 2.. Everett and Sawyer showed that a neural timing signal on the afternoon of proestrus was necessary for ovulation.

Female rats housed in 14L:10D had LH surges at 16:00 and ovulated 9–11 hours later at 01:00 (A). When the rats were treated with Nembutal (pentobarbital) at 14:00, the LH surge and ovulation were delayed by 24h (B). When the rats were treated with Nembutal at 16:00, the LH surge and ovulation occurred at the usual times (C). These experiments showed that the “LH release apparatus” was a timed neural signal that acted during the “time limits of pituitary activation” to induce the LH surge [20].

Figure 3.. The molecular circadian timekeeping mechanism and clock output in mammals.

A. The transcription factors BMAL1 and CLOCK heterodimerize and bind to E-boxes in the promotor regions of the Cry and Per genes, which are then transcribed and translated. CRY and PER heterodimerize, are phosphorylated (not shown), and then feedback to inhibit transactivation by BMAL1-CLOCK. B. BMAL1-CLOCK also binds to E-boxes to drive rhythmic transcription of many clock-controlled genes, including ERα and ERβ, which are outputs of the molecular clock.

Figure 4.. Estrogens and the circadian system interact in the HPG axis.

The SCN regulates activation of GnRH neurons via direct VIPergic projections to the POA and indirect AVPergic projections to kisspeptin (KISS) neurons in the AVPV. As the ovarian follicle develops, it releases increasing amounts of estrogens. On the afternoon of proestrus, high levels of estrogens coincide with the SCN-dependent daily timing signal to stimulate the GnRH surge, and subsequently the LH surge and ovulation.

Figure 5.. Estradiol regulates daily metabolic rhythms in female mice.

Female C57BL/6J mice were cycling (gonadally intact: A,D), ovariectomized (OVX: B,E) or ovariectomized and implanted with Silastic tubing that delivered physiological levels of estradiol (C,F). A-C. Representative actograms of eating behavior rhythms recorded during fed low-fat diet (LFD) and high-fat diet (HFD) feeding. D-F. Circular histograms show the amplitude of the eating behavior rhythm was reduced by HFD in OVX, but not in cycling females or in OVX females treated with estradiol (length of arrow is amplitude). G. The phase of the liver PER2::LUC rhythm was advanced 4h by HFD in OVX females compared to cycling and estradiol-treated OVX females. *p<0.05. Adapted from [126, 127].