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.

Introduction

Most biological processes, from gene expression to complex behaviors, fluctuate on an ~24-hour cycle and are called circadian rhythms (the Latin “circa diem” means “around a day”) [1]. Circadian rhythms are generated by endogenous molecular clocks so they persist in the absence of external input. However, they also entrain to, or synchronize with, environmental cycles caused by the rotation of the earth on its axis [2]. In this way, circadian rhythms allow animals to anticipate predictable, daily changes in the environment to optimize the timing of behavior and physiology and improve fitness and longevity [3], [4], [5].

The mammalian circadian system is a multi-oscillator network organized hierarchically to coordinate internal rhythms with external cycles [6]. Nearly every cell in the body has a circadian rhythm and timing of cellular clocks are coordinated within tissues and organs [7]. In mammals, the suprachiasmatic nucleus (SCN) in the hypothalamus is at the top of the hierarchy. The SCN receives input about ambient lighting from the retina and entrains to the light-dark cycle. The SCN then coordinates the timing, or phases, of circadian clocks in central and peripheral tissues in the body.

Estrogens regulate a myriad of biological processes from gene expression to reproduction to complex behaviors [8], [9], [10], [11]. Estrogens are steroid hormones mostly produced by ovaries, but also by the brain, adipose tissue, stomach, bone, and skin in female rodents [10]. Estrogen signaling is mediated by several types of estrogen receptors that are expressed throughout the body [8].

Decades of research have demonstrated that the circadian and endocrine systems interact to coordinate the timing of hormone production and secretion with reproductive physiology and behaviors [11], [12], [13]. Recent studies, many of them using estrogen receptor knockout and circadian reporter mice, have elucidated additional interactions between estrogens and the circadian system. In this article, we synthesize current understanding of the interplay between estrogens and the circadian system with a focus on female rodents.