Development and Modulation of Female Reproductive Function by Circadian Signals

Abstract

Female reproductive success requires multifaceted, temporally coordinated hormone secretion. The circadian timing system is central to this complex neuroendocrine regulation, with circadian disruption associated with irregular ovulatory cycles, reduced fertility, increased miscarriage rates, and anomalous fetal development. Because living in the modern world is associated with relatively chronic circadian disruption due to limited sunlight exposure during the day and exposure to artificial light at night, this issue is of broad concern. The master mammalian circadian pacemaker in the suprachiasmatic nucleus communicates monosynaptically to neuroendocrine cells in the brain to mediate the hormonal events required for ovulation and pregnancy maintenance. Likewise, maternal hormones cross the placenta to drive rhythmic fetal processes critical for typical development. The present overview describes the means by which the circadian timing system integrates with the reproductive axis to regulate female reproductive functioning. Likewise, the negative consequences of circadian disruptions on female reproductive health, and the mechanisms underlying these deleterious outcomes, are considered.

Key References

• de Roux et al. (2003)—The authors investigated individuals with hypophysiotropic hypogonadism and mice lacking the GPR54 gene, establishing a critical role for this G-protein coupled receptor, the cognate receptor for Kiss1 gene protein products (i.e., kisspeptin), as critical for reproductive function.

• Endo and Watanabe (1989)—This article describes the effects of non-24 h days on female reproduction in mice. The authors found that mice maintained on a 22 or 26 h light:dark cycle exhibit decreased mating behavior and experience higher rates of fetal resorption, reduced embryo weights, and delayed development.

• Kriegsfeld et al. (2006)—Based on the discovery of gonadotropin-inhibitory hormone (GnIH) in birds, the authors provided the first, broad characterization of GnIH (also known as RFamide-related peptide-3) in mammals (i.e., rats, mice and hamsters), establishing a more general modulatory role for this neuropeptide across species.

• Mendez et al. (2012)—This article demonstrated a role for melatonin in fetal development and rhythm generation/synchronization. The authors established that exposure of pregnant rats to constant light during the second half of gestation negatively affects fetal development, with embryos exhibiting intrauterine growth retardation and disrupted adrenal clock genes and clock-controlled genes as well as altered corticosterone rhythms. However, when mothers received melatonin during their subjective night, reproductive function was rescued.

• Miller et al. (2006)—This article examined reproduction of Clock mutant mice, establishing an important role for circadian rhythms in female reproductive function. The authors found that Clock mutant mice exhibit disruptions in estrous cyclicity and pregnancy maintenance, including higher rates of fetal resorptions and fewer pregnancies reaching full term.

• Seminara et al. (2003)—This article employed complementary approaches in humans and mice to investigate the onset of puberty. The authors found that mutations in the G-protein coupled receptor, GPR54, the cognate receptor kisspeptin, caused idiopathic hypophysiotropic hypogonadism in both mice and humans. This finding was key to identifying a critical role for kisspeptin in reproductive functioning.

• Takayama et al. (2003)—This article demonstrated a role for melatonin in timing parturition. The authors found that female rats lacking melatonin deliver pups throughout the day and night, unlike melatonin-proficient rats who enter parturition during the day. Melatonin administration to rats exclusively during the dark phase restored parturition to daytime.

• Tsutsui et al. (2000)—This article identified a hypothalamic peptide that inhibits gonadotropin release in a vertebrate pituitary and named it gonadotropin-inhibitory hormone (GnIH). This finding represented a discovery with broad implications for understanding reproductive axis regulation.