The circadian rhythm, which is necessary for reproduction, is controlled by clock genes. In the mouse uterus, the oscillation of the circadian clock gene has been observed. The transcription of the core clock gene period (Per) and cryptochrome (Cry) is activated by the heterodimer of the transcription factor circadian locomotor output cycles kaput (Clock) and brain and muscle Arnt-like protein-1 (Bmal1). By binding to E-box sequences in the promoters of Per1/2 and Cry1/2 genes, the CLOCK-BMAL1 heterodimer promotes the transcription of these genes. Per1/2 and Cry1/2 form a complex with the Clock/Bmal1 heterodimer and inactivate its transcriptional activities. Endometrial BMAL1 expression levels are lower in human recurrent-miscarriage sufferers. Additionally, it was shown that the presence of BMAL1-depleted decidual cells prevents trophoblast invasion, highlighting the importance of the endometrial clock throughout pregnancy. It is widely known that hormone synthesis is disturbed and sterility develops in Bmal1-deficient mice. Recently, we discovered that animals with uterus-specific Bmal1 loss also had poor placental development, and these mice also had intrauterine fetal death. Furthermore, it was shown that time-restricted feeding controlled the uterine clock’s circadian rhythm. The uterine clock system may be a possibility for pregnancy complications, according to these results. We summarize the most recent research on the close connection between the circadian clock and reproduction in this review.

Inadequate dietary habits in youth are known to increase the risk of onset of various diseases in adulthood. Previously, we found that female college students who skipped breakfast had higher incidences of dysmenorrhea, suggesting that breakfast skipping interferes with ovarian and uterine functions. Since dietary habits can be managed by education, it is preferable to establish a convenient screening system for meal skipping that is associated with dysmenorrhea as part of routine services of health service centers. In this study, we recruited 3172 female students aged from 18 to 25 at Kanazawa University and carried out an annual survey of the status of students’ health and lifestyle in 2019, by a questionnaire. We obtained complete responses from 3110 students and analyzed the relationship between dietary habits, such as meal skipping and history of dieting, and menstrual disorders, such as troubles or worries with menstruation, menstrual irregularity, menstrual pain, and use of oral contraceptives. The incidence of troubles or worries with menstruation was significantly higher in those with breakfast skipping (p < 0.05) and a history of dieting (p < 0.001). This survey successfully confirmed the positive relationship between breakfast skipping and menstrual pain (p < 0.001), indicating that this simple screening test is suitable for picking up breakfast skippers who are more prone to gynecologic disorders. In conclusions, since dysmenorrhea is one of the important clinical signs, breakfast skipping may become an effective marker to predict the subsequent onset of gynecological diseases at health service centers. Considering educational correction of meal skipping, breakfast skipping is a potential and preventable predictor that will contribute to managing menstrual disorders from a preventive standpoint in the future.

There are growing concerns that poor dietary behaviors at young ages will increase the future risk of chronic diseases in adulthood. We found that female college students who skipped breakfast had higher incidences of dysmenorrhea and irregular menstruation, suggesting that meal skipping affects ovarian and uterine functions. Since dysmenorrhea is more prevalent in those with a past history of dieting, we proposed a novel concept that inadequate dietary habits in adolescence become a trigger for the subsequent development of organic gynecologic diseases. Since inadequate feeding that was limited during the non-active phase impaired reproductive functions in post-adolescent female rats, we hypothesize that circadian rhythm disorders due to breakfast skipping disrupts the hypothalamic–pituitary–ovarian axis, impairs the reproductive rhythm, and leads to ovarian and uterine dysfunction. To explain how reproductive dysfunction is memorized from adolescence to adulthood, we hypothesize that the peripheral clock system also plays a critical role in the latent progression of reproductive diseases together with the central system, and propose naming this concept “adolescent dietary habit-induced obstetric and gynecologic disease (ADHOGD)”. This theory will contribute to analyzing the etiologies of and developing prophylaxes for female reproductive diseases from novel aspects. In this article, we describe the precise outline of the above hypotheses with the supporting evidence in the literature.