Embryo implantation in the uterus is an essential process for successful pregnancy in mammals. In general, the endocrine system induces sufficient embryo receptivity in the endometrium, where adhesion-promoting molecules increase and adhesion-inhibitory molecules decrease. Although the precise mechanisms remain unknown, it is widely accepted that maternal–embryo communications, including embryonic signals, improve the receptive ability of the sex steroid hormone-primed endometrium. The embryo may utilize repulsive forces produced by an Eph–ephrin system for its timely attachment to and subsequent invasion through the endometrial epithelial layer. Importantly, the embryonic signals are considered to act on maternal immune cells to induce immune tolerance. They also elicit local inflammation that promotes endometrial differentiation and maternal tissue remodeling during embryo implantation and placentation. Additional clarification of the immune control mechanisms by embryonic signals, such as human chorionic gonadotropin, pre-implantation factor, zona pellucida degradation products, and laeverin, will aid in the further development of immunotherapy to minimize implantation failure in the future.

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.

Recently, it was demonstrated that the expression of BMAL1 was decreased in the endometrium of women suffering from recurrent spontaneous abortion. To investigate the pathological roles of uterine clock genes during pregnancy, we produced conditional deletion of uterine Bmal1 (cKO) mice and found that cKO mice could receive embryo implantation but not sustain pregnancy. Gene ontology analysis of microarray suggested that uterine NK (uNK) cell function was suppressed in cKO mice. Histological examination revealed the poor formation of maternal vascular spaces in the placenta. In contrast to WT mice, uNK cells in the spongiotrophoblast layer, where maternal uNK cells are directly in contact with fetal trophoblast, hardly expressed an immunosuppressive NK marker, CD161, in cKO mice. By progesterone supplementation, pregnancy could be sustained until the end of pregnancy in some cKO mice. Although this treatment did not improve the structural abnormalities of the placenta, it recruited CD161-positive NK cells into the spongiotrophoblast layer in cKO mice. These findings indicate that the uterine clock system may be critical for pregnancy maintenance after embryo implantation.

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.

We previously reported that skipping breakfast is associated with menstrual disorders of female college students during postadolescent maturation. In this study, we investigated the effects of meal timing during circadian cycle on the ovarian function using young female rats. Considering that rats are nocturnally active, 8-wk-old female Wistar rats were classified into 3 groups: fed during the daytime only (nonactive phase), night-time only (active phase), or control group I (without time or calorie restriction, free access to a standard caloric diet, 20.0% protein, 62.9% carbohydrate, and 7.0% fat, 3.95 kcal/g) for 4 wk. The changes in body weight and frequency of ovulation in each group were evaluated by a weight scale and a vaginal smear, respectively. At the end of the period of dietary restriction, ovaries were removed, and the numbers of growing follicles (mean diameter >250 µm) and corpora lutea (>600 µm) were examined using hematoxylin-eosin-stained tissue sections. In addition, 8-wk-old female rats were fed only during the night-time for 4 wk under a 20%-reduced food supply of the control group II (without any restriction). In the daytime-fed group, the frequency and number of ovulations were significantly decreased compared with those in the control group I (P < 0.05), with a reduced body weight gain concomitant with about 20% of reduction in the daily food intake. In contrast, in the night-time-fed group, even when a 20% reduction in the daily food intake was loaded, their estrus cyclicity did not change despite significant reductions in weight gain and food intake compared with control group II. These findings indicate that restricting food intake to the inactive phase impairs ovarian function in postadolescent female rats, suggesting that the timing of food intake during circadian cycle is one of the crucial factors interfering with the reproductive function.