To summarize the role of melatonin and circadian rhythms in determining optimal female reproductive physiology, especially at the peripheral level.
Design
Databases were searched for the related English-language literature published up to March 1, 2014. Only papers in peer-reviewed journals are cited.
Setting
Not applicable.
PATIENT(S): Not applicable.
INTERVENTION(S): Melatonin treatment, alterations of the normal light:dark cycle and light exposure at night.
MAIN OUTCOME MEASURE(S): Melatonin levels in the blood and in the ovarian follicular fluid and melatonin synthesis, oxidative damage and circadian rhythm disturbances in peripheral reproductive organs.
RESULT(S): The central circadian regulatory system is located in the suprachiasmatic nucleus (SCN). The output of this master clock is synchronized to 24 hours by the prevailing light-dark cycle. The SCN regulates rhythms in peripheral cells via the autonomic nervous system and it sends a neural message to the pineal gland where it controls the cyclic production of melatonin; after its release, the melatonin rhythm strengthens peripheral oscillators. Melatonin is also produced in the peripheral reproductive organs, including granulosa cells, the cumulus oophorus, and the oocyte. These cells, along with the blood, may contribute melatonin to the follicular fluid, which has melatonin levels higher than those in the blood. Melatonin is a powerful free radical scavenger and protects the oocyte from oxidative stress, especially at the time of ovulation. The cyclic levels of melatonin in the blood pass through the placenta and aid in the organization of the fetal SCN. In the absence of this synchronizing effect, the offspring may exhibit neurobehavioral deficits. Also, melatonin protects the developing fetus from oxidative stress. Melatonin produced in the placenta likewise may preserve the optimal function of this organ.
CONCLUSION(S): Both stable circadian rhythms and cyclic melatonin availability are critical for optimal ovarian physiology and placental function. Because light exposure after darkness onset at night disrupts the master circadian clock and suppresses elevated nocturnal melatonin levels, light at night should be avoided.
PMID 24996495 24996495 DOI 10.1016/j.fertnstert.2014.06.014 10.1016/j.fertnstert.2014.06.014 Reiter et al. 2014, Reiter 2014
Cite this article
Reiter, R. J., Tamura, H., Tan, D. X., & Xu, X. Y. (2014). Melatonin and the circadian system: contributions to successful female reproduction.. Fertility and sterility, 102(2), 321-8. https://doi.org/10.1016/j.fertnstert.2014.06.014
Reiter RJ, Tamura H, Tan DX, Xu XY. Melatonin and the circadian system: contributions to successful female reproduction.. Fertility and sterility. 2014;102(2):321-8. doi:10.1016/j.fertnstert.2014.06.014
Goldstein CA et al., 2016·Current Sleep Medicine Reports
Adequate sleep is crucial for general health and wellbeing. Although the neuronal control of the reproductive axis and sleep-generating neurons share an anatomical location, little is known regarding the impact of sleep and circadian disruption on fertility in women. Animal models have established clear circadian control of the pre-ovulatory luteinizing hormone surge. Additionally, disruption of the circadian timing system by exposure to abnormal light-dark cycles or mutations of core clock genes results in diminished reproductive capacity in animals. Abnormalities in menstruation, fertility, and early pregnancy maintenance in female shift workers provide evidence for a role of circadian rhythms in the reproductive health of women. Reproductive hormones may modify sleep, and the relationship is bidirectional such that sleep disruption may alter the profile of reproductive hormone secretion. Therefore, sleep, apart from its circadian timing, may also have relevance in attaining pregnancy. Additionally, infertility is associated with psychological distress which may result in poor quality sleep. The interaction between psychological distress and disturbed sleep in reproduction has garnered minimal attention and may be a crucial factor to consider during the evaluation and treatment of infertility. This work reviews animal models and evidence in women that suggest a role for sleep and circadian rhythms in reproductive health and reveals areas that require future investigation.
Infertility remains a common and often unresolved condition afflicting certain couples. Numerous animal studies have demonstrated that alterations in the light-dark cycle can affect reproduction as mediated by the pineal gland and its hormone, melatonin. To examine whether a similar disruption could affect human fertility, a pilot study was conducted with infertile women enrolled in a Natural Family Planning program.
Ecochard R et al., 2024·Fertil Steril·
Open Access
To study whether the menstrual cycle has a circaseptan (7 days) rhythm and whether it is associated with the lunar cycle (also defined as the synodic month, it is the cycle of the phases of the Moon as seen from Earth, averaging 29.5 days in length).
Cross-sectional study. A total of 35,940 European and North American women aged 18-40 years. Exposure: Data were collected in real-life conditions. No intervention was performed. The onset of menstruation was assessed in prospectively measured menstrual cycles (311,064 cycles) over 3 full years (2019-2021). Associations were calculated between the onset of menstruation and the day of the week, and between the onset of menstruation and the lunar phase. In this large data set, a circaseptan (7-day) rhythmicity of menstruation was observed, with a peak (acrophase) of menstrual onset on Thursdays and Fridays. This circaseptan rhythm was observed in every age group, in every phase of the lunar cycle, and in all seasons. This feature was most pronounced for cycle durations between 27 and 29 days. In winter, the circaseptan rhythm was found in cycles of 27-29 days, but not in other cycle lengths. A circalunar rhythm was also statistically significant, but not as clearly defined as the circaseptan rhythm. The peak (acrophase) of the circalunar rhythm of menstrual onset varied according to the season. In addition, there was a small but statistically significant interaction between the circaseptan rhythm and the lunar cycle. Although relatively small in amplitude, the weekly rhythm of menstruation was statistically significant. Menstruation occurs more often on Thursdays and Fridays than on other days of the week. This is particularly true for women whose cycles last between 27 and 29 days. Circalunar rhythmicity was also statistically significant. However, it is less pronounced than the weekly rhythm.
The ability of morphine to block ovulation in animals prompted investigation of the frequency and mechanisms of menstrual abnormalities in women addicted to narcotic analgesics. Menstrual histories obtained from 76 former heroin addicts receiving daily methadone maintenance revealed that more than one-half of these women had experienced menstrual abnormalities while taking heroin or methadone. In order to determine the specific physiologic effects of narcotic analgesics on reproductive function, detailed endocrinologic studies were carried out in seven of these patients who complained of amenorrhea or irregular menses while receiving methadone. Four of the seven women manifested abnormalities of the control of gonadotropin secretion. Three of these four failed to exhibit cyclic gonadotropin release, as evidenced by an absence of increased levels of follicular phase follicle-stimulating hormone, midcycle gonadotropin peaks or luteal phase progesterone increments. In the fourth patient a prolonged follicular phase (30 days) of the menstrual cycle was detected. One of these four patients also had low basal gonadotropin levels and failed to exhibit luteinizing hormone increments greater than control levels in response to ethinyl estradiol (positive feedback). The remaining three women exhibited normal patterns of gonadotropin secretion during the observation period. In these women, menstrual bleeding occurred in response to withdrawal from luteal phase (10 to 20 ng/ml) progesterone levels and to exogenous ethinyl estradiol, suggesting normal uterine responsivity to progesterone and estrogen. Although not documented, it is likely that oligo-ovulation was the cause of the irregular menses in these three patients. Amenorrhea is commonly associated with methadone ingestion or heroin addiction and appears to be related to an alteration of the hypothalamic mechanisms controlling gonadotropin secretion. Tolerance to these effects of methadone may develop after chronic ingestion.