Melatonin Promotes Uterine and Placental Health: Potential Molecular Mechanisms

Abstract

The development of the endometrium is a cyclic event tightly regulated by hormones and growth factors to coordinate the menstrual cycle while promoting a suitable microenvironment for embryo implantation during the “receptivity window”. Many women experience uterine failures that hamper the success of conception, such as endometrium thickness, endometriosis, luteal phase defects, endometrial polyps, adenomyosis, viral infection, and even endometrial cancer; most of these disturbances involve changes in endocrine components or cell damage. The emerging evidence has proven that circadian rhythm deregulation followed by low circulating melatonin is associated with low implantation rates and difficulties to maintain pregnancy. Given that melatonin is a circadian-regulating hormone also involved in the maintenance of uterine homeostasis through regulation of numerous pathways associated with uterine receptivity and gestation, the success of female reproduction may be dependent on the levels and activity of uterine and placental melatonin. Based on the fact that irregular production of maternal and placental melatonin is related to recurrent spontaneous abortion and maternal/fetal disturbances, melatonin replacement may offer an excellent opportunity to restore normal physiological function of the affected tissues. By alleviating oxidative damage in the placenta, melatonin favors nutrient transfer and improves vascular dynamics at the uterine–placental interface. This review focuses on the main in vivo and in vitro functions of melatonin on uterine physiological processes, such as decidualization and implantation, and also on the feto-maternal tissues, and reviews how exogenous melatonin functions from a mechanistic standpoint to preserve the organ health. New insights on the potential signaling pathways whereby melatonin resists preeclampsia and endometriosis are further emphasized in this review.

Curcumin and Endometriosis

“…The use of melatonin in endometriosis reverses the lipoperoxidation and decreases antioxidants activities observed after pinealectomy of rat models [180]. Melatonin leads to the reduction in endometriotic foci and histopathologic scores with increased levels of SOD [181]. SCID animals which received melatonin present a reduction in endometriosis lesions in oophorectomized rats [182].…”

Chronodisruption: effects on reproduction, transgenerational health of offspring and epigenome

“…Additionally, melatonin seems to enhance placental perfusion and prevent arterial insufficiency, hypercoagulation, inflammatory and oxidative damage (Lee et al 2019a), and also protect from hypoxia/reoxygenation-induced damage in placental trophoblasts by regulating autophagy and apoptosis (Sagrillo-Fagundes et al 2018). Thus, even though the exact mechanisms are not known, the current data indicates the likely importance of maternal circadian signals such as melatonin, in driving rhythmic placental function (Chuffa et al 2019). In addition, the raised triglyceride levels observed in human placentas from pregnancies with large-for-gestational age infants are found to be associated with upregulated expression of the clock gene BMAL1 (Papacleovoulou et al 2017).…”

“…The role of melatonin in oocyte quality, ovarian and luteal function, fertilization, embryo implantation, pregnancy and parturition in women undergoing assisted reproductive treatment and in patients with PCOS undergoing intrauterine insemination and incidence of endometriosis and preeclampsia have also been reported (Chuffa et al 2019, Scarinci et al 2019. For instance, melatonin treatment resulted in beneficial effects in pregnant mice, especially those subjected to long photoperiodic exposure by enhanced embryo implantation, increased E2 levels during pregnancy and up-regulated p53 expression by activating melatonin receptors MT1/2 in the uterus (Zhang et al 2017).…”

Effects of altered photoperiod due to COVID-19 lockdown on pregnant women and their fetuses

“…Melatonin derived from the placenta acts at all levels of the maternal-placental-fetal system as an autocrine, paracrine, and endocrine molecule that modulates circadian endocrine rhythms and protects placental tissues via free radical scavenging, indirect antioxidant effects, and immune regulation (Lanoix et al 2012;Reiter et al 2014b). Changes in placental circadian rhythms with reduced melatonin production are associated with increased risk of preterm delivery, uterine growth restriction, and preeclampsia, resulting in perinatal death, preterm births, fetal growth restriction, and retardation of brain development (Chuffa et al 2019;Reiter et al 2014b). Importantly, deficiency of melatonin production or suppression of melatonin levels by prolonged light exposure at night is related to spontaneous abortion, as found in the absence of chromosomal anomalies or uterine malfunctions (Berbets et al 2019;Tamura et al 2008b).…”