Exploring melatonin's multifaceted role in female reproductive health: From follicular development to lactation and its therapeutic potential in obstetric syndromes

Qihui Li: Investigation, Writing – original draft, Visualization. Tenghui Zheng: Investigation, Visualization. Jiaming Chen: Investigation, Writing – original draft. Baofeng Li: Investigation, Visualization. Qianzi Zhang: Investigation, Visualization. Siwang Yang: Writing – original draft. Jiayuan Shao: Investigation, Visualization. Wutai Guan: Writing – review & editing. Shihai Zhang: Supervision, Project administration, Writing – review & editing.

After birth, milk is one of the predominant connections between mothers and their neonates. Besides the well-known role of prolactin (PRL), which stimulate the proliferation of mammary gland epithelial cells (MECs) and milk synthesis in mammals [264] , [265] , recent evidence indicates that melatonin can regulate the mammary gland development. The MT1 is highly expressed on the surface of acinar and ductal epithelial cells in human breast tissue [266] and in MECs of female goats [267] , cows [268] and mice [269] . These data indicate that melatonin might play a role in lactation. Currently, most evidence directs to a negative role of melatonin in mammary gland development and milk synthesis. For example, higher circulating melatonin concentrations due to melatonin implants or induced by short photoperiods, reduce milk production in goats [270] , [271] . Decreased milk production and milk fat concentration is also observed in cows with melatonin implants [268] , [272] . From a mechanistic perspective, melatonin inhibits PRL secretion [267] . Support for this comes from studies in which it is shown that intraventricular injection of a physiological dose of melatonin (1 ng/mL) inhibits pup suckling-induced oxytocin and PRL secretion in rodents [273] , and a shortened photoperiod-induced increase in melatonin levels leads to a decrease in PRL secretion in sheep [274] . Inhibition of PRL secretion by melatonin has also been observed in cows [275] . Proper development of mammary glands is a prerequisite for lactation. Melatonin appears to have an inhibitory effect on mammary gland development, thus negatively affecting lactation. Evidence for this comes from a study in female mice where a pharmacological dose of melatonin (200 μg) delayed the onset of rapid mammary growth and reduced the number of MECs and duct growth [276] . Besides, overexpression of MT1 receptors in the mammary glands of pregnant and lactating female mice is associated with hypoplastic mammary lobular vacuoles and inhibition of MECs proliferation [269] . Similarly, inhibition of mammary gland growth by melatonin is reported in adolescent heifers [277] and goats [267] . Mechanistically, melatonin inhibits Stat5 expression through an MT1-mediated pathway [278] , [279] . Stat5 plays a role in the breast tissue differentiation, ductal epithelial cell survival, and lactation-related gene expression [280] . The loss of Akt1 interferes with the expression and phosphorylation of Stat5 [281] . In human breast tumors, Akt expression is inversely correlated with melatonin concentration [282] , while high expression of MT1 receptors in mammary gland tissue of pregnant and lactating mice inhibits Akt1 protein levels in the gland epithelium [283] . Furthermore, high MT1 expression is also associated with low levels of Wnt4 expression [269] , which mediates the differentiation of mammary ducts [284] . The opposite is also shown as Cashmere goats [285] and ewe [286] treated with melatonin have a higher milk fat content than control goats, but lower milk protein and lactose levels [285] . In addition, melatonin treatment increased the milk fat and casein content, but reduced the lactose concentration in dairy cows when treated in the late lactation period [272] . Other studies in Asaf and Lacuna ewes [287] , Sarda sheep [288] , Holstein dairy cows [289] report that melatonin treatment has a weak or no influence on milk production and milk composition. We support the notion that high serum melatonin level has an inhibitory effect on lactation in periodically breeding animals, such as dairy goats and sheep, as they are in estrous in autumn and winter terms (short light periods and high levels of serum melatonin) and parturient in spring and early summer (long light periods and low levels of serum melatonin) [290] . Their reproductive to lactation stage transition seems to be compatible with serum melatonin concentrations. In addition, animal species, growth stage, and dosage/time of melatonin administration might be responsible for the discrepancy among different studies, implicating that the role of melatonin in the egulation of lactation in persistent estrous animals require further investigation. To explore the toxic effects of melatonin, scientists tried to determine the half-lethal dose of melatonin in mice as early as in 1967. However, even if melatonin was given 800 mg/kg BW, no acute effects occurred in these animals [291] . Subsequently, a large number of toxicity studies were performed in infants, children, adolescents, adults, surgical patients, critically ill patients, as well as elderly, and all results show that short-term use of melatonin is safe, even at extreme high doses [13] . Currently, 1 to 10 mg is considered the standard dose for melatonin treatment in humans once a time [292] . However, due to the lack of adequate human studies, pregnant women and lactating women should be cautious in taking exogenous melatonin. Next to this, melatonin has also been reported beneficial for children suffering from insomnia [293] , [294] . Similarly, long-term safety of melatonin use in children and adolescents requires further investigation. Here, we summarize the important role of melatonin in female reproduction and lactation. Melatonin plays a role throughout female reproduction, beginning with protection of oocyte quality, influencing embryo implantation and fetal development up to parturition. In addition, as a broad-spectrum antioxidant, anti-inflammatory agent, anti-cancer factor and regulator of reproductive hormone release, melatonin can also be considered as an in general beneficial factor in reproduction. Melatonin participates in protecting the placenta, fetus, and mother from various pregnancy-related diseases such as preeclampsia, endometriosis, polycystic ovary syndrome. and ovarian aging. In addition, melatonin also delays physiological ovarian aging. The effects of melatonin on mammary gland development and milk production are less positive as elevated melatonin levels negatively affect serum prolactin concentration, interfere with breast development, and are detrimental to lactation. Finally, the use of melatonin appears to be safe, and so far, there is no tangible evidence of toxic effects. In future research, the following points should be taken in consideration: First, many experimental protocols use melatonin at pharmacological concentrations to achieve significant results. Second, the time of melatonin administration, animal’s developmental stage and gender differences. Thirdly, the specific differences in tissue responses to melatonin and to the rhythmicity in melatonin levels under physiological conditions when applying melatonin treatment. Besides, pay attention to the local and systemic effects: at present, in in vitro studies only cells are exposed to melatonin treatment, however, under normal physiological conditions, melatonin has a wide range of effects on different organs that may influence each other. At last, the interaction between hormones is well known, and many effects of melatonin might be related to allowing, antagonizing or cooperating with other hormones, but the research on this aspect is scanty at present.

This article does not contain any studies with human or animal subjects.

Melatonin is an amphiphilic indoleamine that widely occurs both in vertebrates and invertebratesLerner, Case [1] . In mammals, melatonin was originally thought to be solely secreted by the pineal gland during darkness and participate in the regulation of circadian and seasonal rhythms [2] . Currently we know that many other organs in the body are capable of melatonin synthesis such as the skin, retina, cerebellum, kidney, liver, pancreas and ovary [3] . Melatonin, directly or indirectly, regulates various physiological processes in the body such as sleep and wakefulness, body temperature, hormone secretion and reproduction [4] . In addition, melatonin acts as a natural antioxidant, anti-inflammatory factor, anti-tumor agent, and regulator of cellular metabolism and apoptosis [5] . Melatonin is synthesized from tryptophan, which is first converted to serotonin by hydroxylation and decarboxylation followed by the conversion of serotonin into N-acetyl serotonin by the enzyme arylalkylamine N-acetyltransferase (AANAT). N-acetyl serotonin is subsequently methylated to form melatonin, a step that requires the enzyme hydroxyindole-O-methyltransferase (HIOMT) [6] . Currently, MT1 and MT2 are two major high-affinity melatonin receptors, which been identified in mammals. They are found on hypothalamic neurons that control pituitary gonadotropin release [7] , [8] and in the anterior pituitary where they play a direct role in the regulation of gonadotropin release [9] . Additionally, the presence of MT1 and MT2 is well documented in human reproductive tissues, including mammary gland epithelial cells [10] , ovarian granulosa cells, luteal cells [11] and the uterine myometrium [12] , suggesting that melatonin may also affect the functioning of these cells. The discovery that melatonin has the ability to scavenge free radicals has greatly broadened the understanding of its benefits to the reproductive system. As an “amphiphilic” molecule, melatonin and its metabolites such as cyclic 3-hydroxymeratonine, N1-acetyl-N2-formyl-5-methoxykynurenine and N1-acetyl yl-5-methoxykynurenamine are effective scavengers of ROS [13] . Besides, melatonin has an indirect antioxidant effect by increasing the expression of antioxidant enzymes such as glutathione peroxidase (GPX), superoxide dismutase (SOD), and catalase (CAT) [14] , [15] . Abnormal melatonin secretion is associated with several diseases related to human reproduction [16] . For example, aberrant melatonin levels in serum or tissues have been reported in women suffering from preeclampsia, polycystic ovary syndrome or endometriosis [16] , implicating that exogenous melatonin might be considered a candidate drug for alleviate these diseases. Here, we provide an overview of the melatonin in female reproduction, such as follicle growth, embryo implantation, pregnancy and childbirth. Besides, we discuss the potential of melatonin as a therapy in relieving preeclampsia, polycystic ovary syndrome, endometriosis, and in delaying physiological ovarian aging. Finally, the function of melatonin in lactation and the safety of melatonin use during lactation is summarized.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.