{"paper_id":"2824fc9c-9bf6-4571-98cf-e28e3ae5e178","body_text":"Copyright © 2024 Korean Academy of Sleep Medicine  145\nINTRODUCTION\nMelatonin is a hormone produced by the pineal gland in the \nbrain that plays a crucial role in regulating circadian rhythm, \nsleep-wake cycles, and mood [1]. Recent research has shed light \non the impact of melatonin on female reproductive physiology \n[2]. Studies have shown that melatonin influences the menstrual \ncycle, ovulation, and fertility [3-5]. The hormone has been shown \nMelatonin in Female Fertility: Multifaceted Role \nFrom Reproductive Physiology to Therapeutic  \nPotential in Polycystic Ovary Syndrome,  \nEndometriosis, and Ovarian Failure\nSuparna Parua1*, Gargi Roy Choudhury2*, Soumita Bhattacharya3, Anukona Hazra1,  \nSulagna Dutta4, Pallav Sengupta5, and Koushik Bhattacharya1\n1School of Paramedics and Allied Health Sciences, Centurion University of Technology and Management, Odisha, India \n2Department of Physiotherapy, Nopany Institute of Health Care Studies, Kolkata, India \n3Department of Physiology, Vijaygarh Jyotish Roy College, Jadavpur, Kolkata, India \n4Basic Medical Sciences Department, College of Medicine, Ajman University, Ajman, UAE \n5Department of Biomedical Sciences, College of Medicine, Gulf Medical University, Ajman, UAE\nMelatonin, synthesized by the pineal gland, plays a pivotal role in female reproductive physiology. In addition to its established function in reg-\nulating circadian rhythms, melatonin influences critical reproductive processes, such as ovulation, menstrual cycle regulation, and fertility. Re-\ncent studies underscore melatonin’s regulatory effects on the hypothalamic-pituitary-gonadal axis, influencing the secretion of gonadotropins, \nincluding follicle-stimulating hormone and luteinizing hormone. Furthermore, melatonin has been implicated in the pathophysiology of re-\nproductive disorders, such as polycystic ovary syndrome and endometriosis, where its antioxidant and anti-inflammatory properties may en-\nhance ovarian function and fertility. Melatonin also plays a protective role against oxidative stress in granulosa cells, thereby improving oocyte \nquality and increasing the potential for successful fertilization. These effects position melatonin as a promising therapeutic agent in assisted \nreproductive technologies, such as in vitro fertilization. Studies demonstrate that melatonin supplementation mitigates the harmful effects \nof reactive oxygen species on ovarian cells, enhancing embryo development and improving pregnancy outcomes. By counteracting oxidative \nstress and apoptosis in reproductive tissues, melatonin emerges as a crucial factor in promoting reproductive health.\nKeywords: Female reproductive health; Infertility; Melatonin; Menstrual cycle; Ovulation\nReceived: July 30, 2024   Revised: September 30, 2024   Accepted: October 28, 2024\nCorresponding author: Pallav Sengupta, PhD, Department of Biomedical Sciences, College of Medicine, Gulf Medical University, 4184, Ajman, UAE.\nTel: 971-503083217, E-mail: pallav_cu@yahoo.com\nCorresponding author: Koushik Bhattacharya, PhD, School of Paramedics and Allied Health Sciences, Centurion University of Technology and Management, Khurda \nRoad, Bhubaneswar, Odisha, India.\nTel: 91-8013911946, E-mail: koushik22.2009@rediffmail.com\n*These authors contributed equally to this work.\ncc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-\nnc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.\nREVIEW ARTICLE\neISSN 2635-9162  /  https://chronobiologyinmedicine.org\nChronobiol Med 2024;6(4):145-162  /  https://doi.org/10.33069/cim.2024.0022\nCIM\nto impact the secretion of other hormones involved in the regu-\nlation of reproductive functions, such as follicle-stimulating hor-\nmone (FSH) and luteinizing hormone (LH) [6]. Additionally, mel-\natonin has been linked to menstrual irregularities, polycystic ovary \nsyndrome (PCOS), and infertility [7-9]. This highlights the need \nfor further research to fully understand the role of melatonin in \nfemale reproductive physiology and its potential as a therapeutic \ntarget for reproductive disorders. \n\nMelatonin and Female Reproduction\n146 / CIM\nDisruptions to the normal production and secretion of melato-\nnin, such as exposure to artificial light at night or disruptions to \nthe sleep-wake cycle, have been linked to menstrual irregularities, \nchanges in ovulatory function, and infertility [10,11]. Moreover, \nmelatonin has a regulatory effect on the onset of puberty [12,13]. \nIt acts on the hypothalamic-pituitary-gonadal (HPG) axis, which \nis the primary hormonal control system that regulates reproduc-\ntive function [2,13]. During puberty, the pineal gland becomes \nless active, leading to a decrease in melatonin levels. This decrease \nin melatonin levels allows for an increase in gonadotropin-releas-\ning hormone (GnRH) secretion from the hypothalamus, which \nstimulates the pituitary gland to release LH and FSH [14-16]. LH \nand FSH then stimulate the gonads (ovaries in females, testes in \nmales) to produce and secrete sex hormones, such as estrogen \nand testosterone, respectively. The sex hormones then act on the \nHPG axis, leading to the onset of puberty, the maturation of the \nreproductive organs, and the development of secondary sexual \ncharacteristics [17]. It is important to note that melatonin is just \none of several factors that regulate the onset of puberty, and its \nexact role may vary between individuals and populations. Nev-\nertheless, melatonin plays a key role in the regulation of the HPG \naxis and the onset of puberty.\nAdditionally, research has shown that melatonin supplementa-\ntion may have therapeutic benefits for certain reproductive health \nconditions, such as PCOS and endometriosis, which are both as-\nsociated with female infertility [9,18]. Thus, the purpose of this \narticle is to thoroughly review and present the association be-\ntween melatonin and female reproductive functions, which has \nbeen largely neglected and remains elusive, unlike the numerous \nstudies conducted on other endocrine factors and hormones.\nPROPERTIES AND PHYSIOLOGICAL \nEFFECTS OF MELATONIN\nEpiphysis cerebri or “pineal gland” is situated near the cortex \nof the brain, between two hemispheres join which is also known \nas the diencephalon. This pineal gland releases a serotonin-de-\nrived hormone called “melatonin” hormone, also known as N-\nacetyl-5-methoxytryptamine. Lerner, one of the renowned skin \nspecialists, had done an experiment in the year of 1958 on a frog \nand had observed a change in the complexion of the frog skin \nand assumed the action of melatonin [19]. A few years later, ap-\nproximately in the year 1960, Lerner and his colleagues described \nthe chemical formulae of melatonin [19]. Previously, more con-\ncisely from the last 50 to 60 years back, it was believed that mela-\ntonin has effects only on various physiological processes. For ex-\nample, pubertal attainment [6], aging process [20], circadian \nrhythms [21], sleep-wakefulness cycle [22], etc. Melatonin also \nhas its effects on other parts of the human body, as it regulates \nneuroendocrine functions [23], and functions of the cardiovascu-\nlar system [24], besides its oncostatic effects [25]. Intake of exoge-\nnous melatonin not only as medicine but also in other forms also \nvery crucially acts on the sleep cycle and body temperature con-\ntrolling mechanism in humans. The sleep-inducing effect of mel-\natonin expands by heat loss due to more body temperature at the \ntime of sleeping [26-28]. The sleep-inducing effects of melatonin \nhave been observed with oral doses ranging from 0.3 mg to 1.0 mg \nin healthy individuals [29]. While often termed “hypnotic, ” mela-\ntonin is more accurately described as a “soporific, ” as it induces \ndizziness and modulates circadian rhythms, making it a chrono-\nbiotic [30,31].\nTHE PHOTONEUROENDOCRINE \nSYSTEM\nThe duration of the diurnal and nocturnal rhythms can be re-\nceived at the level of retina in mammals which is also known as \nthe photoperiodic effect. This rhythm or periodical surge has oc-\ncurred through a multisynaptic neural pathway for the melato-\nnin hormone secretion to the epiphysis cerebri also known as the \npineal gland [32]. The suprachiasmatic nucleus of the hypothala-\nmus mainly controls the biological clock by regulating the release \nof pineal melatonin [33]. The production of melatonin internally \nis been reduced by exposing it to bright light naturally or artifi-\ncially. After sunset, melatonin is released in adults between 19:30 \nand 21:30 hrs, and in children aged 6 to 12 years, between 19:00 \nand 21:00 hrs [34]. The hormonal depiction of the photoperiod \nvaries according to the daytime or the diurnal period by the du-\nration of the secretion of the melatonin hormone [35]. During \nthe daytime, the administration of melatonin creates a half-life of \n35– 45 minutes [36].\nMELATONIN AND FEMALE \nREPRODUCTIVE PHYSIOLOGY\nMelatonin and its role in sexual maturation\nIn a transverse study, melatonin level was tested from serum \nduring the nighttime among 367 individuals starting from the age \nof 3 days to 90 years of age [37]. After close observation, these re-\nsearchers have inferred that between 1 and 3 years of age the chil-\ndren have the highest level of nighttime serum melatonin concen-\ntration. On the other hand, the researchers examined individuals \nfrom childhood through puberty and into young adulthood, ob-\nserving a gradual reduction averaging 80% during these stages. \nThis study can be related to a previous study where it explained \nthe gradual reduction of 75% in the nighttime serum melatonin \nconcentration as analyzed between children aged of 1 years to 5 \nyears up to young adults [37]. Pubertal maturation development \nis related to the few signs and symptoms of the reduction in the \nnighttime serum melatonin concentration [37]. Conversely, the \nexpansion of tanner stages is also correlated with this nocturnal \nserum concentration of melatonin [38]. These observations sug-\ngest that external melatonin sources may suppress GnRH secre-\ntion, potentially affecting pubertal maturation in children [39,40]. \nAdditionally, melatonin use has become prevalent in diagnosing \nsleep disorders in children and adolescents, raising questions about \n\nSuparna Parua, et al\nCIM / 147\nits impact on pubertal onset due to altered nocturnal serum mel-\natonin concentrations.\nPhysiological crosstalk between melatonin and puberty\nThe development of children into an adult capable of maintain-\ning the normal human reproductive cycle is allied with proper \nmagnification and maturation of accessory sex organs. The jour-\nney from childhood to adulthood needs to follow some proper \nsteps, which are still unknown, fully [41,42]. The hormonal chang-\nes occur in a rhythmic manner which indicates the onset of pu-\nberty. The onset of puberty is related to the release of GnRH [43]. \nThe GnRH neuronal axons are extended from the hypothalamic \npreoptic area up to the arcuate nucleus [17,42]. The hypothala-\nmus maintains the gonadal hormone functions via the pituitary \n(known as the HPG axis). It helps to keep the hormonal milieu \nwhen a child is in his mother’s womb, i.e., from the embryonic \nstage, the hormonal axis becomes organized, and after parturi-\ntion to puberty onset this hormonal axis remains hibernated [44]. \nThe exact mechanisms that trigger the onset of puberty remain \nunclear. However, the activation of GnRH secretion, along with \nthe suppression of GnRH inhibitors, is thought to play a key role \nin pubertal maturation. In addition to GnRH activators and in-\nhibitors, neurotransmitters and neuropeptides also play a crucial \nrole. These signals, originating from the hypothalamus, are influ-\nenced by peripheral or gonadal signals. Several studies have iden-\ntified various factors influencing the initiation of puberty [45], \nincluding 1) sex-specific differences, 2) genetic inheritance, 3) nu-\ntritional status, 4) circadian rhythm patterns, 5) endometrial con-\nditions, 6) hormonal influences such as leptin, ghrelin, IGF-I, and \nsex steroids, and 7) environmental disruptions affecting hormon-\nal regulation. Hershey (1996) identified the Kiss-1 gene, named \nafter Hershey’s Kisses, which encodes kisspeptins that act via the \nGPR54 receptor (KISS1R) [46]. Kisspeptin-10 was recognized in \n2005 as a major regulator of GnRH neuronal activity [47], criti-\ncally linking kisspeptin to reproductive and electrophysiological \nfunctions [48-50]. Other regulatory molecules also contribute to \nthe onset of puberty [17].\nBased on a few animal studies, exposure to a specific photope-\nriod condition leads to the suppression of kisspeptin following \nmelatonin administration [51]. The expression of kisspeptin can \nbe affected to some extent by the diminishing effect of decreased \nphotoperiod due to reduced melatonin levels internally, which \ncan also be referred to as surgical pineal gland abolition [52]. A \nrelevant study explained that the first administration of melato-\nnin decreases the level of the outcome of kisspeptin gene expres-\nsion, whereas extended administration will lead to an uplift in \nthe level of kisspeptin gene expression [53]. This will excite the \ngonadal axis. Therefore, it can be inferred that melatonin impacts \nthe functions of the reproductive system depending on the ad-\nministration in different phases. The above-mentioned findings \nare based on the review of some collected research studies, ex-\nploring the outcome of melatonin on adolescence and the fre-\nquent changes of kisspeptin gene expression.\nAnimal studies \nExogenous melatonin administration delays sexual maturation \nin children, and long-term use is prohibited. Seasonal breeding \nmodels, including sheep and hamsters (Syrian and Siberian), have \nshown that the pulsatile release of melatonin is regulated inter-\nnally. This mechanism parallels the transition from the nonbreed-\ning to breeding season, similar to adolescence [54-57]. Several \nhomogeneities could be put out within adolescence and transfor-\nmation to nonbreeding season. For example, one experiment per-\nformed on female sheep which is at the age before puberty and \nseasonally nonbreeding showed that the LH surge which is the \nmain reason for ovulation, does not happen, even though inborn \nability and the neuronal connection are as normal as compared \nwith other mammals [58,59]. Then, the LH level becomes re -\nduced. Before adolescence, secretion of LH becomes rhythmical \nbut at the time of nonbreeding season the LH release is tremen-\ndously lesser [58]. However, these uniformities are exciting but \nthe total hormonal and neuronal regulation that controls the re-\nproductive system is still an uncertainty [41]. Several studies have \nexplored the effect of melatonin on puberty and its modulation \nby photoperiod. One study found that administering melatonin \nfor 10 days during the pre-pubertal stage delayed puberty in male \nhamsters, normally reaching puberty at 25 days [60,61]. Howev-\ner, similar treatment in prepubertal gilts yielded no significant \neffects [62]. In ewe lambs, melatonin delayed puberty by about \nfour weeks compared to controls [62], while in Suffolk ewe lambs, \nit advanced puberty by three weeks [63]. Pinealectomy in ewe \nlambs also delayed puberty [62]. In Soay ewes, changes in kiss-\npeptin levels correlated with altered melatonin secretion and re-\nproductive development [64]. The Soay ewe typically breeds \nduring autumn and winter when longer nights correspond with \nincreased melatonin secretion. In contrast, male Syrian hamsters, \nas long-day breeders, show reduced melatonin levels during short-\ner nights in spring and summer. However, whether kisspeptin cells \nactivate melatonin receptors under these conditions remains un-\nclear [60]. Simonneaux et al. [65] suggested that RFRP-3, part of \nthe RF-amid peptide family, inhibits GnRH release, potentially \ninfluencing reproductive timing.\nHuman studies\nVery few studies have been done only on human beings and \nprimarily are based on the dosage of melatonin and secondarily \non the onset of puberty. An arbitrarily controlled trial also known \nas meldos trial where the children and youth experienced the max-\nimum dosage of melatonin for their uncontrollable insomnia [66]. \nA total strength of 69 participants who were in the age between 6 \nto 12 years had experienced the meldos trial. Out of those 69 sub-\njects only 59 of them had enclosed the datasheet of the first re-\nport [66]. The study involved children who had been taking mel-\natonin for at least six months. They were asked questions about \npuberty, such as the Tanner scaling for male and female subjects, \nand their parents’ experiences of their first menstrual cycle or ejac-\nulation. However, only 19 participants had reached puberty with-\n\nMelatonin and Female Reproduction\n148 / CIM\nin the normal age range. The same cohort from the initial study \nwas reassessed after 9 or 12 years. Of the 33 participants in the \nfollow-up, pubertal timing was compared to general population \ndata. The study revealed that 31.3% of participants experienced \ndelayed puberty, compared to 17% in the control group [67]. In a \nlong-term study, children with developmental disorders related \nto their neurological or biological sleep patterns, which were un-\ntreatable, were treated with melatonin [68]. The study had specific \ncriteria, including a double-blind, placebo-controlled crossover \ntrial of sustained-release melatonin. The participants were inter-\nviewed by phone every three months for up to 3.8 years. Of the \nfive children with major neuro-developmental disorders, which \nwere observed before the melatonin treatment, puberty was ob-\nserved at the age of 12 to 15 years. The remaining children com-\npleted puberty within normal limits, with an average age of 13.4± \n1.4 years. Overall, very few studies have investigated the timing \nof puberty in young children and adolescents who received pro-\nlonged melatonin treatment. The three studies available have a \nsmall sample size, limited scope, and poor measures of puberty \ntiming, making it difficult to draw any definitive conclusions.\nMagee et al. [69] recommended the probability of the vulnera-\nbility of humans to light in puberty. Given one observation, men-\narche was found to be more susceptible among the blind girls be-\nfore their usual age but this information was not accepted [45]. \nAccording to other studies as recommended in the winter season \nthan in the summer females are more prone to menarche [70,71] \nimplying that light can be an obstruction at the beginning of pu-\nberty. Colder regions such as the Arctic region are correlated with \ndecreased pituitary-gonadal function at a less frequent rate of \nconception which can be an opposite phenomenon in compari-\nson with earlier findings [72]. According to the studies, it was \nfound that melatonin level decreases at a speed-up rate at the \ntime of adolescence in humans [73,74] and after a close observa-\ntion, so, as an inference, the beginning of puberty (among the ad-\nolescents in between Tanner stage II and III) followed by the re-\nduction in melatonin synthesis and secretion [73].\nEvidence of melatonin receptor expression in ovarian \ncells\nThe physiological functions of melatonin are interceded not \nonly by definite membrane-bound receptors but also through the \nnuclear binding sites. Nuclear binding sites relate to the members \nof the nuclear receptor superfamily of RZR/ROR [75]. Research-\ners have identified three different types of melatonin receptors that \nare located on the membrane of mammalian cells, and they have \nreplicated three corresponding proteins. Among these three sub-\ntypes, MT1 and MT2 are two of the receptors that belong to the \nseven transmembrane G-protein coupled receptor family [76].\nThe third subtype of melatonin receptors is known as MT3, \nwhich is also identified as quinone reductase 2. In some animals, \nthis subtype serves as both an enzyme and a receptor for melato-\nnin [77,78]. When MT1 or MT2 receptors are stimulated in target \ncells, it can lead to the inhibition of adenylate cyclase activity. This \nis part of the signal transduction pathway [79]. The activation of \nMT1 and MT2 receptors typically results in a reduction of cyclic \nadenosine 3’ ,5’-monophosphate (cAMP) production, which is \ntypically triggered by forskolin. This, in turn, leads to a decrease \nin the activity of protein kinase A. These biochemical pathways are \ncommonly involved in the functioning of MT1 and MT2 recep-\ntors [80]. These receptors can give rise to a signal transduction \nmechanism. Melatonin triggers various second messenger path-\nways by communicating with the same receptor subtype based on \nthe tissue, organ, and species. MT1 and MT2 melatonin recep-\ntors are observed in different rodent tissues. Human melatonin \nreceptors are found in a variety of organs, including the brain, skin, \nretina, cardiovascular system, immune cells, liver, gallbladder, in-\ntestine, mammary glands, fat cells, prostate, uterus, and kidney [81].\nOvarian function appears to be influenced by melatonin, with \nhigher melatonin concentrations observed in human ovarian \nfollicular fluid (FF) compared to plasma [81]. Melatonin modu-\nlates granulosa cell (GC) functions, including folliculogenesis and \nsteroidogenesis, as demonstrated in hamsters [82] and humans \n[83]. MT1 and MT2 melatonin receptors are present in human \nGCs, luteal cells [84,85], and rat ovaries [86].\nFunctions of melatonin in the growth and development \nof follicles\nEndocrine, paracrine, and autocrine mechanisms are the three \ndifferent processes involved in follicular development within the \novary. The first stage of the folliculogenesis process involves the \naccumulation of several primordial follicles. The subsequent stag-\nes that the process of folliculogenesis involves are the primary, \npreantral, and antral stages. After these three stages, they follow \nthe preovulatory and ovulatory stages where they become capa-\nble of releasing the ovum which is able for fertilization. Based on \ndifferent species, the growth of preantral and early antral stages \ncrucially becomes important on the level of circulating FSH. Out \nof the bulk amount, only a few of them had been allotted from \nthe ovarian follicular reserve during the development of follicles \nin each reproductive cycle [87]. Individuals who are receiving in \nvitro fertilization (IVF) treatment typically have follicles that are \nfilled with fluid and are larger in size. These large follicles have a \nhigh amount of melatonin concentration as compared to small \nfluid-filled follicles. Melatonin and its two precursors, serotonin \nand N-acetyl-serotonin along with their two synthesizing en -\nzymes NAT and HIOMT can be observed in human ovaries and \nits homogenates [88], which may indicate a possibility of intra-\novarian synthesis of melatonin and its release into the FF . Nowa-\ndays, by current studies, it is observed that a huge quantity of \nmelatonin which is identified in the ovary and from the circula-\ntion, the preovulatory FF can be derived. This observation has \ncome to an end by observing the rat and cat ovaries which con-\ntain 3-H melatonin [89]. With this content, 3 mg of melatonin \nwas administered in tablet form to the women receiving fertility \ntreatment, FF contained a high concentration of melatonin as \ncompared to control [90]. After the maturation of follicles, they \n\nSuparna Parua, et al\nCIM / 149\nbecome dependent on LH rather than FSH, which may be a \nmechanism related to the selection of follicles for their develop-\nment. The selection of follicles is related to the mRNA expression \ntiming and LH receptor encoding in GCs [91]. The expression of \nLH has been observed in an increased version than FSH in GCs \nby administering a dosage of melatonin (10 pM to 100 nM) in \nhuman GCs [85].\nThe growth and differentiation of ovarian cells are significantly \ninfluenced by sex steroids. The theca cells and GCs of the ovary \nare essential for steroid biosynthesis, highlighting the interde-\npendence of these two cell types in estrogen (E) production [92]. \nThis mechanism is explained by the two-cell, two-gonadotropin \nmodel. Steroidogenic enzymes, such as P450-side chain cleavage \nenzyme (P450scc), P450 17-alpha-hydroxylase/C-17, 20-lyase \n(P450 c17), and P450 aromatase, regulate the biosynthesis of pro-\ngesterone (P), androstenedione (A), and estradiol (E2). These en-\nzymes are activated by cAMP within theca cells and GCs, which \nis modulated by FSH and LH through membrane-bound recep-\ntors [93]. In porcine theca cells, the key steroidogenic genes, CY-\nP11A, CYP17, and CYP19, are regulated by cAMP . Alongside go-\nnadotropins, estrogen drives the growth and differentiation of GCs \n[92]. Progesterone plays a limited yet crucial role in follicular de-\nvelopment and ovulation, as shown by studies on progesterone re-\nceptor knockout mice, where ovulation was absent [94,95]. An-\ndrogens promote premature follicular growth but also induce \natresia and apoptosis [96,97]. Melatonin influences sex steroid \nsynthesis during follicular maturation. Notably, melatonin in-\ncreases P and A production in mouse pre-antral follicles, while \nreducing CYP11A and CYP17 expression [98,99].\nFollowing the separation of theca cells and GC, melatonin de-\ncreases the progesterone synthesis by theca cells, but it does not \naffect the GCs. Melatonin may directly repress follicular or thecal \nsteroid synthesis pathway by cAMP regulation. The inferences \nare constant with information elaborating that melatonin clogs \nthe expression of steroidogenic dreadful regulatory proteins \n[100]. It is trusted that steroidogenic acute regulatory protein de-\ntermines the transfer of cholesterol through the intermembrane \nspace into the inner membrane space, where P450scc converts \ncholesterol into pregnenolone. Melatonin (10 nM) administration \nfor three hours decreased the steroidogenic regulatory protein ex-\npression (chronic) activated by human chorionic gonadotrophin \n(hCG) in mouse Leydig tumor cells. On the other hand, the un-\ndeviating effect of melatonin on the synthesis of follicular steroid is \nnot so simple; it is dependent on the thecal cell and GC type, the \nlength of treatment (acute or chronic), experimental model (cell \nculture or culture of follicles), species, and dosage. The growth fac-\ntors that are synthesized regionally such as insulin-like growth fac-\ntors (IGF), members of the transforming growth factor b (TGF-b) \nsuperfamily (inhibins, activins, and bone morphogenic proteins \n[BMP]), work together with gonadotropins across the total follic-\nular growth. At the time of follicular development, the IGFs are \nsynthesized by the GC [101]. IGFs are mitogenic as well as anti-\napoptotic peptides that ensure variation with the metabolic effect \nas insulin is conducted by attaching to specific high-affinity mem-\nbrane receptors. The activation of DNA synthesis happens only \nby IGF-1 and IGF-2 with relation to the secretion of E2 and pro-\ngesterone from human GCs and the granulose luteal cells [101].\nIGF-1 acts as antiapoptotic in ovarian follicles but ovarian apop-\ntosis is controlled by the IGF-binding proteins [102]. The cultured \nhuman GCs activate or enhance IGF-1 production by adminis-\ntration of melatonin (0.01 to 10 mg/mL) [103]. A recent study by \nPicinato et al. [104] elaborated that a melatonin dosage of 0.1 mM \ninfluences the IGF-1 receptor and initiates two intracellular sig-\nnaling pathways: the p13K/AKT, which is majorly involved with \ncell metabolism, and the MEK/ERKs, which takes part in cell \ngrowth and development with the differentiation. The IGF-β su-\nperfamily was communicated by ovarian cells and oocytes in a de-\nvelopmental, step-related manner, and their functions between \ntwo ovaries regulate the follicular development. TGF-β is pro-\nduced in case of humans by both the theca cells and GC [105]. \nThe TGF-β also enhances the reveal of FSH receptors [106], which \nmultiplies FSH stimulated aromatase activity along with the pro-\nduction of progesterone and the attraction of LH receptor by GC \n[107]. In human benign prostate epithelial cells, melatonin stim-\nulates the production of TGF-β [108]. In the growth of antral fol-\nlicles, members of the TGF-β superfamily, including BMPs and \ngrowth and differentiation factor-9 (GDF-9), play an important \nrole. Oocytes can manufacture the BMP-15 and GDF-9 which may \nexert their controlling effect on gonadotropins. The BMP-15 had \nbeen observed to weaken the actions of FSH on rat granulose cells \nby suppressing the FSH receptor expression [109]. GDF-9 has an-\nother function of reducing the E2 and progesterone production \nby activating the FSH and has a major function in the weakening \nof FSH stimulated LH receptor construction [110]. Following the \naforementioned findings, the relationship between melatonin, \nBMP-15, and GDF-9 in growing follicles has been studied. Atre-\nsia, which is an apoptotic process, is supposed to be controlled by \nthe proapoptotic and antiapoptotic factors. It was elaborated pre-\nviously the relationship between follicular atresia, apoptosis, and \nnitric oxide (NO) emergence in the development of follicles with-\nin different sized follicles. No variation regarding the concentra-\ntions between nitrite and nitrate has been observed. Small sized \nfollicles contain more apoptotic cells compared with the large sized \nfollicles [111]. Small sized follicles due to poor response regarding \ngonadotropins undergo degeneration through the programmed \ncell death. Zhang et al. [112] proposed that, oxidative stress also \nstimulate the process of apoptotic mechanism during atresia. At \nthe time of follicular growth, phagocytic macrophages increase \nin their number [100]. Reactive oxygen species (ROS) are known \nto be generated or synthesized by the endothelial cells [113]. The \nROS in GCs of antral follicles, which are steroidogenically active, \ndeliver more amount of energy which is needed by the cells [114]. \nIn atretic follicle, oxidative stress mediated apoptosis are being \nregulated by the reduced levels of few antioxidant enzymes like \nSOD, catalase, etc. [115].\nUsually, aformentioned enzymes prevent the GCs from vandal-\n\nMelatonin and Female Reproduction\n150 / CIM\nization and obstruct atresia [116]. The atretic degeneration is \nshown to be controlled by the members of BCl2 family. After \ncomparing with wild-type (BCl2, p/p) ovaries, it had been ob-\nserved that reduction of BCl2 family can affect the quantity of \nhealthy follicle numbers rather increasing the numbers of abnor-\nmal follicles [117]. The over declaration of BCl2 on GCs of grow-\ning follicles can lead to decreased apoptosis of the aforementioned \ncells [118]. Casp3-/- follicles, another type of follicle, have shown \nnot to be discarded as caspases or casps enhance follicular atresia \n[119]. Recent studies have explained that melatonin protects the \nattraction of the mitochondrial pathway of apoptosis by influenc-\ning BCl2 declaration and decreasing casps-3 activity. Melatonin \n(10 mg/kg) injection markedly protects hepatocyte apoptosis in \nmice infused at the time of malarial infection by obstructing the \ncasps-3 activity [120]. Rats with more age express the changes \nwithin the apoptosis in the liver and moreover enhances cyto-\nchrome-c mitochondrial emancipation, relative declaration of Bax \nto BCl2, and activity of casps-3, but after the administration of \nmelatonin by drinking water (20 mg/L) for nearly about 4 weeks \nor a month, the aforementioned changes were overridden [121].\nThe accumulation of signals other than ovary but internal fol-\nlicular factors exhibits the gateway of the follicle either towards \ndevelopment or atresia. Melatonin also helps the growing follicle \nby rummaging the reactive nitrogen species (RNS) and ROS sys-\ntem as well as energizing the antioxidant enzyme activities. It \nalso controls not only the antioxidant enzymes as well as the an-\ntiapoptotic/proapoptotic protein gene expression. The higher \nconcentration of melatonin in the growing follicles can also be a \nmajor factor in inhibiting atresia. For this reason, a follicle before \novulation can be fully developed and will provide an oocyte for \nfertilization.\nMelatonin and ovulation\nA decrease in LH secretion and hindrance in oocyte release can \nbe continuous ingestion of external melatonin along with proges-\nterone in women. On the other hand, the aforementioned com-\nbination exaggerates the luteal phase of progesterone, not affect-\ning at all the FSH or inhibiting the E2 secretion [122]. On the \ncontrary, in the case of men, the LH level was severely decreased \nbecause of melatonin treatment [123]. These changes in the hor-\nmonal level are due to the activation of hypothalamic gonadotro-\npin release supported by melatonin [123]. Melatonin can also do \nits work by attaching itself directly to granulose cells inside the \novary [84]. MT1 and MT2, the two types of melatonin receptors, \nare to be found in the human GCs, which can improve the LH \nmRNA receptor [85]. The LH is mostly required for the begin-\nning of luteinization. The LH surge stimulates some structural \nand biochemical changes which promote the breakage of Graaf-\nian follicles resulting in the release of oocytes and followed by \nmaturation of corpus luteum (CL). After the hCG administration, \nthe hormonal regulation becomes shifted from E2 to progester-\none by inhibiting 17α-hydroxylase-c17-20-lyase activity [124]. \nThe drastic progesterone production is necessary for the mainte-\nnance of CL and ovulation. As compared melatonin with E2 and \nP , the concentrations of both are higher in large follicles than in \nsmall follicles. Importantly, there is a positive integrity between \nthe progesterone and melatonin concentrations [81]. Increased \nconcentration of melatonin in primary follicles before ovulation \nmight be related to progesterone production which concludes in \nluteinization and ovum release.\nThe local increase in the concentration of ovarian prostaglan-\ndin (PG), angiotensin II [125], and NO synthase (NOS) [125] has \nbeen observed during ovulation. The above-mentioned substanc-\nes play an important role in the process of ovulation. At the time \nof follicular rupture, the collagen that is observed in the follicular \nwall becomes damaged along with a huge amount of vascular dil-\natation and permeability [126]. The increased level of follicular \nPGE2 level is needed for a successful ovulation. Treatment with \nmelatonin (20 mg/kg body weight) markedly elevates the PGE2 \nconcentrations in the gastric mucosa of rats [127]. Melatonin treat-\nment (20 mg/kg body weight) via intraperitoneal injection also \nelevates the PGE2 levels in the esophageal tissue of rats [128]. On \nthe other hand, the physiological melatonin concentration will \ncease the nor-epinephrine-induced activation of PGE2 in the me-\ndial basal thalamus of rats [129]. The above-discussed relationship \nbetween melatonin and PGE2 could be a way to relate whether \nthese two hormones are responsible for creating any change in \nthe ovulation process or not. Ovulation can be likened to an in-\nflammatory process, during which RNS and ROS are generated \n[130]. Oocytes and theca cells in mice express endothelial nitric \noxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) \n[96]. During ovulation, macrophages and neutrophils in the ova-\nry produce large quantities of ROS, facilitating apoptosis of ovar-\nian cells [81,115]. Melatonin and its metabolites, known for their \nantioxidant properties, effectively scavenge ROS and RNS [131-\n134]. Elevated melatonin levels in follicles prior to ovulation pro-\ntect GCs and oocytes from oxidative damage during ovulation.\nMelatonin on oocyte quality and embryo\nPoor oocyte quality is a primary cause of female infertility, of-\nten resulting from ROS produced during ovulation [135]. Specif-\nic ROS, including OH-, O2-, and H2O2, cause lipid degradation, \nDNA damage, and apoptosis [136], leading to two-cell inhibition, \nprogrammed cell death, and impaired fertilization [137,138]. Re-\nduction in antioxidant enzyme levels, such as GPX, was keenly \nobserved in the FF of women with sterility which was unexplained \n[139]. Along with this, more levels of H2O2, a type of oxidant, had \nbeen observed in fragmented embryos in lieu of non-fragmented \nembryos, and oocytes that were not fertilized have also been re-\nported [140]. More usage of antioxidants, which can be a reason \nfor increased ROS levels at the time of incubation of embryos with \npoor quality, has been informed [141]. The comparison between \nROS production and the rummaging ability of antioxidants has \nbeen considered an important factor for the development and \nmaturation of oocytes and their fertilization. Medicines that pro-\ntect the oocyte and its neighboring feeder cells from any destruc-\n\nSuparna Parua, et al\nCIM / 151\ntion are of real importance. The observance of maximum mela-\ntonin receptors in GCs [83,85] expresses that indoleamine might \nbe a molecule that is more helpful in the follicle. Intrafollicular \nlevels of 8-hydroxy-2’-deoxi guanosine (8-OHDG, marker of de-\nstroyed DNA products) in women with poor quality oocytes are \nmarkedly more compared with normal quality of oocyte in pa-\ntients with IFV transfer of embryos, and intrafollicular density of \n8-OHDG and hexanoyl lysine adduct (HEL, a lipid peroxidation \nbiomarker), are noticeably decreased by 3 mg melatonin/day or \n600 mg Vit-E/day dosage [90]. Along with this, before the em-\nbryo transfer cycle, the fertility rate was around 50%, but, after \nmelatonin treatment, the IVF embryo transfer cycle was improved \n[90]. On the other hand, melatonin also assertively influences \nboth antioxidant enzyme activity and gene expression. The ad-\nministration of 5 mg/kg body weight melatonin increases the \nSOD activity [142], whereas 1 nM of physiological serum level of \nmelatonin influences the gene expression of all the three antioxi-\ndant enzymes (i.e., Cu-Zn-SOD; Mn-SOD; and GPx) [143]. Mel-\natonin might be a boon to those women who were suffering from \npoor-quality oocytes. It also maintains the proper maturation of \noocytes [98]. The pregestational steroid, 17α, 20β- dihydroxy-\n4-pregnen-3-one (17α, 20β-DP), is known to have an impact on \noocyte maturation [144]. It works on receptors located on the \nmembrane of the oocyte and enhances the activation factor for \npromoting maturation in the cytoplasm of the oocyte which can \ninduce the final maturation [145]. The maturation-promoting fac-\ntor of the oocyte goes through a significant morphological change \nin association with the meiotic cell cycle, where cleavage of the oo-\ncyte nuclear envelope or germinal vesicle appearing in between \nprophase and metaphase is normally regarded as a mask in the \ndevelopment of oocyte maturation [146]. A melatonin dosage of \n50 to 500 pg/mL preceded the action of maturation-inducing hor-\nmone in both the maturation-promoting and factor and lysis of \ngerminal vesicles of oocytes [147]. \nAccording to a few studies, melatonin is also responsible for in-\nducing epigenetic moderation in oocytes [148,149]. The DNA \nmethyl transferase inhibitory effects could be brought to apply by \nmelatonin only after obscuring target sequences or by plugging \nthe active site of the enzyme [150]. Epigenetic modifications can \nlead to the interaction of melatonin with nuclear melatonin re-\nceptors. Melatonin markedly enhances the effects of trans-activa-\ntion of these receptors [151]. The nuclear melatonin receptors have \nan important function in the bending of DNA [152]. The epigen-\netic modification induced by melatonin and affected by the nu-\nclear melatonin receptors, can on the other hand alter the super-\nstructure of DNA. As per the above discussion, melatonin plays \nthe role of a mediator that passes the environmental stimulus to \noocytes interconnections within environmental factors and epi-\ngenetic inheritance system. The presence of melatonin in the cul-\nture medium carries through not only in the fertilization of mice \nbut also premature development of embryonic tissue [153] appar-\nently by working as a non-compelling radical rummager. Pres-\nently, Rodriguez-Osorio et al. [154] informed that 10 nM melato-\nnin administration has an assertive effect on cleavage rates in \nporcine embryos. In addition to this, in the culture medium, mel-\natonin has changed the rate of progression of thawed blastocysts \nwith a maximum hatching rate after a close observation of 24 \nhours [155]. Within 1 pM to 100 nM dosage of administration, \nno nullative effects of melatonin on the development of embryos \nwere seen [156], even after administration of high dosage also at \nthe time of pregnancy [157].\nMelatonin in pregnancy outcome and fetal development\nSeveral studies have demonstrated the role of melatonin in preg-\nnancy. Maternal melatonin crosses the placenta, exposing the fe-\ntus to daily rhythms of low and high concentrations, contributing \nto the circadian regulation of fetal organ function. Melatonin also \nsupports embryo development, as observed by increased blasto-\ncyst formation in mouse embryos cultured with melatonin [153]. \nAdditionally, melatonin positively influences in vitro develop-\nment in rodent embryos at the 2-cell stage [158] and facilitates \novine blastocyst maturation [159]. Suppression of the maternal \nplasma melatonin circadian rhythm by continuous exposure to \nlight during the second half of the gestation period showed sev-\neral effects on fetal development. Firstly, it generated intrauterine \ngrowth retardation. Secondly, in the fetal adrenal gland in vivo, it \ndistinctly affected the mRNA expression level of the clock genes \nand clock-controlled genes, as well as it reduced the content and \nmodified the rhythm of corticosterone. Thirdly, a revamped in vi-\ntro fetal adrenal response to adrenocorticotropic hormone (ACTH) \nof both corticosterone production and relative expression of clock \ngenes and steroidogenic genes was observed. All these changes \nwere reversed when the mother received a daily dose of melato-\nnin during the subjective night [160].\nTorres-Farfan et al. [161] reported that maternal melatonin in-\nfluenced a reduced cortisol production in the fetal adrenal gland \nof the capuchin monkey. In another study on sheep, it was found \nthat melatonin had direct inhibitory effects on the noradrenalin-\nstimulated fetal cerebral artery contraction, the release of glycerol \nby brown adipose tissue, and on ACTH-induced secretion of cor-\ntisol by the fetal adrenal gland. Low levels or a deficient circadian \nrhythm of the fetal corticosterone may be the cause of the intra-\nuterine growth retardation that has been previously reported. The \ndeficiency of maternal melatonin (induced by pinealectomy) dur-\ning the early stages of gestation was found to disturb the drinking \nbehavior of rat pups, an effect that was reversed by the adminis-\ntration of exogenous melatonin to the dam [162]. Melatonin is \ncrucial in normal placental development and function, a function \nsupported by the placenta melatonin receptor expression during \nearly pregnancy [90].\nMoreover, an oral dose of 75 mg of melatonin was shown to in-\nhibit the release of gonadotrophin hormones, which has enlight-\nened the experimental works on melatonin-based contraception \nmethods [122] previously, like intrauterine device, levonorg -\nestrel-releasing intrauterine system methods of the recent era \n[163]. \n\nMelatonin and Female Reproduction\n152 / CIM\nMelatonin and luteal function\nProgesterone (P) plays a pivotal role in implantation and preg-\nnancy regulation by modulating GC functions and follicular rup-\nture during ovulation [94,164]. LH receptor activation in follicu-\nlar cells due to the LH surge induces ovum release and initiates \nluteinization, transforming the follicle into the CL [165]. Theca \ninterna and GC undergo biochemical and morphological chang-\nes, rapidly differentiating into luteal cells [165]. These structural \nand genetic alterations culminate in follicular cells’ terminal dif-\nferentiation into P-producing cells. LH surge also influences PR \nand cyclooxygenase-2 (cox-2) gene expression in GCs [166,167]; \nabsence of PR or cox-2 results in infertility in mice. They bring up \npre-ovulatory follicles, but they are unable to ovulate [167]. In the \nluteal phase, there is a higher level of melatonin rather than the \nproliferative or follicular phase of the menstrual cycle [168]. The \ncells of GC-luteal phases contain melatonin binding sites in hu-\nmans [83,85], and the release of progesterone from human luteal \ncells is been directly stimulated by melatonin [85]. Melatonin can \nchange or improve luteal functions. This melatonin not only stim-\nulates to production of progesterone by GCs-luteal cells [83] but \nalso, at dosages of 10 pM to 100 pM, markedly increases the ex-\npression of mRNA of LH receptor in the GCs-luteal cells of hu-\nmans and inhibits the expression of GnRH receptor [85]. Melato-\nnin elevates progesterone secretion, stimulated by hCG, probably \nby the enhanced expression of the LH receptor. On the other hand, \nfew results or reports imposed a nullified expression of melatonin \nin the growing and luteinized GCs [81,103] on account of proges-\nterone production. In another study [169], it has been document-\ned that GCs, isolated from porcine ovaries, when administered 1 \nng/mL to 100 mg/mL dosage of melatonin, showed inhibition of \nprogesterone production and secretion by GC cells. cAMP , a sec-\nond messenger, plays an important role in the steroidogenesis pro-\ncess and can be inhibited by the action of melatonin. Short-term \nincubation of 48 hours inferred the negative effect of melatonin \non the release of progesterone whereas long-term incubation led \nto an assertive effect. It is been hypothesized that at the beginning, \nmelatonin plays an inhibitory role on cAMP . However, as it pro-\nceeds further, the inducing effect of melatonin on LH receptor \nmRNA expression and cooperative effect on GCs become prom-\ninent. The cytotoxicity, which occurs by the free radicals within \nlong-term cultured GCs, may be prevented by melatonin by its \nantioxidant ability, which may be direct or sometimes indirect. \nROS production may repress progesterone production and can \nprompt CL regression [170]. Melatonin apparently prevents CL \nfrom ROS production and thus maintains the functional physiol-\nogy of CL. Presently, a recent study [171] has imposed a manda-\ntory effect of melatonin on the morphology of the endometrium \nand the implantation of the embryo.\nThe researchers elaborated on the speed or rate of implantation \nand the level of progesterone in the serum was been reduced in \nthe rats whose pineal glands were atomized, whereas on the other \nhand, the decreased serum progesterone levels were consolidated \nto the normal level by administering day to day melatonin intra-\nvenously in the dosage of 2 mg/kg body weight. Enhanced mela-\ntonin in the luteal phase and early pregnancy may increase pro-\ngesterone production by the luteal cells, which is essential for the \ndesired and healthy pregnancy. Several biochemical and endo-\ncrine factors are related to excessive information and create an \nimpact on the production of progesterone by luteal cells. hCG, \nLH, PRL [172], cytokines [173], and growth factors [91] induce \nthe production of progesterone, whereas PGF-2α [174], oxytocin \n[175], cytokines [176], and ROS [170] reduces progesterone pro-\nduction. PGF-2α is of major importance because of its strong au-\ntocrine/paracrine actions that conclude the suppression of CL. A \n10 mM dose of melatonin can insulate the secretion of PGF-2α \nfrom the uterus of a rat [177]. Melatonin in the range of 0.1 to 1 \nmm has been observed to inhibit the expression of the Cox-2 gene, \nwhich is responsible for producing the PGF-2α synthesizing en-\nzyme, in a murine macrophage cell line [178]. Melatonin also en-\nhances PRL secretion [178,179] and plugs the release of oxytocin \nfrom the hypothalamohypophyseal system of the rat [180], rep-\nresenting the necessity of indoleamine for the maintenance of pro-\ngesterone synthesis and the function of luteum by making the \nbetter usage of different mechanisms.\nMelatonin and parturition\nMelatonin is an endocrine signal of nighttime duration [181] \nand was certainly expected to have regulatory effects on the tim-\nings of parturition. Takayama et al. [182], regarding female rats \nsubjected to pinealectomy resulting in the loss of endogenous, \nshowed that their estrous cycles or their ability to get impregnat-\ned were not perturbed. However, a failure in the delivery of young \nones in the daytime was observed (dawn being the normal birth-\ning phase for nocturnal animals such as rodents). Moreover, de-\nlivery was noted randomly across a 24-hour light-dark cycle. In-\nterestingly, administration in the evening (when the endogenous \nlevels would normally increase) had impressive effects in the re-\ngeneration of normalcy in the daytime birth, whereas morning \nadministration of melatonin was ineffective, which sharply hints \nthat melatonin may discharge the role of a circadian “gating” sig-\nnal in this event of birth of rats being under circadian control. This \ninsinuates the significant role of the clock in the entire reproduc-\ntive process. However, we must be cautious while generalizing this \ndata to humans, considering we are dominantly diurnal whereas \nthe majority of animals are nocturnal.\nThe mode of action of melatonin on the mammalian uterus re-\nmains unclear and appears to be species-specific. Studies in rodents \nhave shown that pharmacological doses of melatonin inhibit uter-\nine contractility and interact with melatonin-specific binding sites \nin the uterus [183-185]. Additionally, melatonin inhibits prosta-\nglandin synthesis in rodent tissues [177,178] and regulates calci-\num signaling, including in vascular smooth muscle [186]. How-\never, caution is required when extrapolating these findings to \nhumans, as they are primarily derived from nocturnal species \nwith different parturition physiology. Human labor predomi-\nnantly occurs during the night phase, contrary to the pattern ob-\n\nSuparna Parua, et al\nCIM / 153\nserved in nocturnal rodents [187,188]. The nocturnal secretion of \nmelatonin and its effects on uterine contractions in other mam-\nmals suggest that melatonin may act as a temporal regulator in \nthe process of uterine contractions during human parturition. \nStudies have shown that melatonin and oxytocin have a signifi-\ncant positive synergistic effect on the contraction of human myo-\nmetrial smooth muscle cells, resulting in enhanced IP3 signaling \nand an increase in contraction induced by oxytocin. These results \nmay explain the high frequency of uterine contractions that occur \nduring the night in the later stages of pregnancy, which can ulti-\nmately lead to labor at night [189,190]. Recently, it has been iden-\ntified the synergistic action of melatonin and oxytocin on myo-\nmetrial smooth, muscle cell induction of the core circadian gene \nhbMAL1 [191]. BMAL1 is the transcription factor at the core of \nthe circadian system [192,193] as its basic function is the modu-\nlation of expression of the genes whose promoters contain the E-\nbox motif which includes the melatonin receptors. Oxytocin (OT) \nanalogs serve as pivot tools in obstetric practices. Uninterrupted \ninfusions of OT antagonists are now being used for the induction \nof labor and prolonging pregnancy in case of preterm labor. How-\never, only very high amounts of hormones are shown to be effec-\ntive in case of prolonged labor induction due to receptor desen-\nsitization [194]. Unfortunately, high dosage of oxytocin is often \naccompanied by serious side effects including fetal distress, uter-\nine rupture, and postpartum atony and bleeding. Tracing a syner-\ngism between melatonin and oxytocin could lead to the develop-\nment of new melatonin combined with OT medical dosage for \nlabor induction without considerable side effects of high levels of \nadministered oxytocin. Conversely, the studies accounting for the \npopular inhibitory effect of light on the circulating melatonin lev-\nels have provided substantial evidence that nocturnal uterine con-\ntractions common to later pregnancy are under melatonin control \n[195,196].\nThe regulation of melatonin receptor MTNR1B in the myome-\ntrium of laboring pregnant women, compared to non-pregnant \nwomen, has been observed, showing suppression during most of \ngestation and de-suppression near parturition [189]. Similar pat-\nterns were noted for MTNR1A and MTNR1B expression, with \nincreased melatonin binding towards the end of pregnancy [196]. \nWhile progesterone maintains uterine dormancy during preg-\nnancy [197,198], changes in its signaling due to melatonin recep-\ntor activation in the myometrium remain unclear. Melatonin re-\nceptor proteins were detected in women entering preterm labor, \nsuggesting potential sensitivity to contraction and preterm labor \nvia premature receptor expression [199,200].\nMELATONIN AND FEMALE \nREPRODUCTIVE P ATHOPHYSIOLOGY\nMelatonin and PCOS\nPCOS is a type of hormonal disease that results in sterility be-\ncause of anovulation in a woman at her reproductive age. Not only \nsterility but women with PCOS can also have some other features \nlike hyperandrogenism, hyper-insulinemia, insulin resistance, hir-\nsutism, obesity, chronic anovulation, and polycystic ovaries. Re-\nduced quantity of oocytes along with the quality of the embryo \nmight be a reason for sterility in women with PCOS [201]. Any \ntype of stress may reduce the quality of female reproductive as \nwell as endocrine functions. In PCOS, the ROS produced by oxi-\ndative stress might be responsible for the reduced quality of oo-\ncytes. The oxidative stress induced by ROS might be a reason ROS \nfor the low quality of oocytes. The generation of ROS from the \ncells that are mononuclear is enhanced in women who are suffer-\ning from PCOS [202]. It significantly increased serum lipid per-\noxidation has been proven by few studies [203]. Malondialdehyde, \na product developed due to lipid peroxidation, is enhanced in the \nFF of women with PCOS [204]. On the other hand, the apoptotic \nGC ratio is also higher in women with PCOS [205]. Due to oxi-\ndative stress GCs and oocytes can be damaged by the peroxida-\ntion of lipids, protein oxidation, and damage of DNA inside the \nfollicle. The most important enzymatic metabolite of melatonin, \nurinary 6-sulfatoxymelatonin, is enhanced significantly in PCOS \nwomen compared with non-PCOS women [206]. Enhanced mel-\natonin increased LH release [86,207], the amplitude of LH [207], \nand the response of LH to GnRH [208]. Along with this, melato-\nnin might decrease peripheral tissue sensitivity to insulin [209]. \nOn the other hand, the suppression in melatonin levels due to \npinealectomy and exposure to intermittent light enhances the up-\nliftment of a few features of PCOS in rats [210].\nWomen with PCOs have less amount of indoleamine in their \nfollicles, while also having higher concentrations of serum level. \nAn elevated level of serum melatonin indicates a lower level of \nmelatonin in the ovary. An enhanced level of melatonin in the FF \nis necessary for the growth and proliferation of the follicle, ovula-\ntion, and maintaining the quality of the oocyte. Decreased serum \nmelatonin levels might be a reason for anovulation and reduced \nquality of oocytes in the case of PCOS women. The 16 kDa hor-\nmone named leptin is majorly synthesized in the adipose tissue \nand gets elevated in obese persons [211]. Amidst circulation, \nleptin gets attached to protein(s) [212], which might change its \nphysiological activity [213]. Leptin maintains metabolic balance \nand intake of food and gets attached to specific cellular receptors \nby affecting the reproductive system [214]. The disbalance in the \nleptin system is concerned with the pathological conditions in \nthe reproductive organs with PCOS [215]. The function of the \nleptin hormone is to promote the process of steroidogenesis and \nmaturation of follicles. On the other hand, the concentration of \nleptin higher than the normal level might produce adverse effects \n[216]. The level of leptin in the serum of PCOS women is remark-\nably higher than compared to normal women [217]. In addition, \nthe FF has the same concentration of leptin as in the serum level \n[218], cells of the ovary along with GCs, thermal cells, and inter-\nstitial cells that expose a particular leptin receptor [219]. Leptin \nmodifies the production of steroids by action on GCs and theca \ncells in vitro [220], which represents a straight intraovarian effect \nthat happens in vivo. Women who see with PCOS have been re-\n\nMelatonin and Female Reproduction\n154 / CIM\nported with elevated levels of leptin in FF [217]. Supplementation \nof melatonin daily to rats represses body weight, plasma leptin \nlevels, and adiposity [221]. However, two factors, such as pine-\nalectomy and melatonin administration, have been observed to \ninfluence serum leptin levels. Specifically, melatonin has been \nshown to enhance leptin expression in adipocytes of rats in the \npresence of insulin [222,223]. Through a few specific receptors like \nG-protein coupled receptors, MT1 and MT2 receptors act straight-\nly on melatonin [224]. The stimulation of these receptors may \nrelease a changing effect on the synthesis of heparin by decreas-\ning cAMP levels. Furthermore, the correlation between reduced \nmelatonin and elevated leptin in the FF of women with PCOS is \nnot expressed yet. More studies and research are required to ex-\nplain the proper relationship between the aforementioned two \nconditions, which may be major in acknowledging the patho-\nphysiology of PCOS.\nMelatonin and endometriosis\nA persistent provoking disease that is specified by implanta-\ntion and growth of the endometrial tissue at the out-sided line \nwithin the uterine cavity. It is a usual gynae-related disorder that \ncontains an increasingly repeated nature and has been diagnosed \nto affect 21% to 44% of sterile and 4%– 22% of non-sterile women \n[225,226]. It is related to persistent pelvic pain, continuous dys-\nmenorrhea, dyspareunia, and sterility. Usually, the extrauterine \nimplantation location is in the reliant parts of the pelvis, most im-\nportantly, the ovaries, the pelvic walls, and the posterior cul-de-\nsac. The reason for endometriosis is not known still. It is trusted \nto be a multifarious disease related to a usual proactive response \nin the peritoneal cavity. One of the theories explains that at the \ntime of menstruation, the release of endometrial fragments may \npass within the oviduct or fallopian tubes and repetitively arriving \nthe peritoneal cavity. These fragments of endometrium may at-\ntach on the serosal surfaces of the peritoneal cavity and with ev-\nery monthly followed menstrual cycle they may go through de-\nvelopment and bleeding. At this location, the oxidative stress \ninducers contain erythrocytes, apoptotic cells of the endometri-\num with not digested endometrial cells in the menstrual effluent \n[227]. The ROS has a close relation to the process of proliferation \nand pathophysiology of a disorder. Peritoneal fluid (PF) volume \nin women who have endometriosis has been enhanced with the \nelevated number of macrophages in the PF compared with con-\ntrol women. Stimulated macrophages increase oxidative stress, \nthe formation of lipid peroxide, and other by-products resulting \nin the relation of peroxides with apolipoprotein. PF macrophages \nsynthesize more amounts of ROS in the case of endometriosis pa-\ntients [228]. The ROS reaches a centralized pelvic inflammatory \nreaction, which results in elevated concentrations of cytokines, \ngrowth factors, PGs, and other inflammatory products. Non-at-\ntached iron and heme play a significant role in the synthesis of \nROS. Their sedimentation is elevated in the vicinity of the perito-\nneum where the endometrial implants are done [227]. Persistent-\nly, the activity of iNOS and the production of NO by the macro-\nphages of the peritoneum are markedly increased in women with \nendometriosis [229]. The decrease of adhesions is done by mela-\ntonin, a powerful free radical scavenger [230]. However, the im-\nportance of melatonin in endometriosis is still not known but two \ninteresting research articles have explained the participation of \nmelatonin in maintaining the pathogenicity of endometriosis. \nGüney et al. [231] have proved the antioxidant, anti-inflammato-\nry, and immune-modulatory results of melatonin on endometrial \nexplants in the model of rat endometriosis. Melatonin adminis-\ntration (10 mg/kg) each day intraperitoneally, markedly decreased \nthe explant volume in correlation with the control group. On the \nother hand, after the endometrial transfer COX-2-positive cells \nwere remarkably reduced in rats treated with melatonin (91% vs. \n18.1%). On the contrary, in melatonin-treated rats, the transfer of \nendometrial malondialdehyde was markedly suppressed, where-\nas the work of SOD and catalase (CAT) were enhanced in the rats \nwith melatonin treated. This administered that melatonin is a rea-\nson for regression and withering of the endometrium lesions by \nreducing the oxidative stress [231]. According to a study by Paul \net al. [232], it was approved that melatonin also plays a significant \nrole in the protection and suppression of endometriosis in mice. \nThey had pointed out a pioneered diagnostic marker, matrix me-\ntalloproteinases (MMP-9)/tissue blockers of metalloproteinase \n(TIMP-1), pronouncing ratio in determining disease succession and \nseriousness and melatonin treatment intraperitoneally 48 mg/kg \nwith accumulation of lipid peroxidation and oxidation of protein \nin the peritoneal endometriosis. Melatonin also reduces the com-\nposition and activity of pro-MMP-9 and enhances TIMP-1 expres-\nsion. The outcome determines a role for melatonin in protecting \nand elevating the suppression of endometriosis through the main-\ntenance of MMPs.\nMelatonin and premature ovarian failure\nPremature ovarian failure (POF) is diagnosed in women under \n40 years, when elevated gonadotropins, sex steroid deficiency, and \namenorrhea are observed [233]. POF may arise from a genetically \ndetermined low ovarian follicle count at birth, proliferative follic-\nular depletion (atresia), or follicular dysfunction [234]. The etiol-\nogy of POF includes chromosomal and genetic abnormalities, au-\ntoimmune disorders, viral infections, and iatrogenic factors such \nas pelvic surgery, chemotherapy, and radiotherapy. Chemothera-\npy and radiotherapy, commonly used for malignancy treatment, \nare well-established causes of POF , contributing to follicular de-\npletion and dysfunction through cytotoxic effects on ovarian tis-\nsue. However, changed chemotherapy and radiotherapy regimens \nfor malignancy in youth have proceeded to be enhanced for long-\nterm existence. One situation has been a curtailment in ovarian \nstorage and therefore an enhanced prevalence of POF . The danger \ndiagnosis proceeding to POF elevates, with age after adolescence, \nwith different strong chemotherapy subjugation with accumulat-\ned chemotherapy and radiation therapy [235]. The demonizing \neffects of ionizing radiation are turnabout by direct and indirect \nmechanisms. The straight action synthesizes delicate molecules \n\nSuparna Parua, et al\nCIM / 155\ninside the cells and leads to the genesis of disorders; however, the \nunintended actions of ionizing radiation come out when it reacts \nwith water molecules in the cells, concluding in the production of \nvigorously reactive free radical, like OH-, H- with aqueous elec-\ntron. An approximate 60% to 70% of tissues and cellular DNA \nvandalism influenced by ionizing radiation is trusted to be an \nout-turn of OH- [236]. If the toxicity present in both the ovaries \ndue to radiation exposure should be known as gonadotoxicity \n[237]. A dose-dependent damage of the primary follicles was ob-\nserved after enhancing the doses of radiation, according to Gos-\nden et al. [238]. In contrast other studies have assured the high \nefficiency of melatonin against ionizing radiation effects [236]. \nWhen melatonin acts on OH-, it will be turned into a halfway in-\ndolyl (melatonyl) radical which is less reactive as well as less harm-\nful too. Therefore, when melatonin combines with OH-, a highly \nreactive harmful substance is converted into a less harmful sub-\nstance through a radical transformation, resulting in complete \nacquisition [239]. This intermediate molecule then binds with a \nsecond hydroxide (OH-) molecule to form cyclic 3-hydroxy mel-\natonin, which demonstrates its effectiveness as a radioprotective \nmolecule by scavenging the free radicals produced by ionizing ra-\ndiation [240]. The prior treatment with melatonin decreases the \nplasma and red blood cell levels which can be an inference malo-\nndialdehyde influenced oxidative entire body from the condition \nof being exposed to radiation. On the other hand, melatonin also \nenhanced the levels SOD and GPx [241]. Thus, due to its scaveng-\ning effects, melatonin may prevent molecular damage caused by \nradiation by increasing the activity of antioxidant enzymes. The \nadministration of melatonin effectively mitigates the detrimental \neffects of radiation when administered prior to exposure. Howev-\ner, it does not confer protective benefits if administered after ra-\ndiation exposure has occurred [240]. When anticancer drugs are \ngiven in various malignant diseases in young women, there is \nmarked loss of primordial follicles and reduce the function of \nGCs and oocytes [241]. The cytotoxic effect of chemotherapy is \nmostly drug, dose, and age-dependent [242]. Generation of ROS \nin mitochondria induced by anticancer medication, such as alkyl-\nating agents (like cyclophosphosphamide, ifosfamide, etc.), plati-\nnum agents (such as cisplatin), and antitumor antibiotics (like \ndoxorubicin, daunorubicin, bleomycin, etc.), also contribute to \ncytotoxicity [243,244]. Melatonin antagonizes this ROS-induced \ncytotoxicity by acting as an antioxidant agent and it also promotes \napoptosis of cancer cells. The administration of melatonin at the \ndose of 10 mg/kg of body weight with a chemotherapeutic agent \nreduces the occurrence of thrombocytopenia, neurotoxicity, car-\ndiotoxicity, and asthenia [245]. Studies have proven that melato-\nnin is highly effective in protecting against doxorubicin-induced \ncardiotoxicity by reducing glutathione and malondialdehyde lev-\nels in cardiac tissue [244]. Melatonin is also expected to protect \nthe cell damage due to autoimmune disorders like premature \novarian failure in which ovarian autoantibodies are produced \nagainst GCs, theca cells, and zona pellucida leads to autoimmune \nlymphocytic oophoritis. Autoimmune mechanisms are mostly \ninvolved in the pathogenesis of likely 30% of cases of POF [246]. \nMany other autoimmune disorders like Addison’s disease, diabe-\ntes mellitus, hypothyroidism, myasthenia gravis, systemic lupus \nerythematosus, and rheumatoid arthritis are also caused by in-\ncreased activity of peripheral T-lymphocytes [234,247]. The mel-\natonin is a widely known immune modulator [248]. There are \nspecific melatonin binding sites on lymphocytes and monocytes \n[249]. After binding at these sites, melatonin regulates the func-\ntions of lymphocytes and monocytes [250] and th1/th2 balance \ncytokine [251]. It acts as an anti-inflammatory and anti-apoptotic \neffect [252]. A study conducted in mice showed that when mela-\ntonin was given in the dose of 5 mg/kg body weight via IV injec-\ntions 1 hour before antibodies administration, then melatonin \nrestored the oocyte meiotic maturation and survival [253]. Thus, \nmelatonin may be a promising agent with beneficial effects on \nimmune-mediated ovarian pathology.\nMELATONIN IN REPRODUCTIVE AGING\nIn contrast to early childhood, where elevated melatonin levels \nare associated with suppressed gonadotropin secretion, low mel-\natonin levels in elderly individuals are linked to reproductive ag-\ning, marked by increased gonadotropin secretion [254]. Research \nshows that plasma melatonin levels decline with age, and the noc-\nturnal melatonin peak shifts earlier [255,256]. The onset of meno-\npause, characterized by diminished ovarian follicular reserve and \naltered hormonal secretion, signifies the end of reproductive fer-\ntility. This process results in menstrual cycle cessation and is clini-\ncally associated with increased gonadotropin secretion from the \nanterior pituitary due to the loss of ovarian function. A previous \nreport indicated mitigation of depression, along with improved \nmood and sleep quality following melatonin administration to \nperimenopausal and postmenopausal women [257]. However, \nthis was not confirmed in a study by Amstrup et al. [258], which \nfound no significant effect on quality of life or sleep quality in 81 \npostmenopausal women who were given pharmacological mela-\ntonin nightly for a year. However, the authors did mention a non-\nsignificant trend toward improved sleep quality in a subgroup of \nmelatonin-treated women who had sleep disturbances at the ini-\ntial baseline. Toffol et al. [259] showed that postmenopausal wom-\nen have reduced night-time serum melatonin levels than peri-\nmenopausal women; however, no correlations were found between \nserum melatonin and FSH or estradiol levels, Beck Depression \nInventory score, State-Trait Anxiety Inventory score, Basic Nordic \nSleep Questionnaire (BNSQ) insomnia score, BNSQ sleepiness \nscore, subjective sleep score, climacteric vasomotor score, or qual-\nity of life. The apparent inconsistency in the aforementioned stud-\nies is probably reconcilable, since, in the Bellipanni and Amstrup \ninvestigations [257,258], pharmacological levels of melatonin (3 \nmg/night for 6– 12 months) were administered, while the Toffol \nstudy [259] analyzed physiological and psychological correlations \nwith the naturally reduced endogenous melatonin levels. Lately, \nhowever, long-term pharmacological melatonin administration \n\nMelatonin and Female Reproduction\n156 / CIM\nwas shown to decrease psychosomatic symptoms in postmeno-\npausal women after 12 months of treatment in a double-blind, \nplacebo study [260].\nThis is consistent with numerous previous studies on the use of \npharmacological melatonin in the treatment of sleep disturbanc-\nes in elderly men and women [261]. Some studies have proposed \na role for melatonin in ovarian aging, given the supportive and \npleiotropic effects of melatonin on ovarian activities, including \nthe suppression of oxidative stress, protection of mitochondrial \nintegrity, etc. [262]. However, as most of the research to date has \nbeen in rodents, neither a clear etiological connection between \ndeclining endogenous melatonin levels and human menopause \nhas not been adequately demonstrated, nor have sufficiently pow-\nered clinical trials with melatonin administration to premeno-\npausal women been reported [263,264].\nMELATONIN AND IVF\nOne of the important causes of female infertility is the poor \nquality of oocytes. The ROS are normally generated inside the \novarian follicle, during ovulation, and an increased production \ncould serve as a cause of impaired oocyte maturation. Consider-\ning its well-established role in foraging free radicals, treatment \nwith melatonin during human pregnancy may help reduce the \nhigh oxidative stress. Therefore, it could be a possible treatment \nfor some forms of infertility. Melatonin has been studied in assist-\ned reproductive technology aiming to enhance the oocyte quality \nand conception rates following IVF . Administering melatonin, \nwhich was started before IVF cycles and continued during preg-\nnancy, was found to improve pregnancy outcomes. Successful \nfertilization and pregnancy rates were improved due to melato-\nnin treatment. The fertilization rate was 50% higher in the mela-\ntonin treatment regimen as compared to the previous melatonin-\nfree cycle (20.2%) [265,266]. \nMoreover, maternal melatonin treatment has been observed to \nsignificantly improve placental antioxidant enzyme gene expres-\nsion [267]. Maternal and/or embryo-fetal toxicity effects, due to \nmelatonin treatment, have never been reported as such. A medi-\nan lethal dose in mice could not even be confirmed because no \nincreased mortality rate was observed, even after following the \nadministration of extremely high doses of up to 800 mg/ kg mel-\natonin [268].\nCONCLUSION\nMelatonin significantly impacts female reproductive physiolo-\ngy, from ovulation to overall fertility regulation, suggesting its po-\ntential as a therapeutic intervention for conditions such as PCOS \nand endometriosis. Its potent antioxidative effects reduce oxida-\ntive stress in ovarian cells, enhancing oocyte quality and fertility. \nMelatonin supplementation holds promise for infertility manage-\nment, particularly in assisted reproductive technologies, where \nits application has been linked to improved pregnancy outcomes. \nContinued research is essential to fully understand melatonin’s \nmultifaceted role in reproductive health and its therapeutic po-\ntential in broader clinical settings.\nConflicts of Interest\nThe authors have no potential conflicts of interest to disclose.\nAvailability of Data and Material\nData sharing not applicable to this article as no datasets were \ngenerated or analyzed during the study.\nAuthor Contributions\nConceptualization: Suparna Parua, Gargi Roy Choudhury, Pallav \nSengupta, Koushik Bhattacharya. Methodology: Suparna Parua, \nGargi Roy Choudhury, Soumita Bhattacharya. Project adminis-\ntration: Pallav Sengupta, Koushik Bhattacharya. Resources: all \nauthors. Supervision: Pallav Sengupta, Koushik Bhattacharya. Val-\nidation: Pallav Sengupta, Koushik Bhattacharya. Writing—origi-\nnal draft: all authors. Writing—review & editing: all authors.\nORCID iDs\nSuparna Parua \nhttps://orcid.org/0009-0003-8798-1226\nGargi Roy Choudhury \nhttps://orcid.org/0000-0001-9038-3161\nSoumita Bhattacharya \nhttps://orcid.org/0009-0007-6707-4740\nAnukona Hazra \nhttps://orcid.org/0009-0003-3221-9031\nSulagna Dutta \nhttps://orcid.org/0000-0002-7893-5282\nPallav Sengupta \nhttps://orcid.org/0000-0002-1928-5048\nKoushik Bhattacharya \nhttps://orcid.org/0000-0003-0153-4357\nFunding Statement\nNone\nAcknowledgments\nNone\nREFERENCES\n1. Samuel DS, Duraisamy R, Kumar MP . Pineal gland-a mystic gland. Drug \nInvent Today 2019;11:55-58.\n2. Olcese JM. Melatonin and female reproduction: an expanding universe. \nFront Endocrinol (Lausanne) 2020;11:85.\n3. Asma A, Marc-André S. 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