Gynecological Endocrinology

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Melatonin: a “Higgs boson” in human reproduction Svetlana Dragojevic Dikic, Ana Mitrovic Jovanovic, Srdjan Dikic, Tomislav Jovanovic, Aleksandar Jurisic & Aleksandar Dobrosavljevic To cite this article: Svetlana Dragojevic Dikic, Ana Mitrovic Jovanovic, Srdjan Dikic, Tomislav Jovanovic, Aleksandar Jurisic & Aleksandar Dobrosavljevic (2015) Melatonin: a “Higgs boson” in human reproduction, Gynecological Endocrinology, 31:2, 92-101, DOI: 10.3109/09513590.2014.978851 To link to this article:

Published online: 07 Nov 2014.

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Date: 14 October 2016, At: 01:23 ISSN: 0951-3590 (print), 1473-0766 (electronic) Gynecol Endocrinol, 2015; 31(2): 92–101 ! 2014 Informa UK Ltd. DOI: 10.3109/09513590.2014.978851


Melatonin: a ‘‘Higgs boson’’ in human reproduction Svetlana Dragojevic Dikic1,2, Ana Mitrovic Jovanovic1,2, Srdjan Dikic2,3, Tomislav Jovanovic2,4, Aleksandar Jurisic1,2, and Aleksandar Dobrosavljevic1 1

Department of Obstetrics and Gynecology ‘‘Narodni front’’, 2Medical Faculty, University of Belgrade, Belgrade, Serbia, 3University Medical Center ‘‘Bezanijska kosa’’, Belgrade, Serbia, and 4Institute of Physiology, Clinical Center of Serbia, Belgrade, Serbia



As the Higgs boson could be a key to unlocking mysteries regarding our Universe, melatonin, a somewhat mysterious substance secreted by the pineal gland primarily at night, might be a crucial factor in regulating numerous processes in human reproduction. Melatonin is a powerful antioxidant which has an essential role in controlling several physiological reactions, as well as biological rhythms throughout human reproductive life. Melatonin, which is referred to as a hormone, but also as an autocoid, a chronobiotic, a hypnotic, an immunomodulator and a biological modifier, plays a crucial part in establishing homeostatic, neurohumoral balance and circadian rhythm in the body through synergic actions with other hormones and neuropeptides. This paper aims to analyze the effects of melatonin on the reproductive function, as well as to shed light on immunological and oncostatic properties of one of the most powerful hormones.

Cancer, immune function, melatonin, reproductive function, reproductive health

Introduction In 2012, the physicists of the European Organization for Nuclear Research (CERN), Switzerland, publicized the discovery of the Higgs boson, ‘‘the world’s most wanted particle’’. Almost 50 years after the Higgs boson was first mentioned, this advancement has brought about the completion of the standard model of particle physics, which describes all the existing particles and the forces acting upon them. This unique subatomic particle provides mass to all elementary particles, and it is owing to it that matter exists. The particle is the basic unit, or quantum, of the Higgs field, an entity that all particles pass through [1] (Figure 1). As the Higgs boson could be a key to unlocking mysteries of our Universe, melatonin, a somewhat mysterious substance secreted by the pineal gland primarily at night, might be the crucial factor in regulating numerous processes in human reproduction. Lerner et al. [2] first isolated melatonin as a pineal gland product and pioneered a new research field in reproductive physiology. Now, melatonin [indoleamine (N-acetyl-5-methoxytryptamine)] is considered to be a hormone with a universal photoperiodic signal, and a molecule with diverse physiological functions [3]. Apart from being synthesized and released at night by the pineal gland, the hormone is also produced in small quantities by other extrapineal organs – the retinas, the skin, the alimentary canal, bone marrow cells, ovaries and many other tissues [4–8]. Further studies have also revealed that this indoleamine is ubiquitous and can be synthesized by virtually all the cells containing a nucleus [9]. Melatonin, which is locally

Address for correspondence: Svetlana Dragojevic Dikic, Department of Obstetrics and Gynecology ‘‘Narodni front’’, Medical Faculty, University of Belgrade, Radoja Domanovica 19, 11050 Belgrade, Serbia. Tel/Fax: +381 11 380 6238. E-mail: [email protected]; [email protected]

History Received 27 September 2014 Accepted 16 October 2014 Published online 7 November 2014

produced in different tissues and organs, functions as a paracoid or autocoid that has a significant influence on the regulation of homeostatic and neurohumoral balance [10]. Having been recognized as a pineal hormone possessing skin lightening properties and conveying information about environment to different parts of the body, melatonin was later also identified as a significant regulator of seasonal and circadian rhythm with the ability to entrain biological rhythms and control reproductive functions in a wide variety of species. It is a pleiotropic compound generated in different tissues which has multiple and various effects on several physiological processes. Melatonin has a crucial role in a number of significant physiological processes, such as circadian rhythms, sleep regulation and reproductive, neuroendocrine, cardiovascular, neuroimmunological and oncostatic actions [11–16]. As numerous studies have shown that melatonin is a potent and immediate free-radical scavenger, it appears to be a multifunctional and unique antioxidant [17]. Scientific evidence of melatonin’s important role in follicle and corpus luteal function, pregnancy, puberty, and parturition time has been provided, indicating melatonin’s crucial role in reproductive functions [18–20]. Melatonin has a significant impact on the female reproductive system; the hormone is considered essential for both folliculogenesis and spertmatogenesis, influencing steroid production and activity and modifying cellular signals on target tissues. It has been implied that melatonin takes part in the control of pubertal onset, timing of ovulation, sexual maturation and pregnancy protection and that it has potential utilities in menopausal medicine as well. [21]. Melatonin is a natural antioxidant with immunoenhancing and oncostatic properties. Also, melatonin is an important freeradical scavenger, protecting body and brain cells against genetic damage, which is thought to be a precursor to cancer. According to these data, melatonin is a master regulator of reproductive and general health throughout the life course [21,22].

DOI: 10.3109/09513590.2014.978851

Figure 1. Higgs boson image: Thomas McCauley/Lucas Taylor/CERN/ CMS Collaboration. A reconstructed event in the CMS detector. The event shows the possible decay oh the Higgs boson to a pair of photons. CERN: The European Organization for Nuclear Research, CMS: Compact Muon Detector.

Melatonin: synthesis, secretion, and receptors Melatonin, a universal photoperiodic hormone, is a small lipophilic indoleamine with a molecular weight of 232; it is synthesized from tryptophan, an essential amino acid, via serotonin [3,21]. After being hydroxylated to 5 hydroxy-tryptophan, tryptophan is converted into serotonin. Serotonin is acetylated to form N-acetylserotonin by the rate-limiting enzyme alkylamine N-acetyltransferase (NAT). N-acetylserotonin is then converted into melatonin by acetylserotonin O-methyltransferase (ASMT). Pineal generation of melatonin follows a circadian rhythm characterized by low production levels during the day and high production levels at night; the circadian pattern of melatonin generation is by controlled by the suprachiasmatic nucleus (SCN), the main circadian oscilator. Light information received by the retina passes primarily through the retinohypothalamic pathway and is transmitted to the SCN, where a circadian clock exists. This transmission enables the synchronization of circadian clock phases with the light–dark cycle over 24 hours. SCN fibers pass through the paraventricular hypothalamic nucleus, medial forebrain bundle, and reticular formation influencing the intermediolateral horn cells of the spinal cord which contains preganglionic sympathetic neurons. The postganglionic sympathetic fibers of the superior cervical ganglion terminate on the pinealocytes and regulate melatonin synthesis by secreting norepinephrine. Norepinephrine, secreted by the nerve terminals derived from the superior cervical ganglion, stimulates the pineal cells, primarily via b-adrenergic receptors, thereby accelerating the synthesis of cyclic AMP, the second messenger, to induce NAT activity during melatonin biosynthesis [23–25]. This pathway is actually activated at night, as the nervous activities of the superior cervical ganglion are inhibited by light stimulation (Figure 2). Therefore, darkness is the only condition for the synthesis of melatonin, whereas sleep is not a precondition for it. Exposure to light during the night inhibits the synthesis of melatonin and its secretion, which leads to circadian desynchronization and it could result in various diseases and cell aging [26]. In human beings, melatonin secretion is at its highest level from the age of 3 to the age of 5 and it starts to decrease from puberty onwards. Its values are rather invariable until the age of 35–40 and the final decrease in amplitude occurs when low levels are observed in old age. However, there are huge differences in the amplitude of the melatonin rhythm among individuals and it

Melatonin and human reproduction


has not been proven yet whether these differences have an impact on human health [26,27]. The circadian rhythm of melatonin secretion is noted not only in blood but also in most body fluids, including saliva, cerebrospinal fluid and follicular fluid, as well as in breast milk, due to extrapineal melatonin production. Melatonin’s activity is mostly performed through membrane-bound receptors MT1 and MT2 [28]. There are intramembrane areas in these membrane receptors and they are members of the superfamily of G-protein coupled receptors. The third binding site, first identified as MT3, was later defined as the enzyme quinone reductase [29]. Melatonin’s activity also includes binding to nuclear receptors, such as retinoid Z receptor (RZR) and retinoid orphan receptor (ROR), or cytoplasmic proteins, such as the calcium-binding proteins calmodulin or tubulin [30]. Certain studies have implied that modulation in the expression and function of nuclear receptors is a mechanism for expressing melatonin’s biological effects. By binding to nuclear receptors, melatonin changes the transcription of a number of genes that take part in cellular proliferation (e.g. 5-lipoxygenase, p21, or bone sialoprotein) [31,32]. Melatonin receptors are distributed over a variety of tissues and organs; as a result, time information based on melatonin concentration is transmitted to tissues throughout the body enabling a proper regulation of many physiological functions. Up to now, it has been confirmed that melatonin receptors can be found in the brain, spinal cord, pituitary gland, retina, spleen, thymus, adrenal gland, liver, kidney, heart, lungs, testes, ovaries, blood vessels, lymphocytes, as well as in osteoblasts [21,33].

Melatonin: reproductive functions There is scientific evidence for the huge role melatonin plays in human reproduction. It plays a part in controlling and regulating various reproductive functions and it has a significant influence on the female genital system. Several studies have shown there is a clear correlation between melatonin and gonadotropins and/or steroids, which suggests that melatonin may be involved in sexual maturation, control of pubertal onset, folliculogenesis, oocyte maturation, ovulation, pregnancy and menopause [21,34–37]. Melatonin is a key to regulating seasonal variation in gonadal activity, i.e. circadian variation is present in ovulation, as in summer it typically occurs in the morning, whereas in winter it commonly occurs in the evening. Melatonin may influence gonadal function indirectly via its effect on gonadotropinreleasing hormone (GnRH) and gonadotropin secretion or directly via local melatonin synthesis in gonads, which influences steroid production and action, and modification of cellular signals for target tissues. In mammals, it has been proven that melatonin influences their reproductive function by activating melatonin receptor sites within the hypothalamo–pituitary–gonadal axis. The activation of MT1 and MT2 subtype receptors by melatonin results in a decline in cyclic AMP production and protein kinase A activity and attenuation of GnRH-induced gonadotropin secretion. A decrease in gonadotropin discharge is caused by melatoninactivated suppression of GnRH-stimulated calcium signaling [34]. Both calcium influx through voltage-dependent calcium channels and calcium mobilization from intracellular stores are hindered by melatonin. Inhibition of calcium influx, most likely in a cyclic AMP/protein kinase C-dependent manner, and the accompanying calcium-induced calcium release from ryanodine-sensitive intracellular pools by melatonin, brings about delayed GnRH-induced calcium signaling [38–40]. This tonic inhibitory effect melatonin has on GnRH activity gradually declined during evolution due to a reduction in functional melatonin receptor expression. Recent studies have pointed at the potential effect melatonin may have on


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Gynecol Endocrinol, 2015; 31(2): 92–101

Figure 2. Pathway of melatonin synthesis in the human pineal gland. This pathway is actually activated during the night without light stimuli, as the nervous activities of the superior cervical ganglion are inhibited by light stimulation. At night, the postganglionic sympathetic neurons ending in the pineal gland release norepinephrine, which activates primarily b-adrenergic receptors to stimulate a cascade of molecular events that culminate in melatonin production and release. Additional details related to these events are summarized in the text. ASMT: acetylserotonin O-methyltransferase, NAT: N-acetyltransferase.

gonadotropin-inhibitory hormone (GnIH), a multifunctional neuropeptide. GnIH expression and synthesis increase on short days, and they seem to be immediately controlled by melatonin by means of the Mel 1c receptor expressed on GnIH neurons [34,41]. Melatonin and puberty The precise mechanisms controlling puberty onset are not fully known. Ovaries and/or testes maturation is triggered by secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) under the impact of pulsative GnRH secretion. What triggers the function of the hypothalamus is still controversial, the central control unit of the brain and melatonin’s influence being one of the possible explanations. Reactivation of the hypothalamic–pituitary axis starts approximately at the age of 10 due to a progressive rise in the amplitude and frequency of GnRH pulses and accordingly the pulsatile secretion of FSH and LH. It is thought that melatonin’s nocturnal secretory pattern exerts an inhibiting effect on hypothalamic GnRH secretion in humans [42]. It has been assumed that before puberty, the concentrations of melatonin are too high for hypothalamic activation to occur. However, at the age of 9 or 10, the drop in the level of serum melatonin below the threshold value (500 pmol/l ¼ 115 pg/ml) is a trigger for GnRH, after which pubertal changes start occurring. The high level of nocturnal melatonin secretion has been found in children with delayed puberty whereas low melatonin levels have been noticed in children with precocious puberty. According to these findings, melatonin may be a part of the event cascade preceding the hypothalamic–pituitary–gonadal axis awakening at

puberty [43,44]. In some instances and in some species, melatonin is called progonadotrophic. Surely, melatonin is neither antigonadotrophic nor progonadotrophic per se. More precisely, the changing duration of the nocturnal melatonin message is a passive signal for the hypothalamo–pituitary–gonadal axis regarding the time of year [45,46]. Melatonin has an important role in the pubertal onset, but it is hard to separate melatonin’s effect from the complicated interplay of neuropeptides, neurotransmitters and neurosteroids. Melatonin: follicular maturation, oocyte quality and embryo development Melatonin’s roles in reproduction are concentrated on its direct activity in ovaries [34]. The ovary is a ‘‘master’’ gland in the female reproductive system. It influences the balanced and highly orchestrated function of almost all the organs and glands through the production of numerous hormones, primarily steroids and paracrine/autocrine factors, including melatonin. Recent studies have pointed to the prospect of expanding ovarian function from purely reproductive purposes to diminishing the effects of menopausal diseases, heart disease and some types of cancer [47]. Although it has long been generally accepted that melatonin inhibits reproductive functions in animals, recent reports suggested that melatonin actually promotes these functions [21,48]. Melatonin is engaged in various reproductive events such as folliculogenesis, follicular atresia, ovulation, oocyte maturation, corpus luteum (CL) function and early embryo development. Melatonin receptors are found in ovarian granulosa and theca

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cells, both of which occur in mature follicles and CL, and these cells promote steroid hormone production. It is hypothesized that melatonin is directly involved in the growth and maturity of oocytes, as well as in the inhibition of factors which might impair oocyte quality [21]. Additionally, the data collected by measuring concentrations of melatonin in human ovarian follicular fluid (FF) showed significantly higher melatonin concentrations when compared to plasma levels; moreover, the concentrations of melatonin in follicular fluids increased depending on follicular growth. Higher melatonin concentrations in the follicular fluid are retained by both active melatonin ovarian transport from the blood stream in the FF and ovarian melatonin synthesis (primarily by granulosa cells) [49,50]. One of the most significant functions of melatonin was ascertained by showing that melatonin had radical scavenger properties; indeed, melatonin was discovered to reduce concentrations of highly reactive hydroxyl radicals resulting from both oxygen- and nitrogen-based reactants in vitro and in vivo [51,52]. Furthermore, melatonin boosts the expression and activity of antioxidative enzymes [superoxide dismutase (SOD), glutathione peroxidase (GPX)] and it inhibits the activity of the pro-oxidative enzyme nitric oxide synthase (NOS) [26]. Melatonin has been noted to diminish a damaged DNA product [8-hydroxy-2-deoxygyanosine (8-OHdG)] and the product resulting from lipid oxidation (hexanoyl-lysine adduct) in the FF [46]. The level of oxidatively damaged molecules in the FF is in direct correlation with ovum quality. Additionally, it has been proven that melatonin stimulates maturation-inducing hormone [MIH (17 a, 20 b-dihydroxy-4-pregnen-3-one)], which heightens oocyte maturation [46,50,53] (Figure 3). Melatonin and its metabolites (cyclic 3-hydroxmelatonin, N1-acetyl-N2-formyl-5-methoxytryptamine, N1-acetyl-5-methoxykynuramine, and 6-hydroxyl-melatonin) with expanded free-radical scavenging properties are powerful antioxidants [26,50]. Ovulation includes processes resembling a local inflammatory response; both reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated, bringing about oocyte oxidative damage [50,54]. Although surplus ROS can also account for oxidative stress leading to oocyte and granulosa cell structure damage, locally generated ROS seem to play a crucial part in follicular rupture, and ROS also act as second messengers which modulate the expression of genes governing the physiological processes of oocyte maturation. ROS have to be constantly deactivated to retain only a small

Melatonin and human reproduction


amount that is required for maintaining the normal cell function [55–58]. It is well known that endogenous antioxidant enzymes with non-enzymatic antioxidants, such as melatonin and its metabolites, are found in the follicles operating to quench or diminish ROS and RNS. Failure or shortage of these oocyte defenses may bring about the development of oxidative stress with oocyte damage [59]. Moreover, ROS could be produced in larger amounts due to certain conditions, including infections, inflammation, chemotherapy, radiation, and superovulation like in infertility therapy. It has already been noted that melatonin is capable of promoting embryo development in various species. When inseminated mice embryos were cultured in medium with melatonin, higher fertilization and blastocyst rates were noticed [60]. The effect melatonin has on embryo development appears to be due to its antioxidative activity, at least to a certain degree. A recent study has proven that melatonin treatment is beneficial for infertile women who have undergone an assisted reproductive technique (ART)/in vitro fertilization – embryo transfer (i.e. IVFET) program. Those women were given 3 mg of melatonin a day from day 5 of the previous menstrual cycle to the day of oocyte retrieval; the percentage of good embryos (day 2 after insemination) was substantially higher in comparison with the control cycle where there was no melatonin treatment [61]. The collected data suggested melatonin played a part in embryo development and oocyte maturation. Melatonin treatment for reproductive function restoration and infertility leads to elevated fertilization and pregnancy rates due to increased intra-follicular melatonin concentrations with a consequent reduction in intra-follicular oxidative damage [62]. Melatonin may become a beneficial treatment for enhancing ovarian function, oocyte quality and embryo development in infertile women, particularly those who fail to get pregnant because of poor oocyte quality and those whose reproductive life is coming to an end [61]. Additionally, melatonin could create new opportunities for managing various ovarian diseases including endometriosis, chronic anovulation, polycystic ovary syndrome, as well as premature ovarian insufficiency [50]. Melatonin and pregnancy Pregnancy is a physiological state characterized by elevated metabolic demands for tissue oxygen. This heightened need for

Figure 3. Some of the proposed function of melatonin in the Graafian follicle. ROS: reactive oxygen speies, RNS: reactive nitrogen species, MIH: maturation-inducing hormone, NOS: nitric oxide synthase.


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oxygen results in an increased production of reactive oxygen species (ROS), which can damage cell membranes by lipid peroxidation. In the course of pregnancy, the placenta is the major source of peroxidized lipids; the serum concentration of peroxidized lipids rises in pregnant women. Moreover, pregnancy has a negative impact on some antioxidant enzymes’ activity (e.g. superoxide dismutase and glutathione peroxidase) in the liver and placenta [63,64]. It has been noticed that elevated levels of oxidative stress and unbalanced levels of some micronutrients in mother’s blood are the reason for some pregnancy-related disorders. However, some studies have pointed to the protective effect melatonin has on both the fetus and the mother during pregnancy, as well as melatonin’ s responsibility for preserving the integrity of tissues (placenta, fetus) against nitro-oxidative stress due to toxic radicals and related reactants primarily produced in mitochondria [65,66]. A significant number of experimental and clinical conditions have proven melatonin to be effective in diminishing molecular damage and tissue loss, and also in enhancing physiological outcomes in situations when great free-radical destruction commonly occurs. In normal pregnant women, melatonin levels rise during gestation with substantially higher levels after 32 weeks [67]. Melatonin is transmitted from maternal circulation to fetal circulation, thus producing a day– night difference in melatonin concentration in fetal circulation. Melatonin receptors are expressed in the human fetal SCN and in several regions of the human fetal brain [68,69]. Melatonin could also improve progesterone synthesis by the corpus luteum and later by the placenta to assist maintaining the pregnancy, while hindering the premature release of oxytocin [46]. In the placenta, melatonin acts in a similar protective way against nitro-oxidative stress; likewise, melatonin diminishes the vasospastic effect of H2O2 on the human umbilical artery. Melatonin also counteracts mannitol and catalase, two antioxidants that reduce this suppressive effect [70]. It has been discovered that melatonin protects the fetus from oxidative stress owing to ROS and RNS [46]. Several pregnancy-related diseases and conditions could benefit from melatonin treatment. In this context, a special attention should be paid to preeclampsia, a major disorder which occurs in approximately 5–7% of all pregnancies worldwide and is a leading cause of premature delivery and fetal growth retardation [71]. In spite of the fact that the pathophysiology of preeclampsia is still unidentified, elevated oxidative stress is thought to be one of the possible triggers [72,73]. Most important signs are high systolic and diastolic blood pressure, and proteinuria that occurs during the second half of pregnancy. Maternal complications include kidney or liver failure, cerebral edema with seizures, HELLP syndrome (hemolysis, elevated liver enzymes, and thrombocytopenia) and (rarely) death. Preeclampsia is specially connected with increased lipid peroxidation in both maternal circulation and the placenta. Many studies have proposed melatonin as a useful treatment for preeclampsia owing to its antioxidant properties. [34,46,65,74]. It has been discovered that melatonin is efficient against oxidized low-density lipoprotein (LDL)-induced inhibition of nitric oxide (NO) generation in the endothelium of human umbilical arteries. Therefore, by inhibiting LDL oxidation, melatonin could provide protection against oxidized LDL-induced impairment of endothelial function in women with preeclampsia [53]. Placental infarction in preeclamptic women leads to fetal growth retardation. Due to the fact that the placenta transports melatonin from maternal circulation to fetal circulation and that a damaged placenta is not likely to transfer indoleamine as efficiently as a healthy one, the observation that melatonin maintains the integrity of this tissue may have important implications for protecting the fetus as well. Melatonin’s other significant traits have also been reported, some of them being its antihypertensive and anticonvulsive

Gynecol Endocrinol, 2015; 31(2): 92–101

activity [75,76]. Hence, melatonin may have a beneficial effect on certain parameters that are changed in preeclampsia, providing protection to both the fetus and the mother. In addition, melatonin might reduce the abortion rate and recurrent pregnancy loss due to its antioxidant properties to suppress placental free-radical damage [77,78]. It has also been shown that melatonin might belong to the mechanisms underlying the induction of parturition; melatonin may stimulate the myometrium via its own receptors or via synergic action with oxytocin through gap junction activity, which is crucial in stimulating synchronous myometrial contractions [79,80]. According to presented data, melatonin could be of great importance for restoring and maintaining a healthy pregnancy and fetal development. Melatonin and menopause The long list of symptoms/signs/medical problems that affect postmenopausal women have a negative effect on the quality of their lives. These problems mostly pertain to hot flushes, night sweats, sleep deprivation, mood disturbances, vulvovaginal atrophy, bone loss and fractures, sexual dysfunction, muscle loss, cardiovascular diseases, breast cancer, loss of memory, loss of cognition, and possibly Alzheimer’s disease. The severity of the symptomatology related to hormone deficiency, oxidative cell damage and immune deficiency due to aging varies between races and from person to person. With longer life expectancy and the increased number of world population, it is expected that there will have been more than 1.1 billion postmenopausal women by 2025 [81–85]. Improving the quality of life is essential in this vulnerable period; therefore, promoting education and research in all aspects of women’s health, including a search for optimal preventive and therapeutic strategies, is of great importance. Management of menopausal women should be multidisciplinary and individualized, including counseling, emotional support, lifestyle modification, diet, nutritional supplement advice, nonhormonal therapy and hormonal therapy, which should be individualized according to type, dose, route and duration of the therapy and to women’s symptoms, general health, family history and personal risk factors [86,87]. By using individualized treatment, benefits will generally outweigh the potential risks. Melatonin may also be useful for treating women who are near the end of the reproductive phase of their life and postmenopausal women due to its beneficial effects on various significant physiological functions, including circadian rhythms and sleep regulation and reproductive, neuroendocrine, cardiovascular, neuroimmunological and oncostatic actions, and considering that melatonin levels decrease with age [46]. Bellipani et al. [88] confirmed in their study that melatonin treatment could reverse hormonal and menopause-related neurovegetative disturbances, as well as menopause-related depression; melatonin treatment was also shown to restore menstrual cyclicity and fertility in perimenopausal or menopausal women. Melatonin may aid prolonging reproductive health for women seeking fertility, particularly those who are approaching or entering menopause, in terms of the ability to get pregnant and deliver healthy offspring [61,88]. The presence of melatonin receptors was also proven in osteoblasts derived from human jaw bones and ilia, and melatonin accelerated the proliferative differentiation of osteoblasts and increased collagen production [89]. According to such findings, it is expected that melatonin may prevent osteoporosis and accelerate fracture healing (bone regeneration), which is important in the menopausal period [21]. As a powerful antioxidant with immunoenhancing properties, melatonin may also have a significant role in preventing cardiovascular diseases; Reiter [90] suggested that melatonin could be an efficient treatment for hypertension. Several studies have shown that

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melatonin’s antioxidant properties could aid diminishing the severity of Alzheimer’s disease, which is characterized by inflammation and brain damage caused by free radicals, by acting against cellular brain changes found in dementia patients [91,92]. Breast cancer risk increases with aging; the risk of breast cancer in association with hormone replacement therapy (HRT) in menopause has already been recognized, but the risk also depends on the type, dose, route and duration of HRT, as well as individual risk factors [87]. In addition, increased light exposure of sufficient intensity at night possibly diminishes circulating melatonin levels and resets the circadian pacemaker of the SCN; the reduced melatonin levels could be a permissive factor in breast cancer cell growth initiation [93]. In breast cancer cells, melatonin inhibits the expression of estrogen-responsive, cancer-related genes as well [94]. Therefore, it is expected that combining melatonin with a variety of anticancer therapies may bring additional efficacy. Melatonin is derived from serotonin, which has a role in mood control, so changes in melatonin levels could be responsible for the links between chronic fatigue, depression, sleep and mood disturbances. Sleep is a thalamic function supported by melatonin that acts by enhancing spindle formation [95]. Presumably acting on the major circadian clock, i.e. SCN, melatonin plays an essential part in regulating bodily rhythms, including synchronizing sleep with the normal period of darkness. Melatonin has been successfully used to treat insomnia and circadian sleep disorders, which could be of great importance in menopausal management strategies [96]. In connection with using melatonin as a treatment for sleep disturbance, melatonin might also be used to prevent and treat ‘‘jet lag’’ disorder [26]. Moreover, as it has been recently discovered, novel melatonin agonists (ramelteon and agomelatine) have been found to have more effect in improving sleep efficiency in elderly insomniacs [97]. The melatonergic antidepressant agomelatine, i.e. N-[2-(7-Methoxy-1-naphthyl)ethyl] acetamide, with both MT1/MT2 receptor agonist properties, without significant affinities to muscarinic, adrenergic, dopaminergic, or histaminergic receptors and with selective antagonism to 5HT2c receptors, and ramelteon, i.e., N-{2-[(8S)-1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethyl}propanamide, with high selectivity for MT1 and MT2 melatonin receptors, have revolutionized the treatment of insomnia and depressive disorders with no reports of significant or serious adverse effects [98,99]. As melatonin has both sleep-enhancing and chronobiotic characteristics, the use of melatonergic antidepressants is considered even more effective in treating elderly patients suffering from depressive disorders and sleep deprivation [97].

Melatonin: immune function and cancer related to reproductive health Melatonin is a natural antioxidant with immunoenhancing properties. There are numerous natural mechanisms against carcinognesis; these mechanisms belong to two major categories: immune and non-immune mechanisms. Immunosurveillance, which belongs to the first category, is one of the most important processes which detect and eliminate cancerous cells. Melatonin has an important immunomodulatory role in immunocompromised states related to various diseases, particularly during aging, and the activating lymphocytes and monocytes/macrophages by melatonin may prevent tumor development [100,101]. Daily and seasonal changes in immune function correspond to biosynthesis and secretion of melatonin [102]. Additionally, the synthesis of melatonin by human lymphocytes proves the hypothesis that melatonin regulates immune function. Some other studies have shown that the melatonin synthesized by human T cells helps the control of interleukin (IL)-2 generation by acting as an intracrine, autocrine and/or paracrine substance

Melatonin and human reproduction


[8,103]. Melatonin receptors can be found in the monocyte/ macrophage lineage [104]. Melatonin distribution boosts the production of monocytes and natural killer (NK) cells in bone marrow and spleen within 7–14 days since the beginning of the treatment [105]. Both these cell types belong to the non-splenic immune system, so according to the collected data, melatonin can be effective in stopping neoplastic growth and in devastating infected cells. Stimulation of monocyte production by melatonin may be accounted for either by its direct action on melatonin receptors in monocytes or by its sensitizing action on monocytes to stimulants (cytokines, such as IL-3, IL-4, or granulocyte macrophage colony-stimulating factor) [106]. Natural killer cells play a significant part in immunosurveillance against neoplasia and virus-infected cells [107]. The increase in the number of NK cells caused by melatonin is associated with a heightened production of cytokines, such asIL2, IL-6, IL-12 and interferon (IFN)-g by T helper (Th)-1 lymphocytes and monocytes [105,108]. The fact that melatonin receptors are found on T lymphocytes accounts for melatonin’s activity in releasing cytokines that improve NK activity and raise the number of NK cells. Being members of the immunocompetent-cell family, which take part in the innate immune response, NK cells are supposed to work together with other T cells, in particular suppressor T cells, during early phases of the autoimmune response [109]. Lymphocytes have a significant role in fighting neoplasia by recruiting immune system cells and activating antigen-specific effector cells. The importance of CD4+ Th cell stimulation in cancer chemotherapy has been recognized. CD4+ lymphocytes discharge IFN-g and tumor necrosis factor (TNF)-a, which activate and control cytotoxic T cell responses [110,111]. Th-1 cells directly kill tumor cells by discharging cytokines that activate ‘‘death’’ receptors on the surface of a tumor cell. Melatonin also favors Th-2 responses; not only does it stimulate the secretion of IFN-g and IL-2, it also stimulates the release of IL-10 [112]. Additionally, melatonin’s immunoenhancing properties depend not only on its ability to improve cytokine generation but on its antiapoptotic and antioxidant activities as well [113]. These properties are of great importance for protection and improving of reproductive health. There are significant scientific studies about melatonin as an oncostatic agent against various types of tumor, such as melanoma, breast cancer, ovarian and colorectal cancer [114–122]; many reports have focused on melatonin as mammary gland tumor suppressant [26,34,93,123–125]. It has been shown that melatonin suppresses tumor development both in vivo and in vitro. There are several mechanisms through which melatonin can show its oncostatic activity: (1) its direct pro-apoptotic, genemediated actions on tumor cells; (2) its antioxidant actions; (3) diminishing the uptake of crucial factors of tumor growth and tumor growth signaling molecules [e.g. linoleic acid (LA)]; and (4) improving immune mechanisms in the body, which has been shown to be a significant oncostatic property [110]. Despite the fact that melatonin affects the expression of a wide spectrum of genes, its primary effectors tend to be connected with the genes regulating the cell cycle, adhesion, and transport. This finding is in accordance with accepted data on melatonin’s impact on cell proliferation, apoptosis, and adhesion. Importantly, melatonin has also shown to have an evident impact on the expression of genes related to oncogenesis (e.g. Mybl1, Rasa1, Mllt3, Enigma homolog 2) and calcium metabolism (Kcnn4 and Dcamkl1) [126]. Considering the fact that melatonin considerably limits free radical-mediated cell damage, the indoleamine reduces cancer inception. Once tumors are formed, melatonin reduces their growth and the possibility of metastasis by suppressing the uptake of growth factors, e.g. LA, and by inhibiting telomerase activity (26). Telomerase is a specialized ribonucleoprotein polymerase


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which extends the telomeres of eukaryotic chromosomes [127]. The telomeres have a fundamental role in preserving the integrity of chromosomal structures; due to the fact that the telomeres constantly shorten (when cells divide), the chromosomes become unstable and more vulnerable to fragmentation. Additionally, melatonin inhibits angiogenesis through endothelin-1 synthesis attenuation. Endothelin-1 directly stimulates both endothelial and perivascular cells. Moreover, it indirectly stimulates angiogenesis by increasing the release of vascular endothelial growth factor (VEGF), a great pro-angiogenic substance. Finally, fibroblasts and cancer cells are stimulated by endothelin-1 to produce proangiogenic proteases [128]. Considering the fact that endothelin-1 acts in multiple ways on stimulating tumor angiogenesis, any agent that limits endothelin-1 synthesis may negatively influence tumor growth by taking away all the oxygen and nutrients from the cancer. A recent paper has reported that endothelin-converting enzyme-1 [129], a zinc-dependent metalloproteinase which splits inactive endothelin precursors to form mature endothelin-1, is suppressed by melatonin. If melatonin exerts a similar inhibiting effect on the blood vessel invasion in tumors, this activity may mean a substantial contribution to the suppressing effects manifested by melatonin in the field of tumor growth inhibition. This field of research is currently investigated. Melatonin’s breast cancer risk protection in women is of great importance. In recent years, low melatonin levels following lightinduced suppression of melatonin synthesis have been blamed for the elevated risk for breast cancer among women working night shifts [124,125,130]. Depending on the balance of the circadian rhythm, generation of melatonin at night could be a ‘‘regulatory signal’’ for the carcinogenic process, or it could be a ‘‘natural restraint’’ on tumor inception, development and/or progression. Some studies have investigated the protective role melatonin has in mammary carcinogenesis of postmenopausal women with advanced breast cancer. Urinary levels of melatonin in these women are lower than those in the control group [131]. The suppressing effect melatonin has on mammary carcinogenesis has been accounted for by melatonin’s impact on immune modulation. Additionally, it has been reported that in steroid-responsive tumors, such as breast cancer, melatonin interferes with estrogen receptor control, transactivation and intracellular signal transduction cascades, which results in attenuation of steroid stimulatory actions [132]. There have been suggested three different mechanisms for inhibiting the progression of breast cancer by melatonin: (1) by indirect neuroendocrine mechanism regulation, which includes melatonin down-regulation of the hypothalamo– pituitary–gonadal axis and a consequent reduction in estrogen levels; (2) by acting on receptor sites within the tumor, altering estrogen receptor function therefore acting as a selective estrogen receptor modulator (SERM); and (3) by regulating the enzymes involved in estrogen biosynthesis in peripheral tissues and thus acting as a selective estrogen enzyme modulator (SEEM) [27]. Considering the fact that melatonin down-regulates the aromatase, sulfatase and 17 b-hydroxyl steroid-dehydrogenase pathways and elevates the activity and expression of estrogen-sulfotransferase, this indoleamine could protect mammary tissue from excessive estrogen influence. Therefore, melatonin possesses both SERM and SEEM properties, the crucial properties needed for possible prevention and treatment of estrogen-dependent mammary tumors [133].

Conclusions Melatonin, a pineal and extrapineal hormone, represents a key factor in the regulation of numerous human reproduction processes. Clearly, melatonin regulates the seasonal and photoperiod-dependent day aspects of reproductive events. The fact that

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melatonin has been found to be a direct free-radical scavenger and an indirect, powerful, multifunctional antioxidant has greatly lengthened the list of mechanisms owing to which indoleamine is beneficial for reproductive physiology. Depending on its production site and the target organ, melatonin can act as a hormone, autacoid, hypnotic, immunomodulator or a biological modifier. Melatonin plays a part in different significant physiological functions, including circadian rhythms and sleep regulation. Melatonin plays a particularly important role in controlling and regulating a variety of reproductive functions with a significant impact on the female genital system. Melatonin is implicated in the control of pubertal onset, sexual maturation, timing of ovulation, reproductive life potential, and pregnancy protection, as well as in alleviation of menopause-related symptoms and disorders. Melatonin may also be beneficial not only for preserving reproductive health but also in general health. Due to its crucial role in regulating circadian, immunological, reproductive and neurobiological mechanisms, melatonin, with its chronopsychophysiological properties, has been proven to be a master regulator of reproductive health. Additionally, with its immunological and oncostatic properties, melatonin is one of the best ‘‘intracellular defenders’’ with a potential to act on many target tissues and organs; melatonin may be considered the ‘‘Higgs boson’’ of human reproduction. Many uses related to melatonin still remain a mystery and require further research. The major objective of future research is to investigate optimal melatonin supplementation in different pathophysiological conditions and make an optimal selection of patients who may benefit from antioxidant and immunomodulating melatonin therapy. This therapy may be used for ovarian function and fertility recovery and pregnancy protection, as well as for the prevention and treatment of serious neurodegenerative and malignant disorders [134]. The time for clinical melatonin use is obviously approaching; therefore, investigation of its use is essential not only for reproductive well-being but also for improving general health and life in humans.

Acknowledgements The authors thank Professor Russel Reiter (University of Texas Health Science Center) for useful instructions during the preparation of this manuscript and for permission to use and adapt figures from his work.

Declaration of interest The authors report no conflicts of interest.

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Melatonin: a "Higgs boson" in human reproduction.

As the Higgs boson could be a key to unlocking mysteries regarding our Universe, melatonin, a somewhat mysterious substance secreted by the pineal gla...
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