Gynecological Endocrinology

ISSN: 0951-3590 (Print) 1473-0766 (Online) Journal homepage: http://www.tandfonline.com/loi/igye20

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: http://dx.doi.org/10.3109/09513590.2014.978851

Published online: 07 Nov 2014.

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Date: 14 October 2016, At: 01:23

http://informahealthcare.com/gye ISSN: 0951-3590 (print), 1473-0766 (electronic) Gynecol Endocrinol, 2015; 31(2): 92–101 ! 2014 Informa UK Ltd. DOI: 10.3109/09513590.2014.978851

REVIEW ARTICLE

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

Abstract

Keywords

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

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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

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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

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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

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[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.

References 1. Cho A. The discovery of the Higgs boson. Science 2012;338: 1524–5. 2. Lerner AB, Case JD, Takahashi Y, et al. Isolation of melatonin, the pineal gland factor that lightens melanocytes. J Am Chem Soc 1958; 80:2587–92. 3. Brzezinski A. Melatonin in humans. New Engl J Med 1997;336: 186–95. 4. Pang SF, Allen AE. Extra-pineal melatonin in the retina: its regulation and physiological function. Pineal Res Rev 1986;4:55–96. 5. Slominski A, Wortsman J, Tobin, DJ. The cutaneous serotoninergic/ melatoninergic system securing a place under sun. FASEB J 2005; 19:176–94. 6. Bubenik GA. Gastrointestinal melatonin: localisation, function and clinical relevance. Dig Dis Sci 2002;47:2336–48. 7. Conti A, Conconi S, Hertens S, et al. Evidence of melatonin synthesis in mouse and human bone marrow cells. J Pineal Res 2000;28:193–202. 8. Carrillo-Vicco A, Calvo JR, Abreu P, et al. Evidence of melatonin synthesis by human lymphocytes and its physiological significance: possible role in intracrine, autocrine, and/or paracrine substance. FASEB J 2004;18:537–9.

DOI: 10.3109/09513590.2014.978851

9. Korkmaz A, Manchester LC. Reactive nitrogen species; devastating intracellular players and melatonin as a defender. J Exp Integr Med 2011;1:63–5. 10. Tan DX, Manchester LC, Hardeland R, Lopez-Burillo S, Mayo JC. Melatonin: a hormone, a tissue factor, an autocoid, a paracoid, and an antioxidant vitamin. J Pineal Res 2003;34:75–8. 11. Gillette MU, Tischkau SA. Suprachiasmatic nucleus: the brain’s circadian clock. Recent Prog Horm Res 1999;54:33–58. 12. Reiter RJ. Pineal melatonin: cell biology of its synthesis and of its physiological interactions. Endocr Rev 1991;12:151–80. 13. Cardinali DP, Pevet P. Basic aspects of melatonin action. Sleep Med Rev 1998;2:175–90. 14. Reiter RJ, Tan DX, Korkmaz A. The circadian melatonin rhythm and its modulation: possible impact on hypertension. J Hypertens Suppl 2009;27:17–20. 15. Srinivasan V, Maestroni GJ, Cardinali DP, et al. Melatonin, immune function and aging. Immun Ageing 2005;2:1–10. 16. Korkmaz A, Tamura H, Manchester IC, et al. Combination of melatonin and a peroxisome proliferator-activated receptor-gamma agonist induces apoptosis in a breast cancer cell line. J Pineal Res 2009;46:115–16. 17. Droge W. Free radicals in the physiological control of cell function. Physiol Rev 2002;82:47–95. 18. Brzezinski A, Seibel MM, Lynch HJ, et al. Melatonin in human preovulatory follicular fluid. J Clin Endocrinol Metab 1987;64: 865–7. 19. Tamura H, Nakamura Y, Takiguchi S, et al. Pinealectomy of melatonin implantation does not affect prolactin surge or lutal function in pseudopregnant rats. Endocr J 1998; 45:377–83. 20. Tamura H, Nakamura Y, Trron MP, et al. Melatonin and pregnancy in the human. Reprod Toxicol 2008;25:291–303. 21. Hattori A. The basic information for melatonin. Mod Physician 2007;27:1053–6. 22. Yonei Y, Hattori A, Tsutsui K, et al. Effects of melatonin: basic studies and clinical applications. Anti-aging Med 2010;7:85–91. 23. Pang SF, Li L, Ayre EA, et al. Neuroendocrinology of melatonin n in reproduction: recent developments. J Clin Neuroanatomy 1998;14: 157–66. 24. Berson DM, Dunn FA, Takao M. Phototransduction by retinal ganglion cells that set the circadian clock. Science 2002;295: 1070–3. 25. Gerdin MJ, Masana MI, Rivera-Bermudez MA, et al. Melatonin desensitizes endogenous MT2 melatonin receptors in the rat suprachiasmatic nucleus. Relevance for defining the periods of sensitivity of the mammalian circadian clock to melatonin. FASEB J 2004;18:1646–56. 26. Reiter RJ, Gultekin F, Flores LJ, et al. Melatonin: potential utility for improving public health. TAF Prev Med Bull 2006;5:131–58. 27. Dullo P, Chaudhary R. Short review of reproductive physiology of melatonin. Pak J Physiol 2009;5:46–8. 28. Dubocovich ML, Markowska M. Functional MT1 and MT2 melatonin receptors in mammals. Endocrine 2005;27:101–10. 29. Nosjean O, Ferro M, Coge F, et al. Identification of the melatoninbinding site MT3 as the quinone reductase 2. J Biol Chem 2000;275: 31311–17. 30. Wiesenberg I, Missbach M, Carlberg C. The potential role of the transcrition factor RZR/ROR as a mediator of nuclear melatonin signaling. Restor Neurol Neurosci 1998;12:143–50. 31. Benitez-King G. Melatonin as a cytoskeletal modulator: implications for cell physiology and disease. J Pineal Res 2006;40:1–9. 32. Calberg C. Gene regulation by melatonin. Ann N Y Acad Sci 2000; 917:387–96. 33. Ishii H, Tanaka N, Kobayashi M. Gene structures, biochemical characterization and distribution of rat melatonin receptors. J Physiol Sci 2009;59:37–47. 34. Srinivasan V, Spence WD, Pandi-Perumal SR, et al. Melatonin and human reproduction: shedding light on the darkness hormone. Gynecol Endocrinol 2009;25:779–85. 35. Boczek-Leszczyk E, Juszczak M. The influence of melatonin on human reproduction. Pol Merkur Lekarski 2007;23:128–30. 36. Wojtowicz M, Jakiei G. Melatonin and its role in human reproduction. Ginekol Pol 2002;73:1231–7. 37. Maganhin CC, Carbonel AA, Hatty JH, et al. Melatonin effects on the female genital system: a brief review. Rev Assoc Med Bras 2008; 54:267–71.

Melatonin and human reproduction

99

38. Pandi-Perumal SR, Trakht I, Srinivasan V, Spence DW, et al. Physiological effects of melatonin: role of melatonin receptors and signal transduction pathways. Prog Neurobiol 2008;85:335–53. 39. Zemkova H, Vanecek J. Inhibitory effect of melatonin on gonadotrophin-releasing hormone induced Ca2+ oscillations in pituitary cells of newborn rats. Neuroendocrinology 1997;65:276–83. 40. Malpaux B, Migaud M, Tricoire R, Chemineau P. Biology of mammalian photoperiodism and the critical role of pineal gland and melatonin. J Biol Rhytms 2001;16:336–47. 41. Bentley GE, Ubuka T, McGuire NL, et al. GnRH: a multifunctional neuropeptide. J Neuroendocrinol 2009;21: 276–8. 42. Silman RE. Melatonin and the human gonadotrophin-releasing hormone pulse generator. J Endocrinol 1991;128:7–11. 43. Waldhauser F, Boepple PA, Schemper M, et al. Serum melatonin in central precocious puberty is lower than in age-matched prepubertal. J Clin Endocrinol Metab 1991;73:793–6. 44. Cavallo A. Melatonin and human puberty: current perspectives. J Pineal Res 1993;15:115–21. 45. Brzezinski A. Melatonin and human reproduction: why the effect is so elusive? In: Pandy-Perumal SR, Cardinali DP, eds. Melatonin: from molecules to therapy. New York: Nova Science Publishers; 2007:219–25. 46. Reiter RJ, Tan DX, Manchester LC, et al. Melatonin and reproduction revised. Biol Reprod 2009;81:445–56. 47. Richards JS, Panges SA. The ovary: basic biology and clinical implications. J Clin Invest 2010;120:963–72. 48. Soares Jr JM, Masana MI, Ersahin C, Dubovich ML. Functional melatonin receptors in rat ovaries at various stages of th estrous cycle. J Pharmacol Exp Ther 2003;306:694–702. 49. Reiter RJ, Tan DX, Fuentes-Broto L. Melatonin: a multitasking molecule. Prog Brain Res 2010;181:127–51. 50. Tamura H, Nakamura Y, Korkmaz A, et al. Melatonin and the ovary: physiological and pathological implications. Fertil Steril 2009;92: 328–43. 51. Tan DX, Manchester LC, Terron MP, Reiter RJ. One molecule, many derivates: a never-ending interaction of melatonin with reactive oxygen and nitrogen species? J Pineal Res 2007;42:28–42. 52. Tamura H, Takasaki A, Taketani T, et al. Melatonin as free radical scavenger in the ovarian follicle. Endocr J 2013;60:1–13. 53. Tamura H, Nakamura Y, Terron MP, et al. Melatonin and pregnancy in the human. Reprod Toxicol 2008;25:291–303. 54. Espey LL. Current status of the hypothesis that mammalian ovulation is comparable to an inflammatory reaction. Biol Reprod 1994;50:233–8. 55. Droge W. Free radicals in the physiological control of cell function. Physiol Rev 2002;82:47–95. 56. Hensley K, Robinson KA, Gabbita SP, et al. Reactive oxygen species, cell signaling, and cell injury. Free Radic Biol Med 2000; 28:1456–62. 57. Fetehi AN, Roelen BA, Colenbrander B, et al. Presence of cumulus cells during in vitro fertilization protects the bovine oocyte against oxidative stress and improves first cleavage but does not affect further development. Zygote 2005;13:177–85. 58. Tatemoto H, Muto N, Sunagawa I, et al. Protection of porcine oocytes against cell damage caused by oxidative stress during in vitro maturation: role of superoxide dismutase activity in porcine follicular fluid. Biol Reprod 2004;71:1150–7. 59. Guerin P, El Mouatassim S, Menezo Y. Oxidative stress and protection against reactive oxygen species in the preimplantation embryo and its surroundings. Hum Reprod Update 2001;7:175–89. 60. Ishizuka B, Kuribayashi Y, Murai K, et al. The effect of melatonin on in vitro fertilization and embryo development in mice. J Pineal Res 2000;28:48–51. 61. Tamura H, Takasaki A, Taketani T, et al. The role of melatonin as an antioxidant in the follicle. J Ovarian Res 2012;5:1–9. 62. Tamura H, Takasaki A, Miwa I, et al. Oxidative stress impairs oocyte quality and melatonin protects oocyte from free radical damage and improves fertilization rates. J Pineal Res 2008;44: 280–7. 63. Walsh SW, Wang Y. Secretion of lipid peroxides by the human placenta. Am J Obstet Gynecol 1993;169:1462–6. 64. Mover-Lev H, Ar A. Changes in enzymatic antioxidant activity in pregnant rats exposed to hyperoxia. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 1997;118:353–9.

100

S. Dragojevic-Dikic et al.

65. Milczarek R, Klimek J, Zelewski L. Melatonin inhibits NADPHdependent lipid peroxidation in human placental mitochondria. Horm Metab Res 2000;32:84–5. 66. Nagai R, Watanabe K, Wakatsuki A, et al. Melatonin preserves fetal growth in rats by protecting against ischemia/reperfusion-induced oxidative/nitrosative mitochondrial damage in the placenta. J Pineal Res 2008;45:271–6. 67. Nakamura Y, Tamura H, Kashida S, et al. Changes of serum melatonin level and its relationship to fetoplacental unit during pregnancy. J Pineal Res 2001;30:29–33. 68. Shenker S, Yang Y, Perez A, et al. Antioxidant transport by the human placenta. Clin Nutr 1998;17:159–67. 69. Thomas L, Purvis CC, Drew JE, et al. Melatonin receptors in human fetal brain: 2-[(125)I]iodomelatonin binding and MT1 gene expression. J Pineal Res 2002;33:218–24. 70. Okatani Y, Watanabe K, Hayashi K, et al. Melatonin inhibits vasospastic action of hydrogen peroxide in human umbilical artery. J Pineal Res 1997;22:163–8. 71. Brown MA, Lindheimer MD, de Swiet M, et al. The classification and the diagnosis of the hypertensive disorders of pregnancy: statement from the International Society for the Study of Hypertension in Pregnancy (ISSHP). Hypertens Pregnancy 2001; 20:9–14. 72. Fait V, Sela S, Ophir E, et al. Hyperemesis gravidarum is associated with oxidative stress. Am J Perinatol 2002;19:93–8. 73. Myatt L, Cui X. Oxidative stress in placenta. Histochem Cell Biol 2004;122:369–82. 74. Vanderlelie J, Venardos K, Clifton VL, et al. Increased biological oxidation and reduced anti-oxidant enzyme activity in pre-eclamptic placentae. Placenta 2005;26:53–8. 75. Simko F, Paulis L. Melatonin as a potential antihypertensive treatment. J Pineal Res 2007; 42:319–22. 76. Pagni CA, Zenga F. Posttraumatic epilepsy with special emphasis on prophylaxis and prevention. Acta Neurochir Suppl 2005;93:27–34. 77. Gupta S, Agarwai A, Banerjee J, Alvarez JG. The role of oxidative stress in spontaneous abortion and recurrent pregnancy loss: a systematic review. Obstet Gynecol Surv 2007;62:335–47. 78. Nakamura Y, Tamura H, Kashida S, et al. Changes of serum melatonin level and its relationship to feto-placental unit during pregnancy. J Pineal Res 2001;30:29–33. 79. Sharkey JT, Puttaramu R, Word RA, Olcese J. Melatonin synergizes with oxytocin to enhance contractility of human myometrial smooth muscle cells. J Clin Endocrinol Metab 2009;94:421–7. 80. Carlomagno G, Nordio M, Chiu TT, Unfer V. Contribution of myoinositol and melatonin to human reproduction. Eur J Obstet Gynecol Reprod Biol 2012;159:267–72. 81. WHO Scientific Group. Research on the Menopause in the 1990s. WHO Technical Report Series No 866. Geneva:WHO; 1996. 82. Pines A, Sturdee DW, MacLennan AH, et al. The heart of the WHI study: time for hormone therapy policies to be revised. Climacteric 2007;10:267–9. 83. Anderson E, Hamburger S, Liu JH, Rebr RW. Characteristics of menopausal women seeking assistance. Am J Obstet Gynecol 1987; 156:428–33. 84. Williams RE, Levine KB, Kalilani L, et al. Menopause-specific questionnaire assessment in US population-based studz shows negative impact on health-related quality of life. Maturitas 2009; 62:153–9. 85. Pollycove R, Naftolin F, Simon JA. The evolutionary origin and significance of menopause. Menopause 2011;18:336–42. 86. Archer DF, Baber RJ, Barlow D, et al. Updated IMS recommendations on postmenopausal hormone therapy and preventive strategies for midlife health. Climacteric 2011;14:302–20. 87. De Villiers TJ, Gass MLS, Haines CJ, et al. Global consensus statement on menopausal hormone therapy. Climacteric 2013;16: 203–4. 88. Bellipani G, Marzo F, Blasi F, Di Marzo A. Effects of melatonin in perimenopausal and menopausal women: our personal experience. Ann N Y Acad Sci 2005;1057:393–402. 89. Satomura K, Tobiume S, Tokuyama R, et al. Melatonin at pharmacological doses enhances human osteoblastic differentiation in vitro and promotes mouse cortical bone formation in vivo. J Pineal Res 2007;42:231–9. 90. Reiter RJ, Korkmaz A. Clinical aspects of melatonin. Saudi Med J 2008;29:1537–47.

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

91. Rodriguez MI, Escames G, Lo´pez L, et al. Chronic melatonin treatment reduces the age-dependent inflammatory process in senescence-accelerated mice. J Pineal Res 2007;42:272–9. 92. Masilamoni JG, Jesudason EP, Dhandayuthapani S, et al. The neuroprotective role of melatonin against amyloid beta peptide injected mice. Free Radical Res 2008;42:661–73. 93. Stevens RG. Circadian disruption and breast cancer: from melatonin to clock genes. Epidemiology 2005;16:254–8. 94. Girgert R, Hanf V, Emons G, Gru¨ndker C. Membrane-bound melatonin receptor MT1 down-regulates estrogen responsive genes in breast cancer cells. J Pineal Res 2009;47:23–31. 95. Jan JE, Reiter RJ, Wasdell MB, Bax M. The role of the thalamus in sleep, pineal melatonin production, and circadian rhythm sleep disorders. J Pineal Res 2009;46:1–7. 96. Brzezinski A, Vangel MG, Wurtman RJ, et al. Effects of exogenous melatonin on sleep: a meta analysis. Sleep Med Rev 2005;9:41–50. 97. Srinivasan V, Cardinali DP, Pandi-Perumal SR, Brown GM. Melatonin agonists for treatment of sleep and depressive disorders. J Exp Integr Med 2011;1:149–58. 98. Roth T, Seiden D, Sainati S, et al. Effects of ramelteon on patientreported sleep latency in older adults chronic insomnia. Sleep Med 2006;7:312–18. 99. Guillenminault C. Efficacy of agomelatine versus venlafaxine on subjective sleep of patients of major depressive disorder. Eur Neuropsychopharmacol 2005;15:419–20. 100. Burnet M. Somatic mutation and chronic disease. Br Med J 1965;1: 338–42. 101. Cardinalli DP, Esquino AI, Srinivasan V, Pandi-Perumal SR. Melatonin and the immune system in aging. Neuroimmunomodulation 2008;15:272–8. 102. Nelson RJ, Drazen DL. Melatonin mediates seasonal changes in immune function. Ann N Y Acad Sci 2000;917:404–15. 103. Lardone PJ, Carrillo-Vico A, Naranjo MC, et al. Melatonin synthesized by Jurkat human leukemic T cell line is implicated in IL-2 production. J Cell Physyiol 2006;206:273–9. 104. Garcia-Maurino S, Pozo D, Calvo JR, Guerrero JM. Correlation between nuclear melatonin receptor expression and enhanced cytokine production in human lymphocytes and monocytic cell lines. J Pineal Res 2000;29:129–37. 105. Currier NL, Sun LZ, Miller SC. Exogenous melatonin: quantitative enhancement in vivo of cells mediating non.specific immunity. J Neuroimmunol 2000;104:101–8. 106. Maestroni GJ, Covacci V, Conti A. Hematopoietic rescue via T-cell-dependent, endogenous granulocyte-macrophage colonystimulating factor induced by the pineal neurohormone melatonin in tumor-bearing mice. Cancer Res 1994;54:2429–32. 107. Herberman RB, Ortaldo JR. Natural killer cells: their roles in defenses against disease. Science 1981;214:24–30. 108. Garcia-Maurino S, Gonzales-Haba MG, Calvo JR, et al. Melatonin enhances IL-2, IL-6, and IFN-gamma production by human circulating CD4+ cells: a possible nuclear receptor-mediated mechanism involving T helper type 1 lymphocytes and monocytes. J Immunol 1997;159:574–81. 109. Jiang H, Chess L. An integrated view of suppresor T cell subset in immunoregulation. J Clin Invest 2004;114:1198–208. 110. Ossendorp F, Toes RE, Offringa R, et al. Importance of CD4+ T helper cell responses in tumor immunity. Immunol Lett 2000;74: 75–9. 111. Knutson KL, Disis ML. Tumor antigen-specific T helper cells in cancer immunity and immunotherapy. Cancer Immunol Immunother 2005;54:721–8. 112. Raghavendra V, Singh V, Kulkarni SK, Agrewala JN. Melatonin enhances Th-2 cell mediated immune responses: lack of sensitivity to reversal by naltrexone or benzodiapine receptor antagonist. Mol Cell Biochem 2001;221:57–62. 113. Srinivasan V, Pandi-Perumal SR, Brzezinski A, et al. Melatonin, immune function and cancer. Recent Pat Endocr Metab Immune Drug Discov 2011;5:109–23. 114. Karbownik M, Lewinski A, Reiter RJ. Anticarcinogenic actions of melatonin which involve antioxidative processes: comparison with other antioxidants. Int J Biochem Cell Biol 2001;33:735–53. 115. Karbownik M, Reiter RJ, Burkhardt S, et al. Melatonin attenuates estradiol-induced oxidative damage to DNA: relation to cancer prevention. Exp Biol Med 2001;226:707–12.

Melatonin and human reproduction

DOI: 10.3109/09513590.2014.978851

116. Reiter RJ. Potential biological consequences of excessive light exposure: melatonin suppression, DNA damage, cancer and neurodegenerative disease. Neuroendocrinol Lett 2002;23:9–13. 117. Vijayalaxmi Dr, Thomas Jr CR, Reiter RJ, Herman TS. Melatonin: from basic research to cancer treatment clinics. J Clin Oncol 2002; 20:2575–601. 118. Blask DE, Dauchy RT, Sauer LA. Putting cancer to sleep at night: the neuroendocrine/circadian melatonin signal. Endocrine 2005;27: 179–88. 119. Mills F, Wu P, Seely D, Guyott G. Melatonin in the treatment of cancer: a systematic review of randomized trials and meta-analysis. J Pineal Res 2005;39:360–6. 120. Cabrera J, Negrin G, Estevez F, et al. Melatonin decreases cell proliferation and induces melanogenesis in human melanoma SK-MEL-1 cells. J Pineal Res 2010;49:45–54. 121. Karasek M, Kowalski AJ, Zylinska K. Serum melatonin circadian profile in women suffering from the genital tract cancers. Neuro Endocrinol Lett 2000;21:109–13. 122. Winczyk K, Fuss-Chmielewska J, Lawnicka H, et al. Luzindole but not 4-phenyl-2-propionamidotetralin (4P-PDOT) diminishes the inhibitory effect of melatonin on murine Colon 38 cancer growth in vitro. Neuroendocrinol Lett 2009;30:657–62. 123. Molis TM, Spriggs LL, Jupiter Y, Hill SM. Melatonin modulation of estrogen-related proteins, growth factors, and proto-oncogenesis in human breast cancer. J Pineal Res 1995;18:93–103. 124. Blask DE, Brainard GC, Dauchy RT, et al. Melatonin-depleted blood from premenopausal women exposed to light at night stimulates growth of human breast cancer xenografts in nude rats. Cancer Res 2005;65:11174–84. 125. Blask DE, Dauchy RT, Brainard GC, Hanifin JP. Circadian stagedependent inhibition of human breast cancer metabolism and

126. 127. 128. 129.

130.

131. 132. 133. 134.

101

growth by the nocturnal melatonin signal: consequences of its disruption by light at night in rats and women. Integr Cancer Ther 2009;8:347–53. Anisimov VN, Popovich IG, Zabezhinski MA, et al. Melatonin as antioxidant, geroprotector and anticarcinogen. Biochem Biophys Acta 2006;1757:573–89. Greider CW, Blackburn EH. Identification of specific telomere terminal transferase activity in tetrahymena extracts. Cell 1985;43: 405–13. Knowles J, Loizidou M, Taylor I. Endothelin-1 and angiogenesis in cancer. Curr Vasc Pharmacol 2005;3:309–14. Kilic E, Kilic U, Reiter RJ, et al. Prophylactic use of melatonin protects against focal cerebral ischemia in mice: role of endothelin converting enzyme-1. J Pineal Res 2004;37: 247–51. Schernhammer ES, Berrino F, Krough V, et al. Urinary 6-Sulphatoxymelatonin levels and risk of breast cancer in premenopausal women: the ORDET cohort. Cancer Epidemiol Biomarkers Prev 2010;19:729–37. Bartsch C, Bartsch H, Jain AK, et al. Urinary melatonin levels in human breast cancer patients. J Neural Transm 1981;52: 281–94. Sanchez-Barcelo EJ, Cos S, Mediavilla D, et al. Melatoninestrogen interactions in breast cancer. J Pineal Res 2005;38: 217–22. Cos S, Gonzalez A, Martinez-Campa C, et al. Melatonin as a selective estrogen enzyme modulator. Curr Cancer Drug Targets 2008;8:691–702. Reiter JR, Rosales-Corral AS, Manchester CL, Tan DX. Peripheral reproductive organ health and melatonin: ready for prime time. Int J Mol Sci 2013;14:7231–72.