Open access peer-reviewed chapter
Abstract
Melatonin is a neurotransmitter released from the pineal gland. The presence of receptor sites in the hypothalamus, pituitary gland, ovaries, and testicles and secretion of pituitary hormones (FSH and LH) are some of the effects of this hormone on reproduction. In addition to its systemic effect, it also showed an effect on ovarian physiology with the detection of high levels in the follicular fluid and the presence of melatonin receptors in the ovarian cells. In addition, it has been determined that melatonin affects follicular growth, oocyte maturation, ovulation, and luteal function. It has been stated that the effects of melatonin on the male reproductive system are indirectly effective through the gonads and indirectly by affecting the hormones. Again, some studies have expressed that melatonin has strong antioxidant properties and affects reproductive physiology due to this effect. This section discusses the effect of melatonin on male and female reproductive physiology.
Keywords
- melatonin
- reproduction
- physiology
- FSH
- LH
- ovarium
- testes
- oxidative stress
1. Introduction
Melatonin is a hormone secreted by the pineal gland and is known to be involved in the regulation of many body functions and the regulation of circadian and seasonal rhythms [1]. This hormone is rhythmically released from the epiphysis at night [2]. Since its release is regulated according to the nighttime, its secretion occurs with the internal reflection of the external photoperiod [3]. Melatonin is also called the “hormone of darkness”. It has been determined that melatonin is synthesized in the lacrimal gland, retina, erythrocytes, platelets, and some cells in the gastrointestinal tract other than the pineal gland, but this synthesis has little effect on the plasma melatonin level [4, 5, 6, 7]. The main synthesis site of melatonin is pinealocytes, and it is synthesized from tryptophan in these cells. Tryptophan is first converted to 5-hydroxytryptophan by the enzyme tryptophan hydroxylase. Then 5-hydroxytryptophan is converted to serotonin by amino acid decarboxylase. Serotonin is converted to N-acetyl serotonin by the enzyme N-acetyl transferase. N-acetyl serotonin is converted to melatonin by the enzyme methyltransferase. Thus, the synthesized melatonin is released into the blood circulation [8, 9]. Around 19.00–20.00, melatonin secretion begins to increase, reaches its highest point between 02.00 and 04.00 at night, and decreases with the increase of daylight in the morning. It starts to decrease between 07.00 and 09.00 in the morning [10, 11, 12]. Melatonin takes part in many biological and physiological regulations in the body. It is effective on biorhythm (circadian rhythm) and also has direct and indirect effects on the reproductive system, regenerating our cells, regulating the immune system, anticarcinogen, antioxidant, antiaging, and reproductive system [13]. This chapter, it is aimed to explain the physiological effects of melatonin, which has important bodily effects in the body, on the female and male reproductive systems.
2. Melatonin synthesis
Melatonin is synthesized from tryptophan in pinealocytes in the pineal gland. Synthesis stages are, respectively: Tryptophan is converted to 5-hydroxytryptophan by the enzyme tryptophan hydroxylase. Then 5-hydroxytryptophan is converted to serotonin by the amino acid decarboxylase enzyme. Serotonin is converted to N-acetyl serotonin by the enzyme N-acetyl transferase. N-acetyl serotonin is converted to melatonin by the enzyme methyltransferase. Thus, the synthesized melatonin is released into the blood circulation [8, 9]. The regulation of melatonin synthesis is controlled by the retinohypothalamic pathway and a system that surrounds the suprachiasmatic nuclei and contains multiple synapses within this pathway. Stimuli from the retina reach the hypothalamus and then this information reaches the pineal gland via peripheral postganglionic sympathetic fibers and melatonin is synthesized [9]. It activates protein kinase C (PKC) via β- and α1-adrenergic receptors on pinealocytes with increased norepinephrine stimulation at night. PKC activation increases the Ca2+ movement in the cell, resulting in an increase in the concentration of intracellular cyclic adenosine monophosphate (cAMP). This increase activates protein kinase A (PKA) (Figures 1 and 2). Activated PKA increases AANAT activity [14]. Once synthesized, it is directly secreted into the cerebrospinal fluid and blood of the third ventricle and reaches all body tissues in a very short time. After melatonin is released, it is transported by diffusion and some carrier molecules [15]. Melatonin can regulate a variety of physiological functions, from the well-known modulation of sleep/wake cycles and circadian rhythms to the maintenance and regulation of neural development and immune system and endocrine functions [16]. These effects of the melatonin are mediated by G protein-linked melatonin receptors MT1 and MT2. In addition, activation of a putative cytoplasmic melatonin receptor MT3 is also effective [17]. When melatonin binds to these receptors, due to the connection between the receptors and Gai/o proteins, it causes activity in the target tissue by regulating the levels of cAMP and calcium, the second messenger, as well as by regulating the activation of PKC subtypes (Figure 3) [19]. As a result of various studies, it has been determined that these receptors of Melatonin are in various structures of the brain belonging to the nervous system [20] as well as in nonneural tissues such as the immune system, endocrine system, bone, gastrointestinal system, cardiovascular system and reproductive organs, which we will focus on [21]. Again, as a result of a study, it was determined that melatonin causes various activities in various tissues through a mechanism independent of its receptors [22].
3. Melatonin receptors and their functions
It has been reported that melatonin synthesized by the pineal gland has 3 groups of receptors. These are MT1 receptors with high affinity. They are MT2 and MT3 receptors with low affinity [23, 24, 25]. MT1 stimulation from these receptors suppresses adenylate cyclase activity in the target tissue. It has been determined that these receptors are involved in retinal function, cerebral artery contraction, circadian rhythm, renal function, and reproduction. As a result of the stimulation of MT2 and MT3 receptors, phosphoinositol hydrolysis takes place in the target tissue [24, 25]. These receptors are located in the body of the brain, cardiovascular system, coronary and cerebral arteries, retina, ventricular wall, aorta, liver, and gall bladder, enterocytes, cecum, skin, colon, and appendix vermiformis, parotid gland, immune system cells, exocrine pancreas, kidney, platelets, ovary/granulosa cells, myometrium, placenta, and fetal kidney.
4. Effects of melatonin on the female reproductive system
Various studies have shown the effect of melatonin on the female reproductive system. It has been determined that this effect is by binding directly to the receptors in the cells in the ovary and through the hypothalamic/pituitary axis.
4.1 Direct effects of melatonin on the female reproductive system
Melatonin is considered to have an inhibitory effect on the hypothalamus-pituitary-gonads system. Demonstration of melatonin receptors in the ovary and structures such as mammary glands supports this effect. Studies have shown that melatonin receptors in rat ovarian tissue are more in the proestrus cycle than in the metestrus cycle and that granulosa cells are the main site for the MT1 receptor [26, 27]. The concentration of melatonin in follicular fluid was found to be ten times higher than in plasma. The source of the melatonin in the follicular fluid in circulation. The follicles receive this hormone from the bloodstream. The amount of hormone intake varies depending on the follicular growth period. The larger the follicles, the more melatonin is taken from the blood. Studies have reported that melatonin acts as an antioxidant in follicles and contributes to progesterone production by luteinizing granulosa cells [28]. Melatonin levels in humans during pregnancy and delivery are higher compared to the postpartum period [29]. Increased melatonin levels before birth may serve as an important circadian signal for the time of birth. Maternal melatonin originates from the maternal pineal gland and increases with the activities of placental hormones [28]. Melatonin, which is present in human follicular fluid in conjunction with plasma and does not affect granulosa cells’ steroidogenesis and follicular function, directly affects ovarian function [30]. Periodic fluctuations are seen in the follicular fluid that fills the antral cavity, and there is more melatonin in the preovulatory follicle than in the serum level [31]. As a result of these findings, it is concluded that melatonin is synthesized in the ovary and released into the follicular fluid [32]. Studies have shown that LH receptors increase in granulosa cells as a result of melatonin administration [30]. Similarly, melatonin has been reported to affect sex steroid hormone production in follicular maturation during ovulation [33]. During follicular growth, locally produced insulin-like growth factors and transforming growth factor-β together with gonadotropins show efficacy [34]. In one study, it was reported that Melatonin stimulated the production of IGF-I in human granulosa cells [34]. Melatonin is also known to induce the IGFI receptor and activate the P13K/AKT signaling pathway, which is associated with cell metabolism, and the MEK/ERK signaling pathway, which is involved in cell growth, proliferation, and differentiation [35]. The TGF-β superfamily is found in ovarian cells and acts as an intraovarian regulator of follicle development [36]. As a result of studies, it has been determined that TGF-β is produced by both theca and granulosa cells in humans [37, 38]. Studies have shown that melatonin treatment increases TGF-β gene expression in mice [39]. Recent studies have shown that melatonin causes induction of Bcl2 expression and a decrease in Caspase-3 activity, thus protecting tissue from induction of the mitochondrial pathway of apoptosis [40]. The increase in follicular melatonin is an important factor for escaping from growing follicle deatresia, and the amount of intrafollicular melatonin is directly related to atresia [40]. It is stated that the increased amount of melatonin in the follicle may be associated with increased progesterone production after luteinization and ovulation. Local productions of ovarian progesterone, angiotensin-II, and nitric oxide synthetase (NOS) also increase with ovulation [41]. These vasoactive molecules have a fundamental role in the control of follicular blood flow [40]. An increase in progesterone and estradiol levels is required for successful ovulation [42]. Although there is no clear information about the relationship between melatonin, prostaglandin, and estradiol in anovulation, a study on rats showed that melatonin treatment in the gastric mucosa significantly increased the concentration of prostaglandin and estradiol [42]. ROS emerging in folliculogenesis suppresses the production of prostaglandin, which stimulates the synthesis of melatonin from granulosa cells, and induces corpus luteum transformation [43]. In addition to these properties, melatonin also protects the corpus luteum from damage by reactive oxygen species that inhibit progesterone production in human luteal cells.
4.2 Indirect effects of melatonin on the female reproductive system
Considering the indirect effects of melatonin on the female reproductive system. Melatonin exerts its indirect inhibitory effect on the gonads by suppressing the production and secretion of GnRH at the hypothalamus level, inhibiting the release of LH (Luteinizing hormone) from the pituitary, as well as suppressing LH secretion by acting directly on the pituitary by changing the levels of intracellular second messengers such as Ca 2+ and cAMP. Melatonin also increases the secretion of opioid substances that reduce GnRH secretion, such as endorphins [44].
5. Effects of melatonin on the male reproductive system
Various studies have shown that melatonin has some effects on the male reproductive system as well as the female reproductive system. It has been determined that this effect is by binding to the receptors of Sertoli and Leydig cells in the testicles and via the hypothalamus/pituitary axis.
5.1 Direct effects of melatonin on the male reproductive system
When the direct effects of melatonin on testicular tissue are examined, it has been stated that melatonin affects testicular development by binding to the relevant receptors in the testis [45] and in a study, exogenous melatonin administration in rats caused a decrease in testicular size [46, 47]. Various studies have shown that MT1 and MT2 are expressed in the testes of young and adult rats [45]. In a study, it was observed that the external application of Melatonin had negative effects on the seminiferous tubules in the testicles of old male mice [48]. It has also been reported that the administration of melatonin causes shrinkage in testicular tissue and low spermatid count in rats [49]. In another study, significant morphological changes occurred in the tubular and interstitial compartments of the testicles in hamsters exposed to short-term sunlight for a long time [50]. In addition, it was determined that melatonin significantly reduced the volume of mitochondria and nongranular endoplasmic reticulum, which are organelles containing enzymes that have an important role in androgen biosynthesis in mice Leydig cells [51]. Looking at the mechanism of testosterone production, it was determined that the LH hormone released from the adenohypophysis stimulates the cAMP signal in Sertoli cells [52]. It was also stated that melatonin did not suppress the activity of P450scc and thus decreased steroid synthesis. It was determined that StAR protein expression regulated by melatonin LH or cAMP was significantly reduced [53]. Another pathway that is effective in the testosterone release mechanism is that GnRH does so by increasing cytosolic Ca2+ concentrations and activating protein kinase C [52]. In some studies using the fluorescent Ca2+ indicator, it has been reported that melatonin suppresses the release of GnRH-dependent Ca2+ from intracellular stores, thereby reducing cellular Ca2+ levels and suppressing testosterone release [54]. In addition to the aforementioned mechanisms, melatonin has been reported to regulate testosterone production by interacting with the CRH system in the testicles [55, 56]. It has been determined that the CRH hormone is produced in the testicles as well as the hypothalamus. CRH released from the testicles acts as an important negative autocrine regulator of LH-induced testosterone production [57]. In a study, it was reported that Melatonin administration significantly increased the levels of mRNA related to CRH in Leydig cells [58]. Another hormone involved in testicular function is Estrogen. In immature males, the main production site of estrogen is Sertoli cells. Estrogen receptor-alpha (ERα), one of the estrogen receptors, was found in Leydig cells, while ERβ, another estrogen receptor subtype, was found in Sertoli and germ cells [59, 60]. Studies show that ERβ plays a role in the regulation of Leydig cell proliferation and testosterone production in adult mouse testicles. The cytochrome P450 aromatase (P450arom) enzyme is a key enzyme found in the endoplasmic reticulum of various tissues and is responsible for the production of estrogen from androgens. P450arom enzyme has been identified in Leydig cells of several species [61]. Melatonin has been reported to reduce estrogen biosynthesis by inhibiting the activity and expression of aromatase [62, 63, 64]. It has been determined that the administration of melatonin in Leydig and Sertoli cells obtained from rams increases testosterone production by increasing the expression of stem cell factor and insulin-like growth factor-1 [65]. In addition, it was determined that melatonin administration regulated lactate metabolism in Sertoli cells. Lactate released from Sertoli cells provides nutritional support to cells and prevents apoptosis [66]. As a result of the studies, it has been determined that the level of melatonin in the semen is related to infertility [67, 68, 69, 70]. Especially in rams, melatonin level is directly related to sperm quality. Although rams can produce semen throughout the year, the quality of sperm outside the breeding season has been found to be low [71]. In the studies, it was determined that the application of melatonin outside of the breeding season increased sperm volume in the semen [72, 73, 74]. It was also determined that the dividing ability of oocytes fertilized by spermatozoa treated with melatonin increased. This increase is mediated by the increase of hyaluronidase enzyme activity by the administration of melatonin [75, 76].
5.2 Indirect effects of melatonin on the male reproductive system
When the indirect effects of melatonin on the male reproductive system are examined, it has been determined that there is an effect, especially on the hypothalamus-pituitary axis. In a study, it was determined that the application of melatonin to the hypothalamus significantly reduced testicular weight [77, 78, 79]. It was concluded that it showed this effect by suppressing GnRH secretion. In another study, it was determined that the administration of melatonin to mice caused a decrease in testicular and seminal vesicle mass, thus causing a decrease in sperm count [80]. GnIH, a hormone that suppresses the release of GnRH, was determined in a study conducted on quails in 2000 [81, 82, 83]. It has been determined that the effect of melatonin on GnRH secretion is mediated by this hormone. It has been determined that melatonin stimulates the release of GnIH by binding to the MT1 receptor, thus suppressing the release of GnRH [84, 85]. It has been determined that melatonin hormone androgen receptor and ABP levels are decreased in animals with seasonal reproduction. In some animals, it has been determined that tonin has positive effects on the male reproductive system. For example, it has been determined that it has indirect effects as well as direct effects on rams. Melatonin administration has been found to increase the testosterone concentration of somatic cells in ram testis tissue [86, 87]. Kispeptins, which are stimulators of GnRH neurons, have been found to be highly effective in transmitting the melatonin message [88, 89, 90]. In a study, it was determined kisspeptin expression decreased and atrophy occurred in the gonaon in winter days when the daylight decreased in Syrian hamsters. It has been determined that the level of testosterone increases with the injection of kisspeptin [91, 92]. In a study with zebrafish, it was determined that melatonin administration could induce the expression of Kiss1 and Kiss2 and GnRH3 genes in brain tissue and an increase in LH-β in the pituitary gland [93]. This induced gonad development. However, in a study in rats, it was reported that the administration of melatonin suppressed the release of FSH and LH, thus suppressing spermatogenesis in Sertoli cells and delaying sexual maturation [94]. Again, it was determined that the administration of melatonin to rats in the fetal period suppressed LHRH release and significantly reduced the LH level [95, 96]. Melatonin administration is thought to inhibit LH release by reducing Ca2+ flow and cAMP concentrations in the pituitary gland [97].
6. The relationship between melatonin and oxidative stress
Oxidative stress is a cell-damaging condition that can result from decreased antioxidants and/or increased production of reactive free radicals such as reactive oxygen species and/or reactive nitrogen species (ROS/RSN) [98, 99]. Increased free radical production causes cell damage, leading to an increase in various damage markers (MDA, 8-OhDH, TNF-alpha) [100, 101]. In many cases, the body protects the cell against the increase in oxidative stress by the regulation of antioxidant defense systems (GSH, SOD, CAT, GPx) [102, 103, 104, 105, 106, 107]. If oxidative stress can be neutralized, there is usually no adverse contribution to disease pathology. If antioxidant defense induction is inadequate or absent, concomitant cellular and tissue damage often occurs. Some diseases can be directly caused by oxidative stress, but in most diseases, oxidative stress is a consequence and can often only be a secondary event [108, 109, 110]. However, it plays an important role in promoting additional tissue damage in most diseases. When oxidative stress is excessive, it can be prevented by using various substances that have antioxidant properties or suppressing oxidative stress to prevent cell damage [111, 112]. One of the substances used for this purpose is melatonin. As a result of various studies, it has been determined that melatonin reduces oxidative stress and protects the cell against oxidative damage. Some studies have stated that it prevents cell damage by improving MDA levels [113, 114, 115, 116]. The effect of melatonin on reducing MDA occurs through several mechanisms. For example; Melatonin detoxifies a large number of free radicals such as peroxynitrite anion [117] and hydroxyl radical [118] detoxifies hydroxyl radical [119]. It has also been determined that peroxynitrous acid [120] cleans oxidizing particles such as nitric oxide [121] and thus prevents lipid peroxidation. Due to these effects, It has been reported that the effects of melatonin on oxidative stress are direct free radical scavenger and indirect antioxidant [122]. Again, as a result of studies, it was determined that Melatonin increased the level of antioxidant GSH, and also caused an increase in antioxidant enzyme activities such as GPX, SOD, and CAT. It has been determined that these effects are caused by an increase in mRNA expression by stimulating the melatonin receptors on the cell membrane [123]. It has also been determined that melatonin inhibits the nuclear translocation of NF-κB [124]. It has been determined that melatonin inhibits oxidative stress-induced DNA damage by suppressing oxidative stress [125]. Studies have shown that melatonin inhibits apoptosis by decreasing caspase-3 activity and activating the PI3K/AKT pathway, and it preserves membrane integrity. Activation of the PI3K/AKT pathway also increases gene expression such as Nrf2 [126], which plays an important role in the antioxidant defense system. These findings explain the cell-protective mechanism of melatonin against oxidative stress.
7. Conclusion
Melatonin is a hormone mainly synthesized from the pineal gland, and it has been shown by some studies that it has various effects on the immune system, oxidative stress, and reproduction, as well as taking part in the regulation of circadian rhythm. In this study, we focused on the direct, indirect, and antioxidant effects of melatonin on the female and male reproductive systems and the molecular mechanisms of these effects. As a result, melatonin affects the male and female reproductive systems directly via the gonads via secondary messengers and indirectly by stimulating various receptors/molecules via the hypothalamus-pituitary axis. These effects are in the direction of supporting reproduction in some living things and suppressing in others. In addition, melatonin prevents cell damage by increasing antioxidant enzyme activity and scavenging free radicals, especially in female and male gonads, thus preventing cell damage.
Figure 1.
Biosynthetic pathway of the melatonin.
Figure 2.
Synthesis of melatonin from tryptophan under the influence of light in the pineal gland [
Figure 3.
MT 1 and MT 2 melatonin receptor signaling. PKA, protein kinase a; cAMP response element-binding protein; MT, melatonin receptor; Akt, threonine protein kinase B (PKB; also known as Akt); cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; CREB, IP3, inositol trisphosphate; MAPK, mitogen-activated protein kinase [
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