**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 hypothalamuspituitary-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

#### *An Overview of Effects on Reproductive Physiology of Melatonin DOI: http://dx.doi.org/10.5772/intechopen.108101*

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].
