Melatonin: a potential target for regulating ovarian function

Abstract

Objective

This review explores the important role of melatonin in ovarian function.

Background

The main manifestations of ovarian dysfunction are a decline in oocyte quality and a reduction in the number of follicles and oocytes. Current evidence suggests that environmental pollution, fungi, mycotoxins, drugs, and lifestyle are risk factors affecting ovarian function. Melatonin (MT) is an endogenous hormone synthesized by pineal gland cells, which has strong endogenous effects on scavenging free radicals and antioxidant damage. Previous studies have shown that melatonin plays a beneficial role in oocyte maturation, fertilization, and embryonic development. It can protect these cells from oxidative damage by clearing excessive free radicals, thereby regulating ovarian function and delaying ovarian aging.

Conclusions

This article reviews and discusses the relationship between melatonin and ovarian function regulation, including the synthesis and secretion of melatonin, the local synthesis and main role of melatonin in the ovaries, and the alleviating effect of melatonin on ovarian function decline caused by different injury factors.

Significance

This review provides important theoretical basis for clinical regulation of ovarian function.

Introduction

The female reproductive cycle is mainly regulated by endocrine signals between the hypothalamus–pituitary and the ovary. Ovarian aging can lead to a shortened reproductive cycle, decreased ovarian function, decreased fertility, and increased risk of infertility [1]. Considering an increase in mean maternal age at childbirth in most high-resourced countries over the last 2 decades, improving ovarian function and increasing the success rate of pregnancy has become a hot topic. In clinical practice, ovarian aging is divided into three stages: diminished ovarian reserve (DOR), premature ovarian insufficiency (POI), and premature ovarian failure (POF) [2]. Ovarian aging has a genetic basis, regulating ovarian activity by controlling the excessive cellular signaling pathways of different types of cells in the ovary. There are various factors that can affect these paths, thereby reducing their efficiency. Genetic factors, environmental factors, and immune factors are all important risk factors for ovarian dysfunction, but most causes are complex. Hormone replacement therapy remains the most effective option for ovarian dysfunction, but its effectiveness is limited. In addition, long-term use of hormones has been associated with increased risk of cancer [3, 4]. Therefore, searching for safe and effective drugs for treating ovarian aging is urgently required.

MT has two endogenous sources in mammals, including humans. One is from the pineal gland, where less than 5% of melatonin is synthesized. Melatonin production is influenced by day and night, with the highest amount synthesized and released into the blood and cerebrospinal fluid at night; another source is from multiple tissues throughout the body, where most of the melatonin is synthesized, possibly in the mitochondria of these cells [5]. MT exhibits high solubility in both water and lipids and can readily pass through the blood–brain barrier as well as the cell membrane. It can be found in the blood, cerebrospinal fluid, follicular fluid, and seminal vesicle fluid. Besides regulating energy metabolism, glucose homeostasis, and circadian rhythms (24-h internal clock), MT has an antioxidant effect [6]. Secretion of MT has also been associated with glucose and lipid metabolism disorders, immune alteration, cancer, bone metabolism, and age-related diseases [7–9]. Previous studies have also shown that MT can delay ovarian aging [11, 12], regulate ovarian biological rhythms, promote follicle formation, and improve oocyte quality [14, 15] and fertilization rate and play an important role in oocyte maturation, fertilization, and embryonic development [15]. In this study, we discussed the relationship between melatonin and ovarian function, with a focus on the involvement of melatonin in the decline of ovarian function caused by different factors of damage, as well as its specific forms of regulation of ovarian function.

Synthesis and secretion of MT

MT, also known as 5-methoxy-N-acetyltryptamine, has a molecular weight of 232.3. Its synthesis and secretion are significantly correlated with environmental light and exhibit diurnal rhythmic changes. Its concentration peaks at night and drops to a trough during the day [17]. The biosynthesis of MT in the pineal gland is based on tryptophan as the raw material (Fig. 1). Tryptophan, which is first converted to 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase (TPH) and then to 5- hydroxytryptamine (5-HT, also known as serotonin) by amino acid decarboxylase (AAD), is further converted to N-acetyl -5- hydroxytryptamine (NAS) by serotonin N -acetyltransferase (AANAT), and this N-acetyl-5-hydroxytryptamine (NAS) undergoes methylation by acetylserotonin O-methyltransferase (ASMT) to ultimately form MT [18, 19]. Under normal physiological conditions, the circadian photoreceptors of the retina in humans and mammals perceive changes in light and dark, converting them into signals that are mediated by the retinal hypothalamic tract (RHT) and transmitted to the suprachiasmatic nucleus (SCN). The signal then descends through the medial forebrain tract to the middle lateral cell column of the spinal cord, where the preganglionic fibers reach the superior cervical ganglia. Pineal cells are then stimulated by norepinephrine secreted by the nerve endings of the superior cervical ganglion. This process, regulated by b-adrenergic receptors, accelerates the synthesis of the second messenger ring AMP and induces arylalkylamine N-acetyltransferase (NAT) activity [18, 20]. Recent studies have found that changes in IL-10 levels and downstream pathways during immune responses may be key regulatory factors in regulating melatonin synthesis in the pineal and extra-pineal gland [21].

Fig. 1.

Synthesis of MT in the pineal gland

The synthesis of MT occurs in the pineal gland and extracorporeal tissues of the pineal gland and is essentially present in all biological fluids, including cerebrospinal fluid, saliva, bile, synovial fluid, amniotic fluid, and breast milk. Its effects are mainly achieved through two mechanisms [22, 23]: (1) action mediated by non-receptors: in this case, MT serves as a free radical scavenger with relatively small molecular weight and high lipophilic structural characteristics by directly entering cells and organelles; (2) action mediated in a receptor-dependent manner: MT acts through two high-affinity G-protein coupled receptors MT1 and MT2. These membrane MT receptors are heterotrimeric Gi/Go and Gq/11 protein-coupled receptors that interact with downstream messengers such as adenylate cyclase, phospholipase A2, and phospholipase C, typically reducing the production of cAMP and cGMP and/or increasing the formation of diacylglycerol and IP3 [24].

The synthesis of MT outside the pineal gland does not exhibit a circadian rhythm, and it is not released into the bloodstream. Instead, it acts locally in its source cells and may act in paracrine substances in neighboring cells [25]. With the help of specific melatonin antibodies, MT has been detected in various extra-pineal gland tissues, including the brain, retina, lens, cochlea, Hadrian’s gland, airway epithelium, skin, gastrointestinal tract, liver, kidney, thyroid, pancreas, thymus, spleen, immune system cells, carotid body, reproductive tract, and endothelial cells, and melatonin synthase has been found in most of these tissues [26]. Meanwhile, precursors of MT, 5-hydroxytryptamine, and acetylserotonin, as well as their synthases NAT and ASMT, have also been found in the human ovary, indicating that MT can also be produced in granulosa cells, follicles, and oocytes [20].

Synthesis of melatonin in ovaries

As early as 1999, researchers discovered that, similar to the pineal gland, the human ovary might synthesize melatonin from serotonin through the sequential action of NAT and HIOMT. Using reverse-phase high-performance liquid chromatography combined with fluorescence detection, they demonstrated the presence of melatonin (N-acetyl-5 -methoxytryptamine), its precursors serotonin (5-hydroxytryptamine), and N- acetylserotonin in human ovarian extracts. Moreover, they detected the activities of two melatonin-synthesizing enzymes, NAT and HIOMT, in human ovarian homogenates[27]. In addition, melatonin receptors MT1 and MT2 are present in humans and other mammals, encoded by the MTNR1A gene on chromosome 4 at q35 · 1 and the MTNR1B gene on chromosome 11 at q21-q22, respectively [14]. The melatonin receptor encoding gene has been studied in various mammals and other animals, and is expressed in granulosa cells, cumulus cells, and corpus luteum cells. In female animals, melatonin receptors can be involved in regulating processes such as oocyte maturation and primordial follicle activation [28]. Melatonin receptors can also be expressed in chicken granulosa cells, and the addition of melatonin activates the mTOR signaling pathway through its receptors to regulate the proliferation and apoptosis of chicken granulosa cells [29].

The role of melatonin in the ovaries

Oxidative stress

MT secreted by the pineal gland is mainly present in mitochondria and is an important antioxidant in the human body. It can limit cellular oxidative stress and protect the nucleus and mitochondrial DNA from damage [12, 30]. MT and its metabolites, such as cyclo3-hydroxyMT (C3OHM), can directly scavenge free radicals, including neutralizing oxidative factors such as superoxide anion (O²⁻) and hydroxyl radical (OH). In addition, MT can directly chelate oxygen and nitrogen reactive species, increasing antioxidant enzyme activity, such as superoxide dismutase (SOD) and glutathione peroxidase (GPx). Some membrane receptors of MT can also increase antioxidant enzyme activity and mRNA expression [24].

ROS has an important role in female reproductive function [31]. In a healthy body, ROS and antioxidants remain in balance. Yet, oxidative stress occurs when the balance is disrupted towards an overabundance of ROS. Excessive ROS can also have adverse effects on oocytes due to oxidative stress, leading to infertility [32]. In a study on oocyte follicular fluid from women undergoing in vitro fertilization and embryo transfer (IVF-ET), the concentration of MT in follicular fluid was positively correlated with progesterone concentration and negatively correlated with the concentration of oxidative stress marker 8-hydroxy-2ʹ-deoxyguanosine (8-OHdG), as well as progesterone and 8-OHdG concentrations [33]. Luteinized granulosa cells, obtained during oocyte extraction, were then incubated with H₂O₂ (30, 50, 100 μm) in the presence or absence of MT (1, 10, 100 μg/mL). The authors found that H₂O₂ significantly inhibits progesterone production by luteinized granulosa cells but also that MT overcomes the inhibitory effect of H₂O₂. Therefore, it was concluded that MT protects granulocytes that undergo luteinization from ROS in follicles and contributes to progesterone production during ovulation [33].

Ovarian and oocyte development

MT benefits female reproductive processes, mainly follicular growth, embryonic development, and oocyte maturation. The ovaries and granulosa cells produce a large amount of MT in the follicular fluid, and its concentration level is highly correlated with ovarian reserve function [34]. The main mechanism through which MT regulates ovarian and oocyte development seems to be related to its ability to eliminate the accumulation of ROS in the egg, prevent DNA damage and cell apoptosis, restore the defects of maternal aging oocytes, weaken the aging process of the egg, and improve fertility. Also, MT promotes follicular development, increases the number and quality of follicles, improves egg quality, and regulates hormone secretion, affecting the ovarian microenvironment and promoting follicular development and ovulation [35, 36].

After the age of 40, the quality and quantity of oocytes decrease, subsequently reducing the fertility rates [37]. A previous study found that MT supplementation may reverse defective phenotypes in elderly oocytes through a Sirt1/Sod2-dependent mechanism, and inhibition of Sirt1 activity eliminates MT-mediated improvement in aging oocyte quality [34]. Cryopreservation can cause freezing damage to oocytes and impair their developmental ability. For cryopreserved oocytes, MT can improve the effectiveness of animal oocyte cryopreservation by inhibiting oxidative stress and maintaining oocyte permeability, thereby improving oocyte quality [38].

Ovarian steroid hormone synthesis

MT has a crucial role in regulating reproductive hormone levels and activity by activating the gonadal axis in the hypothalamus–pituitary gland [39]. For example, studies have found that the expression of MT1 and MT2 receptors in rats’ secondary and tertiary follicles and corpus luteum and their ability to bind MT vary during the estrous cycle [40]. Also, the effect of MT on gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) has been explored in some species [39]. A study on the luteal cells of pregnant sows revealed that MT stimulates the production of GnRH and LH in the luteal cells. Also, MT can exert its potential role in luteal function by regulating the release and synthesis of GnRH and LH in luteal cells [41].

CYP11A1, CYP17A1, and CYP19A1 are steroid hormone synthesis-related genes whose expression is increased by circulating MT ablation after pinealectomy [42]. Supplementing MT reduces the expression of CYP17A1, which mainly occurs in interstitial and interstitial cells [42]. Another study found that MT can prevent ovarian damage and fertility loss caused by cisplatin [43]. In a female rat study, mRNA results of the cisplatin treatment group showed a significant decrease in mRNA expression of steroid synthesis genes Cyp19A1, Cyp17A1, Cyp11a1, HSD17B3, and STAR, while MT treatment significantly reversed this process [44].

Apoptosis

Granulosa cells play an important role in follicular development, oocyte maturation, and sex hormone secretion. Research has found that palmitic acid (PA) can impair fertility by inhibiting the survival of human granulosa cells and inducing apoptosis. Treatment with 200–800 μM PA can reduce cell survival rate, induce apoptosis, enhance the expression of apoptosis related genes, and activate the expression of ER stress marker genes. Treatment with MT 1–10 μM can inhibit cell survival rate, apoptosis, caspase-3 activation induced by 400 μM PA, and reduce the expression of BAX, CHOP, and GRP78 [36]. Melatonin, as a safe and multifunctional compound, has shown promise in controlling endoplasmic reticulum stress. By regulating the functions of endoplasmic reticulum and mitochondria, melatonin helps maintain cellular homeostasis by reducing oxidative stress, inflammation, and apoptosis. Melatonin can directly or indirectly interfere with ER-related sensors and downstream targets of UPR, affecting cell death, autophagy, inflammation, molecular repair, and more [45]. Another study showed that MT can prevent apoptosis of pig granulosa cells during follicular atresia through its membrane receptor and free radical scavenging activity [46].

Gene mutation

Genetic mutations are closely related to ovarian aging. Genetic mutations may lead to the accumulation of free radicals in cells, increasing the risk of oxidative stress damage [47, 48]. MT may be a potential target for delaying ovarian aging, which can be alleviated through antioxidant effects and reduce the risk of genetic mutations [49]. For example, in vitro and in vivo data confirmed that the Immp2l gene, which plays an important role in the growth and development of ovarian follicles, enhances ROS levels, inhibits Wnt16, increases β-catenin, and reduces the levels of steroid hormone synthesis gene Cyp19A1 and estrogen while increasing the aging phenotype of granulosa cells to induce granulosa cell aging [50]. The same study proved that MT treatment can also delay the progression of granulosa cell aging by reversing this process [50].

Insufficient MT in follicular fluid is a reversible cause of late age-related aneuploidy in oocytes. Supplementing MT can eliminate accumulated ROS-induced DNA damage, protect oocytes from late age-related meiotic defects and aneuploidy, and potentially improve oocyte quality and assist reproductive technology efficiency in older women [34]. In addition, a meta-analysis involving 2553 patients with polycystic ovary syndrome and 3152 controls showed that mutations in the MT receptor (MTNR) gene are associated with the occurrence of polycystic ovary syndrome, and the MTNR1B rs10830963 and MTNR1B rs2119882 polymorphisms were associated with the risk of PCOS [51].

Melatonin’s participation in regulating ovarian function damage induced by different factors

Environmental pollutants

Different pollutants, such as particulate matter, plastic particles, and polycyclic aromatic hydrocarbons in the air, are considered major factors in human diseases, including respiratory diseases, cardiovascular diseases, central nervous system dysfunction, and cancer [52]. Benzo (a) pyrene (BaP) is the most representative environmental pollutant among polycyclic aromatic hydrocarbons, which can form DNA adducts through covalent binding with DNA or produce excessive ROS to induce mutations and carcinogenesis. BaP is a “potent ovotoxicant”, and exposure to BaP can disrupt steroid balance, alter the expression of ovarian estrogen receptors, and lead to premature ovarian failure through rapid depletion of the primordial follicle pool [53]. Previous studies have shown that BaP and its metabolites benzo (a) pyridine-7, 8-dihydroglycol-9 and 10-epoxide (BPDE) inhibit the expression of MT receptors (MTRs) in early pregnancy in mice and reduce levels of estrogen and progesterone in the ovaries [54]. In addition, BaP metabolites can promote the formation of follicular atresia by inducing cell apoptosis, thereby damaging normal follicular growth [55]. Xu et al. found that MT can improve oxidative stress, counteract phosphorylation of the PI3K/AKT/GSK3β signaling pathway, reduce ovarian cell apoptosis, and alleviate BaP-induced ovarian dysfunction [56]. Furthermore, Manisalidis et al. reported that MT can effectively inhibit the increase in ROS levels and apoptosis rate in pig oocytes exposed to BaP, restoring meiosis in oocytes [53].

The reproductive lifespan of women largely depends on the size of the primordial follicular pool established in the early stages. Dibutyl phthalate (DBP) is a popular plasticizer and a known environmental endocrine disruptor, posing a potential threat to reproductive health [57]. Exposure to DBP during pregnancy can disrupt the breakdown of germ cell cysts and the assembly of primordial follicles in the fetal ovary, damaging women’s fertility [58]. MT significantly alleviates oxidative stress, reduces autophagy, and restores NOTCH2 signaling, reversing its impact on hair follicle formation [59]. In addition, MT has a protective effect on improving embryo implantation and protecting intrauterine embryos from bisphenol A (BPA)-induced oxidative stress and early embryo loss [60].

BPA, another endocrine-disrupting chemical, is widely used as a plasticizer in the manufacturing process of epoxy resins and polycarbonate plastics. It is highly used in many daily products, such as beverages, food bottles, toys, and medical materials [61]. MT can reduce the increase and proliferation of estradiol-induced by BPA in porcine ovarian granulosa cells in vitro [62]. Above data suggest that MT is considered a potential and promising agent that has an important role in preventing reproductive hormone disorders caused by chemicals in environmental pollution.

Fungi and mycotoxins

Mycotoxins produced by Fusarium are common pollutants in food and animal feed, posing a threat to human health, especially reproductive health [63, 64]. A fungal toxin of the Fusarium genus, zearalenone (ZEA), is a non-steroidal estrogen that easily binds to estrogen receptors, leading to an imbalance in estrogen levels and possibly female reproductive diseases [65]. After absorption, ZEA forms α-zearalenol and β-zearalenol. β-Zearalenol may cause ovarian dysfunction and promote ovarian aging. In addition, other fungal toxins from Fusarium oxysporum have also attracted similar attention, including various types of monocytogenes. Among them, T-2 and its key metabolite HT-2 have shown certain reproductive toxicity in vivo and in vitro, manifesting as decreased fertility, impaired reproductive organ structure and function, and loss of male and female gametogenesis ability [66, 67]. Yang et al. found that β-zearalenol and HT-2 inhibit proliferation and induce BGC apoptosis in bovine ovarian granulosa cells (BGC) in a dose-dependent manner. However, this process may be alleviated by MT [68]. In addition, aflatoxin B1 (AFB1), one of the most common fungal toxins from Fusarium, causes harmful effects on the human and animal reproductive systems by inducing oxidative stress [69]. Cheng and colleagues found that MT protects in vitro matured porcine oocytes from the toxicity of AFB1. The results showed that exposure to AFB1 during in vitro oocyte maturation (IVM) significantly damaged nuclear and cytoplasmic maturation in a dose- and time-dependent manner. Yet, after supplementing relatively high concentrations of MT (10^–3 mol/L) during IVM, the damaged development rate and blastocyst quality were reversed, reaching levels comparable to the control group [70].

Similarly, MT has an alleviating effect on ovarian toxicity induced by deoxynivalenol (DON), which can protect ovarian granulosa cells from the adverse effects of DON through antioxidant and anti-inflammatory effects [71] and inhibition of endoplasmic reticulum stress and transcription factor FOX1 (Forkhead box O1) [72].

Drug damage

Studies have shown that chemotherapy is a risk factor for ovarian failure, with older women having a higher risk compared to younger women [73]. Cisplatin is a commonly used chemotherapy drug. Histopathological data confirmed changes in ovarian tissue in patients treated with cisplatin [74], manifested as damaged follicles and corpus luteum, bleeding, and inflammatory infiltration, as well as weak PAS reactions in the zona pellucida, increased deposition of ovarian collagen, and significant expression of caspase-3 immune response in granulosa cells, follicular membrane cells, stromal cells, and oocytes. Al-Shahat et al. found that MT can alleviate cisplatin-induced ovarian dysfunction by altering steroid development, inflammation, apoptosis, oxidative stress, and PTEN/PI3K/Akt/mTOR/AMPK signaling pathways in female rats [44]. The beneficial effect of MT was also observed in female C57BL/6 J mice [75]. In addition to preventing cisplatin-induced ovarian damage, studies reported that MT can prevent cyclophosphamide-induced loss of primordial follicles and protect fertility [76, 77]. All these studies suggest that MT has an important role in preventing ovarian damage caused by chemotherapy drugs. Chemotherapy directly or indirectly affects organs in a short-term or sustained manner.

In addition, MT also has a protective effect on ovarian function damage caused by glucocorticoids. Under stress induced by physical constraints, MT can release the ovaries from glucocorticoid-induced oxidative stress through the Nrf2 and HO-1 signaling pathways [79]. This discovery was further confirmed by Bai et al., who showed that after inducing oxidative stress through intraperitoneal dexamethasone injection, MT can alleviate oxidative stress and protect the ovaries through the FOXO1 signaling pathway [80].

Lifestyle

Health problems like hypertension, overweight, metabolic diseases, joint and skeletal problems, etc., can be caused by an unhealthy lifestyle, such as smoking and a bad dietary habit. Smoking has been proven to impair ovarian function and is closely related to infertility, pregnancy complications, and fetal miscarriage. Tobacco contains harmful chemicals such as nicotine and tar, which can deplete protective antioxidants and ultimately lead to oxidative stress [49]. Wang et al. have shown that nicotine exposure may adversely affect the establishment of ovarian reserve in mice by inducing local cellular stress to alter the assembly of primitive follicles but also found that MT can counteract this adverse effect [81]. A study on 72 female Wistar Albino rats suggested that smoking reduces the number of primordial, primary, and secondary follicles and that using a certain dose of MT may be related to a decrease in apoptosis index and induction of antioxidant activity in tissues [82]. Another study also demonstrated that MT improves mouse fetal oocyte damage caused by nicotine exposure during pregnancy in F1 and F2 offspring and can prevent nicotine-damaged fetal oocyte formation and subsequent follicle formation [83].

In addition to smoking, a bad dietary habit can also affect the body’s redox state [84]. When excessive intake of carbohydrates occurs, the excess carbohydrates in the body combine with proteins to form advanced glycation end products, which bind to specific proteins distributed on the membranes of oocytes, stromal cells, and granulosa cells, promoting ROS production through NF-κB and NADPH oxidase [85]. Roberts et al. used a new rodent model of diet-induced obesity and found that rats fed a high-fat and high-sugar diet not only showed signs of metabolic disorders, but also exhibited polycystic ovaries and irregular estrus cycles [86]. At present, nutritional supplements and complementary therapies have been used as adjunctive drugs for traditional lifestyle therapies in polycystic ovary syndrome, with melatonin being one of them [87]. A prospective study have reported that 2–6 months of melatonin treatment reduce androgens, LH, anti-Müllerian hormone, and BMI, and increased FSH [88].

Conclusion

The ovaries, as a natural biological clock, control the aging process in women. Ovarian dysfunction is caused by various pathogenic factors, such as decreased ovarian reserve function and early-onset ovarian insufficiency, mainly manifested as a decrease in the number of follicles and a decrease in the quality of oocytes. Oxidative stress damage is considered a mechanism of ovarian aging, and more and more studies have found that mitochondrial dysfunction, gene mutations, premature ovarian failure, and polycystic ovary syndrome are closely related to ovarian aging, all of which interact with oxidative stress. Oxidative stress is usually associated with mitochondrial dysfunction, and both can lead to ovarian cell apoptosis, forming a vicious cycle in which ovarian activity and the quantity and quality of oocytes also decrease. The meiotic maturation of oocytes depends on strict spindle assembly and chromosome allocation, and the large amount of mitochondria stored in the cytoplasm of oocytes is an important source of energy to support this process and subsequent early embryonic development. MT has an anti-apoptotic effect due to its antioxidant properties. Mitochondria are closely related to free radicals, and they produce ROS through electron transporters and oxidative phosphorylation processes. ROS attacks the lipid membranes of cells and subcellular components, causing lipid peroxidation reactions of unsaturated fatty acids in the biofilm, damaging membrane integrity and permeability, and subsequently leading to cell death.

Environmental pollution, chemotherapy drugs, mycotoxins, and unhealthy lifestyles can all affect ovarian function (Fig. 2), and MT plays different roles in different species, regulating ovarian function through antioxidant, ovarian, and oocyte development pathways (Table 1). The ovaries mainly secrete estrogen and progesterone. Estrogen is crucial for the development of female secondary sexual characteristics, the maintenance of normal reproductive system functions, and bone health. It promotes the growth of the endometrium, preparing it for embryo implantation. Progesterone, based on the action of estrogen, further thickens the endometrium, providing support for embryo development. During pregnancy, it inhibits uterine contractions to prevent miscarriage. When toxins affect ovarian function, the secretion of estrogen and progesterone may be abnormal. Some environmental toxins may interfere with the signaling pathways within ovarian cells, leading to abnormal follicular development and thus a reduction in the synthesis of estrogen and progesterone. This can cause menstrual cycle disorders, decreased fertility, and other problems. In recent years, the incidence rate of POI, DOR, and POF has increased year by year, which has seriously affected women’s fertility and quality of life. Under the background of delayed childbearing age and the liberalization of the policy of multiple births, melatonin is expected to become a new target for regulating ovarian function. However, there are more relevant basic research and less clinical research. Its efficacy needs to be further verified by multi center, large sample, randomized and controlled clinical trials. Although the external factors that lead to ovarian dysfunction may be similar, the damage caused by genetic programming defense mechanisms is patient dependent, and the defects in these mechanisms may be caused by mutations/deletions in nuclear and mitochondrial genes. Therefore, the treatment of each patient must be considered in conjunction with their corresponding medical history and current clinical conditions, and targeted treatment plans must be developed.

Fig. 2.

Factors effecting MT secretion and its effect on ovarian function

Table 1.

Main functions of melatonin in ovaries of different species

Species	Melatonin regulation results	Dose/concentrations of melatonin	References
Rat	Increases mRNA expression of steroid synthesis genes Cyp19A1, Cyp17A1, Cyp11a1, HSD17B3, and STAR	5 ml/kg	[44]
Rat	Reduces the expression of Bax, Bcl-2, and caspase-3	10 mg/kg	[89]
Rat	Affects cell apoptosis, antioxidant activity, and the number of primordial follicles, primary follicles, and secondary follicles	20 mg/kg	[82]
Mouse	Enhances the expression of SIRT1 to inhibit excessive PINK1/Parkin-mediated mitochondrial autophagy	100 pM	[90]
Mouse	Reducing ROS-induced endoplasmic reticulum stress to protect against epirubicin induced ovarian injury	60 mg/kg	[91]
Cattle	Promotes the diameter of bovine follicles and the growth of secondary oocytes	10–7 M	[92]
Cattle	Inhibition of oxidative stress and apoptosis of bovine granulosa cells	0.01 μM	[13]
Cattle	Promotes the proliferation of bovine follicular membrane cells and inhibiting steroid production	10 μM	[93]
People	Inhibits BMP-6 signaling which plays an important role in maintaining progesterone production	1000 nM	[94]
People	Eliminated DNA damage induced by accumulated reactive oxygen species, protecting oocytes from late stage age-related meiotic defects and aneuploidy	100 mg/kg	[34]
Pig	Regulates the release and synthesis of GnRH and LH in luteal cells	100 pg/mL	[41]
Pig	Prevents apoptosis of porcine granulosa cells during follicular atresia through membrane receptors and their free radical scavenging activity	1 ng/mL	[46]
Sheep	Reduces intracellular ROS content, caspase-3 activity, DNA fragmentation, and abundance of pro apoptotic transcripts BAX and CASP3, while increasing the abundance of GDF9 and GPX1	10–9 M	[95]

Abbreviations

AFB1

Aflatoxin B1

ASMT

Acetylserotonin O-methyltransferase

BaP

Benzo (a) pyrene

BGC

Bovine ovarian granulosa cells

BPA

Bisphenol A

DBP

Dibutyl phthalate

DOR

Diminished ovarian reserve

GnRH

Gonadotropin releasing hormone

HIOMT

Hydroxyindole oxy methyltransferase

IVF-ET

In vitro fertilization and embryo transfer

IVM

In vitro oocyte maturation

LH

Luteinizing hormone

MT

Melatonin

MTNR

MT receptor

NAT

N-Acetyltransferase

PA

Palmitic acid

POF

Premature ovarian failure

POI

Premature ovarian insufficiency

RHT

Retinal hypothalamic tract

ROS

Reactive oxygen species

SCN

Suprachiasmatic nucleus

SOD

Superoxide dismutase

THP

Tryptophan hydroxylase

ZEA

Zearalenone

Author contributions

JHH and LLR wrote the main manuscript text, TTY and KYX prepared Figs. 1–2 and YTL prepared tables 1. All authors reviewed the manuscript.

Funding

This study was supported by Zhejiang Province Traditional Chinese Medicine Science and Technology Plan Project (2023ZR137); Shaoxing Science and Technology Plan Project (2023A14039).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

The authors declare no competing interests.