Melatonin in ovarian function and dysfunction: Molecular mechanisms and therapeutic potential

Abstract

Melatonin (MT) is a natural indoleamine compound. In addition to regulating sleep and circadian rhythms, MT exhibits antioxidative, anti-inflammatory, anti-apoptotic, and ovarian protective properties. Recent studies have shown that MT alleviates polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI), ovarian injury, and age-related ovarian function decline. This review establishes an integrated mechanistic model in which oxidative stress, mitochondrial dysfunction, inflammatory responses, and autophagic imbalance collectively contribute to the pathogenesis of ovarian disorders, while melatonin acts as a pleiotropic regulator that counteracts these interconnected pathological pathways. Furthermore, this review also discusses recent advances regarding the inhibitory effects of melatonin on ovarian tumors. Although MT shows considerable clinical promise, further research is needed to determine its optimal dosage, administration regimens, and therapeutic targets to facilitate its clinical translation.

Introduction

Ovarian function is fundamental to female reproductive health and relies on the precise coordination of follicular development, steroidogenesis, ovulation, and oocyte maturation. Disruption of ovarian homeostasis contributes to a broad spectrum of reproductive disorders, including infertility, PCOS, POI, ovarian injury, age-related ovarian dysfunction, and ovarian cancer [1–3]. Over recent decades, the prevalence of these disorders has increased substantially, likely owing to environmental stressors, metabolic disturbances, delayed childbearing, and lifestyle changes [4, 5]. Although these conditions differ in etiology and clinical presentation, accumulating evidence indicates that they share several common pathological features, including oxidative stress, mitochondrial dysfunction, chronic inflammation, circadian rhythm disruption, aberrant follicular activation, and accelerated follicular depletion [6, 7]. These processes impair oocyte quality, diminish ovarian reserve, and promote malignant transformation in some cases.

MT, an indoleamine originally identified as a pineal hormone regulating circadian rhythms, has attracted considerable attention owing to its diverse biological functions beyond sleep regulation [8, 9]. In addition to circadian synchronization, MT exerts antioxidant, anti-inflammatory, anti-apoptotic, and mitochondria-protective effects, thereby contributing to metabolic, immune, and reproductive homeostasis [10, 11]. Importantly, MT is also synthesized locally in ovarian tissues, including granulosa cells, oocytes, and follicular fluid, where it acts through autocrine and paracrine mechanisms to support follicular development and oocyte competence [12, 13]. Accumulating evidence has demonstrated protective effects of MT in various ovarian disorders. In PCOS, MT improves endocrine dysfunction, insulin resistance, oocyte quality, and reproductive outcomes [14]. In POI and chemotherapy-induced ovarian injury, MT preserves ovarian reserve, reduces follicular atresia, and inhibits granulosa cell apoptosis [15, 16]. MT also mitigates ovarian aging by improving mitochondrial function and maintaining follicular homeostasis [17]. In ovarian cancer, MT exhibits potential oncostatic effects through the inhibition of tumor growth, invasion, and metastasis, as well as the induction of apoptosis [18]. Mechanistically, MT acts through both receptor-dependent and receptor-independent pathways, regulating oxidative stress, mitochondrial function, autophagy, inflammation, and circadian rhythms [6, 13]. These effects involve multiple signaling networks, including MT1/MT2 receptors, Nrf2/HO-1, PI3K/Akt, and SIRT1/AMPK pathways.

Despite growing interest, evidence remains dispersed across models, and clinical translation is hindered by heterogeneous dosages, routes, and a lack of large-scale trials [19]. This review establishes an integrated model in which oxidative stress, mitochondrial dysfunction, inflammation, and autophagic imbalance drive ovarian disorders, while MT counteracts these pathways. We first outline the mechanisms by which MT maintains ovarian homeostasis, then summarize therapeutic evidence for MT in PCOS, POI, ovarian injury, aging, and cancer, and finally discuss translational challenges.

Literature search strategy

This narrative review was based on a structured literature search performed in PubMed, Web of Science, and ScienceDirect databases. Publications from 2015 to 2025 were primarily considered, although seminal earlier studies were also included when relevant.

Search terms included: “melatonin”, “ovary”, “ovarian function”, “polycystic ovary syndrome”, “premature ovarian insufficiency”, “ovarian aging”, “oxidative stress”, “mitochondria”, “autophagy”, and “female infertility”, “ovarian cancer”.

Studies were selected based on:

• relevance to ovarian biology.

• mechanistic insights.

• translational significance.

• availability of preclinical or clinical evidence.

This review was intended as a narrative synthesis rather than a systematic review; therefore, formal PRISMA methodology and risk-of-bias assessment were not applied. Literature was selected to capture both disease-specific and mechanism-focused insights, highlighting the interconnected regulatory networks in ovarian function.

Overview of MT biosynthesis and sources

MT is an evolutionarily conserved indoleamine synthesized from tryptophan through a multistep enzymatic pathway involving serotonin, arylalkylamine N-acetyltransferase (AANAT), and acetylserotonin O-methyltransferase (ASMT) [20].

Although the pineal gland is the primary source of circulating MT responsible for circadian rhythm regulation, MT is also synthesized in multiple extra-pineal tissues, including the gastrointestinal tract, immune cells, and reproductive organs [21]. In addition to systemic production, local MT synthesis has been identified within ovarian tissues, suggesting the presence of an intra-ovarian melatonergic system.

Within the female reproductive system, MT is highly enriched in follicular fluid and ovarian microenvironments, where both granulosa cells and oocytes serve as local sources of MT [22] (Fig. 1). Recent evidence further indicates that MT synthesis may also occur at the mitochondrial level, as key biosynthetic enzymes such as AANAT have been detected in mitochondria, suggesting a potential subcellular source of MT in ovarian cells [23, 24].

Fig. 1.

Sources of MT and local mitochondrial synthesis in the ovary

Collectively, MT in the ovary originates from endocrine circulation, local ovarian synthesis, and potentially mitochondrial production, forming a multi-source regulatory system that provides the basis for its involvement in ovarian physiology and pathology.

Molecular mechanisms of MT in ovarian protection

Regulation of oxidative stress and mitochondrial homeostasis

Oxidative stress drives ovarian dysfunction and reproductive aging. During follicular development, granulosa cells produce ROS via mitochondrial respiration. Excessive ROS disrupts mitochondrial function, damages lipids, proteins, and DNA, impairs steroidogenesis and oocyte maturation, and accelerates follicular atresia [25, 26]. MT, an antioxidant and mitochondria associated molecule, protects ovarian cells through multiple mechanisms. MT is enriched in mitochondria, helps maintain redox homeostasis, preserves membrane potential and ATP production, reduces mitochondrial ROS, and supports normal granulosa cell and oocyte function [19].

Beyond direct ROS scavenging, MT orchestrates signaling and transcriptional programs. MT inhibits MAPK associated stress pathways (MAP3K8–FOS and p38 MAPK), reducing ROS and preventing mitochondrial apoptosis [27, 28]. MT also reinforces endogenous antioxidant defenses by restoring SOD, CAT, GPX, and PRDX family members, limiting lipid peroxidation and preserving mitochondrial membrane potential [29–31]. The mitochondrial protective effects of MT are evident under pathological oxidative stress. Fan et al. reported that MT reduced deoxynivalenol induced ROS, restored mitochondrial potential and ATP production, and upregulated Sod and Gshpx [32]. Al Shahat et al. found that MT reversed cisplatin induced suppression of antioxidant defenses (SOD, CAT, GSH, TAC), reduced MDA, and improved mitochondrial resistance [33]. In PCOS models, MT upregulated Gpx1 and Sod1, reducing ROS and enhancing oocyte antioxidant capacity [34].

MT also acts at transcriptional and epigenetic levels. Ma et al. showed that MT promotes Nrf2 activation by inhibiting an upstream open reading frame (uORF) in the 5′ UTR of Nrf2 mRNA, relieving translational suppression and increasing Nrf2 protein synthesis; subsequent Nrf2/KEAP1 activation enhances HO-1, CAT, and SOD2 [35]. Fang et al. demonstrated that MT activates RORα and promotes demethylation of antioxidant gene promoters (SOD1, GPx4, CAT), enhancing transcriptional activity and cumulus cell redox capacity [36]. Finally, emerging evidence shows MT protects aging ovarian cells by regulating cuproptosis and ferroptosis. In women of advanced maternal age undergoing IVF, MT improved pregnancy rates and modulated ATP7B and GPX4 in cumulus cells, while restoring mitochondrial function, glycolytic activity, and TCA cycle genes [37].

In summary, oxidative stress and mitochondrial dysfunction form a self-amplifying cycle. MT interrupts this cycle through direct ROS scavenging, enhancement of antioxidant defenses, Nrf2/KEAP1 activation, epigenetic regulation, and modulation of ferroptosis/cuproptosis pathways. Thus, mitochondrial homeostasis is a central mechanism linking MT’s antioxidant, anti-apoptotic, and cytoprotective effects across ovarian pathologies.

Regulation of apoptosis and follicular survival

Excessive granulosa cell apoptosis and premature primordial follicle activation are primary drivers of ovarian reserve depletion. Thus, preserving ovarian function requires suppressing apoptosis and maintaining follicular quiescence. MT protects ovarian function via receptor mediated and mitochondrial dependent mechanisms. MT primarily acts through high-affinity G protein-coupled receptors MT1 and MT2, activating Gi/o-dependent signaling. Ligand binding inhibits adenylate cyclase, reduces cAMP, and modulates downstream kinases involved in oxidative stress, mitochondrial homeostasis, and apoptosis [13]. MT1 signaling appears to play a dominant role in ovarian protection.

A key downstream axis is PTEN–PI3K/Akt–FOXO3a, which maintains primordial follicle quiescence. FOXO3a acts as a gatekeeper; its nuclear export triggers premature follicle activation. Barberino et al. showed that MT upregulated PTEN, suppressed aberrant Akt phosphorylation, and prevented FOXO3a nuclear export in cyclophosphamide treated ovaries, thereby reducing premature activation and caspase-3-mediated apoptosis while preserving mitochondrial integrity [38]. Granulosa cell survival is further supported by MT’s mitochondrial protection and oxidative stress regulation. Zhang et al. reported that MT increased MT1 expression and activated AMPK signaling, reducing ROS, stabilizing mitochondrial membrane potential, and maintaining energy homeostasis in aging ovarian tissue [39]. MT also shifts the Bcl-2/Bax ratio toward an anti-apoptotic state via MT1-dependent Nrf2/HO-1 signaling during oocyte cryopreservation [40], with similar effects in cisplatin-induced injury [41] and ovarian transplantation [42].

Additionally, MT suppresses excessive cAMP accumulation in the ovarian microenvironment, promoting coordinated oocyte maturation while preserving developmental competence [43]. In summary, MT integrates MT1/MT2, PTEN–Akt–FOXO3a, AMPK, and Nrf2 pathways to suppress granulosa cell apoptosis, maintain mitochondrial function, and prevent premature follicle activation. Notably, most evidence comes from rodents or invitro systems; the relative contributions of receptor dependent versus receptor independent pathways remain unclear, and further studies in human ovarian tissue are needed.

Regulation of autophagy and mitochondrial quality control

Autophagy degrades damaged proteins and organelles to maintain cellular homeostasis. In ovarian tissue, autophagy and mitophagy are critical for follicular development, oocyte maturation, mitochondrial quality control, and long-term function; their dysregulation contributes to granulosa cell dysfunction, follicular atresia, and ovarian aging [44]. MT preserves ovarian homeostasis by regulating autophagic and mitophagic pathways, acting on upstream regulators and downstream effectors to maintain granulosa cell viability and mitochondrial integrity.

MT suppresses excessive autophagy through multiple mechanisms. Cao et al. showed that MT inhibits JNK signaling, reduces BECN1 expression, and promotes BCL-2/BECN1 complex formation, preventing granulosa cell death [45]. Xie et al. reported that MT activates the PI3K/AKT/mTOR axis, elevating PI3K, p-AKT, and p-mTOR, while reducing Beclin-1 and LC3 and restoring P62; this inhibits excessive autophagic flux, reduces apoptosis, and improves ovarian morphology and endocrine function [46]. Additionally, FOXO-mediated signaling contributes to MT-dependent autophagy regulation: Shen et al. showed that MT suppresses FOXO1 expression and nuclear translocation, reducing transcriptional activation of Beclin-1 and LC3 and preventing excessive autophagy [47]. Thus, MT restrains harmful over-autophagy while preserving basal autophagic activity. Beyond general autophagy, MT-mediated mitophagy regulation is context-dependent. Xu et al. reported that MT upregulates SIRT1 and inhibits FOXO1, promoting PINK1/Parkin-mediated clearance of dysfunctional mitochondria [48]. Conversely, under severe oxidative stress, Jiang et al. found that MT suppresses PINK1 expression and inhibits Parkin recruitment, preventing excessive mitophagic flux and preserving mitochondrial structural integrity [49].

In summary, MT bidirectionally regulates autophagy and mitophagy via PI3K/AKT/mTOR, SIRT1, FOXO1, and PINK1/Parkin pathways, maintaining mitochondrial quality control, granulosa cell survival, and ovarian functional homeostasis.

Regulation of circadian rhythm and ovarian endocrine homeostasis

Circadian rhythm synchronizes physiological processes with environmental cues. Through neuroendocrine and metabolic pathways, circadian signaling regulates energy homeostasis, steroidogenesis, follicular development, and reproduction [50]; its disruption promotes oxidative stress, inflammation, mitochondrial dysfunction, and endocrine imbalance [21].

MT protects ovarian function partly by restoring circadian networks. As a circadian regulator and locally synthesized molecule, MT links environmental rhythmicity with ovarian physiology, coordinating mitochondrial homeostasis, endocrine function, and follicular development via clock-associated pathways. At the cellular level, MT regulates ovarian clock genes to maintain mitochondrial function. Chen et al. showed that MT restored Clock expression in granulosa cells, re-establishing coordination between mitophagy and mitochondrial dynamics. This reduced ROS, suppressed NLRP3 inflammasome activation, and alleviated mitochondrial dysfunction and pyroptosis in PCOS-associated injury [51]. Thus, MT re-couples circadian signals with mitochondrial quality control within ovarian cells.

Beyond cellular clock regulation, circadian signaling governs the HPO axis and steroidogenesis, and MT exerts systemic effects. Li et al. demonstrated that circadian disruption dysregulated the HPO axis, causing abnormal LH pulsatility and LHβ transcription changes; MT supplementation partially restored HPO rhythmicity, reduced oxidative stress, and suppressed apoptosis [52]. Similarly, Chu et al. reported that impaired rhythmicity reduced ovarian MT signaling gene expression, suppressed the AR–CYP19A1 axis, and disrupted androgen-to-estrogen conversion, contributing to hyperandrogenism [53]. Restoring circadian homeostasis reversed these abnormalities, indicating clock-regulated steroidogenic pathways maintain normal ovarian function. In summary, MT integrates circadian, mitochondrial, neuroendocrine, and steroidogenic pathways. By restoring rhythmicity at cellular and systemic levels, MT supports ovarian endocrine homeostasis and reproductive function. Most mechanistic evidence derives from experimental models; further studies are needed to clarify how circadian restoration contributes to MT’s therapeutic effects across ovarian pathologies.

Regulation of inflammatory responses and immune homeostasis

Chronic low-grade inflammation drives ovarian aging and dysfunction. Persistent activation of NF-κB and MAPK promotes oxidative stress, mitochondrial dysfunction, granulosa cell apoptosis, and follicular depletion [54]. MT exerts anti-inflammatory effects by coordinating inflammatory signaling, mitochondrial homeostasis, and immune regulation. NF-κB is a key target of MT. Fan et al. showed that MT suppressed TLR4-mediated NF-κB and MAPK (ERK/JNK/p38) activation in deoxynivalenol-induced granulosa cell injury, reducing TNF-α, IL-6, and IL-1β while preserving mitochondrial function and limiting apoptosis [32]. Thus, MT directly intercepts pro-inflammatory signaling while preserving mitochondrial integrity.

Beyond direct pathway inhibition, MT regulates ovarian inflammation via epigenetic, post-transcriptional, and ER stress mechanisms. Zhu et al. reported that MT suppressed the ROS–YTHDF2–MAPK–NF-κB axis, reducing SASP activation and alleviating inflammatory senescence in ovarian surface epithelial cells [55]. MT also attenuates ER stress: in high-fat diet-induced obese mice, Nagagata et al. showed MT reduced ovarian inflammatory mediators (TNF-α, IL-6, IL-1β, Resistin) and ER stress genes (Atf4, Ddit3, Gadd45a) [56]. In an LPS-induced diminished ovarian reserve model, Shi et al. showed MT reduced IL-1β and IL-18, restored mitochondrial fusion-fission balance, and preserved AMH and GDF9 [57]. Similarly, MT suppressed NF-κB and inflammatory cytokines in cisplatin-induced injury [33]. Collectively, these studies show that inflammatory signaling, mitochondrial dysfunction, ER stress, and follicular loss are interconnected targets of MT.

SIRT1 signaling is another mediator of MT-dependent immune regulation. In bisphenol S-induced injury, MT upregulated SIRT1 and suppressed NF-κB/COX-2/iNOS, reducing TNF-α, CRP, and nitric oxide while improving follicular development [58]. In LPS-induced toxicity, MT enhanced SIRT1 activity, inhibited NF-κB/COX-2, and modulated PI3K/p-Akt and ERK1/2, reducing inflammatory cytokines [59]. MT also protected against radiation-induced ovarian inflammation by reducing TNF-α, IL-1β, IL-6, and suppressing NF-κB and caspase-3 [60]. In summary, MT coordinates NF-κB, MAPK, and SIRT1 pathways to reduce oxidative stress, ER stress, and inflammation, maintaining a favorable ovarian microenvironment. Most evidence remains preclinical; future studies should clarify MT’s immunomodulation in human ovarian disorders (Fig. 2).

Fig. 2.

Unified mechanistic framework of MT-mediated ovarian protection

Disease-specific implications of MT in ovarian dysfunction

MT and PCOS

PCOS is characterized by hyperandrogenism, ovulatory dysfunction, insulin resistance, and polycystic ovarian morphology, with ovarian pathophysiology involving chronic inflammation, oxidative stress, and circadian disruption [61].

MT has been reported to improve endocrine dysfunction, alleviate insulin resistance, enhance oocyte quality, and improve reproductive outcomes in PCOS [14]. Mechanistically, MT upregulates antioxidant genes including Gpx1 and Sod1 in a dose-dependent manner, reducing intracellular ROS and enhancing oocyte antioxidant capacity [34]. MT also suppresses TLR4-mediated NF-κB and MAPK activation, reducing pro-inflammatory cytokine production [32]. In addition, MT activates the PI3K/AKT/mTOR axis, inhibiting excessive autophagic flux and reducing apoptosis in granulosa cells [46]. Furthermore, MT restores expression of the core circadian gene Clock in ovarian granulosa cells, re-establishing coordination between mitophagy and mitochondrial dynamics, thereby reducing ROS accumulation, suppressing NLRP3 inflammasome activation, and alleviating mitochondrial dysfunction and pyroptosis [51]. Clinical studies suggest that MT supplementation improves oocyte quality and reduces follicular oxidative stress, although optimal dosing remains to be standardized [14].

MT in POI and ovarian injury

POI and various forms of ovarian injury (chemotherapy, radiation, toxicant exposure) share a common final pathway of premature primordial follicle activation and excessive granulosa cell apoptosis, leading to early depletion of ovarian reserve [62]. In cyclophosphamide-treated ovaries, MT upregulates PTEN, suppresses aberrant Akt phosphorylation, and prevents FOXO3a nuclear export, thereby attenuating premature follicle activation, preserving mitochondrial integrity, and reducing caspase-3-mediated apoptosis [38]. In cisplatin-induced ovarian injury, MT reduces ROS accumulation, restores mitochondrial membrane potential and ATP production, upregulates antioxidant enzyme genes, and shifts the Bcl-2/Bax ratio toward an anti-apoptotic state [41]. MT also modulates mitophagy in a context-dependent manner: under severe oxidative stress, it suppresses PINK1 expression and inhibits Parkin recruitment to prevent excessive mitophagic flux, while under other conditions it may promote PINK1/Parkin-mediated clearance of dysfunctional mitochondria [49]. These mechanisms collectively preserve ovarian reserve and reduce follicular atresia. Although most evidence remains preclinical, these findings provide a rationale for further clinical investigation [63, 64].

MT and ovarian aging

Ovarian aging is driven by cumulative mitochondrial dysfunction, chronic low-grade inflammation, and disruption of follicular homeostasis. MT improves mitochondrial function, maintains follicular homeostasis, and supports oocyte developmental competence in the context of ovarian aging [17]. Specifically, MT activates the SIRT3/FoxO3a antioxidant pathway, reducing mitochondrial oxidative stress and improving fertility in aged mice [65]. MT also activates the nuclear receptor RORα and promotes demethylation of antioxidant gene promoters including SOD1, GPx4, and CAT, thereby enhancing antioxidant transcriptional activity and suppressing apoptosis [36]. In naturally aged mice, MT administration delays ovarian reserve exhaustion and follicle atresia through the PI3K-AKT-FOXO3 pathway [66]. Additionally, MT reduces cellular senescence and the senescence-associated secretory phenotype in human ovarian surface epithelial cells by suppressing the ROS–YTHDF2–MAPK–NF-κB signaling axis [55]. Clinical evidence from women of advanced maternal age undergoing IVF shows that MT supplementation improves clinical pregnancy and live birth rates, accompanied by modulation of cuproptosis- and ferroptosis-related genes such as ATP7B and GPX4 in cumulus cells [37].

MT and ovarian cancer

Ovarian cancer (OC) remains a lethal gynecological malignancy due to late diagnosis, high metastatic potential, and frequent development of chemoresistance. Evidence suggests that MT possesses anti-tumor properties in OC and may represent an adjunctive strategy in oncologic and reproductive medicine [67, 68].

Experimental studies have shown that MT suppresses OC cell proliferation, reduces colony formation, and promotes cancer cell death in multiple OC models. MT treatment has also been associated with reduced migratory and invasive capacity, suggesting a role in limiting metastatic progression [69, 70].

MT also influences OC metabolism and tumor microenvironment homeostasis. Evidence suggests that MT may partially reverse the glycolytic phenotype of OC cells, reduce lactate accumulation, and alter mitochondrial metabolic activity, thereby potentially impairing metabolic pathways that support tumor growth [71, 72].

MT may also modulate tumor aggressiveness by reducing stemness-associated characteristics and suppressing stress-related tumor progression. In OC stem-like cells, MT reduced colony formation and altered expression of invasion-related molecules. Moreover, MT alleviated chronic stress-associated OC metastasis in experimental models, suggesting a link between circadian signaling, neuroendocrine stress responses, and tumor progression [70, 73].

Thus, MT possesses multifaceted anti-tumor potential in OC, including suppression of proliferation, metastasis, metabolic adaptation, and tumor microenvironment dysregulation. Although most evidence remains preclinical, these findings suggest that the biological effects of MT may extend beyond reproductive regulation and ovarian aging, with potential implications for gynecologic oncology.

Representative preclinical studies investigating the protective effects of MT on ovarian dysfunction are summarized in Table 1.

Table 1.

Representative preclinical studies investigating the protective effects of MT on ovarian dysfunction

Disease	Model	MT dose	Main findings	Molecular mechanism	Ref
PCOS	DHEA-induced rat + KGN cells	50 mg/kg/day gavage (rat); 200 µM (KGN)	Improved ovarian function and reduced apoptosis	PI3K/Akt-mediated inhibition of excessive autophagy	[46]
	PCOS patients + DHEA mouse + KGN cells	50 mg/kg/day gavage (mouse); 200 µM (KGN)	Improved mitochondrial dysfunction and reduced pyroptosis	Clock-mediated regulation of mitochondrial dynamics and mitophagy	[51]
	DHT-PCOS mice + KGN cells	10 mg/kg/day gavage (mouse); 100 pM (KGN)	Restored mitochondrial membrane potential and reduced mitochondrial injury	PDK1/Akt-SIRT1 pathway	[74]
	DHT-PCOS mice + human granulosa cells	10 mg/kg/day gavage (mouse); 100 pM (KGN)	Reduced excessive mitophagy and improved mitochondrial function	SIRT1/PINK1/Parkin pathway	[75]
	Letrozole-induced rat	2 mg/kg/day i.p. (rat)	Improved hormonal profile, glucose metabolism and follicular development	Regulation of steroidogenesis and ovarian morphology	[76]
	TG-induced mouse	20 mg/kg/day oral (mouse)	Improved ovarian reserve, reduced oxidative stress and apoptosis	SIRT1/FoxO3a/Nrf2 signaling	[77]
POI	Granulosa-cell starvation model	500 ng/L (COV434)	Reduced apoptosis and excessive autophagy	PI3K/Akt/mTOR-mediated autophagy inhibition	[78]
	Cyclophosphamide-induced mouse	50 mg/kg/day i.p. (mouse)	Preserved primordial follicles and fertility	Maintenance of AMH expression and inhibition of mitochondrial apoptosis	[79]
	CUMS-induced mouse		Restored mitochondrial homeostasis and reduced autophagy	eIF2α/ATF4 pathway inhibition	[80]
	PM2.5-induced POI model	15 mg/kg/day i.p. (mouse, every other day); 50 µM (KGN)	Reduced ferroptosis and ovarian dysfunction	Nrf2-mediated ferroptosis inhibition	[81]
	Epirubicin-induced ovarian damage	60 mg/kg/day i.p. (mouse)	Preserved follicle reserve and hormone levels, reduced apoptosis	ROS/ER stress-mediated apoptosis inhibition	[64]
Ovarian injury	BPA-treated granulosa cells	15 µM (human GCs)	Restored FSHR and Cx43 expression, improved granulosa cell function	FSHR–Cx43 signaling restoration	[82]
	Zearalenone-induced ovarian injury	40 mg/kg/day i.p. (mouse); 100 µM (GRM02)	Reduced oxidative stress and DNA damage	ATM–Chk2–p53 pathway modulation	[83]
	DEHP-induced human granulosa cell injury	10 µM (human GCs)	Improved mitochondrial function and reduced apoptosis	AMPK–PGC1α–Drp1 pathway	[84]
	Excessive autophagy model (CHO cells)	1 nM (CHO cells)	Restored AMH and mitochondrial function	ERK-dependent autophagy suppression	[85]
	Naturally aged mice	100 µg/mL in drinking water (mouse)	Improved follicle reserve, oocyte quality and fertility	SIRT1 activation, telomere maintenance, autophagy regulation	[86]
Ovarian aging	Naturally aged mice	10 mg/kg/day drinking water (mouse); 100 µg/mL (granulosa cells)	Reduced mitochondrial oxidative stress and improved fertility	SIRT3/FoxO3a antioxidant pathway	[87]
	Naturally aged mice	15 mg/kg/day i.p. (mouse); 100 nM (ovary culture)	Delayed ovarian reserve exhaustion and follicle atresia	PI3K-AKT-FOXO3 pathway inhibition	[65]
	Immp2l mutant mice	30 mg/kg/day i.p. (mouse); 10 µM (granulosa cells)	Reversed accelerated ovarian aging and restored estrogen production	ROS-Wnt/β-catenin-estrogen pathway	[66]
Ovarian aging	HOSEpiC senescence model	1 µM (HOSEpICs)	Reduced cellular senescence and inflammatory SASP	YTHDF2-MAPK-NF-κB pathway	[55]
	Naturally aged mice & KGN cells	10 mg/kg/day drinking water (mouse); 300 µM (KGN)	Alleviated ovarian aging via epigenetic regulation	YTHDF2/m6A/UBE3C/P53 axis	[88]

Clinical translation and future perspectives

Translational evidence and therapeutic potential

Translational evidence suggests that MT may exert beneficial effects in reproductive medicine, particularly through regulation of oxidative stress, mitochondrial homeostasis, and oocyte competence. Several randomized clinical studies and meta-analyses support the therapeutic potential of MT in assisted reproductive technologies (ART) and ovarian dysfunction [89].

In available clinical studies, MT supplementation has shown effects on oocyte and embryo quality during ART procedures. A pilot double-blind randomized placebo-controlled trial showed that oral MT administration increased follicular fluid MT concentrations during ovarian stimulation, although significant differences in clinical pregnancy rates were not observed, likely due to the limited sample size. The study demonstrated the feasibility of MT supplementation in IVF settings [90].

Recent randomized controlled studies indicated that MT may improve reproductive outcomes in women with diminished ovarian reserve (DOR). MT administration increased the number of retrieved oocytes, fertilization rates, embryo quality, and biochemical pregnancy rates while reducing follicular oxidative stress markers [91, 92].

Additional prospective clinical evidence showed that MT supplementation during embryo culture improved blastocyst development and increased the proportion of high-quality embryos in patients with repeated poor-quality embryos and frozen-thawed embryos [93].

An umbrella review of meta-analyses based on randomized controlled trials concluded that MT supplementation generally exhibits a favorable safety profile and may improve selected reproductive outcomes, particularly embryo quality in ART settings [89]. MT should not replace established therapies such as metformin in PCOS, hormone replacement therapy in POI, or standard ART protocols [94, 95]. Rather, it may serve as an adjunctive intervention that enhances ovarian function by modulating interconnected pathways involved in oxidative stress, mitochondrial homeostasis, inflammation, autophagy, and circadian regulation. However, current evidence has several limitations (see below). Clinical studies investigating MT supplementation in women with ovarian dysfunction are summarized in Table 2.

Table 2.

Clinical studies investigating MT supplementation in women with ovarian dysfunction

Ovarian Dysfunction	Population	MT Regimen	Main Findings	Ref
PCOS	58 women with PCOS	10 mg/day for 12 weeks	Improved sleep quality, depression and anxiety scores; reduced insulin, HOMA-IR, total cholesterol and LDL-C; increased insulin sensitivity (QUICKI)	[96]
	84 women with PCOS	MT and/or magnesium for 8 weeks	Reduced TNF-α levels; MT plus magnesium increased total antioxidant capacity (TAC) and improved hirsutism	[97]
	51 women with PCOS receiving metformin	MT + metformin for 3 months	Increased antioxidant markers (FRAP and total thiol); improved oxidative stress profile	[98]
	216 women with PCOS receiving metformin	MT + sildenafil for 12 weeks	Improved menstrual cyclicity, depression severity, sexual function and health-related quality of life	[99]
DOR	68 women undergoing ART	3 mg/day before ovarian stimulation	Increased retrieved oocytes, fertilization rate, embryo quality, TAC and biochemical pregnancy rate; reduced follicular oxidative stress	[91]

Clinical evidence for POI, ovarian aging, chemotherapy-induced ovarian injury, and OC remains limited, with current support derived mainly from preclinical studies

Safety and dosage considerations

MT is generally safer than many conventional drugs. It is well tolerated across a broad dosage range, with most adverse effects being mild and transient. Commonly reported side effects include drowsiness, headache, dizziness, nausea, and transient daytime sleepiness. A meta-analysis of high-dose MT (≥ 10 mg/day) in adults concluded that MT did not significantly increase serious adverse events or treatment discontinuation. However, mild adverse events, particularly drowsiness, headache, and dizziness, appeared moderately increased. Safety reporting in current trials is insufficient and heterogeneous, so definitive conclusions on long-term high-dose safety are lacking [100].

Recent reviews support the favorable tolerability of MT while highlighting the need for caution. Although MT exhibits antioxidant, anti-inflammatory, and immunomodulatory properties, evidence on its long-term safety, optimal dosage, and population-specific effects remains incomplete. Potential effects (e.g., nightmares, grogginess, circadian disruption) occur in some individuals, especially with prolonged or inappropriate use [101]. Emerging evidence raises concerns about indiscriminate or excessive exogenous MT use. The distinction between endogenous and exogenous MT is poorly understood. Caution is advised for children, pregnant women, and the elderly, who lack long-term safety data [102]. Mechanistically, MT has high antioxidant capacity and mitochondrial protection, partly explaining its low toxicity. MT scavenges reactive species, boosts endogenous antioxidant enzymes, and suppresses pro-oxidative pathways [103].

However, several limitations remain. Studies vary in dosage, duration, formulation, and timing, complicating comparisons. Most studies are short-term with small samples; evidence on chronic high-dose exposure is limited. Future studies should standardize protocols, assess long-term safety, and identify populations that benefit or are vulnerable. Given MT’s chronobiological properties, future studies should assess whether timing affects efficacy and safety in women with ovarian disorders.

Limitations of current evidence

Despite growing evidence on MT in ovarian physiology and disorders, several limitations should be acknowledged.

First, studies show considerable heterogeneity in MT dosage, administration route, treatment duration, and evaluated outcomes. This variability complicates direct comparisons and hinders standardized protocols. Moreover, diverse endpoints have been assessed—oxidative stress markers, hormonal profiles, oocyte quality, embryo development, pregnancy outcomes, and ovarian reserve parameters—contributing to inconsistent results across the literature [25].

Second, most clinical studies have small sample sizes and short follow-up periods. Although several randomized controlled trials report improved oocyte quality, embryo development, fertilization rates, and biochemical pregnancy outcomes, evidence on long-term reproductive outcomes—particularly live birth rates and sustained ovarian function—remains limited [91].

Third, much of the mechanistic evidence comes from animal models and in vitro experiments. While these studies provide insights into MT’s roles in regulating oxidative stress, mitochondrial homeostasis, apoptosis, autophagy, inflammation, and circadian signaling, their translational applicability to human ovarian disorders requires further validation through well-designed clinical studies [104].

Finally, unresolved questions remain about the optimal timing, dosage, formulation, and duration of MT supplementation for different pathological conditions. Additionally, the long-term safety of chronic MT administration in reproductive medicine has not been fully established. Future research should prioritize large-scale multicenter randomized controlled trials, standardized protocols, and long-term follow-up assessments to better define MT’s clinical utility in ovarian health and disease.

Conclusion

MT exerts pleiotropic effects on ovarian physiology and pathology through the coordinated regulation of oxidative stress, mitochondrial function, inflammation, apoptosis, autophagy, and circadian signaling, thereby supporting ovarian homeostasis and reproductive competence. Growing experimental and clinical evidence suggests potential benefits of MT in PCOS, POI, ovarian injury, age-related ovarian dysfunction, and preliminary evidence suggests potential effects in ovarian cancer.

Recent advances have identified ovarian mitochondria as both targets and potential sources of MT, providing new insights into its role in maintaining mitochondrial integrity, cellular bioenergetics, and ovarian function. Through both receptor-dependent and receptor-independent mechanisms, MT may serve as a regulator linking redox balance, metabolism, and reproductive processes.

Nevertheless, current evidence remains largely derived from experimental models, while clinical studies are limited by small sample sizes, heterogeneous study designs, and insufficient long-term follow-up. Consequently, the optimal dose, timing, and long-term safety of MT supplementation have yet to be established.

Future studies should prioritize well-designed multicenter clinical trials and further investigate the biological significance of local and mitochondrial MT synthesis in the ovary. A better understanding of these mechanisms may facilitate the development of more targeted MT-based interventions for preserving ovarian function and improving reproductive outcomes.

Abbreviations

MT

Melatonin

PCOS

Polycystic Ovary Syndrome

POI

Premature Ovarian Insufficiency

ROS

Reactive Oxygen Species

RNS

Reactive Nitrogen Species

AANAT

Aralkylamine N-acetyltransferase

ASMT

Acetylserotonin O-methyltransferase

ATP

Adenosine Triphosphate

mtDNA

Mitochondrial DNA

MT1 (MTNR1A)

Melatonin Receptor 1 A

MT2 (MTNR1B)

Melatonin Receptor 1B

Nrf2

Nuclear Factor Erythroid 2-related Factor 2

HO-1

Heme Oxygenase-1

PI3K

Phosphoinositide 3-Kinase

Akt

Protein Kinase B

AMPK

AMP-activated Protein Kinase

SIRT1

Sirtuin 1

SIRT3

Sirtuin 3

PTEN

Phosphatase and Tensin Homolog

FOXO1

Forkhead Box O1

FOXO3a

Forkhead Box O3a

BCL-2

B-cell Lymphoma 2

Bax

BCL-2-associated X Protein

mTOR

Mammalian Target of Rapamycin

JNK

c-Jun N-terminal Kinase

BECN1

Beclin 1

LC3

Microtubule-associated Protein 1 Light Chain 3

PINK1

PTEN-induced Kinase 1

HPO axis

Hypothalamic-Pituitary-Ovarian Axis

NLRP3

NLR Family Pyrin Domain Containing 3

NF-κB

Nuclear Factor Kappa-B

TLR4

Toll-like Receptor 4

ERK

Extracellular Signal-regulated Kinase

TNF-α

Tumor Necrosis Factor-α

IL-1β

Interleukin-1β

IL-6

Interleukin-6

IL-18

Interleukin-18

COX-2

Cyclooxygenase-2

iNOS

Inducible Nitric Oxide Synthase

CRP

C-reactive Protein

AMH

Anti-Müllerian Hormone

GDF9

Growth Differentiation Factor 9

IVF

In Vitro Fertilization

ART

Assisted Reproductive Technology

DOR

Diminished Ovarian Reserve

OC

Ovarian Cancer

mtDNA

Mitochondrial DNA

ATP

Adenosine Triphosphate

MAPK

Mitogen-Activated Protein Kinase

KEAP1

Kelch-like ECH-Associated Protein 1

SOD

Superoxide Dismutase

CAT

Catalase

GPX

Glutathione Peroxidase

GSH

Glutathione

MDA

Malondialdehyde

TAC

Total Antioxidant Capacity

Parkin

Parkin (E3 ubiquitin ligase)

YTHDF2

YTH N⁶-Methyladenosine RNA Binding Protein 2

p53

Tumor Protein p53

TAC

Total antioxidant capacity

FSHR

Follicle-Stimulating Hormone Receptor

Authors’ contributions

Xuanrui Zhao drafted the initial manuscript, conducted literature search and analysis, and created the figures. Yan Zhang participated in the figure creation and manuscript editing. Kaixin Ding contributed to figure preparation. Ziying Qiu was involved in the literature search. Yinan Wang and Xiaowei Yu reviewed the manuscript and provided guidance. All authors read and approved the final manuscript.

Funding

The study was supported-by grants from the Natural-Science Foundation of Jilin JLSRCZX2025-011.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Consent for publication

All authors have approved this submission and publication.

Competing interests

The authors declare no competing interests.