Melatonin's Role in Reproductive Health and Fertility
Executive Summary
Melatonin (N-acetyl-5-methoxytryptamine), a neurohormone primarily known for regulating circadian rhythms, demonstrates profound and multifaceted effects on male and female reproductive health. Emerging evidence from preclinical and clinical studies positions it as a promising adjunctive therapy for infertility and various reproductive disorders. Its therapeutic potential stems from a combination of potent antioxidant, anti-inflammatory, anti-apoptotic, and hormonal-modulating properties.
Key evidence indicates that melatonin supplementation in assisted reproductive technology (ART) settings significantly improves outcomes. A meta-analysis of randomized controlled trials (RCTs) found that melatonin increases clinical pregnancy rates by 43% (Odds Ratio = 1.43) and enhances the retrieval of mature oocytes. This is attributed to its ability to protect gametes from oxidative stress, a critical factor in fertility. In women, melatonin concentrates in follicular fluid at levels exceeding those in plasma, where it shields developing oocytes from damage, supports granulosa cells, and promotes progesterone synthesis. In men, it has been shown to improve sperm motility, DNA integrity, and cryopreservation success.
Despite these promising findings, several knowledge gaps persist. The hormone's effect on testosterone synthesis is complex and context-dependent, with studies showing both stimulatory and inhibitory effects. Furthermore, while clinical pregnancy rates are improved, most studies lack the statistical power to demonstrate a significant increase in live birth rates—the ultimate clinical endpoint. Optimal dosing protocols remain undefined, with clinical use ranging from 2 to 10 mg/day. This briefing synthesizes the current understanding of melatonin's mechanisms, clinical applications, and existing controversies in reproductive medicine.
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1. Foundational Principles of Melatonin Action
1.1 Biosynthesis and Regulation
Melatonin is synthesized from tryptophan, with its production primarily occurring in the pineal gland. This process is under the strict control of the suprachiasmatic nucleus (SCN), the body's master circadian clock. Light exposure suppresses melatonin synthesis, while darkness stimulates its release, creating a distinct nocturnal surge in circulating levels. Beyond the pineal gland, melatonin is also produced locally in peripheral tissues, including the reproductive organs (ovaries and testes), where it exerts autocrine and paracrine effects.
1.2 Receptor-Mediated Effects
Melatonin primarily acts through two high-affinity G protein-coupled receptors, MT1 (MTNR1A) and MT2 (MTNR1B). These receptors are widely expressed throughout the reproductive system, including:
• Hypothalamus and pituitary gland
• Ovarian granulosa cells
• Testicular Leydig and Sertoli cells
• Spermatozoa
• Uterine endometrium and myometrium
Activation of these receptors, which couple to Gαi/o and Gαq proteins, leads to decreased intracellular cAMP levels and modulation of calcium signaling, influencing cellular processes from hormone secretion to cell survival.
2. Core Molecular Mechanisms of Action
Melatonin's beneficial effects on reproductive health are driven by four principal molecular mechanisms.
2.1 Potent Antioxidant Properties
Melatonin is a highly effective antioxidant that operates through two distinct pathways:
• Direct Scavenging: Its amphiphilic nature allows it to cross all biological barriers, including the blood-testis barrier, to directly neutralize a wide range of reactive oxygen species (ROS) such as hydroxyl radicals (•OH) and hydrogen peroxide (H₂O₂). Notably, its metabolites also possess antioxidant activity, creating a cascading effect.
• Indirect Effects (Nrf2 Pathway): Melatonin activates the Keap1-Nrf2-ARE signaling pathway, a master regulator of cellular antioxidant defenses. This leads to the increased expression and activity of critical antioxidant enzymes, including superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT).
2.2 Mitochondrial Protection
Melatonin preferentially accumulates in mitochondria, the primary source and target of cellular ROS. It protects these organelles by:
• Stabilizing mitochondrial membrane potential (ΔΨm).
• Preventing electron leakage from the electron transport chain.
• Enhancing ATP synthesis efficiency.
• Preventing the opening of the mitochondrial permeability transition pore (mPTP), a key step in apoptosis.
• Regulating mitophagy to clear damaged mitochondria. Recent evidence shows that reproductive cells, such as porcine oocytes, can synthesize their own melatonin, suggesting a localized protective mechanism.
2.3 Anti-Apoptotic Mechanisms
Melatonin robustly protects reproductive cells from programmed cell death (apoptosis) by:
• Upregulating anti-apoptotic proteins like Bcl-2.
• Downregulating pro-apoptotic proteins such as Bax and caspases-3 and -9.
• Preventing cytochrome c release from mitochondria.
• Inhibiting the NLRP3 inflammasome. This is critical for preventing follicular atresia (death of ovarian follicles) and protecting sperm from damage.
2.4 Anti-Inflammatory Effects
Melatonin mitigates inflammation by inhibiting the NF-κB signaling pathway, which in turn reduces the production of pro-inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6), COX-2 expression, and prostaglandin synthesis. These properties are particularly relevant for inflammatory reproductive disorders like endometriosis and PCOS.
3. Impact on Male Reproductive Function
3.1 Regulation of Testosterone Synthesis
Melatonin's influence on testosterone production is complex, varying by species, dose, and physiological context. It modulates key steroidogenic enzymes such as StAR, P450scc, and 3β-HSD.
• Protective Role: In scenarios of oxidative stress or obesity, melatonin tends to upregulate StAR and increase testosterone production.
• Receptor-Mediated Role: A study using mouse Leydig cells showed that depleting the MT1 receptor led to a greater than 60% decrease in testosterone levels, highlighting the importance of receptor signaling.
• Anti-Aromatase Activity: Melatonin inhibits aromatase (CYP19A1), the enzyme that converts testosterone to estrogen, which may favor higher testosterone levels.
3.2 Sperm Quality and Function
Melatonin has demonstrated significant benefits for multiple sperm parameters.
3.3 Caveats and Considerations
Despite positive findings, caution is warranted. One 6-month crossover study administering 3 mg/day of melatonin to healthy men found that 2 of 8 participants experienced a significant, reversible decrease in sperm concentration and motility, which coincided with altered testosterone-to-estradiol ratios.
4. Impact on Female Reproductive Function
4.1 Follicular Fluid and Oocyte Development
Melatonin plays a critical protective role within the ovarian follicle. Concentrations of melatonin in human preovulatory follicular fluid are substantially higher than in blood plasma and increase with follicular size. This localized melatonin:
• Protects Oocytes: Scavenges ROS generated during ovulation, shielding the oocyte from oxidative damage.
• Supports Granulosa Cells: Prevents apoptosis in granulosa cells, which are essential for follicle development and hormone production.
• Promotes Progesterone Synthesis: Supports the luteinization of granulosa cells and progesterone production by the corpus luteum.
4.2 Clinical Evidence in IVF Outcomes
Multiple clinical studies support the use of melatonin supplementation to improve outcomes in women undergoing IVF.
A 2024 study on women of advanced maternal age found that melatonin improved outcomes by modulating novel cell death pathways (cuproptosis and ferroptosis) and reprogramming energy metabolism in cumulus and granulosa cells.
5. Therapeutic Applications in Specific Disorders
5.1 Polycystic Ovary Syndrome (PCOS)
Women with PCOS often have reduced follicular fluid melatonin levels. Supplementation has shown multiple benefits:
• Metabolic: Reduced BMI and enhanced insulin sensitivity.
• Hormonal: Decreased total testosterone levels and hirsutism.
• Antioxidant: Reduced markers of oxidative stress (MDA) and inflammation (hs-CRP).
• Mechanistic: Improves ovarian mitochondrial function by regulating the circadian gene CLOCK.
5.2 Endometriosis
Melatonin's anti-inflammatory and antioxidant properties are promising for endometriosis. In animal models, 10 mg/kg of melatonin significantly decreased endometrial explant volume and reduced COX-2-positive inflammatory cells from 91% to 18%. A 2024 study identified a novel mechanism whereby melatonin inhibits endometriosis growth by binding to and inhibiting EGFR phosphorylation.
5.3 Premature Ovarian Insufficiency (POI)
Melatonin shows potential to preserve ovarian function in POI by:
• Promoting protective autophagy in granulosa cells via FOXO3A activation.
• Inhibiting the pro-apoptotic PI3K/AKT/mTOR pathway.
• Enhancing estrogen secretion and expression of estrogen receptor 1 (ESR1).
6. Clinical Guidance and Safety Profile
6.1 Dosing Protocols from Clinical Evidence
6.2 Safety and Considerations
Melatonin is generally safe, with mild side effects such as vivid dreams, daytime fatigue, and nausea. Key considerations include:
• Timing: Must be taken 1-2 hours before bedtime to align with natural circadian rhythms.
• Natural Conception: High doses during the follicular phase may potentially interfere with ovulation.
• Pregnancy/Lactation: Not recommended due to limited safety data.
• Drug Interactions: May interact with anticoagulants, immunosuppressants, and diabetes medications.
7. Key Controversies and Knowledge Gaps
• Contradictory Effects on Testosterone: Melatonin's impact on steroidogenesis is bidirectional, acting as an inhibitor in some contexts (e.g., seasonal breeders) and a stimulator in others (e.g., states of oxidative stress). The factors determining this response are not fully understood.
• Lack of Live Birth Rate Data: While clinical pregnancy rates are consistently improved, most studies are not large enough to demonstrate a statistically significant effect on live birth rates, the most important clinical outcome.
• Optimal Dosing: Clinical trials have used a wide range of doses (2-10 mg/day) without establishing a clear dose-response relationship, making standardization difficult.
• Receptor-Mediated vs. Independent Effects: The relative contributions of direct antioxidant activity versus MT1/MT2 receptor signaling to melatonin's protective effects remain to be fully elucidated.
8. Future Research Directions
Future research should prioritize:
• Large-Scale RCTs: Adequately powered trials with live birth rates as the primary endpoint.
• Personalized Medicine: Developing biomarkers to identify patients most likely to benefit.
• Combination Therapies: Investigating synergistic effects with compounds like myo-inositol and CoQ10.
• Male Fertility Trials: Conducting large-scale clinical trials for male factor infertility.
• Epigenetic Mechanisms: Exploring melatonin's influence on DNA methylation in gametes and embryos.
Executive Summary
Melatonin (N-acetyl-5-methoxytryptamine), a neurohormone primarily known for regulating circadian rhythms, demonstrates profound and multifaceted effects on male and female reproductive health. Emerging evidence from preclinical and clinical studies positions it as a promising adjunctive therapy for infertility and various reproductive disorders. Its therapeutic potential stems from a combination of potent antioxidant, anti-inflammatory, anti-apoptotic, and hormonal-modulating properties.
Key evidence indicates that melatonin supplementation in assisted reproductive technology (ART) settings significantly improves outcomes. A meta-analysis of randomized controlled trials (RCTs) found that melatonin increases clinical pregnancy rates by 43% (Odds Ratio = 1.43) and enhances the retrieval of mature oocytes. This is attributed to its ability to protect gametes from oxidative stress, a critical factor in fertility. In women, melatonin concentrates in follicular fluid at levels exceeding those in plasma, where it shields developing oocytes from damage, supports granulosa cells, and promotes progesterone synthesis. In men, it has been shown to improve sperm motility, DNA integrity, and cryopreservation success.
Despite these promising findings, several knowledge gaps persist. The hormone's effect on testosterone synthesis is complex and context-dependent, with studies showing both stimulatory and inhibitory effects. Furthermore, while clinical pregnancy rates are improved, most studies lack the statistical power to demonstrate a significant increase in live birth rates—the ultimate clinical endpoint. Optimal dosing protocols remain undefined, with clinical use ranging from 2 to 10 mg/day. This briefing synthesizes the current understanding of melatonin's mechanisms, clinical applications, and existing controversies in reproductive medicine.
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1. Foundational Principles of Melatonin Action
1.1 Biosynthesis and Regulation
Melatonin is synthesized from tryptophan, with its production primarily occurring in the pineal gland. This process is under the strict control of the suprachiasmatic nucleus (SCN), the body's master circadian clock. Light exposure suppresses melatonin synthesis, while darkness stimulates its release, creating a distinct nocturnal surge in circulating levels. Beyond the pineal gland, melatonin is also produced locally in peripheral tissues, including the reproductive organs (ovaries and testes), where it exerts autocrine and paracrine effects.
1.2 Receptor-Mediated Effects
Melatonin primarily acts through two high-affinity G protein-coupled receptors, MT1 (MTNR1A) and MT2 (MTNR1B). These receptors are widely expressed throughout the reproductive system, including:
• Hypothalamus and pituitary gland
• Ovarian granulosa cells
• Testicular Leydig and Sertoli cells
• Spermatozoa
• Uterine endometrium and myometrium
Activation of these receptors, which couple to Gαi/o and Gαq proteins, leads to decreased intracellular cAMP levels and modulation of calcium signaling, influencing cellular processes from hormone secretion to cell survival.
2. Core Molecular Mechanisms of Action
Melatonin's beneficial effects on reproductive health are driven by four principal molecular mechanisms.
2.1 Potent Antioxidant Properties
Melatonin is a highly effective antioxidant that operates through two distinct pathways:
• Direct Scavenging: Its amphiphilic nature allows it to cross all biological barriers, including the blood-testis barrier, to directly neutralize a wide range of reactive oxygen species (ROS) such as hydroxyl radicals (•OH) and hydrogen peroxide (H₂O₂). Notably, its metabolites also possess antioxidant activity, creating a cascading effect.
• Indirect Effects (Nrf2 Pathway): Melatonin activates the Keap1-Nrf2-ARE signaling pathway, a master regulator of cellular antioxidant defenses. This leads to the increased expression and activity of critical antioxidant enzymes, including superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT).
2.2 Mitochondrial Protection
Melatonin preferentially accumulates in mitochondria, the primary source and target of cellular ROS. It protects these organelles by:
• Stabilizing mitochondrial membrane potential (ΔΨm).
• Preventing electron leakage from the electron transport chain.
• Enhancing ATP synthesis efficiency.
• Preventing the opening of the mitochondrial permeability transition pore (mPTP), a key step in apoptosis.
• Regulating mitophagy to clear damaged mitochondria. Recent evidence shows that reproductive cells, such as porcine oocytes, can synthesize their own melatonin, suggesting a localized protective mechanism.
2.3 Anti-Apoptotic Mechanisms
Melatonin robustly protects reproductive cells from programmed cell death (apoptosis) by:
• Upregulating anti-apoptotic proteins like Bcl-2.
• Downregulating pro-apoptotic proteins such as Bax and caspases-3 and -9.
• Preventing cytochrome c release from mitochondria.
• Inhibiting the NLRP3 inflammasome. This is critical for preventing follicular atresia (death of ovarian follicles) and protecting sperm from damage.
2.4 Anti-Inflammatory Effects
Melatonin mitigates inflammation by inhibiting the NF-κB signaling pathway, which in turn reduces the production of pro-inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6), COX-2 expression, and prostaglandin synthesis. These properties are particularly relevant for inflammatory reproductive disorders like endometriosis and PCOS.
3. Impact on Male Reproductive Function
3.1 Regulation of Testosterone Synthesis
Melatonin's influence on testosterone production is complex, varying by species, dose, and physiological context. It modulates key steroidogenic enzymes such as StAR, P450scc, and 3β-HSD.
• Protective Role: In scenarios of oxidative stress or obesity, melatonin tends to upregulate StAR and increase testosterone production.
• Receptor-Mediated Role: A study using mouse Leydig cells showed that depleting the MT1 receptor led to a greater than 60% decrease in testosterone levels, highlighting the importance of receptor signaling.
• Anti-Aromatase Activity: Melatonin inhibits aromatase (CYP19A1), the enzyme that converts testosterone to estrogen, which may favor higher testosterone levels.
3.2 Sperm Quality and Function
Melatonin has demonstrated significant benefits for multiple sperm parameters.
| Parameter | Effect of Melatonin |
| Sperm Motility | Improves progressive motility and enhances velocity parameters. |
| DNA Integrity | Reduces DNA fragmentation and protects against oxidative DNA damage. |
| Membrane Integrity | Reduces lipid peroxidation, preserving membrane function for fertilization. |
| Capacitation | Prevents premature capacitation and acrosome reaction. |
| Cryopreservation | Enhances post-thaw viability and motility by protecting against freeze-thaw damage. |
Despite positive findings, caution is warranted. One 6-month crossover study administering 3 mg/day of melatonin to healthy men found that 2 of 8 participants experienced a significant, reversible decrease in sperm concentration and motility, which coincided with altered testosterone-to-estradiol ratios.
4. Impact on Female Reproductive Function
4.1 Follicular Fluid and Oocyte Development
Melatonin plays a critical protective role within the ovarian follicle. Concentrations of melatonin in human preovulatory follicular fluid are substantially higher than in blood plasma and increase with follicular size. This localized melatonin:
• Protects Oocytes: Scavenges ROS generated during ovulation, shielding the oocyte from oxidative damage.
• Supports Granulosa Cells: Prevents apoptosis in granulosa cells, which are essential for follicle development and hormone production.
• Promotes Progesterone Synthesis: Supports the luteinization of granulosa cells and progesterone production by the corpus luteum.
4.2 Clinical Evidence in IVF Outcomes
Multiple clinical studies support the use of melatonin supplementation to improve outcomes in women undergoing IVF.
| Study Type / Patient Group | Common Dose | Key Findings |
| Meta-analysis (10 RCTs) | 3 mg/day | Increased clinical pregnancy rate (OR=1.43, p<0.01); increased number of mature oocytes. |
| Unexplained Infertility | 3-6 mg/day | Increased number and percentage of mature oocytes retrieved; decreased oxidative stress markers. |
| Previous IVF Failure | 3 mg/day | Significantly increased fertilization rate (50% vs. 23%); reduced number of degenerate oocytes. |
| Advanced Maternal Age (≥38) | 2 mg/day (≥8 weeks) | Increased clinical pregnancy rate (46% vs. 20%) and live birth rate (33% vs. 15%). |
| PCOS (+ Myo-inositol) | 3 mg/day | Increased percentage of high-quality (Grade I) embryos (46% vs. 26%). |
5. Therapeutic Applications in Specific Disorders
5.1 Polycystic Ovary Syndrome (PCOS)
Women with PCOS often have reduced follicular fluid melatonin levels. Supplementation has shown multiple benefits:
• Metabolic: Reduced BMI and enhanced insulin sensitivity.
• Hormonal: Decreased total testosterone levels and hirsutism.
• Antioxidant: Reduced markers of oxidative stress (MDA) and inflammation (hs-CRP).
• Mechanistic: Improves ovarian mitochondrial function by regulating the circadian gene CLOCK.
5.2 Endometriosis
Melatonin's anti-inflammatory and antioxidant properties are promising for endometriosis. In animal models, 10 mg/kg of melatonin significantly decreased endometrial explant volume and reduced COX-2-positive inflammatory cells from 91% to 18%. A 2024 study identified a novel mechanism whereby melatonin inhibits endometriosis growth by binding to and inhibiting EGFR phosphorylation.
5.3 Premature Ovarian Insufficiency (POI)
Melatonin shows potential to preserve ovarian function in POI by:
• Promoting protective autophagy in granulosa cells via FOXO3A activation.
• Inhibiting the pro-apoptotic PI3K/AKT/mTOR pathway.
• Enhancing estrogen secretion and expression of estrogen receptor 1 (ESR1).
6. Clinical Guidance and Safety Profile
6.1 Dosing Protocols from Clinical Evidence
| Application | Recommended Dose | Timing / Duration |
| Standard IVF Cycles | 3 mg/day | From day 5 of the cycle until oocyte retrieval, taken at 22:00. |
| Poor Oocyte Quality | 3-6 mg/day | From initial consultation through ovarian stimulation. |
| Advanced Maternal Age | 2 mg/day | For at least 8 weeks prior to an IVF cycle. |
| PCOS | 5-10 mg/day | For 12 weeks, often combined with myo-inositol. |
| Luteal Phase Support | 3 mg/day | Throughout the luteal phase. |
6.2 Safety and Considerations
Melatonin is generally safe, with mild side effects such as vivid dreams, daytime fatigue, and nausea. Key considerations include:
• Timing: Must be taken 1-2 hours before bedtime to align with natural circadian rhythms.
• Natural Conception: High doses during the follicular phase may potentially interfere with ovulation.
• Pregnancy/Lactation: Not recommended due to limited safety data.
• Drug Interactions: May interact with anticoagulants, immunosuppressants, and diabetes medications.
7. Key Controversies and Knowledge Gaps
• Contradictory Effects on Testosterone: Melatonin's impact on steroidogenesis is bidirectional, acting as an inhibitor in some contexts (e.g., seasonal breeders) and a stimulator in others (e.g., states of oxidative stress). The factors determining this response are not fully understood.
• Lack of Live Birth Rate Data: While clinical pregnancy rates are consistently improved, most studies are not large enough to demonstrate a statistically significant effect on live birth rates, the most important clinical outcome.
• Optimal Dosing: Clinical trials have used a wide range of doses (2-10 mg/day) without establishing a clear dose-response relationship, making standardization difficult.
• Receptor-Mediated vs. Independent Effects: The relative contributions of direct antioxidant activity versus MT1/MT2 receptor signaling to melatonin's protective effects remain to be fully elucidated.
8. Future Research Directions
Future research should prioritize:
• Large-Scale RCTs: Adequately powered trials with live birth rates as the primary endpoint.
• Personalized Medicine: Developing biomarkers to identify patients most likely to benefit.
• Combination Therapies: Investigating synergistic effects with compounds like myo-inositol and CoQ10.
• Male Fertility Trials: Conducting large-scale clinical trials for male factor infertility.
• Epigenetic Mechanisms: Exploring melatonin's influence on DNA methylation in gametes and embryos.
