Overview: Melatonin in Reproductive Medicine
Melatonin (MT) is best known for its role in regulating circadian rhythms, but it also plays a part in reproductive biology. Growing interest in MT supplementation stems from its antioxidant, anti-inflammatory, and mitochondrial-supporting properties, which may influence oocyte quality, embryo development, and implantation processes. As assisted reproductive technology (ART) expands to help more people realize parenthood, researchers have begun to systematically evaluate whether MT can improve ART outcomes.
What the Systematic Review and Meta-Analysis Examined
This review pools data from randomized controlled trials and observational studies to evaluate whether adding melatonin to standard ART protocols affects key outcomes. Primary endpoints typically include clinical pregnancy rate, live birth rate, fertilization rate, embryo quality, and miscarriage rate. Secondary outcomes may cover oocyte quality measures, hormonal profiles, and adverse events. The goal is to determine whether MT supplementation offers clinically meaningful benefits without introducing safety concerns.
Key Findings and Implications
Across multiple studies, MT supplementation often shows a trend toward improved oocyte quality and higher clinical pregnancy rates. Some trials report enhanced embryo quality and increased fertilization success, which can contribute to better overall ART performance. Importantly, the meta-analysis considers heterogeneity among studies—differences in MT dose, timing of administration, duration of use, patient populations (e.g., age, underlying infertility causes), and ART protocols (fresh vs. frozen cycles).
Overall, the evidence suggests a potential positive effect of MT on ART outcomes, particularly in specific subgroups or under particular regimens. However, results are not uniformly consistent across all trials, and some studies fail to demonstrate a significant improvement. This variability underscores the need for standardized dosing strategies and well-designed trials with adequate power to detect meaningful differences.
Biological Rationale for Melatonin in ART
Several mechanisms may explain potential benefits: MT’s antioxidant action can mitigate oxidative stress in follicular fluid and the developing embryo, potentially preserving mitochondrial function and cellular integrity. Its anti-apoptotic properties may reduce granulosa cell death, supporting follicular development. Additionally, MT could influence luteal function and endometrial receptivity, both critical for implantation and sustained pregnancy.
Safety Considerations and Practical Tips
Most trials report MT as well-tolerated, with few adverse events attributed to supplementation. Nevertheless, safety in pregnancy and long-term offspring outcomes remains a priority, and clinicians often weigh potential benefits against unknown long-term risks. If MT is considered, clinicians typically discuss dosing ranges that have appeared in studies, timing relative to ovarian stimulation, and whether MT should be used in conjunction with heparin, GnRH analogs, or other ART components.
Practical considerations for patients include discussing MT use with a fertility specialist, ensuring quality-controlled supplements, and clarifying expectations about success rates. It is important to recognize that MT is not a guaranteed solution and should be viewed as a potential adjunct to evidence-based ART protocols.
Gaps in Knowledge and Future Research Directions
Despite encouraging signals, heterogeneous study designs and small sample sizes limit definitive conclusions. Future research should aim for large-scale, multicenter randomized trials with standardized MT dosing, clear timing relative to stimulation and embryo transfer, and uniform outcome reporting. Subgroup analyses by age, ovarian reserve, and specific infertility etiologies may reveal which patients benefit most. Longitudinal monitoring of offspring health could address lingering safety questions.
Bottom Line for Clinicians and Patients
Melatonin supplementation in the context of ART shows promise for enhancing certain reproductive outcomes, but results are not yet conclusive. Clinicians should remain cautious, personalize treatment plans, and stay informed about emerging evidence. Patients considering MT should consult their fertility team to weigh potential benefits against uncertainties and to ensure that any supplementation aligns with their overall ART strategy.
