Introduction
Melatonin (MT) is recognized for its role in regulating circadian rhythms and protecting cells from oxidative stress. Growing evidence suggests that MT may influence reproductive biology by improving oocyte quality, reducing oxidative damage, and potentially enhancing endometrial receptivity. This has spurred a wave of randomized and non-randomized studies examining MT as an adjunct to assisted reproductive technology (ART), including in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Here, we synthesize what is known from a systematic review and meta-analysis of available trials, focusing on clinically meaningful outcomes such as pregnancy rates, live birth, embryo quality, and safety.
What the evidence says about MT and ART outcomes
Across randomized controlled trials and observational studies, MT supplementation has been evaluated at various doses and timings, from pre-conception to early embryo development. The central premise is that MT’s antioxidant and anti-apoptotic properties may mitigate follicular and embryonic stress, thereby improving the ovarian response, oocyte competence, and endometrial environment. The systematic review collates data on key outcomes:
- Pregnancy rate per initiated cycle, clinical pregnancy rate, and live birth rate
- Oocyte retrieval metrics, fertilization rates, and embryo quality scores
- Miscarriage rates and safety signals, including any adverse events
Overall findings from the meta-analysis suggest a potential benefit of MT in certain settings, but the magnitude and consistency of effects vary. Several trials report higher clinical pregnancy rates and improved embryo quality with MT, particularly in patients with diminished ovarian reserve or poor oocyte quality. However, other studies show no significant differences compared with standard ART protocols. The discordance may reflect heterogeneity in study design, MT dosage, duration of supplementation, baseline MT levels, and the specific ART protocols used.
Biological plausibility and mechanisms
MT’s proposed actions in reproduction include scavenging reactive oxygen species, stabilizing mitochondrial function, and modulating signaling pathways involved in folliculogenesis and luteal support. By reducing oxidative stress in the follicular microenvironment and improving mitochondrial efficiency, MT could theoretically enhance oocyte maturation and fertilization potential. In the endometrium, MT may influence receptivity and local immune interactions, potentially impacting implantation success.
Quality of the evidence
As with many supplements studied in ART, the evidence base is mixed in quality. Some trials are small, single-center studies with risk of bias related to blinding and allocation concealment. Others are more robust, yet still limited by variable endpoints and differing MT formulations (e.g., dosage ranges from 3 mg to 10 mg daily, timing from preconception to during ovarian stimulation). Heterogeneity complicates direct pooling of results and may attenuate detectable benefits in meta-analytic estimates.
Clinical implications and practical considerations
For clinicians and patients considering MT in the ART pathway, several practical points emerge:
– MT may be worth considering in select populations, such as those with poor oocyte quality or elevated oxidative stress markers, after individualized risk-benefit discussion.
– Optimal dosing and treatment duration remain unclear. The lack of standardized protocols means that extrapolating a “one-size-fits-all” regimen is inappropriate.
– Safety profiles across trials are generally favorable, but long-term data on offspring outcomes are limited. Informed consent should cover the current uncertainty and potential unknown risks.
Limitations and areas for future research
Major gaps include the need for larger, well-powered randomized trials with consistent outcome definitions, standardized MT dosing regimens, and longer follow-up for live birth and neonatal outcomes. Future studies should also explore patient subgroups most likely to benefit, and consider MT’s interaction with other ART adjuncts and lifestyle factors.
Conclusion
Melatonin supplementation in the ART setting shows promise for improving certain reproductive endpoints, particularly embryo quality and clinical pregnancy rates in selected patients. However, evidence regarding live birth and overall efficacy remains inconclusive due to heterogeneity and limited trial quality. Clinicians should weigh potential benefits against uncertainties and tailor recommendations to individual patient contexts while awaiting more definitive data.
