Introduction
Melatonin (MT) is more than a sleep hormone. It plays a multifaceted role in reproductive biology, influencing oocyte quality, embryo development, and endometrial receptivity. With infertility affecting millions worldwide, researchers have explored MT supplementation as a potential adjunct to assisted reproductive technology (ART) protocols. This article synthesizes current evidence from randomized trials and observational studies to assess whether melatonin improves ART outcomes and whether its use is safe for patients undergoing IVF or related techniques.
What Is Melatonin and Why Might It Help with ART?
Melatonin acts as an antioxidant, anti-inflammatory agent, and regulator of circadian rhythms. In the context of ART, MT may help protect oocytes and embryos from oxidative stress, improve mitochondrial function, and modulate hormonal signaling critical for folliculogenesis and endometrial preparation. These biological properties underpin the rationale for MT supplementation in people undergoing IVF or other ART procedures.
Methods: How the Review Was Conducted
The systematic review gathered randomized controlled trials and high-quality observational studies that examined MT supplementation in ART settings. Primary outcomes included clinical pregnancy rate, live birth rate, and ongoing pregnancy. Secondary outcomes encompassed fertilization rate, mature (MII) oocyte yield, embryo quality, implantation rate, miscarriage, and safety signals such as adverse events. Data were pooled using meta-analytic techniques when studies were sufficiently homogeneous, and subgroup analyses explored factors like MT dose, route of administration, timing, and patient age.
Key Findings: What the Evidence Suggests
Across eligible studies, melatonin showed a trend toward improved clinical pregnancy rates and embryo quality in some ART cohorts, particularly when used as an adjunct to ovarian stimulation or during embryo culture. The magnitude of benefit varied between trials, and the overall quality of evidence ranged from moderate to low due to limitations such as small sample sizes, heterogeneity in MT dosing, and risk of bias in several studies. Importantly, several trials did not demonstrate a clear effect on live birth rates, underscoring the need for larger, well-designed trials to confirm clinically meaningful benefits.
Embryo Quality and Oocyte Protection
Several studies reported higher quality embryos and improved oocyte maturation with MT supplementation. The proposed mechanisms include reduced oxidative damage, improved mitochondrial integrity, and more stable meiotic spindle function. While encouraging, these surrogate endpoints must be interpreted cautiously, as they do not always translate into higher live birth rates.
Pregnancy Outcomes and Safety
Some trials observed higher clinical pregnancy rates, but findings on ongoing pregnancy and live birth were inconsistent. Safety data were generally reassuring, with no consistent signal of increased adverse events, though reporting varied and long-term outcomes remain underexplored. For patients, the risk–benefit balance should be discussed with clinicians, considering individual fertility goals and potential interactions with ovarian stimulation protocols.
Subgroup Insights: Who Might Benefit Most?
Preliminary evidence hints that younger patients or those with poorer baseline oocyte quality might experience greater gains from MT supplementation. Dose-response patterns were not uniform, suggesting that optimal dosing and timing require refinement in future trials. Route of administration (oral vs. adjunctive use during culture) also appeared to influence outcomes in some datasets.
Clinical Implications and Practical Guidance
For clinicians, MT supplementation could be considered as a personalized adjunct to ART in select patients, with careful monitoring and clear expectations about potential benefits. Given heterogeneity in study designs, a cautious approach—using modest doses and short pre-treatment windows—may be reasonable until more definitive evidence emerges. Patients should discuss MT use with their fertility team, including potential interactions with medications used in ovarian stimulation and luteal phase support.
Limitations and Future Directions
Limitations across the literature include small sample sizes, inconsistent MT formulations, and varied endpoints. Future high-quality randomized trials should standardize dosing, timing, and outcome measures, and explore long-term safety in offspring. Meta-analyses that stratify by age, infertility etiology, and MT exposure duration will help clarify which patient groups are most likely to benefit.
Conclusion
Melatonin shows promise as a supportive adjunct to ART, with potential improvements in embryo quality and clinical pregnancy in some studies. However, current evidence does not consistently demonstrate a clear impact on live birth rates, and more robust research is needed. Clinicians should individualize recommendations, balancing potential advantages against uncertainties while keeping patients well informed.
