Pharmacological vs non-pharmacological treatment in the management of Relative Energy Deficiency in Sport (RED-S): A systematic review and meta-analysis

Objective

To conduct a systematic review assessing the impact of pharmacological and non-pharmacological interventions on Relative Energy Deficiency in Sport (RED-S).

Design

Systematic review and meta-analysis

Data source CINHAL, MEDLINE, SportDiscus, ERIC, Embase from inception until July 2025.

Eligibility criteria for selecting studies Experimental, quasi and pre-experimental literature that investigated interventions designed to support the symptoms of RED-S.

Results

A total of 19 studies (15 non-pharmacological interventions, 4 pharmacological interventions) were included in the review. Non-pharmacological interventions demonstrated positive benefits on menstrual function recovery, energy availability, fat mass and body fat percentage. Pharmacological interventions demonstrated positive results for biomarkers. Non-pharmacological Interventions were limited by quality.

Conclusion

Current evidence base favours non-pharmacological management as an initial response for managing RED-S. Initial pharmacological management appears appropriate in specific situations. Further research is needed to help develop understanding.

What is already known on this topic

• Evidence is limited, with few high quality randomised controlled trials comparing treatment options.

• Management of RED-S prioritises non-pharmacological approaches, mainly nutritional rehabilitation, training load adjustments, and education to address LEA. With pharmacological treatments reserved for persistent or severe cases.

What this study adds

• Non-pharmacological interventions identified moderate to high effect size improvements on menstrual function recovery and energy availability. However, evidence was supported by low confidence from the GRADE assessment.

• Non-pharmacological interventions demonstrated moderate to very high effect size, supported by meta-analysis, for body composition measures such as fat mass and fat percentage. Evidence was supported with moderate confidence from the GRADE assessment.

• Both pharmacological and non-pharmacological studies targeted hormonal changes and biomarkers. Non-pharmacological studies identified low confidence in evidence, despite demonstrating moderate to high effect size with meta-analysis, showing further considerations are needed for hormonal changes and biomarkers. Pharmacological studies identified moderate confidence in evidence showing in moderate effect size evidence for BMD markers and hormonal profiling, but low confidence in clinically meaningful effects of changes in bone turnover markers.

How this study might affect research, practice or policy

• Findings from the current review apply to female groups of athletes primarily engaged in distance or endurance-based sports. Most studies were conducted in university settings, and the most common type of intervention involved dietary adaptations, delivered in 80% of interventions by a dietitian or expert in nutrition. These parameters should be considered within clinical recommendations given and taken into consideration for future research, practice and policy.

• The development and adoption of standardised definitions and core outcomes are urgently needed to ensure constancy and comparability across studies.

• Future trials should investigate the combined use of non-pharmacological and pharmacological strategies, aiming to clarify optimal treatment sequencing, potential synergistic effects, and personalised approaches to RED-S management.