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

Pharmacological vs non-pharmacological treatment in the management of Relative Energy Deficiency in Sport (RED-S): A systematic review and meta-analysis | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Pharmacological vs non-pharmacological treatment in the management of Relative Energy Deficiency in Sport (RED-S): A systematic review and meta-analysis A Wood , View ORCID Profile A Soundy doi: https://doi.org/10.1101/2025.07.18.25331767 A Wood 1 Aimee Wood, Department of Physiotherapy, School of Sport, Exercise and Rehabilitaion Sciences, University of Birmingham , B15 2TT Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: axw035{at}student.bham.ac.uk A Soundy 2 Andrew Soundy, Department of Physiotherapy, School of Sport, Exercise and Rehabilitaion Sciences, University of Birmingham , B15 2TT. Email: Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for A Soundy For correspondence: A.A.Soundy{at}bham.ac.uk Abstract Full Text Info/History Metrics Supplementary material Data/Code Preview PDF Abstract 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. Introduction Relative Energy Deficiency in Sport (RED-S) a relatively new and evolving clinical model that is defined as “ A syndrome of impaired physiological and/or psychological functioning experienced by female and male athletes that is caused by exposure to problematic (prolonged and/or severe) low energy availability (LEA). The detrimental outcomes include, but are not limited to, decreases in energy metabolism, reproductive function, musculoskeletal health, immunity, glycogen synthesis and cardiovascular and haematological health, which can all individually and synergistically lead to impaired well-being, increased injury risk and decreased sports performance ” 1 . LEA results when the energy intake of an athlete is insufficient to meet the demands of both exercise and normal physiological function 2 . The term RED-S stems from and the earlier term "Female Athlete Triad" (initially defined in 1993 3 as the interrelationship between disordered eating, amenorrhoea, and osteoporosis). RED-S recognizes a broader range of health and performance consequences in both female and male athletes. This syndrome is associated with a wide array of clinical outcomes, including menstrual dysfunction, impaired bone health, compromised immune function, gastrointestinal disturbances, fatigue, reduced cardiovascular and metabolic function, and poor mental health 4 , 5 . Contributing factors to RED-S are multifactorial and may include excessive training, inadequate nutrition, mental health challenges, disordered eating or eating disorders, poor sleep, illness, or undiagnosed medical conditions 2 . RED-S is highly prevalent in elite sport settings; for instance, studies report signs of LEA in both male volleyball players and professional female football players, with many athletes at risk of developing the full spectrum of RED-S 6 , 7 . Around 70% of elite athletes have a medium to high risk of RED-S 8 , but studies have also shown a higher prevalence of symptoms. For instance, an Australian study found that 80% of elite and pre-elite athletes exhibited at least one RED-S-related symptom, and 37% presented with two or more 9 . Prevalence is not only applicable in a sports setting, but also clinical as Functional Hypothalamic Amennorhea (FHA) accounts for 20-35% of secondary amenorrhea cases 10 . The widespread prevalence and serious health implications of RED-S underscore the importance of effective management strategies, both pharmacological and non-pharmacological, that have been identified in athletic populations 2 as such strategies help mitigate the impact of RED-S on athletes 1 . Currently, non-pharmacological treatment forms the cornerstone of RED-S management, with an emphasis on addressing the underlying issue of LEA. These strategies primarily involve educational initiatives aimed at increasing awareness and understanding of RED-S among athletes, coaches, and healthcare professionals (a primary intervention strategy 11 ). In addition, tertiary prevention strategies centred around individualized nutritional interventions are critical and show promising effect 11 , focusing on increasing overall energy intake to restore energy balance and support physiological recovery 12 . Modifications to training load, either by reducing volume or intensity, are also commonly implemented to decrease Energy Expenditure (EE) and allow for physiological restoration 13 . These non-pharmacological approaches are often effective in reversing early symptoms of RED-S and remain the first-line treatment, particularly in the absence of severe clinical manifestations. Where non-pharmacological modalities of treatment are ineffective (notably in particular groups like females with resistant amenorrhoea or with low bone mineral density (BMD)), not appropriate, or when physiological effects mean immediate intervention is required, pharmacological strategies can be considered 14 . Supportive treatments, such as calcium, vitamin D, and iron supplementation, are often implemented as part of a broader therapeutic strategy 11 , 15 . Although more specific strategies have been tested and utilised. For instance, transdermal 17β-oestradiol with cyclic progesterone has been shown to be more effective than combined oral contraceptives (COCs) in improving BMD in oligo-amenorrhoeic athletes 16 . Further to this, treatments like hormone replacement or bone-active agents may target complications such as low bone density when conservative measures fail 16 , 17 . Treatments such as these can be considered controversial due to long-term safety concerns 18 and further research is required to clarify their role in RED-S management. Recent reviews, including those by Tenforde et al. 19 and Melin et al. 16 , provide important insights into the pathophysiology and management of RED-S. However, they largely focus on descriptive frameworks rather than interventional comparisons, and there is a noticeable lack of high-quality comparative evidence on treatment efficacy. The International Olympic Committee’s (IOC) narrative review on primary, secondary, and tertiary prevention strategies underscores the importance of addressing LEA as the root cause, recommending tailored nutritional rehabilitation, training adjustments, and multidisciplinary care 11 . Past reviews consistently call for more evidence-based guidelines and emphasize that most pharmacological options address secondary outcomes (e.g., menstrual restoration or bone health) rather than the underlying LEA. To date, no systematic review or meta-analysis has directly compared the efficacy, risks, and outcomes of pharmacological versus non-pharmacological treatments for RED-S. This gap is critical given the rising prevalence of RED-S and the growing diversity of affected athletic populations. Thus, the present systematic review and meta-analysis aims to fill this gap by rigorously evaluating available interventions for RED-S. Methods A systematic review was undertaken and reported according to the PRISMA checklist 20 . A protocol was developed and published on the 17 June 2025 on PROSPERO (reference: CRD420251073240). Eligibility criteria Studies were included if they met the following conditions as set out by the acronym PICOS. Participants To be included studies need to include female athletes classified as elite, recreational, pre-elite, club, active or other level. All athletes had to have characteristics identified within the remit of REDs 1 . Studies were included if they identified participants with oligo-amenorrhea, LEA, FHA, and/or exercise-related menstrual dysfunction (ExMD). Studies were excluded if participants were male, had a clinical diagnosis of a psychological disorder or mental illness, were currently using hormonal contraceptives, or had Polycystic Ovary Syndrome (PCOS) or Endometriosis. Studies using the same group of participants without assessing different outcome measures were excluded. Intervention Interventions were grouped as pharmacological or non-pharmacological interventions. Pharmacological interventions were included if they utilised Oestrogen therapy, Hormone Replacement Therapy (HRT), or calcium supplementation. Non-pharmacological interventions were included if they were based around diet alteration or dietary supplements, exercise, education or consultation. Interventions were excluded if they did not directly target RED-S, if their outcome measures were not relevant to RED-S-related outcomes (see outcome eligibility criteria below), or if they focused exclusively on psychological measures (such as disordered eating, eating disorders, body image) without addressing the broader spectrum of RED-S symptoms. Outcomes Studies were included if they utilised outcomes that included measures related to menstrual resumption, energy or dietary improvement related outcome measures, physiological measures related to REDS for instance, weight, fat mass, body percentage weight, cortisol, identification of hormones, BMD. Alternative studies could be included inf they identified physical or functional measures change (e.g., strength improvements) or psychological measures (e.g., mood, body image scale). Study Design Studies were included if they reported on the experience of, or outcomes from an intervention-based study. Experimental, quasi experimental and pre-experimental designs were included. Conference proceedings, thesis and ongoing research were included to reduce the risk of publication bias. Studies were excluded if they did not report on the experience of, or outcomes from, an intervention-based study. Non-experimental designs such as case studies, observational studies, cross-sectional studies, and purely descriptive research were excluded. Reviews, editorials, opinion pieces, and commentaries were also excluded. Studies that were unpublished without accessible data, duplicate publications, and conference abstracts without full data were excluded unless further data were available. Other criteria Date restrictions were not applied to the search dates. No restriction on language was made. Search Strategy A blind search by two authors (AW,AS), supported by the management software Covidence© was undertaken from a total of five electronic databases. This included; CINHAL, MEDLINE, SportDiscus, ERIC, Embase from inception until July 2025. The following key words were utilised; Relative energy deficiency in sport, OR RED-S, OR female athlete triad OR low energy deficiency OR amenorrhea OR Oligomenorrhea OR menstrual disturbance AND Intervention OR treatment OR therapy AND female OR women. In addition to this, three electronic search engines including Google Scholar, ScienceDirect and Findit.Bham were searched for the first 30 pages using the terms ‘females and relative energy deficiency and sport’. Grey literature was searched using the Grey Matters search engine. Citation chasing was undertaken with all included articles and all identified previous reviews. Selection process Two blind authors (AW, AS) undertook the selection process using the Covidence© software. A separate academic with experience in systematic reviews was available to arbitrate discussions when a decision could not be made. Both authors entered decisions by title, then abstract then through reading full text independently. Data items A pre-determined extraction data tool devised in Microsoft Excel identified specific variables that included demographic variables (study title, journal, design, type of intervention, geographical location, population, age, sport, athlete level, participant identifying group, if a clinical diagnosis was obtained, and method of assessment). Intervention variables were identified according to Tidier guidelines 21 , tabulated and outcome measures (identification of all outcomes, and identification of primary and secondary outcome measures) were considered which were then grouped by domains. Study risk of bias assessment Study risk of bias assessment was undertaken using the ROB-2 tool 22 for randomised control trials, or the Robins-I Version 2 tool 23 for non-randomised control trials. For other types of design or instance case control or case series the JBI critical appraisal tools were utilised ( https://jbi.global/critical-appraisal-tools ). See supplementary file for the assessment. Effect measures Mean differences were considered where possible for all outcome measures. Synthesis A narrative synthesis documented results by outcome domain. The following outcome domain areas were identified: (a) Physiological (including, menses and menses restoration, weight, cortisol, identification of hormones, BMD). (b) Physical and functional (including measures of strengths or function) and (c) psychological outcomes (including mood, body image scale, or eating disorder questionnaire). Meta-analysis was possible and conducted for three outcome measures as part of the synthesis for non-pharmacological interventions. No other meta-analysis was possible due to the limited evidence currently available. Certainty assessment GRADE 24 as used to assess certainty of outcome measure results and supplement narrative synthesis and meta-analysis. Equity, diversity, and inclusion statement Authors used the narrative synthesis to identify common demographics and intervention characteristics. The group selected within the eligibility and represented across studies are reasonably homogenous due to the individuals representing studies mainly from the USA, from University based settings and representing female endurance and distance sports/athletes. Patient and public involvement No patient or public involvement in this review was undertaken. Results Search output A total of 3156 articles were examined by both reviewers. A total of 261 were input into Covidence database of which 162 were identified for screening and 19 studies met the inclusion criteria for this systematic review. This comprised of 15 25 – 39 (15/19, 79%) non-pharmacological interventions and 4 40 – 43 (4/19, 21%) pharmacological interventions. See Figure 1 for the PRISMA flow diagram. Download figure Open in new tab Figure 1 A PRISMA 2020 flow diagram produced by Covidence to identify the blind search process undertaken by two authors Download figure Open in new tab Figure 2 A meta-analysis showing the benefit of nutrition-based interventions on an individual’s fat mass. Download figure Open in new tab Figure 3 A forest plot showing the benefit of nutrition-based interventions on percentage body fat Demographics A total of 759 female participants were included (n= 759). This included individuals most often in the age bracket 18-35 years. Where possible (n=12 studies, n=473 participants) an aggregated mean age was calculated as 20.9 years. The most included group of females was female ‘athletes’ (n=12/19, 63%), followed by ‘exercising’ or ‘active’ females (n=5/19, 26%). Non-pharmacological trials included 9 (9/15, 60%) as athletes, 5 as ‘exercising’ or ‘active’ females (5/15, 33.33%) and 1 (1/15, 7%) identified without classification. Pharmacological trials included athletes (3/4, 75%) and one study included ballet dancers (1/4, 25%). The classification of included sports most often related to a multi-sport 7/19 (37%; 6/15, 40% for non-pharmacological and 1/4, 25% pharmacological) or multi-sport with the term endurance or distance 10/19 (53%; 8/15, 53% for non-pharmacological and 2/4, 50% for pharmacological). The most common specific sport mentioned was running, followed by cycling. Although exact numbers for these specific sports would be hard to determine due to the use and inclusion of multi-sports. The most common country location for studies was the USA (n=12/19, 60%) including 10/15 (67%) for non-pharmacological interventions and 2/4 (50%) for pharmacological, this was followed by Germany (n=3/19, 16%) all coming from non-pharmacological interventions. See Table 1 for a summary of non-pharmacological interventions and Table 2 for a summary of pharmacological interventions. View this table: View inline View popup Table 1 Summary characteristics of non-pharmacological interventions View this table: View inline View popup Download powerpoint Table 2 Summary characteristics of pharmacological interventions Intervention characteristics The most common characteristics across studies was as follows. The classification system used to identify athletes most often identified Amenorrhea (n=6/19) as a clinical inclusion criterion for participation. Common intervention components included (a) increasing energy intake/diet supplementation (n=10/19; 53%; 10/15, 67% for non-pharmacological interventions) and (b) dietary/nutritional counselling or advice (out of all studies, n=6/19, 32%) and 6/15 (40%) for non-pharmacological interventions was the most prevalent intervention component. The average duration of intervention for non-pharmacological interventions was 28.3 ± 15.8 weeks (n=12/15, 80%). The setting selected for the intervention was most often described as a ‘university’ setting (n=8/19, 42%), this included 8/15 (53%) for non-pharmacological studies. Staff involved in the interventions were most often identified as dietitians (n=12/19) 12/15 (80%) for non-pharmacological studies and 1/4 (25%) for pharmacological interventions, or as researchers (n=9/19, 47%), including 8/15 (53%) for non-pharmacological interventions and 1/4 (25%) of pharmacological evidence. View this table: View inline View popup Download powerpoint Table 3 A summary table for non-pharmacological studies (using Tidier sub-headings) View this table: View inline View popup Download powerpoint Table 4 Tider summary table for intervention studies Synthesis & Certainty Assessment Findings are provided below for non-pharmacological evidence and pharmacological evidence. A supplementary file is available that provides the assessment of critical appraisal (quality) and certainty assessment. Non-pharmacological Among the studies assessing non-pharmacological interventions, the most frequently reported outcomes were menstrual function recovery (n= 8/15, 53%), improvements in energy availability (EA) (n= 5/15, 33%), changes in body composition (n= 7/15, 47%), and alterations in relevant biomarkers (n= 9/15, 60%). These were reported below. Menstrual function recovery Menstrual function recovery was utilised as an outcome measure in eight (n= 8/15, 53%) of the included papers. Seven (n= 7/8, 88%) reported statistically significant improvements (p-values ranging from <0.01 to 0.05), with large, estimated effect sizes (0.8–1.2). One case report lacked statistical analysis but described clinically meaningful recovery in both participants. All nine studies were judged to show clinically meaningful outcomes, primarily associated with increased EA through nutritional (n= 5/8, 63%) or non-pharmacological interventions (n= 1/8, 13%) or both nutritional and non-pharmacological interventions (n= 2/8, 25%). Six (6/8, 75%) studies reported number of intervention participants that experienced improved or recovery of menses. Of the 142 intervention group participants, 47 (47/142, 33%) had partial or full recovery of menses. Confidence in evidence: Summary of evidence contributing to certainty rating: GRADE study ratings included 1 very low, 5 low, and 2 high. Overall confidence rating: Low, although findings can be taken with reasonable confidence due to consistency of evidence. Energy availability: Changes in EA were evaluated in five studies (n= 5/15, 33%). All five reported statistically significant improvements (p-values ranging from <0.01 to 0.05), with estimated effect sizes between 0.5 and 1.0. Each study demonstrated clinically meaningful improvements, achieved through increased caloric intake (n=5/15, 33%). Confidence in evidence: Summary of evidence contributing to certainty rating: GRADE study ratings included 5 low. Overall confidence rating: Low, although findings can be taken with reasonable confidence due to consistency of evidence. Body composition measures: Body Composition was measured in seven (n= 7/15, 47%) of the non-pharmacological papers. Six (n= 6/7, 86%) reported statistically significant improvements in at least one parameter—such as body weight, fat mass, or body fat percentage—with p-values ranging from <0.001 to 0.05 and effect sizes between 0.5 and 2.5. One study did not report statistical significance but showed large, estimated effects. All seven studies were considered clinically meaningful, with improvements primarily associated with increased energy intake. Meta-analysis was undertaken for the measures of changes in fat mass and percentage of body fat. Confidence in evidence: Summary of evidence contributing to certainty rating: GRADE study ratings included 5 low and 2 very high. Overall confidence rating: Moderate, although findings can be taken with reasonable confidence as evidence is supported by meta-analysis. Hormonal and blood biomarkers: Biomarkers related to RED-S were analysed in nine (n= 9/15, 60%) studies. Eight (n= 8/9, 89%) reported statistically significant improvements ( p < 0.05), with effect sizes ranging from 0.5 to 0.8. The most assessed markers included serum leptin, triiodothyronine (TT3), cortisol, oestradiol, and luteinizing hormone (LH) pulsatility. One study, while lacking statistical testing, demonstrated substantial changes in multiple biomarkers and was considered clinically meaningful. All nine studies reported clinically meaningful outcomes, supporting the utility of biomarker monitoring in evaluating recovery in RED-S and the effectiveness of dietary and non-pharmacological interventions. A meta-analysis (see Figure 4 ) was possible regarding the reporting of TT3 by three studies. Download figure Open in new tab Figure 4 A forest plot showing the T3 biomarker changes from non-pharmacological interventions Confidence in evidence: Summary of evidence contributing to certainty rating: GRADE study ratings included 6 low, 3 very high and 8 with moderate effect. Overall confidence rating: Low, evidence effected by quality downgrades and meta-analysis favouring control group. Further evidence is required. Pharmacological: Studies examining pharmacological treatments commonly assessed BMD (n= 4/4, 100%), hormonal profiles (e.g., oestrogen, L, follicle-stimulating hormone (FSH)) (n= 3/4, 75%), recovery of menstrual function (n= 3/4, 75%) and bone turnover markers (n= 1/4, 25%) as indicators of skeletal health and remodelling. Bone mineral density markers: BMD was assessed in four (n= 4/4, 100%) pharmacological studies, with two (n= 2/4, 50%) reporting statistically significant improvements ( p =0.021 and 0.05) and moderate effect sizes of approximately 0.8. Both significant studies demonstrated clinically meaningful increases in BMD, primarily following oestrogen replacement therapy. However, two studies did not find significant changes in BMD. Confidence in evidence: Summary of evidence contributing to certainty rating: GRADE study ratings included 1 very low, 1 low, 1 high, and 1 very high. Overall confidence rating: Moderate, findings can be taken with reasonable confidence due to consistency of evidence. Hormonal profiling: Hormonal profiles were evaluated in four (n= 4/4, 100%) studies, with two (n= 2/4, 50%) showing significant improvements ( p < 0.05) in key hormones such as oestradiol and progesterone, with effect sizes around 0.7–0.8. One study reported normalization of hormonal levels in treatment groups despite no baseline significance testing. Three (n= 3/4, 75%) studies assessing hormonal outcomes were considered clinically meaningful. Confidence in evidence: Summary of evidence contributing to certainty rating: GRADE study ratings included 1 very low, 1 low, and 1 very high, 1. Overall confidence rating: Moderate, findings can be taken with reasonable confidence due to consistency of evidence despite quality. Menstrual function recovery: Menstrual function recovery was reported in three (n= 3/4, 75%) studies, all demonstrating statistically significant improvements (p-values ranging from p <0.05 to 0.0001). These improvements were deemed clinically meaningful, indicating effective restoration of menstrual function with pharmacological treatment. Confidence in evidence: Summary of evidence contributing to certainty rating: GRADE study ratings included 1 very low, 1 low, 1 high, 1 with large effect and dose-response. Overall confidence rating: Moderate, findings can be taken with reasonable confidence due to consistency of evidence. Bone turnover markers: Bone turnover markers were evaluated in one (n= 1/4, 25%) study, which found significant changes in markers including P1NP and IGF-1 ( p = 0.016), with clinically meaningful effects observed. Confidence in evidence: Summary of evidence contributing to certainty rating: GRADE study ratings included 1 study rated as high certainty. Overall confidence rating: Low, further evidence is required to repeat results. Discussion This review provides initial insight and certainty of evidence considering the effectiveness of non-pharmacological interventions compared to pharmacological interventions. Non-pharmacological interventions demonstrated consistent improvements across multiple outcome domains, including recovery of menstrual function, EA, body composition, and hormonal biomarkers. Pharmacological interventions, utilising oestrogen therapy and hormone replacement showed some effectiveness in improving BMD, restoring menstrual function and enhancing hormonal profiles. However, the certainty of evidence across both intervention types was limited by methodological weakness and number of contributing studies. The discussion now provides consideration to the main findings by intervention type. Non-pharmacological interventions Menstrual function recovery Despite the overall low quality of evidence, all studies consistently demonstrated clinically meaningful improvements in menstrual function following non-pharmacological interventions. These findings align with broader physiological and clinical literature. Mechanistically, energy deficiency resulting from insufficient fuel availability suppresses the hypothalamic-pituitary-ovarian (HPO) axis, leading to menstrual dysfunction 44 . Supporting this, research shows that LH pulsatility is disrupted when EA drops below a clinical threshold, highlighting that EA rather than body fat or exercise alone is the primary regulator of reproductive function in active women 45 . Clinical evidence further supports this, with several studies showing that dietary or training modifications can restore menses within several months in affected athletes 46 , 47 . Current studies vary widely in how recovery is defined, often relying on menstrual bleeding alone 46 – 49 . which does not confirm ovulation or hormonal restoration 50 , 51 . Menstrual bleeding alone does not guarantee hormonal balance or ovulation. Highlighting the need for standardised, hormonally validated definitions in future research. Future research should adopt standardised, hormonally validated definitions of menstrual recovery to improve consistency and clinical relevance. In addition, longer follow-up periods and consistent use of hormonal markers are needed to assess the long-term health impacts of interventions on reproductive, bone, and overall health in female athletes with RED-S. Energy availability EA was identified as improving following interventions. These findings are strongly supported by past research demonstrating the central role of EA in hormonal, reproductive, and metabolic regulation. Low EA has been shown to impair LH pulsatility, suppress resting metabolic rate, and reduce oestrogen and IGF-1 levels, negatively affecting reproductive and bone health 52 , 53 . Importantly, even modest increases in EA can reverse these changes, restoring LH pulsatility, resuming menstrual function, and normalising metabolic function, highlighting EA as a key modifiable factor in both the development and recovery from RED-S. Improvements in bone health have also been observed with prolonged energy restoration, though severe cases may require combined nutritional and pharmacological intervention 54 . Accurate measurement of EA remains a major challenge due to the difficulty of precisely assessing dietary intake, exercise, and fat-free mass. Common reliance on self-reported data and indirect proxy markers, such as menstrual dysfunction, resting metabolic rate, and hormonal changes (reduced leptin and T3), introduces variability and error, limiting confidence in current findings 17 , 52 . Therefore, future research needs improved, objective methods to accurately quantify EA in free-living athletes, alongside standardized and sensitive biomarkers, to strengthen the evidence base and guide effective RED-S management. Body composition Consistent and clinically relevant improvements in body composition were observed across studies. Past evidence highlights the complexity of using body composition as a primary indicator of recovery in RED-S. Although improvements in fat mass and body weight may reflect enhanced EA and nutritional rehabilitation 17 , they are not universally required for physiological recovery. Critically, key outcomes such as the return of menses and improvements in BMD, central to RED-S recovery, can occur independently of significant changes in body composition 55 . This is particularly relevant in athletes who are constitutionally lean, where minimal or no changes in fat mass may accompany full recovery of hormonal and metabolic function 56 . Moreover, reliance on body composition alone may overlook meaningful clinical progress or delay appropriate intervention if weight change is minimal. As such, current consensus, including the 2023 IOC statement on RED-S 1 emphasises that body composition should not be used in isolation to define recovery. Instead, it should be interpreted within a broader clinical framework, incorporating menstrual status, hormonal markers, non-pharmacological changes, and performance indicators. This multidimensional approach is essential for accurately monitoring recovery and tailoring individualised treatment strategies in athletes affected by RED-S. Biomarkers Endocrine markers, particularly serum leptin and triiodothyronine (TT3), along with LH and oestradiol, showed consistent, clinically meaningful improvements across studies, indicating recovery of metabolic and reproductive function in RED-S. The current findings are consistent with previous literature highlighting the utility of endocrine biomarkers as sensitive indicators of physiological recovery in RED-S. Increases in serum leptin, an adipocyte-derived hormone that signals energy sufficiency to the hypothalamus, are closely associated with improvements in reproductive function 57 , 58 . Similarly, elevations in triiodothyronine (TT3), a well-established marker of metabolic adaptation, reflect reversal of energy-conserving mechanisms and restoration of metabolic homeostasis 17 . Additional improvements in cortisol, oestradiol and LH pulsatility further support the reactivation of the hypothalamic–pituitary–gonadal (HPG) axis 19 , 52 . Given the low certainty of current evidence, future research must focus on high-quality, standardised studies to validate endocrine biomarkers as reliable indicators of RED-S recovery. Markers like leptin, TT3, oestradiol, and LH pulsatility show promise but are limited by inconsistent measurement, variability, and unclear clinical thresholds 17 , 52 . To improve utility, studies should standardise biomarker timing, consider menstrual cycle, diurnal variation, and assay methods, and establish validated cut-offs. Longitudinal research linking hormonal changes to clinical outcomes such as menstrual resumption and bone health is needed. Importantly, biomarkers should be combined with clinical assessments, symptom tracking, and performance measures for a comprehensive evaluation 16 . Rigorous validation of these markers is essential to enhance RED-S diagnosis, monitoring, and management. Pharmacological Interventions Bone mineral density BMD outcomes in RED-S interventions were inconsistent across studies, with some evidence suggesting hormonal therapies may support bone health when nutritional recovery alone is inadequate. These findings align with existing evidence suggesting that while hormonal therapies may offer some benefit to BMD 55 , their effectiveness remains inconsistent. For instance, a review by Indirli et al., 59 reported that hormone therapies using oestrogen or leptin showed limited impact on bone metabolism in women with FHA This variability is likely since such treatments do not address the underlying cause of RED-S: chronic low EA. Pharmacological interventions may alleviate certain symptoms but risk masking the broader physiological dysfunction if used in isolation 17 , 60 . As such, current evidence supports their use only as adjuncts in cases where nutritional rehabilitation and restoration of EA, the foundation of RED-S treatment, have not been sufficient, or where bone health is severely compromised 61 . Menstrual function recovery Although pharmacological interventions have shown promise in supporting menstrual recovery in RED-S, current evidence, particularly from non-pharmacological studies, suggests that nutritional and non-pharmacological strategies may offer equally, if not more, effective outcomes, albeit from a smaller and methodologically limited evidence base. Evidence supporting the current findings aligns with established physiological mechanisms indicating that hormonal therapy in RED-S may obscure true recovery. Combined oral contraceptives (COCs) and other exogenous hormone regimens induce withdrawal bleeding through artificial endometrial shedding, without restoring endogenous ovulatory cycles or HPG axis function 62 , 63 . As such, withdrawal bleeding can be misinterpreted as menstrual recovery, potentially delaying appropriate treatment interventions targeting LEA. This masking effect is well-documented and underscores the need for more accurate markers of reproductive recovery. Objective indicators such as serum progesterone levels, LH pulsatility, or basal body temperature tracking are recommended to assess ovulatory function and HPG axis restoration 64 . Given these considerations, hormonal therapies should be used with caution and only as adjuncts to primary nutritional and non-pharmacological strategies that address the underlying energy deficiency central to RED-S. Hormonal profiles Hormonal interventions demonstrated significant and clinically meaningful effects on oestrogen and progesterone levels, with oestradiol notably higher in treatment groups compared to those receiving oral contraceptives. But certainty of evidence is mixed. Ackerman et al. 16 demonstrated that improvements in BMD can occur without endogenous hormonal normalization, as menstrual function did not resume during treatment with transdermal oestrogen. This indicates that symptom recovery, such as bone health improvement, may happen independently of menstrual and hormonal recovery when exogenous hormones are administered. Interpreting endocrine responses in this context is complex because exogenous hormones, like transdermal oestradiol or COC’s, suppress endogenous hormone production via negative feedback on the HPG axis 16 , 65 . This suppression can create misleading hormonal profiles that suggest normalization without true recovery of natural reproductive function, such as ovulation and menstrual cycles 65 . Therefore, clinical improvements in outcomes may reflect the direct effects of hormone therapy rather than restoration of endogenous endocrine function 16 . These complexities highlight the need for comprehensive assessment of RED-S recovery that goes beyond hormone levels to include clinical symptoms and functional reproductive status 17 . Bone turnover markers Analysis of bone turnover markers, specifically P1NP and IGF-1, showed statistically and clinically significant changes indicative of meaningful effects on bone metabolism, supported by high-certainty evidence; however, findings are limited by being based on a single study, highlighting the need for further research to validate their utility in monitoring bone health in athletes with RED-S. These findings are supported by literature recognizing bone turnover markers such as P1NP and IGF-1 as sensitive indicators of bone metabolism 66 . However, their clinical utility is challenged by variability in assay methods, biological fluctuations, and influences from nutrition, exercise, and hormonal status 67 . The limited number of studies reporting these markers, alongside inconsistent measurement protocols and definitions, further complicates cross-study comparisons 68 . Nevertheless, bone turnover markers provide valuable early insight into bone remodelling processes that may occur before detectable changes in BMD, emphasizing the importance of standardized assessment methods and additional research to fully establish their role in monitoring bone health in RED-S. Limitations of the evidence Most included studies forming the evidence were rated as having moderate to high risk of bias, and the consistency of using a standard set of reporting outcome measures was poor. This limits the strength of the evidence base. Reporting on intervention fidelity, participant compliance, and follow-up was often incomplete or unclear, reducing confidence in the consistency and applicability of reported outcomes. These methodological limitations highlight the need for more robust, standardised research in this field. Another limitation is that the standard deviation of change used in the meta-analysis for the Dueck 29 was estimated. Implications for practice / clinical implications The current review mostly included females from sports and events that are categorised as distance and endurance related, most non-pharmacological evidence utilised interventions that changed or adapted dietary intake and the most common environment was a University laboratory or location. Effective management of RED-S should prioritise restoring EA through non-pharmacological interventions. The current evidence consistently utilises dietary approaches delivered by dietitians. Recovery should not be assessed by menstrual status or body composition alone; instead, clinicians should adopt a multidimensional approach that incorporates hormonally validated markers (e.g., leptin, TT3, LH, oestradiol) and behavioural changes to ensure accurate diagnosis, monitoring, and long-term management. Hormonal therapies in RED-S may provide benefits for bone health and symptom management but should be used cautiously and only when nutritional rehabilitation and energy restoration are insufficient, as they do not address the underlying cause and can mask true reproductive recovery. Pharmacological treatments like COCs may induce withdrawal bleeding without restoring ovulatory function, emphasizing the need to prioritise nutritional and non-pharmacological interventions alongside objective monitoring. Additionally, bone turnover markers such as P1NP and IGF-1 show potential as sensitive indicators of bone metabolism, though their clinical utility is currently constrained by variability and limited evidence, underscoring the need for standardized assessment and further research. Conclusion This review has provided consistent evidence from non-pharmacological interventions, primarily dietary adaptations, demonstrating beneficial effects on the restoration of menses, EA, fat mass and body fat percentage. Hormonal changes and biomarkers are currently supported by more consistent evidence from pharmacological studies compared to non-pharmacological studies. Further research is needed. 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