Energy deficiency in exercising women can lead to physiological consequences. No gold standard exists to accurately estimate energy deficiency, but measured-to-predicted resting metabolic rate (RMR) ratio has been used to categorize women as energy deficient. The purpose of the study was to (a) evaluate the accuracy of RMR prediction methods, (b) determine the relationships with physiological consequences of energy deficiency, and (c) evaluate ratio thresholds in a cross-sectional comparison of ovulatory, amenorrheic, or subclinical menstrual disturbances in exercising women (n = 217). Dual-energy X-ray absorptiometry (DXA) and indirect calorimetry provided data on anthropometrics and energy expenditure. Harris-Benedict, DXA, andCunningham (1980 and equations were used to estimate RMR and RMR ratio. Group differences were assessed (analysis of variance and Kruskal-Wallis tests); logistic regression and Spearman correlations related ratios with consequences of energy deficiency (i.e., low total triiodothyronine; TT 3 ). Sensitivity and specificity calculations evaluated ratio thresholds. Amenorrheic women had lower RMR (p < .05), DXA ratio (p < .01), Cunningham 1980 (p < .05) and Cunningham 1991 (p < .05) ratio, and TT 3 (p < .01) compared with the ovulatory group. Each prediction equation overestimated measured RMR (p < .001), but predicted (p < .001) and positively correlated with TT 3 (r = .329-.453). A 0.90 ratio threshold yielded highest sensitivity for Cunningham 1980 (0.90) and Harris-Benedict (0.87) methods, but a higher ratio threshold was best for DXA (0.94) and Cunningham 1991 (0.92) methods to yield a sensitivity of 0.80. In conclusion, each ratio predicted and correlated with TT 3 , supporting the use of RMR ratio as an alternative assessment of energetic status in exercising women. However, a 0.90 ratio cutoff is not universal across RMR estimation methods.Keywords: female athlete triad, menstrual disturbances, metabolic suppression Energy deficiency in exercising women is associated with severe consequences including reproductive dysfunction (De Souza et al., 2007b;Williams et al., 2015) and impaired bone health , a condition referred to as the Female Athlete Triad (Triad) Nattiv et al., 2007). When energy intake fails to meet metabolic demands, metabolizable fuels are repartitioned toward the physiological processes necessary for survival (i.e., locomotion, cellular maintenance, and thermoregulation) and away from those energetic processes deemed unnecessary for survival (i.e., growth and reproduction). This results in suppression of metabolism, energy expenditure, and thyroid hormones (Wade et al., 1996), contributing to the development The authors are with the Women'

STUDY QUESTION Does increased daily energy intake lead to menstrual recovery in exercising women with oligomenorrhoea (Oligo) or amenorrhoea (Amen)? SUMMARY ANSWER A modest increase in daily energy intake (330 ± 65 kcal/day; 18 ± 4%) is sufficient to induce menstrual recovery in exercising women with Oligo/Amen. WHAT IS KNOWN ALREADY Optimal energy availability is critical for normal reproductive function, but the magnitude of increased energy intake necessary for menstrual recovery in exercising women, along with the associated metabolic changes, is not known. STUDY DESIGN, SIZE, DURATION The REFUEL study (trial # NCT00392873) is the first randomised controlled trial to assess the effectiveness of 12 months of increased energy intake on menstrual function in 76 exercising women with menstrual disturbances. Participants were randomised (block method) to increase energy intake 20–40% above baseline energy needs (Oligo/Amen + Cal, n = 40) or maintain energy intake (Oligo/Amen Control, n = 36). The study was performed from 2006 to 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS Participants were Amen and Oligo exercising women (age = 21.0 ± 0.3 years, BMI = 20.8 ± 0.2 kg/m2, body fat = 24.7 ± 0.6%) recruited from two universities. Detailed assessment of menstrual function was performed using logs and measures of daily urinary ovarian steroids. Body composition and metabolic outcomes were assessed every 3 months. MAIN RESULTS AND THE ROLE OF CHANCE Using an intent-to-treat analysis, the Oligo/Amen + Cal group was more likely to experience menses during the intervention than the Oligo/Amen Control group (P = 0.002; hazard ratio [CI] = 1.91 [1.27, 2.89]). In the intent-to-treat analysis, the Oligo/Amen + Cal group demonstrated a greater increase in energy intake, body weight, percent body fat and total triiodothyronine (TT3) compared to the Oligo/Amen Control group (P &lt; 0.05). In a subgroup analysis where n = 22 participants were excluded (ambiguous baseline menstrual cycle, insufficient time in intervention for menstrual recovery classification), 64% of the Oligo/Amen + Cal group exhibited improved menstrual function compared with 19% in the Oligo/Amen Control group (χ2, P = 0.001). LIMITATIONS, REASONS FOR CAUTION While we had a greater than expected dropout rate for the 12-month intervention, it was comparable to other shorter interventions of 3–6 months in duration. Menstrual recovery defined herein does not account for quality of recovery. WIDER IMPLICATIONS OF THE FINDINGS Expanding upon findings in shorter, non-randomised studies, a modest increase in daily energy intake (330 ± 65 kcal/day; 18 ± 4%) is sufficient to induce menstrual recovery in exercising women with Oligo/Amen. Improved metabolism, as demonstrated by a modest increase in body weight (4.9%), percent body fat (13%) and TT3 (16%), was associated with menstrual recovery. STUDY FUNDING/COMPETING INTEREST(S) This research was supported by the U.S. Department of Defense: U.S. Army Medical Research and Material Command (Grant PR054531). Additional research assistance provided by the Penn State Clinical Research Center was supported by the National Center for Advancing Translation Sciences, National Institutes of Health, through Grant UL1 TR002014. M.P.O. was supported in part by the Loretta Anne Rogers Chair in Eating Disorders at University of Toronto and University Health Network. All authors report no conflict of interest. TRIAL REGISTRATION NUMBER NCT00392873 TRIAL REGISTRATION DATE October 2006 DATE OF FIRST PATIENT’S ENROLMENT September 2006

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We examine the scientific evidence supporting The Female Athlete Triad and Relative Energy Deficiency in Sport (RED-S) syndromes. More research is necessary to advance the understanding of both syndromes; however, it is premature to consider RED-S as an evidence-based syndrome. Future research should specifically define RED-S components, determine its clinical relevance, and establish the causality of relative energy deficiency on RED-S outcomes.

The prevalence of osteoporosis among women aged 50 years and older is expected to reach 13.6 million by 2030. Alternative non-pharmaceutical agents for osteoporosis including nutritional interventions are becoming increasingly popular. Prunes (dried plums) (Prunus domestica L.) have been studied as a potential whole food dietary intervention to mitigate bone loss in preclinical models of osteoporosis and in osteopenic postmenopausal women. Sixteen preclinical studies using in vivo rodent models of osteopenia or osteoporosis have established that dietary supplementation with prunes confers osteoprotective effects both by preventing and reversing bone loss. Increasing evidence from ten studies suggests that in addition to anti-resorptive effects, prunes exert anti-inflammatory and antioxidant effects. Ten preclinical studies have found that prunes and/or their polyphenol extracts decrease malondialdehyde and nitric oxide secretion, increase antioxidant enzyme expression, or suppress NF-κB activation and pro-inflammatory cytokine production. Two clinical trials have investigated the impact of dried plum consumption (50–100g/day for 6–12 months) on bone health in postmenopausal women and demonstrate promising effects on bone mineral density and bone biomarkers. However, less is known about the impact of prune consumption on oxidative stress and inflammatory mediators in humans and their possible role in modulating bone outcomes. In this review, the current state of knowledge on the relationship between inflammation and bone health is outlined. Findings from preclinical and clinical studies that have assessed the effect of prunes on oxidative stress, inflammatory mediators, and bone outcomes are summarized, and evidence supporting a potential role of prunes in modulating inflammatory and immune pathways is highlighted. Key future directions to bridge the knowledge gap in the field are proposed.

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Background Dietary consumption of prunes has favorable impacts on bone health, however, more research is necessary to improve upon study designs and refine our understandings. Objectives We evaluated the effects of prunes (50 g or 100 g/day) on bone mineral density (BMD) in postmenopausal females during a 12-month dietary intervention. Secondary outcomes include effects on bone biomarkers. Study Design The single center, parallel arm 12-month randomized controlled trial (RCT; NCT02822378) tested the effects of 50 g and 100 g prunes vs. a Control group on BMD (every 6 months) and bone biomarkers in postmenopausal females. Results 235 females (age 62.1 ±5.0 yr) were randomized into Control (n = 78), 50 g Prune (n = 79), or 100 g Prune (n = 78) groups. Compliance was 90.2 ± 1.8% and 87.1 ± 2.1% in the 50 g and 100 g Prune groups. Dropout was 22%; however, the dropout rate was 41% for the 100 g Prune group (compared to other groups 10% Control; 15% 50 g Prune; (p &lt; 0.001)). A group × time interaction for total hip BMD was observed in Control vs 50 g Prune groups (p &lt; 0.05), but not in Control vs 100 g Prune groups (p &gt; 0.05). Total hip BMD decreased -1.1 ± 0.2% in the Control group at 12 months, while the 50 g Prune group preserved BMD (-0.3 ± 0.2%) at 12 months (p &lt; 0.05). While hip fracture risk (FRAX) worsened in the Control group at 6 months compared to baseline (10.3 ± 0.5% vs 9.8 ± 0.5%, p &lt; 0.05), FRAX score was maintained in the pooled (50g + 100 g) Prune groups. Conclusions A 50 g daily dose of prunes can prevent loss of total hip BMD in postmenopausal females after six months, which persisted for 12-months. Given that there was high compliance and retention at the 50 g dosage over 12 months, we propose that the 50 g dose represents a valuable non-pharmacological treatment strategy that can be used to preserve hip BMD in postmenopausal females and possibly reduce hip fracture risk. Clinical Trials Registry Number: NCT02822378