Randomised controlled trial of the effects of increased energy intake on menstrual recovery in exercising women with menstrual disturbances: the 'REFUEL' study

Abstract

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 < 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.

Keywords: REFUEL; amenorrhoea; energy deficiency; exercising women; female athlete triad; menstrual recovery; nutritional intervention; oligomenorrhoea.

© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Figures

Figure 1.

Abbreviated study design with measures pertinent to this analysis. Modified from Williams et al. (2019) with permission from Elsevier.

Figure 2.

Flow chart of subject enrollment during the study for this sample and the reasons for dropout during the study. OCs, oral contraceptives.

Figure 3.

Results of recurrent event cox proportional hazard survival model for the intervention. Hazard ratios are depicted by closed black circles; 95% confidence intervals depicted by horizontal lines. Women in the Oligo/Amen + Cal group were 1.9 times more likely to experience menses compared with the Oligo/Amen Control group. Baseline fat mass significantly influenced the model; the higher a participant’s fat mass at baseline, the greater her hazard of experiencing menses. A one unit (kg) increase in fat mass at baseline increased the hazard of experiencing menses by 8%.

Figure 4.

Menses and censoring for the Oligo/Amen groups. This figure plots descriptive features for each participant in the Oligo/Amen + Cal group (A) and the Oligo/Amen Control group (B). The length of time spent in the study is represented by a single line for each participant. Red lines indicate women with amenorrhoea at baseline; black lines indicate women who were not amenorrhoeic (i.e. oligomenorrhoeic or ambiguous baseline menstrual status). Events, i.e. a menses, are indicated with either a solid red square (amenorrhoeic women) or solid black circle (oligomenorrhoeic/ambiguous women). Censoring times (when the study was completed or the participant dropped out) are indicated with an open circle or square.

Figure 5.

Estimated marginal means and results of the generalised linear fixed effects model for the two study groups. Results are for five time points during the study (Baseline (BL), Month 3, Month 6, Month 9, Post-study) for a) energy intake, b) exercise energy expenditure, c) body weight, d) percent body fat, e) lean mass, f) fat mass, and g) TT3. The Oligo/Amen + Cal group is depicted in blue squares; the Oligo/Amen Control group is depicted by red circles. P-values of the fixed effects in the model and study group*time interaction are displayed for each model. *Indicates significant change from baseline (P < 0.05). aIndicates significant differences between groups at that time point (P < 0.05). TT3, total triiodothyronine; BW, body weight; FM, fat mass.