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

Hum Reprod. 2021 Jul 19;36(8):2285-2297. doi: 10.1093/humrep/deab149.


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.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Energy Intake
  • Exercise
  • Female
  • Humans
  • Menstruation Disturbances*
  • Menstruation*
  • Oligomenorrhea
  • United States
  • Young Adult

Associated data

  • ClinicalTrials.gov/NCT00392873