Multiple eumenorrheic cycles are necessary to observe a significant increase in estrogen exposure and ovulation in exercising women with functional hypothalamic oligo/amenorrhea undergoing a nutritional intervention: Insights from the REFUEL study

Background: Due to consequences of energy-related oligo-/amenorrhea (Oligo/Amen) among exercising females, recovery of menses (ROM) is a priority. ROM is inconsistently defined and rarely reported with reproductive hormone (estrogen, progesterone) data, making it difficult to know when females achieve adequate recovery. Objective: The purpose of this secondary analysis of the REFUEL randomized controlled trial was to explore the ovarian hormone environment and quality of menstrual recovery among varying ROM definitions. Methods: ROM was assessed in exercising females with Oligo/Amen (n = 33) who participated in a 12-month intervention of increased energy intake. Four ROM definitions (onset of menses, 1 menstrual cycle <36 days, 2 cycles <36 days, or 3 cycles <36 days) demonstrating advancing degrees of recovery were evaluated. Urinary metabolites of estrogen (estrone-1-glucuronide) and progesterone (pregnanediol glucuronide) were measured daily in a baseline and recovery menstrual cycle; the change in ovarian hormone exposure from baseline to recovery menstrual cycle was analyzed for each ROM definition. The proportion of ovulatory versus anovulatory recovery cycles and the proportion of exercising females who experienced a relapse of Oligo/Amen post recovery were calculated. Results: During the intervention, 58% percent (19/33) of females satisfied at least one ROM definition. There was no change in average ovarian hormone exposure from baseline to the recovery cycle until females experienced three consecutive cycles <36 days, when estrogen exposure significantly increased (+154.7 ng/mL*day, +32.5%, p <.04). As females achieved more consecutive cycles <36 days, the number of ovulatory cycles increased (ROM-1: 31% ovulatory vs. ROM-2 and ROM-3: 54% and 44% ovulatory, respectively) and the occurrence of relapse after recovery decreased (ROM-1 relapse: 53% vs. ROM-2 and ROM-3 relapse: 15% and 22%, respectively). Conclusion: Multiple eumenorrheic cycles may be necessary to observe a significant increase in estrogen exposure, ovulation, and a decrease in relapse after recovery.