SAT-133 - Irisin Affects Estrous Cycle Variability by Increasing Proestrus and Reducing Metestrus Duration in C57Bl/6J Mice

Introduction: Energy metabolism and reproduction are closely related. Irisin is a myokine primarily involved in energy metabolism. Initial studies by our group and others have demonstrated that irisin directly affects female reproductive system.

Aim: In this study, we explored how chronic irisin treatment affects ovarian cycle regularity and stage distribution in healthy C57Bl/6J mice.

Methods: Thirty 8-weeks-old C57Bl/6J female mice received placebo (Controls, n = 10), lower dose irisin (100 μg/kg, n = 10), or higher dose irisin (500 μg/kg, n = 10) via intraperitoneal injections, three times per week for six weeks. The ovarian cycle of 12 mice (four per condition) was followed daily by vaginal cytology during a two weeks baseline and six weeks treatment period. Ovarian stage variation (primary index of cycle irregularity), transition rate, and the proportion of days in each stage were calculated. Baseline level vs. treatment data were compared within each group using the Wilcoxon signed-rank test. Between-group comparisons during treatment were made using the Mann-Whitney U test.

Results: Pooling both irisin groups (n = 8) revealed a significant difference between baseline and treatment groups—an increased stage variation (from 0.723 to 1.171, p = 0.008), increased proestrus proportion (from 1.8 to 17.1%, p = 0.008), and decreased metestrus (from 30.4 to 16.3%, p = 0.008). In the lower irisin-dose group, cycle variance showed 82% increase (from 0.723 to 1.317) with a marked shift toward proestrus (from 1.8 to 19.0%) and diestrus (from 23.2 to 35.5%), and reductions in estrus (from 48.2 to 31.0%) and metestrus (from 26.8 to 14.5%) (within-group comparisons were non-significant). Interestingly, the higher-dose irisin treatment displayed milder effects—cycle variance increased to 1.026, which was significantly lower than both control (1.060, p = 0.029) and lower irisin dose (1.317, p = 0.029). Diestrus duration was significantly greater in the lower dose (35.5%) compared to the higher dose irisin (23.4%, p = 0.028). Controls showed no significant changes in the estrous cycle over time.

Conclusions: Chronic irisin treatment disrupts estrous cyclicity in healthy C57Bl/6J mice, with increased cycle irregularity, a shift toward prolonged proestrus and reduced metestrus. The dose-response effect of irisin treatment was nonlinear, with 100 μg/kg producing greater irregularity than 500 μg/kg, suggesting complex regulation of the hypothalamic-pituitary-gonadal axis by irisin. These findings have potential implications for certain health conditions in women (e.g., menstrual abnormalities in female athletes) and safety implications for future irisin-based interventions. Hormone levels are pending and will be presented.

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