Sex Differences in Genital Area Hyperpigmentation Induced by 5-Fluorouracil Administration in Mice

Pigmentation is one of the most prominent side effects caused by anticancer drugs, especially in female patients, as these changes in appearance can decrease QOL. A typical drug causing such pigmentation is 5-fluorouracil (5-FU); we have previously shown that 5-FU-induced pigmentation is associated with increased adrenocorticotropic hormone (ACTH) and reactive oxygen species (ROS) levels. In male Hos:HRM-2 mice, 5-FU administration resulted in pigmentation appearing in the genital area, accompanied by elevations in neutrophils, ACTH, and ROS. By contrast, female mice showed increases in neutrophils and noradrenaline, but not in ACTH or ROS levels; furthermore, they did not develop pigmentation. In addition, estradiol levels were markedly decreased in female mice, which may have enhanced neutrophil apoptosis and suppressed ROS production. In addition, noradrenaline reflects the stress response and may contribute to the decrease in estradiol, suggesting the hypothalamus-pituitary-adrenal axis and sex hormones may interact in the formation of sex differences. These results suggest that sex differences exist in the development of 5-FU-induced hyperpigmentation and that fluctuations in estradiol and associated changes in neutrophils, ROS, and ACTH may underlie this phenomenon.