Abstract
Perimenopause is a transitional phase leading to female reproductive senescence, which can cause vasomotor symptoms and increase the risk of osteoporosis, obesity, and metabolic-related disturbances in middle-aged and older women. Nevertheless, little is known regarding the underlying mechanisms linked to menopausal transition, which could be of great value in designing new interventions addressed to improve the health of both perimenopausal and postmenopausal women. We used an ovarian-intact middle-aged model of rats resembling the characteristics of human perimenopause and applied liquid and gas chromatography quadrupole time-of-flight mass spectrometry approaches for the determination of polar and lipid-related metabolites to identify characteristic circulating signatures across perimenopause. The gradual loss of regularity in the estrous cycle occurring during the natural transition to reproductive senescence was associated with altered circulating levels of estradiol, progesterone, and luteinizing hormone (LH) and, in rats that were in an acyclic state, with ovary atrophy and with a lack of stromal luteinization and corpus luteum. These results were accompanied by progressively significant changes in the 144 lipid-related metabolites detected in serum as the estrous cycles were losing regularity. Furthermore, we identified 18 lipid-related metabolites-including 9 phosphatidylcholines, 4 lysophosphatidylcholines, 2 phosphatidylethanolamines, cholesterol ester (18:2), 5α-androstane-3,17-diol, and 17,18-dihydroxyarachidonic acid-that already changed with the transition from a regular to an irregular estrous cycle and anticipated the changes in blood progesterone, LH, and cholesterol levels that occurred in acyclic rats. These metabolites could be used as a potential multivariate biomarker of early perimenopause. The translational applicability of these findings deserves further research.