Circadian rhythm disruption induces PCOS-like phenotypes by interfering with ovarian steroid hormone synthesis pathways

ChengYu Feng; LiYing Guo; Xin Gao; Xia Ji; Ying Liu; JiWei Liu; ShuJun Liu; Yang Liu; LiBing Ma; XiaoYing He

doi:10.1016/j.jsbmb.2026.106980

Circadian rhythm disruption induces PCOS-like phenotypes by interfering with ovarian steroid hormone synthesis pathways

J Steroid Biochem Mol Biol. 2026 May:259:106980. doi: 10.1016/j.jsbmb.2026.106980. Epub 2026 Feb 28.

Authors

ChengYu Feng¹, LiYing Guo¹, Xin Gao¹, Xia Ji², Ying Liu³, JiWei Liu³, ShuJun Liu³, Yang Liu³, LiBing Ma³, XiaoYing He⁴

Affiliations

¹ School of life science and technology, Inner Mongolia University of Science & Technology, Baotou 014010, China.
² Department of Gynaecology and Obstetrics, Inner Mongolia Baogang Hospital, Baotou 014010, China.
³ School of life science and technology, Inner Mongolia University of Science & Technology, Baotou 014010, China; Inner Mongolia Key Laboratory of Life Health and Bioinformatics School of Life Science and Technology, Inner Mongolia University of Science and Technology, Baotou 014010, China.
⁴ School of life science and technology, Inner Mongolia University of Science & Technology, Baotou 014010, China; Inner Mongolia Key Laboratory of Life Health and Bioinformatics School of Life Science and Technology, Inner Mongolia University of Science and Technology, Baotou 014010, China. Electronic address: hxy1124@163.com.

PMID: 41771452
DOI: 10.1016/j.jsbmb.2026.106980

Abstract

Stressors are a critical contributor to reproductive dysfunction. This study investigated whether experimentally induced chronic stress leads to infertility and elucidated its disruptive mechanisms on the female reproductive endocrine system. Three chronic stress models were established in female ICR mice: chronic restraint stress (CRS), circadian rhythm disruption (CR), and chronic unpredictable mild stress (CUMS). Systemic evaluations revealed that the CR model most significantly activated the hypothalamic-pituitary-adrenal (HPA) axis, as indicated by elevated corticosterone and epinephrine levels. Macro- and micro-level quantitative analyses demonstrated that CR treatment significantly reduced body weight, ovarian and uterine coefficients, increased atretic follicles, disrupted estrous cycles, and decreased litter size. Hormonal assays showed decreased levels of luteinizing hormone (LH), progesterone, estradiol, and melatonin, while testosterone levels were elevated. This pattern of alterations closely resembled the endocrine profile of polycystic ovary syndrome (PCOS). Further ovarian transcriptome analysis identified 538 differentially expressed genes. Key estrogen synthesis genes (Star, Cyp19a1, Cyp17a1, 3β-Hsd, 17β-Hsd) and rate-limiting enzymes were significantly downregulated. Notably, expression of luteinizing hormone receptor (Lhr) showed compensatory upregulation, suggesting a feedback response to impaired steroidogenesis. Functional enrichment analysis highlighted significant alterations in steroid hormone synthesis, cAMP signaling, and metabolic pathways. Our findings suggest that circadian rhythm disruption impairs reproductive function primarily through downregulating key genes in the estrogen synthesis pathway. This work confirms the induction of a PCOS-like phenotype by artificial stress and reveals novel mechanistic insights, thereby identifying potential therapeutic targets for stress-associated PCOS.

Keywords: Circadian rhythm; Environmental stress; Estrogen synthesis; Ovarian dysfunction; PCOS-like phenotype.

MeSH terms

Animals
Circadian Rhythm*
Disease Models, Animal
Female
Hypothalamo-Hypophyseal System / metabolism
Mice
Mice, Inbred ICR
Ovary* / metabolism
Phenotype
Pituitary-Adrenal System / metabolism
Polycystic Ovary Syndrome* / etiology
Polycystic Ovary Syndrome* / metabolism
Polycystic Ovary Syndrome* / pathology
Stress, Psychological / metabolism