Research Progress on Comorbidity Mechanisms of Mental Disorders and Reproductive System Diseases

doi:10.12280/gjszjk.20260024

Abstract

Abstract:

Both mental disorders and reproductive system diseases represent major challenges of global public health. The two conditions frequently co-occur clinically, mutually influencing each other and forming a vicious cycle. Research confirms that mental disorders share common pathophysiological mechanisms with female infertility, polycystic ovary syndrome, endometriosis, diminished ovarian reserve, recurrent implantation failure, recurrent spontaneous abortion, and male infertility. The core mechanisms primarily involve hormonal imbalance caused by dysfunction of the hypothalamic-pituitary-adrenal axis and sympathetic nervous system, activation of immune inflammation and alterations in the cytokine profile, oxidative stress damage to gametes and embryos, abnormal epigenetic regulation, and potential effects of the microbiota-gut-brain axis. These mechanisms intertwine to form a complex network, revealing both the biological nature of mental disorders as independent risk factors for reproductive system diseases, and elucidating the pathophysiological processes through which reproductive system diseases conversely increase susceptibility to mental disorders. However, the specific mechanisms underlying the comorbidity of mental disorders and reproductive system diseases are not completely clear. We review the research progress in the aforementioned comorbidity mechanisms, providing a theoretical basis for deepening our understanding of their intrinsic biological connections and developing interdisciplinary precision diagnosis and treatment strategies.

Key words: Mental disorders, Genital diseases, female, Infertility, male, Comorbidity, Immunologic factors, Oxidative stress, Epigenomics

WEI Qian, HE Yu-jie. Research Progress on Comorbidity Mechanisms of Mental Disorders and Reproductive System Diseases[J]. Journal of International Reproductive Health/Family Planning, 2026, 45(3): 236-241.

References 44

[1]	GBD 2021 Diseases and Injuries Collaborators. Global incidence, prevalence, years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries in 204 countries and territories and 811 subnational locations, 1990—2021: a systematic analysis for the Global Burden of Disease Study 2021[J]. Lancet, 2024, 403(10440):2133-2161. doi: 10.1016/S0140-6736(24)00757-8..
[2]	Desmeules C, Corbeil O, Huot-Lavoie M, et al. Psychotic Disorders and exosomes: An overview of current evidence and future directions[J]. Psychiatry Res, 2024, 339:116066. doi: 10.1016/j.psychres.2024.116066.
[3]	Hanna MR, Caspi A, Houts RM, et al. Co-occurrence between mental disorders and physical diseases: a study of nationwide primary-care medical records[J]. Psychol Med, 2024, 54(15):1-13. doi: 10.1017/S0033291724002575.
[4]	Zhang L, Chen W, Hou Y, et al. Incidence, Prevalence, Deaths and dalys of diseases of the female reproductive system from 1990 to 2021 across 204 countries: data, with critical re-analysis, from the global burden of disease Study[J]. Int J Surg, 2025, 111(12):9166-9177. doi:10.1097/js9.0000000000003558.
[5]	Hwang YJ, Lee J, Hwang J, et al. Psychiatric Considerations of Infertility[J]. Psychiatry Investig, 2024, 21(11):1175-1182. doi: 10.30773/pi.2024.0239.
[6]	Zou W, Tang L, Wallis C. "My Body is Betraying Me": Exploring the Stigma and Coping Strategies for Infertility Among Women Across Ethnic and Racial Groups[J]. Health Commun, 2025, 40(12):2612-2623. doi: 10.1080/10410236.2025.2470984.
[7]	Braverman AM, Davoudian T, Levin IK, et al. Depression, anxiety, quality of life, and infertility: a global lens on the last decade of research[J]. Fertil Steril, 2024, 121(3):379-383. doi: 10.1016/j.fertnstert.2024.01.013.
[8]	Jo M, Brännström M, Akins JW, et al. New insights into the ovulatory process in the human ovary[J]. Hum Reprod Update, 2025, 31(1):21-47. doi: 10.1093/humupd/dmae027.
[9]	Han Y, Lin X. The relationship between psychological stress and ovulatory disorders and its molecular mechanisms: a narrative review[J]. J Psychosom Obstet Gynaecol, 2024, 45(1):2418110. doi: 10.1080/0167482X.2024.2418110.
[10]	Li M, Sun K, Mei Y, et al. Perspective Exploring Novel Associations of IL-18 Levels as a Mediator of the Causal Links between Major Depression and Reproductive Health[J]. Depress Anxiety, 2024, 2024:9234876. doi: 10.1155/2024/9234876.
[11]	Yang Q, Tao J, Xin X, et al. Association between depression and infertility risk among American women aged 18-45 years: the mediating effect of the NHHR[J]. Lipids Health Dis, 2024, 23(1):178. doi: 10.1186/s12944-024-02164-3.
[12]	Li Y, Zhang J, Zheng X, et al. Depression, anxiety and self-esteem in adolescent girls with polycystic ovary syndrome: a systematic review and meta-analysis[J]. Front Endocrinol(Lausanne), 2024, 15:1399580. doi: 10.3389/fendo.2024.1399580.
[13]	Pirim D, Bağcı FA. Dissecting the shared molecular mechanisms underlying polycystic ovary syndrome and schizophrenia etiology: a translational integrative approach[J]. Syst Biol Reprod Med, 2025, 71(1):1-12. doi: 10.1080/19396368.2025.2499475.
[14]	Del Río JP, Tsompanidis A, Gaspar PA, et al. Women with polycystic ovary syndrome (PCOS): Likelihood of cooccurring neuropsychiatric conditions and the dual hit hypothesis[J]. Front Neuroendocrinol, 2025, 77:101188. doi: 10.1016/j.yfrne.2025.101188.
[15]	Sarkisian KI, Yang JL, Marshall C, et al. Allopregnanolone in the pathogenesis of the psychiatric comorbidities of polycystic ovarian syndrome[J]. J Steroid Biochem Mol Biol, 2025, 250:106719. doi: 10.1016/j.jsbmb.2025.106719.
[16]	Cambier S, Gouwy M, Proost P. The chemokines CXCL8 and CXCL12: molecular and functional properties, role in disease and efforts towards pharmacological intervention[J]. Cell Mol Immunol, 2023, 20(3):217-251. doi: 10.1038/s41423-023-00974-6. pmid: 36725964
[17]	Yang FC, Zhou Y, Zhang SY, et al. Depression and anxiety in patients with endometriosis-associated chronic pain: Neuroimmune mechanisms mediated by inflammatory factors[J]. World J Psychiatry, 2025, 15(10):107147. doi: 10.5498/wjp.v15.i10.107147.
[18]	Cuffaro F, Russo E, Amedei A. Endometriosis, Pain, and Related Psychological Disorders: Unveiling the Interplay among the Microbiome, Inflammation, and Oxidative Stress as a Common Thread[J]. Int J Mol Sci, 2024, 25(12):6473. doi: 10.3390/ijms25126473.
[19]	Albadawi EA. Structural and functional changes in the hippocampus induced by environmental exposures[J]. Neurosciences(Riyadh), 2025, 30(1):5-19. doi: 10.17712/nsj.2025.1.20240052.
[20]	Mokhtari T, Irandoost E, Sheikhbahaei F. Stress, pain, anxiety, and depression in endometriosis-Targeting glial activation and inflammation[J]. Int Immunopharmacol, 2024, 132:111942. doi: 10.1016/j.intimp.2024.111942.
[21]	Bashir ST, Redden CR, Raj K, et al. Endometriosis leads to central nervous system-wide glial activation in a mouse model of endometriosis[J]. J Neuroinflammation, 2023, 20(1):59. doi: 10.1186/s12974-023-02713-0.
[22]	卵巢储备功能减退临床诊治专家共识专家组, 中华预防医学会生育力保护分会生殖内分泌生育保护学组. 卵巢储备功能减退临床诊治专家共识[J]. 生殖医学杂志, 2022, 31(4):425-434. doi: 10.3969/j.issn.1004-3845.2022.04.001.
[23]	Sun J, Guo Y, Fan Y, et al. Decreased expression of IDH1 by chronic unpredictable stress suppresses proliferation and accelerates senescence of granulosa cells through ROS activated MAPK signaling pathways[J]. Free Radic Biol Med, 2021, 169:122-136. doi: 10.1016/j.freeradbiomed.2021.04.016.
[24]	Puriastuti AC, Maramis MM, Annas JY, et al. How does chronic unpredictable mild stress affect the number of mature oocytes? An experimental study[J]. Int J Reprod Biomed, 2025, 23(4):303-312. doi: 10.18502/ijrm.v23i4.18782. pmid: 40766855
[25]	Zhou Z, Li Y, Ding J, et al. Chronic unpredictable stress induces anxiety-like behavior and oxidative stress, leading to diminished ovarian reserve[J]. Sci Rep, 2024, 14(1):30681. doi: 10.1038/s41598-024-76717-y.
[26]	Weng L, Hong H, Zhang Q, et al. Sleep Deprivation Triggers the Excessive Activation of Ovarian Primordial Follicles via β2 Adrenergic Receptor Signaling[J]. Adv Sci(Weinh), 2024, 11(41):e2402393. doi: 10.1002/advs.202402393.
[27]	Gershon E, Issler O, Schroeder M, et al. Mild chronic stress promotes female fertility via the ovarian CRF receptor[J]. Cell Commun Signal, 2025, 23(1):372. doi: 10.1186/s12964-025-02371-0. pmid: 40813666
[28]	中国医师协会生殖医学专业委员会, 中国女医师协会生殖医学专业委员会. 反复种植失败临床诊治中国专家共识[J]. 中华医学杂志, 2023, 103(2):89-100. doi: 10.3760/cma.j.cn112137-20221105-02317.
[29]	孙利静, 孟月茹, 张召义, 等. 反复种植失败患者焦虑抑郁症状与情绪调节策略的相关性研究[J]. 山东大学学报(医学版), 2025, 63(10):89-97. doi: 10.6040/j.issn.1671-7554.0.2024.1436.
[30]	Wu J, Lin S, Huang P, et al. Maternal anxiety affects embryo implantation via impairing adrenergic receptor signaling in decidual cells[J]. Commun Biol, 2022, 5(1):840. doi: 10.1038/s42003-022-03694-1. pmid: 35982177
[31]	Chan KL, Poller WC, Swirski FK, et al. Central regulation of stress-evoked peripheral immune responses[J]. Nat Rev Neurosci, 2023, 24(10):591-604. doi: 10.1038/s41583-023-00729-2. pmid: 37626176
[32]	中华医学会妇产科学分会产科学组, 复发性流产诊治专家共识编写组. 复发性流产诊治专家共识(2022)[J]. 中华妇产科杂志, 2022, 57(9):653-667. doi: 10.3760/cma.j.cn112141-20220421-00259.
[33]	Jiang L, Yang X, Liu C, et al. Dual Mechanisms of Chronic Stress in Recurrent Pregnancy Loss: Progesterone Deficiency and Inflammatory Amplification[J]. Compr Physiol, 2025, 15(5):e70063. doi: 10.1002/cph4.70063.
[34]	Gan YL, Lin WJ, Fang YC, et al. FKBP51 is involved in LPS-induced microglial activation via NF-κB signaling to mediate neuroinflammation[J]. Life Sci, 2024, 351:122867. doi: 10.1016/j.lfs.2024.122867.
[35]	He W, Zhao Y, Yin L, et al. The transcription factor XBP1 regulates mitochondrial remodel and autophagy in spontaneous abortion[J]. Int Immunopharmacol, 2025, 152:114398. doi: 10.1016/j.intimp.2025.114398.
[36]	Wang S, Zhou J. Epidemiological characteristics and risk factors of reproductive dysfunction in male infertility: a meta-analysis[J]. Hormones(Athens), 2025, 24(4):1157-1175. doi: 10.1007/s42000-025-00689-5.
[37]	Merrill RM, Song D, Ashton MK. Comparing the Strength of Associations Between Male Genital Problems and Mental Illnesses and Sleep Disorders[J]. Am J Mens Health, 2024, 18(1):15579883241228243. doi: 10.1177/15579883241228243.
[38]	Li R, Du Y, Li K, et al. Single-cell transcriptome profiling implicates the psychological stress-induced disruption of spermatogenesis[J]. Mol Ther Nucleic Acids, 2024, 35(1):102158. doi: 10.1016/j.omtn.2024.102158.
[39]	Yang T, Liu X, Kang C, et al. Chronic psychological stress induces testicular oxidative stress affecting reproductive behavior in rats[J]. Reprod Biol, 2025, 25(1):100934. doi: 10.1016/j.repbio.2024.100934.
[40]	Zhai W, Tian H, Liang X, et al. Androgen blockage impairs proliferation and function of Sertoli cells via Wee1 and Lfng[J]. Cell Commun Signal, 2024, 22(1):498. doi: 10.1186/s12964-024-01875-5. pmid: 39407201
[41]	Wang HQ, Wu XL, Zhang J, et al. Meiotic transcriptional reprogramming mediated by cell-cell communications in humans and mice revealed by scATAC-seq and scRNA-seq[J]. Zool Res, 2024, 45(3):601-616. doi: 10.24272/j.issn.2095-8137.2023.414.
[42]	Ohno H, Yamamuro Y, Aizawa S. Chronic social defeat stress alters DNA methylation profiles of male germ cells in mice[J]. Biochem Biophys Res Commun, 2025, 758:151650. doi: 10.1016/j.bbrc.2025.151650.
[43]	Alves D, Toffoli LV, Silva WR, et al. Chronic restraint stress associations with sperm global DNA hypermethylation: Impacts on male reproductive function in rats[J]. Physiol Behav, 2025, 301:115058. doi: 10.1016/j.physbeh.2025.115058.
[44]	Wang W, Qikai W, Zilin W, et al. Depression, anxiety, and stress impair sperm quality via dysregulation of the mitochondrial PDK-PDC axis[J]. Reprod Biol Endocrinol, 2025, 23(1):127. doi: 10.1186/s12958-025-01458-0.