PriMera Scientific Medicine and Public Health (ISSN: 2833-5627)

Literature Review

Volume 6 Issue 3

Effect of Long-term COVID-19 on the Female Reproductive System: A Literature Review

Meena Bai*, Navyatha Annareddy, Babar Anum, Labdhi N. Mehta, Mohsin Sajjad, Nayanika Tummala, Madho Mal and Rizwanullah Hameed

February 26, 2025

DOI : 10.56831/PSMPH-06-198

View PDF

Abstract

Long Covid arises in individuals previously infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), irrespective of whether they exhibited symptomatic or asymptomatic infection. This condition typically emerges around four weeks following recovery from the acute phase of the illness, persisting for weeks, months, and sometimes even years thereafter. Clinical diagnosis relies on a history of new, recurring, or ongoing health issues, often presenting with a perplexing array of symptoms and typically normal test results, leading to a delay in the diagnosis and management. The documented common symptoms of long-term COVID-19 are fatigue, insomnia, post-exertional malaise, cognitive dysfunction, and muscle aches [1].

References

  1. Pollack B., et al. “Female reproductive health impacts of Long COVID and associated illnesses including ME/CFS, POTS, and connective tissue disorders: A literature review”. Frontiers in Rehabilitation Sciences 4 (2023).
  2. Turchiano F., et al. “Is There a Role for SARS-CoV-2/COVID-19 on the Female Reproductive System?”. Frontiers in Physiology 13 (2022).
  3. Li Z., et al. “Role of angiotensin-converting enzyme 2 in neurodegenerative diseases during the COVID-19 pandemic”. Aging (Albany NY) 12 (2020): 24453-24461.
  4. Bansal R, Gubbi S and Koch CA. “COVID-19 and chronic fatigue syndrome: An endocrine perspective”. Journal of Clinical & Translational Endocrinology 27 (2022): 100284.
  5. MacCallum-Bridges C., et al. “The impact of COVID-19 vaccination prior to SARS-CoV-2 infection on prevalence of long COVID among a population-based probability sample of Michiganders, 2020-2022”. Annals of Epidemiology 92 (2024): 17-24.
  6. Pollack B., et al. “Female reproductive health impacts of Long COVID and associated illnesses including ME/CFS, POTS, and connective tissue disorders: A literature review”. Frontiers in Rehabilitation Sciences 4 (2023).
  7. Aassve A., et al. “The COVID-19 pandemic and human fertility”. Science 369.6502 (2020): 370-371.
  8. Li F., et al. “Impact of COVID-19 on female fertility: a systematic review and meta-analysis protocol”. BMJ Open 11 (2021): e045524.
  9. Gorman CN., et al. “Transient Premature Ovarian Insufficiency Post-COVID-19 Infection”. Cureus 15.4 (2023): e37379.
  10. M Mihm, S Gangooly and S Muttukrishna. “The normal menstrual cycle in women”. Animal Reproduction Science 124.3-4 (2011): 229-236.
  11. Sonya S Dasharathy., et al. “Menstrual Bleeding Patterns Among Regularly Menstruating Women”. American Journal of Epidemiology 175.6 (2012): 536-545.
  12. Demir O, Sal H and Comba C. “Triangle of COVID, anxiety and menstrual cycle”. J Obstet Gynaecol 41.8 (2021): 1257-1261.
  13. Lebar V., et al. “The Effect of COVID-19 on the Menstrual Cycle: A Systematic Review”. J. Clin. Med 11 (2022): 3800.
  14. Davis HE., et al. “Characterizing long COVID in an international cohort: 7 months of symptoms and their impact”. EClinicalMedicine 38 (2021): 101019.
  15. Newson L, Lewis R and O’Hara M. “Long COVID and menopause—the important role of hormones in long COVID must be considered”. Maturitas 152 (2021): 74.
  16. Pollack B., et al. “Female reproductive health impacts of Long COVID and associated illnesses including ME/CFS, POTS, and connective tissue disorders: A literature review”. Frontiers in Rehabilitation Sciences 4 (2023).
  17. Błażejewski G and Witkoś J. “The Impact of COVID-19 on Menstrual Cycle in Women”. J Clin Med 12.15 (2023): 4991.
  18. Alvergne A., et al. “A retrospective case-control study on menstrual cycle changes following COVID-19 vaccination and disease”. iScience 26.4 (2023): 106401.
  19. Pollack B., et al. “Female reproductive health impacts of Long COVID and associated illnesses including ME/CFS, POTS, and connective tissue disorders: A literature review”. Frontiers in Rehabilitation Sciences 4 (2023).
  20. Machado K and Ayuk P. “Post-COVID-19 condition and pregnancy”. Case Reports in Women's Health 37 (2023).
  21. Wang L., et al. “Review of the 2019 novel coronavirus (SARS-CoV-2) based on current evidence”. Int J Antimicrob Agents 55.6 (2020): 105948. Epub 2020. Erratum in: Int J Antimicrob Agents 56.3 (2020): 106137.
  22. Chadchan SB., et al. “The SARS-CoV-2 receptor, angiotensin-converting enzyme 2, is required for human endometrial stromal cell decidualization”. Biol Reprod 104.2 (2021): 336-343.
  23. Jackson CB., et al. “Mechanisms of SARS-CoV-2 entry into cells”. Nat Rev Mol Cell Biol 23.1 (2022): 3-20.
  24. Alvergne A, Vlajic WM and Hogqvist TV. “Do sexually transmitted infections exacerbate negative premenstrual symptoms? Insights from digital health”. Evol Med Public Health 2018.1 (2018): 138-150.
  25. Chadchan SB., et al. “The SARS-CoV-2 receptor, angiotensin-converting enzyme 2, is required for human endometrial stromal cell decidualization”. Biol Reprod 104.2 (2021): 336-343.
  26. Qi J., et al. “The scRNA-seq Expression Profiling of the Receptor ACE2 and the Cellular Protease TMPRSS2 Reveals Human Organs Susceptible to SARS-CoV-2 Infection”. International Journal of Environmental Research and Public Health 18.1 (2021): 284.
  27. Aolymat I, Khasawneh AI and Al-Tamimi M. “COVID-19-associated mental health impact on menstrual function aspects: dysmenorrhea and premenstrual syndrome, and genitourinary tract health: a cross sectional study among Jordanian medical students”. Int J Environ Res Public Health 19.3 (2022): 1439.
  28. Xiao M., et al. “Metatranscriptomic analysis of host response and vaginal microbiome of patients with severe COVID-19”. Sci China Life Sci 65.7 (2022): 1473-1476.
  29. Li J., et al. “Effect of COVID-19 on Menstruation and Lower Reproductive Tract Health”. Int J Womens Health 15 (2023): 1999-2013.
  30. Cui P., et al. “Severe acute respiratory syndrome coronavirus 2 detection in the female lower genital tract”. Am J Obstet Gynecol 223.1 (2020): 131-134.
  31. Aslan MM., et al. “SARS-CoV-2 is not present in the vaginal fluid of pregnant women with COVID-19”. J Matern Fetal Neonatal Med 35.15 (2022): 2876-2878.
  32. Qiu L., et al. “SARS-CoV-2 Is Not Detectable in the Vaginal Fluid of Women with Severe COVID-19 Infection”. Clin Infect Dis 71.15 (2020): 813-817.
  33. Schwartz A., et al. “Detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vaginal swabs of women with acute SARS-CoV-2 infection: a prospective study”. BJOG 128.1 (2021): 97-100.
  34. Balc’h L., et al. “Herpes simplex virus and cytomegalovirus reactivations among severe COVID-19 patients”. Crit. Care 24 (2020): 530.
  35. Perera MR., et al. “Human cytomegalovirus infection of epithelial cells increases SARS-CoV-2 superinfection by upregulating the ACE2 receptor”. J. Infect. Dis 227 (2023): 543-553.
  36. Charvet B., et al. “SARS-CoV-2 induces human endogenous retrovirus type W envelope protein expression in blood lymphocytes and in tissues of COVID-19 patients”. medRxiv (2022).
  37. Qin H., et al. “Association between obesity and the risk of uterine fibroids: A systematic review and meta-analysis”. J. Epidemiol. Community Health 75 (2021): 197-204.
  38. Stewart EA., et al. “Epidemiology of uterine fibroids: A systematic review”. BJOG Int. J. Obstet. Gynaecol 124 (2017): 1501-1512.
  39. Raglan O., et al. “Risk factors for endometrial cancer: An umbrella review of the literature”. Int. J. Cancer 145 (2019): 1719-1730.
  40. Rabaan AA., et al. “Diverse immunological factors influencing pathogenesis in patients with COVID-19: A review on viral dissemination, immunotherapeutic options to counter cytokine storm and inflammatory responses”. Pathogens 10 (2021): 565.
  41. Eskenazi B., et al. “Diabetes mellitus, maternal adiposity, and insulin-dependent gestational diabetes are associated with COVID-19 in pregnancy: The INTERCOVID study”. Am. J. Obstet. Gynecol (2022): 227.
  42. Jasim FM and yas khudhair Obada A. “COVID-19 and Infertility (Cross-Sectional Study) World Bull”. Public Health 15 (2022): 156-167.
  43. Fernando SR., et al. “ACE inhibitors on ACE1, ACE2, and TMPRSS2 expression and spheroid attachment on human endometrial Ishikawa cells”. Reprod. Biol 22 (2022): 100666.
  44. Chadchan SB., et al. “The SARS-CoV-2 receptor, angiotensin-converting enzyme 2, is required for human endometrial stromal cell decidualization”. Biol Reprod 104.2 (2021): 336-343.
  45. Racilan AM., et al. “Angiotensin-converting enzyme 2, the SARS-CoV-2 cellular receptor, is widely expressed in human myometrium and uterine leiomyoma”. J. Endometr. Pelvic Pain Disord 13 (2021): 20-24.
  46. Dai Y-J., et al. “Comprehensive analysis of two potential novel SARS-CoV-2 entries, TMPRSS2 and IFITM3, in healthy individuals and cancer patients”. Int. J. Biol. Sci 16 (2020): 3028.
  47. Delforce SJ., et al. “Expression of renin-angiotensin system (RAS) components in endometrial cancer”. Endocr. Connect 6 (2017): 9-19.
  48. Wang J, Zhao H and An Y. “ACE2 Shedding and the Role in COVID-19”. Front. Cell. Infect. Microbiol (2022).
  49. Nagy B., et al. “A dramatic rise in serum ACE2 activity in a critically ill COVID-19 patient”. Int. J. Infect. Dis 103 (2021): 412-414.
  50. Smith JC., et al. “Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract”. Dev. Cell 53 (2020): 514-529.e3.
  51. Sharma P., et al. “COVID-19 and diabetes: Association intensify risk factors for morbidity and mortality”. Biomed. Pharmacother 151 (2022): 113089.
  52. Delforce SJ., et al. “Expression of renin-angiotensin system (RAS) components in endometrial cancer”. Endocr. Connect 6 (2017): 9-19.
  53. Huang Y., et al. “Comprehensive and Integrative Analysis of Two Novel SARS-CoV-2 Entry Associated Proteases CTSB and CTSL in Healthy Individuals and Cancer Patients”. Front. Bioeng. Biotechnol 10 (2022): 780751.
  54. Hoffmann M., et al. “SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor”. Cell 181 (2020): 271-280.e8.
  55. Fernando SR., et al. “ACE inhibitors on ACE1, ACE2, and TMPRSS2 expression and spheroid attachment on human endometrial Ishikawa cells”. Reprod. Biol 22 (2022): 100666.
  56. Dai Y-J., et al. “Comprehensive analysis of two potential novel SARS-CoV-2 entries, TMPRSS2 and IFITM3, in healthy individuals and cancer patients”. Int. J. Biol. Sci 16 (2020): 3028.
  57. Xiao M., et al. “Metatranscriptomic analysis of host response and vaginal microbiome of patients with severe COVID-19”. Sci China Life Sci 65.7 (2022): 1473-1476.
  58. Jin A., et al. “Elevated expression of CD147 in patients with endometriosis and its role in regulating apoptosis and migration of human endometrial cells”. Fertil. Steril 101 (2014): 1681-1687.e1.
  59. Onishi K., et al. “A systematic review of matrix metalloproteinases as potential biomarkers for uterine fibroids”. FS Rev 3 (2022): 227-241.
  60. Nakamura K., et al. “Role of emmprin in endometrial cancer”. BMC Cancer 12 (2012): 191.
  61. Lim S, Zhang M and Chang TL. “ACE2-Independent Alternative Receptors for SARS-CoV-2”. Viruses 14 (2022): 2535.
  62. Hoffman PJ., et al. “Molecular characterization of uterine fibroids and its implication for underlying mechanisms of pathogenesis”. Fertil. Steril 82 (2004): 639-649.
  63. Divine LM., et al. “AXL modulates extracellular matrix protein expression and is essential for invasion and metastasis in endometrial cancer”. Oncotarget 7 (2016): 77291.
  64. Kitsou K, Lagiou P and Magiorkinis G. “Human endogenous retroviruses in cancer: Oncogenesis mechanisms and clinical implications”. J. Med. Virol 95 (2023): e28350.
  65. Kitsou K, Lagiou P and Magiorkinis G. “Human endogenous retroviruses in cancer: Oncogenesis mechanisms and clinical implications”. J. Med. Virol 95 (2023): e28350.
  66. Strick R., et al. “Proliferation and cell-cell fusion of endometrial carcinoma are induced by the human endogenous retroviral Syncytin-1 and regulated by TGF-β”. J. Mol. Med 85 (2007): 23-38.
  67. Dittmar T., et al. “Cell-cell fusion mediated by viruses and HERV- derived fusogens in cancer initiation and progression”. Cancers 13 (2021): 5363.
  68. Balc’h L., et al. “Herpes simplex virus and cytomegalovirus reactivations among severe COVID-19 patients”. Crit. Care 24 (2020): 530.
  69. Cokić-Damjanović J, Horvat E and Balog A. “Herpes simplex virus and malignancies of female genital organs”. Medicinski Pregled 54 (2001): 432-437.
  70. Wang K, Hao W and Xia H. “Relationship between human papilloma virus-DNA and cytomegalovirus-DNA virus content and risk factors of endometrial cancer and prediction model”. Chin. J. Postgrad. Med 36 (2021): 481-486.
  71. Xiao M., et al. “Metatranscriptomic analysis of host response and vaginal microbiome of patients with severe COVID-19”. Sci China Life Sci 65.7 (2022): 1473-1476.
  72. Costantini S., et al. “New Insights into the Identification of Metabolites and Cytokines Predictive of Outcome for Patients with Severe SARS-CoV-2 Infection Showed Similarity with Cancer”. Int. J. Mol. Sci 24 (2023): 4922.
  73. Loretelli C., et al. “PD-1 blockade counteracts post-COVID-19 immune abnormalities and stimulates the anti-SARS-CoV-2 immune response”. JCI Insight 6 (2021): e146701.
  74. Che Q., et al. “Interleukin 6 promotes endometrial cancer growth through an autocrine feedback loop involving ERK- NF-κB signaling pathway”. Biochem. Biophys. Res. Commun 446 (2014): 167-172.
  75. Borghi C., et al. “Biomolecular basis related to inflammation in the pathogenesis of endometrial cancer”. Eur. Rev. Med. Pharmacol. Sci 22 (2018): 6294-6299.
  76. Heidari F., et al. “Inflammatory, oxidative stress and anti-oxidative markers in patients with endometrial carcinoma and diabetes”. Cytokine 120 (2019): 186-190.
  77. Zeng X., et al. “IL6 induces mtDNA leakage to affect the immune escape of endometrial carcinoma via cGAS-STING”. J. Immunol. Res (2022): 3815853.
  78. Loretelli C., et al. “PD-1 blockade counteracts post-COVID-19 immune abnormalities and stimulates the anti-SARS-CoV-2 immune response”. JCI Insight 6 (2021): e146701.
  79. Pasanen A., et al. “PD-L1 expression in endometrial carcinoma cells and intratumoral immune cells: Differences across histologic and TCGA-based molecular subgroups”. Am. J. Surg. Pathol 44 (2020): 174-181.
  80. Garcia-Diaz A., et al. “Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression”. Cell Rep 19 (2017): 1189-1201.
  81. Østergaard L. “SARS CoV-2 related microvascular damage and symptoms during and after COVID-19: Consequences of capillary transit-time changes, tissue hypoxia and inflammation”. Physiol. Rep 9 (2021): e14726.
  82. Dun EC., et al. “Infiltration of tumor-associated macrophages is increased in the epithelial and stromal compartments of endometrial carcinomas”. Int. J. Gynecol. Pathol 32 (2013): 576-584.
  83. Xiao L., et al. “Endometrial cancer cells promote M2-like macrophage polarization by delivering exosomal miRNA-21 under hypoxia condition”. J. Immunol. Res (2020): 9731049.
  84. Jensen AL., et al. “A subset of human uterine endometrial macrophages is alternatively activated”. Am. J. Reprod. Immunol 68 (2012): 374-386.
  85. Breisnes H., et al. B57. Cutting Edge Covid Research. American Thoracic Society; Washington, DC, USA: 2022. COVID-19 Effects on Lung Extracellular Matrix Remodeling, Wound Healing, and Neutrophil Activity: A Proof-of- Concept Biomarker Study (2022): A3165.
  86. Guizani I., et al. “SARS-CoV-2 and pathological matrix remodeling mediators”. Inflamm. Res 70 (2021): 847-858.
  87. Zannotti A., et al. “Macrophages and immune responses in uterine fibroids”. Cells 10 (2021): 982.
  88. Islam MS., et al. “Extracellular matrix in uterine leiomyoma pathogenesis: A potential target for future therapeutics”. Hum. Reprod. Update 24 (2018): 59-85.
  89. Ren X., et al. “Single-cell transcriptomic analysis highlights origin and pathological process of human endometrioid endometrial carcinoma”. Nat. Commun 13 (2022): 6300.
  90. Allen CN., et al. “SARS-CoV-2 Causes Lung Inflammation through Metabolic Reprogramming and RAGE”. Viruses 14 (2022): 983.
  91. Allen CN., et al. “SARS-CoV-2 Causes Lung Inflammation through Metabolic Reprogramming and RAGE”. Viruses 14 (2022): 983.
  92. Schneider WM., et al. “Genome-scale identification of SARS-CoV-2 and pan-coronavirus host factor networks”. Cell 184 (2021): 120-132.e14.
  93. McGuire MM., et al. “Whole exome sequencing in a random sample of North American women with leiomyomas identifies MED12 mutations in majority of uterine leiomyomas”. PLoS ONE 7 (2012): e33251.
  94. Prusinski Fernung LE, Al-Hendy A and Yang Q. “A preliminary study: Human fibroid Stro- 1+/CD44+ stem cells isolated from uterine fibroids demonstrate decreased DNA repair and genomic integrity compared to adjacent myometrial Stro-1+/CD44+ cells”. Reprod. Sci 26 (2019): 619-638.
  95. Kee J., et al. “SARS-CoV-2 disrupts host epigenetic regulation via histone mimicry”. Nature 610 (2022): 381-388.
  96. Berta DG., et al. “Deficient H2A. Z deposition is associated with genesis of uterine leiomyoma”. Nature 596 (2021): 398-403.
  97. García-Sanz P., et al. “Chromatin remodelling and DNA repair genes are frequently mutated in endometrioid endometrial carcinoma”. Int. J. Cancer 140 (2017): 1551-1563.
  98. Islam MS., et al. “Extracellular matrix in uterine leiomyoma pathogenesis: A potential target for future therapeutics”. Hum. Reprod. Update 24 (2018): 59-85.
  99. Falahati Z, Mohseni-Dargah M and Mirfakhraie R. “Emerging roles of long non-coding RNAs in uterine leiomyoma pathogenesis: A review”. Reprod. Sci 29 (2022): 1086-1101.