Micro-Environmental Approach of Female Reproductive Diseases: Interactions Between Sex Hormones and Pathogens from Inflammation to Malignancy

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Mohamad Mowafaq Alharoun
Sahar Abdelkareem Ayed Alghweiri
Abdallah Hasan Kasim Obeidat
Ahed J Alkhatib


Both health and disease are significantly influenced by the female genital tract's distinct microenvironment, which plays a role in the reproductive process. This tract contains a wide variety of components, including, but not limited to, microbes, hormones, metabolites, and components of the immune system. The interactions that take place between these components have the potential to both ascertain the status of one's health as well as the presence or absence of illness. The purpose of this study was to conduct a literature review on the most recent developments in thought and trends regarding the hemostasis and interactions of the microenvironmental factors that are found in the genital tract. This review was to focus on the most recent developments in thought and trends regarding the hemostasis and interactions of the microenvironmental factors. The results of this research offered evidence that confirmed the conclusions of previous studies and highlighted how important it is to keep the immediate surroundings clean.

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Mohamad Mowafaq Alharoun, Sahar Abdelkareem Ayed Alghweiri, Abdallah Hasan Kasim Obeidat, & Ahed J Alkhatib. (2023). Micro-Environmental Approach of Female Reproductive Diseases: Interactions Between Sex Hormones and Pathogens from Inflammation to Malignancy. Journal of Coastal Life Medicine, 11(1), 1952–1961. Retrieved from https://www.jclmm.com/index.php/journal/article/view/614


Aagaard K., Ma J., Antony K. M., Ganu R., Petrosino J., Versalovic J. (2014). The placenta harbors a unique microbiome. Sci. Transl. Med. 6, 237ra265. 10.1126/scitranslmed.3008599.

Aldunate M., Srbinovski D., Hearps A. C., Latham C. F., Ramsland P. A., Gugasyan R., et al. (2015). Antimicrobial and immune modulatory effects of lactic acid and short chain fatty acids produced by vaginal microbiota associated with eubiosis and bacterial vaginosis. Front. Physiol. 6, 164. 10.3389/fphys.2015.00164.

Altmäe S., Esteban F. J., Stavreus-Evers A., Simón C., Giudice L., Lessey B. A., et al. (2014). Guidelines for the design, analysis and interpretation of ‘omics’ data: focus on human endometrium. Hum. Reprod. Update 20, 12–28. 10.1093/humupd/dmt048.

Bataineh MT, A. L., Soares, N. C., Semreen, M. H., Cacciatore, S., Dash, N. R., Hamad, M., et al. (2021). Candida albicans PPG1, a serine/threonine phosphatase, plays a vital role in central carbon metabolisms under filament-inducing conditions: A multi-omics approach. PloS One 16 (12), e0259588. doi: 10.1371/journal.pone.0259588.

Bataineh, M. T. A., Cacciatore, S., Semreen, M. H., Dash, N. R., Soares, N. C., Zhu, X., Mousa, M. K., Salam, J. S. A., Zerbini, L. F., Hajjo, R., & Hamad, M. (2022). Exploring the effect of estrogen on Candida albicans hyphal cell wall glycans and ergosterol synthesis. Frontiers in cellular and infection microbiology, 12, 977157. https://doi.org/10.3389/fcimb.2022.977157.

Bedoya A. M., Tate D. J., Baena A., Cordoba C. M., Borrero M., Pareja R., et al. (2014). Immunosuppression in cervical cancer with special reference to arginase activity. Gynecol. Oncol. 135, 74–80. 10.1016/j.ygyno.2014.07.096.

Benner M., Ferwerda G., Joosten I., Van Der Molen R. G. (2018). How uterine microbiota might be responsible for a receptive, fertile endometrium. Hum. Reprod. Update 24, 393–415. 10.1093/humupd/dmy012.

Borgogna J. C., Shardell M. D., Santori E. K., Nelson T. M., Rath J. M., Glover E. D., et al. (2020). The vaginal metabolome and microbiota of cervical HPV-positive and HPV-negative women: a cross-sectional analysis. Bjog 127, 182–192. 10.1111/1471-0528.15981.

Brazil JC, Parkos CA. Pathobiology of neutrophil-epithelial interactions. Immunol Rev (2016) 273:94–111. doi:10.1111/imr.12446.

Cassone, A. (2015). Vulvovaginal candida albicans infections: pathogenesis, immunity and vaccine prospects. BJOG: Int. J. Obstetrics Gynaecology. 122 (6), 785–794. doi: 10.1111/1471-0528.12994.

Ceccarani C., Foschi C., Parolin C., D’antuono A., Gaspari V., Consolandi C., et al. (2019). Diversity of vaginal microbiome and metabolome during genital infections. Sci. Rep. 9, 14095. 10.1038/s41598-019-50410-x.

Chen C., Song X., Wei W., Zhong H., Dai J., Lan Z., et al. (2017). The microbiota continuum along the female reproductive tract and its relation to uterine-related diseases. Nat. Commun. 8, 875. 10.1038/s41467-017-00901-0.

Cheng, G., Yeater, K. M., Hoyer, L. L. (2006). Cellular and molecular biology of candida albicans estrogen response. Eukaryotic Cell. 5 (1), 180–191. doi: 10.1128/EC.5.1.180-191.2006.

Collado M. C., Rautava S., Aakko J., Isolauri E., Salminen S. (2016). Human gut colonisation may be initiated in utero by distinct microbial communities in the placenta and amniotic fluid. Sci. Rep. 6, 23129. 10.1038/srep23129.

De Goffau M. C., Lager S., Sovio U., Gaccioli F., Cook E., Peacock S. J., et al. (2019). Human placenta has no microbiome but can contain potential pathogens. Nature 572, 329–334. 10.1038/s41586-019-1451-5.

Delgado-Diaz D. J., Tyssen D., Hayward J. A., Gugasyan R., Hearps A. C., Tachedjian G. (2019). Distinct Immune Responses Elicited From Cervicovaginal Epithelial Cells by Lactic Acid and Short Chain Fatty Acids Associated With Optimal and Non-optimal Vaginal Microbiota. Front. Cell Infect. Microbiol. 9, 446. 10.3389/fcimb.2019.00446ز

Deshmukh H., Way S. S. (2019). Immunological Basis for Recurrent Fetal Loss and Pregnancy Complications. Annu. Rev. Pathol. 14, 185–210. 10.1146/annurev-pathmechdis-012418-012743

Diamantis A, Androutsos G. Highlights from the history of hormonal cytology. Hormones (Athens) (2008) 7:184–6.

Diamantis A, Androutsos G. Highlights from the history of hormonal cytology. Hormones (Athens) (2008) 7:184–6.

Fernandes J. V., Ta D. E. M. F., Jc D. E. A., Cobucci R. N., Mg D. E. C., Andrade V. S., et al. (2015). Link between chronic inflammation and human papillomavirus-induced carcinogenesis (Review). Oncol. Lett. 9, 1015–1026. 10.3892/ol.2015.2884.

France M. T., Mendes-Soares H., Forney L. J. (2016). Genomic Comparisons of Lactobacillus crispatus and Lactobacillus iners Reveal Potential Ecological Drivers of Community Composition in the Vagina. Appl. Environ. Microbiol. 82, 7063–7073. 10.1128/AEM.02385-16.

Gajer P., Brotman R. M., Bai G., Sakamoto J., Schutte U. M., Zhong X., et al. (2012). Temporal dynamics of the human vaginal microbiota. Sci. Transl. Med. 4, 132ra152. 10.1126/scitranslmed.3003605.

Ghaemi M. S., Digiulio D. B., Contrepois K., Callahan B., Ngo T. T. M., Lee-Mcmullen B., et al. (2019). Multiomics modeling of the immunome, transcriptome, microbiome, proteome and metabolome adaptations during human pregnancy. Bioinformatics 35, 95–103. 10.1093/bioinformatics/bty537.

Ghartey J., Bastek J. A., Brown A. G., Anglim L., Elovitz M. A. (2015). Women with preterm birth have a distinct cervicovaginal metabolome. Am. J. Obstet. Gynecol. 212, 776.e771–776.e712. 10.1016/j.ajog.2015.03.052.

Gujjar, P. R., Finucane, M., Larsen, B. (1997). The effect of estradiol on candida albicans growth. Ann. Clin. Lab. Science. 27 (2), 151–156.

Hirata, T., Osuga, Y., Yoshino, O., Hirota, Y., Harada, M., Takemura, Y, et al. (2005). Development of an experimental model of endometriosis using mice that ubiquitously express green fluorescent protein. Human Reproduction 20 (8), 2092–2096. doi: 10.1093/humrep/dei012.

Hooper L. V., Littman D. R., Macpherson A. J. (2012). Interactions between the microbiota and the immune system. Science 336, 1268–1273. 10.1126/science.1223490.

Icard P., Shulman S., Farhat D., Steyaert J. M., Alifano M., Lincet H. (2018). How the Warburg effect supports aggressiveness and drug resistance of cancer cells? Drug Resist. Update 38, 1–11. 10.1016/j.drup.2018.03.001.

Ilhan Z. E., Laniewski P., Thomas N., Roe D. J., Chase D. M., Herbst-Kralovetz M. M. (2019). Deciphering the complex interplay between microbiota, HPV, inflammation and cancer through cervicovaginal metabolic profiling. EBioMedicine 44, 675–690. 10.1016/j.ebiom.2019.04.028.

Ismail A. Q. T. (2018). Does placental MDSC-mediated modulation of arginine levels help protect the foetus from auxotrophic pathogens? J. Matern. Fetal Neonatal Med. 31, 1667–1669. 10.1080/14767058.2017.1319935.

Kropf P., Baud D., Marshall S. E., Munder M., Mosley A., Fuentes J. M., et al. (2007). Arginase activity mediates reversible T cell hyporesponsiveness in human pregnancy. Eur. J. Immunol. 37, 935–945. 10.1002/eji.200636542.

Kruger P, Saffarzadeh M, Weber AN, Rieber N, Radsak M, Von Bernuth H, et al. Neutrophils: between host defence, immune modulation, and tissue injury. PLoS Pathog (2015) 11:e1004651. doi:10.1371/journal.ppat.1004651.

Kumwenda, P., Cottier, F., Hendry, A. C., Kneafsey, D., Keevan, B., Gallagher, H., Tsai, H. J., & Hall, R. A. (2022). Estrogen promotes innate immune evasion of Candida albicans through inactivation of the alternative complement system. Cell reports, 38(1), 110183. https://doi.org/10.1016/j.celrep.2021.110183

Kyongo J. K., Jespers V., Goovaerts O., Michiels J., Menten J., Fichorova R. N., et al. (2012). Searching for lower female genital tract soluble and cellular biomarkers: defining levels and predictors in a cohort of healthy Caucasian women. PloS One 7, e43951. 10.1371/journal.pone.0043951.

Lahoz-Beneytez J, Elemans M, Zhang Y, Ahmed R, Salam A, Block M, et al. Human neutrophil kinetics: modeling of stable isotope labeling data supports short blood neutrophil half-lives. Blood (2016) 127:3431–8. doi:10.1182/blood-2016-03-700336.

Laniewski P., Ilhan Z. E., Herbst-Kralovetz M. M. (2020). The microbiome and gynaecological cancer development, prevention and therapy. Nat. Rev. Urol. 17, 232–250. 10.1038/s41585-020-0286-z.

Li, H., Zang, Y., Wang, C., Li, H., Fan, A., Han, C., Xue, F. (2020). The Interaction Between Microorganisms, Metabolites, and Immune System in the Female Genital Tract Microenvironment. Frontiers in cellular and infection microbiology, 10, 609488. https://doi.org/10.3389/fcimb.2020.609488.

MacIntyre D. A., Chandiramani M., Lee Y. S., Kindinger L., Smith A., Angelopoulos N., et al. (2015). The vaginal microbiome during pregnancy and the postpartum period in a European population. Sci. Rep. 5, 8988. 10.1038/srep08988.

Macklaim J. M., Fernandes A. D., Di Bella J. M., Hammond J. A., Reid G., Gloor G. B. (2013). Comparative meta-RNA-seq of the vaginal microbiota and differential expression by Lactobacillus iners in health and dysbiosis. Microbiome 1, 12. 10.1186/2049-2618-1-12.

McMillan A., Rulisa S., Sumarah M., Macklaim J. M., Renaud J., Bisanz J. E., et al. (2015). A multi-platform metabolomics approach identifies highly specific biomarkers of bacterial diversity in the vagina of pregnant and non-pregnant women. Sci. Rep. 5, 14174. 10.1038/srep14174.

Mei C., Yang W., Wei X., Wu K., Huang D. (2019). The Unique Microbiome and Innate Immunity During Pregnancy. Front. Immunol. 10, 2886. 10.3389/fimmu.2019.02886.

Mitchell C., Manhart L. E., Thomas K., Fiedler T., Fredricks D. N., Marrazzo J. (2012). Behavioral predictors of colonization with Lactobacillus crispatus or Lactobacillus jensenii after treatment for bacterial vaginosis: a cohort study. Infect. Dis. Obstet. Gynecol. 2012, 706540. 10.1155/2012/706540.

Nemeth T, Mocsai A. Feedback amplification of neutrophil function. Trends Immunol (2016) 37:412–24. doi:10.1016/j.it.2016.04.002.

Nicolas-Avila JA, Adrover JM, Hidalgo A (2017). Neutrophils in homeostasis, immunity, and cancer. Immunity, 46:15–28. doi:10.1016/j.immuni.2016.12.012.

Nuriel-Ohayon M., Neuman H., Koren O. (2016). Microbial Changes during Pregnancy, Birth, and Infancy. Front. Microbiol. 7, 1031. 10.3389/fmicb.2016.01031.

Parkos CA. Neutrophil-epithelial interactions: a double-edged sword. Am J Pathol (2016) 186:1404–16. doi:10.1016/j.ajpath.2016.02.001.

Postler T. S., Ghosh S. (2017). Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System. Cell Metab. 26, 110–130. 10.1016/j.cmet.2017.05.008.

Pruski P., Lewis H. V., Lee Y. S., Marchesi J. R., Bennett P. R., Takats Z., et al. (2018). Assessment of microbiota:host interactions at the vaginal mucosa interface. Methods 149, 74–84. 10.1016/j.ymeth.2018.04.022.

Ravel J., Gajer P., Abdo Z., Schneider G. M., Koenig S. S., Mcculle S. L., et al. (2011). Vaginal microbiome of reproductive-age women. Proc. Natl. Acad. Sci. U.S.A. 108 Suppl 1, 4680–4687. 10.1073/pnas.1002611107.

Salinas-Muñoz, L., Campos-Fernández, R., Mercader, E., Olivera-Valle, I., Fernández-Pacheco, C., Matilla, L., García-Bordas, J., Brazil, J. C., Parkos, C. A., Asensio, F., Muñoz-Fernández, M. A., Hidalgo, A., Sánchez-Mateos, P., Samaniego, R., & Relloso, M. (2018). Estrogen Receptor-Alpha (ESR1) Governs the Lower Female Reproductive Tract Vulnerability to Candida albicans. Frontiers in immunology, 9, 1033. https://doi.org/10.3389/fimmu.2018.01033.

Sasaki S, Nagata K, Kobayashi Y. Regulation of the estrous cycle by neutrophil infiltration into the vagina. Biochem Biophys Res Commun (2009) 382:35–40. doi:10.1016/j.bbrc.2009.02.112.

Scott A. J., Alexander J. L., Merrifield C. A., Cunningham D., Jobin C., Brown R., et al. (2019). International Cancer Microbiome Consortium consensus statement on the role of the human microbiome in carcinogenesis. Gut 68, 1624–1632. 10.1136/gutjnl-2019-318556.

Serrano M. G., Parikh H. I., Brooks J. P., Edwards D. J., Arodz T. J., Edupuganti L., et al. (2019). Racioethnic diversity in the dynamics of the vaginal microbiome during pregnancy. Nat. Med. 25, 1001–1011. 10.1038/s41591-019-0465-8.

Sherrard J., Wilson J., Donders G., Mendling W., Jensen J. S. (2018). 2018 European (IUSTI/WHO) International Union against sexually transmitted infections (IUSTI) World Health Organisation (WHO) guideline on the management of vaginal discharge. Int. J. STD AIDS 29, 1258–1272. 10.1177/0956462418785451.

Smith S. B., Ravel J. (2017). The vaginal microbiota, host defence and reproductive physiology. J. Physiol. 595, 451–463. 10.1113/JP271694.

Song J., Wang X., Guo Y., Yang Y., Xu K., Wang T., et al. (2019). Novel high-coverage targeted metabolomics method (SWATHtoMRM) for exploring follicular fluid metabolome alterations in women with recurrent spontaneous abortion undergoing in vitro fertilization. Sci. Rep. 9, 10873. 10.1038/s41598-019-47370-7ز

Srinivasan S., Morgan M. T., Fiedler T. L., Djukovic D., Hoffman N. G., Raftery D., et al. (2015). Metabolic signatures of bacterial vaginosis. mBio 6, e00204-15. 10.1128/mBio.00204-15.

Suarez SS, Pacey AA. Sperm transport in the female reproductive tract. Hum Reprod Update (2006) 12:23–37. doi:10.1093/humupd/dmi047.

Swee M, Wilson CL, Wang Y, Mcguire JK, Parks WC. Matrix metalloproteinase-7 (matrilysin) controls neutrophil egress by generating chemokine gradients. J Leukoc Biol (2008) 83:1404–12. doi:10.1189/jlb.0108016.

Tao Z., Zhang L., Zhang Q., Lv T., Chen R., Wang L., et al. (2019). The Pathogenesis Of Streptococcus anginosus In Aerobic Vaginitis. Infect. Drug Resist. 12, 3745–3754. 10.2147/IDR.S227883.

Tavares-Murta B. M., De Resende A. D., Cunha F. Q., Murta E. F. (2008). Local profile of cytokines and nitric oxide in patients with bacterial vaginosis and cervical intraepithelial neoplasia. Eur. J. Obstet. Gynecol. Reprod. Biol. 138, 93–99. 10.1016/j.ejogrb.2007.06.015.

Van Der Veer C., Hertzberger R. Y., Bruisten S. M., Tytgat H. L. P., Swanenburg J., De Kat Angelino-Bart A., et al. (2019). Comparative genomics of human Lactobacillus crispatus isolates reveals genes for glycosylation and glycogen degradation: implications for in vivo dominance of the vaginal microbiota. Microbiome 7, 49. 10.1186/s40168-019-0667-9.

Wagner, R. D., Johnson, S. J. (2012). Probiotic lactobacillus and estrogen effects on vaginal epithelial gene expression responses to candida albicans. J. Biomed. science. 19 (1), 1–8. doi: 10.1186/1423-0127-19-58.

Wang Q., Wurtz P., Auro K., Makinen V. P., Kangas A. J., Soininen P., et al. (2016). Metabolic profiling of pregnancy: cross-sectional and longitudinal evidence. BMC Med. 14, 205. 10.1186/s12916-016-0733-0.

Watson E., Reid G. (2018). Metabolomics as a clinical testing method for the diagnosis of vaginal dysbiosis. Am. J. Reprod. Immunol. 80, e12979. 10.1111/aji.12979.

Wira CR, Rodriguez-Garcia M, Patel MV. The role of sex hormones in immune protection of the female reproductive tract. Nat Rev Immunol (2015) 15(4):217–30. doi:10.1038/nri3819.

Workowski K. A., Bolan G. A. (2015). Sexually transmitted diseases treatment guidelines 2015. MMWR Recomm. Rep. 64, 1–137.

Zec K, Volke J, Vijitha N, Thiebes S, Gunzer M, Kurts C, et al. Neutrophil migration into the infected uroepithelium is regulated by the crosstalk between resident and helper macrophages. Pathogens (2016) 5:15. doi:10.3390/pathogens5010015.

Zhang, X., Essmann, M., Burt, E. T., Larsen, B. (2000). Estrogen effects on candida albicans: A potential virulence-regulating mechanism. J. Infect. diseases. 181 (4), 1441–1446. doi: 10.1086/315406.