Impact of hormonal treatments for endometriosis on the reproductive microbiome: a systematic review

Stefania Luppi^1,2Ghergana Alexandrova Topouzova¹Giuseppina Campisciano¹Elena Giolo¹Teresa Bulfone¹Francesca Rossi¹Gabriella Zito¹GIUSEPPE RICCI^1,2Manola Comar^1,2Eva Andreuzzi^1*

• ¹Institute for Maternal and Child Health Burlo Garofolo (IRCCS), Trieste, Italy
• ²Universita degli Studi di Trieste, Trieste, Italy

Introduction: The reproductive microbiome plays a key role in disease progression and fertility in women with endometriosis. Vaginal and endometrial dysbiosis has been increasingly linked to inflammation, impaired reproductive outcomes, and symptom severity. Although estro-progestins, progestins, and GnRH agonists are widely used, their impact on microbial communities remains poorly understood, highlighting the need to clarify microbiome–therapy interactions. This systematic review aims to comprehensively synthesize current evidence on how hormonal therapies influence the reproductive microbial environment and to offer insights for optimizing clinical management of endometriosis. Methods: Literature screening and data extraction followed PRISMA guidelines using PubMed, Scopus, and Google Scholar. The search combined terms on endometriosis, hormonal therapy, and reproductive microbiome. Non-English studies, reviews, and those without original data were excluded. Risk of bias was assessed with ROBINS-I-V2, and microbial composition and diversity were analyzed and synthesized qualitatively. Results: The literature search retrieved 577 publications, of which 6 met eligibility criteria and were analyzed. The evidence collected through sequencing or culture-based methods suggested that the use of hormonal therapies to treat endometriosis may impact both vaginal and endometrial microbiome, favoring the colonization of bacterial species associated with infertility. GnRHa resulted to foster the dominance of potentially pathogenic bacteria, as Gardnerella and Streptococcaceae, in the endometrium, and supporting bacterial vaginosis by increasing intermediate flora (Nugent score 4-6). A similar effect on the vaginal environment has been reported upon the use of oral contraceptive pills, which was shown to prompt the increase of Prevotella, Ureaplasma, Streptococcus anginosus and Streptococcus agalactiae, among other pathogenic microbes, and to enhance the Bacillota/Bacteroidota ratio. Discussion: Despite affected by several limitations and heterogeneity of included studies, this review provides a preliminary overview of the possible pejorative effect of hormonal therapy on the reproductive microbiome of endometriosis patients. Whilst further investigations are required to consolidate these findings, the observations raised offer a valuable basis for opening a discussion about improving management strategies for affected women. By highlighting confounding factors overlooked in the selected papers, the present work will also be functional to optimize the design of future studies. Systematic Review Registration: PROSPERO (registration number: CRD420251042858)