Association between the vaginal microbiota, menopause status, and signs of vulvovaginal atrophy

Objective: The vaginal microbiota helps protect the female genital tract from disease. We sought to describe the composition of the vaginal microbiota in premenopausal, perimenopausal, and postmenopausal women and to explore the association between the microbiota and vulvovaginal atrophy (VVA). Methods: Eighty-seven women (aged 35-60 y) were classified as premenopausal (n = 30), perimenopausal (n = 29), or postmenopausal (n = 28) according to Stages of Reproductive Aging Workshop guidelines. Midvaginal bacterial community composition was characterized by 16S ribosomal RNA gene analysis. Results: Bacterial communities clustered into six community state types (CSTs), of which four were dominated by Lactobacillus crispatus, Lactobacillus gasseri, Lactobacillus iners, or Lactobacillus jensenii, and two (CST IV-A and CST IV-B) had low relative abundance of Lactobacillus. CST IV-A was characterized by Streptococcus and Prevotella, whereas CST IV-B was characterized by Atopobium. There were significant associations between menopause stage and CST (P = 0.004) and between VVA and CST (P = 0.002). Perimenopausal women were more likely to be classified as CST IV-A or L. gasseri CST, whereas postmenopausal women were often classified as CST IV-A. CSTs dominated by L. crispatus and L. iners were more prevalent in premenopausal women. Nineteen participants had signs of mild or moderate VVA. Compared with women with no VVA, the vaginal microbiota of women with mild or moderate atrophy had 25-fold greater odds of being classified as CST IV-A versus L. crispatus CST (adjusted odds ratio, 25.89; 95% credible interval, 2.98-406.79). Conclusions: A distinct bacterial community state (CST IV-A) with a low relative abundance of Lactobacillus is associated with VVA. Future studies recruiting a larger number of women are needed to replicate the findings. This study provides an impetus for future longitudinal studies designed to manage, modulate, and restore vaginal microbiota homeostasis, which would provide stronger evidence for a causal relationship with VVA and ultimately improve the treatment and prevention of atrophic vaginitis in menopause.

[1]  H. Viernstein,et al.  Randomized, double-blind, placebo-controlled study of oral lactobacilli to improve the vaginal flora of postmenopausal women. , 2008, European journal of obstetrics, gynecology, and reproductive biology.

[2]  Peter J. Schmidt,et al.  The 2022 hormone therapy position statement of The North American Menopause Society , 2022, Menopause.

[3]  Pierre Legendre,et al.  DISTANCE‐BASED REDUNDANCY ANALYSIS: TESTING MULTISPECIES RESPONSES IN MULTIFACTORIAL ECOLOGICAL EXPERIMENTS , 1999 .

[4]  E. Boyko,et al.  Prevalence and determinants of vaginal flora alterations in postmenopausal women. , 2003, The Journal of infectious diseases.

[5]  P. Gajer,et al.  Comparison of Storage Conditions for Human Vaginal Microbiome Studies , 2012, PloS one.

[6]  S. Kingsberg,et al.  Resistance and barriers to local estrogen therapy in women with atrophic vaginitis. , 2013, The journal of sexual medicine.

[7]  A. Burke,et al.  A cohort effect of the sexual revolution may be masking an increase in human papillomavirus detection at menopause in the United States. , 2013, The Journal of infectious diseases.

[8]  M. Ferris,et al.  Cultivation-Independent Analysis of Changes in Bacterial Vaginosis Flora Following Metronidazole Treatment , 2007, Journal of Clinical Microbiology.

[9]  M. Ronaghi.  Pyrosequencing sheds light on DNA sequencing. , 2001, Genome research.

[10]  S. Hillier,et al.  Vaginal microflora in postmenopausal women who have not received estrogen replacement therapy. , 1997, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[11]  M. Plummer,et al.  CODA: convergence diagnosis and output analysis for MCMC , 2006 .

[12]  G. Reid,et al.  Evaluation of the bacterial vaginal flora of 20 postmenopausal women by direct (Nugent score) and molecular (polymerase chain reaction and denaturing gradient gel electrophoresis) techniques. , 2002, The Journal of infectious diseases.

[13]  G. Reid,et al.  Detection of Atopobium vaginae in Postmenopausal Women by Cultivation-Independent Methods Warrants Further Investigation , 2004, Journal of Clinical Microbiology.

[14]  A. Burke,et al.  Contributions of recent and past sexual partnerships on incident human papillomavirus detection: acquisition and reactivation in older women. , 2012, Cancer research.

[15]  L. Shuster,et al.  Vulvovaginal atrophy. , 2010, Mayo Clinic proceedings.

[16]  G. Reid,et al.  Vaginal microbial diversity among postmenopausal women with and without hormone replacement therapy. , 2005, Canadian journal of microbiology.

[17]  David H. Martin,et al.  The Microbiota of the Vagina and Its Influence on Women's Health and Disease , 2012, The American journal of the medical sciences.

[18]  C. Castelo-Branco,et al.  Management of post-menopausal vaginal atrophy and atrophic vaginitis. , 2005, Maturitas.

[19]  J. Nicholson,et al.  Gut microbiota: Dietary and social modulation of gut microbiota in the elderly , 2012, Nature Reviews Gastroenterology &Hepatology.

[20]  K. Schleifer,et al.  Phylogenetic identification and in situ detection of individual microbial cells without cultivation , 1995 .

[21]  R. Lehrer,et al.  Inerolysin, a Cholesterol-Dependent Cytolysin Produced by Lactobacillus iners , 2010, Journal of bacteriology.

[22]  L. Bakken.  Separation and Purification of Bacteria from Soil , 1985, Applied and environmental microbiology.

[23]  R. Cruickshank.  The conversion of the glycogen of the vagina into lactic acid , 1934 .

[24]  J. Marrazzo,et al.  Molecular identification of bacteria associated with bacterial vaginosis. , 2005, The New England journal of medicine.

[25]  E. Bosmans,et al.  Definition of a type of abnormal vaginal flora that is distinct from bacterial vaginosis: aerobic vaginitis , 2002, BJOG : an international journal of obstetrics and gynaecology.

[26]  Philip Heidelberger,et al.  Simulation Run Length Control in the Presence of an Initial Transient , 1983, Oper. Res..

[27]  Rob Knight,et al.  UCHIME improves sensitivity and speed of chimera detection , 2011, Bioinform..

[28]  J. Graf,et al.  Directed Culturing of Microorganisms Using Metatranscriptomics , 2011, mBio.

[29]  J. Simon,et al.  Understanding the menopausal experiences of professional women , 2009, Menopause.

[30]  C. Christiansen,et al.  An update on the antiestrogenic effect of smoking: a literature review with implications for researchers and practitioners , 2004, Menopause.

[31]  W. Shen,et al.  The Correlation Between Human Papillomavirus Positivity and Abnormal Cervical Cytology Result Differs by Age Among Perimenopausal Women , 2013, Journal of lower genital tract disease.

[32]  J. Tiedje,et al.  Naïve Bayesian Classifier for Rapid Assignment of rRNA Sequences into the New Bacterial Taxonomy , 2007, Applied and Environmental Microbiology.

[33]  R. Brotman,et al.  Bacterial vaginosis assessed by gram stain and diminished colonization resistance to incident gonococcal, chlamydial, and trichomonal genital infection. , 2010, The Journal of infectious diseases.

[34]  Jean M. Macklaim,et al.  Vaginal Microbiome and Epithelial Gene Array in Post-Menopausal Women with Moderate to Severe Dryness , 2011, PloS one.

[35]  J. Remon,et al.  Mucosal Irritation Potential of Personal Lubricants Relates to Product Osmolality as Detected by the Slug Mucosal Irritation Assay , 2008, Sexually transmitted diseases.

[36]  R. Wahl,et al.  Hyperosmolar sexual lubricant causes epithelial damage in the distal colon: potential implication for HIV transmission. , 2007, The Journal of infectious diseases.

[37]  J. Marrazzo,et al.  Temporal Variability of Human Vaginal Bacteria and Relationship with Bacterial Vaginosis , 2010, PloS one.

[38]  P. Brigidi,et al.  The aging gut microbiota: New perspectives , 2011, Ageing Research Reviews.

[39]  M. Soules,et al.  Executive summary: Stages of Reproductive Aging Workshop (STRAW) Park City, Utah, July, 2001. , 2001, Menopause.

[40]  R. Nappi,et al.  Vaginal Health: Insights, Views & Attitudes (VIVA) – results from an international survey , 2012, Climacteric : the journal of the International Menopause Society.

[41]  P. Gajer,et al.  Vaginal microbiome of reproductive-age women , 2010, Proceedings of the National Academy of Sciences.

[42]  Jacques Ravel,et al.  Rapid fluctuation of the vaginal microbiota measured by Gram stain analysis , 2010, Sexually Transmitted Infections.

[43]  A. Lethaby,et al.  Local oestrogen for vaginal atrophy in postmenopausal women. , 2003, The Cochrane database of systematic reviews.

[44]  A. Burke,et al.  Differences in the concentration and correlation of cervical immune markers among HPV positive and negative perimenopausal women. , 2011, Cytokine.

[45]  Andrew D. Martin,et al.  MCMCpack: Markov chain Monte Carlo in R , 2011 .

[46]  Connie Celum,et al.  Bacterial Vaginosis Associated with Increased Risk of Female-to-Male HIV-1 Transmission: A Prospective Cohort Analysis among African Couples , 2012, PLoS medicine.

[47]  R. Weiss,et al.  The Slippery Slope: Lubricant Use and Rectal Sexually Transmitted Infections: A Newly Identified Risk , 2012, Sexually transmitted diseases.

[48]  K. Bradshaw,et al.  Management of vulvovaginal atrophy-related sexual dysfunction in postmenopausal women: an up-to-date review , 2012, Menopause.

[49]  Adrian E. Raftery,et al.  [Practical Markov Chain Monte Carlo]: Comment: One Long Run with Diagnostics: Implementation Strategies for Markov Chain Monte Carlo , 1992 .

[50]  J. Fortenberry,et al.  Association of Atopobium vaginae, a recently described metronidazole resistant anaerobe, with bacterial vaginosis , 2004, BMC infectious diseases.

[51]  N. Panay,et al.  Recommendations for the management of postmenopausal vaginal atrophy , 2010, Climacteric : the journal of the International Menopause Society.

[52]  F. Bushman,et al.  The Macaque Gut Microbiome in Health, Lentiviral Infection, and Chronic Enterocolitis , 2008, PLoS pathogens.

[53]  Robert C. Edgar,et al.  BIOINFORMATICS APPLICATIONS NOTE , 2001 .

[54]  P. Nyirjesy.  Postmenopausal vaginitis , 2007, Current infectious disease reports.

[55]  Jeanne M. Marrazzo,et al.  Bacterial Communities in Women with Bacterial Vaginosis: High Resolution Phylogenetic Analyses Reveal Relationships of Microbiota to Clinical Criteria , 2012, PloS one.

[56]  K. Eyster,et al.  What Happened to WHI: Menopausal Hormonal Therapy in 2012 , 2012, Clinical obstetrics and gynecology.

[57]  E. Ozkinay,et al.  The effectiveness of live lactobacilli in combination with low dose oestriol (Gynoflor) to restore the vaginal flora after treatment of vaginal infections , 2005, BJOG : an international journal of obstetrics and gynaecology.

[58]  Zaid Abdo,et al.  Temporal Dynamics of the Human Vaginal Microbiota , 2012, Science Translational Medicine.

[59]  Gary King,et al.  Toward a Common Framework for Statistical Analysis and Development , 2008 .