Clinical trial NCT05122065: Menopausal Vaginal Microbiome
Official title: Defining the Vaginal Microbiome and the Vaginal pH of Menopausal Women With and Without Genitourinary Syndrome and With and Without Hormone Replacement Therapy
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Menopause
Hormone Replacement Therapy
Genitourinary Syndrome of Menopause
Keywords: vaginal microbiome
menopause
hormone replacement therapy
Genitourinary syndrome of menopause
Lead sponsor: FemTec Health Inc.
Sponsor class: INDUSTRY
First posted: 2021-11-16
Enrollment: 432
Sex: FEMALE
Minimum age (years): 40
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Participants will be postmenopausal women with or without self-reported GSM that either follow or do not follow an HRT plan.

Brief summary: In this study the investigators will analyze the vaginal microbiome of menopausal women in order to shed light on its potential implication on menopausal symptoms and quality of life. Moreover, the investigators will assess the effect of hormone replacement treatment on symptoms and overall quality of life during menopause and whether women under hormone replacement treatment have distinct vaginal microbiome profiles.


Eligibility criteria: Inclusion Criteria:

* Women who are females from birth
* Women between 40-70 years old
* Women that are US residents, understand, and speak English
* Women of all race and ethnicities
* Women that are postmenopausal (at least 12 consecutive months without a period)
* Women with a naturally occuring menopause
* Women willing to abstain from all sexual activity, feminine hygiene products (eg. douches, wipes, washes, sprays, powders, moisturizers/lubricants, deodorant suppositories, tablet suppositories, anti-itch creams, hot tubs) on the vaginal area, and any vaginal suppositories for 48 hours before sampling
* Women who are healthy (without GSM)
* Women who have GSM:

  1. with formal diagnosis of GSM, or
  2. who regularly experience a couple of the following symptoms: (i) vaginal dryness, vaginal burning, vaginal discharge \& genital itching, vaginal irritation, (ii) light bleeding, discomfort or pain during or after intercourse, decreased lubrication during intercourse, decreased arousal, orgasm, libido, (iii) painful or difficult urination (dysuria), urinary frequency and urgency, recurrent UTIs (Urinary Tract Infections).
* Women who either take or do not take HRT, including estrogen-only medicines, combination of estrogen/progestin medicines, combination of estrogen/other medicines.

Exclusion Criteria:

* Women suffering from gynecological diseases including polycystic ovary syndrome, endometriosis, pelvic inflammatory disease, active HPV (human papillomavirus) or herpes simplex virus in the past few months, BV (Bacterial Vaginosis), yeast infections, or positive for any STD (Sexually Transmitted Disease; genital warts, chlamydia, gonorrhea, syphilis, trichomoniasis), HIV (Human Immunodeficiency Virus), cancer, type I diabetes, type II diabetes, chronic kidney disease.
* Women having any genital surgery including removal of one or both ovaries, uterus or cervix.
* Women whose menopause occurred by surgical operation (hysterectomy, oophorectomy), or drug/treatment (eg. chemotherapy, radiation therapy).
* Women using douches daily or weekly.
* Women who use on a regular basis one of the following: metformin, antihistamines, antidepressants, corticosteroids, boric acid, laxatives, antifungal/antimycotic medication.
* Women using any oral or vaginal prebiotics, probiotics, or antibiotics in the past 6 months.
* Women who take progestin-only medicines including progestin-only HRT.

Primary outcomes:
measure: Vaginal microbiome sample collection
timeFrame: Baseline
Secondary outcomes:
measure: Demographic questionnaire
timeFrame: Baseline
measure: Day-to-Day Impact of Vaginal Aging (DIVA) questionnaire
timeFrame: Baseline
measure: Menopause Rating Scale (MRS) questionnaire
timeFrame: Baseline
measure: Brief Resilience Scale (BRS) questionnaire
timeFrame: Baseline
measure: Vaginal pH -at home test kit
timeFrame: Baseline
measure: Facial Skin Type Test
timeFrame: Baseline
measure: Body Hydration Test
timeFrame: Baseline
Other outcomes:
Locations:
Study officials:
affiliation: FemTec Health Inc.
name: Kimberly Capone, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Farage MA, Miller KW, Sobel JD. Dynamics of the vaginal ecosystem - hormonal influences. Infectious Diseases: Research and Treatment. 2010. doi: 10.4137/IDRT.S3903
citation: Gliniewicz K, Schneider GM, Ridenhour BJ, Williams CJ, Song Y, Farage MA, Miller K, Forney LJ. Comparison of the Vaginal Microbiomes of Premenopausal and Postmenopausal Women. Front Microbiol. 2019 Feb 14;10:193. doi: 10.3389/fmicb.2019.00193. eCollection 2019.
citation: Muhleisen AL, Herbst-Kralovetz MM. Menopause and the vaginal microbiome. Maturitas. 2016 Sep;91:42-50. doi: 10.1016/j.maturitas.2016.05.015. Epub 2016 Jun 1.
citation: Angelou K, Grigoriadis T, Diakosavvas M, Zacharakis D, Athanasiou S. The Genitourinary Syndrome of Menopause: An Overview of the Recent Data. Cureus. 2020 Apr 8;12(4):e7586. doi: 10.7759/cureus.7586.
citation: Lobo RA. Hormone-replacement therapy: current thinking. Nat Rev Endocrinol. 2017 Apr;13(4):220-231. doi: 10.1038/nrendo.2016.164. Epub 2016 Oct 7.
citation: Nguyen TM, Do TTT, Tran TN, Kim JH. Exercise and Quality of Life in Women with Menopausal Symptoms: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Int J Environ Res Public Health. 2020 Sep 26;17(19):7049. doi: 10.3390/ijerph17197049.
citation: Gloor GB, Macklaim JM, Pawlowsky-Glahn V, Egozcue JJ. Microbiome Datasets Are Compositional: And This Is Not Optional. Front Microbiol. 2017 Nov 15;8:2224. doi: 10.3389/fmicb.2017.02224. eCollection 2017.
citation: Hillmann B, Al-Ghalith GA, Shields-Cutler RR, Zhu Q, Gohl DM, Beckman KB, Knight R, Knights D. Evaluating the Information Content of Shallow Shotgun Metagenomics. mSystems. 2018 Nov 13;3(6):e00069-18. doi: 10.1128/mSystems.00069-18. eCollection 2018 Nov-Dec.
citation: Yang Q, Wang Y, Wei X, Zhu J, Wang X, Xie X, Lu W. The Alterations of Vaginal Microbiome in HPV16 Infection as Identified by Shotgun Metagenomic Sequencing. Front Cell Infect Microbiol. 2020 Jun 23;10:286. doi: 10.3389/fcimb.2020.00286. eCollection 2020.
citation: Oliver A, LaMere B, Weihe C, Wandro S, Lindsay KL, Wadhwa PD, Mills DA, Pride DT, Fiehn O, Northen T, de Raad M, Li H, Martiny JBH, Lynch S, Whiteson K. Cervicovaginal Microbiome Composition Is Associated with Metabolic Profiles in Healthy Pregnancy. mBio. 2020 Aug 25;11(4):e01851-20. doi: 10.1128/mBio.01851-20.
citation: Feehily C, Crosby D, Walsh CJ, Lawton EM, Higgins S, McAuliffe FM, Cotter PD. Shotgun sequencing of the vaginal microbiome reveals both a species and functional potential signature of preterm birth. NPJ Biofilms Microbiomes. 2020 Nov 12;6(1):50. doi: 10.1038/s41522-020-00162-8.
citation: Nappi RE, Martini E, Cucinella L, Martella S, Tiranini L, Inzoli A, Brambilla E, Bosoni D, Cassani C, Gardella B. Addressing Vulvovaginal Atrophy (VVA)/Genitourinary Syndrome of Menopause (GSM) for Healthy Aging in Women. Front Endocrinol (Lausanne). 2019 Aug 21;10:561. doi: 10.3389/fendo.2019.00561. eCollection 2019.
citation: Jenabi E, Shobeiri F, Hazavehei SM, Roshanaei G. Assessment of Questionnaire Measuring Quality of Life in Menopausal Women: A Systematic Review. Oman Med J. 2015 May;30(3):151-6. doi: 10.5001/omj.2015.34.
citation: Davis SR, Lambrinoudaki I, Lumsden M, Mishra GD, Pal L, Rees M, Santoro N, Simoncini T. Menopause. Nat Rev Dis Primers. 2015 Apr 23;1:15004. doi: 10.1038/nrdp.2015.4.
citation: Whiteley J, DiBonaventura Md, Wagner JS, Alvir J, Shah S. The impact of menopausal symptoms on quality of life, productivity, and economic outcomes. J Womens Health (Larchmt). 2013 Nov;22(11):983-90. doi: 10.1089/jwh.2012.3719. Epub 2013 Oct 1.
citation: Portman DJ, Gass ML; Vulvovaginal Atrophy Terminology Consensus Conference Panel. Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women's Sexual Health and the North American Menopause Society. Menopause. 2014 Oct;21(10):1063-8. doi: 10.1097/GME.0000000000000329.
citation: The NAMS 2020 GSM Position Statement Editorial Panel. The 2020 genitourinary syndrome of menopause position statement of The North American Menopause Society. Menopause. 2020 Sep;27(9):976-992. doi: 10.1097/GME.0000000000001609.
citation: Briggs P. Genitourinary syndrome of menopause. Post Reprod Health. 2020 Jun;26(2):111-114. doi: 10.1177/2053369119884144. Epub 2019 Oct 23.
citation: Castelo-Branco C, Biglia N, Nappi RE, Schwenkhagen A, Palacios S. Characteristics of post-menopausal women with genitourinary syndrome of menopause: Implications for vulvovaginal atrophy diagnosis and treatment selection. Maturitas. 2015 Aug;81(4):462-9. doi: 10.1016/j.maturitas.2015.05.007. Epub 2015 May 30.
citation: Barrientos-Duran A, Fuentes-Lopez A, de Salazar A, Plaza-Diaz J, Garcia F. Reviewing the Composition of Vaginal Microbiota: Inclusion of Nutrition and Probiotic Factors in the Maintenance of Eubiosis. Nutrients. 2020 Feb 6;12(2):419. doi: 10.3390/nu12020419.
citation: Godha K, Tucker KM, Biehl C, Archer DF, Mirkin S. Human vaginal pH and microbiota: an update. Gynecol Endocrinol. 2018 Jun;34(6):451-455. doi: 10.1080/09513590.2017.1407753. Epub 2017 Dec 22.
citation: Kiss H, Kogler B, Petricevic L, Sauerzapf I, Klayraung S, Domig K, Viernstein H, Kneifel W. Vaginal Lactobacillus microbiota of healthy women in the late first trimester of pregnancy. BJOG. 2007 Nov;114(11):1402-7. doi: 10.1111/j.1471-0528.2007.01412.x. Epub 2007 Sep 17.
citation: Juliana NCA, Suiters MJM, Al-Nasiry S, Morre SA, Peters RPH, Ambrosino E. The Association Between Vaginal Microbiota Dysbiosis, Bacterial Vaginosis, and Aerobic Vaginitis, and Adverse Pregnancy Outcomes of Women Living in Sub-Saharan Africa: A Systematic Review. Front Public Health. 2020 Dec 10;8:567885. doi: 10.3389/fpubh.2020.567885. eCollection 2020.
citation: Ceccarani C, Foschi C, Parolin C, D'Antuono A, Gaspari V, Consolandi C, Laghi L, Camboni T, Vitali B, Severgnini M, Marangoni A. Diversity of vaginal microbiome and metabolome during genital infections. Sci Rep. 2019 Oct 1;9(1):14095. doi: 10.1038/s41598-019-50410-x.
citation: Mendling, W. Normal and abnormal vaginal microbiota. LaboratoriumsMedizin. 2016; 40(4): 239-246. doi: 10.1515/labmed-2016-0011
citation: Superti F, De Seta F. Warding Off Recurrent Yeast and Bacterial Vaginal Infections: Lactoferrin and Lactobacilli. Microorganisms. 2020 Jan 17;8(1):130. doi: 10.3390/microorganisms8010130.
citation: Amabebe E, Anumba DOC. The Vaginal Microenvironment: The Physiologic Role of Lactobacilli. Front Med (Lausanne). 2018 Jun 13;5:181. doi: 10.3389/fmed.2018.00181. eCollection 2018.
citation: Qi W, Li H, Wang C, Li H, Fan A, Han C, Xue F. The effect of pathophysiological changes in the vaginal milieu on the signs and symptoms of genitourinary syndrome of menopause (GSM). Menopause. 2020 Aug 17;28(1):102-108. doi: 10.1097/GME.0000000000001644.
citation: Brotman RM, Shardell MD, Gajer P, Fadrosh D, Chang K, Silver MI, Viscidi RP, Burke AE, Ravel J, Gravitt PE. Association between the vaginal microbiota, menopause status, and signs of vulvovaginal atrophy. Menopause. 2014 May;21(5):450-8. doi: 10.1097/GME.0b013e3182a4690b.
citation: Shen J, Song N, Williams CJ, Brown CJ, Yan Z, Xu C, Forney LJ. Effects of low dose estrogen therapy on the vaginal microbiomes of women with atrophic vaginitis. Sci Rep. 2016 Apr 22;6:24380. doi: 10.1038/srep24380.
citation: Geng L, Huang W, Jiang S, Zheng Y, Zhou Y, Zhou Y, Hu J, Li P, Tao M. Effect of Menopausal Hormone Therapy on the Vaginal Microbiota and Genitourinary Syndrome of Menopause in Chinese Menopausal Women. Front Microbiol. 2020 Nov 20;11:590877. doi: 10.3389/fmicb.2020.590877. eCollection 2020.
citation: Mitchell CM, Srinivasan S, Zhan X, Wu MC, Reed SD, Guthrie KA, LaCroix AZ, Fiedler T, Munch M, Liu C, Hoffman NG, Blair IA, Newton K, Freeman EW, Joffe H, Cohen L, Fredricks DN. Vaginal microbiota and genitourinary menopausal symptoms: a cross-sectional analysis. Menopause. 2017 Oct;24(10):1160-1166. doi: 10.1097/GME.0000000000000904.
citation: Hummelen R, Macklaim JM, Bisanz JE, Hammond JA, McMillan A, Vongsa R, Koenig D, Gloor GB, Reid G. Vaginal microbiome and epithelial gene array in post-menopausal women with moderate to severe dryness. PLoS One. 2011;6(11):e26602. doi: 10.1371/journal.pone.0026602. Epub 2011 Nov 2.
citation: Ma ZS, Li L. Quantifying the human vaginal community state types (CSTs) with the species specificity index. PeerJ. 2017 Jun 27;5:e3366. doi: 10.7717/peerj.3366. eCollection 2017.
citation: Ginkel PD, Soper DE, Bump RC, Dalton HP. Vaginal flora in postmenopausal women: the effect of estrogen replacement. Infect Dis Obstet Gynecol. 1993;1(2):94-7. doi: 10.1155/S1064744993000225.
citation: Heinemann C, Reid G. Vaginal microbial diversity among postmenopausal women with and without hormone replacement therapy. Can J Microbiol. 2005 Sep;51(9):777-81. doi: 10.1139/w05-070.
citation: Nelson HD. Commonly used types of postmenopausal estrogen for treatment of hot flashes: scientific review. JAMA. 2004 Apr 7;291(13):1610-20. doi: 10.1001/jama.291.13.1610.
citation: Galhardo CL, Soares JM Jr, Simoes RS, Haidar MA, Rodrigues de Lima G, Baracat EC. Estrogen effects on the vaginal pH, flora and cytology in late postmenopause after a long period without hormone therapy. Clin Exp Obstet Gynecol. 2006;33(2):85-9.
citation: Setty P, Rekedal L, Warren MP. Vaginal estrogen use and effects on quality of life and urogenital morbidity in postmenopausal women after publication of the Women's Health Initiative in New York City. Menopause. 2016 Jan;23(1):7-10. doi: 10.1097/GME.0000000000000493.
citation: Quince C, Walker AW, Simpson JT, Loman NJ, Segata N. Shotgun metagenomics, from sampling to analysis. Nat Biotechnol. 2017 Sep 12;35(9):833-844. doi: 10.1038/nbt.3935.
citation: Rausch P, Ruhlemann M, Hermes BM, Doms S, Dagan T, Dierking K, Domin H, Fraune S, von Frieling J, Hentschel U, Heinsen FA, Hoppner M, Jahn MT, Jaspers C, Kissoyan KAB, Langfeldt D, Rehman A, Reusch TBH, Roeder T, Schmitz RA, Schulenburg H, Soluch R, Sommer F, Stukenbrock E, Weiland-Brauer N, Rosenstiel P, Franke A, Bosch T, Baines JF. Comparative analysis of amplicon and metagenomic sequencing methods reveals key features in the evolution of animal metaorganisms. Microbiome. 2019 Sep 14;7(1):133. doi: 10.1186/s40168-019-0743-1.
citation: Durazzi F, Sala C, Castellani G, Manfreda G, Remondini D, De Cesare A. Comparison between 16S rRNA and shotgun sequencing data for the taxonomic characterization of the gut microbiota. Sci Rep. 2021 Feb 4;11(1):3030. doi: 10.1038/s41598-021-82726-y.
citation: Ravel J, Gajer P, Abdo Z, Schneider GM, Koenig SS, McCulle SL, Karlebach S, Gorle R, Russell J, Tacket CO, Brotman RM, Davis CC, Ault K, Peralta L, Forney LJ. Vaginal microbiome of reproductive-age women. Proc Natl Acad Sci U S A. 2011 Mar 15;108 Suppl 1(Suppl 1):4680-7. doi: 10.1073/pnas.1002611107. Epub 2010 Jun 3.
citation: Mancabelli L, Tarracchini C, Milani C, Lugli GA, Fontana F, Turroni F, van Sinderen D, Ventura M. Vaginotypes of the human vaginal microbiome. Environ Microbiol. 2021 Mar;23(3):1780-1792. doi: 10.1111/1462-2920.15441. Epub 2021 Feb 28.
citation: Beck D, Foster JA. Machine learning techniques accurately classify microbial communities by bacterial vaginosis characteristics. PLoS One. 2014 Feb 3;9(2):e87830. doi: 10.1371/journal.pone.0087830. eCollection 2014.
citation: Pérez-Gómez JF, Canul-Reich J, Hernández-Torruco J, Hernández-Ocaña B. Predictor selection for bacterial vaginosis diagnosis using decision tree and relief algorithms. Applied Sciences. 2020; 10(9):3291. doi: 10.3390/app10093291
citation: Lee YH, Kang GU, Jeon SY, Tagele SB, Pham HQ, Kim MS, Ahmad S, Jung DR, Park YJ, Han HS, Shin JH, Chong GO. Vaginal Microbiome-Based Bacterial Signatures for Predicting the Severity of Cervical Intraepithelial Neoplasia. Diagnostics (Basel). 2020 Nov 26;10(12):1013. doi: 10.3390/diagnostics10121013.
citation: Loomba R, Seguritan V, Li W, Long T, Klitgord N, Bhatt A, Dulai PS, Caussy C, Bettencourt R, Highlander SK, Jones MB, Sirlin CB, Schnabl B, Brinkac L, Schork N, Chen CH, Brenner DA, Biggs W, Yooseph S, Venter JC, Nelson KE. Gut Microbiome-Based Metagenomic Signature for Non-invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease. Cell Metab. 2019 Sep 3;30(3):607. doi: 10.1016/j.cmet.2019.08.002. No abstract available.
citation: Li J, Zhao F, Wang Y, Chen J, Tao J, Tian G, Wu S, Liu W, Cui Q, Geng B, Zhang W, Weldon R, Auguste K, Yang L, Liu X, Chen L, Yang X, Zhu B, Cai J. Gut microbiota dysbiosis contributes to the development of hypertension. Microbiome. 2017 Feb 1;5(1):14. doi: 10.1186/s40168-016-0222-x.
citation: Armour CR, Nayfach S, Pollard KS, Sharpton TJ. A Metagenomic Meta-analysis Reveals Functional Signatures of Health and Disease in the Human Gut Microbiome. mSystems. 2019 May 14;4(4):e00332-18. doi: 10.1128/mSystems.00332-18. eCollection 2019 Jul-Aug.
citation: Lloyd-Price J, Mahurkar A, Rahnavard G, Crabtree J, Orvis J, Hall AB, Brady A, Creasy HH, McCracken C, Giglio MG, McDonald D, Franzosa EA, Knight R, White O, Huttenhower C. Strains, functions and dynamics in the expanded Human Microbiome Project. Nature. 2017 Oct 5;550(7674):61-66. doi: 10.1038/nature23889. Epub 2017 Sep 20.
citation: Huang AJ, Gregorich SE, Kuppermann M, Nakagawa S, Van Den Eeden SK, Brown JS, Richter HE, Walter LC, Thom D, Stewart AL. Day-to-Day Impact of Vaginal Aging questionnaire: a multidimensional measure of the impact of vaginal symptoms on functioning and well-being in postmenopausal women. Menopause. 2015 Feb;22(2):144-54. doi: 10.1097/GME.0000000000000281.
citation: Heinemann LA, Potthoff P, Schneider HP. International versions of the Menopause Rating Scale (MRS). Health Qual Life Outcomes. 2003 Jul 30;1:28. doi: 10.1186/1477-7525-1-28.
citation: Smith BW, Dalen J, Wiggins K, Tooley E, Christopher P, Bernard J. The brief resilience scale: assessing the ability to bounce back. Int J Behav Med. 2008;15(3):194-200. doi: 10.1080/10705500802222972.
citation: Tsementzi D, Pena-Gonzalez A, Bai J, Hu YJ, Patel P, Shelton J, Dolan M, Arluck J, Khanna N, Conrad L, Scott I, Eng TY, Konstantinidis KT, Bruner DW. Comparison of vaginal microbiota in gynecologic cancer patients pre- and post-radiation therapy and healthy women. Cancer Med. 2020 Jun;9(11):3714-3724. doi: 10.1002/cam4.3027. Epub 2020 Apr 1.
citation: Lee JE, Lee S, Lee H, Song YM, Lee K, Han MJ, Sung J, Ko G. Association of the vaginal microbiota with human papillomavirus infection in a Korean twin cohort. PLoS One. 2013 May 22;8(5):e63514. doi: 10.1371/journal.pone.0063514. Print 2013.
citation: Wang X, Ji X. Sample Size Estimation in Clinical Research: From Randomized Controlled Trials to Observational Studies. Chest. 2020 Jul;158(1S):S12-S20. doi: 10.1016/j.chest.2020.03.010.