OBJECTIVE: To evaluate the effect of iatrogenic menopause on the physiology of the vagina of the ewe and to evaluate if vaginal changes in ewes can be translated to women with genitourinary syndrome of menopause (GSM). METHODS: Preclinical research with Dohne Merino ewes. Iatrogenic menopause was induced by bilateral ovariectomy (OVX). Animals were randomized for surgery, blinded for allocation and outcome assessment. Differences between groups were determined by linear regression analyses at 5 months after OVX. Outcome measures were vaginal epithelial thickness, pH, vaginal maturation value, vaginal maturation index, epithelial glycogen accumulation, content of elastin fibers, collagen, and vascularity. RESULTS: OVX ewes (n = 20) showed epithelial thinning of the vaginal wall from 146 μm to 47 μm (mean, P < 0.001). Furthermore, epithelial glycogen accumulation and vascularity of the vaginal wall significantly decreased (43% and 23%, respectively) as compared with the control group (no intervention; n = 5). No significant differences were found for other outcome measures. CONCLUSION: This study established the ewe as a suitable large animal model for GSM. Furthermore, the similar relevant outcomes in humans and ewes hold great value for future translational research for the evaluation and optimization of different treatment modalities for GSM.

Amsterdam Reproduction and Development Research Institute Amsterdam Netherlands

Cardiovascular Research Unit Cape Hearth Center University of Cape Town Cape Town South Africa

Department of Development and Regeneration KU Leuven Leuven Belgium

Department of Obstetrics and Gynaecology Amsterdam UMC Location University of Amsterdam Amsterdam Netherlands

Department of Obstetrics and Gynaecology Groote Schuur Hospital University of Cape Town Cape Town South Africa

Institute for the Care of Mother and Child 3rd Faculty of Medicine Charles University Prague Czech Republic

Pelvic Floor Unit University Hospitals KU Leuven Leuven Belgium

Zobrazit více v PubMed

Portman DJ, Gass ML. 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;21(10):1063-1068.

Mac Bride MB, Rhodes DJ, Shuster LT. Vulvovaginal atrophy. Mayo Clin Proc. 2010;85(1):87-94.

Nappi RE, Palacios S. Impact of vulvovaginal atrophy on sexual health and quality of life at postmenopause. Climacteric. 2014;17(1):3-9.

Tan O, Bradshaw K, Carr BR. Management of vulvovaginal atrophy-related sexual dysfunction in postmenopausal women: an up-to-date review. Menopause. 2012;19(1):109-117.

Santoro N, Komi J. Prevalence and impact of vaginal symptoms among postmenopausal women. J Sex Med. 2009;6(8):2133-2142.

Palacios S, Henderson VW, Siseles N, Tan D, Villaseca P. Age of menopause and impact of climacteric symptoms by geographical region. Climacteric. 2010;13(5):419-428.

Couri BM, Lenis AT, Borazjani A, Paraiso MFR, Damaser MS. Animal models of female pelvic organ prolapse: lessons learned. Expert Rev Obstet Gynecol. 2012;7(3):249-260.

Mackova K, Mazzer AM, Mori Da Cunha M, et al. Vaginal Er:YAG laser application in the menopausal ewe model: a randomised estrogen and sham-controlled trial. BJOG. 2021;128(6):1087-1096.

Hympanova L, Rynkevic R, Mori Da Cunha M, et al. The ewe as an animal model of vaginal atrophy and vaginal Er:YAG laser application. Menopause. 2020;28(2):198-206.

Urbankova I, Callewaert G, Blacher S, et al. First delivery and ovariectomy affect biomechanical and structural properties of the vagina in the ovine model. Int Urogynecol J. 2019;30(3):455-464.

Richardson C. Diagnosis of pregnancy in the ewe by vaginal biopsy. Br Vet J. 1972;128(6):316-330.

Restall BJ. Histological observations on the reproductive tract of the ewe. Aust J Biol Sci. 1966;19(4):673-686.

Abecia JA, Forcada F, González-Bulnes A. Hormonal control of reproduction in small ruminants. Anim Reprod Sci. 2012;130(3-4):173-179.

Weber MA, Limpens J, Roovers J. Assessment of vaginal atrophy: a review. Int Urogynecol J. 2015;26(1):15-28.

Blomgren B, Johannesson U, Bohm-Starke N, Falconer C, Hilliges M. A computerised, unbiased method for epithelial measurement. Micron. 2004;35(5):319-329.

Kilkenny C, Parsons N, Kadyszewski E, et al. Survey of the quality of experimental design, statistical analysis and reporting of research using animals. PLoS One. 2009;4(11):e7824.

Hooijmans CR, Rovers MM, de Vries RB, Leenaars M, Ritskes-Hoitinga M, Langendam MW. SYRCLE's risk of bias tool for animal studies. BMC Med Res Methodol. 2014;14:43.

Diedrich CM, Guler Z, Hympanova L, et al. Evaluation of the short-term host response and biomechanics of an absorbable poly-4-hydroxybutyrate scaffold in a sheep model following vaginal implantation. BJOG. 2022;129(7):1039-1049.

Guler Z, Roovers JP. Role of fibroblasts and myofibroblasts on the pathogenesis and treatment of pelvic organ prolapse. Biomolecules. 2022;12(1):94.

Verhorstert KWJ, Gudde AN, Kortz BS, et al. Animal experimental research assessing urogynecologic surgical mesh implants: outcome measures describing the host response, a systematic review and meta-analysis. Neurourol Urodyn. 2021;40(5):1107-1119.

Vodegel EV, Kastelein AW, Jansen C, et al. The effects of oestrogen on vaginal wound healing: a systematic review and meta-analysis. Neurourol Urodyn. 2022;41(1):115-126.

Kastelein AW, de Graaf BC, Latul YP, et al. Ultra-high-frequency ultrasound: promising technique to visualize pelvic floor mesh in vivo. Ultrasound Obstet Gynecol. 2021;57(4):653-654.

Weber MA, Diedrich CM, Ince C, Roovers JP. Focal depth measurements of the vaginal wall: a new method to noninvasively quantify vaginal wall thickness in the diagnosis and treatment of vaginal atrophy. Menopause. 2016;23(8):833-838.

Kastelein AW, Diedrich CM, Jansen C, Zwolsman SE, Ince C, Roovers JWR. Validation of noninvasive focal depth measurements to determine epithelial thickness of the vaginal wall. Menopause. 2019;26(10):1160-1165.

Miller EA, Beasley DE, Dunn RR, Archie EA. Lactobacilli dominance and vaginal pH: why is the human vaginal microbiome unique? Front Microbiol. 2016;7:1936.

Flores SA, Hall CA. Atrophic vaginitis [Updated 2022 Oct 31]. StatPearls [Internet]. StatPearls Publishing LLC; 2023. https://www.ncbi.nlm.nih.gov/books/NBK564341/

Zong W, Stein SE, Starcher B, Meyn LA, Moalli PA. Alteration of vaginal elastin metabolism in women with pelvic organ prolapse. Obstet Gynecol. 2010;115(5):953-961.

Werb Z, Banda MJ, McKerrow JH, Sandhaus RA. Elastases and elastin degradation. J Invest Dermatol. 1982;79(Suppl 1):154s-159s.

Ulrich D, Edwards SL, Su K, et al. Influence of reproductive status on tissue composition and biomechanical properties of ovine vagina. PLoS One. 2014;9(4):e93172.

Moalli PA, Talarico LC, Sung VW, et al. Impact of menopause on collagen subtypes in the arcus tendineous fasciae pelvis. Am J Obstet Gynecol. 2004;190(3):620-627.