Anatomy and Physiology
The genital and lower urinary tract share a common embryologic origin in women, with the urethra, bladder trigone, vulvar vestibule, and the upper vagina all derived from the same estrogen receptor (ER)-rich primitive urogenital sinus tissue. The vulva is also derived from the urogenital sinus, but the epithelium of the labia majora is of ectodermal origin. The vagina is composed of an inner stratified squamous epithelium, a middle muscular layer, and an outer fibrous layer. In the presence of endogenous estrogen after puberty and before menopause, the lining of the vagina is characterized by a thickened, rugated surface that is well vascularized and lubricated in most women.
Estrogen is a dominant regulator of vaginal and lower urinary tract physiology. Estrogen receptor-α is present in the vaginal tissues of both premenopausal and postmenopausal women, whereas ER-β appears to have no or low expression in postmenopause vaginal tissue. Estrogen therapy (ET) does not appear to affect the presence of ER-β.[15,16] Estrogen receptor density is highest in the vagina, with decreasing density across the external genitalia to the skin. The density of the androgen receptor is the reverse. There are low levels in the vagina and higher levels in the external genitalia. Progesterone receptors are found in the vagina and the transitional epithelium of the vulvovaginal junction.
Estrogen receptors have also been found on autonomic and sensory neurons in the vagina and vulva. Estrogen therapy has been reported to decrease the density of sensory nociceptor neurons in the vagina. This function may serve to decrease the discomfort associated with GSM. With respect to the lower urinary tract, estrogen and progesterone receptors have been identified in the urethra, bladder, and pelvic floor muscles.
The changing physiology of the vaginal epithelium after menopause is not completely understood. On the basis of a cell-culture model that used vaginal-cervical epithelial cells, diminished estrogen levels and aging were found to be independent factors in decreasing vaginal-cervical paracellular permeability, a change potentially related to vaginal dryness. With atrophy, wet-mount microscopy shows more than one white blood cell per epithelial cell and immature vaginal epithelial cells with relatively large nuclei (parabasal cells). Cytology shows an increase in parabasal and intermediate cells, and superficial cells decrease or are absent. Immune cell populations seem to be similar or slightly decreased in number, with similar cytolytic capacity as before menopause.[21–23] However, some studies show differences in inflammatory markers in the vaginal fluid of postmenopausal women compared with premenopausal women.
Hormone changes throughout the life cycle influence the vaginal microbiome from birth through postmenopause.[25,26] During the reproductive years, the presence of a microbial community dominated by Lactobacillus species is associated with a lower pH and lower risk for bacterial vaginosis (BV), sexually transmitted infections, UTIs, and HIV infection.[27–35]
After menopause, women are less likely to have a Lactobacillus-dominant vaginal bacterial community and less likely to have a low vaginal pH.[26,36,37] Although cultivation-based studies show a significantly lower quantity of vaginal Lactobacillus in postmenopausal women, several newer sequencing studies observe that close to half have a high proportion of lactobacilli.[38,39] In one study, a higher proportion of Lactobacillus correlated inversely with examiner-reported dryness in postmenopausal women, but in another study, there was no association between Lactobacillus dominance and the severity of patient-reported symptoms.
The vaginal bacteria community of postmenopausal women has many similarities with that of reproductive-aged women with BV: high pH, higher diversity, and an abnormal Nugent score. In many women with GSM, however, these abnormalities reflect a decline in lactobacilli rather than an increase in the prevalence of pathogens.[42,43] Treatment with systemic or topical estrogen is associated with an increase in detection of vaginal lactobacilli.[44,45] This suggests that for many postmenopausal women, the best approach to promoting a healthy vaginal microbial community is not antibiotic therapy (as though treating BV) but rather vaginal estrogen therapy.
Menopause. 2020;27(9):976-992. © 2020 The North American Menopause Society