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Estrogen modulation of epithelial permeability in cervical-vaginal cells of premenopausal and postmenopausal women.

ABSTRACT: To understand how menopause affects estrogen regulation of epithelial permeability.Experimental study using human normal epithelial vaginal-ectocervical cells obtained from premenopausal and postmenopausal women. Endpoints were paracellular permeability (determined in terms of the resistance of the lateral intercellular space [RLIS] and tight junctions [RTJ]); cellular G-actin; nonmuscle myosin type II-B (NMMII-B) filamentation and magnesium-adenosine triphosphatase activity; and occludin expression (in terms of expression of the functional 65-kd and truncated 50-kd forms).Estrogen induced an early transient decrease in RLIS that correlated in time with increases in cellular G-actin and NMMII-B magnesium-adenosine triphosphatase activity and with decreases in NMMII-B filamentation and a slower decrease in RTJ that correlated with up-regulation of the 50-kd form of occludin. Estrogen modulation of G-actin NMMII-B and occludin could be described in terms of interaction with the estrogen receptor mechanism. The potency of estrogen effects was similar in cells of premenopausal and postmenopausal women, but the effects occurred earlier in cells of premenopausal women. RLIS returned to baseline faster in cells of postmenopausal women, and the effect was associated with faster reversal of estrogen changes in NMMII-B despite the continued presence of estrogen in the culture medium, suggesting that desensitization of the actin-myosin effects to estrogen actions occur distal to the estrogen receptor.The results suggest that the transient estrogen decrease in RLIS is mediated by modulation of actomyosin, and it is affected by the aging process. In contrast, the late persistent decrease in RTJ is mediated by occludin degradation and is unrelated to aging.

SUBMITTER: Gorodeski GI

PROVIDER: S-EPMC2366810 | biostudies-literature | 2007 Nov-Dec

REPOSITORIES: biostudies-literature

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Estrogen modulation of epithelial permeability in cervical-vaginal cells of premenopausal and postmenopausal women.

Gorodeski George I GI

Menopause (New York, N.Y.) 20071101 6

<h4>Objective</h4>To understand how menopause affects estrogen regulation of epithelial permeability.<h4>Design</h4>Experimental study using human normal epithelial vaginal-ectocervical cells obtained from premenopausal and postmenopausal women. Endpoints were paracellular permeability (determined in terms of the resistance of the lateral intercellular space [RLIS] and tight junctions [RTJ]); cellular G-actin; nonmuscle myosin type II-B (NMMII-B) filamentation and magnesium-adenosine triphosphat ...[more]

PMID: 17572644

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Project description:For decades hormone therapy (HT) has been prescribed to treat the symptoms of menopause, such as vaginal dryness, itching and burning. Here we sought to compare the vaginal microbiomes of postmenopausal women who received low dose estrogen therapy to those of premenopausal and postmenopausal women, and to do so in conjunction with assessing the alleviation of symptoms associated with vaginal atrophy. In this study vaginal swab samples were obtained from 45 women who were classified as either premenopausal, postmenopausal, or postmenopausal and undergoing HT. The vaginal microbiomes of these women were characterized by 16S rRNA gene sequencing and bacterial abundances were quantified by qPCR. We found that the vaginal communities from our cohort could be divided into six clusters (A-F) based on differences in the composition and relative abundances of bacterial taxa. Communities in cluster A were dominated by Lactobacillus crispatus, and those of cluster B were dominated by Gardnerella vaginalis. Communities in cluster C had high proportions of L. iners, while those in cluster D were more even and included several co-dominant taxa. Communities in clusters E and F were dominated by Bifidobacterium and L. gasseri, respectively. The vaginal communities of most postmenopausal women receiving HT (10/15) were dominated by species of lactobacilli and belonged to clusters A, C, and F (P < 0.001). This sharply contrasts with vaginal communities of postmenopausal women without HT, most of which (10/15) were in cluster D, depleted of lactobacilli, and had about 10-fold fewer total bacteria (P < 0.05). The vaginal communities of women in each study group differed in terms of the dominant bacterial species composition and relative abundance. Those of postmenopausal women receiving HT significantly differed from those of postmenopausal women without HT and were most often dominated by species of Lactobacillus. Noteworthy, HT greatly improved vaginal atrophy scores, decreased vaginal pH, and significantly increased bacterial numbers in comparison to postmenopausal women not receiving HT.

Project description:To understand estrogen regulation of proton (H(+)) secretion by human vaginal-ectocervical epithelial cells and the mechanisms involved.Primary-tertiary cultures of human normal vaginal-ectocervical epithelial cells were generated from surgical specimens of premenopausal women (aged 37-46 years) and of postmenopausal women (aged 53-65 years). Cells were grown on filters, and measurements were made of changes in extracellular pH (pHo) in the contraluminal (CL) and luminal (L) solutions 30 minutes after shifting cells to basic salt solution.Upon shifting cells to basic salt solution, CL-pHo decreased from 7.4 to 7.25, and was not affected by removal of intracellular estrogens or treatment with estradiol. L-pHo decreased from 7.4 to 7.05 in cells of premenopausal women, and from 7.4 to 7.20 in cells of postmenopausal women. Removal of intracellular estrogens attenuated the decrease in L-pHo in cells of premenopausal women (only to 7.20). In cells of premenopausal women stripped of estrogens, treatment with 10 nM 17beta-estradiol restored the decrease in L-pHo. In estrogen-stripped cells of postmenopausal women, treatment with estradiol augmented luminal acidification but to a lesser degree than in cells of premenopausal women (L-pHo of 7.15 vs 7.05). In cells of pre- and postmenopausal women, the addition in the L solution of bafilomycin-A(1), a specific inhibitor of the vacuolar-H(+)-ATPase (V-H(+)-ATPase), blocked the decrease in L-pHo.Human vaginal-ectocervical epithelial cells acidify constitutively their luminal solution, and the effect is mediated by active H(+) secretion by V-H(+)-ATPase expressed predominantly in the apical cell membrane. Estrogen deprivation attenuates, and treatment with 17beta-estradiol augments, active H(+) secretion. Finally, cells of postmenopausal women actively secrete H(+) via apically located V-H(+)-ATPase, but the effect is lesser, and estrogen failed to augment active H(+) secretion, as in cells of premenopausal women. These data suggest that in addition to hypoestrogenism, other factors of the aging process affect the capacity of vaginal-ectocervical cells to secrete acid.

Project description:BACKGROUND:Previous work has shown that the vaginal microbiome decreases in Lactobacillus predominance and becomes more diverse after menopause. It has also been shown that estrogen therapy restores Lactobacillus dominance in the vagina and that topical estrogen is associated with overactive bladder symptom improvement. We now know that the bladder contains a unique microbiome and that increased bladder microbiome diversity is associated with overactive bladder. However, there is no understanding of how quickly each pelvic floor microbiome responds to estrogen or if those changes are associated with symptom improvement. OBJECTIVE:This study aimed to determine if estrogen treatment of postmenopausal women with overactive bladder decreases urobiome diversity. STUDY DESIGN:We analyzed data from postmenopausal participants in 2 trials (NCT02524769 and NCT02835846) who chose vaginal estrogen as the primary overactive bladder treatment and used 0.5 g of conjugated estrogen (Premarin cream; Pfizer, New York City, NY) twice weekly for 12 weeks. Baseline and 12-week follow-up data included the Overactive Bladder questionnaire, and participants provided urine samples via catheter, vaginal swabs, perineal swabs, and voided urine samples. Microbes were detected by an enhanced culture protocol. Linear mixed models were used to estimate microbiome changes over time. Urinary antimicrobial peptide activity was assessed by a bacterial growth inhibition assay and correlated with relative abundance of members of the urobiome. RESULTS:In this study, 12 weeks of estrogen treatment resulted in decreased microbial diversity within the vagina (Shannon, P=.047; Richness, P=.043) but not in the other niches. A significant increase in Lactobacillus was detected in the bladder (P=.037) but not in the vagina (P=.33), perineum (P=.56), or voided urine (P=.28). The change in Lactobacillus levels in the bladder was associated with modest changes in urgency incontinence symptoms (P=.02). The relative abundance of the genus Corynebacterium correlated positively with urinary antimicrobial peptide activity after estrogen treatment. CONCLUSION:Estrogen therapy may change the microbiome of different pelvic floor niches. The vagina begins to decrease in diversity, and the bladder experiences a significant increase in Lactobacillus levels; the latter is correlated with a modest improvement in the symptom severity subscale of the Overactive Bladder questionnaire.

Dataset Information

Estrogen modulation of epithelial permeability in cervical-vaginal cells of premenopausal and postmenopausal women.

Publications

Estrogen modulation of epithelial permeability in cervical-vaginal cells of premenopausal and postmenopausal women.

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