A study of 17beta-estradiol-regulated genes in the vagina of postmenopausal women with vaginal atrophy.
BACKGROUND
Vaginal atrophy (VA) is a prevalent disorder in postmenopausal women that is characterized by decreased epithelial thickness, reduced vaginal maturation index (VMI) and increased vaginal pH. Current medical therapy consists of local or systemic replacement of estrogens.


OBJECTIVE
The goal of this study was to understand, at a molecular level, the effect of estradiol (E2) on the vaginal epithelium.


METHODS
Nineteen women were treated with E2 delivered through a skin patch at a dose of 0.05mg/day for 12 weeks. The diagnosis of VA was confirmed by a VMI with < or =5% superficial cells and vaginal pH>5.0. Vaginal biopsy samples were collected at baseline and after treatment. Differentially expressed mRNA transcripts in these biopsies were determined by microarray analysis.


RESULTS
All 19 subjects had increased VMI (>5%) and/or reduced pH (< or =5) following treatment. Most subjects also had increased serum E2 levels and reduced serum FSH levels. Transcriptional profiling of vaginal biopsies identified over 3000 E2-regulated genes, including those involved in several key pathways known to regulate cell growth and proliferation, barrier function and pathogen defense.


CONCLUSIONS
E2 controls a plethora of cellular pathways that are concordant with its profound effect on vaginal physiology. The data presented here are a useful step toward understanding the role of E2 in vaginal tissue and the development of novel therapeutics for the treatment of VA.
Cotreau
Monette M
MM
Discovery Translational Medicine, Wyeth Research, Cambridge, MA, United States.
Chennathukuzhi
Vargheese M
VM
Harris
Heather A
HA
Han
Lixin
L
Dorner
Andrew J
AJ
Apseloff
Glen
G
Varadarajan
Usha
U
Hatstat
Ellyn
E
Zakaria
Marjorie
M
Strahs
Andrew L
AL
Crabtree
Judy S
JS
Winneker
Richard C
RC
Jelinsky
Scott A
SA
D000279:Administration, Cutaneous; D000328:Adult; D000368:Aged; D001284:Atrophy; D001706:Biopsy; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002979:Climacteric / Q000187:drug effects / Q000235:genetics*; D055233:Cornified Envelope Proline-Rich Proteins; D051183:Desmoglein 1 / Q000235:genetics; D004848:Epithelium / Q000187:drug effects / Q000473:pathology; D004958:Estradiol / Q000008:administration & dosage* / Q000097:blood; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D053506:Matrix Metalloproteinase 10 / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine; D011991:Receptors, Virus; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects; D014621:Vagina / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*
C106330:CXCR6 protein, human; D055233:Cornified Envelope Proline-Rich Proteins; C495297:DSG1 protein, human; D051183:Desmoglein 1; C524769:LCE3D protein, human; D008565:Membrane Proteins; D012333:RNA, Messenger; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine; D011991:Receptors, Virus; D004958:Estradiol; D005640:Follicle Stimulating Hormone; D053506:Matrix Metalloproteinase 10