Adenomyosis--a result of disordered stromal differentiation.
Adenomyosis is a fairly frequent disorder in adult women characterized by the haphazard location of endometrial glands and stroma deep within the myometrium of the uterus. This study compared the effects on uterine development of the selective estrogen receptor modulators, tamoxifen, toremifene, and raloxifene with estradiol when given orally to female mice on days 2 to 5 after birth. Uterine adenomyosis was found in all (14 of 14) mice dosed with tamoxifen and most mice (12 of 14) treated with toremifene, but in none of the vehicle-dosed controls, in only one animal treated with raloxifene at 42 and 90 days after dosing and in none of the mice treated with estradiol at 42 days. At 6 days, the uterus in the groups that developed a high incidence of adenomyosis showed histological evidence of disturbed differentiation of the myometrium. Gene-expression XY-scatterplots using Clontech mouse 1.2 Atlas mouse cDNA expression arrays analyzing total uterine RNA showed nerve growth factor-alpha, preadipocyte factor-1, and insulin-like growth factor-2 were key genes differentially modified by tamoxifen or toremifene treatment, relative to the controls. As these genes may play an important role in regulating differentiation and development of the myometrium, these data suggest that adenomyosis may be caused primarily by defects in the formation of the myometrium.
Parrott
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Medical Research Council Toxicology Unit, Hidgkin Building, Lancaster Rd., Leicester LE1 9HN, United Kingdom. elp8@le.ac.uk
Butterworth
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Green
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White
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Greaves
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D000284:Administration, Oral; D000375:Aging; D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000187:drug effects; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation / Q000187:drug effects; D004715:Endometriosis / Q000473:pathology*; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006131:Growth Inhibitors / Q000235:genetics; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D009215:Myometrium / Q000166:cytology* / Q000187:drug effects / Q000473:pathology; D020932:Nerve Growth Factor / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D009929:Organ Size / Q000187:drug effects; D020849:Raloxifene Hydrochloride / Q000494:pharmacology; D012097:Repressor Proteins / Q000235:genetics; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D017154:Stromal Cells / Q000166:cytology* / Q000187:drug effects / Q000473:pathology; D013629:Tamoxifen / Q000494:pharmacology; D017312:Toremifene / Q000494:pharmacology; D014599:Uterus / Q000166:cytology* / Q000187:drug effects / Q000254:growth & development
D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; D006131:Growth Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D012097:Repressor Proteins; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D007335:Insulin-Like Growth Factor II; D017312:Toremifene; D020932:Nerve Growth Factor