toremifene and Endometriosis

Adenomyosis has been reported in a number of different animal species, whereas endometriosis appears limited to humans and non-human primates. This suggests a different aetiology of the two conditions. Adenomyosis develops spontaneously in certain strains of laboratory mice. Its incidence in mice can be markedly enhanced by systemic exposure to various hormonal agents, including prolactin, progesterone, synthetic progestins, certain oestrogenic agents, as well as tamoxifen and toremifene. The precise hormonal changes necessary remain unclear, although the evidence suggests that adenomyosis in this model is not due to a simple oestrogenic effect. Study of the pathological and molecular alterations in this model indicates that disturbances to the uterine stroma, blood vessels and myometrium are also important factors in the development of adenomyosis.

Topics: Animals; Cats; Disease Models, Animal; Dogs; Endometriosis; Endometrium; Estrogen Antagonists; Female; Humans; Mice; Myometrium; Pituitary Gland; Primates; Progesterone; Progestins; Rats; Tamoxifen; Toremifene; Uterine Diseases

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.

Topics: Administration, Oral; Aging; Animals; Animals, Newborn; Body Weight; Calcium-Binding Proteins; Cell Differentiation; Endometriosis; Estradiol; Female; Gene Expression Regulation; Growth Inhibitors; Insulin-Like Growth Factor II; Intercellular Signaling Peptides and Proteins; Membrane Proteins; Mice; Myometrium; Nerve Growth Factor; Oligonucleotide Array Sequence Analysis; Organ Size; Raloxifene Hydrochloride; Repressor Proteins; Selective Estrogen Receptor Modulators; Stromal Cells; Tamoxifen; Toremifene; Uterus