Inhibition of in situ expression of aromatase P450 in leiomyoma of the uterus by leuprorelin acetate.
We have shown that in situ estrogen synthesized in leiomyoma of the uterus plays a possible role in the promotion of leiomyoma cell growth via an autocrine/paracrine mechanism. In the present study, we demonstrated that leuprorelin acetate, a GnRH agonist widely used for treatment of uterine leiomyoma by down-regulation of pituitary-ovarian function, suppressed the expression of aromatase P450 (an estrogen synthetase) in leiomyoma cells. Given the role of in situ estrogen in leiomyoma cell growth, the inhibition of in situ estrogen synthesis may play a role in GnRH agonist-induced rapid regression of leiomyomas. Quantitative RT-PCR revealed that in women receiving no medication uterine leiomyomas express aromatase P450 mRNA at levels 20 times higher than that in the surrounding myometrium. Leuprorelin acetate treatment (1.88 mg every 4 wk, sc injection) for 12-24 wk reduced the expression of aromatase P450 mRNA in leiomyoma tissue as well as in the myometrium, to approximately one tenth of that in the myometrium of untreated women. Suppression of aromatase P450 expression was also demonstrated by Western blot analysis and aromatase activity assay of microsomal fractions prepared from leiomyomas. On the other hand, no differences in the levels of activity and mRNA of aromatase P450 were observed between leiomyoma cells obtained from women treated with and without leuprorelin acetate injections when cells were cultured ex vivo and stimulated by various combinations of stimulants such as dexamethasone + IL-1beta. The addition of various concentrations of E2 did not affect the aromatase activity of leiomyoma cells, suggesting that deprivation of circulating (ovarian) estrogen is not a cause of decreased expression of aromatase during leuprorelin acetate therapy. On the other hand, 8-d treatment with leuprorelin acetate (100 nmol/liter) reduced dexamethasone + IL-1beta-induced activity and a mRNA level of aromatase by 28% and 42%, respectively. These results indicated that leuprorelin acetate inhibits the expression of aromatase P450 in leiomyoma cells, which contributes to the rapid regression of leiomyoma during leuprorelin acetate therapy.
Shozu
M
M
Department of Obstetrics and Gynecology, School of Medicine, Kanazawa University, Kanazawa 920-0934, Japan. shozu@med.kanazawa-u.ac.jp
Sumitani
H
H
Segawa
T
T
Yang
H J
HJ
Murakami
K
K
Inoue
M
M
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001141:Aromatase / Q000096:biosynthesis*; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D003864:Depression, Chemical; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000502:physiology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists; D006801:Humans; D066298:In Vitro Techniques; D007889:Leiomyoma / Q000201:enzymology*; D016729:Leuprolide / Q000494:pharmacology*; D008593:Menopause / Q000502:physiology; D009363:Neoplasm Proteins / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D014594:Uterine Neoplasms / Q000201:enzymology*
D018931:Antineoplastic Agents, Hormonal; D004967:Estrogens; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D007987:Gonadotropin-Releasing Hormone; D004958:Estradiol; D001141:Aromatase; D016729:Leuprolide