title: Progesterone is essential for maintenance and growth of uterine leiomyoma.
abstract: Uterine leiomyomata (ULs) represent the most common tumor in women and can cause abnormal uterine bleeding, large pelvic masses, and recurrent pregnancy loss. Although the dependency of UL growth on ovarian steroids is well established, the relative contributions of 17beta-estradiol and progesterone are yet to be clarified. Conventionally, estradiol has been considered the primary stimulus for UL growth, and studies with cell culture and animal models support this concept. In contrast, no research model has clearly demonstrated a requirement of progesterone in UL growth despite accumulating clinical evidence for the essential role of progesterone in this tumor. To elucidate the functions of ovarian steroids in UL, we established a xenograft model reflecting characteristics of these tumors by grafting human UL tissue beneath the renal capsule of immunodeficient mice. Leiomyoma xenografts increased in size in response to estradiol plus progesterone through cell proliferation and volume increase in cellular and extracellular components. The xenograft growth induced by estradiol plus progesterone was blocked by the antiprogestin RU486. Furthermore, the volume of established UL xenografts decreased significantly after progesterone withdrawal. Surprisingly, treatment with estradiol alone neither increased nor maintained the tumor size. Although not mitogenic by itself, estradiol induced expression of progesterone receptor and supported progesterone action on leiomyoma xenografts. Taken together, our findings define that volume maintenance and growth of human UL are progesterone dependent.
authors.affiliation: Division of Reproductive Biology Research, Northwestern University Feinberg School of Medicine, Department of Obstetrics and Gynecology, 4th Floor, Suite 4-127, 303 East Superior Street, Chicago, Illinois 60611, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ishikawa
authors.forename: Kazutomo
authors.initials: K
authors.lastname: Ishi
authors.forename: Vanida Ann
authors.initials: VA
authors.lastname: Serna
authors.forename: Rafael
authors.initials: R
authors.lastname: Kakazu
authors.forename: Serdar E
authors.initials: SE
authors.lastname: Bulun
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kurita
mesh_terms: D000818:Animals; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D007889:Leiomyoma / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D015735:Mifepristone / Q000494:pharmacology; D009215:Myometrium / Q000378:metabolism; D011374:Progesterone / Q000378:metabolism* / Q000494:pharmacology; D011980:Receptors, Progesterone / Q000378:metabolism; D014183:Transplantation, Heterologous; D014594:Uterine Neoplasms / Q000378:metabolism* / Q000473:pathology*
chemical_list: D047628:Estrogen Receptor alpha; D011980:Receptors, Progesterone; D015735:Mifepristone; D011374:Progesterone; D004958:Estradiol