Lessons learned from the preclinical drug discovery of asoprisnil and ulipristal for non-surgical treatment of uterine leiomyomas.
BACKGROUND
Uterine leiomyoma is the most common benign tumor in women during the reproductive years. Menorrhagia is the common symptom and accounts for the most frequent indication for hysterectomy. Thus, development of a novel drug for non-surgical treatment of uterine leiomyoma is needed for the betterment of women's health.


METHODS
This review introduces a translational research initiated by use of the levonorgestrel-releasing intrauterine system (LNG-IUS) for contraceptive purposes. During follow-up, a patient informed that heavy menstrual bleeding caused by uterine myoma was strikingly reduced after the insertion of device. The patient's unexpected comment led the authors to perform clinical trials of LNG-IUS for the management of menorrhagia in women with uterine myomas and striking reduction in menorrhagia was obtained by the use of LNG-IUS. MRI examination, however, revealed that the volume of myomas decreased in some, but increased in the other instances. This unexpected finding with MRI directed the authors to characterize the effects of progesterone (P4) and progesterone receptor modulators (PRMs) on uterineleiomyoma cell growth in vitro.


CONCLUSIONS
In consistence with the in vitro data obtained, randomized controlled clinical trials of PRMs in patients with uterine leiomyomas at several institutions have demonstrated that oral administration of PRMs (asoprisnil and ulipristal) for 3 months reduced leiomyoma volume, resulting in a significant improvement of the associated symptoms. However, a novel pattern of PRM-associated endometrial changes was recognized in the endometrial pathology, demonstrating unusual epithelial types not seen in the normal menstrual cycle of a premenstrual woman. Thus, follow-up studies to determine whether the novel endometrial changes remain, disappear or progress to something else are needed for the possible long-term use of PRMs for the treatment of uterine leiomyoma.
Kobe Children's Hospital and Feto-Maternal Medical Center, 1-1-1 Takakuradai, Suma-ku, Kobe 654-0081 ,  Japan   +81 78 732 0030 ;  +81 78 732 0140 ;  maruotakeshi@w7.dion.ne.jp.
Takeshi
T
Maruo
Noriyuki
N
Ohara
Shigeki
S
Yoshida
Koji
K
Nakabayashi
Hiroko
H
Sasaki
Qin
Q
Xu
Hiroya
H
Matsuo
Regine
R
Sitruk-Ware
Hideto
H
Yamada