Altered hormonal responsiveness of proliferation and apoptosis during myometrial maturation and the development of uterine leiomyomas in the rat

Uterine leiomyomas are responsive to the ovarian steroids, estrogen and pro gesterone; however, a mechanistic understanding of the role of these hormon es in the development of this common gynecologic lesion remains to be eluci dated. We have used the Eker rat uterine leiomyoma model to investigate how ovarian hormones regulate or promote the growth of these tumors. Prolifera tive and apoptotic rates were quantitated in normal uterine tissues and lei omyomas in response to endogenous ovarian steroids. In 2- to 4-mo-old anima ls, cell proliferation in the normal uterus corresponded with high serum le vels of steroid hormones during the estrous cycle, and apoptosis occurred i n the rat uterus in all cell types following sharp, cyclical declines in se rum hormone levels, It is interesting that the responsiveness of uterine me senchymal cells changed between 4 and 6 mo of age, with significant decreas es in both proliferative and apoptotic rates observed in myometrial and str omal cells of cycling animals. Leiomyomas displayed much higher levels of p roliferation than did age-matched myometrium; however, their apoptotic inde x was significantly decreased in comparison with normal myometrium. This di sregulation between proliferative and apoptotic responses, which were tight ly regulated during ovarian cycling in the normal myometrium, may contribut e to the disruption of tissue homeostasis and underlie neoplastic growth of these tumors.