Effects of GnRH analogues, `add-back' steroid therapy, antiestrogen and antiprogestins on leiomyoma and myometrial smooth muscle cell growth and transforming growth factor-beta expression

Abstract

The objective of this study was to elucidate the biological significance of GnRH and antiprogestins and antiestrogen in leiomyoma and their interactions with ovarian steroid 'add-back' therapy. Leiomyoma and myometrial smooth muscle cells (LSMC and MSMC) were isolated and exposed to GnRH agonist (leuprolide acetate, LA), 17beta-estradiol (E2), medroxyprogesterone acetate (MPA), GnRH antagonist (Antide), estrogen antagonist, ICI182780 (Fulvestrant) and progesterone antagonists RU486 (Mifepristone) and ZK98299 (Onapristone) and combinations thereof. The rate of DNA synthesis, cell proliferation and transforming growth factor-beta (TGF-beta) expression were then determined. In both cell types, we found that in a dose-dependent manner, LA inhibited, whereas E2, MPA and the combination of E2 + MPA stimulated, the rate of DNA synthesis in these cells. Antide reversed the inhibitory effect of LA, while LA partly inhibited the stimulatory effect of the steroids. In addition, RU486, ICI182780 and ZK98299 at 0.1 micro mol/l or higher doses inhibited the rate of DNA synthesis and partly reversed the effects of E2 and/or MPA. We also found that LSMC expressed elevated levels of TGF-beta1 compared with MSMC. In both cell types, the effects of LA, E2, MPA, RU, ZK and ICI and combinations thereof on TGF-beta1 production were reflective of their effects on DNA synthesis. In line with this, TGF-beta1 was found to stimulate DNA synthesis and the E2-, TGF-beta1- or E2 + TGF-beta1-induced DNA synthesis was found to be inhibited by TGF-beta1 neutralizing antibodies and/or LA. In conclusion, the results provide further evidence that GnRH agonist- and RU486-induced leiomyoma regression is mediated in part through an interactive mechanism that results in altered cell growth and suppression of TGF-beta production.

Two-dimensional gel electrophoresis analysis of the leiomyoma interstitial fluid reveals altered protein expression with a possible involvement in pathogenesis

“…Tumor growth is strongly dependent on estrogen and progesterone, and both have a mitogenic effect on leiomyoma cells (5). Estrogen and progesterone seem to have a mitogenic effect on leiomyoma cells and to act by influencing (directly and indirectly) other hormones and a large number of growth factors, cytokines and apoptotic factors (6).…”

Medical Management of leipmyomas-emphasis for different geographical regions

“…When given for 3-6 months, mifepristone reduced UL size and symptoms and induced amenorrhoea in 63-100%of women [22] . Mifepristone induces a significant decrease in uterine volume, a significant reduction in Pg receptors content without affecting the estrogen receptor level [8,23] . Under in vivo conditions RU486 also altered the rate of DNA synthesis and growth factors and proteases expression in MSMC or LSMC primary cultures [8] .…”

“…Mifepristone induces a significant decrease in uterine volume, a significant reduction in Pg receptors content without affecting the estrogen receptor level [8,23] . Under in vivo conditions RU486 also altered the rate of DNA synthesis and growth factors and proteases expression in MSMC or LSMC primary cultures [8] . 17 β-estradiol inhibited whereas Medroxyprogesterone acetate (MPA) enhanced the expression of miR 21 and miR 26 a in MSMC and LSMC respectively, and the expression of miRNAs was also the target of ICI 182780 and RU486 respectively [24] .…”

“…Although add back therapy takes care of the hypoestrogenic side effects further selective estrogen receptor modulators (SERM) like raloxiphene and tamoxiphene [7][8][9] and selective progesterone receptor modulators (SPRM) like CDB2814 (ulipristal acetate), CDB 4124, asoprisnil (J865) and RU486 (Mifepristone) underwent trials. Although uripristal acetate (UPA) has received approval after several therapeutic multicentric trials and is available in many western and European countries, it is still not available in developing countries like India and the basic aim of this review is to highlight the importance of using a SPRM agent prior to surgery to avoid or make it easier and offer an alternative to surgery and highlight the advantages and disadvantages of surgery in patients desiring fertility and how use of UPA prior to hysteroscopy if must, may decrease the morbidity of surgery and decrease the chances of a laparotomy to a laparoscopy and make hysteroscopy a single step from two step process and in countries like India where no UPA available alternative of using mifepristone is discussed.…”

Associative non-malignant endometrial hyperplasias: rational the­rapeutic approach

“…Кроме этого, на фоне терапии Бусерелином-Депо происхо-дит существенное уменьшение активности так назы-ваемых экстрацеллюлярных сигналрегулирующих киназ и киназ фокальной адгезии, которые являются неотъемлемыми звеньями внутриклеточных сиг-нальных путей, активируемых половыми гормонами и факторами роста [1][2][3][4][5][6][7][8][9].…”