A randomized, placebo-controlled, dose-ranging trial comparing fulvestrant with goserelin in premenopausal patients with uterine fibroids awaiting hysterectomy

Donnez, Jacques; Vivancos, Blas Hervais; Kudela, M; Audebert, A; Jadoul, Pascale

doi:10.1016/s0015-0282(03)00261-9

Cited by 38 publications

(11 citation statements)

References 34 publications

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“…First, our results are consistent with the recent finding from a randomized clinical trial that there is no difference in endometrial thickness between premenopausal women with uterine fibroids treated with placebo and with long-acting monthly intramuscular injections of 50, 125, 250 mg ICI [108] . Two earlier, smaller studies from the same research group, however, have reported a lower proliferative index in endometrium from women treated with ICI [109,110] .…”

Section: Possible Explanation For An Apparently Unsuccessful Clinicalsupporting

confidence: 91%

Inhibition of Proliferation of Endometrial Stromal Cells by Trichostatin A, RU486, CDB-2914, N-Acetylcysteine, and ICI 182780

Wu¹,

Guo²

2006

Gynecol Obstet Invest

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Background: All current major medications in treating endometriosis are effective in treating pain, most likely through suppression of proliferation of the implants, yet their effectiveness is relatively short term and they all have many undesirable, and sometimes severe, side effects. There is pressing need for novel, more effective medications in treating endometriosis with less and/or milder side effects. Methods: Using a recently established immortalized endometrial stromal cell line, we carried out cell proliferation assays for cells treated with trichostatin A (TSA), RU486, CDB-2914, and N-acetylcysteine, and ICI 182780. Gene expression levels for PR-A, PR-B, AR, Fas and FasL were measured. Protein expression levels for ERα, ERβ, and AR were also measured. Results: Cell proliferation assay results for NAC, H₂O₂, CDB, and RU486 were nearly identical or similar to what have been reported based on primary cell cultures or in vivo studies. TSA, CDB, RU486 and NAC all had various antiproliferative effects. TSA had a more potent and longer lasting antiproliferative effect than CDB and NAC, even in the presence of an oxidant, H₂O₂. Its antiproliferative effect was concentration-dependent. ICI did not have a significant antiproliferative effect. PR-A, PR-B, AR, and FasL expression were all increased as compared with untreated cells. Conclusions: The cell line appears to be an adequate model for stromal components of endometriotic implants. That ICI has no inhibitory effect on endometrial proliferation may explain why a phase II clinical trial on its use to treat endometriosis did not advance to later stages. The upregulation of PR-B and AR may be responsible for antiproliferative effects induced by TSA, a histone deacetylase inhibitor (HDACI). HDACIs may be promising therapeutics in treating endometriosis due to their antiproliferative effects as well as the potential to restore gene dysregulation through chromatin remodeling.

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Section: Possible Explanation For An Apparently Unsuccessful Clinicalsupporting

confidence: 91%

Inhibition of Proliferation of Endometrial Stromal Cells by Trichostatin A, RU486, CDB-2914, N-Acetylcysteine, and ICI 182780

Wu¹,

Guo²

2006

Gynecol Obstet Invest

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“…Currently, there are no definitive FDA-approved agents for long-term medical treatment of uterine leiomyoma, as there is a remarkable lack of randomized trial data demonstrating the effectiveness of medical therapies 35. However, there are several candidate agents like GnRH analogues (leuprolide and goserelin), progesterone receptor antagonists (mifepristone), and more recently selective progesterone-receptor modulators such as ulipristal that have been shown to reduce uterine leiomyoma volume, reduce heavy menstrual bleeding, and restore hemoglobin levels in limited preliminary clinical studies 36–43. Recent findings suggest that volume maintenance and growth of human uterine leiomyomas are heavily progesterone dependent, and hence antiprogesterone could reverse leiomyoma growth effects.…”

Section: Discussionmentioning

confidence: 99%

Treatment of symptomatic uterine fibroids with green tea extract: a pilot randomized controlled clinical study

Roshdy¹,

Rajaratnam²,

Maitra³

et al. 2013

IJWH

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BackgroundUterine fibroids (UFs, also known as leiomyoma) affect 70% of reproductive-age women. Imposing a major burden on health-related quality-of-life (HRQL) of premenopausal women, UF is a public health concern. There are no effective medicinal treatment options currently available for women with symptomatic UF.ObjectivesTo evaluate the efficacy and safety of green tea extract (epigallocatechin gallate [EGCG]) on UF burden and quality of life in women with symptomatic UF, in a double-blinded, placebo-controlled randomized clinical trial.MethodsA total of 39 reproductive-age women (age 18–50 years, day 3 serum follicle-stimulating hormone <10 \U/mL) with symptomatic UF were recruited for this study. All subjects had at least one fibroid lesion 2 cm3 or larger, as confirmed by transvaginal ultrasonography. The subjects were randomized to oral daily treatment with either 800 mg of green tea extract (45% EGCG) or placebo (800 mg of brown rice) for 4 months, and UF volumes were measured at the end, also by transvaginal ultrasonography. The fibroid-specific symptom severity and HRQL of these UF patients were scored at each monthly visit, using the symptom severity and quality-of-life questionnaires. Student’s t-test was used to evaluate statistical significance of treatment effect between the two groups.ResultsOf the final 39 women recruited for the study, 33 were compliant and completed all five visits of the study. In the placebo group (n = 11), fibroid volume increased (24.3%) over the study period; however, patients randomized to green tea extract (n = 22, 800 mg/day) treatment showed significant reduction (32.6%, P = 0.0001) in total UF volume. In addition, EGCG treatment significantly reduced fibroid-specific symptom severity (32.4%, P = 0.0001) and induced significant improvement in HRQL (18.53%, P = 0.01) compared to the placebo group. Anemia also significantly improved by 0.7 g/dL (P = 0.02) in the EGCG treatment group, while average blood loss significantly decreased from 71 mL/month to 45 mL/month (P = 0.001). No adverse effects, endometrial hyperplasia, or other endometrial pathology were observed in either group.ConclusionEGCG shows promise as a safe and effective therapeutic agent for women with symptomatic UFs. Such a simple, inexpensive, and orally administered therapy can improve women’s health globally.

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“…In a phase 1 study of healthy postmenopausal volunteers whose endometrium was stimulated with ethinylestradiol, one single administration of fulvestrant at a dose of 250 mg was shown to significantly inhibit the estrogen-stimulated thickening of the endometrium compared with placebo [24]. However, in a study of premenopausal patients with uterine fibroids awaiting hysterectomy, fulvestrant did not significantly alter fibroid volume or endometrial thickness or change endpoints such as endometrial histology or vaginal bleeding compared to goserelin [25]. Few case reports suggest the potential of fulvestrant as an effective therapy for patients with hormone receptor-positive uterine cancer [26,27].…”

Section: Introductionmentioning

confidence: 95%

Prospective assessment of the endometrium in postmenopausal breast cancer patients treated with fulvestrant

Morales

Neven

Timmerman

et al. 2008

Breast Cancer Res Treat

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This prospective study assessed the endometrial effects of fulvestrant, a pure estrogen-receptor antagonist, in postmenopausal women with breast cancer. This singlecenter study enrolled postmenopausal patients who had an intact uterus at baseline with progressive metastatic breast cancer on tamoxifen followed by an oral aromatase inhibitor (AI). Fulvestrant (250 mg) was administered every 28 ± 3 days via IM injection. Transvaginal ultrasonography (TVUS) was performed at baseline and after 3 months of therapy. Primary and secondary endpoints were changes from baseline in double endometrial thickness (DET) and uterine volume (UV), respectively. No interventions were performed on any asymptomatic uterine abnormalities that were detected at baseline. In total, 32 women were enrolled. Five patients had no repeat TVUS because of early progression before 3 months, leaving 27 evaluable patients for final analysis. After 3 months therapy, mean DET had significantly decreased by 23.08% (P = 0.010). Mean UV also decreased by 10.88%, although this change was not significant (P = 0.119). After 3 months of therapy, none reported vaginal bleeding, there were no changes noted in most of the uterine pathologies present at baseline and no new uterine abnormalities were detected. We observed that 3 months of fulvestrant treatment resulted in a significant decrease in endometrial growth and a non-significant decrease in UV in postmenopausal women with metastatic breast cancer previously exposed to tamoxifen and AIs. Furthermore, no new uterine pathologies were detected, indicating that fulvestrant behaves as a pure antiestrogen at the uterine level.

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A randomized, placebo-controlled, dose-ranging trial comparing fulvestrant with goserelin in premenopausal patients with uterine fibroids awaiting hysterectomy

Cited by 38 publications

References 34 publications

Inhibition of Proliferation of Endometrial Stromal Cells by Trichostatin A, RU486, CDB-2914, N-Acetylcysteine, and ICI 182780

Inhibition of Proliferation of Endometrial Stromal Cells by Trichostatin A, RU486, CDB-2914, N-Acetylcysteine, and ICI 182780

Treatment of symptomatic uterine fibroids with green tea extract: a pilot randomized controlled clinical study

Prospective assessment of the endometrium in postmenopausal breast cancer patients treated with fulvestrant

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