Publications

Management of uterine fibroids: an update of the evidence.

Evid Rep Technol Assess (Full Rep). 2007 Jul;(154):1-122.

Viswanathan M, Hartmann K, McKoy N, Stuart G, Rankins N, Thieda P, Lux LJ, Lohr KN.

OBJECTIVES: The RTI International-University of North Carolina at Chapel Hill Evidence-based Practice Center (RTI-UNC EPC) systematically updated evidence on the management of uterine fibroids, specifically incidence and prevalence of fibroids, treatment outcomes, comparisons of treatment, modifiers of outcomes, and costs. DATA SOURCES: We searched MEDLINE(R), Cochrane Collaboration resources, and Embase. REVIEW METHODS: We included studies published in English from February 2000 through August 2006. We excluded studies with low sample size (based on study design, cases series < 100 and cohorts < 40) or lack of relevance to uterine fibroids. Of 107 included studies, 3 were good quality, 56 fair, and 48 poor. RESULTS: The cumulative incidence by age 50 is 70 percent to 80 percent; black women are more likely to get fibroids at younger ages. Appearance of new fibroids and growth of existing fibroids after treatment are poorly studied. Trials of preoperative medical management indicate that treatment reduces fibroid volume but do not provide sufficient evidence of improvement in important operative outcomes. When women are treated for reasons other than symptom relief, such as when pregnancy is desired, weak evidence supports treating submucous fibroids via hysteroscopy. No well-conducted trials in U.S. populations directly compared treatment options, including the option of expectant management, or followed women to determine whether the intervention met their treatment objectives. Common procedures such as hysterectomy and myomectomy, including choice among types of myomectomy, still cannot be meaningfully compared. Studies comparing uterine artery embolization (UAE) with other procedures reported procedure time and length of stay favoring UAE, but inconsistency of the direction of effect for complications and absence of key information on longer-term outcomes suggest that this evidence base is inadequate to comment on the relative risks and benefits of UAE versus hysterectomy or myomectomy. Costs of fibroid treatment, despite shorter average lengths of stay, are rising. CONCLUSIONS: The dearth of high-quality evidence supporting the effectiveness of most interventions for uterine fibroids is remarkable, given how common this problem is. The current state of the literature does not permit definitive conclusions about benefit, harm, or relative costs to help guide women's choices. Significant research gaps include well-conducted trials in U.S. populations that directly compare interventions on short- and, especially, long-term outcomes, studies on therapeutics for medical management, and information on treatment decisions for women who desire a pregnancy.

Uterine fibroid tumors: diagnosis and treatment.

Am Fam Physician. 2007 May 15;75(10):1503-8.

Am Fam Physician. 2007 May 15;75(10):1452-3.

Evans P, Brunsell S.
Georgetown University-Providence Hospital Family Practice Residency Program, Colmar Manor, Maryland 20722, USA.

The incidence of uterine fibroid tumors increases as women grow older, and they may occur in more than 30 percent of women 40 to 60 years of age. Risk factors include nulliparity, obesity, family history, black race, and hypertension. Many tumors are asymptomatic and may be diagnosed incidentally. Although a causal relationship has not been established, fibroid tumors are associated with menorrhagia, pelvic pain, pelvic or urinary obstructive symptoms, infertility, and pregnancy loss. Transvaginal ultrasonography, magnetic resonance imaging, sonohysterography, and hysteroscopy are available to evaluate the size and position of tumors. Ultrasonography should be used initially because it is the least invasive and most cost-effective investigation. Treatment options include hysterectomy, myomectomy, uterine artery embolization, myolysis, and medical therapy. Treatment must be individualized based on such considerations as the presence and severity of symptoms, the patient's desire for definitive treatment, the desire to preserve childbearing capacity, the importance of uterine preservation, infertility related to uterine cavity distortions, and previous pregnancy complications related to fibroid tumors.

Progesterone receptor modulator CDB-2914 induces extracellular matrix metalloproteinase inducer in cultured human uterine leiomyoma cells.

Mol Hum Reprod. 2008 Jan 23

Xu Q, Ohara N, Liu J, Amano M, Sitruk-Ware R, Yoshida S, Maruo T.
Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan.

Effects of progesterone receptor modulator CDB-2914 on the expression of the extracellular matrix (ECM) components were examined in cultured human uterine leiomyoma and myometrial cells. Extracellular matrix metalloproteinase inducer (EMMPRIN), matrix metalloproteinases (MMPs), tissue inhibitors of MMP (TIMPs), and collagen levels were assessed by Western blot analysis, MMP activity assay, and real-time RT-PCR. RNA interference (RNAi) of EMMPRIN was performed using small interfering mRNA. In cultured leiomyoma cells, CDB-2914 treatment at concentrations greater than or equal to 10(-8) M significantly increased EMMPRIN, MMP-1, and MMP-8 protein contents and MMP-1, MMP-2, MMP-3, and MMP-9 mRNA levels, and activity of MMP-1, MMP-2, MMP-3 and MMP-9 in the medium. TIMP-1 and TIMP-2 were significantly decreased at mRNA and protein levels by CDB-2914 treatment at concentrations greater than or equal to 10(-7) M in these cells. CDB-2914 treatment decreased types I and III collagen protein contents. However, CDB-2914 treatment did not affect the ECM component expression in cultured myometrial cells. RNAi of EMMPRIN abrogated CDB-2914-mediated both induction of MMPs and reduction of TIMPs and collagens in cultured leiomyoma cells. These results suggest that CDB-2914 modulates the expression of EMMPRIN, MMPs, TIMPs, and collagens in cultured leiomyoma cells without comparable effects on myometrial cells.

Progesterone receptor modulator CDB-2914 down-regulates vascular endothelial growth factor, adrenomedullin and their receptors and modulates progesterone receptor content in cultured human uterine leiomyoma cells.

Hum Reprod. 2006 Sep;21(9):2408-16. Epub 2006 May 23.

Xu Q, Ohara N, Chen W, Liu J, Sasaki H, Morikawa A, Sitruk-Ware R, Johansson ED, Maruo T.
Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, Kobe, Japan.

BACKGROUND: This study was conducted to evaluate the effects of graded concentrations (10(-8), 10(-7) and 10(-6) M) of progesterone receptor (PR) modulator CDB-2914 on the protein contents of PR, of vascular endothelial growth factor (VEGF), adrenomedullin (ADM) and their receptors in cultured human uterine leiomyoma and matching myometrial cells. METHODS: PR-A, PR-B, VEGF-A, VEGF-B, VEGF receptor (VEGFR)-1, VEGFR-2, ADM and ADM receptor (ADMR) contents were assessed by Western blot analysis. RESULTS: Treatment with 100 ng/ml progesterone increased VEGF-A, VEGF-B and ADM contents in cultured leiomyoma cells and normal myometrial cells. The concomitant treatment with 10(-6) M CDB-2914 significantly decreased the progesterone-induced VEGF-A, VEGF-B and ADM contents in cultured leiomyoma cells but not in normal myometrial cells. CDB-2914 treatment alone decreased VEGFR-1, VEGFR-2 and ADMR contents in cultured leiomyoma cells but not in normal myometrial cells. CDB-2914 treatment increased PR-A and decreased PR-B contents in cultured leiomyoma cells in a dose-dependent manner compared with untreated cultures, whereas no significant changes in PR isoform contents were observed in normal myometrial cells. CONCLUSIONS: These results suggest that CDB-2914 down-regulates VEGF, ADM and their receptor contents and modulates PR isoform contents in cultured leiomyoma cells in a cell-type-specific manner.

J Clin Endocrinol Metab. 1993 Feb;76(2):513-7.

Regression of uterine leiomyomata in response to the antiprogesterone RU 486.

Murphy AA, Kettel LM, Morales AJ, Roberts VJ, Yen SS.
Department of Reproductive Medicine, University of California, San Diego School of Medicine, La Jolla 92093-0802.

Uterine leiomyomata are steroid hormone dependent tumors which possess receptors for estrogen (ER) and progesterone (PR). We reasoned that an antiprogesterone (RU 486) may induce regression of leiomyomata by withdrawal of progesterone action and/or by its interference of estrogen action. Accordingly, we examined the effects of daily administration of RU 486 (50 mg) for a period of 3 months in 10 patients with uterine leiomyomata and regular menstrual cycles. Baseline ultrasound examinations were obtained and repeated monthly during treatment as a measure of leiomyomata volume. Hormonal parameters were monitored by blood samples obtained prior to treatment and daily for 7 days, weekly for 4 weeks and monthly for the duration of therapy. Myomectomy or hysterectomy was performed in 6 of 10 patients at the end of treatment. Leiomyomata and myometrial tissue was obtained for immunocytochemical analysis of ER and PR protein. Amenorrhea was induced in all patients during treatment. Leiomyomata volume (mean +/- SE) decreased 21.9 +/- 4.8% after 4 weeks, 39.5 +/- 6.6% (P < 0.001) after 8 weeks, and 49.0 +/- 9.2% (P < 0.001) after 12 weeks of treatment compared to pretreatment measurements. Serum LH levels (P < 0.005), but not FSH levels, more than doubled during the first 3 weeks of treatment with a concomitant increase in serum androstenedione (P < 0.006) and testosterone (P < 0.0001) levels. These elevated hormonal levels returned to baseline at 4 weeks without further changes during the remainder of treatment. A significant rise in serum dehydroepiandrosterone sulfate (P < 0.0001) and cortisol (P < 0.01) was seen at 12 weeks, suggesting an antiglucocorticoid effect of RU 486 has occurred. Serum estradiol, estrone, progesterone, sex hormone binding protein, thyroid-stimulating hormone, and PRL were unchanged from early follicular phase values. PR but not ER immunoreactivity was significantly reduced in both leiomyomata and myometrium after RU 486 treatment compared with tissues from untreated patients, suggesting that regression of tumors may be attained through a direct antiprogesterone effect. However, an alteration in ER functionality cannot be excluded. We conclude that RU 486 is well tolerated, safe, and effective; thus, it may prove to be a novel mode of management for uterine leiomyomata.

PIP: Under the hypothesis that the antiprogesterone RU 486 may induce regression of leiomyomata by withdrawal of progesterone action and/or by its interference with estrogen action, the effects of daily administration of 50 mg RU 486 for 3 months were examined in 10 patients with uterine leiomyomata. Monthly ultrasound examinations measured volume of leiomyomata. Myomectomy or hysterectomy was performed in 6 of 10 patients at the end of the treatment. Leiomyomata and myometrial tissue were obtained for immunocytochemical analysis of estrogen receptor (ER) and progesterone receptor (PR) proteins. Amenorrhea was induced in all patients. Leiomyomata volume decreased 21.9 +or- 4.8% after 4 weeks, 39.5 +or- 6.6% (p 0.001) after 8 weeks, and 49.0 +or- 9.2% (p 0.001) after 12 weeks of treatment compared to pretreatment measurements. Serum luteinizing hormone (LH) levels (p 0.005), but not follicle-stimulating hormone (FSH) levels, more than doubled during the first 3 weeks of treatment, with a concomitant increase in serum androstenedione (p 0.006) and testosterone (p 0.0001) levels which returned to baseline at 4 weeks and remained unchanged afterwards. A significant rise in serum dehydroepiandrosterone sulfate (p 0.0001) and cortisol (p 0.01) was seen at 12 weeks, suggesting an antiglucocorticoid effect of RU 486. PR, but not ER, immunoreactivity was significantly reduced in both leiomyomata and myometrium after RU 486 treatment compared with tissues from untreated patients, suggesting the regression of tumors through a direct antiprogesterone effect. There was a significant decrease in PR staining in both leiomyomata and myometrium of RU 486-treated patients when compared to controls. Using image analysis, significantly (p 0.05) more PR immunoreactivity was seen in leiomyomata of treated or control patients when compared to their respective myometrium. ER immunoreactivity was significantly greater (p 0.05) in control leiomyomata when compared to control myometrium, while no difference in ER immunoreactivity was seen between leiomyomata and myometrium of treated patients. RU 486 proved to be safe and effective for a novel mode of management for uterine leiomyomata.

The activites of progesterone receptor isoform A and B are differentially modulated by their ligands in a gene-selective manner.

Joyce C.L. Leo and Valeria C.L. Lin
School of Biological Sciences, Nanyang Technology University, Singapore
School of Applied Science, Republic Polytechnic, Signapore

The selective progesterone receptor modulator CDB4124 inhibits proliferation and induces apoptosis in uterine leiomyoma cells.

Luo X, Yin P, Coon V JS, Cheng YH, Wiehle RD, Bulun SE.

Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, Shandong, People's Republic of China.

OBJECTIVE: To evaluate the effects of selective P receptor (PR) modulator CDB4124 on cell proliferation and apoptosis in cultured human uterine leiomyoma smooth muscle (LSM) cells and control myometrial smooth muscle (MSM) cells in matched uteri. DESIGN: Laboratory research. SETTING: Academic medical center. PATIENT(S): Premenopausal women (n = 12) undergoing hysterectomy for leiomyoma-related symptoms. INTERVENTION(S): Treatment of primary LSM and MSM cells with CDB4124 (10(-8)-10(-6) M) or vehicle for 24, 48, or 72 hours. MAIN OUTCOME MEASURE(S): Western blot for protein expression of proliferating cell nuclear antigen, cleaved polyadenosine 5'-diphosphate-ribose polymerase, Bcl-2, and Krüppel-like transcription factor 11; 93-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide (MTT) assay to evaluate viable cell numbers; and real-time polymerase chain reaction (PCR) to quantify messenger RNA (mRNA) levels. RESULT(S): Treatment with CDB4124 significantly decreased levels of the proliferation marker proliferating cell nuclear antigen, the number of viable LSM cells, and the antiapoptotic protein Bcl-2. On the other hand, treatment with CDB4124 increased levels of the apoptosis marker cleaved polyadenosine 5'-diphosphate-ribose polymerase and the tumor suppressor Krüppel-like transcription factor 11 in a dose- and time-dependent manner in LSM cells. In matched MSM cells, however, CDB4124 did not affect cell proliferation or apoptosis. CONCLUSION(S): CDB4124 selectively inhibits proliferation and induces apoptosis in LSM but not in MSM cells. Copyright © 2009 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

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