Publications
2 Feb 2012
Uterine Fibroids and Evidence-Based Medicine — Not an Oxymoron
Uterine Fibroids
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Editorial
Uterine Fibroids and Evidence-Based Medicine — Not an Oxymoron
Elizabeth A. Stewart, M.D.
N Engl J Med 2012; 366:471-473February 2, 2012
This article has no abstract; the first 100 words appear below.
The 2011 report from the Agency for Healthcare Research and Quality on comparative management of uterine fibroids noted, “Despite the prevalence and possible complications of uterine fibroids, few published studies examining the effectiveness of treatment strategies exist.”1 Few therapies are approved by the Food and Drug Administration (FDA) for fibroids; leuprolide acetate, a gonadotropin-releasing hormone (GnRH) agonist, was approved in 1995 for preoperative treatment of fibroids, with the addition of iron. In the past decade, uterine-artery embolization and magnetic-resonance–guided focused ultrasound surgery have also been therapeutic options. Surgeries for fibroids, especially hysterectomy, still predominate, and fibroids remain the leading cause . . .
Disclosure forms provided by the author are available with the full text of this article at NEJM.org
SOURCE INFORMATION From the Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN
2 Feb 2012
Ulipristal Acetate versus Leuprolide Acetate for Uterine Fibroids
Uterine Fibroids
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Ulipristal Acetate versus Leuprolide Acetate for Uterine Fibroids
Jacques Donnez, M.D., Ph.D., Janusz Tomaszewski, M.D., Ph.D., Francisco Vázquez, M.D., Ph.D., Philippe Bouchard, M.D., Boguslav Lemieszczuk, M.D., Francesco Baró, M.D., Ph.D., Kazem Nouri, M.D., Luigi Selvaggi, M.D., Krzysztof Sodowski, M.D., Elke Bestel, M.D., Paul Terrill, Ph.D., Ian Osterloh, M.R.C.P., and Ernest Loumaye, M.D., Ph.D. for the PEARL II Study Group
N Engl J Med 2012; 366:421-432February 2, 2012
BACKGROUND The efficacy and side-effect profile of ulipristal acetate as compared with those of leuprolide acetate for the treatment of symptomatic uterine fibroids before surgery are unclear.
METHODS In this double-blind noninferiority trial, we randomly assigned 307 patients with symptomatic fibroids and excessive uterine bleeding to receive 3 months of daily therapy with oral ulipristal acetate (at a dose of either 5 mg or 10 mg) or once-monthly intramuscular injections of leuprolide acetate (at a dose of 3.75 mg). The primary outcome was the proportion of patients with controlled bleeding at week 13, with a prespecified noninferiority margin of −20%.
RESULTS Uterine bleeding was controlled in 90% of patients receiving 5 mg of ulipristal acetate, in 98% of those receiving 10 mg of ulipristal acetate, and in 89% of those receiving leuprolide acetate, for differences (as compared with leuprolide acetate) of 1.2 percentage points (95% confidence interval [CI], −9.3 to 11.8) for 5 mg of ulipristal acetate and 8.8 percentage points (95% CI, 0.4 to 18.3) for 10 mg of ulipristal acetate. Median times to amenorrhea were 7 days for patients receiving 5 mg of ulipristal acetate, 5 days for those receiving 10 mg of ulipristal acetate, and 21 days for those receiving leuprolide acetate. Moderate-to-severe hot flashes were reported for 11% of patients receiving 5 mg of ulipristal acetate, for 10% of those receiving 10 mg of ulipristal acetate, and for 40% of those receiving leuprolide acetate (P<0.001 for each dose of ulipristal acetate vs. leuprolide acetate).
CONCLUSIONS Both the 5-mg and 10-mg daily doses of ulipristal acetate were noninferior to once-monthly leuprolide acetate in controlling uterine bleeding and were significantly less likely to cause hot flashes. (Funded by PregLem; ClinicalTrials.gov number, NCT00740831.)
Supported by PregLem.
Dr. Donnez reports receiving payment for serving on a scientific advisory board from PregLem, payment from stocks sold in October 2010 from the company's full acquisition by Gedeon Richter Group, and lecture fees from Serono, Merck, Organon, and Ferring; Dr. Bouchard, receiving payment for serving on a scientific advisory board from PregLem, payment from stocks sold in October 2010 from the company's full acquisition by Gedeon Richter Group, and lecture fees from HRA Pharma, Theramex, Pierre Fabre, and PregLem; Dr. Bestel, being an employee of PregLem and receiving payment from stocks sold in October 2010 from the company's full acquisition by Gedeon Richter Group; Dr. Terrill, being an employee of MDSL International and receiving payment to his institution for consultancy and contracted data-management and statistical support; Dr. Osterloh, receiving payment to his institution for consultancy from OsterMed; and Dr. Loumaye, being an employee of PregLem and receiving payment from stocks sold in October 2010 from the company's full acquisition by Gedeon Richter Group. No other potential conflict of interest relevant to this article was reported.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
Members of the PGL4001 (Ulipristal Acetate) Efficacy Assessment in Reduction of Symptoms Due to Uterine Leiomyomata (PEARL II) study group are listed in the Supplementary Appendix, available at NEJM.org.
We thank Venkat Ramanan of PregLem for assistance with the preparation of the manuscript with the support of Tove Anderson and Nigel Eastmond of Darwin Healthcare Communications.
SOURCE INFORMATION From Cliniques Universitaires Saint-Luc Catholic University of Louvain, Brussels (J.D.); Prywatna Klinika Polozniczo-Ginekologiczna, Bialystok (J.T.), Gabinet Lekarski Specjalistyczny Sonus, Warsaw (B.L.), and Centrum Medyczne Krzysztof Sodowski, Katowice (K.S.) — all in Poland; Clinica Ginecologica El Centro de Estudios de Obstetricia y Ginecología Asociado, Lugo, Spain (F.V.); Hôpital St. Antoine, Assistance Publique–Hôpitaux de Paris and University Paris 6, Paris (P.B.); Hospital Vall d'Hebrón, Department of Gynecology, Barcelona (F.B.); Medical University Vienna, Vienna (K.N.); Clinica Ostetrica e Ginecologica II, Università degli Studi di Bari, Bari, Italy (L.S.); PregLem, Geneva (E.B., E.L.); and MDSL International, Maidenhead (P.T.), and OsterMed, Birmingham (I.O.) — both in the United Kingdom.
Address reprint requests to Dr. Donnez at the Saint-Luc Catholic University of Louvain, Av. Hippocrate 10, Brussels 1200, Belgium.
2 Feb 2012
Ulipristal Acetate versus Placebo for Fibroid Treatment before Surgery
Uterine Fibroids
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Ulipristal Acetate versus Placebo for Fibroid Treatment before Surgery
Jacques Donnez, M.D., Ph.D., Tetyana F. Tatarchuk, M.D., Ph.D., Philippe Bouchard, M.D., Lucian Puscasiu, M.D., Ph.D., Nataliya F. Zakharenko, M.D., Ph.D., Tatiana Ivanova, M.D., Ph.D., Gyula Ugocsai, M.D., Ph.D., Michal Mara, M.D., Ph.D., Manju P. Jilla, M.B., B.S., M.D., Elke Bestel, M.D., Paul Terrill, Ph.D., Ian Osterloh, M.R.C.P., and Ernest Loumaye, M.D., Ph.D. for the PEARL I Study Group
N Engl J Med 2012; 366:409-420February 2, 2012
BACKGROUND the efficacy and safety of oral ulipristal acetate for the treatment of symptomatic uterine fibroids before surgery are uncertain.
METHODS We randomly assigned women with symptomatic fibroids, excessive uterine bleeding (a score of >100 on the pictorial blood-loss assessment chart [PBAC, an objective assessment of blood loss, in which monthly scores range from 0 to >500, with higher numbers indicating more bleeding]) and anemia (hemoglobin level of ≤10.2 g per deciliter) to receive treatment for up to 13 weeks with oral ulipristal acetate at a dose of 5 mg per day (96 women) or 10 mg per day (98 women) or to receive placebo (48 women). All patients received iron supplementation. The coprimary efficacy end points were control of uterine bleeding (PBAC score of <75) and reduction of fibroid volume at week 13, after which patients could undergo surgery.
RESULTS At 13 weeks, uterine bleeding was controlled in 91% of the women receiving 5 mg of ulipristal acetate, 92% of those receiving 10 mg of ulipristal acetate, and 19% of those receiving placebo (P<0.001 for the comparison of each dose of ulipristal acetate with placebo). The rates of amenorrhea were 73%, 82%, and 6%, respectively, with amenorrhea occurring within 10 days in the majority of patients receiving ulipristal acetate. The median changes in total fibroid volume were −21%, −12%, and +3% (P=0.002 for the comparison of 5 mg of ulipristal acetate with placebo, and P=0.006 for the comparison of 10 mg of ulipristal acetate with placebo). Ulipristal acetate induced benign histologic endometrial changes that had resolved by 6 months after the end of therapy. Serious adverse events occurred in one patient during treatment with 10 mg of ulipristal acetate (uterine hemorrhage) and in one patient during receipt of placebo (fibroid protruding through the cervix). Headache and breast tenderness were the most common adverse events associated with ulipristal acetate but did not occur significantly more frequently than with placebo.
CONCLUSIONS Treatment with ulipristal acetate for 13 weeks effectively controlled excessive bleeding due to uterine fibroids and reduced the size of the fibroids. (Funded by PregLem; ClinicalTrials.gov number, NCT00755755.)
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
Drs. Donnez and Tatarchuk contributed equally to this article.
We thank Venkat Ramanan of PregLem for coordinating the manuscript writing with the support of Arthur Smyth Medina, Tove Anderson, and Nigel Eastmond of Darwin Healthcare Communications.
SOURCE INFORMATION From Cliniques Universitaires Saint-Luc Catholic University of Louvain, Brussels (J.D.); the Department of Endocrine Gynecology, Kiev City Clinical Hospital No. 16 (T.F.T.), and the Department of Gynecology, Kiev City Clinical Hospital No. 9 (N.F.Z.) — both in Kiev, Ukraine; Hôpital St. Antoine, Assistance Publique–Hôpitaux de Paris and University Paris 6, Paris (P.B.); Spitalul Clinic Judetean de Urgenta, Sectia de Obstetrica Ginecologie I, Targu Mures, Romania (L.P.); Kursk State Medical University, Kursk, Russia (T.I.); Dr. Bugyi Istvan Hospital of Szentes, Department of Obstetrics and Gynecology, Szentes, Hungary (G.U.); Department of Obstetrics and Gynecology, 1st Faculty of Medicine of Charles University, Prague, Czech Republic (M.M.); Dr. Jilla Hospital, Aurangabad, India (M.P.J.); PregLem, Geneva (E.B., E.L.); and MDSL International, Maidenhead (P.T.), and OsterMed, Birmingham (I.O.) — both in the United Kingdom.
Address reprint requests to Dr. Donnez at the Saint-Luc Catholic University of Louvain, Av. Hippocrate 10, Brussels 1200, Belgium.
Members of the PGL4001 (Ulipristal Acetate) Efficacy Assessment in Reduction of Symptoms Due to Uterine Leiomyomata (PEARL I) study group are listed in the Supplementary Appendix, available at NEJM.org.
23 Sep 2011
Selective progesterone receptor modulators in reproductive medicine
Uterine Fibroids
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Fertil Steril. 2011 Nov;96(5):1175-89. Epub 2011 Sep 23.
Bouchard P, Chabbert-Buffet N, Fauser BC.
SOURCE Endocrinology Unit, AP-HP Hospital Saint-Antoine, Paris, France.
ABATRACT
OBJECTIVE: To discuss the mechanism of action of selective progesterone receptor modulators (SPRMs) and summarize the preclinical and clinical efficacy and safety data supporting the potential use of these compounds for gynecologic indications.
DESIGN: Relevant publications from 2005 onward were identified using a PubMed search. Additional relevant articles were identified from citations within these publications.
SETTING: None.
PATIENT(S): None.
INTERVENTION(S): None.
MAIN OUTCOME MEASURE(S): None.
RESULT(S): Mifepristone was first developed as a progesterone receptor antagonist and licensed for pregnancy termination because of the unique property of this compound to terminate pregnancy when associated with prostaglandins. Then SPRMs were developed, and among those ulipristal acetate, an efficient emergency contraceptive. Because SPRMs effectively inhibit endometrial proliferation and reduce endometriotic lesions in animal models, this suggests a possible role in the treatment of endometriosis in humans. Finally, a number of double-blind, randomized, placebo-controlled trials have demonstrated the efficacy of asoprisnil, mifepristone, telapristone acetate, and ulipristal acetate in reducing leiomyoma and uterine volume, and suppressing bleeding in women with uterine fibroids.
CONCLUSION(S): Mifepristone in combination with prostaglandins has been licensed for pregnancy termination because of its unique ability is this area. Ulipristal acetate is available for emergency contraception. Several SPRMs hold further promise as an effective medical therapy for patients suffering from endometriosis and leiomyoma.
Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
25 Feb 2011
Inhibition of steroid sulfatase decreases endometriosis in an in vivo murine model.
Endometriosis
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Hum. Reprod. (2011) 26(6): 1362-1370 first published online March 25, 2011
Inhibition of steroid sulfatase decreases endometriosis in an in vivo murine model
S. Colette, S. Defrère, J.C. Lousse, A. Van Langendonckt, J.P. Gotteland, E. Loumaye, and J. Donnez,
SOURCE Université Catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Department of Gynecology, Cliniques Universitaires St Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium.
ABSTRACT
BACKGROUND Steroid sulfatase (STS) is involved in estrogen biosynthesis and expressed in eutopic and ectopic endometrium of disease-free and endometriosis patients. The present study was designed to investigate its role in endometriosis development.
METHODS Human endometrial explants were cultured on inserts for 24 h to assess the effectiveness of an STS inhibitor (STS-I), estradiol-3-O-sulfamate (E2MATE), on STS activity in endometrial tissue. Endometriosis was induced in mice, and E2MATE (or vehicle alone) was given orally for 21 days. Plasma estradiol levels were measured, and STS activity was assessed in murine organs (uterus, liver and leukocytes) and in lesions. Lesion number, weight and size (morphometry) were quantified. Lesion STS and progesterone receptor (PR) expression, proliferation and apoptosis rates were determined by immunohistochemistry.
RESULTS In vitro, addition of 1 µM E2MATE to the culture medium resulted in decreased STS activity in endometrial explants (P < 0.001). Treatment of mice with E2MATE (1.0 and 0.5 mg/kg) did not modify plasma estradiol levels, but inhibited STS activity in murine uterus (P < 0.05), liver (P < 0.001) and leukocytes (P < 0.001), as well as in induced lesions (P < 0.05). E2MATE reduced lesion weight (P < 0.01) and size (P < 0.05), but had no impact on proliferation or apoptosis rates, nor STS protein expression. Stromal edema was observed in the uterus of animals treated with E2MATE, but not in the stroma of lesions. Increased PR expression was detected in endometriotic lesions (P < 0.001).
CONCLUSIONS E2MATE was shown to effectively inhibit STS activity in endometrial tissue in vitro. In vivo, E2MATE decreased endometriosis development without affecting systemic estradiol levels. Use of STS-I could therefore be of potential interest in endometriosis treatment
