[Show abstract][Hide abstract] ABSTRACT: Objective:
To investigate the efficacy and safety of repeated 12-week courses of 5 or 10 mg daily ulipristal acetate for intermittent treatment of symptomatic uterine fibroids.
Double-blind, randomized administration of four 12-week courses of ulipristal acetate.
Four hundred fifty-one subjects with symptomatic uterine fibroid(s) and heavy menstrual bleeding.
Four repeated 12-week treatment courses of daily 5 or 10 mg ulipristal acetate.
Main outcome measure(s):
Endometrial safety and general safety, laboratory parameters, amenorrhea, controlled bleeding, fibroid volume, quality of life (QoL), and pain.
Efficacy results, such as bleeding control and fibroid volume reduction, were in line with previously published data. Pain and QoL showed marked improvements from screening, even during the off-treatment intervals. The safety profile of ulipristal acetate was confirmed, and repeated treatment courses did not increase the occurrence of adverse reactions. There were no significant changes in laboratory parameters during the study. The percentage of subjects with endometrial thickness ≥16 mm was 7.4% (all subjects) after the first treatment course and returned to below screening levels (4.9%) in subsequent treatment courses. As in previous studies, ulipristal acetate did not increase the occurrence of endometrial features of concern. The frequency of nonphysiological changes did not increase with repeated treatment. They were observed in 17.8% and 13.3% of biopsies after treatment courses 2 and 4, respectively, and were reversible after treatment cessation.
The results of this study demonstrate the efficacy and further support the safety profile of repeated intermittent treatment of symptomatic fibroids with ulipristal acetate.
Clinical trial registration number:
ClinicalTrials.gov (www.clinicaltrials.gov) registration number NCT01629563 (PEARL IV).
Preview · Article · Oct 2015 · Fertility and sterility
[Show abstract][Hide abstract] ABSTRACT: Objective
To investigate the efficacy and safety of ulipristal acetate (UPA) for long-term treatment of symptomatic uterine fibroids.
Repeated intermittent open-label UPA courses, each followed by randomized double-blind norethisterone acetate (NETA) or placebo.
European clinical gynecology centers.
Two hundred and nine women with symptomatic fibroids including heavy menstrual bleeding.
Patients received up to four 3-month courses of UPA 10 mg daily, immediately followed by 10-day double-blind treatment with NETA (10 mg daily) or placebo.
Main Outcome Measure(s)
Amenorrhea, fibroid volume, endometrial histology.
After the first UPA course, amenorrhea occurred in 79% of women, with median onset (from treatment start) of 4 days (interquartile range, 2–6 days). Median fibroid volume change was −45% (interquartile range, −66%; −25%). Amenorrhea rates were 89%, 88%, and 90% for the 131, 119, and 107 women who received treatment courses 2, 3, and 4, respectively. Median times to amenorrhea were 2, 3, and 3 days for treatment courses 2, 3, and 4, respectively. Median fibroid volume changes from baseline were −63%, −67%, and −72% after treatment courses 2, 3, and 4, respectively. All endometrial biopsies showed benign histology without hyperplasia; NETA did not affect fibroid volume or endometrial histology.
Repeated 3-month UPA courses effectively control bleeding and shrink fibroids in patients with symptomatic fibroids.
Clinical trial registration
ClinicalTrials.gov (www.clinicaltrials.gov) registration numbers NCT01156857 (PEARL III) and NCT01252069 (PEARL III extension).
Full-text · Article · Jun 2014 · Fertility and sterility
[Show abstract][Hide abstract] ABSTRACT: Background Endometriosis is the presence in inappropriate sites of tissue that normally lines the uterus. It can cause pain and subfertility. Different treatments for endometriosis are available, one of which is laparoscopic ('key hole') surgery, performed to remove visible areas of endometriosis. Cochrane review authors assessed the evidence on the use of laparoscopic surgery to treat pain and fertility problems in women with endometriosis. Laparoscopic surgical techniques include ablation, which means destruction of a lesion (for example by burning), and excision, which means cutting a lesion out. Study characteristics We included 10 randomised controlled trials (involving 973 participants). They were conducted in Australia, Canada, Egypt, Iran and the United Kingdom. Most compared laparoscopic ablation or excision versus diagnostic laparoscopy only. Four of the 10 studies reported their source of funding. The evidence was current to July 2013. Key results We found that laparoscopic surgery may be of benefit in treating overall pain and subfertility associated with mild to moderate endometriosis. Laparoscopic excision and ablation were similarly effective in relieving pain, although this result came from a single study. There was insufficient evidence on adverse events to allow any conclusions to be drawn regarding safety. Quality of the evidence The quality of the evidence was moderate with regard to the effectiveness of laparoscopic surgery. Additional studies are needed in this field, and these should report adverse events as an outcome.
[Show abstract][Hide abstract] ABSTRACT: What is the individualized bleeding experience of women with fibroids and anaemia in a 3 month randomized placebo controlled trial (PEARL I) of the selective progesterone receptor modulator (SPRM), ulipristal acetate (UPA)?
In contrast to continuing excessive regular menstruation in the placebo group, a majority of women treated with UPA (63.1% of those on 5 mg/day and 71.3% of those on 10 mg/day) experienced the rapid onset of amenorrhoea or minimal blood loss [pictorial blood loss assessment chart (PBAC) < 12]. The remainder experienced various patterns of bleeding and intensity of blood loss that are described for the first time, including an association of irregular bleeding on UPA with sub-mucous fibroids.
The majority experience on UPA is amenorrhoea but the bleeding experience of the others has not been characterized.
A 13 week randomized controlled trial in women, eligible for surgery for uterine fibroids and anaemia, comparing placebo (n = 48), UPA 5 mg (n = 95) or UPA 10 mg (n = 94). The treatment aim was fibroid shrinkage and the primary definitions and outcomes are published elsewhere; here the secondary outcome measure of vaginal bleeding pattern is described.
Women, 18-50 years old, with fibroids and haemoglobin ≤10.2 g/dl, justifying surgery. At least one fibroid was 3-10 cm diameter and uterus ≤16 weeks pregnancy size. All used the daily PBAC methodology in a screening cycle (Ps) and throughout treatment, and for the 4 weeks preceding Week 26 and Week 38 in those who did not have surgery. An excessive menstruation is PBAC > 100. The bleeding patterns were characterized using the classification of Belsey, developed under auspices of WHO.
In the placebo group, all women had an excessive screening PBAC [median 376; interquartile range (IQR) 241-574]; 81.3% of them had regular menstrual bleeding and the intensity of bleeding remained similar, so that the median PBAC in the next three periods was 90, 92 and 93% of the screening value. Four of the 48 women had spontaneous improvement in bleeding and one developed amenorrhoea and elevation of gonadotrophins. In the placebo group, 22 women provided Week 26 and 21 women provided Week 38 PBAC data. The median Week 26 PBAC (312: IQR 102-524) and Week 38 PBAC (236; IQR 103-465) indicated ongoing excessive bleeding. In the UPA group, screening PBAC confirmed excessive bleeding (UPA 5 mg, median 358; IQR 232-621; UPA 10 mg, median 330; IQR 235-542). UPA was initiated from the start of a menstruation (P1) and no women had regular periods on treatment. Following P1 through the whole of the remaining 13 weeks of UPA treatment amenorrhoea or minimal loss (PBAC < 12 for whole phase) occurred in 63.1% (UPA 5 mg) or 71.3% (UPA 10 mg). The characterization of the individualized bleeding experience of the remaining women on 5 mg and 10 mg UPA, respectively, were infrequent bleeding in 17.9 and 12.8%; frequent or prolonged bleeding or both in 12.7 and 11.7% and irregular bleeding in 5.3 and 3.2%. In those with prolonged, frequent or irregular bleeding there was a high chance that sub-mucous fibroids were present (UPA 5 mg 100% and UPA 10 mg 78.6%) but no correlation with progesterone receptor modulator-associated endometrial changes.
The follow-up PBAC data at Week 26 and Week 38 are only valid for women who did not have surgical intervention. These groups may not be representative of the groups at screening.
This first detailed description of these SPRM bleeding patterns provides clinicians with an indication of potential responses in women using the SPRM UPA and provides an extended definition of bleeding in untreated women with excessive bleeding and fibroids.
Funded by PregLem/Gedeon Richter. D.H.B. is a member of the Scientific Advisory Board of PregLem, and in this role participated in the study design and supervision. Stock originally held in PregLem was given up when PregLem was incorporated into Gedeon Richter; D.H.B. does not currently hold stock. M.A.L. has received payment from Gideon Richter to attend a meeting to present these data (Barcelona, April 2013) but no financial support in preparing the manuscript. B.C.J.M.F. is a member of the Scientific Advisory Board of PregLem and has received fees and grant support from the following companies: Andromed, Ardana, Auxogyn, Ferring, Genovum, Gedeon Richter, Merck Serono, MSD, Organon, Pantharei Bioscience, PregLem, Roche, Schering, Schering Plough, Serono, Watson Laboratories and Wyeth. P.T. is a paid statistical consultant for PregLem SA. E.B. is a full time employee of PregLem and received payment from stocks sold in October 2010 from the company's full acquisition by Gedeon Richter Group.
ClinicalTrials.gov Identifier: NCT00755755 (PEARL I).
[Show abstract][Hide abstract] ABSTRACT: Selective progesterone receptor modulators (SPRMs) have beneficial effects in reducing the size of uterine fibroids and the amount of bleeding, but their endometrial effects have not been seen with other agents. This report describes the morphology of the endometrium after 3 mo of treatment with the SPRM, ulipristal acetate (UPA). In 2 Phase III randomized double-blind controlled clinical trials, 546 patients with uterine myomas were treated with 5 or 10 mg of UPA daily for 13 wk or placebo or gonadotropin-releasing hormone agonist. Endometrial biopsies were taken at screening, end of treatment (13 wk), and after treatment-free follow-up (38 wk). Biopsies were assessed independently by 3 pathologists according to a preset morphologic scheme. After 13 wk, the UPA-treated endometrium showed altered architectural glandular features including extensive cystic dilatation. The glandular epithelium appeared inactive or contained abortive subnuclear vacuolization, occasional mitoses, and apoptosis. Abnormal stromal vessels were commonly seen. There was a high level of agreement between pathologists on the presence or the absence of nonphysiological changes. One case of hyperplasia without atypia and 4 polyps were seen at 13 wk of UPA treatment. Six months after treatment, the endometrium returned to normal histology in the majority of the patients, with 1 polyp and no cases of hyperplasia in the UPA-treated groups, and 2 hyperplasias (1 with and 1 without atypia) in the placebo or the gonadotropin-releasing hormone-agonist groups. Mild reversible thickening of the endometrium occurs in a minority of cases. It is important that pathologists are aware of the spectrum of changes induced by SPRMs to avoid misdiagnoses of endometrial hyperplasia or polyps.
Full-text · Article · Sep 2012 · International journal of gynecological pathology: official journal of the International Society of Gynecological Pathologists
[Show abstract][Hide abstract] ABSTRACT: Lipid profiles in women with early breast cancer receiving anastrozole with or without risedronate were examined within an international Phase III/IV study to assess for possible treatment related changes. Postmenopausal women with hormone receptor-positive breast cancer were assigned to 1 of 3 strata by risk of fragility fracture. Patients with the highest risk for fracture received anastrozole plus risedronate (A + R). Moderate-risk patients were randomized in a double-blind manner to A + R or anastrozole and placebo (A + P). Lower-risk patients received anastrozole (A) alone. Serial fasting blood samples were assessed for changes in lipid parameters relative to baseline after 12 months of treatment with anastrozole with or without risedronate. Samples were centrally analyzed for low-density lipoprotein cholesterol (LDL-cholesterol), high-density lipoprotein (HDL) cholesterol, total cholesterol (TC) and triglycerides (TG). Analysis was performed as primary analysis population for lipids (A plus A + P), lipid intention to treat population and secondary population (A + R). Of the 119 patients treated with A plus A + P, there were 66 patients eligible for inclusion in the primary analysis population. Of the 115 patients treated with secondary population (A + R) there were 65 patients eligible for lipid profiling. For LDL-cholesterol, HDL-cholesterol, TC and TG there were no significant changes between the baseline and 12 months assessments to suggest that any of these therapies have a negative impact on the lipid profile. In this study of postmenopausal women with early breast cancer receiving adjuvant anastrozole with or without risedronate, there was no adverse effect on LDL-cholesterol, HDL-cholesterol, TC or TG values over the 12 months monitoring period.
No preview · Article · Jul 2012 · Breast Cancer Research and Treatment
[Show abstract][Hide abstract] ABSTRACT: Women may seek to prolong their reproductive span for a variety of reasons. For many this implies reproduction at a late age, possibly driven by lifestyle decisions, but for others affected by a natural or a cancer treatment-induced premature ovarian failure it may simply mean seeking to achieve the normal reproductive span. The range of interventions now available to address the issue of prolonging reproductive life has never been greater, although several of the approaches discussed remain in the realm of future application through being dependent on ongoing scientific developments.
No preview · Article · Mar 2011 · Annals of the New York Academy of Sciences
[Show abstract][Hide abstract] ABSTRACT: PURPOSE To investigate the management of bone health in women with early breast cancer (EBC) who were scheduled to receive anastrozole. PATIENTS AND METHODS Postmenopausal women with hormone receptor-positive EBC were assigned to one of three strata by risk of fragility fracture. Patients with the highest risk (H) received anastrozole 1 mg/d plus risedronate 35 mg/wk orally. Patients with moderate-risk (M) were randomly assigned in a double-blind manner to anastrozole and risedronate (A + R) or to anastrozole and placebo (A + P). Patients with lower-risk (L) received anastrozole (A) alone. Calcium and vitamin D were recommended for all patients. Lumbar spine and total hip bone mineral density (BMD) were assessed at baseline, 12 months, and 24 months. Results At 24 months, in the M group, treatment with A + R resulted in a significant increase in lumbar spine and total hip BMD compared with A + P treatment (2.2% v -1.8%; treatment ratio, 1.04; P < .0001; and 1.8% v -1.1%; treatment ratio, 1.03; P < .0001, respectively). In the H stratum, lumbar spine and total hip BMD increased significantly (3.0%; P = .0006; and 2.0%; P = .0104, respectively). Patients in the L stratum showed a significant decrease in lumbar spine BMD (-2.1%; P = .0109) and a numerical decrease in total hip BMD (-0.4%; P = .5988). Safety profiles for anastrozole and risedronate were similar to those already established. CONCLUSION In postmenopausal women at risk of fragility fracture who were receiving adjuvant anastrozole for EBC, the addition of risedronate at doses established for preventing and treating osteoporosis resulted in favorable effects in BMD during 24 months.
Full-text · Article · Feb 2010 · Journal of Clinical Oncology
[Show abstract][Hide abstract] ABSTRACT: Endometriosis is the presence of tissue that normally lines the uterus in inappropriate sites (usually within the pelvic cavity). It can cause fertility problems and symptoms such as painful menstruation and painful sexual intercourse. Hormonal drugs including the oral contraceptive pill are used but have adverse effects and are not suitable for women wishing to become pregnant. Laparoscopic surgery (where small incisions are made in the abdomen) is performed to remove visible areas of endometriosis. The review of trials found that laparoscopic surgery may be of benefit in treating subfertility associated with mild to moderate endometriosis. However, the two studies on the subject show conflicting results. Additional studies in this field are needed before definitive conclusions can be drawn.
Full-text · Article · Jan 2010 · Cochrane database of systematic reviews (Online)
[Show abstract][Hide abstract] ABSTRACT: Endometriosis is the presence of tissue that normally lines the uterus in inappropriate sites (usually within the pelvic cavity). It can cause fertility problems, painful menstruation and painful sexual intercourse. Hormonal drugs such as the oral contraceptive pill are used but may have adverse effects and are not suitable for women wishing to become pregnant. Laparoscopic surgery (where small incisions are made in the abdomen) is performed to remove visible areas of endometriosis. The review of trials found that laparoscopic surgery is effective in treating pelvic pain associated with endometriosis. More research is needed.
Full-text · Article · Oct 2009 · Cochrane database of systematic reviews (Online)
[Show abstract][Hide abstract] ABSTRACT: The fractures that result from osteoporosis create a huge burden for both individuals affected and for societies across the world. This is especially aggravated as population age. Optimal policy in the management of osteoporosis should provide alleviation of suffering by reducing fracture events. In most health systems the interest is in achieving this at manageable cost. An important initiative is the WHO programme to provide tools for the individualisation of fracture risk which would have similarities to the approach familiar to doctors in the management of coronary heart disease risk. With individualised fracture risk it should be possible to focus resources on fracture prevention in those people most at risk. It is then a matter for the healthcare system to provide policies which guide clinicians on how far down the gradient of risk the system care afford to resource. This is the basis for a cost-effective approach. The paper explores the factors that enable valid risk assessment to be made and the difficulties that result for clinicians if resources are limited and affect the level of intervention that might be preferred.
[Show abstract][Hide abstract] ABSTRACT: The evidence concerning the effects of hormone therapy (HT) has been greatly expanded by the publication of very large randomized controlled trials. A consequence has been concern among women about the risks of HT such that the number of menopausal women using HT for relief of menopausal symptoms has declined. It is now appropriate to look at the best evidence available and to consider current policies. Women in the early postmenopausal phase, generally younger than 60 years of age, who are troubled by menopausal symptoms should be reassured that, for their circumstances, medical management of menopause in the form of HT is appropriate. If they go on to use HT for several years, it is possible that they will experience skeletal and coronary health benefits, but the evidence for such benefits is a matter of ongoing debate.
No preview · Article · May 2008 · Annals of the New York Academy of Sciences
[Show abstract][Hide abstract] ABSTRACT: The four approaches to hysterectomy for benign disease are abdominal hysterectomy (AH), vaginal hysterectomy (VH), laparoscopic hysterectomy (LH) and robotic-assisted hysterectomy (RH).
To assess the effectiveness and safety of different surgical approaches to hysterectomy for women with benign gynaecological conditions.
We searched the following databases (from inception to 14 August 2014) using the Ovid platform: Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; Cumulative Index to Nursing and Allied Health Literature (CINAHL) and PsycINFO. We also searched relevant citation lists. We used both indexed and free-text terms.
We included randomised controlled trials (RCTs) in which clinical outcomes were compared between one surgical approach to hysterectomy and another.
At least two review authors independently selected trials, assessed risk of bias and performed data extraction. Our primary outcomes were return to normal activities, satisfaction, quality of life, intraoperative visceral injury and major long-term complications (i.e. fistula, pelvi-abdominal pain, urinary dysfunction, bowel dysfunction, pelvic floor condition and sexual dysfunction).
We included 47 studies with 5102 women. The evidence for most comparisons was of low or moderate quality. The main limitations were poor reporting and imprecision. Vaginal hysterectomy (VH) versus abdominal hysterectomy (AH) (nine RCTs, 762 women)Return to normal activities was shorter in the VH group (mean difference (MD) -9.5 days, 95% confidence interval (CI) -12.6 to -6.4, three RCTs, 176 women, I(2) = 75%, moderate quality evidence). There was no evidence of a difference between the groups for the other primary outcomes. Laparoscopic hysterectomy (LH) versus AH (25 RCTs, 2983 women)Return to normal activities was shorter in the LH group (MD -13.6 days, 95% CI -15.4 to -11.8; six RCTs, 520 women, I(2) = 71%, low quality evidence), but there were more urinary tract injuries in the LH group (odds ratio (OR) 2.4, 95% CI 1.2 to 4.8, 13 RCTs, 2140 women, I(2) = 0%, low quality evidence). There was no evidence of a difference between the groups for the other primary outcomes. LH versus VH (16 RCTs, 1440 women)There was no evidence of a difference between the groups for any primary outcomes. Robotic-assisted hysterectomy (RH) versus LH (two RCTs, 152 women)There was no evidence of a difference between the groups for any primary outcomes. Neither of the studies reported satisfaction rates or quality of life.Overall, the number of adverse events was low in the included studies.
Among women undergoing hysterectomy for benign disease, VH appears to be superior to LH and AH, as it is associated with faster return to normal activities. When technically feasible, VH should be performed in preference to AH because of more rapid recovery and fewer febrile episodes postoperatively. Where VH is not possible, LH has some advantages over AH (including more rapid recovery and fewer febrile episodes and wound or abdominal wall infections), but these are offset by a longer operating time. No advantages of LH over VH could be found; LH had a longer operation time, and total laparoscopic hysterectomy (TLH) had more urinary tract injuries. Of the three subcategories of LH, there are more RCT data for laparoscopic-assisted vaginal hysterectomy and LH than for TLH. Single-port laparoscopic hysterectomy and RH should either be abandoned or further evaluated since there is a lack of evidence of any benefit over conventional LH. Overall, the evidence in this review has to be interpreted with caution as adverse event rates were low, resulting in low power for these comparisons. The surgical approach to hysterectomy should be discussed and decided in the light of the relative benefits and hazards. These benefits and hazards seem to be dependent on surgical expertise and this may influence the decision. In conclusion, when VH is not feasible, LH may avoid the need for AH, but LH is associated with more urinary tract injuries. There is no evidence that RH is of benefit in this population. Preferably, the surgical approach to hysterectomy should be decided by the woman in discussion with her surgeon.
[Show abstract][Hide abstract] ABSTRACT: Vaginal hysterectomy should be performed in preference to abdominal hysterectomy where possible Abdominal hysterectomy involves removal of the uterus through a large incision on the lower abdomen; vaginal hysterectomy involves removal of the uterus via the vagina, with no abdominal incision; laparoscopic hysterectomy involves 'keyhole surgery' small incisions on the abdomen and the uterus is removed with surgery undertaken with the aid of a surgical telescope called a laparoscope inserted through the umbilicus (belly button), often in conjunction with vaginal surgery. Laparoscopic hysterectomy may be further subdivided depending on the extent of the surgery performed laparoscopically compared to that performed vaginally. This review found that vaginal hysterectomy meant a shorter stay in hospital, quicker return to normal activities and fewer infections and episodes of raised temperature after surgery compared to abdominal hysterectomy. Laparoscopic hysterectomy meant were less blood loss and a smaller drop in blood count, a shorter stay in hospital, quicker return to normal activities, fewer wound infections and episodes of raised temperature after surgery compared to abdominal hysterectomy, but laparoscopic hysterectomies are longer operations and have a greater risk of damaging the bladder or ureter (the tube leading to the bladder from the kidney). No benefits of laparoscopic versus vaginal hysterectomy were found and laparoscopic hysterectomies are longer operations. The authors concluded that vaginal hysterectomy should be performed in preference to abdominal hysterectomy where possible; where vaginal hysterectomy is not possible, a laparoscopic approach may avoid the need for an abdominal hysterectomy. More research is needed.
Full-text · Article · Feb 2006 · Cochrane database of systematic reviews (Online)