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The Cochrane Database of Systematic... Nov 2017Uterine fibroids occur in up to 40% of women aged over 35 years. Some are asymptomatic, but up to 50% cause symptoms that warrant therapy. Symptoms include anaemia... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Uterine fibroids occur in up to 40% of women aged over 35 years. Some are asymptomatic, but up to 50% cause symptoms that warrant therapy. Symptoms include anaemia caused by heavy menstrual bleeding, pelvic pain, dysmenorrhoea, infertility and low quality of life. Surgery is the first choice of treatment. In recent years, medical therapies have been used before surgery to improve intraoperative and postoperative outcomes. However, such therapies tend to be expensive.Fibroid growth is stimulated by oestrogen. Gonadotropin-hormone releasing analogues (GnRHa) induce a state of hypo-oestrogenism that shrinks fibroids , but has unacceptable side effects if used long-term. Other potential hormonal treatments, include progestins and selective progesterone-receptor modulators (SPRMs).This is an update of a Cochrane Review published in 2000 and 2001; the scope has been broadened to include all preoperative medical treatments.
OBJECTIVES
To assess the effectiveness and safety of medical treatments prior to surgery for uterine fibroids.
SEARCH METHODS
We searched the Cochrane Gynaecology and Fertility Group specialised register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL in June 2017. We also searched trials registers (ClinicalTrials.com; WHO ICTRP), theses and dissertations and the grey literature, handsearched reference lists of retrieved articles and contacted pharmaceutical companies for additional trials.
SELECTION CRITERIA
We included randomised comparisons of medical therapy versus placebo, no treatment, or other medical therapy before surgery, myomectomy, hysterectomy or endometrial resection, for uterine fibroids.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by The Cochrane Collaboration.
MAIN RESULTS
We included a total of 38 RCTs (3623 women); 19 studies compared GnRHa to no pretreatment (n = 19), placebo (n = 8), other medical pretreatments (progestin, SPRMs, selective oestrogen receptor modulators (SERMs), dopamine agonists, oestrogen receptor antagonists) (n = 7), and four compared SPRMs with placebo. Most results provided low-quality evidence due to limitations in study design (poor reporting of randomisation procedures, lack of blinding), imprecision and inconsistency. GnRHa versus no treatment or placebo GnRHa treatments were associated with reductions in both uterine (MD -175 mL, 95% CI -219.0 to -131.7; 13 studies; 858 participants; I² = 67%; low-quality evidence) and fibroid volume (heterogeneous studies, MD 5.7 mL to 155.4 mL), and increased preoperative haemoglobin (MD 0.88 g/dL, 95% CI 0.7 to 1.1; 10 studies; 834 participants; I² = 0%; moderate-quality evidence), at the expense of a greater likelihood of adverse events, particularly hot flushes (OR 7.68, 95% CI 4.6 to 13.0; 6 studies; 877 participants; I² = 46%; moderate-quality evidence).Duration of hysterectomy surgery was reduced among women who received GnRHa treatment (-9.59 minutes, 95% CI 15.9 to -3.28; 6 studies; 617 participants; I² = 57%; low-quality evidence) and there was less blood loss (heterogeneous studies, MD 25 mL to 148 mL), fewer blood transfusions (OR 0.54, 95% CI 0.3 to 1.0; 6 studies; 601 participants; I² = 0%; moderate-quality evidence), and fewer postoperative complications (OR 0.54, 95% CI 0.3 to 0.9; 7 studies; 772 participants; I² = 28%; low-quality evidence).GnRHa appeared to reduce intraoperative blood loss during myomectomy (MD 22 mL to 157 mL). There was no clear evidence of a difference among groups for other primary outcomes after myomectomy: duration of surgery (studies too heterogeneous for pooling), blood transfusions (OR 0.85, 95% CI 0.3 to 2.8; 4 studies; 121 participants; I² = 0%; low-quality evidence) or postoperative complications (OR 1.07, 95% CI 0.43 to 2.64; I² = 0%; 5 studies; 190 participants; low-quality evidence). No suitable data were available for analysis of preoperative bleeding. GnRHa versus other medical therapies GnRHa was associated with a greater reduction in uterine volume (-47% with GnRHa compared to -20% and -22% with 5 mg and 10 mg ulipristal acetate) but was more likely to cause hot flushes (OR 12.3, 95% CI 4.04 to 37.48; 5 studies; 183 participants; I² = 61%; low-quality evidence) compared with ulipristal acetate. There was no clear evidence of a difference in bleeding reduction (ulipristal acetate 5 mg: OR 0.71, 95% CI 0.3 to 1.7; 1 study; 199 participants; moderate-quality evidence; ulipristal acetate 10 mg: OR 0.39, 95% CI 0.1 to 1.1; 1 study; 203 participants; moderate-quality evidence) or haemoglobin levels (MD -0.2, 95% CI -0.6 to 0.2; 188 participants; moderate-quality evidence).There was no clear evidence of a difference in fibroid volume between GnRHa and cabergoline (MD 12.71 mL, 95% CI -5.9 to 31.3; 2 studies; 110 participants; I² = 0%; low-quality evidence).The included studies did not report usable data for any other primary outcomes. SPRMs versus placebo SPRMs (mifepristone, CDB-2914, ulipristal acetate and asoprisnil) were associated with greater reductions in uterine or fibroid volume than placebo (studies too heterogeneous to pool) and increased preoperative haemoglobin levels (MD 0.93 g/dL, 0.5 to 1.4; 2 studies; 173 participants; I² = 0%; high-quality evidence). Ulipristal acetate and asoprisnil were also associated with greater reductions in bleeding before surgery (ulipristal acetate 5 mg: OR 41.41, 95% CI 15.3 to 112.4; 1 study; 143 participants; low-quality evidence; ulipristal acetate 10 mg: OR 78.83, 95% CI 24.0 to 258.7; 1 study; 146 participants; low-quality evidence; asoprisnil: MD -166.9 mL; 95% CI -277.6 to -56.2; 1 study; 22 participants; low-quality evidence). There was no evidence of differences in preoperative complications. No other primary outcomes were measured.
AUTHORS' CONCLUSIONS
A rationale for the use of preoperative medical therapy before surgery for fibroids is to make surgery easier. There is clear evidence that preoperative GnRHa reduces uterine and fibroid volume, and increases preoperative haemoglobin levels, although GnRHa increases the incidence of hot flushes. During hysterectomy, blood loss, operation time and complication rates were also reduced. Evidence suggests that ulipristal acetate may offer similar advantages (reduced fibroid volume and fibroid-related bleeding and increased haemoglobin levels) although replication of these studies is advised before firm conclusions can be made. Future research should focus on cost-effectiveness and distinguish between groups of women with fibroids who would most benefit.
Topics: Antineoplastic Agents, Hormonal; Blood Loss, Surgical; Chemotherapy, Adjuvant; Dopamine Agonists; Estrogen Antagonists; Female; Gonadotropin-Releasing Hormone; Humans; Hysterectomy; Leiomyoma; Myometrium; Operative Time; Preoperative Care; Progestins; Randomized Controlled Trials as Topic; Uterine Neoplasms
PubMed: 29139105
DOI: 10.1002/14651858.CD000547.pub2 -
Cancer Treatment Reviews Jan 2018Combining targeted agents and endocrine therapy (ET) improves outcomes in hormone receptor-positive metastatic breast cancer patients but increases the risk of adverse... (Meta-Analysis)
Meta-Analysis Review
Risk of adverse events with the addition of targeted agents to endocrine therapy in patients with hormone receptor-positive metastatic breast cancer: A systematic review and meta-analysis.
BACKGROUND
Combining targeted agents and endocrine therapy (ET) improves outcomes in hormone receptor-positive metastatic breast cancer patients but increases the risk of adverse events (AEs). This meta-analysis aims to estimate the comparative risk of AEs with ET in addition to targeted agents in this setting.
METHODS
A systematic literature search of MEDLINE, EMBASE, Cochrane Library and conference proceedings up to July 17th 2017 was conducted to identify randomized controlled trials investigating ET with or without CDK4/6, mTOR, PI3K inhibitors and anti-HER2 agents. We calculated summary risk estimates (odds ratio, OR) and 95% confidence intervals (CI) for each AE within each class of targeted agents for each trial, and pooled analysis using the random and fixed effect models.
RESULTS
Sixteen studies (n=8529 patients) were included. The addition of targeted agents to ET was associated with a significant higher risk of grade 3-4 AEs: OR 2.86 (95% CI 2.49-3.27) for CDK4/6 inhibitors, 1.88 (95% CI 1.39-2.53) for mTOR inhibitors, 2.05 (95% CI 1.63-2.58) for PI3K inhibitors, and 2.48 (95% CI 1.09-5.66) for anti-HER2 agents. The highest class-specific risks were neutropenia grade 3-4 for CDK4/6 inhibitors (OR 40.77; 95% CI 19.52-85.19), stomatitis grade 3-4 for mTOR inhibitors (OR 11.92; 95% CI 3.68-38.57), hyperglycemia grade 3-4 for PI3K inhibitors (OR 40.93; 95% CI 10.08-166.22) and diarrhea for anti-HER2 agents (OR 9.93; 95% CI 4.71-20.95).
CONCLUSIONS
Adding targeted agents to ET is associated with a significant increased risk of AEs. The risk of developing different AEs varies largely according to the type of agent used.
Topics: Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Diarrhea; Humans; Hyperglycemia; Molecular Targeted Therapy; Neutropenia; Odds Ratio; Phosphoinositide-3 Kinase Inhibitors; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; TOR Serine-Threonine Kinases
PubMed: 29108713
DOI: 10.1016/j.ctrv.2017.09.009 -
JBRA Assisted Reproduction Sep 2017For all the steps of in vitro fertilization to occur successfully, factors such as the quality of retrieved oocytes and endometrial receptivity to the embryo must be... (Review)
Review
For all the steps of in vitro fertilization to occur successfully, factors such as the quality of retrieved oocytes and endometrial receptivity to the embryo must be ensured. Current studies have shown that endometrial receptivity can be optimized using dedicated exogenous progesterone for luteal phase support in assisted reproduction cycles. But it has not yet been established the benefits of additional use of estradiol in this support. Analyzing pituitary suppression protocols that employ GnRH antagonists, this review will address literature publications between the years 2000-2016, shedding light on this issue to answer questions about the benefits of supplementation.
Topics: Adult; Estradiol; Female; Fertilization in Vitro; Gonadotropin-Releasing Hormone; Humans; Luteal Phase; Pregnancy; Pregnancy Outcome; Randomized Controlled Trials as Topic
PubMed: 28837035
DOI: 10.5935/1518-0557.20170046 -
The Cochrane Database of Systematic... Jul 2017Endometriosis is defined as the presence of endometrial tissue (glands and stroma) outside the uterine cavity. This condition is oestrogen-dependent and thus is seen... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Endometriosis is defined as the presence of endometrial tissue (glands and stroma) outside the uterine cavity. This condition is oestrogen-dependent and thus is seen primarily during the reproductive years. Owing to their antiproliferative effects in the endometrium, progesterone receptor modulators (PRMs) have been advocated for treatment of endometriosis.
OBJECTIVES
To assess the effectiveness and safety of PRMs primarily in terms of pain relief as compared with other treatments or placebo or no treatment in women of reproductive age with endometriosis.
SEARCH METHODS
We searched the following electronic databases, trial registers, and websites: the Cochrane Gynaecology and Fertility Group (CGFG) Specialised Register of Controlled Trials, the Central Register of Studies Online (CRSO), MEDLINE, Embase, PsycINFO, clinicaltrials.gov, and the World Health Organization (WHO) platform, from inception to 28 November 2016. We handsearched reference lists of articles retrieved by the search.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) published in all languages that examined effects of PRMs for treatment of symptomatic endometriosis.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures as expected by the Cochrane Collaboration. Primary outcomes included measures of pain and side effects.
MAIN RESULTS
We included 10 randomised controlled trials (RCTs) with 960 women. Two RCTs compared mifepristone versus placebo or versus a different dose of mifepristone, one RCT compared asoprisnil versus placebo, one compared ulipristal versus leuprolide acetate, and four compared gestrinone versus danazol, gonadotropin-releasing hormone (GnRH) analogues, or a different dose of gestrinone. The quality of evidence ranged from high to very low. The main limitations were serious risk of bias (associated with poor reporting of methods and high or unclear rates of attrition in most studies), very serious imprecision (associated with low event rates and wide confidence intervals), and indirectness (outcome assessed in a select subgroup of participants). Mifepristone versus placebo One study made this comparison and reported rates of painful symptoms among women who reported symptoms at baseline.At three months, the mifepristone group had lower rates of dysmenorrhoea (odds ratio (OR) 0.08, 95% confidence interval (CI) 0.04 to 0.17; one RCT, n =352; moderate-quality evidence), suggesting that if 40% of women taking placebo experience dysmenorrhoea, then between 3% and 10% of women taking mifepristone will do so. The mifepristone group also had lower rates of dyspareunia (OR 0.23, 95% CI 0.11 to 0.51; one RCT, n = 223; low-quality evidence). However, the mifepristone group had higher rates of side effects: Nearly 90% had amenorrhoea and 24% had hot flushes, although the placebo group reported only one event of each (1%) (high-quality evidence). Evidence was insufficient to show differences in rates of nausea, vomiting, or fatigue, if present. Mifepristone dose comparisons Two studies compared doses of mifepristone and found insufficient evidence to show differences between different doses in terms of effectiveness or safety, if present. However, subgroup analysis of comparisons between mifepristone and placebo suggest that the 2.5 mg dose may be less effective than 5 mg or 10 mg for treating dysmenorrhoea or dyspareunia. Gestrinone comparisons Ons study compared gestrinone with danazol, and another study compared gestrinone with leuprolin.Evidence was insufficient to show differences, if present, between gestrinone and danazol in rate of pain relief (those reporting no or mild pelvic pain) (OR 0.71, 95% CI 0.33 to 1.56; two RCTs, n = 230; very low-quality evidence), dysmenorrhoea (OR 0.72, 95% CI 0.39 to 1.33; two RCTs, n = 214; very low-quality evidence), or dyspareunia (OR 0.83, 95% CI 0.37 to 1.86; two RCTs, n = 222; very low-quality evidence). The gestrinone group had a higher rate of hirsutism (OR 2.63, 95% CI 1.60 to 4.32; two RCTs, n = 302; very low-quality evidence) and a lower rate of decreased breast size (OR 0.62, 95% CI 0.38 to 0.98; two RCTs, n = 302; low-quality evidence). Evidence was insufficient to show differences between groups, if present, in rate of hot flushes (OR 0.79, 95% CI 0.50 to 1.26; two RCTs, n = 302; very low-quality evidence) or acne (OR 1.45, 95% CI 0.90 to 2.33; two RCTs, n = 302; low-quality evidence).When researchers compared gestrinone versus leuprolin through measurements on the 1 to 3 verbal rating scale (lower score denotes benefit), the mean dysmenorrhoea score was higher in the gestrinone group (MD 0.35 points, 95% CI 0.12 to 0.58; one RCT, n = 55; low-quality evidence), but the mean dyspareunia score was lower in this group (MD 0.33 points, 95% CI 0.62 to 0.04; low-quality evidence). The gestrinone group had lower rates of amenorrhoea (OR 0.04, 95% CI 0.01 to 0.38; one RCT, n = 49; low-quality evidence) and hot flushes (OR 0.20, 95% CI 0.06 to 0.63; one study, n = 55; low quality evidence) but higher rates of spotting or bleeding (OR 22.92, 95% CI 2.64 to 198.66; one RCT, n = 49; low-quality evidence).Evidence was insufficient to show differences in effectiveness or safety between different doses of gestrinone, if present. Asoprisnil versus placebo One study (n = 130) made this comparison but did not report data suitable for analysis. Ulipristal versus leuprolide acetate One study (n = 38) made this comparison but did not report data suitable for analysis.
AUTHORS' CONCLUSIONS
Among women with endometriosis, moderate-quality evidence shows that mifepristone relieves dysmenorrhoea, and low-quality evidence suggests that this agent relieves dyspareunia, although amenorrhoea and hot flushes are common side effects. Data on dosage were inconclusive, although they suggest that the 2.5 mg dose of mifepristone may be less effective than higher doses. We found insufficient evidence to permit firm conclusions about the safety and effectiveness of other progesterone receptor modulators.
Topics: Danazol; Dysmenorrhea; Dyspareunia; Endometriosis; Estrenes; Female; Gestrinone; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Leuprolide; Mifepristone; Norpregnadienes; Oximes; Prevalence; Randomized Controlled Trials as Topic; Receptors, Progesterone
PubMed: 28742263
DOI: 10.1002/14651858.CD009881.pub2 -
Is hormonal therapy effective in advanced endometrial cancer? A systematic review and meta-analysis.Gynecologic Oncology Oct 2017Hormonal therapy (HT) is used commonly in the treatment of advanced endometrial cancer (EC). However, a 2010 Cochrane Review did not show a survival benefit for HT.... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Hormonal therapy (HT) is used commonly in the treatment of advanced endometrial cancer (EC). However, a 2010 Cochrane Review did not show a survival benefit for HT. Here, we quantify its effects and explore the influence of clinico-pathologic factors and hormone receptor (HR) status on overall response rates (ORR).
METHODS
A systematic search of electronic databases identified publications of HT in advanced EC. Data from individual studies reporting ORR, median progression-free (PFS) or overall survival (OS) were weighted by individual study sample size and pooled in a meta-analysis. Outcomes of estrogen (ER) and progesterone receptor (PgR) subgroups were collected. Studies of first- and second-line HT were analyzed independently. Mixed studies were included if subgroup data based on previous HT exposure were provided. Meta-regression was performed to evaluate the influence of clinico-pathologic factors on outcomes.
RESULTS
Thirty-nine studies were included, with seven providing subgroup data based on HR status. First-line HT was associated with a mean ORR of 21.6% and clinical benefit rate (CBR) of 36.7%. Median PFS and OS were 2.8 and 10.2months respectively. ORR was 20.4% in clinical trials and 25.3% in observational studies. Magnitude of ORR was lower in older age, adenosquamous histology and high grade. ORR was higher in ER+ (26.5%) and PgR+ (35.5%) disease, and lower in ER- (9.2%) or PgR- (12.1%) tumors. Second-line ORR was 18.5%. CBR was 35.8%, but was significantly associated with timing of stable disease assessments in first- and second-line. Meta-regression performed in mixed and second-line studies showed an association between previous HT and greater ORR (β 0.561; p=0.024), suggesting potential confounding by indication (re-treatment of good responders to first-line HT).
CONCLUSION
HT is associated with modest ORR in advanced EC, and is greatest in HR+ tumors. Response rates in second-line are likely dependent on response to previous HT.
Topics: Antineoplastic Agents, Hormonal; Drug Therapy, Combination; Endometrial Neoplasms; Female; Gonadal Hormones; Hormone Antagonists; Humans; Selective Estrogen Receptor Modulators; Survival Analysis
PubMed: 28689667
DOI: 10.1016/j.ygyno.2017.07.002 -
Human Reproduction Update Sep 2017Non-classic congenital hyperplasia (NCAH) due to 21-hydroxylase deficiency is a common autosomal recessive disorder characterized by androgen excess. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Non-classic congenital hyperplasia (NCAH) due to 21-hydroxylase deficiency is a common autosomal recessive disorder characterized by androgen excess.
OBJECTIVE AND RATIONALE
We conducted a systematic review and critical assessment of the available evidence pertaining to the epidemiology, pathophysiology, diagnosis and management of NCAH. A meta-analysis of epidemiological data was also performed.
SEARCH METHODS
Peer-reviewed studies evaluating NCAH published up to October 2016 were reviewed. Multiple databases were searched including MEDLINE, EMBASE, Cochrane, ERIC, EBSCO, dissertation abstracts, and current contents.
OUTCOMES
The worldwide prevalence of NCAH amongst women presenting with signs and symptoms of androgen excess is 4.2% (95% confidence interval: 3.2-5.4%). The clinical consequences of NCAH expand from infancy, i.e. accelerated growth, to adolescence and adulthood, i.e. premature pubarche, cutaneous symptoms and oligo-ovulation in a polycystic ovary syndrome (PCOS)-like clinical picture. The diagnosis of NCAH relies on serum 17-hydroxyprogesterone (17-OHP) concentrations. A basal 17-OHP concentration ≥2 ng/ml (6 nmol/l) should be used for screening if more appropriate in-house cut-off values are not available. Definitive diagnosis requires a 17-OHP concentration ≥10 ng/ml (30 nmol/l), either basally or after cosyntropin-stimulation. Molecular genetic analysis of the CYP21A2 gene, which is responsible for 21-hydroxylase activity, may be used for confirmation purposes and should be offered to all patients with NCAH along with genetic counseling because these patients frequently carry alleles that may result in classic CAH, the more severe form of the disease, in their progeny. Treatment must be individualized. Glucocorticoid replacement therapy may benefit pediatric patients with accelerated growth or advanced bone age or adult women seeking fertility, whereas adequate control of menstrual irregularity, hirsutism and other cutaneous symptoms is best served by the use of oral contraceptive pills and/or anti-androgens. Some women may need ovulation induction or assisted reproductive technology to achieve pregnancy. Patients with NCAH have a higher risk of miscarriage and may benefit from glucocorticoid treatment during pregnancy.
WIDER IMPLICATIONS
Evidence-based diagnostic and treatment strategies are essential for the proper management of women with NCAH, especially considering that these patients may need different therapeutic strategies at different stages during their follow-up and that appropriate genetic counseling may prevent the occurrence of CAH in their children.
Topics: 17-alpha-Hydroxyprogesterone; Adolescent; Adrenal Hyperplasia, Congenital; Adult; Androgen Antagonists; Female; Hirsutism; Humans; Infertility, Female; Menstruation Disturbances
PubMed: 28582566
DOI: 10.1093/humupd/dmx014 -
The Cochrane Database of Systematic... May 2017Among subfertile women undergoing assisted reproductive technology (ART), hormone pills given before ovarian stimulation may improve outcomes. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Among subfertile women undergoing assisted reproductive technology (ART), hormone pills given before ovarian stimulation may improve outcomes.
OBJECTIVES
To determine whether pretreatment with the combined oral contraceptive pill (COCP) or with a progestogen or oestrogen alone in ovarian stimulation protocols affects outcomes in subfertile couples undergoing ART.
SEARCH METHODS
We searched the following databases from inception to January 2017: Cochrane Gynaecology and Fertility Group Specialised Register, The Cochrane Central Register Studies Online, MEDLINE, Embase, CINAHL and PsycINFO. We also searched the reference lists of relevant articles and registers of ongoing trials.
SELECTION CRITERIA
Randomised controlled trials (RCTs) of hormonal pretreatment in women undergoing ART.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures recommended by Cochrane. The primary review outcomes were live birth or ongoing pregnancy and pregnancy loss.
MAIN RESULTS
We included 29 RCTs (4701 women) of pretreatment with COCPs, progestogens or oestrogens versus no pretreatment or alternative pretreatments, in gonadotrophin-releasing hormone (GnRH) agonist or antagonist cycles. Overall, evidence quality ranged from very low to moderate. The main limitations were risk of bias and imprecision. Most studies did not describe their methods in adequate detail. Combined oral contraceptive pill versus no pretreatmentWith antagonist cycles in both groups the rate of live birth or ongoing pregnancy was lower in the pretreatment group (OR 0.74, 95% CI 0.58 to 0.95; 6 RCTs; 1335 women; I = 0%; moderate quality evidence). There was insufficient evidence to determine whether the groups differed in rates of pregnancy loss (OR 1.36, 95% CI 0.82 to 2.26; 5 RCTs; 868 women; I = 0%; moderate quality evidence), multiple pregnancy (OR 2.21, 95% CI 0.53 to 9.26; 2 RCTs; 125 women; I = 0%; low quality evidence), ovarian hyperstimulation syndrome (OHSS; OR 0.98, 95% CI 0.28 to 3.40; 2 RCTs; 642 women; I = 0%, low quality evidence), or ovarian cyst formation (OR 0.47, 95% CI 0.08 to 2.75; 1 RCT; 64 women; very low quality evidence).In COCP plus antagonist cycles versus no pretreatment in agonist cycles, there was insufficient evidence to determine whether the groups differed in rates of live birth or ongoing pregnancy (OR 0.89, 95% CI 0.64 to 1.25; 4 RCTs; 724 women; I = 0%; moderate quality evidence), multiple pregnancy (OR 1.36, 95% CI 0.85 to 2.19; 4 RCTs; 546 women; I = 0%; moderate quality evidence), or OHSS (OR 0.63, 95% CI 0.20 to 1.96; 2 RCTs; 290 women, I = 0%), but there were fewer pregnancy losses in the pretreatment group (OR 0.40, 95% CI 0.22 to 0.72; 5 RCTs; 780 women; I = 0%; moderate quality evidence). There were no data suitable for analysis on ovarian cyst formation.One small study comparing COCP versus no pretreatment in agonist cycles showed no clear difference between the groups for any of the reported outcomes. Progestogen versus no pretreatmentAll studies used the same protocol (antagonist, agonist or gonadotrophins) in both groups. There was insufficient evidence to determine any differences in rates of live birth or ongoing pregnancy (agonist: OR 1.35, 95% CI 0.69 to 2.65; 2 RCTs; 222 women; I = 24%; low quality evidence; antagonist: OR 0.67, 95% CI 0.18 to 2.54; 1 RCT; 47 women; low quality evidence; gonadotrophins: OR 0.63, 95% CI 0.09 to 4.23; 1 RCT; 42 women; very low quality evidence), pregnancy loss (agonist: OR 2.26, 95% CI 0.67 to 7.55; 2 RCTs; 222 women; I = 0%; low quality evidence; antagonist: OR 0.36, 95% CI 0.06 to 2.09; 1 RCT; 47 women; low quality evidence; gonadotrophins: OR 1.00, 95% CI 0.06 to 17.12; 1 RCT; 42 women; very low quality evidence) or multiple pregnancy (agonist: no data available; antagonist: OR 1.05, 95% CI 0.06 to 17.76; 1 RCT; 47 women; low quality evidence; gonadotrophins: no data available). Three studies, all using agonist cycles, reported ovarian cyst formation: rates were lower in the pretreatment group (OR 0.16, 95% CI 0.08 to 0.32; 374 women; I = 1%; moderate quality evidence). There were no data on OHSS. Oestrogen versus no pretreatmentIn antagonist or agonist cycles, there was insufficient evidence to determine whether the groups differed in rates of live birth or ongoing pregnancy (antagonist versus antagonist: OR 0.79, 95% CI 0.53 to 1.17; 2 RCTs; 502 women; I = 0%; low quality evidence; antagonist versus agonist: OR 0.88, 95% CI 0.51 to 1.50; 2 RCTs; 242 women; I = 0%; very low quality evidence), pregnancy loss (antagonist versus antagonist: OR 0.16, 95% CI 0.02 to 1.47; 1 RCT; 49 women; very low quality evidence; antagonist versus agonist: OR 1.59, 95% CI 0.62 to 4.06; 1 RCT; 220 women; very low quality evidence), multiple pregnancy (antagonist versus antagonist: no data available; antagonist versus agonist: OR 2.24, 95% CI 0.09 to 53.59; 1 RCT; 22 women; very low quality evidence) or OHSS (antagonist versus antagonist: no data available; antagonist versus agonist: OR 1.54, 95% CI 0.25 to 9.42; 1 RCT; 220 women). Ovarian cyst formation was not reported. Head-to-head comparisonsCOCP was compared with progestogen (1 RCT, 44 women), and with oestrogen (2 RCTs, 146 women), and progestogen was compared with oestrogen (1 RCT, 48 women), with an antagonist cycle in both groups. COCP in an agonist cycle was compared with oestrogen in an antagonist cycle (1 RCT, 25 women). Data were scant but there was no clear evidence that any of the groups differed in rates of live birth or ongoing pregnancy, pregnancy loss or other adverse events.
AUTHORS' CONCLUSIONS
Among women undergoing ovarian stimulation in antagonist protocols, COCP pretreatment was associated with a lower rate of live birth or ongoing pregnancy than no pretreatment. There was insufficient evidence to determine whether rates of live birth or ongoing pregnancy were influenced by pretreatment with progestogens or oestrogens, or by COCP pretreatment using other stimulation protocols. Findings on adverse events were inconclusive, except that progesterone pretreatment may reduce the risk of ovarian cysts in agonist cycles, and COCP in antagonist cycles may reduce the risk of pregnancy loss compared with no pretreatment in agonist cycles.
Topics: Contraceptives, Oral; Estrogens; Female; Fertilization in Vitro; Gonadotropin-Releasing Hormone; Humans; Infertility, Female; Live Birth; Ovarian Hyperstimulation Syndrome; Ovulation Induction; Pregnancy; Pregnancy Rate; Pregnancy, Multiple; Progestins; Randomized Controlled Trials as Topic; Sperm Injections, Intracytoplasmic; Treatment Outcome
PubMed: 28540977
DOI: 10.1002/14651858.CD006109.pub3 -
European Journal of Obstetrics,... Jul 2017Ulipristal acetate is increasingly used for several clinical indications, like emergency contraception and pre-treatment of uterine fibroids. It has mixed progesterone... (Review)
Review
Ulipristal acetate is increasingly used for several clinical indications, like emergency contraception and pre-treatment of uterine fibroids. It has mixed progesterone agonist and antagonist effects in the myometrium and endometrium. Due to its progesterone antagonistic effect, an unopposed estrogen effect could occur which could cause (pre-)malignant lesions in the endometrium. Several studies have been performed to evaluate this possible increased risk for endometrial malignancies when using ulipristal acetate. The specific spectrum of morphological changes due to ulipristal acetate, named progesterone receptor modulator associated endometrial changes (PAEC), occurs to be reversible after discontinuing ulipristal acetate. In this systematic review we provide a detailed overview of the literature on histopathological endometrial changes and imaging characteristics of the endometrium in ulipristal acetate users. We performed an extensive search in Embase.com, Wiley/Cochrane Library and PubMed in accordance with the prisma guidelines. All studies published as full papers in peer reviewed journals using ulipristal acetate reporting on endometrial changes were included, independent of clinical indication, dosage taken and duration of therapy. No language restrictions were applied. Ten studies with a total of 1450 participants were included. Seven were randomized clinical trials and three prospective cohort studies. A quality assessment of all included studies was performed. In only five of ten studies an endometrial biopsy was performed during treatment. All of these studies described specific histological non-physiological endometrial changes (PAEC) due to ulipristal acetate, varying from 41 to 78.8% of all patients. Three of these studies also performed follow-up biopsies after discontinuing ulipristal acetate. The percentage of PAEC decreased from 62% to 0%, 78.8% to 0% and from 59% to 6-7% after the treatment period. In six of 1450 women (0.4%) endometrial hyperplasia was reported during or after ulipristal acetate use. Five were simple hyperplasia, one biopsy showed simple atypical endometrial hyperplasia that resolved into benign secretory endometrium by the end of the treatment. One case of endometrial adenocarcinoma was reported, however this does not seem to be related to ulipristal acetate use, since it was already present at the baseline biopsy. In eight of ten studies a transvaginal ultrasound or MRI was performed at any moment to assess the endometrial thickness before, during and after treatment. Most studies showed a transient increase of endometrial thickness during treatment, which returned to normal within a few weeks after discontinuing ulipristal acetate. Based on the literature found in this systematic review, follow-up after a maximum of four courses of ulipristal acetate did not report any non-reversible (pre-)malignant lesions of the endometrium. Most studies focused on short term use of ulipristal acetate and their follow-up period was limited. Therefore, we believe more information concerning long term (intermittent) use is needed before it can be concluded that its use is completely safe.
Topics: Contraceptive Agents, Female; Endometrium; Female; Humans; Leiomyoma; Norpregnadienes
PubMed: 28482329
DOI: 10.1016/j.ejogrb.2017.04.042 -
The Cochrane Database of Systematic... Apr 2017Uterine fibroids are smooth muscle tumours arising from the uterus. These tumours, although benign, are commonly associated with abnormal uterine bleeding, bulk symptoms... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Uterine fibroids are smooth muscle tumours arising from the uterus. These tumours, although benign, are commonly associated with abnormal uterine bleeding, bulk symptoms and reproductive dysfunction. The importance of progesterone in fibroid pathogenesis supports selective progesterone receptor modulators (SPRMs) as effective treatment. Both biochemical and clinical evidence suggests that SPRMs may reduce fibroid growth and ameliorate symptoms. SPRMs can cause unique histological changes to the endometrium that are not related to cancer, are not precancerous and have been found to be benign and reversible. This review summarises randomised trials conducted to evaluate the effectiveness of SPRMs as a class of medication for treatment of individuals with fibroids.
OBJECTIVES
To evaluate the effectiveness and safety of SPRMs for treatment of premenopausal women with uterine fibroids.
SEARCH METHODS
We searched the Specialised Register of the Cochrane Gynaecology and Fertility Group, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PsycINFO, the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and clinical trials registries from database inception to May 2016. We handsearched the reference lists of relevant articles and contacted experts in the field to request additional data.
SELECTION CRITERIA
Included studies were randomised controlled trials (RCTs) of premenopausal women with fibroids who were treated for at least three months with a SPRM.
DATA COLLECTION AND ANALYSIS
Two review authors independently reviewed all eligible studies identified by the search. We extracted data and assessed risk of bias independently using standard forms. We analysed data using mean differences (MDs) or standardised mean differences (SMDs) for continuous data and odds ratios (ORs) for dichotomous data. We performed meta-analyses using the random-effects model. Our primary outcome was change in fibroid-related symptoms.
MAIN RESULTS
We included in the review 14 RCTs with a total of 1215 study participants. We could not extract complete data from three studies. We included in the meta-analysis 11 studies involving 1021 study participants: 685 received SPRMs and 336 were given a control intervention (placebo or leuprolide). Investigators evaluated three SPRMs: mifepristone (five studies), ulipristal acetate (four studies) and asoprisnil (two studies). The primary outcome was change in fibroid-related symptoms (symptom severity, health-related quality of life, abnormal uterine bleeding, pelvic pain). Adverse event reporting in the included studies was limited to SPRM-associated endometrial changes. More than half (8/14) of these studies were at low risk of bias in all domains. The most common limitation of the other studies was poor reporting of methods. The main limitation for the overall quality of evidence was potential publication bias. SPRM versus placebo SPRM treatment resulted in improvements in fibroid symptom severity (MD -20.04 points, 95% confidence interval (CI) -26.63 to -13.46; four RCTs, 171 women, I = 0%; moderate-quality evidence) and health-related quality of life (MD 22.52 points, 95% CI 12.87 to 32.17; four RCTs, 200 women, I = 63%; moderate-quality evidence) on the Uterine Fibroid Symptom Quality of Life Scale (UFS-QoL, scale 0 to 100). Women treated with an SPRM showed reduced menstrual blood loss on patient-reported bleeding scales, although this effect was small (SMD -1.11, 95% CI -1.38 to -0.83; three RCTs, 310 women, I = 0%; moderate-quality evidence), along with higher rates of amenorrhoea (29 per 1000 in the placebo group vs 237 to 961 per 1000 in the SPRM group; OR 82.50, 95% CI 37.01 to 183.90; seven RCTs, 590 women, I = 0%; moderate-quality evidence), compared with those given placebo. We could draw no conclusions regarding changes in pelvic pain owing to variability in the estimates. With respect to adverse effects, SPRM-associated endometrial changes were more common after SPRM therapy than after placebo (OR 15.12, 95% CI 6.45 to 35.47; five RCTs, 405 women, I = 0%; low-quality evidence). SPRM versus leuprolide acetate In comparing SPRM versus other treatments, two RCTs evaluated SPRM versus leuprolide acetate. One RCT reported primary outcomes. No evidence suggested a difference between SPRM and leuprolide groups for improvement in quality of life, as measured by UFS-QoL fibroid symptom severity scores (MD -3.70 points, 95% CI -9.85 to 2.45; one RCT, 281 women; moderate-quality evidence) and health-related quality of life scores (MD 1.06 points, 95% CI -5.73 to 7.85; one RCT, 281 women; moderate-quality evidence). It was unclear whether results showed a difference between SPRM and leuprolide groups for reduction in menstrual blood loss based on the pictorial blood loss assessment chart (PBAC), as confidence intervals were wide (MD 6 points, 95% CI -40.95 to 50.95; one RCT, 281 women; low-quality evidence), or for rates of amenorrhoea (804 per 1000 in the placebo group vs 732 to 933 per 1000 in the SPRM group; OR 1.14, 95% CI 0.60 to 2.16; one RCT, 280 women; moderate-quality evidence). No evidence revealed differences between groups in pelvic pain scores based on the McGill Pain Questionnaire (scale 0 to 45) (MD -0.01 points, 95% CI -2.14 to 2.12; 281 women; moderate-quality evidence). With respect to adverse effects, SPRM-associated endometrial changes were more common after SPRM therapy than after leuprolide treatment (OR 10.45, 95% CI 5.38 to 20.33; 301 women; moderate-quality evidence).
AUTHORS' CONCLUSIONS
Short-term use of SPRMs resulted in improved quality of life, reduced menstrual bleeding and higher rates of amenorrhoea than were seen with placebo. Thus, SPRMs may provide effective treatment for women with symptomatic fibroids. Evidence derived from one RCT showed no difference between leuprolide acetate and SPRM with respect to improved quality of life and bleeding symptoms. Evidence was insufficient to show whether effectiveness was different between SPRMs and leuprolide. Investigators more frequently observed SPRM-associated endometrial changes in women treated with SPRMs than in those treated with placebo or leuprolide acetate. As noted above, SPRM-associated endometrial changes are benign, are not related to cancer and are not precancerous. Reporting bias may impact the conclusion of this meta-analysis. Well-designed RCTs comparing SPRMs versus other treatments are needed.
Topics: Amenorrhea; Antineoplastic Agents, Hormonal; Estrenes; Female; Humans; Leiomyoma; Leuprolide; Menstruation; Mifepristone; Norpregnadienes; Oximes; Pelvic Pain; Quality of Life; Randomized Controlled Trials as Topic; Receptors, Progesterone; Uterine Neoplasms
PubMed: 28444736
DOI: 10.1002/14651858.CD010770.pub2 -
Biomedicine & Pharmacotherapy =... Jun 2017Endometriosis is a gynaecological disease that is characterised by the presence of endometrium like tissue-epithelium and stroma that develops outside the uterine... (Review)
Review
PURPOSE AND OBJECTIVE
Endometriosis is a gynaecological disease that is characterised by the presence of endometrium like tissue-epithelium and stroma that develops outside the uterine cavity, which is responsible for pelvic pain and infertility. Even though several medical therapies exist for the treatment of endometriosis, each of the drug class has its own limitations such as cost of treatment, side-effects and its short-term effect on the symptoms of endometriosis. In this review, we have attempted to summarize the current status and challenges of drug development for endometriosis.
METHODS
A systematic review was done and all the RCTs were selected from the identified hits. We included studies that explored the usage of therapeutic drugs on endometriosis patients from inception till November 2016. The search term used was 'Endometriosis' using PubMed and Clinicaltrials.gov. For the final analysis, 60 articles were analyzed and we identified the newly emerging drug therapies for endometriosis treatment and have briefed their current status and challenges in drug development for endometriosis. The quality of the selected studies was assessed based on the degree of bias.
RESULTS
The current classes of drugs that have shown promising therapeutic results include Gonadotropin- releasing hormone (GnRH) antagonists, aromatase inhibitors (AI), and selective progesterone and estrogen receptor modulators, dopamine receptor-2-agonists and statins. The drugs that failed midway during development include tanezumab, rosiglitazone, infliximab, pentoxifylline, telapristone acetate, asoprisnil and raloxifene.
CONCLUSION
From the literature review, it appears that the most promising molecules for the treatment of endometriosis in the near future include elagolix, mifepristone, TAK-385, KLH-2109 and ASP1707 and cabergoline. It remains to be seen if these molecules would succeed large phase 3 clinical trials and overcome the regulatory hurdles to become an essential tool in the gynaecologist's armamentarium against endometriosis.
Topics: Animals; Drug Discovery; Endometriosis; Female; Humans; Pharmaceutical Preparations
PubMed: 28407578
DOI: 10.1016/j.biopha.2017.03.092