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The Cochrane Database of Systematic... Aug 2019Heavy menstrual bleeding (HMB) is a menstrual blood loss perceived by women as excessive that affects the health of women of reproductive age, interfering with their...
BACKGROUND
Heavy menstrual bleeding (HMB) is a menstrual blood loss perceived by women as excessive that affects the health of women of reproductive age, interfering with their physical, emotional, social and material quality of life. Whilst abnormal menstrual bleeding may be associated with underlying pathology, in the present context, HMB is defined as excessive menstrual bleeding in the absence of other systemic or gynaecological disease. The first-line therapy is usually medical, avoiding possibly unnecessary surgery. Of the wide variety of medications used to reduce HMB, oral progestogens were originally the most commonly prescribed agents. This review assesses the effectiveness of two different types and regimens of oral progestogens in reducing ovulatory HMB.This is the update of a Cochrane review last updated in 2007, and originally named "Effectiveness of cyclical progestagen therapy in reducing heavy menstrual bleeding" (1998).
OBJECTIVES
To determine the effectiveness, safety and tolerability of oral progestogen therapy taken either during the luteal phase (short cycle) or for a longer course of 21 days per cycle (long cycle), in achieving a reduction in menstrual blood loss in women of reproductive age with HMB.
SEARCH METHODS
In January 2019 we searched Cochrane Gynaecology and Fertility's specialized register, CENTRAL, MEDLINE, Embase, CINAHL and PsycInfo. We also searched trials registers, other sources of unpublished or grey literature and reference lists of retrieved trials. We also checked citation lists of review articles to identify trials.
SELECTION CRITERIA
Randomized controlled trials (RCTs) comparing different treatments for HMB that included cyclical oral progestogens were eligible.
DATA COLLECTION AND ANALYSIS
Two review authors independently selected trials for inclusion, assessed trials for risk of bias and extracted data. We contacted trial authors for clarification of methods or additional data when necessary. We only assessed adverse events if they were separately measured in the included trials. We compared cyclical oral progestogen in different regimens and placebo or other treatments. Our primary outcomes were menstrual blood loss and satisfaction with treatment; the secondary outcomes were number of days of bleeding, quality of life, compliance and acceptability of treatment, adverse events and costs.
MAIN RESULTS
This review identified 15 randomized controlled trials (RCTs) with 1071 women in total. Most of the women knew which treatment they were receiving, which may have influenced their judgements about menstrual blood loss and satisfaction. Other aspects of trial quality varied among trials.We did not identify any RCTs comparing progestogen treatment with placebo. We assessed comparisons between oral progestogens and other medical therapies separately according to different regimens.Short-cycle progestogen therapy during the luteal phase (medroxyprogesterone acetate or norethisterone for 7 to 10 days, from day 15 to 19) was inferior to other medical therapy, including tranexamic acid, danazol and the progestogen-releasing intrauterine system (Pg-IUS (off of the market since 2001)), releasing 60 mcg of progesterone daily, with respect to reduction of menstrual blood loss (mean difference (MD) 37.29, 95% confidence interval (CI) 17.67 to 56.91; I = 50%; 6 trials, 145 women). The rate of satisfaction and the quality of life with treatment was similar in both groups. The number of bleeding days was greater on the short cycle progestogen group compared to other medical treatments. Adverse events (such as gastrointestinal symptoms and weight gain) were more likely with danazol when compared with progestogen treatment. We note that danazol is no longer in general use for treating HMB.Long-cycle progestogen therapy (medroxyprogesterone acetate or norethisterone), from day 5 to day 26 of the menstrual cycle, is also inferior to the levonorgestrel-releasing intrauterine system (LNG-IUS), releasing tranexamic acid and ormeloxifene, but may be similar to the combined vaginal ring with respect to reduction of menstrual blood loss (MD 16.88, 95% CI 10.93 to 22.84; I = 87%; 4 trials, 355 women). A higher proportion of women taking norethisterone found their treatment unacceptable compared to women having Pg-IUS (Peto odds ratio (OR) 0.12, 95% CI 0.03 to 0.40; 1 trial, 40 women). However, the adverse effects of breast tenderness and intermenstrual bleeding were more likely in women with the LNG-IUS. No trials reported on days of bleeding or quality of life for this comparison.The evidence supporting these findings was limited by low or very low gradings of quality; thus, we are uncertain about the findings and there is a potential that they may change if we identify other trials.
AUTHORS' CONCLUSIONS
Low- or very low-quality evidence suggests that short-course progestogen was inferior to other medical therapy, including tranexamic acid, danazol and the Pg-IUS with respect to reduction of menstrual blood loss. Long cycle progestogen therapy (medroxyprogesterone acetate or norethisterone) was also inferior to the LNG-IUS, tranexamic acid and ormeloxifene, but may be similar to the combined vaginal ring with respect to reduction of menstrual blood loss.
Topics: Danazol; Female; Humans; Intrauterine Devices, Medicated; Medroxyprogesterone Acetate; Menorrhagia; Progesterone; Progestins; Quality of Life; Randomized Controlled Trials as Topic; Tranexamic Acid
PubMed: 31425626
DOI: 10.1002/14651858.CD001016.pub3 -
The Cochrane Database of Systematic... Feb 2019Menorrhagia or heavy menstrual bleeding (HMB) is an excessive blood loss that impairs a woman's quality of life, either physical, emotional, social or material. It is... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Menorrhagia or heavy menstrual bleeding (HMB) is an excessive blood loss that impairs a woman's quality of life, either physical, emotional, social or material. It is benign and not associated with pregnancy or any other gynaecological or systemic disease. Medical treatments used to reduce excessive menstrual blood loss (MBL) include prostaglandin synthetase inhibitors, antifibrinolytics, oral contraceptive pills, and other hormones. The combined oral contraceptive pill (COCP) is claimed to have a variety of beneficial effects, inducing a regular shedding of a thinner endometrium and inhibiting ovulation, thus having the effect of both treating HMB and providing contraception. More recently, a contraceptive vaginal ring (CVR) has been trialled to investigate whether this treatment can provide similar benefits to COCP while lessening hormonal systemic exposure. This review is an update of a review which originally focused on COCP alone. The scope of the review has been widened to consider other types of delivery of combined hormonal contraceptives for reduction of MBL.
OBJECTIVES
To determine the efficacy of combined hormonal contraceptives (pills, vaginal ring or patch) compared with other medical therapies, placebo, or no therapy in the treatment of HMB. A secondary objective was to compare the COCP with the CVR.
SEARCH METHODS
We searched the Gynecology and Fertility Group trials register, MEDLINE, Embase, CENTRAL, CINAHL and PsycINFO (search dates: Oct 1996, May 2002, June 2004, April 2006, June 2009, July 2017 and September 2018) for all randomised controlled trials (RCTs) of COCP and CVR for the treatment of HMB. We also searched trial registers and the reference lists of retrieved studies for additional trials.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) of the use of COCP or CVR compared with no treatment, placebo, or other medical therapies for women with HMB and regular menstrual cycles.
DATA COLLECTION AND ANALYSIS
All assessments of trial quality and data extraction were performed unblinded by at least two review authors. Our primary review outcomes were treatment success, menstrual bleeding (assessed objectively, semi-objectively or subjectively), and participant satisfaction with treatment. Secondary outcomes were adverse events, quality of life, and haemoglobin level.
MAIN RESULTS
We identified eight RCTs involving 805 participants. Two trials comparing COCP with placebo were considered to be moderate quality and the remaining studies were low to very low quality, mainly because of serious risk of bias from lack of blinding and concerns over precision.COCP versus placeboCOCP, with a step-down oestrogen and step-up progestogen regimen, improved response to treatment (return to menstrual 'normality') (OR 22.12, 95% CI 4.40 to 111.12; 2 trials; 363 participants; I = 50%; moderate-quality evidence), and lowered MBL (OR 5.15, 95% CI 3.16 to 8.40; 2 trials; 339 participants; I = 0%; moderate-quality evidence) when compared to placebo. The results suggested that, if the chance of 'successful' treatment was 3% in women taking placebo, then COCP increased this chance from 12% to 77% in women with unacceptable HMB. Minor adverse events, in particular breast pain, were more common with COCP. No study in this comparison reported semi-objectively assessed MBL or participant satisfaction with treatment.COCP versus other medical treatmentsNon-steroidal anti-inflammatory drugs (NSAIDs)There was insufficient evidence to determine whether the COCP reduced MBL when compared to NSAIDs (mefenamic acid and naproxen). No study in this comparison reported semi-objectively assessed MBL, subjectively assessed MBL, participant satisfaction with treatment or adverse events.Levonorgestrel-releasing intrauterine system (LNG IUS)The LNG IUS was more effective than COCP in reducing MBL (OR 0.21, 95% CI 0.09 to 0.48; 2 trials; 151 participants; I = 0%; low-quality evidence) but it was not clear whether satisfaction with treatment or adverse effects varied according to which treatment was used. No study in this comparison reported semi-objectively assessed MBL or subjectively assessed MBL.Contraceptive vaginal ring (CVR) versus other medical treatmentsCOCP COCP was compared with CVR in two trials. There were discrepancies between some of the findings and there was no evidence of a benefit for one treatment compared to the other for response to treatment, MBL or participant satisfaction with treatment. There was a greater likelihood of nausea with COCP. No study in this comparison reported objectively assessed MBL or subjectively assessed MBL.ProgestogensCVR was compared to long course progestogens in one trial. It is possible that CVR increased the odds of satisfaction; but we are uncertain whether CVR improved MBL. The evidence was based on small numbers of participants and was very low quality, so definitive conclusions could not be reached. No study in this comparison reported objectively assessed MBL, subjectively assessed MBL, or adverse events.
AUTHORS' CONCLUSIONS
Moderate-quality evidence suggests that the combined oral contraceptive pill over six months reduces HMB in women with unacceptable HMB from 12% to 77% (compared to 3% in women taking placebo). When compared with other medical options for HMB, COCP was less effective than the LNG IUS. Limited evidence suggested that COCP and CVR had similar effects. There was insufficient evidence to determine comparative efficacy of combined hormonal contraceptives with NSAIDs, or long course progestogens.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Contraceptive Agents, Female; Contraceptives, Oral, Combined; Danazol; Drug Therapy, Combination; Female; Humans; Intrauterine Devices, Medicated; Levonorgestrel; Mefenamic Acid; Menorrhagia; Naproxen; Nausea; Placebos; Progestins; Randomized Controlled Trials as Topic
PubMed: 30742315
DOI: 10.1002/14651858.CD000154.pub3 -
Medicine Sep 2017Corticosteroid sparing is required in 15% to 40% of adults with persistent or chronic primary immune thrombocytopenic purpura (ITP). Herein, the efficacy of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Corticosteroid sparing is required in 15% to 40% of adults with persistent or chronic primary immune thrombocytopenic purpura (ITP). Herein, the efficacy of immunomodulatory drugs (dapsone, interferon alpha, danazol, and hydroxychloroquine as second-third-line therapies in ITP is investigated.
METHODS
MEDLINE was searched for studies that included patients with persistent or chronic primary ITP and published before the end of December 2014. Two investigators independently extracted data regarding study design, patient characteristics, dosage schedule, time to response, and occurrence of adverse events. The pooled overall response rate (ORR; platelet count >30 × 10 L) and the complete response rate (CRR; platelet count >100 × 10 L) were evaluated to determine drug efficacy by calculating weighted mean proportion using a fixed or random-effects model according to heterogeneity (I > 50%). The study was performed following the MOOSE and PRISMA guidelines.
RESULTS
A total of 28 studies (415 patients) were included (dapsone: k = 7 studies, n = 80; danazol: k = 12, n = 224; interferon alpha: k = 8, n = 83; hydroxychloroquine: k = 1, n = 28). The mean patient age was 50 years (female sex 70%, splenectomy 47%). The ORR and CRR were 55% (95% CI: 44%-66%, I = 0%) and 21% (95% CI: 13%-31%, I = 0%), respectively, for dapsone; 42% (95% CI: 22%-65%, I = 63%) and 18% (95% CI: 10%-29%, I = 9%), respectively, for interferon alpha; and 58% (95% CI: 42%-72%, I = 67%) and 29% (95% CI: 19%-42%, I = 63%), respectively, for danazol. The ORR was 50% (95% CI: 32%-67%) for hydroxychloroquine (data not available for CRR). Meta-regression analysis found a correlation between the ORR for interferon alpha and the splenectomized status of the patient (P = .02) and between the CRR for danazol and disease duration (P < .001). In total, 73%, 51%, 30%, and 0% of patients who received danazol, dapsone, interferon alpha, and hydroxychloroquine experienced side effects, respectively.
CONCLUSION
The ORR was equivalent for hydroxychloroquine, danazol, and dapsone in ITP. Regarding their low CRR, patients at high risk of infection or at low risk of bleeding should benefit from these treatments. Thanks to their best efficacy and safety profiles, dapsone and hydroxychloroquine in patients with antinuclear antibodies should be preferred over danazol and interferon alpha.
Topics: Humans; Immunomodulation; Purpura, Thrombocytopenic, Idiopathic
PubMed: 28906353
DOI: 10.1097/MD.0000000000007534 -
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 -
The Cochrane Database of Systematic... Jul 2014This review has been replaced by a new full review with the same title 'Pre‐operative endometrial thinning agents before endometrial destruction for heavy menstrual... (Review)
Review
This review has been replaced by a new full review with the same title 'Pre‐operative endometrial thinning agents before endometrial destruction for heavy menstrual bleeding' published in issue 11 of The Cochrane Library 2013; authors are Yu Hwee Tan and Anne Lethaby. The editorial group responsible for this previously published document have withdrawn it from publication.
Topics: Danazol; Endometrium; Estrogen Antagonists; Female; Gonadotropin-Releasing Hormone; Goserelin; Humans; Hysteroscopy; Menorrhagia; Progestins
PubMed: 25070909
DOI: 10.1002/14651858.CD001124.pub2