BACKGROUND: Myomectomy has potential risks of complications. To reduce these risks, medical pre-treatment can be applied to reduce fibroid size and thereby potentially decrease intra-operative blood loss, the need for blood transfusion and emergency hysterectomy. The aim of this systematic review and meta-analysis is to study the effectiveness of medical pre-treatment with Gonadotropin-releasing hormone agonists (GnRHa) or ulipristal acetate prior to laparoscopic or laparotomic myomectomy on intra-operative and post-operative outcomes.
METHODS: 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 GnRHa or ulipristal acetate as medical pre-treatment independent of route of administration or dosage before laparotomic or laparoscopic myomectomy were included. The primary outcome was duration of surgery. Secondary outcomes were duration of enucleation, blood loss, degree of difficulty of surgery, identification of cleavage planes, proportion of vertical incisions, conversion rate, frequency of blood transfusions, post-operative complications, duration of hospital stay, frequency of recurrence of fibroids, frequency of uterine adhesions, recovery time and quality of life. No language restrictions were applied. Meta-analysis were performed where possible.
FINDINGS: Twenty-three studies were included. In laparotomic myomectomy, pre-treatment with GnRHa decreases intra-operative blood loss with 97.39ml (95% CI -111.80 to -82.97) compared to no pre-treatment or placebo. Pre-treatment with GnRHa before laparoscopic myomectomies also shows a reduction in intra-operative blood loss by 23.03ml (95% CI -40.79 to -5.27) and in the frequency of blood transfusions (OR 0.17, 95% CI 0.05 to 0.55) compared to no pre-treatment. Only two retrospective cohort studies reported on pre-treatment with ulipristal acetate compared to no pre-treatment before laparoscopic myomectomy showing a statistically significant reduction in intra-operative blood loss, duration of surgery and frequency of blood transfusions after pre-treatment with ulipristal acetate.
CONCLUSION: Administration of GnRHa prior to laparotomic myomectomy reduces blood loss and might decrease uterine adhesion formation. Pre-treatment with GnRHa before laparoscopic myomectomy reduces blood loss, the frequency of blood transfusions and might increase recurrence rate of fibroids, however it should be taken into account that some results are mainly based on cohort studies. Other pre-treatment agent ulipristal acetate has not been investigated sufficiently for relevant surgical outcomes.
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 placeboGnRHa 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 therapiesGnRHa 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 placeboSPRMs (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.
BACKGROUND: Uterine fibroids are common, often symptomatic and a third of women need repeated time off work. Consequently 25% to 50% of women with fibroids receive surgical treatment, namely myomectomy or hysterectomy. Hysterectomy is the definitive treatment as fibroids are hormone dependent and frequently recurrent. Medical treatment aims to control symptoms in order to replace or delay surgery. This may improve the outcome of surgery and prevent recurrence.
PURPOSE: To determine whether any medical treatment can be recommended in the treatment of women with fibroids about to undergo surgery and in those for whom surgery is not planned based on currently available evidence.
STUDY SELECTION: Two authors independently identified randomised controlled trials (RCT) of all pharmacological treatments aimed at the treatment of fibroids from a list of references obtained by formal search of MEDLINE, EMBASE, Cochrane library, Science Citation Index, and ClinicalTrials.gov until December 2013.
DATA EXTRACTION: Two authors independently extracted data from identified studies.
DATA SYNTHESIS: A Bayesian network meta-analysis was performed following the National Institute for Health and Care Excellence-Decision Support Unit guidelines. Odds ratios, rate ratios, or mean differences with 95% credible intervals (CrI) were calculated.
RESULTS AND LIMITATIONS: A total of 75 RCT met the inclusion criteria, 47 of which were included in the network meta-analysis. The overall quality of evidence was very low. The network meta-analysis showed differing results for different outcomes.
CONCLUSIONS: There is currently insufficient evidence to recommend any medical treatment in the management of fibroids. Certain treatments have future promise however further, well designed RCTs are needed.
BACKGROUND: fibromi uterini (noti anche come leiomiomi) sono i tumori pelvici benigni più comuni tra le donne. Essi possono essere asintomatici, o possono essere associata a sintomi pelvici, come sanguinamento e dolore. Il trattamento medico di questa condizione è limitata e l'ormone di rilascio delle gonadotropine (GnRH) analoghi sono gli agenti più efficaci. Il trattamento a lungo termine con tali agenti, tuttavia, è limitato a causa dei loro effetti collaterali. L'aggiunta di altri farmaci durante il trattamento con analoghi del GnRH, una strategia nota come terapia add-back, può limitare questi effetti collaterali. Si teme, tuttavia, che la terapia add-back può anche limitare l'efficacia degli analoghi del GnRH e che potrebbe non essere in grado di prevenire completamente gli effetti negativi.
OBIETTIVI: valutare a breve termine (entro 12 mesi) l'efficacia e la sicurezza della terapia add-back per le donne che usano analoghi del GnRH per fibromi uterini connessi con eccessivo sanguinamento uterino, dolore pelvico, o sintomi urinari.
METODI DI RICERCA: Abbiamo cercato database elettronici, compresi i disturbi mestruali e Cochrane Subfertility Group (MDSG) specialistica Register, CENTRAL, MEDLINE, PubMed, EMBASE, lillà, CINAHL, PsycINFO; e registri elettronici di processi in corso, tra cui ClinicalTrials.gov, Controlled Trials correnti, Organizzazione Mondiale della Sanità (OMS) Clinical Trials Registry Platform internazionali. Tutte le ricerche sono stati da database di nascita a 16 Giugno 2014.
CRITERI DI SELEZIONE: studi controllati randomizzati (RCT) che includeva le donne con fibromi uterini sperimentare sanguinamento irregolare o intenso uterino, dolore pelvico ciclico o non ciclico, o sintomi urinari, e che la terapia di trattamento rispetto ad un analogo del GnRH più add-back contro un GnRH da solo o in combinazione con il placebo analogica erano eleggibili per l'inclusione.
RACCOLTA DATI E ANALISI: Due autori recensione indipendente i titoli identificati e abstract per i record potenzialmente ammissibili. Due revisori recensione studi eleggibili e dati estratti in modo indipendente. Due autori hanno valutato indipendentemente rischio degli studi »di parzialità. Hanno valutato la qualità delle prove utilizzando criteri GRADO.
PRINCIPALI RISULTATI: Quattordici RCT sono stati inclusi nella revisione. I dati sono stati estratti da 12 studi (622 donne). L'outcome primario era la qualità della vita (QoL).Aggiungere-back la terapia con medrossiprogesterone (MPA): studi riportati QoL o sanguinamento uterino. Non c'è stata evidenza di effetti in relazione alla massa ossea (differenza media standardizzata (SMD) 0,38, 95% intervallo di confidenza (IC) -0,62 a 1,38, 1 studio, 16 donne, P = 0,45, la prova di bassa qualità) e MPA è stato associato con un volume uterino più grande (differenza media (MD) 342,19 centimetri (3), 95% CI 77,58-606,80, 2 studi, 32 donne, I (2) = 0%, le prove di bassa qualità).Tibolone: questo è stato associato ad una più alta qualità di vita, ma la stima era imprecisa e l'effetto potrebbe essere clinicamente insignificante, piccolo o grande (SMD 0,47, 95% CI 0,09-0,85, 1 studio, 110 donne, P = 0,02, la prova di bassa qualità) . E 'stato anche associato ad una diminuzione della perdita di massa ossea, che potrebbe essere insignificante, piccola o moderata (SMD 0,36, 95% CI 0,03-0,7, 3 studi, 160 donne, I (2) = 7%, le prove di qualità moderata). Tibolone può, tuttavia, sono stati associati a volumi più grandi uterini (MD 23,89 centimetri (3), 95% CI = 8,13-39,66, 6 studi, 365 donne, I (2) = 0%, la prova di qualità moderata) e più sanguinamento uterino (risultati non sono stati combinati, ma tre studi hanno dimostrato una maggiore sanguinamento con tibolone, mentre gli altri due studi hanno dimostrato nessun sanguinamento in entrambi i gruppi). Quattro studi (268 donne; non in pool a causa della estrema eterogeneità) hanno riportato un grande vantaggio sui sintomi vasomotori nel gruppo tibolone.Raloxifene: non vi era alcuna prova di un effetto sulla qualità di vita (SMD 0,11, 95% CI -0,57 a 0,34, 1 studio, 74 donne, P = 0,62, la prova di bassa qualità), mentre c'è stato un impatto benefico sulla massa ossea (SMD 1.01 , 95% CI 0,57-1,45, 1 studio, 91 donne, P <0,00001, la prova di bassa qualità). Non c'erano prove evidenti di effetto sul volume uterino (MD 27,1 centimetri (3), 95% CI -17,94 a 72,14, 1 studio, 91 donne, P = 0,24, la prova di bassa qualità), sanguinamento uterino o la gravità dei sintomi vasomotori (MD 0,2 vampate di calore / giorno, il 95% CI -0,34 a 0,74, 1 studio, 91 donne, P = 0,46, prove di bassa qualità).Estriolo: studi hanno riportato QoL, formato uterino, sanguinamento uterino e sintomi vasomotori. Aggiungere-back con estriolo può aver portato ad una diminuzione la perdita di massa ossea, dai risultati di un singolo studio (SMD 3,93, 95% CI 1,7-6,16, 1 studio, 12 donne, P = 0,0005, prove di bassa qualità).Ipriflavone: studi hanno riportato QoL, dimensioni dell'utero o sanguinamento uterino. Iproflavone è risultato associato ad una diminuzione perdita di massa ossea in un singolo studio (SMD 2,71, 95% CI 2,14-3,27, 1 studio, 95 donne, P <0,00001, la prova di bassa qualità); non vi era alcuna prova di un effetto sul tasso di sintomi vasomotori (RR 0.67, 95% CI 0,44-1,02, 1 studio, 95 donne, P = 0,06, la prova di bassa qualità).Estrogeni coniugati: studi riportati QoL, dimensione uterina, sanguinamento uterino e sintomi vasomotori. Uno studio ha suggerito che l'aggiunta di estrogeni coniugati agli analoghi del GnRH portato ad una diminuzione più grande del volume uterino nel gruppo placebo (MD 105,2 centimetri (3), il 95% CI 27,65-182,75, 1 studio, 27 donne, P = 0.008, di qualità molto bassa prova).Nove di 12 studi erano ad alto rischio di bias in almeno un dominio, più comunemente la mancanza di cecità. Tutti gli studi hanno seguito i partecipanti per un massimo di sei mesi. Questo breve termine di follow-up è generalmente insufficiente per osservare alcun effetto significativo del trattamento sulla salute delle ossa (come il verificarsi di fratture), limitando i risultati.
Conclusioni degli autori: C'erano prove bassa o moderata di qualità che tibolone, raloxifene, estriolo e ipriflavone aiutano a preservare la densità ossea e che MPA e tibolone può ridurre i sintomi vasomotori. Volume uterino ingrandita di un effetto pregiudizievole associato ad alcune terapie add-back (MPA, tibolone e estrogeni coniugati). Per gli altri confronti, esiti di interesse non sono stati segnalati o di studio i risultati sono stati inconcludenti.
Myomectomy has potential risks of complications. To reduce these risks, medical pre-treatment can be applied to reduce fibroid size and thereby potentially decrease intra-operative blood loss, the need for blood transfusion and emergency hysterectomy. The aim of this systematic review and meta-analysis is to study the effectiveness of medical pre-treatment with Gonadotropin-releasing hormone agonists (GnRHa) or ulipristal acetate prior to laparoscopic or laparotomic myomectomy on intra-operative and post-operative outcomes.
METHODS:
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 GnRHa or ulipristal acetate as medical pre-treatment independent of route of administration or dosage before laparotomic or laparoscopic myomectomy were included. The primary outcome was duration of surgery. Secondary outcomes were duration of enucleation, blood loss, degree of difficulty of surgery, identification of cleavage planes, proportion of vertical incisions, conversion rate, frequency of blood transfusions, post-operative complications, duration of hospital stay, frequency of recurrence of fibroids, frequency of uterine adhesions, recovery time and quality of life. No language restrictions were applied. Meta-analysis were performed where possible.
FINDINGS:
Twenty-three studies were included. In laparotomic myomectomy, pre-treatment with GnRHa decreases intra-operative blood loss with 97.39ml (95% CI -111.80 to -82.97) compared to no pre-treatment or placebo. Pre-treatment with GnRHa before laparoscopic myomectomies also shows a reduction in intra-operative blood loss by 23.03ml (95% CI -40.79 to -5.27) and in the frequency of blood transfusions (OR 0.17, 95% CI 0.05 to 0.55) compared to no pre-treatment. Only two retrospective cohort studies reported on pre-treatment with ulipristal acetate compared to no pre-treatment before laparoscopic myomectomy showing a statistically significant reduction in intra-operative blood loss, duration of surgery and frequency of blood transfusions after pre-treatment with ulipristal acetate.
CONCLUSION:
Administration of GnRHa prior to laparotomic myomectomy reduces blood loss and might decrease uterine adhesion formation. Pre-treatment with GnRHa before laparoscopic myomectomy reduces blood loss, the frequency of blood transfusions and might increase recurrence rate of fibroids, however it should be taken into account that some results are mainly based on cohort studies. Other pre-treatment agent ulipristal acetate has not been investigated sufficiently for relevant surgical outcomes.
