月经过多的药物治疗研究进展

月经过多首选药物治疗,最终目标是使经血减少到可接受的水平,尽可能减少不良反应。月经过多常用抗纤维蛋白溶解药、非甾体抗炎药、左炔诺孕酮宫内缓释系统、复方激素避孕药等药物治疗,也可用去氨加压素、口服孕酮化合物以及中医药等治疗。     

The levonorgestrel-releasing intrauterine system in heavy menstrual bleeding: a benefit-risk review

Heavy menstrual bleeding (HMB) is a common problem in women of reproductive age and can cause irritation, inconvenience, self-consciousness and fear of social embarrassment. Our objective was to review and appraise literature identified from the MEDLINE and EMBASE databases to evaluate the clinical evidence and provide an update on the risks and benefits of using the levonorgestrel-releasing intrauterine system (LNG-IUS) in the treatment of HMB. The LNG-IUS consistently reduces menstrual blood loss (MBL) in women with HMB, including those with underlying uterine pathology or bleeding disorders. The available data suggest that it reduces MBL to a greater extent than other medical therapies, including combined oral contraceptives, oral progestogens (both short- or long-cycle regimens), tranexamic acid and oral mefenamic acid. In addition, the LNG-IUS and endometrial ablation appear to reduce MBL to a similar extent. The adverse effects reported with the LNG-IUS in women with HMB are similar to those typically observed in women using the system for contraception. Uterine perforations were not reported in any of the studies reviewed, but expulsion rates may be higher than in the general population of LNG-IUS users. Overall, the LNG-IUS has a positive effect on most quality-of-life domains, at least comparable to those achieved with hysterectomy or endometrial ablation, and is consistently a cost-effective option across a variety of countries and settings. In conclusion, the LNG-IUS is an effective treatment option for women with HMB, including those with underlying organic pathology or bleeding disorders.     

Menorrhagia. Current drug treatment concepts.

Since menorrhagia occurs in 9 to 14% of populations of healthy women, many general practitioners will encounter menorrhagia-related problems. Menorrhagia is difficult to objectify and the choice of treatment between the available drugs is not always an easy one. In this survey, the available knowledge on menorrhagia diagnosis, underlying pathophysiology and treatment, especially medicinal treatment, are discussed. Overall, a practical approach is emphasised. The desire for contraception as well as the underlying cause of menorrhagia determine the drug of choice in the treatment of menorrhagia. If contraception is desired, oral combination contraceptives and continuously dosed progestogens, orally or as a medicated intrauterine device (IUD), are the first choice drugs for essential menorrhagia, and for fibroid- and bleeding disorder-associated menorrhagia. If no contraception is desired, the first choice treatments are drugs that need to be administered only during menstruation, such as prostaglandin synthesis inhibitors or antifibrinolytics. Of these, antifibrinolytics reduce menstrual blood loss to the greatest extent, whereas prostaglandin synthesis inhibitors have the lowest incidence of side effects. Prostaglandin synthesis inhibitors also have the extra advantage of diminishing dysmenorrhoea. There is no place for ergometrine in the treatment of menorrhagia. No studies are available as yet on the combination of various drug treatment modalities, although such an evaluation would be desirable.     

Tranexamic acid: a review of its use in the management of menorrhagia

Tranexamic acid (Transamin), Cyklokapron, Exacyl, Cyklo-f) is a synthetic lysine derivative that exerts its antifibrinolytic effect by reversibly blocking lysine binding sites on plasminogen and thus preventing fibrin degradation.In a number of small clinical studies in women with idiopathic menorrhagia, tranexamic acid 2-4.5 g/day for 4-7 days reduced menstrual blood loss by 34-59% over 2-3 cycles, significantly more so than placebo, mefenamic acid, flurbiprofen, etamsylate and oral luteal phase norethisterone at clinically relevant dosages. Intrauterine administration of levonorgestrel 20 microg/day, however, produced the greatest reduction (96% after 12 months) in blood loss; 44% of patients treated with levonorgestrel developed amenorrhoea. Tranexamic acid 1.5 g three times daily for 5 days also significantly reduced menstrual blood loss in women with intrauterine contraceptive device-associated menorrhagia compared with diclofenac sodium (150 mg in three divided doses on day 1 followed by 25 mg three times daily on days 2-5) or placebo. Tranexamic acid, mefenamic acid, etamsylate, flurbiprofen or diclofenac sodium had no effect on the duration of menses in the studies that reported such data.In a large noncomparative, nonblind, quality-of-life study, 81% of women were satisfied with tranexamic acid 3-6 g/day for 3-4 days/cycle for three cycles, and 94% judged their menstrual blood loss to be 'decreased' or 'strongly decreased' compared with untreated menstruations. The most commonly reported drug-related adverse events are gastrointestinal in nature. The total incidence of nausea, vomiting, diarrhoea and dyspepsia in a double-blind study was 12% in patients who received tranexamic acid 1g four times daily for 4 days for two cycles (not significantly different to the incidence in placebo recipients). In conclusion, the oral antifibrinolytic drug tranexamic acid is an effective and well tolerated treatment for idiopathic menorrhagia. In clinical trials, tranexamic acid was more effective at reducing menstrual blood loss than mefenamic acid, flurbiprofen, etamsylate and oral luteal phase norethisterone. Although it was not as effective as intrauterine administration of levonorgestrel, the high incidence of amenorrhoea and adverse events such as intermenstrual bleeding resulting from such treatment may be unacceptable to some patients. Comparative studies of tranexamic acid with epsilon - aminocaproic acid, danazol and combined oral contraceptives, as well as long-term tolerability studies, would help to further define the place of the drug in the treatment of menorrhagia. Nevertheless, tranexamic acid may be considered as a first-line treatment for the initial management of idiopathic menorrhagia, especially for patients in whom hormonal treatment is either not recommended or not wanted.     

Lessons learned from the preclinical drug discovery of asoprisnil and ulipristal for non-surgical treatment of uterine leiomyomas

Introduction: Uterine leiomyoma is the most common benign tumor in women during the reproductive years. Menorrhagia is the common symptom and accounts for the most frequent indication for hysterectomy. Thus, development of a novel drug for non-surgical treatment of uterine leiomyoma is needed for the betterment of women's health. Area covered: This review introduces a translational research initiated by use of the levonorgestrel-releasing intrauterine system (LNG-IUS) for contraceptive purposes. During follow-up, a patient informed that heavy menstrual bleeding caused by uterine myoma was strikingly reduced after the insertion of device. The patient's unexpected comment led the authors to perform clinical trials of LNG-IUS for the management of menorrhagia in women with uterine myomas and striking reduction in menorrhagia was obtained by the use of LNG-IUS. MRI examination, however, revealed that the volume of myomas decreased in some, but increased in the other instances. This unexpected finding with MRI directed the authors to characterize the effects of progesterone (P4) and progesterone receptor modulators (PRMs) on uterineleiomyoma cell growth in vitro. Expert opinion: In consistence with the in vitro data obtained, randomized controlled clinical trials of PRMs in patients with uterine leiomyomas at several institutions have demonstrated that oral administration of PRMs (asoprisnil and ulipristal) for 3 months reduced leiomyoma volume, resulting in a significant improvement of the associated symptoms. However, a novel pattern of PRM-associated endometrial changes was recognized in the endometrial pathology, demonstrating unusual epithelial types not seen in the normal menstrual cycle of a premenstrual woman. Thus, follow-up studies to determine whether the novel endometrial changes remain, disappear or progress to something else are needed for the possible long-term use of PRMs for the treatment of uterine leiomyoma.     

Lessons learned from the preclinical drug discovery of asoprisnil and ulipristal for non-surgical treatment of uterine leiomyomas

Introduction: Uterine leiomyoma is the most common benign tumor in women during the reproductive years. Menorrhagia is the common symptom and accounts for the most frequent indication for hysterectomy. Thus, development of a novel drug for non-surgical treatment of uterine leiomyoma is needed for the betterment of women's health.

Area covered: This review introduces a translational research initiated by use of the levonorgestrel-releasing intrauterine system (LNG-IUS) for contraceptive purposes. During follow-up, a patient informed that heavy menstrual bleeding caused by uterine myoma was strikingly reduced after the insertion of device. The patient's unexpected comment led the authors to perform clinical trials of LNG-IUS for the management of menorrhagia in women with uterine myomas and striking reduction in menorrhagia was obtained by the use of LNG-IUS. MRI examination, however, revealed that the volume of myomas decreased in some, but increased in the other instances. This unexpected finding with MRI directed the authors to characterize the effects of progesterone (P4) and progesterone receptor modulators (PRMs) on uterineleiomyoma cell growth in vitro.

Expert opinion: In consistence with the in vitro data obtained, randomized controlled clinical trials of PRMs in patients with uterine leiomyomas at several institutions have demonstrated that oral administration of PRMs (asoprisnil and ulipristal) for 3 months reduced leiomyoma volume, resulting in a significant improvement of the associated symptoms. However, a novel pattern of PRM-associated endometrial changes was recognized in the endometrial pathology, demonstrating unusual epithelial types not seen in the normal menstrual cycle of a premenstrual woman. Thus, follow-up studies to determine whether the novel endometrial changes remain, disappear or progress to something else are needed for the possible long-term use of PRMs for the treatment of uterine leiomyoma.     

Management of menorrhagia associated with chemotherapy-induced thrombocytopenia in women with hematologic malignancy

Abnormal uterine bleeding in women with a blood dyscrasia, such as leukemia, or who experience thrombocytopenia secondary to myelosuppressive chemotherapy is a clinical condition associated with significant morbidity. Consequently, effective management is necessary to prevent adverse outcomes. Prevention of menorrhagia, defined as heavy regular menstrual cycles with more than 80 ml of blood loss/cycle or a cycle duration longer than 7 days, in this patient population is the goal of therapy. Gonadotropin-releasing hormone analogs (e.g., leuprolide) are promising therapies that have been shown to decrease vaginal bleeding during periods of thrombocytopenia and to have minimal adverse effects other than those associated with gonadal inhibition. In patients who experience menorrhagia despite preventive therapies, or in patients who have thrombocytopenia and menorrhagia at diagnosis, treatment is indicated. For these women, treatment options may include platelet transfusions, antifibrinolytic therapy (e.g., tranexamic acid), continuous high-dose oral contraceptives, cyclic progestins, or other therapies for more refractory patients such as danazol, desmopressin, and recombinant factor VIIa. Hormonal therapies are often the mainstay of therapy in women with menorrhagia secondary to thrombocytopenia, but data for these agents are sparse. The most robust data for the treatment of menorrhagia are for tranexamic acid. Most women receiving tranexamic acid in randomized trials experienced meaningful reductions in menstrual bleeding, and this translated into improved quality of life; however, these trials were not performed in patients with cancer. Further clinical trials are warranted to evaluate both preventive and therapeutic agents for menorrhagia in premenopausal women with cancer who are receiving myelosuppressive chemotherapy.     

左炔诺孕酮宫内缓释系统治疗子宫腺肌病中远期临床观察

目的 观察子宫腺肌病(AM)患者放置左炔诺孕酮宫内缓释系统(LNG-IUS)后的中远期临床疗效和安全性.方法 对36例子宫腺肌病患者放置LNG-IUS,记录放置前1个月、放置后第1～5年的痛经评分、月经量、子宫内膜厚度变化,同时阴道超声测量子宫及双侧卵巢体积并抽取晨血查生殖激素水平、血红蛋白含量、血清CA125水平及肝...     

左炔诺孕酮宫内缓释系统治疗子宫腺肌症中远期效果的研究

目的：研究左炔诺孕酮宫内缓释系统（LNG-IUS）治疗子宫腺肌症的中远期效果,以助于临床应用及临床咨询工作。方法通过比较33例子宫腺肌症患者LNG-IUS治疗前后的疼痛评分、月经量PBAC评分、血红蛋白水平变化,评估其中远期疗效。结果 LNG-IUS治疗前和治疗1、2、3、4、5年后的疼痛评分分别为（7.7±2.3）、（2.0±2.0）、（1.9±1.8）、（1.8±1.8）、（1.8±1.4）、（1.4±0.9）分,LNG-IUS治疗前和治疗1、2、3、4、5年后的疼痛评分比较,差异有统计学意义（P〈0.01）;LNG-IUS治疗前和治疗1、2、3、4、5年后的月经量PBAC评分分别为（126.82±78.51）、（7.58±6.31）、（7.46±5.43）、（7.35±4.06）、（7.28±3.28）、（6.98±2.19）分,LNG-IUS治疗前和治疗1、2、3、4、5年后的月经量PBAC评分比较,差异有统计学意义（P〈0.01）;LNG-IUS治疗前和治疗1、2、3、4、5年后的血红蛋白分别为（111.41±19.32）、（121.38±8.56）、（125.42±8.02）、（128.65±7.21）、（127.61±4.05）、（128.49±2.96）g/L,LNG-IUS治疗前和治疗1、2、3、4、5年后的血红蛋白水平比较,差异有统计学意义（P〈0.05）。结论 LNG-IUS治疗子宫腺肌症能有效缓解疼痛、减少月经量及提高血红蛋白水平。     

Management of dysfunctional uterine bleeding.

Dysfunctional uterine bleeding, although not usually life-threatening, can cause disruption and discomfort for many women. It has often been poorly researched in the past, possibly because of the difficulty in measuring menstrual blood loss. Several different therapies are available and individual women can choose from a number of options. Nonsteroidal anti-inflammatory drugs such as mefenamic acid or indomethacin will be the first choice for many women as they have few side effects and it is only necessary to take them when menstrual bleeding occurs. When contraception is also required, combined oral contraceptives are helpful. Progestogen and danazol therapy are also effective, although side effects do occur. A new development has been the levonorgestrel-containing intrauterine contraceptive device which has been shown to result in large decreases in menstrual blood loss. For those women who would like a surgical approach but do not want to undergo hysterectomy, the relatively new technique of endometrial resection results either in amenorrhoea or reduced menstrual blood loss in the majority of women.     

The Mirena levonorgestrel system

The levonorgestrel intrauterine system is a safe, efficacious, long-term contraceptive device. Additionally, it results in a decrease in the volume of menstrual blood loss in women with normal periods and those with menorrhagia. It may also have a role in the treatment of other benign gynecological disorders, such as adenomyosis or endometriosis, and it has been advocated as a means of delivering progestogen to the endometrium as part of combined hormone replacement therapy. Despite the beneficial effect on menstrual volume, compliance is sometimes limited by breakthrough bleeding during the first months of use. The precise mechanism of this bleeding is unclear, but it may be related to a direct effect of levonorgestrel on endometrial vascular development. Detailed counseling is crucial to explain this anticipated side effect in order to reduce unnecessary discontinuation of treatment.     

Risk-benefit assessment of drugs used for the treatment of menstrual disorders

This article considers the benign yet debilitating conditions of menorrhagia, dysmenorrhoea and irregular menstrual bleeding. Surprisingly little has been reported in the literature concerning these common ailments which can detract from the quality of female life during the reproduction years. Both dysmenorrhoea and menorrhagia are subjective complaints, but despite accurate means of measuring menstrual blood loss such quantification is rarely performed. This lack of diagnostic accuracy is a cause for concern, especially as both medical and surgical treatment are not without risk. The therapeutic alternatives which are commonly prescribed in an attempt to rectify such menstrual disorders are discussed. These include the nonsteroidal anti-inflammatory agents, the combined oral contraceptives, danazol, progestogens, antifibrinolytics, haemostatics, luteinising hormone releasing hormone analogues and clomiphene. The results of clinical trials which have utilised these various agents are considered in terms of both the effectiveness of treatment and its potential adverse effects.     

Treatment of premenstrual dysphoria with selective serotonin re-uptake inhibitors: focus on safety

Many women experience physical or mood symptoms associated with the menstrual cycle. For approximately 3 – 8% of women, the symptoms are severe enough to significantly affect social, domestic and occupational functioning. This cluster of primarily emotional and behavioural symptoms is now labelled premenstrual dysphoric disorder (PMDD). Women who meet criteria for PMDD do not usually respond to conservative interventions; selective serotonin re-uptake inhibitors (SSRIs) taken either daily or intermittently are considered to be an effective first-line therapy for this population. In this paper, the authors report on the efficacy and tolerability of SSRIs that are currently recognised as the treatment of choice for PMDD.     

曼月乐和口服药物治疗月经过多的有效性的meta分析

目的评价左炔诺孕酮宫内释放系统[levonorgestrel-releasing intrauterine system,LNG-IUS,商品名：曼月乐（Mirena）]和口服药物在月经过多治疗中的有效性。方法检索Cochrane Library、MEDLINE、EMBASE、ISI Web、BMJ、CBM、中国生物医学文献数据库、万方医学数据库、CNKI等数据库。纳入曼月乐和口服药物对比治疗月经过多的随机对照试验,对其方法学质量进行评价。用RevMan 5.0软件进行统计分析。结果①共纳入7篇符合要求的RCT文献,共计1 154例患者。②根据随机方法、分配隐藏、盲法、失访、基线比较和等级描述等对所纳入的研究行质量评估,结果其中7篇文献为高质量文献,1篇文献为低质量文献。Meta分析结果：曼月乐的有效率高于口服药物（12个月OR=3.51,95%CI=[1.95,6.3],P=0.000 1）;曼月乐组的PBAC减小量百分比低于口服药物组（6个月RR=31.83,95%CI=[1.07,62.59],P=0.04;12个月RR=58.39,95%CI=[10.10,107.28],P=0.02）;曼月乐组的MBL减小量百分比低于口服药物组（12个月时RR=66.91,95%CI=[42.61,91.20],P=0.000 01）;曼月乐组的血红蛋白增高比口服药物明显（治疗12个月RR=1.37,95%CI=[1.04,1.70],P=0.000 01）。结论曼月乐对月经过多的治疗安全有效,是一种较好的保守性治疗手段。     

Levonorgestrel intra-uterine system for menorrhagia

In 1996, we concluded that the levonorgestrel intra-uterine system (levonorgestrel IUS; Mirena--Schering Health Care) was an effective contraceptive. The product is now also licensed as a treatment for "idiopathic menorrhagia", with the claim that it "may be particularly useful in women with idiopathic menorrhagia requiring (reversible) contraception". We assess the efficacy and safety of levonorgestrel IUS in the management of heavy menstrual bleeding.     

Benefit-risk assessment of the levonorgestrel intrauterine system in contraception.

The levonorgestrel-releasing intrauterine system (IUS) is a long-acting, fully reversible method of contraception. It is one of the most effective forms of contraception available, and combines the advantages of both hormonal and intrauterine contraception. The levonorgestrel-releasing IUS also gives the users many non-contraceptive benefits: the amount of menstrual bleeding and the number of days of menstrual bleeding are reduced, which makes it suitable for the treatment of menorrhagia (heavy menstrual blood loss). Dysmenorrhoea (painful menstruation) and premenstrual symptoms are also relieved. In addition, the levonorgestrel-releasing IUS provides protection for the endometrium during hormone replacement therapy. The local release of levonorgestrel into the uterine cavity results in a strong uniform suppression of the endometrial epithelium as the epithelium becomes insensitive to estradiol released from the ovaries. This accounts for the reduction in menstrual blood loss. All possible patterns of bleeding are seen among users of the levonorgestrel-releasing IUS; however, most of the women who experience total amenorrhoea continue to ovulate. The first months of use are often characterised by irregular, scanty bleeding, which in most cases resolves spontaneously. The menstrual pattern and fertility return to normal soon after the levonorgestrel-releasing IUS is removed. The contraceptive efficacy is high with 5-year failure rates of 0.5-1.1 per 100 users. The absolute number of ectopic pregnancies is low, as is the rate per 1000 users. The levonorgestrel-releasing IUS is equally effective in all age groups and the bodyweight of the user is not associated with failure of the method. In Western cultures continuance rates among users of the levonorgestrel-releasing IUS are comparable with those of other long-term methods of contraception. Premature removal of the device is most often associated with heavy menstrual bleeding and pain, as with other long-term methods of contraception, and is most common in the youngest age group. When adequately counselled about the benign nature of oligo- or amenorrhoea, most women are very willing to accept life without menstruation. The risk of premature removal can be markedly diminished with good pre-insertion counselling, which also markedly increases user satisfaction. User satisfaction is strongly associated with the information given at the time of the levonorgestrel-releasing IUS insertion. Thus, the benefits of the levonorgestrel-releasing IUS make it a very suitable method of contraception for most women.     

病灶切除联合GnRH-a及LNG-IUS综合治疗大型弥漫性子宫腺肌病临床体会

目的 探讨病灶切除联合GnRH-a及LNG-IUS综合治疗大型弥漫型子宫腺肌病的近远期临床疗效,寻求症状严重的大型弥漫型子宫腺肌病年轻患者的适当治疗措施.方法 选取2012年4月至2014年4月本院收治的大型弥漫性子宫腺肌病10例,采用病灶切除联合术后GnRH-a治疗3个月,停药后月经复潮第5天宫内放置LNG-IUS(左炔诺酮宫内缓释系统),对比治疗前后子宫体积的大小、月经量、血红蛋白值、疼痛程度等症状变化.结果 随访治疗后3、6、12、24个月10例患者月经量明显减少,血红蛋白值上升,贫血症状改善,子宫体积缩小,形态趋于正常,痛经缓解率100％,治疗前后差异均有统计学意义(P＜0.05).结论 对于大型弥漫性子宫腺肌病年轻患者先采用病灶切除减少子宫体积,再序贯采用GnRH-a+宫内放置LNG-IUS三管齐下联合治疗达到长期控制子宫腺肌病症状,预防复发,不失成为可靠的长期治疗管理措施.     

左炔诺孕酮宫内缓释系统治疗子宫内膜增生症的临床观察

目的探讨左炔诺孕酮宫内节育系统(LNG-IUS)对子宫内膜增生症的治疗作用。方法 2011年1月至2012年1月我院收治的100例子宫内膜增生症患者,随机分为对照组(孕激素组)和试验组(LNG-IUS组)各50例。对照组于诊断性刮宫术后第5天给予孕激素(醋酸甲羟孕酮),试验组于诊断性刮宫术后第5天宫腔内置入LNG-IUS,比较两组治疗前、后月经量改变情况、血红蛋白水平、子宫内膜厚度及不良反应发生情况。结果对照组治疗1个疗程后,月经量过多者21例,治愈率58%;试验组月经过多者4例,治愈率92%,两组比较差异具有统计学意义(P<0.05)。试验组治疗1个疗程后,血红蛋白水平高于对照组,且子宫内膜厚度低于对照组。对照组不良反应为体重增加、恶心、头晕及肝肾功能损害,而试验组仅有子宫不规则的点状出血。结论左炔诺孕酮宫内缓释系统对子宫内膜增生症的治疗效果优于常规口服孕激素,且不良反应少。     

Aminocaproic acid and menstrual loss in women using intrauterine devices.

A controlled study of the effect of aminocaproic acid 3 g six-hourly taken by mouth during menstruation was carried out on 56 women for eight months from the time of insertion of a Lippes D intrauterine device (IUD). Thirty-five women presenting with menorrhagia in association with an IUD were also treated during three out of six consecutive menses. A highly significant reduction in menstrual loss was observed during treatment in both groups.     

Tranexamic acid therapy for heavy menstrual bleeding

Introduction: Heavy menstrual bleeding (HMB, also known as menorrhagia) is an important health problem that interferes with women's quality of life. It is one of the most common reasons why women are seen by their family doctors in primary care and is a condition frequently treated by surgery.

Areas covered: This review covers the pharmacology of tranexamic acid in brief and concentrates on its use in the treatment of HMB. Papers published in the English language between January 1985 and November 2010 were reviewed using Medline, Embase, Cinahl and the Cochrane Database of Systematic Reviews. Search terms were ‘heavy menstrual bleeding’, ‘tranexamic acid’ and ‘menorrhagia’.

Expert opinion: Tranexamic acid, a competitive inhibitor of plasminogen activation, has been used to treat HMB for well over four decades. Although several treatment options are available for HMB, tranexamic acid is particularly useful in women who either desire immediate pregnancy or for whom hormonal treatment is inappropriate. Tranexamic acid is a well-tolerated, cost-effective drug that reduces menstrual blood loss in the range of 34 – 59%. It improves the health-related quality of life in women in HMB.