- Email: [email protected]
Medical management of menstrual disorders
International Congress Series 1266 (2004) 63 – 68
www.ics-elsevier.com
Medical management of menstrual disorders Juha S. Tapanainen * Department of Obstetrics and Gynecology, University of Oulu, P.O. Box 5000, FIN-90014 Oulu, Finland
Abstract. A vast majority of women experience menstrual disorders some time in their life. Complaints of excessive menstrual loss, in particular, have a substantial impact on gynecological services. It is estimated that 5% of women consult their physician with menstrual problems each year, and up to 30% of reproductive age women suffer from menorrhagia. Menorrhagia is defined as blood loss of more than 80 ml per cycle, but already lower amounts may result in iron-deficient anemia. Before starting the medication for heavy menstrual bleeding, the possible organic cause should be assessed, and the age, pregnancy desires, general health and patient preference should be considered. The combined oral contraceptive pills (COCPs), prostaglandin inhibitors and tranexamic acid are still recommended as the first line of therapy for menorrhagia, especially in nulliparous women. All of these also have the added advantage of relieving dysmenorrhea. Other drugs, such as danazol and gonadotropin-releasing hormone agonists (GnRHa), reduce menstrual blood loss effectively, but due to side effects, their use is limited to special cases. Luteal progestins are widely used for the treatment of heavy menstrual bleeding, but women with regular ovulatory cycles suffering from menorrhagia do not benefit from the treatment. D 2004 Published by Elsevier B.V. Keywords: Menstrual disorder; Menorrhagia; Prostaglandin inhibitor; Tranexamic acid; Contraceptive pill
1. Introduction Menstruation normally starts between the ages of 11 and 13 years, and stops between 45 and 50 years of age. The average blood loss per period is between 30 and 40 ml. The most common menstrual disorders are dysfunctional uterine bleeding, premenstrual syndrome (PMS) and dysmenorrhea. A vast majority of women suffer from these symptoms during their reproductive life span, but dysfunctional uterine bleeding occurs most commonly during adolescence and in premenopause when the cycles are or become anovulatory. The patterns of abnormal uterine bleeding include menorrhagia, polymenorrhea, oligoamenorrhea and metrorrhagia. Menorrhagia means excessive menstrual bleeding; in polymenorrhea, bleeding episodes occur in less than 21 days; oligomenorrhea means scanty menstruation or long menstrual periods over 35 days; and metrorrhagia means irregular bleeding at any time between menstrual periods.
* Tel.: +358-8-3153172; fax: +358-8-3154310. E-mail address: [email protected] (J.S. Tapanainen). 0531-5131/ D 2004 Published by Elsevier B.V. doi:10.1016/j.ics.2004.01.106
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Table 1 Medical treatment of menorrhagia Prostaglandin synthetase inhibitors Drugs affecting coagulation system Tranexamic acid Ethamsylate Combined oral contraceptive pills Standard-cycle pills Trimonthly-cycle pills Progestins Other Danazol GnRH agonists
This chapter will concentrate on the medical treatment of excessive menstrual bleeding (Table 1), and other menstrual disorders will be touched only briefly. The use of the levonorgestril intrauterine system for the treatment of menorrhagia will be discussed in chapter XX. 2. Menorrhagia Menorrhagia is defined as blood loss of 60 – 80 ml per cycle [1,2]. Women with regular but heavy or long-lasting menstrual bleeding are more likely to have ovulatory cycles, while menorrhagia with intermenstrual bleeding or spotting is often associated with unovulatory cycles and may result in hyperplasia due to the unopposed, continuous estrogen effect. The prevalence of endometrial hyperplasia in cases of normal weight women under 45 years of age is 2.3%, but it is already 8% in women over 45 [3]. Eighty percent of women with menorrhagia have no anatomical pathology, such as uterine fibroids, polyps or adenomyosis, and over one-third of the women undergoing hysterectomy for heavy bleeding have their normal uteri removed [4,5]. 3. Menstrual disorders in adolescence The maturation of the hypothalamic – pituitary– ovarian axis takes place during the first 2 years after menarche, but in 20% of adolescents anovulatory cycles, last up to 5 years [6]. Adolescent females suffering from menstrual disorders are concerned about their personal image, and, therefore, early treatment is very important. The treatment strategies depend on the etiology of the pathologic causes of anovulation. The most important are polycystic ovary syndrome (PCOS), hypothalamic dysfunction associated with exercise and eating disorders, and endocrinopathies. Coagulation disorders are a common cause of menorrhagia in teenagers. These include thrombocytopenia, idiopathic thrombocytogenic purpura, platelet dysfunction and von Willebrandt disease [7]. Because coagulopathies are found in 10– 30% of adolescents with excessive menstrual bleeding [8,9], they have to be excluded before starting the medical treatment of other causes of menorrhagia. The adolescent who is heavily bleeding (juvenile metropathy) needs immediate hormonal intervention. She should take oral contraceptives containing 30– 35 Ag ethinyl estradiol four times a day for 2 days; thereafter, the dose should be reduced over 3 days to 1 tablet a day. If necessary, a
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contraceptive pill containing 50 Ag ethinyl estradiol should be used. After 5 days of acute treatment, the patient should start a new 21- or 28-pill pack and continue the therapy for several months [6,10]. The most common problems related to menstruation in adolescence are dysmenorrhea and irregular or heavy bleeding, and they can often be treated successfully with nonsteroidal anti-inflammatory drug (NSAIDs) and/or oral contraceptive pills. 4. Medical management of menorrhagia 4.1. Prostaglandin synthetase inhibitors The rationale in using NSAIDs was based on their ability to decrease endometrial prostaglandin levels, which are elevated in menorrhagia [11]. NSAIDs decrease menstrual blood loss by 20 –50% [12]. The NSAIDs used most often include acetylsalicylic acid, diclofenac, ibuprofen, indomethacin, mefenamic acid and meclofenamic acid. Mefenamic acid is the most commonly studied of these drugs, but data comparing different NSAIDs in the treatment of menorrhagia are limited. Nevertheless, it is widely accepted that the clinical efficacy of different NSAIDs is similar. Based on the Cochrane Review by Lethaby et al. [13], they are more effective than placebo but less effective than tranexamic acid or danazol [14]. Compared with other treatments, like luteal progestin, ethamsylate, oral contraceptive pills or the levonorgestril intrauterine system, no differences were observed but most studies were underpowered [13]. Moreover, small, nonrandomized cohort studies have shown that the levonorgestril intrauterine system used for contraceptive purposes decreases menstrual bleeding after 12 months by more than 90% [15,16]. Randomized trials have shown that its effectiveness in the treatment of menorrhagia is similar [17,18]. To obtain optimal effect, the treatment with NSAIDs should be started a few days before menstruation, on the first day of menses at the latest, and should be continued until cessation of bleeding. Furthermore, the dosage should be high enough based on the recommendations of the manufacturer. 4.2. Drugs affecting coagulation system Plasminogen activators cause fibrinolysis, and their tissue concentrations increase in the endometrium of women with heavy menstrual bleeding. Tranexamic acid, a plasminogen activator inhibitor, has been used for the treatment of menorrhagia for a long time. The other drug, ethamsylate, reduces capillary bleeding by affecting platelet function and has also been in clinical use for a number of years. There are several studies on the effect of tranexamic acid in menorrhea but only one comparing tranexamic acid with ethamsylate. In this study by Bonnar [19,20], tranexamic acid (1 g four times daily for cycle days 1 –5) was significantly more effective. No significant differences were found in the subjective assessment by the study subjects, although there was a trend in favour of tranexamic acid. Moreover, in the Cochrane Review by Lethaby et al. [20], tranexamic acid was also found to be more effective in reducing heavy menstrual bleeding than placebo, NSAIDs and luteal phase progestin. It reduced menstrual blood flow by 25 –50%. Tranexamic acid had no more adverse events than placebo, and long-term studies have failed to demonstrate any increase in the risk of thrombosis. There are no studies comparing tranexamic acid with contraceptive pills and the levonorgestril intrauterine system.
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4.3. Combined oral contraceptive pill Combined oral contraceptive pills (COCPs) have been used for years for the treatment of menorrhagia. Their efficacy was first recognized by women using pills only for contraception, and later on, this observation was confirmed objectively in several trials [12]. The reduction of menstrual bleeding by oral contraceptives is probably a result of induced atrophy in the endometrium. Besides contraception, COCPs have several beneficial effects, such as good cycle control and antiandrogenic effects, which make them acceptable for long-term therapy. Although there are a large number of studies on the effect of COCPs on menorrhagia, there is only one randomized, controlled trial comparing the efficacy of COCP, mefenamic acid, naproxen and danazol [21,22]. The crossover trial was small, consisting of 45 patients, and there were no significant differences in menstrual blood loss between the treatments. The overall blood loss reduced 43% in the COCP group. Trimonthly-cycle oral contraceptive therapy has been used to postpone withdrawal bleeding and reduce the frequency of menstruation. Typically, it consists of 84 days of estrogen –progestin, followed by a pill-free interval of 7 days, and reduces the yearly number of withdrawal bleeding episodes from 12 to 4 [23 – 25]. The contraceptive effectiveness and the side effect profile [26] of extended COCP regimens are similar to those of standard COCP. Thus, this therapy will offer a good alternative for women suffering from menorrhagia, at least, later in reproductive age. 4.4. Progestins The use of progestin in the anovulatory patient to coordinate menstrual cycle is effective when given cyclically in the luteal phase (c.d. 15 – 24), but a patient with regular menstrual cycle and menorrhagia do not benefit from the treatment [12]. However, progestin therapy for 21 days of the cycle [27,28], or injectable long-acting progestins [29], reduce menstrual blood flow by inducing endometrial atrophy. Progestin therapy administered from cycle days 5 to 26 may be beneficial for some patients, but due to side effects such as mood changes, nausea, headache, tiredness and atherogenic changes in lipid profile, it is limited for the short-term use [28]. In the Cochrane Review [28], cyclical progestin administered during the luteal phase was found to be less effective when compared with tranexamic acid, danazol or the levonorgestril intrauterine system. The subdermal contraceptive implant system (Norplant) somewhat reduces menstrual blood loss when used for contraceptive purposes [30], but for the treatment of excessive menstrual bleeding, it is not effective enough. Thus, oral or subdermal progestins are not the first line therapy for menorrhagia, but the 21 days’ treatment may be useful for some women with anovulatory irregular cycles and intermenstrual bleeding associated with excessive menstrual bleeding. 4.5. Other medical treatments Danazol is a synthetic androgen derived from testosterone. It has both antiestrogenic and antiprogestogenic activity. It reduces estrogen levels and thereby causes endometrial atrophy and amenorrhea in some women [31]. In the Cochrane Review by Beaumont et al. [14], despite wide confidence intervals, danazol (100 –200 mg daily) was found to be more
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effective in reducing menstrual blood flow than placebo, progestins, NSAIDs and oral contraceptive pills, but it has more side effects than NSAIDs and progestins. The commonly reported side effects were acne, weight gain, headache, nausea and tiredness [14]. There are no randomized trials comparing danazol with tranexamic acid or the levonorgestril intrauterine system. Thus, danazol is effective for the treatment of severe menorrhagia, but due to its side effect profile and the need for continuing treatment, its use is limited to special cases. Gonadotropin-releasing hormone agonists (GnRHa) are an alternative for the treatment of heavy menstrual bleeding. By downregulating pituitary gonadotropin secretion, they cause a hypoestrogenic state and endometrial atrophy. GnRHas are very effective in reducing menstrual blood loss [32], but long-term treatment is not possible due to hypoestrogenic symptoms and bone loss. 5. Conclusions Before starting medication for heavy menstrual bleeding, the possible organic cause should be excluded. There are several drugs available for the medical treatment of menorrhagia, but only a few of them are effective enough and meet patient acceptability. Traditional drugs, NSAIDs and tranexamic acid are still useful, safe and can be used long-term. The dosage has to be high enough and the medication should be started at the latest on the first day of menstruation. For young women and especially for those requiring contraception, combined oral contraceptive pills are often the drug of choice and, in the case of dysmenorrhea, can be combined with NSAIDs. Trimonthly-cycle oral contraceptive therapy may offer a useful alternative for women suffering from menorrhagia. Cyclical progestins are not effective enough for menorrhagia unless given monthly for 21 days. Danazol and GnRHas reduce menstrual blood loss significantly but cannot be recommended for first-line therapy or long-term use because of their side effects. References [1] L. Hallberg, et al., Menstrual blood loss and iron deficiency, Acta Med. Scand. 180 (1966) 639 – 650. [2] B.J. Cohen, Y. Gibor, Anemia and menstrual blood loss, Obstet. Gynecol. Surv. 35 (1980) 597 – 618. [3] C.M. Farquhar, et al., An evaluation of risk factors for endometrial hyperplasia in premenopausal women with abnormal menstrual bleeding, Am. J. Obstet. Gynecol. 181 (1999) 525 – 529. [4] A. Clarke, et al., Indications for and outcome of total abdominal hysterectomy for benign disease: a prospective cohort study, Br. J. Obstet. Gynaecol. 102 (1995) 611 – 620. [5] D. Gath, P. Cooper, A. Day, Hysterectomy and psychiatric disorder: I. Levels of psychiatric morbidity before and after hysterectomy, Br. J. Psychiatry 140 (1982) 335 – 350. [6] E.H. Qiunt, Y.R. Smith, Abnormal uterine bleeding in adolescents, J. Midwifery Women’s Health 48 (2003) 186 – 191. [7] J.A. Bevan, et al., Bleeding disorders: a common cause of menorrhagia in adolescents, J. Pediatr. 138 (2001) 856 – 861. [8] Y.R. Smith, E.H. Quint, R.B. Hertzberg, Menorrhagia in adolescents requiring hospitalization, J. Pediatr. Adolesc. Gynecol. 11 (1998) 13 – 15. [9] C. Duflos-Cohade, M. Amandruz, E. Thibaud, Pubertal metrorrhagia, J. Pediatr. Adolesc. Gynecol. 9 (1996) 16 – 20. [10] G.B. Slap, Menstrual disorders in adolescence, Baillie´re’s Best Pract. Res., Clin. Obstet. Gynaecol. 17 (2003) 75 – 92.
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[11] S.K. Smith, et al., Prostaglandin synthesis in the endometrium of women with ovular dysfunctional uterine bleeding, Br. J. Obstet. Gynaecol. 88 (1981) 434 – 442. [12] G.A. Irvine, I.T. Cameron, Medical management of dysfunctional uterine bleeding, Baillie´re’s Best Pract. Res., Clin. Obstet. Gynaecol. 13 (1999) 189 – 202. [13] A. Lethaby, C. Augood, K. Duckitt, Nonsteroidal anti-inflammatory drugs for heavy menstrual bleeding (Cochrane Review), The Cochrane Library, Issue, vol. 4, Wiley, Chichester, UK, 2003. [14] H. Beaumont, et al., Danazol for heavy menstrual bleeding (Cochrane Review), The Cochrane Library, Issue, vol. 4, Wiley, Chichester, UK, 2003. [15] J.K. Andersson, G. Rybo, Levonorgestrel-releasing intrauterine device in the treatment of menorrhagia, Br. J. Obstet. Gynaecol 97 (1990) 690 – 694. [16] T. Luukkainen, J. Toivonen, Levonorgestrel-releasing IUD as a method of contraception with therapeutic properties, Contraception 52 (1995) 269 – 276. [17] I. Milsom, et al., A comparison of flurbiprofen, tranexamic acid, and a levonorgestrel-releasing intrauterine contraceptive device in the treatment of idiopathic menorrhagia, Am. J. Obstet. Gynecol. 164 (1991) 879 – 883. [18] R. Hurskainen, et al., Quality of life and cost-effectiveness of levonorgestrel-releasing intrauterine system versus hysterectomy for treatment of menorrhagia: a randomised trial, Lancet 357 (2001) 273 – 277. [19] J. Bonnar, B.L. Sheppard, Treatment of menorrhagia during menstruation: randomised controlled trial of ethamsylate, mefenamic acid, and tranexamic acid, Br. Med. J. 313 (1996) 579 – 582. [20] A. Lethaby, C. Farquhar, I. Cooke, Antifibrinolytics for heavy menstrual bleeding (Cochrane Review), The Cochrane Library, Issue, vol. 4, Wiley, Chichester, UK, 2003. [21] I.S. Fraser, et al., Blood and total fluid content of menstrual discharge, Obstet. Gynecol. 65 (1985) 194 – 198. [22] V. Iyer, C. Farquhar, R. Jepson, Oral contraceptive pills for heavy menstrual bleeding (Cochrane Review), The Cochrane Library, Issue, vol. 4, Wiley, Chichester, UK, 2003. [23] N.B. Loudon, et al., Acceptability of an oral contraceptive that reduces the frequency of menstruation: the tri-cycle pill regimen, Br. Med. J. 2 (1977) 487 – 490. [24] P.J. Sulak, et al., Extending the duration of active oral contraceptive pills to manage hormone withdrawal symptoms, Obstet. Gynecol. 89 (1997) 179 – 183. [25] J.B. Braunstein, et al., Economics of reducing menstruation with trimonthly-cycle oral contraceptive therapy: comparison with standard-cycle regimens, Obstet. Gynecol. 102 (2003) 699 – 708. [26] L. Miller, J.P. Hughes, Continuous combination oral contraceptive pills to eliminate withdrawal bleeding: a randomized trial, Obstet. Gynecol. 101 (2003) 653 – 661. [27] G.A. Irvine, et al., Randomised comparative trial of the levonorgestrel intrauterine system and norethisterone for treatment of idiopathic menorrhagia, Br. J. Obstet. Gynaecol. 105 (1998) 592 – 598. [28] A. Lethaby, G. Irvine, I. Cameron, Cyclical progestogens for heavy menstrual bleeding (Cochrane Review), The Cochrane Library, Issue, vol. 4, Wiley, Chichester, UK, 2003. [29] I.S. Fraser, Bleeding arising from the use of exogenous steroids, Baillie´re’s Best Pract. Res., Clin. Obstet. Gynaecol. 13 (1999) 203 – 222. [30] C.G. Nilsson, P. Holma, Menstrual blood loss with contraceptive subdermal levonorgestrel implants, Fertil. Steril. 35 (1981) 304 – 306. [31] T.H. Chimbira, et al., Reduction of menstrual blood loss by danazol in unexplained menorrhagia: lack of effect of placebo, Br. J. Obstet. Gynaecol. 87 (1980) 1152 – 1158. [32] R.W. Shaw, H.M. Fraser, Use of a superactive luteinizing hormone releasing hormone (LHRH) agonist in the treatment of menorrhagia, Br. J. Obstet. Gynaecol. 91 (1984) 913 – 916.
www.ics-elsevier.com
Medical management of menstrual disorders Juha S. Tapanainen * Department of Obstetrics and Gynecology, University of Oulu, P.O. Box 5000, FIN-90014 Oulu, Finland
Abstract. A vast majority of women experience menstrual disorders some time in their life. Complaints of excessive menstrual loss, in particular, have a substantial impact on gynecological services. It is estimated that 5% of women consult their physician with menstrual problems each year, and up to 30% of reproductive age women suffer from menorrhagia. Menorrhagia is defined as blood loss of more than 80 ml per cycle, but already lower amounts may result in iron-deficient anemia. Before starting the medication for heavy menstrual bleeding, the possible organic cause should be assessed, and the age, pregnancy desires, general health and patient preference should be considered. The combined oral contraceptive pills (COCPs), prostaglandin inhibitors and tranexamic acid are still recommended as the first line of therapy for menorrhagia, especially in nulliparous women. All of these also have the added advantage of relieving dysmenorrhea. Other drugs, such as danazol and gonadotropin-releasing hormone agonists (GnRHa), reduce menstrual blood loss effectively, but due to side effects, their use is limited to special cases. Luteal progestins are widely used for the treatment of heavy menstrual bleeding, but women with regular ovulatory cycles suffering from menorrhagia do not benefit from the treatment. D 2004 Published by Elsevier B.V. Keywords: Menstrual disorder; Menorrhagia; Prostaglandin inhibitor; Tranexamic acid; Contraceptive pill
1. Introduction Menstruation normally starts between the ages of 11 and 13 years, and stops between 45 and 50 years of age. The average blood loss per period is between 30 and 40 ml. The most common menstrual disorders are dysfunctional uterine bleeding, premenstrual syndrome (PMS) and dysmenorrhea. A vast majority of women suffer from these symptoms during their reproductive life span, but dysfunctional uterine bleeding occurs most commonly during adolescence and in premenopause when the cycles are or become anovulatory. The patterns of abnormal uterine bleeding include menorrhagia, polymenorrhea, oligoamenorrhea and metrorrhagia. Menorrhagia means excessive menstrual bleeding; in polymenorrhea, bleeding episodes occur in less than 21 days; oligomenorrhea means scanty menstruation or long menstrual periods over 35 days; and metrorrhagia means irregular bleeding at any time between menstrual periods.
* Tel.: +358-8-3153172; fax: +358-8-3154310. E-mail address: [email protected] (J.S. Tapanainen). 0531-5131/ D 2004 Published by Elsevier B.V. doi:10.1016/j.ics.2004.01.106
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J.S. Tapanainen / International Congress Series 1266 (2004) 63–68
Table 1 Medical treatment of menorrhagia Prostaglandin synthetase inhibitors Drugs affecting coagulation system Tranexamic acid Ethamsylate Combined oral contraceptive pills Standard-cycle pills Trimonthly-cycle pills Progestins Other Danazol GnRH agonists
This chapter will concentrate on the medical treatment of excessive menstrual bleeding (Table 1), and other menstrual disorders will be touched only briefly. The use of the levonorgestril intrauterine system for the treatment of menorrhagia will be discussed in chapter XX. 2. Menorrhagia Menorrhagia is defined as blood loss of 60 – 80 ml per cycle [1,2]. Women with regular but heavy or long-lasting menstrual bleeding are more likely to have ovulatory cycles, while menorrhagia with intermenstrual bleeding or spotting is often associated with unovulatory cycles and may result in hyperplasia due to the unopposed, continuous estrogen effect. The prevalence of endometrial hyperplasia in cases of normal weight women under 45 years of age is 2.3%, but it is already 8% in women over 45 [3]. Eighty percent of women with menorrhagia have no anatomical pathology, such as uterine fibroids, polyps or adenomyosis, and over one-third of the women undergoing hysterectomy for heavy bleeding have their normal uteri removed [4,5]. 3. Menstrual disorders in adolescence The maturation of the hypothalamic – pituitary– ovarian axis takes place during the first 2 years after menarche, but in 20% of adolescents anovulatory cycles, last up to 5 years [6]. Adolescent females suffering from menstrual disorders are concerned about their personal image, and, therefore, early treatment is very important. The treatment strategies depend on the etiology of the pathologic causes of anovulation. The most important are polycystic ovary syndrome (PCOS), hypothalamic dysfunction associated with exercise and eating disorders, and endocrinopathies. Coagulation disorders are a common cause of menorrhagia in teenagers. These include thrombocytopenia, idiopathic thrombocytogenic purpura, platelet dysfunction and von Willebrandt disease [7]. Because coagulopathies are found in 10– 30% of adolescents with excessive menstrual bleeding [8,9], they have to be excluded before starting the medical treatment of other causes of menorrhagia. The adolescent who is heavily bleeding (juvenile metropathy) needs immediate hormonal intervention. She should take oral contraceptives containing 30– 35 Ag ethinyl estradiol four times a day for 2 days; thereafter, the dose should be reduced over 3 days to 1 tablet a day. If necessary, a
J.S. Tapanainen / International Congress Series 1266 (2004) 63–68
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contraceptive pill containing 50 Ag ethinyl estradiol should be used. After 5 days of acute treatment, the patient should start a new 21- or 28-pill pack and continue the therapy for several months [6,10]. The most common problems related to menstruation in adolescence are dysmenorrhea and irregular or heavy bleeding, and they can often be treated successfully with nonsteroidal anti-inflammatory drug (NSAIDs) and/or oral contraceptive pills. 4. Medical management of menorrhagia 4.1. Prostaglandin synthetase inhibitors The rationale in using NSAIDs was based on their ability to decrease endometrial prostaglandin levels, which are elevated in menorrhagia [11]. NSAIDs decrease menstrual blood loss by 20 –50% [12]. The NSAIDs used most often include acetylsalicylic acid, diclofenac, ibuprofen, indomethacin, mefenamic acid and meclofenamic acid. Mefenamic acid is the most commonly studied of these drugs, but data comparing different NSAIDs in the treatment of menorrhagia are limited. Nevertheless, it is widely accepted that the clinical efficacy of different NSAIDs is similar. Based on the Cochrane Review by Lethaby et al. [13], they are more effective than placebo but less effective than tranexamic acid or danazol [14]. Compared with other treatments, like luteal progestin, ethamsylate, oral contraceptive pills or the levonorgestril intrauterine system, no differences were observed but most studies were underpowered [13]. Moreover, small, nonrandomized cohort studies have shown that the levonorgestril intrauterine system used for contraceptive purposes decreases menstrual bleeding after 12 months by more than 90% [15,16]. Randomized trials have shown that its effectiveness in the treatment of menorrhagia is similar [17,18]. To obtain optimal effect, the treatment with NSAIDs should be started a few days before menstruation, on the first day of menses at the latest, and should be continued until cessation of bleeding. Furthermore, the dosage should be high enough based on the recommendations of the manufacturer. 4.2. Drugs affecting coagulation system Plasminogen activators cause fibrinolysis, and their tissue concentrations increase in the endometrium of women with heavy menstrual bleeding. Tranexamic acid, a plasminogen activator inhibitor, has been used for the treatment of menorrhagia for a long time. The other drug, ethamsylate, reduces capillary bleeding by affecting platelet function and has also been in clinical use for a number of years. There are several studies on the effect of tranexamic acid in menorrhea but only one comparing tranexamic acid with ethamsylate. In this study by Bonnar [19,20], tranexamic acid (1 g four times daily for cycle days 1 –5) was significantly more effective. No significant differences were found in the subjective assessment by the study subjects, although there was a trend in favour of tranexamic acid. Moreover, in the Cochrane Review by Lethaby et al. [20], tranexamic acid was also found to be more effective in reducing heavy menstrual bleeding than placebo, NSAIDs and luteal phase progestin. It reduced menstrual blood flow by 25 –50%. Tranexamic acid had no more adverse events than placebo, and long-term studies have failed to demonstrate any increase in the risk of thrombosis. There are no studies comparing tranexamic acid with contraceptive pills and the levonorgestril intrauterine system.
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4.3. Combined oral contraceptive pill Combined oral contraceptive pills (COCPs) have been used for years for the treatment of menorrhagia. Their efficacy was first recognized by women using pills only for contraception, and later on, this observation was confirmed objectively in several trials [12]. The reduction of menstrual bleeding by oral contraceptives is probably a result of induced atrophy in the endometrium. Besides contraception, COCPs have several beneficial effects, such as good cycle control and antiandrogenic effects, which make them acceptable for long-term therapy. Although there are a large number of studies on the effect of COCPs on menorrhagia, there is only one randomized, controlled trial comparing the efficacy of COCP, mefenamic acid, naproxen and danazol [21,22]. The crossover trial was small, consisting of 45 patients, and there were no significant differences in menstrual blood loss between the treatments. The overall blood loss reduced 43% in the COCP group. Trimonthly-cycle oral contraceptive therapy has been used to postpone withdrawal bleeding and reduce the frequency of menstruation. Typically, it consists of 84 days of estrogen –progestin, followed by a pill-free interval of 7 days, and reduces the yearly number of withdrawal bleeding episodes from 12 to 4 [23 – 25]. The contraceptive effectiveness and the side effect profile [26] of extended COCP regimens are similar to those of standard COCP. Thus, this therapy will offer a good alternative for women suffering from menorrhagia, at least, later in reproductive age. 4.4. Progestins The use of progestin in the anovulatory patient to coordinate menstrual cycle is effective when given cyclically in the luteal phase (c.d. 15 – 24), but a patient with regular menstrual cycle and menorrhagia do not benefit from the treatment [12]. However, progestin therapy for 21 days of the cycle [27,28], or injectable long-acting progestins [29], reduce menstrual blood flow by inducing endometrial atrophy. Progestin therapy administered from cycle days 5 to 26 may be beneficial for some patients, but due to side effects such as mood changes, nausea, headache, tiredness and atherogenic changes in lipid profile, it is limited for the short-term use [28]. In the Cochrane Review [28], cyclical progestin administered during the luteal phase was found to be less effective when compared with tranexamic acid, danazol or the levonorgestril intrauterine system. The subdermal contraceptive implant system (Norplant) somewhat reduces menstrual blood loss when used for contraceptive purposes [30], but for the treatment of excessive menstrual bleeding, it is not effective enough. Thus, oral or subdermal progestins are not the first line therapy for menorrhagia, but the 21 days’ treatment may be useful for some women with anovulatory irregular cycles and intermenstrual bleeding associated with excessive menstrual bleeding. 4.5. Other medical treatments Danazol is a synthetic androgen derived from testosterone. It has both antiestrogenic and antiprogestogenic activity. It reduces estrogen levels and thereby causes endometrial atrophy and amenorrhea in some women [31]. In the Cochrane Review by Beaumont et al. [14], despite wide confidence intervals, danazol (100 –200 mg daily) was found to be more
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effective in reducing menstrual blood flow than placebo, progestins, NSAIDs and oral contraceptive pills, but it has more side effects than NSAIDs and progestins. The commonly reported side effects were acne, weight gain, headache, nausea and tiredness [14]. There are no randomized trials comparing danazol with tranexamic acid or the levonorgestril intrauterine system. Thus, danazol is effective for the treatment of severe menorrhagia, but due to its side effect profile and the need for continuing treatment, its use is limited to special cases. Gonadotropin-releasing hormone agonists (GnRHa) are an alternative for the treatment of heavy menstrual bleeding. By downregulating pituitary gonadotropin secretion, they cause a hypoestrogenic state and endometrial atrophy. GnRHas are very effective in reducing menstrual blood loss [32], but long-term treatment is not possible due to hypoestrogenic symptoms and bone loss. 5. Conclusions Before starting medication for heavy menstrual bleeding, the possible organic cause should be excluded. There are several drugs available for the medical treatment of menorrhagia, but only a few of them are effective enough and meet patient acceptability. Traditional drugs, NSAIDs and tranexamic acid are still useful, safe and can be used long-term. The dosage has to be high enough and the medication should be started at the latest on the first day of menstruation. For young women and especially for those requiring contraception, combined oral contraceptive pills are often the drug of choice and, in the case of dysmenorrhea, can be combined with NSAIDs. Trimonthly-cycle oral contraceptive therapy may offer a useful alternative for women suffering from menorrhagia. Cyclical progestins are not effective enough for menorrhagia unless given monthly for 21 days. Danazol and GnRHas reduce menstrual blood loss significantly but cannot be recommended for first-line therapy or long-term use because of their side effects. References [1] L. Hallberg, et al., Menstrual blood loss and iron deficiency, Acta Med. Scand. 180 (1966) 639 – 650. [2] B.J. Cohen, Y. Gibor, Anemia and menstrual blood loss, Obstet. Gynecol. Surv. 35 (1980) 597 – 618. [3] C.M. Farquhar, et al., An evaluation of risk factors for endometrial hyperplasia in premenopausal women with abnormal menstrual bleeding, Am. J. Obstet. Gynecol. 181 (1999) 525 – 529. [4] A. Clarke, et al., Indications for and outcome of total abdominal hysterectomy for benign disease: a prospective cohort study, Br. J. Obstet. Gynaecol. 102 (1995) 611 – 620. [5] D. Gath, P. Cooper, A. Day, Hysterectomy and psychiatric disorder: I. Levels of psychiatric morbidity before and after hysterectomy, Br. J. Psychiatry 140 (1982) 335 – 350. [6] E.H. Qiunt, Y.R. Smith, Abnormal uterine bleeding in adolescents, J. Midwifery Women’s Health 48 (2003) 186 – 191. [7] J.A. Bevan, et al., Bleeding disorders: a common cause of menorrhagia in adolescents, J. Pediatr. 138 (2001) 856 – 861. [8] Y.R. Smith, E.H. Quint, R.B. Hertzberg, Menorrhagia in adolescents requiring hospitalization, J. Pediatr. Adolesc. Gynecol. 11 (1998) 13 – 15. [9] C. Duflos-Cohade, M. Amandruz, E. Thibaud, Pubertal metrorrhagia, J. Pediatr. Adolesc. Gynecol. 9 (1996) 16 – 20. [10] G.B. Slap, Menstrual disorders in adolescence, Baillie´re’s Best Pract. Res., Clin. Obstet. Gynaecol. 17 (2003) 75 – 92.
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[11] S.K. Smith, et al., Prostaglandin synthesis in the endometrium of women with ovular dysfunctional uterine bleeding, Br. J. Obstet. Gynaecol. 88 (1981) 434 – 442. [12] G.A. Irvine, I.T. Cameron, Medical management of dysfunctional uterine bleeding, Baillie´re’s Best Pract. Res., Clin. Obstet. Gynaecol. 13 (1999) 189 – 202. [13] A. Lethaby, C. Augood, K. Duckitt, Nonsteroidal anti-inflammatory drugs for heavy menstrual bleeding (Cochrane Review), The Cochrane Library, Issue, vol. 4, Wiley, Chichester, UK, 2003. [14] H. Beaumont, et al., Danazol for heavy menstrual bleeding (Cochrane Review), The Cochrane Library, Issue, vol. 4, Wiley, Chichester, UK, 2003. [15] J.K. Andersson, G. Rybo, Levonorgestrel-releasing intrauterine device in the treatment of menorrhagia, Br. J. Obstet. Gynaecol 97 (1990) 690 – 694. [16] T. Luukkainen, J. Toivonen, Levonorgestrel-releasing IUD as a method of contraception with therapeutic properties, Contraception 52 (1995) 269 – 276. [17] I. Milsom, et al., A comparison of flurbiprofen, tranexamic acid, and a levonorgestrel-releasing intrauterine contraceptive device in the treatment of idiopathic menorrhagia, Am. J. Obstet. Gynecol. 164 (1991) 879 – 883. [18] R. Hurskainen, et al., Quality of life and cost-effectiveness of levonorgestrel-releasing intrauterine system versus hysterectomy for treatment of menorrhagia: a randomised trial, Lancet 357 (2001) 273 – 277. [19] J. Bonnar, B.L. Sheppard, Treatment of menorrhagia during menstruation: randomised controlled trial of ethamsylate, mefenamic acid, and tranexamic acid, Br. Med. J. 313 (1996) 579 – 582. [20] A. Lethaby, C. Farquhar, I. Cooke, Antifibrinolytics for heavy menstrual bleeding (Cochrane Review), The Cochrane Library, Issue, vol. 4, Wiley, Chichester, UK, 2003. [21] I.S. Fraser, et al., Blood and total fluid content of menstrual discharge, Obstet. Gynecol. 65 (1985) 194 – 198. [22] V. Iyer, C. Farquhar, R. Jepson, Oral contraceptive pills for heavy menstrual bleeding (Cochrane Review), The Cochrane Library, Issue, vol. 4, Wiley, Chichester, UK, 2003. [23] N.B. Loudon, et al., Acceptability of an oral contraceptive that reduces the frequency of menstruation: the tri-cycle pill regimen, Br. Med. J. 2 (1977) 487 – 490. [24] P.J. Sulak, et al., Extending the duration of active oral contraceptive pills to manage hormone withdrawal symptoms, Obstet. Gynecol. 89 (1997) 179 – 183. [25] J.B. Braunstein, et al., Economics of reducing menstruation with trimonthly-cycle oral contraceptive therapy: comparison with standard-cycle regimens, Obstet. Gynecol. 102 (2003) 699 – 708. [26] L. Miller, J.P. Hughes, Continuous combination oral contraceptive pills to eliminate withdrawal bleeding: a randomized trial, Obstet. Gynecol. 101 (2003) 653 – 661. [27] G.A. Irvine, et al., Randomised comparative trial of the levonorgestrel intrauterine system and norethisterone for treatment of idiopathic menorrhagia, Br. J. Obstet. Gynaecol. 105 (1998) 592 – 598. [28] A. Lethaby, G. Irvine, I. Cameron, Cyclical progestogens for heavy menstrual bleeding (Cochrane Review), The Cochrane Library, Issue, vol. 4, Wiley, Chichester, UK, 2003. [29] I.S. Fraser, Bleeding arising from the use of exogenous steroids, Baillie´re’s Best Pract. Res., Clin. Obstet. Gynaecol. 13 (1999) 203 – 222. [30] C.G. Nilsson, P. Holma, Menstrual blood loss with contraceptive subdermal levonorgestrel implants, Fertil. Steril. 35 (1981) 304 – 306. [31] T.H. Chimbira, et al., Reduction of menstrual blood loss by danazol in unexplained menorrhagia: lack of effect of placebo, Br. J. Obstet. Gynaecol. 87 (1980) 1152 – 1158. [32] R.W. Shaw, H.M. Fraser, Use of a superactive luteinizing hormone releasing hormone (LHRH) agonist in the treatment of menorrhagia, Br. J. Obstet. Gynaecol. 91 (1984) 913 – 916.