Specific treatment for menorrhagia is based on a number of factors, including:
Patient's age Patient's overall health and medical history The extent of the condition The cause of the condition Tolerance for specific medications, procedures or therapies Effects of the condition on the patient's lifestyle Patient's opinion or personal preference
Therapeutic options for the control of menorrhagia in women with underlying bleeding disorders include medical treatments (such as anti-fibrinolytics, combined hormonal contraceptives, intranasal and subcutaneous DDAVP, oral contraceptives, levonorgestrel intrauterine device and clotting factor replacement) and surgical treatments (such as endometrial ablation and hysterectomy). They are similar to the treatment options for menorrhagia in general with the exception of DDAVP and clotting factor replacement. However, management of women with inherited bleeding disorders requires additional monitoring of the haemostatic parameters and awareness of the increased risk of bleeding with any surgical interventions. Therefore management of menorrhagia in these women should be provided by a multidisciplinary team including a haematologist and gynaecologist
Medical treatment of menorrhagia
Antifibrinolytics. Increased uterine fibrinolytic activity is found in women with menorrhagia compared to those with normal menstrual loss; this increased fibrinolysis is most likely due to high levels of endometrium-derived plasmin and plasminogen activators [57,58]. Tranexamic acid is an antifibrinolytic agent that reversibly blocks lysine-binding sites on plasminogen and prevents fibrin degradation [59]. Using oral doses ranging from 500 mg or 1 g four times daily for 4-7 days per cycle, tranexamic acid reduces menstrual blood loss by 34-59% over two to three cycles in women with menorrhagia [60-64]. Oral tranexamic acid is generally well tolerated by women with menorrhagia. Nausea and diarrhoea are the most common side effects. The rate of adverse events experienced by users of tranexamic acid is similar to users of placebo, non-steroidal anti-inflammatory drugs (NSAIDs), cyclic progestins or ethamsylate [65]. Epidemiological population studies have not indicated that antifibrinolytic use is associated with thromboembolic events [66-69], but cases have been reported.
The recommended oral dose of tranexamic acid for the treatment of menorrhagia is 1 g three to four times daily for 3-4 days (maximum total daily dose of 4 g), starting from the onset of menstruation [70].
Combined oral contraceptives (COCs). COCs are a highly reliable method of birth control. They are also useful for cycle regulation and reduction in the incidence of dysmenorrhea and premenstrual tension. COCs are reported to be effective [3] in reducing menstrual blood loss in women with bleeding disorders, but the response is variable and unpredictable [71] and there are no studies confirming their efficacy using objective measures of clinical response [72]. In recent years, the extended or continuous administration of COC (>28 days of active pills) has been reported as a successful regime in the treatment of endometriosis, dysmenorrhea, and other menstruation-association symptoms [73-76]. The Cochrane systematic review of continuous versus cyclical use of COC concluded that continuous COC administration has similar, if not better, effect on improving bleeding patterns and may improve menstruation associated symptoms [77]. This regimen could be very helpful in the management of menorrhagia in women with bleeding disorders as this regimen allows women to control the timing and reduce the frequency of their menstruation. It may also be more effective than the cyclical regimen in reducing menstrual blood loss. Increased risk of thrombosis is the main concern associated with the use of COCs. However, women with bleeding disorders have a low inherited thrombotic risk. Serious side effects of COC are uncommon, but include hypertension and, very rarely, impaired liver function and hepatic tumours [22]. Other less serious side effects include nausea, vomiting, headache, breast tenderness, breakthrough bleeding, fluid retention, depression and skin reactions.
Desmopressin. Desmopressin (1-desamino-8-d-arginine vasopression, DDAVP) is a synthetic analogue of the antidiuretic hormone vasopressin. It increases plasma concentration of FVIII and VWF through endogenous release [78-80]. Desmopressin is available in several formulations. It can be administered parenterally via intravenous or subcutaneous injection, or nasally as a spray. The chosen route of administration is dependent on the purpose of its use and the magnitude of the effect required. The optimal haemostatic effect of DDAVP is achieved with a dosage of 0.3 µg/kg, which increases plasma FVIII and VWF levels two- to sixfold after intravenous or subcutaneous administration [81,82]. Intranasal administration of DDAVP is an attractive route because it allows patients to treat themselves at home without delay in the event of bleeding episodes, e.g. at the onset of menstruation, and without the use of needles [83,84]. The effect of intranasal administration of 300 µg with a metered-dose spray is comparable with that of 0.2 µg/kg intravenous injection [78,85]. There are a few side effects related to its vasomotor effects as mild tachycardia, headache and flushing. Due to the antidiuretic effect of DDAVP, there is a small risk of hyponatraemia and potentially of water intoxication. Case series have shown that subcutaneous [86] and intranasal DDAVP [87] are effective in the management of menorrhagia in women with bleeding disorders who respond to DDAVP. Relying on women's subjective assessment of reduction in menstrual flow, desmopressin was associated with an efficacy as excellent or good in 86% and 92% of women treated with subcutaneous and intranasal DDAVP, respectively in several uncontrolled studies [86,87]. However, a small, randomized trial found no significant reduction in menstrual blood flow compared with placebo [88].
Progestins. A cyclical progestin taken in late cycle (e.g. on days 15-24) is not recommended for the treatment of ovulatory menorrhagia, since it does not significantly reduce the volume of heavy menstrual bleeding [89]. Progestin on days 5-26 effectively reduces menstrual blood loss, but due to its adverse effects, it is suitable only for short-term therapy [90]. Oral progestins in high doses alone, or in combination with DDAVP or clotting factor concentrate, may be useful in the treatment of acute menorrhagia in women with inherited bleeding disorders. They should only be used in the short-term, since long-term therapy reduces bone mineral density and increases the risk of osteoporosis [3]. Other forms of progestins, injections or implants, have not been evaluated in women with menorrhagia, but studies in women without menorrhagia have shown that a considerable proportion of women experience amenorrhoea with such therapies.
Nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs (e.g. mefenamic acid and naproxen) have been shown to be more effective than placebo in reducing menstrual blood loss but less effective than either tranexamic acid or danazol [91]. NSAIDs have the added advantage of reducing menstrual pain and menstrual migraine. However, their use is contraindicated in women with inherited bleeding disorders due to their anti-aggregatory effect on platelet function
Ethamsylate. Ethamsylate is a haemostatic agent that maintains platelet and capillary integrity and affects prostaglandin synthesis. There are no data on the efficacy of this treatment in women with bleeding disorders, but in view of its mode of action, it may have a different effect on heavy menstrual loss in these women, which warrants further studies [22].
Gonadotrophin-releasing hormone (GnRH). GnRH agonists induce amenorrhoea [92-94], but data on their effectiveness in the treatment of menorrhagia related to bleeding disorders are lacking. Due to their numerous adverse effects, they are not recommended for long-term treatment of menorrhagia. GnRH agonists can be used if surgery is soon or for other temporary reasons (e.g. when traveling).
Levonorgestrel-releasing intrauterine system (LNG-IUS). The LNG-IUS releases 20 mg of LNG every 24 h over a recommended duration of use of 5 years. It suppresses endometrial growth causing the glands of the endometrium to become atrophic and the epithelium inactive [95]. It reduces menstrual blood loss significantly (by 74-97%) and improves quality of life considerably [95]. The effectiveness of the treatment is comparable with the results of endometrial ablation and hysterectomy, and patient satisfaction is similar [96-98]. Additional benefits may include alleviation of menstrual pain [98-100] and premenstrual symptoms [97]. Insertion of the IUS is associated with a small risk of uterine perforation and infection [101,102]. The side effects include those related to an intrauterine device, for example, irregular bleeding and expulsion of the device [96]. The commonest side effect is irregular bleeding or spotting in the first 3-6 months after insertion. It usually settles after 6-12 months in the majority of cases. Hormonal adverse effects (breast tenderness, bloating, nausea) are slightly more common during the first year than they are if endometrial resection or thermal balloon is used [97,98]. IUS reduces anxiety and depressed mood. IUS has probably no effect on sexual function [103,104]. The use of LNG-IUS in women with inherited bleeding disorders has been evaluated in 16 women (13 VWD, two FXI deficiency and one Hermansky-Pudlak syndrome) with menorrhagia not responding to medical treatment and the outcome was very good [105]. All women in this trial had mild to moderate bleeding disorders; therefore, further studies are required to evaluate the effectiveness of LNG-IUS in women with severe factor deficiencies. Women with bleeding disorders could potentially be at risk of bleeding at the time of insertion. Adequate haemostatic coverage is recommended especially in women with severe forms of bleeding disorders.
Clotting factor. Clotting factor replacement, with either recombinant or plasma-derived factor concentrate, will be required in some women with bleeding disorders, especially in adolescents [106], those with severe deficiency and when they present acutely. The role of clotting factors replacement as prophylaxis in severe bleeders need to be analysed.
Surgical treatment for menorrhagia
Surgical interventions for diagnosis or treatment of menorrhagia are commonly performed and may be required in some women who do not tolerate medical treatments or where such treatments have failed. Women with inherited bleeding disorders are at a greater risk of bleeding complications from surgery, including increased perioperative and delayed (7-10 days after surgery) bleeding. Appropriate preoperative coagulation screening and adequate haemostatic coverage during any gynaecological procedure is crucial to minimize the risk of haemorrhagic complications. Therefore, in case of surgery, a strict collaboration among haematological, gynaecological and the surgical/anaesthetic teams is essential to ensure an optimal outcome. Hysterectomy. Hysterectomy is an established, effective and definitive treatment for menorrhagia associated with high patient satisfaction [3,22]. However, hysterectomy is a major surgical procedure with significant physical and emotional complications and social and economic costs. Hysterectomy also has a risk of long-term complications, including the possibility of early ovarian failure, and urinary and sexual problems. For these reasons, less invasive alternatives (e.g. endometrial resection and ablation) have been developed for the treatment of menorrhagia. Endometrial ablation. Endometrial ablative techniques, which destroy the lining of the uterus, are increasingly used today as an effective alternative to hysterectomy for the management of heavy menstrual bleeding. They have a shorter operating time and hospital stay, quicker recovery and fewer postoperative complications than hysterectomy [107]. Preoperative administration of a GnRH analogue increases amenorrhoea during the first year after the procedure, but in the longer term there are no differences in menstrual blood loss compared with women who took no preoperative treatment [108]. Routine use of GnRH analogues before the procedure is, thus, not recommended. A disadvantage of endometrial ablation is that the results may not be permanent in one third to one half of women who undergo the procedure.