- Email: [email protected]
Medical management of dysfunctional uterine bleeding
Reviews in Gynaecological Practice 3 (2003) 81–84
Review
Medical management of dysfunctional uterine bleeding Alison Porteous a , Andrew Prentice b,∗ b
a The Rosie Hospital, Box 224, Robinson Way, Cambridge CB2 2SW, UK University Department of Obstetrics and Gynaecology, The Rosie Hospital, Box 223, Robinson Way, Cambridge CB2 2SW, UK
Received 28 February 2003; accepted 3 March 2003
Abstract Dysfunctional uterine bleeding is the diagnosis in the majority of cases of menorrhagia. The symptom of menorrhagia accounts for a significant proportion of referrals to gynaecologists. There is no hormonal defect in dysfunctional uterine bleeding, however, disturbances in endometrial mediators have been noted. The majority of cases are associated with ovulatory cycles, when cycle control is not an issue, and can thus be treated with non-hormonal methods such as prostaglandin synthetase inhibitors and antifibrinolytics. Those patients with anovulatory cycles may benefit from exogenous control of the pattern of bleeding with hormonal preparations. When effective contraception is also required the use of either the combined oral contraceptive or the levonorgestrel releasing intrauterine system (IUS) are suitable choices. National guidelines exist for the management of menorrhagia. If appropriate attention is made to such guidelines, in addition to the individuals’ symptoms and requirements, then the avoidance of inappropriate investigations, referrals and treatments may be achieved. The medical management of dysfunctional bleeding should ideally be based in the community. Referral to hospital being reserved for those cases where menorrhagia is thought to de due to underlying pathology or when initial treatment appears to fail. © 2003 Elsevier Science B.V. All rights reserved. Keywords: Dysfunctional uterine bleeding; Menorrhagia; Medical therapy
1. Introduction Dysfunctional uterine bleeding is the commonest cause of menorrhagia and it is a diagnosis of exclusion made in the absence of underlying medical, haematological or pelvic pathology. Menorrhagia is defined as a menstrual blood loss of greater than 80 ml per month. Discrepancies between subjective impressions of menstrual loss and objective measurements may in part be accounted for by the fact that much of the fluid volume of menstruation may be from other sources than blood [1]. In addition, the perception of loss is affected by social and psychological factors such as emotional upset, marital problems and fear of cancer. It is the subjective perception of menstrual loss rather than the objective loss that is important in determining requests for consultation and treatment. As many as 20% of women may be affected by excessive menstrual loss during their reproductive years [2]. Of all gynaecological referrals from general practice, menstrual disorders accounts for up to 21%, and of these menorrhagia is the main symptom [3]. The rate of referral varies consid∗ Corresponding author. Tel.: +44-1223-336876; fax: +44-1223-215327. E-mail address: [email protected] (A. Prentice).
erably between different practices and there has been wide variation in the management of dysfunctional uterine bleeding. Evidence-based guidelines have been produced with the aim providing recommendations for the management of menorrhagia [4].
2. Pathophysiology Dysfunctional uterine bleeding can be classified as either ovulatory or anovulatory. The distinction between these types is critical in the rational management of this condition. Ovulatory dysfunctional uterine bleeding is the more common diagnosis. With ovulatory dysfunctional bleeding there is regular ovulation and heavy regular menstrual loss with maintenance of hormonal cyclicity. Alterations in the production of prostaglandins (PG) and in fibrinolytic activity have been noted in the endometrium of women experiencing menorrhagia and these are thought to play a role in this condition. A shift in endometrial synthesis of PG, toward more PGE2 and less PGF2␣, in women with menorrhagia was first suggested by Smith in 1981 [5]. PGE2 has vasodilatation and antiplatelet aggregation effects whereas PGF2␣ produce vasoconstriction and platelet aggregation,
1471-7697/$ – see front matter © 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S1471-7697(03)00018-2
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A. Porteous, A. Prentice / Reviews in Gynaecological Practice 3 (2003) 81–84
thus prostaglandins are thought to be mediators in the regulation of menstrual loss. Increased fibrinolytic activity has been demonstrated in the endometrium of women with increased menstrual loss [6]. Anovulatory bleeding accounts for approximately 10% of cases where women complain of excess menstrual loss [7]. In this situation, irregular bleeding occurs and cycle control is an additional problem. Anovulatory problems are more common at the extremes of reproductive life. Normal menstrual bleeding is in response to withdrawal of progesterone and oestradiol. Failure of ovulation results in an absence of progesterone and consequently lack of secretory change in the endometrium. Unopposed oestrogen causes persistent or proliferative or hyperplastic endometrium followed by oestrogen withdrawal bleeds. Bleeding of this type is often heavy or prolonged.
3. Clinical assessment When assessing a patient who is complaining of heavy menstrual loss, it is important to ascertain the nature of her complaint and the impact it is having on her. In the management of dysfunctional bleeding, the management of the illness is as important as the management of the disease. It must be remembered that dysfunctional uterine bleeding is a diagnosis of exclusion, thus attempts should be made to detect any obvious underlying pathological cause for menorrhagia before concluding that this is the diagnosis. 3.1. History and examination Within the history, it is important to clarify the pattern, duration and severity of her bleeding. The patients’ perception of the heaviness of her menstrual loss and the effect on her quality of life are important. Associated gynaecological symptoms may indicate relevant underlying pathology. A general enquiry should reveal any symptoms of anaemia, medical disorders or bleeding diathesis in addition to any factors that would contraindicate specific treatments. A general, abdominal and pelvic examination should be performed [4] to detect any signs of anaemia and exclude any obvious underlying pathology. 3.2. Investigation Prior to requesting any investigation, it is a basic principle of good practice to decide if the result would alter the management of the patient. The aim of investigation with regard to this situation is to assess the physical effect of excess menstrual loss on the patient and to exclude other conditions. A full blood count is the only investigation that should be routinely requested [4]; it will give a reflection of the actual blood loss by identifying if there is iron deficiency anaemia. Blood loss in excess of 80 ml per month is often associated with anaemia.
4. Treatment of dysfunctional uterine bleeding The various aims of treatment of dysfunctional uterine bleeding are listed below: • • • • •
Reduction in heaviness of menstrual loss. Reduction in irregularity of menstrual loss. Reduction of anaemia. Improvement in quality of life. Avoidance of unnecessary anxiety.
In considering which management option is appropriate for an individual, it is important to consider various aspects including their concerns regarding their symptoms and their expectations of management. It is helpful to define what is the problem of most importance to them, is it the heaviness or the irregularity of bleeding that concerns them? What are their contraceptive or fertility requirements? There is great importance in adequate counselling of a patient regarding any treatment as this should lead to increased adherence to therapy. In some cases, reassurance that there is no significant underlying pathology or that the loss is not excessive may be all that is required. Prior to commencing any medication, it is important to consider the rational behind its use, contraindications and possible adverse effects. In addition, other potential beneficial effects and cost will have an influence on choice of treatment. The various medical treatments commonly used are listed below: • Iron (to treat secondary anaemia). • Non-hormonal medication: ◦ Prostaglandin synthetase inhibitors. ◦ Antifibrinolytics. • Hormonal medication: ◦ Combined oral contraceptive pill. ◦ Oral progestogens. ◦ Levonorgestrel releasing intrauterine system. ◦ Danazol. 4.1. Non-hormonal treatments In the majority of cases of menorrhagia, there is no hormonal abnormality and thus no rational for hormonal therapy. Non-hormonal medications are thus the first line of therapy and are taken during menstruation rather than throughout cycle. Thus, adherence to therapy is likely to be good. Such medication is appropriate for those planning to conceive, as it is not contraceptive. Non-steroidal anti-inflammatory drugs (NSAIDs) reduce prostaglandin levels and are thus a rational therapy. The ability of mefenamic acid to reduce excessive menstrual bleeding was first described by Anderson et al. in 1976 [8]. Non-steroidal anti-inflammatory drugs act mainly by inhibiting the cyclooxygenase system a controlling step in the production of cyclic endoperoxidases from arachidonic acid. In addition, fenmates, which is the group of NSAIDs to which
A. Porteous, A. Prentice / Reviews in Gynaecological Practice 3 (2003) 81–84
mefenamic acid belongs, have an additional inhibitory effect by binding to prostaglandin receptors [9]. Mefenamic acid may also act through improvement in platelet aggregation and degranulation and through vasoconstriction [10]. Non-steroidal anti-inflammatory drugs are more effective than placebo at reducing heavy menstrual bleeding, but less effective than either tranexamic acid or danazol [11]. Gastrointestinal effects are less likely with mefenamic acid than naproxen [11]. NSAIDs reduce menstrual loss by approximately a third. Tranexamic acid is an inhibitor of fibrinolysis, its effect on menstrual loss was initially reported in 1967 [12]. For the treatment of menorrhagia, it is given at a dose of 1–1.5 g three to four times daily for 3–4 days and the only contraindication to its use is thrombo-embolic disease. Anxieties that tranexamic acid might cause thrombo-embolism have been unfounded. It has been shown to reduce menstrual loss by approximately 50% [13]. 4.2. Hormonal medications Hormonal medications are useful in that they can exert an exogenous control of the menstrual cycle. A non-contraceptive benefit noted in women taking the combined oral contraceptive pill is that it reduces blood loss [14]. The combined oral contraceptive pill taken in a cyclical manner leads to the regular shedding of a thinner endometrium. Unfortunately there is lack of sufficient data to confirm this effect of the pill [15] although a wealth of anecdotal experience is testimony to its effectiveness. One small study [16] has shown an overall reduction of menstrual blood loss of 43% in women taking the combined oral contraceptive pill and no significant difference in loss between groups treated with combined oral contraceptive, mefenamic acid, low dose danazol or naproxen. A more recent trial [17] has looked at third generation contraceptives, it found them to be effective in between 80 and 93% of cases of heavy menstruation with average reduction of menstrual blood loss of up to 69%. The provision of good cycle control and in addition contraception makes the combined oral contraceptive pill an acceptable long-term therapy for many women. There is, however, a reluctance to use the pill in the age group most commonly most affected by dysfunctional uterine bleeding. 4.3. Oral progestogens The first subjective study using progestogens for the treatment of menorrhagia was published in 1960 [18]. Of the various medical treatments for menorrhagia, oral progestogens have been the most widely prescribed in many western countries. There is little objective evidence to support the use of oral progestogens, especially in women with ovulatory menstruation. Only high dose progestogens used in a cyclical manner are effective (3 out of 4 weeks). They are
83
useful in the anovulatory patient to co-ordinate and regulate bleeding. In a Cochrane systematic review [19], norethisterone was the only oral progestogen assessed and there were no studies identified as comparing progestogens with placebo. Most data is in relation to the use of progestogen during luteal phase and this shows that there is no benefit compared with other medical treatment and in fact significantly less effect than antifibrinolytics and danazol. One trial [20] has compared norethisterone given from days 5 to 26 with the levonorgestrel releasing intrauterine system (IUS). This showed significant reduction in blood loss but less effect and lower patient acceptability than when the intrauterine system was used. Side effects of prolonged use of high dose progestogens may include: fatigue mood changes, weight gain, nausea, bloating, oedema, headaches, depression, loss of libido, irregular bleeding and atherogenic changes on lipid profile. 4.4. Progesterone/progestogen releasing intrauterine systems Intrauterine devices were primarily devised for use as contraceptives. The addition of progesterone/progestogens was initially in an attempt to reduce the chance of expulsion of the devices. Progestasert was the first hormonally impregnated intrauterine device; from it, there is release of 65 g of progesterone per day, re-insertion of this device being required every 18 months. This device is no longer available. Mirena is an IUS that releases 20 g of levonorgestrel each day. It was first licensed for use in the UK in 1995 and in 12 other countries by 1998. Replacement of the device is required every 5 years. Endometrial proliferation is prevented and consequently there is a reduction in duration and quantity of menstrual loss. Despite being a relatively new intervention, use of the IUS has been rapidly adopted for treatment of menorrhagia based mainly on reports from case series rather than full evaluation in randomised controlled trials. One study [21] looked at 50 women and found that menstrual loss was reduced in 74% of them within 3 months, 82% within 9 months, and that the additional benefit of reduced dysmenorrhoea occurred in 80%. In a Cochrane systematic review [22], there were no trials identified comparing such devices with either placebo or no treatment. There were only five trials that met the criteria of that review, the majority looking at the levonorgestrel system. Studies have shown up to a 90% reduction in menstrual loss from women treated with levonorgestrel intrauterine system [22]. Additional benefits of this method are its contraceptive effect, reduction in dysmenorrhoea and a possible reduction in the incidence of pelvic inflammatory disease. Disadvantages of the IUS is that insertion may be regarded as invasive by some and in addition may require local anaesthesia and dilatation, in nulliparous and perimenopausal women. Frequent intermenstrual bleeding and spotting is likely during the first few months. Use of this method is expensive if it is discontinued prior to the 5
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A. Porteous, A. Prentice / Reviews in Gynaecological Practice 3 (2003) 81–84
years but much cheaper than the surgical alternatives it may prevent. 4.5. Danazol Danazol was first used in the treatment of dysfunctional uterine bleeding in 1979 [23]. It is a synthetic steroid with weak androgenic properties in addition to antioestrogenic and antiprogestogenic activity. Its action results in endometrial atrophy and consequently reduced menstrual loss and leads to amenorrhoea in many women [24]. Danazol at a dose of 200 mg per day has been shown to reduce menstrual blood loss by 60 % [25]. Due to the androgenic properties danazol may cause acne, seborrhoea and hirsutism. Other side effects include weight gain, irritability, musculoskeletal pains, hot flushes and breast atrophy. Long-term treatment may affect the liver and may cause benign hepatic adenomas. A systematic review of the use of danazol [26] identified nine randomised controlled trials, however, many had small sample sizes. From this review, danazol appears to be more effective than placebo, progestogens, NSAIDs and contraceptive pill at reducing menstrual blood loss. Danazol reduces the duration of menstruation compared with NSAIDs and intrauterine system. However, danazol caused more adverse events than NSAIDs and progestogens. The use of danazol may be limited by its side effects, unacceptability to many women and the need for continuation of therapy.
5. Conclusions The majority of cases of dysfunctional uterine bleeding can be adequately managed within the community setting. Benefits of treatment within primary care include: continuity of care, avoidance of delay in commencing treatment, and avoidance of unnecessary investigations and procedures. In addition, hospital resources can then be concentrated on those cases in which more intervention is required. Medical management of dysfunctional bleeding is appropriate if a rational approach to this problem is followed as outlined in national guidelines. Optimal care will have considerable impact on physical, psychological and economic functions of the individual and society. References [1] Frazer IS, McCarron G, Markham R, Resta T. Blood and total fluid content of menstrual discharge. Obstet Gynaecol 1985;65:194–8. [2] Jacobs A, Butler EB. Menstrual blood loss in iron-deficiency anaemia. Lancet 1965;II:407–9. [3] Coulter A, Bradlow J, Agass M, Mertin-Bates C, Tulloch A. Outcomes of referrals to gynaecology outpatient clinics for menstrual problems: an audit of general practice records. Br J Obstet Gynaecol 1991;98:789–98.
[4] Royal College of Obstetricians and Gynaecologists. The initial management of menorrhagia. Evidence-based clinical guidelines. No. 1. London: RCOG; 1998. [5] Smith SK, Abel MH, Kelly RW, Baird DT. Prostaglandin synthesis in the endometrium of women with ovular dysfunctional bleeding. Br J Obstet Gynaecol 1981;88:434–42. [6] Gleeson N, Devitt M, Sheppard BL, Bonnar J. Endometrial fibrinolytic enzymes in women with normal menstruation and dysfunctional uterine bleeding. Br J Obstet Gynaecol 1993;100:768–71. [7] Cameron IT, Haining R, Lumsden MA. The effects of mefenamic acid and norethisterone on measured menstrual blood. Obstet Gynecol 1990;76:85–8. [8] Anderson ABM, Haynes PJ, Guillebaud J, Turnbull AC. Reduction of menstrual blood loss by prostaglandin-synthetase inhibitors. Lancet 1976;I:774–6. [9] Rees MCP. Effects of fenmates on PG binding. Lancet 1988;II:541–2. [10] van Eijkeran MA, Christiaens GCML, Geuze HJ, Haspels AA, Sixma JJ. Effects of mefenamic acid on menstrual hemostasis in essential menorrhagia. Am J Obstet Gynecol 1992;166:1419–28. [11] Lethaby A, Augood C, Duckitt K. Non-steroidal anti-inflammatory drugs for heavy menstrual bleeding (Cochrane review). In: The Cochrane library, issue 3. Oxford: Update Software; 2002. [12] Nilsson IM, Rybo G. Acta Obstet Gynaecol 1967;90:78–83. [13] Preston J, Cameron IT, Adams EJ, Smith SK. Comparative study of tranexamic acid and norethisterone in the treatment of ovulatory menorrhagia. Br J Obstet Gynaecol 1995;102:401–6. [14] Mishell DR. Non-contraceptive health benefits of oral steroidal contraceptives. Am J Obstet Gynecol 1982;142:809–16. [15] Iyer V, Farquhar C, Jepson R. Oral contraceptive pills for heavy menstrual bleeding (Cochrane review). In: The Cochrane library, issue 4. Oxford: Update Software; 2002. [16] Fraser IS, McCarron G. Randomised controlled trial of two hormonal and two prostaglandin inhibiting agents in women with a complaint of menorrhagia. Aust N Z J Obstet Gynaecol 1991;31:66–70. [17] Agarwal N, Kripilani A. Medical management of dysfunctional uterine bleeding. Int J Gynaecol Obstet 2001;75(2):199–201. [18] Bishop PMF, Cabral de Almedia JC. Treatment of functional menstrual disorders with norethisterone. Br Med J 1960;I:1103–10. [19] Lethaby A, Irvine GA, Cameron IT. Cyclical progestogens for heavy menstrual bleeding (Cochrane review). In: The Cochrane library, issue 3. Oxford: Update Software; 2002. [20] Irvine GA, Cambell-Brown MB, Lumseden MA, Heikkaila A, Walker JJ, Cameron IT. Randomised comparative trial of the levonorgestrel intrauterine system and norethisterone for treatment of idiopathic menorrhagia. Br J Obstet Gynaecol 1988;105(6):592–8. [21] Barrington JW, Bowen-Simpkins P. The levonorgestrel intrauterine system in the management of menorrhagia. Br J Obstet Gynaecol 1997;104:614–6. [22] Lethaby A, Cooke I, Rees M. Progesterone/progestogen releasing intrauterine system for heavy menstrual bleeding (Cochrane review). In: The Cochrane library, issue 4. Oxford: Update Software; 2002. [23] Chimbira TH, Anderson ABM, Bolton FG. The effect of danazol on menorrhagia, coagulation mechanisms, haematological indices and body weight. Br J Obstet Gynaecol 1979;86:46–50. [24] Chimbira TH, Anderson ABM, Naish C, et al. Reduction of menstrual loss by danazol in unexplained menorrhagia: lack of effect by placebo. Br J Obstet Gynaecol 1980;87:1152–8. [25] Dockeray CJ, Sheppard BL, Bonnar J. Comparison between mefenamic acid and danazol in the treatment of established menorrhagia. Br J Obstet Gynaecol 1989;96:840–4. [26] Beaumont H, Augood C, Duckitt K, Lethaby A. Danazol for heavy menstrual bleeding (Cochrane review). In: The Cochrane library, issue 3. Oxford: Update Software; 2002.
Review
Medical management of dysfunctional uterine bleeding Alison Porteous a , Andrew Prentice b,∗ b
a The Rosie Hospital, Box 224, Robinson Way, Cambridge CB2 2SW, UK University Department of Obstetrics and Gynaecology, The Rosie Hospital, Box 223, Robinson Way, Cambridge CB2 2SW, UK
Received 28 February 2003; accepted 3 March 2003
Abstract Dysfunctional uterine bleeding is the diagnosis in the majority of cases of menorrhagia. The symptom of menorrhagia accounts for a significant proportion of referrals to gynaecologists. There is no hormonal defect in dysfunctional uterine bleeding, however, disturbances in endometrial mediators have been noted. The majority of cases are associated with ovulatory cycles, when cycle control is not an issue, and can thus be treated with non-hormonal methods such as prostaglandin synthetase inhibitors and antifibrinolytics. Those patients with anovulatory cycles may benefit from exogenous control of the pattern of bleeding with hormonal preparations. When effective contraception is also required the use of either the combined oral contraceptive or the levonorgestrel releasing intrauterine system (IUS) are suitable choices. National guidelines exist for the management of menorrhagia. If appropriate attention is made to such guidelines, in addition to the individuals’ symptoms and requirements, then the avoidance of inappropriate investigations, referrals and treatments may be achieved. The medical management of dysfunctional bleeding should ideally be based in the community. Referral to hospital being reserved for those cases where menorrhagia is thought to de due to underlying pathology or when initial treatment appears to fail. © 2003 Elsevier Science B.V. All rights reserved. Keywords: Dysfunctional uterine bleeding; Menorrhagia; Medical therapy
1. Introduction Dysfunctional uterine bleeding is the commonest cause of menorrhagia and it is a diagnosis of exclusion made in the absence of underlying medical, haematological or pelvic pathology. Menorrhagia is defined as a menstrual blood loss of greater than 80 ml per month. Discrepancies between subjective impressions of menstrual loss and objective measurements may in part be accounted for by the fact that much of the fluid volume of menstruation may be from other sources than blood [1]. In addition, the perception of loss is affected by social and psychological factors such as emotional upset, marital problems and fear of cancer. It is the subjective perception of menstrual loss rather than the objective loss that is important in determining requests for consultation and treatment. As many as 20% of women may be affected by excessive menstrual loss during their reproductive years [2]. Of all gynaecological referrals from general practice, menstrual disorders accounts for up to 21%, and of these menorrhagia is the main symptom [3]. The rate of referral varies consid∗ Corresponding author. Tel.: +44-1223-336876; fax: +44-1223-215327. E-mail address: [email protected] (A. Prentice).
erably between different practices and there has been wide variation in the management of dysfunctional uterine bleeding. Evidence-based guidelines have been produced with the aim providing recommendations for the management of menorrhagia [4].
2. Pathophysiology Dysfunctional uterine bleeding can be classified as either ovulatory or anovulatory. The distinction between these types is critical in the rational management of this condition. Ovulatory dysfunctional uterine bleeding is the more common diagnosis. With ovulatory dysfunctional bleeding there is regular ovulation and heavy regular menstrual loss with maintenance of hormonal cyclicity. Alterations in the production of prostaglandins (PG) and in fibrinolytic activity have been noted in the endometrium of women experiencing menorrhagia and these are thought to play a role in this condition. A shift in endometrial synthesis of PG, toward more PGE2 and less PGF2␣, in women with menorrhagia was first suggested by Smith in 1981 [5]. PGE2 has vasodilatation and antiplatelet aggregation effects whereas PGF2␣ produce vasoconstriction and platelet aggregation,
1471-7697/$ – see front matter © 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S1471-7697(03)00018-2
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thus prostaglandins are thought to be mediators in the regulation of menstrual loss. Increased fibrinolytic activity has been demonstrated in the endometrium of women with increased menstrual loss [6]. Anovulatory bleeding accounts for approximately 10% of cases where women complain of excess menstrual loss [7]. In this situation, irregular bleeding occurs and cycle control is an additional problem. Anovulatory problems are more common at the extremes of reproductive life. Normal menstrual bleeding is in response to withdrawal of progesterone and oestradiol. Failure of ovulation results in an absence of progesterone and consequently lack of secretory change in the endometrium. Unopposed oestrogen causes persistent or proliferative or hyperplastic endometrium followed by oestrogen withdrawal bleeds. Bleeding of this type is often heavy or prolonged.
3. Clinical assessment When assessing a patient who is complaining of heavy menstrual loss, it is important to ascertain the nature of her complaint and the impact it is having on her. In the management of dysfunctional bleeding, the management of the illness is as important as the management of the disease. It must be remembered that dysfunctional uterine bleeding is a diagnosis of exclusion, thus attempts should be made to detect any obvious underlying pathological cause for menorrhagia before concluding that this is the diagnosis. 3.1. History and examination Within the history, it is important to clarify the pattern, duration and severity of her bleeding. The patients’ perception of the heaviness of her menstrual loss and the effect on her quality of life are important. Associated gynaecological symptoms may indicate relevant underlying pathology. A general enquiry should reveal any symptoms of anaemia, medical disorders or bleeding diathesis in addition to any factors that would contraindicate specific treatments. A general, abdominal and pelvic examination should be performed [4] to detect any signs of anaemia and exclude any obvious underlying pathology. 3.2. Investigation Prior to requesting any investigation, it is a basic principle of good practice to decide if the result would alter the management of the patient. The aim of investigation with regard to this situation is to assess the physical effect of excess menstrual loss on the patient and to exclude other conditions. A full blood count is the only investigation that should be routinely requested [4]; it will give a reflection of the actual blood loss by identifying if there is iron deficiency anaemia. Blood loss in excess of 80 ml per month is often associated with anaemia.
4. Treatment of dysfunctional uterine bleeding The various aims of treatment of dysfunctional uterine bleeding are listed below: • • • • •
Reduction in heaviness of menstrual loss. Reduction in irregularity of menstrual loss. Reduction of anaemia. Improvement in quality of life. Avoidance of unnecessary anxiety.
In considering which management option is appropriate for an individual, it is important to consider various aspects including their concerns regarding their symptoms and their expectations of management. It is helpful to define what is the problem of most importance to them, is it the heaviness or the irregularity of bleeding that concerns them? What are their contraceptive or fertility requirements? There is great importance in adequate counselling of a patient regarding any treatment as this should lead to increased adherence to therapy. In some cases, reassurance that there is no significant underlying pathology or that the loss is not excessive may be all that is required. Prior to commencing any medication, it is important to consider the rational behind its use, contraindications and possible adverse effects. In addition, other potential beneficial effects and cost will have an influence on choice of treatment. The various medical treatments commonly used are listed below: • Iron (to treat secondary anaemia). • Non-hormonal medication: ◦ Prostaglandin synthetase inhibitors. ◦ Antifibrinolytics. • Hormonal medication: ◦ Combined oral contraceptive pill. ◦ Oral progestogens. ◦ Levonorgestrel releasing intrauterine system. ◦ Danazol. 4.1. Non-hormonal treatments In the majority of cases of menorrhagia, there is no hormonal abnormality and thus no rational for hormonal therapy. Non-hormonal medications are thus the first line of therapy and are taken during menstruation rather than throughout cycle. Thus, adherence to therapy is likely to be good. Such medication is appropriate for those planning to conceive, as it is not contraceptive. Non-steroidal anti-inflammatory drugs (NSAIDs) reduce prostaglandin levels and are thus a rational therapy. The ability of mefenamic acid to reduce excessive menstrual bleeding was first described by Anderson et al. in 1976 [8]. Non-steroidal anti-inflammatory drugs act mainly by inhibiting the cyclooxygenase system a controlling step in the production of cyclic endoperoxidases from arachidonic acid. In addition, fenmates, which is the group of NSAIDs to which
A. Porteous, A. Prentice / Reviews in Gynaecological Practice 3 (2003) 81–84
mefenamic acid belongs, have an additional inhibitory effect by binding to prostaglandin receptors [9]. Mefenamic acid may also act through improvement in platelet aggregation and degranulation and through vasoconstriction [10]. Non-steroidal anti-inflammatory drugs are more effective than placebo at reducing heavy menstrual bleeding, but less effective than either tranexamic acid or danazol [11]. Gastrointestinal effects are less likely with mefenamic acid than naproxen [11]. NSAIDs reduce menstrual loss by approximately a third. Tranexamic acid is an inhibitor of fibrinolysis, its effect on menstrual loss was initially reported in 1967 [12]. For the treatment of menorrhagia, it is given at a dose of 1–1.5 g three to four times daily for 3–4 days and the only contraindication to its use is thrombo-embolic disease. Anxieties that tranexamic acid might cause thrombo-embolism have been unfounded. It has been shown to reduce menstrual loss by approximately 50% [13]. 4.2. Hormonal medications Hormonal medications are useful in that they can exert an exogenous control of the menstrual cycle. A non-contraceptive benefit noted in women taking the combined oral contraceptive pill is that it reduces blood loss [14]. The combined oral contraceptive pill taken in a cyclical manner leads to the regular shedding of a thinner endometrium. Unfortunately there is lack of sufficient data to confirm this effect of the pill [15] although a wealth of anecdotal experience is testimony to its effectiveness. One small study [16] has shown an overall reduction of menstrual blood loss of 43% in women taking the combined oral contraceptive pill and no significant difference in loss between groups treated with combined oral contraceptive, mefenamic acid, low dose danazol or naproxen. A more recent trial [17] has looked at third generation contraceptives, it found them to be effective in between 80 and 93% of cases of heavy menstruation with average reduction of menstrual blood loss of up to 69%. The provision of good cycle control and in addition contraception makes the combined oral contraceptive pill an acceptable long-term therapy for many women. There is, however, a reluctance to use the pill in the age group most commonly most affected by dysfunctional uterine bleeding. 4.3. Oral progestogens The first subjective study using progestogens for the treatment of menorrhagia was published in 1960 [18]. Of the various medical treatments for menorrhagia, oral progestogens have been the most widely prescribed in many western countries. There is little objective evidence to support the use of oral progestogens, especially in women with ovulatory menstruation. Only high dose progestogens used in a cyclical manner are effective (3 out of 4 weeks). They are
83
useful in the anovulatory patient to co-ordinate and regulate bleeding. In a Cochrane systematic review [19], norethisterone was the only oral progestogen assessed and there were no studies identified as comparing progestogens with placebo. Most data is in relation to the use of progestogen during luteal phase and this shows that there is no benefit compared with other medical treatment and in fact significantly less effect than antifibrinolytics and danazol. One trial [20] has compared norethisterone given from days 5 to 26 with the levonorgestrel releasing intrauterine system (IUS). This showed significant reduction in blood loss but less effect and lower patient acceptability than when the intrauterine system was used. Side effects of prolonged use of high dose progestogens may include: fatigue mood changes, weight gain, nausea, bloating, oedema, headaches, depression, loss of libido, irregular bleeding and atherogenic changes on lipid profile. 4.4. Progesterone/progestogen releasing intrauterine systems Intrauterine devices were primarily devised for use as contraceptives. The addition of progesterone/progestogens was initially in an attempt to reduce the chance of expulsion of the devices. Progestasert was the first hormonally impregnated intrauterine device; from it, there is release of 65 g of progesterone per day, re-insertion of this device being required every 18 months. This device is no longer available. Mirena is an IUS that releases 20 g of levonorgestrel each day. It was first licensed for use in the UK in 1995 and in 12 other countries by 1998. Replacement of the device is required every 5 years. Endometrial proliferation is prevented and consequently there is a reduction in duration and quantity of menstrual loss. Despite being a relatively new intervention, use of the IUS has been rapidly adopted for treatment of menorrhagia based mainly on reports from case series rather than full evaluation in randomised controlled trials. One study [21] looked at 50 women and found that menstrual loss was reduced in 74% of them within 3 months, 82% within 9 months, and that the additional benefit of reduced dysmenorrhoea occurred in 80%. In a Cochrane systematic review [22], there were no trials identified comparing such devices with either placebo or no treatment. There were only five trials that met the criteria of that review, the majority looking at the levonorgestrel system. Studies have shown up to a 90% reduction in menstrual loss from women treated with levonorgestrel intrauterine system [22]. Additional benefits of this method are its contraceptive effect, reduction in dysmenorrhoea and a possible reduction in the incidence of pelvic inflammatory disease. Disadvantages of the IUS is that insertion may be regarded as invasive by some and in addition may require local anaesthesia and dilatation, in nulliparous and perimenopausal women. Frequent intermenstrual bleeding and spotting is likely during the first few months. Use of this method is expensive if it is discontinued prior to the 5
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years but much cheaper than the surgical alternatives it may prevent. 4.5. Danazol Danazol was first used in the treatment of dysfunctional uterine bleeding in 1979 [23]. It is a synthetic steroid with weak androgenic properties in addition to antioestrogenic and antiprogestogenic activity. Its action results in endometrial atrophy and consequently reduced menstrual loss and leads to amenorrhoea in many women [24]. Danazol at a dose of 200 mg per day has been shown to reduce menstrual blood loss by 60 % [25]. Due to the androgenic properties danazol may cause acne, seborrhoea and hirsutism. Other side effects include weight gain, irritability, musculoskeletal pains, hot flushes and breast atrophy. Long-term treatment may affect the liver and may cause benign hepatic adenomas. A systematic review of the use of danazol [26] identified nine randomised controlled trials, however, many had small sample sizes. From this review, danazol appears to be more effective than placebo, progestogens, NSAIDs and contraceptive pill at reducing menstrual blood loss. Danazol reduces the duration of menstruation compared with NSAIDs and intrauterine system. However, danazol caused more adverse events than NSAIDs and progestogens. The use of danazol may be limited by its side effects, unacceptability to many women and the need for continuation of therapy.
5. Conclusions The majority of cases of dysfunctional uterine bleeding can be adequately managed within the community setting. Benefits of treatment within primary care include: continuity of care, avoidance of delay in commencing treatment, and avoidance of unnecessary investigations and procedures. In addition, hospital resources can then be concentrated on those cases in which more intervention is required. Medical management of dysfunctional bleeding is appropriate if a rational approach to this problem is followed as outlined in national guidelines. Optimal care will have considerable impact on physical, psychological and economic functions of the individual and society. References [1] Frazer IS, McCarron G, Markham R, Resta T. Blood and total fluid content of menstrual discharge. Obstet Gynaecol 1985;65:194–8. [2] Jacobs A, Butler EB. Menstrual blood loss in iron-deficiency anaemia. Lancet 1965;II:407–9. [3] Coulter A, Bradlow J, Agass M, Mertin-Bates C, Tulloch A. Outcomes of referrals to gynaecology outpatient clinics for menstrual problems: an audit of general practice records. Br J Obstet Gynaecol 1991;98:789–98.
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