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Managing perimenopausal menorrhagia
Maturitas 66 (2010) 251–256
Contents lists available at ScienceDirect
Maturitas journal homepage: www.elsevier.com/locate/maturitas
Review
Managing perimenopausal menorrhagia Kirsten Duckitt ∗ Medical Staff Office, Campbell River and District Hospital, 375 2nd Avenue, Campbell River, British Columbia, Canada V9W 3V1
a r t i c l e
i n f o
Article history: Received 11 January 2010 Received in revised form 15 March 2010 Accepted 16 March 2010
Keywords: Menorrhagia Perimenopause Iron deficiency anaemia Levonorgestrel-releasing IUS Endometrial ablation Hysterectomy
a b s t r a c t Menorrhagia is a significant health problem for many women. It increases with age and peaks during the perimenopause. Although historically, hysterectomy as been the mainstay for treatment there are many effective medical and surgical alternatives to hysterectomy that may be eminently suitable for perimenopausal women as menopause will intervene in due course. The incidence, aetiology, initial management and effective treatment options are discussed in this review article. © 2010 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aetiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Initial management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Watchful waiting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Medical treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Combined oral contraceptive pill (COC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Levonorgestrel-releasing IUS (Mirena) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other progestogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Surgical treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endometrial ablation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Uterine artery embolization (UAE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hysterectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Provenance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Menorrhagia is a significant health problem for many women and it is more common as menopause approaches. This review
∗ Tel.: +1 250 287 7454; fax: +1 250 287 4384. E-mail address: [email protected]. 0378-5122/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2010.03.013
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aims to review the extent of the problem and discuss management including effective treatment options. 2. Incidence Normal menstrual loss increases with age [1]. Menorrhagia is heavy menstrual bleeding and is classically defined as a loss of >80 ml/cycle [1,2]. In practice this is a research definition and blood
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flow is difficult to measure out with clinical trials. Therefore, the diagnosis of menorrhagia is based primarily upon the woman’s history of excessive volume of blood loss or duration of bleeding. However, women’s perceptions of what is heavy do not always correlate with objective measurements and may depend on how they perceive the flow to have changed. In one population study, a quarter of women with loss <80 ml thought their flow was heavy while 40% of women who did have objectively defined menorrhagia thought their flow was light to moderate [1]. Population studies indicate that about 10% of women report menorrhagia at some point in their lives [3]. The annual rate of presentation to health services with heavy menstrual bleeding increases from around 2% per year to between 4 and 5% once over 40 years of age with its peak between 45 and 49 years of age [4]. Many women are referred to specialists and it is thought that 12% of gynaecology outpatient referrals are for menorrhagia in the UK [5,6]. A similar referral rate is seen in New Zealand [7] and it is thought to be similar in all developed countries. Up until quite recently a referral to a gynaecologist for menorrhagia meant a 43% chance of a hysterectomy [5] but recently hysterectomy rates have been declining in the UK [8]. 3. Aetiology As with both extremes of reproductive life, a major feature of the perimenopausal period is that of intermittent ovulation or even chronic anovulation. As there is no corpus luteum, progesterone levels are low. The ovaries are still working enough to produce oestrogen. This allows continued proliferation of the endometrium. However, eventually the thickened endometrium outgrows its blood supply, undergoes focal necrosis and shedding begins. However as the shedding is not uniform, and the usual progesterone and prostaglandin related changes have not taken place, bleeding tends to be irregular, prolonged and heavy. It is this chronic endogenous oestrogen stimulation of the endometrium, unopposed by adequate progesterone levels that can lead to endometrial hyperplasia and cancer. During the perimenopausal period, some women will remain ovulatory. Menorrhagia in this case is thought to be due to distortion of the endometrial architecture, thus explaining why many uteri removed at hysterectomy for menorrhagia appear normal [9] as it is not so much a structural defect that causes menorrhagia, rather it is a hormonal disruption of the usual events of the menstrual cycle or abnormalities at a sub cellular level in the endometrium. Menorrhagia can also be caused by fibroids, endometrial polyps and is also associated with adenomyosis, although this is usually a diagnosis made histologically after a hysterectomy. 4. Initial management The main aims of history taking, examination and investigations are to confirm menorrhagia, rule out endometrial hyperplasia and cancer and to detect any specific pathology [10]. Taking a history, as always, is important as there are features in a woman’s history that seem to correlate with menorrhagia as objectively defined (see Table 1). Finding microcytic anaemia or low ferritin stores also correlate with objectively defined menorrhagia but their absence does not rule out menorrhagia. To a certain extent it may not matter if the woman’s complaint correlates with a population derived upper centile of normality or not. What matters is whether her quality of life is affected and whether any iron deficiency anaemia is present that may have adverse physiological consequences and cause ill health. Interestingly, menstrual complaints in general often get reframed as menorrhagia by family doctors [11] who then initiate a referral based on this, so for the
Table 1 Features in history suggestive of excessive blood flow (adapted from Warner et al.). Changing sanitary protection less than every 3 h Using >20 pads or tampons/cycle Changing protection during the night Passing clots > in size than 1 in Bleeding lasting longer than 7 days Presence of iron deficiency anaemia (but absence of anaemia does not exclude menorrhagia)
specialist it is important to get an exact picture of the pattern and amount of bleeding and identify what the woman’s concerns are. In Warner’s study only 38% of the women referred for menstrual problems to a specialist clinic were intolerant of the amount of blood lost even though it was the reason for referral for 60–70% of them. It may be the unpredictability of knowing when their period is going to appear rather than the heaviness that is bothering them. Equally it may be associated pain that is affecting their quality of life more than the heavy flow. Identifying the woman’s particular concerns will lead to better tailored treatment options. Abdominal and pelvic examinations are important for several reasons. Occasionally the bleeding may not be uterine in origin as is sometimes the case with gross cervical pathology. Forgotten IUDs can sometimes be a surprising find on examination as can prolapsed uterine fibroids protruding through the cervix. The size of the uterus and location of any fibroids should be determined as this may influence treatment options. An endometrial biopsy should be carried out if the bleeding is irregular, intermenstrual or if there are other risk factors present for endometrial hyperplasia or cancer especially a weight over 90 kg or a transvaginal endometrial thickness ≥12 mm (see Table 2). A cervical smear is necessary if due or if intermenstrual or postcoital bleeding is present. A full blood count should be obtained. Hypothyroidism can cause menstrual irregularity and menorrhagia so if there is a family history of thyroid disease or other indicators of thyroid disease then thyroid function tests should also be ordered but are not necessary in all cases. A pelvic ultrasound may be useful if examination findings are abnormal, if findings are uncertain due to the woman’s body habitus or if reassurance and no treatment is required but is not necessary in all cases. Hysteroscopy is not necessary in most cases as an initial investigation but is useful for women in whom initial treatment has failed or in women who have intrauterine abnormalities seen on ultrasound [4,7,12,13]. 5. Treatment options Treatment options for menorrhagia in general are inevitably influenced by whether the woman has completed their family or not but this will not be an issue for most women in the perimenopausal period. The size of their uterus also plays a part in advising women of their treatment choices as uteri over 10–12 weeks gestation size may not be suitable for either the levonorgestrel-releasing IUS or some types of endometrial ablation. What treatments women choose can also affected by the provision of information prior to the outpatient consultation although exactly how this affects choices may depend on how this information is provided. [14,15]. Women’s treatment choices are also affected by their level of education and employment status [16]. The stage of their reproductive life and severity of their symptoms also seems to be linked to women’s treatment preferences [16]. Treatment options include adopting a conservative wait and see approach, using medical treatments which may be oral or intrauterine, surgical treatments such as endometrial ablation and hysterectomy and radiological treatments such as uterine artery embolization. These will be considered in turn.
K. Duckitt / Maturitas 66 (2010) 251–256 Table 2 Guidelines on when to perform an endometrial biopsy in cases of abnormal uterine bleeding. NICE Guideline on Heavy Menstrual Bleeding (UK 2007)
SOGC Guideline on Abnormal Uterine Bleeding (Canada 2001)
If appropriate, a biopsy should be taken to exclude endometrial cancer or atypical hyperplasia. Indications for a biopsy include, for example, persistent intermenstrual bleeding, and in women aged 45 and over treatment failure or ineffective treatment. Clinicians should perform endometrial sampling based on the methods available to them. An office endometrial biopsy should be obtained if possible in all women presenting with abnormal uterine bleeding, over 40 years of age or weighing more than or equal to 90 kg.
Guidelines for the Management of Heavy Menstrual Bleeding (New Zealand, 1998)
The following women with heavy menstrual bleeding are recommended to have a transvaginal ultrasound of the endometrium Weight ≥90 kg Age ≥45 years old Other risk factors for endometrial hyperplasia or carcinoma such as infertility or nulliparity, family history of colon or endometrial cancer, exposure to unopposed oestrogens If transvaginal ultrasound is not available then an endometrial sample should be taken If the endometrial thickness on TVS is ≥12 mm an endometrial sample should be taken to exclude endometrial hyperplasia
Kaiser Permanente, Southern California (USA 2006)
Women over the age of 40. Women less than forty with risk factors judged sufficient to warrant biopsy. These include features suggestive of chronic anovulation (irregular menses, infertility); and weight greater than 90 kg.
6. Watchful waiting If you could advise each woman with perimenopausal menorrhagia as to the date when she will stop her periods permanently i.e. her age at menopause, many women might choose to adopt a wait and see approach. The mean age of the menopause in women in developed countries is 51.4 ± 0.19 (SE) years with smokers reaching menopause on average 1.74 years earlier but unfortunately there is no good way of predicting the date for each individual women and the range of menopausal age is great [17]. Neither FSH, inhibin B, anti-Mullerian hormone or estradiol levels predict the timing of last menstruation or even differentiate between premenopausal, perimenopausal or postmenopausal status and therefore do not influence treatment [18,19]. 7. Medical treatment Systematic reviews show that non-steroidal anti-inflammatory drugs (NSAIDs), tranexamic acid, danazol and intrauterine progestogens are all effective in reducing the amount of blood lost per cycle [20–23]. However, NSAIDs are not as effective as the other three options although do have the advantage of relieving dysmenorrhoea at the same time. While danazol used to be a popular treatment its use has been limited by its androgenic side effects and concern over its effect on the liver with long term use. The advantages of tranexamic acid, an antifibrinolytic agent, is the fact that it only has to be taken during the days of heavy bleeding, it has relatively few side effects, is not hormonal and can be used even if pregnancy is desired. The most effective dose is 1 g 3 to 4 times daily. It can reduce the amount of blood lost by 50% [24].
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Previous concerns regarding an increased risk of thrombosis with tranexamic acid use have been disproved [25].
8. Combined oral contraceptive pill (COC) Despite the widespread use of the combined oral contraceptive pill for both heavy and or painful periods there is very little in the way of good evidence to support this use. In fact the Cochrane systematic review that aimed to examine the effect of the oral contraceptive pill on HMB could not draw any valid conclusions due to the paucity of the data [26]. However, a prospective cohort study [27], observed higher mean haemoglobin levels in populations of women taking COC compared to those not taking COC which indirectly suggests that menstrual loss is reduced in women taking COCs. Another uncontrolled trial found that objectively measured menstrual blood loss was significantly lower in 20 women after 6 months contraceptive pill use compared to baseline [28]. Taking the COC continuously rather than cyclically is also becoming more acceptable to women with the advent of several COCs designed and marketed to be taken for longer than 21 days and cause prolonged periods of amenorrhoea which is highly desirable for women with heavy periods [29]. However, the COC will not be suitable for all perimenopausal women as the risks outweigh the benefits in smokers over the age of 35 and women with risk factors for cardiovascular disease such as obesity and hypertension [30], although it does protect against endometrial and ovarian cancer.
9. Levonorgestrel-releasing IUS (Mirena) The levonorgestrel-releasing intrauterine system (LNG IUS) is a polyethylene T-shaped frame that secretes 20 g levonorgestrel/24 h from a reservoir on its stem and is inserted like an IUD into the uterus. It is increasingly used to treat women with menorrhagia although was originally developed for contraception. It provides effective contraception comparable to female sterilization. It results in endometrial atrophy and therefore reduced menstrual loss. However, initially it can cause prolonged periods of spotting as the endometrium sheds erratically on its way to becoming thin. Many women become amenorrhoeic with continued use. It has never been compared in an RCT with placebo but it is more effective than cyclical norethisterone, taken for 21 days, as a treatment for heavy menstrual bleeding [23]. Women with an LNG IUS are more satisfied and willing to continue with treatment but experience more side effects, such as intermenstrual bleeding and breast tenderness [23]. The LNG IUS results in a smaller mean reduction in menstrual blood loss than endometrial ablation but there is no evidence of a difference in the rate of satisfaction with treatment [23]. Women with an LNG IUS experience more progestogenic side effects compared to women having transcervical resection of the endometrium (TCRE) for treatment of their heavy menstrual bleeding but there is no evidence of a difference in their perceived quality of life [23]. The LNG IUS treatment costs less than hysterectomy and there is circumstantial evidence that hysterectomy rates decreased in the UK at the time that it started being used commonly as first line treatment for menorrhagia [8]. A RCT which randomised women to either a LNG IUS or hysterectomy found similar high patient satisfaction in both groups even though there was a 42% hysterectomy rate in the LNG IUS group by 5 years [31]. Neither age nor fibroids was predictive of treatment success with the LNG IUS [32] although women with genuine objective menorrhagia were more satisfied with the LNG IUS. Other benefits of the LNG IUS include fewer hot flushes compared with those having had a hysterectomy [33] and the ability to use it as the progestogen component of HRT.
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10. Other progestogens In the anovulatory woman, progestogens help to coordinate regular uterine shedding when given as a late luteal replacement treatment, on days 19–26 of the cycle [34]. However, the regimen, dose and type of progestogen used varies widely, with little consensus about the optimum treatment approach. No randomised trials were identified which compared progestogens with oestrogens and progestogens or with placebo in the management of irregular bleeding associated with anovulation. Only one small, non-randomised study compared two progestogen regimes in the management of heavy and irregular bleeding in women with confirmed anovulation [35]. The use of progestogens as luteal phase supplementation in the ovulatory woman with menorrhagia is even more questionable. Consequently, an increase in the duration and dosage of progestogen therapy has recently been investigated in patients with ovulatory HMB. Prolonged use of high-dose progestogens can be associated with side effects, which include fatigue, mood changes, weight gain, nausea, bloating, oedema, headaches, depression, loss of libido, irregular bleeding and atherogenic changes in the lipid profile. Progestogens administered from day 15 or 19 to day 26 of the cycle offer no advantage over other medical therapies such as danazol, tranexamic acid, nonsteroidal anti-inflammatory drugs (NSAIDs) and the IUS in the treatment of menorrhagia in women with ovulatory cycles [36]. Progestogen therapy for 21 days of the cycle results in a significant reduction in menstrual blood loss, although women found the treatment less acceptable than intrauterine levonorgestrel. This regimen of progestogen may have a role in the short-term treatment of menorrhagia. A more recent RCT compared the efficacy of three progestin regimens in perimenopausal menorrhagia [37]. One hundred thirty-two women with menorrhagia were included. Women were randomised to three groups of 44 in each, either to get a single shot of depot medroxyprogesterone acetate intramuscularly, or medroxyprogesterone acetate in a daily dose of 5 mg orally, or the LNG IUS. Assessment of blood loss, the duration of bleeding and mean haemoglobin level were improved in all groups. There was no statistically significant difference between the results in the depo or oral medroxyprogesterone groups, but the LNG IUS was superior to both other groups. Mean duration of menstruation was similar in all groups. 11. Surgical treatment Dilatation and curettage (D&C) used to be a very common procedure performed for women with menorrhagia. However, it is ineffective in reducing menstrual blood loss in the long term [38] and is only useful when combined with hysteroscopy for evaluation of the intrauterine cavity. 12. Endometrial ablation Endometrial ablation is less invasive than hysterectomy and preserves the uterus, although not fertility. Many women prefer less invasive surgical treatment even when they are made aware that the success of the treatment is not always assured [39]. These techniques were introduced in the mid 1980s with the aim of removing the entire thickness of the endometrium. The endometrium has great powers of regeneration and to suppress menstruation successfully it is necessary to destroy the full thickness of the endometrium together with the superficial myometrium including the deep basal glands as these are believed to be the primary foci for endometrial regrowth. The initial procedures destroyed endometrium under direct hysteroscopic vision either by excision with an electrosurgical loop or by ablating the
endometrium with some form of thermal energy of sufficient power to produce necrosis (cell death) of the full thickness of the endometrium. The original “gold standard techniques” of laser, TCRE and rollerball ablation require direct hysteroscopic visualisation of the uterus and a steep learning curve is required to acquire the requisite skill. Subsequently, a large number of different techniques have been developed to ‘ablate’ or destroy the lining of the endometrium, most of which are quicker to perform and are therefore more amenable to being performed under local anaesthetic or light sedation. However, hysteroscopy may still be required prior to the newer ablative techniques in order to evaluate the intrauterine cavity and make sure the endometrial ablation is appropriate. A Cochrane systematic review [40] found that there was no difference in outcomes in terms of reduction of HMB or patient satisfaction between the older and newer endometrial ablation methods. However, women undergoing newer ablative procedures were less likely to have fluid overload, uterine perforation, cervical lacerations and hematometra than women undergoing the more traditional type of ablation and resection techniques although were more likely to have nausea and vomiting and uterine cramping. Another Cochrane systematic review [41] compared endometrial ablative techniques with hysterectomy. There was a significant advantage in favour of hysterectomy in the improvement in HMB (OR = 0.04, 0.01 to 0.2 at 1 year) and satisfaction rates (up to 4 years post-surgery) (OR = 0.5, 0.3–0.8 at 2 years) compared with endometrial ablation. Duration of surgery, hospital stay and recovery time were all shorter following TCRE or endometrial ablation, although these outcomes varied between trials. Most adverse events, both major and minor, were significantly more likely after hysterectomy and before discharge from hospital. Repeat surgery because of failure of the initial treatment, either endometrial ablation or hysterectomy, was more likely after endometrial ablation than hysterectomy (OR = 16.7, 5.8–48.6). The total cost of endometrial destruction was significantly lower than the cost of hysterectomy but the difference between the two procedures narrowed over time because of the high cost of re-treatment in the endometrial ablation group. The probability of needing a subsequent hysterectomy after an endometrial ablation varies with age at the time of the endometrial ablation. Between 1999 and 2004, 3681 women underwent endometrial ablation at 30 Kaiser Permanente Northern California facilities. Hysterectomy was subsequently performed in 774 women (21%). When women >45 years of age at initial procedure were compared with women <45 years of age, women aged 45 years or younger were 2.1 times more likely to have hysterectomy (95% confidence interval 1.8–2.4). The subsequent hysterectomy rate approached 40% if the woman was <40 at the time of the endometrial ablation [42]. Age was a more important predictor of subsequent hysterectomy than the setting of endometrial ablation or the presence of leiomyomas. This data, however, is reassuring for perimenopausal women who are likely to be over 45 and will encounter menopause before the need for subsequent hysterectomy occurs.
13. Uterine artery embolization (UAE) UAE is the complete occlusion of both the uterine arteries with particulate emboli. It has been reported to be an effective and safe alternative in the treatment of menorrhagia and other fibroid-related symptoms in women not desiring future fertility. A Cochrane systematic review found 3 RCTs comparing UAE with either hysterectomy or myomectomy for fibroids and fibroidrelated symptoms such as menorrhagia [43]. Follow up varied but was not longer than 2 years. Menstrual loss seemed to be reduced by as much as 85% in the UAE groups with a shorter hospital stay and a quicker return to normal activities. However, there was an
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increase in minor complications, unscheduled visits and hospital readmissions in the UAE groups. Further RCTs are in progress. 14. Hysterectomy Hysterectomy has traditionally been regarded as the definitive surgical treatment for heavy menstrual bleeding but, in spite of a 100% success rate due to complete cessation of menstruation and high levels of satisfaction [44], it is a major surgical procedure with significant physical complications and social and economic costs. These include a high rate of major and minor post-operative complications, including, rarely, death and a long recovery time [45,46]. Complications are more likely when the hysterectomy is performed by the open abdominal route, and vaginal hysterectomy should be performed in preference to abdominal hysterectomy where possible [47]. Debate continues over whether subtotal or total hysterectomies are associated with the best outcomes when the hysterectomy is performed abdominally. However, a Cochrane systematic review shows that subtotal hysterectomy does not show any improved outcomes for sexual, urinary or bowel function when compared with total abdominal hysterectomy [48]. Surgery is shorter and intraoperative blood loss and post-operative fever are less likely with subtotal hysterectomy but women are more likely to experience ongoing cyclical bleeding up to a year after surgery with subtotal hysterectomy when compared to total hysterectomy. 15. Conclusion There are now many medical and surgical alternatives to hysterectomy for the treatment of perimenopausal menorrhagia. However, long term follow up continues to be necessary to make sure that the need for hysterectomy is not just being postponed. RCTs need to correlate their outcomes to age at time of treatment so that better advice about treatment efficacy can be given to women depending on their age. Contributor Kirsten Duckitt researched and wrote article. Conflict of interest No competing interests. Provenance Commissioned and externally peer reviewed. References [1] Hallberg L, Högdahl AM, Nilsson L, Rybo G. Menstrual blood loss—a population study. Variation at different ages and attempts to define normality. Acta Obstet Gynecol Scand 1966;45:320–51. [2] Cole S. Menstrual blood loss and haematological indices. J Reprod Fertil 1971;27:158. [3] McCormick A, Fleming D, Charlton J. Morbidity Statistics from General Practice, Fourth National Study 1991–1992. London: HMSO; 1995. [4] National Collaborating Centre for Women’s and Children’s Health. Heavy menstrual bleeding—NICE guideline No. 44. London: RCOG Press; 2007. [5] Coulter A, Bradlow J, Agass M, Martin-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;98:789–96. [6] Bradlow J, Coulter A, Brooks P. Patterns of referral. Oxford Health Services Research Unit; 1992. [7] Working Party of the National Health Committee New Zealand. Guidelines for the management of heavy menstrual bleeding. Wellington: Ministry of Health; 1998. [8] Reid PC, Mukri F. Trends in number of hysterectomies performed in England for menorrhagia: examination of health episode statistics, 1989 to 2002-3. BMJ 2005;330:938–9.
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[9] Clarke A, Black N, Rowe P, et al. Indications for and outcome of total abdominal hysterectomy for benign disease: a prospective cohort study. Br J Obstet Gynaecol 1995;102:611–20. [10] Warner PE, Critchley HOD, Lumsden MA, Campbell-Brown M, Douglas A, Murray GD. Menorrhagia. I. Measured blood loss, clinical features, and outcome in women with heavy periods: a survey with follow-up data, 190; 2004. p. 1216–1223. [11] Warner P, Critchley HO, Lumsden MA, Campbell-Brown M, Douglas A, Murray G. Referral for menstrual problems: cross sectional survey of symptoms, reasons for referral, and management. BMJ 2001;323:24–8. [12] SOGC Guidelines for the management of abnormal bleeding. www.sogc.org/guidelines/public/106E-CPG-August2001.pdf. [13] Amann M, Anguino H, Bauman RA, et al. Chronic abnormal uterine bleeding in nongravid women. Pasadena (CA): Kaiser Permanente Southern California; 2006 December. [14] Kennedy AD, Sculpher MJ, Coulter A, et al. Effects of decision aids for menorrhagia on treatment choices, health outcomes, and costs: a randomized controlled trial. JAMA 2002;288:2701–8. [15] Vuorma S, Rissanen P, Aalto AM, Hurskainen R, Kujansuu E, Teperi J. Impact of patient information booklet on treatment decision—a randomized trial among women with heavy menstruation. Health Expect 2003;6:290–7. [16] Vuorma S, Teperi J, Hurskainen R, Aalto AM, Rissanen P, Kujansuu E. Correlates of women’s preferences for treatment of heavy menstrual bleeding. Patient Educ Couns 2003;49:125–32. [17] McKinlay SM, Bifano NL, McKinley JB. Smoking and age at menopause in women. Ann Intern Med 1985;103:350–6. [18] Stellato RK, Crawford SL, McKinlay SM, Longcope C. Can follicle-stimulating hormone be used to define menopausal status? Endocr Pract 1998;4: 137–41. [19] Burger HG, Hale GE, Dennerstein L, Robertson DM. Cycle and hormone changes during perimenopause: the key role of ovarian function. Menopause 2008;15:603–12. [20] Lethaby A, Augood C, Duckitt K, Farquhar C. Nonsteroidal anti-inflammatory drugs for heavy menstrual bleeding. Cochrane Database Syst Rev 2007;(4). Art. No.: CD000400, doi:10.1002/14651858.CD000400.pub2. [21] Lethaby A, Farquhar C, Cooke I. Antifibrinolytics for heavy menstrual bleeding. Cochrane Database Syst Rev 2000;(4). Art. No.: CD000249, doi:10.1002/14651858.CD000249. [22] Beaumont HH, Augood C, Duckitt K, Lethaby A. Danazol for heavy menstrual bleeding. Cochrane Database Syst Rev 2007;(3). Art. No.: CD001017, doi:10.1002/14651858.CD001017.pub2. [23] Lethaby A, Cooke I, Rees MC. Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding. Cochrane Database Syst Rev 2005;(4). Art. No.: CD002126, doi:10.1002/14651858.CD002126.pub2. [24] Higham J, Shaw R. Risk-benefit assessment of drugs used for the treatment of menstrual disorders. Drug Safe 1991;6:183–91. [25] Rybo G. Tranexamic acid therapy effective treatment in heavy menstrual bleeding: clinical update on safety. Therap Adv 1991;4:1–8. [26] Farquhar C, Brown J. Oral contraceptive pill for heavy menstrual bleeding. Cochrane Database of Systematic Reviews 2009;(4). Art. No.: CD000154, doi:10.1002/14651858.CD000154.pub2. [27] Ramcharan S, Pellegrin FA, Ray RM, Hsu JP. The Walnut Creek Contraceptive Drug Study. A prospective study of the side effects of oral contraceptives. Volume III, an interim report: a comparison of disease occurrence leading to hospitalization or death in users and nonusers of oral contraceptives. J Reprod Med 1980;25(Suppl. (6)):345–72. [28] Larsson G, Milsom I, Lindstedt G, Rybo G. The influence of a low dose combined oral contraceptive on menstrual blood loss and iron status. Contraception 1992;46:327–34. [29] Sulak PG, Carl J, Gopalakirshnan I, Coffee A, Kuhl TJ. Outcomes of extended oral contraceptive regimes with a shortened hormone free interval to manage breakthrough bleeding. Contraception 2004;70:281–7. [30] Faculty of Sexual Health and Reproductive Health Care. UK Medical Eligibility Criteria for Contraceptive Use (UKMEC 2009) www.fsrh.org. [31] Hurskainen R, Teperi J, Rissanen P, et al. Clinical outcomes and costs with the levonorgestrel-releasing intrauterine system or hysterectomy for treatment of menorrhagia: randomized trial 5-year follow-up. JAMA 2004;291: 1456–63. [32] Ritva Hurskainen, Juha Teperi, Anna-Mari Aalto, et al. Levonorgestrel-releasing intrauterine system or hysterectomy in the treatment of essential menorrhagia: predictors of outcome. Acta Obstet Gynecol Scand 2004;83:401–3. [33] Halmesmaki K, Hurskainen R, Tiitinen A, et al. A randomized controlled trial of hysterectomy or levonorgestrel-releasing intrauterine system in the treatment of menorrhagia-effect on FSH levels and menopausal symptoms. Hum Reprod 2004;19:378–82. [34] Conyngham RB. Norethisterone in menorrhagia. N Z Med J 1965;64: 697–701. [35] Hickey M, Higham JM, Fraser I. Progestogens versus oestrogens and progestogens for irregular uterine bleeding associated with anovulation. Cochrane Database Syst Rev 2007;(4). Art. No.: CD001895, doi:10.1002/ 14651858.CD001895.pub2. [36] Lethaby A, Irvine GA, Cameron IT. Cyclical progestogens for heavy menstrual bleeding. Cochrane Database Syst Rev 2008;(1). Art. No.: CD001016, doi:10.1002/14651858.CD001016.pub2. [37] Küc¸ük T, Ertan K. Continuous oral or intramuscular medroxyprogesterone acetate versus the levonorgestrel releasing intrauterine system in the treat-
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K. Duckitt / Maturitas 66 (2010) 251–256 ment of perimenopausal menorrhagia: a randomized, prospective, controlled clinical trial in female smokers. Clin Exp Obstet Gynecol 2008;35:57–60. Haynes PJ, Hodgson H, Anderson AB. Turnbull AC Measurement of menstrual blood loss in patients complaining of menorrhagia. Br J Obstet Gynaecol 1977;84:763–8. Nagele F, Rubinger T, Magos A. Why do women choose endometrial ablation rather than hysterectomy? Fert Steril 1998;69:1063–6. Lethaby A, Hickey M, Garry R, Penninx J. Endometrial resection/ablation techniques for heavy menstrual bleeding. Cochrane Database of Systematic Reviews 2009;(4). Art. No.: CD001501, doi:10.1002/14651858.CD001501. pub3. Lethaby A, Shepperd S, Farquhar C, Cooke I. Endometrial resection and ablation versus hysterectomy for heavy menstrual bleeding. Cochrane Database of Systematic Reviews 1999;(2). Art. No.: CD000329, doi:10.1002/14651858. CD000329. Longinotti MK, Jacobson GF, Hung YY, Learman LA. Probability of hysterectomy after endometrial ablation. Obstet Gynecol 2008;112:1214–20.
[43] Gupta JK, Sinha A, Lumsden MA, Hickey M. Uterine artery embolization for symptomatic uterine fibroids. Cochrane Database of Systematic Reviews 2006;(1). Art. No.: CD005073, doi:10.1002/14651858.CD005073.pub2. [44] Coulter A, Peto V, Jenkinson C. Quality of life and patient satisfaction following treatment for menorrhagia. Fam Pract 1994;11:394–401. [45] Dicker RC, Greenspan JR, Strauss LT, et al. Complications of vaginal and abdominal hysterectomy among women of reproductive age in the United States. Am J Obstet Gynecol 1982;144:841–8. [46] Wingo PA, Huezo CM, Rubin GL, Ory HW, Peterson HB. The mortality risk associated with hysterectomy. Am J Obstet Gynecol 1985;152:803–8. [47] Nieboer TE, Johnson N, Lethaby A, Tavender E, Curr E, Garry R, van Voorst S, Mol BWJ, Kluivers KB. Surgical approach to hysterectomy for benign gynaecological disease. Cochrane Database Syst Rev 2009;(3). Art. No.: CD003677, doi:10.1002/14651858.CD003677.pub4. [48] Lethaby A, Ivanova V, Johnson N. Total versus subtotal hysterectomy for benign gynaecological conditions. Cochrane Database Syst Rev 2006;(2). No.: CD004993, doi:10.1002/14651858.CD004993.pub2.
Contents lists available at ScienceDirect
Maturitas journal homepage: www.elsevier.com/locate/maturitas
Review
Managing perimenopausal menorrhagia Kirsten Duckitt ∗ Medical Staff Office, Campbell River and District Hospital, 375 2nd Avenue, Campbell River, British Columbia, Canada V9W 3V1
a r t i c l e
i n f o
Article history: Received 11 January 2010 Received in revised form 15 March 2010 Accepted 16 March 2010
Keywords: Menorrhagia Perimenopause Iron deficiency anaemia Levonorgestrel-releasing IUS Endometrial ablation Hysterectomy
a b s t r a c t Menorrhagia is a significant health problem for many women. It increases with age and peaks during the perimenopause. Although historically, hysterectomy as been the mainstay for treatment there are many effective medical and surgical alternatives to hysterectomy that may be eminently suitable for perimenopausal women as menopause will intervene in due course. The incidence, aetiology, initial management and effective treatment options are discussed in this review article. © 2010 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aetiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Initial management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Watchful waiting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Medical treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Combined oral contraceptive pill (COC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Levonorgestrel-releasing IUS (Mirena) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other progestogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Surgical treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endometrial ablation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Uterine artery embolization (UAE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hysterectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Provenance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Menorrhagia is a significant health problem for many women and it is more common as menopause approaches. This review
∗ Tel.: +1 250 287 7454; fax: +1 250 287 4384. E-mail address: [email protected]. 0378-5122/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2010.03.013
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aims to review the extent of the problem and discuss management including effective treatment options. 2. Incidence Normal menstrual loss increases with age [1]. Menorrhagia is heavy menstrual bleeding and is classically defined as a loss of >80 ml/cycle [1,2]. In practice this is a research definition and blood
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flow is difficult to measure out with clinical trials. Therefore, the diagnosis of menorrhagia is based primarily upon the woman’s history of excessive volume of blood loss or duration of bleeding. However, women’s perceptions of what is heavy do not always correlate with objective measurements and may depend on how they perceive the flow to have changed. In one population study, a quarter of women with loss <80 ml thought their flow was heavy while 40% of women who did have objectively defined menorrhagia thought their flow was light to moderate [1]. Population studies indicate that about 10% of women report menorrhagia at some point in their lives [3]. The annual rate of presentation to health services with heavy menstrual bleeding increases from around 2% per year to between 4 and 5% once over 40 years of age with its peak between 45 and 49 years of age [4]. Many women are referred to specialists and it is thought that 12% of gynaecology outpatient referrals are for menorrhagia in the UK [5,6]. A similar referral rate is seen in New Zealand [7] and it is thought to be similar in all developed countries. Up until quite recently a referral to a gynaecologist for menorrhagia meant a 43% chance of a hysterectomy [5] but recently hysterectomy rates have been declining in the UK [8]. 3. Aetiology As with both extremes of reproductive life, a major feature of the perimenopausal period is that of intermittent ovulation or even chronic anovulation. As there is no corpus luteum, progesterone levels are low. The ovaries are still working enough to produce oestrogen. This allows continued proliferation of the endometrium. However, eventually the thickened endometrium outgrows its blood supply, undergoes focal necrosis and shedding begins. However as the shedding is not uniform, and the usual progesterone and prostaglandin related changes have not taken place, bleeding tends to be irregular, prolonged and heavy. It is this chronic endogenous oestrogen stimulation of the endometrium, unopposed by adequate progesterone levels that can lead to endometrial hyperplasia and cancer. During the perimenopausal period, some women will remain ovulatory. Menorrhagia in this case is thought to be due to distortion of the endometrial architecture, thus explaining why many uteri removed at hysterectomy for menorrhagia appear normal [9] as it is not so much a structural defect that causes menorrhagia, rather it is a hormonal disruption of the usual events of the menstrual cycle or abnormalities at a sub cellular level in the endometrium. Menorrhagia can also be caused by fibroids, endometrial polyps and is also associated with adenomyosis, although this is usually a diagnosis made histologically after a hysterectomy. 4. Initial management The main aims of history taking, examination and investigations are to confirm menorrhagia, rule out endometrial hyperplasia and cancer and to detect any specific pathology [10]. Taking a history, as always, is important as there are features in a woman’s history that seem to correlate with menorrhagia as objectively defined (see Table 1). Finding microcytic anaemia or low ferritin stores also correlate with objectively defined menorrhagia but their absence does not rule out menorrhagia. To a certain extent it may not matter if the woman’s complaint correlates with a population derived upper centile of normality or not. What matters is whether her quality of life is affected and whether any iron deficiency anaemia is present that may have adverse physiological consequences and cause ill health. Interestingly, menstrual complaints in general often get reframed as menorrhagia by family doctors [11] who then initiate a referral based on this, so for the
Table 1 Features in history suggestive of excessive blood flow (adapted from Warner et al.). Changing sanitary protection less than every 3 h Using >20 pads or tampons/cycle Changing protection during the night Passing clots > in size than 1 in Bleeding lasting longer than 7 days Presence of iron deficiency anaemia (but absence of anaemia does not exclude menorrhagia)
specialist it is important to get an exact picture of the pattern and amount of bleeding and identify what the woman’s concerns are. In Warner’s study only 38% of the women referred for menstrual problems to a specialist clinic were intolerant of the amount of blood lost even though it was the reason for referral for 60–70% of them. It may be the unpredictability of knowing when their period is going to appear rather than the heaviness that is bothering them. Equally it may be associated pain that is affecting their quality of life more than the heavy flow. Identifying the woman’s particular concerns will lead to better tailored treatment options. Abdominal and pelvic examinations are important for several reasons. Occasionally the bleeding may not be uterine in origin as is sometimes the case with gross cervical pathology. Forgotten IUDs can sometimes be a surprising find on examination as can prolapsed uterine fibroids protruding through the cervix. The size of the uterus and location of any fibroids should be determined as this may influence treatment options. An endometrial biopsy should be carried out if the bleeding is irregular, intermenstrual or if there are other risk factors present for endometrial hyperplasia or cancer especially a weight over 90 kg or a transvaginal endometrial thickness ≥12 mm (see Table 2). A cervical smear is necessary if due or if intermenstrual or postcoital bleeding is present. A full blood count should be obtained. Hypothyroidism can cause menstrual irregularity and menorrhagia so if there is a family history of thyroid disease or other indicators of thyroid disease then thyroid function tests should also be ordered but are not necessary in all cases. A pelvic ultrasound may be useful if examination findings are abnormal, if findings are uncertain due to the woman’s body habitus or if reassurance and no treatment is required but is not necessary in all cases. Hysteroscopy is not necessary in most cases as an initial investigation but is useful for women in whom initial treatment has failed or in women who have intrauterine abnormalities seen on ultrasound [4,7,12,13]. 5. Treatment options Treatment options for menorrhagia in general are inevitably influenced by whether the woman has completed their family or not but this will not be an issue for most women in the perimenopausal period. The size of their uterus also plays a part in advising women of their treatment choices as uteri over 10–12 weeks gestation size may not be suitable for either the levonorgestrel-releasing IUS or some types of endometrial ablation. What treatments women choose can also affected by the provision of information prior to the outpatient consultation although exactly how this affects choices may depend on how this information is provided. [14,15]. Women’s treatment choices are also affected by their level of education and employment status [16]. The stage of their reproductive life and severity of their symptoms also seems to be linked to women’s treatment preferences [16]. Treatment options include adopting a conservative wait and see approach, using medical treatments which may be oral or intrauterine, surgical treatments such as endometrial ablation and hysterectomy and radiological treatments such as uterine artery embolization. These will be considered in turn.
K. Duckitt / Maturitas 66 (2010) 251–256 Table 2 Guidelines on when to perform an endometrial biopsy in cases of abnormal uterine bleeding. NICE Guideline on Heavy Menstrual Bleeding (UK 2007)
SOGC Guideline on Abnormal Uterine Bleeding (Canada 2001)
If appropriate, a biopsy should be taken to exclude endometrial cancer or atypical hyperplasia. Indications for a biopsy include, for example, persistent intermenstrual bleeding, and in women aged 45 and over treatment failure or ineffective treatment. Clinicians should perform endometrial sampling based on the methods available to them. An office endometrial biopsy should be obtained if possible in all women presenting with abnormal uterine bleeding, over 40 years of age or weighing more than or equal to 90 kg.
Guidelines for the Management of Heavy Menstrual Bleeding (New Zealand, 1998)
The following women with heavy menstrual bleeding are recommended to have a transvaginal ultrasound of the endometrium Weight ≥90 kg Age ≥45 years old Other risk factors for endometrial hyperplasia or carcinoma such as infertility or nulliparity, family history of colon or endometrial cancer, exposure to unopposed oestrogens If transvaginal ultrasound is not available then an endometrial sample should be taken If the endometrial thickness on TVS is ≥12 mm an endometrial sample should be taken to exclude endometrial hyperplasia
Kaiser Permanente, Southern California (USA 2006)
Women over the age of 40. Women less than forty with risk factors judged sufficient to warrant biopsy. These include features suggestive of chronic anovulation (irregular menses, infertility); and weight greater than 90 kg.
6. Watchful waiting If you could advise each woman with perimenopausal menorrhagia as to the date when she will stop her periods permanently i.e. her age at menopause, many women might choose to adopt a wait and see approach. The mean age of the menopause in women in developed countries is 51.4 ± 0.19 (SE) years with smokers reaching menopause on average 1.74 years earlier but unfortunately there is no good way of predicting the date for each individual women and the range of menopausal age is great [17]. Neither FSH, inhibin B, anti-Mullerian hormone or estradiol levels predict the timing of last menstruation or even differentiate between premenopausal, perimenopausal or postmenopausal status and therefore do not influence treatment [18,19]. 7. Medical treatment Systematic reviews show that non-steroidal anti-inflammatory drugs (NSAIDs), tranexamic acid, danazol and intrauterine progestogens are all effective in reducing the amount of blood lost per cycle [20–23]. However, NSAIDs are not as effective as the other three options although do have the advantage of relieving dysmenorrhoea at the same time. While danazol used to be a popular treatment its use has been limited by its androgenic side effects and concern over its effect on the liver with long term use. The advantages of tranexamic acid, an antifibrinolytic agent, is the fact that it only has to be taken during the days of heavy bleeding, it has relatively few side effects, is not hormonal and can be used even if pregnancy is desired. The most effective dose is 1 g 3 to 4 times daily. It can reduce the amount of blood lost by 50% [24].
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Previous concerns regarding an increased risk of thrombosis with tranexamic acid use have been disproved [25].
8. Combined oral contraceptive pill (COC) Despite the widespread use of the combined oral contraceptive pill for both heavy and or painful periods there is very little in the way of good evidence to support this use. In fact the Cochrane systematic review that aimed to examine the effect of the oral contraceptive pill on HMB could not draw any valid conclusions due to the paucity of the data [26]. However, a prospective cohort study [27], observed higher mean haemoglobin levels in populations of women taking COC compared to those not taking COC which indirectly suggests that menstrual loss is reduced in women taking COCs. Another uncontrolled trial found that objectively measured menstrual blood loss was significantly lower in 20 women after 6 months contraceptive pill use compared to baseline [28]. Taking the COC continuously rather than cyclically is also becoming more acceptable to women with the advent of several COCs designed and marketed to be taken for longer than 21 days and cause prolonged periods of amenorrhoea which is highly desirable for women with heavy periods [29]. However, the COC will not be suitable for all perimenopausal women as the risks outweigh the benefits in smokers over the age of 35 and women with risk factors for cardiovascular disease such as obesity and hypertension [30], although it does protect against endometrial and ovarian cancer.
9. Levonorgestrel-releasing IUS (Mirena) The levonorgestrel-releasing intrauterine system (LNG IUS) is a polyethylene T-shaped frame that secretes 20 g levonorgestrel/24 h from a reservoir on its stem and is inserted like an IUD into the uterus. It is increasingly used to treat women with menorrhagia although was originally developed for contraception. It provides effective contraception comparable to female sterilization. It results in endometrial atrophy and therefore reduced menstrual loss. However, initially it can cause prolonged periods of spotting as the endometrium sheds erratically on its way to becoming thin. Many women become amenorrhoeic with continued use. It has never been compared in an RCT with placebo but it is more effective than cyclical norethisterone, taken for 21 days, as a treatment for heavy menstrual bleeding [23]. Women with an LNG IUS are more satisfied and willing to continue with treatment but experience more side effects, such as intermenstrual bleeding and breast tenderness [23]. The LNG IUS results in a smaller mean reduction in menstrual blood loss than endometrial ablation but there is no evidence of a difference in the rate of satisfaction with treatment [23]. Women with an LNG IUS experience more progestogenic side effects compared to women having transcervical resection of the endometrium (TCRE) for treatment of their heavy menstrual bleeding but there is no evidence of a difference in their perceived quality of life [23]. The LNG IUS treatment costs less than hysterectomy and there is circumstantial evidence that hysterectomy rates decreased in the UK at the time that it started being used commonly as first line treatment for menorrhagia [8]. A RCT which randomised women to either a LNG IUS or hysterectomy found similar high patient satisfaction in both groups even though there was a 42% hysterectomy rate in the LNG IUS group by 5 years [31]. Neither age nor fibroids was predictive of treatment success with the LNG IUS [32] although women with genuine objective menorrhagia were more satisfied with the LNG IUS. Other benefits of the LNG IUS include fewer hot flushes compared with those having had a hysterectomy [33] and the ability to use it as the progestogen component of HRT.
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10. Other progestogens In the anovulatory woman, progestogens help to coordinate regular uterine shedding when given as a late luteal replacement treatment, on days 19–26 of the cycle [34]. However, the regimen, dose and type of progestogen used varies widely, with little consensus about the optimum treatment approach. No randomised trials were identified which compared progestogens with oestrogens and progestogens or with placebo in the management of irregular bleeding associated with anovulation. Only one small, non-randomised study compared two progestogen regimes in the management of heavy and irregular bleeding in women with confirmed anovulation [35]. The use of progestogens as luteal phase supplementation in the ovulatory woman with menorrhagia is even more questionable. Consequently, an increase in the duration and dosage of progestogen therapy has recently been investigated in patients with ovulatory HMB. Prolonged use of high-dose progestogens can be associated with side effects, which include fatigue, mood changes, weight gain, nausea, bloating, oedema, headaches, depression, loss of libido, irregular bleeding and atherogenic changes in the lipid profile. Progestogens administered from day 15 or 19 to day 26 of the cycle offer no advantage over other medical therapies such as danazol, tranexamic acid, nonsteroidal anti-inflammatory drugs (NSAIDs) and the IUS in the treatment of menorrhagia in women with ovulatory cycles [36]. Progestogen therapy for 21 days of the cycle results in a significant reduction in menstrual blood loss, although women found the treatment less acceptable than intrauterine levonorgestrel. This regimen of progestogen may have a role in the short-term treatment of menorrhagia. A more recent RCT compared the efficacy of three progestin regimens in perimenopausal menorrhagia [37]. One hundred thirty-two women with menorrhagia were included. Women were randomised to three groups of 44 in each, either to get a single shot of depot medroxyprogesterone acetate intramuscularly, or medroxyprogesterone acetate in a daily dose of 5 mg orally, or the LNG IUS. Assessment of blood loss, the duration of bleeding and mean haemoglobin level were improved in all groups. There was no statistically significant difference between the results in the depo or oral medroxyprogesterone groups, but the LNG IUS was superior to both other groups. Mean duration of menstruation was similar in all groups. 11. Surgical treatment Dilatation and curettage (D&C) used to be a very common procedure performed for women with menorrhagia. However, it is ineffective in reducing menstrual blood loss in the long term [38] and is only useful when combined with hysteroscopy for evaluation of the intrauterine cavity. 12. Endometrial ablation Endometrial ablation is less invasive than hysterectomy and preserves the uterus, although not fertility. Many women prefer less invasive surgical treatment even when they are made aware that the success of the treatment is not always assured [39]. These techniques were introduced in the mid 1980s with the aim of removing the entire thickness of the endometrium. The endometrium has great powers of regeneration and to suppress menstruation successfully it is necessary to destroy the full thickness of the endometrium together with the superficial myometrium including the deep basal glands as these are believed to be the primary foci for endometrial regrowth. The initial procedures destroyed endometrium under direct hysteroscopic vision either by excision with an electrosurgical loop or by ablating the
endometrium with some form of thermal energy of sufficient power to produce necrosis (cell death) of the full thickness of the endometrium. The original “gold standard techniques” of laser, TCRE and rollerball ablation require direct hysteroscopic visualisation of the uterus and a steep learning curve is required to acquire the requisite skill. Subsequently, a large number of different techniques have been developed to ‘ablate’ or destroy the lining of the endometrium, most of which are quicker to perform and are therefore more amenable to being performed under local anaesthetic or light sedation. However, hysteroscopy may still be required prior to the newer ablative techniques in order to evaluate the intrauterine cavity and make sure the endometrial ablation is appropriate. A Cochrane systematic review [40] found that there was no difference in outcomes in terms of reduction of HMB or patient satisfaction between the older and newer endometrial ablation methods. However, women undergoing newer ablative procedures were less likely to have fluid overload, uterine perforation, cervical lacerations and hematometra than women undergoing the more traditional type of ablation and resection techniques although were more likely to have nausea and vomiting and uterine cramping. Another Cochrane systematic review [41] compared endometrial ablative techniques with hysterectomy. There was a significant advantage in favour of hysterectomy in the improvement in HMB (OR = 0.04, 0.01 to 0.2 at 1 year) and satisfaction rates (up to 4 years post-surgery) (OR = 0.5, 0.3–0.8 at 2 years) compared with endometrial ablation. Duration of surgery, hospital stay and recovery time were all shorter following TCRE or endometrial ablation, although these outcomes varied between trials. Most adverse events, both major and minor, were significantly more likely after hysterectomy and before discharge from hospital. Repeat surgery because of failure of the initial treatment, either endometrial ablation or hysterectomy, was more likely after endometrial ablation than hysterectomy (OR = 16.7, 5.8–48.6). The total cost of endometrial destruction was significantly lower than the cost of hysterectomy but the difference between the two procedures narrowed over time because of the high cost of re-treatment in the endometrial ablation group. The probability of needing a subsequent hysterectomy after an endometrial ablation varies with age at the time of the endometrial ablation. Between 1999 and 2004, 3681 women underwent endometrial ablation at 30 Kaiser Permanente Northern California facilities. Hysterectomy was subsequently performed in 774 women (21%). When women >45 years of age at initial procedure were compared with women <45 years of age, women aged 45 years or younger were 2.1 times more likely to have hysterectomy (95% confidence interval 1.8–2.4). The subsequent hysterectomy rate approached 40% if the woman was <40 at the time of the endometrial ablation [42]. Age was a more important predictor of subsequent hysterectomy than the setting of endometrial ablation or the presence of leiomyomas. This data, however, is reassuring for perimenopausal women who are likely to be over 45 and will encounter menopause before the need for subsequent hysterectomy occurs.
13. Uterine artery embolization (UAE) UAE is the complete occlusion of both the uterine arteries with particulate emboli. It has been reported to be an effective and safe alternative in the treatment of menorrhagia and other fibroid-related symptoms in women not desiring future fertility. A Cochrane systematic review found 3 RCTs comparing UAE with either hysterectomy or myomectomy for fibroids and fibroidrelated symptoms such as menorrhagia [43]. Follow up varied but was not longer than 2 years. Menstrual loss seemed to be reduced by as much as 85% in the UAE groups with a shorter hospital stay and a quicker return to normal activities. However, there was an
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increase in minor complications, unscheduled visits and hospital readmissions in the UAE groups. Further RCTs are in progress. 14. Hysterectomy Hysterectomy has traditionally been regarded as the definitive surgical treatment for heavy menstrual bleeding but, in spite of a 100% success rate due to complete cessation of menstruation and high levels of satisfaction [44], it is a major surgical procedure with significant physical complications and social and economic costs. These include a high rate of major and minor post-operative complications, including, rarely, death and a long recovery time [45,46]. Complications are more likely when the hysterectomy is performed by the open abdominal route, and vaginal hysterectomy should be performed in preference to abdominal hysterectomy where possible [47]. Debate continues over whether subtotal or total hysterectomies are associated with the best outcomes when the hysterectomy is performed abdominally. However, a Cochrane systematic review shows that subtotal hysterectomy does not show any improved outcomes for sexual, urinary or bowel function when compared with total abdominal hysterectomy [48]. Surgery is shorter and intraoperative blood loss and post-operative fever are less likely with subtotal hysterectomy but women are more likely to experience ongoing cyclical bleeding up to a year after surgery with subtotal hysterectomy when compared to total hysterectomy. 15. Conclusion There are now many medical and surgical alternatives to hysterectomy for the treatment of perimenopausal menorrhagia. However, long term follow up continues to be necessary to make sure that the need for hysterectomy is not just being postponed. RCTs need to correlate their outcomes to age at time of treatment so that better advice about treatment efficacy can be given to women depending on their age. Contributor Kirsten Duckitt researched and wrote article. Conflict of interest No competing interests. Provenance Commissioned and externally peer reviewed. References [1] Hallberg L, Högdahl AM, Nilsson L, Rybo G. Menstrual blood loss—a population study. Variation at different ages and attempts to define normality. Acta Obstet Gynecol Scand 1966;45:320–51. [2] Cole S. Menstrual blood loss and haematological indices. J Reprod Fertil 1971;27:158. [3] McCormick A, Fleming D, Charlton J. Morbidity Statistics from General Practice, Fourth National Study 1991–1992. London: HMSO; 1995. [4] National Collaborating Centre for Women’s and Children’s Health. Heavy menstrual bleeding—NICE guideline No. 44. London: RCOG Press; 2007. [5] Coulter A, Bradlow J, Agass M, Martin-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;98:789–96. [6] Bradlow J, Coulter A, Brooks P. Patterns of referral. Oxford Health Services Research Unit; 1992. [7] Working Party of the National Health Committee New Zealand. Guidelines for the management of heavy menstrual bleeding. Wellington: Ministry of Health; 1998. [8] Reid PC, Mukri F. Trends in number of hysterectomies performed in England for menorrhagia: examination of health episode statistics, 1989 to 2002-3. BMJ 2005;330:938–9.
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