Menorrhagia
Menorrhagia - Summary
Menorrhagia is excessive (heavy) menstrual bleeding (periods) over several consecutive cycles that interferes with the woman's physical, emotional, social, and material quality of life.
About one third of women describe their periods as heavy, and 1 in 20 women aged 30–49 years consult their GP each year regarding heavy menstruation.
In 40–60% of women with menorrhagia, no underlying cause is found (dysfunctional uterine bleeding). Underlying causes of menorrhagia include:
Uterine and ovarian pathologies such as uterine fibroids, endometriosis, and pelvic inflammatory disease.
Systemic diseases and disorders such as coagulation disorders, hypothyroidism, and liver or kidney disease.
Iatrogenic causes such as anticoagulant treatment or chemotherapy.
Menorrhagia may negatively affect quality of life by limiting normal activities, social life, and work. Sex-life may also be affected. Iron deficiency anaemia occurs in about two thirds of women with heavy menstrual bleeding.
Menorrhagia is diagnosed when both the woman and the clinician agree that menstrual bleeding is heavy. Blood loss does not need to be measured accurately.
A full blood count should be performed in all women with suspected menorrhagia to rule out iron deficiency anaemia.
Other investigations are not routinely indicated.
Red flag symptoms that suggest an underlying pathology (such as pelvic inflammatory disease, endometriosis, or endometrial cancer) include:
Persistent postcoital bleeding.
Persistent intermenstrual bleeding.
Dyspareunia.
Dysmenorrhoea.
Pelvic pain.
Vaginal discharge.
The levonorgestrel-releasing intrauterine system (LNG-IUS) (Mirena®) is the preferred first-line management. If this is unsuitable tranexamic acid, nonsteroidal anti-inflammatory drugs, or the combined oral contraceptive should be considered.
Referral for screening and pelvic examination may be necessary if:
There are alarm symptoms suggesting a possible malignancy.
Initial treatment has proved ineffective.
The woman wishes to consider surgical treatment.
Iron deficiency anaemia has failed to respond to treatment.
Secondary care options for management include surgery (endometrial ablation, hysterectomy, uterine artery embolization and myomectomy) or drug treatment with gonadotrophin-releasing hormone analogues.
Have I got the right topic?
This CKS topic covers the medical management of menorrhagia (heavy menstrual bleeding).
This CKS topic is based on the clinical guideline Heavy menstrual bleeding, developed by the National Collaborating Centre for Women's and Children's Health and published by the National Institute for Health and Clinical Excellence (NICE) [National Collaborating Centre for Women's and Children's Health, 2007]. Detailed information about contraceptives that are recommended for the treatment of menorrhagia is available in the section on Menorrhagia, fibroids, previous ectopic pregnancy in the CKS topic on Contraception - assessment.
This CKS topic does not cover the management of intermenstrual or irregular bleeding, postcoital bleeding, postmenopausal bleeding, or menopausal symptoms.
There are separate CKS topics on Amenorrhoea, Anaemia - iron deficiency, Dysmenorrhoea, Endometriosis, Infertility, and Menopause; there is also a referral guideline, published by NICE, for Gynaecological cancer - suspected.
The target audience for this CKS topic is healthcare professionals working within the NHS in the UK, and providing first contact or primary health care.
How up-to-date is this topic?
How up-to-date is this topic?
Changes
February 2013 — minor update. The 2013 QIPP options for local implementation have been added to this topic [NICE, 2013].
October 2012 — minor update. The 2012 QIPP options for local implementation have been added to this topic [NPC, 2012].
September 2012 — minor update. Black triangle removed from Qlaira® tablets.
August 2012 — reviewed. A literature search was conducted in July 2012 to identify evidence-based guidelines, UK policy, systematic reviews, and key RCTs published since the last revision of the topic. No changes to clinical recommendations have been made.
Previous changes
May 2011 — information on Qlaira®, a quadraphasic combined oral contraceptive pill, was added to prescribing information. Issued in June 2011.
May 2011 — the 2010/2011 QIPP options for local implementation have been added to this topic [NPC, 2011]. Issued in June 2011.
January 2011 — correction to the dosage and usage instructions for tranexamic acid. Prescription also corrected. Issued in January 2011.
October 2010 — topic structure revised to ensure consistency across CKS topics — no changes to clinical recommendations have been made.
September 2010 — minor update. A prescription for Rigevidon®, another new ethinylestradiol plus levonorgestrel combined oral contraceptive pill, has been added. Issued in September 2010.
June 2010 — minor update. A prescription for Levest®, a new ethinylestradiol plus levonorgestrel combined oral contraceptive pill, has been added. Issued in June 2010.
February 2009 — minor update to the combined oral contraceptive pill prescriptions. The upper age limit for use has been reduced to 50 years. Issued in March 2009.
June to September 2007 — converted from CKS guidance to CKS topic structure. The evidence-base has been reviewed in detail, and recommendations are more clearly justified and transparently linked to the supporting evidence.
The most important change to the recommendations is that the levonorgestrel-releasing intrauterine system is now recommended first-line for most women with heavy menstrual bleeding.
October 2005 — minor technical update. Issued in November 2005.
July 2005 — updated to incorporate the Referral guidelines for suspected cancer published by the National Institute for Health and Clinical Excellence. Issued in July 2005.
February 2005 — updated to include prescribing advice from the Committee on Safety of Medicines on the effect of depot medroxyprogesterone acetate contraception on bones. Issued in February 2005.
May 2004 — reviewed. Validated in September 2004 and issued in November 2004.
March 2002 — updated to incorporate referral advice from the National Institute for Health and Clinical Excellence. Issued in April 2002.
June 2001 — reviewed. Validated in July 2001 and issued in October 2001.
October 1998 — written.
Update
New evidence
Evidence-based guidelines
No new evidence-based guidelines since 1 July 2012.
HTAs (Health Technology Assessments)
No new HTAs since 1 July 2012.
Economic appraisals
No new economic appraisals relevant to England since 1 July 2012.
Systematic reviews and meta-analyses
No new systematic reviews or meta-analyses since 1 July 2012.
Primary evidence
Randomized controlled trials published since the last revision of this topic:
Gupta, J., Kai, J., Middleton, L., et al. (2013) Levonorgestrel intrauterine system versus medical therapy for menorrhagia. New England Journal of Medicine 368(2), 128-137. [Abstract]
New policies
No new national policies or guidelines since 1 July 2012.
New safety alerts
No new safety alerts since 1 July 2012.
Changes in product availability
No changes in product availability since 1 July 2012.
Goals and outcome measures
Goals
To reduce or stop excessive menstrual bleeding
To prevent or correct iron deficiency anaemia due to heavy menstrual bleeding
To refer women who may benefit from surgical treatments
To improve the quality of life of women with heavy menstrual bleeding
Outcome measures
For full audit criteria on Heavy menstrual bleeding published by the National Institute for Health and Clinical Excellence, see www.nice.org.uk [NICE, 2007].
QIPP — Options for local implementation
QIPP — Options for local implementation
Non-steroidal anti-inflammatory drugs (NSAIDs)
Review the appropriateness of NSAID prescribing widely and on a routine basis, especially in people who are at higher risk of both gastrointestinal (GI) and cardiovascular (CV) morbidity and mortality (e.g. older patients).
If initiating an NSAID is obligatory, use ibuprofen (1200 mg per day or less) or naproxen (1000 mg per day or less).
Review patients currently prescribed NSAIDs. If continued use is necessary, consider changing to ibuprofen (1200 mg per day or less) or naproxen (1000 mg per day or less).
Review and, where appropriate, revise prescribing of etoricoxib to ensure it is in line with MHRA advice and the NICE clinical guideline on osteoarthritis [CSM, 2005; NICE, 2008].
Co-prescribe a proton pump inhibitor (PPI) with NSAIDs for people with osteoarthritis, rheumatoid arthritis, or low back pain (for people over 45 years) in accordance with NICE guidance [NICE, 2008; NICE, 2009a; NICE, 2009b].
Take account of drug interactions when co-prescribing NSAIDs with other medicines (see Summaries of Product Characteristics). For example, co-prescribing NSAIDs with ACE inhibitors or angiotensin receptor blockers (ARBs) may pose particular risks to renal function; this combination should be especially carefully considered and regularly monitored if continued.
Background information
Definition
What is it?
Menorrhagia is excessive (heavy) menstrual blood loss over several consecutive cycles which interferes with a woman's physical, emotional, social, and material quality of life. Menorrhagia can occur alone or in combination with other symptoms [Duckitt and Collins, 2006; National Collaborating Centre for Women's and Children's Health, 2007].
For the purposes of this CKS topic, the terms menorrhagia and heavy menstrual bleeding are used interchangeably.
In research, it is usually defined as an objectively measured blood loss of 60–80 mL or more per menstruation (the average blood loss is 30–40 mL, and 90% of women have losses less than 80 mL) [Apgar et al, 2007].
However, objective measurements of menstrual blood loss are not practical in the clinical setting, and they correlate poorly with a woman's subjective assessment of blood loss and its impact on quality of life [Warner et al, 2004; National Collaborating Centre for Women's and Children's Health, 2007].
Prevalence
How common is it?
Studies vary in their reporting of how common heavy menstrual bleeding is:
About one third of women describe their periods as heavy [Lethaby and Farquhar, 2003].
A prospective cohort study of a general practice with 10,000 registered patients found a 25% 12-month cumulative incidence of menorrhagia symptoms in menstruating women [Shapley et al, 2004].
One in 20 women aged 30–49 years consult their GP each year for heavy menstruation [Vessey et al, 1992].
Menstrual disorders are the second most common gynaecological conditions resulting in hospital referral and 12% of all gynaecological referrals [NHS CRD, 1995].
Causes of menorrhagia
What are the causes of menorrhagia?
In 40–60% of women with menorrhagia, no underlying cause is found. These women are said to have dysfunctional uterine bleeding (unexplained menorrhagia) [Hickey et al, 2007].
Causes of menorrhagia include:
Uterine and ovarian pathologies:
Uterine fibroids (dysmenorrhoea, pelvic pain).
Endometriosis and adenomyosis (dysmenorrhoea, dyspareunia, pelvic pain, difficulty conceiving). See the CKS topic on Endometriosis.
Pelvic inflammatory disease and pelvic infection (for example chlamydia — may also present with vaginal discharge, pelvic pain, intermenstrual and postcoital bleeding, and fever). See the CKS topic on Pelvic inflammatory disease.
Endometrial polyps (intermenstrual bleeding).
Endometrial hyperplasia or carcinoma (postcoital bleeding, intermenstrual bleeding, pelvic pain).
Polycystic ovary syndrome (causing anovulatory menorrhagia and irregular bleeding). See the CKS topic on Polycystic ovary syndrome.
Systemic diseases and disorders:
Coagulation disorders (for example von Willebrand disease).
Hypothyroidism (which may also present with fatigue, constipation, intolerance of cold, and hair and skin changes). See the CKS topic on Hypothyroidism.
Liver or renal disease.
Iatrogenic causes:
Anticoagulant treatment.
Chemotherapy.
Intrauterine contraceptive device (blood loss may be increased by 40–50% over 6–12 months compared with pre-insertion values) [RCOG, 1998].
Tubal sterilization (evidence is conflicting) [Wilcox et al, 1992; Gentile et al, 1998; Basgul et al, 2007].
Complications
Heavy menstrual bleeding may negatively affect quality of life by limiting normal activities, social life, and work [National Collaborating Centre for Women's and Children's Health, 2007].
In three qualitative studies, women described mood changes and becoming self-conscious as key concerns.
A woman's sex life may also be negatively affected.
Iron deficiency anaemia occurs in about two thirds of women with heavy menstrual bleeding [Lethaby and Farquhar, 2003; Duckitt and Collins, 2006].
Diagnosis and assessment
Diagnosis and assessment of menorrhagia (heavy menstrual bleeding)
Diagnosis
How should I diagnose menorrhagia?
Menorrhagia is diagnosed when both the woman and clinician agree menstrual bleeding is heavy after a history has been taken.
It is not necessary to measure blood loss to diagnose menorrhagia.
Basis for recommendation
Basis for recommendation
These recommendations are consistent with clinical guidelines on Heavy menstrual bleeding, published by the National Institute for Health and Clinical Excellence [National Collaborating Centre for Women's and Children's Health, 2007].
History
What should I ask about when taking the history?
The history should set out to define the nature of the bleeding; identify potential underlying causes; and address the woman's ideas, concerns, expectations, and needs.
Ask the woman her age at menarche and for details about her menstrual cycle, for example length of cycle, the number of days of menstruation, for how long she has considered her periods to be heavy, what her periods were like previously, and the impact on her quality of life.
Enquire about symptoms that suggest an underlying pathology, particularly 'red flag' symptoms (for example persistent intermenstrual or postcoital bleeding).
Consider the possibility of an underlying systemic disease, such as hypothyroidism or a coagulation disorder (for example von Willebrand disease).
Take a family history, and in particular ask about endometriosis and coagulation disorders that may have a hereditary component.
Check the woman's smear status.
Ask about current contraceptive use, contraceptive plans, and future plans for a family.
It is important to ascertain the woman's need for contraception as this may impact on the choice of treatment. For more information, see Advice and counselling.
Symptoms suggesting an underlying pathology
Symptoms suggesting an underlying pathology
Underlying pathologies that might be found in women with heavy menstrual bleeding include pelvic inflammatory disease, endometriosis, and endometrial carcinoma. For further information, see Causes of menorrhagia.
Symptoms that may indicate an underlying pathology include:
Persistent postcoital bleeding.
Persistent intermenstrual bleeding.
Dyspareunia.
Dysmenorrhoea.
Pelvic pain and/or pressure symptoms.
Vaginal discharge.
Basis for recommendation
Basis for recommendation
These recommendations are consistent with clinical guidelines on Heavy menstrual bleeding, published by the National Institute for Health and Clinical Excellence [National Collaborating Centre for Women's and Children's Health, 2007].
Examination
When and how should I examine the woman?
Consider abdominal and pelvic examination in the following women:
Women with symptoms suggestive of underlying abnormalities, before further investigations are arranged.
Those in whom initial treatment has proved ineffective.
Those for whom the levonorgestrel-releasing intrauterine system is being considered.
A pelvic examination should include:
Vulval examination for evidence of external bleeding and signs of infection (for example vaginal discharge).
Speculum examination of vagina and cervix. High vaginal, endocervical, and chlamydia swabs should be obtained if infection is suspected.
Bimanual palpation to identify uterine or adnexal enlargement or tenderness.
In addition to an abdominal and pelvic examination, look for systemic signs of underlying disease:
Endocrine disease: hirsutism, striae, thyroid enlargement or nodularity, or changes in skin pigmentation.
Coagulation disorders: bruises or petechiae.
If a woman refuses an examination, refer her directly for investigations as appropriate.
If a woman has fibroids that are palpable abdominally, offer immediate referral or sent her for an ultrasound.
Basis for recommendation
Basis for recommendation
These recommendations are consistent with clinical guidelines on Heavy menstrual bleeding, published by the National Institute for Health and Clinical Excellence [National Collaborating Centre for Women's and Children's Health, 2007], and are based on consensus opinion rather than primary evidence.
Investigations
What investigations should I carry out?
Menstrual blood loss does not have to be measured accurately, and objective measurement is impractical.
Take a full blood count in all women to rule out iron deficiency anaemia.
Iron deficiency anaemia is a strong indicator of excessive menstrual bleeding (see the CKS topic on Anaemia - iron deficiency).
Other blood tests and endocrine investigations are not routinely indicated.
Thyroid function tests should only be carried out if the woman has other symptoms or signs suggestive of thyroid disease (for more information on hypothyroidism, see the CKS topic on Hypothyroidism).
Tests for bleeding disorders (for example von Willebrand disease) should be performed if there are suggestive features in the history or on examination. Investigations should be arranged in conjunction with the local haematology department as many of the tests are not routine. Women who may require screening include:
Those who have had heavy menstrual bleeding since menarche, or a history of excessive bleeding after tooth extraction, operations, or childbirth.
Those with a family history of a coagulation disorder.
Consider opportunistic cervical screening, if appropriate, in line with national recommendations.
Consider arranging for a trans-vaginal pelvic ultrasound to identify structural abnormalities, if the woman has symptoms suggesting an underlying cause for heavy menstrual bleeding, or if she:
Has a uterus that is palpable abdominally.
Has a pelvic mass of uncertain origin on vaginal examination (although also consider urgent referral).
Has had treatment that has proved ineffective.
If a suspicious mass is detected, consider urgent referral to a specialist (rather than referral for ultrasound).
Investigations that may be used in secondary care include hysteroscopy and tissue biopsy for endometrial cancer; for further information, see Management in secondary care.
Basis for recommendation
Basis for recommendation
These recommendations are consistent with clinical guidelines on Heavy menstrual bleeding, published by the National Institute for Health and Clinical Excellence [National Collaborating Centre for Women's and Children's Health, 2007].
Although there is evidence from diagnostic studies to support objective measurements to determine menstrual blood loss, this is generally felt to be impractical in most clinical situations and is unlikely to guide clinical management.
Direct objective measurement of menstrual blood loss includes the alkaline haematin technique.
The pictorial blood loss assessment chart is an indirect measure.
Results from epidemiological studies have found that:
Thyroid disease is not associated with menstrual disorders and therefore should not be routinely tested for.
Coagulation disorders, such as von Willebrand disease, are an identifiable risk factor in women who have experienced heavy bleeding since the menarche.
Management
Management
Scenario: Management: covers the primary care management of menorrhagia and criteria for referral to secondary care.
Scenario: Management
Scenario: Management of menorrhagia (heavy menstrual bleeding)
Advice and counselling
What advice and counselling should I give to a woman with menorrhagia?
Discuss the natural variability and range of menstrual blood loss. For some women, reassurance may be all that is required, and treatment may not be needed.
If reassurance alone is not appropriate, discuss the different treatment options for heavy menstrual bleeding, covering issues such as:
Effectiveness of treatments.
Acceptability of treatments, including likelihood of adverse effects.
The need for contraception.
Implications of treatment on fertility.
Give written information such as patient information leaflets, to explain the condition and treatment options, where appropriate.
Patient information covering heavy menstrual bleeding is published by the National Institute for Health and Clinical Excellence (NICE) and can be found at www.nice.org.uk (pdf).
If asked, advise that no specific lifestyle changes benefit menorrhagia.
If the woman and clinician cannot agree on the most appropriate treatment option, she should be offered the option of a second opinion.
Basis for recommendation
Basis for recommendation
These recommendations are based on clinical guidelines on Heavy menstrual bleeding, published by NICE [National Collaborating Centre for Women's and Children's Health, 2007].
NICE could find no evidence from controlled trials or other types of study that showed any benefit of lifestyle changes (for example diet or exercise). Some studies have identified risk factors (for example smoking and obesity), but these are not currently seen as planned interventions, but as general health-promotion issues.
Prescribing drug treatment
When should I prescribe pharmaceutical treatment in women presenting with menorrhagia?
Pharmaceutical treatment is recommended first-line for woman with menorrhagia who:
Have no symptoms suggestive of underlying pathology including postcoital bleeding, intermenstrual bleeding, dyspareunia, dysmenorrhoea, vaginal discharge, and pelvic pain and/or pressure (these symptoms may indicate pelvic inflammatory disease, endometriosis, or endometrial carcinoma). See History.
Are awaiting the results of investigations.
Basis for recommendation
Basis for recommendation
This recommendation is based on clinical guidelines on Heavy menstrual bleeding, published by the National Institute for Health and Clinical Excellence [National Collaborating Centre for Women's and Children's Health, 2007].
Once major structural or histological abnormalities have been excluded, the cause of menorrhagia is likely to be idiopathic with no obvious underlying pathology. In most cases, this will respond to symptomatic treatment.
Which drug treatment to prescribe
Which pharmaceutical treatment should I prescribe in a woman with menorrhagia?
The levonorgestrel-releasing intrauterine system (LNG-IUS) (Mirena®) is the preferred first-choice for the treatment of menorrhagia, provided that long-term contraception with an intrauterine device is acceptable (anticipated minimum use of 12 months).
Tranexamic acid, nonsteroidal anti-inflammatory drugs (NSAIDs), or the combined oral contraceptive pill (COC) should be considered as second choice treatment, if LNG-IUS is unsuitable.
Tranexamic acid and NSAIDs are suitable if contraception is not desired and are first-choice drugs while investigations or definitive treatment is being organized.
If dysmenorrhoea is present, NSAIDs may be preferred, as they provide relief of menstrual pain.
If an NSAID is to be used, mefenamic acid, naproxen, or ibuprofen should be prescribed.
The COC offers more readily reversible contraception than the LNG-IUS. It also has the benefit of regulating cycles and reducing dysmenorrhoea.
Oral norethisterone or long-acting progestogens should be considered as third choice if the other treatments are unsuitable.
Oral norethisterone should be taken during the follicular and luteal phases (days 5 to 26). It is not an effective form of contraception. However, a dose that is effective in decreasing menstrual blood loss is also likely to inhibit ovulation, and so its use is not appropriate in women wishing to conceive.
Depot medroxyprogesterone acetate (Depo-Provera®) is the recommended long-acting progestogen. It is taken as an intramuscular injection once every 12 weeks.
Danazol, gestrinone, and etamsylate are not recommended for the treatment of menorrhagia.
Gonadotropin-releasing hormone analogues (for example leuprorelin or buserelin) are not recommended for use in primary care, but are an option in secondary care. For more information, see Management in secondary care.
For more information on prescribing drugs to treat menorrhagia, see the Prescribing information sections on Levonorgestrel-releasing intrauterine system, Tranexamic acid, Nonsteroidal anti-inflammatory drugs, Combined oral contraceptives, Oral norethisterone, and Long-acting progestogens.
Basis for recommendation
Basis for recommendation
These recommendations are based on clinical guidelines on Heavy menstrual bleeding, published by the National Institute for Health and Clinical Excellence (NICE) [National Collaborating Centre for Women's and Children's Health, 2007].
The order of treatment recommended by NICE is based on the clinical effectiveness and cost-effectiveness of the available pharmaceutical interventions for menorrhagia. For details of the evidence from controlled trials on menorrhagia treatment, see individual sections of Supporting evidence on:
Levonorgestrel-releasing intrauterine system
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Danazol and etamsylate (not recommended)
CKS recommends mefenamic acid, naproxen, and ibuprofen as the NSAIDs of choice because:
They have been shown to be effective in controlled trials.
They are all licensed for dysmenorrhoea. However, only mefenamic acid is specifically licensed for menorrhagia.
Initial treatment ineffective
What should I do if initial drug treatment is ineffective in a woman with menorrhagia?
If initial treatment fails to produce an adequate reduction in menstrual bleeding (and treatment was complied with), consider three options:
Switch to an alternative pharmaceutical treatment. Oral norethisterone or depot medroxyprogesterone are often suitable if initial treatment was ineffective.
Add on an additional drug. Typically, tranexamic acid can be combined with a nonsteroidal anti-inflammatory drug (NSAID), or an NSAID can be combined with the combined oral contraceptive.
Refer to a specialist.
Basis for recommendation
Basis for recommendation
These are pragmatic recommendations by CKS, based on standard clinical practice. They are consistent with the clinical guideline on Heavy menstrual bleeding, published by the National Institute for Health and Clinical Excellence (NICE) [National Collaborating Centre for Women's and Children's Health, 2007].
NICE recommends on the basis of consensus opinion, that 'when a first pharmaceutical treatment has proved ineffective, a second pharmaceutical treatment can be considered rather than immediate referral to surgery'.
NICE does not make any recommendations on combining treatments, nor is there evidence from controlled trials on the effectiveness of combining treatments. Nevertheless, this is often done in practice and anecdotal evidence suggests that it can be beneficial. For further information on which treatments can be combined, see When to combine treatment.
Further treatment options, including referral, are available from specialist management in secondary care.
Rapidly stopping heavy bleeding
How can I rapidly stop heavy bleeding, if necessary?
Consider stopping heavy menstrual bleeding by prescribing oral norethisterone.
Oral norethisterone, 5 mg three times daily for 10 days, usually stops bleeding within one to three days. Inform the woman that a withdrawal bleed will occur two to four days after stopping treatment.
If bleeding is exceptionally heavy ('flooding'), 10 mg three times daily (off-label dose) may provide better results (get informed consent). This should then be tapered down to 5 mg three times daily for about a week once bleeding has stopped.
Basis for recommendation
Basis for recommendation
These recommendations are mainly pragmatic and are based on the British National Formulary [BNF 63, 2012], manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2010], the available medical literature [Rees, 2003], and expert opinion [Rees, Personal Communication, 2007].
There is no strict definition on what constitutes very heavy bleeding. It ranges from prolonged, heavy menstruation to acute periods of exceptionally heavy bleeding that is difficult to control using sanitary products. In these cases, the woman may desire acute treatment to rapidly stop the bleeding.
CKS could not find any controlled trials that investigated the use of drugs to stop acute and exceptionally heavy menstrual bleeding, but oral progestogens are usually used for this purpose.
The licensed dose of norethisterone to arrest dysfunctional uterine bleeding is 10–15 mg per day [ABPI Medicines Compendium, 2010; BNF 63, 2012]. This should be adequate in most cases; if the higher dose regimen of oral norethisterone (i.e. 30 mg per day, off-label) is considered necessary, informed consent should be sought before starting treatment.
When to refer
When should I refer?
Refer the woman to a specialist if:
There are alarm symptoms suggesting a possible malignancy. Urgent referral is required (within 2 weeks).
Heavy bleeding persists that negatively affects the woman's quality of life, despite adequate trials of pharmaceutical treatment. A routine referral should be made according to local protocols.
The woman wishes to consider surgery rather than persist with medical treatment. A routine referral should be made according to local protocols.
The woman has iron deficiency anaemia that has failed to respond to treatment, and other causes have been excluded. The timing of referral should reflect clinical judgement.
Alarm symptoms
Alarm symptoms
Alarm symptoms or signs suggestive of gynaecological cancer include:
Persistent intermenstrual or postcoital bleeding.
An unexplained vulval lump or vulval bleeding due to ulceration.
A palpable abdominal mass that is not obviously uterine fibroids.
If there are clinical features of cervical cancer, an urgent referral (within 2 weeks) should be made without the need for a smear test, and regardless of previous smear results.
For further information on when to refer to a specialist when a gynaecological cancer is suspected, see the CKS topic on Gynaecological cancer - suspected.
Basis for recommendation
Basis for recommendation
These referral recommendations are based on Referral Advice: A guide to appropriate referral from general to specialist services [NICE, 2001] and Referral guidelines for suspected cancer: quick reference guide [NICE, 2005a], both published by the National Institute for Health and Clinical Excellence.
Specialist services are in a position to:
Confirm, establish, or exclude a diagnosis. Investigations in secondary care include endometrial biopsy, hysteroscopy, and/or pelvic ultrasound.
Advise women on, and oversee where necessary, drug management.
Discuss and undertake surgical operations, such as endometrial ablation and hysterectomy.
For more information on treatments that may be undertaken in secondary care, see Management in secondary care.
Secondary care
What management is available in secondary care?
Secondary care investigations
What investigations can be carried out in secondary care?
An endometrial biopsy for histological examination should be taken to exclude endometrial cancer or atypical hyperplasia, if appropriate, for example in women:
With persistent intermenstrual bleeding.
Aged 45 years and over.
Whose treatment has failed or is ineffective.
Hysteroscopy allows direct visualisation of the uterine cavity and the opportunity to take an endometrial biopsy. It is used as a diagnostic tool when ultrasound results are inconclusive, to determine the exact location of a fibroid or the exact nature of an abnormality.
Dilatation and curettage (D and C) is no longer recommended as a diagnostic tool for heavy menstrual bleeding.
[National Collaborating Centre for Women's and Children's Health, 2007]
Secondary care drug treatments
What drug treatments are available in secondary care?
CKS recommends that therapy with gonadotrophin-releasing hormone (GnRH) analogues (for example leuprorelin and buserelin) should not be initiated in primary care.
They produce a profound hypogonadal effect through downregulation, resulting in no ovulation and no menses.
They may be used under specialist supervision before surgery or when all other treatment options for uterine fibroids, including surgery or uterine artery embolization, are contraindicated. They may also be used to produce temporary endometrial thinning and relief of bleeding before fibroid surgery.
GnRH analogues are effective at treating menorrhagia. Evidence from two randomized controlled trials has shown that:
They are effective at reducing menstrual blood loss (RR 1.39, 95% CI 1.12 to 1.72).
They cause amenorrhoea in most women (89%).
GnRH analogues can cause significant adverse effects that often limit their use. These are principally perimenopausal in nature, including hot flushes, increased sweating, and vaginal dryness (due to oestrogen deficiency).
GnRH analogues are given by subcutaneous or intramuscular injection, or intranasally, and they are usually used for less than 6 months. If treatment with these drugs is required for more than 6 months or if adverse affects are experienced, 'add-back' treatment with supplemental oestrogens and progestogens is recommended.
[National Collaborating Centre for Women's and Children's Health, 2007]
Secondary care surgical treatments
What surgical treatments are available in secondary care?
Surgical treatments are almost always used as second-line options in the treatment of menorrhagia, despite the long-term effectiveness (and irreversible nature) of surgery. A systematic review found that surgery improved control of bleeding compared with pharmaceutical treatments after 5 years (OR 1.99, 95% CI 0.84 to 4.73). However, this does not take into account the reversibility of pharmaceutical treatments and other risks with surgery.
Surgery should be reserved for:
Use on the woman's request (following full counselling on the advantages and disadvantages).
Difficult-to-treat cases where pharmaceutical treatment has failed to be sufficiently effective or is contraindicated.
[National Collaborating Centre for Women's and Children's Health, 2007]
Endometrial ablation
Endometrial ablation involves destroying the endometrium (lining) and the superficial myometrium (muscle) of the uterus. The process also prevents the woman from having children in the future. The technique was first developed in the mid-1990s, and has since evolved.
First generation techniques consisted of transcervical resection with an electrosurgical loop to destroy tissue or the use of a heated rollerball. These require highly-trained surgeons and are now recommended only where hysteroscopic myomectomy is needed.
Second generation techniques were developed to be simpler to use, and are now recommended as standard. These include methods using thermal balloons, microwaves, radiowaves, and cryotherapy.
There is good evidence from controlled trials that endometrial ablation techniques lead to clinically significant improvements in menstrual blood loss as well as improvements in quality of life. Endometrial ablation is generally preferred to hysterectomy in most women, as it is a less drastic option. It is recommended by the National Institute for Health and Clinical Excellence, provided:
Bleeding is having a severe negative impact on the woman's quality of life.
Pharmaceutical treatment has been tried but was ineffective, or was not suitable, and a surgical solution is appropriate.
The woman does not want to conceive in the future (although contraception may still be needed).
The uterus is normal or has fibroids less than 3 cm in diameter, or is no bigger than a 10 week pregnancy.
[National Collaborating Centre for Women's and Children's Health, 2007]
Hysterectomy
Hysterectomy is the surgical removal of the uterus and may also involve removal of the cervix, fallopian tubes, and/or ovaries (oophorectomy). It is a major surgical procedure with a risk of serious complications. It requires weeks of physical recovery post-operatively and may have psychological complications.
Hysterectomy was considered the only viable surgical treatment until the mid-1990s; however, since then, other effective techniques have become available. This is reflected in the numbers of hysterectomies performed in the UK: 24,355 in 1993 compared with 10,559 in 2002 (most of this reduction will have been due to alternative surgical treatments and improved pharmaceutical treatments for menorrhagia).
In general, other less invasive techniques are preferred to hysterectomy for the surgical treatment of menorrhagia, as it is beneficial for most women to retain their uterus. The National Institute for Health and Clinical Excellence recommends that, after a thorough discussion with the woman about the benefits and disadvantages of hysterectomy, it should be considered when:
The woman requests it.
Other treatment options have failed, are contraindicated, or are declined by the woman.
There is a wish for amenorrhoea, and the woman no longer wishes to retain her uterus or fertility.
Removal of the ovaries (oophorectomy) at the same time as hysterectomy is not recommended unless:
There is a family history of breast or ovarian cancer (refer for genetic counselling first).
There are symptoms related to ovarian dysfunction such as premenstrual syndrome (a trial of pharmaceutical ovarian suppression should be used first).
The woman expressly requests it (after appropriate counselling).
[National Collaborating Centre for Women's and Children's Health, 2007]
Uterine artery embolization/myomectomy
Uterine artery embolization and myomectomy
Uterine artery embolization and myomectomy are both techniques primarily aimed at reducing the size of, or removing, uterine fibroids, but both have benefits in reducing menstrual blood loss. Previously, hysterectomy was seen as the only viable surgical option for these women.
Uterine artery embolization involves blocking the uterine arteries by injection of particles from a catheter inserted into the femoral artery, causing fibroids to shrink.
Myomectomy is the surgical removal of fibroids through laparotomy, laparoscopically, or hysteroscopically. Its main disadvantage is that uterine fibroids can grow back, requiring further surgery.
The National Institute for Health and Clinical Excellence recommends that [National Collaborating Centre for Women's and Children's Health, 2007]:
Uterine artery embolization, myomectomy, or hysterectomy, should be considered when the woman has large fibroids and heavy menstrual bleeding with other accompanying symptoms, such as dysmenorrhoea or pressure symptoms; or the woman has large fibroids that are causing bleeding that is having a severe impact on the woman's quality of life.
Myomectomy should be considered for women who want to retain their uterus.
Uterine artery embolization is recommended for women who want to retain their uterus and avoid invasive surgery.
Important aspects of prescribing information relevant to primary healthcare are covered in this section specifically for the drugs recommended in this CKS topic. For further information on contraindications, cautions, drug interactions, and adverse effects, see the electronic Medicines Compendium (eMC) (http://medicines.org.uk/emc), or the British National Formulary (BNF) (www.bnf.org).
Primary care treatments for menorrhagia
Summary of primary care treatments for menorrhagia
Table 1 shows the characteristics of pharmacological interventions used to treat menorrhagia in primary care.
Table 1. Drug treatments for menorrhagia in primary care.| Treatment | Regimen, duration | When to consider?* | Contraceptive? | Comment |
|---|---|---|---|---|
| Levonorgestrel-releasing intrauterine system | Intrauterine device, used for a minimum of 6 months and replaced after 5 years | Preferred choice | Yes | Requires fitting by a qualified practitionerThe most effective pharmacological treatment for reducing blood loss available in primary care |
| Tranexamic acid | Tablet taken for 3–4 days after start of bleeding | Second choice† | No | Effective at reducing bleedingCan be combined with an NSAID |
| Nonsteroidal anti-inflammatory drugs | Tablet taken for duration of bleeding (or started just before) | Second choice† | No | Reduces blood loss and menstrual painMefenamic acid, naproxen, or ibuprofen are recommended |
| Combined oral contraceptive | Regular tablet taken throughout cycle (except during the pill-free interval) | Second choice | Yes | Reduces blood loss, regulates cycles, and reduces dysmenorrhoeaNumerous other advantages and disadvantages |
| Oral norethisterone (high dose) | Tablet taken from days 5–26 of the cycle | Third choice‡ | No | Unpleasant adverse effects, may not be tolerated by some women |
| Depot medroxyprogesterone acetate | Intramuscular injection; lasts 12 weeks | Third choice | Yes | Likely to cause amenorrhoea |
Levonorgestrel-releasing intrauterine system
For more information on the use of the levonorgestrel-releasing intrauterine system, see Scenario: Intrauterine system in the CKS topic on Contraception - IUS/IUD. This gives comprehensive information on the device, based on guidelines published by the National Institute for Health and Clinical Excellence [National Collaborating Centre for Women's and Children's Health, 2005], and the Faculty of Sexual and Reproductive Healthcare (FSRH), formerly the Faculty of Family Planning and Reproductive Healthcare (FFPRHC) [FFPRHC, 2004].
Who it is suitable for
Which women with menorrhagia is the levonorgestrel-releasing intrauterine system suitable for?
The levonorgestrel-releasing intrauterine system is regarded as the first-choice treatment for menorrhagia.
It is a long-acting treatment, and the woman should be advised that it is intended for use for a minimum of 12 months.
Basis for recommendation
This information is taken from the clinical guideline on Heavy menstrual bleeding, published by NICE [National Collaborating Centre for Women's and Children's Health, 2007].
How it is used
How is the levonorgestrel-releasing intrauterine system used in women with menorrhagia?
The levonorgestrel-releasing system (LNG-IUS) is marketed as Mirena® in the UK and provides contraception as well as being an effective treatment for menorrhagia.
The LNG-IUS should only be fitted by a suitably qualified practitioner after a full history and physical examination has been undertaken, to ascertain any contraindications that may make it unsuitable. If the expertise is not available to fit the LNG-IUS, the woman should be referred to a family planning clinic for treatment.
The woman should be fully informed about the disadvantages as well as the benefits of the device. Consent (preferably written) should be obtained from the woman before fitting the device.
Mirena® is effective for 5 years, after which time it should be removed or replaced.
Basis for recommendation
This information is taken from the clinical guidelines The levonorgestrel–releasing intrauterine system in contraceptive and reproductive health and Intrauterine contraception issued by the Faculty of Sexual and Reproductive Healthcare, formerly the Faculty of Family Planning and Reproductive Healthcare (FFPRHC) [FFPRHC, 2004; FSRH, 2007], and the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2012a].
Adverse effects
What are the adverse effects of the levonorgestrel-releasing intrauterine system?
The main initial adverse effect of the levonorgestrel-releasing intrauterine system (IUS) is a change in bleeding pattern, which may become irregular or heavy at first. Women should be advised to persevere with treatment for a minimum of six cycles, as the benefit of treatment may not be seen until this point.
Progestogenic adverse effects, such as breast tenderness and mood changes, are not usually marked with the levonorgestrel-releasing IUS, because only small amounts of hormone are released directly to their target of action (i.e. cervical mucous and endometrium). Functional ovarian cysts have occasionally been reported and normally resolve once treatment is stopped (ultrasound monitoring is recommended).
Other adverse effects reported include abdominal pain, peripheral oedema, pelvic pain, back pain, and, rarely, hirsutism or hair loss, migraine, rash, or itching.
Basis for recommendation
This information is taken from the clinical guideline on Heavy menstrual bleeding, published by NICE [National Collaborating Centre for Women's and Children's Health, 2007] and the British National Formulary [BNF 63, 2012].
Tranexamic acid
Who it is suitable for
Which women is tranexamic acid suitable for?
Tranexamic acid is suitable for women who:
Do not want hormonal treatment (i.e. contraception), long-acting treatment, or invasive treatment.
Do not have significant dysmenorrhoea.
Are awaiting investigation or definitive treatment.
Women should be advised that tranexamic acid is a symptomatic treatment — it will reduce blood loss but will not affect the underlying cause or directly benefit other symptoms, such as menstrual pain.
Tranexamic acid is not suitable for the following groups of women [ABPI Medicines Compendium, 2011]:
Women with:
A history of (or active) thromboembolic disease.
Severe renal impairment (risk of accumulation).
History of convulsions.
Fibrinolytic conditions following consumption coagulopathy.
Women taking medication that can affect blood clotting (including the combined oral contraceptive).
[National Collaborating Centre for Women's and Children's Health, 2007]
How to prescribe
How should I prescribe tranexamic acid?
Treatment with tranexamic acid should only be started once heavy bleeding has started, whereupon two 500 mg tablets should be taken three times a day, for up to 4 days. For very heavy menstrual bleeding, dose may be increased to a maximum of 4 g (8 tablets) daily [ABPI Medicines Compendium, 2011].
The dose of tranexamic acid should be reduced in moderate renal insufficiency, and it should be avoided in more severe disease. For more information, consult the Summary of Product Characteristics.
Tranexamic acid can be used for an indefinite number of cycles as long as it is relieving heavy blood loss. However, if it is found to be ineffective, treatment should be stopped after 3 months.
[National Collaborating Centre for Women's and Children's Health, 2007].
Adverse effects
What are the adverse effects of tranexamic acid?
Tranexamic acid is generally well tolerated, and adverse effects do not usually interfere with compliance, as the drug is taken only for a short duration each month.
Gastrointestinal effects, such as indigestion and diarrhoea, and headache are most common but affect less than 1% of women.
Visual disturbances or thromboembolic events are very rare and require immediate cessation of treatment.
Basis for recommendation
This information is taken from the clinical guideline on Heavy menstrual bleeding, published by NICE [National Collaborating Centre for Women's and Children's Health, 2007] and the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2011].
Nonsteroidal anti-inflammatory drugs
A full discussion of the contraindications, adverse effects, monitoring issues, and interactions of nonsteroidal anti-inflammatory drugs (NSAIDs) is beyond the scope of this guidance. However, a summary of these are given in the following sections. For further information on prescribing mefenamic acid, naproxen or ibuprofen, see the CKS topic on NSAIDs - prescribing issues.
Who it is suitable for
Which women are nonsteroidal anti-inflammatory drugs suitable for?
Nonsteroidal anti-inflammatory drugs (NSAIDs) are suitable for women who:
Do not want hormonal treatment (i.e. contraception), long-acting treatment, or invasive treatment.
Are awaiting investigation or definitive treatment.
Have dysmenorrhoea.
Women should be advised that NSAIDs are a symptomatic treatment — they will reduce blood loss and menstrual pain (dysmenorrhea) but will not affect the underlying cause.
NSAIDs should be avoided or carefully monitored in women who:
Have previously experienced bronchospasm, urticaria, angioedema, rhinitis, or a severe skin reaction with aspirin or an NSAID.
Have a history of peptic ulceration or gastrointestinal bleeding, or are at risk of these conditions.
Have asthma, hypertension, renal impairment, or heart failure.
Are receiving low-dose aspirin.
Are pregnant.
Basis for recommendation
This information is taken from the clinical guideline on Heavy menstrual bleeding, published by NICE [National Collaborating Centre for Women's and Children's Health, 2007] and the British National Formulary [BNF 63, 2012].
Choice of regimen
Which regimen of nonsteroidal anti-inflammatory drugs should I prescribe?
Mefenamic acid, naproxen, and ibuprofen are the recommended nonsteroidal anti-inflammatory drugs (NSAIDs) because:
They have been shown to be effective in controlled trials.
They are all licensed for dysmenorrhoea. However, only mefenamic acid is specifically licensed for menorrhagia.
Advise the woman to start the NSAID on the first day of bleeding and to continue until bleeding stops or reduces to satisfactory levels. The following doses are recommended:
Mefenamic acid — 500 mg three times daily.
Naproxen — 500 mg as the first dose, then 250 mg every 6–8 hours.
Ibuprofen — 400 mg three or four daily.
NSAIDs can be used for an indefinite number of cycles as long as they are relieving heavy blood loss and not causing significant adverse effects. If they are found to be ineffective, treatment should be stopped after 3 months.
Basis for recommendation
The information on doses of NSAIDs is taken from the British National Formulary [BNF 63, 2012].
The recommendation that NSAIDs can be used indefinitely if effective, but stopped after 3 months if ineffective, is based on the clinical guideline on Heavy menstrual bleeding, published by NICE [National Collaborating Centre for Women's and Children's Health, 2007].
Adverse effects
What are the adverse effects of nonsteroidal anti-inflammatory drugs?
Generally speaking, the risk of severe adverse effects (gastrointestinal or cardiovascular) from nonsteroidal anti-inflammatory drugs (NSAIDs) are reduced in people younger than 65 years of age who are taking NSAIDs for short periods. Women receiving NSAIDs to reduce the symptoms of menorrhagia on a monthly basis are unlikely to experience severe or life-threatening adverse effects.
The lowest dose and duration of NSAID therapy that adequately controls symptoms should be used.
The most common adverse effects are indigestion or diarrhoea, which are rarely a cause for concern. Peptic ulceration is a rarer but more severe adverse effect. Women should be advised to stop medication and seek advice if symptoms suggestive of a serious condition develop (for example severe gastric discomfort or blood in stools).
Basis for recommendation
This information is taken from the clinical guideline on Heavy menstrual bleeding, published by NICE [National Collaborating Centre for Women's and Children's Health, 2007] and Reminder: gastrointestinal toxicity and NSAIDs, published by the Medicines and Healthcare products Regulatory Agency (MHRA), formerly the Committee on Safety of Medicines [CSM, 2003].
Combined oral contraceptives
For more information on prescribing the combined oral contraceptive pill (COC), including details on the advantages and disadvantages of the COC, and contraindications and adverse effects, see the Scenario: Combined oral contraceptive pill in the CKS topic on Contraception - combined hormonal methods. This gives comprehensive information on the COC, based on guidelines published by the National Institute for Health and Clinical Excellence [National Collaborating Centre for Women's and Children's Health, 2005], and the Faculty of Sexual and Reproductive Healthcare [FSRH, 2011].
Who it is suitable for
Which women is the combined oral contraceptive suitable for?
The combined oral contraceptive (COC) is suitable for women who:
Do not want to conceive, but do not desire long-term or invasive treatment.
Desire improved cycle control.
Have dysmenorrhoea but do not want to, or cannot, take nonsteroidal anti-inflammatory drugs.
Advise the woman that the COC has many benefits but also has some risks and disadvantages.
See the section on advantages, disadvantages, and risks in the CKS topic on Contraception - combined hormonal methods for detailed information on the advantages, disadvantages, and risks of combined oral contraceptives.
Basis for recommendation
This information is taken from the clinical guideline on Heavy menstrual bleeding, published by NICE [National Collaborating Centre for Women's and Children's Health, 2007].
Prescribing choice
Which combined oral contraceptive pill should I prescribe?
A monophasic combined oral contraceptive (COC) with 30-35 micrograms ethinylestradiol combined with norethisterone or levonorgestrel is recommended for women with menorrhagia [FSRH, 2011].
Norethisterone- and levonorgestrel-containing COCs may have a lower relative risk of thromboembolism than those containing desogestrel or gestodene, although the absolute risk is very small for all COCs (especially in younger women who do not smoke).
There is no evidence from controlled trials about the effectiveness of COCs containing less ethinylestradiol (i.e. 20 micrograms) [National Collaborating Centre for Women's and Children's Health, 2007]. However, although contraceptive efficacy is similar with both doses, breakthrough bleeding is more common with the lower dose.
There is no evidence to support the use of biphasic or triphasic over monophasic preparations.
Qlaira® is a quadraphasic combined oral contraceptive pill licensed for the treatment of heavy menstrual bleeding in women without organic pathology who desire oral contraception [ABPI Medicines Compendium, 2012b]. CKS found no studies comparing its efficacy with other combined oral contraceptives.
How to prescribe
How should I prescribe the combined oral contraceptive pill?
Before prescribing the combined oral contraceptive (COC), blood pressure and body mass index should be measured, and a full history should be taken, encompassing [FFPRHC, 2007]:
General information on previous and existing medical conditions, and relevant family history.
Specific questions about migraine, hyperlipidaemia, blood clotting disorders, hypertension, and smoking status.
Concomitant drug use, including non-prescription and herbal remedies.
Note: CKS does not recommend the use of the COC in girls aged less than 13 years, even if it is not being used as a contraceptive (see the section on Scenario: Prescribing to young people in the CKS topic on Contraception - assessment). In practice, heavy menstrual bleeding is rare in this age group. If there is insufficient response to tranexamic acid or nonsteroidal anti-inflammatory drugs, seek specialist advice.
Oral norethisterone
Who it is suitable for
Which women is oral norethisterone suitable for?
Oral norethisterone is regarded as a third-choice treatment by the National Institute for Health and Clinical Excellence. It is suitable for women in whom:
Other treatments (i.e. the levonorgestrel-releasing intrauterine system, tranexamic acid, nonsteroidal anti-inflammatory drugs, or combined oral contraceptives) are unsuitable or not wanted.
Other treatments have been tried but are ineffective.
Advise the woman that the use of oral norethisterone to treat menorrhagia is not an effective method of contraception.
Oral norethisterone can also quickly arrest severe acute menstrual bleeding ('flooding').
Oral norethisterone should be used with caution in women who have conditions that will worsen with fluid retention, including epilepsy, hypertension, migraine, and asthma. It should not be used in women with [ABPI Medicines Compendium, 2010; BNF 63, 2012]:
A history of, or predisposition to, thromboembolism.
Liver cancer.
Genital or breast cancer (unless progestogens are being used in the management of these conditions).
Severe arterial disease.
Undiagnosed vaginal bleeding.
Acute porphyria.
A history during pregnancy of idiopathic jaundice, severe pruritus, or pemphigoid gestationis.
[National Collaborating Centre for Women's and Children's Health, 2007]
How to prescribe
How should I prescribe oral norethisterone?
Prescribe a relatively high dose of oral norethisterone (5 mg three times daily) from days 5–26 of the menstrual cycle (the follicular and luteal phases). This is not a licensed regimen and requires informed consent.
The licensed regimen of oral norethisterone, used only during the luteal phase (days 19–26) [ABPI Medicines Compendium, 2010], is no longer recommended and should be avoided, as it is ineffective.
An extended trial of treatment with norethisterone is recommended, although there is no information on the ideal duration of the course (but probably lasting several months).
Higher doses are recommended if the woman has severe acute menstrual bleeding that requires immediate arresting; for more information, see Rapidly stopping heavy bleeding.
[National Collaborating Centre for Women's and Children's Health, 2007]
Adverse effects
What are the adverse effects of oral norethisterone?
The most common adverse effects of oral norethisterone (affecting more than 1% of women) are weight gain, bloating, breast tenderness, headaches, and acne. These are usually transient and mild, but they are unpleasant enough to be an important factor when choosing treatment.
Depression is a rare adverse effect (affecting fewer than 1 in 10,000 women).
[National Collaborating Centre for Women's and Children's Health, 2007].
Long-acting progestogens
For more information on prescribing long-acting progestogens, see the section on Progestogen–only injectable in the CKS topic on Contraception - progestogen-only methods. This gives comprehensive information based on guidelines published by the National Institute for Health and Clinical Excellence [National Collaborating Centre for Women's and Children's Health, 2005] and the Faculty of Sexual and Reproductive Healthcare (FSRH), formerly the Faculty of Family Planning and Reproductive Healthcare (FFPRHC) [FSRH, 2009].
Who it is suitable for
Which women is a long-acting progestogen suitable for?
A long-acting progestogen is regarded as a third-choice treatment by the National Institute for Health and Clinical Excellence. It is suitable for women in whom:
Treatment with other drugs (i.e. the levonorgestrel-releasing intrauterine system, tranexamic acid, nonsteroidal anti-inflammatory drugs, or combined oral contraceptives) is unsuitable or not wanted.
Other treatments have been tried but are ineffective.
Long-term contraception is desired, with the possibility of amenorrhoea.
Prescribing choice
Which long-acting progestogen should I prescribe?
Medroxyprogesterone acetate (Depo-Provera®) is the recommended long-acting progestogen. It is given as an intramuscular injection and provides treatment of menorrhagia and contraception for 12 weeks:
No long-acting progestogens are licensed for the treatment of menorrhagia, and informed consent should be sought before proceeding with treatment.
Two other options are available, but they have not been specifically recommended by the National Institute for Health and Clinical Excellence:
A depot injection of 200 mg norethisterone enantate (Noristerat®) provides 8 weeks of contraceptive cover.
A subdermal implant of etonogestrel (Implanon®) provides up to 3 years of contraceptive cover.
[National Collaborating Centre for Women's and Children's Health, 2007]
How to prescribe
How should I prescribe depot medroxyprogesterone acetate?
Before administering depot medroxyprogesterone acetate (Depo-Provera®), take a full history to exclude pregnancy and comorbid conditions which preclude use of the drug. The woman should be fully informed about the advantages and disadvantages of treatment.
Other than being effective at reducing menorrhagia, long-acting progestogens are also very effective contraceptives which are usually well tolerated.
A major disadvantage is that it may take up to 1 year for fertility to return after stopping treatment. In addition, not all women desire amenorrhoea.
Other possible adverse effects include weight gain, erratic menstrual bleeding for the first few months, and bone thinning.
[National Collaborating Centre for Women's and Children's Health, 2007]
When to combine treatment
When should treatment be combined in women with menorrhagia?
Treatment can be combined when initiating pharmaceutical therapy, or an additional drug can be added to the initial treatment if improvement in symptoms is not satisfactory.
Tranexamic can be combined with a nonsteroidal anti-inflammatory drug (NSAID) if menstrual bleeding and dysmenorrhoea are problematic.
An NSAID may be used with a combined oral contraceptive (COC), especially if dysmenorrhoea is problematic.
Do not combine tranexamic acid with the COC or the levonorgestrel intrauterine system (LNG-IUS).
There are no recommendations on whether an NSAID may be combined with the LNG-IUS, although in practice this is probably acceptable.
If combined medication is being considered because bleeding or pain is very severe, reconsider the cause, and consider referral.
Basis for recommendation
These are pragmatic recommendations from CKS, and are based on standard practice in response to common clinical situations, taking into account documented contraindications and drug interactions. They are consistent with the clinical guideline Heavy menstrual bleeding published by the National Institute for Health and Clinical Excellence [National Collaborating Centre for Women's and Children's Health, 2007].
CKS could find no guidelines, reviews, or controlled trials on the safety or effectiveness of combining drugs to treat menorrhagia.
Tranexamic acid is at least as effective as NSAIDs at reducing blood loss, but does not relieve menstrual pain. Therefore, a practical approach is to combine both treatments when bleeding is substantial and the woman has dysmenorrhea.
CKS did not find any evidence that these drugs interact.
Tranexamic acid is limited to a (maximum) four-day regimen. Therefore it is practical to use an NSAID if additional coverage is needed.
Some clinicians will start with an NSAID and only add in tranexamic acid if bleeding remains problematic.
Tranexamic acid should not be combined with the COC, as theoretically there is an increased risk of thrombosis, although this has not been reported in practice [ABPI Medicines Compendium, 2011].
There is no advice on what additional treatment may be used in conjunction with the LNG-IUS.
It is important to monitor the effectiveness of the LNG-IUS, especially during the first 6 months. There is a risk that tranexamic acid or an NSAID could mask a poor response to treatment with LNG-IUS.
In practice, many women will use an NSAID for associated dysmenorrhoea, especially ibuprofen, which is available over-the-counter.
Evidence
Evidence
Supporting evidence
Comparison of drugs that reduce blood loss
Comparative efficacy of drugs in primary care at reducing blood loss
Table 1 shows the relative effectiveness of pharmacological treatments in reducing menstrual blood loss.
Table 1. Summary of evidence base for pharmacological interventions in menorrhagia.| Treatment | Reduction in blood loss (%) | Source of evidence | Additional comment |
|---|---|---|---|
| Levonorgestrel-releasing intrauterine system | 71–90 | Several high-quailty RCTs | Compared favourably with other treatments in head-to-head trials in terms of effectiveness and patient satisfaction |
| Tranexamic acid | 29–58 | Several high-quality RCTs | No long-term outcomes have been reported |
| Nonsteroidal anti-inflammatory drugs | 20–49 | Several high-quality RCTs | Mefenamic acid most effective, ibuprofen significantly less effectiveAlso effective treatment for menstrual pain |
| Combined oral contraceptive | 43 | One small RCT (n = 45) | Other benefits including regulation of cycles and reduction in breast pain |
| High-dose oral progestogen* | 83 | One small RCT (n = 44) | Not as effective or preferred as the levonorgestrel-releasing intrauterine systemRequires long-term use |
| Long-acting progestogen | 22–47† | No direct evidence from RCTs | Data extrapolated from large trials of women requiring long-term contraception |
| Danazol | About 50 | Several high-quality RCTs | Use limited by frequent, clinically significant adverse effects |
| Etamsylate | About 13 | Several high-quality RCTs | Least effective treatment for menorrhagia |
Drugs to treat menorrhagia
Evidence on individual drugs to treat menorrhagia
The supporting evidence in this section is based mainly on the evidence reviews and statements from the clinical guidelines on Heavy menstrual bleeding, published by the National Institute for Health and Clinical Excellence [National Collaborating Centre for Women's and Children's Health, 2007]. For details of the primary studies and systematic reviews that NICE used to make their recommendations and a full bibliography, see their full guideline at www.nice.org.uk.
Subsequent to the publication of the NICE clinical guidelines on Heavy menstrual bleeding, CKS identified other studies conducted on drugs to treat menorrhagia. These studies have been incorporated into the relevant evidence sections.
Levonorgestrel-releasing intrauterine system
Evidence on the levonorgestrel-releasing intrauterine system
The LNG-IUS has local and systemic hormonal effects, and inhibits endometrial proliferation, thickens the cervical mucous, and, in a small proportion of women, inhibits ovulation.
The system is most useful in women seeking contraception over longer time frames (it is licensed for 5 years).
The LNG-IUS has been shown to be effective by several randomized controlled trials (RCTs) and by uncontrolled case series. The National Institute for Health and Clinical Excellence identified two systematic reviews and a subsequent RCT.
One systematic review combined RCTs in a meta-analysis and found LNG-IUS compared favourably to other forms of pharmaceutical interventions.
Amenorrhoea was greater after 3 months (OR 8.67, 95% CI 1.52 to 49.35) compared with all other treatments.
The proportion of woman unwilling to continue treatment was lower (OR 0.27, 95% CI 0.10 to 0.67) compared with all other treatments.
One systematic review and a subsequent RCT did not combine data in a meta-analysis, but reported reductions in mean blood loss by LNG-IUS ranging from 71–96% in various RCTs.
For a comparison with other pharmacological treatments, see Drugs in reducing blood loss.
Subsequent to NICE, CKS identified three systematic reviews and one RCT on the use of the LNG-IUS for treating heavy menstrual bleeding.
One systematic review analyzed the available literature for economic and health-related quality of life outcome data associated with the use of the LNG-IUS in the management of heavy menstrual bleeding. The authors reported that treating heavy menstrual bleeding with the LNG-IUS was cost-effective, and that irrespective of the measuring instrument used, health-related quality-of-life outcomes were found to be improved to a degree similar to (or in some cases more than) that achieved with a hysterectomy or endometrial ablation [Blumenthal et al, 2011].
Another systematic review analyzed five trials investigating the effect of the LNG-IUS on idiopathic menorrhagia in 230 women. Results showed that after year 2 and year 5, the decrease in menstrual blood loss was greater than 96%. Also, haemoglobin and serum ferritin levels increased significantly [Endrikat et al, 2012].
The third systematic review analyzed the available evidence on the risks and benefits of using the LNG-IUS in the treatment of heavy menstrual bleeding, compared with other medical treatments, including combined oral contraceptives, oral progestogens, tranexamic acid, mefenamic acid, and endometrial ablation. Results showed that the LNG-IUS reduced menstrual blood loss to a greater extent than other medical treatments except endometrial ablation (menstrual blood loss was reduced to a similar extent). The authors concluded that the LNG-IUS was an effective option for treating heavy menstrual bleeding, even for women with underlying pathology or bleeding disorders [Kaunitz and Inki, 2012].
The RCT (n = 165) compared the efficacy and safety of the LNG-IUS with oral medroxyprogesterone acetate in the treatment of idiopathic heavy menstrual bleeding. The results showed that the LNG-IUS reduced menstrual blood loss more effectively (–128.8 mL, range –393.6 to +1242.2 mL) than oral medroxyprogesterone acetate (–17.8 mL, range –271.5 to +78.6mL, p < 0.001). The LNG-IUS also had a higher likelihood of treatment success (84.8%) compared with oral medroxyprogesterone acetate (22.2%, p < 0.001) [Kaunitz et al, 2010].
Tranexamic acid
Evidence on tranexamic acid
Tranexamic acid is an antifibrinolytic agent which affects uterine haemostasis and reduces bleeding. It does not alter the underlying pathology of the condition or reduce symptoms other than blood loss.
There is good evidence from randomized controlled trials (RCTs) that tranexamic acid is effective at reducing blood loss. The National Institute for Health and Clinical Excellence identified three systematic reviews. Although each review had different methodologies and inclusion criteria (some included women with intrauterine devices), all concurred that tranexamic acid offered a clinically significant benefit in reducing blood loss.
Overall, tranexamic acid, taken at a dose of 2.0 to 4.5 grams per day, for 3–5 days, reduced blood loss by 29 to 58%.
However, there were no long-term studies on effectiveness.
For a comparison with other pharmacological treatments, see Drugs in reducing blood loss.
Subsequent to NICE, CKS identified two systematic reviews and two RCTs on the use of tranexamic acid for treating heavy menstrual bleeding.
One systematic review looked at the use of tranexamic acid in the treatment of heavy menstrual bleeding and concluded that tranexamic acid is well tolerated, cost effective, and reduces menstrual blood loss by 34 to 59%. It improves health-related quality of life in women with heavy menstrual bleeding, and is especially useful in women who do not wish to take (or cannot take) hormonal contraception [Lumsden and Wedisinghe, 2011].
The second systematic review [Naoulou and Tsai, 2012] assessed the efficacy of tranexamic acid in the treatment of idiopathic and non-functional heavy menstrual bleeding, compared with other medical treatments. The evidence showed that tranexamic acid resulted in:
A 34–54% reduction in menstrual blood loss.
A 46–83% improvement in the measured quality-of-life parameters, compared with 15–45% for oral norethisterone treatment.
A 70% decrease in blood loss compared with placebo (p < 0.001).
A potential benefit in fibroid patients with menorrhagia (limited evidence, further studies are needed).
One RCT (n = 189) assessed the efficacy and safety of tranexamic acid in the treatment of heavy menstrual bleeding compared with placebo [Lukes et al, 2010]. Results showed that:
The women in the tranexamic acid group had a significantly greater reduction in menstrual blood loss of 69.6 mL (40.4%) compared with 12.6 mL (8.2%) in the placebo group (p < 0.001).
Compared with the placebo group, the tranexamic acid group experienced significant improvements in limitations in social or leisure and physical activities (p < 0.005), and self-perceived menstrual blood loss (p < 0.01).
Most of the adverse effects reported were mild to moderate in severity, and the incidence of gastrointestinal adverse events was comparable with placebo.
One RCT (a multicentre, long-term, open-label study) assessed the long-term safety of tranexamic acid [Muse et al, 2011]. Safety was assessed by treatment-emergent adverse event monitoring, physical examinations, laboratory results, ophthalmologic examinations, and electrocardiography. Results showed that:
The majority of the treatment-emergent adverse events were mild to moderate in severity and were largely considered unrelated to study treatment. The most commonly reported treatment-emergent adverse events among women in the intent-to-treat population (n = 723) were headache, menstrual discomfort, and back pain.
Long term treatment with tranexamic acid was well tolerated and improved measures of health-related quality of life in women with cyclic heavy menstrual bleeding.
Nonsteroidal anti-inflammatory drugs
Evidence on nonsteroidal anti-inflammatory drugs
It is probable that the mechanism of action of NSAIDs in menorrhagia is due to their inhibition of cyclooxygenase, an enzyme involved in prostaglandin synthesis. Prostaglandins are implicated in inflammatory response, pain pathways, uterine bleeding, and uterine cramps.
There is evidence from two systematic reviews identified by the National Institute for Health and Clinical Excellence (NICE) that NSAIDs are effective at reducing blood loss in women with menorrhagia. Both reviews concluded that NSAIDs produced a clinically significant reduction in blood loss, varying between 20–49%, depending on the study.
NSAIDs were not found to be as effective as tranexamic acid or the synthetic steroid danazol. However, they were found to be as well tolerated as tranexamic acid and better tolerated than danazol.
For a comparison with other pharmacological treatments, see Drugs in reducing blood loss.
The choice of NSAID for the treatment of menorrhagia with associated menstrual pain is based on evidence from one of the systematic reviews identified by NICE.
Mefenamic acid is licensed for the treatment of menorrhagia and has been shown to be effective in randomized controlled trials, reducing menstrual blood loss (MBL) by 29.0% (95% CI 27.9 to 30.2%).
Naproxen and ibuprofen are not licensed for menorrhagia but are licensed for dysmenorrhoea. Naproxen has been shown to have similar effectiveness as mefenamic acid (reduction in MBL 26.4%, 95% CI 24.6 to 28.3%). Ibuprofen is probably less effective (MBL 16.2%, 95% CI 13.6 to 18.7%). However, ibuprofen has a relatively good safety profile and can be considered an option if it is found to be effective in the individual woman.
Diclofenac was also found to be effective by two trials (reduction in MBL 26.9%, 95% CI 23.3 to 30.6%). However, it is not licensed for the treatment of menorrhagia or dysmenorrhoea.
Combined oral contraceptives
Evidence on combined oral contraceptives
The combined oral contraceptive (COC) is believed to work by causing regular blood loss and a thinner endometrium. The withdrawal bleed is thus less than that seen during a normal cycle.
There is relatively little evidence from randomized controlled trials (RCTs) to verify the effectiveness of treatment with COCs on blood loss, although the use of the COC in dysmenorrhoea is an accepted clinical practice. The National Institute for Health and Clinical Excellence found two systematic reviews, which in turn identified a solitary RCT (n = 45) that compared use of the COC (ethinylestradiol, 30 micrograms, combined with levonorgestrel, 150 micrograms) with naproxen, mefenamic acid, and danazol.
The COC reduced mean blood loss by 43%, which was greater than naproxen, but less than mefenamic acid or danazol.
The dose of ethinylestradiol used is greater than some COCs available (no trials were found that used the 20 microgram dose).
For a comparison with other pharmacological treatments, see Drugs in reducing blood loss.
Subsequent to NICE, CKS identified two RCTs and a pooled analysis (of two RCTs) on the use of combined oral contraceptives for treating heavy menstrual bleeding.
One double-blind RCT (n = 231) investigated the efficacy and safety of estradiol valerate/dienogest compared with placebo for the treatment of heavy idiopathic menstrual bleeding [Fraser et al, 2011a]. The primary end-point was the proportion of women with a return to 'menstrual normality' during a 90-day efficacy phase. Secondary end-points included changes in menstrual blood loss, and iron metabolism parameters.
The mean reduction in menstrual blood loss in the estradiol valerate/dienogest group was 69.4% (median 79.2%) compared with 5.8% (median 7.4%) in the placebo group.
The mean adjusted between-treatment difference in the menstrual blood loss volume was 373 ml in favour of estradiol valerate/dienogest (95% confidence interval 490, 255 ml; p < 0.0001).
There were significant improvements in iron metabolism with estradiol valerate/dienogest but not with placebo.
Serious adverse events occurred in both the groups (each n = 2). A total of 14 women (9.7%) in the estradiol valerate/dienogest group and 5 women (6.2%) in the placebo group prematurely discontinued treatment due to adverse events, headache being the most prevalent.
Another double-blind RCT investigated the efficacy of an estradiol valerate/dienogest oral contraceptive regimen in women with heavy and/or prolonged menstrual bleeding without organic pathology (the regimen was designed to deliver oestrogen in a step-down and progestogen in a step-up manner through each 28–day treatment cycle) [Jensen et al, 2011]. The study randomized women aged 18 years or older with prolonged, frequent, or heavy menstrual bleeding to treatment with estradiol valerate/dienogest or placebo (ratio 2:1 respectively) for 196 days. The primary variable was complete resolution of qualifying abnormal menstrual symptoms, including a 50% or greater reduction in pretreatment menstrual blood loss volume in women with heavy menstrual bleeding.
There were no marked differences in the characteristics of estradiol valerate/dienogest (n = 120) and placebo (n = 70) recipients.
The proportion of complete responders was significantly higher in the estradiol valerate/dienogest group (35/120; 29.2%) compared with the placebo group (2/70, 2.9%, p < 0.001) in the intention to treat population. This was also the case when results were analyzed in the population of participants with evaluable data (35/80; 43.8%) compared with the placebo group (2/48, 4.2%, p < 0.001).
The mean reduction in menstrual blood loss in the estradiol valerate/dienogest group from the run-in phase to the efficacy phase was substantial (-353 mL [309 mL]; mean -64.2%; median -70.6%) and significantly greater than that in the placebo group (-130 mL [338 mL]; mean -7.8%; median -18.7%; p < 0.001).
Significant improvements in haemoglobin, haematocrit, and ferritin were seen with estradiol valerate/dienogest, but not with placebo.
The pooled analysis assessed the efficacy of estradiol valerate/dienogest for the treatment of heavy and/or prolonged menstrual bleeding without organic pathology based on the analysis of data from two identically designed double-blind RCTs [Fraser et al, 2011b]. Women aged 18 years and over with heavy and/or prolonged menstrual bleeding were randomized to estradiol valerate/dienogest (n = 269) or placebo (n = 152) for 196 days during which changes in menstrual blood loss were assessed. The pooled analysis showed that:
Estradiol valerate/dienogest rapidly reduces blood loss in women with heavy and/or prolonged menstrual bleeding. This effect is achieved at the first withdrawal bleed after treatment is initiated and is sustained for the duration of the treatment.
The reduction in menstrual blood loss was also associated with a decrease in the number of sanitary protection items used and an improvement in iron metabolism parameters.
Both RCTs and the pooled analysis showed that estradiol valerate/dienogest is an effective treatment in women with heavy and/or prolonged menstrual bleeding without organic pathology. However, further studies are needed to compare estradiol valerate/dienogest with other medical treatments for heavy menstrual bleeding.
Oral norethisterone
Evidence on oral norethisterone
Progesterone is secreted in the luteal phase of the ovarian cycle and is responsible for the secretory phase of the endometrium. Norethisterone is an analogue of progesterone (i.e. a progestogen). However, its mechanism of action in preventing menorrhagia is not fully understood.
Evidence from randomized controlled trials (RCTs) to support the use of oral progestogens is limited. The National Institute for Health and Clinical Excellence identified two systematic reviews and an RCT that investigated their efficacy.
The systematic reviews focussed on the use of progestogens used exclusively during the luteal phase of the ovarian cycle. One review concluded that progestogens had no significant effect on blood loss. The other review found that all the active drugs norethisterone was compared with produced a greater reduction in blood loss.
One RCT investigated the long-term effect of norethisterone used during the follicular and luteal phase compared with the levonorgestrel intrauterine system (LNG-IUS).
Norethisterone caused an 83% reduction in blood loss, which was less than that for LNG-IUS (94%).
More women were satisfied with LNG-IUS (66%) than norethisterone (22%).
Progestogens other than norethisterone may also be effective in treating menorrhagia, but have not been studied. For a comparison of norethisterone with other pharmacological treatments, see Drugs in reducing blood loss.
Long-acting progestogens
Evidence on long-acting progestogens
Long-acting progestogens have an extended duration of action that allows for much less frequent dosing, which some women may prefer. Their prolonged duration of action often results in long-term amenorrhoea (absence of periods).
The National Institute for Health and Clinical Excellence (NICE) did not find any direct evidence from randomized controlled trials (RCTs) on the use of long-acting progestogens in the treatment of menorrhagia. Instead, evidence was extrapolated from studies that used amenorrhoea as an outcome, taken from the NICE guideline Long-acting reversible contraception [NICE, 2005b].
One large RCT (n = 3172) found that medroxyprogesterone acetate caused amenorrhoea in 12% of women within the first year of use, and 24% in the second year of use.
In another large RCT (n = 1216) of women mainly from the developing world, 10% experienced amenorrhoea after 3 months, increasing to 41–47% after 1 year.
For a comparison of the effectiveness of long-acting progestogens compared with other pharmacological treatments, see Drugs in reducing blood loss.
Danazol and etamsylate (not recommended)
Evidence on danazol and etamsylate (not recommended)
Danazol is a synthetic androgenic steroid with anti-oestrogenic and anti-progestogenic properties. It inhibits proliferation of the endometrium:
The National Institute for Health and Clinical Excellence (NICE) identified two systematic reviews and a subsequent primary study that showed danazol is an effective treatment in reducing blood loss.
Danazol was found to reduce blood loss by about 50%.
Danazol was found to be more effective than nonsteroidal anti-inflammatory drugs (NSAIDs) or progestogens. However, it also caused significantly more adverse effects than these drugs. Some of these adverse effects are severe enough to warrant stopping treatment (mainly androgenic-related adverse effects).
After analyzing the benefit–risk ratio and considering the availability of other treatments, NICE concluded that danazol should not be recommended for the treatment of menorrhagia.
Etamsylate reduces capillary bleeding by correcting anomalies of platelet adhesion without unduly affecting the fibrin cascade.
NICE identified three systematic reviews that assessed the use of etamsylate. Together, these found that:
Etamsylate reduced menstrual blood loss by an average of 13%.
Etamsylate was not as effective as NSAIDs or antifibrinolytic drugs.
NICE concluded that, given the other drug treatments available, etamsylate was not effective enough to be recommended.
For a comparison of the effectiveness of danazol and etamsylate with other pharmacological treatments, see Drugs in reducing blood loss.
Search strategy
Scope of search
A literature search was conducted for guidelines, systematic reviews and randomized controlled trials on primary care management of menorrhagia.
Search dates
2007 - July 2012
Key search terms
Various combinations of searches were carried out. The terms listed below are the core search terms that were used for Medline and these were adapted for other databases. Further details are available on request.
exp Menorrhagia/, menorrhagia.tw., heavy menstrual bleeding.tw.
Table 1. Key to search terms.| Search commands | Explanation |
|---|---|
| / | indicates a MeSh subject heading with all subheadings selected |
| .tw | indicates a search for a term in the title or abstract |
| exp | indicates that the MeSH subject heading was exploded to include the narrower, more specific terms beneath it in the MeSH tree |
| $ | indicates that the search term was truncated (e.g. wart$ searches for wart and warts) |
Sources of guidelines
National Institute for Health and Clinical Excellence (NICE)
Scottish Intercollegiate Guidelines Network (SIGN)
Royal College of General Practitioners
National Guidelines Clearinghouse
Guidelines International Network
NHS Scotland National Patient Pathways
Agency for Healthcare Research and Quality
Institute for Clinical Systems Improvement
National Health and Medical Research Council (Australia)
Royal Australian College of General Practitioners
British Columbia Medical Association
University of Michigan Medical School
Michigan Quality Improvement Consortium
National Resource for Infection Control
UK Ambulance Service Clinical Practice Guidelines
RefHELP NHS Lothian Referral Guidelines
Medline (with guideline filter)
Driver and Vehicle Licensing Agency
NHS Health at Work (occupational health practice)
Sources of systematic reviews and meta-analyses
Systematic reviews
Protocols
Database of Abstracts of Reviews of Effects
Medline (with systematic review filter)
EMBASE (with systematic review filter)
Sources of health technology assessments and economic appraisals
NIHR Health Technology Assessment programme
NHS Economic Evaluations
Health Technology Assessments
Canadian Agency for Drugs and Technologies in Health
International Network of Agencies for Health Technology Assessment
Sources of randomized controlled trials
Central Register of Controlled Trials
Medline (with randomized controlled trial filter)
EMBASE (with randomized controlled trial filter)
Sources of evidence based reviews and evidence summaries
Central Services Agency COMPASS Therapeutic Notes
Sources of national policy
Health Management Information Consortium (HMIC)
Patient experiences
Patient.co.uk - Patient Support Groups
Sources of medicines information
The following sources are used by CKS pharmacists and are not necessarily searched by CKS information specialists for all topics. Some of these resources are not freely available and require subscriptions to access content.
British National Formulary (BNF)
electronic Medicines Compendium (eMC)
European Medicines Agency (EMEA)
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