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DOI: 10.1177/1755738013497351

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Postmenopausal bleeding ostmenopausal bleeding (PMB) is one of the most common reasons for referral to gynaecology services. This is due to the concern of possible underlying malignancy, as approximately 10% of women with PMB will have endometrial cancer. With growing use of hormone replacement therapy there is increased uncertainty as to what constitutes unscheduled bleeding and careful history and examination is required. Although benign conditions represent the most frequent cause of PMB, all women will require urgent referral and investigation in secondary care.

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The GP curriculum and postmenopausal bleeding

Clinical example 3.06: Women’s health outlines the various roles of the GP in managing postmenopausal bleeding, including management of menopause and hormone replacement therapy, detecting early signs of cancer and making prompt referrals. More specifically, it is expected that GP trainees can: . Recognise common signs and symptoms of, and know how to manage, gynaecological disease . Intervene urgently with suspected malignancy . Demonstrate an understanding of the important risk factors in the diagnosis and management of women’s problems . Discuss the psychological component of women’s health and the need, in some cases, to provide women patients with additional emotional and organisational support

The menopause refers to the permanent cessation of menstruation and can be accurately determined after 12 months of amenorrhoea. Postmenopausal bleeding (PMB) is therefore defined as any vaginal bleeding that occurs after this time. The average age of menopause is 51.5 years, with approximately 10% of women reaching it by age 45, 80% by age 52 and 95% by age 55 years (Bradshaw & Tait, 2011). The most common causes of PMB are benign, with the majority of cases being attributed to lower genital tract atrophy, and endometrial and cervical polyps. However, it is important to bear in mind that patients who present ! The Author(s) 2013. Reprints and permissions: sagepub.co.uk/journalsPermissions.nav

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Sections in Clinical example 3.09: End of life care are also applicable to patients with postmenopausal bleeding. Trainees should be able to: . Communicate effectively with the patient, their family and carer(s) regarding difficult information about disease progression and prognosis . Explain the importance of the social and psychological impact of cancer on the patient’s family, friends, dependants and employers

with PMB have between a 10 and 15% risk of underlying endometrial cancer, with a range of 4–24% depending on risk factors (Bradshaw & Tait, 2011). It is therefore important that cases in which patients present with PMB be treated as suspected cancer until proven otherwise. Bleeding can arise from the vulva, vagina, cervix, uterine cavity, fallopian tubes. It may also be related to ovarian pathology. It can sometimes be difficult to establish the source of bleeding, and so extra-genital areas such as the urethra, bladder and bowel also need to be considered. Please see Box 1 for a full list of causes of PMB.

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Box 1. Causes of postmenopausal bleeding. . . . . . . . .

Atrophic endometritis and vaginitis Endometrial or cervical polyps Endometrial hyperplasia Endometrial carcinoma Cervical carcinoma Ovarian carcinoma Exogenous oestrogens Cervicitis

History ........................................................... It is important for clinicians to first confirm a woman’s menopausal status, by asking details of her last menstrual period and establishing whether 12 months of amenorrhoea have elapsed. Also, it is important to establish that bleeding is coming from the genital tract; ask about any history of urinary frequency, haematuria or recurrent urinary tract infections, which may suggest a urological cause for bleeding. Passing blood with stool or seeing blood on wiping may suggest haemorrhoids, anal fissures or polyps, or a gastrointestinal cancer. Having established that the history is one of PMB, the onset, duration and severity of the bleeding needs to be determined; women who have more than one episode of PMB are at higher risk of endometrial cancer (Burbos et al., 2010). Furthermore, clinicians should assess for possible underlying risk factors for endometrial cancer when taking a history from a woman with PMB. These risk factors are discussed below. Ask about the woman’s smear history, as cervical cancer can cause PMB. A woman presenting with PMB should also be asked about her sexual activity; although cervicitis is uncommon in postmenopausal women, particularly when compared to younger age groups, a sexually transmitted infection (STI) can be a cause of PMB. In postmenopausal women a lack of oestrogen causes thinning of the vaginal tissue, resulting in microabrasion during intercourse and thus an increased risk of infection. According to the UK Health Protection Agency figures for 2002 to 2006 the rates of several STIs, including chlamydia and gonorrhoea, are increasing among women aged 45 years and over (Drew & Sherrard, 2008). Patients taking hormone replacement therapy (HRT) should be asked specific questions about the preparation of HRT (cyclical or continuous) that they are taking, their compliance with this, and the pattern of their bleeding. Unopposed oestrogen should never be used in women with a uterus as this increases the relative risk of endometrial cancer by around five to six times after 5 years of use. The introduction of progesterone reduces this risk to around 1.5 times (Scottish Intercollegiate Guidelines Network (SIGN), 2002). Box 2 outlines the questions

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Box 2. Questions to ask women with abnormal bleeding on HRT. . When does bleeding occur with respect to the oestrogen and progesterone phase? Ideally, women on cyclical regimes should not experience withdrawal bleeding before completion of the progesterone component of the preparation. . How long does the bleeding last and how heavy is it? It is abnormal for women to experience heavy or prolonged bleeding at the end of, or after, the progesterone phase when taking cyclical HRT. . Was there a period of amenorrhoea before HRT was started? Irregular bleeding with continuous combined HRT preparation is less likely when there has been 12 months of amenorrhoea. . Is there a problem that suggests poor compliance? Missed tablets may lead to irregular bleeding. . Is there a reason to suspect poor gastrointestinal absorption? Gastroenteritis, coeliac disease and inflammatory bowel disease may affect gastrointestinal absorption of oestrogen and progesterone. . Is the patient taking any other drugs? Warfarin, aspirin and other medications that inactivate platelet function could cause irregular bleeding. Tibolone can increase the activity of anticoagulants, and drugs such as barbiturates, rifampicin, carbamazepine and phenytoin can increase the breakdown of oestrogens, thus reducing their activity. Questions reproduced from SIGN. Investigation of Post-Menopausal Bleeding, (SIGN publication 61), 2002, with permission

that should be asked when assessing patients who have abnormal bleeding while taking HRT.

Cyclical HRT Cyclical HRT, also known as sequential HRT, is often recommended for women who have menopausal symptoms but who are still menstruating, or whose last period was in the previous 12 months. Cyclical regimens can cause abnormal bleeding that is heavy or prolonged at the end of or after the progesterone phase, or that occurs at any time (breakthrough bleeding). There are two types of cyclical HRT: . Monthly HRT: oestrogen is taken every day with progestogen added from day 14 to day 28 of the cycle . Three-monthly HRT: oestrogen is taken every day with progestogen added for 14 days once every

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13 weeks (i.e. bleeding occurs on a 3-monthly basis). This regime is used less frequently due to an increased risk of hyperplasia, atypical hyperplasia and adenocarcinoma associated with the reduced progesterone dose (Feeley & Wells, 2001)

Continuous combined HRT Continuous combined HRT is recommended for women who are postmenopausal. It involves taking oestrogen and progestogen every day without a break. Continuous combined preparations are designed to induce amenorrhoea, although many women will experience breakthrough bleeding within the first 6 months. Bleeding that occurs after the first 6 months of treatment or after amenorrhoea has been established should be considered abnormal.

Examination ........................................................... Women presenting with PMB should have an abdominal, speculum and pelvic examination in the primary care setting. Note should also be made of their body mass index (BMI) and blood pressure. Abdominal and pelvic palpation may reveal very little, but it is important not to miss a pelvic mass. On speculum examination the vulva and vaginal walls should be closely inspected, looking for signs of atrophy or any lesions suggestive of a dermatological condition or malignancy. The presence of endocervical polyps may be revealed and, rarely, an advanced endometrial or cervical cancer may be seen on, or protruding through, the cervix. The examination is also a chance to carry out any cervical screening that may be due, and it may be appropriate take vaginal swabs if a STI is suspected. Sometimes the examination may reveal what seems to be an obvious cause for the bleeding. However, this should not be accepted as the sole explanation without further assessment of the endometrial cavity.

The PMB clinic ........................................................... Under the National Institute for Health and Care Excellence (NICE) 2005 guidelines, an urgent (2-week wait) referral to secondary care should be made for all women who present with PMB. These women will generally be seen in a dedicated PMB or rapid access clinic. The introduction of specialist ‘one-stop’ clinics has enabled clinical examination, ultrasound and endometrial assessment (usually via Pipelle biopsy) to be carried out at the same time, allowing the possibility of malignancy to be promptly excluded. The tests employed require high sensitivity and specificity for this purpose, and should also aid diagnosis of benign conditions.

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Women presenting with PMB should have a transvaginal ultrasound, with the decision to investigate further based on the endometrial thickness, visualisation of intrauterine pathology, or if symptoms are recurrent. If ultrasound is not readily available then it is acceptable to perform an endometrial biopsy as the initial investigation (Goodman, 2013). Outpatient endometrial sampling has high sensitivity and low complication rates, although it may miss intrauterine or adnexal pathology and may not be tolerated by some women. Currently there is no pathway for investigation that also takes into consideration the underlying factors that may put a patient at higher risk of endometrial cancer. Figure 1 provides a suggested algorithm for the investigation of women presenting with PMB.

Continuation of HRT prior to investigation There is uncertainty as to whether HRT should be stopped prior to investigation of PMB. Cyclical HRT leads to an increase in the endometrial thickness and continuous combined HRT leads to endometrial atrophy, however, neither should cause a problem with histological examination as long as the pathologist is aware the patient is on a hormonal preparation. Indeed, stopping HRT may induce a withdrawal bleed, which could result in loss of tissue that is needed for assessment. The decision to stop HRT prior to investigation may depend on the patient’s wishes but there is no clear indication for discontinuing it.

Transvaginal ultrasound Transvaginal ultrasound (TVS) has largely superseded transabdominal ultrasound in the assessment of the endometrium. This is because TVS gives a better resolution and therefore improved assessment of the endometrial lining and morphology. In general, it is assumed that the thicker the endometrium the greater the likelihood of an underlying endometrial cancer. In women taking cyclical HRT the endometrial thickness will vary during the cycle and so TVS measurements should take place during the first half of the cycle. TVS also has the advantage of being able to detect the presence of endometrial polyps or adnexal pathology. In women presenting with PMB (which is not recurrent) and who have an endometrial thickness of less than 3 mm, endometrial cancer can be excluded with a high degree of certainty. The risk of endometrial cancer in women with PMB is 0.07% if the endometrial thickness is less than 4 mm; this rises to 7.3% if the endometrial thickness is more than 5 mm (Smith-Bindman, Weiss, & Feldstein, 2004).

Endometrial biopsy Endometrial biopsy is warranted if the endometrial thickness is greater than 5 mm, or if symptoms are recurrent. Those women with an endometrial thickness of less than 3 mm can be reassured and discharged without the need for further investigation.

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Historically, endometrial biopsy was carried out using dilation and curettage, but this investigation is no longer first line as it is blind and does not allow visualisation of the endometrial cavity. Endometrial biopsy can instead be obtained using endometrial samplers, such as a ‘Pipelle’ in the outpatient setting. These plastic tubes can be inserted into the cavity and the plunger withdrawn to create a negative pressure that allows aspiration of tissue into the device. These devices are effective at diagnosing hyperplasia and cancer; the detection rate of endometrial cancer using a Pipelle device is quoted as 99.6% (Bakour, Timmermans, Mol, & Khan, 2012). However, they may miss benign lesions, particularly endometrial polyps. A Pipelle biopsy in conjunction with TVS may be all the investigations required to reassure a patient with PMB. However, if endometrial sampling has not been possible due to cervical stenosis, an inability to tolerate the procedure, or there is a concern that pathology is

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Figure 1. Algorithm for suggested diagnostic strategies in women with postmenopausal bleeding. Adapted from Bakour et al. (2012). Management of women with postmenopausal bleeding: evidence-based review. The Obstetrician and Gynaecologist. 14, 243–249.

present or may have been missed, a hysteroscopy is indicated.

Hysteroscopy Hysteroscopy is the gold standard in evaluation of the endometrial cavity. It allows the operator to directly visualise the cavity and thus assess for the presence of any pathology. Hysteroscopy can be carried out in the outpatient setting using local anaesthetic, or as a day case procedure under general anaesthesia. In the outpatient setting a thin, flexible hysteroscope is used with carbon dioxide or liquid distension to distend the cavity. The intrauterine cavity can be clearly visualised and small polyps and fibroids can be removed. The procedure is reliable, usually well tolerated, and has a low complication rate. The exact procedure carried out will depend on local service provision, but facilities should be available to allow hysteroscopy and biopsy to be performed under

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general anaesthetic if the outpatient procedure is not possible, or if the patient has a preference for general anaesthetic.

Risk factors for endometrial cancer ........................................................... The exact cause of endometrial carcinoma is unknown, but there are a number of risk factors, many of which share an underlying common pathway of excess oestrogen production. See Box 3 for a full list of risk factors for endometrial cancer. Box 3. Risk factors for endometrial cancer. Increasing age Nulliparity Early menarche (less than 10 years of age) Late menopause (more than 52 years of age) Obesity (BMI greater than 30 kg/m2) Diabetes mellitus Hypertension Polycystic ovarian syndrome Unopposed oestrogen therapy Tamoxifen (depending on duration of use) Endometrial hyperplasia (particularly atypical hyperplasia) . Hereditary non-polyposis colorectal cancer . . . . . . . . . . .

Age The age at which a woman presents with PMB is significant. The risk of endometrial cancer in women less than 50 years of age is 1%, rising to almost 25% in women aged 80 years and above (Bakour et al., 2012).

Obesity and diabetes The physiological states seen in both obesity and type-2 diabetes have several commonalities that increase the risk of endometrial cancer. Both conditions lead to an increase in insulin levels (hyperinsulinaemia) and insulin-like growth factor-1, each of which is linked with endometrial cancer. Obesity (which is often associated with type-2 diabetes) also results in a higher conversion of steroids to oestrone in adipose tissue; the risk of endometrial cancer in postmenopausal women who are obese is 18%. It is 21% for those who have diabetes, but rises as high as 29% for postmenopausal women who are both diabetic and obese (Bakour et al., 2012).

Tamoxifen While tamoxifen has an anti-oestrogen effect on breast tissue, it has a weakly oestrogenic effect on the endometrium and thereby increases the incidence of

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endometrial cancer three-fold. The increased risk is not related to the dose of tamoxifen, but instead is related to the duration of treatment. The relative risk is 2 for 2–5 years of use, and 6.9 for more than 5 years of use (Bradshaw & Tait, 2011). The risk remains high for at least 5 years after completion of treatment (Swerdlow & Jones, 2005).

Hereditary non-polyposis colorectal cancer Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant condition that is characterised by a familial aggregation of colorectal cancer as well as extra-colonic cancers, of which endometrial cancer is one. The estimated lifetime risk of developing endometrial cancer in women with HNPCC is approximately 42–60% (SIGN, 2002). In contrast with most endometrial cancer, that which occurs in association with HNPCC is often pre-menopausal.

Differential diagnosis ........................................................... Lower genital tract atrophy A lack of oestrogen following the menopause can lead to loss of lubrication in the vagina and changes to the vaginal mucosa. On speculum examination, the vaginal walls can be seen to be thin, pale and dry. There is also a loss of rugation and the fragile tissue has a tendency to bleed. Atrophy of the vagina and endometrium accounts for 60–80% of cases of PMB (Brand, 2007). Vaginal atrophy can be treated with topical oestrogen, either in the form of cream, pessaries or vaginal tablets. Treatment is usually daily for 2 weeks and then twice a week for 3 months. If this is contraindicated (e.g. history of oestrogen-dependent breast cancer) or not desired by the patient, then water- based lubricating gels, such as Replens, can be used.

Endometrial and cervical polyps Genital tract polyps account for between 2 and 12% of cases of PMB (Brand, 2007). Cervical polyps grow in the endocervical canal, and are often pedunculated. They are caused by high levels of oestrogen and in 25% of cases are associated with endometrial polyps as well. Figure 2 demonstrates an example of a cervical polyp. The incidence of endometrial polyps varies with age, peaking in the fifth decade of life. They grow under the influence of oestrogen and regress after menopause. They are commonly associated with tamoxifen use, due to its weakly positive oestrogenic effect on the endometrium. Cervical polyps are often pedunculated, allowing them to be removed with forceps in primary care or an outpatient gynaecology clinic. However, if they are large and broad based they may be better removed under general

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Figure 2. Cervical polyp. Dr P. Marazzi/SPL

anaesthetic. Endometrial polyps can be removed during outpatient or day case hysteroscopy. Although many clinicians would advocate removal of endometrial polyps, it has recently been questioned as to whether they need be removed at all, particularly in asymptomatic women. A multicentre study by Ferrazzi et al. (2009) found only one case of a grade-1 endometrial cancer in 1152 asymptomatic women with endometrial polyps. Another cohort study found no difference in the recurrence rate of PMB between those women who had a polypectomy, those who had a normal hysteroscopy, and those patients who had just office endometrial sampling (Timmermans et al, 2008). Ultimately, the decision as to whether a polyp is removed or not needs to be made in secondary care.

Endometrial hyperplasia Endometrial hyperplasia is caused by excessive proliferation of the endometrium and can be simple or complex, with or without atypia. The primary cause of hyperplasia is a relative excess of oestrogen, compared with progesterone. The diagnosis is made histologically, with simple and complex hyperplasia being characterised based on the glandular architecture, and then the presence of any cytological atypia. Postmenopausal women who are obese and nulliparous are at greatest risk of developing hyperplasia. The risk of progression to cancer is variable depending on the nature of hyperplasia. The risk of cancer developing in simple hyperplasia without atypia is 1%, with the majority of cases resolving spontaneously. This is also the case in complex hyperplasia without atypia, which has a 3% risk of progression to endometrial cancer. In simple hyperplasia with atypia the risk is 8% and, worryingly, in complex hyperplasia with atypia there is a 30% risk of endometrial cancer (Bradshaw & Tait, 2011). Patients diagnosed with hyperplasia (without atypia) can be treated conservatively with oral progestogens, used either alone or in combination with oestrogen in the form of HRT. The levonorgestrel intrauterine device (Mirena) has also been advocated. These women will need endometrial resampling within the following 3 to 6 months,

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and hysterectomy is advised if PMB persists or the disease has not regressed. Patients with atypical hyperplasia should be discussed in a gynaecology oncology multidisciplinary meeting, where hysterectomy is normally advised. Patients need to be counselled pre-operatively that there is up to 50% chance of finding carcinoma at the time of hysterectomy, and that further investigations for cancer staging and treatment may be required.

Endometrial cancer Endometrial cancer is the most common gynaecological cancer and the fourth most common cancer in women in the UK, with 7703 cases diagnosed in 2008. It has been estimated that the lifetime risk of developing endometrial cancer is 1 in 46 for women in the UK (Cancer Research UK, 2011a). Most women with the disease (90%) will present with PMB, although it is important to remember that some women may only present with an increase in vaginal discharge (Bakour et al., 2012). Treatment of endometrial cancer is usually surgical, comprising total abdominal hysterectomy and bilateral salpingo-oophorectomy. Adjuvant therapy with radiotherapy, chemotherapy or hormonal therapy is considered in more advanced or high-risk disease.

Other gynaecological causes Lichen sclerosus is a dermatological condition of the genital skin, usually affecting the labia, vestibule, clitoris and perineum. The underlying cause is unknown, but there is an association with other autoimmune conditions. Patients present with vulval itching and irritation, and on examination the skin can be red and sore with areas of hyperkeratosis or white plaques. The skin has a tendency to tear, which can cause bleeding. The risk of progression to cancer is low but the condition needs to be monitored, usually on a yearly basis if the condition is stable. Treatment is with an initial 3-month course of potent topical steroids, such as clobetasol ointment (Dermovate), which may be continued on an as required basis to keep symptoms at bay. It is also important to consider the diagnosis of cervical cancer when a woman first presents with PMB. Although cervical cancer is more common in pre-menopausal women, a second peak in incidence is seen among women aged 80–84 years, which is due to increasing cancer incidence with age. In the UK between 2007 and 2009, an average of 21% of new cervical cancer cases occurred in people aged 65 years and over (Cancer Research UK, 2011b). Treatment includes radical hysterectomy and/or radiotherapy and chemotherapy, depending on the stage of the disease. Vulval and vaginal cancers are rare gynaecological cancers, but often present with PMB. Risk factors for vulval cancer are smoking, lichen sclerosus and immune

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suppression. Patients often present with a mass or ulcer that can bleed. Vaginal cancer is commonly seen in the upper third of the vagina and is often a result of secondary spread from primary cancers of the cervix, endometrium, ovary or bowel.

Non-gynaecological causes When the origin of bleeding is unclear or not obviously from the genital tract then other sites such as the urethra, bladder and bowel need to be considered. Haemorrhoids, anal fissures and polyps, as well as urological and gastrointestinal cancers can present with what a patient may believe is vaginal bleeding.

Recurrent PMB ........................................................... There is no robust data on when women with recurrent PMB should be reinvestigated. A detailed risk assessment for endometrial cancer is required, taking into account the possibility of false negative results. Patients who have recurrent or on-going bleeding should be considered for reinvestigation after 6 months.

Key points . PMB is a common complaint in primary care that requires urgent referral for further investigation . The principle aim is to rule out underlying endometrial cancer . Most PMB is caused by benign conditions . The assessment of women who experience unscheduled bleeding while taking HRT can be difficult; a detailed history is required . Most women are investigated with one or more of TVS, endometrial biopsy and hysteroscopy

References and further information . Bakour, S., Timmermans, A., Mol, B., & Khan, K. (2012). Management of women with postmenopausal bleeding: Evidence-based review. The Obstetrician and Gynaecologist, 14(4), 243–249. doi: 10.1111/j.1744-4667.2012.00129.x . Bradshaw, K., & Tait, D. (2011). Postmenopausal bleeding. Disorders of menstruation. Oxford, UK: Blackwell Publishing, pp.166–182. doi: 10.1002/ 9781444391824.ch11 . Brand, A. (2007). The woman with postmenopausal bleeding. Australian Family Physician, 36(3), 116–120. Retrieved from www.racgp.org.au/afp/ 200703/200703brand.pdf . Burbos, N., Musonda, P., Giarenis, I., Shiner, A., Giamougiannis, P., Morris, E., & Nieto, J. (2010). The Norwich DEFAB risk assessment tool. British

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Journal of Obstetrics and Gynaecology, 24(7), 736–741. doi: 10.1080/014436104100009394 Munot, S., & Lane, G. (2008). Modern management of postmenopausal bleeding. Trends in Urology Gynaecology and Sexual Health, 13(5), 20–24. doi: 10.1002/tre.84 NICE. (2005). Referral guidelines for suspected cancer. Retrieved from www.nice.org.uk/niceme dia/pdf/cg027niceguideline.pdf RCGP. Clinical example 3.06: Women’s health. Retrieved from www.rcgp.org.uk/gp-training-andexams//media/Files/GP-training-and-exams/ Curriculum-2012/RCGP-Curriculum-3-06Womens-Health.ashx RCGP. Clinical example 3.09: End of care life. Retrieved from www.rcgp.org.uk/gp-training-andexams//media/Files/GP-training-and-exams/ Curriculum-2012/RCGP-Curriculum-3-09-End-OfLife-Care.ashx Royal College of Obstetricians and Gynaecologists. (2007). Polycystic ovary syndrome, long term consequences. Green-top guideline 33. Retrieved from www.rcog.org.uk/guidelines Royal College of Obstetricians and Gynaecologists. (2008). Standards for gynaecology. Report of a working party. Retrieved from www.rcog.org.uk/ files/rcog-corp/uploaded-files/WPRGynStandards 2008.pdf SIGN. (2002). Investigation of post-menopausal bleeding. Retrieved from www.sign.ac.uk/pdf/ sign61.pdf Smith-Bindman, R., Weiss, E., & Feldstein, V. (2004). How thick is too thick? When endometrial thickness should prompt biopsy in postmenopausal women without vaginal bleeding. Ultrasound in Obstetrics & Gynaecology, 24(5), 558–565. doi: 10.1002/uog.1704

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Miss Rebecca Pugh ST5 Obstetrics and Gynaecology, Hillingdon Hospital Email: [email protected] Miss Anna Humphries ST5 Obstetrics and Gynaecology, Kingston Hospital

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. Swerdlow, A., & Jones, M. (2005). Tamoxifen treatment for breast cancer and risk of endometrial cancer: A case control study. Journal of the National Cancer Institute, 97(5), 375–384. doi: 10.1093/jnci/dji057 . Tepper, R., Beyth, Y., Altaras, M. M., Zalel, Y., Shapira, J., Cordoba, M., & Cohen, I. (1999). Value of sonohysterography in asymptomatic postmenopausal tamoxifen-treated patients. Journal of Clinical Pathology, 52, 278–282. Retrieved from www.ncbi.nlm.nih.gov/pmc/articles/PMC501333/ pdf/jclinpath00277-0038.pdf . The National Collaborating Centre for Primary Care. (2005). Referral guidelines for suspected cancer in adults and children. Retrieved from www.nice.org.uk/nicemedia/pdf/CG027 fullguideline.pdf . Timmermans, A., van Doorn, L., Opmeer, B., Kroeks, M., Duk, M., Bouwmeester, A., & Mol, B. (2008). Follow–up of women after a first episode of postmenopausal bleeding and endometrial thickness greater than 4 millimetres. The Obstetrician and Gynaecologist, 111(1), 137–143. doi: 10.1097/01.AOG.0000296654.43944.e6 . Timmermans, A., Veerema, S., van Kerkvoorde, T. C., van der Voet, L. F., Opmeer, B. C., Bongers, M. Y., & Mol, B. W. J. (2009). Should endometrial polyps be removed in patients with postmenopausal bleeding? An assessment of study designs and report of a failed randomised controlled trial. British Journal of Obstetrics and Gynaecology, 116(10), 1391–1395. doi: 10.111/j.1471-0528. 2009.02234.x . World Health Organization. (1996). Research on the menopause in the 1990’s. WHO technical support series 866. Retrieved from www.whqlibdoc. who.int/trs/WHO_TRS_866.pdf