Vaginal bleeding in perimenopausal women

Perimenopausal bleeding, although very common, need not be a worrying presenting symptom. When associated with new onset menopausal symptoms such as night sweats and hot flushes, the most likely cause is dysfunctional uterine bleeding. This often confusing term refers to abnormal bleeding at the extremes of reproductive age with no obvious underlying pathology. This diagnosis should only be given once the patient has been investigated. Bleeding occurs as a result of the lack of oestrogen following the depletion of the oocyte numbers that occurs with age. The lack of high levels of circulating oestrogen in the perimenopause may also cause atrophic vaginitis, which may also cause vaginal bleeding.

Post menopausal bleeding (PMB) warrants urgent investigation and management. Up to 8% of women will be found to have an endometrial carcinoma.¹ The vast majority of women  will have a benign cause for the bleeding and patients need to be reassured. In the primary care setting a risk assessment will help decide which patients are more likely to have a sinister cause for the bleeding, although all cases of PMB require an urgent assessment by a specialist.

The low levels of systemic oestrogen can cause vaginal bleeding in the perimenopause and menopause. There are however other local and systemic causes that can cause abnormal vaginal bleeding. Local causes include vaginal or cervical lacerations, cervical or uterine polyps. A cervical malignancy is rare if a woman has had regular and normal three yearly smears throughout her life.

Uterine fibroids of the sub mucous subtype can also cause an abnormal bleeding pattern, in this age group, but this is rare. Fibroids usually cause heavy bleeding in younger women. An important cause of abnormal uterine bleeding includes endometrial hyperplasia. It is a rare cause of abnormal bleeding in the perimenopause and menopause. The complex subtype with cellular nuclear changes like atypia, is a precursor to endometrial cancer and up to 46% of cases have an underlying coexisting endometrial malignancy.²

Unlike, cervical intraepithelial neoplasia (CIN) where the natural history and development to cervical cancer is well understood, complex endometrial hyperplasia is not as well understood. A more drastic surgical approach is therefore  usually offered, to eliminate the risk of endometrial cancer.

Systemic causes such as a coagulopathy, liver disease or  haematological conditions can present with vaginal bleeding in this age group.

The source of bleeding can sometimes be mistaken, so ruling out bleeding from the urethra or bladder as well as from the rectum will help confirm vaginal bleeding.

It is well known that almost 90% of diagnoses are made by taking a thorough but focused history. The amount of bleeding is not associated with the likelihood of a sinister as opposed to a benign cause.

A change of a previously regular bleeding pattern and in particular a shortening of a cycle, together with menopausal symptoms herald the climacteric period. This may last between a few months to a number of years. Associated symptoms such as night sweats, hot flushes and mood disturbances point to a lack of circulating oestrogen. Inspection of the perineum may reveal an atrophic vulva and vagina with contact bleeding.

The introitous may also be stenosed and an attempted bimanual examination may be painful. Urinary urgency can also be a result of low levels of oestrogen affecting the urothelium. Urethritis and a urethral caruncle may also be confused as vaginal bleeding.

Vulval dermatosis such as lichen sclerosus may also cause  bleeding. These often present with vulval irritation or superficial dysparunea. A white, atrophic vulva with a figure of eight pattern is characteristic of lichen sclerosus.

A risk factor based assessment will help triage higher risk patients. Age increases the risk of endometrial cancer due the greater number of years that the endometrium is exposed to oestrogen. Women below 50 years have a 0.4 in 100,000 risk. This increases to 6.4 in 100,000 in women aged 50-59 years, and rises even further to 7.3 in 100,000 in women over 80 years of age. Other risk factors for endometrial cancer and hyperplasia include an early menarche and nulliparity. Both are due to a greater exposure of oestrogen.

Obesity, diabetes, hypertension and smoking are all associated with a higher risk of endometrial pathology.³ Adipose tissue increases the peripheral conversion of androgens to oestrogen and this causes higher levels of oestrogen to act on the endometrium.

A long standing history of oligomenorhoea (infrequent periods), in a woman with known polycystic ovarian syndrome (PCOS) increases the risk of endometrial hyperplasia.

Postcoital (PCB) and intermenstrual bleeding (IMB) suggest a cervical cause for the bleeding. A normal smear history reduces the risk for cervical malignancy. Cusco speculum examination enables retrieving a smear sample if clinically indicated. This also enables the identification of  a cervical polyp. The polyp’s pedicle may in fact be located in the uterine fundus so avulsing a polyp if unsure of its origin may cause profuse bleeding or even a perforation of an atrophic post menopausal uterus.

A history of tamoxifen intake increases the possibility of endometrial hyperplasia.⁴ This drug, commonly used in oestrogen receptor positive breast cancer, has an oestrogen agonist effect on the endometrium (while an oestrogen antagonist on the breast tissue). Other drugs such as unopposed oestrogen (without progesterone) are known to cause endometrial hyperplasia or malignancy, so women with a uterus are  strongly recommended to have progesterone add back therapy. Bleeding disorders including the use of warfarin outside the therapeutic range may also be the cause of abnormal bleeding.

A family history of gynaecological malignancy such as endometrial or male bowel cancer will point to hereditary gynaecological cancer such as hereditary non polyposis colorectal cancer (HNPCC) as a potential cause for the bleeding. HNPCC has an autosomal dominant pattern of inheritance and is the second commonest familial gynanecological cancer after BRCA1. The lifetime risk of endometrial cancer in women with HNPCC is 40-60%.⁵

The main aim of investigating PMB or perimenopausal bleeding is to exclude endometrial pathology, most notably endometrial carcinoma. Perimenopausal bleeding is far less likely to be due to endometrial cancer as opposed to PMB in which 8% of women will have an endometrial cancer. With PMB this risk rises with age. It is also important to ensure that women are sufficiently reassured following normal tests when benign symptomatic disease is identified.

Trans vaginal ultrasound imaging

Trans vaginal ultrasound imaging (TVUSS) has a higher sensitivity and specificity when compared to abdominal ultrasound imaging.⁶ TVUSS is well accepted and widely available in the UK. In general, the thicker the endometrium the higher the likelihood of endometrial cancer. In the case of PMB, a thin endometrium on TVUSS should reassure the patient and clinician that the risk of significant pathology is low. This group of women may not need any further investigation unless there is a recurrence of bleeding, in which case a tissue diagnosis is important.

TVUSS imaging can also diagnose endometrial polyps, which will require further investigation usually by means of a hysteroscopy and polypectomy.

The endometrial thickness, below which, should offer reassurance, remains debatable. The higher the endometrial thickness cut-off level used, the lower the sensitivity and specificity of the test. A higher cut-off level for further investigation will result in more cases of cancer being missed but reducing the number of women without cancer referred for further investigation.

Using an endometrial  thickness of 5mm will reduce the risk of PMB being due to endometrial carcinoma from around 10% to 1.7%.⁷ However, no endometrial cut off level completely excludes possible early endometrial carcinoma. This needs to be explained in the clinical consultation. A risk assessment, as discussed earlier, will help categorise high risk women who despite a thin endometrium will benefit from further investigation. For example women on tamoxifen, women who are obese or diabetic or have had a recurrent PMB. Patients who have an episode of bleeding on HRT should also ideally have an endometrial biopsy.

Overall, using a cut off level of 3mm will reduce the likelihood of an endometrial cancer, in PMB from 10% to 0.4%. If the clinician and the woman judge that the level of reassurance is acceptable, then no further action is needed. If the level of reassurance is not acceptable or the patient is considered to be of higher risk, then an endometrial biopsy should be offered. There are a number of methods for obtaining an endometrial biopsy.

Dilation and curettage (D&C) may only sample up to 60% of the endometrium. This makes D&C less successful compared to an outpatient pipelle biopsy. The latter samples a greater surface area of the endometrium. Thus, D&C should only be used when outpatient pipelle biopsy is unsuccessful in obtaining a tissue biopsy.⁸

Outpatient pipelle biopsy, although effective in identifying endometrial cancer, has a procedure failure rate of around 10%. This method may also miss endometrial polyps, so should ideally not be used if a uterine polyp is suspected.

Hysteroscopy

Hysteroscopy allows the operator to directly visualise the endometrial cavity. This enables directed biopsy to specific areas of the endometrium as well as the ability to perform polypectomies. Outpatient hysteroscopy has the benefit of avoiding an anaesthetic in a patient with surgical comorbidities. It is rarely poorly tolerated⁹ and successful in around 96% with no special training needed.¹⁰ Outpatient hysteroscopy appears to have an accuracy and acceptability equivalent to inpatient hysteroscopy under general anaesthetic (GA). When endometrial sampling offers  no tissue diagnosis, a negative hysteroscopy excludes the possibility of endometrial cancer.¹¹

One stop clinics are becoming increasingly available in the UK. In such a clinic the patient will have a clinical assessment, TVUSS and an endometrial biopsy usually by an outpatient hysteroscopy. This enables a rapid diagnosis and reduces patient travel and the need for a further appointment. For this to work a dedicated team of doctors and nurses is needed with adequate training and expertise. Patients should have a dedicated number to call to enable phone follow up.

The gold standard investigation for investigating PMB or perimenopausal bleeding is a hysteroscopy and biopsy.

Treatment will depend on the cause of vaginal bleeding. Removing polyps can usually be performed in the outpatient setting. Removing fibroids is debatable in this age group because with the menopause, fibroid-related bleeding will usually abate.

Local topical vaginal oestrogen will help reduce the symptoms of atrophic vaginitis and does not increase the risk of endometrial cancer. When a diagnosis of simple hyperplasia is made, women can be offered oral pregestogens or the progesteronic MIRENA intra uterine system (IUS). A biopsy 3-6 months after the progesteronic treatment will help confirm that the hyperplasia has resolved.¹²

A diagnosis of complex atypical hyperplasia is treated surgically (TAH + BSO). Women in the perimenopause with dysfunctional bleeding can be reassured that they do not need treatment provided they are not affected by the erratic nature of bleeding.

• Ensure that the complaint of vaginal bleeding is not urethral or rectal
• A speculum examination to rule out local causes of bleeding and in particular cervical pathology should be performed at presentation. However, the finding of likely causes such as a cervical polyp, or atrophic vaginitis do not exclude the possibility of endometrial pathology.
• Initial investigations such as ultrasound can be performed in the primary care setting
• Overall patients should be reassured and told that the risk of malignancy is low. Perimenopausal bleeding is less likely to be associated with significant endometrial pathology compared to PMB.
• High risk women should be identified by history and referred to a specialist or to a one stop clinic

Women with perimenopausal bleeding and menopausal symptoms who are found not to have  endometrial pathology can be offered HRT on an individualised basis. Sequential combined HRT (bleed preparations) may increase the risk of endometrial cancer if used for more than five years.  Continuous combined HRT (no bleed preparations) is considered not to confer this risk. Women with recurrent postmenopausal bleeding despite a thin endometrium (<4mm) on TVUSS, should warrant further investigation with hysteroscopy and endometrial biopsy.

• Patients who are generally unwell with cachexia and weight loss with PMB should be referred to a hospital for urgent investigations
• Higher risk women include: nulliparous, those on tamoxifen, obese, diabetic, PCOS
• Recurrent post-menopausal bleeding.

Conflict of interest: none declared

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Solon Riris, Despina Mavridou, Eleni Mavridou

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