Postmenopausal bleeding

What is postmenopausal bleeding?

Postmenopausal bleeding (PMB) is defined for practical purposes as vaginal bleeding occurring after twelve months of amenorrhoea, in a woman of the age where the menopause can be expected.

Hence it does not apply to a young woman, who has had amenorrhoea from anorexia nervosa, or a pregnancy followed by lactation. However, it can apply to younger women following premature ovarian insufficiency or premature menopause.

Unscheduled bleeding in women of menopausal age taking hormone replacement therapy (HRT) should be managed in the same way from a practical perspective. 'Unscheduled bleeding' is defined as non-cyclical bleeding still continuing six months after commencing HRT or after six months of amenorrhoea. (Note that cyclical bleeding is an expected effect of sequential/cyclical HRT preparations, and that vaginal bleeding is a common adverse side-effect of HRT in the first six months of use.)

Although PMB usually has a benign cause, the priority is to exclude malignancy.

How common is PMB? (Epidemiology)

PMB is a common problem representing 5% of all gynaecology outpatient attendances. These are most commonly to eliminate endometrial cancer as the cause of the bleed.

Risk factors for endometrial cancer¹

Many risk factors relate to oestrogen exposure:

• Unopposed oestrogen-only HRT.

• Tamoxifen use - it has an anti-oestrogen effect on the breast, but a pro-oestrogen effect on the uterus and bones.

• Low parity or infertility.

• Early menarche and late menopause.

• Increasing age.

• Polycystic ovarian disease.

• Hereditary non-polyposis colorectal carcinoma.

• Obesity combined with diabetes.

• Hypertension.

Protective factors for endometrial cancer

• Use of combined oral contraceptives decreases risk.

• Grand multiparity.

Causes of PMB (aetiology)

• Vaginal atrophy. The most common cause of PMB.

• Use of HRT.

• Endometrial hyperplasia; simple, complex, and atypical.

• Endometrial cancer.

• Endometrial polyps or cervical polyps.

• Cervical cancer.

• Uterine sarcoma (rare).

• Ovarian cancer, especially oestrogen-secreting (theca cell) ovarian tumours.

• Vaginal cancer (very uncommon).

• Vulval cancer may bleed, but the lesion should be obvious.

• Non-gynaecological causes including trauma or a bleeding disorder.

Management of PMB

History and examination may possibly indicate cause, but it is generally accepted that PMB should be treated as malignant, until proved otherwise.

This requires referral to a gynaecologist with an appointment within two weeks² .

An abdominal and pelvic examination, including speculum examination to visualise the cervix, should ideally be carried out in primary care prior to referral; visualising an abnormal cervix affects the referral pathway.³

Diagnosing PMB (investigations)

Transvaginal ultrasound scan (TVUS)

TVUS is an appropriate first-line procedure to identify which women with PMB are at higher risk of endometrial cancer⁴ .

The mean endometrial thickness in postmenopausal women is much thinner than in pre-menopausal women. Thickening of the endometrium may indicate the presence of pathology. In general, the thicker the endometrium, the higher the likelihood of important pathology, ie endometrial cancer being present.

The British Gynaecological Cancer Society's 2021 guidelines recommend a cutoff endometrial thickness of 4mm; women with postmenopausal bleeding and an endometrial thickness of <4mm (without any irregularities in the endometrium) can be reassured without any further investigations, unless there is recurrent PMB.³

There is some uncertainty regarding the optimal cutoff for endometrial thickness. More recent data suggest that the average endometrial thickness in postmenopausal women has increased with time; some advocate a threshold of 5mm to improve specificity.³

Endometrial biopsy

A definitive diagnosis in PMB is made by histology. Historically, endometrial samples have been obtained by dilatation and curettage. Nowadays it is more usual to obtain a sample by endometrial biopsy, which can be undertaken using samplers. It is most often done as an outpatient procedure, in a hospital or community clinic, or sometimes a GP surgery.^{5 6}

When an adequate sample is obtained, the Pipelle® method has high diagnostic accuracy, with a positive predictive value of 81.7% and a negative predictive value of 99.1%.¹ However, adequate samples can be difficult to obtain. One study showed that only 34% of patients had an adequate sample. This percentage rose to 60% when evaluating women with an endometrial thickness of at least 5 mm.

NB: every method of sampling the endometrium has the potential to miss some cancers; a hysteroscopy is warranted if there is persistent abnormal vaginal bleeding despite a negative endometrial biopsy.³

Hysteroscopy

Hysteroscopy and biopsy (curettage) are the preferred diagnostic technique to detect polyps and other benign lesions. Hysteroscopy may be performed as an outpatient procedure, although some women will need GA.⁷

Referral to 'one stop' specialised clinics is ideal.⁸ At such clinics several investigations are available to complement clinical evaluation, including ultrasound, endometrial sampling techniques and hysteroscopy. Following such assessment, reassurance can be given or further investigations or treatment can be discussed and arranged.

Caution

Most women with PMB will not have significant pathology but the dictum remains that postmenopausal bleeding is cancer until proved otherwise.

• PMB in women on HRT still needs investigation (see "What is postmenopausal bleeding?" above for definition).

• An obvious lesion such as atrophic vaginitis does not exclude another lesion.

• Some women are unable to distinguish between vaginal and urinary bleeding and some are unable to distinguish rectal bleeding.

Tamoxifen

Women with breast cancer who take tamoxifen on a long-term basis are at increased risk of endometrial cancer. In view of the increased risk of endometrial cancer associated with tamoxifen therapy, there is a case for heightened vigilance for PMB by both the women and the clinician(s) responsible for their care. Tamoxifen can cause other changes to the endometrium, and ultrasound may be more difficult to interpret. All women with PMB who are on tamoxifen would normally have hysteroscopy and biopsy in addition to ultrasonography.³