Endometrial cancer rate in Hormone replacement therapy users with postmenopausal bleeding: Retrospective cohort study

Main findings

The endometrial cancer detection rate was very low for patients under 60 years of age referred with PMB whilst using HRT. This knowledge could help triage referrals so that patients can be relatively reassured at presentation and directed to the clinic best suited to manage their presenting problem. This may be within the primary care setting involving a GP with a specialist interest in menopause or women’s health or by referring to a specialist menopause/HRT clinic in secondary care for patients with bleeding on HRT on a non-urgent basis, preserving the 2 week wait referral clinics for those most likely to have significant pathology. This is very dependent on the services available in the local area to determine the most appropriate setting for review and if necessary investigation.

Strengths and limitations

This study evaluated a large number of patients referred over a two-year period both before and during the COVID pandemic. All patient outcomes were analysed to determine the significance of HRT with regards to diagnosis. This study confirms previously published data regarding the frequency of irregular vaginal bleeding within the initial two years of use and when there may be changes to the preparation including type or dose of therapy.^2,3 Other work also revealed similar very low detection rates of significant endometrial pathology in women using HRT. ⁴

This study was limited by its retrospective nature investigating referrals within a single unit. The numbers of patients on HRT were not matched to non-HRT but this was representative of our referral population. Review of patient case notes could provide limited detail of HRT use or recent changes.

Interpretation

Up to 77% of women commencing continuous combined HRT will report irregular bleeding within the first few months. This decreases to 10% after nine months unless using transdermal preparation when up to 20% may still report irregular bleeding.^9–12 This is even more common with sequential users with up to 40% reporting irregular bleeding.^10,13,14 The Million Women Study reported HRT had significant and contrasting effect on the risk of endometrial cancer depending on preparation and the women’s BMI over a follow-up period of 3.4 years. Continuous combined users had a reduced risk of endometrial cancer but for those on cyclical preparations the risk was not significantly different from non-users. ¹⁵

Feeley and Wells concluded in their review that there is a low probability of clinically relevant pathology when an endometrial biopsy is obtained from women using HRT. ¹⁶ This statement was predominantly based on a large UK multicentre study that demonstrated no endometrial hyperplasia or malignancy in women using combined continuous HRT, even after previous sequential HRT with a diagnosis of hyperplasia. ¹⁷ The ten year study by Mossa et al demonstrated a higher incidence of abnormal uterine bleeding amongst postmenopausal women using HRT as well as an increased endometrial thickness (ET). This was measured using transvaginal sonography (TVS) with 5 mm or more classed as increased. Despite these findings, there was no correlation with any significant difference in malignant endometrial pathology. ¹⁸

A randomised control trial of 246 patients aged 41–57 years with minimum 12 months amenorrhoea commenced on one of two HRT regimens. Vaginal bleeding was reported in approximately 40% at six months regardless of regimen used and 30% at nine months. This reduced to under 20% at one year. No endometrial cancer was detected with either regimen following endometrial sampling of all patients at 12 months. ⁴ In addition, a large cross-sectional study including 750 women using HRT demonstrated that they were significantly less likely to be diagnosed with endometrial cancer (odds ratio 0.229). ¹⁹ In a recent retrospective study comparing women with unscheduled bleeding on sequential or continuous HRT, the presence of hyperplasia without atypia was similar in both groups (0.5 and 0.4%, respectively). With regards to hyperplasia with atypia or endometrial cancer the incidence was 2% and 1%, respectively. ²⁰

Lou et al conducted a review of the literature in 2017 regarding unscheduled bleeding on HRT and whether endometrial assessment is necessary. They concluded unscheduled bleeding is common with both sequential and continuous HRT at least within the initial 6 months of use. They also state two-week wait pathway referral is unnecessary given the low probability of malignancy; however, beyond the initial six months endometrial assessment is warranted. ²¹

NICE guidance for suspected cancer diagnosis recommends women aged 55 years and over with PMB are referred on a suspected cancer pathway for an appointment within two weeks. For women aged under 55 years, however, it suggests this referral pathway should be a consideration but is not mandatory due to the rarity of malignancy in these women. ²² Our data is supportive of this advice and may assist in providing reassurance both the patient and care provider regarding managing these symptoms within the primary care setting or by routine referral processes to specialist clinics if available. Many women will choose to commence HRT prior to a full year of amenorrhoea making it difficult to determine if they are truly postmenopausal or if their symptoms are due to ongoing ovarian activity or HRT itself. By NICE guidance, the definition is stated as unexplained vaginal bleeding more than 12 months after menstruation has stopped. This allows, therefore, some interpretation with regards to the use of HRT. The British Gynaecological Cancer Society (BGCS) recommends in addition to those with PMB as defined by NICE, women who have stopped HRT for at least six weeks presenting with persistent or new onset unexplained bleeding should be referred urgently. ²³ Our study provides further evidence of the low cancer detection rate in HRT users under 60 years of age and may facilitate the production of clearer guidance regarding how these patients should be managed. Ideally this should be collaborative guidance from the BGCS and British Menopause Society as well as NICE for realistic expectation of how these patients can be managed.

The review article by Dave et al provides recommendations on the initial assessment plan for unscheduled bleeding on HRT. This specifies that with less than six months use of continuous combined HRT no investigation is necessary. Beyond this timeframe, transvaginal ultrasound (TVUSS) to evaluate ET should be requested. For patients on sequential HRT with heavy, prolonged or breakthrough bleeding in more than two cycles TVUSS should be requested. Different acceptable values of ET were specified with an ET of 5 mm or more requiring endometrial assessment (either biopsy alone or with the addition of hysteroscopy) for continuous combined HRT users and an ET of 7 mm warranting endometrial assessment in sequential HRT use. An endometrium of less than 5 mm does not require further investigation as the risk of endometrial cancer in this group is reduced by 90% regardless of the HRT regimen used. If bleeding persists or recurs this should be re-evaluated. Consideration is also required in the presence of high-risk factors including raised BMI or Lynch syndrome or a family history suggestive of Lynch syndrome. ²⁴ The findings of our study with a very low rate of endometrial cancer concur with this review. The limitation of this review is that it is only available in The Obstetrician and Gynaecologist journal and is unlikely to be readily accessible by primary care providers. Incorporation of this review into new guidance would be beneficial to both primary and secondary care services to streamline referrals and manage patient ideas, concerns and expectations.