Unscheduled bleeding and endometrial cancer in women on postmenopausal hormone replacement therapy and their matched controls: protocol for a descriptive cohort study using the Orchid-e database

Hormone replacement therapy (HRT) with oestrogen and progestogen is a common medical treatment for alleviating symptoms of menopause. Since 2015, its use has been increasing in the UK. Unscheduled bleeding can be a symptom of endometrial cancer, and guidelines state that women experiencing this should have an urgent referral for suspected endometrial cancer. However, unscheduled bleeding is also common in women taking HRT, particularly in the first few months after starting HRT or if there is a change in regimen. Current guidelines may result in women on HRT receiving referrals that are not necessary and undergoing unpleasant and invasive tests such as hysteroscopy. However, there is a lack of current information to guide recommendations. This protocol describes a cohort study in the ORCHID-e database of anonymised patient records from English primary care. We will use a cohort of women aged over 40 years starting on HRT with oestrogen and progestogen, age matched to women who have not started HRT. Exposure will be a prescription for oestrogen containing HRT with no previous prescription for oestrogen containing HRT in the previous year. Index date in each matched set will be the date of this prescription. Prescriptions for progestogen containing drugs will not be used to define the exposure, but this information will be extracted to describe the study population and for sensitivity analyses. Outcomes will be consultations for unscheduled bleeding, urgent referrals for suspected endometrial cancer, and diagnosis of endometrial cancer. Women will be followed up until they change exposure status or are otherwise censored. Women who start taking HRT in follow-up will re-enter the cohort in the exposed group. We will describe proportions of women with a code for consulting with unscheduled bleeding, proportions of those women referred for further investigation on the pathway for suspected endometrial cancer, and proportions diagnosed with endometrial cancer within one year of referral. We will investigate the diagnostic accuracy of unscheduled bleeding for endometrial cancer separately for women on HRT and those not on HRT. Analyses will be done by 6-month categories of time since index, age, calendar year, sociodemographic variables, risk factors for endometrial cancer, type of HRT. Lay SummaryMenopause is when a womans periods stop for good. This usually happens between the ages of 45 and 55, but it can happen earlier. During menopause, the level of the hormone oestrogen falls, which can cause symptoms such as hot flushes, night sweats, poor sleep, low mood and vaginal dryness. For some women these symptoms are mild, but for others they can be very difficult and affect daily life. Many women use hormone replacement therapy (HRT) to help manage symptoms of the menopause by replacing some of the hormones their body no longer makes. The use of HRT has been increasing, including higher doses, starting at younger and finishing at older ages. Bleeding is a common side effect in women starting on HRT. It is also a symptom of womb cancer. Current guidelines for womb cancer are that women who have unscheduled bleeding after the menopause should have an urgent referral for further tests for possible cancer. However, these guidelines were written when fewer women were taking HRT. Some women on HRT might be undergoing unnecessary investigations for suspected womb cancer. Right now, doctors do not have enough clear information to know if current guidance needs to change. In this study, we will use safely stored health records where no one can be identified. We will look at women aged 40 and over who have recently started HRT, and compare them with women of the same age who are not using HRT. By following this information over time, we can see what happens to them. We will look atHow often women and other people with a womb contact their GP because of unscheduled bleeding. How often they are then sent for urgent tests that check for cancer. How often cancer is found within a year of these tests. How useful unscheduled bleeding is as a warning sign of cancer for people using HRT. If there is enough information, we will also look at whether results are different for people depending on factors such as how long they have been using HRT, their age, the type of HRT they take, their background, where they live, their general health, and their social class. The results will help us to understand how women on HRT with unscheduled bleeding are referred for further investigations on the suspected cancer pathway. They will provide evidence for the development of new guidelines for unexpected bleeding and cancer of the womb that are more relevant to women on HRT.