Temporal Clustering of Endometrial Cancer and Hyperplasia in HRT Users with Unscheduled Bleeding: A Retrospective NHS Cohort Study

Background: Unscheduled bleeding in postmenopausal women on hormone replacement therapy (HRT) represents a common but poorly characterised clinical challenge. Whilst endometrial cancer affects approximately 9% of women with unexplained postmenopausal bleeding, existing evidence in HRT users is largely restricted to women under 60 years and short-duration regimens, leaving a critical evidence gap in contemporary all-age clinical practice. Whether the same investigative urgency is warranted for HRT users experiencing unscheduled bleeding as for women with unexplained postmenopausal haemorrhage remains unresolved. Objectives: To determine the diagnostic yield of endometrial cancer and hyperplasia amongst postmenopausal women presenting with unscheduled bleeding whilst on HRT, and to explore potential associations with HRT regimens and clinical risk factors. Methods: This retrospective observational study analysed 343 postmenopausal women presenting with unscheduled bleeding whilst on HRT at a single tertiary centre between September 2023 and February 2024. All patients underwent transvaginal ultrasound and endometrial sampling according to institutional protocol. Descriptive statistics were used to characterise outcomes, with exploratory analyses of potential risk factors. Given the symptomatic and selected nature of this cohort, all proportions represent the diagnostic yield within an investigated population rather than population-level incidence estimates. Results: Amongst 343 women (mean age 56.2 ± 7.4 years), nine cases (2.6%) of endometrial abnormalities were identified: four malignancies (1.2%), four endometrial hyperplasia without atypia (1.2%), and one complex atypical hyperplasia (0.3%). Only five cases (1.5%) required surgical intervention. All four endometrial cancers were Stage IA (FIGO 2009; three Grade 1, one Grade 2; no LVSI), corresponding to Stage IA2mNSMP under FIGO 2023. None required adjuvant therapy. Strikingly, 88.9% of all abnormal cases occurred within two years of HRT initiation, with no endometrial pathology identified amongst the 45 women using systemic HRT for more than five years—a temporal pattern not previously reported. Conclusions: In this retrospective all-age NHS cohort, the diagnostic yield of endometrial cancer was 1.2% in HRT users with unscheduled bleeding, with only 1.5% requiring surgical intervention. All cancers were early-stage (FIGO 2009 Stage IA; FIGO 2023 Stage IA2mNSMP) and required no adjuvant therapy. A previously unreported temporal clustering of pathology within the first two years of HRT initiation generates a hypothesis that early unscheduled bleeding may unmask pre-existing rather than HRT-induced endometrial abnormalities. These observations are hypothesis-generating and should not be interpreted as evidence of endometrial safety. These findings apply specifically to symptomatic women presenting for investigation and cannot be generalised to asymptomatic HRT users. Prospective validation in larger cohorts with baseline endometrial assessment is required before any clinical conclusions can be drawn. What This Study Adds: (1) A real-world cancer detection proportion of 1.2% in an all-age contemporary NHS cohort. (2) A previously undescribed temporal pattern with pathology clustering within two years of HRT initiation and no pathology in long-term users (n = 45), generating a testable hypothesis about pre-existing versus HRT-induced disease. (3) Dual FIGO 2009/2023 staging demonstrating that molecular classification added no treatment-discriminatory value in this early-detection context.