Abstract
Although hormone replacement therapy (HRT) use is associated with elevated endometrial cancer(EC) risk, little evidence assesses potential effect-modifiers on HRT-related EC in a long-term follow-up. In this large-scale longitudinal cohort study, we tried to evaluate the association between different HRT types/methods use and risk of EC, and reveal this risk within different body mass index (BMI) groups. In whole cohort, 677 EC occurred during mean 11.6 years follow-up. Cox proportional hazards regression was used to estimate multivariable-adjusted hazards ratios (HRs) and 95% confidence intervals (CIs) with HRT status (never, former, or current) for risk of EC incidence. Current HRT use was not significantly associated with EC risk (HR for current vs. never HRT use: 1.13; 95% CI: 0.92, 1.38) in the whole cohort, but presented a dose-response effect on increased EC risk (HR for >10-year use vs. never HRT use: 1.73; 95% CI: 1.35, 2.21). Moreover, EC risk differed in distinct regimens or subsets (all Pinteraction < 0.05). Estrogen-only use was associated with elevated EC risk (HR for current vs. never HRT use: 1.51; 95% CI: 1.12, 2.04), but women with high BMI (> 30 kg/m2) who currently use estrogen-only harbored decreased EC risk (HR: 0.56; 95% CI: 0.38, 0.82) compared to counterparts without HRT use. Estrogen-only use is associated with increased EC risk, and precise monitoring of EC development for postmenopausal women with long-term HRT use are urgently needed. BMI could serve as an important surrogate to assess this risk.
Highlights
Obese women who currently use estrogen only harbored decreased endometrial cancer (EC) risk (HR: 0.56; 95% confidence intervals (CIs): 0.38, 0.82, Table 3) compared to counterparts without hormone replacement therapy (HRT) use, but in the normal/underweighted subgroup (
Estrogen-only use was associated with elevated EC risk (HR for current vs. never HRT use: 1.51; 95% CI: 1.12, 2.04; HR for >10-year use vs. never HRT use: 2.92; 95% CI: 2.06, 4.14, Table 2), whereas no relationship between progesterone-only or estrogen plus progesterone combination
Our results found that estrogenonly use for HRT was associated with increased risk of EC development, and an obesity paradox that this association was completely reversed in obese women was confirmed
Summary
In 2020, the number of women aged 50 years and older were up to 69 million, and by 2050, women above 50 are projected to total to 90 million [1]. The mean age of natural menopause is 49 years [2]. Most perimenopausal women would suffer from a series of menopause symptoms such as hot flashes, night sweats, vaginal dryness, and low mood or anxiety, which may persist for a decade or longer [3]. Up to 84% of postmenopausal women experience genitourinary symptoms, such as vulvovaginal atrophy and HRT and Endometrial Cancer incontinence [4]. The burden of menopausal symptoms can considerably affect the personal, social, and work lives of women [3]. Hormone replacement therapy (HRT) is the most effective treatment for such vasomotor and genitourinary symptoms [5]. In high-income countries, there were about 600 million womanyears of HRT use in the period 1970–2019, and about 12 million users in the 2010s, of whom 6 million were in the United States and the United Kingdom alone [6, 7]
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