According to the Women's Health Initiative Study 3, a randomized, double-blind, placebo-controlled trial including 16 608 postmenopausal women, the hazard ratio for invasive ovarian cancer in women assigned to estrogen and progestin compared with placebo was 1.58 (95% CI 0.77 to 3.24)
The WHI poststopping phases trials 5 assessed the risk ovarian cancer. The WHI study did not find an association of CEE+MPA use with an increased risk of ovarian cancer after a mean of 5.6 years (HR 1.41, 95% CI 0.75 to 2.66) and neither after a 13 years cumulative follow-up (HR 1.24, 95% CI 0.83 to 1.87).
A nationwide Swedish population-based cohort study 6 including all 290 186 women aged≥ 40 years having used systemic hormone replacement therapy (HRT) during the study period (years 2005 - 2012), compared with the Swedish female background population. HRT ever-use (all HRT, oestrogen-only [E-HRT]) and oestrogen plus progestin HRT [EP-HRT]) was based on the nationwide Prescribed Drug Registry. The standardised incidence ratio of any cancer was 1.09 (95% CI 1.07 to 1.11) following ever HRT, 1.04 (95% CI 1.01 to 1.06) for E-HRT and 1.14 (95% CI 1.12 to 1.17) for EP-HRT. The highest incidencd ratio was found for EP-HRT among users aged ≥70 years (1.33, 95% CI 1.26 to 1.40). The risk for invasive breast, endometrial or ovarian cancer combined was increased for any HRT (standardised incidence ratio 1.31, 95% CI 1.28 to 1.34).
A meta-analysis 7 used individual participant data of 52 epidemiological studies. During prospective follow-up, 12 110 postmenopausal women, 55% (6601) of whom had used hormone therapy, developed ovarian cancer. Among women last recorded as current users, risk was increased even with <5 years of use (RR 1.43, 95% CI 1.31 to 1.56; p<0.0001). Combining current-or-recent use (any duration, but stopped <5 years before diagnosis) resulted in an RR of 1.37 (95% CI 1. 29 to 1.46; p<0.0001); this risk was similar in European and American prospective studies and for oestrogen-only and oestrogen-progestagen preparations, but differed across the 4 main tumour types (heterogeneity p<0.0001), being definitely increased only for the two most common types, serous (RR 1.53, 95% CI 1.40 to 1.66; p<0.0001) and endometrioid (1.42, 1.20 to 1.67; p<0.0001). Risk declined the longer ago use had ceased, although about 10 years after stopping long-duration hormone therapy use there was still an excess of serous or endometrioid tumours (RR 1.25, 95% CI 1.07 to 1.46, p=0.005). Women who use hormone therapy for 5 years from around age 50 years have about one extra ovarian cancer per 1000 users and, if its prognosis is typical, about one extra ovarian cancer death per 1700 users.
In a cohort study 4 in the UK, 948 576 postmenopausal women without previous cancer or bilateral oophorectomy were followed-up for an average of 5.3 years for incident ovarian cancer and 6.9 years for death. 30% of women were current users and 20% past users of hormone replacement therapy (HRT). During follow-up, 2 273 incident ovarian cancers and 1 591 deaths from the malignancy were recorded. Ovarian cancer was more frequent with current users than never users (RR 1.20, 95% CI 1.09 to1.32 for incident disease and RR 1.23, 95% CI 1.09 to 1.38 for death). The relative risks did not vary appreciably by socioeconomic status, reproductive history, previous use of oral contraceptives, body-mass index, or alcohol and tobacco consumption. For current users, incidence of ovarian cancer increased with increasing duration of use, but did not differ significantly by type of preparation used. Risks associated with HRT varied according to tumour histology (p<0.0001), and in women with epithelial tumours the relative risk for current versus never use of HRT was greater for serous than for mucinous, endometroid, or clear cell tumours. Past users of HRT were not at an increased risk of ovarian cancer (RR 0.98, 95% CI 0.88 to 1.11 for incident and 0.97, 95% CI 0.84 to 1.11 for fatal disease). Over 5 years, the standardised incidence rates for ovarian cancer in current and never users of HRT were 2.6 (95% CI 2.4 to 2.9) and 2.2 (95% CI 2.1 to 2.3) per 1000, respectively; death rates were 1.6 (95% CI 1.4 to 1.8) and 1.3 (95% CI 1.2 to 1.4) per 1 000, respectively - i.e. one extra ovarian cancer in roughly 2 500 users and one extra cancer death in roughly 3 300 users.
A systematic review 1 including 10 studies (9 case-control studies and one cohort study) with a total of 256 257 cases of invasive cancer, 1 case-control study of invasive and borderline cancers (1 684 patients) and 1 case-control study with borderline cancers only (2 882 patients) was abstracted in DARE. Ever use of HRT was associated with an increased risk of developing invasive epithelial ovarian cancer (RR 1.15, 95% CI 1.05 to 1.27). Some heterogeneity was present. Inclusion of studies with borderline carcinoma produced similar results. No trend on increasing risk with increased duration was observed. According to a cohort study of 44 241 postmenopausal women 2, the ever use of estrogen-only was associated with an increased risk of ovarian cancer (rate ratio 1.6, 95% CI 1.2 to 2.0). There was a 7% increase of risk ratio per year of use. The RR for estrogen plus progestin use was 1.1 (5% CI 0.64 to 1.7).
Comment: The quality of evidence is downgraded by inconsistency (variability in results across studies).
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