Estradiol

Epidemiological data

Administrative data

Endpoint:

epidemiological data

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence

Author:

Lancet: Collaborative Group on Hormonal Factors in Breast Cancer

Year:

2019

Bibliographic source:

Lancet 2019; 394: 1159–68

Reference 2

Reference Type:

publication

Title:

Estrogen Metabolism and Risk of Breast Cancer in Postmenopausal Women

Author:

Fuhrman BJ et al.

Year:

2012

Bibliographic source:

J Natl Cancer Inst 2012;104:326–339

Materials and methods

Study type:

other: case control studies prospective and retrospective

Endpoint addressed:

carcinogenicity

Test material

Test material information

Constituent 1

Reference substance name:

Estradiol

EC Number:

200-023-8

EC Name:

Estradiol

Cas Number:

50-28-2

Molecular formula:

C18H24O2

IUPAC Name:

estra-1,3,5(10)-triene-3,17-diol

Method

Type of population:

general

Results and discussion

Results:

Fuhrman et al., 2012:
Nearly all estrogens, estrogen metabolites, and metabolic pathway groups were associated with an increased risk of breast cancer; the serum concentration of unconjugated estradiol was strongly associated with the risk of breast cancer (HR = 2.07, 95% confidence interval [CI] = 1.19 to 3.62). No estrogen, estrogen metabolite, or metabolic pathway group remained statistically significantly associated with the risk of breast cancer after adjusting for unconjugated estradiol. The ratio of the 2-hydroxylation pathway to parent estrogens (HR = 0.66, 95% CI = 0.51 to 0.87) and the ratio of 4-hydroxylation pathway catechols to 4-hydroxylation pathway methylated catechols (HR = 1.34, 95% CI = 1.04 to 1.72) were statistically significantly associated with the risk of breast cancer and remained so after adjustment for unconjugated estradiol.

Lancet, 2019:
Among women with complete information, mean MHT duration was 10 years (SD 6) in current users and 7 years (SD 6) in past users, and mean age was 50 years (SD 5) at menopause and 50 years (SD 6) at starting MHT. Every MHT type, except vaginal oestrogens, was associated with excess breast cancer risks, which increased steadily with duration of use and were greater for oestrogen-progestagen than oestrogen-only preparations. Among current users, these excess risks were definite even during years 1–4 (oestrogen-progestagen RR 1·60, 95% CI 1·52–1·69; oestrogen-only RR 1·17, 1·10–1·26), and were twice as great during years 5–14 (oestrogen-progestagen RR 2·08, 2·02–2·15; oestrogen-only RR 1·33, 1·28–1·37). The oestrogen-progestagen risks during years 5–14 were greater with daily than with less frequent progestagen use (RR 2·30, 2·21–2·40 vs 1·93, 1·84–2·01; heterogeneity p<0·0001). For a given preparation, the RRs during years 5–14 of current use were much greater for oestrogen-receptor-positive tumours than for oestrogen-receptor-negative tumours, were similar for women starting MHT at ages 40–44, 45–49, 50–54, and 55–59 years, and were attenuated by starting after age 60 years or by adiposity (with little risk from oestrogen-only MHT in women who were obese). After ceasing MHT, some excess risk persisted for more than 10 years; its magnitude depended on the duration of previous use, with little excess following less than 1 year of MHT use.

Strengths and weaknesses:

Fuhrman et al., 2012:
Limitations
The study population was restricted to postmenopausal women who were not using menopausal hormone therapy at the time of blood collection, which may limit the generalizability of the findings. There was limited inter-individual variation in serum concentrations of estrogens and estrogen metabolites and high correlations among many of the analytes. There was no adjustment for multiple comparisons and thus, some of the findings could be due to chance.



Lancet, 2019:
One limitation of all the available epidemiological evidence is that there is still not long enough follow-up after cessation of prolonged MHT use by women who had started some years of hormonal treatment at around the time of menopause. If excess risks in past users are real and persist much longer than 15 years, there will be some additional hazard after age 70 years. Another limitation is that the collaboration sought information only on breast cancer incidence, not mortality, and incidence can depend on the sensitivity and frequency of mammographic screening. Breast cancer detection rates could have been reduced somewhat by the increase in breast density that is caused by hormonal treatment, 21–23 or increased somewhat in populations where screening frequency is associated with MHT use, as in the US. 24 The largest prospective study was, however, from the UK, where there is a nationwide mammographic screening programme. In that study, MHT use was not materially associated with screening uptake but as associated with an increase not only in breast cancer incidence (of similar magnitude to that in all prospective studies; appendix p 34) but also in 20-year breast cancer mortality. This increase in breast cancer mortality was greater for oestrogen-progestagen than for oestrogen-only preparations; of the fatal breast cancers, three-quarters with known receptor status were ER+. 25 Cases continue to accrue in the prospective studies, but there is no good reason to expect further follow-up would materially alter the main findings for current users. To limit biases, the main analyses were restricted to prospective studies, allowed for early menopause decreasing breast cancer risk and bringing forward the age when MHT is started, and adjusted for various other potential confounding factors (as other correlates of breast cancer risk might also affect the type or timing of MHT use). Current users were included up to no more than 5 years after their last reported MHT use; among them there were, on average, only 1·4 years between the last report about their MHT use and their index date. Some additional use must have occurred during that period, as must some discontinuation, but both have been allowed for (although RRs in current users must still have been slightly weakened by discontinuation before the index date). With all these safeguards, the findings are trustworthy for the main patterns of use in the prospective studies.

Applicant's summary and conclusion

Executive summary:

Estrogens are recognized causal factors in breast cancer. Interindividual variation in estrogen metabolism may also influence the risk of breast cancer and could provide clues to mechanisms of breast carcinogenesis. Longstanding hypotheses about how estrogen metabolism might influence breast cancer have not been adequately evaluated in epidemiological studies because of the lack of accurate, reproducible, and high-throughput assays for estrogen metabolites.

The authors conducted a prospective case–control study nested within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Participants included 277 women who developed invasive breast cancer (case subjects) and 423 matched control subjects; at PLCO baseline, all subjects were aged 55–74 years, postmenopausal and not using hormone therapy, and provided a blood sample. Liquid chromatography–tandem mass spectrometry was used to measure serum concentrations of 15 estrogens and estrogen metabolites, in unconjugated
and conjugated forms, including the parent estrogens, estrone and estradiol, and estrogen metabolites in pathways defined by irreversible hydroxylation at the C-2, C-4, or C-16 positions of the steroid ring. The authors calculated hazard ratios (HRs) approximating risk in highest vs lowest deciles of individual estrogens and estrogen metabolites, estrogens and estrogen metabolites grouped by metabolic pathways, and metabolic pathway ratios using multivariable Cox proportional hazards models. All statistical tests were two-sided.

Nearly all estrogens, estrogen metabolites, and metabolic pathway groups were associated with an increased risk of breast cancer; the serum concentration of unconjugated estradiol was strongly associated with the risk of breast cancer (HR = 2.07, 95% confidence interval [CI] = 1.19 to 3.62). No estrogen, estrogen metabolite, or metabolic pathway group remained statistically significantly associated with the risk of breast cancer after adjusting for unconjugated estradiol. The ratio of the 2-hydroxylation pathway to parent estrogens (HR = 0.66, 95% CI = 0.51 to 0.87) and the ratio of 4-hydroxylation pathway catechols to 4-hydroxylation pathway methylated catechols (HR = 1.34, 95% CI = 1.04 to 1.72) were statistically significantly associated with the risk of breast cancer and remained so after adjustment for unconjugated estradiol.
Conclusions More extensive 2-hydroxylation of parent estrogens is associated with lower risk, and less extensive methylation of potentially genotoxic 4-hydroxylation pathway catechols is associated with higher risk of postmenopausal breast cancer.

 

In the study reported by the Lancet in 2019 the correlation of breast cancer and MHT was investigated. It was considered that for women of average weight in developed countries, 5 years of MHT, starting at age 50 years, would increase breast cancer incidence at ages 50–69 years by about one in every 50 users of oestrogen plus daily progestagen preparations; one in every 70 users of oestrogen plus intermittent progestagen preparations; and one in every 200 users of oestrogen-only preparations. The corresponding excesses from 10 years of MHT would be about twice as great.