Serum Estradiol and 20 Site-Specific Cancers in Women: Mendelian Randomization Study

Siddhartha Kar*, Siddhartha Kar, John R B Perry, Paul Carter, Mathew Vithayathil, Amy M. Mason, Douglas F Easton, Stephen Burgess

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

18 Downloads (Pure)


The causal role of endogenous estradiol in cancers other than breast and endometrial cancer remains unclear.

This Mendelian randomization study assessed the causal associations of endogenous 17β-estradiol (E2), the most potent estrogen, with cancer risk in women.

As primary genetic instrument, we used a genetic variant in the CYP19A1 gene that is strongly associated with serum E2 levels. Summary statistics genetic data for the association of the E2 variant with breast, endometrial, and ovarian cancer were obtained from large-scale consortia. We additionally estimated the associations of the E2 variant with any and 20 site-specific cancers in 198 825 women of European descent in UK Biobank. Odds ratios (OR) of cancer per 0.01 unit increase in log-transformed serum E2 levels in pmol/L were estimated using the Wald ratio.

Genetic predisposition to higher serum E2 levels was associated with increased risk of estrogen receptor (ER)-positive breast cancer (OR 1.02; 95% CI, 1.01-1.03; P = 2.5 × 10−3), endometrial cancer overall (OR 1.09; 95% CI, 1.06-1.11; P = 7.3 × 10−13), and endometrial cancer of the endometrioid histology subtype (OR 1.10; 95% CI, 1.07-1.13; P = 2.1 × 10−11). There were suggestive associations with breast cancer overall (OR 1.01; 95% CI, 1.00-1.02; P = 0.02), ovarian cancer of the endometrioid subtype (OR 1.05; 95% CI, 1.01-1.10; P = 0.02), and stomach cancer (OR 1.12; 95% CI, 1.00-1.26; P = 0.05), but no significant association with other cancers.

This study supports a role of E2 in the development of ER-positive breast cancer and endometrioid endometrial cancer but found no strong association with other cancers in women.
Original languageEnglish
Pages (from-to)e467-e474
JournalJournal of Clinical Endocrinology and Metabolism
Issue number2
Early online date3 Oct 2021
Publication statusPublished - 18 Jan 2022

Bibliographical note

Publisher Copyright:
© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.


  • cancer
  • estrogens
  • Mendelian randomization


Dive into the research topics of 'Serum Estradiol and 20 Site-Specific Cancers in Women: Mendelian Randomization Study'. Together they form a unique fingerprint.

Cite this