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The lancet oncology · Nov 2013
Multicenter StudyThe sex hormone system in carriers of BRCA1/2 mutations: a case-control study.
- Martin Widschwendter, Adam N Rosenthal, Sue Philpott, Ivana Rizzuto, Lindsay Fraser, Jane Hayward, Maria P Intermaggio, Christopher K Edlund, Susan J Ramus, Simon A Gayther, Louis Dubeau, Evangelia Ourania Fourkala, Alexey Zaikin, Usha Menon, and Ian J Jacobs.
- Department of Women's Cancer, UCL EGA Institute for Women's Health, University College London, London, UK. Electronic address: M.Widschwendter@ucl.ac.uk.
- Lancet Oncol. 2013 Nov 1; 14 (12): 122612321226-32.
BackgroundPenetrance for breast cancer, ovarian cancer, or both in carriers of BRCA1/BRCA2 mutations is disproportionately high. Sex hormone dysregulation and altered end-organ hormone sensitivity might explain this organ-specific penetrance. We sought to identify differences in hormone regulation between carriers of BRCA1/2 and women who are negative for BRCA1/2 mutations.MethodsWe assessed endometrial thickness for each menstrual cycle day (as an index of hormone regulation) in 393 scans from 228 women in the UK Familial Ovarian Cancer Screening Study (UK FOCSS) known to carry either mutation and 1573 scans from 754 women known to be negative for the mutations. To quantify differences in endometrial thickness we focused on days 10-14 and days 21-26, and calculated the area under the curve. We then compared serum oestradiol and progesterone titres during these days of the menstrual cycle in the same groups. Follicular and luteal oestradiol and progesterone serum titres were grouped into quartiles and odds ratios were calculated with logistic regression.FindingsFollicular phase endometrial thickness of carriers of the mutations adjusted for age and day of the menstrual cycle was higher (odds ratio [OR] 1·11, 95% CI 1·03-1·20; p=0·0063) and luteal phase endometrial thickness lower (0·90, 0·83-0·98; p=0·027) than for women negative for the mutations. Median luteal phase titres of progesterone were 121% higher (p=0·00037) in carriers than in women negative for the mutations, and for oestradiol were 33% higher (p=0·007)-ie, 59% of carriers had concentrations of serum progesterone that would have been in the top quartile of concentrations in the control group (OR 8·0, 95% CI 2·1-52·57; p=0·008).InterpretationCarriers of BRCA1/BRCA2 mutations are exposed to higher titres of oestradiol and progesterone-known risk-factors for breast cancer. Higher titres of oestradiol in carriers are compatible with this hormone having a role in ovarian carcinogenesis in such women. Our findings could not be explained by differential contraceptive pill use.Copyright © 2013 Widschwendter et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd. All rights reserved.
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