Journal Article

The sex hormone system in carriers of BRCA1/2 mutations: a case-control study

Edlund, Christopher K, Fraser, Lindsay, Jacobs, Ian J, Dubeau, Louis, Philpott, Sue, Gayther, Simon A, Widschwendter, Martin, Zaikin, Alexey, Rizzuto, Ivana, Ramus, Susan J, Rosenthal, Adam N, Hayward, Jane, Menon, Usha, Fourkala, Evangelia Ourania, Intermaggio, Maria P

2013

Overview

Penetrance 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. We 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. Follicular 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). Carriers 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. Eve Appeal, European Union, Cancer Research UK, and US National Institutes of Health.

• Publisher: Elsevier Ltd,Elsevier Limited
• Subject: Area Under Curve / Biomarkers, Tumor - blood / Biomarkers, Tumor - genetics / BRCA1 Protein - genetics / BRCA2 Protein - genetics / Breast Neoplasms - blood / Breast Neoplasms - diagnostic imaging / Breast Neoplasms - genetics / Breast Neoplasms - physiopathology / Case-Control Studies / Contraceptive Agents, Female - therapeutic use / Endometrium - diagnostic imaging / Endometrium - metabolism / Endometrium - physiopathology / Estradiol - blood / Female / Genetic Predisposition to Disease / Genetic testing / Hematology, Oncology and Palliative Medicine / Heterozygote / Humans / Insulin-like growth factors / Logistic Models / Medical screening / Menstrual Cycle / Menstruation / Mutation / Odds Ratio / Ovarian cancer / Ovarian Neoplasms - blood / Ovarian Neoplasms - diagnostic imaging / Ovarian Neoplasms - genetics / Ovarian Neoplasms - physiopathology / Penetrance / Phenotype / Progesterone - blood / Regression analysis / Steroids / Ultrasonic imaging / Ultrasonography / United Kingdom / Womens health