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Premenopausal Mammographic Density in Relation to Cyclic Variations in Endogenous Sex Hormone Levels, Prolactin, and Insulin-like Growth Factors

¹ Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine; ² Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research; ³ The Academic Department of Biochemistry, The Royal Marsden Hospital, London, United Kingdom; ⁴ Centre for Reproductive Biology, The Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom; ⁵ University Department of Clinical Science at North Bristol, Southmead Hospital, Bristol, United Kingdom; and ⁶ Cancer Screening Evaluation Unit and ⁷ Cancer Research UK Epidemiology and Genetics Group, The Institute of Cancer Research, Sutton, Surrey, United Kingdom

Requests for reprints: Isabel dos Santos Silva, Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, The Institute of Cancer Research, Keppel Street, London WC1E 7HT, United Kingdom. Phone: 44-20-7927-2113; Fax: 44-20-7436-4230; E-mail: isabel.silva{at}lshtm.ac.uk.

Key Words: breast cancer • mammographic density • steroid hormones and receptors • growth factors and receptors • prolactin

Mammographic density is strongly associated with breast cancer risk, and endogenous hormones, which are risk factors for breast cancer, may be involved in the mechanism. This cross-sectional study of 494 premenopausal women is the first to account for cyclic variations in estrogen levels, by measuring urinary estrone glucuronide (E1G) in the periovulatory and luteal phases of the menstrual cycle, and to assess the role of androgens. Computer-assisted density readings were obtained from digitized mammograms. Mean ovulatory E1G level and daily E1G load were both positively associated with percent density before adjustment for body mass index (BMI), with women in the top fourth having 10.2% (95% CI: 2.9%, 18.1%) and 8.9% (1.7%, 16.7%), respectively, higher density than those in the bottom fourth (P_trend before/after BMI adjustment = 0.006/0.11 and 0.01/0.13, respectively). Neither the peak nor luteal E1G levels were predictive of density after adjustment for E1G levels at other points in the cycle. The plasma androgens testosterone, androstenedione, and dehydroepiandrosterone sulfate were negatively associated with density. In mutually adjusted analyses, density was positively associated with insulin-like growth factor (IGF)-I and negatively with IGF-II (P_trend = 0.006 for both) but not with IGF binding protein-3. There was also weak evidence of a positive association of prolactin with density. The study supports the hypothesis that endogenous hormones affect density in premenopausal women; in particular, it shows a positive association between estrogen levels and density and suggests that the mean level throughout the cycle is the most biologically relevant measure. Most of these hormone-density associations were attenuated with further adjustment for BMI. [Cancer Res 2009;69(16):6490–99]