The results are compatible with the hypothesis that the increase in breast cancer risk with increasing BMI among postmenopausal women is largely the result of the associated increase in estrogens, particularly bioavailable estradiol.

Summary This is the first prospective study of unnary measures of the two major competing pathways of oestrogen metabolism, 16a-hydroxyoestrone (16a-OHE1) and 2-hydroxyoestrone (2-OHEl), in Correspondence to: EN Meilahn two irreversible and mutually exclusive pathways to form: (1) 16a-hydroxyoestrone or (2) 2-hydroxyoestrone. These are the major metabolic pathways for oestrogen with 4-hydroxylation as a minor pathway. albeit one that produces a carcinogenic product. The 2-and l6a-hydroxylation appear to compete for the limited oestrone substrate pool. and a rise in the extent of one hydroxvlation pathway will result in a shift of substrate towards the alternate and will reduce the absolute amount of the product of the competing, pathway.The 16at-and 2-OHE I metabolites are thought to have markedlv different biological properties. The major metabolites of oestrogen hydroxylated at the C-16a position (16a-hydroxyoestrone and oestriol) are oestrogenic (Martucci and Fishman.

Summary The associations between serum concentrations of oestradiol, progesterone, testosterone and sex hormone-binding globulin (SHBG) and risk of breast cancer in premenopausal women were investigated in a prospective study of breast cancer on the island of Guernsey. Sixty-two women diagnosed with breast cancer an average of 8 years subsequent to blood collection were matched for day of menstrual cycle, age and year of blood collection with 182 control subjects. Cases had a 12% higher mean oestradiol concentration over the whole menstrual cycle (P = 0.17) with a large difference at mid-cycle (75% higher, P = 0.04). Differences between cases and control subjects in progesterone (luteal phase), testosterone and SHBG were small and not statistically significant: luteal phase progesterone 9% lower in cases, P = 0.64; testosterone 4% higher, P = 0.57; SHBG 8% higher, P = 0.24. The small difference in oestradiol concentration could be aetiologically important, but larger prospective studies are needed.

The associations between serum concentrations of insulin-like growth factor-I (IGF-I), IGF-II and IGF-binding proteins (IGFBP)-3 and risk of breast cancer were investigated in a nested case -control study involving 117 cases (70 premenopausal and 47 postmenopausal at blood collection) and 350 matched controls within a cohort of women from the island of Guernsey, UK. Women using exogenous hormones at the time of blood collection were excluded. Premenopausal women in the top vs bottom third of serum IGF-I concentration had a nonsignificantly increased risk for breast cancer after adjustment for IGFBP-3 (odds ratio (OR) 1.71; 95% confidence interval (CI): 0.74 -3.95; test for linear trend, P ¼ 0.21). Serum IGFBP-3 was associated with a reduction in risk in premenopausal women after adjustment for IGF-I (top third vs the bottom third: OR 0.49; 95% CI: 0.21 -1.12, P for trend ¼ 0.07). Neither IGF-I nor IGFBP-3 was associated with risk in postmenopausal women and serum IGF-II concentration was not associated with risk in pre-or postmenopausal women. These data are compatible with the hypothesis that premenopausal women with a relatively high circulating concentration of IGF-I and low IGFBP-3 are at an increased risk of developing breast cancer. It is well established that insulin-like growth factor-I (IGF-I) and IGF-II can stimulate cell proliferation and inhibit cell death in many tissue types (Pollak, 2000) including normal and malignant breast cancer cells (Sachdev and Yee, 2001). The bioavailability of circulating IGF ligands is complex; at least six IGF-binding proteins (IGFBPs) have been identified, the most abundant of which is IGFBP-3. This binds approximately 75 -90% of circulating IGF-I and IGF-II and may be the most important determinant of IGF bioavailability (Jones and Clemmons, 1995).There is considerable between-person variation in the circulating concentrations of IGF-I, IGF-II and their binding proteins, believed to be due to genetic and environmental factors (Jones and Clemmons, 1995;Harrela et al, 1996). This variation may be important because epidemiological evidence suggests that elevated levels of serum IGF-I, as absolute concentrations or relative to IGFBP-3, may be associated with an increased risk of breast cancer in premenopausal women (Peyrat et al, 1993;Bruning et al, 1995;Bohlke et al, 1998;Hankinson et al, 1998;Petridou et al, 2000;Toniolo et al, 2000;Kaaks et al, 2002;Krajcik et al, 2002;Muti et al, 2002;Yu et al, 2002;Keinan-Boker et al, 2003). There are limited data on the association between serum IGF-II concentration and breast cancer risk (Holdaway et al, 1999;Li et al, 2001;Yu et al, 2002;Gr nbaek et al, 2004).The aim of this study is to examine the associations between serum concentrations of IGF-I, IGF-II and IGFBP-3 and subsequent breast cancer risk in a case -control study nested within a cohort of women on the island of Guernsey. MATERIALS AND METHODS The Guernsey cohortBetween 1977 and 1991, 6127 women aged 35 years or older who lived on the British island of Guernsey were re...

(SHBG) and risk of breast cancer in post-menopausal women were investigated in a prospective study on the island of Guernsey. Sixty-one women who developed breast cancer an average of 7.8 years after blood collection were matched for age, year of blood collection and number of years post-menopausal with 179 control subjects. Women using exogenous hormones at the time of blood collection were excluded from the study. Women who subsequently developed breast cancer had a 29% higher geometric mean oestradiol concentration than control women (P = 0.004). The odds ratio for breast cancer in the top third compared with the lowest third of the oestradiol concentration distribution was 5.03 (95% confidence interval 2.02-12.49, Pfor trend < 0.001). Adjusting for testosterone and SHBG concentrations did not substantially alter the odds ratio for oestradiol. Although testosterone and SHBG concentrations were associated with breast cancer risk, the concentrations of these hormones were correlated with those of oestradiol; the associations were not statistically significant after adjusting for oestradiol concentration. These data provide evidence that serum oestradiol concentrations in post-menopausal women may have a substantial effect on breast cancer risk.