Epidemiological studies provide strong evidence of a role for endogenous sex hormone levels in the aetiology of breast cancer  and suggest that levels may be partly genetically determined. Quantification of hormone levels in premenopausal women, however, is difficult because of their cyclical nature. In particular, oestrogen has a marked peak in the follicular phase and a further wider peak in the luteal phase.
We developed a protocol to capture peak follicular phase urinary oestrone glucuronide (E1G), and luteal phase E1G in healthy premenopausal women. Repeated measurements of creatinine-adjusted E1G levels, in 789 women, were used to describe features of the E1G curve such as mean and peak follicular E1G, and luteal E1G. A total of 691 tagging SNPs capturing common variation in genes within the oestrogen synthesis and metabolism pathways were successfully genotyped. Geometric mean urinary E1G levels and endogenous plasma hormone levels were estimated and tested for an association with the genotype of each SNP.
We identified a rare SNP (minor allele frequency 7%), in which the minor allele was associated with a 20% reduction in circulating levels of E1G in healthy premenopausal women (P < 10-8). We are currently genotyping this SNP in 12,000 breast cancer cases and 12,000 controls to test whether the reduction in circulating oestrogen levels is also associated with a reduction in breast cancer risk.
Circulating hormone levels in premenopausal women may provide a useful intermediate phenotype in the search for low-penetrance breast cancer risk alleles.