164 AR = androgen receptor; BMI = body mass index; CAG = cytosine adenine guanine; GGC = guanine guanine cytosine.
Breast Cancer Research Vol 5 No 3 Lillie et al.
IntroductionThe role of androgens in breast cancer etiology has been a subject of both curiosity and confusion. It is still unclear by which mechanisms testosterone exerts its activity in the female breast, and whether the effects are predominantly proliferative or anti-proliferative on breast cells at physiologic levels. In the present review we evaluate the results from epidemiologic studies on the role of circulating testosterone and a functional polymorphism in the androgen receptor (AR) in breast cancer. We also highlight some of the epidemiologic challenges in addressing these questions.
Sources of endogenous testosteroneThere are two main sources of androgens in women. Testosterone is produced directly by the ovary and by conversion of the adrenal androgens dehydroepiandrosterone and dehydroepiandrosterone-sulfate into androstenedione, and then further to testosterone in peripheral tissue [1]. In premenopausal women, approximately 25% of circulating testosterone is secreted directly from the adrenal gland and 25% from the ovary, whereas the remaining 50% is produced by peripheral conversion of androstenedione [2]. Testosterone levels vary over the menstrual cycle with peak levels mid-cycle, and diurnally with highest levels in the early morning [3].Testosterone and androstenedione are produced by the interstitial cells of the ovarian stroma and may continue to respond to gonadotopins and produce testosterone after the menopause [4]. In normal postmenopausal women the ovarian vein has been observed to have higher concentrations of testosterone than is found in peripheral blood; bilateral oophorectomy results in reductions in testosterone levels by as much as 50% [5].Several smaller cross-sectional studies have found lower testosterone levels in postmenopausal than premenopausal women [6][7][8] or lower levels in perimenopausal than premenopausal women [2]. Large longitudinal studies that have followed women through the menopausal transition have observed either no significant change in testosterone [2,9] or a 15% decrease in both testosterone and androstenedione at menopause [10]. In one study of women aged 50-89 years testosterone levels were lowest at the time of the menopause, whereas women older than 70 years or more than 20 years postmenopause had levels approximating those of premenopausal women [11].
ReviewThe role of androgens and polymorphisms in the androgen receptor in the epidemiology of breast cancer
AbstractTestosterone binds to the androgen receptor in target tissue to mediate its effects. Variations in testosterone levels and androgen receptor activity may play a role in the etiology of breast cancer. Here, we review the epidemiologic evidence linking endogenous testosterone to breast cancer risk. Paradoxically, results from observational studies that have examined polymorphisms in the androgen receptor suggest that the low-activ...