Increased catechol estrogen metabolism as a risk factor for nonfamilial breast cancer

• Published in: Cancer Vol. 69; no. 2; pp. 457 - 465
• Main Authors: Lemon, Henry M., Heidel, Jack W., Rodriguez‐Sierra, Jorge F.
• Format: Journal Article
• Language: English
• Published: New York Wiley Subscription Services, Inc., A Wiley Company 15.01.1992; Wiley-Liss
• Subjects: Adolescent; Adult; Asian Continental Ancestry Group; Biological and medical sciences; Breast Neoplasms - ethnology; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Estrogens, Catechol - metabolism; European Continental Ancestry Group; Female; Gynecology. Andrology. Obstetrics; Humans; Medical sciences; Menstrual Cycle - urine; Meta-Analysis as Topic; Middle Aged; Models, Biological; Retrospective Studies; Risk Factors; Steroid 16-alpha-Hydroxylase; Human; Mammary gland diseases; Risk factor; Estrogen; Female; Pyrocatechol; Mammary gland; Malignant tumor; Metabolism; Epidemiology
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/1097-0142(19920115)69:2<457::AID-CNCR2820690231>3.0.CO;2-8

The metabolism of estrone (E1) or estradiol‐17β (E2) to catechols seldom has been investigated in biochemical studies related to the risk of development of human breast cancer, as a result of the extreme lability and reactivity of these hormones. A method of indirect calculation was developed in which estimated catechol estrogen excretion (ECE) from urinary excretion of E1, E2, and estriol (E3) was used, based on the obligate reciprocal relation between 16 α‐hydroxylase activity (r3) and estrogen 2/4 hydroxylase function (r2). This relationship is expressed by r2 × r3 = K, the estrogen oxidative constant. From published data relating chiefly to 2‐OH estrone excretion, K = 12.4 ± M 0.8 (standard error of the mean). Urinary E1 + E2 excretion rates reflect nonprotein‐bound plasma ovarian estrogen concentrations available for cell metabolism, which influence the value of K. The equation: \documentclass{article}\pagestyle{empty}\begin{document}$$ {\rm r}_2 = [{\rm E}1\, + \,{\rm E}2]\,{\rm k}/[{\rm E}3\, + \,16\alpha {\rm OH}\,{\rm E}1] = {\rm ECE} $$\end{document} gives a median correlation coefficient between actual catechol estrogen excretion and ECE in μg/24 hours of +0.88 (range, 0.61 to 0.97). When tested against the best product isolation analysis of catechol estrogen excretion, ECE was 95% accurate. Using this method a metaanalysis was conducted of published fractional estrogen excretion collected from 2846 healthy women worldwide aged 15 to 59 years, with a risk of breast cancer varying fivefold. Overall ECE was 78% to 97% higher in high‐risk women of all ages and menstrual cycle phases (P < 0.001, by Wilcoxon test). With increasing cancer risk (as estimated by the authors), ECE rose linearly exponentially with a slope of 0.149 (follicular phase) and 0.136 (luteal phase). The correlation coefficient (R2) between the two variables was 0.77 and 0.57, respectively (P < 0.05). These data derived from calculations of ECE in healthy women confirmed recent analytic results of a twofold increase in the ratio of 2‐OH E1/4‐OH E1 in healthy Finnish women compared with recent Japanese migrants to Hawaii. In Finnish women with breast cancer, this ratio increased further (almost twofold). Metaanalysis supported the conclusion that increased rates of oxidation of estradiol 17‐β to 2‐OH catechols supply the principal proximal human mammary carcinogens active after menarche.