Estrogen Clearance: Genetic Insights into Optimal Treatment Choices

Although it is known for its pivotal role in the female body, estrogen is a vital hormone for both men and women. On a molecular level estrogen’s effects are mediated by the estrogen receptor (ER), a dimeric nuclear protein that binds to DNA and controls gene expression. The functions of estrogen are wide ranging, from reducing bowel motility to controlling the type of melanin being produced in the skin. Early in life estrogen influences the development of female secondary sexual characteristics during puberty, including breast development, widening of the hips, and female fat distribution. However, estrogen is most known for its powerful effects on the female reproductive cycle, helping to regulate ovulation and prepare the uterus for implantation. Though estrogen is essential for maintaining proper health, an imbalance of estrogen has been shown to promote disease.

At the heart of understanding how estrogen imbalance can play a role in disease development is understanding that there are three types of estrogen. The three major endogenous estrogens in females that have estrogenic hormonal activity are estrone, estradiol, and estriol. Estradiol is the most potent form as well as the most common form found in the female body. Estrogen is naturally opposed by progesterone and maintaining a proper balance of these hormones is important both to the function of the body and to the reduction of estrogen dependent cancers. 1 Estrogen related cancers are typically found in the reproductive system, and their formation can be influenced by both genetic and environmental factors.1 Genetic factors that affect cancer development can be due to changes in estrogen receptor function, metabolism and excretion.

Estrogen is metabolized in several different ways, with one of the most prominent using phase I enzymes CYP1A1 and CYP1B1 in partnership with the phase II enzymes COMT and GSTP1. For instance, CYP1A1 and CYP1B1 metabolizes estrogen to catecholestrogens. COMT has been demonstrated to play a role in estrogen metabolism through inactivation of these catecholestrogens.2 Catecholestrogen inactivation decreases the cancer-causing potential of these metabolites, while simultaneously increasing the amount of 2-methoxyestradiol, a metabolite that has been shown to inhibit the growth of breast cancer cells.3, 4,5 Additionally, COMT polymorphisms have been shown to exert an effect on estradiol levels.3,4 Met/Met allele carriers exhibit a 2-3 fold decrease in their ability to degrade catecholestrogens, which may result in higher estradiol levels than Val/Val allele carriers.4,6 Estradiol clearance is also diminished in both the Met/Met and Met/Val genotypes as opposed to Val/Val genotypes, however there is no significant difference in estrone levels.7 Dysfunction in this pathway can promote cancer, specifically breast cancer.1,8 Catecholestrogens (2-OHE2, 4-OHE2, 2-OHE1, and 4-OHE1) are the intermediate metabolite produced by CYP1A1 and CYP1B1 and have been shown in studies to promote cancer growth in breast cell lines2,3,9, in contrast to methoxyestrogen which has been shown to protect against the formation of breast cancer.4 Genetics play an important role in determining the rate at which each enzyme in the estrogen metabolism pathway performs it job. An example is the combination of a fast CYP1A1 enzyme and a slow COMT enzyme which increases risk for buildup of catecholestrogens thus increasing the chance of developing breast cancer. 10

Cancer prevention is about balance. It is important to make sure the proper ratios of estrogens are in balance and are being fully metabolized. It is equally important to make sure progesterone and estrogen are in proper proportions with each other. Partnering genetic testing with salivary hormone testing to identify bioavailable levels of hormone, and to understand a patients’ genotype can help a practitioner identify areas of weakness. These areas maybe in metabolism and/or enzyme function. Treatment solutions would include; routine screening, hormone balancing and supplementation with cofactors to help support enzyme function. These are powerful tools for cancer prevention.

Resources:
1. Crooke P et al. Estrogens, Enzyme Variants, and Breast Cancer: A Risk Model. Cancer Epidemiol Biomarkers Prev 2006; 15(9):1620-9.
2. Ball P and R Knuppen. Catecholoestrogens (2-and 4-hydroxyoestrogens): chemistry, biogenesis, metabolism, occurrence and physiological. Acta Endocrinol Suppl (Copenh). 1980;232:1-127.
3. Dawling S et al. Catechol-O-Methyltransferase (COMT)-mediated Metabolism of Catechol Estrogens: Comparison of Wild-Type and Variant COMT Isoforms. Cancer Res. 2001; 61:6716-6722.
4. Lakhani NJ et al. 2-Methoxyestradiol, a Promising Anticancer Agent. Pharmacotherapy. 2003; 23:165-172.
5. Lavigne JA et al. The Effects of Catechol-O-Methyltransferase Inhibition on Estrogen Metabolite and Oxidative DNBA Damage Levels in Estradiol-treated MCF-7 Cells. Cancer Research. 2001; 61:7488-7494.
6. Eriksson AL et al. The COMT val158met polymorphism Is Associated with Early Pubertal Development, Height and Cortical Bone Mass in Girls. Pediatr Res. 2005 Jul;58(1):71-7.
7. Worda C et al. Influence of the catechol-O-methyltransferase (COMT) codon 158 polymorphism on estrogen levels in women. Human Reproduction. 2003; 18(2):262-266.
8. Parl F et al. Estrogen Metabolism and Breast Cancer A Risk Model. Ann N Y Acad Sci. 2009 Feb; 1155: 68–75.
9. Dawling S et al. Catechol-O-Methyltransferase (COMT)-mediated Metabolism of Catechol Estrogens. Cancer Res September 15 2001 (61) (18) 6716-6722
10. Cavalieri e et al. Molecular origin of cancer: Catechol estrogen-3,4-quinones as endogenous tumor initiators. Proc Natl Acad Sci U S A. 1997 Sep 30; 94(20): 10937–10942.