Highlights
- •The susceptibility to the prothrombotic effect of oral contraceptives (OC) differs.
- •The role of the first pass-metabolism of ethinylestradiol therefore was studied.
- •Genetic variation in UGT2B7 may, in part, explain thrombosis risk in OC users.
Abstract
Background
Use of ethinylestradiol, one of the active ingredients in combined oral contraceptives,
affects the incidence of venous thrombosis. To explain why some women develop thrombosis
when using oral contraceptives and others do not, we hypothesized a role for the first-pass
metabolism of ethinylestradiol in the liver. We set out to determine the association
between genetic variation in the first-pass metabolism of ethinylestradiol, venous
thrombosis risk and the effect on Sex-hormone-binding-globulin (SHBG) levels.
Methods
Premenopausal women were included from two case-control studies: LETS (103 cases;
159 controls) and MEGA (397 cases; 796 controls). Haplotype-tagging SNPs were selected
in 11 candidate genes; COMT, CYP1A2, CYP2C9, CYP3A4, CYP3A5, SULT1A1, SULT1E1, UGT1A1,
UGT1A3, UGT1A9, UGT2B7. Venous thrombosis risk was expressed as odds ratios (OR) with
95% confidence intervals (CI). For SHBG levels, mean differences with 95%CI were estimated
in combined oral contraceptive-using control subjects from the MEGA study.
Results
Two copies of haplotype D in the UGT2B7 gene increased venous thrombosis risk (ORLETS: 3.78; ORMEGA: 2.61) as well as SHBG levels (mean difference 27.6 nmol/L, 95%CI: −61.7 to 116.9 compared with no copies) in oral contraceptive users and not in non-users.
In oral contraceptive users, haplotype A and B in the CYP3A4 gene were associated
with venous thrombosis risk, but not in non-users; however, the effect on SHBG levels
was not directional with the risk. None of the other haplotypes were associated with
venous thrombosis.
Conclusion
Genetic variation in the UGT2B7 gene may, in part, explain venous thrombosis risk
in combined oral contraceptive users.
Keywords
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References
- Venous thromboembolic disease and combined oral contraceptives: results of international multicentre case-control study. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception.Lancet. 1995; 346: 1575-1582
- Population-based study of risk of venous thromboembolism associated with various oral contraceptives.Lancet. 1997; 349: 83-88
- Risk factors for fatal venous thromboembolism in young women: a case–control study.Int J Epidemiol. 1992; 21: 48-52
- Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation.Lancet. 1994; 344: 1453-1457
- Thromboembolic disease and the steroidal content of oral contraceptives. A report to the committee on safety of drugs.BMJ. 1970; 2: 203-209
- Oral contraceptives and venous thromboembolism: findings in a large prospective study.BMJ (Clin Res Ed). 1986; 292: 526
- Higher risk of venous thrombosis during early use of oral contraceptives in women with inherited clotting defects.Arch Intern Med. 2000; 160: 49-52
- Hormonal contraception and risk of venous thromboembolism: national follow-up study.BMJ. 2009; 339: b2890
- The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case–control study.BMJ. 2009; 339: b2921
- Enzymology of human cytosolic sulfotransferases.FASEB J. 1997; 11: 206-216
- Human sulfotransferases and their role in chemical metabolism.Toxicol Sci. 2006; 90: 5-22
- Pharmacogenetics of soluble sulfotransferases (SULTs).Naunyn Schmiedebergs Arch Pharmacol. 2004; 369: 55-68
- Sulfotransferase (SULT) 1A1 polymorphic variants *1, *2, and *3 are associated with altered enzymatic activity, cellular phenotype, and protein degradation.Mol Pharmacol. 2006; 69: 2084-2092
- Sulfotransferase 1E1 is a low km isoform mediating the 3-O-sulfation of ethinylestradiol.Drug Metab Dispos. 2004; 32: 1299-1303
- Pharmacokinetic drug interactions involving 17alpha-ethinylestradiol: a new look at an old drug.Clin Pharmacokinet. 2007; 46: 133-157
- Pharmacogenomics of human UDP-glucuronosyltransferase enzymes.Pharmacogenomics J. 2003; 3: 136-158
- Specificity and regioselectivity of the conjugation of estradiol, estrone, and their catecholestrogen and methoxyestrogen metabolites by human uridine diphospho-glucuronosyltransferases expressed in endometrium.J Clin Endocrinol Metab. 2004; 89: 5222-5232
- Expression of UGT1A and UGT2B mRNA in human normal tissues and various cell lines.Drug Metab Dispos. 2008; 36: 1461-1464
- Role of human cytochrome P450 1A1, 1A2, 1B1, and 3A4 in the 2-, 4-, and 16alpha-hydroxylation of 17beta-estradiol.Metabolism. 2001; 50: 1001-1003
- Oxidation of 17 alpha-ethynylestradiol by human liver cytochrome P-450.Mol Pharmacol. 1988; 33: 500-508
- Characterization of the oxidative metabolites of 17beta-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms.Endocrinology. 2003; 144: 3382-3398
- Influence of the catechol-O-methyltransferase (COMT) codon 158 polymorphism on estrogen levels in women.Hum Reprod. 2003; 18: 262-266
- Comparison of pharmacodynamic properties of various estrogen formulations.Am J Obstet Gynecol. 1982; 144: 511-518
- Sex hormone binding globulin capacity as an index of oestrogenicity or androgenicity in women on oral contraceptive steroids.Clin Endocrinol (Oxf). 1979; 10: 39-45
- Can changes in sex hormone binding globulin predict the risk of venous thromboembolism with combined oral contraceptive pills?.Acta Obstet Gynecol Scand. 2002; 81: 482-490
- The Leiden Thrombophilia Study (LETS).Thromb Haemost. 1997; 78: 631-635
- No association between the common MTHFR 677C → T polymorphism and venous thrombosis: results from the MEGA study.Arch Intern Med. 2007; 167: 497-501
- Malignancies, prothrombotic mutations, and the risk of venous thrombosis.JAMA. 2005; 293: 715-722
- PLINK: a tool set for whole-genome association and population-based linkage analyses.Am J Hum Genet. 2007; 81: 559-575
- Mesenteric vein thrombosis associated with intravaginal contraceptives: a case report and review of the literature.J Thromb Thrombolysis. 2003; 15: 105-108
- Cerebral venous sinus thrombosis associated with a combined contraceptive ring.Neurologist. 2011; 17: 105-106
- Comparison of cycle control with a combined contraceptive vaginal ring and oral levonorgestrel/ethinyl estradiol.Am J Obstet Gynecol. 2002; 186: 389-395
- Efficacy and safety of a contraceptive vaginal ring (NuvaRing) compared with a combined oral contraceptive: a 1-year randomized trial.Contraception. 2005; 71: 176-182
- Venous thrombosis in users of non-oral hormonal contraception: follow-up study, Denmark 2001–10.BMJ. 2012; 344e2990
- Venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive system users.Obstet Gynecol. 2007; 109: 339-346
- Extended case-control study results on thromboembolic outcomes among transdermal contraceptive users.Contraception. 2010; 81: 408-413
- Risk of nonfatal venous thromboembolism in women using a contraceptive transdermal patch and oral contraceptives containing norgestimate and 35 microg of ethinyl estradiol.Contraception. 2006; 73: 223-228
- ORTHO EVRA and venous thromboembolism: an update.Contraception. 2010; 81: 452-453
- DNA polymorphisms in sex hormone pathway genes and risk of esophageal squamous cell carcinoma.Cancer Prev Res. 2010; 3: B27
- Association of variants in estrogen-related pathway genes with prostate cancer risk.Prostate. 2013; 73: 1-10
Article info
Publication history
Published online: June 01, 2017
Accepted:
May 22,
2017
Received:
May 15,
2017
Identification
Copyright
© 2017 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
