help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2008-0450
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Canonico, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Canonico, M.
Related Collections
Right arrow Female Endocrinology
The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 8 3082-3087
Copyright © 2008 by The Endocrine Society

Synergism between Oral Estrogen Therapy and Cytochrome P450 3A5*1 Allele on the Risk of Venous Thromboembolism among Postmenopausal Women

Marianne Canonico, Elodie Bouaziz, Laure Carcaillon, Céline Verstuyft, Anne Guiochon-Mantel, Laurent Becquemont, Pierre-Yves Scarabin for the Estrogen Thromboembolism Risk (ESTHER) Study Group

Institut National de la Santé et de la Recherche Médicale Unit 780 (M.C., L.C., P.-Y.S.), Cardiovascular Epidemiology Section, and Université Paris-Sud, Institut Fédératif de Recherche 69, Villejuif, F- 94807 France; Laboratoire de Génétique moléculaire, Pharmacogénétique et Hormonologie (E.B., C.V., A.G.-M., L.B.), Hôpital Bicêtre, and Department of Pharmacology (C.V., L.B.), Université Paris-Sud, Le Kremlin-Bicêtre, F-94275 France; and Institut National de la Santé et de la Recherche Médicale Unit 693 (A.G.-M.), "Récepteurs stéroïdiens, Physiopathologie endocrinienne et métabolique", Institut Fédératif de Recherche 93, Université Paris-Sud, Faculté de médecine Paris sud, Le Kremlin-Bicêtre, F-94276 France

Address all correspondence and requests for reprints to: Marianne Canonico, Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 780 (U780), Cardiovascular Epidemiology Section, 16 avenue Paul Vaillant Couturier, Villejuif Cedex, F- 94807 France. E-mail: marianne.canonico{at}inserm.fr.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Hormone therapy increases the risk of venous thromboembolism (VTE) among postmenopausal women. This effect may be modulated by the expression of cytochromes P450 3A5 (CYP3A5) and 1A2 (CYP1A2) which are involved in the hepatic metabolism of estrogens.

Objective: The objective was to investigate the impact of CYP3A5 and CYP1A2 genetic polymorphisms on the association of VTE with hormone therapy.

Design: We conducted a case-control study.

Setting: This study was conducted in eight French hospital centers and in the general population.

Patients: CYP3A5 and CYP1A2 genotypes were evaluated among 195 cases with a first documented episode of idiopathic VTE and 533 controls matched for center, age, and admission date.

Outcome Measure: The outcome measure was hormone therapy by route of estrogen administration.

Results: Overall, oral but not transdermal estrogen increased VTE risk [odds ratio (OR) = 4.5, 95% confidence interval (CI) = 2.6–7.6, and OR = 1.2, 95% CI = 0.8–1.8, respectively]. The allele frequency of CYP3A5*1 was 9 and 10% among cases and controls (OR = 1.0; 95% CI = 0.6–1.5) and that of CYP1A2*1F was 72 and 71% among cases and controls (OR = 1.5; 95% CI = 0.8–2.8). Compared with nonusers, OR for VTE in users of oral estrogen was 3.8 (95% CI = 2.1–6.7) among patients without CYP3A5*1 allele and 30.0 (95% CI = 4.4–202.9) among patients with this allele (test for interaction P = 0.04). By contrast, there was no significant interaction between CYP3A5*1 allele and transdermal estrogen on VTE risk. There is no interaction between CYP1A2 genetic polymorphism and hormone therapy on VTE risk.

Conclusions: Women with CYP3A5*1 allele using oral estrogen can define a subgroup at high VTE risk. Additional data are needed to assess the relevance of this genetic biomarker in the medical management of menopause.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
Oral estrogen therapy is known to increase the risk of venous thromboembolism (VTE) among postmenopausal women (1, 2), whereas recent data suggest that transdermal estrogen use is safe (3, 4). The increased VTE risk among users of oral estrogen is attributed to the coagulation activation due to the hepatic first-pass effect of oral estrogen. Oral but not transdermal estrogen induces an increase in the estrone to 17β-estradiol ratio and induces proteins synthesis (5). In the liver, both estrone and 17β-estradiol are catabolized by several hepatic enzymes that catalyze the formation of specific metabolites (6). In particular, the human cytochromes P450 3A5 (CYP3A5) and 1A2 (CYP1A2) are implicated in the hepatic metabolism of estrogens (7). CYP3A5 is mainly expressed in the liver and has a strong genetic basis. Its expression is linked to the single-nucleotide polymorphism (SNP) 6986A->G in intron 3 that causes alternative splicing and a nonfunctional truncated protein (8). Low expression of CYP3A5 is found in homozygous carriers of the CYP3A5*3 allele, whereas homozygous and heterozygous carriers of the CYP3A5*1 allele exhibit high expression of CYP3A5 (8). With regard to CYP1A2, several polymorphisms, including the SNP –163C->A in the intron 1 (CYP1A2*1F), have been characterized in the past few years (9). Although data on this specific mutation effect are somewhat controversial (10), this polymorphism may be correlated to CYP1A2 inducibility, especially in smokers (11, 12). Whether or not the mutations of CYP3A5 and CYP1A2 influence the association of VTE with oral estrogens remains unknown. Therefore, in the ESTHER study, we investigated the impact of the CYP3A5 and CYP1A2 genetic polymorphisms on the association between hormone therapy by route of estrogen administration and VTE risk among Caucasian postmenopausal women.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
The ESTHER study is a multicenter case-control study aimed to investigate the impact of the route of estrogen administration on VTE risk among postmenopausal women aged 45–70 yr. The study was carried out in France in eight hospital centers and in the general population between 1998 and 2006. A detailed description has been published (3, 4, 13).

Selection of cases and controls

During 1998–2006, 208 hospital cases with a first documented episode of idiopathic VTE were recruited consecutively, and 426 hospital controls were matched by center, 2-yr age band, and admission date. Each case was matched with one to three controls on an individual basis. Hospital controls had to have been admitted in the same hospital with a diagnosis a priori unrelated to estrogen use, including diseases of eye, ear, skin, respiratory and alimentary tracts, bones and joints, kidneys, infectious diseases, and diabetes. Moreover, between 1999 and 2002, we consecutively included 63 outpatient cases from three hematology outpatient clinics and their community controls (n = 184) selected at random from electoral rolls and matched by age and area of residence.

Both hospital and outpatient cases were excluded if they reported a personal history of VTE, had a contraindication for hormone therapy (breast cancer, cardiovascular diseases, etc.), or had a predisposing factor for VTE (history within the previous month of surgical intervention, trauma with immobilization for longer than 8 d, illness necessitating bed rest for longer than 8 d, known cancer, or systemic inflammatory disease) or a known thrombophilia. Outpatient cases were also excluded if they were referred for estrogen advice after a VTE. Controls were subject to the same exclusion criteria as were cases. The protocol was approved by Institut National de la Santé et de la Recherche Médicale and the local ethics committee. Written and informed consent was obtained from all women.

Ascertainment of cases

Diagnoses of VTE required confirmation by imaging procedures. Pulmonary embolism was defined as the presence of one of the following: helical computed tomography showing at least one intraluminal defect in one segmental pulmonary artery, high probability ventilation/perfusion scan according to criteria from the Prospective Investigation of Pulmonary Embolism Diagnosis, or pulmonary angiography showing a clot. Deep venous thrombosis was diagnosed using compression ultrasonography. Events were adjudicated within each center but also centrally for outpatient cases. Events were validated by investigators blinded to estrogen.

Data collection

Cases and controls were identified without knowledge of estrogen use, and they were interviewed at hospital with a standardized questionnaire. Individual race was defined by self-reporting of parent’s ethnicity. Menopause was defined by amenorrhea for more than 12 months or bilateral ovariectomy or hysterectomy and age older than 52 yr. Women were classified as current users of hormone therapy if they reported use of estrogen within the past 3 months before the case admission date. Identification of hormone type was assessed during the direct interview by showing pictures of available hormone therapy. Current smokers were women who had smoked within the 3 months before inclusion. Varicose veins were defined as a reported history of varicose veins or stripping. Family history of VTE was defined as the occurrence of VTE before 65 yr in a first-degree relative. Hypertension was defined as self-reported systolic pressure greater than 140 mm Hg, diastolic pressure greater than 90 mm Hg, or use of antihypertensives. Diabetes mellitus was defined as a self-reported history of physician-diagnosed diabetes or use of antidiabetics or both.

Genotyping analyses

Venous blood was obtained from the antecubital vein and anticoagulated with EDTA. DNA was extracted centrally by the salt precipitation method, and purified genomic DNA was stored at –20 C. Genotyping for allelic variations was performed using the TaqMan allelic discrimination assay (Applied Biosystems, Foster City, CA). CYP1A2*1F genotyping was performed as previously described (11, 12). Intron 3 of CYP3A5 gene was amplified using the following primers: forward, 5'-ACC CAG CTT AAC GAA TGC TCT ACT-3', and reverse, 5'-GAA GGG TAA TGT GGT CCA AAC AG-3'. The following fluorescent probes (VIC and FAM) were used: VIC, 5'-TTT TGT CTT TCA ATA TCT CTT-3' for detecting CYP3A5*1 allele, and FAM, 5'-TTG TCT TTC AGT ATC TCT T-3' for detecting CYP3A5*3 allele. Amplification was performed in a final volume of 15 µl containing TaqMan Universal PCR Master Mix, 200 nM of each probe and 900 mM of each primer. The PCR program was started with 2 min at 50 C, 10 min at 95 C, followed by 35 cycles consisting of 92 C for 15 sec and 60 C for 1 min. The post-PCR-generated fluorescence intensity was quantified using an ABI 7000 Sequence Detector System software version 1.2.3 (Applied Biosystems, Courtaboeuf, France). Each SNP genotyping procedure was performed in duplicate (separate experiments) for each patient. Sequenced wild-type homozygous, heterozygous, or muted homozygous patient samples were used as controls. All PCR reagents were purchased from Applied Biosystems (Courtaboeuf, France). Finally, genotypes were obtained for 195 cases (109 with pulmonary embolism and 86 with deep venous thrombosis) and 533 controls. This genetic investigation was a designed post hoc study.

Statistical analysis

Continuous data are expressed as means and SD, and qualitative variables are given as absolute values and percentages. Two-tailed Student’s t test was used for comparison of continuous variables, and {chi}2 test for qualitative variables. The {chi}2 test was used to compare the observed numbers of each genotype with those expected under Hardy-Weinberg equilibrium.

Crude odds ratios (OR) and 95% confidence intervals (CI) were estimated using an unconditional logistic regression. The original matching was taken into account by adjustment for age, center, and admission date. Further adjustments included potential confounding variables such as obesity, family history of VTE, and varicose veins.

First, we estimated the VTE risk associated with hormone therapy by route of estrogen administration and with genetic mutations of CYP3A5 and CYP1A2. Second, stratified analyses were performed to estimate the impact of hormone therapy by the route of estrogen administration and CYP3A5 genetic status. Finally, we estimated the VTE risk in relation to CYP3A5 genetic status and hormone therapy by route of estrogen administration using the nonusers of hormone therapy with CYP3A5*3/*3 genotype as the reference group. Interactions between hormone therapy and genetic status were tested using a multiplicative OR model.

Statistical analyses were performed using SAS statistical software (version 9.1; SAS Institute Inc., Cary, NC).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
General characteristics of cases and controls and distribution of CYP3A5 and CYP1A2 genotypes are given in Table 1Go. One hundred ninety-five cases (164 hospital and 31 outpatient cases) and 533 controls (353 hospital and 180 community controls) were successfully genotyped for one or both studied genetic polymorphisms. Women were exclusively Caucasians. Mean body mass index was higher in cases than in controls, and obesity was more frequent among cases than controls. Cases were more likely than controls to have reported a family history of VTE, personal history of varicose veins, and use of oral estrogen therapy.


View this table:
[in this window]
[in a new window]

  		TABLE 1. Characteristics of cases and controls

 
Most current users of estrogen therapy received 17β-estradiol; no controls and only two cases used conjugated equine estrogens. Regarding transdermal estrogen users, more than 95% of women received preparations delivering 50 µg 17β-estradiol per day or less. Transdermal estrogen was used alone or combined with either micronized progesterone, pregnane derivatives, or norpregnane derivatives. In current users of oral estrogen therapy, the mean dose of estradiol was 1.5 mg/d, ranging from 0.5–2 mg daily. Oral estrogen was administrated alone or combined with micronized progesterone, pregnane derivatives, norpregnane derivatives, or nortestosterone derivatives.

The distributions of CYP3A5 and CYP1A2 genotypes in the control subjects were consistent with those predicted under the conditions of Hardy-Weinberg equilibrium (P > 0.05 for CYP3A5 and CYP1A2). The frequencies of the CYP3A5*1 allele and CYP1A2*1F allele among controls (9.2 and 70.8%, respectively) were close to those expected in the Caucasian population.

Table 2Go shows the OR of VTE by hormone therapy or genetic status. Overall, oral but not transdermal estrogen increased VTE risk (OR = 4.5, 95% CI = 2.6–7.6 and OR = 1.2, 95% CI = 0.8–1.8, respectively, after adjustment for age, center, admission date, obesity, and family history of VTE and varicose veins). Neither CYP3A5*3 allele nor CYP1A2*1F allele was significantly associated with VTE risk (OR = 1.0, 95% CI = 0.6–1.5 and OR = 1.5, 95% CI = 0.8–2.8, respectively, after complete adjustment). With respect to CYP1A2, stratified analyses by smoking status did not change the results (data not shown).


View this table:
[in this window]
[in a new window]

  		TABLE 2. OR of VTE by hormone therapy use or genetic mutations (CYP3A5*1 allele and CYP1A2*1F allele)

 
Table 3Go shows the VTE risks in relation to hormone therapy (by route of estrogen administration) stratified by CYP3A5 genotype status. Compared with nonusers, OR for VTE in current users of oral estrogen was 3.8 (95% CI = 2.1–6.7) among patients without the CYP3A5*1 allele and 30.0 (95% CI = 4.4–202.9) among women who carry at least one copy of CYP3A5*1 allele. The interaction between CYP3A5*1 allele and oral estrogen on VTE risk was significant (P = 0.048). By contrast, there was no significant interaction between CYP3A5*1 allele and transdermal estrogen use on VTE risk (OR = 1.0, 95% CI = 0.1–1.7 among patients without CYP3A5*1 allele and OR = 3.2, 95% CI = 0.9–9.6 among patients with CYP3A5*1 allele). Stratified analyses by both genotype status of CYP1A2 and smoking status showed no significant difference in VTE risk associated with hormone therapy by route of estrogen administration (data not shown).


View this table:
[in this window]
[in a new window]

  		TABLE 3. OR of VTE in relation to hormone therapy by genotype status of CYP3A5

 
Finally, Fig. 1Go displays the VTE risk according to CYP3A5 genotype status and hormone therapy by route of estrogen administration using the nonusers without the CYP3A5*1 allele as the reference group. Women with the CYP3A5*1 allele treated by oral estrogen defined a subgroup at high VTE risk.


Figure 1
View larger version (7K):
[in this window]
[in a new window]

  		FIG. 1. Risk of VTE in relation to hormone therapy by route of estrogen administration and CYP3A5 genetic status. Values are OR [95% CI] adjusted for age, center, admission date, obesity, and family history of VTE and varicose veins.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This report shows a synergism between CYP3A5*1 allele and oral estrogen use on VTE risk. Oral estrogen users who carry CYP3A5*1 allele can define a subgroup at high VTE risk. By contrast, there is no interaction between CYP3A5*1 allele and transdermal estrogen use on VTE risk. On the other hand, there is no interaction between CYP1A2 genetic polymorphism and hormone therapy on VTE risk.

To our knowledge, the present study is the first to investigate the influence of CYP3A5 genetic polymorphism on the relation between hormone therapy and VTE risk. Previous studies have investigated the influence of CYP3A5 genetic polymorphisms in other conditions. First, the impact of this mutation on the metabolism of several drugs has been studied namely in solid-organ transplantation. CYP3A5 is involved in tacrolimus metabolism and modulates its oral disposition. Allograft recipients carrying the CYP3A5*1 allele need higher daily doses of tacrolimus to achieve plasma target concentrations because of an increased hepatic and intestinal metabolism (14, 15). Second, the CYP3A5 genetic polymorphism has been investigated in relation to blood pressure. Despite conflicting results, CYP3A5*1 allele emerged as a risk factor for hypertension (16, 17, 18, 19). The mechanism underlying this association could be based on the sodium reabsorption increase among carriers of CYP3A5*1 allele, possibly via cortisol and/or aldosterone metabolism (16). Finally, CYP3A5 is involved in estrogen metabolism (7), and CYP3A5 genetic polymorphism has been studied in estrogen-dependent diseases, especially breast cancer. CYP3A5 SNP may be implicated in a substantial increase in tamoxifen metabolism and thus leads to a lower efficacy of this therapy on the survival of patients with estrogen-receptor-positive tumors. So, women who did not carry the CYP3A5*1 allele were more likely to have a recurrence-free survival with prolonged tamoxifen treatment (20).

The impact of the CYP3A5*3 SNP on the relation between oral estrogen use and VTE risk is biologically plausible. When administrated by oral route, estrogen therapy results in a substantial increase in plasma estrone concentration leading to a nonphysiological ratio of estrone to estradiol close to 5. By contrast, transdermal estrogen leads to plasma estrone to estradiol ratios close to 1, which is similar to that in menstruating women and does not alter liver protein production (5, 21). In the liver, there is a dynamic mutual conversion system between estradiol and estrone, and both these estrogens are metabolized by cytochrome P450 (22). Estrogen metabolism can lead to a deactivation and elimination of parent hormone or, alternatively, may result in the production of metabolites that have altered hormonal properties (23). Estrogen metabolism by CYP3A5 leads in particular to 4-hydroxy derivatives (24) and to 16{alpha}-hydroxy derivatives (25). These metabolites could be involved in a more important hormone-responsive process as a result of changes in both the strength of estrogen receptor binding and the dissociation rate of the metabolite-receptor complex (26, 27, 28, 29). Because it is now well known that an enhanced estrogenic exposure is an important determinant of VTE risk (3, 30, 31), oral estrogen users who carry the CYP3A5*1 allele might be at higher risk for VTE.

One potential limitation of our study is that observational studies are subject to bias. The validity of the ESTHER study has already been discussed (3, 4, 13). In the present analysis, potential biases include confounding factors, missing values, and misrepresentation of genotypic distribution. First, elevated levels of VTE risk factors, including age, obesity, and family history of VTE, varicose veins, and prothrombotic mutations (either factor V Leiden or G20210A prothrombin mutation) could explain our findings related to oral estrogen use by CYP3A5 genetic polymorphism. However, the proportion of women at high VTE risk was similar among oral estrogen users who carry the CYP3A5*1 allele compared with other different subgroups. Furthermore, adjustment for these potential confounding factors made little change to the results, and there was no interaction of CYP3A5 genetic polymorphism with the prothrombotic mutations, especially factor V Leiden. In addition, the characteristics of hormone therapy in this subgroup at high VTE risk did not significantly differ from the other ones, especially regarding the daily estrogen doses. Second, DNA was not available for 76 cases (28.0%) and for 77 controls (12.6%), and these missing data could result in a bias. However, this bias would have to have occurred differentially according to the hormone therapy use and to the genetic status to affect the results. Finally, another bias could be related to a misrepresentation of genotypic frequencies in our sample. However, the allelic frequency of the CYP3A5*1 allele among controls was not significantly different according to hormonal therapy.

Our findings could have clinical implications in the medical management of menopause. Pulmonary embolism accounts for about one third of the excess incidence of potentially fatal events due to hormone therapy (30). Recent guidelines now recommend that women are prescribed the lowest effective dose of hormone therapy for the shortest time possible (31). Whereas there is little increased risk of stroke and breast cancer within the first year of treatment, pulmonary embolism has become the major potentially fatal event due to short-term hormone therapy use. Therefore, detection of women at high risk is important in assessing the benefit/risk profile of hormone therapy. Our study shows that the increase in VTE risk in oral estrogen users is more pronounced among women who carry the CYP3A5*1 allele. By contrast, transdermal estrogen therapy may be safe with respect to thrombotic risk and does not interact with CYP3A5 genetic polymorphism. These findings could provide additional information for VTE risk stratification among women who require hormone therapy. However, these data need to be confirmed, and performance characteristics of this genetic biomarker, including cost-effectiveness analyze, should be assessed. Further research could also include an in vitro determination of the effects of different estrogen metabolites by CYP3A5. In addition, the effect of transdermal estrogen use on VTE risk should to be assessed in randomized controlled trials.


   Footnotes
 
This work was supported by the Fondation de France, by the Fondation pour la Recherche Médicale (FRM) and INSERM, and by grants from Aventis, Besins International, Sanofi, and Servier Institute.

P.-Y. Scarabin was the principal investigator and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design were the responsibility of P.-Y. Scarabin, E. Oger, and G. Plu-Bureau; acquisition of data was the responsibility of E. Oger, G. Plu-Bureau, J. Conard, M. T. Barrellier, G. Meyer, D. Wahl, N. Trillot, H. Lévesque, C. Verstuyft, L. Carcaillon, E. Bouaziz, L. Becquemont, A. Guiochon-Mantel, M. Canonico, and P.-Y. Scarabin; analysis and interpretation of data were the responsibility of C. Verstuyft, L. Carcaillon, E. Bouaziz, L. Becquemont, A. Guiochon-Mantel, M. Canonico, and P.-Y. Scarabin; and drafting of the manuscript was the responsibility of C. Verstuyft, L. Carcaillon, E. Bouaziz, L. Becquemont, A. Guiochon-Mantel, M. Canonico, and P.-Y. Scarabin.

Clinical centers included Département de Médecine Interne, Hôpital de la Cavale Blanche, Brest (E. Oger and D. Mottier); Service d'Exploration Fonctionnelle, Centre Hospitalier de Caen (M. T. Barrellier); Unité Hémostase-Thrombose, Hôtel-Dieu, Paris (J. Conard and G. Plu-Bureau); Service de Médecine Interne et Médecine Générale, Service d'Hématologie Biologique, Centre Hospitalier et Universitaire de Nancy (D. Wahl, T. Lecompte, and E. de Maistre); Département de Pneumologie, Hôpital Européen Georges Pompidou, Paris (G. Meyer and M. T. Guillanneuf); Laboratoire d'Hématologie, Hôpital Cardiologique, Lille (N. Trillot and B. Jude); Département de Médecine Interne, Centre Hospitalier de Rouen (H. Lévesque and N. Cailleux); and Département de Médecine Vasculaire, Hôpital Purpan, Toulouse (P. Léger and A. Elias).

DNA analysis was done at the Laboratory of Molecular Genetics, Pharmacogenetics, and Hormonology and INSERM U693, "Récepteurs stéroïdiens, Physiopathologie endocrinienne et métabolique" (C.V., E.B., L.B., and A.G.-M.).

The coordinating center was INSERM U780 (G. Plu-Bureau, E. Oger, L. Carcaillon, M. Canonico and P.-Y. Scarabin).

The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Disclosure Statement: The authors have nothing to disclose.

First Published Online July 15, 2008

Abbreviations: CI, Confidence interval; CYP, cytochrome P450; ESTHER, Estrogen and Thromboembolism Risk; OR, odds ratio; SNP, single-nucleotide polymorphism; VTE, venous thromboembolism.

Received February 27, 2008.

Accepted May 15, 2008.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J 2002 Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 288:321–333[Abstract/Free Full Text]
  2. Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, Bonds D, Brunner R, Brzyski R, Caan B, Chlebowski R, Curb D, Gass M, Hays J, Heiss G, Hendrix S, Howard BV, Hsia J, Hubbell A, Jackson R, Johnson KC, Judd H, Kotchen JM, Kuller L, LaCroix AZ, Lane D, Langer RD, Lasser N, Lewis CE, Manson J, Margolis K, Ockene J, O'Sullivan MJ, Phillips L, Prentice RL, Ritenbaugh C, Robbins J, Rossouw JE, Sarto G, Stefanick ML, Van Horn L, Wactawski-Wende J, Wallace R, Wassertheil-Smoller S 2004 Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 291:1701–1712[Abstract/Free Full Text]
  3. Scarabin PY, Oger E, Plu-Bureau G 2003 Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet 362:428–432[CrossRef][Medline]
  4. Canonico M, Oger E, Plu-Bureau G, Conard J, Meyer G, Levesque H, Trillot N, Barrellier MT, Wahl D, Emmerich J, Scarabin PY 2007 Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study. Circulation 115:840–845[Abstract/Free Full Text]
  5. De Lignieres B, Basdevant A, Thomas G, Thalabard JC, Mercier-Bodard C, Conard J, Guyene TT, Mairon N, Corvol P, Guy-Grand B, et al 1986 Biological effects of estradiol-17β in postmenopausal women: oral versus percutaneous administration. J Clin Endocrinol Metab 62:536–541[Abstract/Free Full Text]
  6. Martucci CP, Fishman J 1993 P450 enzymes of estrogen metabolism. Pharmacol Ther 57:237–257[CrossRef][Medline]
  7. Lee AJ, Cai MX, Thomas PE, Conney AH, Zhu BT 2003 Characterization of the oxidative metabolites of 17β-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms. Endocrinology 144:3382–3398[Abstract/Free Full Text]
  8. Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J, Watkins PB, Daly A, Wrighton SA, Hall SD, Maurel P, Relling M, Brimer C, Yasuda K, Venkataramanan R, Strom S, Thummel K, Boguski MS, Schuetz E 2001 Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 27:383–391[CrossRef][Medline]
  9. Sachse C, Brockmoller J, Bauer S, Roots I 1999 Functional significance of a C->A polymorphism in intron 1 of the cytochrome P450 CYP1A2 gene tested with caffeine. Br J Clin Pharmacol 47:445–449[CrossRef][Medline]
  10. Cornelis MC, El-Sohemy A, Kabagambe EK, Campos H 2006 Coffee, CYP1A2 genotype, and risk of myocardial infarction. JAMA 295:1135–1141[Abstract/Free Full Text]
  11. Han XM, Ou-Yang DS, Lu PX, Jiang CH, Shu Y, Chen XP, Tan ZR, Zhou HH 2001 Plasma caffeine metabolite ratio (17X/137X) in vivo associated with G-2964A and C734A polymorphisms of human CYP1A2. Pharmacogenetics 11:429–435[CrossRef][Medline]
  12. Funck-Brentano C, Raphael M, Lafontaine M, Arnould JP, Verstuyft C, Lebot M, Costagliola D, Roussel R 2006 Effects of type of smoking (pipe, cigars or cigarettes) on biological indices of tobacco exposure and toxicity. Lung Cancer 54:11–18[CrossRef][Medline]
  13. Straczek C, Oger E, Yon de Jonage-Canonico MB, Plu-Bureau G, Conard J, Meyer G, Alhenc-Gelas M, Levesque H, Trillot N, Barrellier MT, Wahl D, Emmerich J, Scarabin PY 2005 Prothrombotic mutations, hormone therapy, and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration. Circulation 112:3495–3500[Abstract/Free Full Text]
  14. Thervet E, Anglicheau D, King B, Schlageter MH, Cassinat B, Beaune P, Legendre C, Daly AK 2003 Impact of cytochrome p450 3A5 genetic polymorphism on tacrolimus doses and concentration-to-dose ratio in renal transplant recipients. Transplantation 76:1233–1235[CrossRef][Medline]
  15. Ng FL, Holt DW, MacPhee IA 2007 Pharmacogenetics as a tool for optimising drug therapy in solid-organ transplantation. Expert Opin Pharmacother 8:2045–2058[CrossRef][Medline]
  16. Fromm MF, Schmidt BM, Pahl A, Jacobi J, Schmieder RE 2005 CYP3A5 genotype is associated with elevated blood pressure. Pharmacogenet Genomics 15:737–741[Medline]
  17. Kivisto KT, Niemi M, Schaeffeler E, Pitkala K, Tilvis R, Fromm MF, Schwab M, Lang F, Eichelbaum M, Strandberg T 2005 CYP3A5 genotype is associated with diagnosis of hypertension in elderly patients: data from the DEBATE Study. Am J Pharmacogenomics 5:191–195[CrossRef][Medline]
  18. Lieb W, Bolbrinker J, Doring A, Hense HW, Erdmann J, Schunkert H, Kreutz R 2006 No association of the CYP3A5*1 allele with blood pressure and left ventricular mass and geometry: the KORA/MONICA Augsburg echocardiographic substudy. Clin Sci (Lond) 111:365–372[Medline]
  19. Ho H, Pinto A, Hall SD, Flockhart DA, Li L, Skaar TC, Cadman P, O'Connor DT, Wagner U, Fineberg NS, Weinberger MH 2005 Association between the CYP3A5 genotype and blood pressure. Hypertension 45:294–298[Abstract/Free Full Text]
  20. Wegman P, Elingarami S, Carstensen J, Stal O, Nordenskjold B, Wingren S 2007 Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer. Breast Cancer Res 9:R7
  21. Slater CC, Hodis HN, Mack WJ, Shoupe D, Paulson RJ, Stanczyk FZ 2001 Markedly elevated levels of estrone sulfate after long-term oral, but not transdermal, administration of estradiol in postmenopausal women. Menopause 8:200–203[CrossRef][Medline]
  22. Kuhl H 2005 Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric 8(Suppl 1):3–63
  23. Shou M, Korzekwa KR, Brooks EN, Krausz KW, Gonzalez FJ, Gelboin HV 1997 Role of human hepatic cytochrome P450 1A2 and 3A4 in the metabolic activation of estrone. Carcinogenesis 18:207–214[Abstract/Free Full Text]
  24. Tsuchiya Y, Nakajima M, Yokoi T 2005 Cytochrome P450-mediated metabolism of estrogens and its regulation in human. Cancer Lett 227:115–124[CrossRef][Medline]
  25. Cribb AE, Knight MJ, Dryer D, Guernsey J, Hender K, Tesch M, Saleh TM 2006 Role of polymorphic human cytochrome P450 enzymes in estrone oxidation. Cancer Epidemiol Biomarkers Prev 15:551–558[Abstract/Free Full Text]
  26. Liehr JG 2000 Is estradiol a genotoxic mutagenic carcinogen? Endocr Rev 21:40–54[Abstract/Free Full Text]
  27. Swaneck GE, Fishman J 1988 Covalent binding of the endogenous estrogen 16{alpha}-hydroxyestrone to estradiol receptor in human breast cancer cells: characterization and intranuclear localization. Proc Natl Acad Sci USA 85: 7831–7835
  28. Huang Z, Guengerich FP, Kaminsky LS 1998 16{alpha}-Hydroxylation of estrone by human cytochrome P4503A4/5. Carcinogenesis 19:867–872[Abstract/Free Full Text]
  29. Zhu BT, Conney AH 1998 Functional role of estrogen metabolism in target cells: review and perspectives. Carcinogenesis 19:1–27[Abstract/Free Full Text]
  30. Rosendaal FR, Helmerhorst FM, Vandenbroucke JP 2002 Female hormones and thrombosis. Arterioscler Thromb Vasc Biol 22:201–210[Abstract/Free Full Text]
  31. Simon T, Beau Yon de Jonage-Canonico M, Oger E, Wahl D, Conard J, Meyer G, Emmerich J, Barrellier MT, Guiraud A, Scarabin PY 2006 Indicators of lifetime endogenous estrogen exposure and risk of venous thromboembolism. J Thromb Haemost 4:71–76[Medline]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Canonico, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Canonico, M.
Related Collections
Right arrow Female Endocrinology

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals