title: Associations between tamoxifen, estrogens, and FSH serum levels during steady state tamoxifen treatment of postmenopausal women with breast cancer.
abstract: BACKGROUND
  The cytochrome P450 (CYP) enzymes 2C19, 2D6, and 3A5 are responsible for converting the selective estrogen receptor modulator (SERM), tamoxifen to its active metabolites 4-hydroxy-tamoxifen (4OHtam) and 4-hydroxy-N-demethyltamoxifen (4OHNDtam, endoxifen). Inter-individual variations of the activity of these enzymes due to polymorphisms may be predictors of outcome of breast cancer patients during tamoxifen treatment. Since tamoxifen and estrogens are both partly metabolized by these enzymes we hypothesize that a correlation between serum tamoxifen and estrogen levels exists, which in turn may interact with tamoxifen on treatment outcome. Here we examined relationships between the serum levels of tamoxifen, estrogens, follicle-stimulating hormone (FSH), and also determined the genotypes of CYP2C19, 2D6, 3A5, and SULT1A1 in 90 postmenopausal breast cancer patients.
  
  
  METHODS
  Tamoxifen and its metabolites were measured by liquid chromatography-tandem mass spectrometry. Estrogen and FSH levels were determined using a sensitive radio- and chemiluminescent immunoassay, respectively.
  
  
  RESULTS
  We observed significant correlations between the serum concentrations of tamoxifen, N-dedimethyltamoxifen, and tamoxifen-N-oxide and estrogens (p < 0.05). The genotype predicted CYP2C19 activity influenced the levels of both tamoxifen metabolites and E1.
  
  
  CONCLUSIONS
  We have shown an association between tamoxifen and its metabolites and estrogen serum levels. An impact of CYP2C19 predicted activity on tamoxifen, as well as estrogen kinetics may partly explain the observed association between tamoxifen and its metabolites and estrogen serum levels. Since the role of estrogen levels during tamoxifen therapy is still a matter of debate further prospective studies to examine the effect of tamoxifen and estrogen kinetics on treatment outcome are warranted.
authors.affiliation: Hormone Laboratory, Haukeland University Hospital, Bergen, N-5021, Norway.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gjerde
authors.forename: Jürgen
authors.initials: J
authors.lastname: Geisler
authors.forename: Steinar
authors.initials: S
authors.lastname: Lundgren
authors.forename: Dagfinn
authors.initials: D
authors.lastname: Ekse
authors.forename: Jan Erik
authors.initials: JE
authors.lastname: Varhaug
authors.forename: Gunnar
authors.initials: G
authors.lastname: Mellgren
authors.forename: Vidar M
authors.initials: VM
authors.lastname: Steen
authors.forename: Ernst A
authors.initials: EA
authors.lastname: Lien
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000097:blood / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001943:Breast Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000235:genetics; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D004967:Estrogens / Q000097:blood*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood*; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics; D017698:Postmenopause; D013629:Tamoxifen / Q000097:blood* / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D004967:Estrogens; D013629:Tamoxifen; D005640:Follicle Stimulating Hormone; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; C510164:CYP3A5 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A