title: Sex hormone levels and risk of breast cancer with estrogen plus progestin.
abstract: BACKGROUND
  Although high endogenous sex hormone levels and estrogen plus progestin (E+P) therapy are associated with increased breast cancer risk, it is unknown whether pretreatment levels of sex hormones modify E+P effect on breast cancer.
  
  
  METHODS
  We conducted a nested case-control study within the Women's Health Initiative randomized clinical trial of E+P. The trial enrolled 16608 postmenopausal women aged 50 to 79 years with intact uterus and no breast cancer history. During a mean of 5.6 years of follow-up, 348 incident breast cancer case subjects were identified and matched with 348 control subjects. Case and control subjects had their sex hormone levels measured at baseline (estrogens, testosterone, progesterone, and sex hormone-binding globulin [SHBG]) and year 1 (estrogens and SHBG) using sensitive assays. All statistical tests were two-sided.
  
  
  RESULTS
  Statistically significant elevations in breast cancer risk were seen with greater pretreatment levels of total estradiol (P trend = .04), bioavailable estradiol (P trend = .03), estrone (P trend = .007), and estrone sulfate (P trend = .007). E+P increased all measured estrogens and SHGB at year 1 (all P < .001). The effect of E+P on breast cancer risk was strongest in women whose pretreatment levels of total estradiol, bioavailable estradiol, and estrone were in the lowest quartiles. For example, the odds ratio for E+P relative to placebo was 2.47 (95% confidence interval [CI] = 1.28 to 4.79) in the lowest total estradiol quartile, compared with 0.96 (95% CI = 0.44 to 2.09) in the highest total estradiol quartile; P interaction = .04).
  
  
  CONCLUSIONS
  Women with lower pr-treatment endogenous estrogen levels were at greater risk of breast cancer during E+P therapy compared with those with higher levels. Further studies are warranted to confirm these findings.
authors.affiliation: Affiliations of authors: San Francisco Coordinating Center, California Pacific Medical Center Research Institute, San Francisco, CA (GNF, NP, SRC); Faculty of Health Sciences, University of Balamand, Beirut, Lebanon (GNF); Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA (RTC); Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (JEM); Fred Hutchinson Cancer Research Center, Seattle, WA (GA, AZL); Department of Internal Medicine, University of California-San Francisco, San Francisco, CA (AH, DG); Department of Epidemiology and Biostatistics, University of California-San Francisco, San Francisco, CA (EV); Department of Internal Medicine, University of California-Davis, Sacramento, CA (JSL); Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA (JAC); Department of Internal Medicine, Ohio State University, Columbus, OH (RJ); Department of Preventive Medicine, Stony Brook University, Stony Brook, NY (DL); Department of Medicine, Emory University, Atlanta, GA (LP); Karmanos Cancer Institute, Wayne State University, Detroit, MI (MSS).
authors.forename: Ghada N
authors.initials: GN
authors.lastname: Farhat
authors.forename: Neeta
authors.initials: N
authors.lastname: Parimi
authors.forename: Rowan T
authors.initials: RT
authors.lastname: Chlebowski
authors.forename: Joann E
authors.initials: JE
authors.lastname: Manson
authors.forename: Garnet
authors.initials: G
authors.lastname: Anderson
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Huang
authors.forename: Eric
authors.initials: E
authors.lastname: Vittinghoff
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Lee
authors.forename: Andrea Z
authors.initials: AZ
authors.lastname: Lacroix
authors.forename: Jane A
authors.initials: JA
authors.lastname: Cauley
authors.forename: Rebecca
authors.initials: R
authors.lastname: Jackson
authors.forename: Deborah
authors.initials: D
authors.lastname: Grady
authors.forename: Dorothy S
authors.initials: DS
authors.lastname: Lane
authors.forename: Lawrence
authors.initials: L
authors.lastname: Phillips
authors.forename: Michael S
authors.initials: MS
authors.lastname: Simon
authors.forename: Steven R
authors.initials: SR
authors.lastname: Cummings
mesh_terms: D000368:Aged; D001943:Breast Neoplasms / Q000097:blood* / Q000453:epidemiology*; D016022:Case-Control Studies; D004958:Estradiol / Q000097:blood; D015914:Estrogen Replacement Therapy / Q000009:adverse effects* / Q000379:methods*; D004967:Estrogens / Q000008:administration & dosage*; D004970:Estrone / Q000031:analogs & derivatives / Q000097:blood; D005260:Female; D005500:Follow-Up Studies; D012739:Gonadal Steroid Hormones / Q000097:blood*; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D016017:Odds Ratio; D017698:Postmenopause; D011374:Progesterone / Q000097:blood; D011372:Progestins / Q000008:administration & dosage*; D018570:Risk Assessment; D012307:Risk Factors; D012738:Sex Hormone-Binding Globulin / Q000378:metabolism; D013739:Testosterone / Q000097:blood; D014481:United States / Q000453:epidemiology; D016387:Women's Health
chemical_list: D004967:Estrogens; D012739:Gonadal Steroid Hormones; D011372:Progestins; D012738:Sex Hormone-Binding Globulin; D004970:Estrone; D013739:Testosterone; D011374:Progesterone; D004958:Estradiol; C017296:estrone sulfate
references.citation: JAMA. 2008 Mar 5;299(9):1036-45
references.pmid: 18319414
references.citation: Cancer Epidemiol Biomarkers Prev. 2009 Jan;18(1):169-76
references.pmid: 19124495
references.citation: JAMA. 2002 Jul 17;288(3):321-33
references.pmid: 12117397
references.citation: Cancer Epidemiol Biomarkers Prev. 2010 Apr;19(4):903-6
references.pmid: 20332268
references.citation: Ann Epidemiol. 2003 Oct;13(9 Suppl):S18-77
references.pmid: 14575939
references.citation: J Natl Cancer Inst. 2011 Apr 6;103(7):562-70
references.pmid: 21330633
references.citation: Menopause. 2010 May-Jun;17(3):622-9
references.pmid: 20215977
references.citation: J Natl Cancer Inst. 2012 Apr 4;104(7):517-27
references.pmid: 22427684
references.citation: Ann Epidemiol. 2003 Oct;13(9 Suppl):S5-17
references.pmid: 14575938
references.citation: J Clin Endocrinol Metab. 1999 Oct;84(10):3666-72
references.pmid: 10523012
references.citation: JAMA. 2011 Apr 6;305(13):1305-14
references.pmid: 21467283
references.citation: JAMA. 2010 Oct 20;304(15):1684-92
references.pmid: 20959578
references.citation: JAMA. 2006 Apr 12;295(14):1647-57
references.pmid: 16609086
references.citation: J Natl Cancer Inst. 2002 Apr 17;94(8):606-16
references.pmid: 11959894
references.citation: JAMA. 2002 Jan 9;287(2):216-20
references.pmid: 11779264
references.citation: JAMA. 2004 Apr 14;291(14):1701-12
references.pmid: 15082697
references.citation: Obesity (Silver Spring). 2011 May;19(5):988-93
references.pmid: 20948523
references.citation: Osteoporos Int. 2010 Jan;21(1):167-77
references.pmid: 19436934
references.citation: J Natl Cancer Inst. 2009 Mar 18;101(6):384-98
references.pmid: 19276457
references.citation: Br J Cancer. 2011 Aug 23;105(5):709-22
references.pmid: 21772329
references.citation: JAMA. 2003 Jun 25;289(24):3243-53
references.pmid: 12824205
references.citation: Cancer Epidemiol Biomarkers Prev. 2005 May;14(5):1047-51
references.pmid: 15894651
references.citation: J Natl Cancer Inst. 2005 Apr 20;97(8):595-602
references.pmid: 15840882
references.citation: J Steroid Biochem. 1982 Jun;16(6):801-10
references.pmid: 7202083
references.citation: J Natl Cancer Inst. 2006 Jan 18;98(2):110-5
references.pmid: 16418513
references.citation: Menopause. 2001 May-Jun;8(3):200-3
references.pmid: 11355042
references.citation: Steroids. 1978 Mar;31(3):393-405
references.pmid: 307289
references.citation: Cancer Prev Res (Phila). 2011 Oct;4(10):1626-35
references.pmid: 21813404
references.citation: Endocr Relat Cancer. 1999 Jun;6(2):165-73
references.pmid: 10731105
references.citation: Cancer Epidemiol Biomarkers Prev. 2002 Oct;11(10 Pt 1):1065-71
references.pmid: 12376508