title: Red-clover-derived isoflavones and mammographic breast density: a double-blind, randomized, placebo-controlled trial [ISRCTN42940165].
abstract: BACKGROUND
  Isoflavones are hypothesized to protect against breast cancer, but it is not clear whether they act as oestrogens or anti-oestrogens in breast tissue. Our aim was to determine the effects of taking a red clover-derived isoflavone supplement daily for 1 year on mammographic breast density. Effects on oestradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), lymphocyte tyrosine kinase activity and menopausal symptoms were also assessed.
  
  
  METHODS
  A total of 205 women (age range 49-65 years) with Wolfe P2 or DY mammographic breast patterns were randomly assigned to receive either a red clover-derived isoflavone tablet (26 mg biochanin A, 16 mg formononetin, 1 mg genistein and 0.5 mg daidzein) or placebo. Change in mammographic breast density, serum oestradiol, FSH, LH, menopausal symptoms and lymphocyte tyrosine kinase activity from baseline to 12 months were assessed.
  
  
  RESULTS
  A total of 177 women completed the trial. Mammographic breast density decreased in both groups but the difference between the treatment and placebo was not statistically significant. There was a significant interaction between treatment group and oestrogen receptor (ESR1) PvuII polymorphism for the change in estimated percentage breast density (mean +/- standard deviation): TT isoflavone 1.4 +/- 12.3% and TT placebo -9.6 +/- 14.2%; CT isoflavone -5.2 +/- 12.0% and CT placebo -2.8 +/- 10.3%; and CC isoflavone -3.4 +/- 9.7% and CC placebo -1.1 +/- 9.5%. There were no statistically significant treatment effects on oestradiol, FSH, or LH (assessed only in postmenopausal women), or on lymphocyte tyrosine kinase activity. Baseline levels of menopausal symptoms were low, and there were no statistically significant treatment effects on frequency of hot flushes or other menopausal symptoms.
  
  
  CONCLUSIONS
  In contrast to studies showing that conventional hormone replacement therapies increase mammographic breast density, the isoflavone supplement did not increase mammographic breast density in this population of women. Furthermore, there were no effects on oestradiol, gonadotrophins, lymphocyte tyrosine kinase activity, or menopausal symptoms.
authors.affiliation: MRC Dunn Human Nutrition Unit, Cambridge, UK.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Atkinson
authors.forename: Ruth M L
authors.initials: RM
authors.lastname: Warren
authors.forename: Evis
authors.initials: E
authors.lastname: Sala
authors.forename: Mitch
authors.initials: M
authors.lastname: Dowsett
authors.forename: Alison M
authors.initials: AM
authors.lastname: Dunning
authors.forename: Catherine S
authors.initials: CS
authors.lastname: Healey
authors.forename: Shirley
authors.initials: S
authors.lastname: Runswick
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Day
authors.forename: Sheila A
authors.initials: SA
authors.lastname: Bingham
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects; D000368:Aged; D016588:Anticarcinogenic Agents / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D015415:Biomarkers; D001940:Breast / Q000033:anatomy & histology / Q000187:drug effects*; D003238:Connective Tissue / Q000187:drug effects; D004311:Double-Blind Method; D004958:Estradiol / Q000097:blood; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D019833:Genistein / Q000494:pharmacology / Q000652:urine; D019584:Hot Flashes / Q000188:drug therapy; D006801:Humans; D007529:Isoflavones / Q000302:isolation & purification / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use / Q000652:urine; D007986:Luteinizing Hormone / Q000097:blood; D008214:Lymphocytes / Q000201:enzymology; D008327:Mammography; D008593:Menopause / Q000187:drug effects; D008875:Middle Aged; D010936:Plant Extracts / Q000302:isolation & purification / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000097:blood; D029921:Trifolium / Q000737:chemistry*
chemical_list: D016588:Anticarcinogenic Agents; D015415:Biomarkers; D007529:Isoflavones; D010936:Plant Extracts; C487928:Promensil; C007768:formononetin; D004958:Estradiol; C004742:daidzein; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D019833:Genistein; D011505:Protein-Tyrosine Kinases; C004541:biochanin A