PHYTOESTROGENS AND BREAST CANCER [in Menopause - Hormones and Cancer Proceedings]
edited by M. Neves -e-Castro and B.G. Wren 2002
[MHC CH 8 p67-115]

Outline and Commentary on the 2002 Proceedings
by Timothy D. Bilash MD, MS, OBGYN
June 2003
www.DrTimDelivers.com

Authors
H. Adlercreutz [MHC CH 8]
Department of Clinical Chemistry
PL 60, FIN-00014
University of Helisinki
Helisinki
Finland

1. The precursors of biologically active phytoestrogens detected in man are found mainly in soybean products, whole-grain cereal food, seeds, berries, tea, legumes and some vetgetables, such as carrots and Brussel sprouts.
   
   1. plant lignan and isoflavonoid glycosides found in these foods are converted by intestinal bacteria to hormone-like compounds.
      
   2. the weakly estrogenic diphenols formed have been shown to influence sex hormone production, metabolism, mechanism of action and biological activity, and influence many intracellular steroid metabolizing enzymes.
      
   3. compounds included in the group of phytoestrogens have changed over time because of new compounds detected which have weak estrogenic activity such as the mamalian lignands and some flavonoids and the elimination of the fungal or mycoestrogens, the resorcyclic acid lactones, from the group because they are not plant estrogens.
      
   4. other estrogenic plant compounds that do not have two phenolic groups and have completely different structures not included in this definition of phytoestrogens
      
      
2. Isoflavones
   
   
   1. dietary isoflavones are found in soy. smaller amounts of isoflavones in other beans, peanuts, some vegetables, and fruits
      
      1. genistein (soy)
         
      2. daidzen (soy)
         
      3. glycitein (soy)
         
      4. coumestrol occurs in only a few foods not normally consumed in western culture, alfalfa sprouts and brussel sprouts
         
      5. the most estrogenic of these compounds are coumestrol, genistein, and equol (metabolite of daidzen, produced in small amounts by all, and large amounts by only about 30% of people both in western countries and in Asia)
         
      6. be aware of variation in laboratory assays
         
         
   2. enterodiol and enterolactone are formed from plant lignan glycoside precursors by the activity of gut microflora in the proximal colon. intestinal bacteria seem to play a significant role in the maintenance of the plasma enterolactone concentration.
      
      1. secoisolariciresinol is converted to enterodiol and this is converted to enterolactone (flaxseed)
         
      2. marairesinol is converted directly to enterolactone
         
      3. new enterolactone precursors are pinoresinol, laricirerinol, syringaresinol, 7-hydroxymatairesinol and arctigenin, the first three of which are indentified in rye bread
         
      4. urinary excretion of enterolactone
         
         1. increased with increased serum hormone binding globulin (SHBG)
            
         2. decreased with increased free estradiol and free testosterone
            
         3. increased with fiber intake
            
            
   3. breast cancer
      
      
      1. soy
         
         1. few effects found in prospective studies for soy in adults
            
         2. may be more significant neonatally and in children
            
         3. isoflavonoids in plasma and urine are good biomarkers for intake of soy products, but may not be the active components from the diet
            
            
      2. equol
         
         1. vegetarians and subjects who consumed more carbohydrates and less fat have higher equol excretion in urine
            
            1. likely that higher equol excretion reflected a more healthy diet
               
            2. high equol producers may have particularly low risk of breast cancer due to both reductions in sex hormone levels and alteration of endogenous estrogen metabolism
               
               1. [ISLT] progestogen-like effect
                  
               2. positive effect may depend on estrogen levels
                  
            3. reviews are mixed on effects of equol. may be more associated with isoflavones and lignans and the heathier diet which lowers risk, rather than directly related to breast cancer risk.
               
               1. low excretion of lignans was found in healthy breast cancer patients, along with the low equol excretion
                  
               2. SHBG efects may be due to associated soy consumption (more free hormones though)
                  
               3. associated grain consumption may increase enterolactone levels
                  
                  
      3. enterolactone plasma/ urine levels in individuals in a Finnish study
         
         1. intake of grain calories or grain fiber/kg body weight correlated with the excretion of enterolactone in urine
            
            1. correlation between grain fiber intake and urinary enterolactone was 0.707
               
            2. rye bread seemed to be the best source of lignans
               
               1. plasma levels were almost 3x higher after consumption of rye bread than with white bread
                  
               2. both types of bread were consumed at least 200g/day with no other cereals permitted
                  
            3. berries, fruits and vegetables also contibuted to lignan excretion
               
         2. smoking decreased plasma levels
            
         3. obstipation, whole grain food intake, vegetables, berries and fruits increased plasma levels
            
         4. a healthy lifestyle and diet seem to explain only a small part of the individual variations
            
         5. antibiotics immediately reduces the formation of mammalian lignans to very low levels for a long time, sometimes for more than a year.
            
         6. enterolactone levels were low in breast cancer individuals, higher in cancer free individuals
            
            
      4. countries with high legume consumption have lower disease rates***
         
         1. consumption of a lignan-rich food and fiber (which contains lignans) seems more consistently related to lowered risk than effect of dietary soybeans
            
         2. many different compounds other than soy (protease inhibitors, phytic acid, B-sisterol) are active compounds
            
         3. diet composition with regard to fatty acids, animal and plant protein, and various carbohydrates and fibers likely plays an essential role
            
         4. vegetarians have higher levels of isoflavonoids in plasma and urine
            
         5. in Hawaii, Japanese women excrete more isoflavones than Caucasian women
            
         6. subjects in low risk areas for breast cancer excrete high hevels of isoflavones and lignans
            
         7. chimpanzees in captivity are very resistant to breast cancer and excrete large amounts of isoflavonoids and lignans with high relative amounts of equol.
            
            
      5. increased risk
         
         1. breast cancer subjects excrete low amounts of isoflavones and lignans
            
         2. within 6 months of immigrating to Hawaii from the Orient , immigrants that still consuming a very low fat diet excreted roughly 1/10th of the amounts of isoflavonoids than Japanese women in Japan, similar to omnivore levels.
            
            
      6. adult animal studies
         
         1. soy
            
            1. no effects seen with soy alone
               
            2. no effect seen with soy and high isoflavonoids
               
            3. lower non-significant risk in groups receiving high isoflavonoid diet
               
            4. lowers SHBG in plasma (???progestogenic effect, other cofactors)
               
         2. flaxseed contains very high amounts of secoisolariciresinol (SDG)
            
            1. flaxseed oil and particularly the purified SDG seem to inhibit the growth of mammary tumors in experimental rat studies
               
               1. both initiation and promotion
                  
            2. SDG converted to enterolactone and enterodiol
               
               
      7. neonatal/ prepubertal rat studies
         
         1. genistein
            
            1. given to rats prepubertally or neonatally (conception until 21 days postpartum) at physiologic or greater amounts gave protection against 7,12-dimethylbenz anthracene (DMBA)-induced experimental breast cancer
               
            2. concluded that genistein (Lamatiniere et al)
               
               1. enhanced breast cell differentiation
                  
               2. stimulates transforming growth factor (TGFa)
                  
               3. stimulates epidermal growth factor receptor (EGF)
                  
               4. down regulates EGF-signaling pathway in terminal end buds and terminal ducts of adult mammary glands, which may resist breast tumorogenesis
                  
            3. may have estrogenic effects, and high estrogen in pregnancy may increase or lower breast cancer and prostate cancer risk in offspring, but evidence not definitive
               
               1. phytoestrogens are readily transfered from mother to fetus
                  
               2. phytoestrogens during pregnancy may have an antiestrogenic (?progestogenic) effect in the high estrogen environment
                  
                  
      8. phytoestrogen summary
         
         
         1. soy is at most slightly protective for breast cancer
            
         2. high soy doses increase invasiveness of breast cancer, soy metabolites are estrogenic
            
         3. soy may be beneficial early in life, protecting from breast carcinogens later in life
            
         4. a fiber and lignan diet seems protective for breast cancer
            
         5. enterolactone may be a good biomarker of decreased breast cancer risk, but the mechanism is unkown
            
            
            
            

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