PROGESTERONE THERAPY AND BREAST CANCER

[in Menopause - Hormones and Cancer Proceedings]
edited by M. Neves -e-Castro and B.G. Wren 2002
[MHC CH 13 p117-121]

1. epidemiological data indicates a slight to moderate duration-dependent increase in the relative risk of diagnosing breast cancer during use of HRT and hormonal contraceptives, which normalizes after 5-10 years of discontinuation.
   
   
2. three major theraputic combinations
   
   1. estrogen only
      
   2. estrogen in cyclic combination with progestogen
      
   3. estrogen in continous combination with progestogen
      
   4. all have different effects in the endometrium and other target organs
      
   5. few studies comparing these for the breast
      
      
3. the interpretation of epidemiological data is complicated by a lack of basic understanding as to how sex steroids influence the breast and regulate epithelial proliferation.
   
   1. in vitro
      
      1. estrogens enhance breast cell proliferation
         
      2. addition of progestogen may reduce this effect
         
   2. in vivo
      
      1. proliferation of breast epithelial cells is seen during the luteal phase when progesterone levels are high
         
         
4. proliferation results from FNA
   
   1. an increased breast epithelial cell proliferation in women using combined oral contraceptives, with marked individual variation in response to treatment
   2. positive correlation of proliferation and circulating levels of levonorgestrel progestogen
   3. negative correlation of proliferation and levels of free testosterone
      
      
5. mammographic density results
   
   1. reflects the relative amount of fat, connective and epithelial tissues
      
   2. high amounts of connective and epithelial cells increase density on mammogram
      
   3. Wolfe classification
      
      1. N1, normal breast, primarliy fat with at most ficrous connective tissue strands
         
      2. P1, prominent ductal pattern in up to 1/4 of the breast volume
         
      3. P2, prominent ductal pattern in more than 1/4 of the breat volume
         
      4. Dy, extrememely dense parenchyma which usually denotes connective tissue hyperplasia
         
         
   4. in this study, CEE/MPA(conjugated equine estrogens/medroxyprogesterone acetate) had similar wolfe increase to E2/NE(estradiol/norethinodrone)[see table1p118 all increase].
      1. Estrogen alone had little increase except at higher dosing [table2 p119 all increase]
         
         
         1. PEPI trial and others (cline/von schoulz) have reported that different regimens for HRT have different impacts on mammograhic density
            
            1. increase in density more frequent in women on combined estrogen-progestogen than on estrogen alone
               
            2. increase with estrogen alone is small (E)
               
            3. women with continuous combined show 40-50% with increased density (E/P continuous)
               
            4. many women have no increase in density, there is individual variation in response
               
               
         2. no consensus on the interpretation of breast density and histological findings in breast cancer
            
            1. may correlate with increased risk of tumor (stimulation)
               
            2. may make diagnosis of tumors more difficult (increased density hides tumors)
               
               
         3. increase in mammographic density appears to be an early event that occurs during the first few months of therapy, and thereafter remains stable during long term treatment with the same regimen
            
            1. [ISLT] would then be more likely to have suspicious mammogram requiring biopsy in previous users, and so would initially find more breast cancers than in group who did not have previous hormone exposure (surveillance/detection bias, comparison mammogram, do more biopsies, find more cancer that is already there)
               
            2. [ISLT] increase in density would hide tumors in the just initiating hormone group unless more likely to read as suspicious
               
            
            
      2. macaques monkey experimental model
         
         1. surgically postmenopausal macaques were given HRT
            
         2. proliferative response after combined treatment with conjugated equine estrogens plus medroxyprogesterone acetate was much more pronounced than for treatment with estrogen alone.
            
            1. progestogen augments response to estrogen thru several mechanisms depending on dosing/endogenous exposure
               
            2. would expect to see an initial proliferative response because hormone deficient
               
            3. [ISLT] would be similar to late menopausal status (loss of steroids from the ovary, particularly estrogen).
               
               
      3. there is no consensus about the proliferative effects of the addition of progestogen to estrogen treatment
         
         1. effects of progestogen vary by type, duration of exposure and the estrogenic environment
            
         2. both estrogen and progestogen in high doses have a growth supressing effect and have been used to treat breast cancer
            
         3. 5-10mg of norethindrone(northisterone) in combination with estrogen appears to reduce the rick of breast cancer recurrence
            
            1. norethisterone (norethindrone) is highly progestogenic and mildly androgenic
               
         4. [ISLT] progestin dose is too low in some studies and some HRT formulations
         5. [ISLT] hi Free Testosterone serum levels secondary to low SHBG decreases mamographic density and normal breast cell proliferation [see Peter Conner et al, Fertility and Sterility, 81(6):June2004]
            
            
            
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