PROGESTINS AND BREAST CANCER RISK: STATE OF THE CONTROVERSY [in Menopause - Hormones and Cancer Proceedings]
edited by M. Neves -e-Castro and B.G. Wren 2002
[MHC CH 14 p123-128]

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

Authors
R. Sitruk-Ware and G. Plu-Bureau [CH 14]
Center for Biomedical Research
Population Control Council
1230 York Avenue
New York, NY 10021
USA

1. The use of progestins with estrogen is a recent phenomena. Progestin has been used since the early 1980's in Scandinavia and the UK. The FDA recommended the addition of progestins to various estrogen regimens in 1990, and the use became widespread.
   
   
2. non-differentiated terminal end buds are susceptible to malignant transformation by carcinogens
   
   1. carcinogen applied to immature undifferentiated terminal end buds, followed by administration of sex steroids, led to transformed cells and cancer
      
   2. sex steroids applied first to immature animals at the stage of undifferentiated terminal end buds led to maturation and differentiation of the alveolar buds, which did not undergo any malignant transformation when carcinogen was applied (ie, after the steroids had already cause differentiation)
      
   3. suggests that malignant transformation comes before sex steroid exposure, not after, and prior sex steroid exposure is protective against malignant transformation
      
      
3. steroid effects
   
   
   1. Era receptors and Pr receptors are expressed in the same cells
      
      1. these cells act as steroid sensors and control proliferation through paracrine mechanisms onto other cells
         
         
   2. Estrogen stimulates growth of the breast ductal system
      
      1. very low estrogen concentrations express Pr receptors
         
      2. estradiol (not progesterone) was the major mitogen in epithelial breast cells [Laidlaw and colleagues]
         
      3. high doses of estradiol are required to induce proliferation
         
      4. estrogen also stimulates immature (Type 1) terminal bud growth, but not mature (Type 3 & 4) terminal bud growth
         
      5. long term estrogen therapy increased cell proliferation and the percentage of breast made up of glandular tissue
         
         
   3. Progestin acted as a proliferative agent with estrogen, transforming the ducts into differentiated (mature) lobules (branching)
      
      1. increase in the terminal duct lobular units is observed when progestin was used with estrogen
         
      2. progesterone transforms the terminal end buds into alveolar buds and differentiated lobules ready for milk secretion
         
         1. Type 1 immature lobules exhibit a high rate of cell proliferation (estrogen sensitive) [Russo and colleaques 2001]
            
         2. Type 2 lobules appear after pregnancy and evolve into highly differentiated Type 3 & Type 4 lobules with very low cell proliferation (estrogen insensitive)
            
      3. nulliparous women have up to 80% Type 1 lobules
         
      4. parous women have Type 3 lobules
         
      5. after menopause, breast tissue involutes
         
         
   4. under HRT, breast tissue grows again and Type 1 lobules reappear
      
      1. in parous women these lobules have markers of the previous differentiated (mature) state
         
         
   5. should not interpret tissue proliferation as necessarily involving undifferentiated and transformed cells rather than normal cells
      
      
   6. combined growth effects of estrogen and progesterone
      
      1. low estrogen = "on your mark"
         
      2. progestin/estrogen = "get set, one cycle and wait"
         
         1. breast cells in the late phase of the cell cycle are driven into the S phase of DNA synthesis by progestins
            
         2. this effect is transient, with further application of progestin supressing the cyclins, halting breast cell division in the early G1 phase. [Musgrove and associates]
            
      3. high estrogen = "go"
         
         
   7. effect of estrogen, progestin on cancer risk summary (see above)
      
      1. estrogen only --> immature lobules/ ducts, more cancer risk
         
      2. estrogen/progestin --> mature lobules, low cancer risk
         
         
4. balance between estrogenic and progestogenic components of HRT vary with the dose and regimen
   
   
   1. MPA is a derivative of progesterone
      
      1. 19-norprogesterone derivates (17OHprog ones) preferred for HRT in Southern Europe
         
         1. medroxyprogesterone actetate
            
         2. megestrol
            
      2. no direct estrogenic effects like NE
         
      3. exhibits only slight androgenic effects
         
         1. decreases SHBG
         2. less direct androgenic effects compared to 19-NorTestosterone derivatives
            
         3. [ISLT] MPA effect on Free Testosterone depends on functional status of ovary, the net of two effects:
            1. increases Free Testosterone fraction from decreased SHBG
            2. decreases ovarian production of androgens more (treats hirsuitism)
            3. [ISLT] different effects depending on pre/peri/menopausal status
      4. exhibits glucocorticoid-like activity (displaces Free Cortisol from Cortisol Binding Globulin (CBG)
         
   2. (NE) norethindrone acetate (1x) and levonorgestrel (100x) have direct androgenic properties
      
      1. norethindrone also has weak estrogenic effect at Er receptors
         
   3. oral micronized estradiol or estradiol valerate lead to high circulating levels of estrone due to liver metabolism, with high total circulating levels of estrogen
      
      
5. tumor proliferation
   
   
   1. results of proliferation testing is unclear, as breast cells would react to the cumulative effect of estrogens and progesterone secreted over several cycles, rather than to daily changes in hormone production
      
      1. different progestins may induce different effects
         
         1. augment Er receptors vs reduce Er receptors
            
      2. the role of progesterone could not be separated from the role of estrogen
         
         
   2. MCF7 tumor cell proliferation (Catherino and co-workers)
      
      1. promegestrone (R5020) shown to decrease cell proliferation (in normal breast cells)
         
      2. MPA and nomegestrol acetate do not induce proliferation
         
      3. norgestrel and gestodene stimulate proliferation (Er receptor mediated)
         
         
   3. follicular phase study, women undergoing surgery for benign breast disease
      
      1. randomly treated with estradiol, progesterone or placebo, and mitoses in the epithelial cells in normal part of the breast was counted
         
         1. after estradiol tx, both estradiol concentration in the breast and number of mitoses was high (0.83/1000)
            
         2. in placebo, the number of mitoses was low (0.50/1000)
            
         3. after progesterone tx, progesterone concentration was high, mitoses low (0.17/1000)
            
         4. authors concluded that in vivo, high intratissue concentrations of progesterone decrease the mitotic activity of normal lobular epithelial cells
            
         5. [ISLT] implies a dose effect for progestin
            
            
6. meta-review [Oxford 1997]
   
   1. reviewed most of the epidemiological studies
      
   2. 17,000 cancer cases; 32,000 controls
      
   3. breast cancer risk in HRT users was RR = 1.14 compared to non-users
      
   4. risk increased 2.3% per year of use
      
      1. current users at diagnosis, hormones for >5 years
         
      2. RR = 1.6 > 15 years
         
      3. increased risk for lean women (BMI >25 kg/m2) receiving HRT for more than 5 years
         
   5. no significant difference between the users of estrogen or combined estrogen plus progestin
      
      
7. more recent studies
   
   
   1. in general
      
      1. indicated a higher risk from users of combined HRT
         
      2. percentage of combined HRT use was low (around 5%)
         
      3. 5 percent had unknown hormone therapy
         
      4. there was no information about the risk factors
         
         
   2. Ross and co-workers
      
      1. lower risk of breast tumors, used continuous HRT
         
      2. conjugated equine estrogen and MPA
         
         
   3. Magnussen and colleagues
      
      1. lower risk of breast tumors, used sequential HRT
         
      2. swedish cohort
         
      3. oral estradiol or estradiol valerate plus norethindrone or levonorgestrel progestin
         
      4. higher levels of total estogen (estrone up to 466 pg/ml) in those that received 2mg oral estradiol than other regimens
         
         
   4. premenopausal women with benign breast disease (Plu-Bureau)
      
      1. progestins appeared to be beneficial
         
      2. cohort study
         
      3. 1150 premenopausal French women with benign breast disease
         
      4. followup of 10 years
         
      5. progestin use and the duration of use were not found to be significantly associated with breast cancer risk
         
      6. linear decrease in breast cancer risk with duration of progestin use
         
      7. does not support the hypothesis that progestins increase the risk of breast cancer
         
      8. 19-nortestosterone derivatives were found to be significantly associated with a lower risk of breast cancer (RR = 0.48)
         
         1. [ISLT] use of 19-nortestosterone derivatives as off study medications in placebo group would lower breast cancer risk relative to Prempro group in WHI
            
      9. [ISLT] supports either continuous or adequate cyclic progestin lowers risk
         
         
8. Trends in progestin consumption in the world
   
   1. USA lagged behind Europe in use of progestins in HRT
      
      1. 12x higher progestin use in France than USA in 1985, 3x in 1995
         
      2. lower risk of breast cancer in France trend seen compared to the USA
         
   2. curve analysis does not permit the establishment of any causal relationship between progestin consumption and breast cancer incidence however in population studies
      
      
      

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