NEW MECHANISMS OF ACTION FOR
TIBOLONE IN BREAST CANCER
[in Menopause - Hormones and Cancer Proceedings]
edited by M. Neves -e-Castro and B.G. Wren 2002
[CH 5 p37-47]

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

Authors
H.J. Kloosterboer [MHC CH 5]
N.V. Organon
Research and Development Laboratories
5340 BH Oss
The Netherlands


1. Clear evidence that steroid hormones have a role in breast cancer is lacking because of lack of studies
   
   1. thinking has been that estrogen + progestin may affect breast more adversely
      
   2. progestin potentiates estrogen effect at low dose
      
      
2. Apoptosis*** (this is a key idea)
   
   
   1. programmed cell death
      
   2. part of natural cell life cycle
      
   3. new important mechanism in breast cancer
      
      1. cancer cells dont grow faster, actually grow slower in advanced stage
         
      2. cancer cells dont undergo programmed death
         
         
3. Receptors
   
   
   1. receptor binding types
      
      
      1. Estrogen receptors
         
         1. Estrogen receptor Era (required for breast development)
            
         2. Estrogen receptor Erb (no effect on breast development)
            
      2. Progestin receptors
         
         1. Progesterone receptors PrA & PrB
            
            1. only one of the two required for breast development (redundancy)
               
            2. not required for normal alveoli in all breast epithelium ??? [p37]
               
      3. Androgen
         
      4. Glucocorticoid
         
      5. Mineralcorticoid
         
         
   2. normally proliferating breast cells do not contain receptors for either estradiol or progesterone, whereas proliferating breast cancers cells do.
      
      1. hi proliferation of normal breast epithelial cells seen during the luteal phase in humans
         
         
4. Tibolone
   
   
   1. used in Europe for menopause complaints and osteoporosis
      
      1. less pain and tenderness
         
      2. lower mammogram density
         
      3. exhibits estrogenic and progestogenic properties, but has different effects than other HRT preparations
         
         
   2. combined effects of tibolone and metabolites are similar in human, monkey (and rat except for endometrium)
      
      1. prevents bone loss thru Er comparable to estrogens
         
         1. antiandrogen did not affect bone sparing of tibolone
            
            1. bone effect thru Er
               
            2. ???androgen effect is thru progesterone receptor or tibolone metabolites
               
      2. treats hot flushes and vaginal atrophy
         
         1. Er effects of metabolites
            
            
   3. [see table 1 p39] tibilone receptor activation
      
      
   4. tibolone parent steroid
      
      1. tibolone has short half-life
         
         1. rapidly metabolized via 3BHSD (3b-hydroxysteroid dehydrogenase)
            
         2. not evident in high concentrations because of rapid metabolism
            
         3. tibolone not metabolized via pregnenolone
            
         4. [see fig 1 p38] metabolism of Tibilone
            
      2. doesnt activate Er receptor
         
         1. lacks aromatic A-ring with 3-OH group for Er binding
            
         2. binds Er only at high concentrations
            
      3. some binding to Progesterone (Pr) and Androgen (Ar) receptors
         
         1. lacks 3-keto-delta4 configuration for good binding to Pr and Ar
            
         2. tibolone activates Pr and Ar receptors
            
            
   5. 3a-,3b-(OH) tibolone metabolites
      
      1. Estrogenic
         
      2. 3a, 3b (OH) metabolites bind to Era and Erb receptors
         
         1. do not bind to Pr, androgen, glucocorticoid or mineralcorticoid receptors
            
         2. 3a-OH concentration 4x> 3b-OH
            
         3. Era 10x > Erb binding
            
      3. 7hr half-life
         
      4. mostly found in inactive sulfated form
         
         1. 3b sulfated form not usually found
            
            
   6. delta4-isomer tibolone metabolite
      
      1. Progestogenic activity with prolonged action
         
         1. long 1/2 life (7a-methyl group)
            
         2. compared to progesterone which is quickly inactivated by reduction of double bond in A ring
            
      2. Androgenic activity
         
      3. delta4 isomer binds, activates Pr, Ar receptors, but not Er, glucocorticoid or mineralcorticoid receptors
         
         
5. in human endometrium, progestagenic activity of tibolone dominates
   
   1. due to local formation of the progestagenic delta4 isomer from 3b-(OH) tibolone metabolite
      
   2. completely inhibits proliferation of the endometrium in postmenopausal women and monkeys
      
      1. rat not good model for human endometrium
         
         1. tibolone preferentially metabolised to estrogenic 3OH-metabolites
            
         2. no local delta4 isomer in rats, estrogenic effect stimulates uterine growth
            
         3. but still anti-tumor in rat in spite of estrogenic properties
            
            1. progestogenic effects dominate as in OCP's
               
            2. longer half life (anti-estrogen effect)
               
               
6. no breast stimulation seen with tibolone, in contrast to estrogen
   
   
   1. tibolone compared to antiestrogens, androgens which have different mechanisms
      
      1. tibolone/metabolites diminishes ligand levels for estrogen receptor (steroid levels)
         
      2. antiestrogens (tamoxifen) modify the estrogen receptor itself
         
      3. Androgens have an antiestrogenic effect on the breast
         
         1. mixed estrogen effect, thru RNA steroid effects in cytoplasm and not receptors
            
         2. but tibolone effect on breast not directly thru androgen receptors
            
            1. [ISLT] could still have an indirect androgen effect thru 17BHSD and delta4 isomer
               
      4. PEPI trial- medroxyprogesterone actetate and progestin
         
         1. women receiving conjugated estrogen plus progestin had an increase in mammographic density (20% medroxyprogesterone acetate, 16% micronized progesterone), indicating more stroma or ductal and glandular tissue
            
         2. Almost all increases in mammographic density occurred within the first year
         3. both cyclic and continuous E/P dosing
            
         4. 0% (CI= 0.0% to 4.6%) in the placebo group
         5. 3.5% (CI= 1.0% to 12.0%) in the CEE group
         6. 23.5% (CI= 11.9% to 35.1%) in the CEE plus cyclic MPA group
         7. 19.4% (CI= 9.9% to 28.9%) in the CEE plus daily MPA group
         8. 16.4% (CI= 6.6% to 26.2%) in the CEE plus cyclic MP
            
            
   2. DMBA model on human breast
      
      1. tibolone reduced tumor growth similar to tamoxifen
         
         1. Tibilone doers not increase mammographic density
            
         2. Tibolone anti-tumor effect not direct anti-Estrogen (1)
            
            1. is not Er blocker
               
            2. does not inhibit aromatase in model systems
               
               1. placental aromatase on androstenedione (A -> E1) is not inhibited by tibolone
                  
               2. effect of tibolone on breast aromatase is unknown
                  
            3. see below for sulfatase effects, metabolite effects
               
         3. Tibolone anti-tumor effect not direct Androgenic (2)
            
            1. antiandrogen flutamide with tibolone does not reverse tumor inhibition (nude mice)
               
            2. [ISLT] no local formation of delta4 isomer in mice
               
            3. [ISLT] SBG increase mitigates androgenic effect
               
               
   3. Tibolone almost completely prevented initiation of breast tumor growth given at the time of induction***
      
      1. Tibolone anti-tumor effect is mostly Progestogenic (3)***
         
         1. cell proliferation is inhibited by tibolone
            
         2. apoptosis is stimulated by tibolone in normal breast cells and breast cancer cells
            
         3. delta4 isomer and pure progestin ORG2057 show similar apoptopic effects to tibolone
            
      2. Estrogenic metabolites of tibolone (3a-OH, 3b-OH)
         
         1. no mitogenic activities in normal breast epithelial cells
            
         2. even antiproliferative effects at high concentrations!
            
         3. stimulate apoptosis at high concentrations (different from estradiol)
            
         4. less expression of Ki67 and Pr (steroid secretion) than with estrogen seen in nude mice
            
      3. Tibolone and metabolites also inhibit sulfatase activity***
         
         1. 3-0H tibolone metabolites inhibit sulfatase in breast (E1S -> E1)
            
            1. may limit estrogenic effects of estrogen in breast
               
               1. sulfatase, sulfotransferase determine the amount of active estrogenic metabolites
                  
               2. high levels of estrone sulfate are present in breast tissue (E1 -> E1S)
                  
                  1. source of active estrogens via sulfatase (E1S -> E1)
                     
                  2. major determinant of estrone sulfate to estradiol
                     
                  3. may also limit 3a-OH tibolone sulfate to active non-sulfate
                     
               3. sulfated estrogens and 3OH-sulfated tibolone thus not hydolyzed to non-sulfated Er active forms in endometrium
                  
            2. irreversible inhibition in some tumor lines by 3-OH metabolite
               
         2. already shown for tibolone in endometrium
            
         3. forms a low estrogenic environment, in which progestogens are known to inhibit breast proliferation
            
            1. [ISLT] low estrogen environment accentuates delta4 isomer effect
               
      4. Sulfotransferase activity may be induced by locally formed tibolone progestogenic forms in endometrium
         
         1. conversion to sulfated forms
            
         2. other progestins shown to induce sulfotransferase in endometrium
            
         3. Sulfotransferase (E1-> E1S), may also be induced by tibolone to limit active forms
            
            1. tested by Cherite
               
            2. non-genomic effect
               
      5. Androgenic activity
         
         1. delta4 isomer is androgenic
            
         2. [ISLT] possibility of androgenic effect of delta4 isomer in risk reduction
            
            1. delta4 isomer has direct androgenic effects
               
            2. androgens have an anti-estrogen effect in the breast
               
            3. MPA binds to androgen receptor in low estrogen environment
               
               1. [ISLT] MPA binds to androgen receptor in this situation
                  
      6. [ISLT] Tibilone has indirect anti-androgen, anti-estrogen activity
         
         1. less Testosterone and Estradiol
            
            1. 17BHSD-I weakly inhibited by 3-OH tibolone metabolites
               
               1. less E1->E2, less A ->Testosterone
                  
            2. 17BHSD-II induced by tibolone
               
               1. more E2 -> E1, more Testosterone ->Androstenedione
                  
      7. see fig 1 pg10 Steroid Interconversion Pathways
         
         
         

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