SERMs and AIs Flashcards
Where is oestrogen produced?
Follicle cells in developing oocyte
Adrenal cortex
What is the primary effect of oestrogen on epithelial cells?
Proliferation (ductal epithelial cells in breast, epithelial cells in endometrium)
What are the target tissues for oestrogen?
- Breast
- Endometrium
- Bone
- CVS, CNS
What is the relationship between oestrogen and breast cancer?
Oestrogen stimulates proliferation of estrogen receptor positive (ER+) breast cancer cells, increasing the accumulation of mutations.
It does not directly induce DNA mutations to cause BC.
How do estrogens bind to estrogen receptors?
DIfferent forms of endogenous estrogens (17beta-estradiol, estrone, ethinyl estradiol) all have -OH groups which bind to ER.
What are the two types of ERs and what roles do they play?
ERα
- Always an activator
- More important in breast and uterus
- Mammary gland development
ERβ
- Sometimes a repressor
- Suppresses mammary gland proliferation
- More important in CNS
What do agonist ligands and antagonist ligands of estrogen receptors do?
Agonist ligands induce conformations that allow ER to stably interact with activator proteins.
Conversely, antagonist ligands allow conformations to interact with repressor proteins.
What is oestrogen’s impact on bone health?
ERα and Erβ are expressed in bone
- Estradiol increase @ pubery → long bone growth
- Estradiol maintains bone density in adults (inhibits osteoclasts, promotes osteoblast survival)
What are SERMs?
Selectrive estrogen receptor modulators - Compounds that exhibit tissue-specific ER agonist/antagonist activity/
What is the mechanism of action behind SERMs?
ER ligand binding domain (LBD) consists of 12 alpha-helices: 11 form a pocket and 12th forms the lid.
When 17b-estradiol binds the LBD, the 12th helix (lid) closes over the estradiol and exposes amino acids essential for co-activator binding.
SERMs are larger - they don’t allow the lid to close, and thus co-activators cannot bind = ANTAGONIST effect
Are SERMs steroidal?
No - except for fulvestrant
What effect do SERMs have on breast and bone?
Thus, what are they used to treat?
Anti-oestrogenic effect on breast. (treat BC)
Estrogenic effect on bone. (treat osteoporosis)
Two examples of SERMs
Tamoxifen
Raloxifene
How can adjuvant hormone therapy (e.g. SERMs) help in different stages of breast cancer?
Early BC = eradicate micro-metastases
Late BC = improve survival in bone metastases
High risk of BC = prevention effect
Describe tamoxifens mechanism of action
SERM action
Binds to ERα, antagonises estrogen and blocks proliferation.
Useful for all 3 uses:
- Decreased further occurence in early BC
- Improved survival in metastatic BC
- Prevention
Tamoxifen is a partial agonist in other tissues beside breast. What is the effect of ths?
PArtial agonist in bone - maintains bone density
Partial agonist in endometrium - increases risk of endometrial cancer, but still worth using.
Contraindications for prescribing tamoxifen?
- Pregnant/breast-feeding
- Smoker
- Past Hx of DVT/PE/stroke
Describe how raloxifene is different to tamoxifen
Also used to treat and prevent BC, but not as effective.
However, it does not have agonist effect on endometrium - NO increased endometrial cancer risk! (unlike tamoxifen!)
Main use = osteoporosis. ER agonist in bone, decreasing osteoclast activity.
What SERM is used to treat osteoporosis in post-menopausal women?
Raloxifene
What are two types of non-SERM adjuvant therapies in BC?
Aromatase inhibitors
Ovarian function suppression
What is the mechanism of action for aromatase inhibitors?
Aromatase converts androgens to 17b-estradiol.
Inhibitors block this, used to treat ER+ BC.
Which has a better survival benefit in post-menopausal women - tamoxifen or aromatase inhibitors?
Aromatase inhibitors.
For who are aromatase inhibitors indicated/contraindicated?
Aromatase inhibitors can only be used in post-menopausal women.
It is contraindicated pre-menopausally, as shutting down aromatase would result in overcompensation of FSH/LH.
Examples of aromatase inhibitors?
Anastrozole
Letrozole
Giving an example - how do ovarian function suppressors help BC?
Goserelin - GnRH agonist.
Pulsatile and cyclical GnRH release stimulates FSH and LH to be released.
Goserelin produces continuous GnRH release, which does NOT stimulate FSH/LH release.
How is goserelin administered?
For who is it indicated?
Subcutaneous implant.
For pre-menopausal women.
Can goserelin be used in combination with SERMs or other non-SERM adjuvant therapy?
Yes.
Can be used with tamoxifen or aromatase inhibitors, as goserelin removes the negative feedback involved.
Australian Adjuvant Hormone Guidelines on:
- BC prevention in high risk women
- BC treatment in pre-meno women
- BC treatment in high risk post-meno
- BC treatment in low risk post-meno
- Tamoxifen
- Tamoxifen
- Aromatase inhibitors
- Tamoxifen
