SERMs and AIs

Question 1

Where is oestrogen produced?

Answer 1

Follicle cells in developing oocyte

Adrenal cortex

Question 2

What is the primary effect of oestrogen on epithelial cells?

Answer 2

Proliferation (ductal epithelial cells in breast, epithelial cells in endometrium)

Question 3

What are the target tissues for oestrogen?

Answer 3

• Breast
• Endometrium
• Bone
• CVS, CNS

Question 4

What is the relationship between oestrogen and breast cancer?

Answer 4

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.

Question 5

How do estrogens bind to estrogen receptors?

Answer 5

DIfferent forms of endogenous estrogens (17beta-estradiol, estrone, ethinyl estradiol) all have -OH groups which bind to ER.

Question 6

What are the two types of ERs and what roles do they play?

Answer 6

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

Question 7

What do agonist ligands and antagonist ligands of estrogen receptors do?

Answer 7

Agonist ligands induce conformations that allow ER to stably interact with activator proteins.

Conversely, antagonist ligands allow conformations to interact with repressor proteins.

Question 8

What is oestrogen’s impact on bone health?

Answer 8

ERα and Erβ are expressed in bone

• Estradiol increase @ pubery → long bone growth
• Estradiol maintains bone density in adults (inhibits osteoclasts, promotes osteoblast survival)

Question 9

What are SERMs?

Answer 9

Selectrive estrogen receptor modulators - Compounds that exhibit tissue-specific ER agonist/antagonist activity/

Question 10

What is the mechanism of action behind SERMs?

Answer 10

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

Question 11

Are SERMs steroidal?

Answer 11

No - except for fulvestrant

Question 12

What effect do SERMs have on breast and bone?

Thus, what are they used to treat?

Answer 12

Anti-oestrogenic effect on breast. (treat BC)

Estrogenic effect on bone. (treat osteoporosis)

Question 13

Two examples of SERMs

Answer 13

Tamoxifen

Raloxifene

Question 14

How can adjuvant hormone therapy (e.g. SERMs) help in different stages of breast cancer?

Answer 14

Early BC = eradicate micro-metastases

Late BC = improve survival in bone metastases

High risk of BC = prevention effect

Question 15

Describe tamoxifens mechanism of action

Answer 15

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

Question 16

Tamoxifen is a partial agonist in other tissues beside breast. What is the effect of ths?

Answer 16

PArtial agonist in bone - maintains bone density

Partial agonist in endometrium - increases risk of endometrial cancer, but still worth using.

Question 17

Contraindications for prescribing tamoxifen?

Answer 17

• Pregnant/breast-feeding
• Smoker
• Past Hx of DVT/PE/stroke

Question 18

Describe how raloxifene is different to tamoxifen

Answer 18

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.

Question 19

What SERM is used to treat osteoporosis in post-menopausal women?

Answer 19

Raloxifene

Question 20

What are two types of non-SERM adjuvant therapies in BC?

Answer 20

Aromatase inhibitors

Ovarian function suppression

Question 21

What is the mechanism of action for aromatase inhibitors?

Answer 21

Aromatase converts androgens to 17b-estradiol.

Inhibitors block this, used to treat ER+ BC.

Question 22

Which has a better survival benefit in post-menopausal women - tamoxifen or aromatase inhibitors?

Answer 22

Aromatase inhibitors.

Question 23

For who are aromatase inhibitors indicated/contraindicated?

Answer 23

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.

Question 24

Examples of aromatase inhibitors?

Answer 24

Anastrozole

Letrozole

Question 25

Giving an example - how do ovarian function suppressors help BC?

Answer 25

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.

Question 26

How is goserelin administered?

For who is it indicated?

Answer 26

Subcutaneous implant.

For pre-menopausal women.

Question 27

Can goserelin be used in combination with SERMs or other non-SERM adjuvant therapy?

Answer 27

Yes.

Can be used with tamoxifen or aromatase inhibitors, as goserelin removes the negative feedback involved.

Question 28

Australian Adjuvant Hormone Guidelines on:

1. BC prevention in high risk women
2. BC treatment in pre-meno women
3. BC treatment in high risk post-meno
4. BC treatment in low risk post-meno

Answer 28

1. Tamoxifen
2. Tamoxifen
3. Aromatase inhibitors
4. Tamoxifen