Endocrine Therapy: SERMs and SERDs

Question 1

Cancer Development

Answer 1

Arising from hormone-responsive tissues (breast, prostate, uterus) remain responsive to hormones and hormone receptor agonists/antagonists

Question 2

Estrogen drives and decreases

Answer 2

Drives proliferation

Decreased apoptosis

Question 3

Estrogen Synthesis

Answer 3

All estrogens come from cholesterol

Tesosterone is converted to estradiol

Question 4

Aromatase converts:

Answer 4

o Testosterone → estradiol

o Androstenedione → estrone

Question 5

Pre-Menopausal Estrogen Production

Answer 5

 Hypothalamus release GnRH to make FSH and LH which inturn goes to the ovaries
 10% of estrogen comes from peripheral tissues (adrenal gland, breast, liver, adipose tissues)(90% of estrogen gets made here)

Question 6

Post-Menopausal Estrogen Production

Answer 6

 Ovaries stops making estrogen so there is only like 10% of estrogen in the circulation from the peripheral tissues

Question 7

Premenopausal Women- Estrogen Deprivation

Answer 7

o Ovariectomy + Tamoxifen (blocked the 10% from the peripheral tissues)

Question 8

Postmenopausal Women – Estrogen Deprivation

Answer 8

Aromatase Inhibitors

Question 9

Estrogen Receptors

Answer 9

o AF1: growth factor binding domain
o AF2: Ligand binding domain
o Estrogen alpha is the most important in breast cancer and is a little larger

Question 10

Mode of Action of Estradiol

Answer 10

o Once estrogen comes in contact with the receptor it dimerizes
o AF1/2 are formed which then recruit coactivator(different transcription factors)
o It then binds to estrogen response genes
o Once they bind, they generate more and more RNA which leads to more transcription

Question 11

Selective Estrogen Receptor Modulators (SERMs) Drugs

Answer 11

 Raloxifene (evista) - Osteoporosis
 Tamoxifen (nolvadex)
 Toremifene (fareston)

Question 12

SERMs MOA

Answer 12

 Bind to estrogen receptors and acts like an antagonizers to cut of estrogen compounds

Question 13

SERMS + Breast and Uterus

Answer 13

 Binding in the breast leads to no proliferation

 Binding in the uterus leads to uterine cell proliferation

Question 14

Tamoxifen Use

Answer 14

breast cancer, chemopreventative for breast cancer

Question 15

Tamoxifen MOA

Answer 15

Binds to estrogen receptors, it causes abnormal organization of the receptor which leads to the AF2 not attaching → most of estrogen effects are lost
- AF2 regulates most of the estrogenic transcription

Question 16

Tamoxifen and Toremifiene SE

Answer 16

•	Hot flashes
•	Decreased libido
•	Tumor flare
o	Increased tumor growth that comes down
•	Vaginal Bleeding
•	Thrombosis
•	Cataracts
•	Endometrial cancer

Question 17

Fulvestrant Use and MOA

Answer 17

 Use: Metastatic breast cancer
 MOA: Binds to estrogen receptors and no matter where it has antagonistic effects → no estrogen effects (pure anti-estrogen)
- IM once monthly