Estrogen Pharm

Question 1

What is the most important component of estrogen?

Answer 1

Phenolic A ring - most important for receptor binding

Question 2

Estrogen Synthesis in Diff Populations

Answer 2

• Pre-menopause - cholesterol –> androstenedione by theca cells –> estradiol by aromatase in granulosa cells (menstrual fluctuation)
• HUGE levels in pregnancy
• Post-menopausal - adipose stromal cells convert DHEA –> estradiol (levels similar to males)
• Men - Androstenedione –> estradiol by aromatization mostly in extra-gonadal tissues (+ some produced in testes)

Question 3

How does estrogen work at cell?

Answer 3

• ER = Part of Nuclear Receptor Family - conserved DNA binding domain, more unique ligand binding domain and divergent amino terminal domain that acts as transcription factor (activates or represses transcription)
• ERs bind specific regions w/in promotor region called estrogen response elements
• Transcriptional co-activators directly or indirectly regulate transcription (cooperation)

Question 4

Alpha v Beta ERs

Answer 4

• Both widely expressed throughout body EXCEPT uterus which has only low beta form (mainly alpha)
• Estradiol is a potent ligand for both but receptors have some unique gene targets –> distinct effects on specific tissues and cell types
• Alpha - uterus and bone
• Beta - colon, granulosa cells and required for efficient folliculogenesis
• Can form alpha-alpha or beta-beta homodimers or alpha-beta heterodimers

Question 5

Estrogen Metabolism

Answer 5

• Lipophilic (rapid and wide distribution)
• LIMITED BY rapid liver metabolism–> 16 alpha hydroxylated form, 17-keto form, sulfate and glucouronidated forms –> excreted in urine
• Sulfate and glucouronidated forms undergo enterohepatic recirculation
• Short plasma half-life
• Effected by menstrual cycle, smoking, menopause, genetic polymorphisms, diseases

Question 6

2 Estrogen Derivatives

Answer 6

1 - Sub at C17 position –> dec first pass effect so can be used orally

    - Ex) Ethinyl estrogen
    - Ex) Mestranol (methylated version of ethinyl estrogen de-methylated by liver)

2 - Conjugated equine estrogens - mix of estrogen sulfates including estrone, equilin and 17-alpha dihydroequilin
- Hydrolyzed by enzymes in lower gut and absorbed thru intestinal epithelium

Question 7

Fulvestrant

Answer 7

• ER antagonist for ER+ breast cancer resistant to tamoxifen
• monthly IM injection
• triggers ER degradation

Question 8

Tamoxifene

Answer 8

• SERM
• agonist in bone to dec risk osteoporosis BUT agonist in uterus so inc risk uterine cancer
• Side effects = hot flashes, vaginal atrophy, hair loss, vomiting, inc risk thromboembolism
• ORAL
• Uses - for ER+ and ER+/PR+ tumors
• If high risk for breast cancer, can use tamoxifen prophylactically

Question 9

Raloxifene

Answer 9

• SERM
• for osteoporosis b/c ER agonist in bone BUT not agonist in uterus or breast so no inc risk cancer
• ORAL

Question 10

SERM-Resistant Breast Cancer

Answer 10

• HER2-neu receptor –> activated AIB1 which is a ER coactivator that dec antagonistic activity of tamoxifen-bound ERs
• So tumors high in HER2-neu and AIB1 are more likely tamoxifen resistant
• Can use ER antagonists

Question 11

Aromatase Inhibitors (2 types, uses)

Answer 11

• Dec estrogen in peripheral tissues (do not block ovary estrogen prod)
• Good for breast cancer tx for postmenopausal women
  alone or combined w/ tamoxifen
• Steroidal/ Type I - suicide substrates converted to reactive intermediates by aromatase (irreversible inactivation of aromatase)
  
  • formestance, exemestane
• Nonsteroidal / Type II - reversibly interact w/ heme group of aromatase
  
  • anastrozole, letrozole, vorozole