40 Questions
What is the function of tamoxifen in relation to ER-alpha?
Inhibits the transcriptional activity of ER-alpha
What is the effect of estradiol versus tamoxifen on ER-alpha?
Estradiol is transcriptionally active, while tamoxifen is transcriptionally inactive
Which compound is a prodrug that requires hepatic O-demethylation to become an active ER ligand?
Mestranol
What is the role of coactivators in ER activation?
Enhance the transcriptional activity of ER by binding to it
Which type of substituent on the D-ring enhances the oral availability of estrogens?
17a-ethinyl substituent
What effect does the binding of anti-estrogens like tamoxifen have on estrogen receptor-alpha?
Prevents the recruitment of co-activators to ER-alpha
What is the mechanism of action of fulvestrant (ICI-182780) on estrogen receptor-alpha?
Prevents binding of co-activators to ER-alpha
What is the function of raloxifene in relation to estrogen receptor signaling?
Partially transcriptionally active as an ER ligand
Which of the following is a common use of drugs targeting the estrogen receptor?
Treating osteoporosis
Which type of ER modulator is used to treat breast cancer chemoprevention and chemotherapy?
ER antagonists
What is the most appropriate function of estrogen receptor alpha (ERa)?
Transcription factor activation
Where are the Zinc atoms contained in the estrogen receptor?
In the DNA binding domain
Which of the following tissues expresses both ERa and ERb?
All of the above
Which of the following best describes the estrogen receptor (ER) function?
A ligand-activated transcription factor
What is a common treatment for oral contraception that targets the estrogen receptor?
ER agonists
Which of the following is true about estrogen receptor signaling?
It activates transcription factors to regulate gene expression
What is the main difference between tamoxifen and fulvestrant in terms of ER binding?
Fulvestrant competes for ER binding and induces ER degradation while tamoxifen only competes for ER binding
Which function does fulvestrant not perform on the estrogen receptor?
Inducing ER dimerization
Which statement best describes the function of fulvestrant?
Fulvestrant is a pure estrogen antagonist without agonist properties
Which type of breast cancer is fulvestrant used to treat?
Estrogen receptor-positive metastatic breast cancer
Which of the following statements about fulvestrant is true?
Fulvestrant bears a penta-fluorinated alkyl-substituent
In which scenario would fulvestrant be used?
When hormonal therapies such as tamoxifen have failed
What is the impact of fulvestrant on estrogen signaling?
Fulvestrant completely inhibits estrogen signaling
Which of the following is a common use for fulvestrant?
Treatment of estrogen receptor-positive metastatic breast cancer in postmenopausal women
What is the function of 4-hydroxytamoxifen in breast tissue?
It acts as an antagonist to inhibit transcription of estrogen-responsive genes.
What gene variant may impact the effectiveness of tamoxifen in some patients?
CYP2D6
What potential side effect has tamoxifen been linked to in some women?
Endometrial cancer
What is the role of CYP2D6 in tamoxifen metabolism?
It converts tamoxifen into its more potent metabolites.
What is the approved use of raloxifene in postmenopausal women?
Treatment and prevention of osteoporosis
What other use of raloxifene was approved by the FDA in 2007?
As a chemopreventive medication against invasive breast cancer
What is the effect of tamoxifen on bone tissue?
It has anti-osteoporotic effects.
What are poor metabolizers of tamoxifen characterized by?
Lower levels of endoxifen and poorer clinical outcomes.
Which of the following estrogenic agents can undergo enterohepatic recycling?
1, 2, 3, 4
What is the route of administration for conjugated equine estrogens (CEE)?
Oral, transdermal, or intravaginal
What is the purpose of the estradiol transdermal system?
To release estradiol through a rate-limiting membrane continuously upon application to intact skin
What are the five estrogenic agents that target the estrogen receptor?
Equilin sulfate, 17a-dihydroequilin, estrone sulfate, equilenin, estradiol
What is the mechanism of action of the estradiol transdermal patch?
The estradiol transdermal patch releases estradiol in a continuous manner
What is the purpose of the enterohepatic recycling of E1-S?
To increase the half-life of E1-S
What is the purpose of hormonal replacement therapy (HRT) for the treatment of menopausal symptoms?
To replace the hormones that are no longer produced by the body after menopause
What is the advantage of using transdermal patches for systemic delivery of hormones?
Transdermal patches bypass the first-pass metabolism in the liver
Study Notes
Estrogen Receptor Signaling
- Estrogen Receptor (ER) is a ligand-activated transcription factor.
- Estrogen Response Element (ERE) is present in the promoter region of target genes.
- ERα (Estrogen Receptor alpha) and ERβ (Estrogen Receptor beta) are two subtypes of ER.
ERα Ligand Binding
- Estradiol (E2) is a natural ligand that binds to ERα, causing a conformational change that activates transcription.
- Tamoxifen and fulvestrant are anti-estrogens that bind to ERα, causing a conformational change that prevents the recruitment of co-activators.
- 4-OH-tamoxifen is an active metabolite of tamoxifen.
Estrogen Receptor Ligands
- Estradiol (E2) is a potent ER ligand.
- 17α-ethinylestradiol (EE) is a metabolically stable ER ligand.
- Raloxifene is a selective ER modulator (SERM) that targets osteoporosis and breast carcinogenesis.
- Diethylstilbestrol (DES) is a synthetic ER ligand.
Targeting ERα
- Estradiol and tamoxifen have different effects on ERα, with estradiol causing a transcriptionally active conformation and tamoxifen causing a transcriptionally inactive conformation.
- Fulvestrant is a pure ER antagonist that binds to ERα, competing with estradiol, and also induces ERα degradation.
Steroid Hormone Receptors
- The classic model of steroid hormone receptors involves ligand binding, causing a conformational change that activates transcription.
- ERα is a ligand-activated nuclear transcription factor.
Exam Questions
- Fulvestrant is a potent anti-estrogen that binds to ERα, competing with estradiol, and induces ERα degradation.
- Tamoxifen is metabolized by CYP2D6 to 4-OH-tamoxifen, which is a more potent metabolite.
Enterohepatic Recycling
- Enterohepatic recycling of estrogens occurs through intestinal microbial deconjugation and reuptake of free estrogens.
- Estrone sulfate (E1-S) and conjugated equine estrogen (CEE) undergo enterohepatic recycling.
Hormonal Replacement Therapy
- Hormonal replacement therapy is used to treat menopausal symptoms.
- Estrogen-only therapy involves the use of estradiol acetate, conjugated equine estrogens (CEE), or micronized 17β-estradiol.
- Estrogen/progestin combinations involve the use of CEE + medroxyprogesterone acetate (MPA) or ethynylestradiol (EE) + norethindrone.
Transdermal Patches
- Transdermal patches are used for systemic delivery of estrogen and other cardiovascular agents, analgesics, and hormones.
- Estradiol transdermal system is designed to release estradiol continuously upon application to intact skin.
Explore drugs targeting the estrogen receptor, including their use in oral contraception, breast cancer chemoprevention, chemotherapy, infertility treatment, hormone replacement therapy [HRT], and osteoporosis. Learn about SERM [selective ER modulators], ER agonists, and ER antagonists. Study the medicinal chemistry of Estrogen Receptor alpha.
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