L29 - Pharmacology of sex hormones and antagonists Flashcards
Describe the reaction that forms sex hormones?
Precursor = Cholesterol
Shortening of hydrocarbon side chain + hydroxylation of steroid nucleus
List 3 types of estrogens and their site of biosynthesis?
1) Liver and peripheral tissue (breast, adipocyte): convert from estradiol:
- Estrone
- Estriol
2) Ovarian follicles, Corpus luteum, Placenta:
- Estradiol
Describe the biosynthesis of estrogen?
1) Testosterone»_space; Estradiol
2) Androstenedione»_space; Estrone
Both reactions mediated by AROMATASE
Define the gene locus and forms of estrogen receptor?
2 isoforms:
- ERα = 6q25.1
- ERβ = 14q23.2
Describe the intracellular effects of Estrogen + estrogen receptor?
Estrogen + ER
>> ER conformation change ⇒ translocation to nucleus ⇒ bind to estrogen response element (in target genes) ⇒ recruit coactivators***** ⇒ initiate gene transcription ⇒ specific hormonal effects
Describe the intracellular effects of Antagonist + estrogen receptor?
Antagonist + ER ⇒ ER conformation change ⇒ translocation to nucleus ⇒ bind to estrogen response element (in target gene) ⇒ recruit co-repressors***** ⇒ reduce gene transcription
List 3 physiological effects of estrogen?
- Increase bone mass by decreasing bone resorption
- Promote secondary sexual characteristics
- Increase HDL
- Promote coagulation
List 3 risks of increased estrogen levels?
- Increase risk of uterine bleeding by causing endometrial hyperplasia
- Increase risk of thromboembolic events
- Increase risk of breast cancer
List 4 major clinical applications of estrogen?
- Birth control
- Replacement in estrogen deficiency
- Postmenopausal hormonal therapy
- Osteoporosis
(others: acromegaly, infertility…)
2 causes and 3 symptoms of Estrogen deficiency.
Causes:
Primary hypogonadism
Failure of ovaries (surgical removal; premature menopause)
Symptoms:
Delayed secondary sexual characteristics in female
Stunted growth and bone development
Infertility
Explain how estrogen acts as birth contol?
inhibition of ovulation through negative feedback suppression of FSH and LH
List 4 ways to admin estrogen?
- Oral intake (first-pass metabolism, low bioavailability, ADR)
- Intramuscular injection: aqueous-, oil-based preparations
- Transdermal patch: Slow sustained release
- Direct local administration: e.g. contraceptive rings
Which forms of estrogen admin increases half-life and reduces first pass metabolism?
Transdermal patch
Ethinyl estradiol (oral)
Intra-muscular injection
Name one Estrogen full antagonist/ SERD?
Fulvestrant
MoA and Indication of Fulvestrant?
binds to estrogen receptor»_space; make ER more hydrophobic, unstable, misfold»_space; protein degradation
1) hormone receptor-positive metastatic breast cancer
2) Locally advanced unresectable disease in postmenopausal women
ADR of Fulvestrant?
nausea, injection site reactions**, weakness, and elevated transaminase
List 2 major SERMs.
1) tamoxifen
2) raloxifene
(clomiphene, toremifene,ospemifene)
Explain how SERM exert different effect on diff. tissue?
Different tissues have different sensitivity to endogenous estrogens
> > SERMs display selective agonism (estrogenic) / antagonism (antiestrogenic) for estrogen receptors depending on tissue type
MoA of Tamoxifen?
Prodrug
metabolized by cytochrosome-p450 »_space; 4- hydroxytamoxifen (4-OHT)
» Partial agonist/inhibitor of estrogen receptor in diff. tissue: Block estrogen receptor in breast
Indications of Tamoxifen? (4)
Chemoprevention of breast cancer in high risk group
ER-positive breast cancer
reduction of contralateral breast cancer
ovarian cancer
ADR of Tamoxifen?
increased risk of Endometrial cancer (caused by partial agonism)
reduced cognition, hot flushes,
nausea and vomiting
Action of Raloxifene on bone, liver, breast and uterus?
estrogenic effects in bone and liver
anti-estrogenic effects in the breast and uterus (no uterine cancer, better than tamoxifen)
Indication for Raloxifene?
prevention and treatment of osteoporosis in postmenopausal women
alternative to estrogens in patients with risk and history of cancer
ADR of Raloxifene?
Extensive hepatic effect, First-pass metabolism
hot flushes
joint pain
blood clots, pulmonary thrombolism
3 endogenous sites of progestogen / progesterone synthesis? What regulates release?
- Corpus luteum after ovulation
- Placenta during pregnancy
- Adrenal cortex (Zona reticularis)
LH regulate Porgesterone syn.
Describe the action of Progesterone receptors? Isoforms?
Nuclear receptor (2 isoforms: PR-A & PR-B)
PR-A or PR-B plus co-activators and co-repressors = effect on gene transcription (same as estrogen)
Name one synthetic progestogen. Indications?
Medroxyprogesterone acetate
- Hormonal therapy of postmenopausal women (+ estrogen)
- Control abnormal uterine bleeding (counter estrogen on endometrial hyperplasia)
- Treatment of gynaecological cancers (e.g. endometrial cancer)
- Contraception and birth control (block ovulation and sperm capacitation)
- Appetite stimulation
4 admins of Progestins?
- Oral intake - extensive first pass metabolism
- Oral Ester form: Reduce hepatic metabolism
- Intramuscular injection: Oil-based preparations
- Depot preparation (deposit drug in a localized mass) ⇒ Slow sustained release
Difference between progesterone and progestin?
Progestin = synthetic
Less first-pass metabolism + longer t1/2
List 4 ADR of Progestin (synthetic)?
- Increases the risk of fatal blood clots
- hair loss
- anxiety and depression
- Increases the risk of breast cancer
List 4 advantages of progesterone over progestin?
- Beneficial for cardiovascular health vs fatal blood clots
- Stimulates hair growth vs hair loss
- Calms mood and promotes sleep vs anxiety and depression
- Prevents breast cancer vs increase risk
Define the 2 types of Postmenopausal hormone therapy?
Estrogen-only therapy (ET), for after hysterectomy (no uterus)
Estrogen plus progestogen therapy (EPT) for those with uterus = prevent uterine cancer
List the admin. methods for Postmenopausal hormonal therapy (HT)?
Systemic effects:
oral tablet, patch, gel, emulsion, spray, or injection
Local vaginal symptoms: cream, ring
List symptoms under Postmenopausal syndrome?
Decreased production of female hormones (estrogen and progesterone):
- bone loss
- hot flushes
- insomnia
- vaginal dryness
- increased risk of cardiometabolic diseases
Primary indication for Postmenopausal hormonal therapy (HT)?
Osteoporosis
List some benefits and risks of Postmenopausal hormonal therapy (HT)?
Benefits: treat symptoms under postmenopausal syndrome
Risks: long term use: breast cancer, heart attack and stroke
Name one progesterone antagonist. MoA?
Mifepristone (RU-486)
competitive progesterone receptor antagonist in the presence of progesterone**
> > Blockade of uterine progesterone receptor
detachment of blastocyst; decrease hCG production
reduce progesterone secretion by corpus luteum
Abortion
Preparation of Mifepristone?
Mifepristone combined with misoprostol
> > block progesterone action + uterine contraction
> > termination of early pregnancy
ADR of Mifepristone?
Vaginal bleeding, abdominal pain
List the 3 types of androgens and their site of production?
Testosterone = Testis (Leydig cells)
Dihydrotestosterone (DHT) = most active, made at Epididymis, skin, liver, brain
Dehydroepiandrosterone(DHEA)/ androstenolone = adrenal cortex
Define the precursors of the 3 types of androgens?
Testosterone = from cholesterol
Dehydroepiandrosterone = cholesterol
DHT = enzyme 5alpha-reductase: convert from testosterone
Describe the endogenous regulation of Testosterone release?
GnRH»_space; FSH and LH»_space; Testosterone or DHT
Testosterone or DHT negatively feedback inhibit Anterior pituitary and Hypothalamus
Describe the mechanism of Androgen activating androgen receptor.
Androgen + Androgen receptor
⇒ AR conformation change and dimerize
⇒ translocation to nucleus
⇒ bind to androgen response element (in target gene)
⇒ recruit co-activators or co-repressors
⇒ initiate gene transcription for specific hormonal effects
List 7 physiological effects of androgens?
- Increase muscle mass, strength
- Increase erythropoiesis
- Increase bone density
- Increase sebum production, hair growth
- Sexual characteristics and drive
- Increase prostate mass, cell turnover
- Promote cognition
2 clinical uses of androgens?
Replacement in androgen deficiency: promote growth, secondary sexual characteristics, postmenopausal women
Anti-aging: Increase lean body mass & hematocrit, reduce bone loss
ADR of androgens?
increased risk of heart attack and stroke
5 admin methods of androgen?
- Oral intake: rapid absorption and inactivation
- Intramuscular injection of Ester form
- Alkylated androgen (reduce hepatic metabolism)
- Transdermal patch, cream, gel: slow, sustained release
- Subcutaneous pellets
Explain why ester forms of androgen causes less hepatic reactions?
Ester form
⇒ hydrolysis to release testosterone
⇒ bypass hepatic metabolism
Name one Androgen inhibitor. MoA?
Finasteride
5α-reductase inhibitor: Block conversion of testosterone to more active dihydrotestosterone (DHT) - mainly in prostate
Indication of Finasteride?
benign prostatic hyperplasia
Chemoprevention of prostate cancer
Treatment of male pattern baldness (hair loss)
ADR of Finasteride?
chills, cold sweats, confusion and dizziness.
Name one Androgen receptor antagonist? MoA?
Flutamide = selective antagonist of androgen receptors
+ blocking GnRH (gonadotropin-releasing hormone)
Indications for Flutamide?
prostate cancer
androgen-dependent skin and hair conditions
hyperandrogenism in women
Admin and ADR of Flutamide?
Oral administration
ADR due to adrogen deprivation:
- gynecomastia, breast tenderness, sexual dysfunction and hot flushes
