ERS29 Pharmacology Of Sex Hormones And Antagonists Flashcards
Sex hormones
Produced by Gonads
- Conception
- Embryonic maturation
- Development of Primary + Secondary sexual characteristics
ALL from Cholesterol
- Shortening of hydrocarbon side chain
- Hydroxylation of steroid nucleus
3 main types:
- Estrogen
- Progestogens
- Androgens
Estrogens
- Estrone
- from Estradiol
- formed in liver (mainly) + peripheral tissues (breast, adipose tissue) - Estriol
- from Estradiol
- formed in liver (mainly) + peripheral tissues (breast, adipose tissue) - Estradiol (most active)
- from Ovaries:
—> Ovarian follicles (before ovulation)
—> Corpus luteum (after ovulation)
—> Placenta (during pregnancy)
Biosynthesis and Metabolism of Estrogens
Precursor: Testosterone
Key enzyme: Aromatase (mainly in liver)
Testosterone —> Estradiol —> Estrone —> Estriol
Androstenedione —> Estrone —> Estriol
Structure of Estrogen receptor
- Ligand-binding / Inhibitor-binding domain (LBD) (e.g. Heat-shock protein HSP: an inhibitor)
- mediate ligand-binding
- ***mediate regulation of NLS - Dimerisation sites
- 橫跨 LBD, DBD - Nuclear localisation signal (NLS)
- 屬於LBD
- hinge between LBD and DBD
—> allow dimerised protein to go into nucleus - DNA-binding domain (DBD)
- Zinc finger domain
- bind to HRE - Transactivation domain (TAD) / Variable / Regulatory domain
- mediate activating effect of receptor
- ***offer specificity
MOA of Estrogen
Estrogen receptor (ER):
member of superfamily of Nuclear receptor
—> transcription factor modulate gene expression
2 isoforms encoded by different genes
—> difference in length of Transactivation domain (mediate activating effect of receptor, ***offer specificity):
- ERα: 6q25.1
- ERβ: 14q23.2
MOA: Estrogen bind to ER —> ER conformation change —> translocation to nucleus —> bind to Estrogen Response Element —> recruit ***Co-activators —> gene transcription —> specific hormonal effects
Antagonist:
- different ER conformational change
- recruit ***Co-repressors —> reduce gene transcription
***Effects of Estrogen
Good:
- ↓ Bone resorption —> ↑ Bone mass
- ↑ HDL, ↓ LDL —> CVS protection
- Promote coagulation
Bad:
- ↑ Uterine bleeding (∵ Endometrial hyperplasia)
- ↑ Endometrial cancer
- ↑ Breast cancer
- ↑ Thromboembolic events
***Clinical applications of Estrogens
- Contraception
- mediated by ***inhibition of ovulation through -ve feedback suppression of FSH, LH - Replacement in Estrogen deficiency
- Primary hypogonadism
- Stimulate development of ***Secondary sexual characteristics (for 11-13 yo)
- Stimulate growth, bone development
- Treatment of failure of ovaries (∵ surgical removal / premature menopause)
—> Progestin may be needed - ***Postmenopausal hormonal therapy
- ***Osteoporosis treatment
- Infertility, Pregnancy support, Tall stature (Estrogen suppress IGF1, ↑ rate of skeletal maturation by acting on epiphyseal always cartilage), Acromegaly, Breast enhancement etc.
Estrogens administration and absorption
- Oral
- 1st pass metabolism (hepatic effect) —> Low bioavailability
- Ethinyl Estradiol —> ↓ 1st pass —> longer t1/2 - ***IM injection
- aqueous / oil-based —> longer t1/2 - ***Transdermal patch
- slow sustained release
- avoid 1st pass
- minimise hepatic effect - Local administration
- contraceptive rings
Estrogen full antagonists: Fulvestrant
Fulvestrant
Aka Selective Estrogen Receptor Degraders (SERD)
MOA: Bind to ER —> making ER more ***hydrophobic —> ER unstable + misfolded —> ***ER degradation
Indication:
- Hormone receptor-positive metastatic Breast cancer
- Locally advanced unresectable disease in postmenopausal women
SE (Safe drug):
- Nausea
- Injection site reactions
- Weakness
- Elevated transaminase
Selective Estrogen Receptor Modulators (SERMs)
Estrogen-related compounds:
- Selective Agonism / Antagonism for ER
- depends on tissue type
—> different degree of sensitivity to endogenous estrogens
—> Estrogenic / Antiestrogenic effect - **Tamoxifen, Toremifene, **Raloxifene, Clomiphene, Ospemifene
Tamoxifen
- Prodrug
- metabolised by ***CYP2D6, 2A4 in liver —> active metabolite (e.g. 4-hydroxytamoxifen, much higher affinity to ERα, ERβ than Estradiol)
MOA:
- Partial agonist / inhibitor of ER (tissue-dependent)
- ***Breast: Block ER (inhibitor)
Indication:
- Chemoprevention of Breast cancer in high risk group
- ***Early / Advanced ER-positive Breast cancer
- Reduction of Contralateral Breast cancer
- Ovarian cancer (maybe)
SE:
- ***↑ Endometrial cancer (∵ partial agonism)
- reduced cognition
- hot flushes
- N+V
Raloxifene
- Estrogenic effects in Bone + Liver
- Antiestrogenic effects (or no effect) in Breast + Uterus
Indication:
- ***Osteoporosis prevention / treatment in postmenopausal women
- alternative to Estrogens in patients with risk / history of cancer
Pharmacokinetics:
- Absolute bioavailability: 2% (extensive 1st pass)
SE:
- hot flushes
- joint pain
- ***blood clots
- pulmonary thromboembolism
***Progestogens
Regulated by LH
Low level in Follicular phase —> Higher level in Luteal phase —> Highest in pregnancy
Primary function: ***Maintaining pregnancy
- Secretion from endometrium
- Decidualisation
- Uterine quiescence
- ↓ Immune response to fetus
- ↑ Maternal ventilation
- Prepare breast for lactation
Produced by:
- Corpus luteum (2nd half of menstrual cycle)
- Placenta
- Adrenal cortex (Male / Female)
Receptor (PR):
- Nuclear receptors (PR-A, PR-B) —> transcription factor
- MOA ~ ER
—> PR-A/B + Co-activators/repressors —> ↑/↓ gene transcription
Clinical applications of Progestins
Synthetic Progestogens (e.g. ***Medroxyprogesterone acetate)
- ***Contraception (prevent ovulation + capacitation of sperms)
- Hormonal therapy of ***postmenopausal women (in combination with Estrogens)
- Control abnormal uterine bleeding (↓ effect of Estrogen on endometrial growth/hyperplasia —> ↓ bleeding) (***High Progesterone blocks Estrogen actions)
- Gynaecological cancers e.g. ***Endometrial cancer
- Appetite stimulation
Progestins administration and absorption
- Oral
- 1st pass metabolism (low bioavailability, hepatic effects) (free progesterone t1/2: 5 mins)
—> use synthetic form (i.e. Progestin) of Progesterone - ***Ester form
- ↓ 1st pass —> longer t1/2 - ***IM injection
- oil-based —> longer t1/2 - Depot preparation
- slow sustained release
Progesterone vs Progestin
Progesterone
- Natural (Bio-identical)
- Hepatic effect, short t1/2
Effects (Debatable)
- CVS protection
- hair growth
- calm mood, promote sleep
- prevent breast cancer
Progestin
- Synthetic
- Stable to 1st pass, longer t1/2
Effects (Debatable)
- risk of fatal blood clots
- hair loss
- anxiety, depression
- risk of breast cancer
Progesterone antagonists: Mifepristone
Competitive PR antagonist (***in presence of progesterone)
MOA:
Blockade of uterine PR
—> detachment of blastocyst
—> ↓ hCG production
—> cannot luteinise Corpus luteum
—> further ↓ progesterone production by Corpus luteum (vicious cycle)
—> cannot maintain pregnancy (equivalent to Progesterone withdrawal)
Indication:
- Termination of early pregnancy (combined with Misoprostol (prostaglandin analogs: contraction of uterus + expulsion of fetus))
SE:
- vaginal bleeding
- abdominal pain
Postmenopausal hormonal therapy
Postmenopausal syndrome:
↓ female hormone production (Estrogen + Progestogens)
—> **Bone loss, **Hot flushes, Insomnia, ***Vaginal dryness, Risk of cardiometabolic diseases (Estrogen CVS protective)
Primary indication of Estrogen hormonal therapy: Osteoporosis
2 types of Hormonal therapy:
-
**Estrogen-only (ET)
- for those without uterus due to **hysterectomy - ***Estrogen + Progestogen (EPT)
- for those with a uterus —> Estrogen alone ↑ uterine cancer —> combined with Progestogen to ↓ risk of uterine cancer
Administration:
- oral tablet, patch, gel, emulsion, spray, injection (systemic effects)
- cream, ring (local vaginal symptoms)
Benefits:
- Ameliorate hot flashes, vaginal dryness, night sweats, bone loss, improve sleep
- **Risk associated with long-term use of EPT
- Breast cancer
- Thromboembolic events —> Heart attack, Stroke
Dosage:
- Lowest effective dose
- Shortest duration
- Personalised approach
Androgens
Anabolic / Masculinising effects in both male / female
Types of androgens:
- Testosterone (major form)
- 95% from Testes - DHT (most active)
- 5α-reductase (catalyse Testosterone —> DHT in Epididymides, Skin, Liver, Brain) - Dehydroepiandrosterone (minor, from adrenal cortex)
Negative feedback regulation of androgen secretion
GnRH (Hypothalamus)
—> FSH, LH (Anterior pituitary)
—> Testosterone (Leydig cells)
Testosterone / DHT
—> inhibit production of GnRH + FSH + LH
MOA of androgens
Androgen receptor (AR): - Nuclear receptor —> transcription factor
Androgen bind to AR —> AR conformation change —> Dimerisation from 2 monomeric AR —> translocation to nucleus —> bind to ARE —> recruit co-activators / co-repressors —> gene transcription / suppression —> specific hormonal effects
Effects of androgens
Good:
- ↑ Muscle mass, strength
- ↑ Bone density
- Promote cognition
- ***↑ Erythropoiesis
Bad:
- ↑ Sebum production, hair growth (during puberty)
- ↑ ***Prostate mass, cell turnover
Clinical applications of androgens
- Replacement of androgen deficiency
- **enhance growth
- stimulate development of **secondary sexual characteristics
- can also be used in postmenopausal women - ***Fight with ageing (androgen levels decline with ageing)
- ↑ Lean body mass
- ↑ Haematocrit
- ↓ Bone loss
—> Long term benefits controversial - Abuse in sports to ↑ strength, aggressiveness
SE:
- possibly ↑ risk of Heart attack, Stroke
Androgens administration and absorption
- Oral
- absorb rapidly and metabolised by liver
- 1st pass effect -
**IM injection
- **Ester form
—> hydrolysis to release Testosterone —> bypass hepatic metabolism
- ***Alkylated androgens
—> ↓ hepatic metabolism - ***Transdermal patch, Skin cream, Gel
- slow sustained release
- minimise hepatic effect - SC pellets
Androgen inhibitor: Finasteride
5α-reductase inhibitor
MOA:
Block conversion of Testosterone to DHT (esp. in prostate)
Indication:
- ***BPH
- Chemoprevention of ***Prostate cancer (25% reduction)
- ***Male pattern baldness (∵ DHT weakening effect on hair follicles)
Pharmacokinetics:
- Oral, 65% bioavailability
SE (Minor):
- chills
- cold sweats
- confusions
Androgen receptor antagonists: Flutamide
Selective antagonist of Androgen receptors
Indication:
- Prostate cancer (in combination with blocking GnRH)
- Androgen-dependent skin / hair conditions
- Hyperandrogenism in women
Pharmacokinetics:
- Oral TDS (∵ short t1/2)
SE (associated with androgen deprivation):
- gynaecomastia
- breast tenderness
- sexual dysfunction
- hot flashes
Summary
HRT:
- Insufficient production of hormones
- Problem with development of gonads
- Removal of gonads
Blockade of hormonal effects (for excessive hormone production / overactivation of receptors)
- via Block receptor / Block synthesis (or combination)
- Hormone-dependent cancers
—> Breast cancer
—> Prostate cancer
Summary of drugs
Estrogen: 1. Estrogen —> Contraception —> Estrogen deficiency, Secondary sexual characteristics, Growth —> Postmenopausal symptoms —> Osteoporosis
- Estrogen full antagonists
- Fulvestrant —> Hormone receptor-positive metastatic Breast cancer - Selective Estrogen Receptor Modulators (SERMs)
- Tamoxifen —> ER-positive Breast cancer
- Raloxifene —> Osteoporosis with cancer history
Progesterone:
- Progesterone
- Medroxyprogesterone acetate —> Contraception, Postmenopausal symptoms, Abnormal uterine bleeding, Endometrial cancer - Progesterone antagonists
- Mifepristone —> Termination of early pregnancy
Estrogen + Progesterone:
1. Postmenopausal hormonal therapy
Androgen:
1. Androgen
—> Androgen deficiency, Secondary sexual characteristics, Growth
—> ↑ Lean body mass,↑ Haematocrit, ↓ Bone loss
- Androgen inhibitor
- Finasteride (5α-reductase inhibitor) —> BPH, Prostate cancer prevention, Male pattern baldness - Androgen receptor antagonists
- Flutamide —> Prostate cancer, Hyperandrogenism in women
