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ERS > ERS29 Pharmacology Of Sex Hormones And Antagonists > Flashcards

ERS29 Pharmacology Of Sex Hormones And Antagonists Flashcards

1
Q

Sex hormones

A

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:

  1. Estrogen
  2. Progestogens
  3. Androgens
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2
Q

Estrogens

A
  1. Estrone
    - from Estradiol
    - formed in liver (mainly) + peripheral tissues (breast, adipose tissue)
  2. Estriol
    - from Estradiol
    - formed in liver (mainly) + peripheral tissues (breast, adipose tissue)
  3. Estradiol (most active)
    - from Ovaries:
    —> Ovarian follicles (before ovulation)
    —> Corpus luteum (after ovulation)
    —> Placenta (during pregnancy)
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3
Q

Biosynthesis and Metabolism of Estrogens

A

Precursor: Testosterone
Key enzyme: Aromatase (mainly in liver)

Testosterone —> Estradiol —> Estrone —> Estriol
Androstenedione —> Estrone —> Estriol

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4
Q

Structure of Estrogen receptor

A
  1. Ligand-binding / Inhibitor-binding domain (LBD) (e.g. Heat-shock protein HSP: an inhibitor)
    - mediate ligand-binding
    - ***mediate regulation of NLS
  2. Dimerisation sites
    - 橫跨 LBD, DBD
  3. Nuclear localisation signal (NLS)
    - 屬於LBD
    - hinge between LBD and DBD
    —> allow dimerised protein to go into nucleus
  4. DNA-binding domain (DBD)
    - Zinc finger domain
    - bind to HRE
  5. Transactivation domain (TAD) / Variable / Regulatory domain
    - mediate activating effect of receptor
    - ***offer specificity
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5
Q

MOA of Estrogen

A

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
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6
Q

***Effects of Estrogen

A

Good:

  1. ↓ Bone resorption —> ↑ Bone mass
  2. ↑ HDL, ↓ LDL —> CVS protection
  3. Promote coagulation

Bad:

  1. ↑ Uterine bleeding (∵ Endometrial hyperplasia)
  2. ↑ Endometrial cancer
  3. ↑ Breast cancer
  4. ↑ Thromboembolic events
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7
Q

***Clinical applications of Estrogens

A
  1. Contraception
    - mediated by ***inhibition of ovulation through -ve feedback suppression of FSH, LH
  2. 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
  3. ***Postmenopausal hormonal therapy
  4. ***Osteoporosis treatment
  5. Infertility, Pregnancy support, Tall stature (Estrogen suppress IGF1, ↑ rate of skeletal maturation by acting on epiphyseal always cartilage), Acromegaly, Breast enhancement etc.
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8
Q

Estrogens administration and absorption

A
  1. Oral
    - 1st pass metabolism (hepatic effect) —> Low bioavailability
    - Ethinyl Estradiol —> ↓ 1st pass —> longer t1/2
  2. ***IM injection
    - aqueous / oil-based —> longer t1/2
  3. ***Transdermal patch
    - slow sustained release
    - avoid 1st pass
    - minimise hepatic effect
  4. Local administration
    - contraceptive rings
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9
Q

Estrogen full antagonists: Fulvestrant

A

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
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10
Q

Selective Estrogen Receptor Modulators (SERMs)

A

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
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11
Q

Tamoxifen

A
  • 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:

  1. Chemoprevention of Breast cancer in high risk group
  2. ***Early / Advanced ER-positive Breast cancer
  3. Reduction of Contralateral Breast cancer
  4. Ovarian cancer (maybe)

SE:

  • ***↑ Endometrial cancer (∵ partial agonism)
  • reduced cognition
  • hot flushes
  • N+V
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12
Q

Raloxifene

A
  • Estrogenic effects in Bone + Liver
  • Antiestrogenic effects (or no effect) in Breast + Uterus

Indication:

  1. ***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
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13
Q

***Progestogens

A

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:

  1. Corpus luteum (2nd half of menstrual cycle)
  2. Placenta
  3. Adrenal cortex (Male / Female)

Receptor (PR):
- Nuclear receptors (PR-A, PR-B) —> transcription factor
- MOA ~ ER
—> PR-A/B + Co-activators/repressors —> ↑/↓ gene transcription

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14
Q

Clinical applications of Progestins

A

Synthetic Progestogens (e.g. ***Medroxyprogesterone acetate)

  1. ***Contraception (prevent ovulation + capacitation of sperms)
  2. Hormonal therapy of ***postmenopausal women (in combination with Estrogens)
  3. Control abnormal uterine bleeding (↓ effect of Estrogen on endometrial growth/hyperplasia —> ↓ bleeding) (***High Progesterone blocks Estrogen actions)
  4. Gynaecological cancers e.g. ***Endometrial cancer
  5. Appetite stimulation
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15
Q

Progestins administration and absorption

A
  1. Oral
    - 1st pass metabolism (low bioavailability, hepatic effects) (free progesterone t1/2: 5 mins)
    —> use synthetic form (i.e. Progestin) of Progesterone
  2. ***Ester form
    - ↓ 1st pass —> longer t1/2
  3. ***IM injection
    - oil-based —> longer t1/2
  4. Depot preparation
    - slow sustained release
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16
Q

Progesterone vs Progestin

A

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
17
Q

Progesterone antagonists: Mifepristone

A

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
18
Q

Postmenopausal hormonal therapy

A

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:

  1. **Estrogen-only (ET)
    - for those without uterus due to **    hysterectomy
  2. ***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
19
Q

Androgens

A

Anabolic / Masculinising effects in both male / female

Types of androgens:

  1. Testosterone (major form)
    - 95% from Testes
  2. DHT (most active)
    - 5α-reductase (catalyse Testosterone —> DHT in Epididymides, Skin, Liver, Brain)
  3. Dehydroepiandrosterone (minor, from adrenal cortex)
20
Q

Negative feedback regulation of androgen secretion

A

GnRH (Hypothalamus)
—> FSH, LH (Anterior pituitary)
—> Testosterone (Leydig cells)

Testosterone / DHT
—> inhibit production of GnRH + FSH + LH

21
Q

MOA of androgens

A 
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
22
Q

Effects of androgens

A

Good:

  • ↑ Muscle mass, strength
  • ↑ Bone density
  • Promote cognition
  • ***↑ Erythropoiesis

Bad:

  • ↑ Sebum production, hair growth (during puberty)
  • ↑ ***Prostate mass, cell turnover
23
Q

Clinical applications of androgens

A
  1. Replacement of androgen deficiency
    - **enhance growth
    - stimulate development of **    secondary sexual characteristics
    - can also be used in postmenopausal women
  2. ***Fight with ageing (androgen levels decline with ageing)
    - ↑ Lean body mass
    - ↑ Haematocrit
    - ↓ Bone loss
    —> Long term benefits controversial
  3. Abuse in sports to ↑ strength, aggressiveness

SE:
- possibly ↑ risk of Heart attack, Stroke

24
Q

Androgens administration and absorption

A
  1. Oral
    - absorb rapidly and metabolised by liver
    - 1st pass effect
  2. **IM injection
    - **    Ester form
    —> hydrolysis to release Testosterone —> bypass hepatic metabolism
    - ***Alkylated androgens
    —> ↓ hepatic metabolism
  3. ***Transdermal patch, Skin cream, Gel
    - slow sustained release
    - minimise hepatic effect
  4. SC pellets
25
Q

Androgen inhibitor: Finasteride

A

5α-reductase inhibitor

MOA:
Block conversion of Testosterone to DHT (esp. in prostate)

Indication:

  1. ***BPH
  2. Chemoprevention of ***Prostate cancer (25% reduction)
  3. ***Male pattern baldness (∵ DHT weakening effect on hair follicles)

Pharmacokinetics:
- Oral, 65% bioavailability

SE (Minor):

  • chills
  • cold sweats
  • confusions
26
Q

Androgen receptor antagonists: Flutamide

A

Selective antagonist of Androgen receptors

Indication:

  1. Prostate cancer (in combination with blocking GnRH)
  2. Androgen-dependent skin / hair conditions
  3. Hyperandrogenism in women

Pharmacokinetics:
- Oral TDS (∵ short t1/2)

SE (associated with androgen deprivation):

  • gynaecomastia
  • breast tenderness
  • sexual dysfunction
  • hot flashes
27
Q

Summary

A

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

28
Q

Summary of drugs

A 
Estrogen:
1. Estrogen
—> Contraception
—> Estrogen deficiency, Secondary sexual characteristics, Growth
—> Postmenopausal symptoms
—> Osteoporosis
  1. Estrogen full antagonists
    - Fulvestrant —> Hormone receptor-positive metastatic Breast cancer
  2. Selective Estrogen Receptor Modulators (SERMs)
    - Tamoxifen —> ER-positive Breast cancer
    - Raloxifene —> Osteoporosis with cancer history

Progesterone:

  1. Progesterone
    - Medroxyprogesterone acetate —> Contraception, Postmenopausal symptoms, Abnormal uterine bleeding, Endometrial cancer
  2. 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

  1. Androgen inhibitor
    - Finasteride (5α-reductase inhibitor) —> BPH, Prostate cancer prevention, Male pattern baldness
  2. Androgen receptor antagonists
    - Flutamide —> Prostate cancer, Hyperandrogenism in women

ERS (41 decks)

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