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MBBS II ERS > L29 - Pharmacology of sex hormones and antagonists > Flashcards

L29 - Pharmacology of sex hormones and antagonists Flashcards

1
Q

Describe the reaction that forms sex hormones?

A

Precursor = Cholesterol

Shortening of hydrocarbon side chain + hydroxylation of steroid nucleus

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2
Q

List 3 types of estrogens and their site of biosynthesis?

A

1) Liver and peripheral tissue (breast, adipocyte): convert from estradiol:
- Estrone
- Estriol

2) Ovarian follicles, Corpus luteum, Placenta:
- Estradiol

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3
Q

Describe the biosynthesis of estrogen?

A

1) Testosterone&raquo_space; Estradiol
2) Androstenedione&raquo_space; Estrone

Both reactions mediated by AROMATASE

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4
Q

Define the gene locus and forms of estrogen receptor?

A

2 isoforms:

  • ERα = 6q25.1
  • ERβ = 14q23.2
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5
Q

Describe the intracellular effects of Estrogen + estrogen receptor?

A

Estrogen + ER

>> ER conformation change 
⇒ translocation to nucleus 
⇒ bind to estrogen response element (in target genes) 
⇒ recruit coactivators*****
⇒ initiate gene transcription 
⇒ specific hormonal effects
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6
Q

Describe the intracellular effects of Antagonist + estrogen receptor?

A 
Antagonist + ER ⇒ ER conformation change
⇒ translocation to nucleus 
⇒ bind to estrogen response element (in target gene) 
⇒ recruit co-repressors***** 
⇒ reduce gene transcription
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7
Q

List 3 physiological effects of estrogen?

A
  • Increase bone mass by decreasing bone resorption
  • Promote secondary sexual characteristics
  • Increase HDL
  • Promote coagulation
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8
Q

List 3 risks of increased estrogen levels?

A
  • Increase risk of uterine bleeding by causing endometrial hyperplasia
  • Increase risk of thromboembolic events
  • Increase risk of breast cancer
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9
Q

List 4 major clinical applications of estrogen?

A
  • Birth control
  • Replacement in estrogen deficiency
  • Postmenopausal hormonal therapy
  • Osteoporosis
    (others: acromegaly, infertility…)
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10
Q

2 causes and 3 symptoms of Estrogen deficiency.

A

Causes:
Primary hypogonadism
Failure of ovaries (surgical removal; premature menopause)

Symptoms:
Delayed secondary sexual characteristics in female
Stunted growth and bone development
Infertility

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11
Q

Explain how estrogen acts as birth contol?

A

inhibition of ovulation through negative feedback suppression of FSH and LH

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12
Q

List 4 ways to admin estrogen?

A
  1. Oral intake (first-pass metabolism, low bioavailability, ADR)
  2. Intramuscular injection: aqueous-, oil-based preparations
  3. Transdermal patch: Slow sustained release
  4. Direct local administration: e.g. contraceptive rings
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13
Q

Which forms of estrogen admin increases half-life and reduces first pass metabolism?

A

Transdermal patch

Ethinyl estradiol (oral)

Intra-muscular injection

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14
Q

Name one Estrogen full antagonist/ SERD?

A

Fulvestrant

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15
Q

MoA and Indication of Fulvestrant?

A

binds to estrogen receptor&raquo_space; make ER more hydrophobic, unstable, misfold&raquo_space; protein degradation

1) hormone receptor-positive metastatic breast cancer
2) Locally advanced unresectable disease in postmenopausal women

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16
Q

ADR of Fulvestrant?

A

nausea, injection site reactions**, weakness, and elevated transaminase

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17
Q

List 2 major SERMs.

A

1) tamoxifen
2) raloxifene

(clomiphene, toremifene,ospemifene)

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18
Q

Explain how SERM exert different effect on diff. tissue?

A

Different tissues have different sensitivity to endogenous estrogens

> > SERMs display selective agonism (estrogenic) / antagonism (antiestrogenic) for estrogen receptors depending on tissue type

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19
Q

MoA of Tamoxifen?

A

Prodrug

metabolized by cytochrosome-p450 &raquo_space; 4- hydroxytamoxifen (4-OHT)
» Partial agonist/inhibitor of estrogen receptor in diff. tissue: Block estrogen receptor in breast

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20
Q

Indications of Tamoxifen? (4)

A

Chemoprevention of breast cancer in high risk group

ER-positive breast cancer

reduction of contralateral breast cancer

ovarian cancer

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21
Q

ADR of Tamoxifen?

A

increased risk of Endometrial cancer (caused by partial agonism)

reduced cognition, hot flushes,

nausea and vomiting

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22
Q

Action of Raloxifene on bone, liver, breast and uterus?

A

estrogenic effects in bone and liver

anti-estrogenic effects in the breast and uterus (no uterine cancer, better than tamoxifen)

23
Q

Indication for Raloxifene?

A

prevention and treatment of osteoporosis in postmenopausal women

alternative to estrogens in patients with risk and history of cancer

24
Q

ADR of Raloxifene?

A

Extensive hepatic effect, First-pass metabolism

hot flushes

joint pain

blood clots, pulmonary thrombolism

25
Q

3 endogenous sites of progestogen / progesterone synthesis? What regulates release?

A
  • Corpus luteum after ovulation
  • Placenta during pregnancy
  • Adrenal cortex (Zona reticularis)

LH regulate Porgesterone syn.

26
Q

Describe the action of Progesterone receptors? Isoforms?

A

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)

27
Q

Name one synthetic progestogen. Indications?

A

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
28
Q

4 admins of Progestins?

A
  1. Oral intake - extensive first pass metabolism
  2. Oral Ester form: Reduce hepatic metabolism
  3. Intramuscular injection: Oil-based preparations
  4. Depot preparation (deposit drug in a localized mass) ⇒ Slow sustained release
29
Q

Difference between progesterone and progestin?

A

Progestin = synthetic

Less first-pass metabolism + longer t1/2

30
Q

List 4 ADR of Progestin (synthetic)?

A
  • Increases the risk of fatal blood clots
  • hair loss
  • anxiety and depression
  • Increases the risk of breast cancer
31
Q

List 4 advantages of progesterone over progestin?

A
  • 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
32
Q

Define the 2 types of Postmenopausal hormone therapy?

A

Estrogen-only therapy (ET), for after hysterectomy (no uterus)

Estrogen plus progestogen therapy (EPT) for those with uterus = prevent uterine cancer

33
Q

List the admin. methods for Postmenopausal hormonal therapy (HT)?

A

Systemic effects:
oral tablet, patch, gel, emulsion, spray, or injection

Local vaginal symptoms: cream, ring

34
Q

List symptoms under Postmenopausal syndrome?

A

Decreased production of female hormones (estrogen and progesterone):

  • bone loss
  • hot flushes
  • insomnia
  • vaginal dryness
  • increased risk of cardiometabolic diseases
35
Q

Primary indication for Postmenopausal hormonal therapy (HT)?

A

Osteoporosis

36
Q

List some benefits and risks of Postmenopausal hormonal therapy (HT)?

A

Benefits: treat symptoms under postmenopausal syndrome

Risks: long term use: breast cancer, heart attack and stroke

37
Q

Name one progesterone antagonist. MoA?

A

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

38
Q

Preparation of Mifepristone?

A

Mifepristone combined with misoprostol

> > block progesterone action + uterine contraction

> > termination of early pregnancy

39
Q

ADR of Mifepristone?

A

Vaginal bleeding, abdominal pain

40
Q

List the 3 types of androgens and their site of production?

A

Testosterone = Testis (Leydig cells)

Dihydrotestosterone (DHT) = most active, made at Epididymis, skin, liver, brain

Dehydroepiandrosterone(DHEA)/ androstenolone = adrenal cortex

41
Q

Define the precursors of the 3 types of androgens?

A

Testosterone = from cholesterol

Dehydroepiandrosterone = cholesterol

DHT = enzyme 5alpha-reductase: convert from testosterone

42
Q

Describe the endogenous regulation of Testosterone release?

A

GnRH&raquo_space; FSH and LH&raquo_space; Testosterone or DHT

Testosterone or DHT negatively feedback inhibit Anterior pituitary and Hypothalamus

43
Q

Describe the mechanism of Androgen activating androgen receptor.

A

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

44
Q

List 7 physiological effects of androgens?

A
  • 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
45
Q

2 clinical uses of androgens?

A

Replacement in androgen deficiency: promote growth, secondary sexual characteristics, postmenopausal women

Anti-aging: Increase lean body mass & hematocrit, reduce bone loss

46
Q

ADR of androgens?

A

increased risk of heart attack and stroke

47
Q

5 admin methods of androgen?

A
  1. Oral intake: rapid absorption and inactivation
  2. Intramuscular injection of Ester form
  3. Alkylated androgen (reduce hepatic metabolism)
  4. Transdermal patch, cream, gel: slow, sustained release
  5. Subcutaneous pellets
48
Q

Explain why ester forms of androgen causes less hepatic reactions?

A

Ester form
⇒ hydrolysis to release testosterone
⇒ bypass hepatic metabolism

49
Q

Name one Androgen inhibitor. MoA?

A

Finasteride

5α-reductase inhibitor: Block conversion of testosterone to more active dihydrotestosterone (DHT) - mainly in prostate

50
Q

Indication of Finasteride?

A

benign prostatic hyperplasia

Chemoprevention of prostate cancer

Treatment of male pattern baldness (hair loss)

51
Q

ADR of Finasteride?

A

chills, cold sweats, confusion and dizziness.

52
Q

Name one Androgen receptor antagonist? MoA?

A

Flutamide = selective antagonist of androgen receptors

+ blocking GnRH (gonadotropin-releasing hormone)

53
Q

Indications for Flutamide?

A

prostate cancer

androgen-dependent skin and hair conditions

hyperandrogenism in women

54
Q

Admin and ADR of Flutamide?

A

Oral administration

ADR due to adrogen deprivation:

  • gynecomastia, breast tenderness, sexual dysfunction and hot flushes

MBBS II ERS (37 decks)

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