L29 - Pharmacology of sex hormones and antagonists

Question 1

Describe the reaction that forms sex hormones?

Answer 1

Precursor = Cholesterol

Shortening of hydrocarbon side chain + hydroxylation of steroid nucleus

Question 2

List 3 types of estrogens and their site of biosynthesis?

Answer 2

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

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

Question 3

Describe the biosynthesis of estrogen?

Answer 3

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

Both reactions mediated by AROMATASE

Question 4

Define the gene locus and forms of estrogen receptor?

Answer 4

2 isoforms:

• ERα = 6q25.1
• ERβ = 14q23.2

Question 5

Describe the intracellular effects of Estrogen + estrogen receptor?

Answer 5

Estrogen + ER

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

Question 6

Describe the intracellular effects of Antagonist + estrogen receptor?

Answer 6

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

Question 7

List 3 physiological effects of estrogen?

Answer 7

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

Question 8

List 3 risks of increased estrogen levels?

Answer 8

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

Question 9

List 4 major clinical applications of estrogen?

Answer 9

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

Question 10

2 causes and 3 symptoms of Estrogen deficiency.

Answer 10

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

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

Question 11

Explain how estrogen acts as birth contol?

Answer 11

inhibition of ovulation through negative feedback suppression of FSH and LH

Question 12

List 4 ways to admin estrogen?

Answer 12

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

Question 13

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

Answer 13

Transdermal patch

Ethinyl estradiol (oral)

Intra-muscular injection

Question 14

Name one Estrogen full antagonist/ SERD?

Answer 14

Fulvestrant

Question 15

MoA and Indication of Fulvestrant?

Answer 15

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

Question 16

ADR of Fulvestrant?

Answer 16

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

Question 17

List 2 major SERMs.

Answer 17

1) tamoxifen
2) raloxifene

(clomiphene, toremifene,ospemifene)

Question 18

Explain how SERM exert different effect on diff. tissue?

Answer 18

Different tissues have different sensitivity to endogenous estrogens

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

Question 19

MoA of Tamoxifen?

Answer 19

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

Question 20

Indications of Tamoxifen? (4)

Answer 20

Chemoprevention of breast cancer in high risk group

ER-positive breast cancer

reduction of contralateral breast cancer

ovarian cancer

Question 21

ADR of Tamoxifen?

Answer 21

increased risk of Endometrial cancer (caused by partial agonism)

reduced cognition, hot flushes,

nausea and vomiting

Question 22

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

Answer 22

estrogenic effects in bone and liver

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

Question 23

Indication for Raloxifene?

Answer 23

prevention and treatment of osteoporosis in postmenopausal women

alternative to estrogens in patients with risk and history of cancer

Question 24

ADR of Raloxifene?

Answer 24

Extensive hepatic effect, First-pass metabolism

hot flushes

joint pain

blood clots, pulmonary thrombolism

Question 25

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

Answer 25

- Corpus luteum after ovulation - Placenta during pregnancy - Adrenal cortex (Zona reticularis) LH regulate Porgesterone syn.

Question 26

Describe the action of Progesterone receptors? Isoforms?

Answer 26

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)

Question 27

Name one synthetic progestogen. Indications?

Answer 27

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

Question 28

4 admins of Progestins?

Answer 28

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

Question 29

Difference between progesterone and progestin?

Answer 29

Progestin = synthetic Less first-pass metabolism + longer t1/2

Question 30

List 4 ADR of Progestin (synthetic)?

Answer 30

* Increases the risk of fatal blood clots * hair loss * anxiety and depression * Increases the risk of breast cancer

Question 31

List 4 advantages of progesterone over progestin?

Answer 31

* 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

Question 32

Define the 2 types of Postmenopausal hormone therapy?

Answer 32

Estrogen-only therapy (ET), for after hysterectomy (no uterus) Estrogen plus progestogen therapy (EPT) for those with uterus = prevent uterine cancer

Question 33

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

Answer 33

Systemic effects: oral tablet, patch, gel, emulsion, spray, or injection Local vaginal symptoms: cream, ring

Question 34

List symptoms under Postmenopausal syndrome?

Answer 34

Decreased production of female hormones (estrogen and progesterone): - bone loss - hot flushes - insomnia - vaginal dryness - increased risk of cardiometabolic diseases

Question 35

Primary indication for Postmenopausal hormonal therapy (HT)?

Answer 35

Osteoporosis

Question 36

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

Answer 36

Benefits: treat symptoms under postmenopausal syndrome Risks: long term use: breast cancer, heart attack and stroke

Question 37

Name one progesterone antagonist. MoA?

Answer 37

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

Question 38

Preparation of Mifepristone?

Answer 38

Mifepristone combined with misoprostol >> block progesterone action + uterine contraction >> termination of early pregnancy

Question 39

ADR of Mifepristone?

Answer 39

Vaginal bleeding, abdominal pain

Question 40

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

Answer 40

Testosterone = Testis (Leydig cells) Dihydrotestosterone (DHT) = most active, made at Epididymis, skin, liver, brain Dehydroepiandrosterone(DHEA)/ androstenolone = adrenal cortex

Question 41

Define the precursors of the 3 types of androgens?

Answer 41

Testosterone = from cholesterol Dehydroepiandrosterone = cholesterol DHT = enzyme 5alpha-reductase: convert from testosterone

Question 42

Describe the endogenous regulation of Testosterone release?

Answer 42

GnRH >> FSH and LH >> Testosterone or DHT Testosterone or DHT negatively feedback inhibit Anterior pituitary and Hypothalamus

Question 43

Describe the mechanism of Androgen activating androgen receptor.

Answer 43

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

Question 44

List 7 physiological effects of androgens?

Answer 44

- 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

Question 45

2 clinical uses of androgens?

Answer 45

Replacement in androgen deficiency: promote growth, secondary sexual characteristics, postmenopausal women Anti-aging: Increase lean body mass & hematocrit, reduce bone loss

Question 46

ADR of androgens?

Answer 46

increased risk of heart attack and stroke

Question 47

5 admin methods of androgen?

Answer 47

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

Question 48

Explain why ester forms of androgen causes less hepatic reactions?

Answer 48

Ester form ⇒ hydrolysis to release testosterone ⇒ bypass hepatic metabolism

Question 49

Name one Androgen inhibitor. MoA?

Answer 49

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

Question 50

Indication of Finasteride?

Answer 50

benign prostatic hyperplasia Chemoprevention of prostate cancer Treatment of male pattern baldness (hair loss)

Question 51

ADR of Finasteride?

Answer 51

chills, cold sweats, confusion and dizziness.

Question 52

Name one Androgen receptor antagonist? MoA?

Answer 52

Flutamide = selective antagonist of androgen receptors + blocking GnRH (gonadotropin-releasing hormone)

Question 53

Indications for Flutamide?

Answer 53

prostate cancer androgen-dependent skin and hair conditions hyperandrogenism in women

Question 54

Admin and ADR of Flutamide?

Answer 54

Oral administration ADR due to adrogen deprivation: - gynecomastia, breast tenderness, sexual dysfunction and hot flushes