Sex hormones and disease

Question 1

Briefly describe the release and regulation of sex hormones?

Answer 1

Question 2

Describe the synthesis of the sex hormones?

Answer 2

Question 3

Which enzymes are potential targets in the synthesis of sex hormones?

Answer 3

Aromatase (testosterone > oestradiol and androstenedione > oestrone)

5a reductase (testosterone > dihydrotestosterone)

Question 4

Describe the clinical uses of oestrogens?

Answer 4

Children: hypogonadism

Adults: primary amenorrhoea, contraception, menopause

Question 5

Describe the benefits and risks associated with postmenopausal hormone therapy?

Answer 5

BENEFITS

Improved bone density
Relief from flushes, fatigue and vaginal dryness
Reverses atrophy of vulva, vagina and urethra
Improved sleep
Reduced incidence of colorectal cancers
Reduced CHD incidence
Possible reduced incidence of Alzheimer’s

RISKS

Breast tenderness, nausea, fluid retention
Increased risk breast and uterine cancer
Increased risk of thromboembolism/stroke

Question 6

How do the benefits and risks of postmenopausal hormone therapy weigh up?

Answer 6

Benefits believed to outweigh risks

Question 7

Describe the mechanism of action of oestrogen?

Answer 7

Cross membrane > activates cytoplamic receptors > homodimers formed > homodimers interact with EREs in nucleus > gene activation/repression

Potential to form heterodimers with different transcription factors > activate signalling in different ways

Receptor may be located on the membrane > fast actions

Question 8

Why are some of the actions of oestrogen rapid, whilst others are slower?

Answer 8

Fast actions as a result of binding membrane receptors

Slower actions associated with intracellular receptors

Question 9

Describe different ways in which the signalling of oestrogen may be altered?

Answer 9

Different receptor location

Interaction with different transcription factors

Different receptor subtypes

Question 10

Describe how oestrogen is thought to be involved with breast cancer?

Answer 10

Binding to ER stimulates growth

Binding to ER also switches on progesteron receptor > growth and differentiation

Question 11

Describe the ER and PR receptor levels in breast cancer?

Answer 11

Pre-menopausal: 60-65% ER/PR +ve

Post-menopausal: 70-75% ER/PR +ve

Question 12

What are SERMs?

What are they used for?

Answer 12

Selective oestrogen receptor modulators

Oestrogen blockade > application in breast cancer

Question 13

What is tamoxifen and what is it used for?

Answer 13

Partial agonist at oestrogen receptors

Palliative treatment of metastatic breast cancer
Adjuvant after lumpectomy

Question 14

Describe the adverse effects of tamoxifen?

Answer 14

Endometrial hyperplasia, polyps and cancer
Thromboembolic events
Thrombocytopenia
Ocular toxicity
Menopausal symtpoms

Resistance > tumours may recur

Question 15

What is exemestane?

What is it used for?

Answer 15

Aromatase inhibitor

Decrease oestrogen production > inhbit receptor activation > applications in breast cancer to improve disease free survival after tamoxifen

Question 16

Describe the adverse effects of aromatase inhibitors?

Answer 16

Increased bone loss and fracture risk
Increased arthralgia
Potential poorer lipid profile, hepatic steatosis and metabolic syndrome
Menopausal signs

Question 17

Describe the effect of androgens?

Answer 17

Anabolic and masculinising effects in males and females

Question 18

Which androgens are synthesised in males and females?

Answer 18

Testosterone and dihydrotestosterone

Question 19

Where are androgen receptors located?

Answer 19

Nucleus

Question 20

Describe the process of androgen receptor activation?

Answer 20

Testosterone released from SHBG > enters cell > converted to DHT by 5a reductase > binds nuclear and cytoplasmic androgen receptors > gene transcription

Question 21

Describe the actions of testosterone and dihydrotestosterone?

Answer 21

TESTOSTERONE
Gonadotrophin release
Spermatogenesis
Sexual differentiation
Anabolic effects

DHT
Prostate development
External virilisation
Sexual maturation

Question 22

Describe the therapeutic uses of androgens?

Answer 22

Androgenic: hypogonadism

Anabolic: senile osteoporosis, recovery from surgery and chronic diseases

Growth: pituitary dwarfism

Endometriosis

Question 23

Describe the non-therapeutic uses of androgens?

Answer 23

Increase lean body mass

Muscle strength

Aggressiveness

Question 24

Describe the adverse effects of androgens?

Answer 24

Increase LDL, decrease HDL

Females: acne, facial hair, deep voice, male pattern baldness, excessive muscle development and menstrual irregularities

Males: priapism (penis stays erect), impotence, decreased spermatogenesis, gynaecomastia

Children: premature closure of epiphyseal plates, abnormal sexual maturation

Question 25

Which antiandrogens are available?

Answer 25

Receptor antagonists: cyproterone, flutamide

5a reductase inhibitors: finasteride

Question 26

What is cyproterone?

What is it used for?

Answer 26

Androgen receptor antagonist

Used in prostate cancer in males and androgenisation in females

Question 27

What is flutamide?

What is it used for?

Answer 27

Androgen receptor antagonist

Used for metasatic prostate cancer

Question 28

What is finasteride?

What is it used for?

Answer 28

5a reductase inhibitor

Used for benign prostatic hypertrophy and hair loss

Question 29

Give a brief summary of the drugs that can be used to block sex hormones, including their targets?

Answer 29

Aromatase inhibitor: exemestane

5a reductase inhibitor: finasteride

Oestrogen receptor blockers: tamoxifen, raloxifene, fulvestrant

Androgen receptor blockers: cyproterone, flutamide