Sex hormones and disease Flashcards
Briefly describe the release and regulation of sex hormones?
Describe the synthesis of the sex hormones?
Which enzymes are potential targets in the synthesis of sex hormones?
Aromatase (testosterone > oestradiol and androstenedione > oestrone)
5a reductase (testosterone > dihydrotestosterone)
Describe the clinical uses of oestrogens?
Children: hypogonadism
Adults: primary amenorrhoea, contraception, menopause
Describe the benefits and risks associated with postmenopausal hormone therapy?
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
How do the benefits and risks of postmenopausal hormone therapy weigh up?
Benefits believed to outweigh risks
Describe the mechanism of action of oestrogen?
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
Why are some of the actions of oestrogen rapid, whilst others are slower?
Fast actions as a result of binding membrane receptors
Slower actions associated with intracellular receptors
Describe different ways in which the signalling of oestrogen may be altered?
Different receptor location
Interaction with different transcription factors
Different receptor subtypes
Describe how oestrogen is thought to be involved with breast cancer?
Binding to ER stimulates growth
Binding to ER also switches on progesteron receptor > growth and differentiation
Describe the ER and PR receptor levels in breast cancer?
Pre-menopausal: 60-65% ER/PR +ve
Post-menopausal: 70-75% ER/PR +ve
What are SERMs?
What are they used for?
Selective oestrogen receptor modulators
Oestrogen blockade > application in breast cancer
What is tamoxifen and what is it used for?
Partial agonist at oestrogen receptors
Palliative treatment of metastatic breast cancer
Adjuvant after lumpectomy
Describe the adverse effects of tamoxifen?
Endometrial hyperplasia, polyps and cancer
Thromboembolic events
Thrombocytopenia
Ocular toxicity
Menopausal symtpoms
Resistance > tumours may recur
What is exemestane?
What is it used for?
Aromatase inhibitor
Decrease oestrogen production > inhbit receptor activation > applications in breast cancer to improve disease free survival after tamoxifen
Describe the adverse effects of aromatase inhibitors?
Increased bone loss and fracture risk
Increased arthralgia
Potential poorer lipid profile, hepatic steatosis and metabolic syndrome
Menopausal signs
Describe the effect of androgens?
Anabolic and masculinising effects in males and females
Which androgens are synthesised in males and females?
Testosterone and dihydrotestosterone
Where are androgen receptors located?
Nucleus
Describe the process of androgen receptor activation?
Testosterone released from SHBG > enters cell > converted to DHT by 5a reductase > binds nuclear and cytoplasmic androgen receptors > gene transcription
Describe the actions of testosterone and dihydrotestosterone?
TESTOSTERONE
Gonadotrophin release
Spermatogenesis
Sexual differentiation
Anabolic effects
DHT
Prostate development
External virilisation
Sexual maturation
Describe the therapeutic uses of androgens?
Androgenic: hypogonadism
Anabolic: senile osteoporosis, recovery from surgery and chronic diseases
Growth: pituitary dwarfism
Endometriosis
Describe the non-therapeutic uses of androgens?
Increase lean body mass
Muscle strength
Aggressiveness
Describe the adverse effects of androgens?
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
Which antiandrogens are available?
Receptor antagonists: cyproterone, flutamide
5a reductase inhibitors: finasteride
What is cyproterone?
What is it used for?
Androgen receptor antagonist
Used in prostate cancer in males and androgenisation in females
What is flutamide?
What is it used for?
Androgen receptor antagonist
Used for metasatic prostate cancer
What is finasteride?
What is it used for?
5a reductase inhibitor
Used for benign prostatic hypertrophy and hair loss
Give a brief summary of the drugs that can be used to block sex hormones, including their targets?
Aromatase inhibitor: exemestane
5a reductase inhibitor: finasteride
Oestrogen receptor blockers: tamoxifen, raloxifene, fulvestrant
Androgen receptor blockers: cyproterone, flutamide
