Androgens and Antiandrogens Flashcards
Describe the events that occur in the HPG axis to regulate gametogenesis.
- hypothalamus –> GnRH (pulsatile)
- GnRH (+) ant pit –> LH and FSH
- LH (+) Leydig cells –> testosterone
- FSH (+) Sertoli cells –> steroid hormone-binding protein and inhibin
- testosterone, FSH, androgen-binding protein (+) spermatogenesis
negative feedback:
6. inhibin (-) pituitary –> FSH
7. testosterone (-) hypothalamus –> GnRH
Which cells synthesize testosterone? What is the precursor of testosterone?
leydig cells; cholesterol
Via which pathways can testosterone act? (consider enzymes and different hormones, and where it acts)
- amplification path: 5-alpha-reductase converts T to DHT; gonads, prostate, skin, hair
- direct path: T acts on liver, muscle, adipose tissue
- diversification path: aromatase converts T to E2; brain and bone
- inactivation path: deactivate T; hepatic oxidation and conjugation –> renal excretion
What are the mechanisms of action of androgen?
- androgen-dependent pathway (slow classic genomic mechanism)
- androgen-independent pathway (slow classic genomic mechanism)
- rapid non-genomic mechanisms
When is the androgen-dependent mechanism of action activated?
when androgen levels are high
When is the androgen-independent mechanism of action activated?
activation of Arby phosphorylation mediated by receptors downstream growth factor receptors
When are the rapid non-genomic mechanisms of action activated?
when androgen levels are low
Before puberty, does an increase of androgens prevent or stimulate reaching full height?
prevent
metabolic effects of androgens?
- increase protein synthesis
- decrease protein breakdown
- decrease HDL levels
- stimulate erythrocyte production
- more prone to acne
- salt and water retention
(i.e. anabolic and block catabolism)
Rank the following characteristics of T and DHT:
- affinity for androgen receptor
- dissociation rate
- affinity for androgen receptor: T < DHT (twofold)
- dissociation rate: T > DHT (fivefold)
pharmacological uses of androgens?
- androgen replacement therapy: hypogonadism, pituitary deficiency, aging
- anabolic agents
- osteoporosis
pharmacological uses of antiandrogens?
- benign prostatic hyperplasia (BHP)
- prostate cancer
- precocious puberty
- hair loss
- hirsutism
pharmacological uses of selective androgen receptor modulators (SARMs)?
no FDA-approved indications; promise for safe use in treatment of prostate cancer, male hormonal contraception, breast cancer, etc.
primary vs secondary hypogonadism? what can be used to treat hypogonadism?
- primary = defect of testes
- secondary = defect of HPG axis
- treatment: androgen replacement therapy
Which hormone does androgen replacement therapy use?
only testosterone
Besides hypogonadism, what can androgen replacement therapy be used to treat?
andropause (decrease in T levels in aging males)
What are therapeutic uses of androgens (besides andropause and hypogonadism)?
- anemia (erythrocyte production)
- osteoporosis
- protein anabolic agents –> increase muscle mass
- male contraceptive –> inhibit GnRH via negative feedcback
adverse effects of androgen therapy?
- serious adverse effects are rare
What are the different types/MOA of antiandrogens?
- testosterone synthesis inhibitors
- 5-alpha-reductase inhibitors
- AR blockers
list the following for ketoconazole:
- class of drug
- MOA
- class: antiandrogen; T synthesis inhibitor
- MOA: inhibit 17-alpha-hydroxylase
list the following for abiraterone acetate:
- class of drug
- MOA
- uses
- antiandrogen; T synthesis inhibitor
- MOA: inhibit 17-alpha-hydroxylase and 17, 20 lyase
- uses: androgen dependent PC
list the following for finasteride:
- class of drug
- MOA
- uses
- class: antiandrogen; 5-alpha-reductase inhibitor
- MOA: inhibit conversion of T to DHT
- uses: BPH
list the following for flutamide:
- class of drug
- MOA
- uses
- class: antiestrogen; AR blocker
- MOA: nonsteroidal competitive antagonists of AR
- uses: prostate cancer
list the following for darolutamide:
- class of drug
- MOA
- class: antiandrogen; AR blocker
- MOA: second generation blocker; inhibit AR nuclear translocation
list the following for SARMs:
- MOA
- uses
- MOA: bind AR and display tissue selective activation of androgenic signaling
- uses: muscle wasting, osteoporosis, breast cancer, prostate cancer
Which drug is highly attractive for doping in sports and illegal bodybuilding use? why?
SARMs; anabolic effects