Androgens Flashcards
Describe HPG axis in males.
GnRH secreted in pulsatile fashion (30-120 mins)
Stimulates pituitary to release LH, FSH
FSH stimulates sertoli cell to produce ABP, inhibin (negative feedback on pituitary)
LH stimulated Leydig cell to produce testosterone (negative feedback on pituitary and hypothalamus)
What effect would inhibition of 17alpha-hydroxylase have on GnRH, LH, testosterone and DHT?
Would decrease testosterone, DHT
Increase GnRH, LH
What effect would inhibition of 5alpha-reductase have on levels of GnRH, LH, testosterone, and DHT?
Decrease GnRH, LH, DHT
no change to testosterone
Key androgen functions in males?
Androgenic effects: maturation and function of male reproductive tract (pubertal development, sperm production)
production of secondary male sexual characteristics (beard growth, sebum formation)
Metabolic effects: Stimulate resting metabolic rate inhibits lipid accumulation lower plasma glucose Skeleton: enhances bone formation, helps close growth plates RBC: increases EPO Muscle: increased synthesis, decreased breakdown Liver: increased LDL, decreased HDL
How are GnRH analogs used to treat prostate cancer? Name 2.
Constant (NOT pulsatile) stimulation of GnRH receptors
- Initially increases LH testosterone production, which leads to desensetization/downregulation of pituitary GnRH receptors
Leuprolide, goserelin
How are GnRH antagonists used to treat prostate cancer? Name 1.
Decrease testosterone production with no LH/FSH surge
Degarelix
What are contraindications and side effects of ED drugs?
Priaprism
Low BP
Sudden vision loss
Serious cardiac events (rare)
What primary sites synthesize androgens?
Testosterone by Leydig cells in testes (and ovaries)
Adrenal cortex produces low potency androgens (converted to testosterone)
What are the forms of testosterone in the blood? Which ones are bioavailable?
albumin bound is bioavailable
sex hormone-binding globulin is chemically unavailable
True or False? Testosterone binds to a plasma membrane receptor and initiates a cell signaling cascade
False; enters the cell and binds to androgen receptor which translocates to nucleus and regulates transcription
Causes of hypergonadotropic hypogonadism? (is this primary or secondary?)
This is primary androgen deficiency.
Causes:
Cryptorchidism
Klinefelter syndrome
Medications (chemo)
Causes of hypogonadotropic hypogonadism?
Problem in hypothalamus or pituitary; low testosterone in setting of low LH, FSH
Methyltestosterone:
class, MOA, route of administration, pharmacokinetics
17-alkylated testosterone derivative; anabolic steroids
In animals stimulated anabolic effects; didn’t work in humans?
oral or sublingual; alkyl group prevents first-pass liver metabolism
Testosterone enanthate:
class, MOA, route of administration, pharmacokinetics
testosterone esters
Mimics testosterone, binds to androgen receptor
given IM; lipophilic with slow release, ester fatty acid slows liver metabolism
Testosterone: class, MOA, route of administration, pharmacokinetics
acts like endogenous testosterone
binds to androgen receptor
given as transdermal or topical gel; high first-pass metabolism
Adverse effects of androgen therapy
Premature growth plate closure
Hepatic dysfunction (esp with anabolic steroids)
Dyslipidemia (decreased HDL, increased LDL)
Fluid retention
Mental disturbance
Therapeutic uses of anti-androgens?
Hirsutism
Precocious puberty, BPH, prostate cancer, alopecia
Contraindications/side effects of GnRH agonists?
Sexual dysfunction Bone mineral density loss Anemia Fatigue Initial testosterone surge (growth of prostate cancer :( )
Contraindications/side effects of 5alpha-reductase inhibitors?
Impotence gynecomastia (infrequent)
Lowered PSA levels
- false negative for prostate cancer screening (but we’re not supposed to use PSA to screen anyway soo…)
Adverse effects PDE5 inhibitors
Serious cardiac events
Low BP in combination with nitrates/nitrites
Priapism
Sudden vision loss. :( (loss of blood flow to optic nerve)
Flutamide, bicalutamide
Class/MoA? Uses? Adverse effects?
Androgen receptor antagonist, competitive inhibitor of androgen receptor
Used to treat prostate cancer
mild gynecomastia, reversible liver toxicity
Limited effectiveness, because testosterone levels increase (d/t increased LH)
Enzalutamide
Class/MoA? Uses?
Competitively inhibits androgen receptor AND inhibits nuclear translocation/DNA binding/coactivator recruitement
Used to treat prostate cancer?
Leuprolide, goserelin
Class/MoA?
GnRH agonists; act by constantly stimulating GnRH receptors causing eventual downregulation/desensitization
Degarelix
Class/MoA, special powers
Immediately and reversibly binds to pituitary GnRH receptors
Faster onset, worse better than Leuprolide
Abiraterone
Class/MoA, Uses, Side effects?
Blocks 17-alpha-hydroxylase (will block synthesis of DHEA, androstenedione, testosterone, DHT)
used for metastatic prostate cancer
Side effects: adrenal insufficiency with stress (because inhibited cortisol production),
hepatic toxicity,
hypertension hypokalemia, fluid retention (d/t intermediates shunted into aldosterone sx pathway)
Finasteride, dutasteride
Class/MoA, uses, adverse effects
steroid-like inhibitors of 5alpha-reductase (block formation of DHT)
used to treat BPH, alopecia (Propecia)
Can reduce overall cases of prostate cancer, but increased rate of higher grades! Lower PSA levels, impotence and gynecomastia (rare)
Sildenafil, vardenafil, tadalafil
Class/MoA, uses, side effects and contraindications, pharmacokinetics
PDE5 inhibitors; block degradation of cGMP to 5’GMP, maintaining smooth muscle relaxation
Used to treat ED, doesn’t work well for those with cavernous nerve dysfunction
Serious cardiac, low BP, priaprism
Tadalafil has longest time time peak concentration, longest half-life; all are metabolized by CYP 3A4 (careful with HIV drugs like ritonavir!)
What’s the mechanism of penile erection?
Nervous stimulation causes endothelial cells to release NO,
activates guanylyl cyclase in muscle cells
increased cGMP levels
increased activity of protein kinase, chanels open
Ca++ leaves cell, smooth muscle relaxes
