Androgens

Question 1

Describe HPG axis in males.

Answer 1

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)

Question 2

What effect would inhibition of 17alpha-hydroxylase have on GnRH, LH, testosterone and DHT?

Answer 2

Would decrease testosterone, DHT

Increase GnRH, LH

Question 3

What effect would inhibition of 5alpha-reductase have on levels of GnRH, LH, testosterone, and DHT?

Answer 3

Decrease GnRH, LH, DHT

no change to testosterone

Question 4

Key androgen functions in males?

Answer 4

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

Question 5

How are GnRH analogs used to treat prostate cancer? Name 2.

Answer 5

Constant (NOT pulsatile) stimulation of GnRH receptors
- Initially increases LH testosterone production, which leads to desensetization/downregulation of pituitary GnRH receptors

Leuprolide, goserelin

Question 6

How are GnRH antagonists used to treat prostate cancer? Name 1.

Answer 6

Decrease testosterone production with no LH/FSH surge

Degarelix

Question 7

What are contraindications and side effects of ED drugs?

Answer 7

Priaprism

Low BP

Sudden vision loss

Serious cardiac events (rare)

Question 8

What primary sites synthesize androgens?

Answer 8

Testosterone by Leydig cells in testes (and ovaries)

Adrenal cortex produces low potency androgens (converted to testosterone)

Question 9

What are the forms of testosterone in the blood? Which ones are bioavailable?

Answer 9

albumin bound is bioavailable

sex hormone-binding globulin is chemically unavailable

Question 10

True or False? Testosterone binds to a plasma membrane receptor and initiates a cell signaling cascade

Answer 10

False; enters the cell and binds to androgen receptor which translocates to nucleus and regulates transcription

Question 11

Causes of hypergonadotropic hypogonadism? (is this primary or secondary?)

Answer 11

This is primary androgen deficiency.

Causes:
Cryptorchidism
Klinefelter syndrome
Medications (chemo)

Question 12

Causes of hypogonadotropic hypogonadism?

Answer 12

Problem in hypothalamus or pituitary; low testosterone in setting of low LH, FSH

Question 13

Methyltestosterone:

class, MOA, route of administration, pharmacokinetics

Answer 13

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

Question 14

Testosterone enanthate:

class, MOA, route of administration, pharmacokinetics

Answer 14

testosterone esters

Mimics testosterone, binds to androgen receptor

given IM; lipophilic with slow release, ester fatty acid slows liver metabolism

Question 15

Testosterone: class, MOA, route of administration, pharmacokinetics

Answer 15

acts like endogenous testosterone

binds to androgen receptor

given as transdermal or topical gel; high first-pass metabolism

Question 16

Adverse effects of androgen therapy

Answer 16

Premature growth plate closure

Hepatic dysfunction (esp with anabolic steroids)

Dyslipidemia (decreased HDL, increased LDL)

Fluid retention

Mental disturbance

Question 17

Therapeutic uses of anti-androgens?

Answer 17

Hirsutism

Precocious puberty, BPH, prostate cancer, alopecia

Question 18

Contraindications/side effects of GnRH agonists?

Answer 18

Sexual dysfunction
Bone mineral density loss
Anemia
Fatigue
Initial testosterone surge (growth of prostate cancer :( )

Question 19

Contraindications/side effects of 5alpha-reductase inhibitors?

Answer 19

Impotence gynecomastia (infrequent)

Lowered PSA levels
- false negative for prostate cancer screening (but we’re not supposed to use PSA to screen anyway soo…)

Question 20

Adverse effects PDE5 inhibitors

Answer 20

Serious cardiac events

Low BP in combination with nitrates/nitrites

Priapism

Sudden vision loss. :( (loss of blood flow to optic nerve)

Question 21

Flutamide, bicalutamide

Class/MoA? Uses? Adverse effects?

Answer 21

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)

Question 22

Enzalutamide

Class/MoA? Uses?

Answer 22

Competitively inhibits androgen receptor AND inhibits nuclear translocation/DNA binding/coactivator recruitement

Used to treat prostate cancer?

Question 23

Leuprolide, goserelin

Class/MoA?

Answer 23

GnRH agonists; act by constantly stimulating GnRH receptors causing eventual downregulation/desensitization

Question 24

Degarelix

Class/MoA, special powers

Answer 24

Immediately and reversibly binds to pituitary GnRH receptors

Faster onset, worse better than Leuprolide

Question 25

Abiraterone

Class/MoA, Uses, Side effects?

Answer 25

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)

Question 26

Finasteride, dutasteride

Class/MoA, uses, adverse effects

Answer 26

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)

Question 27

Sildenafil, vardenafil, tadalafil

Class/MoA, uses, side effects and contraindications, pharmacokinetics

Answer 27

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!)

Question 28

What’s the mechanism of penile erection?

Answer 28

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