Androgens, Antiandrogens, ED Drugs

Question 1

Describe the HPG axis in males

Answer 1

GnRH released from hypothalamus in pulsatile fashion
Pituitary gonadotrophs release LH and FSH
Testosterone sec from Leydig cells
Testosterone negatively feeds back at Hypothalamus and Anterior Pituitary

Question 2

Describe the biosynthetic pathway for testosterone and dihydrotestosterone by describing effects that inhibiting 17-alpha-hydroxylase and 5-alpha-hydroxylase will have on levels of GnRH, LH, testosterone, and dihydrotestosterone (DHT)

Answer 2

In leydig cells - testosterone synthesized
Cholesterol - under infl of LH changes to Pregnenolone - then 17-Hydroxypregnenolone - Dehydroepiandrosterone - Androstenedione - Testosterone under influence of 17-BETA-HSD

Inhibiting 17-alpha-hydroxylase Decreases cortisol and testosterone levels and increases adrenal aldosterone, which causes fluid retention, hypertension, and hypokalemia.

Inhibiting 5-alpha-hydroxylase decreases levels of DHT

Question 3

Describe the function of androgens in males

Answer 3

Sexual Reproduction, Secondary Male Sexual Characteristics
Beard, Prostate, Sebum Formation, Penis, Sperm

Anabolic Effects: Enhanced bone formation, estrogen closes epiphyseal plates, Increased EPO, Inc protein synthesis

Used to Stimulate Sexual development/inc height if delayed puberty, hypogonadal tx, aging problems, Osteoporosis, Endometriosis, Anabolic effects

Question 4

Describe the pharmacokinetic difference between testosterone, testosterone esters, and 17-alpha-alkylated derivatives of testosterone

Answer 4

Testosterone: low oral bioavailability, need to administer in patch or topical gel

Testosterone Ester: has a fatty acid attached, high lipophilicity, slow release, given IM, slower metabolism, long duration

17-alpha-alkylated derivative of testosterone: signif slower catabolism in liver, given ORALLY, LIVER TOXICITY/hepatic cancer

Question 5

Describe why both GnRH analogs (LEUPROLIDE and GOSERELIN) and GnRH antagonists (DEGARELIX) can be used to treat prostate cancer

Answer 5

GnRH analogs (Leuprolide and Goserelin) upregulate GnRH and increases LH and T initially, but over time it desensitized and downregulates GnRH receptors and decreases T

GnRH antagonists (Degarelix) has faster onset and lowers everything, no T surge in beginning

Question 6

Methyltestosterone

MOA:
Contraindications:

Answer 6

MOA: Given orally, boosts testosterone levels

Contraindications: if there are liver problems, dont bc it can cause liver toxicities

Question 7

Testosterone Enanthate

MOA:
Contraindications:

Answer 7

MOA: Given IM, boosts testosterone levels

Contraindications:

Question 8

Testosterone

MOA:
Contraindications:

Answer 8

MOA: Given Transdermally to boost T levels

Contraindications:

Question 9

Flutamide and Bicalutamide

MOA:
Contraindications:

Answer 9

MOA: Competitively inhibit androgen receptors
Use: Prostate CA

Contraindications: cause gynecomastia, mild liver toxicity
Administer prior to GnRH analog tx to prevent T surge

Question 10

Enzalutamide

MOA:
Contraindications:

Answer 10

MOA: Competitively inhibits the androgen receptors, AND also Nuclear translocation of AR, DNA binding, Coactivator recruitment

Contraindications:

Question 11

Leuprolide, Goserelin

MOA:
Contraindications:

Answer 11

MOA: GnRH receptor agonists, increase GnRH/LH/T initially, but over time decreases do to downregulation of GnRH receptors

Contraindications:

Question 12

Degarelix

MOA:
Contraindications:

Answer 12

MOA: GnRH receptor antagonist, decrease LH, FSH, T, faster onset than the GnRH agonists

Contraindications:

Question 13

Abiraterone

MOA:
Contraindications:

Answer 13

MOA: Inhibits17-alpha-hydroxylase, and 17,20-lyase in the production of androgens

Used for metastatic prostate cancer

Contraindications: can cause hepatic toxicity, HTN, Hypokalemia, fluid retention (blocks 17-alpha hydroxylase and increases aldosterone release)

Question 14

Finasteride, Dutasteride

MOA:
Contraindications:

Answer 14

MOA: Inhibit 5-alpha-reductase to decrease DHT

Used for BPH, not Prostate cancer

Finasteride also used to treat Male Pattern Baldness

Contraindications: NEVER take in PREGNANCY, may cause impotence/gynecomastia/artificially lower PSA levels leading to false negative prostate screening

Question 15

Sildenafil, Vardenafil, Tadafil, Avanafil

MOA:
Contraindications:

Answer 15

MOA: Inhibit PDE5, which increases cGMP levels in smooth muscle of penis - relax - erection

Tadafil has longest 1/2 life
Avanafil has quickest onset of action
Sildenafil and Tadafil tx pulmonary HTN
Sildenafil and Vardenafil have food interactions, dont take with fatty meal

Contraindications: DONT combine with NITRITES - can dangerously lower BP