Male Urogenital Disorders

Question 1

Where do you find aromatase?

Answer 1

Sertoli cells (converts T to E) 
E helps with sperm maturation

Question 2

Androstenedione –> Testosterone

Answer 2

17b-hydroxylase

17-ketoreductase

Question 3

Estrone –> Estradiol

Answer 3

17b-hydroxylase

17-ketoreductase

Question 4

What stimulates prostate cancer cells to grow?

Answer 4

Androgens

Clinically imp - cuz shrinking size of tumor cells via androgen direction therapy

Question 5

GnRH/LHRH (natural)

Answer 5

Gonadorelin

Question 6

GnRH/LHRH agonists

Answer 6

1. Leuprolide

2. Nafarelin (nasal)

Question 7

GnTH/LHRH antagonist

Answer 7

Degarelix

Question 8

Other GnRH drugs

Answer 8

1. Goserelin
2. Hisrelin
3. Triptorelin
   * These will be the distractors on the test*

Question 9

Degarelix

Answer 9

• GnRH/LHRH antagonist
• reduce T quickly (2-3 days)
• treats ADVANCED prostate cancer
• given s.q. (Monthly injection)
• SE: injection site probs (pain, redness, swelling), increased liver enzymes

Question 10

Leuprolide

Answer 10

• continuous administration –> desensitized Rc after an ‘initial’ surge in androgen biosynthesis
• initial surge then drop later due to desensitization
• testicles shrink over time (chemical castration)
• these are placed as small implants under skin
• given from 1x a month up to 1x a year
• BOARDS*
• Other LHRH analogs: goserelin, triptorelin, histrelin

Question 11

Contraindications for GnRH/LHRH Rc agonists

Answer 11

• if given continuously in men whose cancer has metastasized to bones you get bone pain, if it’s spread to spine even a short-term increase in tumor growth due to the flare can compress SC and cause pain or paralysis
• Avoid flare by giving anti-androgens for few weeks when starting treated with GnRH Rc agonists

Question 12

Androgen Rc antagonists

Answer 12

1. Biclutamide
2. Flutamide
3. Nilutamide
   * Never used by themselves in USA*
   - these are non-steroidal
   - compete with T and DHT for Rc
   - No AR dimerization, transport or transcription

Question 13

Bicalutamide

Answer 13

• (qd), p.o
• used with Leuprolide or other GnRH agonists
• 1x a day

Question 14

Flutamide

Answer 14

• (tid), p.o.
• used with GnRH/LHRH agonists
• prototype: 3x a day

Question 15

Nilutamide

Answer 15

• p.o.

- used in combo with surgical castration

Question 16

Clinical sig - Anti-androgens

Answer 16

• used in combo with Leuprolide to suppress effects of residual adrenal T or T ‘flare’ from GnRH agonists
• Palliative for metastatic prostate cancer (reduced bone pain, better performance status, inc sense of well being)

Question 17

Disruption of Androgen Biosynthesis

Answer 17

1. Abiraterone

2. Ketoconazole

Question 18

Abiraterone

Answer 18

• blocks CYP17 –> lowers tumor production of androgen
• used in ADVANCED PC that is still growing despite low T from GnRH antagonist/agonist
• Abiraterone acetate inhibits 17alpha-hydroxylase/C17,20-lyse (CYP17) in testicular, adrenal, prostatic tumor tissues (needed in these tissues for androgen synthesis)
• Benefit - inhibitor of androgen synthesis in prostate tumor cells!
• SE: derives from its inhibition of cortisol synthesis and enchacement of ALDO synthesis (to avoid this must be administered with prednisone or another comparable corticoid)

Question 19

CYP17

Answer 19

Catalyzes

1. conversion of pregenolone and progesterone to 17alpha-hydroxy derivatives
2. Formation of DHEA and androstenedione, respectively, by C17,20-lyase activity
   - inhibition of CYP17 deranged cortical production by adrenals
   - it is used with prednisone or other corticoids

Question 20

Ketoconzaole

Answer 20

• block androgen production
• treats men recently diagnosis with advanced PC
• lowers T promptly, tried if other forms of androgen deprivation therapy fail
• blocks cortisol so take corticosteroid to prevent SE
• SIGNIFICANT HEPATOTOXICITY!!!!!!!!!!

Question 21

High-grade PC risk with BPH drugs

Answer 21

• receiving treatment for BPH is Finasteride and Dutasteride

- less tumors but higher-grade tumors

Question 22

HCG

Answer 22

• LH analog: heterdimeric protein with an alpha-subunit identical to LH, FSH and a unique beta subunit
• LONGER half life than LH
• stimulates leydig cells to make T
• used in men for secondary hypogonadism and desire to become fertile
• LESS expensive than FSH prep

Question 23

Secondary hypogonadism

Answer 23

• infertility,
• distortion of E synthesis
• exogenous androgens, anabolic steroids like androstenedione, T overexposure all suppressing GnRH/FSH/LH –> less T made (negative feedback inhibition)

Question 24

SERM: selective estrogen Rc modulator

Answer 24

Clomiphene (also tomoxifen, raloxifene, toremifene)

• occupies E Rc without activating it (estradiol antagonist) – tricks hypothalamus to conclude that E levels low so now you get LHRH stimulation and more LH and T production (body senses low levels of E and 17-hydroxyprogesterone, androstenedione and T up-regulated)
• loading does necessary for initiate dose….has a long half life
• tested in athletes taking steroids! Take it to mask effects of steroids
• used for enhanced recovery of T production after anabolic steroid cycles
• extensive anabolic steroid exposure causes testicular atrophy
• HCG injection to limit fails after extended anabolic steroid use

Question 25

Aromatase inhibitors

Answer 25

• blocking E production from T
  1. Anastrazole
  2. Letrazole

(Also testolactone, exemestane)