Androgens

Question 1

FSH and LH in Males vs Females

Answer 1

• FSH
  
  • Females: Stimulates growth and development of ovarian follicules; promotes estrogen secretion by ovaries
  • Males: Required for sperm production
• LH
  
  • Females: responsible for ovulation, formation of corpus lutem, regulation ovarian secretion female sex hormones
  • Males: cells in testes to create testosterone.

Question 2

Androgen Synthesis

Answer 2

• Prevenlant forms: androstenedione, testosterone, dihydroxtestosterone
• Androstenedione produced in testes, adrenal cortex, and ovaries
• Testosterone in the testes and ovaries
• Small amounts dihydroxtestosterone in the adrenal cortex
• Males have 40-60x more testosterone
• Females behaviorally more sensitive
• Testosterone is produced by Leydig cells
• In Sertoli cells, testeosterone for spermatogenesis

Question 3

Androgen Synthesis Pathway

Answer 3

Question 4

Physiological effects of androgens

Answer 4

• Stimulates development of secondary sex characteristics
  
  • ​growth of larynx/thickening of vocal cords
  • Hair growth
  • Penis/package growth
  • Essential for spermatogenesis
  • Maintains sexual function
• Stimulates skeletal growth and epiphyseal closure
  
  • ​Inhibits osteoporosis
  • Largely through conversion to estrogen
• Increase lean body mass and decrease fat
• Decreases HDL levels
• Stimulates secretory proteins in liver and induces enzymes involved in drug metabolism
• Stimulates sebecous glands and hair follicles
• Psychological and behavioral effects
  
  • attention, memory, spatial ability

Question 5

Feedback Control in HPT

Answer 5

Question 6

Androgen Insensitivity Syndrome

Answer 6

• Patients have X/Y male genotype but female phenotype
  
  • Normal to high levels of estrogen and progesterone
  • Infertile
  • 1/60,000
• Biochemical Mechanism
  
  • Mutation in androgen receptor
  • Receptor is X linked
  • Typical partial function loss
  • Total loss of function causes complete form:
    
    • No uterus/ovaries
    • Abdominal testes
    • No pubic/axillary hair
    • High estrogen levels
    • Breast development
    • Tall and athletic women

Question 7

Spinal Bulbar Muscular Dystrophy (Kennedy’s Disease)

Answer 7

• Affected males have muscle cramps and progressive weakness due to degeneration of motor neurons in the brain stem and spinal cord
• Age of onset/severity varies from adolescent to old age, mostly in middle adult life
  
  • Doesn’t compromise longevity
  • Neuromuscular and endocrine manifestations
• Biochemal Mechanism
  
  • Expansion of CAG (glutamine-Q) repeat in androgen receptor gene
  • PolyQ repeat in androgen receptor protein
  • Binding of polyQ AR to testosterone causes aggregation in neurons
  • Length of polyQ determines age of onset (longer=earlier)

Question 8

Therapeutic Purposes of Androgens

Answer 8

• HRT
  
  • Males with hypogonadism
  • Gender reassignment
  • Loss of testicular funx from disease/cancer
  • Middle aged and older men
• Menopause
  
  • Increase libido
  • Treat bone density loss, lean mass
  • Depression/low energy
• Endrometriosis
  
  • Danazol (testosterone derivative) inhibits FSH and LH to decrease estrogen and atrophy ectopic tissue
• Chronic Wasting Condition
  
  • HIV/cancer
• Male Contraceptive
  
  • Testosterone and progestin trials are promising.

Question 9

Adverse Effects of Testosterone

Answer 9

• Virilization (females looking manly)
• Feminization (males)
• Precocious puberty
• Stunted growth
• Prostate enlargment
• Atherosclerosis
• Hepatic carcinoma
• Choelstatic jaundice
• Edema

Question 10

3 Strategies to Modulate Androgen Production

Answer 10

• GnRH analogs
  
  • Act as GnRH recetor antagonists when administered continuously
    
    • Decreases pitutiary secretion of LH and FSH
  • Act as GnRH receptor agonists when administered pulsatile
    
    • Increases pituitary LH and FSH
  • Leuoprolide used to treat hormone-responsive cancer
    
    • Breast/prostate
• 5 alpha reductase inhibitor
  
  • Block conversion of testosterone to more potent dihydrotestosterone
  • Increased testosterone and possibly estradiol
• Androgen Recetor Antagonist
  
  • Prevent binding of testosterone and dihydroxytestosterone

Question 11

5 alpha reductase inhibitors

Answer 11

• Block dihydroxytestosterone production
  
  • Finasteride blocks type 2 isozyme, dutasteride blocks both
• Used for
  
  • Prostate cancer
  • BPH
  • Male patterened baldness
• Side Effects
  
  • Libido loss
  • ED
  • Gyno

Question 12

Androgen Receptor Antagonist (steroidal)

Answer 12

• Spirnolactone, Cyproterone
• Prevent binding of testosterone and dihyrotestoterone to AR
• Used for
  
  • Prostate cancer
  • BPH
  • Male patterened baldness
  • Female hairness
  • Priapism
  • Hypersexuality
  • Precoucius puberty
  • Male-to-female transgender
• Side Effects
  
  • Liver toxicity
  • Adrenal funx suppression
  • Depression
  • Gyno
  • ED

Question 13

Androgen Receptor Antagonist (Non-steroidal)

Answer 13

• Prevent binding of testosterone and dihydrotestoterone to AR
• Bicalutamide, Nilutamide, Flutamide
• Used for:
  
  • Prostate cancer
  • Female hairness
• Side Effects
  
  • Gyno
    
    • Tamoxifen can counter this
  • Mild liver damage
    
    • Reversed with discontinuation
  • GI effects
    
    • Bicalutamide better than flutamide