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Flashcards in Androgen Pharmacology Deck (26)
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Two principal androgens in males

  • Testosterone
  • 5a-dihydrotestosterone (DHT)


Regulation of androgen biosynthesis

  • T biosynthesis controlled by LH which increases production of pregnenolone from cholesterol
    • T synthesis regulated by HPT axis
    • Estradiol formed from testosterone + aromatase - very potent inhibitor of GnRH and LH secretion
  • Timing: T secretion high in 3 phases of life:
    • Fetal phase (male phenotypic differentiation)
    • Neonatal phase (role unclear)
    • Adult phase (secondary sex characteristics, spermatogenesis, anabolic effects, libido)
  • Location:
    • Prostate, scrotum, penis, hair, skin have high concentration of 5a-reductase (converts T to DHT) - location of enzymes contributes to regulation of androgen production


Genomic MOA of androgens

  • T and DHT readily cross cell and nuclear membrane --> bind to nuclear androgen receptors
  • Binding leads to dimerization and interaction with androgen response elements on DNA --> recruits other co-regulators (activators or repressors) --> results in changes (turning on or off) of transcription of target genes


Non-genomic postulated androgen actions

  • Intracellular ion concentration changes
  • Membrane fluidity
  • Can take effect over a shorter time frame
  • Mediated by membrane bound receptors (mAR)
  • Overall activity: modification of transcription factors via phosphorylation or dephosphorylation


Therapeutic uses of androgens

  • Hypogonadism
  • Osteoporosis associated with androgen deficiency
  • Muscle wasting associated with AIDS
  • HRT in aging men 
    • Only treat if T is consistently below 200ng/dL and associated with problematic symptoms - assess prostate risk


Causes of hypogonadism

  • Primary causes
    • Klinefelter's, congenital, issue with Leydig cells, trauma, radiation, tumor
  • Secondary causes
    • Low FSH/LH usually due to pituitary tumor
  • Tertiary causes
    • Hypothalamus, extreme stress shuts down GnRH secretion, Kallman's syndrome
  • Postpubertal testicular failure
    • Characterized by low libido, prostate and seminal vesicle regression, low semen volume, decreased bone mass
  • Delayed puberty
    • Not reaching puberty by age 15-17


Pros and cons of male HRT

  • Pros: 
    • More energy, better libido, mood
  • Cons:
    • Decreased sperm count
    • Testicular atrophy
    • Mild gynecomastia
    • Edema
    • Increased LDL
    • Polycythemia (increased hematocrit)
    • Sleep apnea
    • Hepatic carcinoma
    • BPH
    • Possibly prostate cancer


Modifications of T that increase bioavailability

  • Esterification of lipophilic fatty acid to 17-b-hydroxyl group of T
    • Makes T even more lipophilic than native moelcule
    • Increases half-life of testosterone
    • Esters given parenterally or as a patch
  • Alkylation at 17-a position of T molecule retards its catabolism by liver
    • Such alkylated derivatives of testosterone are available, orally active, and hepatotoxic
    • Alkylated derivatives have been abused by athletes/body builders


Preparations of T available in US

  • Methyltestosterone / Fluoxymesterone
  • Testosterone enanthate
  • Testosterone cypionate
  • Testosterone


Methyltestosterone: administration/type, dose/frequency, notes

  • Methyltestosterone: Android, Testred
  • Fluoxymesterone: Halotestin
  • Administration/type:
    • Oral / 17-a alkylated derivatives
  • Dose/frequency:
    • 10-20mg/day
  • Notes:
    • Hepatotoxic, not used much
    • Al-kill-ated


Testosterone enanthate: administration/type, dose/frequency, notes

  • Delatestryl
  • Administration/type:
    • Parenteral/ 17-b-OH esterified derivatives
  • Dose/frequency:
    • 200 mg / 10-14 days
  • Notes:
    • Positive: effective and initiation and maintenance of virilization; freedom from daily admin


Testosterone cypionate: notes

  • Negative: deep muscular administration
  • Serum level variance affects energy, mood, libido proportional to interval length


Testosterone: administration/type, dose/frequency, notes

  • Androderm, Testoderm
  • Adminstration/type:
    • Transdermal gel or patch / the real deal (no more sac patch)
  • Dose/frequency:
    • 5mg/day
  • Positive:
    • Maintenance of stable testosterone serum levels = less fluctuation in mood, libido, energy


Side effects of androgens

  • Sustained erections
    • May not be considered a negative side effect but can --> priapism
  • Decreased sperm count
  • Testicular atrophy because of decreased LH/FSH
  • Mild gynecomastia
  • Edema
  • Increased LDL
  • Polycythemia (increased hematocrit)
  • Sleep apnea
  • Hepatic carcinoma (17a-alkyl analogs)
  • BPH
  • Possibly prostate cancer - recent literature seems to indicate that androgen therapy does increase risk


Steps to make testosterone prescriptions safer

  • Monitor serum testosterone concentrations
  • Do prostate screening before starting therapy and while on therapy
  • Monitor hematocrit at regular intervals


Uses of anti-androgens used in clinic

  • Prostate cancer
  • BPH which is largely DHT driven
  • Male baldness
  • Hirsutism
  • Precocious puberty in boys
    • Causes premature epiphyseal plate closure resulting in short stature
  • Acne


Types of anti-androgens used in the clinic

  • Leuprolide
    • -relins
    • -relixs
  • Ketoconazole
  • Abiraterone Acetate
  • Finasteride
  • Cyproterone Acetate
  • Flutamide/Bicalutamide


Leuprolide (-relins): type / common uses / notes

  • Buserelin, Nafarelin, Histrelin, Goserelin, Deslorelin
  • GnRH agonists
    • Inhibitor of testosterone synthesis + secretion
  • Common uses: prostate cancer
  • Notes:
    • Results in initial surge of GnRH release followed by down-regulation of GnRH receptors and action
    • Administered intranasally, by injection (daily/monthly/quarterly) or implant (1-12 months)


Leuprolide (-relixs): type / common uses / notes

  • Cetrorelix, Ganirelix, Abarelix, Degarelix
  • GnRH antagonist
    • Inhibitor of testosterone synthesis + secretion
  • Common uses: prostate cancer
  • Notes:
    • Synthetic peptides that block GnRH binding - no initial surge of GnRH
    • Administered by injection, IP, IM


Ketoconazole: type / notes

  • CYP450 inhibitor
  • Anti-fungal, reversible testosterone synthesis inhibitor
  • Side effects: hypertension, hypokalemia


Abiraterone acetate: type / notes

  • CYP450 inhibitor
  • Used for prostate cancer
  • Notes:
    • Irreversible testosterone synthesis inhibitor
    • Side effects: hypertension, hypokalemia


Finasteride: type / common uses / notes

  • 5a-reductase inhibitor
  • Common uses: male pattern baldness and BPH
  • Notes:
    • Given orally
    • Drug of choice for above conditions due to inhibition of testosterone --> DHT conversion
    • Increased risk of missing high grade tumor


Cyproterone acetate: type / notes

  • Androgen receptor antagonist
  • Steroid with progesterone-like effects at pituitary/hypothalamus/tissues
  • Act at receptors as if androgens, inducing negative feedback --> decreased GnRH --> decreased LH/FSH --> decreased T


Flutamide/Bicalutamide: type / notes

  • Androgen receptor antagonist
  • Non-steroidal anti-androgen
  • Inhibits uptake of androgen and its nuclear binding in target tissues
  • Increases GnRH, LH/FSH, testosterone
  • Give with GnRH agonist


Side effects of anti-androgens

  • Decreased muscle strength
  • Impotence
  • Decreased libido
  • Osteoporosis
  • Gynecomastia
  • Hot flashes and sweating
  • Increased risk of high grade prostate cancer (finasteride)


Androgen abuse in the US

  • Used to increase muscle mass, bone mass, lean body mass, retention of nitrogen
  • All anabolic hormones tested thus far are also androgenic
  • Strategies include cycling, mixing, and matching preparations and formulation "stacking"
  • Not regulated, sold in gyms after being smuggled, buy them on the internet
  • 1.5-2.2% of 8th-12th graders reported using steroids in 2007
  • Often it's the alkylated, oral kind which are abused --> hepatotoxic
  • Injections run the risk of HIV or hepatitis
  • "Small balls, extended boners" 
  • Illegal without prescription