Androgen Pharmacology Flashcards
1
Q
Two principal androgens in males
A
- Testosterone
- 5a-dihydrotestosterone (DHT)
2
Q
Regulation of androgen biosynthesis
A
- 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
3
Q
Genomic MOA of androgens
A
- 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
4
Q
Non-genomic postulated androgen actions
A
- 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
5
Q
Therapeutic uses of androgens
A
- 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
6
Q
Causes of hypogonadism
A
- 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
7
Q
Pros and cons of male HRT
A
- 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
8
Q
Modifications of T that increase bioavailability
A
- 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
9
Q
Preparations of T available in US
A
- Methyltestosterone / Fluoxymesterone
- Testosterone enanthate
- Testosterone cypionate
- Testosterone
10
Q
Methyltestosterone: administration/type, dose/frequency, notes
A
- 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
11
Q
Testosterone enanthate: administration/type, dose/frequency, notes
A
- 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
12
Q
Testosterone cypionate: notes
A
- Negative: deep muscular administration
- Serum level variance affects energy, mood, libido proportional to interval length
13
Q
Testosterone: administration/type, dose/frequency, notes
A
- 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
14
Q
Side effects of androgens
A
- 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
15
Q
Steps to make testosterone prescriptions safer
A
- Monitor serum testosterone concentrations
- Do prostate screening before starting therapy and while on therapy
- Monitor hematocrit at regular intervals
16
Q
Uses of anti-androgens used in clinic
A
- 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
17
Q
Types of anti-androgens used in the clinic
A
- Leuprolide
- -relins
- -relixs
- Ketoconazole
- Abiraterone Acetate
- Finasteride
- Cyproterone Acetate
- Flutamide/Bicalutamide
18
Q
Leuprolide (-relins): type / common uses / notes
A
- 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)
19
Q
Leuprolide (-relixs): type / common uses / notes
A
- 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
20
Q
Ketoconazole: type / notes
A
- CYP450 inhibitor
- Anti-fungal, reversible testosterone synthesis inhibitor
- Side effects: hypertension, hypokalemia
21
Q
Abiraterone acetate: type / notes
A
- CYP450 inhibitor
- Used for prostate cancer
- Notes:
- Irreversible testosterone synthesis inhibitor
- Side effects: hypertension, hypokalemia
22
Q
Finasteride: type / common uses / notes
A
- 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
23
Q
Cyproterone acetate: type / notes
A
- 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
24
Q
Flutamide/Bicalutamide: type / notes
A
- 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
25
Q
Side effects of anti-androgens
A
- Decreased muscle strength
- Impotence
- Decreased libido
- Osteoporosis
- Gynecomastia
- Hot flashes and sweating
- Increased risk of high grade prostate cancer (finasteride)
26
Q
Androgen abuse in the US
A
- 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
