Androgens Flashcards
Testosterone synthesized where?
Can also be synthesized?
Leydig cells of testes, and in ovaries
in peripheral tissues and testes from low potency androgens from the adrenal cortex
HPG Axis
Hypothalamus releases GnRH
GnRH acts on Pituitary to release gonadotropes LH AND FSH
LH acts on Leydig cells to produce TESTOSTERONE
FSH acts on Sertoli cell to produce ABP and INHIBIN
Testosterone negative feedback inhibits hypothalamic release of GnRH
Inhibin negative feedback on pituitary gonadotropes release
Prominent pathway of testosterone synthesis in human testis
Cholesterol to pregnenolone (cholesterol desmolase)
Pregnenolone to 17-a-pregnenolone (17-a hydroxylase)
17-a-pregnenolone to DHEA (17-a-hydroxylase)
DHEA to Androstenedione (3-beta-HSD)
Androstenedione to Testosterone (17-BETA-hydroxylase)
Testosterone to Dihydrotestosterone (5-a-reductase) in some tissues
Forms of testosterone in the blood
albumin bound - physiologically active
SHBG bound - not physiologically active
Free
Testosterone MOA (3 paths)
Testosterone
Estradiol
DHT
All act on respective receptor to pass into nucleus
Then bind respective receptors again to ALTER TRANSCRIPTION
Androgen effects on skeleton
reduces bone reabsorption, enhances formation
estradiol facilitates closure of growth plates at puberty
Androgen general effects
increases resting metabolic rate
inhibits lipid accumulation
lower blood glucose
Androgen effects on RBC’s
increases EPO
Androgen effects on muscle
increase protein synthesis, inhibits protein breakdown
Primary hypogonadism
loss of negative feedback causes HYPERGONADOTROPIC HYPOGONADISM
Cryptorchidism
Klinefelter
Medications
Secondary hypogonadism causes
hypothalamus/pituitary
morbid obesity
decrease in gonadotropins
low testosterone with low LH and FSH
Therapeutic androgen preps and route of admin
Methyltestosterone - oral/sublingual
Testosterone enanthate - intramuscular
Testosterone - transdermal, topical
Testosterone esters (1)
Used for
Characteristics
Testosterone enanthate
Replacement in hypogonadal men
longer duration, slower metabolism
17-alkylated derivatives (1)
characteristics
methyltestosterone
significantly slower liver metabolism
liver toxicity and hepatic cancer
Therapeutic Uses of anti-androgens
hirsutism in females
precocious puberty
BPH
Prostate cancer
Alopecia
4 types of anti-androgens
Androgen receptor inhibitor
GnRH agonists
GnRH antagonists
Steroid synthesis inhibitors
Non-steroidal anti-androgens (3)
MOA
Flutamide, Bicalutamide, Enzalutamide
competiive ANTAGONIST AT ANDROGEN RECEPTOR
prostate cancer
mild gynecomastia, reversible liver toxicity
Enzalutamide important differences
ADDITIONAL EFFECTS
inhibits nuclear translocation of AR
blocks DNA binding
Blocks co-activator recruitment
GnRH Receptor Agonists (2)
MOA
Leuprolide, Goserelin
initially INCREASES LH AND TESTOSTERONE PRODUCTION
OVER TIME LEADS TO DESENSITIZATION AND DOWN-REGULATION OF GnRH receptors on pituitary gonadotropes
Side Effects of GnRH Agonists
sexual dysfunction
bone mineral density loss
anemia
fatigue
prostate cancer growth
GnRH Receptor Antagonists
Degarelix
BLOCKS RECEPTOR
faster onset
no LH/Testosterone surge
Androgen Biosynthetic inhibitor
ABIRATERONE
BLOCKS 17-ALPHA-HYDROXYLASE
metastatic prostate cancer
combo with prednisone
adrenal insufficiency, hepatic toxicity, HTN, hypokalemia, fluid retention
5-alpha reductase inhibitors (2)
clinical
adverse
finasteride, dutasteride
BPH, androgenic alopecia
reduce overall cases of prostate cancer, but increase grades of prostate cancer, impotence, gynecomastia, lowers PSA levels
major causes of erectile dysfunction (2)
name some others
vasculogenic
drug-induced
psychogenic, neurogenic, hormonal
PDE5 INhibitors (3)
adverse effects
Sildenafil, Vardenafil, Tadalafil
serious cardiac effects, dangerously low BP with nitrates, priapism
