androgen pharmacology Flashcards
general androgen half life
Test and its metabolites are degraded rapidly by the liver, making it difficult to sustain effective levels in the plamsa
- Identify the two principal androgens in males.
testosterone and DHT
List the inactive metabolites of Testosteron
androsterone and etiocholanolone
Where are levels of DHT highest
prostate, scrotum, penis, hair and skin
Sites of testosterone syntesis in males vs females
men: most in leydig cells, small amount from adrenals. Females: small amounts come from both ovary and adrenal gland
What stimulates testosterone synthesis
LH stimulates leydig cells- increases synthesis of pregnenolone from cholesterol.
What is the major pathway by which T is synthesized in leydig cells
Cholesterol > pregnenolone > > DHEA > androstenedione > T > DHT
Testosterone forms in the blood
40% is bound to sex hormone binding globulin and is not biologically active. 2% is unbound and the rest is bound to albumin. The portion bound to albumin is biologically active since it freely dissociates from albumin
Where is GnRH released from
arcuate nucleus and anterior hypothalamus
Is E or T more potent at inhibiting GnRH and LH release
Estrogen is more potent
Name time periods where T secretion is high in male
fetal phase, neonatal phase and adult phase
- Characterize the genomic mechanisms of action of androgens.
T or DHT binds to nuclear androgen receptor > dimerization > interacts with hormone response elements on DNA > trxn of target genes
- Characterize the non-genomic mechanisms of action of androgens.
- T or DHT binds membrane associated androgen receptor (mAR) > activates L-type Ca Channels > increased Ca > activation of PKC > activate PKA and MAPK > gene trx. 2. T or DHT binds mAR > activation of PLC > increased IP3 > release of intracellular Ca > activation of RAS/MEK/ERK pathway. 3. DHT metabolite interacts with GABA receptor > increased intracellular Cl and membrane potential. 4. T interacts with membrane bilayer phospholipids > changes flexibility and alters Na/K pump and Ca ATPase functions
- Explain the therapeutic uses of androgens
hypogonadism, osteoporosis, muscle wasting associated with AIDS, hormone therapy replacement in aging men.
compare primary, secondary and tertiary hypogonadism
primary: low T and normal or high LH/FSH. Secondary: defect at level of pituitary, low T and low FSH and LH, normal GnRH. Tertiary: defect at level of hypothalamus, low GnRH, Low FSH/LH.
Causes of tertiary hypogonadism
Kallmans syndrome (failure of GnRH neurons to migrate from olfactory placode) or acquired during illness or high stress.
When should low T in older men be treated
If T is consistently <200mg/dl and accompanied by problematic Sx
- Discuss the modifications of testosterone that increase its bioavailability
- Esterification of 17 beta hydroxyl group makes T more lipid soluble and they can be given parenterally or as a patch. 2. Alkylation of 17 alpha position slows degradation by liver making oral administration more effective. They are toxic to the liver.
What is the structure of most anabolic steroids
17alpha alkylated androgens which are toxic to the liver. These include axandrolone, stanozolol, fluoxymesterone, danazol
- List the formulations of testosterone available in US
Oral (not used for long periods due to hepatotoxicity): methyltestosterone (android, testred) and fluoxymesterone (halotestin). Parenteral: testosterone enanthate (delatestryl) and testosterone cypionate (virilon). Transdermal: testosterone ( androderm, testoderm). Gels and buccal tablets also
Side effects of androgen therapy
testicular atrophy (decreased LH/FSH), gynecomastia, virilization in women, elevation of LDL, polycythemia, jaundice and hepatic carcinoma (17a-alkyl analogs), BPH, prostate cancer???
Monitoring tests during T therapy
Screen for prostate cancer before therapy and while on therapy. Hematocrit should be measured before treatment and again after 3-6 months then yearly.
- Explain the therapeutic uses of androgen antagonists.
Prostate cancer, benign prostatic hyperplasia, male baldness, hirsutism, precocious puberty in boys, acne
List the types of anti-androgens
- Inhibitors of T secretion/synthesis: GnRH agonists or antagonists, drugs that block Cty P 450. 2. 5 alpha reductase inhibitors. 3. Androgen receptor antagonists
List GnRH agonists and how they work
leuprolide, buserelin, nafarelin, histrelin, goserelin and deslorelin. Result in initial surge of GnRH followed by down-regulation of GnRH receptors and action
List GnRH antagonists and how they work
cetrorelix, ganirelix, abarelix and degarelix. Block GnRH binding.
List drugs that block Cyt P 450 and side effcts
Ketoconazole and abiraterone acetate. SE: hypertension and hypokalemia due to excess mineralocorticoids and adrenocorticoid insufficiency
List 5 alpha reductase inhibitor and its uses
Finasteride- used for BPH and male baldness. Both are DHT driven processes
List the androgen receptor antagonists and their affects on GnRH, FSH/LH and testosterone
- cyproterone acetate- steroid with progesterone like effects. Decreases GnRH, LH/FSH and testosterone. 2. Flutamide and bicalutamide- non-steroidal. Blocks negative feedback. Increases GnRH, LH/FSH and testosterone. Given with GnRH agonist
Side effects of anti-androgens
decreased muscle strength, impotence, decreased libido, gynecomastia, osteoporosis, hot flashes/sweating, increased risk of prostate cancer (finasteride)
List the top selling anabolic steroids through the internet
injectable: deca durabolin, testosterone enanthate, trenbolone, primolobone, equipoise, sustanon, and winstol. Oral: anavar, Tbol, dianabol, proviron
