Androgens Flashcards
-Where is testosterone mainly synthesized? What cells?
-In testes and ovaries – Leydig cells
Hypothalamic-Pituitary-Gonadal axis
-Describe this sucker
1) gonadotropin-releasing hormone (GnRH) synthesized and released by hypothalamus
- pulsatile release
2) GnRH binds to gonadotropes=release of lutinizing hormone (LH) + follicle stimulating hormone
3) LH bind leydig cells–> testosterone production + secretin
- testosterone diffuses to sertoli cells=spermatogenesis
- acts on other cells via blood
4) FSH stimulates sertoli cells to produce ABP-androgen binding protein–>concentrates testosterone at the site of spermatogenesis
5) FSH stim sertoli cells to produce inhibin–>inh FSH production @ ant pit
Negative feedback pathways of the Hypothalamic-pit-gonadal axis:
1) Testosterone –> inh ant pituitary release of LH + inh GnRH release by hypothala
2) testosterone and its products converted into 5alhpa-dihydrotestosterone and estradiol –> inh ant pit release of LH
3) FSH stim sertoli cells to produce inhibin–>inh FSH production @ ant pit
What enzyme do LEydig cells have that is different from the adrenal cortex? What does it convert?
- 17beta-hydroxysteroid dehydrogenase (17beta-HSD)
- converts androstenedione to testosterone
Testosterone in the blood…
bound to albumin (weak binding - considered bioavailable) or bound to sex hormone-binding globulin (SHBG-strong binding=not bioavailable)
Testosterone MOA & conversion products:
- binds to intracellular androgen receptor (AR) –> inc or dec gene transcription
- converted to 5alpa-dihydrotestosterone in prostate(DHT)= way hgiher biological activity when bound to AR then - longer t.5
- converted to estradiol by CYP19 (aromatase-in many tissues)
5alpha-Dihydrotestosterone role in male vs testosterone role:
- 5alpha role=dev of penis, scrotum, urethra, prostate, sebum, beard, sperm production,
- testosterone role = epidydimis, vas deferens,
- both do: seminal vesicles, sperm production, penis size
Anabolic effects of androgens:
- stimulates resting metabolic rate
- inh lipid accumulation in adipocytes, stimulates lipolysis, inh differentiation of adipocyte precursors
Androgen effects on skeleton:
- reduces bone reabsorption and enhances bone formation
- testosterone converted to estradiol = estrdiol closes epiphyseal plate (stops bone growth)
Androgen effects on RBC:
-inc erythropoietin production
Androgen effect on muscle:
inc protein synthesis and inh protein breakdown
Primary hypogonadism:
- what happens?
- causes?
1) problem is testicular dysf=dec in testosterone production
- loss of neg feedback=inc in circulating gonadotrophins (hypergonadotropic hypognadsm)
2) Causes: cryptorchidism(undescended testes); kleinfelters; medication (chemo)
Secondary hypogonadism
-what happens?
-problem is w/ hypothalapituitary or morbid obesity
dec is circulating gonadotrophins (hypogonadotropic hypognadsm)
-low testosterone with low LH and FSH
Which hypogonadism has low and which has high levels of circulating gonadotropins?
primary has HYPERGONADOTROPIC hypogonadism bc loss of neg feedback (testicular dysfunction)
secondary has HYPOGONADOTROPIC hypogonadism (hypothala/pit are broken)
relationship bw metabolic syndrome and hypogonadism:
- go hand in hand (obesity+insulin resistance+ hypogonadism)
- testosterone converted to estradiol by adipose
- What does adipose tissue do to testosterone?
- What effect does this have?
- testosterone converted to estradiol by adipose
- estradiol effects–> inh LH release from pit ==> reduced testosterone levels ==> less Testosterone means more adipose and its a viscious cycle
Hypogonadism - what dec leydig cells production of testosterone?
insulin resistance due to adipose tissue
Hypogonadism - what dec hypothala/pit producion of LH (and less LH = dec stimulation of leydig cells to produce testosterone)?
leptin, adipokines, and estradiol from adipose tissue
As we age what happens to free testosterone?
decreases and associated wtih a much of conditionss -prostate cancer -libido -cognition muscle stretngth -mood ...etc
androgen therapeutic uses:
- stimulate sexual dev + inc in height in teens
- repleacement therapy in hypogonadal men
- aging-maintain vitality/vigor, reduce bone loss, sexual dysf
- osteoporosis
- gynecological disorders
- anabolic effects a) debilitated states-AIDS,prolonged immobilization b) athletics
17alpha-alkylated androgen drugs? route of administration?
- methyltestosterone (oral + sublingual)
- fluoxymesterone (oral)
- danzaol (oral)
testosterone ester androgen drugs? route of administration?
(fatty acids added to testosterone)
- testosterone enanthate (IM)
- testosterone cypionate (IM)
-slower metabolism and longer duration
Which androgen drug is administrated as a transdermal/topical gel?
testosterone itself bro
testosterone ester androgen drugs- benefit to use?
- slower metabolism and longer duration
- fatty acid attached = fat soluble = given intramuscular
17 alkylated androgen drugs - benefit to use?
- more anabolic effects and less androgenic effects (dont want these effects)
- oral
Androgen therapy (abuse) - AEs (DOSE DEPENDENT):
1) musculoskeletal
- premature epiphyseal closure
- inc muscle and tendon injuries (cant handle inc muscle mass)
2) hepatic dysf (with 17-alkyated)
- cholestatic jaundice
- peliosis
- carcinoma
3) lipid metabolism
- dec HDL
- inc LDL
- inc risk for atherosclerosis and MI
4) edema- fluid retention (HTN)- Renal dysf
5) mental disturb
- mood swing, aggression, depression, pschosis
antiandrogen- uses?
-female=hirsutism
-male=
precocious puberty
prostatis hyperplasia/cancer
alopecia
contraceptive
-psychosocial deviance (chemical castration)
GnRH analogs
- the drugs?
- use to treat?
- Leuprolide
- Goserelin
-prostate cancer
GnRH analogs:
- compared to actual GnRH hormone?
- effects?
- problems?
1) inc receptor binding affinity and dec proteolysis vs regular GnRH
2) inc LH and testosterone production
3) over time get de-sensitization and down reg of GnRH receptors on pituitary
- need AR receptor antagonist bc initial testosterone surge can inc (prostate)cancer growth
GnRH antagonist
- name the drugs?
- benefits to use/effects?
- Degarelix
- faster onset that GnRH agonsits
- no LH (testosterone) surge
- reduce LH/FSH production and release
- dec testosterone production –> more effective testosterone suppression
Degarelix is what kind of drug?
what does it do?
GnRH antagonist
- faster onset that GnRH agonsits
- no LH (testosterone) surge
- reduce LH/FSH production and release
- dec testosterone production –> more effective testosterone suppression
Testosterone synthesis inh drugs??
- spironolactone
- ketoconazole
Spironolactone
- type?
- used for?
- MOA?
- testosterone synth inh
- used to treat hirsutism
- lowers androgen synth by reducing 17alpha-hydroxylase activity
- competitive inh of androgen receptor (MOSTLY THIS
Ketoconazole
- tpe?
- use for?
- MOA?
- anti-fungal but also testosterone synth inh
- inh 17alpha-hydroxylase acitivty
- not generally used to inh androgen synth bc it also inh cortisol synthesis
5alpha-reductase inh drugs:
- name these guys
- used for?
- side effects?
- Finasteride
- Dutasteride
- reduce prostate growth in BPH
- reduce baldness but at high levels reduces hair growth
-impotence and gynecomastia are infrequent
Androgen receptor antagonists
-name the drugs
- flutamide
- nilutamide
- bicalutamide
Flutamide
- type?
- MOA?
- TX?
- AE?
- use?
- androgen receptor antagonist
- competitive antagonisms at androgen receptor
- treats prostate cancer; prevents testosterone sruge if given prior to GnRH administration
- mild gynecomastia
- reversible liver tox
