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androgens
R-GU
52
Medical
Graduate
10/08/2010

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Term
what are the androgens?
Definition
testosterone, androstenedione, and dehydroepiandrosterone (DHEA - sold as a supplement)
Term
what does aromatase do?
Definition
this enzyme is involved in some estrogen production
Term
where are the androgens produced?
Definition
in the testes (leydig cells), adrenal glands, and the ovaries (theca cells). they are then transported to target tissues.
Term
what is the major product of the testis? at what rate? how much is stored?
Definition
testosterone is produced at a rate of 5-7 mg/day and 9 ug is stored in the testis.
Term
where is testosterone produced in women? at what rate?
Definition
testosterone is produced in the ovaries and adrenals in women at a rate of .25 mg/24 hrs (may be higher in some women and interrupt the menstrual cycle).
Term
does testosterone production include CYP?
Definition
yes, progesterone is converted to androstenedione via CYP. this plays a role in some of the drugs prescribe for prostate CA (want to reduce testosterone production).
Term
what happens to testosterone when it reaches the prostate? what is the implication of this for anti-prostate CA drugs?
Definition
*5-alpha reductase metabolizes testosterone to 5-alpha dihydro-testosterone (DHT) in the prostate. (5 alpha reductase also does this in the testes, hair follicles, and adrenal glands - but testosterone is unchanged muscle/kidney). b/c in prostate CA testosterone levels need to be lower - this enzyme is often the target of anti-prostate CA drugs.
Term
is DHT more powerful than testosterone?
Definition
yes
Term
what is testosterone production stimulated by?
Definition
luteinizing hormone (LH), which is produced by the anterior pituitary. receptors for LH are found on leydig cells. estradiol is also stimulated by LH.
Term
what is the path of hormonal stimulation for the androgen production in the gonads?
Definition
hypothalamus: gonadotropin releasing hormone -> pituitary: LH/FSH -> gonads: testosterone, estrogen, progesterone
Term
what is the path of hormonal stimulation for the androgen production in the adrenal cortex?
Definition
hypothalamus: corticotropin releasing hormone -> pituitary: adrenocorticotropin -> adrenal cortex: glucocorticoids, mineralocorticoids, and androgens (5% of testosterone)
Term
what is the function of the sertoli cells? how are they regulated hormonally?
Definition
the sertoli cells are where spermatogenesis occurs as well as production of transferrin (androgen-binding) and inhibin (negative feedback for FSH) occur. the sertoli cells are primarily stimulated by FSH from the anterior pituitary.
Term
what androgens are produced by the adrenal glands?
Definition
dehydro*epi*androsterone, androstenedione and testosterone
Term
what does adrenocorticotropin stimulate production of?
Definition
adrenocorticotropin stimulates production of cortisol and sex steroids by the adrenals
Term
what is sex hormone binding globulin? what agents increase its levels?
Definition
sex hormone binding globulin is a serum glycoprotein derived from the liver which strongly binds to testosterone - inactivating it, and thus regulating its bioavailability in circulation. *estrogen will increase its levels (females 2-3 x males) as will *thyroxine. *androgens, growth hormone, and insulin will decrease sex hormone binding globulin levels.
Term
what are the pharmacological actions of anabolic steroids (subgroup of androgens)?
Definition
stimulation of sperm production, erythropoiesis, positive nitrogen balance, and growth/development of hair/bone/muscle.
Term
what is the major clinical use of anabolic steroids?
Definition
primary testicular insufficiency
Term
what are the available injectable androgen products?
Definition
testosterone cypionate (2-3 wks), testosterone enanthate (2-3 wks), and testosterone propionate (1-3 days). these are all IM injection and have rapid biotransformation.
Term
what is the transdermal androgen product available? ADRs?
Definition
the transdermal testosterone patch is applied to scrotum/abdominal/upper arm skin and is thinner than the epidermis. FDA warning: accelerated development of 2ndary sex characteristics in young pediatric pts in contact w/pt using this product.
Term
what are the androgen products "out there"?
Definition
fluoxymesterone, oxandrolone, oxymetholone, methyltestosterone, and nandrolone
Term
what are the anabolic steroids?
Definition
a subgroup of androgens, synthetic derivatives of testosterone which have more *anabolic action than androgenic. this includes: increased muscle mass, increased physical performance, and increased linear growth in children.
Term
what are the anabolic steroid products available?
Definition
oxandrolone, oxymetholone, and stanozolol
Term
how can androgen therapy help treat pts with primary testicular failure?
Definition
androgen therapy increases expression of secondary sex characteristics: hair/beard growth, deepening of voice, muscle development, and phallic enlargement in boys. however androgen therapy will not help with infertility.
Term
what is secondary testicular failure? can androgens be used to treat it?
Definition
secondary testicular failure: insufficient stimulation of the testes by pituitary gonadotropins or hypogonadotropic hypogonadism. androgens can be used to treat this.
Term
can androgens be given to short children/teenagers to increase height?
Definition
yes, though this is controversial due to the fact that the role of androgens is not completely established, and the fact that androgens can cause premature closure of epiphyseal plates (if too much is used and negative feedback gets tripped) as well as virilization. if androgens are used for short children/teens, growth hormone is preferably combined (better mimics the natural system).
Term
why might androgens be used to tx aplastic anemia?
Definition
androgens can increase stimulation of erythropoiesis
Term
can androgens be used to tx inoperable breast CA?
Definition
yes, which will decrease estrogen levels
Term
can androgens be used to tx malnutrition?
Definition
yes, this will help stave off protein breakdown in critical areas such as heart muscle
Term
what is danazol?
Definition
a weaker androgen used to tx endometriosis, fibrocystic breast disease and PMS (MOA: reduction of estrogen)
Term
is there an association between lower endogenous testosterone levels and fall risk in elderly pts?
Definition
yes. lower endogenous testosterone levels did not correlate w/overall performance - just fewer falls.
Term
how has testosterone supplementation been shown to affect MS pts?
Definition
MS pts treated w/testosterone (12 mo of 100 mg testosterone in a 10 g gel daily) showed an increased cognitive performance, slowing of brain atrophy, and an increase in lean body mass.
Term
what ADRs are associated with androgen supplementation?
Definition
priapism, suppression of gonadotropin, gynecomastia, wt gain, Na+ retention (edema/HTN), decreased HDLs (possible *atherosclerosis), hepatoxicity (jaundice/*peliosis hepatitis*/hepatocellular CA), virilization (stop if appears: irreversible), BPH/prostatic CA, and decreased size of testis/spermatogenesis (due to negative feedback). *ADRs: dose-related*
Term
can androgens ever be prescribed to pregnant pts?
Definition
no, never
Term
what is 'roid rage?
Definition
a feeling of invincibility to physical challenges associated w/androgen
Term
can anabolic drugs also cause inappropriate enlargement of genitalia (penis/clitoris), premature development of pubic hair, advanced bone age (restricts growth), increased libido, and aggressive behavior?
Definition
yes - this has to be included on androgel/tesim boxes now
Term
can testosterone supplements increase prostate CA growth/metastasis?
Definition
yes
Term
what is acne conglobata?
Definition
a possible ADR associated w/anabolic steroid use
Term
what are male contraindications for androgen supplementation?
Definition
breast, prostate CA
Term
what are female contraindications for androgen supplementation?
Definition
pregnancy (known/suspected)
Term
what are contraindications for androgen supplementation in all pts?
Definition
serious cardiac, hepatic or renal disease
Term
what are the 2 different kinds of anti-androgen action? what might these be used for?
Definition
suppression of androgen synthesis or blockade of androgen receptors. possible application: tx of androgen stimulated tumors.
Term
what anti-androgens are used to suppress androgen synthesis? what is their MOA?
Definition
goserelin, leuprolide, and nafarelin are gonadotropin releasing hormone analogues which inhibit androgen synthesis via negative feedback inhibition.
Term
what are indications for goserelin, leuprolide, and nafarelin, the gonadotropin releasing hormone analogues? ADRs?
Definition
prostate CA pts. ADRs: small increased risk for DM, heart attack, stroke, and sudden death.
Term
what characterizes leuprolide? why might it cause increased testosterone synthesis at the start of tx? does it treat the prostate CA or it's symptoms? how can it be used to tx women/children?
Definition
this synthetic nona-peptide analog of GnRH suppresses synthesis of androgens via negative feedback. there is an *initial increase in testosterone levels (worsening of symptoms) at the start of tx* until the body adjusts to what is happening. leuprolide will tx the symptoms of prostate CA (decreases testosterone), but *not the CA itself. leuprolide will also tx symptoms of endometriosis in women (decreases estrogen), but is category X for pregnant pts. leuprolide can also be used to tx precocious puberty in children.
Term
what characterizes goserelin as an anti-androgen?
Definition
this is installed as an implant and is a synthetic decapeptide analogue of *luteinizing hormone-releasing hormone* - also known as a GnRH agonist analogue. it is used as palliative tx for advanced prostate CA.
Term
what characterizes nafarelin as an anti-androgen?
Definition
nafarelin is a nasal spray and *powerful GnRH agonist analog which suppresses synthesis of androgens via negative feedback. used BID, after 4 wks (and an initial increase in androgens), gonadal steroidogenesis will decrease. nafarelin is used for hormonal mangement of endometriosis - *including pain relief and reduction of endometric lesions (can treat the problem rather than just giving pt NSAIDs or narcotics).
Term
how can ketoconazole be used as an anti-androgen?
Definition
ketoconazole reduces CYP in testicular microsomes, which reduces synthesis and hydroxylation of androgens. this can give some feminizing effects such as gynecomastia/impotence/oligospermia. it is being investigated in tx for prostate CA or GnRH-independent precocious puberty in boys.
Term
what is the MOA for 5-alpha reductase inhibitors as an anti-androgen?
Definition
5-alpha reductase inhibitors decrease the biotransformation of steroid precursors to active androgens - *DHT, not testosterone is active in the prostate
Term
is finasteride?
Definition
finasteride is a PO steroid-like inhibitor of 5-alpha reductase, which can decrease DHT levels in 8 hrs and lasts 24 hrs (40-50% metabolized). finasteride looks very similar to androgens, which is why it is able to block their processing enzyme.
Term
what is dutasteride
Definition
similar to finasteride, but a slower onset of action and a greater half-life
Term
what is flutamide? major ADR?
Definition
a nonsteroidal androgen receptor *blocker which is used w/LHRH agonists in tx of prostatic/metastatic CA. major ADR: hepatic injury (not recommended w/ALT > 2x ULN)
Term
can spironolactone be used to block androgen receptors?
Definition
yes. it is a steroid and also decreases CYP in testicular microsomes.
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