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76 Cards in this Set

  • Front
  • Back
What is the main circulating androgen in men?
Testosterone and the substrates it converts to bind to what receptor?
Testosterone - androgen receptor
Dihydrotestosterone - androgen receptor
Estradiol - estrogen receptor
Male sexual differentiation and male puberty changes are due to:
Male hypogonadism is treated by:
Testosterone is synthesized where in men and in women?

What is converted into testosterone?
Men - leydig cells in testis

Women - corpus luteum and adrenal cortex

Plasma cholesterol enters the Leydig cell and is eventually converted into testosterone after a number of steps
Fetal testes begin secreting testosterone during which trimester in utero?
first - principle factor of male sexual differentiation
During what ages does serum testosterone concentration increase greatly to cause puberty changes?
12 to 17 years old
What regulates the production of testosterone?
Luteinizing hormone (LH)
Active and inactive metabolites of testosterone and their effect:
5alpha-reductase catalyzes converstion to dihydrotestosterone - binds to androgen receptor with higher affinity and activates gene expression more efficiently

Aromatase catalyzes conversion to estradiol - produces 85% of estradiol in men (occurs especially in liver and adipose)

androsterone and eticholanolone in liver
Effects of testosterone occur via androgen receptor:
ligand-receptor complex binds DNA and acts as a TF complex and stimulates gene expression

*dihydrotestosterone has effects in tissues where testosterone does not due to its higher affinity

*Tissue specific coactivators and corepressors allow for different actions in different tissues
Effects of androgen deficiency at different stages of life
During fetal development: incomplete sexual differentiation

Before completion of puberty: failure to complete puberty

After completion of puberty: regression of pubertal effects
Oral testosterone is not effective because:
hepatic catabolism of testosterone is too rapid
Androgen deficiency therapeutic preparations - oral and IM
* Testosterone enanthate (Delatestryl) or cypionate (Depo-Testosterone) are dissolved in oil and administered IM Q2-4 weeks
*Testosterone undecanoate (Andriol) is dissolved in oil and ingested orally and absorbed into lymphatic circulation, bypassing hepatic catabolism
*17alpha-alkylated androgens are effective orally, with retarded hepatic catabolism
Androgen deficiency therapeutic preparations - Transdermal
*Testoderm applied to scrotal skin
*Androderm, Testoderm TTS for nonscrotal skin with chemicals to facilitate absorption
*Androgel employs a hydroalcoholic gel which is applied to nonscrotal skin

*all applied once a day
Side effects of testosterone and modified testosterone
*Testosterone has no side effects
*Modified testosterone: acne, gynecomastia, more aggressive sexual behavior
- in excessive dose: erythrocytosis, salt and water retention, peripheral edema
- BPH and prostate cancer may occur in long term use
Therapeutic uses of testosterone in boys with GH deficiency
*Testosterone accelerates epiphyseal maturation, leading initially to a growth spurt but then to epiphyseal closure and permanent cessation of linear growth.
*Short boys due to GH deficiency should be treated with GH before their hypogonadism is treated with testosterone
Therapeutic uses of testosterone - Bone mass & athletes
*testosterone increases bone mineral density and lean mass, decreases fat mass in aged men
*Some athletes take androgens to improve their performance (Testosterone esters, hCG, DHEA)
Therapeutic uses of testosterone - AIDS
used to treat muscle wasted associated with AIDS, which is accompanied by hypogonadism, increasing muscle mass and strength
Antiandrogen MOA
*GnRH analogs inhibit testosterone synthesis by inhibiting LH secretion
*Require daily injection and have significant histamine-releasing properties
*GnRH "superactive" analogs, given repeatedly, down-regulate GnRH receptor, used for metastatic prostate cancer
Antiandrogen drugs
*Flutamide (Evlexin) and bicalutamide (Casodex) are potent androgen receptor antagonists
- not very effective when used alone, but used primarily in conjunction with GnRH analog to treat metastatic prostate cancer, blocking the action of adrenal androgens, which are not inhibited by GnRH analogs

*bicalutamide has less hepatotoxicity and needs to be taken once a day instead of TID for flutamide
5alpha-reductase inhibitors - drugs for BPH
*finasteride (Proscar), especially for type II enzyme, blocking conversion of testosterone to dihyrdrotestosterone, especially in male external genitalia
*dutasteride (Avodart) for Type I and II enzymes
*Impotence is infrequent side effect

*finasteride is also approved for treatment of male pattern baldness (Propecia)
adrenal cortex releases:
glucocorticoids (cortisol)
mineralcorticoids (aldosterone)
sex hormones (testosterone)
adrenal medulla releases:
Adrenocorticotropic hormone is produced by ? and stimulates the secretion of ?
*ACTH is AKA corticotropin
*produced by anterior pituitary
*stimulates the adrenal cortex to secrete glucocorticoids (regulate carb metabolism) and mineralcorticoids (regulate fluid & electrolyte balance)
ACTH secretion is regulated by:
corticotropin releasing hormone (CRH) in the hypothalamus
ACTH is synthesized as part of what larger precursor protein?
pro-opiomelanocortin (POMC) liberated through proteolytic cleavage by prohormone convertase 1
The outer zona glomerulosa of the adrenal cortex secretes? and have ? & ?

The inner zonae fasciculata/reticularis secretes ? and express ? & ?
the mineralcorticoid aldosterone; angiotensin II receptors and aldosterone synthetase

the glucocorticoid cortisol and androgens; steroid 17alpha-hydroxylase & 11beta-hydroxylase that catalyze producation of glucocorticoids
ACTH acutely stimulates mineralcorticoid production by zona glomerulosa, this zone is predominately regulated by:
angitensin II and extracellular K+
The effects of persistently elevated ACTH:
- mineralcorticoid levels intitially increase and then return to normal
- induce hyperplasia and hypertrophy of inner zones of adrenal cortex, with overproduction of cortisol and adrenal androgens
MOA of ACTH action to increase steroid hormone production
*mediated at the level of de novo biosynthesis

*ACTH binds to ACTH receptor, MC2R, a G protein coupled receptor
* ACTH receptor activates Gs, which activates adenylyl cyclase and increase cAMP
*most of the enzymes required are members of cytP450 superfamily

*Rate limiting components: mobilization of cholesterol, delivery to P450scc in inner mitochondrial matrix, conversion of cholesterol to pregnenolone by cholesterol side-chain cleavage enzyme
Pituitary corticotropes are regulated by:
corticotropin-releasing hormone (CRH) produced by CRH neurons of hypothalamus
appropriate levels of glucocorticoids maintained by:
hypothalamus-pituitary-adrenal (HPA) axis
Three characteristic modes of regulation of HPA axis
1) diurnal rhythm in basal steroidgenesis
2) negative feedback regulation by adrenal corticosteroids
3) marked increase in steroidgenesis in response to stress
The influence of CNS on the regulation of ACTH secretion
CNS signals (stress) converge on CRH neurons in hypothalamus, released CRH binds to and activates CRH receptors on corticotropes, ultimately ACTH synthesis and secretion
the influence of Arginine vasopressin (AVP) on the regulation of ACTH secretion
acts as a secretagogue for corticotropes, significantly potentiating effects of CRH
*produced by hypothalamus, plays a role in stress repsonse, does not increase ACTh synthesis
Negative feedback of glucocorticoids
*major mechanism to maintain circulating glucocorticoid levels

*Glucocorticoids inhibit ACTH secretion via direct/indirect actions on CRH neurons and via direct effects on corticotropes
*In pituitary, glucocorticoids act through glucocorticoid receptor to inhibit expression of POMC in corticotropes and inhibit ACTH secretion
The major clinical use of ACTH is to:
test the integrity of HPA axis to identify patients needeing supplement steroid coverage in stressful situations
* cosyntropin (Cortrosyn) is synthetic ACTH peptide - administered IM or IV and cortisol levels measured just before given and 30 min after
- increase in cortisol greater than 18-20 microgram/dl indicates normal response
Cushing's syndrome: overproduction of ACTH
*70% caused by pituitary adenome or ectopic ACTH-secreting tumors
- rest are caused by adrenal gland cancers
*obesity and facial rounding
*80-90% treated by surgery, drugs that inhibit cortisol synthesis or ACTH release are used as adjunctive therapy
What is the main glucocorticoid and the main mineralcorticoid in humans and their rate of secretion?
glucocorticoid - cortisol (10mg/day - more in AM than PM)
mineralcorticoid - aldosterone (0.125mg/day)
Effects of corticosteroids
Alterations in carb, protein, and lipid metabolism
Maintenance of fluid & electrolyte balance
Preservation of normal function of cardiovascular, immune, endocrine, and nervous system
Preservation of kidney, and skeletal muscl
*Endow organism with capacity to resist stressful circumstances
Antiinflammatory/immunesuppressive actions of corticosteroids
*provide physiological protective mechanisms
*immune mediates associated with inflammatory response decrease vascular tone and can lead to cardivascular collapse if unopposed by adrenal corticosteroids
- suppress T-cell proliferation
Glucocorticoids required in other hormone mechanisms:
* Lipolysis by adipocytes need lipolytic hormones and cortisol
* Effects of norepinephrine and epinephrine on lipolysis also require glucocorticoids
Several glucocorticoids (??) have modest mineralcorticoid activity
*prednisone and cortisol

*In doses maximally affecting electrolyte balance, aldosterone has no significant glucocorticoid activity
Which is the prodrug?

Cortisol or Cortisone

Prednisone or Prednisolone

Which drug has high antiinflammatory and Na+-retaining activity?
- when used as glucocorticoid, it won't be used as mineralcorticoid and vice versa
Corticosteroid MOA
*intereact with specific receptors to regulate expression of corticosteroid-responsive genes in target tissues
- some actions may be immediate and are mediated by membrane-bound receptors
Glucocorticoid receptor (GR) MOA
*GR resides in cytoplasm in inactive form
*Binding of steroid results in activation and translocation to nucleus
*In nucleus, GR bidns to DNA as dimer in the region called glucocorticoid responsive elements (GREs)
*GR interacts with TFs and proteins of basal transcription apparatus
*Protein-protein interactions with other TFs NF-kappaB and AP-1 are important for GR function
If you knock out the GR in mice, what happens?

If you make GR unable to bind to DNA sequence, what happens?
the mouse dies immediately - receptor is required for life

the mouse is okay - binding is not a necessary step
Mineralcorticoid receptor (MR) MOA
ligand-activated TF and binds to similar hormone responsive element as the GR
*MR interacts with a different set of TFs than GR, thus regulating different genes
True or false: aldosterone and cortisol bind to MR with different affinity?
Falso, they bind with the same affinity.

*Type 2 isozyme of 11beta-hydroxysteroid DH in kidney, colon, and salivary gland metabolize cortisol to cortisone which can't bind MR
- aldosterone escapes this metabolism
Corticoidsteroids effect on carbohydrate and protein metabolism
Diminsh glucose utilization, increase protein breakdown, activate lipolysis, provide amino acids and glycerol for gluconeogenesis
*Net result is increase in blood glucose levels, protecting glucose-dependent tissues from starvation
Mineralcorticoids effect on electrolyte and water balance
*Aldosterone is most potent naturally occurring corticosteroid for fluid and electrolyte balance
*act on distal tubules and collecting ducts of kidney to enhance reabsorption of Na+ from tubular fluid, increase urinary excretion of K+ and H+

*In the gut, steroids interfere with Ca++ uptake; In the kidney, they increase Ca++ secretion
- lead to decreased body Ca++ store
Steroids effect on skeletal muscle and CNS
*Permissive concentrations are required for normal function of muscle

*Exert indirect effects on CNS through maintenance of BP, plasma glucose concentrations, electrolyte concentrations
*Can affect bood and behavior
Steroids effect on cardiovascular system
*HTN results from mineralocortticoid-induced changes in renal Na+ excretion
*Increased atherosclerosis, cerebral hemorrhage, stroke, and hypertensive cardiomyopathy
*Aldosterone induces interstitial cardiac fibrosis
*enhance vascular reactivity to other vasoactive substances
Glucocorticoids effects on antiinflammatory and immunosuppressive actions
*Alter immune response of lymphocytes
*Can revent or suppress inflammation in response to radiant, mechanicall, chemical, infectious, immunological stimuli
* Inhibit production of factors cricial in generating inflammatory response
*decreased release of vasoactive and chemoattractive factors
*inhibit cytokines and prevent the life threatening consequences of full-blown inflammatory response
What % of cortisol in plasma is bound to protein? Reversibly or irreversibly? What proteins bind corticosteroids?
90% is bound reversibly.
*Corticosteroid-binding globulin (CBG) and albumin are proteins that bind
- CBG has high affinity to cortisol and low affinity to aldosterone
Corticosteroids are inactivated where and how?
Reduction of 4,5 double bond by Type II enzyme occurs at both hepatic and extrahepatic sites to yield inactive compounds
- subsequent reduction of 3-ketone occurs only in liver
- conjugation of sulfate or glucuronide occurs in liver or kidney
Why is prednisone 4 times more potent than hydrocortisone?
It has a 2nd double bond across fromt he 4,5 double bond
The liver activates which produrgs and with what enzyme?
Prednisone and cortisone by Type I enzyme
Toxic effects of sudden withdrawal of steroid therapy
*most severe is acute adrenal insufficiency
*fever, myalgias, arthralgias, malaise, nausea, vomiting, HTN
Toxic effects of continued use of supraphysiological doses of corticosteroid
*Fluid and electrolyte aabnormalities, HTN, hyperglycemia, increased susceptibility to infection, osteoporosis, myopathy, behavioral disturbance, cataract, growth arrest, weigth gain around important organs
Therapeutic principles to consider for steroid use
*Consider risks and benefits.
* Dose determined by trial and error
*Single dose or short course is not harmful
*As duration increases past 1 week, there's time- and dose-dependent increase in risks of disabling and potentially lethal effects
*Neither specific nor curative
*Risk of adrenal insufficiency with abrupt cessation
Acute adrenal insufficiency management
*Immediate management includes IV therapy with isotonic sodium chloride solution suplemented with 5% glucose and corticosteroids & appropriate therapy for precipitating causes (infection, trauma, hemorrhage)
*Initial IV bolus 100mg of cortisol and then given by continuous infusion 50-100mg Q8h
- as pt. stabilizes, dose may be decreased to 25mg Q6-8h, thereafter, pts. are treated as chronic adrenal insufficiency
Chronic adrenal insufficiency management
*require daily treatment with cortisol 20-30mg/day
*To mimic diurnal rhythm of cortisol secretion, glucocortiocoids are given in div doses, 2/3 in AM and 1/3 in afternoon
*Most pts require mineralcorticoid: fludrocortisone acetate in 0.05-0.2mg/day
Indicators of improvement of adrenal insufficiency:
disappearance of hyperpigmentation and resolution of electrolyte abnormalaities
Congenital adrenal hyperplasia (CAH)
*A group of genetic disorders in which one of the corticosteroid biosynthesis enzymes is deficient
*increase release of ACTH and/or angitensin II
*In 90% pts, CAH results from mutations in CYP21
*All pts with CAH require susbstitutiont herapy with hydrocortisone or a suitable congener
Mutation of CYP21 cause:
CYP21 is the enzyme that converts progesterone to cortisone, but it cannot occur with the mutation so there is an increased amount of testosterone
Use of glucocorticoids with systemic lupus erthematosus
*Lupus - inflammation of internal organs; "butterfly rash"
*Initial prednisone (1mg/kg/day in div doses) followed by consolidation to single daily dose with subsequent tapering to minimal effective dose
Use of glucocorticoids with rheumatoid arthritis
*Recommended as temporizing agents for diseases that fail to respond to first line therapy
*5-10mg of prednisone per day
*In noninflammatory degenerative joint diseases (osteoarthritis), glucocorticoids may be administered by local injection
Use of glucocorticoids with renal diseases
*Pts with nephrotic syndrome secondary to minimal change disease have glucocorticoid as first line therapy
*Initial daily dose of prednisone 1-2mg/kg for 6 wks, followed by tapering over 6-8 wks
*more than 95% of pts have remission within 3 months
Use of glucocorticoids with allergic disease
*Onset of action is delayed - anaphlactic pts require epinephrine
*Medrol 4-48mg for limited duration allergies
*In severe diseases, IV Medrol 125mg Q6h is appropriate
Uses of glucocorticoids with bronchial asthma
*For less severe, acute exacerbations, pts treated with brief courses of oral glucocorticoids, 30-60mg prednisone QD x5
*For chronic, long-term use of glucocorticoids is used
*In severe asthma attacks w/ hospitalization, parenteral glucocorticoids needed
*Inhaled steroids for children
Top 5 inhalers for asthma & Top 3 nasal sprays for seasonal allergies
Triamcinolone acetate
beclomethasone dipropionate
Flovent HFA (fluticasone propionate)

Flonase (fluticasone)
Nasonex (mometasone)
Nasacort AQ (trimacinolone acetonide)
Use of glucocorticoids for ocular and skin diseases
*Used to suppress eye inflammation
*0.1% dexamethasone sodium phosphate soln, 2gtts Q4h while awake, 0.05% ointment QHS

Eczema: Kenalog (triamcinolone), lotrisone (clotrimazole/betamethasone)
*can't be used longer than 2 wks
Use of glucocorticoids for GI diseases
*indicated for inflammatory bowel disease (chronic ulcerative colitis & Crohn's disease)
*In mild ulcerative colitis, hydrocortisone (100mg) can be given as retention edema
*In sever acute exacerbation, oral prednisone (10-30mg/day) given
Treatment for Cushing's disease (hypercorticism)
Adrenocortical steroid inhibitors
*aminoglutethimide (Cytadren) inhibits P450scc
- production of all classes of steroid hormones inhibited
- also inhibits P450-11beta and aromatase

*Ketoconazole (Nizoral) - antifungal agent
- inhibits adrenal and gonadal steroidgenesis at higher doses
- Most efefctive inhibitor in Cushing's***
- 600-800mg/day in 2 div doses

*mifepristone (RU486) - progesterone receptor antagonist inhibits GR at higher doses
- blocks feedback regulation of HPA axis and increases ACTH and cortisol levels