Promoting Synthesis and Growth

Opposite of catabolism

• Most potent adrogen secreted is testosteron
• 50X greater in adults than in prepubescent children
• Levels in Adult Males:
• ~0.6 mg/ml
• 95% from testes (Leydig cells)
• 5% from adrenal cortex
• Levels in Adult Female:
• ~0.03 mg/ml
• Synthesis in adrenal cortex and ovaries 40-65%
• Peripheral conversion of DHEA 35-60%
• Synthesis is derived from cholesterol
• Difference between androgens/MCC/GCC is minor oxidation points
• Minor chemical differences = major effects in vivo

• Release of GnRH from the hypothalamus causes release of LH/FSH from the pituirary
• LH/FSH cause testosterone to be synthesized
• Peripheral testosterone has a negative feedback loop on GnRH, LH, FSH release
• Luteinizing hormone (LH) release from pituitary
• Prior to puberty testosterone is low
• At puberty LH secretion increases  and stimulates the production of testosterone
• Required for spermatogenesis
• Follicle Stimulating Hormone (FSH)
• FHS binds to sertole cell receptors
• Stimulates spermatogenesis
• Spermatogenesis is maintained by testosterone once FHS stimulus is applied  

Role of Dihydrotestosterone

DHT

• Testosterone serves predominantly as a pro-hormone
• Many tissues contain 5-α-reductase activity
• DTH is the active moiety in many tissues
• Cystolic receptor exhibits higher (10X) affinity for DTH than testosterone
• DTH receptor complex is more readily transported to the nucleus
• DTH is necessary for differentiation of the male accessory ducts and external genitalia
• Deficiency is associated with lack of development of male genitalia
• Testosterone not DHT is the active steroid in hypothalamus (feedback inhibition of GnRH) and pituitary (feedback inhibition of LH/FSH)

• Liver
• Stimulation or supression of protein synthesis
• Kidney
• Stimulation of erythropoietin, indirectly increases hepatopiesis
• Hematopoietic System
• Growth of stem cells
• CNS
• Facilitation of libido and sexual function
• Aggresive behavior
• Muscle
• Development of muscle mass and strength
• Skin, sebasceous gland, hair
• Stimulation of beard, axillary, and pubic hair growth
• Increase in Temporal hair recession and balding
• Increase in sebum secretion
• Bone/Cartilage
• Promotion of epiphyseal function
• Maintaince of bone mass
• Larynx and vocal cords
• Enlargement of larynx and thickening of vocal cords
• Mammary Glands
• Development of gynecomastia
• Affected by Androgen:Estrogen ratio

• Testosterone proper is a poor drug
• Exhibits a high first pass effect (oral)
• Injected testosterone is rapidly abs and metabolized
• Has mixed anabolic and androgenic effects
• Type B Testosterone: Methyltestosterone  
• 17α substitution
• Orally active
• NOT metabolized to testosterone proper
• Can cause liver toxicity and cancer with high prolonged dosing
• Type C: Mesterolone
• Ring Alteration
• Orally active
• NOT metabolized to Testerone proper
• Can cause liver toxicity and cancer with high prologned dosin
• Type A: Enanthate or cypionate
• Abs is greatly delayed
• Injected weekly or monthly
• Metabolized to testosterone
• Most preparations involve combos of Type AC or BC changes
• All oral and parenteral preparations exhibit both androgenic and anabolic effects

• Testosterone Esters- 17 β esterification
• Propionate
• Cypionate
• Enanthate
• Undecanoate  

17α substitution

Methyltestosterone

1:1 Andrgoenic to Anabolic ratio

Ring Alteration

Mesterolone

• Nortestosterone Esters
• R = Phenylpropionate
• R = Decanoate
•  Methenolone
• R = Acetate
• R = Enanthate

• Fluoxymesterone
• 1:1-2  Androgenic to Anabolic ratio
• Norethandrolone (ethynortestosterone)
• Methandrostenolone
• 1:3 Androgenic to Anabolic Ratio
• Danazol

Oxymetholone 1:3 Androgenic to Anabolic ratio

Stanozolol 1:3-5 Androgenic to Anabolic ratio

Oxandrolone 1:3-13 Androgenic to Anabolic ratio

• Primary Hypogonadism
• Testosterone: Low
• LH: High
• FSH High
• Sperm Count: Low
• LH and FSH response to GnRH: Normal
• Seminiferous tubule disease
• Testosterone: Normal
• LH: Normal
• FSH High
• Sperm Count: Low
• LH and FSH response to GnRH: Not Done
• Leydig Cell Failure:
• Testosterone: Low
• LH: High
• FSH: Normal
• Sperm Count: Low
• LH and FSH response to GnRH: Not Done
• Pituitary Disease:
• Testosterone: Low
• LH: Low
• FSH Low
• Sperm Count: Low
• LH and FSH response to GnRH: Low
• Hypothalamic Disease
• Testosterone: Low
• LH: Low
• FSH: Low
• Sperm Count: Low
• LH and FSH response to GnRH: Normal   

• Number of genetic/chromosomal causes
• Klinefelters
• Direct damage to the Leydig cells or seminiferous tubules
• Testosterone levels low but gonadotropin levels are high
• Long acting testosterone ester is DOC
•  Enanthate or Cypionate
• Testosterone is measured and titrated into normal range
• Normal events of puberty develop

• Testicular atrophy due to lack of gonadotropins
• Prader-Willi syndrome
• May be due to lack of LH/FSH (hypopituitarism)
• 2º due to a lack of GnRH (hypothalamus)
• Testosterone and gonadotropin levels are low
• Treat underlying hypogonadism if possible
• Gonadotropins have been used
•  Androgens not added until time of normal puberty
• Slowly increased to mimic surge of testosterone

• Androgens stimulate RBC development
• Indirect effect
• Stimulate synthesis of erythropoietin
• Direct effect
• Recruitment of stem cells for RBC production
• Large Pharmacological doses are required
• Useful in treating various anemias
• Effects are greater in females than males
• Large doses required cause androgenic side effects
• All androgens are active
• Contraindicated in aplastic anema
• Causes hepatocellular carcinoma
• Colony stimulating factor should be used instead

• Lack of an active inhibitor of the first component of compliment
• Complement cascade always "on"
• Blood vessel permeability increases
• Painful submucosal swelling develops
• Androgens increase the hepatic synthesis of the active inhibitor
• 17-α-alkylated (Danazol)
• Men and women respond equally  

• Androgens do produce a growth spurt
• Cause epiphyseal calcification
• Growth spurt is limited and treatment is questionable  

• Associated with anti-inflammatory steroid use
• Positive nitrogen balance in hypogonadal individuals  

• Abuse not use
• Questionable effects in males with normal gonadal function
• Increase in muscle mass may be increased aggressiveness
• Leading to greater training limit
• Increased muscle mass is seen in well trained athlete
•  Not seen in normal male 
• More beneficial effect in in females
• Due to decreased amount needed
• Double blind studies yield both positive and negative results

• Androgen production in males drops off sharply after 55
• "Male menopause"
• Subsequent decrease in muscle mass, strength, libifo
• Low androgen doses have shown some benifical effects 

Side Effects of High Androgen Levels

Endogenous or Exogenous

• Virilizing effects (adolescent males and females)
• Acne
• Hitsuitism
• Male Pattern Baldness
• Coarsening of the voice
•  Inhibition of spermatogenesis
• Plasma LH and FSH are decreased (testicular volume decreaes)
• Sperm production is decreased
• Plasma testosterone decreases (not with the 17 β esters)
• May persist for long periods of time after drug discontinuation
• Feminizing side effects
• Testosterone is convereted to an estrogen by an aromatse enzyme (mostly in liver)
• Estradiol concentration 7-fold higher in athletes abusing androgens
• Gynecomastia is MC side effect
• Hepatic abnormalities (cholestatic hepatitis, hepatic adenocarcinoma)
• Changes in lipoprotein profiles (decreases HDL and increases LDL)
• Increase in aggressive behavior ("roid rage") can cause psychotic symptoms

• Some situations where production is (could be) supressed
• Male pattern baldness
• Virilizing syndromes in women (hirsutism)
• Acne (puberty)
• Hyperplasia and carcinoma of the prostate
• Male Contraception
• Orchiectomy-not preferable
• High levels of estrogen to supress androgens
• Not preferable
• Antiandrogens focus on various sites of androgen pathway
• Androgen supression
• Inhibitors of androgen synthesis
• 5α-reductase inhibitors
• Androgen receptor antagonists

• Long acting GnRH analogs
• Pulsatile GnRH signals increase LH/FSH production
• Continuous levels actually has inhibitory effects
•  Leuprolide acetate and Goserelin are drugs used
• Testosterone levels can fall to 10% of normal but there is an initial flare
• Often administered in combination with receptor antagonists
• GnRH antagonists
• Would have inhibitory effect without initial flare
• While some compound effects, iatrogenic effects limit use
• Further research is required

Inhibitors of androgen synthesis

Ketoconazole

• Blocks many steriod synthesis P450s  
• Requires high doses (400-800 mg/d)
• May cause gynecomastia in males
• Increases estrogen:testosterone in males
• Has been tried for prostate cancer- not very promising

5α-reductase inhibitor

Finasteride

• DHT active hormone is most tissues
• Effective in benign prostate hyperplasia
• Blocks hirsutism in women (off label use)  

Androgen receptor antagonists

Cyproterone Acetate

and

Flutamide

• Block effect of androgens on target tissue
• Effective for excess androgen production in women
• Effective for advanced prostate carcinoma
• Often coupled with GnRH agonists (Leuprolide acetate) 

Male Contraception

"Holy Grail" Antiandrogens!

• Testosterone inhibition alone would cause too many side effects
• Combined therapies
• GnRH supression and Testosterone  
• Gossypol
• Phenolic extract of cottonseed
• Destroys elements of semiferous epithelium resulting in impaired spermatogenisis
• Does not effect endocrine function
• Reversible upon discontinuation
• If sperm count does not fall too low
• Also directly decreases sperm motility
• Tried as intravaginal contraceptive