hormonal therapy of prostate cancer
TRANSCRIPT
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Hormonal Therapy forProstate Cancer
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• Prostatic epithelium undergoes atrophyafter castration
• Huggin’s hypothesis Benign prostaticepithelium and prostate ca werebiochemically analogous and they wouldrespond in a similar fashion to androgenablation.
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Androgen Deprivation Therapy (ADT)
• All current forms of androgen deprivation therapy (ADT) Reducing the ability of androgen to activate the ARthroughlowering levels of androgen or by blocking AR binding.
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MECHANISMS OF ANDROGENAXIS BLOCKADE
Approaches for androgen axis:
(1) Ablation of androgen sources,
(2) Inhibiting androgen synthesis,
(3) Antiandrogens
(4) Inhibition of LH-RH and/or LH release
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Ablation of Androgen Sources
• Surgical castration: Bilateral orchiectomyreduces circulating testosterone levels to < 50 ng/dL In 24 hours testosterone reduced by >90%
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• Antiandrogen
• Direct AR blocking effects
• By blocking the testosterone feedback centrally the nonsteroidal antiandrogenscause LH and testosterone levels to increaseThis allows antiandrogen activity without inducing hypogonadism
• Bicalutamide monotherapy appears to have equivalent efficacy to surgical castration
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Inhibition of LH-RH
LH-RH Agonists
• The LH-RH agonists exploit the desensitization of LH-RH receptorsin the anterior pituitary after chronic exposure to LH-RH, thereby shutting down the production of LH and testosterone.
• The initial exposure to more potent agonists of LH-RH results in a flare of LH and testosterone levelsThecoadministration of an antiandrogen functionally blocks the increased levels of testosterone.
• Survival after therapy with an LH-RH agonist was equivalent to that of orchiectomy
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Inhibition of Androgen Synthesis
• Ketoconazole interferes with two cytochrome P450–dependent pathwaysconversion lanosterol to cholesterol is blocked Demonstrated loss of adrenal steroid synthesis and testosterone synthesis
• The effects testosterone levels dropping to the castrate level within 4 hours of administration
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General Complication of Androgen Ablation
• Osteoporosis
• Hot Flashes
• Sexual Dysfunction
• Declines of Cognitive Function
• Increase of fat body mass and loss of muscle mass
• Increase of Diabetes and metabolic syndrome risks
• Cardiovascular morbidity and mortality
• Gynecomastia and mastodynia
• Anemia
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PSA and Posititivity of Bone Scan
• The bone scan positivity rate was 2.3%, 5.3%, 16.2%, 39.2% and 73.4% for PSA levels of 0-9.9, 10-19.9, 20-49.9, 50-99.9 and > 100ng/mL, respectively*
*Abuzallouf S, Dayes I, Lukka H. Baseline staging of newly diagnosed prostate cancer: a summary ofthe literature. J Urol 2004 Jun;171(6 Pt 1):2122-7. http://www.ncbi.nlm.nih.gov/pubmed/15126770
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