Hormonal Therapy forProstate Cancer

• Prostatic epithelium undergoes atrophyafter castration

• Huggin’s hypothesis Benign prostaticepithelium and prostate ca werebiochemically analogous and they wouldrespond in a similar fashion to androgenablation.

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.

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

Ablation of Androgen Sources

• Surgical castration: Bilateral orchiectomyreduces circulating testosterone levels to < 50 ng/dL In 24 hours testosterone reduced by >90%

• 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

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

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

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

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