Hudak et al with 5 alpha-reductase (5AR) inhibitors may play a role in accomplishing some of these goals. The results from the Prostate Cancer Prevention Trial (PCPT) have sparked interest in the various roles of 5AR inhibitors in the management of prostate cancer. In this review, we examine the pharmacology of 5AR inhibitors and how this class of agents relate to the pathophysiology of prostate cancer as well as their role in prevention and treatment of prostate cancer. Androgens and prostate cancer The physiologic functions and pathologic conditions of the prostate, like all other endocrine glands, are regulated by numerous endogenous hormones and growth factors. Testosterone is the predominant circulating androgen in males. It is a steroid hormone, synthesized from cholesterol in Leydig cells within the interstitium of the testis. Its production is stimulated by luteinizing hormone (LH), secreted by the anterior pituitary gland in response to the cyclic release of luteinizing hormone releasing hormone (LHRH) by the hypothalamus. LHRH release, in a negative feedback fashion, is inhibited by testosterone. Greater than 95% of endogenous androgen is produced by the testis, with the remainder produced as androstendione by the adrenal cortex. This small amount of nontesticular androgen has a minimal impact on prostate function in physiologically normal males (Partin and Rodriguez 2002). Testosterone is taken up from the systemic circulation by the prostatic glandular and stromal cells. Once within the prostate, testosterone is rapidly and irreversibly converted to dihydrotestosterone (DHT) by the enzyme 5AR. This leads to a ﬁve-fold higher concentration of DHT versus testosterone within the intracellular prostate, versus an eleven-fold higher concentration of testosterone within the circulation. DHT then binds to the androgen receptor within the cytosol, is actively transported into the nucleus, and serves as a transcription factor for prostatic gene expression and thus prostatic cellular function. The higher concentration of intracellular DHT, in addition to its higher afﬁnity for the androgen receptor, support the importance of 5AR in normal and pathologic prostate physiology (Partin and Rodriguez 2002). In 1974, both Walsh and Imperato-McGinley described the deficiency of 5AR as an inheritable form of pseudohermaphroditism (Imperato-McGinley et al 1974; Walsh et al 1974). Affected individuals known locally as “guevedoces”, literally “penis at 12 years of age”, were originally discovered in a remote village in the Dominican 426 Republic where this enzyme deficiency was highly prevalent. Clinical manifestations of this disorder include the presence of ambiguous genitalia, undescended testicles, a blind vaginal pouch, a small clitoris-like phallus and absence of all internal female reproductive structures. At puberty, the phenotype of these individuals changes to a more normal male pattern manifested by development of a functional penis, deepening of the voice, muscle development, etc. However, adult males with this condition have a diminutive prostate and lack male pattern baldness, facial hair, and acne (Imperato-McGinley et al 1974). Subsequent clinical evaluation of affected individuals with magnetic resonance imaging, trans-rectal ultrasound and prostate biopsy conﬁrmed presence of a small, atrophic prostate. PSA was undetectable and affected individuals developed neither benign prostatic hyperplasia (BPH) nor prostate cancer (Imperato-McGinley et al 1992). Identiﬁcation of individuals with congenital deﬁciency of 5AR has served as a naturally occurring model ultimately leading to the development of a pharmacologic inhibitor of 5AR. Finasteride is an orally active, competitive inhibitor of the nicotinamide adenine dinucleotide phosphate, reduced form (NADPH)-dependent 5AR enzyme’s type 2 isozyme. Despite its steroid structure, it has no afﬁnity for any steroid receptors, including androgens, estrogens, and progesterone (Stoner 1992), allowing the inhibition of 5AR without concomitant binding at other physiologic locales. Guided by early animal models (Brooks et al 1981, 1982; Wenderoth et al 1983), several investigators described the ability of ﬁnasteride to suppress serum DHT to approximately 70% of baseline levels in male humans (Rittmaster et al 1989; Stoner 1990, 1992; Gormley et al 1992). Since that time, several large scale clinical trials have demonstrated the efﬁcacy of ﬁnasteride in the medical management of BPH (Rittmaster et al 1989; Gormley et al 1992; Stoner 1992; McConnell et al 1998, 2003) and in the prevention of prostate cancer (Thompson et al 2003). In the 1990s, dutasteride was identiﬁed as an inhibitor of both isozymes (type 1 and type 2) of 5AR. Nonselective inhibition of both 5AR isozymes produces more than a 90% reduction in serum DHT (Bramson et al 1997). While type 2 5AR is the predominant isozyme within the prostate, its inhibition by ﬁnasteride may lead to up regulation of type 1 5AR at extraprostatic sites (ie, liver and skin) with resultant paracrine effects (elevated serum DHT) on the prostate (Bramson et al 1997). Additionally, dutasteride has a signiﬁcantly longer half life (~180 hours) than ﬁnasteride (5–8 hours) (Steiner 1996; Bramson et al 1997). The clinical Clinical Interventions in Aging 2006:1(4)