INTRODUCTION
Serum testosterone is the main serum androgen and stimulates the in utero differentiation of the Wolffian duct into male internal genitalia and the pubertal development of libido, enlargement of vocal cords, skeletal muscles, and external genitalia, and the initiation of spermatogenesis.1 In target organs, testosterone is reduced to dihydrotestosterone (DHT) by 5α-reductase (5α-R) isozymes (Figure 1).2
Three 5α-R isozymes have been discovered and are ubiquitously expressed in human tissues.3,4 5α-R type 1 (5α;-R1) is expressed mainly in skin, hair follicles (hair bulbs, fibrous and outer epithelial root sheaths), sebaceous glands, and the liver. 5α-R type 2 (5α-R2) is expressed mainly in the prostate, but is also expressed in the inner epithelial root sheath of hair follicles and skin. 5α-R1 and 5α-R2 are mainly involved in the 5α-reduction of steroids.1 5α-R type 3 (5α-R3) is expressed mainly in the liver, kidney, prostate, and skin,4 and is responsible for N-linked glycosylation of nascent proteins.5
DHT is the main intracellular androgen since it is the preferred ligand for androgen receptor (AR) transactivation. It has 2 to 5 times higher binding affinity for AR than testosterone, and a 10-fold higher potency of inducing AR signaling than testosterone.6 DHT is important for in utero differentiation and growth of the prostate gland, external genitalia, and pubertal growth of facial and body hair. It also plays an important role in several human diseases, which include benign prostate hyperplasia (BPH), prostate cancer (CaP), and the androgen-stimulated skin disorders (ASSDs): acne, hirsutism, and androgenic alopecia (AGA).
The discovery of 5α-R2 deficiency sheds light on the role of DHT in human physiology.7 Affected males are born with normal internal but ambiguous external genitalia. At puberty, these individuals undergo partial virilization of the external genitalia, but their secondary sexual hair remains sparse. They develop less AGA and acne despite normal sebum production. Discovery of 5α-R2 deficiency sparked interest in the development of drugs to inhibit 5α-R isozymes for use in the treatment of ASSD, BPH, and CaP.
5α-Reductase Inhibitors8
Numerous compounds, steroidal and nonsteroidal, with different mechanisms of 5α-R inhibition have been developed: 4-azasteroids are 3-keto, 5α-steroids with a nitrogen atom at position 4, and are the most extensively studied 5α-R inhibitors. Two 5α-R inhibitors are approved for human use: finasteride and dutasteride (Table 1).
Finasteride is a potent competitive inhibitor of 5α-R2 but inhibits less effectively 5α-R1. Finasteride 1 mg and 5 mg daily decreased mean serum DHT by 71% and 72%, respectively, after 6 weeks of use.9 Scalp biopsies after 6 weeks of daily finasteride 0.2 mg and 1 mg revealed decreased scalp DHT by 57% and 64%, respectively.9 Finasteride has a half-life of 6 to 8 hours and is approved by the US Food and Drug Administration (FDA) for the treatment of BPH and male AGA at daily doses of 5 mg and 1 mg, respectively.
Dutasteride has a half-life of nearly 5 weeks and is approved only for the treatment of BPH. Dutasteride is 3 times more potent than finasteride at inhibiting 5α-R2 and more than 100
