Observations from studies in eunuchs who have low levels of testicular androgens, and males with genetic 5 alpha -reductase deficiency, who have low levels of dihydrotestosterone (DHT), implicate DHT as a key androgen in the pathogenesis of male pattern hair loss in men. The microsomal enzyme steroid 5 alpha -reductase is responsible for the formation of potent DHT from testosterone as well as for the conversion of androstenedione to 5 alpha -androstanedione. This enzyme that mediates the reduction of Testosterone to DHT via the reduced cofactors (e.g., Nicotinamide adenine dinucleotide phosphate NADPH) is not unique to androgen-sensitive tissue but is an inherent property of skin fibroblasts and hair.
5 alpha – reductase is highest in the dermal papillae, the primary site of the androgen receptor, and higher in androgen-dependent as opposed to androgen-independent, sites. Studies using both plucked hairs and scalp biopsies have demonstrated that 5 alpha -reduced metabolites of testosterone are increased in balding areas of the human scalp as well as in the scalp of the stump-tailed macaques.
Two 5 alpha – reductase genes have been identified that encode type 1 and type 2 isozymes of this protein. Both isozymes are capable of producing DHT from testosterone, but they have different biochemical and pharmacologic properties as well as distinct cell typing and tissue-specific expression patterns.
- 5 alpha – reductase – 1 (5 alpha R-l) has a broad pH optimum centered at pH 7.0, and a Km for testosterone that is twenty-five times that of 5 alpha -Reductase -2. The location of the gene for 5 alpha R-l is on chromosome 5 alpha. 5 alpha R-l has been observed to be more ubiquitously located in the skin, including the scalp. In the hair follicle, 5 alpha R-l appears to primarily concentrate in the sebaceous gland, but has been noted in other parts of the hair follicle including the dermal papillae.
- 5 alpha – reductase -2 (5 alpha R-2) has a pH of 5 alpha.5 alpha and the location of the gene for 5 alpha R-2 is on chromosome 2. Several authors have said that 5 alpha R-2 has been noted in the outer root sheath, inner root sheath, dermal papillae, and dermal fibroblasts.
Women also show increased 5 alpha -reductase activities in balding as compared to nonbalding scalps, but have much lower levels than those seen in men. Studies by Itami and colleagues have also shown that some of the differential response of hair to androgens may be secondary to differences in type or amount of 5 alpha -reductase.
Follicles of axillary hair appear to possess mainly 5 alpha R-l, whereas beard follicles have primarily 5 alpha R-2. This is probably why 5 alpha R-2-deficient patients show scanty beard growth but normal axillary growth at puberty. Studies indicate that 5 alpha R-2 has been found to be higher in androgenetic alopecia follicles than normal controls without any similar differential expression by 5 alpha – reductase. Thus, the regional differences in hair growth could be related to local differences in 5 alpha -reductase.
5 alpha – reductase deficiency is a rare autosomal recessive trait that was first described by Nowakowski and Lenz. Both young women and young men with pattern hair loss have higher levels of 5 alpha – reductase and androgen receptor in frontal hair follicles compared to occipital follicles. In conjunction with the observation that both humans and stump-tailed macaques have beard and frontal scalp hair follicles with higher 5 alpha -reductase activity than hair follicles from the occiput, this implicates the involvement of 5 alpha – reductase -2 in the pathogenesis of androgen-dependent hair growth. The inhibition of this isoenzyme is therefore a rational approach for treatment of androgenetic alopecia.