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Androgenetic alopecia is a genetically determined disorder that is progressive. It occurs through the gradual conversion of terminal hairs into indeterminate hairs and finally to vellus hairs. Following miniaturization of the follicles, fibrous tracts remain. Patients with this disorder usually have a typical distribution of hair loss. As of the moment, the predisposing genes are not yet known. Moreover, the explanation for the paradoxical relation between the molecular steps involved in androgen-dependent beard growth and androgen-dependent scalp hair loss is still insufficient.

5-alpha-reductase

Dihydrotestosterone is implicated as the key androgen in the pathogenesis of male pattern hair loss or balding. This was concluded after studies on castrated men who have low levels of testicular androgens. The same observation was found in males with genetic 5-alpha reductase deficiency.

This enzyme 5-alpha-reductase is responsible for the formation of potent DHT as a by-product of testosterone conversion. The same enzyme is responsible for the conversion of the endogenous steroid androstenedione into 5-alpha-androstanedione. The enzyme’s action is, however, not unique to androgen-sensitive tissues but is rather declared as an inherent property of skin fibroblasts and hair.

The highest concentration of 5-alpha-reductase can be found in the dermal papillae; this is the primary site of the androgen receptor. The level of 5-alpha-reductase is even higher in androgen-dependent, as opposed to androgen-independent, sites. Studies utilizing both plucked hairs and scalp biopsies have shown 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.

The 5-alpha-reductase enzyme has proved difficult to isolate biochemically, but recently at least two human isoenzymes have been identified using molecular biological methods. They are active in different regions of the body, but they both produce DHT that can circulate throughout the body and exert effects in organs other than that where the DHT was produced.

For now, the two are called type 1 and type 2 isoenzymes.

  • 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. 5-alpha reductase is mapped on chromosome 5. It active in different parts of the body but is prominently seen in the skin particularly the scalp. In the hair follicle, isoenzyme appears to primarily concentrate in the sebaceous gland, but has been observed in the different parts of the hair follicle, especially the dermal papillae area.
  • 5-alpha-reductase-2 (5-alpha-R-2) has a lower pH compared to the previous type, registering only 5.5. Its gene location can be found on chromosome 2. It is interesting to note that some researchers stated that this isoenzyme can be found in the outer root sheath, inner root sheath, dermal papillae, and dermal fibroblasts.

Women are not spared of this condition, and although much lower than in their male counterparts, the women show increased 5-alpha-reductase activities in balding as compared to nonbalding scalps. Studies conducted by Itami and colleagues show that there is some degree of differential response of hair to androgens. These responses may be secondary to the differences in type or amount of 5-alpha-reductase found in that particular area.

The two identified isoenzymes can affect or influence the appearance of hair follicles. For instance, the follicles of axillary hair appear to possess mainly 5-alpha-R-l, unlike the follicles of the beard, which primarily have 5-alpha-R-2. This is probably the reason why patients with 5-alpha-R-2-deficiency disorder show a limited beard growth but can experience normal axillary growth during puberty. Differences of hair growth could be related to the differences of the 5-alpha-reductase in the tissues. Studies indicate that the 5-alpha-R-2 is higher in pattern baldness follicles compared to normal controls without any similar differential expression by 5-alpha-reductase.

5-alpha-reductase deficiency is a rare autosomal recessive trait that was first described by Nowakowski and Lenz. Both sexes can be affected. The frontal hair follicles of young women and young men with pattern hair loss have higher levels of 5-alpha-reductase and androgen receptor. This observation is not only limited to humans—this is also found in stump-tailed macaques. This implicates the involvement of 5-alpha-reductase-2 in the pathogenesis of androgen-dependent hair growth. The inhibition of this isoenzyme is therefore considered as a rational management and treatment for people with pattern baldness.

Aromatase

With recent medical advances made in hair biology, it is evident that there are many more steroidogenic enzymes complexes involved in the onset and development of pattern hair loss. Not all women with female pattern hair loss experience high levels of serum androgens or even respond to 5-alpha-Reductase inhibitor drugs. Androgens, because of the possibility of conversion into estrogens, indirectly affect the estrogen receptor-estrogen binding. Researchers have concluded that it is important to explore the role of estrogens as another potential factor in pattern hair loss.

Aromatase (CYP19), a cytochrome P450, is an enzyme involved in the production of estrogen that acts by catalyzing the conversion of testosterone (an androgen) to estradiol (an estrogen). It acts by desaturating a ring of testosterone. The enzymes are found in the endoplastic reticulum of estrogen-producing cells in the adrenal glands, ovaries (only for women), placenta, testicular sertoli (only for men), adipose (fat) tissue, and brain tissues. In theory, these chemical conversions may diminish the amount of intrafollicular testosterone available that is used for conversion to DHT.

The Cytochrome P-450 aromatase in frontal follicles of young women are higher compared to their male counterparts, and hair biologists believe the female scalp may have two to five-fold greater amounts of aromatase against the male scalp. Women have half the amount of 5-alpha-reductase compared to men, but have higher levels of the enzyme aromatase, especially at their frontal hairline. Aromatase is responsible for the formation of the female hormones estrone and estradiol. It also decreases the formation of DHT. Its presence in women may help to explain why the presentation of female hair loss differs from male hair loss, particularly with respect to the preservation of the frontal hairline. This leads researchers to think that aromatase causes such effects on hair pattern loss.

Studies were conducted to measure aromatase activity in isolated intact human occipital hair in order to unravel and explain the pathways of estradiol-mediated effects on the hair follicles. The follicles studied underwent incubation. It was found that Aromatase active mainly within the root sheaths of the hair follicle. However, some cells of the stalk region of the dermal papilla contained aromatase.

The autosomal gene encoding aromatase CYP19 was studied in cases and controls, but no differences were detected. This leads researchers to assume that it is unlikely that the aromatase gene is involved in causing any pre-disposition to alopecia. The estrogen’s role that came from the catalysis of aromatase is unclear. It is unknown whether the estrogens are responsible for suppressing the severity of hair loss, or whether aromatase is primarily reducing the overall load of androgens formed locally in the hair follicle. The role of estrogen in female pattern hair loss still eludes researchers.

 
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