Role of Androgen and Androgen Receptors in Skin Related Disorders
Marwa Ehsan Abd El-Hamid Amin;
Abstract
SUMMARY
A
ndrogens are well known to control the development and functions of the reproductive system in both male and female. The major circulating androgen is testosterone, which is mainly produced by Leydig cells in the male testis; while adrenal glands are also capable of secreting testosterone, but at a much lesser degree.
Testosterone can be metabolized by 5α-reductases into a more potent androgen, 5α- DHT. Both testosterone and DHT can bind to AR, but DHT has ten-fold higher affinity to AR compared to testosterone. While skin is not the major source of androgen synthesis, in sebocytes, sweat glands, and dermal papilla cells, the circulating androgenic pro-hormones, DHEA and androstenedione, can be converted into testosterone and DHT. These potent androgens subsequently regulate dermal physiology through intracrine or paracrine manners.
Androgen receptor belongs to the nuclear receptor superfamily and contains a ligand-binding domain, a DNA-binding domain, and a N-terminal regulatory domain. Upon binding to its ligand (i.e. DHT or testosterone), AR translocates from the cytosol into the nucleus and serves as a transcriptional factor to regulate the expression of its target genes. In addition to androgen-dependent activation, AR function can also be modulated by interaction with various coregulators through binding the AR N-terminal domain or ligand-binding domain.
Acne vulgaris is a multifaceted condition involving keratinization, androgens, sebum production, infections, and genetics. Androgen receptors have been detected in the epithelial cells of sebaceous glands by immunohistochemistry and biochemical binding assays.
There are several possibilities to explain the relation between acne and androgen. First, suppression of an individual type of 5α-reductase might not be sufficient to completely block DHT synthesis due to the redundancy between different types of 5α-reductase, and the sebaceous glands might be sensitive to even tiny amounts of DHT. Second, the newly found type III 5α-reductase might play a more important role in regulating sebum production. Third, in addition to the difference in their potency, testosterone and DHT do not act the same way on AR activation, suggesting that testosterone, rather than DHT, could be a more important regulator in sebum production. Additionally, the participation of AR coregulators might compensate for the deficit in DHT production.
Androgens, which normally stimulate terminal hair production in many sites of the body (e.g. the beard and the axillary regions), exert an opposite effect to suppress hair growth on genetically predisposed frontal and vertex scalp. In the hair follicle, the circulating male hormone, testosterone, is converted by 5α-reductase enzyme into DHT. The dehydro-testosterone level is increased in balding scalp and thus is the more relevant androgen for AGA pathogenesis. The role of AR in AGA disorder has been supported by: (i) no balding is seen in individuals lacking a functional AR (for example, in patients with androgen insensitivity syndrome); and (ii) AR expression in the scalp of AGA patients is site specific–elevated in the frontal and vertex regions but normal in the parietal and occipital regions.
Overproduction of androgens or increased sensitivity of hair follicles to androgens has been the common cause of hirsutism in females. There are two major paths for treating hirsutism. The first is cosmetic treatment, which includes plucking, shaving, waxing, and laser removal of unwanted hairs. The second is hormonal treatment that usually comes in forms of antiandrogens or AR blockers. While these antiandrogen treatments may have adverse side effects in men, the side effects for women who have hirsutism may be averted through a variety of ways, making these the preferred treatment methods. Because hair growth is a very slow cyclical process, it may take several months for drug effects to appear.
The prolonged, markedly elevated, insulin levels, which are associated with resistance and decreased sensitivity, may stimulate the ovary to generate androgens. It is theorized that these high levels of insulin cross-react with insulin-like growth factors, therefore, directly stimulating the overproduction of ovarian androgens. This gives rise to the hyperandrogenism associated with HAIR-AN.
A
ndrogens are well known to control the development and functions of the reproductive system in both male and female. The major circulating androgen is testosterone, which is mainly produced by Leydig cells in the male testis; while adrenal glands are also capable of secreting testosterone, but at a much lesser degree.
Testosterone can be metabolized by 5α-reductases into a more potent androgen, 5α- DHT. Both testosterone and DHT can bind to AR, but DHT has ten-fold higher affinity to AR compared to testosterone. While skin is not the major source of androgen synthesis, in sebocytes, sweat glands, and dermal papilla cells, the circulating androgenic pro-hormones, DHEA and androstenedione, can be converted into testosterone and DHT. These potent androgens subsequently regulate dermal physiology through intracrine or paracrine manners.
Androgen receptor belongs to the nuclear receptor superfamily and contains a ligand-binding domain, a DNA-binding domain, and a N-terminal regulatory domain. Upon binding to its ligand (i.e. DHT or testosterone), AR translocates from the cytosol into the nucleus and serves as a transcriptional factor to regulate the expression of its target genes. In addition to androgen-dependent activation, AR function can also be modulated by interaction with various coregulators through binding the AR N-terminal domain or ligand-binding domain.
Acne vulgaris is a multifaceted condition involving keratinization, androgens, sebum production, infections, and genetics. Androgen receptors have been detected in the epithelial cells of sebaceous glands by immunohistochemistry and biochemical binding assays.
There are several possibilities to explain the relation between acne and androgen. First, suppression of an individual type of 5α-reductase might not be sufficient to completely block DHT synthesis due to the redundancy between different types of 5α-reductase, and the sebaceous glands might be sensitive to even tiny amounts of DHT. Second, the newly found type III 5α-reductase might play a more important role in regulating sebum production. Third, in addition to the difference in their potency, testosterone and DHT do not act the same way on AR activation, suggesting that testosterone, rather than DHT, could be a more important regulator in sebum production. Additionally, the participation of AR coregulators might compensate for the deficit in DHT production.
Androgens, which normally stimulate terminal hair production in many sites of the body (e.g. the beard and the axillary regions), exert an opposite effect to suppress hair growth on genetically predisposed frontal and vertex scalp. In the hair follicle, the circulating male hormone, testosterone, is converted by 5α-reductase enzyme into DHT. The dehydro-testosterone level is increased in balding scalp and thus is the more relevant androgen for AGA pathogenesis. The role of AR in AGA disorder has been supported by: (i) no balding is seen in individuals lacking a functional AR (for example, in patients with androgen insensitivity syndrome); and (ii) AR expression in the scalp of AGA patients is site specific–elevated in the frontal and vertex regions but normal in the parietal and occipital regions.
Overproduction of androgens or increased sensitivity of hair follicles to androgens has been the common cause of hirsutism in females. There are two major paths for treating hirsutism. The first is cosmetic treatment, which includes plucking, shaving, waxing, and laser removal of unwanted hairs. The second is hormonal treatment that usually comes in forms of antiandrogens or AR blockers. While these antiandrogen treatments may have adverse side effects in men, the side effects for women who have hirsutism may be averted through a variety of ways, making these the preferred treatment methods. Because hair growth is a very slow cyclical process, it may take several months for drug effects to appear.
The prolonged, markedly elevated, insulin levels, which are associated with resistance and decreased sensitivity, may stimulate the ovary to generate androgens. It is theorized that these high levels of insulin cross-react with insulin-like growth factors, therefore, directly stimulating the overproduction of ovarian androgens. This gives rise to the hyperandrogenism associated with HAIR-AN.
Other data
| Title | Role of Androgen and Androgen Receptors in Skin Related Disorders | Other Titles | دور هرمون الأندروجين ومستقبلات الأندروجين في الأمراض الجلدية | Authors | Marwa Ehsan Abd El-Hamid Amin | Issue Date | 2015 |
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