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Male Androgenetic Alopecia

William Cranwell, MBBS(Hons), BMedSc(Hons), and also Rodney Sinclair, MBBS, MD, FACD.

Author Information
University of Melbourne room of Medicine, and Epworth Hospital department of Dermatology, 2 Wellington Parade, east Melbourne, Victoria 3002, Australia
University the Melbourne room of Medicine, and Epworth Hospital department of Dermatology, 2 Wellington Parade, east Melbourne, Victoria 3002, Australia

ABSTRACT

Male androgenetic alopecia (MAA) is the most common form of hair ns in men, influence 30-50% of guys by period 50. MAA wake up in a extremely reproducible pattern, preferentially influence the temples, vertex and mid frontal scalp. Return MAA is regularly regarded as a reasonably minor dermatological condition, hair loss results self-image and is a great cause the anxiety and depression in part men. MAA is increasingly established as a risk variable for arterial stiffness and cardiovascular disease. A familial propensity to MAA and also racial variation in the ubiquity is fine recognized, through heredity bookkeeping for around 80% of predisposition. Common levels the androgens are enough to reason hair lose in genetically prone individuals.

The crucial pathophysiological functions of MAA are change in hair cycle development, follicular miniaturization and also inflammation. In MAA, the anagen step decreases through each cycle, if the size of telogen remains continuous or is prolonged. Ultimately, anagen duration i do not care so brief that the farming hair stops working to achieve sufficient size to reach the surface ar of the skin, leave an empty follicular pore. Hair follicle miniaturization is the histological hallmark the androgenetic alopecia. As soon as the arrector chili muscle, i m sorry attaches circumferentially roughly the major follicle, has detached indigenous all secondary follicles and also primary follicles have actually undergone miniaturization and also detachment, hair ns is most likely irreversible.

While numerous men choose not to undergo treatment, topical minoxidil and also oral finasteride room approved through the Food and also Drug administration (USA) because that the treatment of MAA. Both medications prevent more hair loss, yet only partially reverse baldness, and also require consistent use to maintain the effect. Object minoxidil is fine tolerated together a 5% solution. Minor adverse results include itching that the scalp, dandruff and erythema. Finasteride is a potent and also selective antagonist of form II 5 alpha reductase, and is not an anti-androgen. 5 alpha reductase converts testosterone right into dihydrotestosterone (DHT). DHT binding come the scalp hair follicle androgen receptor produces MAA. A daily oral finasteride dose of one milligram reduces scalp dihydrotestosterone by 64% and serum dihydrotestosterone by 68%. Adverse effects, including sexual dysfunction (erectile dysfunction, low libido, anorgasmia) are uncommon, and also most regularly revolve there is no discontinuing treatment. Long-term sexual adverse impacts have been reported on society media and also internet forums, however the true incidence is unknown. Dutasteride inhibits form I and form II 5 alpha reductase, and also may be premium to finasteride in improving hair development in young males. However, adverse sexual side impacts are an ext common with dutasteride than with finasteride. Combining drugs with different mechanisms of activity enhances the efficacy. Subject antiandrogens, prostaglandin analogues, object antifungals, expansion factors, and also laser treatment are all arising medical therapies for MAA, yet absence the vital research come ensure efficacy and safety. Hair transplantation involves removal the hair indigenous the occipital scalp and re-implantation right into the outright vertex and also frontal scalp. With contemporary techniques, graft survive in excess of 90% have the right to be reliably achieved. A combination of these therapeutic options is now obtainable for males experiencing MAA, v favourable cosmetics outcomes possible. For complete coverage the this and all related areas of Endocrinology, please visit our totally free on-line net textbook, www.endotext.org.


INTRODUCTION

Male androgenetic alopecia (MAA, masculine pattern baldness) is the many common reason of hair ns in men. The hair lose is progressive. Gradual conversion the terminal hairs into vellus hairs occurs in a extremely reproducible pattern, denudes the scalp and also leads to baldness. When some degree of androgen-dependent hair loss is universal after puberty, the pervasiveness of alopecia of adequate severity to warrant a diagnosis that balding boosts with proceeding age. Twin studies confirm the hair lose is a genetically established phenomenon. Observational studies in eunuchs have established the androgen-dependent nature of this condition.

The morbidity the MAA is predominately psychological, although baldness is a far-reaching risk variable for both melanoma and also non-melanoma skin cancer of the scalp. MAA has actually a variable psychosocial affect on the influenced individual, but premature MAA is an ext likely to reason emotional distress. MAA is reportedly associated with raised incidence that myocardial infarction, hypertension and also hypercholesterolemia.

Topical minoxidil and also finasteride (5 alpha reductase form II inhibitor) room the only FDA approved treatments for MAA. Both agents arrest development of hair loss and stimulate partial regrowth of hair. Dutasteride (dual 5 alpha reductase form I and also II inhibitor) is an ext potent and also has been much more effective 보다 finasteride in step II trials but phase III trial data room limited. Hair transplantation is commonly practised in the USA and takes advantage of the family member sparing and androgen-resistant nature of donor occipital hairs.

New insights into the pathophysiology, hereditary basis the MAA and, the function of androgens may help in the exploration of extr treatments for androgenetic alopecia.


EPIDEMIOLOGY

Hamilton estimated that 30% to 50% that men arisen MAA by the period of 50 (1). Plenty of Western studies have presented that there space racial as well as age-related differences in the incidence and also pattern that hair ns in MAA (2).

The incidence and severity that MAA is report to be much more common in Caucasian men than other nationalities. It has been it was observed that progressed degrees that alopecia are more frequent and also develop at an earlier age in Caucasian 보다 in Mongolian populaces (3). The beginning of MAA in the Japanese wake up one decade later on than in Caucasians (4). Black, Oriental, aboriginal American and also African-American men are more likely to have preservation of your frontal hair lines, less extensive and also late beginning baldness than Caucasians (1,5-7). A populace study completed in Singapore supports that Chinese men are reported to have actually a reduced incidence that MAA (8).

Age prevalence of MAA has been recorded in numerous study populations. In Australia, a study of 1390 men between the ages of 40 and also 69 was carried out to recognize the prevalence and risk components for MAA. The ubiquity of vertex or complete baldness (Figure 1) (Norwood Hamilton scale) increases with period from 31% (age 40-55) to 53% (age 65-69). A receding frontal hairline was uncovered in 25% of guys aged 40-55 and 31% age 65-69 (9). A survey done in USA report a prevalence of moderate or serious MAA that 53% in the period group 40-49 (10). Enhanced incidence the MAA through aging has additionally been report in korean population, with type III-vertex joining most generally seen in the third to seventh years (11). The pervasiveness of MAA in Singaporean males to be reported to be 63%, enhancing with age, native 32% in ~ 17-26 year to 100% after 80 years (8).


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PSYCHOSOCIAL impact OF MAA

Hair is critical part of one individual"s self-image and its key significance relates come socialization. Hence the results of MAA are predominantly psychological. Several studies show that the an unfavorable self-perception the balding patients shows up to it is in consistent in between Western (12,13) and Asian societies (14). The an unfavorable impact of MAA is regularly trivialized or ignored through unaffected world (15). However, there is proof that tardy by others may compound the psychological difficulties suffered by balding men. A korean study that the tardy of balding guys by women and also non-balding men discovered that their an adverse perception of men with MAA was similar to the psychosocial effects reported by the patients themselves (14). The note, a late of bald men looking much less attractive was found in an ext than 90% of subjects surveyed. This watch was an ext common in females than non-balding men. Such negative perceptions may more impair the social functioning that balding men. A current study shown a high pervasiveness of depression and anxiety in patients experiencing androgenetic alopecia, who regularly utilise avoidant coping tactics (16). It is crucial to keep in mind however, the most affected men deal with well through androgenetic alopecia, without significant impact on your psychosocial function. Thus, those who perform seek aid are likely to it is in in higher emotional distress and also have been dissatisfied with any type of treatment they have received. The many distressed balding men are those with much more extensive hair loss, those that have an extremely early onset and those that think their balding is steady (12). It is necessary for the physician to attend to patients’ emotional responses to alopecia, consisting of anger, anxiety and also depression, including their beliefs about the affect of their problem (16).


MAA AND condition ASSOCIATIONS

Cotton et al. An initial suggested idea that male sample baldness may be a risk aspect for cardiovascular disease (17). This has been ultimately supported by several various other studies (18-21). A current study found that asymptomatic young males with at least Grade 3 peak baldness have a significantly greater risk of arterial stiffness 보다 those v normal hair status(22). However, many of these research studies were performed by non-dermatologists and also no dermatologic input was had for check of MAA diagnoses. This statistically-significant, though weak, associations were discovered in epidemiological, cohort and also case regulate studies. Severe at an early stage onset that MAA in subjects prior to age 30 may be linked with a higher risk because that ischemic love disease. In a retrospective examine of 22,071 American subjects, males experiencing crest balding were shown to have an increased incidence the myocardial infarction contrasted with frontal alopecia (23). One study showed that frontal masculine pattern baldness in young males was connected with raised serum cholesterol level and higher blood pressure compared to males of similar age v no hair ns (23). Boosted incidences of hypertension and elevated aldosterone levels have likewise been discovered in women through female sample hair loss (24,25).

An enhanced incidence of bright prostatic hyperplasia has actually been associated with MAA, and MAA can be very early marker the the an illness (26-28). A current study, however, argued that there is no relationship between androgenetic alopecia, bright prostatic hyperplasia, PSA level and also prostate volume (29). Prostate cancer has additionally been uncovered to be positively connected with MAA in miscellaneous studies (30,31). A huge scale Australian case-control study discovered that crest balding was linked with a 50% rise in danger of prostate cancer and also 11 year follow up data suggests that peak androgenetic alopecia at age of 40 years might be a marker of raised risk that early-onset prostate cancer (31,32). A meta-analysis performed using Medline and Cochrane databases suggests that an raised risk that prostate cancer to be only linked with vertex baldness, whereas various other patterns show up to have actually no association (33). However, associations through high-grade prostate cancer were found in all trends of MAA, being especially far-ranging in guys aged 60-69 years. No clear link in between cardiovascular diseases and MAA has been established. High androgen levels have actually been postulated to cause MAA as well as atherosclerosis and thrombosis, yet some data has shown no association between baldness and established coronary risk components (34). An association and a pathophysiological system for the link between MAA and prostate cancer additionally remains to be established yet may indicate the double dependence the these conditions on dihydrotestosterone (35).


ETIOLOGY

Genetic factors and androgens both play crucial roles in causing “androgenic” hair loss.


Genetics and Androgenetic Alopecia

A familial tendency to MAA and racial sports in the ubiquity of balding is well known (7,36). Pair studies determined heredity as audit for around 80% of the bias to baldness (37). Genetic components modify the magnitude of the hair follicle response to turn around androgens. Those with a solid predisposition go bald in their teenage years, while those through a weak bias may no go bald until they room in your 60s or 70s. Fewer than 15% of men have small or no baldness by the period of 70 (38). Osborne in 1916 said that the baldness gene behaved in one autosomal dominant manner in men and an autosomal recessive fashion in women (39). Happle and Küster were unable to demonstrate a bimodal distribution of phenotypes with plainly unaffected and clearly affected people as is typically seen in autosomal leading disorders (40). In comparison they observed a variety of phenotypes for men and women that seem to follow a common distribution. This, along with the finding the baldness risk boosts with the number of affected family members members, is an ext consistent through polygenic inheritance. Furthermore, they listed that inherited traits early to single gene defects rarely have actually an incidence higher that 1:1000, while polygenic conditions are much an ext common, together is the situation with androgenetic alopecia. The current principle of it gift a polygenic inheritance is supported by an Australian examine that examined the frequency that baldness in the fathers of balding males (41). Of the fifty-four father-son relationships, 81.5% that balding sons had actually fathers who had actually cosmetically far-ranging balding. This figure greatly surpassed the proportion expected of one autosomal leading pattern the inheritance. The exact same authors likewise described an association of male pattern baldness through a polymorphism that the androgen receptor gene ~ above the X chromosome (41,42). The androgen receptor gene restriction fragment size polymorphism was discovered in almost all (98.1%) young fully men, enlarge bald men (92.3%), yet only in 77% of non-bald men. This polymorphism appears to be important for the advancement of MAA, however its visibility in non-bald men indicates that that is necessary however not sufficient to cause the phenotype (41). In addition, several shorter triplet repeat haplotypes were found in greater frequency in bald guys than in common controls. This RFLPs show up to be linked with a practical variant of the androgen receptor (AR) gene. Of note, the androgen receptor gene is located on the X chromosome, i m sorry is passed on from mom to a masculine child. However family research studies have displayed resemblance of hair loss between fathers and sons, which can not be explained by AR gene mutations alone.

These data indicate that various other autosomal genes may additionally be contributing to the phenotype. Several studies have examined the various other candidate genes and chromosomal regions that can add to the hair loss.

Genetic association studies of 5 alpha reductase genes SRD5A1 on chromosome 5 and also SRD5A2 ~ above chromosome 2, utilizing dimorphic intragenic restriction fragment size polymorphisms in 828 families, failure to present an association in between these genes and also MAA (41). Yet the role of the 5 alpha reductase enzyme in MAA is apparent from its duty in the metabolism of testosterone to dihydrotestosterone (DHT) and the impact of 5 alpha reductase inhibitors in treating hair loss. The cytochrome p450 alpha aromatase enzyme has also been found to contribute to androgenetic alopecia. Aromatase diminishes intra-follicular testosterone by catalysing the counter of testosterone to estradiol. Differences exist in the expression that aromatase in balding and also non-balding scalp (43). Yip et al indicate that the aromatase gene (CYP19A1) might predispose to hair ns in females (44).

Hillmer et al sought come identify new susceptibility gene in MAA (45). In a genome vast scan and also fine mapping linkage study carry out on 95 families, they found that over there is strong evidence because that an MAA susceptibility locus on chromosome 3q26 (45). This study can not confirm or exclude the relevance of chromosomes 11q22-q24, 18p11-q22 and also 19p13-q13 in bring about MAA. Another genome-wide association examine completed by Hillmer et al uncovered a highly far-ranging association on chromosome 20p11 suggesting that the 20p11 locus has actually a duty in a yet-to-be-identified androgen-independent pathway (46). A new susceptibility variant on chromosome 7p21.1 says HDAC9 is a third candidate gene because that male-pattern baldness (47).


Genetic experimentation in Androgenetic Alopecia

A gene polymorphism-based diagnostic check that will predict the possibilities of future androgenetic alopecia advance is currently in the industry (42,48). For young patients concerned around hair loss, this check may help to specify the value of early treatment initiation.

In males, the gene test have the right to predict the possibilities for MAA by reporting the presence or lack of a certain variation in the androgen receptor (AR) gene found on the X chromosome. The variant AR gene causes changes in the hair follicle’s solution to dihydrotestosterone, causing alterations in the hair development cycle. A confident test result indicates a 70% opportunity of developing MAA, conversely, a an unfavorable test an outcome indicates a 70% chance of not developing MAA. The test is of value as a screening check in predicting the future possibilities of arising MAA rather than a confirmatory test.

Recently, a gene test has actually been developed that is design to evaluate an individual’s an answer to finasteride therapy. The check is based on far-ranging association of certain variations in the AR gene and also the likelihood that a guy will respond to finasteride therapy (49). The test gives the patient’s CAG repeat length score in the AR gene. A much shorter CAG repeat length (<22) is associated with a higher likelihood the the patience will experience a far-reaching benefit by using finasteride for the therapy of MAA. The hereditary test because that finasteride solution helps determine if the patience will have a slight, moderate, or good response come finasteride treatment.


Hormones and also Androgenetic Alopecia

The function of androgen in male pattern hair ns is fine established. American anatomist James Hamilton observed the castrated males go not construct MAA unless they to be supplemented v testosterone (50).

Measurements the serum androgens, testosterone, dihydroepiandrosterone sulphate (DHEA), and totally free testosterone levels have failed to show a reproducible difference between cases and also controls (51). A research that assessed various hormonal level in MAA and age-matched controls measured elevated levels of cortisol and also androstenedione in those enduring MAA (52). This examine further says a broad selection of hormones may influence androgenetic alopecia. Even though scalp hair loss and hirsutism are necessary features that hyperandrogenism in women, numerous investigations fail to show raised androgen level in women (53). As such it is said that regular levels the androgens are enough to reason hair ns in genetically prone individuals.

The observation that eunuchoidal patients v androgen-insensitivity syndrome and also 5 alpha-reductase deficiency do not go bald suggests that MAA is induced by activation the follicular androgen receptors by DHT (54-56). Patients influenced by Kennedy"s disease, v a useful abnormality the the androgen receptor gene, have a diminished risk the MAA (57). Raised levels the DHT have actually been found in balding scalp compared to non-balding scalp (58).

Intrafollicular androgen over-activity may also be the result of local determinants including one increased variety of androgen receptors, practical polymorphisms that the androgen receptor, raised local manufacturing of DHT, and reduced local degradation of DHT (59).

Similar come the classic steroidogenic organs, such together gonads and also adrenal glands, the skin and its appendages, including hair follicles, sebaceous glands, and also eccrine/apocrine glands, are equipped with every the vital enzymes forced for androgen synthesis and metabolism. The 5 alpha reductase enzyme plays a central role v the intrafollicular conversion of testosterone come the an ext active metabolite DHT (60). DHT binding the androgen receptor through 5 times the avidity that testosterone and is more potent in its capability to reason downstream activation (61). 2 5 alpha reductase isoenzymes have actually been characterized, based on their different pH optima and tissue expression trends (62). Form 1 5 alpha reductase is found immunohistochemically in sebaceous glands, epidermis, eccrine sweat glands, apocrine sweat glands, and hair follicles. In the skin, the activity of the kind 1 5 alpha reductase is focused in sebaceous glands and also is significantly higher in sebaceous glands from the face and also scalp contrasted with non acne-prone areas. North blot studies reveal an abundance of type 1 mRNA in neonatal foreskin keratinocytes, adhered to by adult facial sebocytes, and stronger expression in dermal papilla (DP) indigenous occipital hair cells than from beard (63). That is additionally found in the liver, adrenals and also kidneys. Despite the broad expression sample of form 1 enzyme, the physiological role is uncertain. The type 2 enzyme has actually been uncovered by immunohistochemistry to it is in in the dermal papilla, the inner class of the external root sheath, the sebaceous ducts and also proximal inner source sheath of scalp hair follicles (64). That is likewise found in the prostate, testes, and liver. Form 2 5 alpha reductase accounts for around 80% of circulating DHT (61).

Recent researches by Hoffmann et al show that over there are variety of other enzymes involved in the pathogenesis that androgenetic hair loss. 17beta- and also 3beta-hydroxysteroid dehydrogenases (HSD), with type 2 5 alpha reductase within the dermal papilla, beat a central role in the intrafollicular switch of testosterone to DHT (65). Fritsch et al indicate that little levels of part isoenzymes found in normal states might have essential implications in condition states (66). Steroid sulfatase, 3beta-HSD1, 17beta-HSD3, and form 1 5 alpha reductase space the major steroidogenic enzymes responsible because that the development of potent androgens, vice versa, 17beta-HSD2, 3alpha-HSD, and also aromatase seem come inactivate the excess androgens locally in bespeak to achieve androgen homeostasis in the hair follicles (66).

Human hair follicles, dispersed in specific sites the the body, appear to have an inherited susceptibility because that androgen-dependent growth beginning during puberty. Relying on the body sites, androgens have actually paradoxically various effects on person hair follicles. Androgens wake up hair development in some sites such together the beard, axillary, and also pubic areas and suppress the growth of frontal scalp hair of gene disposed individuals. Itami et al proposed the the second messenger mechanism determines even if it is androgen perceptible follicles will respond to androgens by either miniaturization or improvement (67). Androgen stimulation that cultured moustache dermal papilla cell (DPC) command to enhanced transcription that insulin-like expansion factor 1 (IGF-1) and intensified growth that co-cultured keratinocytes. Androgen stimulation that DPC acquired from balding scalp lead to suppression of expansion of co-cultured keratinocytes. This growth suppression the keratinocytes to be mediated by transforming growth factor-beta1 (TGF-beta1) obtained from DPC from men with MAA, arguing that TGF-beta1 is a paracrine mediator for MAA (68). Beard DPC are known to secrete growth-inducing autocrine growth components in solution to testosterone, top to an increase in dermal papilla size and also enlargement that the hair follicle and also hair cortex. IGF-1 has actually been figured out as a significant component the secreted cytokines (69).

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Hair lose on the scalp progresses in an orderly and reproducible pattern, and also is a role of determinants intrinsic to every hair follicle. In vitro experiment have displayed that the hair follicles are able come self-regulate their solution to androgens by regulating the expression of 5 alpha reductase and also androgen receptor (70-72). This self-regulation is postulated to develop the quantifiable distinction in androgen receptor numbers and also 5 alpha reductase task that is observed in between balding and non-balding locations of the scalp (43,70,71,73). This intrinsic regulation is finest demonstrated in hair transplantation experiments: occipital hairs keep their resistance to MAA as soon as transplanted come the vertex, and scalp hairs from the vertex transplanted come the forearm miniaturise in ~ the very same pace as hairs adjoining the donor website (74).