The Various Probable Androgenetic Alopecia Causes

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Genetic Models of Androgenetic Alopecia

Exactly how does one Inherit Androgenetic Alopecia?
This question still remains unresolved. Different schools believe in different androgenetic alopecia causes but none have been established beyond doubt.

The Probable Causes of Androgenetic Alopecia

The factors having maximum probability of being behind pattern baldness are as follows
  • Paternal inheritance
  • Inheritance from the maternal grandfather
  • Autosomal dominant disorder (usually cited in the scientific literature)
Besides these three models, there is still no conclusive proof available to do away with the polygenic model.
Although different models are selected, few published reports are available to offer a comprehensive familial analysis of androgenetic alopecia. Let's make a separate study of each model, and check its ability to explain inheritance.
Autosomal Dominant Disorder
We may begin by concluding that a single autosomal gene, termed 'B', accounts for genetic predisposition to baldness. It is believed to act in an autosomal dominant manner and autosomal recessive manner in men and women respectively. In other words, men are predisposed to baldness if they inherit either 'BB' or 'Bb'. However, women are predisposed only if they inherit 'BB'.
Argument Against the Hypothesis
As per this theory, a single gene is responsible for androgenetic alopecia. But, in that case there are likely to be two or more distinct phenotypes rather than the continuous distribution of hair loss pattern and hair loss extent observed for the disease. The prevalence of the disease and many different degrees of hair loss clearly points towards a more complex polygenic mode of inheritance of Androgenetic Alopecia,
The Polygenic Hypothesis
If the pattern of androgenetic alopecia follows a normal distribution, it should be able to represent a full range of phenotypes. From no evidence of hair loss, to fully developed and very extensive baldness, which is actually the case. This distribution is more consistent with a polygenic trait where many genes are involved in susceptibility to androgenetic alopecia. It has also been found that hereditary traits determined by a single gene rarely occur at a frequency greater than 1 in 1000. The exact frequency of androgenetic alopecia is difficult to ascertain. However, it has been estimated to be between 40 to 60 percent in men, thus further supporting a more pervasive mode of inheritance.
The Characteristics of a Polygenic Trait
The characteristics of a polygenic trait can be illustrated using a simplified four-gene model. Consider a scenario whereby predisposition to androgenetic alopecia is determined by four distinct genes, each contributing 25%. Each one is equally important for inheritance.

Let us assume that inheritance of two or three of these genes predisposes one to hair loss during middle age, whereas inheritance of all four genes predisposes one to hair loss at a younger age. In reality, androgenetic alopecia might depend on more or less than four genes, each of which might contribute variably to predisposition.
Father-to-son Transmission (Sex-linked inheritance)
A study of the inheritance of baldness - that examined fathers and sons - came up with some interesting findings. 81.5 percent of balding sons were found to have fathers with cosmetically significant baldness. If the model of Autosomal Dominant Inheritance is to be believed, sons might be expected to inherit baldness equally from their mothers and fathers. However, since the results considerably exceeded the autosomal dominant expectation, it does give credence to the polygenic mode of inheritance. This theory seems to be the most likely basis of androgenetic alopecia.
Genes Involved in Androgenetic Alopecia
Various difficulties have hindered the Identification of Genes causing androgenetic alopecia. One major hindrance has been the variation in the onset of baldness. For example, a 30-year-old man with a full head of hair does not necessarily guarantee an absence of genetic predisposition to baldness!

The sequences of several candidate genes have been compared between groups of individuals at maximum risk for baldness and those considered to be least predisposed genetically to androgenetic alopecia. The DNA samples of young males having a significant degree of baldness were compared to older males having no indication of hair loss.

It was on the basis of the above study that the candidate genes for androgenetic alopecia were verified for their contribution towards this hair disease.
The 5a-Reductase Genes
The concentrations of both DHT (Dihydrotestosterone) and 5a-reductase are increased on the balding scalp, with the concentration of testosterone remaining the same. The involvement of DHT - rather than testosterone - in the hair-loss process implicates the genes SRD5A1 and SRD5A2, the genes which encode 5a-reductase enzymes in male-pattern baldness. This is important because 5a-reductase converts testosterone to DHT. However, analyses of these genes using case-control association and familial linkage studies have shown that it is unlikely that they significantly contribute to androgenetic alopecia.
The Aromatase Gene
The enzyme aromatase converts androgens (such as testosterone) to estrogens. It appears to be present in decreased concentrations on the balding scalp areas. The autosomal gene encoding aromatase, CYP19, was compared between cases and controls, but no differences were detected. That suggested that it is unlikely that the aromatase gene is significantly involved in determining predisposition to androgenetic alopecia.
The Y Chromosome
The above studies clearly indicate an involvement of father-to-son transmission of androgenetic alopecia. So, it also raises the hypothesis that a gene on the Y chromosome might contribute to the condition. In addition, the Y chromosome determines sex and the concentrations of sex steroids such as testosterone and DHT. Most of the Y chromosomes of the subjects under observation did not recombine.

But it is possible that mutations contributing to predisposition to androgenetic alopecia occur in genes, which are contained on the ends of the Y chromosome, in the so-called pseudoautosomal regions.

These regions recombine with the X chromosome. Though there is indication of gene involvement in genetic predisposition, further studies are needed for proving it.
Discovery of the First Gene Associated with Androgenetic Alopecia: the AR Gene
Because an increased concentration of androgen receptors is associated with a balding scalp, differences in the DNA sequences of genes encoding the androgen receptor, or in the AR regulatory sequences, might lead to differences in the concentration or activity of the receptor. Such differences might increase sensitivity to DHT in balding individuals, leading to hair loss at an earlier age. On comparing the AR gene sequences found in case and control individuals, a significant difference was observed between the two groups in the frequency of a single base change in the coding region (exon 1) of the gene.

This polymorphism does not alter the amino acid sequence of the protein and is therefore unlikely to be functional. However, it is likely that the polymorphism is tightly linked to other functional sequence changes. All but one of the 54 young, bald men studied carried the non-functional variant of the AR gene.

Interestingly, 77 percent of non-bald men also carried this variant of AR, suggesting that AR is necessary but not sufficient for causing baldness. To date, AR functional mutations that are associated with androgenetic alopecia have not been located. However, the results of this study nevertheless provide good evidence for the involvement of the AR gene in androgenetic alopecia.

On the basis of the above findings, it is believed that it is the difference in the sequence of regulatory regions of the gene that determine genetic predisposition of individuals to baldness. It is the sequence of the regulatory regions that cause relatively subtle increases in androgen-receptor production and activity in the cell.
Further Genetic Research
If the AR gene is necessary but not sufficient for causing baldness, it is possible that other genes might be acting in conjunction with AR. For example, genes other than SRD5A1 and SRD5A2 are the probable candidates for the expression of baldness. Given that the concentration of 5a-reductase is increased in the balding scalp, candidate genes might include those which encode the transcription factors that regulate the production of 5a-reductase. But such genes are yet to be identified. The many other genes, known and unknown, that are involved in androgen production, regulation and responses might also be involved.

In addition to androgen-related genes, genes that are involved in patterning, signaling and hair-follicle morphogenesis are attracting much attention from researchers.

All hair follicles are formed in the uterus. Epidermal signals trigger the formation of dermal papilla. The subsequent dermal signals direct epidermal down growth into the dermis that envelopes the dermal papilla and creates the hair follicle. Then hair-shaft production from the follicle is regulated by signals which are received from both the dermal papilla and lateral signaling between epithelial cells. The genes for these signaling pathways are believed to be probable candidates.
Further Research is Required
Whatever may be the mechanism of action for the genetic expression of baldness, nothing conclusive can yet be said about the genes that are involved. Studies are ongoing and experts are doing their level best to detect the actual cause of androgenetic alopecia.