All steroid hormones act by diffusing through the plasma membrane into the target cell and binding to specific intracellular receptors. Similarly, androgens, like other steroids, diffuse across plasma membranes and combine with a cytosolic or nuclear receptor protein. The cytosol is the internal fluid of the cell where a large part of cell metabolism occurs.
The androgen receptor is an intracellular steroid receptor that specifically binds testosterone and dihydrotestosterone. It has two main forms, A and B that differ in their molecular weight. The androgen-receptor complex undergoes conformational changes in the nucleus, exposing DNA-binding sites, and then binding to specific hormone response elements in the DNA. This binding of androgens to their androgen receptor leads to change of the AR-androgen complex (ARAC) which is then transported into the nucleus where it can bind to regions of DNA that have distinctive binding sites known as androgen-responsive elements (ARE). A wide variety of proteins have this ARE encoded in their DNA. In this way androgens are able to modulate the transcription of various genes that may be activated or suppressed.
Androgen receptor gene
The gene for the androgen receptor is located on the X chromosome at Xq11-12. Although researchers suspect that several genes play a role in androgenetic alopecia, variations in only one gene, AR, have been so far identified in people with this condition. The AR gene provides instructions for making the androgen receptor, which in turn allows the body to respond appropriately to dihydrotestosterone and other androgens.
Androgen receptor deficiency
The androgen receptor is believed to be responsible for determining the sensitivity of cells to androgens. Besides androgen insensitivity, various mutations have been described in the gene encoding the AR in a variety of diseases, including spinal and bulbar muscular atrophy (Kennedy’s disease), and prostate cancer. Some of these are associated with functional changes in AR expression. Androgen resistance syndrome is caused by a mutation of the Androgen Receptor gene located on the X chromosome wherein without functionally active androgen receptors a genetically male fetus will not undergo normal male development in utero and a phenotypically female child will be born.
Variations in the AR gene are also associated with an increased risk of androgenetic alopecia, and expression of the AR has also been suggested by many authors to be increased in balding scalp. Though it is still not clear how these genetic changes increase the risk of patterned hair loss in men and women, the variations appear to result from small changes in the number or types of DNA building blocks that make up the androgen receptor gene. These genetic changes appear to be most frequent in men with pre mature hair loss. In balding men DHT binds to androgen receptors in susceptible hair follicles and, by an unknown mechanism, activates genes responsible for follicular miniaturization. All these lead to the hypothesis that the androgen receptor gene may play a role in regulating the potency of the available androgen to the hair follicle and thus is an ideal candidate for the involvement in the predisposition to androgenetic alopecia.
Androgen receptor function
The first known mechanism of action for androgen receptors discovered was direct regulation of gene transcription. More recently, it has been shown that androgen receptors can have actions that are independent of their interactions with DNA- Androgen receptors interact with certain signal transduction (signal transduction is any process by which a cell converts one kind of signal or stimulus into another) proteins in the cytoplasm.
In some cell types testosterone interacts directly with androgen receptors while in others testosterone is converted by 5-alpha-reductase to dihydrotestosterone, an even more potent agonist for androgen receptor activation. The androgen receptor binds the various steroid hormones in a rank order of affinity: DHT > testosterone > estrogen > progesterone. DHT is produced from testosterone, is roughly three to four times stronger an agonist of the androgen receptor than testosterone, and the receptor-DHT complex is more stable and persists longer in cells. DHT is definitely more effective than testosterone in promoting up-regulation of the androgen receptor, a phenomenon due to both augmentation of the rate of receptor synthesis and an inhibition of receptor turnover.
Interaction of DHT with androgen receptors and androgen responsive elements
It is quite clear that DHT is a pivotal trigger of androgen-mediated effects on the hair follicle and the principal signal transduction cascade: DHT- DHT / androgen receptor –ARE is similar in all hair follicles. However, androgenetic alopecia studies show that DHT makes some hair follicles grow whereas in some other areas terminal hairs get converted to thin Vellus hairs by miniaturization. This leads to the question that something fundamentally different must be present between hair follicle target cells in androgen-dependant sites and in androgen independent hair growth sites. At present this paradox is not understood but evidence points towards the androgen receptor or distinct ARE being involved in this process.
Distribution of androgen receptors in hair follicles
Documentation on the localization of androgen receptors within the hair follicles is controversial and efforts to show differences in the quantitative concentrations of androgen receptors in bald vs. hairy scalp have yielded conflicting results.
The primary location for the androgen receptor in hair appears to be the dermal papillae in both anagen and telogen hairs. The androgen receptor has been found to be present in dermal sheath cells, supporting the concept that dermal sheath cells can replace dermal papilla cells even in androgen-dependent follicles. Authors Sawaya and Price showed a differential distribution of androgen receptor in scalp with 30 percent greater receptor levels in frontal vs. occipital scalp hair follicles of men with Hamilton II to III androgenetic alopecia, i.e., frontal balding. Randall and colleagues showed that the amount of specific high-affinity, low-capacity androgen receptor is higher in cultured dermal papillae cells from androgen-dependent sites (i.e. beard, moustache) than in non-balding scalp.
Although the mechanisms of how androgens act to cause androgenetic alopecia are still unclear, the role of the androgen receptor in pattern hair loss is biologically plausible, and the androgen receptor gene may play a role in regulating the potency of the available androgen to the hair follicle.