Androngenetic Alopecia
The following is essentially a summary of what is currently known about the condition, Androgenetic Alopecia.
Of all the conditions that lead to hair loss, Androgentic Alopecia in the form of Male Pattern Baldness (MPB) is the most common. It is characterized by a process of miniaturization of androgen-sensitive hair follicles to the point where they go from healthy, pigmented, visible hair (terminal hair follicles) to tiny, un-pigmented, almost invisible hair (vellous hair follicles) and the eventual loss of some hair follicle cells themselves (a process called hair cell apoptosis). It is believed that not all of the hair follicle cells that are affected by MPB die off, leaving the majority of the cells alive and intact, only incapable of producing cosmetically significant, terminal hair.
MPB is a form of Androgenetic Alopecia (AGA), characterized by the loss of hair in the frontal, temporal, vertex and crown areas of the head, while leaving the hair on the sides and back of the head (the occipital region) intact. The hair that remains is not sensitive to androgens and will normally continue to grow for life. There is another pattern of hair loss called female pattern baldness (FPB) characterized by a diffuse "thinning out" of hair in affected areas. The pathogenesis of FPB is not as well understood as that of MPB. A common misconception about AGA is that male pattern loss only affects men while female pattern loss only affects women. This is not always the case however; it is possible for either sex to be affected by MPB or FPB.
Androgenetic hair loss appears to be a genetically passed on condition that can be acquired from either the father's or the mother's side of the family or both. So far the precise genes that cause MPB have not been identified but it is known that a specific hormone, a stronger form of the male sex hormone, testosterone, is the key instigator of MPB. This hormone is called dihydrotestosterone (DHT). DHT binds with the androgen receptors of the hair follicles, initiating a chain of events that leads to the miniaturization of the follicles, over successive growth cycles. Currently it is not known what steps are involved in androgen-dependent hair growth (such beard hair) vs. androgen-dependent hair loss.
DHT is formed by the interaction between the enzyme, 5-alpha-reductase (5aR), and testosterone. There are two types of the 5aR enzyme (types I and II), and the type II enzyme is believed to be responsible for the conversion of testosterone to DHT within the hair follicle. Currently, there is one FDA approved drug that specifically targets this enzyme. The drug is called finasteride and it has been approved to treat MPB under the brand name of Propecia. More 5aR inhibiting drugs are on the way.
AGA, presumably mostly in the form of MPB, effects approximately 50% of Caucasian men older than 40. In Asians, African-Americans and Native-Americans the occurrence of AGA is less.
Over 50 years ago, a doctor by the name of Hamilton observed that castrated men did not develop AGA. This observation was a clear sign that the growth of hair follicles in some areas is androgen-dependent. In different areas, androgen-dependent hair behaved differently. Hair can be categorized into the following groups based on their relationship with androgens:
- Androgen-insensitive hair -- hair that are not affected by androgens, like in the occipital regions of the scalp (back and side of head) and eyelashes.
- Androgen-dependent hair -- hair that enlarge and grow in response to androgens (beard, underarm, pubic, chest and leg hair)
- Androgen-sensitive hair -- hair that display a shortening of the growth phase (or anagen phase), resulting in hair miniaturization as exhibited in AGA.
We currently don't know why androgens exert these paradoxical effects with regards to hair growth in different areas of the body, nor do we know which genes are involved. But Hamilton showed that some castrated men that were given injections of testosterone started to lose their hair in a consistent pattern of AGA.
It has also been observed that pseudohermaphrodites that lack the 5aR enzyme had minimal to no beard growth. Since this enzyme is needed to convert testosterone to DHT, this observation seems to indicate that DHT is needed for androgen-dependent growth and in conjunction with studies of castrated men, in androgen-sensitive hair loss.
Also DHT appears to exist in high concentrations in balding areas of the human scalp, as well as in the scalp of stump-tailed macaques (the best animal model for AGA). It's not known whether DHT is created by local metabolism in the scalp or from circulation in the blood; however, we can assume that DHT interacting with hair follicles causes them to miniaturize and thereby produce shorter and thinner hair, resulting in pattern baldness.
Experiments have shown that hair follicle size seems to be based on the size of the dermal papilla (hair generating bulb of cells at the bottom of the hair shaft). So if the dermal papilla are miniaturized or lost, this will result in lost and miniaturized hair. In AGA there is some evidence that some of the dermal papilla are lost, either by a process of programmed cell death called, apoptosis or by cell displacement.
Androgen metabolism appears to be very important when it comes to androgenetic hair loss. Androgen metabolism can be divided into production of androgens (either glandular or extraglandular), the transport of androgens, the interaction of androgens with cells, and the response of cells to interaction with androgens. The synthesis of androgens occurs in several organs including the adrenal glands and gonads, and the influence of the pituitary is involved.
It starts with cholesterol, which is converted to pregnenolone. Through several complex interactions, a category of hormones called 17-ketosteroids are formed. This group makes a set of relatively weak androgens, such as DHEA. These are considered weak androgens due to their low affinity for the androgen receptor. Approximately 75% of DHEA and 95% of sulphated DHEA (or DHEA-S) come from the adrenal gland. The adrenal gland also produces adrenoline, the hormone involved in the fight-flight or stress response in humans.
This brings up a very interesting question. Is there a correlation between a hyper-active adrenal gland, and AGA? And even more interesting, does this imply that there is a causal relationship between stress and AGA? The general consensus is that there may be a correlation between stress and some stress induced telogen effluvium, but it does not appear that stress causes progressive pattern hair loss. However it may be possible that prolonged stress leading to, or caused by, an overactive adrenal gland can lead to increased production of DHEA and DHEA-S, which can then be converted to testosterone, which can get converted to more DHT, ultimately resulting in more DHT in the system and more pronounced AGA or a faster process of follicular miniaturization.
Again, DHEA and DHEA-S can be converted (enzymatically) to the more potent hormone, testosterone, the major circulating androgen. In hair follicles the main pathways involved in conversion of weaker to more potent androgens like testosterone are through the activity of the enzymes 3-beta-HSD and 17-beta-HSD. And the final link in the chain in the creation of DHT is the conversion of testosterone to DHT by the enzyme 5aR.
The ability of DHT to bind with the androgen receptors on a cell is about five times that of testosterone, making one of the goals in fighting androgenetic hair loss to prevent the formation of DHT.
Here is a high level summary of how DHT is formed:
- DHEA gets converted to androstenedione if increased 3-HSD enzyme activity is present
- Androstenedione gets converted to testosterone if 17-HSD activity is present.
- Testosterone gets converted to DHT if 5aR activity is present.
- If target cells convert weak androgens at an accelerated pace, then there will be enhanced conversion of testosterone to DHT.
Also, another reason for increased hair follicle sensitivity to androgens is believed to involve an increase in the number of androgen receptors on the cell. A potential new treatment for hair loss, called fluridil attempts to tackle the hair loss problem from this aspect.
Androgens, like DHT and testosterone initiate their effects on cells, like hair follicles, by binding to a specific type of receptor on the cell. This receptor is called the androgen receptor. You can think of the relationship between free DHT and the androgen receptor as between a key and its lock -- the key in this case is the DHT and the lock is the intracellular androgen receptor. When androgens bind to an androgen receptor this leads to the formation of an androgen-receptor/androgen complex (ARAC) which is then transported into the nucleus of the cell. Once inside the cell, this ARAC can bind to specific regions of DNA that have what are called androgen-responsive elements (ARE). Many different proteins have this ARE. When an ARAC interacts with an ARE, this in effect sends a message to various genes to either be activated or suppressed. It is believed that in the case of androgen-sensitive hair follicles the genes that are activated cause the follicle miniaturization process to occur, thereby causing pattern baldness.
Clearly androgen metabolism is very complex and involves many interactions. Imbalances in any of these interactions can lead to all sorts of androgen related conditions, possibly including AGA. Attempts can be made to address the problem of AGA by tuning at various points. e.g. the amount of weak androgens present that can be converted eventually to DHT, the different enzymes and isoenzymes present in the target cells, the ratio of conversion and back-conversion between weaker and stronger androgens, the ratio of bound vs. unbound androgens in the blood, the affinity of androgens to the androgen receptor, the ratio of androgen receptors to the cells, etc. To complicate matters, most organs differ in their types and amounts of androgen metabolizing enzymes and there is also a difference in these amounts between men and women.
However, androgen-dependent processes are not the result of conversions of the weaker androgens to DHT, but appear to be solely dependent on the binding of DHT to the androgen receptor, and the subsequent uptake of the resulting androgen-receptor/androgen (ARAC) complex into the nucleus. Therefore, the current approaches of finding agents that block the conversion of testosterone to DHT and also of preventing the binding of DHT with the androgen receptor are promising ones. We have already seen the benefits of this approach with finasteride (type II 5aR blocker), dutasteride (type I and II 5aR blocker), and fluridil (androgen receptor inhibitor). Currently, only finasteride in 1mg pill form has been approved for use in the treatment of MPB by the FDA.
DHT-dependent cell functions will only be initiated or amplified if:
- enough weak androgens are present for conversion
- more potent androgens are formed via the action of 5aR
- the activity of androgren inactivating enzymes (like aromatase) is low
- conversion of weaker steroids to DHT is occurring (e.g. via activity of 3-HSD)
- active androgen receptors are present in high numbers.
Deficiency in the production of the 5aR enzyme (that converts testosterone to DHT) is a rare. There are several mutations of the gene that encodes 5aR but not every mutation will cause a complete deficiency of the enzyme so various degrees of deficiency have been observed in people. In general people that have this deficiency have almost no beard growth or Androgenetic hair loss. These people still have testosterone in their system however. This is strong evidence that DHT is the main culprit in pattern hair loss.
It has recently been shown that the main metabolic activity of the type II 5aR can be detected in intact occipital scalp and dermal papilla. If the dermal papilla plays a crucial role during androgen-mediated processes of the hair follicle, it is possible that they might amplify testorsterone driven responses in the hair follicle through the action of type II 5aR.
DHT can be inactivated by an enzyme called 3-alpha-HSD to the weaker androgens androsterone and androstanedial. In theory the back conversion of these weaker steroids to DHT via the enzyme oxidative 3-alpha-HSD may promote DHT dependent hair loss. Since it has recently been demonstrated that such metabolism occurs in the dermal papilla then theoretically a drug that can block this process may also be helpful in preventing or stopping AGA.
Circumstantial evidence also exists that aromatase, which can convert androgens to estrogens may be involved in the pathogenesis of AGA. Estrogens might have a protective effect for hair follicles, helping to keep them in anagen (growth) phase longer.
Conclusions and Future Perspectives
Androgenetic Alopecia is a DHT-dependent disease process, where androgen-sensitive hairs go through successive cycles of hair growth and loss that result in smaller and smaller hairs until they have miniaturized to the point of being tiny, thin, almost invisible vellous hairs that are in a constant resting phase. The type II 5aR enzyme is crucial for the intra-follicular conversion of testosterone to DHT. So far we don't know the genes that are responsible for AGA, nor do we fully understand the molecular steps involved in androgen-dependent beard growth vs. androgen-dependent hair loss.
There is now a considerable opportunity for the scientific community since the mapping of the entire human genome to explore the causes of AGA further and to try to locate the genes involved. This may potentially lead to gene therapy to address the pattern hairloss problem, or better drugs with less side-effects. As well, a better understanding of the signal cascade that leads to the activation of the genes involved in pattern hairloss may yield better, less toxic inhibitors that block a step in the process that leads to AGA.
Let's look forward to the better treatments that are sure to come, and the fuller heads of hair that will result.
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