Androgenic alopecia: A counterproductive outcome of the anabolic effect of androgens
V.K. Soni
Summary
Androgenic alopecia is the commonest type of baldness. It is known to be caused by androgens, but the pathogenesis is not clearly understood. A lot of other factors are also suggested to be responsible, but many questions remain unanswered. This paper proposes a comprehensive theory, which explains how the normal anabolic effects of androgens which are responsible for hair growth become counterproductive in the scalp of some people leading to baldness, though androgens do not have any particular antagonism towards the hair follicles. It describes how androgens mediated protein deposition in the scalp tissues results in structural changes which leads to miniaturisation of hair follicles and thereby turn the hair vellus. It also explains other aspects of androgenic alopecia. This theory for the first time, spell out the steps involved in the progression from recession of hairline to complete baldness.
Introduction
Androgenic alopecia (AGA) is a noncicatricial or potentially reversible type of patterned hair loss. It is the most common type of baldness, which affects men as well as women but it is more common in men. Recession of the hairline is a part of the normal male secondary sexual characteristics. Conversion of some amount of terminal hair to vellus hair is also considered to be a part of the secondary sexual characteristics in males [1]. As much as, 96% of men lose hair to some degree in their life and about 50% of men develop AGA by the age of 50. It is a feature of men who have sufficient circulating androgens [2]. In the absence of testosterone, men neither develop body and facial hair nor grow bald. For example, AGA is never seen in eunuchs [3]. If it occurs only in the later part of life, it might be accepted as a feature of old age but in about 30% of men, AGA appears by the age of 30 [4]. Although it is not a serious condition, it may be a reason for psychological problems especially anxiety and depression [5].
The available explanations for AGA
There are many theories to explain AGA but it is still not clearly understood. Little is known about the molecular mechanism of its pathogenesis [6].
Androgenetic theory is the most accepted explanation so far. Testosterone which is secreted which from puberty onwards is converted into dihydrotestosterone (DHT) by the action of 5-alpha reductase. DHT binds to a receptor in the target cell and activates RNA polymerase leading to the progressive increase of cellular protein which is mainly responsible for most of the effects of the hormone [7]. According to the androgenetic theory, genetically predisposed people have more androgen receptors (ARs) in the scalp and an increased amount testosterone is converted into DHT by 5-alpha reductase type 2. DHT releases certain factors within the dermal papilla which is proposed to cause progressive hair follicle miniaturization and the conversion of terminal hair to the vellus hair in the temporal, vertex and crown areas [8]. The role of the androgens is well established, however, this theory fails to satisfactorily explain why the androgens cause hair loss only in certain specific areas in the scalp, that too in a particular manner, while it is known to cause hair growth in the other parts of the body. Further, why hair do not grow again when the testosterone level decreases?
The androgen is also thought to cause miniaturization of the hair follicle by accelerating the rate of mitosis [9]. The anatomical changes in vasculature were also suggested to be an effect of androgens leading to AGA [10]. It has also been considered to be a polygenic disease [11]. The basic questions remain the same with all these theories.
Inflammatory pathogenesis or a photoaggravated dermatosis has also been suggested to be the cause of AGA [12] and [13]. Can these phenomena be so extensive to affect a large proportion of the population? Why do they affect the specified areas only?
Stress, anxiety and ischemia are the other suggested mechanisms [14] and [15]. Why does ischemia cause hair loss in the specified areas? How does ischemia occur? Why cannot the body overcome ischemia despite the scalp getting the richest subcutaneous blood supply in the body and very good anastomoses present there?
Gravity has also been suggested to cause AGA. The gravitational force pulls the scalp against the skull and puts pressure on the hair follicle. At some point, when the cushion effect of the fat around the follicle decreases, the pressure of the whole scalp becomes sufficient to press the hair follicles so that they stop the growth of hair [16]. This theory does talk about an important factor that is the shift of pressure point after the erect posture of the human beings. Is the scalp pressure under the gravitational force sufficient to press the follicles to cause miniaturization? Further, it does not take into consideration the role of testosterone, a known factor in the pathogenesis of AGA.
The increasing size of the skull after puberty by bone resorption and remodelling has been held responsible for AGA [17]. It remains unanswered whether the significant expansion of the skull is a widespread phenomenon in adults and also if it is sufficient enough to cause miniaturisation of the follicles. Many diseases show excessive growth of the skull, but baldness is not seen in all of them.
Environmental factors have also been found to play a role in the development and/or exacerbation of AGA. For example, smoking was found to be significantly associated with AGA [18].
While these theories explain some or the other aspects of the pathogenesis of AGA, many questions remain unanswered.
The role of the androgens in AGA is proven beyond doubt. The missing link seems to be ‘why and how’ the androgens behave in the reverse manner on the particular areas of the scalp that too in a definite pattern. Secondly, why the miniaturized follicles are so difficult to be stimulated again, though AGA is a noncicatricial type of baldness.
The proposed theory
“Androgenic alopecia is a counter productive out come of the anabolic effect of androgens.”
Androgens are anabolic steroids secreted mainly in the males from puberty onwards. They cause deposition of proteins in the skin including that of the scalp, resulting in thicker, tougher skin with more hair and abundant secretion of sebum. The subcutaneous tissue becomes rugged [7] (Fig. 1).
Full-size image (37K)
Fig. 1. Vicious cycle of compression and compromised supplies.
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Unlike, skin on the other parts of the body, subcutaneous layer of the scalp is very dense and firmly attached. The density and firmness are sufficient enough to prevent extensive haemorrhage and inflammatory swelling within the layers. It also prevents vasoconstriction of the vessels; a natural response to minimize the blood loss, when the scalp is injured [19]. The scalp lies on the hard and smooth surface of the skull which is the uppermost part of the body. Therefore, there is no room for expansion on either way. The thick and rough skin and the rugged subcutaneous tissues adhere more firmly to the underlying and embedded structures in it, and compress the vessels and nerves, which leads to compromised blood and nerve supplies. The fat content in the scalp of the males also decreases after puberty [7]. This makes it even more firm and thus adds to the compression on the neurovascular bundle.
The cells in the affected area try to adjust to this newer situation of compromised supplies by scaling down their activity and size and hence the atrophic changes are initiated. Atrophy is commonly seen in the organs, which once have had rich supply that deteriorated afterwards [20]. Therefore, scalp could be a site for atrophic changes when supply decreases as normally it has the richest subcutaneous supply in the body [19]. The compression on the blood vessels may be slight but the resistance to blood flow increases drastically when the vessels are compressed. According to Poiseuille’s equation, there could be a 16-fold increase in the resistance to flow when the radius of the vessels decreases to half.
The hair follicle migrates into the dermis during the anagen phase. This migration ensures better growth conditions and blood supply which is evident by the angiogenesis around the follicles. A proteolytic activity is required to loosen the dermis to accommodate the growing hair follicles. Thus, migration provides better growth opportunity, but is a high energy-consuming process. As the supplies to the scalp is already being compromised, the supply available to the dermal papilla and the growing follicle also gradually decreases. Consequently, the migration and the maximal growth of the affected follicles are also correspondingly less. This decreased size and activity affect the cellular function and hair growth.
These changes may not decrease the thickness at the beginning but as the condition progresses the scalp becomes thinner and dermal papilla and hair follicles become smaller. The thinner and more tenacious layers of the scalp have less available space and adhere more firmly to the underlying and the embedded structures, and thus, put more pressure on the vessels and nerves and further compromise the blood and nerve supplies. The compromised blood supply to the nerves causes atrophic changes in them and overall, the compromised blood and nerve supplies further aggravate the atrophic changes in the scalp including the hair follicles. The thinner, tenacious and firmly adhered tissue may add to the difficulty in the migration of the hair follicles. Testosterone continues to aggravate the situation. The net result on hair growth is the progressive miniaturization of the hair follicles producing vellus hair instead of the terminal hair.
As the condition progresses, the structural changes because of the compromised supply in the scalp alone become sufficient to further decrease the blood supply and thus a vicious cycle starts (Fig. 1). After this stage, the condition may not reverse even if the testosterone level decreases. The skin gets adjusted to the androgens after some time. Acne, for example, decreases with time despite the presence of androgens. But the structural changes in the scalp and the vicious cycle do not allow it to happen and hair does not grow back in the bald area when the testosterone level decreases. Therefore, once AGA progresses, it continues to grow even after the testosterone level is very low.
The atrophic changes become severe as the condition advances and some of the most affected areas enter into the next level of adjustment that is, hypoplasia; the number of cells decreases. It becomes more severe as the time passes. Although the basic structure of the hair follicles is maintained, the number of cells in the follicles is reduced. This is the stage of permanent miniaturization.
The miniaturised hair follicles as a result of atrophy may again produce terminal hair either normally or following intervention. However, when hypoplasia has occurred in the miniaturised hair follicles, it is extremely difficult to reverse the process.
In the following sections, progression has been presented in stages, but the actual changes are in continuum.
What happens in the normal circumstances
Hairline recession
A few hair on the top of the scalp turn vellus in the normal males after puberty, but on the frontotemporal region almost all the hair turn vellus leading to hairline recession. Why?
The recession of the hairline is a normal phenomenon in the males and seems to be an unfinished task of evolutionary forces to make the forehead broad. The scalp extends up to the superior orbital margin and includes forehead where the hair has become vellus during the course of evolution. The structural changes that are seen in the scalp after complete baldness are already present at the hairless scalp on the forehead. At the junction of the hairy and the hairless parts of the scalp, the changes have started already but are not severe enough to turn all the hair vellus. The normal effect of androgens leading to protein deposition and decreased blood supply exacerbates these structural changes and is sufficient to turn the hair vellus in the transitional area, which can hardly make a few hair follicles vellus on the other parts of the scalp. The extent and shape of the hairline recession are determined by the underlying structure of the skull and scalp, the severity of the androgenic effects and the changes in the scalp. The narrow strip of hair makes the long middle arm of the characteristic ‘M’ shape.
The long middle arm of the ‘M’ seems to be the nature’s manufacturing defect! It is also present on the other parts of the body. In many people hair at the nape of the neck extends as a midline extension, the pubic hair extends up to umbilicus in the midline and in some people we may also find more hair in the midline. There are other such defects in the midline such as frenula at tongue, lips, genitals and brain. We may find a similar defect in some artificially manufactured goods where two parts join. The midline seems to be an area where the tissue of both the sides unites during the embryogenesis and probably some excess tissue remain. The hair here withstand the diminished blood supply for a little longer, but ultimately they also become vellus and the ‘M’ shape disappears.
The hairline recession is not only limited to the normal males but it is also seen in some women and in other situations where the structural changes take place due to the androgens or otherwise. For example, frontal fibrosing alopecia, sportswomen and hormonal disturbances.
Increased dandruff
The occurrence of dandruff is more common in men after puberty. Increased secretion of sebum in the skin cells owing to elevated androgen levels adds to dandruff formation. Additionally the deposition of proteins and decreased blood supply to the scalp also aggravate the condition. The blood supply to the scalp reaches the lowest layers first, spreads to the upper layers next and then reaches the skin. Hence, more amount of blood is available to the dividing cells in the stratum germinatum layer which ensures their normal division. But, at the superficial layers of stratum spinosum and stratum granulosm, the amount of blood supply decreases as a result of the protein deposition and compression. It leads to alterations in the cell cycle in these layers. The skin cells here tend to progress to the next layer at rapidly resulting in faster cornification. This rapid addition to the stratum corneum layer leads to increased shedding of the skin cells resulting in an increase in the dandruff formation. Further, dandruff is an independent factor for hair loss. The associated conditions may further aggravate the situation.
In the normal circumstances, dandruff gradually decreases when the differential proliferation decreases and the equilibrium is established. The sebaceous glands also get adjusted to the effect of the androgens. In those in whom the neurovascular compromise progresses and the supplies are further compromised, dandruff persists and may even increase.
The amount of skin cells lost at the skin surface is higher than that being formed at the basal layers. It leads to thinning of the skin in the advanced stage. The other layers of the scalp, especially subcutaneous layer, also become thin as the condition progresses. It further adds to the above-mentioned basic mechanism and aggravates the atrophic changes.
Dandruff decreases at complete baldness, because at that time the scalp thickness and hair growth decrease, and the demands reach to the extent that the supplies can support. Secondly, the vellus hair producing follicles hardly secrete any sebum.
Genesis of AGA
In the normal circumstances after the hairline recession and some hair turning vellus at the top, equilibrium sets in. Almost as many hair falls are replaced. The overall hair density corresponds to the extent of the structural changes and the available blood supply. As the other parts of the body show aging, the amount of hair also decreases but premature baldness does not develop. However, in those who develop AGA, the supplies are progressively compromised and the structural changes become more pronounced. This may be either because of the more circulating hormones and/or because of the more sensitivity to the androgens owing to more androgen receptors or more 5-alpha-reductase enzymes. It affects more and more hair follicles and their migration, which hampers hair growth. Other mechanical and/or biological factors may also contribute.
Stage of mixed hair
Although the available blood supply is distributed in the whole area, different hair follicles are affected differently by these changes because their places differ anatomically and within the scalp, and they are in different stages of development. Some of them may continue to produce normal hair while others get affected to various degrees. This leads to the stage of mixed hair.
Gradual shortening of the hair
In some follicles, sufficient new cells are added at the base of the follicles to produce hair; the same numbers of the cells are not sustained for a normal duration. In other words, hair is produced normally during the anagen phase, but it passes to the telogen phase earlier and increases the number of follicles in the telogen phase. As the duration of the anagen phase determines the length of the hair, the shorter phase yields a shorter hair, otherwise the diameter is normal.
Gradual thinning of the hair
On the other hand, some of the follicles are affected more and their size and activity are decreased. This affects the hair growing activity of the follicle resulting in the production of thin hair. The thickness of the hair corresponds to the size and activity of the dermal papilla and the follicle cells along with the available resources. The hair diameter further decreases cycle after cycle.
Thus, the hair in the affected area at this stage are a mix of the normal hair, normal but shorter hair and the thin and weak hair. The presence of mixed hair represents the initial stage of AGA, where there is mild-to-moderate reduction of supplies and some structural changes are taking place. This stage may continue for a long time if the underlying mechanism is not aggravated, but generally by the time this stage is reached, sufficient changes would have already taken place in the scalp to make the situation progressive. If the androgenic effects are drastically reduced at this stage, the condition may not progress to baldness. But in the normal circumstances this does not happen and androgens continue to make the structural changes worse.
The hair growing activity is hampered and the number of hair in the telogen phase increases. The hair density is decreased but there is no bald patch till this stage. Firstly, sufficient numbers of hair enters into the anagen phase. Secondly, the available blood supply is distributed in the whole area and the follicles do not enter into the telogen phase from a particular area. These telogen hair are weaker and fall easily while bathing and brushing, as commonly seen during AGA.
Stage of baldness
Appearance of baldness: As the condition progresses, the structural changes in the scalp also add to already compromised supplies and the vicious cycle of structural changes and compromised supply ensues. More and more hair follicles enter into the telogen phase. Their average stay in this phase is increased because they have entered the phase earlier than expected. The reduced activity and the size of the cells would cause them to take more time to enter into the anagen phase. Progression of the condition results in the progressive decreased ratio of the anagen follicles to the telogen follicles.
When this ratio reaches below a threshold level, a bald patch appears at the most affected area. The area and extent of its appearance are determined by the interplay of the biological and mechanical factors. It may not always appear on the area of the highest pressure. In some people, the progression of the recession of the hairline and bald area increases, and in some others it appears on the top of the scalp.
Progression of baldness: The vicious cycle continues to work and the supplies are further compromised. Once it progresses beyond a threshold, the mechanical changes alone are sufficient to aggravate the situation and the vicious cycle continues to operate even when the androgens are no longer as high as in the initial stage. The androgens may determine the pace of progression of baldness, but not the baldness as such. The scalp thickness also decreases. The skin tries to adjust to the androgens after some time. For example, the occurrence of acne reduces with time though the androgen remain there. The same does not happen with AGA because of the mechanical changes in the scalp and the vicious cycle. Once baldness starts, in most of the cases it continues to increase unless there is some intervention. Baldness does not reverse even if the testosterone level is close to nil. More and more follicles enter into the telogen phase early and stay there longer and baldness increases.
The stage of permanent baldness: After the prolonged atrophic changes the number of cells starts decreasing and hypotrophy occurs. The already miniaturized hair follicles now lose the cells and become permanently miniaturized, though the structure of the follicles is maintained. The hypotrophied structures are extremely difficult to be stimulated for growth again.
Thus, androgens which are responsible for the hair growth on the body cause hair loss on the top of the scalp in some people.
What influence the location, extent and the pace of baldness development?
The recession of the hairline, dandruff and AGA are thus the various stages of the spectrum of the severity of the above-mentioned mechanism. The severity of the androgenic effects is dependent on the amount of androgens, 5-alpha-reductase enzyme, the androgen receptors and their sensitivity. If there are no androgens there will be no baldness. When the androgenic effect is sufficient to cause counterproductive effects the other factors also play a role in determining the location, extent and progression of baldness such as the structure and shape of the skull, its prominences and grooves, the pressure points, the structure and the extent of the scalp. There may be other individual specific factors and associated conditions. The final result is the outcome of the interplay of these factors.
Evaluation of the theory
The assumptions and the events discussed in this theory have been noted by many researchers and they comply with the current understanding of AGA.
The phenomenon of hairline recession is universal in the normal males. Dandruff is also seen in more than 50% of the adult population. The stratum corneum of a dandruff-affected scalp shows diverse ultrastructure [21]. This probably results from the fact that the cells progress to the next layer early and have lesser time for normal maturation and differentiation. In the advanced stage of baldness, there is less dandruff as there is no differential cell division and the sebum production is less in the bald areas producing vellus hair.
The secretion of androgens starts at puberty and then reaches the peak in the late teens to early 20s, but AGA in men is generally seen in the third decade and in almost all cases by the fourth decade [2] and [3]. If the direct effect of testosterone on the follicles had been the cause, AGA should have developed earlier. The time lag is due to the reason that the structural changes initiated by androgens take time to result in AGA.
The scalp thickness increases during puberty [22]. It changes with age but the changes in the scalp during AGA are not similar to those occurring with advancing age. Therefore, AGA is not an exacerbated aging but has a local cause [23]. The peripheral factor is thought to be critical in the effect of androgens on the hair growth [24]. The people having a deficiency of 5-alpha-reductase enzyme are found to have low DHT level though the testosterone level remains normal. The hormones in them produce normal virilisation and development of normal libido and other male characteristics such as muscle and skeletal mass, but they have scanty hair on the face and do not develop male pattern baldness. Dihydrotestosterone has five times greater affinity for the androgen receptors [25], [26] and [27]. The androgen receptors on the dermal papilla cells of the balding scalp follicles were more than those of the non-balding scalp follicles in the sample irrespective of the age [28]. Therefore, more androgenic effects are seen in the balding scalp.
In the normal circumstances, the hair follicles grow into the dermis during anaphase to secure better conditions such as nutrients, temperature, hormones, neural stimulus and an appropriate space for the growing hair follicles [29]. In this stage, angiogenesis also takes place around the follicles that provide additional nutrition to the growing follicles [30]. This improved follicle vascularization promotes hair growth and increases hair and hair follicle size [31]. The size of hair follicle corresponds to the volume of the dermal papilla at its base and the amount of extracellular matrix per cell present [32]. The overall the process of terminal hair growth is an energy-consuming process.
On the other hand, during AGA, there is an interesting pattern of blood flow and the availability of oxygen to the scalp decreases. In the balding scalp, the blood flow in the temporal region increases significantly than in the frontal region, but in the non-bald scalp such a difference is not seen. The bald frontal scalp in AGA has significantly lower transcutaneous PO2 than the hair-bearing temporal scalp, whereas in the non-bald people, this difference was not significant. The frontal scalp in AGA was found to have significantly lower transcutaneous PO2 than either frontal or temporal scalp of non-bald people. A relative microvascular insufficiency is found in the balding regions of the scalp in AGA [33]. The subcutaneous blood flow (SBF) in the scalp of the non-balding people was found to be 10 times higher than the previously reported SBF values in other anatomical regions. The SBF in the patients with early male pattern baldness was found to be 2.6 times lower than that of the normal individuals [15]. These statistically significant findings suggest that the supplies to the affected area are definitely low, and therefore, the growth of the follicles is also affected. The final effect on the follicles will understandably be according to the supply available, the stage of development and the anatomical location. Different hair follicles will produce different types of hair. Some follicles might produce smaller hair of normal diameter, which are seen comparatively more during AGA and the smaller hair follicles produce thinner and weaker hair [34]. Thus, a diversity of hair diameter has been found in the balding scalp and is supposed to be the reliable indicator of the balding process [35].
The follicles that are not fully grown sustain the anagen phase for a lesser time and enter into the telogen phase earlier [36]. This leads to a marked reduction in the anagen-to-telogen ratio [37]. Thus, the terminal hair decreases and as the condition progresses, baldness appears and increases with time.
The change in the scalp thickness in AGA till the age of around 40 is not consistent and is only marginally decreased [21]. Thereafter in the advanced stage of AGA, the scalp thickness decreases rapidly and significantly. The subcutaneous tissue forms almost 50% of the thickness and remains almost same in the non-balding people, but decreases in advanced AGA [23]. The protein is deposited in the scalp and fat decreases under the influence of the androgens [7] and [38]. Therefore, once baldness progresses the pressure on the neurovascular bundle increases, and the space available for the follicles to migrate decreases and the condition progresses fast. The vicious cycle starts and the changes are almost irreversible.
The currently available treatments for AGA are able to prevent the disease progression and reverse the miniaturization of hair follicles in most of the patients with mild-to-moderate AGA [39]. These are suppressive and not curative [40]. The effect of these drugs is limited because the structural and the mechanical changes in the scalp are not easier to be reversed and the vicious cycle once established cannot be reversed easily. Only a small proportion of people show satisfactory hair regrowth, while the remaining may either have soft, downy fuzz or may not have hair regrowth at all. Regrowth seems to occur only in the favourable area and the strength and diameter correspond to the degree of the restoration of the supply.
Permanent hair loss has been reported to be a result of the sustained microscopic follicular inflammation with connective tissue remodelling [41]. It can actually be a result of severe atrophy and hypoplasia. The macrophages infiltrate the atrophic tissue as well. Although generally hypoplasia does not occur in the adult tissue, it may occur in the steady-state renewable tissues such as epidermis where the reduction in the stem cells division as a result of attrition of the progenitor cells may lead to an actual decrease of the number of cells. For example, prolonged parental feeding may result in disuse hypoplasia of intestinal mucosa, lupus erythromatosis and lichen atrophicus [20]. Once hypoplasia occurs it may be extremely difficult to be reversed and a stage of permanent miniaturization of the hair follicles ensues. At this stage, the hair growth is very difficult. The medication, therefore, is effective till the stage of atrophy that is mild-to-moderate AGA.
Androgenic alopecia is not seen when castration is done before puberty. If testosterone is given, then AGA can be seen in some castrated individuals who are genetically susceptible. Similar findings were observed in a twin study. In contrast to this, when the castration was done after baldness had appeared, there was no significant regrowth of the hair though testosterone was almost absent [42].
Thus, testosterone definitely plays a role in AGA, but it may not have a direct destructive effect on the follicles. After a certain threshold level, AGA progresses beyond the effect of testosterone and becomes difficult to be controlled by the changes in the testosterone level or the increased blood supply. The reason is the structural changes in the scalp, and the vicious cycle, which is difficult to break. As the disease progresses, the condition further becomes irreversible.
How to test the theory
A chronological recording of the changes in the scalp in the longitudinal studies (or in multiple cross-sectional studies) including the subjects with AGA and the controls will generate data to validate the assumption in the theory. The measurement should include capillary blood flow, PO2, available nutrients, changes in the protein and fat contents and the thickness of the scalp. Measurement of follicles and dermal papilla and the migration of the anagen follicles will also help in understanding the pathophysiology. The concentration of the androgens, receptors and the 5 alpha-reductase should be measured to evaluate the overall androgenic effect.
The changes in the cellular level regarding the activity and the size of cells and their numbers will provide insight into the actual changes taking place.
In individuals with advanced AGA, some will have an extensive hair loss leaving a few hair in the rim (at parietal and occipital region) while others may still have plenty of hair in the rim though completely bald on the top. This discripancy should be studied to find out whether the reason behind this difference is the structure and the extent of the scalp, difference in the skull, types of skin or variation in the androgenic activity or a combination of these.
The cases of ‘werewolf syndrome’ can provide an understanding of the structure of the follicles and the distribution of the receptors in the forehead and why the forehead is devoid of hair in normal individuals.
Consequences of the hypothesis
Effective prevention and treatment strategy for AGA
This theory explains how the events actually take place at the micro and macro levels in the scalp tissues during the various stages of AGA. This will enable us to devise stage-specific strategies for the prevention and treatment of baldness. The newer therapeutic molecule implants and procedures can also be tried which can counter the said mechanisms.
Understanding the other causes of baldness
It may be helpful in understanding the other causes of hair loss which are not associated with androgens. There may be different factors responsible for somewhat similar mechanism as discussed above leading to hair loss, which may be irreversible in certain instances.
Understanding the other vestigial organs
It may also help in understanding how the organs regress and become vestigial.
Explanations of the various situations
Why the narrow horseshoe-shaped band of hair on the parietal and occipital region till late stage in the androgenic alopecia?
Some amount of hair loss also occurs in these areas but the hair fall is not progressive. Firstly, the subcutaneous layers are not as tough as those in the scalp that extends up to the superior nuchal line on the back and the superior temporal lines on the sides, thereafter it merges with the normal skin. Secondly, the underlying muscles allow some expansion, though there is an underlying bone. Thirdly, it is not on the topmost pressure area. Thus, the above-discussed arrangement of the blood vessels being compressed is not very severe in parietal and occipital region and the structural changes and the vicious cycle do not aggravate hair loss. Equilibrium sets in and the number of hair follicles in the anagen phase is maintained as much as the interplay of the biological and the mechanical factors allows. The supplies are normally sufficient to grow enough hair and there is no bald area. However, gradually, over a period of time, the hair in these areas also tend to grow slower and become thinner and weaker. In some severe cases of AGA, hair in this area are also very scanty.
Baldness in women
In comparison with men, there is no secretion of significant amounts of testosterone in women which explains the lack of certain puberty associated changes such as body hair or change of voice in women during puberty. Accordingly, the structural changes in the scalp proposed to be the causative factor of AGA also do not occur. Therefore, there is no significant change in the quality of hair in women till menopause under normal circumstances.
Following menopause, the incidence of androgenic alopecia increases in women and is characterised by diffuse thinning of hair in the frontal and parietal regions while the frontal hairline is preserved. Menopause is the time when other organs and also the skin of the normal individuals show a lot of changes. The age-related changes in the skin are slow till menopause as estrogens are protective, thereafter changes take place rapidly. The diffuse hair loss can be a part of those changes [43].
However, AGA may be observed in some cases before the menopause is attained or afterwards. Certain disorders such as polycystic ovarian syndrome (PCOS) or increased consumption of anabolic steroids are some examples of this situation, wherein there is an exacerbated effect of androgen. This may be either due to elevated levels of the hormone or due to increased sensitivity as a result of increased androgen receptors or 5-alpha-reductase activity in the scalp [44]. When the structural changes occur at an early stage then hairline recession, etc. can also be seen in women at an early stage (such as in sportswomen and in certain hormonal imbalances).
A notable feature here is that although hair loss may be observed in normal women due to certain physiological conditions such as pregnancy, unlike men, such women tend to have a significant amount of hair regrowth [45]. This may be attributed to the fact that structural changes in the scalp as noted in men do not occur in women under normal physiological circumstances.
Genetic predisposition of androgenic alopecia
AGA is said to be transmitted in an autosomal dominant pattern with variable penetrance. However, a definite pattern and transmission of AGA is not seen. The reason according to this theory could be the fact that the underlying factors of pathogenesis such as number, type and sensitivity of the ARs, the 5-alpha-reductase activities, the skin type, and the structure of the scalp and the skull are genetically determined. The hair follicles and sebaceous glands may also differ genetically in how they react to the androgens. The appearance of baldness is the outcome of the interplay of these factors. Therefore, a variation in the inheritance pattern of AGA is found.
Predictions
The galea aponeurotica (GA) is a tough layer of dense fibrous tissue lying between the two parts of the occipitalis muscle and on its sides are anterior and superior auriculares [46]. Interestingly it covers almost the same area as the fully developed bald area in AGA. It is suggested that GA was once a muscular structure in continuation with the other surrounding muscles. In the course of evolution it has become tendinous, because of the mechanism discussed above leading to compression and compromised blood supply. The decreased supplies were not sufficient for the survival of the muscle and hence GA has become a fibrous tissue.
AGA is nothing but a process of the extension of the hairless scalp at the forehead and the top of the head may also become permanently bald in the time to come and the brain would develop other mechanisms to protect itself.
Conclusion
The role of androgens in AGA is proved beyond doubt. Nevertheless, the question remain unanswered is why and how an anabolic hormone which is responsible for hair growth over the body causes increased hair loss on the scalp. According to the proposed theory AGA may be the result of counterproductive effects of androgens. Protein deposition in the target organs, one of the fundamentals to the androgenic effect proves detrimental to the scalp tissue leading to compromised blood and nerve supply. This normally results in hairline recession and some hair loss in men. However, in some cases a vicious cycle of structural changes and compromised supply starts which leads to occurrence of AGA. Thus hairline recession and complete baldness are the two extremes of the spectrum of hair loss owing to the counterproductive effect of androgens.
Conflict of interest
None declared.
Sources of support in the form of grants
None.
Patent information
The method, procedures and the molecules in line with the theory have been applied for patent.
References
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