Baldness: Theory and practice of treatment, part 1

Dehydrotestosterone is mine, my enemy

Vizavi, Habr

Judging by one of the recently published articles, the topic of baldness is quite interesting for the local public, so I decided to write a couple of posts about the disease itself and its treatment methods. To be more precise, it is not exactly a cure, because there is no means for a permanent solution to the problem on the market yet, we are talking about stopping the development and returning lost hair.

No matter how strange it may sound, but most people, even when faced with androgenic alopecia, it is also male–type baldness (hereinafter – AHA), do not understand the nature of the disease.

In the first post there will be a description of the disease itself, what it starts with, and the actual methods of treatment based on blocking dihydrotestosterone (DHT) and androgen receptors. Despite the fact that this approach has become quite outdated over the past 10 years, it is still more than effective.

So, what is AHA?

This is a gradual reduction and degradation of the hair follicle – the organ that "creates" the hair. (Hair is not a living tissue, it does not contain living cells and does not exhibit metabolic activity). As a result of degradation, pigmentation and hair thickness decrease over time, and healthy hair turns into fluffy.

Contrary to popular belief, hair loss does not lead to baldness and, on the contrary, it is absolutely natural. Unlike, for example, nails, hair does not grow constantly, but in cycles, the last stage of the hair growth cycle is its loss. After this stage, the cycle begins again, and with it a new hair grows. But with AHA, the phase of hair growth is reduced, which in turn leads to a reduction in the amount of hair on the scalp.

The growth and development of the hair occurs in a strictly cyclical order: the growth phase (anagen), the degradation phase (catagen), the resting phase (telogen).

In case of successful completion of the entire cycle, the hair grows back in its original form after the completion of the last two phases. In addition to the growth of the hair itself, important parts of the epithelial follicle also develop in the anagen phase: keratinocytes of the hair matrix located around the follicle show the highest activity in this phase of growth. Also in this phase, the newly formed hair undergoes pigmentation (Paus and Cotsarelis, 1999).

During the next phase, catagen, the follicle goes to controlled degradation – an increase in programmed cell death (apoptosis) in most follicular keratinocytes, cessation of pigment secretion, significant extracellular matrix rearrangement, follicle reduction (Paus and Cotsarelis, 1999).

During telogen, the hair comes to a dead state, but is firmly held in the bulbous base of the follicle until it eventually falls out (as a rule, during washing, combing or other mechanical action). It has not yet been established whether the final loss of dead hair (teloptosis) is also an active, controlled growth phase, or it is simply a passive consequence of the regrowth of a new hair in the follicle (Paus and Cotsarelis, 1999; Pierard-Franchimont and Pierard, 2001).

There are great differences in these phases; depending on the location of the hair on the body, the duration of the anagen also varies and determines the type of hair and its length (Paus and Cotsarelis, 1999). On the scalp, the hair is in the anagen phase for 2-7 years, and the duration of telogen is about 100 days, which means the ratio of hair in anagen and telogen is about 9 to 1. For the most part, the amount of new hair on the scalp corresponds to the number of fallen out and is about 100 per day, thereby maintaining full coverage of the scalp.

It is worth understanding that this is a very conditional figure: to determine the "normal" amount of hair that has fallen out, you need to know both the amount of hair on your head (which varies depending on gender, race and hair color) and the duration of the telogen phase, and in general the formula will look like this:
the amount of hair X 0.1 : the duration of the telogen phase in days.

In the terminal stage of degradation, the follicle does not "die off" and continues to function, however, the hair produced by it is too thin and short and visually almost indistinguishable. Over time, the hair growth shaft is closed by connective tissue. In histological examination of a scalp biopsy, miniaturization of terminal hair is often associated with lymphocytic infiltration and, ultimately, fibrosis (Jaworsky et al., 1992; Whiting, 1993). This phase can be considered a "point of no return" for the pharmacological treatment of AHA.

Causes of the emergence and development of AHA

The reason for AHA is considered to be genetically "increased" sensitivity of hair follicles on a certain area of the scalp to androgens – male sex hormones. Studies of men deprived of testicular androgens (in other words, castrates) have proved that testosterone or its metabolites are the root cause of the development of AHA. Men who were deprived of testicles before the end of puberty were never exposed to AHA; the development of AHA was triggered when testosterone was injected into castrated men (Kaufman, 1996). The same data is true for people who have changed their gender.

Nevertheless, even almost complete elimination of androgens only stops the development of AHA, but does not return the follicles to their normal appearance, which suggests that in addition to the androgenic effect, other processes are involved in the development of AHA.

Despite the fact that any androgen is involved in the development of AHA, since they all bind to the same androgen receptor (AR), dihydrotestosterone (DHT) has the greatest effect.

Here, the so-called "dihydrotestosterone paradox" manifests itself, in which DHT causes body hair to grow, but at the same time fall out on the head. DHT is 2-3 times more stable than testosterone and 5 times longer than AR (Grino PB, Griffin JE, Wilson JD 1990).

DHT is synthesized directly in the target tissues (in our case, we are talking about the skin), with the connection of testosterone synthesized in the testicles with the enzyme 5-alpha-reductase.

It should also be noted that there are three types of 5-alpha-reductase, and when interacting with each of them, testosterone forms DHT.

And here there is another paradox: type I is most common in the skin, including the scalp. On the other hand, type II is more common directly in the follicle (Hoffmann R, Happle R. 1999)

How to treat?

!!! important!!! It should be noted that all of the following drugs are strictly prohibited not only for use, but also for any contact between women and men under the age of 25.
The slightest dose of any of them can lead to an incurable pathology of fetal development in a pregnant woman and disrupt the formation of masculinity in men (depending on age).

The FDA currently recognizes only two drugs recommended for the treatment of AHA, these are Finasteride and Minoxidil.

The oldest clinically proven way to combat AHA is to block reductase enzymes so that they cannot convert testosterone to DHT in the target tissues. As already mentioned above, even complete elimination of androgens does not return the hair by itself, just as here, the goal of anti-DHT therapy is to stop the development of the disease, other drugs or methods should return the hair. Although, of course, in the early stages of AGA, blocking DHT or androgen receptors of the scalp in many cases is enough to restore hair simply due to cellular regeneration of follicles.

Finasteride

It is aimed at reducing the level of DHT in the body by blocking type II and type III 5-alpha-reductase, the recommended dosage by the FDA is 1 mg per day preorally. The drug is generally well tolerated, the half-life is only 6-8 hours.

There are a huge number of reports about all kinds of side effects of finasteride, ranging from impotence to dementia. Sometimes it seems that, starting taking it, some people write off any of their illness to him, while others experience almost no side effects, after a decade of regular intake. The side effects are well described by the link.

In addition to oral administration, finasteride can be used externally.

According to the information published by Hasson & Wong, the use of finasteride externally did not cause any side effects even in those patients who reported them with oral administration, the effectiveness of therapy was quite obvious. A month ago, the page with the description of finasteride for external use was deleted, and the order page was closed with a password.

Some manufacturers of lotions containing minoxidil add finasteride to the composition.

And at the moment, Polichem is conducting clinical trials of its own form of finasteride for external use.

Dutasteride

The principle of action is the same as that of finasteride, but the effectiveness of blocking reductases of all types is higher, while it blocks type I reductase, which finasteride does not affect. Side effects are similar to finasteride, but with a slightly higher (1-5%) probability. The half-life is several orders of magnitude higher than that of finasteride, and is 5-6 weeks.

Dutasteride is not applied externally due to the molecular weight, too large for free penetration through the skin. However, if an injectable delivery method is used (for example, mesotherapy), studies show improvement and even the absence of side effects is stated.

Blocking of androgen receptors

As the name implies, the meaning of this therapy is simply to prevent the activation of androgen receptors on the scalp. Since the receptor as a whole is blocked, and not a separate hormone activating it, in theory, such therapy should be several times more effective than blocking DHT, and have a lower chance of side effects. There is no official data on the half-life, however, judging by the dosages in clinical trials, both drugs are recommended to be used twice a day, 1 ml at a 5% concentration.

RU58841 (PSK 3841)

The drug, which was developed for the treatment of acne and AHA, is used exclusively externally, in the form of a lotion, getting into the systemic circulation can cause side effects similar to dutasteride. The research and development of the drug was conducted more than 20 years ago, several cycles of clinical testing on humans were conducted (1, 2), the results of which the company (according to their comments) was quite satisfied, but it never officially entered the market. The reasons have not been officially announced, but there are several versions:

1) That according to the results of clinical studies on humans, the effectiveness was insufficient.
2) That this is due to the expiration of the monopoly patents on the drug, which makes it a commercial failure, and its testing is unprofitable.

At the same time, the drug is manufactured in a variety of private laboratories and is used at will, the typical dosage is 5%.

CB-03-01 (Breezula)

The principle of action of the drug is similar to RU58841; according to users who used both drugs, there was no difference in effectiveness. Currently undergoing clinical testing in Europe at concentrations of 1% and 5% for the treatment of acne and AGA, respectively. According to the results of double-blind testing, Breezula showed a better effect than minoxidil and no systemic side effects. The drug is also sold by third-party companies, despite the fact that a commercial launch is scheduled only next year.

Other drugs

In fact, they are not very relevant here, since in fact they have nothing to do with either DHT or AGA in general, but it would be even more inappropriate to write about them in other articles.

Minoxidil

The second drug approved by the FDA for the treatment of AGA. In essence, it is not a cure for AHA, but only a fairly effective stimulator of the growth of any hair, both healthy and damaged, on the scalp, on the body, everywhere. Minoxidil is effective exclusively in the sulfate form, into which it passes due to the enzyme sulfurtransferase, and individual differences in its concentration in the scalp are the main reason that the effect of it does not manifest itself in everyone and the effectiveness also varies. There is also an active compound, minoxidil sulfate, which does not require sulfurtransferase. It is worth mentioning that there are a huge number of fakes on the market (Ukraine especially "stands out" here, where all stores are littered with a certain drug based on a compound unknown to science minoxidiN), and it is better to overpay for delivery a little, order it in trusted Western stores. The use is the same as with the previous drugs – externally, 1 ml of 5% r-ra twice a day.

Shampoos containing Ketoconazole

In contrast to the popular opinion, DHT is not affected (and it cannot be with such a method of application, too high molecular weight, a solution of water and surfactants is a very poor method of delivery). Nevertheless, they effectively suppress pathogenic microflora, reducing inflammatory processes and improving the delivery of external drugs.

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