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27.05.2011 | Sławomir Ambroziak | 0 komentarzy

Keywords: DHT, testosterone, 5 alpha-reductase, aromatase, estradiol, 3 alpha HSD, 3 beta HSD, 3 alpha adiol, 3 beta adiol, isoflavones, androgenic receptors, alpha estrogen receptors, beta estrogen receptors.

Dihydrotestosterone (DHT) is a metabolite of testosterone – a major anabolic hormone that builds our muscles. The more testosterone in the body, the greater level of DHT. For years it has been believed that DHT has no effect on the muscles and is only responsible for the adverse effects of testosterone – seborrhoea, hair loss and prostate hypertrophy.

However, the results of new research and opinions of athletes seem to contradict those old beliefs… How would you explain the fact that the use of testosterone in conjunction with medications or supplements that inhibit its conversion to DHT gives weaker anabolic effects than the 'pure testosterone treatment’, without similar extra supplementation…?

Does it mean there’s no alternative here? Do high testosterone level and superb muscles have to be associated with acne, male pattern baldness and problems with urinating?

Testosterone kingdom

Every power sports lover knows that testosterone is one of the most anabolic hormones – those that retain the protein in muscle tissue and promote muscle development. Testosterone belongs to a group of androgens – male sex hormones. Although we have already learned about a whole bunch of anabolic hormones such as insulin, GH, or IGF, as well as we have synthesized a wide range of anabolic-androgenic drugs, the popularity of testosterone among athletes has been consistently at the highest level for over half a century. Certain empirical experience of athletes with testosterone is of a great importance as it shows that the hormone efficiently develops strength in proportion to muscle mass, which is particularly important in disciplines with weight limits. Therefore, sport supplements called testosterone boosters are extremely popular as they are believed to help raising levels of testosterone (eg TRIBUSTERON 90). Also, the pharmaceutical forms of the hormone are in demand. Low price highly affects their attractiveness – they are more affordable compared with other anabolics such as IGF or GH. Another thing is a relatively high safety of testosterone, for example, in comparison with that of insulin, which taken imprecisely can lead to serious health problems – even death. What is more, testosterone perfectly enhances the activity of other anabolic steroid, which is a valuable addition to 'treatment’ carried out with a mix of GH, insulin and IGF. Last but not least, testosterone is a compound which use is relatively difficult to be proved by anti-doping committees and which can be easily included in all sorts of doping regimes.

Testosterone is the first hormone that has been used as an anabolic agent before the start of World War II. But we all see that the old testosterone continues to reign among the anabolics.

From Testosterone to DHT

Testosterone enters the muscle cells, where it connects to a specific protein specialized in binding – the androgen receptor (AR). Androgen receptor is also a transcription factor, which – activated by testosterone – stimulates genes to produce proteins. These stimulated genes enhance in turn the synthesis of these biomolecules – both structural proteins, such as contractile proteins of muscle fibres, as well as enzymatic and signaling proteins – and among the latter – for example growth factors and local tissue anabolic hormones, which activate other transcription factors, stimulating next genes to produce more muscle protein. Muscle mass and muscular strength keeps growing…

However, in this direct way testosterone works only in muscle tissue. In other tissues, androgen-dependent or sensitive to their effects, testosterone is only a prohormone. In cells of these tissues, an androgen receptor protein is not the main target for testosterone. The target is a protein enzyme – 5-alpha reductase. 5-alpha reductase influences a conversion of testosterone to DHT, which binds to androgen receptors and stimulates genes to a production of structural, enzymatic and signaling proteins, thus contributing to an organ or tissue enlargement. These events occur just in the prostate, which leads to its hypertrophy and related ailments. Not only is the prostate affected, but also the sebaceous glands. DHT causes that the glands grow and produce more sebum, which in turn favours acne and seborrheic dermatitis development. DHT initiates a process of follicular miniaturization – and consequently – a distinctive androgenic pattern baldness.

So if we increase the level of testosterone in the body – be it with weight training and proper diet and/or dietary supplements, and finally with hormone injections – we significantly develop our muscle mass, but also accelerate the process of hair loss, and we expose ourselves to skin and urological problems.

Different ways for DHT

However, minor problems with acne, alopecia and prostate will not be able to stop sports-loving recreational athletes and their ambition to develop their strength and muscle mass, not to metion professional athletes who are determined to succeed. Now, they usually start to use 5 alpha-reductase inhibitors – drugs that inhibit the activity of this enzyme, and thus block DHT production and lower the levels of this hormone inside the target cells. Amateurs who try to rise the levels of testosterone with training, diet or testosterone boosters, usually use milder herbal agents. Most of these supplements are based on extracts of saw palmetto fruit (ex. PROSTATAN). Whereas other strength enthusiasts, who take AAS such as Undestor, Omnaderen or Testosteronum Prolongatum, usually need to go for something stronger… They may take Finasteride or Dutasteride – therapeutic substances effectively lowering levels of DHT by about 70 and 90 percent respectively. This is dictated by the bitter experiences of previous generations of athletes … For many of them – the long-term taking of high doses of testosterone led to such serious urological problems; for example, they had to undergo a bladder catheterization as well as a surgical treatment of their prostate.

Theoretically, the inhibition of 5 alpha reductase seems to be by all means beneficial … If you block the production of DHT, then – even with some extra testosterone – we will reduce the risk of developig acne, baldness and prostate enlargement. If you reduce the conversion of testosterone to DHT, more hormone will remain unchanged for the development of muscle – and you should remember by now that testosterone works in your muscles without prior conversion to DHT.

Inhibiting the production of DHT also prevents other health problems associated with the use of testosterone. DHT is an important regulator of so called the hypothalamic-pituitary-gonadal axis. The hypothalamus releases GnRH (gonadotrophin-releasing hormone) that in turn stimulates the pituitary gland to secrete gonadotrophin – a hormone stimulatin cells in the testicles and inducing them to produce testosterone. Testosterone produced in the testicles and present in the blood stream circulates now to many tissues (eg muscle, skin, prostate), including the brain. Here, it inhibits the activity of the hypothalamus and pituitary glands, what is called a negative feedback loop, and what constitutes a regulatory mechanism – which limits weight gain of our testicles and production of testosterone, protecting against excessive levels of this hormone in the body. But when we administer high doses of exogenous testosterone for a long time, it effectively suppress gonadotropin secretion that sometimes it may lead to testicles atrophy. However, in the brain, as in most tissues, testosterone becomes active only after its conversion into DHT. It is not difficult to guess that blocking this conversion will neutralise the inhibitory effect of testosterone on the hypothalamus and pituitary glands, and protect the testicles from the disastrous effects of gonadotropin deficiency. It is also worth noting that in guys who use natural methods of increasing testosterone the inhibition of DHT formation will unblock the hypothalamic-pituitary-gonadal axis and will additionally increase the level of testosterone. And yes – when using 5-alpha reductase inhibitors generally higher testosterone levels have been reported.

And a problem occurs…

In theory, everything looks spiffing…!

Not only should 5 alpha-reductase inhibiton protect us against any adverse effects of exogenous testosterone administration, but also at the same time it should strengthen its anabolic activity in the muscle tissue. The problem is that the empirically observed situation is quite different. It has been reported that the addition of 5 alpha reductase inhibitors to 'testosterone treatment’ reduces its anabolic effectiveness. What may be causing this state of things?

It has been long believed that in muscle cells testosterone is not converted to DHT because there is no enzyme catalysing this conversion there ie. 5 alpha-reductase. However, recent studies have shown that the enzyme is also active here and that DHT is also synthesised in muscles. What is more, our liver occurred to be a great source of DHT that reaches our muscles. Our liver produces this hormone of testosterone and secretes it into the bloodstream. Thus, muscles, although they may not require this, can use not only testosterone, but also DHT to stimulate their growth. And here an important note – DHT binds to androgen receptors several times stronger than testosterone and – as it has been observed – is the most potent anabolic androgen, ten times stronger than its precursor.

This could explain the phenomenon of lower efficiency of 'testosterone therapy’ fortified with 5 alpha reductase inhibitors, if not a minor detail. As it turned out, with not quite understandable reasons, enzymes inactivating DHT – 3 alpha-HSD and 3 beta-HSD (but especially – the first one) show a very high activity in the muscle cells. These enzymes rapidly convert DHT, often before it has chance to bind to any receptors, to low active androgens – 3 alpha-adiol and 3 beta-adiol respectively. Therefore, DHT has no chance to show its anabolic properties in muscle tissue, even if it is synthesised inside it or it is transported there from our liver. That was thought until recently, but this belief is changing again…

It turned out that 3 alpha-HSD is an enzyme catalysing the reversible conversion of DHT. Although this hormone is transformed in 3 alpha adiol, but then again it is converted back to DHT. Thus, 3 alpha adiol is not merely 'metabolic waste’ of no anabolic effects, but it creates a kind of alternative form of DHT.

The crux of the matter

But the key to solving our puzzles may be that other DHT metabolite – 3 beta adiol. Imagine how much the researchers must have been surprised when they noticed that the hormone showed estrogen activity? Until then, it was thought that estrogen could be formed as result of a conversion of two androgens – testosterone and androstenedione; and DHT can not be the source of these hormones. Estrogen is a signal molecule, thought of as of female sex hormone. Today, however they are believed to be unisex hormones because they are synthesised by both male and female bodies, and their importance for both sexes is equally important. For example, estrogens are very potent anabolics, even more potent than testosterone. Female muscle mass isn’t on average smaller than male one because women produce a lot of estrogen, but because huge of amounts of gestagens are synthesised in the female body. It is gestagens that are the real, female sex hormones and they don’t occur naturally in the male body (only trace amounts). Progesterone (the most important gestagen) binds to androgen receptors in place of testosterone, which occurs in women only in a limited amount; this binding very weakly stimulates genes to protein production, which also affects the poor muscular development. For a change – estrogen strongly stimulates muscle development, acting through androgen receptors as well as their specific estrogen receptors. It has been proved that testosterone alone is not enough to develop great muscle mass, the hormone needs estradiol (the most important estrogen) in a specific proportion of 80:1. The reason for that is that the estrogens act as so-called androgen sensitisers that bind to androgen receptors together with testosterone or DHT, but in places specializing in binding of so-called transcription coregulators, which enhance their transcriptional activity and determine the high rate of muscle protein anabolism. However, acting on the muscles through its own estrogen receptors, estrogen stimulates mainly the production of another anabolic hormone, IGF, and the transformation of immature satellite cells (myoblasts) into functional muscle cells (myocytes).

AAS users do not currently take estrogen into consideration in their performance enhancement (it is believed that in the past the German Democratic Republic coaches used to administer this hormone to their athletes). The reason for this is that estrogen administration generates extremely unpleasant side effects such as excessive development of male breasts, called gynecomastia, or gynoid obesity (normally displayed in femal subjects) which means that fat tissue is accumulated mainly in the lower part of the body (thighs and buttocks). Under their influence, enlargement of the prostate will be as equally spectacular as under the influence of high doses of testosterone. Estrogens also negatively influence the hypothalamic-pituitary-gonadal, axis, and like DHT they contribute to the loss of testicular tissue, which is the result of prolonged use of high doses of testosterone.

This effect comes from the fact that has been already mentioned above – estradiol is a metabolite of testosterone. The conversion of testosterone to estradiol is catalysed by aromatase, which acts simultaneously with 5 alpha-reductase that converts testosterone into DHT. A high level of testosterone means a high level of estradiol. And when we take high dosages of exogenous testosterone, estradiol levels go sky high very quickly what may cause the adverse effects mentioned above. Therefore, athletes who try to rise testosterone level whether naturally or not tend to lower their estrogen levels at the same. Thus, the first take supplements blocking aromatase activity, while the others certain drugs. It is worth mentioning that herbal aromatase blockers are often added directly to natural testosteron boosters. This can indeed help to avoid the adverse effects of estradiol, but again – as in the case of blocking 5 alpha reductase – it reduces the effectiveness of anabolic 'testosterone therapy. Now we see it very clearly that simultaneous blocking of aromatase and reductase almost completely deprives your muscles of anabolic estrogen, because there is no conversion of estradiol from testosterone nor DHT of 3 beta-adiol.

The strength of a weak hormone

Well, you will probably ask now – why I’m crying over spilled milk? Why am I so concerned about that 3 beta-adiol and pay no attention to estradiol – the most important estrogen?

Estradiol is a potent estrogen, while 3 beta-adiol belongs to the weak estrogens, such as 17 alpha estradiol. It turns out that the difference between strong and weak estrogen activity is based not only on the strength of receptor binding – as it’s in the case of stronger and weaker androgens (eg. DHT and testosterone), but – above all – on an affinity to a particular type of receptor. There are two types of estrogen receptors in the body – alpha ER and beta ER. Potent estrogens have their metabolic effects mainly through binding to alpha ER and activation of alpha ER-dependent genes, while the weak mainly through binding to beta ER and beta ER-dependent genes. This brings us to the crux of the matter…

It occurs that alpha ER are responsible for the most of the negative effects of estrogen on the male body, while beta ER – for the most positive ones. It seems that beta ER make the greatest contribution to the estrogen induced development of muscle tissue. Also, probably through the beta receptors estrogen prevents hair loss and skin problems. We certainly know that the weak estrogens, binding to beta ER, act in our prostate oppositely to their powerful relatives – they prevent prostate hypertrophy and other prostatic diseases. Lab animals that have been deprived of beta estrogen receptor gene tend to rapidly develop a significant prostatic hypertrophy. What is more, these hormones have a positive influence on mental functions and male libido, but their participation in the regulation of hormonal axis and the appearance of feminine attributes of physiognomy in men (gynecomastia, femoral-gluteal obesity) is only small or completely negligible. Hence, their nickname – 'weak estrogens’ – weakly influencing female sex characteristics development.
It is also worth noting that – despite the easy conversion of testosterone to estradiol – it is 3 beta-adiol that is the main active estrogen in the male body; its concentration in the target tissues that are able to produce DHT is on average 100 times higher than the estradiol concentration.

All these facts let us assume that it is primarily a 3 beta-adiol deficiency that is responsible for the reduction of the anabolic effectiveness of testosterone treatment fortified with 5-alpha reductase blockers.

Checkmate, or just a standoff situation…?

It seems that once again we find it really hard to outsmart Mother Nature.

The whole situation resembles a vicious circle… When you raise (either naturally or pharmacologically) the level of testosterone – the composition of our muscles clearly improves, but also levels of DHT – the hormone detrimental to the skin, hair and prostate – increase. When we block the production of DHT – skin, hair and prostate benefit a lot, but at the same time the anabolic activity of testosterone in muscle tissue decreases, which makes us think whether we should interfere with testosterone production while blocking DHT, because if the ultimate effect will be identical as the one with workout only, then what’s the point to make ourselves have to worry about hormone levels…?

This situation is an accurate reflection of therapeutic problems encountered in urology, the treatment of benign prostatic hypertrophy. Here, in the first place, the aim is always to reduce the level of DHT as it is this hormone that’s primarily responsible for the development of this troublesome ailment. In order to reduce the level of DHT 5 alpha-reductase inhibitors such as finasteride or dutasteride are used. This regime is very effective in the first stage of treating this ailment, but it becomes much less effective as the time goes. Trying to figure out the cause of this phenomenon, researchers have found out that a deep deficit 3 beta-adiol in prostate tissue, resulting from a long-term shortage of its precursor – DHT, is the main reason here. This deficit causes that our prostate has no protection that in healthy subjects results from the activity of beta-type estrogen receptors.

After diagnosing the problem entirely, experts have focused on finding and testing weak estrogens administered from the outside – along with 5 alpha reductase blockers – that are capable of replacing endogenous 3 beta-adiol in the prostate in the absence of its precursor, DHT. Weak estrogens would be supposed not only to protect the prostate, but generally promote health and vitality of older men. However, test and registration procedures are extremely time-consuming, thus we do not known when weak estrogens – as new drugs – will be on pharmacy shelves; therefore, some urologists offer an interesting advanced solution. It occurs that some phytoestrogens (plant estrogens), particularly polyphenolic compounds found in soy beans – isoflavones, have all those positive characteristics of the weak estrogens. Isoflavones bind beta-ER more than 20 times stronger than alpha, and therefore – as proved in various studies – show a remarkable protective efficacy against prostate cancer. That is why, more and more professionals encourage us to combine isoflavones with 5 alpha reductase inhibitors in the treatment of prostate diseases.

So maybe it’s worth considering whether or not we would benefit in performance enhacement from the experience of urologists?

Wouldn’t be beneficial to include isoflavones in our testosterone therapy in addition to 5 alpha-reductase and aromatase inhibitors?

In this way, we would inhibit the production of DHT and estradiol (strong, harmful estrogen) and unfortunately 11 beta-adiol, however we could easily replace its useful activity with isoflavones.

These athletes who fancy taking pharmaceuticals will now direct their attention toward selective estrogen receptor modulators (SERMs) such as tamoxifen and raloxifene for these drugs – as it has been revealed earlier – also act mainly through beta-ER. However, since recent studies indicate rather similar affinity of these compounds to both forms of the estrogen receptor, it is still best to remain here unless isoflavones.

Of course I do not recommend to anyone 'steroid therapies’, on the contrary, I strongly agree with people promoting natural performance ehnancement methods. Therefore, I suggest to include isoflavones in traditional testosterone boosters, for example based on ginseng and Tribulus, extracts of saw palmetto fruit (5 alpha-reductase inhibitors) and nettle root extracts (aromatase blockers). These last two components are both often seen in prostate support supplements, such as Prostatin manufactured by Olimp Laboratories.

All our efforts put should result in a situation where we can enjoy a measurable improvement in muscular composition, without worrying about the condition of our skin, hair and prostate.
Moreover, we should enjoy some additional benefits as the isoflavones are potent inhibitors of 5 alpha-reductase and aromatase. However, there is a minor inconvenience ie. these compounds also block 3 beta HSD, thus the conversion of DHT to 11 beta-adiol. This, however, will have no greater significance here, because – as we know – isoflavones themselves will play the role of the latter hormone.

The results of certain studies, in which the administration of isoflavones led to increased anabolic processes and muscle mass development, further convince us that the choice of isoflavones is correct. But that is another issue and another article…