by Thomas Incledon, PhD(c), RD, LD/LN, RPT, NSCA-CPT, CSCS
Introduction
Recently, I was asked by some guys to develop a product that could elevate free testosterone (T) levels. While I think that it is theoretically possible, I know that I’ll have some work to do. Throwing a bunch of ingredients in a pill or capsule, like most companies have done, is not the answer. Each ingredient has to be tested for its effects on the body’s endocrine responses to verify it will do what it is supposed to do. Then they must be tested collectively to determine what interactions may or may not take place. The first article of this series describes how the body controls T synthesis and release and explains why formulating a product to elevate free T is so difficult. Future articles will review various supplements, extracts, diets, and dietary food components to see if they influence this process.
An Overview
Our bodies produce T as part of the hypothalamic-pituitary-testicular axis (HPT Axis). In the brain, the hypothalamus produces gonadotropin-releasing hormone (GnRH), which is also referred to as luteinizing hormone releasing hormone (LHRH). GnRH stimulates the anterior pituitary to produce and release luteinizing hormone (LH). LH then stimulates the testes to produce T. Once produced and secreted into the blood, T can exert its biological actions on skeletal muscle. This very basic overview can be seen in the accompanying chart:
Starting From the Top
GnRH is an important hormone because it starts the whole cascade of events that eventually lead to T production. In order to understand how to maximize T production, it becomes crucial to learn more about GnRH. Looking at the previous chart, it seems that by increasing GnRH release, LH would increase and then T would increase. However, constant infusion of GnRH into someone doesn’t elevate their T levels, it actually suppresses them [1]. It seems somewhat confusing that the same hormone can both stimulate and inhibit T. The confusion is cleared up when the pattern of GnRH release is studied. The cells that produce this hormone don’t do it in a steady continuous fashion, rather they produce and release the hormone in spurts or pulses [2]. This pulsatile release of GnRH from these cells inspired researchers to coin the phrase “GnRH pulse generator” or “LHRH Pulse generator”. The body produces GnRH in a series of pulses throughout the day.
The pulse generator is influenced by signals from the eyes and nose, the pineal gland, and from stress [3]. These signals are converted into neural signals which then serve to stimulate or inhibit the release of GnRH. The links that communicate the information from the nerve cells to the GnRH secreting cells are small molecules collectively referred to as neurotransmitters. Factors that fall into this category include bioamines, neuropeptides, excitatory amino acids, and gaseous neurotransmitters. Examples of some excitatory factors are norepinephrine (acting through b1 receptors), neuropeptide Y, galanin, nitric oxide (NO), substance P, transforming growth factor a (TGFa), and prostaglandin E2 (PGE2). Under the right conditions, any of these factors can stimulate GnRH. However, blocking the release of one or more of these factors can decrease or prevent the release of GnRH. In addition, research on the endocrine effects of fasting indicates that a lack of calories and/or nutrients decreases GnRH release dramatically [4]. After refeeding, the hormonal pattern should return to normal.
I’ve tried to simplify the process so it is easy to follow. Note that in doing so, some of the technical accuracy is lost. For example, some factors may inhibit and stimulate GnRH, depending on the other factors present [5]. Rather than bore you with the details, it’s better to understand the whole picture. Future articles will present this area in depth because I think that the “upstream” stimulation of T may hold some promise. Many factors influence the amount and pattern of GnRH release. By setting up a scenario where the pattern of GnRH release is unchanged, yet the amount of GnRH released with each pulse is maximized, it should theoretically maximize T levels. However, at this point the quest is just getting started.
Journeying Downward
After the hypothalamus has done its job of releasing GnRH (or LHRH), the baton is passed to the anterior pituitary. While this organ has the responsibility of synthesizing many different hormones (FSH, GH, TSH, ACTH, etc) our focus is on the synthesis and release of LH. The pulsatile secretion of the pulse generator causes a similar secretion pattern in LH [6]. The secretory pulses in adult men vary in frequency from 8-14 pulses per 24 hours and in magnitude [7]. LH levels range in men from 1.3 to 13 IU/L (international units per liter). Factors that can influence LH secretion (assuming that GnRH is being produced in a normal pulsatile fashion) include androgens that have not been aromatized to estrogens, estrogens, and opiate blockers [3]. Current thinking, however, is that estrogens inhibit LH release not by acting on the pituitary, but by acting on components of neurons that lie outside the hypothalamus. Many supplement companies have tried to come out with estrogen inhibitors with the logic being that by inhibiting estrogen production in men, there would be less of an inhibitory effect on T production. Later we shall see while this may work acutely, over time the body will figure out how to tone down the biological actions of T.
Arriving At the Source
After LH receives the baton from T, it travels to the testes, attaches to receptors on Leydig cells, and stimulates the synthesis of T via activation of a rate limiting enzyme [3]. T levels don’t just increase indefinitely, though. As T levels increase, more of it is available to inhibit its own production. As T levels increase, T travels in the blood, crosses the blood brain barrier, and makes its way into the brain where it can directly [8, 9] or indirectly [10-12] inhibit GnRH and LH levels. This process whereby T keeps itself in check is called negative feedback inhibition. There is sufficient evidence at this time to show that T (or one of its metabolites) can inhibit its production directly on the testes and indirectly on the hypothalamus or pituitary. So let’s say that we get T levels up, how long will it last before the body will say that’s it, time to go back down? Most likely, the negative feedback effects of T will occur in only a few days.
Obstacles From Afar
As T is produced and released, it can travel in the blood attached to a protein or travel in a “free” state. About 54% of T is bound to albumin and other proteins, 44% is bound irreversibly to SHBG (sex hormone binding globulin, also called TeBG testosterone binding globulin), and the remaining 2% is free or unattached to any proteins [13]. T can be removed from the other proteins, but not from SHBG [14, 15]. This is another way the body regulates androgen action. By increasing and or decreasing SHBG levels (a protein produced by the liver), the fraction of T that can be taken up by tissues can be controlled. The testes also release small amounts of dihydrotestosterone (DHT) [16] and estradiol (E2) [17]. T can be reduced to DHT by the enzyme 5-alpha-reductase or aromatized to E2 by the enzyme aromatase. In humans there are two versions or isozymes of the reductase enzyme [18], while only one version of the aromatase enzyme has been identified [19]. Since there are two isozymes for reductase, an agent that binds an isozyme of reductase in one tissue, may not bind the other version of the enzyme in another tissue. Another point is that many supplement companies have claimed to have a product that could inhibit the conversion of T to E2. The premise being that to increase T levels, the only thing you need to do is suppress brain aromatase levels. As pointed out earlier, while this may decrease the inhibitory effects on the hypothalamus, it will do little for the inhibitory effects of androgens on the anterior pituitary, nor will it address the issue of increased liver production of SHBG.
The Problem Continues
Let’s take another look at that basic diagram. This time we will add in the additional information. Understand that this simple chart does not accurately reflect all the signals bombarding the cells of the HPT Axis, nor does is relate all the subtle details of their interactions. It does give a good general overview, which will allow me to illustrate my next points.
Let’s say you want to take a supplement to increase your testosterone levels. We’ll assume that you are also a normal healthy male and that all the organs in your HPT Axis are intact and functioning. The type of supplement is immaterial at this point. From above we can see if the supplement does increase T levels, the body can respond by increasing the conversion of T to DHT and/or E2. In turn T, DHT, and E2 can all inhibit future production of T. So elevating T by itself does not work well in the long run because the body can compensate for this elevation. Let’s suppose you decide to take a dual anti-reductase agent and anti-aromatase agent in the hopes of reducing the conversion of T to DHT and E2. Several things have to happen. To decrease the release of DHT and E2 from the testes, the agent must somehow get from your gut and survive digestion intact (assuming this is an oral agent), and enter the blood. From there it must travel in the blood to your testes and then somehow bind to the reductase and aromatase enzymes with a high affinity. This might allow more T to be released from the testes and less DHT and/or E2. Now the question you should have at this point is what happens when more T is released from the testes? Earlier it was mentioned that the liver produces SHBG and this is one way the body can regulate T bioactivity in the body. So if total T levels increase, more SHBG will be produced. Then while total T may be elevated, the percentage of free T will be decreased because more T will be bound by SHBG. But the body doesn’t stop there because most of the controls for T production are in the hypothalamus and pituitary. So if an agent can influence T production from the testes directly, the body can still modulate production higher up. Now for an agent to have an effect in the brain, it must be able to cross the blood brain barrier, and this is not an easy task.
Now, you get the point - the always body strives to maintain a “normal” environment. When you look at all those products on the shelf of your local food supplement store, keep some of these things in mind. It is very difficult to elevate T levels enough to put on muscle without the body somehow decreasing T production or its biological activity. The challenge that I have before me is to develop a product that can increase the free fraction of T without the body rebounding and increasing SHBG levels or decreasing T production. While this is no easy task, I’ve always enjoyed a good challenge, and this one will not fail to disappoint me. Stay tuned to T-mag and be the first to find out about some T supplements that will work.
References
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14. Pardridge, W.M. and L.J. Mietus, Transport of protein-bound steroid hormones into liver in vivo. Am J Physiol, 1979. 237(4): p. E367-372.
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19. Corbin, C.J., et al., Isolation of a full-length cDNA insert encoding human aromatase system cytochrome P-450 and its expression in nonsteroidogenic cells. Proc Natl Acad Sci U S A, 1988. 85(23): p. 8948-8952.
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