Jim,
I think this is what is being referred to in most cases. Its a bit of a read, but interesting..
Your thyroid gland secretes two hormones that are going to be of primary importance in understanding Thyroid/GH interaction. The first is thyroxine (T4) and the second is triiodothyronine (T3). T3 is frequently considered the physiologically active hormone, and consequently the one on which most athletes and bodybuilders focus their energies on. T4, on the other hand, is converted in peripheral tissue into T3 by the enzymes in the deiodinase group, of which there are three types- the three iodothyronine deiodinase either catalyze the initiation (D1, D2) or termination (D3) of thyroid hormone effects. The majority of the body’s T3 (about 80%) comes from this conversion via the first two types of deiodinase, while conversion to an inactive state is accomplished by the third type.
It’s important to note that not all of the body’s T4 is converted to T3, however- some remains unconverted. The secretion of T4 is under the control of Thyroid Stimulating Hormone (TSH) which is produced by the pituitary gland. TSH secretion is in turn controlled through release of Thyrotropin Releasing Hormone which is produced in your hypothalamus. So, when T3 levels go up, TSH secretion is suppressed, due to the body’s self regulatory system known as the “negative feedback loop” . This is also the mechanism whereby exogenous thyroid hormone suppresses natural thyroid hormone production. However, it should be noted that thyroid stimulating hormone (like all other hormones) can not work in a vacuum. TSH also requires the presence of Insulin or Insulin-like Growth Factor to stimulate thyroid function (1) When thyroid hormone is present without either insulin or IGF-1, it has no physiological effect (ibid).
Most people think that T3 is just a physiologically active hormone that regulates bodyfat setpoint and has some minor anabolic effects, but in actuality, in some cases of delayed growth in children, T3 is actually too low, while GH levels are normal, and this has a growth limiting effect on several tissues (2) This could be due to T3’s ability to stimulate the proliferation of IGF-1 mRNA in many tissues (which would, of course, be anabolic), or it could be due to the synergistic effect T3 has on GH, specifically on regulation of the growth hormone gene. Although it is largely overlooked in the world of performance enhancement, regulation of the growth hormone response is predominantly determined by positive control of growth hormone gene transcription which is proportional to the concentration of thyroid hormone-receptor complexes, which are influenced by T3 levels. (3)
At this point, just to give you a better understanding of what’s going on, I think it’s prudent to also give a brief explanation of Growth Hormone (GH) as well.
Your body’s GH is regulated by many internal factors, such as hormones and enzymes. hormones. A change in the level of your body’s GH output begins in the hypothalamus with somatostatin (SS) and growth hormone-releasing hormone (GHRH). Somatostatin exerts its effect at the pituitary to decrease GH output, while GHRH acts at the pituitary to increase GH output. Together these hormones regulate the level of GH you have in your body. In many cases, GH deficiency presents with a low level of T3, and normal T4(4). This is of course because conversion of T4-T3 is partially dependant on GH (and to some degree GH stimulated IGF-1), and it’s ability to stimulate that conversion process of T4 into T3.
Interestingly, the hypothalamus isn’t the only place where SS is contained; the thyroid gland also contains Somatostatin-producing cells. This is of interest to us, because in the case of the thyroid, it’s been noted that certain hormones which were previously thought only to govern GH secretion can also influence thyroid hormone output as well. SS can directly act to inhibit TSH secretion or it may act on the hypothalamus to inhibit TRHsecretion. So when you add GH into your body from an outside source, you are triggering the body into releasing SS, because your body no longer needs to produce its own supply of GH…and unfortunately, the release of SS can also inhibit TSH, and therefore limit the amount of T4 your body produces.
But that’s not the only interaction we see between the thyroid and Growth Hormone.
As we learned in high-school Biology class, the body likes to maintain homeostasis, or “normal” operating conditions. This is the body’s version of the status quo, and it fights like hell to maintain the comfort of the status quo (much like moderators on most steroid discussion boards). What we see with thyroid/GH interplay is that physiological levels of circulating thyroid hormones are necessary to maintain normal pituitary GH secretion, due to their directly stimulatory actions. However, when serum concentrations of thyroid hormone increase above the normal range we see an increase in hypothalamic somatostatin action, which suppresses pituitary GH secretion and overrides any stimulatory effects that the thyroid hormone may have had on GH. The suppression of GH secretion by thyroid hormones is probably mediated at the hypothalamic level by a decrease in GHRH release(5).
In addition, as IGF-I production isincreased in the hypothalamus after T3 administration and T3 may participate in IGF-1 mediated negative feedback of GH by triggeringeither increased somatostatin tone and/or decreased GHRH production (6). IGF, interestingly, has the ability to mediate some of T3’s effects independent of GH, but not to the same degree GH can (7.) In fact, IGF-I production isincreased in the hypothalamus after T3, administration it may plausibly participate in negative feedback by triggeringeither increased somatostatin tone and/or decreased GHRH production.So we know that GH lowers T4 (more about this in a sec), but an increase in T3 upregulates GH receptors (8) as well as IGF-1 receptors (9,10).
As can be previously stated, and due to the ability of GH to convert inactive T4 into active T3, GH administration in healthy athletes shows us an entirely predicatble increase in mean free T3 (fT3), and a decrease in mean free T4 (fT4)levels.(11)
hGH converts inactive T4 into active T3
Interaction between GH, IGF-I, T3, and GC. GH stimulates hepatic IGF-I secretion and local production of growth plate IGF-I, and exerts direct actions in the growth plate. Circulating T3 is derived from the thyroid gland and by enzymatic deiodination of T4 in liver and kidne.. The regulatory 5′-DI and 11ßHSD type 2 enzymes may also be expressed in chondrocytes to control local supplies of intracellular T3 and GC. Receptors for each hormone (GHR, IGF-IR, TR, GR) are expressed in growth plate chondrocytes.
So, with the use of GH, what we see is an increased conversion of T4-T3, and possible inhibition of Thyroid Releasing Hormone by Somatostatin, and therefore even though T3 levels may rise, there is no increase in T4 (logically, we see a decrease). Now, as we’ve seen, GH is HIGHLY synergistic with T3 in the body, and as a mater of fact, if you’ve been paying any attention up until this point, you’ll note that the limiting factor on GH’s ability to exert many of it’s effects, is mediated by the amount of T3 in the body.
As noted before, T3 enhances many effects of GH by several mechanisms, including (but not limited to): increasing IGF-1 levels, IGF-1 mRNA levels, and finally by actually mediating the control of the growth hormone gene transcription process as seen below:
Comparison of the kinetics of L-T3-receptor binding abundance to changes in the rate of transcription of the GH gene.(3)
As you can see, T3 levels are directly correlative to GH gene transcription. The scientists who conducted the study which provided the graph above concluded that the amount of T3 present is a regulatory factor on how much GH gene transcription actually occurs. And gene transcription is what actually gives us the effects from GH. This last fact really seems to shed some light on why we need T3 levels to be supraphysiological if we’re going to be using supraphysiological levels of GH, right? Otherwise, the GH we’re using is going to be limited by the amount of T3 our body produces. However, since we’re taking GH, and it is converting more T4 into T3, T4 levels are lowered substantially, and this is the problem with GH. and may actually be THE limiting factor on GH…if we assume that at least some of GH’s effects are enhanced by thyroid hormone, and specifically T3, then what we are looking at is the GH that has been injected is being limited by a lack of T3. But that doesn’t make sense, because if we use T3 + GH, we get a decrease in the anabolic effect of GH.
This is where Mr. Daemon, who had contacted me via an e-mail to my publisher, about Thyroid + GH interaction, was able to shed some light on things. You see, I knew that it couldn’t just be the actual presence of enough T3 along with the GH that was limiting GH’s anabolic effect, because, simply adding T3 to a GH cycle will reduce the anabolic effect of the GH (12.).
Originally, he had said to me that T3 was synergistic with GH, wheras I said that T3 actually reduced the anabolic effects of GH- now I realize we were both correct. Logically this presents a bit of a problem, which I believe can be solved. This came from reading several studies provided to me by Dr.Daemon. the trend I was seeing was that even when Growth Hormone therapy was used, T3 levels needed to be elevated in order to treat several conditions caused by a lack of natural growth hormone. And even if the patient was on GH, T3 levels still needed to be elevated. And what I noticed was that those levels were elevated successfully by using supplemental T4 but not T3.
Here’s why I think this is:
Additional T3 is not all that’s needed here. What’s needed is the actual conversion process of T4-T3, and the deiodinase presence and activity that it involves. This is because Local 5′-deiodination of l-thyroxine (T4) to active the thyroid hormone 3,3′,5-tri-iodothyronine (T3) is catalyzed by the two 5′-deiodinase enzymes (D1 and D2). These enzymes not only “create” T3 out of T4, but actually regulates various T(3)-dependent functions in many tissues including the anterior pituitary and liver. So when there is an excess of T3 in the body, but normal levels of T4, the body’s thyroid axis sends a negative feedback signal., and produces less (D1 and D2) deiodinase, but more of the D3 type, which signals the cessation of the T4-T3 conversion process, and is inhibitory of many of the synergistic effects that T3 has! Remember, Type 3 iodothyronine deiodinase (D3) is the physiologic INACTIVATOR of thyroid hormones and their effects (13)and is well known to have independent interaction with growth factors (which is what GH and IGF-1 are).(14) This is because with adequate T4 and excess T3, (D1 and D2) deiodinase is no longer needed for conversion of T4 into T3, but levels of D3 deiodinase will be elevated. When there is less of the first two types of deidinase, it would seem that the T3 which has been converted to T4 can not exert it’s protein sparing (anabolic effects), as those first two types are responsible for mediation of many of the effects T3 has on the body. This seems to be one of the ways deiodinase contributes to anabolism in the presence of other hormones.
All of this would explain why anecdotally we see bodybuilders who use T3 lose a lot of muscle if they aren’t using anabolics along with it- they’re not utilizing the enzyme that would regulate some of T3’s ability to stimulate protein synthesis, while they are simultaneously signaling the body to produce an inhibitory enzyme (D3). And remember, for decades bodybuilders who were dieting for a contest have been convinced that you lose less muscle with T4 use, but that it’s less effective for losing fat when compared with T3? Well, as we’ve seen, without something (GH in this case) to aid in the conversion process, it would clearly be less effective! Since the deiodinase enzyme is also located in the liver, and we see decreased hepatic nitrogen clearance with GH + T3, it would seem that the D3 enzyme is exerting it’s inhibitory effects, but in the absence of the effects of the first two deiodinase enzymes, it remains unchecked and therefore not only limits the GH’s nitrogen retention capability.
In other words, if we have enough to GH in our body aid in supraphysiological conversion of T4 into T3, but we already have the too much (exogenous) T3, the GH is not going to be converting any excess T4 into T3 after a certain point- which would be a limiting factor in GH’s anabolic effects, when coupled with the act that we’ve allowed the D3 enzyme to inhibit the T3/GH synergy that is necessary.
As further evidence, when we look at certain types of cellular growth (the cartilage cell in this case) we see that GH induced rises in IGF-I stimulates proliferation, whereas T3 is responsible for hypertrophic differentiation. So it would seem that in some tissues, IGF-1 stimulates the synthesis of new cells, while T3 makes them larger. In this particular case, The fact that T4 and (D1) deiodinase is am active component in this system is noted by the authors. They clearly state (paraphrasing) that: “T4 is is converted to T3 by deiodinase (5′-DI type 1) in peripheral tissues…[furthermore]GH stimulates conversion of T4 to T3 , suggesting that some effects of GH may involve this pathway.” The thing I want you to notice is that the authors of this paper state that the that the conversion PATHWAY is probably involved, and not the simple presence of T3. (15 )
Also, that same study notes that T3 has the ability to stimulates IGF-I and expression in tissues that whereas GH has no such effect (ibid).
So what are we doing when we add T3 to GH? We’re effectively shutting down the conversion pathway that is responsible for some of GH’s effects! And what would we be doing if we added in T4 instead of T3? You got it- we’d be enhancing the pathway by allowing the GH we’re using to have more T4 to convert to T3, thus giving us more of an effect from the GH we’re taking. Adding T4 into our GH cycles will actually allow more of the GH to be used effectively!
Remember, the thing that catalyzes the conversion process is the deiodinase enzyme. This is also why using low amounts of T3 would seem (again, anecdotally in bodybuilders) to be able to slightly increase protein synthesis and have an anabolic effect – they aren’t using enough to tell the body to stop or slow down production of the deiodinase enzyme, and hence .Although this analogy isn’t perfect, think of GH as a supercharger you have attached to your car…if you don’t provide enough fuel for it to burn at it’s increased output level, you aren’t going to derive the full effects. Thyroid status also may influence IGF-I expressionin tissues other than the liver.So what we have here is a problem. When we take GH, it lowers T3 levels…but we need T3 to keep our GH receptor levels optimally upregulated. In addition, it’s suspected that many of GH’s anabolic effects are engendered as a result of production of IGF-1, so keeping our IGF receptors upregulated by maintaining adequate levels of T3 seems prudent. But as we’ve just seen, supplementing T3 with our GH will abolish Growth Hormone’s functional hepatic nitrogen clearance, possibly through the effect of reducing the bioavailability of insulin-like growth factor-I (12.)
So we want elevated T3 levels when we take GH, or we won’t be getting ANYWHERE NEAR the full anabolic effect of our injectable GH without enough T3. And now we know that not only do we need the additional T3, but we actually want the CONVERSION process of T4 into T3 to take place, because it’s the presence of those mediator enzymes that will allow the T3 to be synergistic with GH, instead of being inhibitory as is seen when T3 is simply added to a GH cycle. And remember, we don’t only want T3 levels high, but we want types 1 and 2 deiodinase to get us there- and when we take supplemental T3, that just doesn’t happen…all that happens is the type 3 deiodinase enzyme shows up and negates the beneficial effects of the T3 when we combine it with GH.
And that’s where myself and Dr. Daemon ended up, after a week of e-mails, researching studies, and gathering clues.
If you’ve been using GH without T4, you’ve been wasting half your money – and if you’ve been using it with T3, you’ve been wasting your time. Start using T4 with your GH, and you’ll finally be getting the full results from your investment.
References:
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F, Rumpler M, Klaushofer K 1994 Thyroid hormones increase insulin-like growth factor mRNA levels in the clonal osteoblastic cell line MC3T3- E1. FEBS Lett 345: 67–70
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Thyroid morphology and function in adults with untreated isolated growth hormone deficiency. J Clin Endocrinol Metab. 2006 Mar;91(3):860-4. Epub 2006 Jan 4.
Eur J Endocrinol.1995 Dec;133(6):646-53.Influence of thyroid hormones on the regulation of growth hormone secretion. Giustina A, Wehrenberg WB.
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Eur J Endocrinol. 1996 May;134(5):563-7.Insulin-like growth factor I alters peripheral thyroid hormone metabolism in humans: comparison with growth hormone.Hussain MA, Schmitz O, Jorgensen JO, Christiansen JS, Weeke J, Schmid C, Froesch ER
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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 11 5221-5226, 2003. High Dose Growth Hormone Exerts an Anabolic Effect at Rest and during Exercise in Endurance-Trained Athletes M. L. Healy, J. Gibney, D. L. Russell-Jones, C. Pentecost, P. Croos, P. H. Sönksen and A. M. Umpleby
J Hepatol. 1996 Mar;24(3):313-9. Effects of long-term growth hormone (GH) and triiodothyronine (T3) administration on functional hepatic nitrogen clearance in normal man.Wolthers T, Grofte T, Moller N, Vilstrup H, Jorgensen JO
Huang, SA. Physiology and pathophysiology of type 3 deiodinase in humans. Thyroid. 2005 Aug;15(8):875-81. Review.
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F, Rumpler M, Klaushofer K 1994 Thyroid hormones increase insulin-like growth factor mRNA levels in the clonal osteoblastic cell line MC3T3- E1. FEBS Lett 345: 67–70
