the role of SHBG in PCT

I don't know if it is knit-picking or not, but Nandi has posted several times that clomid and nolva increase shgb post-cycle. He has stated that for this reason he began pct immediately after the cessation of his cycle, even with long-acting esters.

Interesting read

What was interesting about it ? They cited the first study I listed, two or three people commented, all of them clearly demonstrating they failed to actually read the study. None of the other issues were brought up, and then they fell back into some debate about DHT that is entirely irrelevant to recovery.

Its your typical AL thread, with people trying to sound like they know something, and nobody stating the obvious, namely that they are making fools of themselves. One guy even stated that lowering SHBG increases clearance, but a competitive inhibitor does not. Come on. Lower SHBG is lower bound androgen, means increase in glucuronidation and faster clearance of natural androgens, while synthetic androgens remain largely unaffected.

Thanks for the reply R2E, we all knew Karl was always ahead of his time

I'll see if I can dig up some more information.

I think you're referring to me with the shbg and increased clearance. The original poster asked if lowering SHBG would increase free (endogenous)T levels and I stated it wouldn't for that reason. The competitive inhibitor should displace T but not necessarily lower SHBG so one could expect an increase in free T but who really knows. This is what the DS product is alledged to so and the point of the discussion.

Numerous studies show exogenous androgesn lower SHBG production. Therefore at the end of a cycle and during PCT levels are already low so trying to lower them would be pointless. Is your theory that increasing SHBG will bind these exogenous/synthetic androgens thus lessening their effect on the HPTA? So endogenous production will return quicker but will be bound to SHBG thus inactivating a majority of it?

I've not formed any theory because I don't have enough information yet. And most of the information is highly contradictory. What concerns me the most is that SHBG is needed for conversion of andro to test, and in people with poor PCT i have observed problems in that area, with normal test and gonadotroph levels, but elevated androstenedione, likely due to build-up.

I can't say for sure there is merit to elevating SHBG yet, although if nandi had figured out a rationale to do so, I'd be inclined to believe there is such a merit, but I am highly questioning the use of lowering SHBG during PCT. I believe it would do more harm than good.

BTW, if I was referring to you, I hope you didn't take the comment personal. It was merely an example of the level of conversation in that thread. I meant nothing derogatory by it.

Posted by: ersatz

I think you're referring to me with the shbg and increased clearance. The original poster asked if lowering SHBG would increase free (endogenous)T levels and I stated it wouldn't for that reason. The competitive inhibitor should displace T but not necessarily lower SHBG so one could expect an increase in free T but who really knows. This is what the DS product is alledged to so and the point of the discussion.

Numerous studies show exogenous androgesn lower SHBG production. Therefore at the end of a cycle and during PCT levels are already low so trying to lower them would be pointless. Is your theory that increasing SHBG will bind these exogenous/synthetic androgens thus lessening their effect on the HPTA? So endogenous production will return quicker but will be bound to SHBG thus inactivating a majority of it?

I think nandi theorized along these lines. The reason SERM's help restore the HTPA is the binding of ER's in the hypothalmus. At least that's what most ppl thought but nandi seemed to believe that increasing SHBG was equally important. Nandi pointed out that both nolva and Clomid ,the primary SERMS used for PCT, both increase SHBG.

I just wanted to clarify my statements, no offence taken. I had a bit of correspondance with Karl before his untimely passing regarding this subject. What Seabiscuit Hogg posted is pretty much what nandi and I discussed. He wasn't absolutely sure that significantly raising SHBG was a good idea. He was certain though that lowering SHBG was pointless during PCT for the aforementioned reasons though.

This subject raised some questions in my mind.(as discussions with nandi often did) If you run SERMs along with AAS do they still increase SHBG or does the exogenous T prevent this? Does SHBG really benefit PCT by binding androgens or is it beneficial just because of andro conversion? Interesting subject, I wish there were more studies done with SERM's.

Well I found several reasons why its potentially beneficial, but I found mostly reasons why lowering it further would not be a good idea. Like I said, I have some data suggesting raising SHBG might be positive, but too much contradiction to actually recommend it. But I can pretty much state that lowering SHBG is not a good idea for PCT.

The androgens would likely supress SHBG increases by tamoxifen, given that they already supress those of estradiol. tamoxifen being a much weaker agonist than estradiol.

Talking about shbg is something that you want to make sure your blood sugar is not low when doing. I find it a very complex subject to wrap yourself around. In many ways it seems to be contradictory since common bbr lore would have us believe that increased levels of shbg are a bad thing because they preferentially bind testosterone leading to an increased level of estrogen (ala swales theory of estrogen imbalance) and a decreased T/E ratio. We even have some promoting proviron to free up testosterone for anabolic effect. The first abstract BC posted is extremely revealing (btw, what is the study ref for that so i can add it to my lib.) since we now have a contradictory notion that increased levels of shbg, as expected, are positively correlated with increased total T but surprisingly are either slightly positivelly correlated with non-bound T or free T remains unchanged. In another study that i posted sometime ago here, a similar conclusion was reached where contrary to prevailing opinion. " we conclude that in eugonadal men, higher SHBG levels are associated with lower levels of non-SHBG-E2 but slightly higher levels of non-SHBG-T. This means that SHBG cannot be regarded as an estrogen amplifier in eugonadal men.". So we may have another reason to wish shbg not to be lower in pct since increased levels of E could lead to continued suppression of the hpta, just a thought.

jb

The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 1 157-162
Copyright � 2005 by The Endocrine Society
Associations of Sex-Hormone-Binding Globulin (SHBG) with Non-SHBG-Bound Levels of Testosterone and Estradiol in Independently Living Men
Willem de Ronde, Yvonne T. van der Schouw, Majon Muller, Diederick E. Grobbee, Louis J. G. Gooren, Huibert A. P. Pols and Frank H. de Jong
Department of Internal Medicine (W.d.R., H.A.P.P., F.H.d.J.), Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands; Julius Center for Health Sciences and Primary Care (Y.T.v.d.S., M.M., D.E.G.), University Medical Center 3508 GA Utrecht, The Netherlands; Department of Endocrinology (W.d.R., L.J.G.G.), Vrije Universiteit Medical Center, 1007 MB Amsterdam, The Netherlands; and Department of Epidemiology and Biostatistics (H.A.P.P.), Erasmus Medical Center, 3000 DR Rotterdam, Netherlands
Address all correspondence and requests for reprints to: Frank H. de Jong, Ph.D., Endocrine Laboratory, Room Ee 516, Department of Internal Medicine, Erasmus MC, PO Box 1738, 3000 DR Rotterdam, The Netherlands. E-mail: [email protected].
Results of in vitro experiments indicate that with increasing concentrations of SHBG, testosterone (T) is preferentially bound to SHBG in comparison with estradiol (E2). In these studies, the ratio of non-SHBG-bound E2 (non-SHBG-E2) to non-SHBG-T increased with increasing levels of SHBG. SHBG has consequently been regarded as an estrogen amplifier. In this cross-sectional study in 399 men aged between 40 and 80 yr we tested whether higher levels of SHBG are associated with a higher estrogen/androgen ratio in vivo. The mean T level of these men was in the eugonadal range [536 � 152 ng/dl (18.6 � 5.26 nmol/liter), mean � SD]. With increasing SHBG levels the non-SHBG-bound fraction of T decreased from 80 to 36% and that of E2 from 89 to 53%. Higher levels of SHBG were associated with higher levels of both total T [regression coefficient (�) after adjustment for age and body mass index, 286 � 15.8; P < 0.001] and total E2 (� = 4.47 � 0.90; P < 0.001). However, SHBG levels were negatively related with levels of non-SHBG-E2 (� = �1.78 � 0.69; P < 0.001), whereas there was a positive association between levels of SHBG and non-SHBG-T (� = 32.0 � 9.78; P = 0.001). Furthermore, we observed a negative relationship between SHBG levels and the E2/T ratio of either total (� = �0.016 � 0.002; P < 0.001) or non-SHBG-bound (� = �0.011 � 0.002; P < 0.001) hormone. Therefore, we conclude that in eugonadal men, higher SHBG levels are associated with lower levels of non-SHBG-E2 but slightly higher levels of non-SHBG-T. This means that SHBG cannot be regarded as an estrogen amplifier in eugonadal men.

I have a bit free time on my hands if anyone wants to crack this discussion open again. Not lots of free time though, so if this gets active forgive me if I don�t participate as frequently as everyone else.

Please bear in mind that I did not design ActivaTe. The (thin) knowledge on this subject I have comes purely through research since the product was released in beta form when I joined the company last year.

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Ok, I recently had a debate with some guy who designed a supplement for PCT and part of its action is to lower SHBG. I pointed out the ludicracy of this, but I wanted to open it up for debate, get some input from everyone here.

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1. ActivaTe was not designed specifically for PCT.

2. It does not lower SHBG. It competitively binds it.

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First of all, the amount of SHBG seems to be fairly irrelevant in terms of the amount of free testosterone. I present you this abstract :

�

RESULTS: Higher levels of SHBG were associated with higher levels of total testosterone in neonates (beta = 0.02 +/- 0.004, r = 0.44, P < 0.001) but not with non-SHBG-T (beta = -0.001 +/- 0.001, r = 0.05, P = 0.52). In adult men there was a significant age related increase in levels of SHBG and an age-related decrease of both total and non-SHBG-T. Higher SHBG was strongly associated with higher total testosterone in all age groups (beta = 0.26, 0.26, 0.26 and 0.23 for 40-50 years, 51-60 years, 61-70 years and 71-80 years, respectively, P < 0.001 for all age groups). Higher SHBG was not or only slightly associated with higher non-SHBG-T beta = 0.02 (P = 0.32), beta = 0.04 (P = 0.03), beta = 0.04 (P = 0.02) and beta = 0.02 (P = 0.16) for 40-50 years, 51-60 years, 61-70 years and 71-80 years, respectively. CONCLUSIONS: In contrast to general belief, SHBG levels barely influence levels of non-SHBG-bound testosterone both in male newborns and healthy adult men: the influence, if any, is positive. Consequently the age related increase of SHBG does not account for the age related decline in non-SHBG-T in healthy adult men.

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I fail to see how this expresses your point. All it shows is the relationship between SHBG, testosterone and free testosterone and age. I fail to see how it demonstrates that lowering or binding SHBG alters free testosterone in healthy men.

Given that the babies have not yet reached adolescence, their results are irrelevant for our purposes, and even if they were, they do not state anything conclusive.

Also, the study indicates that higher SHBG means higher total testosterone, but not higher free testosterone, and that there is an age-related decline in total and free testosterone. This seems like a pretty logical and obvious conclusion. They did nothing to alter SHBG or testosterone to discover the extent for which SHBG governs free testosterone.

If I am wrong, please correct me.

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My guess previous to the debate would have been that you may want to increase SHBG for PCT purposes, to expedite clearance of androgens. Sadly most used androgens don't have much affinity for SHBG, and given the length of PCT, it would be pretty much moot factor. So I'm back to the conclusion there is no point in manipulating SHBG in PCT either way, but definotely not for lowering it.

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I�ll admit I�ve not looked much into the area of lowering SHBG so I will take your word for this. But I do have a question for you.

What good is total testosterone elevation if SHBG is also elevated, meaning no increase in free testosterone? Given that bound-testosterone is essentially inactive and unable to aromatize or interact with the androgen receptor.

Again, bear in mind that ActivaTe does not lower SHBG.

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A second point that came to my attention was that SHBG is needed for the conversion of androstenedione.

Is �needed� may be a stretch of a conclusion.
17-beta hydroxysteroid dehydrogenase is what converts androstenedione to testosterone. If SHBG speeds this up in red blood cells then that is great.

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Of course this only deals with erythrocytes, but I think everyone can follow me in the assumption that a similar process takes place in most cells and for most enzymes.

May I ask how significant the contribution of red blood cell conversion of androstenedione to testosterone is? I dunno myself to be honest so I�m hoping you do. Is it significant at all? How significant is the contribution of the conversion in the liver and gonads?

Do you have anything that shows this effect in vivo in the liver or gonads?

It�s not really a hugely important issue though. I�m not so sure anyone uses anything that lowers SHBG during PCT. I think there is a product that does it though (it claims to do a lot of things), but to name it without full knowledge of it would be bad practice.

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Now, one common problem I have seen with people who haven't run proper PCT is that they often have low but normal LH/FSH as well as test, prior to full recovery, but their androstenedione is off the charts. That indicates that one of the slowest mechanisms to repair in a depressed HPTA is androstenedione to testosterone conversion.

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Seems like a fair conclusion. But what is �low but normal�? Do you mean low total concentrations, but normal balance between them?

Forgive my ignorance.

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i'd like to point out at this time that androgen use decreases SHBG and the use of an estrogen blocker in PCT further decreases that amount. It seems to me that one of the problems when coming off a cycle is actually lowered SHBG. So again, I not only couldn't see a use for decreasing SHBG, from the look of it low SHBG is a contributring factor in slow recovery and muscle loss.

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Since high SHBG is associated with high testosterone, low SHBG being associated with low testosterone seems pretty logical to me.

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Another study, originally done to test the influence of thyroid hormones (1), demonstrates that a surge in SHBG is seen prior to an expected surge in testosterone. This confirms the fact that SHBG is needed for testosterone synthesis, most likely via the aforementioned mechanism for increasing androstenedione conversion.

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It only confirms your theory to the degree that being present at the scene of a crime confirms guilt. That said, your theory is interesting and you should invest some time into looking into it more. There may very well be substance to it.

Are you aware of any studies that show this SHBG surge in healthy adult men (i.e. not hypothyroid patients) without the administration of thyroid hormones? If you can find out whether it occurs during natural testosterone pulsations then you may be onto something.

As a side, I know that there is a connection between thyroid hormones, SHBG and testosterone because I�ve been looking into the link myself recently. It appears as though administration of T3 (50-75mcg) boosts total testosterone and SHBG, but leaves free testosterone unaffected. Those with hyperthyroidism also have very high levels of SHBG and total testosterone, but nothing statistically different with regards to free testosterone. As expected, those with hypothyroidism tend to have low SHBG and total testosterone.

The reason I looked into this was obviously with the idea of combining activate with low-dose T3 (only 25-50mcg for my purposes though) to see if I could alter my typical endomorphic body type. I�ve been experimenting for almost two weeks now to what appears to be good effect.

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So can anyone add anything valid, either for or against decreasing SHBG in post-cycle therapy ?

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Again, bear in mind that ActivaTe does not lower SHBG.

(No insults or hostility please folks, I am not Dr.D).

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[i]
1. ActivaTe was not designed specifically for PCT.

2. It does not lower SHBG. It competitively binds it.

On the first one I won't argue, as I already told Dr.D way back when we had this discussion I've not looked into the other ingredients of activate, and it may be a good product outside of PCT. At the same time use of a competitive SHBG product is questionable at any point, but I don't have all the data on that so I won't express myself pro or contra. For a long time it was simply assumed beneficial.

On the second point I agree that I may have poorly expressed myself. I should state prevents free SHBG from binding endogenous hormones, not lowering SHBG.

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I fail to see how this expresses your point. All it shows is the relationship between SHBG, testosterone and free testosterone and age. I fail to see how it demonstrates that lowering or binding SHBG alters free testosterone in healthy men.

Given that the babies have not yet reached adolescence, their results are irrelevant for our purposes, and even if they were, they do not state anything conclusive.

Also, the study indicates that higher SHBG means higher total testosterone, but not higher free testosterone, and that there is an age-related decline in total and free testosterone. This seems like a pretty logical and obvious conclusion. They did nothing to alter SHBG or testosterone to discover the extent for which SHBG governs free testosterone.

If I am wrong, please correct me.

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No, they did not. The point was that differences in the level of SHBG had no effect on non-SHBG bound testosterone, and that actually the level of SHBG had a slightly positive effect on non-SHBG bound testosterone. SHowing that if you lower or inhibit interaction of SHBG with endogenous hormones, non-SHBG test may go down, but at best simply does not change. So there is no merit to such a change. Just a first argument in a part of the whole though.

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I�ll admit I�ve not looked much into the area of lowering SHBG so I will take your word for this. But I do have a question for you.

What good is total testosterone elevation if SHBG is also elevated, meaning no increase in free testosterone? Given that bound-testosterone is essentially inactive and unable to aromatize or interact with the androgen receptor.

Again, bear in mind that ActivaTe does not lower SHBG.

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The point is that during PCT (and note the title of the thread, this is about PCT) having more free testosterone to interact with the AR or to convert to estrogen or DHT (interacting with their respective receptors) increases negative feedback, for one. Second point is that SHBG is severely depressed in this state to begin with, how much test did you expect this would free up ? That's point number two. The third issue is that SHBG buffers testosterone. When it does not, like when you have too much testosterone created comparative to the available SHBG, as with HCG treatment, you will see a three times greater rise in metabolites of testosterone, like estrogen, instead of actual testosterone, which leads to lower levels of testosterone, more negative feedback and lower levels of gonadotrophins. As a fourth and last point we can state the need for SHBG in recovery of which I stated a few examples, but there may be more. Androgens lower SHBG as a feedback mechanism.

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Is �needed� may be a stretch of a conclusion.
17-beta hydroxysteroid dehydrogenase is what converts androstenedione to testosterone. If SHBG speeds this up in red blood cells then that is great.

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No, is needed. SHBG is crucial in transporting andro in the cell and testosterone out of the cell, that is also why SHBG has a higher affinity for androstenedione than for testosterone. If it does so in red blood cells, its likely to be the case in other cells expressing 17bHSD.

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May I ask how significant the contribution of red blood cell conversion of androstenedione to testosterone is? I dunno myself to be honest so I�m hoping you do. Is it significant at all? How significant is the contribution of the conversion in the liver and gonads?

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That is an answer I cannot provide. On the one hand I imagine its not unimportant, as blood conversion levels were used to promote various first generation prohormones for a long time, on the other hand the relative contribution of blood conversion was not part of my argument either, if you read the initial thread, where I stated that this is a likely process in other cells than eryhtrocytes as well.

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Do you have anything that shows this effect in vivo in the liver or gonads?

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I'd have to look. That sort of questioning is however called fishing, when you know this does not need demonstrating in vivo if the process likely occurs in other cells. Since systemic SHBG is the same all over the body, I fail to see how this is an unsafe extrapolation, lest you see fit to demonstrate otherwise.

I also list my points as examples that SHBG is likley lowered by androgens as a negative feedback response, its in fact very likely SHBG has many other roles in improving recovery. Aside from the 4 or 5 reasons listed here.

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It�s not really a hugely important issue though. I�m not so sure anyone uses anything that lowers SHBG during PCT. I think there is a product that does it though (it claims to do a lot of things), but to name it without full knowledge of it would be bad practice.

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Well I admit I expressed myself poorly, I should have stated outright that it is lowering or inactivating SHBG I meant. And this product particularly was recommended by a man intimately associated with your company. The same man who also suggests the use of supressive hormone during PCT, and that we should all digress 10-15 years back in time and taper off our cycles again.

So bad practice as it may be for you to name such a product, your own product falls in the same class with regards to inactivating SHBG, and moreover someone at your company goes to great lengths to promote its use in PCT, this I consider far worse practice.

More claims made, but removed at the request of DS. The issue will be discussed elsewhere.

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Seems like a fair conclusion. But what is �low but normal�? Do you mean low total concentrations, but normal balance between them?

Forgive my ignorance.

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Not at all, very fair question to ask. Low normal range. Meaning borderline hypogonadal, but still in the normal range. Balance was everything but normal, as andro levels were still above high normal levels.

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Since high SHBG is associated with high testosterone, low SHBG being associated with low testosterone seems pretty logical to me.

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Well that would be the main argument for not lowering or inactivating SHBG during PCT. But i wanted to demonstrate that there were additional reasons this is a bad idea and open it up for more input.

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Are you aware of any studies that show this SHBG surge in healthy adult men (i.e. not hypothyroid patients) without the administration of thyroid hormones? If you can find out whether it occurs during natural testosterone pulsations then you may be onto something.

As a side, I know that there is a connection between thyroid hormones, SHBG and testosterone because I�ve been looking into the link myself recently. It appears as though administration of T3 (50-75mcg) boosts total testosterone and SHBG, but leaves free testosterone unaffected. Those with hyperthyroidism also have very high levels of SHBG and total testosterone, but nothing statistically different with regards to free testosterone. As expected, those with hypothyroidism tend to have low SHBG and total testosterone.

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The point of presenting the study is that, regardless of what causes the surge in SHBG, SHBG surges tend to precede increases in testosterone. We already know from the previous study that the level of SHBG has no real role in the level of free testosterone. Meaning whether its lower or higher, it has no benefit. But during PCT the goal is still to increase both total and free testosterone to normal levels. With inhibition of SHBG you are going to create peaks where the product causes two things :

1) Massive but short release of testosterone over baseline leading to negative feedback due to test, estrogen and DHT

2) followed by a drastic drop in total testosterone since what is not bound rapidly metabolizes, if not to estrogen or DHT, then to hydroxylated and subsequently conjugated metabolites that are excreted.

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(No insults or hostility please folks, I am not Dr.D).

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And again, good thing you are not. Although I'm still waiting on an official stance from your company in regards to his blatant malpractices. Although I commended uhockey for his stance at the time, it seems to now be a rather hypocritical game of distancing when it threatens sales, but keeping him close when he could push sales ...

Posted by: Big Cat

No, is needed. SHBG is crucial in transporting andro in the cell and testosterone out of the cell, that is also why SHBG has a higher affinity for androstenedione than for testosterone. If it does so in red blood cells, its likely to be the So bad practice as it may be for you to name such a product, your own product falls in the same class with regards to inactivating SHBG, and moreover someone at your company goes to great lengths to promote its use in PCT, this I consider far worse practice. Especially since someone else at your company saw fit to distance themselves from Dr.D's claims when they noted his irresponsible behaviour in regards to DHEA was affecting sales, yet here someone else is defending his equally irresponsible claims to use this during PCT, showing that really your company sees fit to defend his practices when it best suits your sales ...

Can you elaborate on this, why is DHEA bad during PCT. there isnt enough data to support claims DHEA is supressive.

Posted by: acecombact1

Can you elaborate on this, why is DHEA bad during PCT. there isnt enough data to support claims DHEA is supressive.

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This effect was accompanied by significantly decreased levels of LH

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the findings indicating that DHEA is probably involved in suppression of the LH fraction.

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while FSH, LH and SHBG levels showed a significant decrease

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sustained baseline elevation of ADG, a distal DHT metabolite, raises concerns about the potential negative impact of DHEA supplementation on the prostate gland.

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whereas both gonadotropins were significantly reduced.

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Thus suggesting a predominant estrogenic effect of DHEA at the level of the uterus and an estrogenic effect on the feedback control of LH secretion

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That's just the first two pages on pubmed after looking for DHEA and LH by the way ... with no studies suggesting otherwise.