TRT in men with low SHBG

[chris_az]

Dear Doctor J and interested parties,

In the UK I have noticed a strong correlation between fellow
patient's poor response to testosterone and low SHBG.

The widely held belief is that high not low SHBG is a problem.

>From my understanding this is because SHBG is of course the binding
protein (binding 98% of testosterone in the typical male), binding
with greater affinity to testosterone than to E2, therefore high
SHBG adversely affects the testosterone to E2 ratio.

Of course high SHBG can be a problem, but I believe it is more than
a coincidence that many, many men who respond poorly to TRT have low
SHBG, I believe that this too is a problem.

>From what I can see the logic goes that low SHBG will result in a
higher level of free testosterone as less is bound and that this can
only be a good thing. However I think that the problem here is that
SHBG is only being viewed in relation to testosterone.

Low SHBG will also cause an increase in free E2.

Now if this is viewed in the context of testosterone it can be said
that the rise in free testosterone is greater than the rise in free
E2 meaning low SHBG is not a problem because of the binding
affinities.

But like I said this is if SHBG and E2 are viewed in the context of
testosterone. But high E2 in itself is surely likely to cause its
own problems.

I believe those with low SHBG are suffering from high E2, more
specifically high free E2 on TRT and that that is the reason for
poor response to TRT.

My thoughts are merely that, I have no prove whatsoever just a hunch.

Symptomatically those with low SHBG on TRT tend to develop
gynecomastia and see no improvement, in fact sometimes a decrease in
libido on commencement of TRT.

Serum E2 is usually toward the top of the range with no test
available for free E2.

Use of A.Is and anti estrogens seem to have had little benefit to
such men, having had very mixed results.

I am one of these men.

My SHBG is 10nmol/l with a range of 13-75nmol/l.

P.S

There maybe another mechanism of action and my theory maybe wrong, it could be that those with low SHBG share an underlying condition that relates to poor response to TRT, but again this is speculating.

Whatever the mechanism, men with low SHBG who are supposedly those that will do best on TRT are paradoxically those who seem to be fairing the worst.

I would very much like to get to the bottom of why this is. I feel by doing so and finding an answer/reason for this may perhaps pave the way to good health via a TRT protocol which would more appropriate for me and men like me.

A penny for your thoughts?


Regards,

Chris

 

[HeadDoc]

I wonder whether there is any data around to suggest the relative prevalance of primary vs. secondary hypogonadism? At least that is the way I am interpreting your observations. Did you and your doc do any tests in the beginning to differentiate which type is involved? Since your shbg was low, was your lh also low? I know hcg is a little hard to come by in the UK, have you tried it?

You are also raising a point about who would require ancillary meds for estrogen and aromitization. Interesting thoughts. From many posts here, we know that some do and some do not require ancillaries. That is more observational than explanatory. Sounds like a good topic for a thesis.

 

[chris_az]

My situation was that the diagnosis was somewhat uncertain despite an MRI and dynamic assessment of the HPTA axis, but I have a long and complicated medical history.

In terms of my thoughts here though, I am not basing them on me because of A) the complications involved in my medical history and B) the fact that this would be an association of one and in that sense insignificant.

The correlation of low SHBG and poor TRT response that I have generally observed is in people in UK via a UK hypogondism forum, people that have not had such complicating factors.

In terms of raising the issue of primary or secondary;

That may or may not be a factor here.

If low SHBG has a statistically significant association with one form of deficiency but not the other, that would be interesting as it may point to the nature of the condition itself and even be used as a diagnostic tool for the assessment of hypogonadism.

However we or at least I do not have information on any study to examine such correlations.

Irrespective of whether primary or secondary forms are linked to low SHBG or not we still have to understand why people on TRT with low SHBG seem to fair badly and what can be done about it?

This is assuming of course for one moment that the association that I have noted isn't just merely coincidental


I am more concerned about the broader facts/details rather than just myself, as I think it is easy to look into my therapy and draw incorrect conclusions from it given other men have not been on the treatments I have.

I will detail my own situation in a different post so as to not cloud the issue as it appears to not just me but a wider number of men

 

[ASaxon]

Thats scary, I have a low SHBG of 10 (RR: 13 71). I guess I really have to watch E2 if this is the case. Im already concerned with it an am looking into which type of T replacement is best for controlling E2 so I guess Im going in the right direction at least.

From the way Im envisioning this, if SHBG is low then TT and FT will be higher on a lower dose of T than someone with higher SHBG. Higher FT, especially in someone who is overweight, will cause a larger conversion of FT to E2 thus raising E2. Seems to make sense but only if FT gets elevated higher than normal. Seems like the amount of E2 would be proportional to the level of FT and the degree by which the patient is overweight.

I would imagine that a lower SHBG would lead to having to take a more careful approach in the balance of dosing T in relation to monitoring E2 and taking an aromatase inhibitor if necessary. I have read that loosing weight can not only raise SHBG (thus being overweight resutls in lower SHBG) but also has the obvious effect of lowering E2 because of the reduction in aromatase conversion. That's the direction I'm hoping to go.

 

[maxzax]

You are also raising a point about who would require ancillary meds for estrogen and aromitization.

Hi Headdoc,

What are ancillary meds?

Sorry for my ignorance.

Thanks!

 

[chris_az]

I must emphasize, this topic is ONLY based on my subjective observations and the association/correlations that I have noted from the men/pathology/symptoms that I have seen.

From what I have noticed, every single person with very low SHBG has struggled on TRT when according to the view held by the status quo they should be the ones benefiting from it most.

All the men that I have seen with very low SHBG have gynecomastia, all have libido issues, and all have struggled to some extent on TRT, despite adequate replacement and in fact varying doses of TRT.

My theory if it is worth anything is;

Forget the effect of very low SHBG on free T, serum T and in fact androgens period at least for a moment just to get a grip on the concept and think of estradiol, not necessarily the basic pathology number but the possible free E2 level and its most obvious physical symptom- gynecomastia.

Think about the concept of Free E2 and how it could cause problems independent of testosterone.....then go back to thinking about the whole picture.

My thoughts are that everyone, you included only considers SHBG and its effects in relation to free T.

I think this might be incorrect.

Gynecomastia smacks of an E2 problem, so too does very low libido despite adequate T replacement.

If my thoughts have any worth at all and I readily accept that they may not and I could be wrong and the associations I have concluded merely a statistical blip/findings of chance.then it is;

Low SHBG by some mechanism causes gynecomastia, lowered libido and general poor response to TRT.

Hopefully Scott you will fair far better than the men I have come across and myself.

 

[SPE]

hmm...

My SHBG was fairly low(don't remember the exact number but my Free T % was 2.64 on a scale of 1.0-2.7), and I've had nothing but success with TRT so far.

 

[Stez]

My SHBG was very low, either at very bottom of range or even under - I can't remember.

My E2 went to the high end of the range on comencement of TRT. I use 1 dim tablet EOD and it seems to keep my wang working though.

I've had the same theory though. If I have low SHBG, Lowish natural test, and High estro, could taking JUST an anti-e such as DIM lower my estro, and also raise my natural test level through negative feedback?

I think I may have to be the guniea pig on this one...

 

[chris_az]

SPE,

How low is fairly low?

Can you tell me SPE and Stez respectively;


What were your pathology results for T, E2 and SHBG prior to any meds?
What are your TRT/protocols including all meds?
What are your levels now for T, E2 and SHBG?

That way I can know if we are comparing apples to apples or apples to pears.

 

[HeadDoc]

Hi Headdoc,

What are ancillary meds?

Sorry for my ignorance.

Thanks!

AI's, I3C/DIM, etc. Meds/supplements for estrogen conttrol.

 

[SPE]

Like I said, don't remember my shbg but a high ft percentage suggests quite low. Anyhow, before meds my Total T was 301(241-827) and Free T was 12.3(9.3-26.5) and E2 was 31(<54) After androgel 5g/day and hcg(which is known to elevate e2) my total T was 757(241-827) and e2 had only risen to 39.

 

[ASaxon]

This was kind of interesting:

Laboratory confirmation becomes an important issue when clinical situations arise that are associated with abnormal sex hormone-binding globulin production. The most common situations involve the presence of excess estrogen, a potent stimulator of hepatic sex hormone-binding globulin synthesis, and include both morbid obesity and normal aging. As excess estrogen increases the circulating levels of sex hormone-binding globulin, the newly formed protein binds up free and loosely bound testosterone, which leads sequentially to a decline in bioavailable testosterone, an increase in secretion of luteinizing hormone, and a rise in testosterone production to restore normal bioavailable testosterone levels.

In patients with normal gonadal function, this sequence of events raises the total testosterone level. However, in patients who have inadequate testosterone production, the total testosterone value remains largely unchanged but with a disproportionate level of tightly bound testosterone and a low level of bioavailable testosterone. As it turns out, most cases of hypogonadism in men result from inadequate ability of the hypothalamic-pituitary axis to secrete luteinizing hormone (ie, secondary, or central, hypogonadism). Consequently, symptomatic patients may have normal levels of total testosterone and luteinizing hormone, suggesting that gonadal function is normal. Further testing of free testosterone or bioavailable testosterone in such patients is required to identify the deficiency.

(Source: http://www.postgradmed.com/issues/2003/10_03/macindoe.htm)

This says that high estrogen levels would lead to an increase in SHBG, not the other way around, because estrogen is a potent stimulator of hepatic [SHBG] synthesis.

Im still dont quite understand this yet.

 

[chris_az]

SPE,

Looking at your results before TRT;

Your E2 given your Testosterone level was a little high, not over the normal range you were given but it was certainly elevated.

On your second pathology your E2 had quote 'only risen to 39'.

The pg/ml reference scale is like measuring temperature in centigrade as opposed to pmol/l which is more akin to Fahrenheit. A nine point rise on the pg/ml scale is a lot the same way a nine point elevation in centigrade is a lot.

39 is darn high normal and not at all healthy!

It equates to 135pmol/l well into the upper third of the normal range.

Did you start to develop any gynecomastia at this level?

I can tell you that lots of men do.

Are you still at this level?

If your libido is unaffected at this level, you have not been developing gynecomastia at all and you still have good erections at this level you are a lucky man.

Perhaps your SHBG is not as low as you think it was?

If it was lower than 13nmol/l I think you would be suffering with the above, at least from what I have seen.

Scott,

The information you have retrieved though very interesting in its own right relates to high SHBG, whereas my thoughts here are about what I believe may be a problem with low SHBG, which I do not think relates so much to androgens but more to an independent high level of free E2.


Incidentally when my E2 increases, my SHBG does not- perhaps this is another indicator of the issue here as it does not follow the information that was detailed within that report.


I wonder whether or not low SHBG could relate to liver issues, given it is made in the liver?

Again speculation and I suppose not too important as we are not going to find the answer as patients by simply discussing matters.

Again looking to what I think is happening from what I have seen;

Low SHBG by some mechanism causes gynecomastia, lowered libido and general poor response to TRT.

If I am right what can be done?

What would be the correct protocol if any?

 

[Stez]

Ok.

Before TRT:

Total Test: 10 on first test, 13 nmol/L (10.0-33.0)
Free Test: 34 pmol/L (60.0-130.0)

Unfortunately I don't have SHBG or Estro before I started TRT. I hadn't found Swale's info at that stage, so I was kind of flying blind.

Sometime into TRT:

Total Test: 31 nmol/L (10.0-33.0)
Free Test: 151 pmol/L (60.0-130.0)
SHBG: 10 nmol/L (13-71)
E2: 236 pmol/L (40-250)

And on a second test;
Total Test: 29 (10-33)
Free Test: 92 (60-130)
E2: 236 (40-250)

I dunno why my free test dropped so much...I may have started going to the gym again after some time off or something. Erectile Function was pretty bad with my estro this high. As soon as I hit some anti-e's it got straight back into action though.

I will get new labs soon, and I'm also on a different regime now. Currently on:
125mg Test Enanthate E6D
250iu HCG on the 2 days prior
1 Indolplex with DIM tablet EOD

Seems to be going alright, though I don't think boners are 100% yet heh

 

[chris_az]

Stez,

So the E2 shot through the roof, erections became affected...I'm guessing libido too though I could be wrong?

Have you put any weight on your chest as well- that would be a degree of gynecomastia?


The fact is there are a lot of men on TRT who do very well and never require anti-estrogens, A.Is or DIM, but then I doubt they have low sHBG.

I think you fall into the category of someone who is more difficult to treat because of low SHBG.

You might to some degree be one more person along the way to validating my theory as opposed to one of the few who presently detract from it.

From my information I have also found out that low testosterone in conjunction with low SHBG is a predictor for syndrome X ortherwise known as the metabolic syndrome.

Perhaps this has some baring, I don't know?


Regarding the mistakes that were made early on with your situation....yea that happened with me too, I think it is quite common and unfortunate as it denies many people, us included crucial information prior to treatment that isn't always easy to obtain at a latter date- even if you come off treatment.

Stez it is good to hear you feel good for the most part on your protocol, I would like to try it, unfortunately like I said the powers that be this side of the atlantic deny me that opportunity.

Who knows, it is possible that your protocol is more likely to work in cases of low SHBG?

You of course are only a case of one, so I do not say this with assurance, I just say it in a.....you never know type of way.

I guess I will not find out for myself if that could allow me and other men with low SHBG to feel well unless the medical community changes its policies in the UK.

 

[SPE]

Chris,
An E2 number of 39 is just fine. Remember, the reference range here is 10-54 I believe, so I'm just above the middle. SWALE has mentioned he LIKES to see E2 at around 35. At the time I was probably taking a little too much hcg and I had just added DHEA which both affected results. At this level I felt great! Also, my T/E ratio increased from 10/1 to almost 20/1! Obviously with the given medications my body had a preference to testosterone rather than estrogen.

 

[chris_az]

Dr Eugene Shippen States that a young health man will have a testosterone to estrogen ratio of around 50-1 and states that a testosterone to estrogen ratio of 20-1 is more akin to that seen in metabolic hypogonadism or andropause.

So 20-1 is NOT a great ratio!!!

And your erection quality may also be telling you that.

Have you noticed any reduction in libido at all and have you developed any gynecomastia/weight on the chest at all during this period, also do you tend to put weight on your hips?

Just some questions

Ok to counter what I have said, I also concede that calibration of equipment affects reference ranges and it maybe that your 39pg/ml isn't as bad as it would first appear.

Basically you can have different reference ranges that are both measuring E2 in pg/ml and both can be correct.

Your saying that 39pg/ml via the individual assay that measured your E2 has a top of 59, so yes that may not be too bad.

On another assay you could have 39pg/ml and a top of the range of 40pg/ml and that would be much worse.

If you are telling me you feel good on TRT who am I too argue?

That would be ridiculous.

What I will say though is that I still think that you are more likely from what I have seen to be someone who would struggle with TRT if your SHBG is low.

Again who knows, maybe your protocol is helping to prevent such problems- though this is speculation.

Again when talking about SHBG, Perhaps it is not as low as mine or Stezs and other men?

I don't know because I don't know what it is.

My E2 is 130pmol/l and the top of my range is 150pmol/l.

Then you think that my Free E2 will be much higher than normal given the low SHBG and then you look at the breasts/gynecomastia and female weight distribution pattern sometimes referred to as gynecoid body type and you say- yes that is an E2 issue!

And that is a pattern that I have seen in other men too, hence the whole raising of the issue.

Maybe on an individual cases by case basis making the association is too crude, I mean many conditions have associated side effects and low SHBG may have its set of side effects, but that doesn't mean that every single person with low SHBG will necessarily have those side effects,

Maybe I am being too crude here; after all I am talking about a correlation/association not an absolute.

I would in your situation find out what SHBG is though, just for interest sake and think it might be an idea to consider the questions I posed for now and future reference/thought.

 

[SWALE]

SHBG binds somewhere between 40 and 60% of total testosterone.

We have to appreciate that Free T is important only within the context of a "biological marker", as the real indicator of androgen action is Bioavailable T.

You have to remember that elevating estrogen also tends to elevate SHBG concentration. Everyone is different, but generally you do not see high estrogen and low SHBG.

As SHBG concentration rises, due to its increased affinity for androgen over estrogen, you not only get more estrogen free, you get MORE AND MORE estrogen free. This makes what we are calling "estrogen dominance".

"Symptomatically those with low SHBG on TRT tend to develop
gynecomastia and see no improvement, in fact sometimes a decrease in
libido on commencement of TRT." I have not noticed this. But I'll keep an eye out for it.

Yours is, unfortunately, a very complicated case.

I should expect that losing weight would LOWER SHBG.

 

[chris_az]

My SHBG was very low even when my weight was also low.

As you say mine is a complicted case, but I have noticed that low SHBG and poor response to TRT in many men.

Interesting.

 

[SWALE]

Yes, men come to me because their bodies are NOT doing what they are supposed to. That is why I say, NOTHING will surprise me anymore.

I do not think much of the T/E ratio thing. I just don't think it has much relevance, when all is taken into consideration.