Freeing Up Testosterone with Average T Levels and/or Higher SHBG

[Cataceous]

...
Cat so what is your opinions of this 2020 NIH report?
...

They start out saying

Adult onset male hypogonadism (AOH) is a common clinical condition whose diagnosis and management are controversial, and is often characterized by a low level of SHBG, but our understanding of why testosterone levels are low when SHBG is low is incomplete.​

​

The correlation with low SHBG is potentially explained when they state

...The level of SHBG ... was inversely proportional to BMI...​

BMI is correlated with adiposity, which in turn is correlated with aromatase. Higher estradiol lowers the set point of the HPTA, lowering free and total testosterone. This is more prosaic than their speculation that SHBG somehow "regulates testicular negative feedback". While I don't entirely dismiss the latter, I say start with the horses before looking for zebras.

Hopefully they are not also guilty of defining hypogonadism in terms of total testosterone rather than free testosterone. As discussed above, if you have low SHBG then you can have normal free testosterone accompanied by seemingly low levels of total testosterone. Example: A normal healthy young man has SHBG of 30 nMol/L and TT of 500 ng/dL. Vermeulen free T is 11.1 ng/dL. His SHBG drops to 10 nMol/L, which doesn't change free T, but TT drops to 340 ng/dL. Now if he reports TT in isolation he's assumed to be hypogonadal, or close to it.

... the level of SHBG was highly positively correlated ... with the total testosterone level in untreated men presenting for evaluation of AOH, but no relationship was found between the level of SHBG and total testosterone among men who were being treated with a transdermal testosterone preparation.​

Untreated men have normal distributions for both free testosterone and SHBG. Total testosterone is a function of these two variables and increases monotonically with free testosterone and with SHBG. Therefore it's only natural for total testosterone to correlate positively with SHBG. Things get more interesting with treated men. It seems likely these men are dosed to achieve normal total testosterone, with little regard for free testosterone. This means that the equation is flipped around, with free testosterone now the dependent variable. If you consider total testosterone as essentially fixed then you're left with comparing this constant to SHBG, which still has a normal distribution. Therefore no correlation is found. I'm a little rusty on random variables, so if there are flaws in this logic then please jump in.

 

[bixt]

Yes this is the question I should have asked! Is there an answer to that question for my situation?

You have tried all the usual items such as sleep, fitness and BF%, which have not worked.

That leaves us with a single option other than TRT which is SERM monotherapy. This will raise that "set point" for testosterone higher and the body will produce more. Try clomid 12.5mg every second day, do bloods after 2 months and assess from there. This tiny dose has the potential to significantly bump up your T production without side effects. Even better theoretically is "enclomiphene" but sadly that is available in very few countries and the results don't necessarily appear to be better than clomid. The side effects of clomid you may read about are caused by high doses. For example bodybuilders using 50-200mg a day for months.

Further reading:

Clomid for Testosterone

Interesting alternative to t-replacement therapy. I am 35, healthy, regular lifter. Recently I was curious about raising my testosterone to assist my general well being and lifting. I have an endocrinologist who put me on Clomid 25mg every other day. Within 30 days my t went from Total T 687 to...

www.rooshvforum.com

Are guys that do well on low dose clomid unicorns...or do they really exist?

They actually EXIST!!! There are certainly some challenges in treating with low dose clomid, specifically in dealing with the varying effect (estrogen antagonist/agonist) of the two isomers enclomiphene and zuclomiphene. However, as I (and Dr Crisler) have said many times...I DO ACHIEVE SUCCESS...

www.excelmale.com

Good luck

 

[tareload]

Things get more interesting with treated men. It seems likely these men are dosed to achieve normal total testosterone, with little regard for free testosterone. This means that the equation is flipped around, with free testosterone now the dependent variable. If you consider total testosterone as essentially fixed then you're left with comparing this constant to SHBG, which still has a normal distribution.

Decent range on the TT for the graph on the right. Note the typo on the ordinate of the left panel. They only share the correlation on the two groups but would have been useful to report the ANOVA/parameter estimate stats. Eyeballing it appears that ANOVA would show significance on left but not on right.

EDIT: whoops I see I missed the reported p-values next to correlations. Reasonably sound conclusions by the author from the data presented and worthy of additional study and analysis.

Fun conjecture by the author.

Discussion
The findings of this study provide further support for the idea that the mechanism for the strong positive correlation between the circulating levels of SHBG and total testosterone in men is more complex than the stoichiometry of a high affinity circulating transport protein which controls metabolic clearance, and its ligand. Instead, the positive correlation in untreated, but not in testosterone-treated men, implies that SHBG regulates testicular negative feedback either directly or by modulating the entry of testosterone or estradiol into cells in the hypothalamus and/or pituitary to control gonadotropin synthesis and secretion, and thereby testosterone levels.

 

[tareload]

Hopefully they are not also guilty of defining hypogonadism in terms of total testosterone rather than free testosterone. As discussed above, if you have low SHBG then you can have normal free testosterone accompanied by seemingly low levels of total testosterone. Example: A normal healthy young man has SHBG of 30 nMol/L and TT of 500 ng/dL. Vermeulen free T is 11.1 ng/dL. His SHBG drops to 10 nMol/L, which doesn't change free T, but TT drops to 340 ng/dL.

Winters seems well versed on this and good point.

FYI...

Adult Onset Hypogonadism

Adult onset hypogonadism (AOH) is an increasingly common condition in which middle-aged to older men present with symptoms that are consistent with androgen deficiency and have a total testosterone level that is below the reference range for young adult men although...

link.springer.com

 

[Cataceous]

Winters seems well versed on this and good point.
...

Now that I've had a chance to look beyond the abstract I see there is a solid underlying reference from Vermeulen suggesting the existence of an additional factor in obesity-linked hypogonadism beyond enhanced aromatization. Winters touches on another explanation:

... leptin activates kisspeptin neurons to stimulate GnRH [17], and leptin deficiency is associated with hypogonadotropic hypogonadism [18]. Moreover, leptin treatment restores the testosterone deficiency that occurs with fasting [19]. As obese individuals are viewed as resistant to leptin, leptin resistance may also play a role in AOH.​

I'm puzzling over this "idea that SHBG regulates testicular negative feedback either directly or by modulating the entry of testosterone or estradiol into cells in the hypothalamus and/or pituitary..." An interpretation of recent research is that SHBG helps get androgens (and estrogens?) into cells, and intracellularly may also help these steroids stay unmetabolized long enough to do something useful. When it comes to negative feedback caused by these hormones, the effect of SHBG would seem to be opposite the hypothesis, with higher levels promoting stronger negative feedback and lower testosterone. Or am I missing something?

 

[tareload]

Now that I've had a chance to look beyond the abstract I see there is a solid underlying reference from Vermeulen suggesting the existence of an additional factor in obesity-linked hypogonadism beyond enhanced aromatization. Winters touches on a different possible factor:

... leptin activates kisspeptin neurons to stimulate GnRH [17], and leptin deficiency is associated with hypogonadotropic hypogonadism [18]. Moreover, leptin treatment restores the testosterone deficiency that occurs with fasting [19]. As obese individuals are viewed as resistant to leptin, leptin resistance may also play a role in AOH.​

I'm puzzling over this "idea that SHBG regulates testicular negative feedback either directly or by modulating the entry of testosterone or estradiol into cells in the hypothalamus and/or pituitary..." An interpretation of recent research is that SHBG helps get androgens (and estrogens?) into cells, and intracellularly may also help these steroids stay unmetabolized long enough to do something useful. When it comes to negative feedback caused by these hormones, the effect of SHBG would seem to be opposite the hypothesis, with higher levels promoting stronger negative feedback and lower testosterone. Or am I missing something?

Winters lays out some of his thinking here:

and here:

To your point, he needs to weave the concept of free E2 and free T into his analysis and discussion. As you point out, too often TT and fT are used interchangeably and their relationship via SHBG isn't fully fleshed out (leaving the interested reader in the dark).

Regarding your question in bold above:

My thinking (for untreated man) is higher levels of SHBG should promote weaker negative feedback at H/P (via the reduced concentration of free T and E2 via aromatase mediated conversion of said fT) per unit of endogenously produced fT. free E2 (primary) and fT (secondary) being what drive negative feedback of gonadotropins. Hence the plot he should also show is SHBG vs accurately measured fT levels (LC-MS/MS + ED).

Thought experiment is to make a step change in SHBG for untreated man and then see response on serum fT.

I am not familiar with any data that shows SHBG directly regulates LH secretion. Hence, we are left with the second part of the argument. If I was the PI my first reaction is to recreate the companion plots this time with SHBG vs accurate fT. Wish we could talk this over at a conference table. Difficult via forum.

 

[Cataceous]

...
My thinking (for untreated man) is higher levels of SHBG should promote weaker negative feedback at H/P (via the reduced concentration of free T and E2 via aromatase mediated conversion of said fT) per unit of endogenously produced fT. free E2 (primary) and fT (secondary) being what drive negative feedback of gonadotropins. Hence the plot he should also show is SHBG vs accurately measured fT levels (LC-MS/MS + ED).

Thought experiment is to make a step change in SHBG for untreated man and then see response on serum fT.
...

A modified thought experiment eliminates the distraction of the system perturbation: The step change in SHBG is accomplished by instantly removing the existing SHBG and replacing it with a higher/lower concentration of SHBG that is already bound to hormones at the correct rates to be at equilibrium with the existing free hormones. There should then be no pressure to change production rates. We've only increased or decreased total hormone levels. This is the no-change scenario I've been promoting. Shouldn't this be the case unless there actually is some independent mechanism by which SHBG affects HPTA feedback?

 

[tareload]

A modified thought experiment eliminates the distraction of the system perturbation: The step change in SHBG is accomplished by instantly removing the existing SHBG and replacing it with a higher/lower concentration of SHBG that is already bound to hormones at the correct rates to be at equilibrium with the existing free hormones. There should then be no pressure to change production rates. We've only increased or decreased total hormone levels. This is the no-change scenario I've been promoting. Shouldn't this be the case unless there actually is some independent mechanism by which SHBG affects HPTA feedback?

Thanks for laying that out. Your scenario above would preclude any hysteresis in the system response I think. No? I'm curious the transient with step change in SHBG production and setpoint/regulation effect.

Good questions.

Any value in translating plots above to fT vs. SHBG?

 

[tareload]

@Cataceous not trying to obfuscate. Just my spider sense going off right now based on previous experience with thyroid system. Examples:

A Review of the Phenomenon of Hysteresis in the Hypothalamus-Pituitary-Thyroid Axis - PubMed

The existence of a phase of prolonged suppression of TSH despite normalization of serum thyroid hormones over a variable period of time during the recovery of thyrotoxicosis has been documented in literature. Conversely, a temporary elevation of TSH despite attainment of euthyroid levels of...

pubmed.ncbi.nlm.nih.gov

Frontiers | A Review of the Phenomenon of Hysteresis in the Hypothalamus–Pituitary–Thyroid Axis

The existence of a phase of prolonged suppression of TSH despite normalization of serum thyroid hormones over a variable period of time during the recovery o...

www.frontiersin.org

Control system there is pretty well modeled as this point with some interesting regulatory fun.

From second paper:

 

[tareload]

A modified thought experiment eliminates the distraction of the system perturbation: The step change in SHBG is accomplished by instantly removing the existing SHBG and replacing it with a higher/lower concentration of SHBG that is already bound to hormones at the correct rates to be at equilibrium with the existing free hormones. There should then be no pressure to change production rates. We've only increased or decreased total hormone levels. This is the no-change scenario I've been promoting. Shouldn't this be the case unless there actually is some independent mechanism by which SHBG affects HPTA feedback?

I'll have to check these out tonight:

Mathematical modeling approaches of cellular endocrinology within the hypothalamo-pituitary-gonadal axis

The reproductive neuroendocrine axis, or hypothalamo-pituitary-gonadal (HPG) axis, is a paragon of complex biological system involving numerous cell t…

www.sciencedirect.com

Analytical construct of reversible desensitization of pituitary-testicular signaling: illustrative application in aging

Luteinizing hormone (LH) administered in pharmacological amounts downregulates Leydig cell steroidogenesis. Whether reversible downregulation of physiological gonadotropin drive operates in vivo is unknown. Most of the analytical models of dose-response ...

www.ncbi.nlm.nih.gov

So much to read.

 

[Cataceous]

"If you consider total testosterone as essentially fixed then you're left with comparing this constant to SHBG, which still has a normal distribution."

Decent range on the TT for the graph on the right. ...

Poor choice of words on my part, as I was thinking more about mean values for total testosterone that would be acquired at multiple SHBG values if N were large enough. Instead, total testosterone might be considered as a separate random variable, subject to the vagaries of the particular doctors overseeing the TRT, but independent of SHBG. If the doctors were instead targeting free testosterone then I expect total testosterone's correlation with SHBG would return.

... Your scenario above would preclude any hysteresis in the system response I think. No? I'm curious the transient with step change in SHBG production and setpoint/regulation effect.
...

I think it's possible the time constants involved in HPTA regulation are long enough that even in more realistic SHBG-manipulation scenarios there would not be a lot of hysteresis. Natesto is a possible proxy, with multiple daily doses not being too suppressive. It's true that in the thought experiment the step change in SHBG production is assumed so that there is no change in equilibrium.

A couple of more realistic scenarios are an injection of SHBG or the administration of a drug that affects SHBG in relative isolation. An injection of SHBG would somewhat imitate a step increase. The SHBG would start sucking up the free hormones, which in a normal HPTA would stimulate additional testosterone production. This would taper off as total testosterone reaches a new value that's consistent with the body's free testosterone set point and the amount of SHBG. I'm not sure what happens with the other complications: Is there a set point for SHBG that reduces production? What is its time constant? How complicated is the function modeling the return of SHBG to baseline?

 

[Dudley]

Vince, do you have a recommendation for magnesium supplementation?

 

[Dudley]

I am not sure I fully follow all of the above, but I can say that the general condition that prompted the start of this thread is a condition I share: "normal" total T, high out-of-range SHBG, and low out-of-range Free T and Bioavailable T using the most sensitive tests available from Discounted Labs. Clomid every other day (for several months) changed my blood work and pushed Free T into low-normal, but had no actual impact on how I felt, my experience in the gym, and my libido and erection. I am now off Clomid and trying Natesto (am in my second month; blood work has returned to more-or-less-identical to what it was before I tried Clomid). Cannot yet tell whether Natesto is changing things for me; if so, it's very very subtle. My doc wanted me to try these before considering moving to some version of TRT. I like his conservative approach but I also am frustrated by where my life is at sexually. At least for me, at age 67, Clomid and probably Natesto don't solve my type of low T.

 

[Cataceous]

I am not sure I fully follow all of the above, but I can say that the general condition that prompted the start of this thread is a condition I share: "normal" total T, high out-of-range SHBG, and low out-of-range Free T and Bioavailable T using the most sensitive tests available from Discounted Labs. Clomid every other day (for several months) changed my blood work and pushed Free T into low-normal, but had no actual impact on how I felt, my experience in the gym, and my libido and erection. I am now off Clomid and trying Natesto (am in my second month; blood work has returned to more-or-less-identical to what it was before I tried Clomid). Cannot yet tell whether Natesto is changing things for me; if so, it's very very subtle. My doc wanted me to try these before considering moving to some version of TRT. I like his conservative approach but I also am frustrated by where my life is at sexually. At least for me, at age 67, Clomid and probably Natesto don't solve my type of low T.

Your doctor gets an A+ in my book. Natesto is a great concept, but it sounds like you're having absorption problems. If those can't be resolved then you may need to move to conventional TRT. Just go into it well informed. Many guys do get good results, especially in the beginning, but down the road some can start to experience subtle and not-so-subtle difficulties that may stem from the HPTA shutdown.

 

[Dudley]

Thanks for this feedback, I agree, I am very happy with my doc. I will even be fine giving Natesto a longer try. I can tell from the discourse in this forum that TRT is great and yet also for some men comes with its own issues or even works significantly less well over time -- and that getting off TRT has its own complexities and can be very uncomfortable. Any thoughts about whether or how I could improve either my absorption of Natesto or in some way boost its impact?

 

[Dudley]

Oh, one more Natesto question: how many mg of T would I ideally be absorbing from Natesto 3x/day? I'm trying to understand whether the issue is more likely absorption, or whether the dose is just lower than what I need. Thanks for any thoughts on that.

 

[Cataceous]

... Any thoughts about whether or how I could improve either my absorption of Natesto or in some way boost its impact?

I haven't used a nasal gel product so I don't have much to offer on the practical side. Maybe we can get one of our Natesto pros to weigh in. @Fortunate ?

Oh, one more Natesto question: how many mg of T would I ideally be absorbing from Natesto 3x/day? I'm trying to understand whether the issue is more likely absorption, or whether the dose is just lower than what I need. Thanks for any thoughts on that.

Are you taking three doses with two pumps per dose? Did you measure testosterone about an hour after taking a dose? I'm not sure about the expected absorption efficiency. I'd think it should be greater than the 10% usually seen with transdermal products. If you're dosing the full 33 mg then you should certainly be absorbing more than 3 mg, and each dose should have a decent, though short-lived effect on serum testosterone.

 

[Dudley]

Yes, doing 3x/ day, 1 pump per nostril so 2 pumps, so yes, 33 mg. Thanks for giving me a sense of what the absorption rate might be. I measured T at the trough, not peak -- fasted in the a.m. before doing my first Natesto for the day. Would it be more meaningful to get the peak rather than the trough reading?

 

[Cataceous]

You need to measure serum peaks with Natesto. It's expected for troughs to be close to the old baseline. The long and low troughs keep your HPTA functional, while the peaks provide the benefits of higher testosterone.

On the absorption issue, I'm now wondering if the small surface area limits the absorption to under 10%. I wouldn't think the product designers would want the absorbed dose to be over 9 mg; the normal range of daily testosterone production in males is 3-9 mg. With Natesto adding to your own production, better absorption would be putting you in supraphysiological territory.

 

[ResearchIt]

I have one last question about the idea of the body choosing a Free T level to target, and Free T being the constant in the equation with Total T and SHBG being the variables.

How would TRT be successful in raising Free T then? With the increase in T, wouldn't the body just increase SHBG to counteract the TRT T in order to keep Free T at it's target level if Free T is constant?

Or, with TRT, is so much T added to the body that the body perhaps maxing out it's SHBG isn't enough to keep Free T from rising?