#22

Yes. And I think more specifically, high iron leads to elevated SHBG which causes low free T.

I have a normal total T, slightly low free T and high SHBG. My iron/ferritin levels are WNL but slightly towards the higher end. So, I donated blood last month to reduce my iron. Will donate again mid November. And test my levels again in December to see if I decreased my SHBG. My prior attempt was I took boron 10mg/day for several months and it did nothing to reduce my SHBG.

On another note, I just got my first shipment of rapamycin! I plan to take my first dose in the morning! So I’m glad to hear that should keep my iron in check!

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#23

Hadn’t heard about iron => high SHBG. Was looking at SHBG lowering the other day myself and saw this at SelfDecode:

Did you try anything else than Boron?

Supplements

The following supplements were found to decrease SHBG production and/or reduce its interaction with sex hormones, though further clinical studies are needed before these findings can be considered conclusive:

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#24

I have been taking all of those except calcium for quite a long time. Well, I was taking krill oil, not fish oil. But I did add the triglyceride form of fish oil recently m. My SHBG is still high. Maybe it would be even higher without the supplements. Who knows.

I first heard of high iron causing elevated SHBG here and have since looked into it further. It’s definitely a thing:

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#25

I am currently wondering if megadosing melatonin causes an increase in SHBG. Melatonin has anti puberty effects and puberty is associated with a reduction in SHBG. My ferritin is quite low and iron is not particularly high.

Calcium is interesting because i have been slightly low on calcium.

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#26

I wonder if these are direct or indirect effects? Do these supplements act on SHBG or do they improve “health” which leads to lower SHBG?

The constrained metabolism model says reproduction is down regulated when physical activity is higher (exercise occurs only when people feel well). Triage theory says long term survival is down regulated in favor of short term survival when threatened by shortages of nutrients.

#27

Yes, I’ve been wondering about some of these questions too.

Perhaps higher SHBG is actually consistent with multiple longevity dimensions
. see eg below.

@stealle did you look into this anything?

@AlexKChen since you know the CR experience do you have a view?

@John_Hemming

Others?

@Joseph_Lavelle what do you think about below?

—

In human and rodent CR individuals SHBG is higher

When body mass index (BMI) is lower and when fasting insulin is lower SHBG is higher. At a given chronological age, higher SHBG has lower cardiovascular disease risk.

—

And based on Mendelian Randomization studies:

SHBG might lower the risk of ischemic heart disease (IHD) in men, with a role independent of testosterone.

Genetically predicted higher SHBG was associated with a lower risk of CKD and better kidney function in men (again independently from testosterone levels), but not in women, suggesting that SHBG may play a role in CKD specifically in men.

In a study that looked at multiple health outcomes; Higher genetically predicted SHBG levels were associated with a reduced risk of hypertension, type 2 diabetes, diabetic complications, coronary atherosclerotic outcomes, gout and benign and malignant neoplasm of uterus, but (mainly in females) an increased risk of varicose veins and fracture

—

And observational: “men with higher SHBG levels (>28.3 vs < or =28.3 nmol/L) had a 52% lower risk (RR, 0.48; 95% CI, 0.33 to 0.69)” of type 2 diabetes

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#28

It is an interesting biomarker. Not all of my labs test for it, but i will focus on a few whilst i constrain melatonin usage. I intend to keep my melatonin usage below 50mg per day. It was averaging 0.5g.

#29

In the video I posted above, Elliot Overton hypothesized that the body is increasing SHBG as a defense mechanism to protect the body from damage that could be caused by elevated RBCs/hematocrit. You see, elevated testosterone can cause a dangerous elevation in RBCs. (That’s one of the things men on testosterone replacement are watching for in their labs) High iron can also cause an elevation in RBCs. The body is trying to protect itself from this abnormal rise in RBCs. The body can only do so much about the iron. But it can do something about testosterone. So, it increases SHBG so it can bind with testosterone. Therefore less free testosterone causing further elevation in RBCs.

So to take it a step further, if you have elevated iron and you can somehow lower it (such as blood donation) then RBC production will decrease. The body reacts by producing less SHBG thus allowing the increase of free testosterone.

Elliot Overton is a very intelligent nutritional therapist and functional medicine practitioner. I highly recommend you check out his videos.

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#30

Very interesting. Thanks.

SHBG appears to be affected by many factors
up and down, but “age” seems to result in higher SHBG and lower T. Chronic inflammation seems to be a driver of higher SHBG, which is odd if higher SHBG lowers risk of T2D, hypertension, CVD. Perhaps it is the U-shaped curve which makes the data hard to interpret. If higher than normal and lower than normal SHBG are negative on health outcomes, how to establish “higher is better”? Higher than what?
Decrease_SHBG_1

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#31

Does not seem like that the (casual) direction generally is inflammation => high SHBG = bad.

Seems/could more be SHBG is anti inflammatory - so (a) having high levels (eg because of CR, low insulin burden, etc) keeps inflammation down, and (b) in some circumstances, if someone ends up with high inflammation the body partially tries to control the inflammation by providing more SHBG.

See eg

—

”The decline in serum SHBG was associated with inflammation, since proinflammatory cytokines such as TNF-α and IL-1ÎČ could inhibit SHBG synthesis (11).”

And

—

Sex-hormone binding globulin (SHBG) is a protein carrier with potential biological anti-inflammatory function, regulating concentrations of testosterone. Low levels of SHBG have been related to increased risk for insulin resistance, obesity, T2DM and metabolic syndrome in men.

“An inverse association was found between levels of hsCRP and levels of testosterone and SHBG, even after adjustment for confounders and IL-6”

Although it does seem mixed with “We found a positive association between IL-6 and SHBG in men. To date, no study has found similar associations and is in contrary to other studies on inflammatory markers (TNF-α and IL-1), reporting a decrease in production of SHBG.”

—

For what it’s worth, my inflammation markers are basically all at the lower bounds (hs-CRP, erythrocyte sedimentation rate (ESR), IL-1, IL-6, IL-8, and IL-12) while my SHBG is high.

—-

https://onlinelibrary.wiley.com/doi/10.1111/cen.14930#:~:text=Sex-hormone%20binding%20globulin%20(SHBG)%20is%20a%20protein%20carrier,function%2C%20regulating%20concentrations%20of%20testosterone.&text=Low%20levels%20of%20SHBG%20have,and%20metabolic%20syndrome%20in%20men.

Association Between Dietary Inflammatory Index and Sex Hormone Binding Globulin and Sex Hormone in U.S. Adult Females - PMC.

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#32

Most of the papers I linked to are Mendelian Randomization studies. In general they look at outcomes over long periods.

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#33

Thanks. I think what you are saying is right. I need to measure my own free T and SHBG. My inflammation markers are very low. In the past my total T was on the low end but I’ve never measured free T or SHBG.

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#34

“Higher genetically predicted SHBG levels were associated with a reduced risk of hypertension, type 2 diabetes, diabetic complications, coronary atherosclerotic outcomes, gout and benign and malignant neoplasm of uterus, but an increased risk of varicose veins and fracture (mainly in females). Higher genetically predicted testosterone levels were associated with a lower risk of type 2 diabetes, coronary atherosclerotic outcomes, gout and coeliac disease mainly in males, but an increased risk of cholelithiasis in females.”

The studies you provided seem to be focused on genetics and “predicted” levels of SHBG and testosterone. That leaves out a number of factors that i understand influence actual outcomes, such as high stress resulting in lower free T
but let’s go with it.

The results point to people with high SHBG, which should mean less free T, having lower risk. But how much less free T? The results also point to people with high testosterone as having low risk. Is that total testosterone, meaning that high total testosterone plus high SHBG equals normal-ish free T (but clearly not high T)?

How does this align with increasing SHBG with age? Doesn’t chronic inflammation increase with age? Is SHBG increasing with age because the low SHBG people are dying out of the population? And same with free T?

#35

Not sure about the answers to many of these questions, but do think the answer to above is yes, chronic inflammation tends to go up as people age.

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#36

Same here. Basically every lab I’ve done (and I’ve done a ton) are optimal with the exception of high SHBG
 and as a result my free T in on the very low end of “normal”

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#37

Thanks, helpful to know.

What you think about above re that this from a longevity and disease perspective might actually be good?

If so the issue may still be a

A. healthspan / libido / energy / muscle bulk

vs.

B. longevity / less disease

type of trade off


i.e my question to you (and others) is, do you think that high SHBG in the context of our situations is bad or good from a longevity standpoint? Have you looked into that?

#38

It is an interesting question. At the moment i am looking at SHBG on a weekly basis seeing if i can bring it down because it has just gone over the normal range. Bringing down inflammation is a top target in the sense of SASP. I have not looked at whether if I can bring down SHBG I may wish to put it back up.

#39

From longevity standpoint I think elevated SHBG can be good in the sense of that is what the body needs to do in order to correct a problem such as inflammation, elevated testosterone, elevated estrogen, or “blood too thick” / elevated RBC production (lots of things can cause elevated RBCs such as smoking, elevated iron, congenital heart disease, pulmonary disease) which can lead to increased clotting, as in you could die from a clot causing a pulmonary embolism or stroke. So, I believe it’s good that your body is correcting a problem for the sake of longevity but the result of elevated SHBG is reducing your free testosterone. So, it’s fixing a big problem while creating a lesser problem. Ideally, I do not think it is desirable to try to increase our SHBG for the sake of longevity. Rather I think we need to figure out the cause of elevated SHBG and address that problem. Ideally, we want normal SHBG and normal free T
 and normal iron levels, low inflammation, normal clotting factors.

In my case, I really don’t know why my SHBG is high and free T on the low end. I have normal total T (around 750). My hsCRP is 0.7, my lipids are excellent, RBCs, HBG HCT all excellent. A1C is 5.1. I take absolutely no medications (except for taking my first dose of rapamycin today) EDIT: I just looked at my labs to refresh my memory and see if anything else stands out. I forgot I do have elevated Lipoprotein (a) at 118 but I don’t think there is much I can do about that. Could that be causing my elevated SHBG? I dunno

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#40

There are a number of avenues to go down to try to lower ldl-c.

Diet: lower saturated fat, calorie restriction, higher soluble fiber
Supplements (lots of maybe’s): flaxseed, berberine, niacin, green tea, vit b5
Meds: the usual

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#41

Thanks for color. Yeah, was not saying to anyone at higher end of SHBG to try and increase it further per se.

More wondering if a longevity eating window/amount, activity, etc, can lead it to be high - and in that case it might
be consistent with longevity (and disease prevention, even if perhaps not optimal for muscle bulk and libido) and not something that needs to/should be managed down if optimizing for longevity.

Interesting my worst blood marker is probably also my Lp(a)