Monday, February 25, 2013

Could the low testosterone problem be a mirage?

Low testosterone (a.k.a. “low T”) is caused by worn out glands no longer able to secrete enough T, right? At least this seems to be the most prevalent theory today, a theory that reminds me a lot of the “tired pancreas” theory () of diabetes. I should note that this low T problem, as it is currently presented, is one that affects almost exclusively men, particularly middle-aged men, not women. This is so even though T plays an important role in women’s health.

There are many studies that show associations between T levels and all kinds of diseases in men. But here is a problem with hormones: often several hormones vary together and in a highly correlated fashion. If you rely on statistics to reach conclusions, you must use techniques that allow you to rule out confounders; otherwise you may easily reach wrong conclusions. Examples are multivariate techniques that are sensitive to Simpson’s paradox and nonlinear algorithms; both of which are employed, by the way, by modern software tools such as WarpPLS (). Unfortunately, these are rarely, if ever, used in health-related studies.

Many low T cases may actually be caused by something other than tired T-secretion glands, perhaps a hormone (or set of hormones) that suppress T production; a T “antagonist”. What would be a good candidate? The figure below shows two graphs. It is from a study by Starks and colleagues, published in the Journal of the International Society of Sports Nutrition in 2008 (). The study itself is not directly related to the main point that this post tries to make, but the figure is.

Look at the two graphs carefully. The one on the left is of blood cortisol levels. The one on the right is of blood testosterone levels. Ignore the variation within each graph. Just compare the two graphs and you will see one interesting thing – cortisol and testosterone levels are inversely related. This is a general pattern in connection with stress-induced cortisol elevations, repeating itself over and over again, whether the source of stress is mental (e.g., negative thoughts) or physical (e.g., intense exercise).

And the relationship between cortisol and testosterone is strong. Roughly speaking, an increase in cortisol levels, from about 20 to 40 μg/dl, appears to bring testosterone levels down from about 8 to 5 ηg/ml. A level of 8 ηg/ml (the same as 800 ηg/dl) is what is normally found in young men living in urban environments. A level of 5 ηg/ml is what is normally found in older men living in urban environments.

So, testosterone levels are practically brought down to almost half of what they were before by that variation in cortisol.

Chronic stress can easily bring your cortisol levels up to 40 μg/dl and keep them there. More serious pathological conditions, such as Cushing’s disease, can lead to sustained cortisol levels that are twice as high. There are many other things that can lead to chronically elevated cortisol levels. For instance, sustained calorie restriction raises cortisol levels, with a corresponding reduction in testosterone levels. As the authors of a study () of markers of semistarvation in healthy lean men note, grimly:

“…testosterone (T) approached castrate levels …”

The study highlights a few important phenomena that occur under stress conditions: (a) cortisol levels go up, and testosterone levels go down, in a highly correlated fashion (as mentioned earlier); and (b) it is very difficult to suppress cortisol levels without addressing the source of the stress. Even with testosterone administration, cortisol levels tend to be elevated.

Isn't possible that cortisol levels go up because testosterone levels go down - reverse causality? Possible, but unlikely. Evidence that testosterone administration may reduce cortisol levels, when it is found, tends to be rather weak or inconclusive. A good example is a study by Rubinow and colleagues (). Not only were their findings based on bivariate (or unadjusted) correlations, but also on a chance probability threshold that is twice the level usually employed in statistical analyses; the level usually employed is 5 percent.

Let us now briefly shift our attention to dieting. Dieting is the main source of calorie restriction in modern urban societies; an unnatural one, I should say, because it involves going hungry in the presence of food. Different people have different responses to dieting. Some responses are more extreme, others more mild. One main factor is how much body fat you want to lose (weight loss, as a main target, is a mistake); another is how low you expect body fat to get. Many men dream about six-pack abs, which usually require single-digit body fat percentages.

The type of transformation involving going from obese to lean is not “cost-free”, as your body doesn’t know that you are dieting. The body “sees” starvation, and responds accordingly.

Your body is a little bit like a computer. It does exactly what you “tell” it to do, but often not what you want it to do. In other words, it responds in relatively predictable ways to various diet and lifestyle changes, but not in the way that most of us want. This is what I call compensatory adaptation at work (). Our body often doesn’t respond in the way we expect either, because we don’t actually know how it adapts; this is especially true for long-term adaptations.

What initially feels like a burst of energy soon turns into something a bit more unpleasant. At first the unpleasantness takes the form of psychological phenomena, which were probably the “cheapest” for our bodies to employ in our evolutionary past. Feeling irritated is not as “expensive” a response as feeling physically weak, seriously distracted, nauseated etc. if you live in an environment where you don’t have the option of going to the grocery store to find fuel, and where there are many beings around that can easily kill you.

Soon the responses take the form of more nasty body sensations. Nearly all of those who go from obese to lean will experience some form of nasty response over time. The responses may be amplified by nutrient deficiencies. Obesity would have probably only been rarely, if ever, experienced by our Paleolithic ancestors. They would have never gotten obese in the first place. Going from obese to lean is as much a Neolithic novelty as becoming obese in the first place, although much less common.

And it seems that those who have a tendency toward mental disorders (e.g., generalized anxiety, manic-depression), even if at a subclinical level under non-dieting conditions, are the ones that suffer the most when calorie restriction is sustained over long periods of time. Most reports of serious starvation experiments (e.g., Roy Walford’s Biosphere 2 experiment) suggest the surfacing of mental disorders and even some cases of psychosis.

Emily Deans has a nice post () on starvation and mental health.

But you may ask: What if my low T problem is caused by aging; you just said that older males tend to have lower T? To which I would reply: Isn’t possible that the lower T levels normally associated with aging are in many cases a byproduct of higher stress hormone levels? Take a look at the figure below, from a study of age-related cortisol secretion by Zhao and colleagues ().

As you can see in the figure, cortisol levels tend to go up with age. And, interestingly, the range of variation seems very close to that in the earlier figure in this post, although I may be making a mistake in the conversion from nmol/l to ηg/ml. As cortisol levels go up, T levels should go down in response. There are outliers. Note the male outlier at the middle-bottom part, in his early seventies. He is represented by a filled circle, which refers to a disease-free male.

Dr. Arthur De Vany claims to have high T levels in his 70s. It is possible that he is like that outlier. If you check out De Vany’s writings, you’ll see his emphasis on leading a peaceful, stress-free, life (). If money, status, material things, health issues etc. are very important for you when you are young (most of us, a trend that seems to be increasing), chances are they are going to be a major source of stress as you age.

Think about individual property accumulation, as it is practiced in modern urban environments, and how unnatural and potentially stressful it is. Many people subconsciously view their property (e.g., a nice car, a bunch of shares in a publicly-traded company) as their extended phenotype. If that property is damaged or loses value, the subconscious mental state evoked is somewhat like that in response to a piece of their body being removed. This is potentially very stressful; a stress source that doesn’t go away easily. What we have here is very different from the types of stress that our Paleolithic ancestors faced.

So, what will happen if you take testosterone supplementation to solve your low T problem? If your problem is due to high levels of cortisol and other stress hormones (including some yet to be discovered), induced by stress, and your low T treatment is long-term, your body will adapt in a compensatory way. It will “sense” that T is now high, together with high levels of stress.

Whatever form long-term compensatory adaptation may take in this scenario, somehow the combination of high T and high stress doesn’t conjure up a very nice image. What comes to mind is a borderline insane person, possibly with good body composition, and with a lot of self-confidence – someone like the protagonist of the film American Psycho.

Again, will the high T levels, obtained through supplementation, suppress cortisol? It doesn’t seem to work that way, at least not in the long term. In fact, stress hormones seem to affect other hormones a lot more than other hormones affect them. The reason is probably that stress responses were very important in our evolutionary past, which would make any mechanism that could override them nonadaptive.

Today, stress hormones, while necessary for a number of metabolic processes (e.g., in intense exercise), often work against us. For example, serious conflict in our modern world is often solved via extensive writing (through legal avenues). Violence is regulated and/or institutionalized – e.g., military, law enforcement, some combat sports. Without these, society would break down, and many of us would join the afterlife sooner and more violently than we would like (see Pinker’s take on this topic: ).

Sir, the solution to your low T problem may actually be found elsewhere, namely in stress reduction. But careful, you run the risk of becoming a nice guy.


WilliamS said...

Ned, the data you present all seems to be for total T, yet you commented that low free T is the "problem" that leads to T supplementation by doctors.

Based on my n=1 at least, total and free T may be highly discordant. At 55, my total T is near the top of the lab range at 9.2 ng/ml, whereas my free T is at the low end of the lab range at 53 pg/ml. Everything T is supposed to do works great, so I don't seem to have a T problem. I assume the lowish free T is physiological for me.

My sex hormone binding protein is "high" according to the lab range at 86 nmol/L, which possibly explains the discordance between total and free T (my docs don't consider the "high" SHBG finding at all significant).

Interesting perhaps that my cortisol (via saliva testing) is at the low end of the lab's range, which is consistent with your thesis in this post, at least with regard to total T.

I had attributed my excellent total T to years of high-intensity strength training (currently Body By Science style) and maybe good diet, too. Just guesswork of course.

I wonder how your thesis here would apply to free T.

Tuck said...

Here's my hypothesis, which ties in with yours nicely:

High blood sugar suppresses testosterone:

""Because glucose intake, and likely food, decreases testosterone, she said, 'This research supports the notion that men found to have low testosterone levels should be reevaluated in the fasting state.'"

Cortisol, of course, stimulates gluconeogenesis in the liver: blood sugar rises. Cortisol is a "stress hormone" because it stimulates production of energy, to provide fuel for the "fight or flight" reaction.

Unfortunately, under a high-carb, low-exercise lifestyle, the body's ability to burn fat rather than glucose atrophies, and the body becomes dependent on glucose for fuel. At that point, running low on blood glucose becomes a stress event, as the brain is in danger: cortisol production surges.

Now the fat-burning mechanism can atrophy, and also be increased through training, a low-carb diet, or through the use of metformin, the diabetes medication.

Art DeVany is not an outlier, therefore, but is an example of the normal human condition: lower carb consumption and a well-developed fat-burning metabolism means the body is not dependent on glucose for fuel, blood glucose trends lower, cortisol is not required to stimulate gluconeogenesis, and testosterone levels can return to normal.

Ned Kock said...

Thanks WilliamS. I corrected that. Btw, was your free measured directly, or estimated?

Testosterone is also bound to albumin (seemingly a good proportion of it), which is also the main carrier of FFAs.

Ned Kock said...

Hi Tuck. Interesting hypothesis. However, there is evidence (I have to find it) that sustained carb restriction also causes T levels to go down, something that is immediately reversed by a carb load. But this may be under glycogen depletion conditions, with athletes – I have to check.

WilliamS said...

Ned, it looks like a direct measurement by liquid chromatography-tandem mass spectrometry (LC-MS/MS) performed by Quest Diagnostics.

Regarding albumin-bound T, Quest says: "Sex hormone binding globulin binds testosterone with high affinity and acts as a reservoir for storage and transport. Albumin, on the other hand, binds testosterone with weak affinity. Free and albumin-bound fractions are available for immediate binding to an available receptor; therefore, the sum of free and albumin-bound testosterone is termed bioavailable testosterone."

Theophilus said...

A castrate is also a noun, namely a person who has been castrated.

Steven Hamley said...

WilliamS, do you eat a low carb diet? Insulin suppresses SHBG

WilliamS said...

Steven, yes I do: not VLC as in the past but quite low carb. especially refined carb, compared to the standard American diet certainly.

Also intermittent fasting, plus the intense HIT strength training, would suggest low insulin. The one time it was measured fasting several years back it was below the detection limit of the test.

Interesting thought, thanks! I'm always dubious of lab ranges, based as they are on people presumably eating SAD and different from me in other ways, too. This could be another example of the problem.

Ned Kock said...

Hi Theophilus. You are correct, thanks; I fixed that.

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joeo said...

In the short term, low-carb plus exercise reduces testosterone:

I suspect that if you go low-carb for longer periods of time, testosterone levels are boosted once you stop the calorie restriction. Especially if you eat a lot of eggs and meat. Surprisingly, hard to find evidence of that though.

joeo said...

Actual stress levels decline as you get older:

cortisal levels and the ability to recover from stress do get worse as you age:

My guess is that older people adjust to their inability to recover from stress by avoiding stress.

Ned Kock said...

Hi joeo. I’d have to look more into this, but it seems to me that perceived stress measures are not good reflections of stress hormone levels in circulation. Someone who is better at managing stress may tend to state that stress levels are not as high as blood hormone levels would indicate.

Stress may end up being frequently “bottled up” in older folks, to the detriment of their health; something that would be consistent with some of the unexpected findings from the Oregon Sudden Unexpected Death Study:

Ned Kock said...

On average, older men are definitely more vulnerable health-wise than younger men. I am just not sure if low T is the main factor here. This generally applies to women as well; the threshold being menopause.

There are some master self-experimenters today, experimenting with supposedly age-slowing drugs, who are in the public eye; one of them being Sylvester Stallone.

I am sure a few things will come out from these self-experiments that will be very instructive.

joeo said...

Retired people don't tend to have stressful lives.

All kinds of bad things happen as you age including fragmented sleep that can result in increased cortisol levels. But the fragmented sleep isn't really due to stress. It is just something that happens to old people.

Henry Dawson said...

I am really amazed by seeing this information about low testosterone.
It is very useful for low testosterone users.

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David Isaak said...

Hi, Ned--

This is a complicated area, and I am glad to see you are exploring the complexities.

Cortisol is an issue, Free T is an issue, and conversion of testosterone to estradiol is an issue. The last times I was measured, my T was pretty high, but my estrogen/estradiol was creeping up, too. So rate of conversion to female hormones is important with age...

I also wonder if by analogy with inuslin there is such a thing a "T sensitivity?" I wonder about this because I have known some relatively elderly women who were given tiny doses of T for muscle and bone loss. Not only did they perk up, their sex drives went through the roof. Obviously women are more "sensitive" to T. WHat's the mechanism?

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Jack C said...


Deficiency of vitamin K2 results in reduced testosterone production in the testis, and vitamin K2 supplementation increases T synthesis. The following link is one of many studies on the subject.

Another factor that results in low testosterone levels is excessive intake of linoleic acid (LA). LA is the precursor of arachidonic acid (AA). AA is the backbone of the two primary endogenous cannabinoids, or endocannabinoids (ECs)anandamide and 2-AG. Endocannabinoids are mild opioids that activate the same receptors, CB-1 and CB-1, that are activated by marijuana. Excessive intake of LA, or increased use of pot, results in increased levels of endocannabinoids which stimulate de novo lipogenesis (conversion of carbohydrates to fat) which can result in fatty liver. Fatty liver leads to reduced testosterone levels and reduced sperm count.

The foregoing can be found on pubmed by searching for "fatty liver, endocannabinoid, testosterone.

The U.S.D.A. dietary guidelines advocate substituting vegetable oil spread (high in LA) for butter, limiting cheese intake to one serving per week, and reducing intake of animal fats and using vegetable fats in lieu of animal fats. Following USDA guidelines results in deficiency of vitamin K2 and excessive intake of LA which in turn cause testosterone deficiency.

Anyone interested in entering the priesthood could help maintain a celibate lifestyle by following USDA dietary guidelines.

Jack C said...

Hi Ned,

I am late to the discussion about testosterone and stress because the bookmark to your site (on my computer) locked on to your December post on eggs and made it appear that there were no posts after that one.

Your interesting hypothesis that hypogonadism may be a mirage prompted me to look into the subject. A web search resulted in a couple of pertinent studies.

A recent study titled "Good stress, bad stress and oxidative stress" (PMID 23490070) concluded that "chronic stress exposure promotes oxidative damage through frequent and sustained of the hypothalmic pituitary axis", BUT, "moderate (compared to low)levels of perceived stress are associated with reduced levels of oxidative damage. It was concluded that manageable levels of stress enhance resistance to oxidative damage.

Another study, "Effects of low testosterone on antioxidant systems in secondary hypogonadism", (PMID 18641414) concluded that "our data suggests that hypogonadism could represent a condition of oxidatve stress". The study found that CoQ10 levels were significantly lower in hypogonadism than in normogonadism and that testosterone treatment of isolated hypogodadism patients induced significant enhancement of both CoQ10 and antioxidant capacity. Indeed, testosterone treatment increased T levels by a factor of 4.2 and increased CoQ10 levels by a factor of 3.7!

It seems reasonable to conclude that oxidative damage is perhaps the primary cause of reduced testosterone levels. Oxidative damage can be caused by many factors including chronic stress. Other causes of oxidative stress known to reduce testosterone levels include:

Zinc deficiency: (PMID 8875519)
Magnesium deficiency: (PMID 20322370)
Vitamin K2 deficiency (PMID 21914161)
Excess LA intake which causeses fatty liver (PMID 22691278)

Low testosterone levels are a real problem, not a mirage. The strong association between low testosterone and increased risk of coronary heart disease is probably due to increased oxidative stress which reduces T and increases CHD risk. The oxidative stress can be due to mental stress as well as many dietary factors.

John Andrews said...

True that! Stress triggers the release of cortisol, testosterone’s mortal enemy. Increasing cortisol translates to decreasing testosterone. Beat stress – stay happy and cheerful, practice yoga or meditation, do any activity that relaxes you. Other ways of improving the body’s hormonal balance are to eat a healthy diet and do vigorous exercise such as weightlifting and strength training. Men who have exceptionally low testosterone should can also go through Ageless Male testimonials. This supplement contains essential vitamins that raise T levels and improve overall male health.

complete said...

One major reason why a lowering of testosterone levels yields a decrease in libido is it can be difficult to maintain an erection due to lower testosterone levels. For many men, having to deal with erectile dysfunction issues can be quite troubling.

However, this will sometimes be the unavoidable case when testosterone levels are diminishing. The equally unavoidable problem would be the frustrations that come with not be able to sustain a firm erection.

That said, low testosterone alone will not cause a weakness in erections. Usually, it is a combination of low testosterone and other factors.

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Anonymous said...

Most likely T3 stimulates Test(either directly or indirectly). My brother suffers from Hypothyroidism, for which he was taking synthetic t3. My brother only felt right on about 10 micrograms of t3. This put his blood t3 way out of range, and his test went from 60 ish percentile to 95th percentile without changing anything else.