Click here to go back to Part 3 of the Wheel of Fire: Walden Pond and Sharknado

NIETZSCHE, A HUNGARIAN, AND UTTER EXHAUSTION

“That which does not kill me makes me stronger.”

– Friedrich Nietzsche, Twilight of the Idols

“Every stress leaves an indelible scar, and the organism pays for its survival after a stressful situation by becoming a little older.”

– Hans Seyle

It is about time to bring all of this together so as to create a more inclusive and practical model of the wheel of fire.  Before doing so, however, it is first necessary to make a brief digression and to address the neurosteroids.  The neurosteroids are important as they are often underappreciated players involved in the hidden relationships between the sympathetic disease, sex hormone dysregulation, and the metabolic syndrome.

Hans Selye on a Hungarian stamp for the World Conference on Stress in 2007. While Seyle was a great endocrinologist and pioneered the idea of "good stress" or "eustress" - one of my favorite overarching scientific concepts of all time, he wasn't without flaws. He happened also to be something of a tobacco industry apologist and consultant in return for scientific funding. Alas, no one's perfect.

Hans Selye on a Hungarian stamp for the World Conference on Stress in 2007. While Seyle was a great endocrinologist and pioneered the idea of “good stress” or “eustress” – one of my favorite overarching scientific concepts of all time, he wasn’t without flaws. He happened also to be something of a tobacco industry apologist and consultant in return for scientific funding. Alas, no one’s perfect.

A schematic of a cholesterol molecule. Without this miraculous conglomeration of atoms we would all be piles of goo. Or, more likely, there would hardly be any life, or lifelike goo, at all. Cholesterol provides structure to cells to make them semi-rigid, which is of course necessary for multicellular structures. Cholesterol also is a steroid and is the basis for all other steroids that we use as hormones, such as cortisol, estrogen, testosterone, progesterone, DHEA, DHEA-S, ALLO, ALLO-THDOC, and all of the other neurosteroids and hormones of the adrenal cortex.

A schematic of a cholesterol molecule. Without this miraculous conglomeration of atoms we would all be piles of goo. Or, more likely, there would hardly be any life, or lifelike goo, at all. Cholesterol provides structure to cells to make them semi-rigid, which is of course necessary for multicellular structures. Cholesterol also is a steroid and is the basis for all other steroids that we use as hormones, such as cortisol, estrogen, testosterone, progesterone, DHEA, DHEA-S, ALLO, ALLO-THDOC, and all of the other neurosteroids and hormones of the adrenal cortex.

The neurosteroids are a group of hormones made out of cholesterol that are either made in the brain, or that act on the brain but are made elsewhere, like the adrenal glands, testes, and ovaries.  Many of them are also sex hormones, or closely related to sex hormones.

Three of the most important neurosteroids include dihydroepiandrostenedione and its sulfate (DHEA and DHEA-S) and allopregnenolone (ALLO).

The neurosteroids have been slowly gaining the attention of researchers and clinicians as we recently discovered that we have been unintentionally interacting with them by way of certain medications.  For instance, there is evidence that certain antidepressants, like Prozac (fluoxetine) may exert a lot of their effects by modulating neurosteroids.  Neurosteroids are also gaining attention as potential therapies for a variety of neurological disorders besides depression.  Examples include epilepsy, multiple sclerosis, chronic pain, depression, anxiety, and TBI.

In other words, it appears that the neurosteroids have been doing some very important things behind closed curtains.  And even though we only figured out that they existed about twenty years ago or so, it looks that they are fundamental to human biology.  Perhaps the most germane role that they play, for our purposes at this juncture anyway, is as part of the sympathetic response.

The sympathetic response is of course natural and necessary.  But, as we have seen, it is wont to get out of control.  The neurosteroids’ main job is to help keep this from happening.  Another way to say this is that the neurosteroids act as a counterweight to a potentially overactive HPA axis.  They tell the hypothalamus to calm down.  By extension, they tell us to relax.

Perhaps the best way to see the role of the neurosteroids is to break down the sympathetic response into a few steps.  Step one and two will be familiar.  Step three will be where the neurosteroids join the fray.

Step one, start with a stressor.  Such may include a Kardashian, a mortgage, or CNN.

Step two, activate the hypothalamus.  Recall the hypothalamic-pituitary-adrenal (HPA) axis from BSSHM.  The hypothalamus is essentially in charge of all of the hormones in the body.  It sends signals down to the pituitary gland, which sits just underneath of it.  The pituitary gland then sends out hormones to the rest of the body, particularly the adrenal glands, which sit atop the kidneys.  The adrenal glands secrete cortisol, which, as you know, is our main stress hormone.  The hypothalamus also sends nerve impulses to the brainstem and then the spinal cord to make our bodies do all of the other stuff associated with fight or flight as discussed in Walden Pond and Sharknado.  The pupils dilate.  The heart races.  The bladder sphincter constricts.  The muscles in the extremities tense up so that you can run away or do a roundhouse kick to an attacking shark’s face.

The all important HPA axis.

The all important HPA axis.

Step three: eventually, if the hypothalamus starts to get in too much of a sympathetic mode, the neurosteroids kick in to counteract some of the bad side effects and bring things back to normal.

Here is the takeaway: the neurosteroids’ main role, as far as the wheel of fire is concerned, is to protect us from too much sympathetic response.  They are the anti-mortgage.  They are the contra-Kardashian.

How the neurosteroids do this is pretty interesting.  It is more or less by way of two mechanisms.  One of the things they do is counteract some of the effects of too much cortisol.  The other important action of neuroteroids is to cause a general relaxation of nervous tissue.  DHEA does both.  ALLO and ALLO-THDOC (allo-tetrahydrodeoxycorticosterone) do more of the latter.

Counteract cortisol and relax the brain.  Both are interesting.  But to me, the way neurosteroids relax the brain is particularly interesting.

“Why is this more interesting?” my imaginary interlocutor might ask.  Because neurosteroids relax the brain by binding to the GABA-A receptor.

“Again, why is this more interesting?” probably everyone is asking by now.  Because the GABA-A receptor is also what a class of drugs called the benzodiazepines bind to. Benzodiazepines are drugs like Ativan (lorazepam), Xanax (alprazolam) and Valium (diazepam).  They are frequently used for anxiety and seizures.

That means that the neurosteroids are like the brain’s own Xanax.  They are what the brain uses to calm itself down.  And while the neurosteroids are like Xanax, they are even better because they cannot be abused.

But here’s where the problem starts.  While the abuse potential of neurosteroids is low, the neurosteroids are not perfect.  For when there is chronic stress or an injury to the brain from something like a TBI, they can eventually run out.  When this happens, the hypothalamus can run amok without any governor keeping it in check.

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The stages of the “General Adaptation Syndrome” as first pioneered by the endocrinologist Hans Selye. Chronic, unmitigated stress can eventually override our body’s capacity to compensate. At this point, we reach “exhaustion”. This is frequently seen in scenarios such as Post Traumatic Stress Disorder, in which the adrenal secretion of cortisol becomes lower in relationship to other stress hormones, such as the secretion of norepinephrine (aka noradrenaline). Conversely, in cases such as major depressive disorder, cortisol is often still elevated, but higher than other compensatory mechanisms, such as the “neurosteroids”, which will be discussed later. This diagram is courtesy of Creative Commons. David G. Myers – Exploring Psychology 7th ed. (Worth) page 398.

In the 1940s, the Hungarian endocrinologist Hans Selye coined the term “General Adaptation Syndrome” to express this phenomenon of certain stress responses going up, then oftentimes going down, or becoming exhausted.  This is what happens when there is too much sympathetic activity.  The neurosteroids become exhausted.

A key finding with exhaustion, however, is that not all hormones go down.  Or if they do all go down, they don’t all go down equally.

That is why it is important that we not just consider the absolute amounts of the neurosteroids and other hormones.  We must also consider the balance of these hormones.  We must look at them in context of the bigger picture.

On a practical level, this means that we need to look at neurosteroid ratios.  Oftentimes something like a cortisol/ALLO ratio or a cortisol/DHEA ratio tells us much more about what is going on than just cortisol, ALLO, or DHEA by themselves.

This sounds rather complicated, but it’s worth getting into the weeds over to see how useful and interesting all these new discoveries and ideas can be.  Let’s continue onward, then, to part five, and show these weeds who’s boss.

This concludes part 4 of The Wheel of Fire: Nietzsche, A Hungarian, and Utter Exhaustion.

Click here for part 5 of the Wheel of Fire: Neuropsychiatry Takes A Spin On The Wheel