Click here to go to part 6 of The Wheel of Fire: Cycles and Epicycles

AN INTENTION TO TREAT

In Medicine, “Intention to Treat” (ITT) has a very specific meaning and it has nothing to do with what I’m going to talk about.  ITT refers to a type of medical study protocol whereby patients are randomized into different treatment arms.  Once they are in the different arms, the physicians and scientists conducting the study intend to treat them with only whatever protocol that arm allows.  Another phrase synonymous with ITT is therefore “once randomized, always randomized.”

But, that’s not what I mean when I say intention to treat.  Rather, what I mean is in reference to what I was taught in medical school:

Only get that test or study that will improve your ability to more correctly make a diagnosis, more perfectly prescribe a treatment, or more successfully recommend or perform a procedure.  All other tests are superfluous.

Thus, while I am involved in research looking at various neurosteroids, other hormonal markers, markers of sympathetic tone, and several other things, at this time not all of these these tests are ready to help me make a better diagnosis, prescribe a better treatment, or do a better procedure.

What I will therefore focus on in this final part of this series are some practical things that physicians and patients can do (or have done to them) now to accurately diagnosis and effectively treat aspects of the wheel of fire.  Everything that I recommend are things I already do in my practice.  Moreover, many are things that I have done to myself.  In my humble opinion, what I recommend should be standard of care for the wheel of fire.  As such, if you are suffering from any of the symptoms or diseases discussed in this series, you should find a physician sufficiently knowledgable to diagnose and treat you in manner similar to that described here.

Let’s begin.

Recall our expanded wheel of fire developed throughout this series and finally brought together in Cycles and Epicycles.

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A more accurate model of the wheel of fire would have millions of interacting parts and be different for each individual.  Even so, this vastly simplified version still can be a powerful heuristic or diagnostic and treatment tool.  While it is pared down, it nonetheless still touches on some of the most important aspects of physiology that we can measure and do something about.

Essentially, there are seven parts.  There is systemic chronic inflammation, which I refer to as the axis of the wheel.  Around this axis there are neuroinflammation and gliopathy, the sympathetic disease, the metabolic syndrome, thyroid axis dysfunction, neurosteroid exhaustion, and sex hormone dysregulation.  Let’s address each of these in turn in regards to diagnostics and treatment.

This is what is required to defeat the wheel of fire. Both from the physician as well as the patient.

This is what is required to defeat the wheel of fire. Both from the physician as well as the patient.

SYSTEMIC CHRONIC INFLAMMATION

Diagnostics:

  1. Laboratory testing: The two most important tests in regard to systemic inflammation are erythrocyte sedimentation rate (how fast the red blood cells settle in a tube), and C-reactive protein (a protein secreted by the liver when there is inflammation).  Very basic labs like a creatine kinases (CK), complete blood count, and complete metabolic panel should also almost always be considered.  If ESR and CRP are elevated, of course the first thing to consider is some sort of infection, acute injury, autoimmune disease (such as rheumatoid arthritis or systemic lupus erythermatosis), or something else systemic like cancer.  If workup for all of these are negative, then it is prudent to consider if the primary problem is with the wheel of fire.
  2. Other testing: Other tests will relatively low downside and potentially large upside include skin antigen sensitivity testing.

Treatment:

If you find yourself out of shape and bitter, I hate to break it to you, but you are closer to the bad guy in The Lion King (Scar) than the good guys (Mustafa and Simba). Both Mustafa and Simba were active, always outside, vigorous, and happy, even during bad times. Scar stayed inside, watched the 24 hour news cycle, sulked, and wondered why nothing good ever happened to him, even during good times. Recall also that the way Simba got in shape was by training in the woods, eating local and organic food, and singing "Hakuna Matata" (it means no worries), while hanging out with his friends. There's a lot to be learned here.

If you find yourself out of shape and bitter, I hate to break it to you, but you are closer to the bad guy in The Lion King (Scar) than the good guys (Mustafa and Simba). Both Mustafa and Simba were active, always outside, vigorous, and happy, even during bad times. Scar stayed inside, watched the 24 hour news cycle, sulked, and wondered why nothing good ever happened to him, even during good times. Recall also that the way Simba got in shape was by training in the woods, eating local and organic food, and singing “Hakuna Matata” (it means no worries), while hanging out with his friends. There’s a lot to be learned here.

The general heuristic for treating systemic chronic inflammation, or the axis, is to directly address the most affected parts of the wheel (metabolic syndrome, sex hormone dysfunction, the sympathetic disease, etc.).  Yet, there are an additional few key things that nearly everyone needs to do that are intuitively obvious but often neglected.

These few key things are not optional.  At least they are not optional if the goal is good health. Or at least better health.  It is imperative that everybody does these things no matter where they are on the wheel of fire.  If your dimmer is set to super low or to brighter than a thousand suns, do these things.  If you have barely passed by a single onramp or if you take every onramp there is on your daily commute, do these things.

Recall from the above diagram that the axis of chronic inflammation is connected to every point along the outer cycle.  Because of this, the following recommendations apply not just to the axis, but to the whole wheel.  Keep this in mind.  Because whatever further recommendations there might be later on, don’t forget to always come back to the following:

  1. Stop behaviors that are obviously self-destructive: cigarette smoking is the prototype of this.  Alcoholism would be another.  There are many more.  Don’t do these.
  2. Get really good sleep: good sleep is likely the most important thing you can do in general for your health.  It may be more important than diet and exercise.  Get a lot and make sure it is good quality.
  3. Eat like your great-great grandparents: In other words, at minimum you should have a relatively low carbohydrate diet, unless you are a professional athlete who is involved in extremely glycolytic activities.  This means around 150 g of carbs daily max.  Avoid bleached flour and processed seed oils like soy and corn oil.  Avoid almost all added sugar, including soft drinks.  Avoid eating out and react with horror at the idea of microwaving something out of a box or plastic wrapper.  Eat a modest amount of animal muscle meat.  This includes things like ground beef, steak, and chicken breasts.  While you should be conservative with muscle meat, be very liberal with good quality eggs and fish.  Use butter, olive and palm oil relatively liberally.  Eat as much veggies as possible.  Eat legumes if you can tolerate them.  Drink mainly water, tea, coffee, and only a small amount of alcohol.
  4. Go outside all of the time: the Sun does more than give you vitamin D.  Certain wavelengths have to hit your suprachiasmatic nucleus to make your brain function well.  This really only happens from the Sun.  Also, when we are outside, we tend to need to walk around slowly and generally do stuff without exhausting ourselves.  This should be our default state when awake.
  5. Lift heavy stuff, stretch, and move fast a couple times a week: be like the lion chasing the gazelle in Walden Pond and Sharknado.  A lion lounges around outside and moves slowly most of the day.  It sleeps a lot.  But then, every now again, it works really hard.  As Deadpool would say, it gives “maximum effort”.  Lions don’t lift weights or sprint every day.  And neither should you.  But they do workout enough to get strong.  Don’t lounge around, pitying yourself for being out of shape as you get in worse shape.  Rather, workout just enough that to continually improve in some capacity but without tempting injury.  In other words, be a lion.  Be Mufasa and Simba.  Don’t be Scar.
  6. Maintain an awesome social lifebabies who are not touched literally die.  Even with good nutrition and everything else in order. Kids and adults have similar fates, though it doesn’t happen as quickly.  Lack of human contact breeds systemic inflammation.  Be a family guy (or girl).  If you are religious, go to church, synagogue, temple, or something similar.  Join a book club.  Hang out on the porch with your friends and ironically listen to Radiohead.
  7. Supplement smartly: I will go into this more when covering the metabolic syndrome as there is considerable overlap here.  But a decent multivitamin probably would not hurt.  The epidemiological studies saying otherwise are likely being fooled by confounding variables.  If you are not getting enough sunlight, supplement with vitamin D3 until your blood levels are between 40-60 ng/ml.  Eat tons of greens to get magnesium (magnesium makes up chlorophyll).  If you find yourself sans greens, then at least take a zinc-magnesium complex regularly.  Vitamin K2 at 50 mcg a day is also likely a good idea for bone and cardiovascular health.  If you are not eating cold water fish like sardines and herring (shame on you if this is true!) then omega-3 fatty acid supplementation is also important.  Unless you have a specific disease or are taking specific medications (there is some controversy about K2 and the blood thinner warfarin, for instance), these recommendations are pretty universal.
  8. Address antigen sensitivity issues: if there are positive responses to an antigen exposure test (such as a scratch test) then there are various ways to treat this.  Foremost is gradual and progressive exposure to facilitate attenuation.  When this fails, the most sensible thing to do is to try and just avoid that antigen.

NEUROINFLAMMATION

Diagnosis:

  1. Neuroradiology: Of course if the patient has a history of a TBI, then an MRI of the brain needs to be done.  Possibly the whole spinal cord as well, depending on symptoms.  Otherwise, there is no good test to evaluate for chronic neuroinflammation of, say, the hypothalamus.  Rather, the diagnosis of “neuroinflammation” is usually made by induction when a variety of symptoms and other findings are taken into account.  Theoretically, something like a functional MRI (fMRI) of the brain could be done, though in everyday practice this is not useful enough to usually meet criteria for my definition of intention to treat.
  2. Labs: When considering any kind of inflammation, CRP and ESR are good tests as mentioned earlier.  The beginnings of a hormonal workup will also aid in the diagnosis.  Recall that the hypothalamus tells the pituitary what to do.  And the pituitary tells most of the endocrine organs downstream what to do.  Thus, luteinizing hormone (LH), follicular stimulating hormone (FSH), ACTH, cortisol (in the morning as this is when cortisol is highest), thyroid stimulating hormone (TSH), and prolactin are all good things to get.

Treatment:

Treatment of neuroinflammation is fourfold.  First, address any distinct pathology seen on radiographic workup (e.g. gross lesion of the CNS, etc).  This of course needs to be deferred to a specialist such as a neurosurgeon.  Next, evaluate for hormonal deficiency that may correlate with neuroinflammation.  This will be addressed more when speaking of sex hormone dysregulation, the neurosteroids, and thyroid axis dyfunction.  Nonetheless, as these are addressed, it is necessary to recheck the above labs periodically (at least every eight weeks in the beginning) to measure progress.  Thirdly, address systemic inflammation.  In this regard, follow the recommendations outlined under Chronic Systemic Inflammation and The Metabolic Syndrome.

Uncle Buck's car is the automotive equivalent of neuroinflammation with glucose as the sole energy substrate.

Uncle Buck’s car is the automotive equivalent of neuroinflammation with glucose as the sole energy substrate.

The fourth treatment of neuroinflammation is somewhat an emerging science but it looks very promising.  It is a dietary intervention that is gaining popularity called the “ketogenic diet”.  The ketogenic diet causes the body to use a breakdown product of fat (a.k.a. ketones) as its primary energy source.  The brain cannot use fat directly and therefore typically only uses glucose.  While the brain cannot burn fat directly, it actually prefers ketones over other sources.  Ketones are thus made in the liver and travel up to the brain.  What is more, ketones burn much more cleanly than glucose.  Compared to ketones, glucose can be considered something of a dirty fuel with a lot of metabolic waste.  Kind of like John Candy’s car in Uncle Buck.  Ketones run more like the engine on a Tesla Model S.  This cleaner burning aspect of ketones is why the ketogenic diet is such an excellent treatment for epilepsy.  It also has shown tremendous outcomes for other neurological disorders, including traumatic brain injury and Alzheimer’s.  I have used the ketogenic diet on myself and many of my patients.  After some adjustment, it is not an especially difficult diet to follow.  Especially if you can supplement with a particular type of fat called medium chain triglycerides.  These are found in spades in coconut oil and there are now excellent powders with this such as this.

The brain on ketones.

The brain on ketones.

THE SYMPATHETIC DISEASE

Diagnosis:

Unfortunately, there are really no good labs to evaluate for chronic sympathetic activity.  There are a few urine metabolites of the catecholamines (norepinephrine and epinephrine) that are used in the fight or flight response.  But even with the sympathetic disease in the context of the wheel of fire, these are often normal or indeterminate.  Rather, these tend only to be elevated when someone has a catecholamine-secreting tumor, like a pheochromocytoma.  Thus, we must rely on more subtle measures of physiology rather than labs or imaging.

  1. Heart rate variability: To date, the best test to measure chronic sympathetic overactivity is heart rate variability.  When someone is in the rest and digest phase, there should be a small variability between each heartbeat.  This is called a physiological or a respiratory arrhythmia.  Interestingly, it’s called a respiratory arrhythmia because each inhalation causes a slight increase in sympathetic tone and decrease in the arrhythmia.  And each exhalation causes an increase in parasympathetic tone and increase in arrhythmia.  But what’s in a name?  Whatever you want to call it, you want this.  This is not a bad arrhythmia like atrial fibrillation.  While there is a variation in the degree of arrhythmia while breathing, an increased baseline sympathetic state will cause the heartbeat to become too regular.  This can be easily measured with an EKG, though something that records the heartbeat for a longer period, such as a 24 hour Holter monitor, or even some more modern commercially available devices that are less cumbersome, can do the trick.
  2. Talk to your patient and measure their vitals: The other obvious things to check are overt manifestations of the sympathetic response: high blood pressure, elevated heartrate, chronic perspiration, and self-reports of anxiety or agitation.  There are fancy ways to measure these too, like measuring the so-called sudomotor activity, but I do not find them to be accurate or helpful.  Heart rate variability and a good physical exam by themselves are the best ways to assess for sympathetic activity.

Treatment:

Marcus Aurelius, Emperor of Rome from 161-180 AD. In one sentence, he has summed up the best treatment for the sympathetic disease far better than I can.

Marcus Aurelius, Emperor of Rome from 161-180 AD. In one sentence, he has summed up the best treatment for the sympathetic disease far better than I can.

  1. Address externalities: The sympathetic response is either a reaction to an external or internal stressor.  The first step is, if possible, fix external stressors.  I address this more below in “Epicycles”.  An example could be chronic pain.  If there is an anatomic or nerve abnormality that can be directly addressed, address that.  This may involve a procedure like a radiofrequency nerve ablation, or even something involving stem cells or other emerging treatments.   Of course I am partial the latter as I am an interventional pain physician.  But these procedures do have a place in treating manifestations of the wheel of fire.   Regarding internal stressors, recall that chronic systemic inflammation is an attack on the body and it elicits a sympathetic reaction.  In order to combat these internal stressors, the whole wheel of fire must be taken account.  Compared to just doing a procedure that’s a bit trickier.
  2. Meditate: meditation is very woo-woo sounding but it is absolutely necessary.  For everyone.  And, don’t get agitated if that word scares you because you were not raised in some eastern tradition (plus, if you find yourself getting agitated, it probably means you need to meditate even more).  Meditation is not necessarily Buddhist.  It is not necessarily even eastern. Remember Marcus Aurelius, the great stoic philosopher and emperor of Rome at the height of its power (and therefore equivalent to king of the known world except for China)?  Well, he meditated every morning by writing in his journal.  And he sure was not a Buddhist.  Buddhist or no, meditation is simply being present in the moment and practicing not being distracted by feelings about the past or anxiety about the future.  Like brushing your teeth and taking a shower, meditation is just good hygiene.  It’s hygiene for your brain.  As such, if you don’t do it, you get the psychological equivalent of gingivitis or B.O.  Do you really want that?

THE METABOLIC SYNDROME

Visceral adipose can vary widely between individuals who, for all intents and purposes, look exactly the same.

Visceral adipose can vary widely between individuals who, for all intents and purposes, look exactly the same.

Diagnosis:

What a poorly understood and inadequately screened for part of the wheel of fire!  An accurate diagnostic and treatment algorithm would cover nearly all of internal medicine and endocrinology.  But I will touch on some of the most immediately practical considerations:

  1. Assess dyslipidemia: Part of the metabolic syndrome is dyslipidemia, or an irregularity of blood triglycerides, low density lipoprotein, and high density lipoprotein.  These need to be checked.  If LDL is really high, a genetic screen needs to be done for an inheritable disorder, such as one of the Familial Hypercholesterolemias.  It is also not a bad idea to measure certain other things like expression of what’s called an apoprotein E allele.  The aproprotein E allele is part of the LDL (and something called intermediate density lipoprotein or IDL).  If someone has two aproprotein E4 variants, they are at higher risk of cardiovascular disease and Alzheimer’s disease.  All that said, unless LDL is through the roof, the main thing to consider is not even LDL, but the ratio of triglycerides to HDL.  Other tests, like carotid intima thickness and coronary calcium scores, are sometimes helpful, but certainly not necessary on everyone.
  2. Assess visceral adipose tissue: Recall the coronal whole body MRI in The Burden of Our Noblesse Oblige and reposted above.  VAT, or the primary culprit for secreting chronic systemic inflammation, is often hidden in plain sight.  Some sort of whole-body scan has to be done to accurately assess it.  A whole body MRI is one such scan, but these are often very expensive.  A DEXA scan focusing on body composition is also a good option.  Inferences as to whole body fat may also be made using displacement tools, such as water or air displacement, though these are not necessarily as good (don’t tell Archimedes!).  While they may not be perfect, however, they may be nonetheless more practical and less expensive.
  3. Assess insulin resistance: it is common for physicians to only care about blood glucose levels when thinking about the metabolic syndrome and diabetes.  But recall that the wheel of fire, and by extension, the metabolic syndrome, exist on a spectrum.  Glucose dysregulation only occurs at the terminus of the metabolic syndrome.  Before that are worsening levels of insulin resistance.  Regarding flat out glucose regulation, we’ve already checked a spot glucose with the complete metabolic profile above.  An even better test is a measure of hemoglobin A1c (Hgb A1c), which will tell us the average glucose over the last 120 days.  I want all of my patients to have a HgbA1c in the low to mid 5’s.  But even if we know the HgbA1c, we still haven’t really measured insulin resistance.  This is done with a HOMA-IR analysis or the QUIKI analysis.  In both of these tests, an algorithm is used to relate the insulin levels to the glucose levels.  Both of these latter tests may be done with a single blood draw with the patient fasting.

Treatment

Metabolic syndrome is complex.  But, by and large, the most salient cause is energy dysregulation.  Recall the explanation of this from The Burden of Our Noblesse oblige.  Too much glucose is toxic to the body.  Both when levels are too high in the blood as well when they are too high in the cells.  The pancreas is more worried about blood levels of glucose.  When these get high, it tells cells in the liver, muscle, and fat to take more in and use it as energy.  Unlike the pancreas, however, liver, muscle, and fat cells don’t really care about how high or low blood sugar is.  They are only thinking about themselves.  If the liver, fat, or muscle cells already have too much glucose, and have exhausted their ability to turn it to glycogen (mainly in the liver, a little bit in muscle) or fat, then they stop listening to insulin.  When the liver, muscle, and fat cells stop listening to insulin, there is insulin resistance.  Insulin resistance is the sine qua non of the metabolic syndrome.

Since the metabolic syndrome is primary a disease of energy overabundance, the most important treatment that usually should be done first and foremost is to decrease caloric intake.

And how do you do this?  The most effective first step is simply to help yourself or your patients realize what and how much they are eating.

Most people are awful at realizing just how unhealthy they eat and at what quantities.  That is why most non-horrible diets work for the first while, whether they are low fat, low carb, shakes, bars, or whatever.  They encourage their participants to pay attention to what they eat and stop fooling themselves.  Some diets tend to be more successful than others in the long run, however.  This is because of a combination of factors.  Some diets are more convenient.  Some diets are genuinely more healthy.  Some diets jive more with pre-existing social norms, etc.

Whichever the case, the first step is to mitigate energy overconsumption while at the same time eating healthy food.  The next thing, of course, is to do steps 1-8 as outlined in the treatment of chronic systemic inflammation above.  The last thing is to consider a few medications and supplements.

There are a variety of medications used already for diabetes that are safe, well tolerated, and may be considered for the metabolic syndrome in general.  Metformin is of course the prototype of this.  Metformin is also very, very interesting as it also has potential anticancer and longevity properties.  Bromocriptine might have similar attributes, but it is less studied in this context.  There are numerous other medications that may similarly work in these ways.

Supplements that show a lot of promise for the metabolic syndrome include alpha-lipoic acidcurcuminsulforaphaneGymnema sylvestralicoricecinnamon, and others.  Curcumin is found in the spice turmeric.  Sulforaphane in broccoli sprouts.  It should go without saying that, when possible, it is better to get these through real food rather than pills.

THYROID AXIS DYSFUNCTION

Diagnosis:

Although I only briefly touched upon it in this series, it is essential to asses the HPT axis when dealing with the wheel of fire.  By this point, we have already assessed it somewhat by measuring TSH.  Now it is time to measure more downstream function.  Frequently only T4 (thyroxine) is measured.  This is insufficient.  The main active version of the thyroid hormone is T3 or triiodothyronine. Further, there is another variant of the thyroid hormone called reverse triiodothyronine or “rT3” that inhibits the activity of T3.  Both of these need to be measured.

A common disease seen among people in the ICU or with cancer is “euthyroid sick syndrome” (ESS).  With ESS, TSH and T4 are normal.  Nonetheless, patients with ESS have symptoms of low thyroid.  While individuals with a hot and spinning wheel of fire might not have cancer or need to go to the ICU, they are nonetheless chronically inflamed and thus at risk of a milder variant of ESS.  Numerous things are likely happening to cause this, but the ones that we can do something about involve T3 and rT3.  In these cases, chronic inflammation lowers the body’s ability to convert T4 to T3 and to break down and clear rT3.  This inflammation may also hinder the ability of T3 to interact efficiently with many tissues.  Thus, while TSH and T4 may be normal, the active variant of the thyroid hormone (T3) is either not sufficiently created from T4, blocked by rT3, or made impotent at the site of the tissues with which it is supposed to interact.

Diagnosis of thyroid dysfunction can quickly become complex and if abnormalities are found, an evaluation by an Endocrinologist is not a bad idea.  Frequently, a thyroid ultrasound may need to be performed and, if a nodule is found, a fine needle aspiration should be done.  Also, if T4 and TSH are abnormal, then it is likely prudent to further work this up with labs like anti-thyroid peroxidase antibodies, anti-thyrotropin receptor antibodies and anti-thyroglobulin antibodies.

Treatment:

Most of the time there is not a nodule or other overt reason for symptoms consistent with thyroid dysfunction.  When this is the case, the most prudent thing to do is to make sure that there is sufficient dietary iodine (required to make T3 and T4) and selenium (required to make the enzymes that make T3 and T4).  Selenium deficiency is an often missed problem in numerous endocrine issues, particularly regarding the thyroid.  If T4 is normal, but T3 is low and/or rT3 high, and all other workup is normal, then it may be prudent to supplement with some form of T3.  There are synthetic and “natural” versions of T3 and it is up to the practitioner and patient which should be used.  Of course, like most thyroid treatment, it is usually a good idea to start low and go slow.

NEUROSTEROID EXHAUSTION

Diagnosis:

The main neurosteroids that I spoke about are cortisol, DHEA, DHEA-S, allopregnenolone (ALLO), and allotetrahydrocorticosterone (ALLO-THDOC).  DHEA and cortisol are easily measured, even with salivary samples.  Salivary sampling can be helpful, especially for something like cortisol, as it allows for measurements throughout the day.  When cortisol is behaving well, it peaks just before the person awakes, then gradually decreases throughout the day.  A failure to peak in the morning, chronically low levels, chronically high levels, or a paradoxical peaking around bedtime are all very helpful findings.  ALLO and ALLO-THDOC are not typically measured in clinical practice (my genius lab director and I are working on it) but they may be helpful.  Surrogate labs include pregnenolone and progesterone as these are precursors for some of the neurosteroids.

Treatment:

One of the most common reasons for neurosteroid exhaustion has to do with the sympathetic disease, as discussed above.  Thus, first line treatment should include all of those recommendations.

Next, consider hormonal supplementation.  While, ALLO and ALLO-THDOC are not currently widely used clinically, it is very reasonable to consider DHEA, hydrocortisone, pregnenolone, and progesterone supplementation depending on laboratory findings.

Pregnenolone is made from cholesterol. As is vitamin D. From pregnenolone are made the remainder of the glucocorticoids, mineralocorticoids, sex hormones, and neurosteroids. This outline show a phenomenon called the "pregnenolone steal". This occurs when elevated sympathetic activity causes increased cortisone production. This "steals" the pregnenolone away from other parts of the pathway, namely from sex hormone production. Source

Pregnenolone is made from cholesterol. As is vitamin D. From pregnenolone are made the remainder of the glucocorticoids, mineralocorticoids, sex hormones, and neurosteroids. This outline show a phenomenon called the “pregnenolone steal”. This occurs when elevated sympathetic activity causes increased cortisone production. This “steals” the pregnenolone away from other parts of the pathway, namely from sex hormone production. Source.

I favor trying pregnenolone first, as this is the precursor to all of the other neurosteroids (and sex steroids).  Thus, pregnenolone monotherapy may be sufficient to increase other downstream hormones.

If pregnenolone by itself does not work, then consider adding morning DHEA and, if cortisol is low, morning hydrocortisone.

If this is done and if progesterone or the other sex hormones are still low, consider then adding them directly.

SEX HORMONE DYSREGULATION

Diagnosis:

And now we have literally come full circle.  I have already discussed in some depth the diagnosis and workup of sex hormone dysregulation in BSSHM.  Essentially, it is important to check the whole hypothalamic-pituitary-gonadal axis.  Gonadotropin releasing hormone is hard to check as it is pulsatile.  But checking LH and FSH are good proxies.  Checking prolactin is also a good idea, though you should have already done that when evaluating neuroinflammation.

Next, check morning free and total testosterone and free and total estradiol (E2).  In your evaluation of the neurosteroids you’ve already checked progesterone and cortisol.

If total testosterone and estrogen are normal but the free levels are low, then you should suspect elevated sex hormone binding globulin (SHBG).  Sometimes in the health and wellness community, an elevated SHBG occurs when someone goes on a low carbohydrate diet.  Insulin and SHBG are similar structurally to each other and when one goes up, the other down (and vice versa).  Thus, with a low carb diet, insulin goes down, SHBG goes up, and free testosterone go down.

This is not necessarily a bad thing.  If there are no symptoms of hypogonadism and the wheel of fire looks nice and cool, then there is likely no need to change.  However, if the patient is experiencing symptoms common with low testosterone, it might be a good idea to add in some potatoes to the diet.

As an aside, this is one of the mechanisms for hirsutism with polycystic ovarian syndrome.  Increased insulin causes SHBG to go down in women, which causes free testosterone to go up.  This elevated free testosterone causes virilizing effects.

While hirsutism is annoying, it is relatively benign.  However, there are a few causes of SHBG elevation that are not so benign.  Elevated estrogen (such as testosterone converted to estradiol by aromatase in adipose tissue) and elevated T4 can cause SHBG to go up.  Increased inflammation, particularly TNF-alpha, will make it go up.  Liver cirrhosis will make it go up.  Hence the need to check all of these.

Part of the diagnosis of sex hormone dysregulation should also focus on ruling out malignancy and focusing on a history of malignancy.  This is particularly for that of the prostate, breast (both men and women), uterus, and ovaries.  Rule out polycythemia.  Make sure there are no urinary tract obstructions.

Treatment:

Treatment of sex hormone dysregulation is similar to that of neurosteroid exhaustion.  First, change all behaviors that may cause sex hormones to behave badly.  Maximize sleep.  Lift weights.  Have sex with your spouse.  Prevent the pregnenolone steal by addressing too much psychological and physical stress.  Eat well and supplement when appropriate.

Only after all of that should you consider hormone supplementation.  And of course how to do this varies between men and women.

Regarding sex hormone replacement for men, as per above, first cover the neurosteroids and start with the upstream hormones like pregnenolone and DHEA.  See how that does.  If this is insufficient, then supplement with the lowest dose possible of testosterone to normalize labs and symptoms.  Recheck a metric of symptoms like the “ADAM” questionnaire on a regular basis.  Consider coming down on dosage if symptoms do well over time.  Follow LH.  Check PSA regularly.

When replacing sex hormones for women, things are slightly more complex.  Again, start with the neurosteroids.  In addition to DHEA and pregnenolone, if you’ve come this far, then, you may have already started supplementing with progesterone.  Sometimes this may be sufficient for symptoms.  If symptoms and labs consistent with low E2 persist, this may also be supplemented.  Typically it is not ideal to give E2 as a monotherapy.  Rather, it is usually a better idea to give estradiol with some progesterone.

Additionally, while testosterone deficiency is most commonly associated with men (it’s named after the testes, after all), women need it too, albeit much less (their blood levels are typically less than one-tenth that of males and supplementation is usually less than one-quarter).  It is common for women with a low libido and low energy and in the context of low T to do very well after modest testosterone supplementation.

Oftentimes, however, the latter is not needed.  Consider again a female with polycystic ovarian syndrome (PCOS).  In this case, testosterone is too high because the elevated insulin and inflammation has decreased SHBG, making free testosterone go up.  For this individual, the last thing that needs doing is increasing testosterone.

Context is everything.

EPICYCLES

Lastly, we have the epicycles.  In regard to their diagnosis and treatment, I am only going to say two things.

One, it is important to reiterate that the epicycles are part of the larger wheel of fire.  Therefore consider them in context with the six phenomena along the outer circle and the axis of chronic systemic inflammation.  It is nigh impossible to treat any one symptom fully without addressing the whole wheel.

Two, use good sense doing what needs to be done to diagnose and treat the most immediate problem at hand.  Make sure to differentiate this from the longer-form treatments necessary to best address more chronic conditions associated with the wheel of fire.

This recommendation is the inverse of a criticism often levied against western medicine. In western medicine, we have become excellent at treating acute problems.  Trauma surgery, ICU care, and acute infectious disease care have made leaps and bounds in their sophistication and effectiveness.

But the problem is that most diseases affecting developed countries today are not acute but chronic.  And, even though we have made such progress with acute care, care for chronic diseases, such as those seen with the wheel of fire, has lagged behind.  The way we currently tend to treat chronic diseases is as acute diseases that last a long time.  This is incorrect.  How they should be treated is something akin to the outline above in dealing with the wheel of fire.

But here’s the rub.  While it is a mistake to treat chronic diseases as prolonged acute diseases, it is equally wrong to treat acute diseases as only sudden onset chronic diseases.  It is right to use propofol to induce anesthesia for a gunshot wound.  It is wrong to use it for chronic insomnia (just ask Michael Jackson).  Likewise, it is right to use dietary approaches to address some of the causes of the wheel of fire.  But it is wrong to use them as first line treatment for a skull fracture.

Chronic pain syndrome.  While it is a vicious cycle itself, it is an epicycle in relation to the large cycle of the wheel of fire.

Chronic pain syndrome. While it is a vicious cycle itself, it is an epicycle in relation to the large cycle of the wheel of fire.

Again, context is key.

The need to properly distinguish and adequately address both the most immediate and the deeper, more subtle conditions is often encountered in my subspecialty, Pain Medicine.  I use the model of the wheel of fire extensively in my practice.  But if someone has a distinct pathology causing some sort of chronic pain, I am usually remiss if I do not try to directly address that.  Fortunately, that can be done with some combination of procedures, therapy, lifestyle changes, and medications.  Or, more succinctly, with something resembling barbells and stem cells.

It is often only when I address this most pressing issue that I can then look with the patient at their particular wheel of fire and start to tease out what may be done to lesson its burden over the long haul.

In other words, while the goal is to eventually get to the root of the problem, it is a good idea to start by going after the low hanging fruit.

CONCLUSION

A long time ago, as nascent inpatient rehab docs, my friends and I discovered some of the hidden relationships between the sex hormones and the metabolic syndrome.  Over time, this fascinating and quite useful model has expanded to encompass a whole host of other phenomena that are not widely linked.

But they should be.  Back pain, generalized osteoarthritis, depression, anxiety, visceral and central adiposity, hypertension, traumatic brain injury, post traumatic stress disorder, chronic opioid use, cancer, Alzheimer’s disease, diabetes type 2, cardiovascular disease, chronic systemic inflammation, and numerous other common ailments are all related.  They are all part of one bright, hot, spinning wheel.

There are many ways to get on this ride and many ways to start with one disease, only to develop several others.  In other words, there are many ways to make the wheel of fire go from bad to worse.  My main hope in writing this essay, or long series of blog posts, is to show that there are also many ways to make it go from bad to better.

Seneca said in letter 88 of his Letters From A Stoic:

You will not die because you are sick but because your are alive.  That end still awaits you when you have been cured.  In getting well again you may be escaping some ill health but not death.

For better or worse, of course he’s right.  For now.  While most of us in medicine are working on combating morbidity and mortality, we’re likely still a ways off from our goals coming to complete fruition.

Yet we are making progress.  And while we have not yet found a way to extend our lifespans infinitely, a more modest, and likely much more attainable, goal may be to drastically improve our healthspans.

By addressing the wheel of fire at all of its points, by slowing it down and cooling it off, perhaps we might be able to add life to our years even if we cannot yet greatly multiple the years of our life.

THIS CONCLUDES THE WHEEL OF FIRE

FIN