Monday, February 22, 2016

Pandaemonium and The Glucose and Gonadotropin Mystery

By: Matt Smith, MD with Alabama Pain Physicians, Comprehensive Pain Care

Several years ago, some of my colleagues and I were the attending physicians of an inpatient rehabilitation unit. It was a great experience. We had all become good friends and we had many similar interests. Among these common interests was that well before becoming attendings we had each become fascinated by the exercise and nutrition world. I was the beneficiary of a hand-me-down squat rack and for the year or so that we worked together, we would literally exercise this interest by meeting after work in my garage four times a week and practice the "slow lifts".

The “slow lifts” are some of the typical exercises done with a barbell. These include such basic movements as squatting and standing back up (the “squat”), picking something off the floor (the “deadlift”), and lifting something overhead (the “press”). For as simple and for as fundamental as these lifts were, we had never done them in earnest before and we were amazed at how the systematic practice of such basic movements yielded relatively profound results.

Our enthusiasm for our personal gains had the happy double benefit of not only helping us reap the rewards of stronger and leaner physiognomies, but it also coincided with our professional responsibilities. We were, after all, the medical doctors in charge of helping some very sick and debilitated people also get stronger, better physiognomies.

It was around this same time that a tremendous paradigm shift was just starting to break through the medical literature in regard to the medical scourge of our generation: the metabolic syndrome. And the relationships between obesity, visceral adipose tissue, systemic inflammation, sex hormones, muscle mass, and pain, and what this had to do with the metabolic syndrome, were just graduating from the nascent phase in becoming well understood. And all of these aspects of the metabolic syndrome were problems that nearly every one of our patients faced. Even before one of our patients had their incident that brought them into inpatient rehab - stroke, massive myocardial infarction, above the knee amputation, or some other horrid problem, our patients typically had nearly every manifestation of this syndrome. In fact, the reason that our patients experienced their MIs, AKAs, and whatnot in the first place were usually a direct result of this selfsame syndrome.

Thus we discovered what by that time was already in the literature for a few years, but which we had never been taught in our formal training. This is that in both males and in females there is a direct correlation between the metabolic syndrome and hypogonadism. In fact, not just a correlation but a multifactorial and complicated process of causation. Furthermore, as time went on, this new paradigm led us to learn that these complex processes extend far beyond mere glucose control, but also link such seemingly disparate things as wound healing, rehabilitation potential, all-cause mortality, pre-menstrual depressive disorder, traumatic brain injury, post-traumatic stress disorder, opioid induced hypogonadism, and chronic pain.

This nuance of the metabolic syndrome and hypogonadism made a particular impact on us when it led us to reconsider the treatment of one of my patients. This unfortunate gentleman was suffering immensely from an above the knee amputation because of severe peripheral vascular disease, ostensibly from poorly controlled diabetes mellitus. He was on metformin and supplemental insulin and nonetheless continued to have persistent markedly elevated blood glucose. Moreover, rather than healing, his surgical wound only got worse. With his poor glucose control, he was losing muscle and becoming rapidly cachectic. Numerous surgical revisions were doing little to slow the progression of a wound that would simply not heal. Instead of getting better with inpatient rehab, he was getting worse. In fact, his condition was so precarious that what had started out as a hopeful rehabilitation potential turned out to be negative rehabilitation potential.

But, remembering some of the research that we had just started delving into, and how testosterone is intimately tied to both glucose regulation and healing, we decided to check his free and total testosterone. He pretty much did not have any.

We then checked his leutinizing hormone. Leutinizing hormone is the hormone secreted from the anterior, or front, of the pituitary gland and responsible for telling the testes to make testosterone. This was virtually zero too.

Thus we immediately started a testosterone supplementation regimen (and of course consulted Endocrinology).

Upon starting testosterone, we noticed within two days a marked improvement in his uncontrolled blood glucose levels. In fact, the improvement was so marked that within a week we had to halve his metformin and decrease his supplemental insulin substantially.

What is more, seemingly overnight his wound started healing. This wound, which was refractory to numerous surgeries and the care of very talented wound specialists, was now healing rapidly on its own. He then re-started his engagement in rehabilitation. He gained strength rapidly. His mood of course vastly improved. He was eventually discharged and, as far as I know, did relatively well thereafter. In the process of all of this workup and treatment, one of the conundrums shared by both us and Endocrinology was why his leutinizing hormone was so low (and we would also discover follicular stimulating hormone and sex hormone binding globulin).

What we would come to understand is that our patient suffered from a phenomenon now called “Male Obesity-Associated Secondary Hypogonadism”, or MOASH for short. MOASH is not one particular disease, but something of a brief glimpse into the fascinating and pervasive interrelatedness between the phenomena of insulin resistance, generalized inflammation, and sex hormone dysfunction. What is even more interesting is how this is related to other, seemingly disparate phenomena, such as chronic pain, opioid use, PTSD, and traumatic brain injury.

To give an adequate description of the complicated web of causality that leads to MOASH and its variants is beyond the scope of this brief article. What is more, we do not totally understand exactly how it works and it is likely that it varies from person to person. Yet, one thing that appears to be a common denominator in most of its manifestations is one of the most dreaded phenomenon in medicine: the positive feedback loop.

Most of the human body works by way of a “negative feedback loop”. Take the normal secretion of the sex hormone testosterone. In the hypothalamus, the hormone gonadotropin releasing hormone (GnRH) is released in a pulsatile fashion. GnRH travels down to the front of the pituitary gland to cause the release of another hormone, “leutenizing hormone” (LH). In men, LH then travels down to the testes to cause certain cells to release testosterone. Once testosterone reaches a certain level in the blood, it tells the hypothalamus and pituitary to stop making GnRH and LH, thus regulating itself. When things are working well, testosterone negates its own production. Hence negative feedback loop.

Imagine why having a positive feedback loop would therefore be bad. What if testosterone did not negate its own production, but spurred it on? In short order, far too much testosterone would be made.

Of course the prototype of the positive feedback loop is cancer. All control is loss and bad things can happen very quickly.

What we witnessed with my patient and many patients thereafter was a positive feedback loop. We now know that low testosterone leads to insulin resistance. Yet insulin resistance also leads to low testosterone. This happens by a confluence of factors. Obesity causes a rise in insulin resistance. It can also cause a decrease in testosterone by converting it into estrogen by the enzyme aromatase, which is expressed heavily in fat cells. Estrogen can cause a dysregulation in GnRH, causing a decrease in testosterone. Low testosterone by itself can lead to poor skeletal muscle development, central adiposity, changes in a hormone called gastric-inhibitory peptide (GIP), and mitochondrial dysfunction. All of these cause worsening of energy metabolism and worse insulin resistance. Further, insulin resistance is part and parcel with a systemic inflammatory state that affects everything (this is why obese people are more likely to get wear and tear arthritis in their hands - they have more inflammation all over). This increased inflammation with insulin resistance leads to a perpetual "sympathetic" or fight or flight response by the body. In fact, the metabolic syndrome is called by some a "sympathetic disease". Part of the fight or flight response is a release of the hormone cortisol from the adrenal cortex. Hypercortisolemia, or having too much cortisol in the blood, is part and parcel with the metabolic syndrome.

And the interactions between cortisol, testosterone, and the metabolism in general make another positive feedback loop. Recall what cortisol does. It makes the liver secrete glucose. It causes fat deposition in unusual places, such as the insensitively-named "buffalo hump". It does all of the things that you do not want done if you already have the metabolic syndrome. Metabolic syndrome thus causes hypercortisolemia. And hypercortisolemia worsens metabolic syndrome.

Thus, low testosterone can lead to poor skeletal muscle development, central adiposity, changes in GIP, and mitochondrial dysfunction. All of these can lead to the metabolic syndrome. In turn, the metabolic syndrome causes a decrease in the hypothalamic and pituitary mediated creation of testosterone by way of hypercortisolemia and gonadotropin dissociation. Metabolic syndrome also makes tissues resistant to testosterone by the effects of cortisol on fat cells and it reduces the amount of existing testosterone by converting it to estrogen with aromatase.

Now, let’s take a step back and consider anxiety disorder, traumatic brain injury, and PtSD. Recall that the metabolic syndrome is a sympathetic disease. It is a fight or flight disorder. But anxiety disorder is also a problem with fight or flight. And so is PTSD. And in many ways so is TBI. Thus it is no wonder that all of these disorders are also now strongly associated with a dysregulation of the sex hormone pathway.

Of course another now well recognized example of this positive feedback loop is with chronic opioid use. Opioids are now well known to dysregulate GnRH firing, causing a further dysregulation of testosterone, and perpetuating again this cycle of inflammation, anxiety, and vicious downward cycle affecting nearly every organ system. This frequently causes the patient to experience worse pain, seeking more opioids, and perpetuating this cycle even further. 

In these ways it seems now clearer that there is a common underlying web of pathologies underlying the metabolic syndrome, pain, chronic systemic inflammation, obesity, anxiety, PTSD, TBI, and hypogonadism. There is something systemic going on. Each patient’s manifestation may be different but there are also many, many commonalities.

According to John Milton in Paradise Lost, Pandaemonium is where all (pan) of the demons (daemonium) are. Thus pandaemonium is an apt demonym in describing the metabolic syndrome and its relationship to so many of the things we see as clinicians. For it involves the whole metabolism. There is not one singular abnormality nor just one aberrant aspect of normal physiology. With the metabolic syndrome, we have all of the metabolic daemons in one place. Seemingly everyone is a player. The sex hormones, the stress hormones, muscle, fat, neurological tissue, reproductive tissue, and likely many other hormones and pretty much every other tissue. This is important because it has not just physical manifestations, but devastating psychological consequences, particularly in regard to depression, cognition, and the experience of pain.


Matthew Thomas Smith, MD is a physician at Alabama Pain Physicians, located at 2868 Acton Road, Vestavia Hills, AL 35243. For more information visit

Alabama Pain Physicians, Comprehensive Pain Care.

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