In this two part series, we are going to delve into an incredibly complex but widespread and vitally important phenomenon that is affecting vastly more people than previously realized. We are going to examine the intricate and pervasive role of how aspects of the metabolic syndrome are related to various other hormonal pathways, particularly those of the sex hormones and the so-called “neurosteroids”. We will also explore how this is intimately related to the often concomitant phenomenon of chronic pain, sarcopenia or inadequate skeletal muscle, and mood disorders. We will then look into how this phenomenon is related to other, seemingly disparate pathologies, such as traumatic brain injury, post traumatic stress disorder, and hypogonadism associated with opioid use. We will conclude by exploring how this newfound paradigm can lead us to more effective treatment, both pharmacological and otherwise.
The reason a better understanding of these interrelated phenomena is so important is because we can now link them to various heretofore seemingly unrelated pathologies. This enables physicians and other health practitioners to potentially greatly improve their proficiency in the diagnosis and treatment of a wide array of extremely common and likely under recognized disease processes. While some of the most obvious fields to benefit from this linkage are endocrinology and psychiatry, this holds no less potential for rehabilitation and pain medicine. But, the truth is that these phenomena are so fundamental to physiology that their implications are not relegated to individual medical subdisciplines. There is essentially no field of medicine that is unaffected.
The insights gained from this newfound knowledge make it difficult not to become excited about the future of medicine. If you are a physician, other type of health care provider, or just interested in this topic, then it is safe to assume that realizing these links and insights will foster some enthusiasm for what is oftentimes an otherwise dry topic.
This was certainly the case with me. My avidity for this development in our understanding of the human body has been growing for some time. And, strangely, the catalyst that originally opened my eyes to the physiological and pathological processes that I previously considered rather mundane and tedious had little to do with my formal medical training or clinical practice. Rather, this catalyst was born of a fortuitous confluence of good friends, PubMed, and an old squat rack.
Let me tell you a story.
Part 1: Pandaemonium and The Glucose and Gonadotropin Mystery
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 the classic lifts that make up the sport of “powerlifting”. Powerlifting is comprised of working out using a few basic movements involving a barbell. These lifts include the back squat, the deadlift, the bench press, and the overhead press. The back squat is simply having a barbell resting around the area of the shoulder blades and doing a squat. A deadlift is simply squatting down and lifting a weight off of the floor. And everybody knows what a bench press is. The overhead press, or in powerlifting lingo, just the “press”, is the raising of a barbell from the upper chest straight up while keeping the rest of the body still. These lifts are all called the “slow lifts” because even though the weights are lifted as fast as possible they move slowly. And the reason they move slowly is because they’re heavy.
This is in contradistinction to the “fast lifts”, which are done with weightlifting (so, yes, weightlifting and powerlifting are two separate things). The “fast lifts” are things like the “clean” (quickly picking up a barbell and resting it over the upper chest), the “snatch” (bringing a barbell from the ground to overhead in one quick movement), and the “jerk” (bringing the bar from the upper chest straight up in the air as the rest of the body quickly drops into a squat position).
The science fiction author Arthur C. Clarke is famous for saying that any sufficiently advanced technology is indistinguishable from magic. This is called “Clarke’s Third Law.” A corollary would be that any sufficiently complicated scientific process that we don’t understand can bring serendipitous results that resemble magic when we accidentally make use of it. Let’s call this Smith’s First Law. Hence, as alluded to by the Red Hot Chili Pepper’s 1991 album, the relationship between blood sugar and sex (hormones) has been somewhat magical. Now we are starting to figure it out a little better however, and it is more like Blood Sugar and Sex Hormone Science.
Anyway, we didn’t do the fast lifts. Due to an inherent lethargy or inertia, and a fear of breaking something orthopedically, or of breaking any of the gardening tools laying about by my squat rack in my garage, we stuck with the slow lifts.
And it was great. We had all been very amateur exercise enthusiasts for some time, but the systematic approach that we were taking was paying tremendous dividends that we hadn’t previously experienced. We did short, efficient workouts. We never exercised too much or risked injury. And we got consistently stronger and leaner. But, as any good powerlifter knows, it is nigh impossible to make consistent gains by exercise alone. Thus, we also became much more interested in nutrition and the underlying physiology of getting in shape in general. This 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.
So, we were finding from the literature that a problem that nearly all of our patients had (the metabolic syndrome) seemed to somehow be related to the sex hormones. This of course piqued our interest. As may be readily seen by any cursory Google search of the term “bro science”, there is nary a male who starts lifting weights without thinking about sex hormones. And while we were all fortunately eugonadal ourselves, this confluence of professional and personal interests only served to increase our enthusiasm for these findings.
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.
The anterior pituitary gland sits pretty much right behind the spot between the eyes in the middle of the head. It sits in a bony groove of the inside of the skull that looks like a turkish chair (so I’ve been told) and is literally called a turkish chair. Except to be fancy, it’s in latin, so it’s called a “sella turcica”. Above the pituitary gland is another gland called the hypothalamus. The hypothalamus basically is the boss of the pituitary gland and gives it instructions by releasing its own hormones, which the pituitary gland then receives. The anterior pituitary is what secretes leutinizing hormone (LH) in response to the hypothalamus sending another hormone called the Gonadotropin Releasing Hormonone (GnRH). LH tells certain cells in the testes (called Leydig cells) to make testosterone. In females, LH tells the follicular cells in the ovaries to make estradiol, or the typically main form of estrogen. Source: “1808 The Anterior Pituitary Complex” by OpenStax College – Anatomy & Physiology, Connexions Web site. http://cnx.org/content/col11496/1.6/, Jun 19, 2013.. Licensed under CC BY 3.0 via Commons – https://commons.wikimedia.org/wiki/File:1808_The_Anterior_Pituitary_Complex.jpg#/media/File:1808_The_Anterior_Pituitary_Complex.jpg
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).
When the gonadotropins, or the hormones from the brain that make other glands secrete the sex hormones, seem to be faulty, this is termed a type of “secondary hypogonadism” or “hypogonadotropic hypogonadism.” However, our patient had none of the common features seen with hypogonadotropic hypogonadism. He had no history of Kallman Syndrome (hypopituitary hypogonadism frequently causing issues with puberty), CNS lesions of the hypothalamus, pituitary, pineal gland, or anywhere else, or hemachromatosis (an inherited disorder causing a buildup of iron in the body that can wreck havoc on a wide variety of tissues).
In other words, besides being a brittle diabetic with nearly every manifestation of severe metabolic syndrome and besides rapidly sliding down the slippery slope to death, he was pretty healthy.
What was going on?
Before I answer, let us back up.
The reason we need to back up is because I’ve somewhat glossed over a very important point that is not readily enough realized by many physicians: sex hormones and the metabolic syndrome are intimately related.
While this is true in both genders, and I will get around to discussing how this is true in women more in part 2, this is most readily apparent in men primarily because getting an idea of sex hormone levels is sometimes more straight forward in men than in women and thus more research has been done on men.
So, let’s talk about testosterone and the metabolic syndrome.
There is a complicated relationship between testosterone, the hormone insulin, blood sugar levels, and inflammation. Moreover, the link between low testosterone and the metabolic syndrome is even more insidious and more dangerous than at first blush as their mutual interactions produce a positive feedback loop that leads to both worsened insulin resistance and decreased testosterone.
A schematic of how the hypothalamus controls the pituitary and how the pituitary causes the testes to secrete testosterone. Testosterone regulates its own secretion by “negative feedback” by acting on both the hypothalamus and the pituitary. Estrogen can also induce this negative feedback.
But before discussing how testosterone is involved with insulin sensitivity, it is important to review some of testosterone’s more well known properties. Testosterone is involved with the normalization of mood, with the maintenance of speedy wound healing, with facilitating recovery from bouts of exercise, and with expediting skeletal muscle growth. These are all well and good and, of course, desirable in the rehab setting.
The relationship between testosterone and insulin resistance, such as that found with the metabolic syndrome, is less clear or well known. While most physicians know the basics of the metabolic syndrome and testosterone, fewer realize that increased skeletal muscle is insulin sensitizing. And while most doctors have a vague notion that exercise helps with diabetes, few know some of the main ways that testosterone, skeletal muscle, and the metabolic syndrome are interconnected.
A somewhat simplified notion of the relationship between testosterone, skeletal muscle, and the metabolic syndrome would go as follows: Testosterone can help muscle grow. Having more muscle makes you be in better shape. Being in better shape is associated with better insulin sensitivity. Thus supplementing with testosterone and slowly getting more muscle should gradually help someone’s metabolic syndrome.
Yet this is not what I found with my patient above or with numerous patients afterwards. Testosterone supplementation caused a near immediate insulin sensitization in cases of severe hypogonadism. So much so that we had to drastically reduce many of their diabetic medications over the course of days. If the only reason that testosterone helps insulin sensitivity is because it augments muscle growth from exercise, then this could not happen. My patients got markedly better before they had a chance to exercise.
And the truth is we still don’t know the full story of why this is. But this phenomenon is well documented in the literature. Testosterone supplementation by itself has been shown to rapidly improve insulin sensitivity and metabolic paramenters. Likewise, as testosterone is converted to estradiol in adipose, aromatase inhibitors such as letrozole have also been shown to profoundly improve insulin sensitivity and other markers, such as serum triglycerides, in a matter of days.
One hypothesis for the rapid improvements in metabolism caused by normalizing testosterone involves something called glucose-dependent insulinotropic polypeptide (GIP). GIP was formerly thought to only act on the pancreas but is now known to act on lipid homeostasis and the transport of glucose across the intestines. Within a week of testosterone normalization, GIP secretion is significantly increased. Perhaps GIP Is a bigger player in the metabolic syndrome than previously imagined. And perhaps testosterone is a bigger player in the regulation of GIP than previously imagined.
Another possibility, and one of the more intriguing theories of how testosterone rapidly improves insulin sensitivity, is via testosterone’s action on the mitochondria. The mitochondria are of course the powerhouses of the cell and responsible for converting glucose and fats into the energy currency of adenosine triphosphate (ATP). They do this by oxidation of breakdown products of fats and sugars in the so-called oxidative phosphorylation or OXPHOS pathway.
Two mitochondria as seen from a scanning electron microscope. The inner membranes inside of the mitochondria are dubbed “christae” and are the location of oxidative phosphorylation. The metabolic syndrome (and many other diseases, such as many types of cancer) are now known to involve dysfunctions in this area of the mitochondria.
However, over the last decade, there has been emerging data that testosterone normalization is strongly linked with gene expression controlling this OXPHOS.
Thus, it makes sense that an individual with profound hypogonadism and profound insulin resistance could have rapid changes in how he utilizes energy when his hypogonadism is improved. The testosterone has rapidly changed a fundamental feature of his whole energy metabolism that was previously lacking. It of course also makes sense why his wounds started healing so much faster, why his mood improved, and why his strength and rehab finally started going in a positive direction.
So, we have at least a partial understanding of why sex hormone normalization can improve insulin sensitivity. But, as mentioned earlier, we have two problems. The first is the effect of testosterone on insulin resistance. The second is the at least equally important problem of the effect of insulin resistance on testosterone. A better understanding of the latter will enable us to understand the dreaded positive feedback loop as well as help us more thoroughly treat this phenomenon.
First, let’s review our physiology.
It starts in the hypothalamus. In a bulge in the middle of the hypothalamus, some neurons secrete a hormone called gonadotropin releasing hormone (GnRH) in a pulsatile manner. This pulsatile manner is important. If GnRH is released continuously, it won’t cause the desired downstream effects. Speaking of downstream, this hormone travels a brief distance through some downstream veins to the front of the pituitary gland. At the pituitary gland, the GnRH causes cells to secrete two other hormones, the aforementioned leutinizing hormone (LH) and follicle stimulating hormone (FSH). In men, LH travels down to the testes and tells certain cells called Leydig cells to make testosterone. In women, LH does a wide variety of things, but, as a counterpart to male LH, female LH tells the ovaries to make estradiol.
Back to testosterone. As testosterone leaves the testes, it then circulates throughout the body and does all of the things that we discussed earlier and likely many other things that we don’t know about yet. And when testosterone reaches a certain concentration, it can also travel back up to the brain, wherein it will tell the hypothalamus and pituitary to lay off for a while.
So, that’s how it’s supposed to happen. The hypothalamus makes GnRH in a pulsatile fashion. GnRH tells the pituitary to make LH. LH tells the testes to make testosterone. Once enough testosterone is made, the testosterone tells the hypothalamus and pituitary to calm down.
Now, let’s take a look at how this all goes haywire with the metabolic syndrome.
Remember, one of the hallmarks of the metabolic syndrome is body-wide systemic inflammation. With increased fat around the organs (the so-called “visceral adipose tissue”) there is a marked increased in the elucidation of inflammatory mediators into the circulation. These include tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and many others. Furthermore, anti-inflammatory mediators, such as interleukin-10 (IL-10) and adiponectin are decreased.
By way of this hormonal milieu, the metabolic syndrome creates a body-wide low level inflammation that plays a part in all of its typical manifestations, ranging from atherosclerosis to hypertension to hypercholesterolemia to cancer to Alzheimer’s to osteoarthritis and beyond.
And, as we know from Alzheimer’s Disease, now also known as diabetes type 3, the brain is not immune from this pandemic of inflammation.
The metabolic syndrome’s two hallmarks are over-nutrition and increased inflammation. This schematic gives some mechanisms by which this leads to neurological problems. Source: http://www.ncbi.nlm.nih.gov/pubmed/22417140
Unfortunately for testosterone (and us), the hypothalamus and pituitary gland are part of the brain. Inflammation of these glands, particularly the hypothalamus, can interfere with the normal pulsation of GnRH, the normal secretion of LH, and lead to a phenomenon called “gonadotropin dissociation.” This gonadotropin dissociation can cause a decrease in LH and hence a decrease in testosterone.
But it is not just from inflammation that the hypothalamus and the pituitary change their tune. As mentioned earlier, an enzyme called aromatase can turn testosterone into estradiol. We know of aromatase primarily because of its role in the adrenal glands.
In the outside of adrenal glands, called the adrenal cortex, aromatase can turn testosterone to estradiol.
But, aromatase is by no means relegated to just the adrenals. Aromatase is strongly expressed by adipocytes, particularly those of the visceral adipose tissue. Thus, as a male becomes more obese, or simply gains more visceral adipose (which can happen without obesity), his testosterone is converted to estradiol. Estradiol can thus go to the hypothalamus and pituitary and strongly inhibit the release of GnRH and LH.
Physiology is complex. The major takeaway is that low testosterone both causes the metabolic syndrome and is caused by the metabolic syndrome. This of course can create a positive feedback loop. Which, as you can imagine, is bad. Source: http://care.diabetesjournals.org/content/34/7/1669.full
And it doesn’t end there. We know that the increased inflammation that is part of the metabolic syndrome causes 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.
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. Behold, another part of the positive feedback loop.
Furthermore, hypercortisolemia also appears to affect testosterone in at least two other ways. The first is that it acts on the hypothalamus and pituitary, causing a further worsened hypothalamic-pituitary-axis dysfunction. The other is that hypercortisolemia can act directly on fat cells and make them resistant to testosterone.
Like how the hypothalamus and pituitary regulate testosterone, they also regulate the stress hormone cortisol.
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.
While these feedback loops are complicated, they can start to explain some of the many phenomena that we see with the metabolic syndrome. And they also explain why my patient had such low LH and why so many things got so much better shortly after we gave him some testosterone.
With this new understanding, it becomes clearer that we don’t need hemachromatosis or a tumor to make sense of his strange labs. My patient was merely subject to these positive feedback loops. In particular, he was experiencing some aspect of gonadotropin dissociation.
One of the hallmarks of a scientific theory becoming more widely accepted is that different people give it different names. Before the metabolic syndrome caught on it was also called “Syndrome X” and “Reaven’s Syndrome.”
Gonadotropin disassociation is now thus also called Male Obesity-Associated Secondary Hypogonadism (MOASH).
Of course, we should be savvy enough by now to realize that not only is MOASH a cumbersome acronym but calling this process Male Obesity-Associated Secondary Hypogonadism is misleading. When it comes to adipose, while central obesity is often present with the metabolic syndrome, it is really energy overabundance, insulin resistance, and systemic inflammation that are its true defining characteristics. Thus a more accurate name than MOASH should be something along the line of simply Metabolic Syndrome-Associated Secondary Hypogonadism.
Whatever we decide to call it, the good news is that there need not be any fringe theories to explain my patient’s findings. Nor do we need to throw up our hands in confusion or plead ignorance. Through the complex interactions that we’ve reviewed, it is clear that there are a variety of mechanisms that can cause leutinizing hormone to be low in the context of the metabolic syndrome and hypogonadism. And this is just one of the many unusual findings in this tangled web of causality.
In summary, the pathophysiology of the metabolic syndrome in relationship to sex hormones is extraordinarily complicated and far reaching. Furthermore, some of its most profound deleterious effects are from at least one manifestation of the most dreaded of all medical phenomena: the positive feedback loop. While the details are complicated, the net result of these positive feedback loops sums to something rather simple: low testosterone can cause the metabolic syndrome and the metabolic syndrome can cause low testosterone.
Negative feedback loops are ubiquitous and of course necessary. In normal circumstances, too much testosterone will regulate itself by turning off its own production. The same is true with cortisol. In fact, the same is true with virtually every other normal physiological process. Of course negative feedback loops are part of the metabolic syndrome too. This is why we found low LH in my patient. LH was being turned down by likely multiple mechanisms. However, because the metabolic syndrome also contains positive feedback loops, it allows for something suboptimal to quickly accelerate its pathological potential and progress to bad and then to life threatening. With a positive feedback loop, the typical checks and balances necessary to maintain homeostasis go by the wayside and pandaemonium ensues.
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. 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 as we will see, devastating psychological consequences, particularly in regard to depression, cognition, and the experience of pain.
In part 2, we will discuss some more of these consequences. In doing so, we will examine more closely how the metabolic syndrome and hypogonadism are related the the epidemic of sarcopenia. We will also discuss and how the metabolic syndrome and hypogonadism further affect the brain.