Part 3 - Vaccinations and Infections

     The National Fibromyalgia Association’s 2006 Internet survey of 2596 individuals found that 26.7% of those who could trace the origin of their FMS to a specific event reported that event to be an illness and 45% felt that infections worsened their FMS symptoms.  However, the reports in the scientific literature are conflicting.

     Only one study has been reported showing that chronic hepatitis B infection may increase the risk of FMS. In this study 25% of patients who had antibodies that were positive for Hepatitis B also had FMS.  Two studies with a total of 202 FMS patients have reported an association of hepatitis C virus infection and FMS.  Conversely, two studies with 267 FMS patients found no association to hepatitis C.  If such an association does exist, one possible pathological mechanism may involve hepatitis C induced changes in cytokines which affect the hypothalamic-pituitary-adrenal axis. 

     If you’re wondering just what are cytokines, then be sure to read the two short reports on cytokines and neuroendocrinology. Until you do here is an introduction to cytokines. They are cellular molecular messengers that the body uses primarily to regulate inflammatory responses. When you hear about cytokines, it will usually be in regard to arthritis but they will also appear in discussions about inflammatory bowel disease and interstitial cystitis – two other conditions that occur in FMS. Cytokines can be released by different types of cells into the circulation or into tissue and they will then bind to specific receptors on other cells and trigger responses in these cells – hence the messenger function. 

     HIV is another infection that has caught the attention of FMS researchers. Dr. Buskila, who is a dedicated Israeli FMS researcher, has found 15 of 51 patients (29%) diagnosed with HIV to also have FMS which was not associated with duration or stage of HIV infection. FMS has been found in 11% and 17% of HIV patients in two other studies.

     Everyone has heard about Lyme disease and it has generated some interesting findings in regard to FMS. A study in the Annuals of Internal Medicine published in 1992 suggested that Lyme disease may trigger FMS but antibiotic treatment was not effective in resolving symtptoms. The confusion of Lyme disease and fibromyalgia was, in part, responsible for one physician stating that approximately half of the 91 courses of antibiotics provided to 100 patients first seen at the Lyme Disease Center at the Robert Wood John Medical School were “probably unwarranted.”  This was most likely due to the infectious organism causing Lyme disease, Mycoplasma, creating symptoms similar to FMS. However, to date, no definitive association exists between FMS and Mycoplasma infection.

     So far, as in most other studies on the causative factors for FMS, there are no clear-cut answers regarding infection or vaccination and FMS. More evidence that work still needs to be done.

Part 2 - Emotionally Traumatic Events

     Emotionally traumatic events have long been considered a cause of Fibromyalgia Syndrome (FMS). However, it has been difficult to attempt to do research in this area primarily because of a statistical peculiarity called Berkson’s bias. If you have read some of the other short reports you may have remembered reading about the odds ratio. The odds ratio is a number that simply tells you about the odds of having a disease or medical condition compared to something else. For example, if you smoke the odds ratio of developing a particular type of cancer may be 6.8 compared to someone not smoking. This simply means you are at almost seven times the risk of developing that cancer by smoking, or it appears at a frequency in smokers that is 700% greater than non-smokers – the numbers mean the same thing.

     Berkson’s bias applies to people with two or more separate medical conditions – say heart disease and diabetes. People with heart disease and diabetes will see their doctor more than someone with just one of those diseases simply because having both diseases usually means they have more problems with both diseases than if they had just one. Berkson’s bias can either falsely elevate or lower an odds ratio depending on whether two medical conditions influence medical care for the other. In the case of FMS, patients who also have a history of physical or sexual abuse or post-traumatic stress disorder may disproportionately seek more medical care. If you are a researcher seeing FMS patients, you may see those FMS patients with a history of physical or sexual abuse more frequently than patients without such a history – this would inflate the odds ratio. Given that the independent consequences of trauma, such as musculoskeletal pain, fatigue, and mood and sleep disturbances overlap with the major core symptoms of FMS, this can be an important bias that confuses the picture when researchers try to separate out cause and effect.

     Stress has also been associated with imbalances in hormones and how the autonomic nervous system functions. Remember, the autonomic nervous system is largely responsible for all the unconscious actions of your body – breathing, heart rate, digestion, etc. A group of FMS researchers has shown that childhood physical abuse and sexual abuse both predicted abnormal cortisol responses in adult patients with FMS. Cortisol is the stress hormone of the body. Likewise, in adults studied immediately after trauma, disrupted cortisol levels are predictive of the later development of PTSD. These findings suggest there may be a neuroendocrine link between trauma, abuse, and dysruptions in the neuroendocrine axis affecting cortisol that could possibly begin in childhood – and that link may be tied to FMS.

     Three notable studies have provided support for an association of sexual and physical abuse and FMS, while two have not. FMS symptoms, if they are going to manifest, can develop up to 18 months after a traumatic event. A group of FMS researchers,  in 1997, compared FMS patients to those with rheumatoid arthritis and noted those with FMS had significantly higher lifetime prevalence rates of all forms of childhood and adult victimization as well as combinations of adult and childhood trauma. The strongest relationship was shown by FMS patients who had been physically assaulted in adulthood. It was also found that the severity of trauma could be correlated to measures of physical disability, psychiatric distress, the ability to adjust to illness, and the quality of sleep in FMS patients; but not to any of these characteristics in those patients with rheumatoid arthritis.  A psychiatrist specializing in FMS, Dr. Boudewijn Van Houdenhove, has found in FMS patients significantly higher prevalences of emotional neglect and abuse and physical abuse; he also identified a subgroup having experienced lifelong victimization. 

     Another group of FMS researchers has conducted the first community-based study of psychosocial trauma in FMS. The use of a community sample reduces the effects of something called reporting bias which is a significant factor when you try to study an issue this sensitive. Reporting bias means that people are reluctant to discuss certain aspects of their history with another individual because they are embarrassed, ashamed or otherwise uncomfortable but they will do so in an anonymous survey. They found that with the exception of actual rape, no self-reported sexual or physical abuse was associated with FMS; women who had been raped were 3.1 times more likely to be diagnosed with FMS.

     This was recently substantiated by a 2010 review that also found that two types of traumatic experiences, sexual assault and physical abuse, were associated with fibromyalgia. This study also looked at males with FMS.  Men with FMS experienced more life-threatening trauma while women had suffered more sexual assaults and abuse. No association was seen for other major life stresses, life threatening trauma, or emotional abuse and neglect.

     The first study examining post-traumatic stress disorder and FMS was published in 1997 and reported FMS in 21% of a group of 29 PTSD patients seen for care at a mental health clinic compared to normal control patients.  However, those PTSD patients with FMS were quite affected by the syndrome, much more so than other FMS patients, suffering pain, poorer quality of life, higher functional impairment, and psychological distress.

     In a 2000 study 56% of 93 FMS patients consecutively referred to a pain management center were found to have significant levels of PTSD-like symptoms.  As before, patients with both PTSD and FMS had significantly greater levels of pain, emotional distress, life interference, and disability with over 85% having significant disability. A separate study found PTSD symptoms in a similar percentage of patients – 57% of 77 FMS patients (40 women and 37 men).  In this study, FMS patients reported the single most important trauma to be the death of a loved one; this characteristic is similar to PTSD patients in general. 

     In regard to irritable bowel syndrome (IBS) and gastrointestinal reflux disease (GERD), both of which are frequently found in FMS patients, women with a history of sexual or physical abuse show a higher prevalence of gastrointestinal disorders. One study has shown abuse to be significantly more prevalent among those with GERD (92%) and IBS (82%). However, this study originated from an academic center and may reflect biases of more severe cases being sent to this center.

     Rather than PTSD being a risk factor for FMS, one FMS researcher, Dr. Karen Raphael and her group from the New Jersey Medical School, have proposed that women with FMS are at risk for PTSD not because they are exposed to more traumatic events compared to other women but because their biological nature makes them more susceptible to developing PTSD. They had the opportunity to test this hypothesis through a natural experiment that began with a community based study of family and psychiatric factors among women with FMS they conducted by telephone surveys. They contacted over 9,000 women in the Manhattan and nearby New Jersey area prior to September 11, 2001.

     After the attack, 2,026 of these participants were randomly contacted and assessed for pain and FMS like symptoms as well as PTSD symptoms. There was no significant increase in symptoms consistent with FMS.  However, after 9/11 the odds of probable PTSD were more than three times greater in women with FMS-like symptoms which were not reduced by controlling for FMS-like symptoms before 9/11. In other words, if a woman had FMS her risk of developing PTSD would be three times greater than a woman without FMS as a result of the 9/11 incident.

     Several studies have addressed the relationship between FMS and soldiers who served in the Gulf War but only two have shown an association. The Canadian Forces Personnel Health Study did not calculate prevalences but reported an odds ratio of 1.81.  The odds ratio of 1.81 means that Canadian soldiers who served in the Gulf War were almost twice as likely to develop FMS as those who did not.  The Iowa Persian Gulf Study found FMS prevalences of 19.2% in deployed veterans compared to 9.6% in non-deployed veterans using a telephone interview. Interestingly, PTSD was identified in only 1.9% of the combat veterans. Remember, the prevalence of FMS in the general population is about 3% - 4%; with 3% in females and 0.5% in males. You would say these numbers are exceptionally high and you would be correct. However, this was a telephone survey and did not include a physical exam. Consequently, there is a high risk for what are called, “false positives,” meaning individuals who test incorrectly positive for the criteria used over the phone for FMS.

     A much more extensive study was done by Dr. Bourdette and his group at the Portland Veteran Affairs Medical Center. They conducted a mail survey of 2022 veterans in the northwest U.S. From that mail survey they selected 443 individuals who agreed to come into their office for a clinic visit and then conducted a FMS examination on 241 patients randomly selected from this group. They calculated what are called minimum prevalence estimates, which means they assumed none of the control population would have FMS, so this would significantly underestimate their numbers. It would be like comparing a new anti-smoking product in a population that smoked to a reference population assuming none of that population smoked.

     Their minimum prevalence estimates of FMS, (remember - calculated assuming none of the non-responders would have FMS), were 2.47% total and 7.4% female and 1.8% male. These prevalence figures are similar to general community estimates of 2.8%.  A very large study conducted by physicians who worked for the Department of Defense looked at all hospitalizations in the Department of Defense medical facilities from October 1988 through July 1997. Gulf War veterans were found to be at a slightly greater risk for FMS, approximately 1.2 times greater. However, the researchers then looked at the conditions the soldiers had before they went into the war, which was possible because the Department of Defense keeps very good medical records on soldiers. Then there was no association. They did find the FMS was three times more common in females than males. Overall, it seems that even though studies show higher rates of PTSD in veterans there is no evidence of also having FMS.

     However, just like in non-soldiers, FMS exacerbates the symptoms of PTSD.  When the symptoms in individuals with both FMS and combat related PTSD were examined it was found those individuals with PTSD had more severe PTSD symptoms than veterans without FMS.  A recent 2010 study describes a chronic musculoskeletal pain syndrome in veterans where those afflicted, similar to FMS patients, reported naturally occurring exercised induced muscle pain as more intense. These individuals were also more sensitive to experimentally applied heat stimulation before and after acute exercise compared to normal control individuals.
The latter finding reflects a phenomenon termed exercised-induced hypoalgesia, in which exercise in healthy individuals renders them less sensitive to experimental pain. In other words, after people exercise heavily they tend to me more tolerant of painful stimulation. This is thought to be due to the natural release of endorphins. In patients with FMS, the opposite is found and patients become more sensitive to pain during and after exercise.

     Perhaps the ultimate test of PTSD is that of the Holocaust. A study by a group of FMS researchers has identified a significantly increased prevalence of FMS among Holocaust survivors who have now lived over six decades after the end of World War II. In survivors of the Nazi Holocaust 24% have developed FMS compared to age matched controls not exposed to Nazi occupation. A rather remarkable finding, and perhaps the best test to date regarding exposure to a traumatic situation and FMS.

Part 1 - Physically Traumatic Events

     The role of physical trauma in the development of Fibromyalgia Syndrome (FMS) continues to be deliberated in the literature. A major difficulty has been the reliance on someone’s ability to recall events that may have occurred thirty years prior. Post-traumatic fibromyalgia is also known as reactive fibromyalgia syndrome and the first paper on the subject was published in 1992. Those researchers reported that 23% of 127 FMS patients reported a specific event – trauma, surgery, or medical illness preceded their FMS. Patients in this group were significantly more affected with 70% losing their job, 34% receiving disability, and 45% having reduced physical activity. Shortly thereafter, in 1994, another study reported a follow-up of 176 FMS patients; 61% reported symptoms after a motor vehicle accident, 12.5% after a work injury, 7% after surgery, 5% after a sports related injury, and 14% after some other type of traumatic injury.

     A 2002 case-control study was published, which is a type of study where people with FMS are matched to healthy, normal individuals in as many characteristics as possible except for their disease, FMS. Then researchers try to find out what was different about people who had developed FMS. When the 136 FMS patients in this study were examined it was found that 39% had evidence of significant trauma within the 6 months prior to the onset of their FMS. The three most frequent types of trauma were surgery (38%), work injuries (14.7%), and childbirth (11.8%). A rather famous and experienced pain researcher, Dr. Dennis Turk, has found that compared to FMS without a known cause, post-traumatic FMS was associated with significantly higher degrees of pain, disability, life interference, affective distress, and lower levels of activity. Post-traumatic patients in his study were also more likely to be receiving opioid pain medications and to have more extensive treatment histories with nerve blocks, physical therapies, and modalities.

     The single event that has received the most attention is whiplash injury which has generated a number of studies and anecdotal reports. One of the more famous accounts is a family of 6 (2 parents and 4 children) who shared a complex of multiple constitutional and psychological symptoms who were evaluated 6 and 8 years after a minor car accident and all found to have FMS.  The major prospective studies, meaning studies that were conducted on people after their accident and followed forward in time, have been conducted by different Israeli researchers and they have reached opposite conclusions.
The first report of 161 cases, published in 1997 by Dr. Buskila and his colleagues suggested that FMS was 13 times more frequent following neck injuries than lower extremity injuries. FMS developed in 21.6% of individuals within 1 year after a motor vehicle accident compared to 1 individual with a lower extremity injury. This generated a number of critical letters to the editor with doctors suggesting possible confounding factors ranging from increased anxiety and sleep disturbances to biases introduced simply because there are more tender points in the upper body around the sites of neck injuries (10 of 18 tender points are in the neck and shoulder region).

     Of the 161 cases identified in 1997, 78 were able to be followed-up 3 years later. Even though 60% still had FMS all of the original cases were able to return to work. Of note, an additional 2009 study by Dr. Buskila found 15% of the survivors of a major train crash in Israel met the American College of Rheumatology’s criteria for FMS 3 years after the event.

     The findings of Dr. Buskila regarding whiplash and FMS remained the only prospective studies in the literature until another group of Israeli researchers, Dr. Tishler and colleagues, published two reports based on 153 patients presenting to the emergency department after whiplash injuries. The first in 2006 provided a mean follow-up of 14.5 months and found no association between injury and FMS with only one patient developing FMS.  A second report in 2010, was able to provide a 3 year follow-up of 126 of these 153 patients and confirmed the results of the authors’ earlier study showing that whiplash injury and FMS were not associated; only three patients in the study group had developed FMS in the intervening time.

     Why such discrepancies exist is still a matter of debate. Some researchers have proposed the potential role of interactions between genetics, prior experience, stress response systems, and central neurobiological pain processing systems as well as cultural differences. There will be a set of future short reports on the central neurobiological pain processing changes in FMS patients. Two studies on the development of chronic widespread pain and motor vehicle accidents suggest that the greatest predictors of persistent pain are related to pre-collision psychological and physiological health.

     Factors that influence if neck or back pain becomes chronic include the severity of pain, being female, having a history of abuse, a family history of chronic widespread pain, and the presence of additional diseases such as irritable bowel syndrome, restless leg syndrome, or migraines. It will be interesting to see how this debate unfolds using the new 2010 American College of Rheumatology criteria. However, until the debate is settled, it is probably best to avoid any whiplash injuries.
 

More Than Just a "Bad Hormone" Day - Part 2

     The first part of this series described some basics about the hypothalamic-pituitary-adrenal axis in FMS and came to the conclusion, in 2004, that nobody quite knew what was going on. The bottom line seemed to be that there was a disruption seen in the normal circadian rhythm for plasma cortisol levels with abnormally elevated concentrations noted in the evening. Well, some researchers tried to look at things more exactly by convincing people to allow them to test their cortisol by taking a saliva sample to measure their cortisol every 10 – 20 minutes for 24 hours rather than what had been done in the past – one 24 hr measurement collected from urine. Some people even allowed researchers to use an intravenous blood sample to be taken every ten minutes – which gave even better results. Now, some more precise numbers began to appear.

     In this more exact study it was noted that evening levels of cortisol were slightly elevated and there was also a delay in the decline of the cortisol levels such that 50% of the FMS patients in the study never met the criteria for having a quiet period; the quiet period is what happens with normal people. In other words, their bodies were never out of the “stress-free” mode. Consequently, the elevated cortisol levels seen in FMS patients in the past were not due to an increase in the amplitude or number of cortisol pulses but rather were due to a constant elevated cortisol state.

     This means, quite simply, that the finding of elevated cortisol levels without a true circadian, or 24 hour rhythm fits the pattern of a decreased resiliency of the HPA axis, i.e. a decreased ability of the HPA axis to return to normal levels after responding to a stressful event. What could be the stressful events that seem to keep the system constantly activated?

     One such stressor could be musculoskeletal pain.  There have been markedly increased daytime cortisol levels, sometimes as much as 30% to 50% higher than normal people, that have been measured in women with temporomandibular (TMJ) joint disorder. A 2010 study noted that in TMJ patients pain catastrophizing was also associated with elevated cortisol levels. Catastrophizing is the association of extremely uncomfortable feelings associated with pain; for example,  pain being described as unbearable or horrible. Catastrophizing also occurs in FMS patients.  Catastrophizing makes up between 7% and 31% of the differences between people who have other types of pain; if you can account for catastrophizing experimentally or statistically then what scientists record about pain between different people in the study becomes equal.

     Two studies have shown that psychological trauma has long lasting effects on the HPA axis. A group of researchers has demonstrated that childhood physical and sexual abuse was positively associated with decreased morning and elevated evening cortisol levels and flattened diurnal cortisol levels – just what is seen in FMS patients.  Another group of FMS researchers found decreased morning cortisol levels and less diurnal cortisol variation in a subset of FMS patients who reported sexual abuse.  Low diurnal cortisol variability has also been associated with lower physical function, lower perceived control over pain and greater pain catastrophizing in patients with other pain conditions, e.g., lumbar disc herniation – so FMS patients are not unique in this regard.

     The effects that a history of abuse may have on the HPA axis combined with the fact that patients with more severe symptoms of FMS tend to have histories of abuse and are seen at tertiary treatment centers from which most study subjects are drawn suggest that some of the inconsistencies that have been noted in the past neuroendocrine research could possibly be due to a failure to recognize that some studies may have included patients who were simply more severely affected with FMS. This is something called Berkson’s Bias. It is a statistical bias, meaning it can artificially give researchers false numbers in their statistical analyses.

     It results when people have two different medical conditions and they tend to seek more medical care because of having two conditions than someone who would seek medical care if they only had one medical condition. This makes sense, if you have diabetes and hypertension, you would end up seeing your doctor more than if you just had hypertension. People who have FMS and also have a history of some type of abuse in childhood may have a more severe form of FMS as well as the psychological problems resulting from the childhood abuse – they have two medical conditions. They seek medical care more than if someone just has “garden variety FMS” (as if there is such a thing as ‘garden variety FMS’), but you get the picture. If the studies come from centers where these people are patients then the numbers can become skewed as these results are applied to everyone with FMS, but  not everyone with FMS has this severe a form of FMS.

     The same thing happens if results are presented as means or averages – then the individual variations are lost. Let’s say someone is a “spendaholic.” They pay the normal household bills, for example they write fifteen checks for $50.00, then write a single check for $500.00 to buy a designer dress. Their husband says, “Where did the money go? They say, “I don’t know, I just paid the bills, see, the average check I wrote was for $78.00.”

     Now, what happens in a FMS patient when their body gets challenged, for example, during exercise? Challenges that stimulate the HPA axis such as exercise generally show a normal cortisol response but exercise challenges in FMS patients have produced exceptionally variable responses. However, a 2010 study where FMS patients have been asked to exercise their legs until they were exhausted showed their HPA axis and their adrenal system did not respond, compared to normal healthy people. Both of these could contribute to the exercise intolerance seen in FMS. What’s happened? Something called “down-regulation.” In down-regulation, as a result of constantly being exposed to higher levels of cortisol, the body has adjusted itself to simply becoming less responsive to the cortisol it is seeing.

     You have an example of this almost every day if you come in from the dark or listen to music. Your eyes adjust to light or dark. The louder the music you listen to, the more your body acclimates to the sound. If you go to a concert and step outside your ears adjust and when you go back into the concert it seems a lot louder than when you left, but the sound hasn’t changed. Have you ever gotten back into your car and forgotten to turn down the radio from when you got out and thought to yourself, “Was the sound that loud before?” You adjusted to the sound of the radio and didn’t even know it.

     Another approach has been to measure adrenal size, which should be reduced in patients with adrenal failure that would have resulted from long-term ACTH or CRH deficiency or enlarged from HPA overactivity. Adrenal size in FMS is not different from normal people indicating there is no sufficiently severe CRH-ACTH deficiency to cause adrenal shrinkage. That doesn’t seem to fit?

     Overall, as of 2010, if there is HPA dysfunction in FMS patients it is now thought to result in a mild, slightly decreased level of cortisol with an impaired ability to respond to stress. Stressful events are “blunted” in their ability to activate the hypothalamic CRH-pituitary ACTH axis which may not result in significantly impaired cortisol levels under normal conditions but could result in decreased cortisol levels in response to stress or even normal activities of daily living. FMS patients will show a marked hypersecretion of ACTH in response to acute stressors as a result of chronic hyposecretion of CRH and a relative adrenal hyporesponsiveness. However, current data do not warrant corticosteroid replacement as general therapy in FMS. That’s the final word so far.

     The HPA axis has been implicated in other aspects of FMS. It has been noted that the expression of pain behaviours was, in part, positively correlated with lower cortisol levels. It has been postulated that if, in healthy individuals, the release of cortisol increases sensory thresholds, the reduced cortisol levels in FMS patients may contribute to higher pain sensitivity. In one subset of a study group, the Multidimensional Pain Inventory, which is a test used to determine particular personality types, a certain personality type, the “interpersonally distressed” was correlated to increased ACTH production and this was the single best predictor of an individual who would describe pain. In other words, this test could be given to someone and if they matched to this personality type, that person would also be found to have both higher ACTH production and start to describe pain right away during their clinic interview.

     Both physical and psychological interventions can improve the functioning of the HPA axis.  A three week multidisciplinary 20 – 30 minute aerobic exercise program, three times per week resulted in reductions in the number of tender points and the ability to tolerate the artificial pain the researchers would apply and improvements in other FMS symptoms. What else was seen? Normalization of cortisol levels.  Cognitive performance tests were also associated with cortisol levels – the more normal the cortisol levels the less people complained of “fibrofog.” Treatment designed to improve how people think during the stress of having a disease termed, “Cognitive Behavioral Stress Management,” improves cortisol levels. For example, reduced evening cortisol levels were obtained in women being treated for stage I or stage II breast cancer.   These results suggest that the problems seen in the endocrine stress response may contribute to the cognitive symptoms of FMS.

     Other neuroendocrine changes involve the hypothalamic-pituitary-growth hormone axis. The hypothalamus controls growth hormone as well by releasing growth hormone releasing factor. In response to growth hormone releasing factor from the hypothalamus, growth hormone (GH) is released from the anterior pituitary and then causes the release of insulin growth factor-1 (IGF-1), previously known as somatomedin C, from the liver. GH is maximally secreted during stage 4 of REM sleep and has its greatest role in keeping muscles healthy.  IGF-1 is used by scientists to measure GH as the release of GH occurs in pulses and it doesn’t stay around in the body very long before being taken up by tissues. There are a large number of FMS patients who have subnormal GH secretion, which was noted by one of the first major researchers in FMS, Dr. Bennett, in 1992.

     In a 1995 study, Dr. Bennett found mean IGF-1 levels in 500 FMS patients to be approximately 60% of normal.  A more recent 2010 study examined GH deficiency in severe FMS patients.  Several of these patients had multiple hormone deficiencies along with GH deficiency. The finding from this study is that FMS may result in a subset of individuals who have a disease of their pituitary gland in which it cannot produce any hormones – this is called “empty sella syndrome.” The name comes from the place where the pituitary lives, the sella, and “empty” means, the sella is empty, the pituitary gland isn’t there, it has degenerated. 

     It was recommended that there may be a subpopulation of FMS patients who would benefit from GH replacement. A 1998 randomized, double-blind, placebo-controlled study (the best study you can do) was conducted by Dr. Bennett who provided daily GH injections to women with FMS over 9 months. He found improvement in overall symptomology and tender point count in 68% of patients.  A 2007 study by another researcher using GH replacement in severe FMS patients found a 60% reduction in mean number of tender points and similar improvements in the scores on the Fibromyalgia Impact Questionnaire in 100% of patients; improvements were noted in the first few months of the one year study.  The difference may be due to the amounts of GH used, the latter researcher used more. However, cost, the fact that the IGF-1 has to be injected daily, and need for IGF-1 monitoring do not make this a practical therapy for all FMS patients.

     Patients with GH deficiency from other causes resemble FMS patients in having reduced exercise capacity, muscle weakness, fatigue, intolerance to cold, and impaired cognition.  GH secretion occurs predominantly during stages 3 and 4 of non-rapid eye movement sleep, the stages showing the most disruption in FMS patients.  The effects of stress are difficult to interpret as chronic psychosocial stress, especially as children, lowers GH levels while acute stress raises levels.  An important observation by Dr. Bennett was that FMS patients with initially normal levels of IGF-1 often had a rapid decline over one to two years after they developed FMS.

     One final note, there are only two reports on the function of the gonads, or sexual organs, in FMS patients. No abnormalities were noted in gonadotropin secretion or gonadal steroid hormone levels in FMS patients in one study. The hormones released by the pituitary are called luteinizing hormone and follicle stimulating hormone (FSH) and they cause the release of estrogen and progesterone from the ovaries. There has only been one study and that found no changes in FSH levels but significantly lower levels of estrogen and a reduced response to luteinizing hormone secretion following experimental stimulation. Neither was correlated to FMS symptoms.

     That pretty much sums up all the research on the neuroendocrine system in FMS. It is a rather complex area and there is certainly going to be more findings coming out in the future. But, at least for now, you know just about as much as the scientists in the field.

More Than Just a "Bad Hormone" Day

     Neuroendocrinology and the neuroendocrine system had their origin with Dr. Geoffrey Harris, (1931 – 1971) of Oxford University, in England, considered the father of endocrinology. Neuroendocrinology refers to how the nervous system is connected with the endocrine or hormone system. The endocrine glands are those glands in the body that secrete hormones. The components in the brain are the hypothalamus, which is deep in the brain, that connects through the blood vessels in the brain via chemical messengers called hypothalamic releasing factors to the pituitary gland, at the base of the brain.  The pituitary gland then releases hormones in response to the type and concentrations of releasing factors it receives from the hypothalamus that influence the function of organs and tissues throughout the body.

     One of the major organs that play a role in FMS is the adrenal glands, which live above the kidneys and produce the fight or flight stress hormones, epinephrine and norepinephrine as well as other hormones, including cortisol. These chemicals, or transmitters, function in the sympathetic nervous system. If you’re not familiar with the sympathetic nervous system, read the short report on “Dysautonomia.” It would be best to read it before going any further into this short report as you may not understand some of the information presented here. The adrenals complete the hypothalamus and pituitary system, making up what is referred to as the hypothalamic-pituitary-adrenal axis (HPA axis).

     A “major player” hormone is adrenocorticotropic hormone () also known as corticotropin. ACTH is released from the pituitary, almost always in response to stress, travels in the bloodstream, and causes the release of cortisol from the adrenal glands. Epinephrine and norepinephrine are the instantaneous responses to stress. Cortisol is the “maintenance” response to stress. Its job is to adjust the body’s major life-support systems based on the amount of “average” stress it seems to be living under. Cortisol is a steroid hormone and when released will increase blood sugars, suppress the immune system, and change how fat, proteins, and carbohydrates are metabolized.

     It was in 1993 that one of the first reports was published suggesting that FMS is related to a neuroendocrine disorder.  It seems to be characterized by a “hyperactive” pituitary releasing ACTH but the adrenals being less than normally responsive.  The normal hypothalamic-pituitary-adrenal (HPA) axis functions by the release of corticotrophin releasing hormone (CRF) from the hypothalamus which causes the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary. This causes cortisol to be released from the adrenal cortex. As the cortisol is flowing through the body in the bloodstream it will also flow through the cerebral circulation, enter the hypothalamus and pituitary gland and then cause something called “feedback inhibition” meaning it shuts down the production of CRF and ACTH preventing the release of additional cortisol.

     The HPA axis is also regulated by the nerve chemical messenger (i.e. neurotransmitter) serotonin, and also by chemical messengers called cytokines, and substance P, which is a nerve messenger released in the process of pain transmission. Given that the serotonin system has a strong influence on the HPA axis it has been proposed that there may be a connection between the reduced levels of serotonin noted in FMS patients and HPA abnormalities. 

     Normally, the circadian, or daily, rhythm of HPA activity is such that a cortisol peak occurs just before awakening and the low point, or the trough, in the evening. Anything stressful is superimposed upon this pattern. The circadian rhythm results from stimulation provided by what have been termed the “pacemaker cells” in the suprachiasmatic nucleus. The suprachiasmic nucleus is one of the smallest collections of neurons in the brain, only about 20,000 cells and about the size of a grain of rice, but it is one of the most important. It lives in the middle of the brain, just above where the nerves from the eyes begin to enter the brain. This small center controls all the 24 hour functions of the body – when to go to sleep, when to wake up and everything in between. It is an amazing structure and every organism in this planet that lives on a 24 hour day schedule has the equivalent of a suprachiasmic nucleus in its brain.

     The HPA system can rapidly correct itself such that stress-induced perturbations can be fixed within 24 hours.  Over ten years ago two physicians proposed that the pituitary-adrenal response to constant stress would start to show up by low levels of cortisol and low levels of HPA activity. The problem is, there is no way to answer the “chicken and egg” question. In other words, is the HPA axis under activity a result of chronic stress or is it there from the beginning?

     FMS has been thought to be a stress related syndrome given that a multitude of stressors have been noted to trigger symptoms.  A group of researchers have found that during childhood or adolescence 51% of the FMS patients in their study had experienced very negative life events compared to 28% of healthy normal people and within the past year 51% of FMS patients again experienced negative life events compared to 24% of normal people. Another group of researchers noted the clinical resemblance of FMS to symptoms seen in patients with a particular medical condition, that of a deficiency of certain hormones – glucocorticoids, known as glucorticoid deficiency. Glucocorticoids are stimulated by cortisol. People with glucocorticoid deficiency have the same symptoms as FMS – debilitating fatigue, arthralgias (joint aches), mylagias (muscle aches), and sleep and mood disturbances, especially in response to stressors. Consequently, there have been a number of studies that have examined the sympathetic nervous system and HPA axis in relation to FMS syndrome but often the findings were contradictory.

     Most studies failed to control for previous trauma, pain levels, post-traumatic stress disorder, or other events that could have possibly affected the HPA axis. This created a problem because these are the same events that would have affected the HPA axis in the first place, and the HPA axis was the subject of the investigation.  Depression is thought to be a confounding factor such that in classical depression cortisol levels tend to be increased.  A recent 2010 study showed a significant association of cortisol release with depression and another study showed a relationship between depression in FMS and cortisol levels in FMS patients. Again, the problem was that there did not seem to be a group of patients who had “clean” histories to be part of the studies.

     Another confounding factor is the phase of the menstrual cycle, which has an effect on reported pain, this is going to be discussed more in the future short reports coming up on pain in FMS. Relative to the HPA axis, the HPA response is higher in certain times in the menstrual cycle. Estrogen levels tend to decrease the response of the adrenals to stress. This is an evolutionary adaptation and it came about so that the developing fetus would be protected from surges of stress related responses while it was in the womb.  

     The earliest report on the neuroendocrinology of FMS was published in 1993 in a small sample of 10 female FMS patients. It showed a hyperactive pituitary response – lots of ACTH was being released but the adrenals were being hypo-responsive. These researchers followed up with a later study in 1998 with a larger group of patients that again found evidence of the HPA axis not functioning the way it should. Cortisol levels were slightly decreased. The pituitary was evidently trying to compensate by secreting lots of ACTH but the adrenals could not produce enough cortisol. Since then, both situations have been seen in FMS patients – hyper- and hypoactive HPA responses. It couldn’t get more confusing.  

     The state of affairs led one of the more prominent researchers in the field in 2004 to conclude, “There is currently no consensus as to the overall state of HPA axis activity in FMS.” Funny things happening in the HPA axis are not unique to FMS patients. For example, chronically stressed individuals have been shown to be at a higher risk for having pain after back surgery because their reduced secretion of cortisol is not able to keep the inflammatory parts of their immune system under control and it kept making irritating compounds called cytokines, which stimulated pain nerves.

     What seems to be the current state of affairs for FMS patients? You’ll have to read the second part of this series to find out, which will also give you some insights as to effects that early childhood abuse may have had on the system.

What are the causes of Fibromyalgia?

(Content coming soon!)