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.