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.