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Article Excerpt
Medical Perspective
FM and CFS are different diseases but closely related. Patients with these diseases have in common a decrease in corticotrophin releasing hormone (CRH) which controls cortisol output from the adrenals. (1-4) Both groups of patients have shown a decrease in levels of arginine vasopressin (AVP), a hormone that controls the ability of the body to release fluid. (1,2,5) With a lack of this hormone the patients would feel increasingly thirsty and have frequent urination--about every 20-30 minutes. Both of these hormones are produced in an area of the brain called the supraoptic nucleus. Another hormone of importance, called oxytocin (OT), is produced by the same nerve cells. The same neurons that make OT also have the capacity of making CRH and AVP. (6) As of September 2007, no one in the medical literature has described an OT deficiency. An attempt to define an OT deficiency will be done here. The vast majority of the medical literature has been written about the medical problems of FM. Hence the bulk of references referred to in this paper pertain to FM.
Oxytocin
OT is a hormone produced in many parts of the body. In the brain, it is produced and released on a daily rhythm with its peak in the human brain occurring at around noon. (7,8) OT is also produced in the posterior retina, in the pineal gland, thymus, pancreas, testicle, ovary, and adrenal glands. Oxytocin's known functions will be discussed later.
Microcirculation: OT is known to be one of the controlling factors of the microcirculation of the human body and brain. (9-12) A decrease in OT can cause problems with decreased circulation in the extremities. Therefore, patients often complain of cold hands and feet, along with history of recurrent headaches. Oxytocins ability to vasodilate the blood vessels is due to its capacity to stimulate the body's cells to produce nitric oxide, a powerful vasodilator of the microcirculation. (9-11) If vasodilation, such as blushing, does not occur when OT is given intramuscularly to a patient, then a serious defect in nitric oxide production is present. This defect of poor circulation is often present among patients with FM patients. (13-15)
Lactation and Libido: OT is released as a mother nurses her baby. (16) Stimulation of the hormone release causes the mother to have an instinct to want to cuddle. As she nurses the child, her desire to cuddle intensifies. This same feeling can be experienced during intimacy--OT has the ability to increase libido. (17,18) Therefore, patients lacking this hormone may often notice that they do not wish to cuddle, to be held, or to be intimate. It has been noticed that stress can restrain the production of OT. (19-25)
Mental Function: OT seems to stimulate the ability of the brain to concentrate, contributes to mental alertness and improves memory. (26) Patients lacking this hormone may find difficulty in concentrating, and feel like they are thinking in a fog. This has been noted in FM. (27-29)
Pain: OT can occupy multiple hormonal receptor sites in the body. My theory is that an empty receptor for OT can potentially cause pain. Administering OT causes the empty OT receptor sites to become full, thereby diminishing or completely obliterating pain. Animal studies reveal that because of this particular characteristic, OT has been an effective tool in weaning addicted animals from narcotics, suggesting that OT has the ability to occupy not only its own receptor sites, but opiate (narcotic) receptor sites as well. (30-36) Oxytocin has been given to humans to kill cancer pain, low back pain, and bowel pain from irritable bowel syndrome. (37-39)
Vision: OT is produced in the posterior retina of the eye. (40) A decrease in OT level can cause problems with intermittent blurring of vision. When OT is given, it can sharpen the vision (clinical observation). In a patient with a reduced level of OT, one can expect complaints of pain in the posterior eye, sometimes so severe that only narcotics provide effective pain relief. Visual disturbances in FM have been observed. (41,42)
Sleep: OT is made in the pineal gland of the brain, as is melatonin, a hormone which enhances sleep. (40,43) In animal studies, as the level of OT goes up in the brain, a deep sleep is induced. (43) (Insomnia is a sleep disorder frequently seen in patients with FM/CFIDS, and could indicate a deficiency in melatonin). It should be noted that recent research indicates that melatonin has the ability to activate the immune system, so the use of this product is usually contraindicated in the presence of autoimmune disease such as lupus, rheumatoid arthritis. (44)
[FIGURE 1 OMITTED]
Ovary: The ovaries make OT (45,46) where it helps in the fine-tuning of progesterone release. (45) When patients lack OT, they may frequently complain of ovarian pain, even though pathology does not support the presence of either cysts or tumors. Ovulation function may be impaired with menstrual irregularity. (41)
Adrenals: OT is synthesized in the adrenal glands where it can stimulate or inhibit steroid production. (21,47-50) Patients with a decreased OT level often complain of flank pain underneath the posterior ribs. Malfunction in the adrenal steroid production has been seen in FM. (51,52)
Thymus: OT is created by the thymus gland (53,54) which utilizes OT to help process white blood cells that help control autoimmunity. Normal levels of OT also help stimulate these cells into greater action. (53-59) For example, it is a known fact that women who nurse their children have a greatly reduced incidence of breast cancer. This hormone may be protective in its ability to prevent breast cancer, through its influences on the immune system. (60)
Pancreas and Bowel Function: OT is produced by the pancreas (61) where it is known to stimulate the production of glucagon, a hormone which helps the intestines to relax. (62,63) Therefore, in treating a patient with decreased levels of this hormone, one would expect to see problems with increased intestinal spasms, secondary to a lack of glucagon production from the pancreas.
Anxiety and Depression: OT can function as an antianxiety agent in the brain. It can also stimulate social behavior. (64) A lack of this hormone may be expressed as antisocial behavior with some anxiety. OT can also function as an antidepressant. (65) In low levels of OT, one would expect to see depression, which has been noticed in FM/CFIDS. (28,66)
Blood Pressure Control: OT can serve as a regulator of cardiovascular function and autonomic nervous system function. (67,68) This explains why patients lacking this hormone have trouble controlling their blood pressure when going from a sitting to upright position, or when standing for a long period of time. This is known as neurally mediated hypotension. They often complain of near syncope (light-headedness) and possible dizziness. (41) OT is found in those sections of the brain where the baroreceptors of the body are controlled. (68) A drop in OT levels in the brain, leads to manifestation of baroreceptor malfunction. Restoration of OT through an oral tablet (Belmar Pharmacy) corrects the symptoms of neurally mediated hypotension (clinical observation).
Body Fluid Control: OT has the capacity to induce the body to mildly retain fluid. This is in part due to its physical and biological similarity to arginine vasopressin. (11,69,70) AVP is a hormone that controls fluid metabolism, pain, and memory. (1,2,5,39,71-73) With a lack of OT, patients have increased thirst. They also have increased urinary output due to decreased ability to retain fluid. (41)
As can be seen, the actions and normal functions which have been associated with the use of OT are broad and varied. The following diagram (Chart 1) helps to illustrate and contrast the known functions of OT and other symptoms of FM, which are not commonly known in the regular medical literature.
Nitric Oxide
As research in FM continues, there is increasing evidence showing disruption of blood microcirculation in patients. This disruption of circulation has been seen in the brain and in the skin. (82-84) A major controller of circulation in the body is a gas called nitric oxide(NO). (85)
When NO is deficient, there is a down regulation of the cardiovascular system. (85) Two research papers have been recently written documenting low levels of nitric oxide in patients with FM. (86,87) Nitric oxide is known to be produced in a 1:1 ratio with citrulline. (85) In FM, citrulline has been found low P=.028. (88) In FM, L-arginine is low normal P=.06. (89) Both L-arginine and citrulline point indirectly to the fact that nitric oxide may be a key factor in understanding FM.
[FIGURE 2 OMITTED]
NO helps to increase dopamine production, increase serotonin production, and decrease pain. (90-96) It also works as an anti-anxiety agent and improves sleep. (97,98) In FM there has been documented decreased serotonin, increased pain, increased anxiety, and decreased restful sleep. (99-106) Low levels of serotonin or dopamine have been associated with depression.
One of the main precursors for making NO is the amino acid L-arginine. (85) As mentioned before, this amino acid has been found at lower than normal levels in FM. L-arginine under the influence of an enzyme called nitric oxide synthase (NOS), can make NO. (85) NOS is also a dioxygensase. This implies that the enzyme is oxygen dependent for NO to be produced. (107) Oxytocin controls microcirculation via NO. (9-12) In the brain, oxytocin can be stimulated by NADPH-diaphorase, the identical enzyme as nitric oxide synthase, except found in certain neurons. This enzyme helps to convert arginine into nitric oxide. AVP is not stimulated by this enzyme. NADPH-diaphorase can be stimulated by nitroglycerin. (108)
Some factors are known to stimulate NOS. They are as follows:
* Exercise -- Known to stimulate the enzyme, (107) exercise also helps FM patients to improve overall. (109)
* Immune System Stimulation of NOS -- The inflammatory cytokines of the immune system are also known to stimulate production of NOS. (85) Theoretically, they can stimulate chronic activation of NOS by chronic infections, such as TB, gonorrhea, syphilis, etc. Inflammatory cytokines can also be activated by silicon such as seen in silicone breast implants or silicon implants in other locations in the body. (110-113) Inflammatory cytokines can also be elevated in the presence of autoimmune disease such as rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, etc. Theoretically, chronic activation of inflammatory cytokines can lead to substrate depletion and hence a breakdown of the system to produce NO.
* Decreased Production of NOS -- Down regulating NOS can be accomplished by the use of glucocorticoids, such as cortisol. (114) This can also occur with interleukin 10 and TGF Beta, which are non-inflammatory cytokines of the immune system. (114)
* Other Factors in NO Production -- The biochemical reaction from L-arginine to NO is calcium dependent. (115) It is also dependent upon an energy molecule named NADPH, which is made in mitochondria by an enzyme known as malate dehydrogenase. (116) Malate dehydrogenase is stimulated by DHEA and thyroid free T3. These hormones stimulate the DNA of mitochondria to produce this enzyme in cells. (116) Studies have been done to show that supplemental use of malic acid can help to decrease the pain in FM. (117)
* Other External Forces -- Other external forces which are known to stimulate NO production include exercise, hyperemia, shear stress, and pulsatile flow. Hypoxia has also been shown to stimulate NO production. (85,107,118) Moist heat, in the sense of a hot bath or hot moist fomentations, helps to decrease FM pain that patients experience. Massage of body tissues in turn behaves as a shearing stress to help decrease FM pain. (119)
L-arginine, as a substrate for making NO can become depleted by different mechanisms. Some of the conditions whereby this can happen are as follows:
* Some FM patients are known to have problems with recurrent herpes virus infections. The amino acid L-arginine is very crucial in the making of herpes viruses. This would make it difficult theoretically to place a patient on L-arginine supplementation therapy.
* One of the major hormones that helps to control fluid metabolism in the body is arginine vasopressin. This hormone is dependent on arginine for its existence. Studies have shown this hormone to be low in FM patients. (1,2,5) This particular hormone not only helps to maintain body fluid balance, but it also helps in the formation of memory. Hence one would expect to see problems with patients having frequent urination, increased thirst, and memory problems. (120)
[FIGURE 3 OMITTED]
Nutrition and Nitric Oxide: Nuts are known to be high in L-arginine. (121,122) Recent work done in the field of nutrition has shown that high levels of fat in the blood inhibits NO release. This effect of fat is neutralized by vitamin E (800 units per day) and vitamin C (1,000 mg per day). (123) Acetylcholine is a major chemical in the bloodstream that stimulates nitric oxide production. There are chemicals in the food chain that destroy acetylcholine. These chemicals are foods in the nightshade family: white potatoes, green and red peppers, tobacco, eggplant, tomatoes, and paprika. (124) It would be advantageous for all FM patients to avoid these foods for one month. They should then introduce them back into the diet one by one every three days to see if pain worsens. If the pain does become worse, then avoidance of this family of food is mandated. Every researcher in FM knows that the tobacco user is among the most difficult patients to care for. The use of tobacco should always be discouraged in FM.
In some FM patients where their medical problems would make it difficult to give them L-arginine, a way to bypass the need for this amino acid supplementation would be to give them nitroglycerin tablets. Nitroglycerin via the cyclic GMP system can make NO. (85) The cyclic GMP system, however, is dependent upon the presence of sulphur for NO production. (125) Cyclic GMP can also be stimulated into production by growth hormone, insulin-like growth factor-1, and DHEA from the adrenals. (126,127) As mentioned earlier in this paper, NO can also be produced by stimulation with oxytocin. (9-11)
Nitric Oxide Receptor: The control of NO release is receptor dependent. The receptor is stimulated to release NO in the presence of acetylcholine. (128) Acetylcholine, being a primary neuroendocrine chemical used by the central nervous system to communicate with muscles. Through choline supplementation, acetylcholine production can be improved. L-arginine has been shown to improve acetylcholine induced blood vessel relaxation. (123) ATP, which is a major energy component in the body, serves as a stimulant for the cellular receptors of the cardiovascular cells to release NO. (129,130) In FM, ATP production has been documented to be low. (131) Another chemical regulating the control of NO production is bradykinin, which is a chemical produced in the body in the presence of an allergic reaction.
[FIGURE 4 OMITTED]
Independent agonist, or independent stimulators of NO release, can be such things as calcium-ATPase inhibitors, polycations, and calcium ionophores/inositol. (85) The phosphatidylinositol pathway, when activated by OT, can independently stimulate release of NO.
Dehydroepiandrosterone
In treating FM/CFIDS patients, a hormone of importance is dehydroepiandrosterone (DHEA). The adrenal glands produce 30-50 mg of DHEA per day compared to 2-3 mg of cortisol. Hence,...
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