Thyroid Function in Neurosomatic Disorders: Stimulation of Trigeminal Nerve Activity with Thyrotropin Releasing Hormone 
By Jay A. Goldstein, M.D.

I use thyrotropin releasing hormone (TRH) nasal spray to treat people with what I term neurosomatic disorders. These illnesses include fibromyalgia syndrome, chronic fatigue syndrome, irritable bowel syndrome, premenstrual syndrome, and a host of other disorders that are not handled properly by the brain and, as a result, the way the brain regulates the body is 
inappropriate. TRH has a number of properties that would make it difficult to treat disorders such as fibromyalgia syndrome. I have been using it for several years intravenously, injecting 500 units with moderate success. At this dose, it primarily affects mood disorders and alertness but can affect all symptoms. There are usually some transient signs of arousal of the autonomic nervous system as manifested by nausea, change in blood pressure, and an urge to urinate. The effects of intravenous TRH usually last a week or two when the medication is effective.TRH enhances norepinephrine, dopamine, and serotonin secretion. Norepinephrine is a major brain neurotransmitter that increases signal-to-noise ratio, i.e., the ability to filter out relevant from irrelevant stimuli. Many patients with neurosomatic disorders are highly distractible and function poorly in environments of stimulus overload such as malls. Their performance also deteriorates in neuropsychological testing 
situations when the amount of information presented is increased even if the information is in the form of helpful cues. Dopamine also increases signal-to-noise ratio, but even more than norepinephrine, it is implicated in reward. Dopamine, acting at the level of the nucleus accumbens, a structure in the basal ganglia of the brain, makes people feel considerably better in general and increases their activity and sensations of pleasure and motivation. The interaction of dopamine with other neurotransmitters in nucleus accumbens is too complex to discuss here. Serotonin, which stabilizes information flow in neural networks in the brain, thus constraining behavioral, affective, and cognitive output, has been found to be decreased in fibromyalgia syndrome in cerebrospinal fluid, as have norepinephrine and dopamine metabolites. TRH has nerve endings on structures in the brain stem called the dorsal raphe nuclei which secrete serotonin. TRH is a string of three amino acids. When amino acids are strung together they are called peptides. When peptides act in the nervous system, they are called neuropeptides. TRH is a neuropeptide in addition to its role in stimulating the release of thyroid-stimulating hormone, which I shall discuss shortly.

A physician can buy TRH in 500 unit ampules of 1 ml. Five hundred units is the usual amount that is administered during a TRH stimulation test, which is performed to measure the amount of TSH the pituitary gland will secrete in response to TRH. The neurons that secrete TRH are in the hypothalamus, right above the pituitary gland in the paraventricular nucleus, 
which also contains other regulatory peptides such as corticotropin-releasing hormone and gonadetropin releasing hormone.We make a dilution of 500 units or 1 ml of TRH in 9 ml of normal saline and put it in a nasal spray bottle. Each spray delivers approximately 3 units of TRH, an amount that one would not think would have a physiologic effect if injected intravenously. However, there must be receptors for TRH somewhere in the nasopharynx or in adjacent ganglia such as the spenopalatine ganglion because patients who respond to one spray of TRH solution in each nostril report that they feel much more alert and much more energized in less than one minute. Gordon Baker, M.D., in Seattle, uses TRH nasal spray to treat multiple chemical sensitivity ("Does it help anything else?" he asked).

I have written extensively about stimulating two of the three branches of the trigeminal nerve, 
which conveys sensory input from the face, with pharmacologic agents. This mode of administration has an effect on brain function because the tract of the trigeminal nerve in the brain stem is an important integrator of sensory information. The solitary tract of the vagus nerve performs a similar function, but is much more difficult to access for external modulation. (Clark KB, Naritoku DK, Smith DC, Browning RA, Jensen RA, 1999) It can only be stimulated electrically with various wave forms intensities and rates. The trigeminal nerve synapses with almost all of the relevant nuclei that would be involved in having a desirable physiologic response in fibromyalgia syndrome. These include the locus ceruleus, the periaqueductal gray, the parabrachial nucleus, the dorsal raphe nucleus, and the ventral tegmental area, which secretes dopamine to the nucleus accumbens. Other important modulatory structures are involved, but I do not want to make this discussion too technical. Since trigeminal nerve function can be altered pharmacologically, electrically, and mechanically, this route allows the use of a wide range of modalities to tune brain function.
One bottle of TRH nasal spray lasts for about 45 days, and patients usually give themselves one spray in each nostril three times a day. There has not yet been a side effect in my experience, except for occasional mild allergy. I have also been using TRH ophthalmic solution, again in a 1:10 dilution with artificial tears. This product works quite well also but perhaps not quite as well as TRH nasal spray. Some patients use both of them. The eyedrops act instantly when they areeffective. There appear to be TRH and NMDA receptors on the cornea as has been demonstrated for substance P (Nakamura M, Ofuji K, Chikama T, Nishida T, 1997). I have had very good success using ketamine eyedrops in varying dilutions from 1:100 down to 1:5. Some of the responses have been quite remarkable. I also make ketamine nasal spray 1:25 and 1:10 and monitor its use because of a slight potential for abuse. Ketamine is an antagonist of glutamate acting at the N-methyl-d-aspartate (NMDA) receptor. NMDA receptor antagonism is probably the most important pharmacologic aspect of treating neurosomatic disorders, and may be accomplished by many different routes with a host of agents. NMDA antagonism in the trigenital system is possible, and should benefit the 
neurosomatic patient (Parada DA, Luccarini P, Woda A, 1997). TRH nasal spray seems to be safe and effective and has the potential in certain patients to ameliorate all symptoms very rapidly. However, as I mentioned previously, it is less apt to help pain than other symptoms. Ketamine in PLO gel transdermally as well as in nasal spray and topical ophthalmic form, are better analgesics than TRH and sometimes are effective when IV ketamine is not.

In general, I do not think that dysfunction of the thyroid or the hypothalamic pituitary thyroid axis plays very much of a role in fibromyalgia syndrome. However, it has been found that many patients with fibromyalgia syndrome have autoimmune thyroiditis, as determined by detectable antimicrosomal thyroid antibodies. In one study (Aarflot T, Bruusgaard D, 1996) 16% of patients with widespread musculoskeletal complaints had detectable thyroid anti-microsomal antibodies. Some patients with fibromylagia syndrome and thyroid autoantibodies have lab tests indicating
borderline hypothyroidism, determined by a high normal thyroid stimulating hormone level, as well as a low normal level of free thyroxine index, a measure of T4, one of the two types of thyroid hormone. Such individuals should probably receive a therapeutic trial of thyroid hormone in the range of 75 to 88 micrograms a day. Thyroid hormone is made by the thyroid gland in two forms, T4, and tyrosine molecule that has four iodides attached to it, and T3, a tyrosine molecule that has three iodides attached to it. The active form of thyroid hormone is T3. In peripheral tissues, T4 has an iodide molecule removed to convert it to T3 so that it can be metabolically active. However, if one wishes to increase thyroid hormone levels in the brain, administering T3 or Cytomel is not a good idea because the mitochondria, the energy producing organelles in the neurons of the brain, are unable to use T3. Instead, they take up T4 and deiodinate the T4 to T3. T3 decreases intraneural thyroid function and suppresses TRH levels in the brain. It thus may be a useful agent to augment antidepressants, but only for those patients who are subclinically hyperthyroid. Most neurosomatic patients are not, but many patients with major depression are (Joffe RT, 1998). Interestingly, several antidepressants, such as desipiramine and fluoxetine, as well as lithium and carbamazepine, enhance the activity of the enzyme that removes the iodine from T4 to increase the tissue concentration of T3. This information is relevant when using thyroid hormone to enhance the effects of antidepressants when treating depression, but it has little value when discussing fibromyalgia syndrome. Antidepressants have little role in this disorder except for cyclic antidepressants, which have an inherent analgesic and sedative effect. Lithium and carbamazepine (Tegretol) have no role at all.  Certainly, thyroid hormones are important. They influence cell respiration and total energy expenditure and the turnover of all metabolically active substances. The mode of action of thyroid hormone intracellularly is too complex to discuss in this space. In clinical 
practice, if a person does not have Hashimoto's thyroiditis and lab tests do not indicate hypothyroidism ( a low T4 and a high TSH), there would be no reason to give thyroid hormone to patients with fibromyalgia. 

The symptoms of hypothyroidism are learned by every physician in medical school. Common signs include an enlarged thyroid, cold intolerance, lethargy, fatigue, weight gain, hair loss (particularly in the lateral third of the eyebrows), coarse dry hair, brittle nails, dry scaly skin, low heart rate, high blood pressure, constipation, menstrual irregularities, elevated cholesterol, depression, poor concentration, decreased speech, difficulty thinking, and a family history of possible autoimmune thyroid disease. This history may include other types of autoimmune diseases as well, such as type 1 diabetes, premature graying, pernicious anemia, vitiligo, and rheumatoid arthritis. Measuring TSH and T4 with a free thyroxine index should be part of every work-up of a person with a neurosomatic disorder since many of the symptoms of hypothyroidism can mimic those of neurosomatic disorders. Even when hypo-thyroidism is corrected, however, it is very common for neurosomatic symptoms to persist. There should be a high index of suspicion for a thyroid disorder in the patient population with fibromyalgia because of the significant incidence of autoimmune thyroiditis.

The preferred treatment for hypothyroidism today is thyroid replacement in the form of L-thyroxine. The brand name that is best known is Synthroid.  It is not recommended to administer natural preparations like Armour thyroid, which might contain too much T3. Such agents might overstimulate noradrenergic function in a susceptible individual, causing numerous symptoms, including a rapid heart rate. In an elderly person or a person with heart disease, cardiac function could be compromised because of a sudden increase in metabolic rate. Dose titration of thyroid hormone should be gradual. One should begin with 25 mcg of L-thyroxine, which may be increased by 25 to 50 mcg increments at four-week intervals until a normal metabolic state is obtained. There have been some articles in the literature about making treatment-resistant patients with depression or rapid cycling bipolar patients, but some physicians find the benefit to be transient. All patients with neurosomatic disorders who I have rendered iatrogenically hyperthyroid have not felt any better. They had no adverse reactions, which would conclude with the reports from the literature about the safety of this approach. However, it should be done slowly.Patients with fibromyalgia syndrome have a blunted TRH test. When a fibromyalgia patient receives 400 or 500 units of TRH, he/she responds with a lower secretion of TSH and thyroid hormone than expected and also a higher increase of prolactin, another hormone that is regulated by TRH. This abnormality is also seen sometimes in depression. The meaning of this finding is somewhat unclear, although it may imply a down regulation of receptors for TRH in the area of the anterior pituitary gland where TSH is secreted. In contrast, the TSH receptors in the neuronal bodies that secrete prolactin might be upregulated. The primary inhibitory factor for prolactin is dopamine, which is decreased in the brain of patients with neurosomatic disorders, although not necessarily in the region that regulates prolactin secretion (the tubero-infundibular region). Abnormal TRH test are difficult to explain in general in the absence of hypo- or hyperthyroidism.

Two other neuropeptides, neurotensin and somatostatin, may inhibit TSH secretion and may be possible factors in the blunted TRH responses that are seen in neurosomatic patients. There may also be enhanced endogenous TRH secretion causing down regulation of TRH receptors.
As far as I know, none of these explanations is sufficient to explain the blunted TRH response. I would prefer the simple reason that there is not enough TRH secreted. The secretion of TRH is mediated not just by dopamine but also by norepinephrine, and both neurotransmitters are low in neurosomatic patients. A certain strain of rat, the Wistar Kyoto rat, has been bred for anxiety and depression. These rats have low levels of TRH precursors. TRH has antidepressant properties in rats and humans. Somatostatin levels are not reduced in my neurosomatic patients because their symptoms are not improved by somatostatin injections. Spinal fluid levels of somatostatin and neurotensin have not been measured in neurosomatic patients to my knowledge.

As you can see by this article, which I have tried to keep as simple as I possibly could, the issue of thyroid dysfunction, particularly low thyroid function, or hypothyroidism, in patients with neurosomatic disorders can become extremely complicated. Practically, though, I only treat patients who are demonstrably hypothyroid by low T4 and high TSH measurements or those that have autoimmune (Hashimoto's thyroiditis with borderline T4 and TSH levels. )

I find antidepressants in general to be of little value in treating the entire symptom complex of neurosomatic disorders, although they treat depression well. Serotonin reuptake inhibitors may actually decrease the intensity of a peripheral painful stimulus (Dirksen R, Van Luijtelaar ELJM, Van Rihn CM, 1998). Thyroid augmentation of antidepressants in the neurosomatic patient has not proven to be beneficial even when raised to hyperthyroid levels, at least in my practice.

Aarflot T, Bruusgaard D, 1996, Association between chronic widespread musculoskeletal complaints in thyroid autoimmunity, results from a community survey. Scan J Prim Health Care 14(2) 111-115.

Bauer M. (1997), High dose thyroxine in prophylaxis resistant affective disorder. Biol Psychiatry 42:1S-2975.

Clark KB, Nartiku DK, Smith DC, Browning RA (1999), Enhanced recognition memory following vagus nerve stimulation in human subjects. Nature Neuroscience 2(1): 79-87.

Dirksen R, Van Luijtelaar ELJM, Van Rijn CM (1998). Selective serotonin re-uptake inhibitors may enhance responses to noxious stimulation. Pharmacol-ogy Biochemistry and Behavior 60(3): 719-725.

Joffe RT (1998). The use of thyroid supplements to augment antidepressant medication. J Clin Psychiatry 59[suppl 5]: 26-29.

Nakamura M, Ofuji K, Chikama T, Nishida T (1997). The NK1 receptor and its participation in the synergistic enhancement of corneal epithelial migration by substance P and insulin-like growth factor-1. Br J Pharmacol 1997 Feb;120(4)547-52.

Parada CA, Luccarini P, Woda A (1997). Effect of an NMDA receptor antagonist on the wind-up of neurons in the trigeminal oralis subnucleus. Brain Research 761:313-320.

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