ENDOCRINE CHANGES IN PATIENTS WITH
CHRONIC ILLNESS FOLLOWING CHEMICAL OVEREXPOSURE
Grace Ziem, MD, Dr.PH
INTRODUCTION
There are tens of thousands of chemicals which can have adverse effects on humans. Different chemicals in different amounts cause different health effects. Routes of exposure are also important. Some exposures result from irritating chemical spills on the skin; others involve skin contact with pesticides and other toxic agents which enter the body through the skin. Some are breathed in entering the brain directly through the nose as well as the body. Some occur as single massive exposures. This can include skin, inhalation or other. For example, some can occur through chemotherapy, by definition exposures sufficient to kill living cells, or exposure to anesthetic agents.
Individuals also differ in their response to chemicals. Pre-existing respiratory inflammation interferes with barrier function and allows for heightened respiratory risk for future exposure to respiratory irritants. Individuals differ in their ability to detoxify. Some are on medications which deplete substances required for detoxification. Others may use caffeine which increases the first step in detoxification. This increases free radical production. Caffeine used to counteract the fatigue from repeated toxic exposure and thus may affect further exposure manifestations. There is also significant genetic variation in detoxification ability. This can affect Phase I (the first step of detoxification) either reducing ability to detoxify or accelerating this step and creating excess free radicals. Genetic variation also occurs in various Phase II steps of detoxification in which the partially metabolized chemical or pharmaceutical (often of petrochemical origin) is linked with a body substance to increase water solubility, helping the body to eliminate the substance through the urine. Use of phase II tends to deplete the body of substances used in those specific detoxification pathways. Some genetic variations in detoxification can be tested through what is referred to as genomic testing, which often focuses upon relatively common inherited variations which can be modified to improve the detoxification process.
Some illnesses can be accurately designated as chemically induced. I have described earlier and listed below criteria for doing this, which of course requires a careful exposure and illness history. In other individuals there can be simultaneous exposures. The patient may not necessarily be able to smell the exposures, possibly because of reduced sense of smell (which can be genetic and/or chemically induced) or may not recall the sequence of events leading to their illness. Some exposures have significantly lower odors than others do. Pesticides/herbicides, for example, often have significant toxicity to the brain; nervous system and other organs yet may have very low odor compared to their toxicity. Some of them may have scented products added, which misleads the exposed individual to feel that they are being exposed to an air freshener or scented products, when in fact they are being exposed to a pesticide/herbicide: by definition chemicals designed to kill living things.
Because of all of these differences discussed above, the manifestations of chemically induced and chemically exacerbated illness can differ widely. This has become increasingly clear to me as a physician with 37 years of medical practice who has evaluated and cared for many hundreds of patients with chemically related illness.
A printer with an overexposure and excess body burden to ultraviolet activated ink must have lights off and shades drawn in the office to reduce neurologic manifestations, including but not limited to severe balance disturbance, from sunlight coming in the window. A chemist with intense but brief exposure to hundreds of chemotherapeutic agents, corrosive in their combination, presents with bronchiolitis obliterans (destruction of the small bronchioles leading to the alveoli, also known as lung sacs. He also has reactive airway disease. His brain and neurologic effects, however, are much milder in comparison.
A wall paper cluster of co-workers, who had prolonged skin contact with adhesives containing glycol ethers have bladder spasms, ongoing rashes and other skin changes in areas of most skin contact brain, neurologic and other bodily effects.
Younger children often present with attention deficit disorder and/or hyperactivity after pesticide or other chemical exposure, but may be without fatigue or widespread aching. Ability to think and concentrate may be impaired or may be relatively normal; especially when there is not exacerbation, such as inhalation exposure, dermal chemical use, or the ingestion of certain foods or chemicals. Food intolerance often manifest more promptly/obviously in these patients.
A Round-up herbicide exposed patient with unintentional oral and dermal exposure experiences loss of consciousness and/or seizures with exacerbation. A chlorinated solvent patient may present with disabling migraines as well as other exposure symptoms. Many patients are exposed to respiratory irritants. These often induce sinus inflammation, with increased sinus headache and increased risk of sinus secondary infection. Other individuals and/or chemical groups can induce predominantly lower airway effects, presenting in an asthma-like fashion.
Some individuals and some chemical classes cause significant disturbances of porphyrin metabolism and exacerbations can be accompanied by porphyrin-related symptoms such as specific color changes in urine, irritability with food deprivation which is not relieved for well over an hour after eating (until the patient can excrete the free radical-inducing porphyrin).
Some patients experience neurogenic vasculitis. This may affect the coronary arteries: a young, previously athletic non-smoking chlorinated solvent patient develops angina with need for nitroglycerin with reduced coronary flow but without arteriosclerosis on angiography. Some neurogenic vasculitis presents as hypertension which can be documented using a log and concurrent blood pressure measurements to be primarily elevated during exposure. Given the common use of pesticides, germicides, carbonless paper and other chemicals in medical care facilities, these patients may be diagnosed as having hypertension of unknown origin unless the patient maintains a log to measure blood pressure in situations not involving exposure.
A group of workers chronically overexposed to sodium hypochlorite develops toxic encephalopathy, reactive airway disease and neurogenic vasculitis with 3 of 14 young non-smokers developing stroke-like events, 2 myocardial infarction (heart attacks) and others with stroke-like and/or angina symptoms with exacerbation.
Thus the effects of chemicals upon an individual patient differ widely, and precise diagnostic labels differ accordingly. No single diagnostic label can accurately convey to the patient, their friends and associates or their treating health-care providers the nature of their illness, because of differences as described by the above examples. These are merely examples and do not include all of the effects of chemical exposure nor all of the exacerbation effects of subsequent low-level exposure.
Illness exacerbation by low level chemical exposure has been documented for over a century, using different terms. In the late 1980s, Dr. Mark Cullen of Yale introduced a set of criteria which described symptoms induced following a chemical overexposure involving exacerbation by subsequent low-level exposure. The name “Multiple Chemical Sensitivity” was given by Dr. Cullen to this phenomenon. As is true for many academic-based physicians, patients seen by Dr. Cullen are commonly given an “evaluation” by residents in training, who may or may not know what questions to ask about exposure, health effects, cognitive and other exacerbations nor what physical examination procedures to perform. The resident describes a summary to Dr. Cullen of a patient who, following a chemical exposure had various symptoms persisting/recurring with various low-level exposures. It was this common summary that Dr. Cullen focused upon in his use of the term multiple chemical sensitivity.
However, as seen by the above descriptions of my patients, who typically have an initial evaluation by me for several hours, major differences occur in type and route of exposure, type of chemical, physical examination findings, clinical presentation, symptoms during exacerbation, and accompanying forms of toxic injury on testing.
Many of my patients with toxic injury have toxic encephalopathy. Diagnostic methods to evaluate this have been characterized extensively by Dr. Kilburn in his useful text entitled Chemical Brain Injury. These patients often have balance disturbance, impairment on other neurophysiologic tests and/or neurocognitive abnormalities. Common accompanying symptoms include but are not limited to difficulty thinking and concentrating, impairment in short-term memory, impaired ability to do complex tasks, even as simple as following a cooking recipe, disturbed balance, seizures, etc. These effects of toxic encephalopathy have been documented to involve reduced blood flow to the brain, a high oxygen-demanding organ. Reduced blood flow may help protect the brain from further chemical exposures, at the cost of reducing function of the high oxygen-demanding brain cell. These effects are toxic encephalopathy; a long recognized condition with an extensive body of literature. Toxic brain injury can be exacerbated by future low-level exposure. However, with increasing understanding of the testing for, clinical presentation of, epidemiologic research about, and disturbed biochemistry of toxic brain injury, with this growing scientific understanding, it is no longer accurate to merely label the toxic encephalopathy effects as “multiple chemical sensitivity”.
Both petrochemical substances as well as numerous non petroleum-derived chemicals are irritants to the respiratory tract. With single high dose or repeated lower dose inhalation, depending upon the individual and the physical and chemical properties of the exposure or chemical mixture, chronic inflammation can be induced in either or both the upper airway (nose, sinus, throat, larynx) and/or the lower airway (bronchi, bronchioles). With our increasing understanding of the pathophysiology and biochemistry of this inflammation, it is increasingly clear that these are different sites of reactive airway disease, a condition long recognized in the medical literature. It is more recently better understood by pathophysiology and biochemistry, with further scientific understanding continuing to develop. These diverse forms of neurogenic respiratory inflammation of neurogenic rhinitis, sinusitis, pharyngitis, laryngitis, “bronchitis”, “asthma” are not precisely described to family, friends, associates or health-care providers as being “multiple chemical sensitivity”. In addition, evaluation and treatment is not identical for all these locations and conditions. Scientific references for the above have been listed earlier.
As in all areas of medicine, the scientific understanding of chemically related illness continues to advance. A few decades ago terms such as “multiple chemical sensitivity” was an early attempt to summarize one feature but is ambiguous and does not describe patient differences.
It is important in medicine to communicate using the most precise designation possible regarding the particular illness, injury or disease manifestation. Given the many diverse examples above, and our ever evolving understanding of toxic encephalopathy, reactive airway disease, neurogenic inflammation, neural sensitization, and other biochemical aspects of toxic injury, it is not precise or accurate to lump together all of these conditions under a single term such as “multiple chemical sensitivity”. “Environmental illness” is an even more misleading term, particularly since the natural environment is hardly the problem. No single diagnosis describes all the features of toxic illness in all patients. It fails to communicate the problem of a specific individual and the diversity of the types of chemical damage that can affect populations of individuals. It also fails to communicate that evaluation; testing and treatment approaches differ.
It is time for us, who are increasingly aware of this diversity and complexity, to adapt our terminology so that we can accurately and precisely convey both for individuals and for groups the variations which occur with toxic-related illness. To illustrate: stroke, angina, diabetes and some other conditions all involve blood vessel disease. However, they obviously manifest in different ways. They require different treatments. One would not treat a stroke with insulin, nor would one treat a diabetic with nitroglycerin. Furthermore, physicians would not merely lump together these conditions as “blood vessel disease”, without using more diagnostic precision. Given our current continually advancing understanding of chemical illness, it is now not precise to lump together all conditions caused by and exacerbated by chemical exposure with one term.
An individual who has hit their thumb with a hammer will experience tenderness with lighter degrees of touching. An individual with a significant burn will experience reduced ability to tolerate irritants. An individual with injury or surgically induced scar formation can experience reduced function, tissue mobility, altered tissue appearance and biochemistry in the scarred area. An individual on multiple pharmaceutical agents will experience increased risk of side effects with the addition of further pharmaceuticals. Thus it should not surprise us that individuals with various forms of chemical damage often are at increased vulnerability to exposures and other conditions which did not affect them prior to their injury. This quality alone, however, does not mean that we would group together a hammered thumb, burned skin, scarred tissue and significantly medicated patients with a single term, simply because they are all at increased risk of exacerbation. Of course after injury, there is often increased vulnerability to further injury. This is a common phenomenon in medicine.
When understanding regarding chemical exacerbation was at a less-developed stage, it is understandable that affected individuals and health-care providers used labels which described this common feature. However, science marches on, and our terms, descriptions and diagnostic categories must accurately convey our current clinical and scientific understanding of the diversity of chemical injury with more precision about each affected individual. It is therefore scientifically appropriate to move away from “one term catches all” to specific and precise communication about toxic injury.
PATIENT SELECTION CRITERIA
Patients selected for this endocrine evaluation were selected according to the following criteria:
1) They were new to the medical practice of Dr. Ziem at the time of the evaluation.
2) They were healthy prior to an identifiable chemical overexposure, with exposure history taken according to accepted principles of occupational and environmental medicine.,
3) Symptoms developed with exposure and improved away from exposure on repeated occasions.
4) Symptoms developed within hours of the causal exposure (not necessarily the first day or the first week of exposure.)
5) Symptoms were consistent with the toxic and pathophysiologic properties of the chemical(s).
6) Chronic symptoms were present at the time of evaluation and the initial non-endocrine history and examination confirmed chronic involvement of two or more organ systems.
7) Only adults were included.
8) None of these patients were included in the data presented by the author in 2001.1
The issue of whether or not these patients had chemical intolerance was not a criteria for inclusion. Illness manifestations varied widely. Toxic encephalopathy of varying degrees of severity was a very common finding on evaluation. Reactive upper and/or lower airway disease was also common. These conditions have been discussed in detail in an earlier paper.1
MELATONIN
Melatonin was evaluated using salivary measurements because most of the melatonin in plasma is protein bound and thus much less active. Protein deficiency is also common in chemically injured patients,1, which may affect the validity of plasma hormone measurements.
Baseline and post-challenge melatonin samples were collected using saliva, which evaluates only the free, active (non-protein bound) hormone. Four baseline samples were collected: between 2-3 a.m., 7-9 a.m., in the afternoon between 2 and 4 p.m., and at bedtime. On a separate day after baseline samples were collected, a 3 mg melatonin challenge capsule was given on an empty stomach 20-30 minutes before the evening meal. The patient was then asked to remain in bright light (to avoid inducing melatonin production by the body) until the post challenge saliva sample was collected 2 hours later to measure melatonin. On a separate day after the baseline and challenge melatonin test was collected, the patient took a 100 mg 5-hydroxytryptophan (5-OHT) capsule challenge on an empty stomach 20-30 minutes before the evening meal. The patient was then asked to remain in dim lighting (TV okay) to avoid interfering with the body's effort to convert 5 hydroxytryptophan into melatonin. Dim lighting was used until the patient collected a post 5-OHT saliva sample 2-3 hours later to again measure melatonin. This tested the ability of the patient to convert 5-OHT into melatonin under ideal conditions (dim lighting in the evening).
This melatonin testing was only available for part of the time of the endocrine evaluation and so was only administered to 11 patients, but without any known selection bias for patients who met the above patient selection criteria. Two patients had insufficient saliva for valid results. The results on the remaining 9 patients (Table I), however, are very significant.
The patients were requested to avoid food, beverages, brushing or flossing for one hour before sample collect, avoid any sublingual hormones the day of testing, and avoid foods such as onions, garlic, cabbage, broccoli, cauliflower on day of collection. These foods are sulfur containing and/or glucuronide-stimulating. Melatonin is conjugated with sulfate, and to a lesser extent glucuronide for elimination.5
Normal ranges in Table I are in the top column in parenthesis. All patients had reduced bedtime melatonin, and the majority of patients had reduced melatonin during the night as well. Giving 3 mg of melatonin under the ideal conditions described above brought the vast majority into physiologic range and over half above physiologic range, despite low baseline levels.
The single patient whose melatonin did not reach normal levels after 3 mg melatonin challenge was the patient who had the lowest baseline levels. This suggests that 3 mg sustained release melatonin is ample for patients with test-confirmed melatonin deficiency and often even in those patients 3 mg of melatonin brings them to above physiologic levels.
Another very significant finding is that the majority of patients could not convert 5- hydroxytryptophan (5-OHT) into melatonin even under ideal conditions (6 of 8 patients) and the remaining two patients had low melatonin after 100 mg of 5-OHT. This strongly suggests that tryptophan or 5-OHT supplements in toxic injury patients are not likely to be effective for treating low melatonin. Virtually all had adequate daytime baseline melatonin levels in both the morning and afternoon.
Low melatonin is very significant. Melatonin is a potent hydroxyl free radical scavenger in every cell of the body., Melatonin is produced in the pineal gland cells (pinealocytes).5 Within these cells, tryptophan is taken up from the blood and converted to 5 hydroxytryptophan, then to serotonin (5-hydroxytryptamine) which in darkness is converted to melatonin.5,, Once melatonin is formed in the pineal cell, it is rapidly released into the blood.5
Thus the findings of low baseline melatonin at night and failure to convert orally administered 5- hydroxytryptophan indicate failure of the pineal cells in chemically injured patients to function normally. The entire biochemical sequence from tryptophan conversion to melatonin synthesis occurs within the pineal cell.5
Impaired energy metabolism4 and reduced co-factors needed for energy metabolism1,4 has been found in the vast majority of tested chronically ill toxic injury patients. Energy metabolism is required for the production of cyclic amp, which is needed for all biochemical processes and critical in the pineal cell's conversion of serotonin to the next intermediate (N-acetylserotonin), which in darkness the pineal cells rapidly convert to melatonin. Thus impaired energy metabolism could be an important factor in low melatonin in toxic injury.
Impaired detoxification1,4 with increased free radicals4 and reduced antioxidant function4 have been found in chronically ill chemically injured patients. Given the role of melatonin as a potent free hydroxyl radical scavenger, antioxidant and detoxification ability may affect baseline melatonin levels. Melatonin is metabolized, and is thus no longer melatonin, when it scavenges free radicals.
The pineal gland receives innervation by sympathetic nerve cells (axons), nerve cells coming from the brain, and from the hypothalamus. Given disturbed adrenal function in chemically induced illness,1,4 the hypothalmus may be affected by chronic toxic illness (via the hypothalamic-pituitary-adrenal axis). As discussed below, failure to ovulate and subsequent estrogen dominance suggest changes in the hypothalamic-pituitary-ovarian axis.
Deficiency of co-factors necessary for conversion of tryptophan to melatonin within the pineal cell could also have a significant effect. 5-hydroxytryptophan requires Vitamin B6 (pyridoxine), often deficient in chemically ill patients,1 to convert to the next step, serotonin (figure 1). Serotonin is methylated to melatonin with S-adenosylmothionine (SAM), whose main source in the body requires the amino acid methionine, often low or deficient in chemically injured patients.1 There could well be additional nutrient co-factors in this multi-step process to forming melatonin as research on melatonin is still in its infancy.
FIGURE 1
B6 SAM
Tryptophan ¾® 5-hydroxytryptophan ¾® Serotonin ¾®Melatonin
THYROID FUNCTION
Salivary specimens were collected on the same day as blood specimens for thyroid testing and sent overnight or by 2 day mail to the laboratory. Patients were asked to not eat onion, brassica family foods or beverages with caffeine on the day of collection and to avoid antacids, bismuth oral preparations, mouthwash, toothpaste or smoking for an hour before collection of the saliva sample. Information was obtained regarding medication use (steroids, beta-blockers, DHEA, amphetamines, L-dopa, decongestants, lithium or thyroid hormones).
Reduced thyroid function can present with symptoms of fatigue, increased cold sensitivity, musculoskeletal aching, elevated cholesterol often with increased LDL, and depressed neurologic function.5 The results of testing for toxic injury patients whose tests were completed are presented in Table II.
Over a fourth (4) of the patients tested have increased pituitary TSH. Three of those had reduced free T3, the active thyroid hormone. The highest TSH patient also had increased thyroid peroxidase (TPO) antibody levels, as found in Hashimoto's autoimmune thyroiditis. Two other hypothyroid patients (patients numbered 11 and 14) also had autoimmune thyroid (TPO) antibodies.
Hashimoto’s thyroid disease is an autoimmune process in which normal thyroid tissue is replaced by lymphocytic tissue which does not have normal thyroid function.5 This destruction of thyroid tissue and thyroid function by the autoimmune process of Hashimoto's often leads to hypothyroidism,5 as was found in all three TPO positive patients tested here.
When Hashimoto first described autoimmune thyroid disease in 1912, it was considered rare.11 Numerous authors in the following decades found increasing rates. Each decade since the thirties described increasing numbers of autoimmune thyroiditis, as seen at the Mayo Clinic. This was felt to represent a true increase in incidence of autoimmune thyroid disease.11
The development of autoimmune thyroid disease depends on abnormal immune function.12 Workers exposed to PCBs had markedly increased antimicrosomal antibodies (TPO): the type found in the chemically injured patients described in this paper. Many chemicals have been found to have potent anti-thyroid effects, including phenol, dihydroxy phenol, thiocyanates, hydroxypyridines, various dihydroxybenzenes, and resorcinol derivatives.12 Chronic illness, especially that affecting the hypothalamic-pituitary-adrenal axis could increase risk of autoimmune thyroid disease.12
It has long been the clinical impression of the author that Hashimoto's thyroid disease is the most common form of autoimmunity in chronically ill chemically poisoned patients, with lupus and lupus-like changes likely the second most common autoimmune disturbance in chemical injury. Sjogrens and scleroderma also appear increased but with less frequency than Hashimoto’s and Lupus.
During the formation of the active thyroid hormone T3, one iodine is removed from the precursor thyroid hormone T4.5 Three patients had reduced thyroid hormone precursor free T4: 2 of these 3 also had reduced active thyroid hormone T3. The other two non-Hashimoto's patients with low active thyroid hormone T3 had lower range of normal levels of precursor T4.
A striking feature of thyroid function in toxic injury patients tested is that only 3 of the 14 patients had normal thyroid function, and one of these three (patient 12) had low normal T4. This does not mean that all chemically injured patients need thyroid supplementation. Patient 2 had very slight elevation of T4, ample T3, and midrange TSH without autoimmunity: supplementation is contraindicated. Temperature on first visit was 97°. Patient 12 has ample T3 despite low normal T4 and midrange TSH: supplemental thyroid is unneeded. Yet the body temperature on first visit of patient 12 was 97.8°. Indeed, the mean temperature at first visit for those with low free T3 was 97.8° while for those without low T3 mean temperature was 97.5°. The author feels that body temperature alone is not an adequate indicator of the need for thyroid supplementation. The vast majority has abnormal energy metabolism.4
However, low thyroid is not the only cause of fatigue in chemically injured patients. All of the patients in Table II have chronic fatigue, although chronic fatigue was not a criteria for thyroid testing or for inclusion in the endocrine evaluation. All patients who met the study criteria were referred for thyroid and other endocrine testing. The fatigue of 13 of the 14 patients on Table II was sufficiently severe to meet the CDC criteria for chronic fatigue syndrome, if there was not another cause for fatigue. The other patient had fatigue equaled to the major CFS criteria but met only two of the minor criteria. If the fatigue of those who were hypothyroid could be sufficiently corrected by thyroid hormone alone, they would probably not meet CFS criteria.
Eleven of the fourteen chemically injured patients in Table II had definite serious toxic encephalopathy by testing. In this paper, this was defined as having at least two of three neurocognitive test abnormalities (attention span, complex mental tasks, short-term memory) that were significantly reduced after the exposure without known symptoms or neurocognitive test abnormality prior to the identified chemical exposure. Of those eleven, 5 also had significantly abnormal Romberg test results and all with abnormal Romberg also had abnormal heel to toe walking: one was mild, and 4 were moderate to severe. Three of the eleven had resting tremor on exam.
Of the three patients in Table II, who did not have abnormalities on at least two of three neurocognitive tests listed above (patients 5, 6, and 7), one had impaired Romberg and definite tremor. Another had impaired attention span and mild tremor; a third had mild tremor and mildly reduced attention span. Two of the three described frequent symptoms of neurologic impairment (difficulty thinking clearly, understanding others, and forgetfulness, etc.). All three had significantly more frequent cognitive symptoms after compared to before the exposure (virtually none before exposure) and more cognitive and neurologic symptoms six months following the exposure than when seen by me later. Neurophysiologic test data could well detect further brain and neurologic abnormalities in these patients, since, neurophysiologic testing is a more sensitive means of testing brain injury. Thus all patients in Table II had some indication of neurotoxicity after, but not before, the described exposure, varying in degree of severity and type of effects even though neurotoxicity was not a criteria for inclusion in the study.
Metabolic factors associated with toxic injury can also impair thyroid function. Reduced antioxidants Vitamin C and Vitamin A can reduce thyroid function, the latter by interfering with the T3 cellular receptor site, reducing T4 entry into tissues,15 and/or affecting T4 conversion to active T3.15, The conversion of T4 to T3 in peripheral tissues is strongly decreased by selenium deficiency,17 common in toxic injury.1 Tissue injury can alter the function of the hypothalamic-pituitary-thyroid axis which improves with selenium supplementation. Adequate omega-3 essential fatty acids (essential lipids), which are anti-inflammatory, assist T3 at the lipid mitochondrial membrane receptor site where T3 is necessary for energy metabolism. Omega-3 essential membrane lipids are very often low or deficient in toxic-induced illness.1 The thyroid hormone, thyroxin, is a protein: protein deficiency is widespread in chronically ill chemically injured patients.1,4 Thyroid hormone is made from the amino acid tyrosine, often deficient in toxic injury patients.1,4 5-hydroxytryptophan requires Vitamin B6 (pyridoxine), often low or deficient in toxic injury,1 to convert to the next step, serotonin.9
Cells communicate by signaling pathways which can involve essential nutrients. Thyroid hormone cellular signaling pathways are intertwined with signaling pathways for Vitamins A and Vitamins D., Thus toxic-induced antioxidant deficiency could reduce the antioxidant, Vitamin A, and affect thyroid function. Antioxidant glutathione deficiency was found in 65% of toxic injury patients with over half exhibiting increased free radicals.1
Chemical injury can impair thyroid function in various ways. Dioxins and PCBs can interfere with the thyroid-steroid-retinoic acid family of nuclear receptors. Organochlorine chemicals interact with thyroid hormone function. Phenolic chemicals can increase autoimmune thyroid disease which improves with removal of the chemicals. Mechanisms of chemical injury to thyroid function include inhibition of iodine trapping by the thyroid cell, blockage of organic thyroid binding, coupling iodothyronines to thyroxine, inhibiting thyroid hormone activity, and production of autoimmune thyroid antibodies.
Many chemicals interfere with thyroid function, usually causing hypothyroidism,5 although this is still not researched for most chemicals.5 Halogenated aromatic hydrocarbons affect thyroid function in humans and animals.5 For example, polybrominated biphenyls (PBBs) can cause hypothyroidism, reduced free T4, and induce thyroid antimicrosomal (TPO) antibodies5, found in several patients discussed in this paper. Hexachlorobenzene, a pesticide, can induce porphyrin disturbance (also found in chemically injured patients) and decrease thyroid hormone levels.5 Several polychlorinated chemicals, including dioxin (TCDD) and polychlorinated biphenyls (PBBs) decrease thyroid hormone levels, cause hyperplasia and hypertrophy of thyroid cells,5 and appear to impair release of thyroid hormone from the thyroid gland. The pesticide DDT at low levels can cause hyperthyroidism and at higher levels can reduce thyroid hormone levels.5 Ethylene thiourea is used as an accelerant in rubber manufacture and a chemical intermediate in making pesticides, fungicides, dyes and chemicals.5 It can lower thyroid hormone levels.5 Bisphenol A, a component of certain adhesives and resins, can competitively bind to thyroid hormone receptors.25 Thus the end result of these various exposures (reduced thyroid function) is similar to the chemically ill patients in this paper.
The author finds that hypothyroid patients (confirmed by testing) often respond well with physiologic doses of a mixture of natural T4 and T3 such as Armour or other natural source, with gradual increasing at weekly intervals of dose until the patient reaches a feeling of most well-being without any symptoms of hyperthyroidism. Thyroid function should then be confirmed by testing to ensure that TSH from the pituitary gland is in physiologic range. Lower TSH levels are desired for autoimmune thyroid patients (TPO positive) than for non-autoimmune patients.
A mixture of T4 and T3 can result in better cognitive improvement, according to the medical literature.
Patients with reduced T3 often feel less fatigue with thyroid supplementation. With auto-immunity, the goal is to keep TSH below average. Without autoimmunity, the author strives to maintain optimal well being, keeping the patient in physiologic range (the added amount of what their body is making and what they are taking), and ideally avoiding suppressing TSH below midrange. For Hashimoto's autoimmune thyroid disease, to reduce the autoimmune process, thyroid supplementation can be more ample, to keep TSH below midrange. Still, it is important to avoid creating symptoms of thyroid excess in supplementation.
ADRENAL FUNCTION
Adrenal cortisol secretion is normally highest in the morning upon arising and gradually declines during the day.5 To correctly evaluate this daily rhythm, salivary samples were collected between 7-8 a.m., 11-12 noon, 4-5 p.m. and 11-12 evening. DHEA salivary evaluation was also done to assess whether this varied with cortisol levels. Patients were asked to not consume beverages with caffeine, chocolate, nor foods such as onions, garlic, cauliflower or broccoli on the day of collection. They were also asked to not eat or drink anything but water, not use antacids, bismuth medications, mouthwash, brush their teeth, or smoke for 30-60 minutes before each sample collection. A history of medication use was obtained, as for other evaluations described above. They were asked, as for other salivary hormones, whether they had a history of gingivitis or bleeding gums. They were asked whether or not the collection day was a regular wake/sleep schedule for them. The author encourages hormonal testing on days that are typical to help ensure that results are representative.
As discussed earlier, salivary cortisol (hydrocortisone) levels have been validated in the literature and reflect the active hormone, in contrast to blood levels, where the vast majority of hydrocortisone is protein-bound and thus not in its active form. Also, driving to a medical facility and venipuncture to obtain blood cortisol can affect the cortisol level, since these activities are physical stressors.
Physical and toxic trauma to body cells at a level which induces chronic illness is a physiologic stressor, as originally described by Hans Selye in 1936. This can result in increased secretion of pituitary ACTH, which then increases cortisol and mineralocorticoids (like aldosterone).5 Other hormones can be affected, including epinephrine, norepinephrine, endorphin, vasopressin, prolactin secretion by the pituitary, and glucagon by the pancreas. When prolonged, activity of the parasympathic nervous system can be suppressed, as well as sex hormone secretion and growth hormone. Prolonged tissue injury as a physiologic stressor and the above hormonal changes can lead to loss of muscle tone, insulin resistance, increased cholesterol, triglycerides, hypertension, fatigue, sleep disturbance, and further inflammatory increase.
With ACTH (adrenocorticotropin) release in the pituitary, cortisol increases within minutes. The main stimulus for ACTH release is CRH (Corticotropic releasing hormone) from the hypothalamus, but other hormones such as vasopressin, oxytocin and catecholamines do so in descending order of importance.5 When cortisol is increased, energy is no longer stored, and processes such as growth, tissue repair, reproduction and immunity are suppressed. Hyperinsulinism, excess catecholamines (epinephrine, norepinephrine), reduced testosterone, progesterone, estrogen, increased oxidative stress, increased inflammatory mediators, and increased need for detoxification via methylation, sulfation and glucuromidation. Detoxification of cortisol occurs mostly in the liver, through glucuromidation, and to a lesser extent, sulfation. Norepinephrine is converted to epinephrine in the adrenal medulla by methylation, and epinephrine also uses O-methylation in its detoxification, requiring 5-adenosylmethionine derived from 5-methyltetrahydrofolate.
In the adrenal medulla, norepinephrine (and epinephrine) is made from tyrosine, which was deficient in 25% of chemically ill patients and borderline low in another 20%.1 Eighty percent of chemically injured patients showed increased urinary vanilmandilate (a breakdown product of norepinephrine and epinephrine),4 which supports the mechanisms discussed here. Sixty percent showed reduced homovanillate,4 a urinary breakdown product of dopa, which the body uses to make norepinephrine and epinephrine.4 Excess cortisol increases protein breakdown, and if chronic, leads to protein deficiency, which is seen in toxic injury patients.1,4
Chronic neuroendocrine activation influences the immune system. The brain produces neurotransmitters such as serotonin and catecholamines, for which there are receptors on specialized immune cells. Sixty percent of toxic injury patients showed increased urinary 5-hydroxyindoleacetate, a breakdown product of serotonin1.
Hyperpigmentation may be seen with elevated ACTH and cortisol, especially at skin areas of pressure (knees, knuckles, elbows, etc.), further pigment increase in normally pigmented areas (areola, genitalia, palmar creases), and recent scars.5
After prolonged elevated cortisol, the adrenal gland can become depleted, and adrenal deficiency develops. The morning cortisol is reduced or low normal in virtually all table III patients: the morning cortisol is the first measurement to drop as the adrenal gland moves to a deficient state. Hypotension can occur with depleted ACTH.5
Based upon the above, and the clinical experience of the author, chemical injury initially increases cortisol, which if not corrected, leads to adrenal depletion. This appears to first affect the times of day when cortisol demand is greatest (in the morning). If it becomes more severe, it involves more than just the morning cortisol. During the transition from excess to depletion, levels could be normal. Also, if exacerbating factors are under control they could be normal.
On table III, patient 8 was of relatively recent onset, and was in the highest current exposure situation. He had severe fatigue, sleep disturbance, severe reactive upper airways on exam and history, toxic encephalopathy with very significant balance impairment on Romberg and heel to toe walking. Neurocognitive function showed moderate reduction in attention span, complex mental tasks and short-term memory. He had severe widespread musculoskeletal pain and extreme tenderness to gentle pressure in multiple soft tissue, muscle and joint sites (despite high body levels of "steroids").
Patients 5, 10 and 11 had nighttime cortisol elevation without significant other abnormalities. All three had severe chronic fatigue of comparable severity to CFS. All three had reactive airway disease documented on history and examination. Reactive airway disease on history used the instrument developed by Dr. Howard Kipen of the Robert Wood Johnson Medical College of New Jersey which showed ability to distinguish between irritant asthma and controls. This used an instrument that evaluated numerous types of exposures.1 All three of these patients had frequent jerking in their sleep and another sleep disturbance: two of the three had frequent insomnia/falling asleep, and two of the three had frequent unwanted falling asleep during the daytime. All had toxic encephalopathy of varying degree of severity documented on history and examination. Patient 5 had abnormal Romberg, tremor but only mild tested changes on cognitive function. Patient 10 had abnormal Romberg and heel to toe walking, mild tremor and mild to moderate testing changes in cognitive function. Patient 11 had mild Romberg changes and mild to moderate cognitive test changes.
Patients 2, 3 and 4 had reduced morning cortisol but differed on other cortisol levels. Patient 4 had serious reduction of all cortisol levels. She had profound fatigue, mild tremor, modest cognitive changes, and reactive airways on exam and history. Patient 3 had elevated noon cortisol, which can occur with missing a meal. She had moderate fatigue, normal balance, slight tremor, mild to moderate cognitive test changes, and reactive airway disease by history. Patient 2 had only morning cortisol reduction but borderline low noon level. He had reactive upper and lower airways on exam and history, significant fatigue, moderate tremor, and mild to moderate cognitive test changes.
It does not appear possible, in the author's experience at this time, to predict the adrenal pattern from either history or exam. There are multiple potential causes of fatigue in toxic injury: reduced thyroid function, impaired energy metabolism, sleep disruption, adrenal insufficiency, toxic encephalopathy, and heightened inflammatory mediators. Since cortisol patterns can vary widely between patients or any individual patient at different times, cortisol rhythm should be tested before supplementation. Patients 2 and 4 could benefit from mild to moderate hydrocortisone supplementation, respectively. Patient 3 needs more information on meals and repeat testing to determine if supplemental hydrocortisone is needed. For patients 1, 5, 6, 7, and 11 supplementation with hydrocortisone is unnecessary. For patient 8, supplementation could be very harmful, further depleting proteins, minerals and other disturbances discussed above.
All patients with adrenal function disturbances, in the author's experience, can benefit from adrenal healing measures discussed earlier.1 If, all these measures are implemented, with exposure control absolutely essential, adrenal function can usually be stabilized. Economic factors often play a critical role in the ability of the patient to reduce exacerbating exposures to respiratory irritants and neurotoxins. Nebulized glutathione has reduced the extent of exacerbation, but is not a substitute for exposure controls at home and, if applicable, work and/or school. This form of glutathione gradually allows more frequent social interaction with a lesser degree of exacerbation. Other antioxidants which reduce the nitric oxide and peroxynitrite vicious cycle of neural sensitization are also recommended.,,,
REPRODUCTIVE HORMONES: WOMEN
Women of Reproductive Age
To evaluate all phases of the menstrual cycle, multiple samples were collected, again using saliva because the hormones there are in their active form, in contrast to blood. Women with regular length (28-32 day) cycles gathered 11 samples beginning with the first day of the menses: day 1-3, 4-6, 7-9, 10-11, 12-13, 14-15, 16-18, 19-21, 22-24, 25-27 and 28-32 or first day of new period, with the patient circling for each sample collected the precise day of collection. (Women with less than four years after last menstrual period, if ovaries were still present, were also tested to see where ovulation was still occurring.
For 30-60 minutes before collection, eating, beverages and brushing teeth was avoided. The sample was collected with no prior mouthwash use that day, after rinsing the mouth with cold water for 3-5 minutes before collection, avoiding early-morning collections and sublingual/oral medication before collection. Collection at the same time of day throughout the cycle was recommended.
Women with more prolonged cycles were spaced with no sample on days 7, 11 or 12, 18 or 19, 22, 31, 35-36 and tube 11 on the first day of the next menses. Both groups recorded the date of first and each subsequent sample collection.
Women with menopausal symptoms, menses 4 or more months apart or with hysterectomy but intact ovaries (and under age 56) recorded basal temperature each a.m. for 3 consecutive months and faxed results to the laboratory to be advised how to time collection accurately. They were all asked to complete questionnaires about collection timing, exercise level, regularity and duration of menses, weight loss, PMS symptoms, smoking, gingivitis/bleeding gums, contraceptive use, whether they had uterus or ovaries removed and what hormone or drug and dosage was used during the monthly cycle of collection.
There are not at this time a sufficient number of test results available for this patient group of reproductive age women for conclusive analysis. However, using the collection method described above, the author has noted over time a striking abnormally high proportion of reproductive age women with known chemical illness (similar selection criteria although endocrine testing not always as closely timed with the first visit). A very common pattern is lack of ovulation with estrogen dominance.
Of the few women who conceived, the vast majority had babies with chronic respiratory symptoms, neurologic changes such as developmental delays, and significant food intolerances. The few babies whose fetal development occurred during maternal causal exposure were more severely affected, reflecting what the author considers to be intrauterine exposure of the child. Several others were born during significant chronic toxic illness symptoms and abnormalities on multiple nutritional laboratory tests. These children presented with more respiratory and neurologic problems than those few children born when the mother's illness had significantly improved. Reduced thyroid function (as seen in many of the patients in this paper) in a pregnant woman can impair and alter brain and neurologic function of the child.34
Thus lack of ovulation and failure to conceive in a large portion of chronically ill toxic injury women of reproductive age has a likely protective effect on a potential fetus. When the mother lacks essential proteins, energy nutrient cofactors and has inadequate antioxidant protection with excess lipid peroxides1,4, this is not a healthy environment for mother or prospective fetus.
However, the resulting hormonal pattern in nonovulating women of reproductive age with chronic toxic illness observed by the author is estrogen dominance. Estrogen encourages cell proliferation (endometrium, breast) while progesterone controls excess growth and encourages cell differentiation. Many of the reproductive age chemically ill women are progesterone deficient
Thus hormonal replacement therapy (HRT) must be based on test results. A common albeit unscientific long-standing practice has been to give many menopausal women estrogens, often those excreted by pregnant horses. This approach is now known to increase risk of breast cancer. The risk could well be significantly greater in patients with toxic illness where estrogen dominance is already present.
Correcting estrogen dominance should be done based on test results throughout the monthly cycle, to determine when levels are normal and when therapy is needed to normalize them. Using natural hormones in HRT is more physiologic and allows post HRT evaluation of whether the patient is in physiologic range. This is done by repeat measurements of hormones throughout the monthly cycle, to look at the sum of the hormones the body is making and what the patient is taking, i.e., the total physiologic hormone level. Synthetic hormones cannot be monitored in this precise manner.
Detoxification of estrogens begins with cytochrome p450 activation (mono-oxidation or hydroxylation). Estradiol and estrone can be metabolized to a 2 hydroxylated form in the liver, brain and some other tissues. This then requires detoxification pathways Phase II of glucuronidation, sulfation and/or O-methylation. Sulfate reserves are often reduced in toxic injury patients4 and other Phase II abnormalities are common.4 O-methylation requires adenosylmethionine (SAM) as a methyl donor, which requires methionine, folate, B12 and B6. Methionine, B12 and B6 deficiencies were found in 29%, 79% and 14% of chronically ill toxic injury patients respectively1, with many more at low normal levels. These factors are needed for O-methylation of 2 hydroxyestrogens, and this O-methylation is a potent inhibitor of tumor cell proliferation.
Specific p450 cytochromes act on different sites of the estrogen molecule: two, four or 16-hydroxylation. These 16 hydroxylated estrogens are associated with increased breast cancer. Thus the ratio of two to 16 hydroxylated byproducts of estrogen metabolism is important in future cancer risk. Another p450 cytochrome, aromatase, convert testosterone and androstendione into estrogen. Thus the effects of estrogen is not only neuroendocrine influenced, but also affected by detoxification and nutrient cofactors.
POST MENOPAUSAL WOMEN
The data available at this time indicates polycystic ovary disease as a problem, with elevation of testosterones. Polycystic ovaries can be associated with prolonged periods of lack of ovulation,5 which was found in premenopausal chemically injured patients as discussed above.
MALE REPRODUCTIVE HORMONES
The information available at this time for males suggest reduced testosterone. Testosterone can be decreased in disorders of the hypothalamic-pituitary system.5 This is often associated with reduced sperm and thus reduced fertility.5 Known chemical causes include dibromochloropropane (DBCP) and related compounds, ethylene glycol and organic chloride compounds.5 Sperm counts in men have been reported to have declined substantially since the 1940s. During this era, petrochemical use also increased dramatically. Abnormal hypothalamic-pituitary-testicular function can occur with chronic illness. In these situations, free testosterone is low but sex hormone binding globulin (SHGB) may be increased, so total testosterone may look better then active free testosterone. This would make salivary testing a better option.
DHEA
DHEA (dehydroepiandrosterone) is primarily produced by the adrenal gland.34 It is commonly reduced in chemically ill patients, noted both in patients of this evaluation and in previously tested chemically injured patients. In healthy individuals it is eventually converted partially into various estrogens and partially to testosterone.34 However, the author has noted, using baseline and post-DHEA hormonal measurements, that the conversions often do not function normally in chemically ill patients. Thus, if DHEA is supplemented directly, the author recommends post-DHEA monitoring to assess various hormone levels to which DHEA has converted. This can help avoid increasing estrogen dominance or unwanted testosterone increase. The author prefers to measure a wider range of reproductive hormones together and focus on supplementing specific "end product" hormones (progesterone, testosterone, and in the less common estrogen deficient patients, the specific deficient estrogens), based on test results of documented deficiency. Testing the wider range of post supplementation hormones is recommended to ensure physiologic range. This is only possible using natural physiologic hormones (i.e., chemically identical structure), since these will be detected by testing and can be adjusted as needed to achieve optimal physiologic range.
CONCLUSION
Chronically ill chemically injured patients frequently show abnormalities in thyroid, adrenal and gonad function. All of these hormonal functions are under control of the hypothalamic pituitary system. The hypothalamus is involved in memory and in temperature regulation,5 both commonly affected in chemically injured patients.1,25 The hypothalamus has nerve cell communication from the olfactory nerve,5 which has no blood-brain barrier to prevent chemical entry from the nose to the brain through the olfactory nerve. Thus there is substantial evidence supporting hypothalamic pituitary impairment with chemical injury in the hormonal data in this paper.
The reproductive effects in both men and women appear to adversely affect the ability to reproduce. Estrogen dominance (found in many reproductive age women patients) if uncorrected can increased risk of breast 34 and potentially uterine cancer. However, rather than estrogen increase, progesterone decrease was typically the cause. Tamoxifen or other anti-estrogen agents would thus not achieve physiologic levels, whereas test-based progesterone supplementation can do so.
Further, other functions of hormones can be disturbed, including but not limited to, enzyme function (often involving nutrient cofactors and/or protein levels). Receptor site function, and hormonal passage into cells and DNA can be affected by disturbed lipid membrane composition and/or increased lipid peroxides, both found in chemically injured patients.1 These could also impair function of hormones that were not studied in this evaluation.
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