Inter-relationships Between the
Environment and Premenstrual
WILLIAM J. REA
Environmental Health Center, 8345 Walnut Hill Lane, Suite 205
Dallas, Texas 75231,
The suggestion that there could be environmental aspects of premenstrual syndrome (PMS) occurred during observations of hundreds of patients with environmentally triggered vascular disease studied in an ultra-controlled environment. It became clear that many women had a history and subsequent course which included PMS.
The PMS symptoms in many of these patients responded favourably to dietary and environmental manipulation including removal of incitants found as a result of inhaled challenge reactions to ambient doses of <0.50 ppm phenol, <0.002ppm formaldehyde, <0.33 ppm chlorine, <0.5 ppm petroleum alcohol, and <0.0034 ppm pesticide (2-4-DNP). These same patients were found to have numerous organochlorine pesticides and volatile organic hydrocarbons in their blood. (See Figure 1 and Table 1.)
In addition animal studies have shown alterations of hormones on exposure to similar toxic chemicals (Rattner et al., 1984). For example monkeys fed a diet with pesticide levels similar to those in the average human diet had abnormal variations in their oestrogen and progesterone levels with irregularities in their menstrual cycles (Hinsdill and Thomas, 1978). These were the first symptoms along with periorbital oedema.
A programme was then devised to systematically evaluate PMS patients on an out-patient basis to see if manipulation of specific environmental incitants could trigger the syndrome. From there a practical approach with subsequent removal of incitants was developed thus allowing relief. This involved the development and intake of less polluted air, water, vitamins, minerals, and hormones. The over-all approach will be discussed in this chapter by considering various aspects:
In order to effectively diagnose and treat the environmental aspects of different diseases, including PMS, it is necessary to understand the following basic principles.
Total Body Burden
Total body load or burden can be defined as the total of all the pollutants that the body takes in and has to handle in order to maintain homeostasis (see Rea, 1980). The pollutants may be biological (pollens, dusts, parasites, viruses, bacteria), chemical (organic or inorganic), or physical pollutants (heat, cold, electromagnetic radiation, radon, positive and negative ions, noise, light, weather changes) (see Rea and Brown, 1986 for more detailed discussion). In order to prevent disease, the body must deal with this burden by either utilization or elimination. If the load is excessive, premenstrual symptoms may occur and not be cleared until the load is reduced.
This principle has been well documented and commonly understood in relation to bacteria and body function. The case of infectious agents of childbed fever is an excellent example of increased total bacterial load. Institution of sterile techniques reduced the total bacterial load resulting in a decrease in maternal mortality. Reduction of bacterial load is practised in nearly every facet of modern civilization. Attempts are made to free most indoor environments of agents which are known to foster infectious diseases including dust, garbage, vermin, human and animal excrement.
No physician today would consider treating a wound with antibiotics alone. He would first eliminate the overload of bacteria present by vigorously cleansing the wound, and applying a sterile bandage thus reducing the total body burden. In fact, zealous attempts to eliminate infectious agents have inadvertently increased exposure to toxic chemical agents through the use of phenol, chlorine, formaldehyde, and various organic solvents for cleaning purposes.
The control of noninfectious pollutants has not been as successful as control of infectious agents. Overall levels of inhalation of sulphur dioxide from car exhausts or refineries, formaldehyde fumes from new clothes, and exposures to radon or electromagnetic fields increase markedly though individual variation due to personal and geographical factors is considerable. As accumulations of pollutants increase, total body burden increases. The accumulation of total body load encompasses two phenomena: (a) sudden massive exposures and (b) gradual toxic build-up of commonly occurring biological, chemical, and/or physical incitants. An acute exposure can be due to a physical trauma such as a car accident or to a toxic injury such as an acute pesticide exposure, or to a massive viral or bacterial exposure. Subtoxic doses of substances may be involved including such common things as pollens, dusts, moulds, water contaminants, food, food contaminants, inhaled ambient doses of chemicals (Rinkel, et al., 1951; Randolph, 1962; Miller, 1972; Dickey, 1976; Speer, 1977), electromagnetic radiation, and positive air ions, or electrical field changes (Becker and Marino, 1982). Additionally, subtoxic doses of multiple different agents acting in synergism or additive fashion can cause insults producing injury resulting in increased sensitivity to small doses of the aforementioned agents.
The total body load or burden tends to disturb many of the body's mechanisms, often becoming too great for persons with hereditary or acquired limitation to handle. Consequently, an individual susceptibility occurs with resulting generalized inflammatory disease or a change in one end-organ as Nadal and Lee (1 977), Matsumura et al. (1 972) and Lee et al. (1 977) showed with nitrogen dioxide, sulphur dioxide or ozone over-exposure resulting in damage to the bronchial mucosa. This was also shown to occur with oral ingestion of foods containing pesticides with resultant disturbances of oestrogen and progesterone levels (Hinsdill and Thomas, 1978).
Masking or Adaptation or Acute Toxicological Tolerance
Masking (Rinkel et al., 195 1) or adaptation (Se lye, 1946) or acute toxicological tolerance (Stokinger, 1965; Mustafa and Tierney, 1978) is a change in the homeostasis induced by the internal or external environment followed by accommodation of body function to a new set point. Adaptation is an acute survival mechanism in which the individual apparently 'gets used to' a constant acute toxic exposure in order to initially survive while paying the price of a long term decrease in efficient functioning and perhaps longevity. Because of this phenomenon, the total body load may increase unknown to an individual. At this point, the toxic substance then appears to no longer bother her. Even though there are no apparent correlated symptoms, repeated exposures continue to damage her immune and enzyme detoxification systems. The eventual result often is end-organ failure. This may account for the 20 -30 year delay of the onset of vascular and pulmonary diseases before end-organ failure manifests itself. The hormone disturbance of PMS will occur with much less delay. Specific avoidance of the inciting substances for four days, will unmask symptoms and allows for their scientific reproduction. After the unmasking, re-exposure will result in an immediate and clearly definable reaction; cause and effect are now easily distinguishable. Failure to unmask for at least four days often results in negative challenge reactions.
The effects of this process can be readily observed in daily practice. Sensitivities are often missed because offending foods are eaten or harmful substances are breathed daily resulting in masking. In the masked state, challenge tests are frequently negative due to the increased activity of the already induced immune and enzyme detoxification systems. Because of the masking of symptoms, a person can no longer perceive the harmful effects of a substance and she believes herself to be 'healthy' until the next stage of disease occurs. The initial signs and symptoms of vascular and gynaecological disease are often obscured due to these masking effects. The acute survival mechanisms involved in bringing the body back to a steady state certainly sustain life, but only on a shortened and less efficient functioning basis. The dysfunction associated with PMS certainly falls into the latter category. Adaptation has been characterized in three stages: alarm, adaptation, and exhaustion (Selye, 1946). The alarm stage triggers an acute response to initial exposure while the adaptation stage is the 'getting used to' response. The exhaustion stage encompasses end-organ failure.
The process of adaptation (stage 2) has two phases. The first is a physiological adjustment to an incitant. This phase is probably defined by narrow limits depending on the quantity of enzymes and other immunodetoxification systems available for induction and response. There is minimal strain on the system with no chronic inflammation or severe metabolic depletion. Development of the second phase of stage 2 signals more severe difficulties. A series of metabolic events occur which strains the availability of ATP and the metabolism of minerals, glucose, carbohydrates, and fats. Enzyme systems, such as the glucose-6-phosphate dehydrogenase, glutathione peroxidase, superoxide dismutase, monoamine oxidase, aryl hydrocarbon hydroxylase, mixed function oxidase, and cytochrome P-450 systems are stimulated. Gradually they are over extended by continuing stress which increases body load by virtue of gradual inability to detoxify substances, therefore the gradual depletion of essential nutritional elements occurs. Finally, end-organ failure or stage 3 maladaptation occurs resulting in heart (Rea, 1978), lung (Mustafa and Tierney, 1978), blood vessel (Rea, 1977), gastrointestinal (Ward, 1985), or genito-urinary (Eroschenko and Osman, 1986) disease. One can see that PMS clearly falls into the 2 B phase.
Studies with common inorganic pollutants such as nitrogen dioxide and ozone soundly support this masking concept (McGrath and Smith, 1984; Menzel, 1976; Crapo et al., 1978). Stokinger and Coffin (1968), Bennett (1962), and the National Research Council (1962) pointed out that although daily exposures to pollutants may initially decrease pulmonary function from 15 per cent to 20 per cent, by the fourth day the pulmonary function returns to control levels, thus demonstrating masking. Rinkel et al. (I 95 1) showed the same phenomenon after repeated ingestion of offending foods. Cellular and metabolic changes then occur. Variations in metabolic changes are dependent on the concentration and virulence of pollutants as well as the volume of offending substances, time, nutritional state of the organism and the presence of other disease (Kon, 1978; Horrobin et al., 1977). Since people get 'used to 'a toxic substance they will continue to increase body burden inadvertently. This phenomenon can occur in any smooth muscle organ and is apparent in the environmentally sensitive PMS patient.
Bipolarity is another factor which contributes to the total body burden. When exposed to a toxic substance, the body initially develops a bipolar response with a stimulatory phase followed by a depressive phase. Initially, induction of the immune and enzyme detoxification system occurs. If the incitant is sufficiently virulent, substantial in amount, or the duration of exposure is extended, the biological enzyme and immune detoxification systems are then depleted (depressed) by overstimulation. Parallel to this pathological phenomenon, an individual may experience the stimulatory reaction in the brain and perceive the inciting substance as not being harmful to her initially, but actually making her feel better or 'high'. Therefore she continues to acquire more exposures either to maintain the 'high' or inadvertently from accidental exposure. After a period of time, however, be it minutes, months or years her body's defenses break down from over use and she develops disabling depression-exhaustion symptoms. These stimulation and depression-exhaustion phenomena have been observed with many pollutant exposures including ozone (National Research Council, 1962; Bennett, 1962; Stokinger, 1965; Stokinger and Coffin, 1968; Mustafa and Tierney, 1978).
Due to initially sufficient immune and enzyme inductivity, the body appears to be tricked into initially tolerating a toxic substance or even liking it, again probably for acute survival, although it is adding to the damaging long-term load due to over-utilization of the nutrient fuel of the induction process and direct toxic damage. The depressive phase occurs when the various metabolic systems become depleted or sustain sufficient toxic damage to the point that they can no longer respond as well to the stimuli. Fixed pathological cellular changes then occur with abnormal healing or scar formation. During the stimulation phase, enzyme and immune induction had occurred initially with increases in energy production (adenosine triphosphate, glucose, protein, lipid metabolism, and enzyme response). When an incitant is acutely removed, a symptomatic withdrawal period may be experienced. This is not to be confused with the depression phase which occurs with continued excessive stimulation. The symptomatic withdrawal period is probably due to a sudden removal of an incitant with a slow three to four day turn off of response systems. A prime example of withdrawal is seen in people drinking alcohol on a Saturday night in order to get high. The withdrawal period is expressed as a 'hang over' on Sunday morning while the depressive phase comes years later with eventual brain and liver deterioration. A second example involves workers who get hang-over-like symptoms on Saturday morning at home following exposures to toxic substances in the workplace during the week. They feel well during the work week, but they experience headaches, muscle aches, shakiness, and impaired ability to function on Saturday through early Sunday. By Sunday afternoon, as their systems rid themselves of the toxic substances and induced systems return to prestimulatory levels, the workers are again able to function well and feel fit to work on Monday. This cycle may be repeated weekly for months or years before the person develops end-stage disease. During this time, the PMS patient continues to accentuate her symptoms. It can easily be seen how this occurrence can lead to an addictive phenomenon (constant withdrawal and re-exposure) as seen in many PMS patients. Cycle observations under controlled conditions have suggested that this stimulatory-addictive withdrawal phenomenon can spill over into cross-reactivity, i.e. an individual working in a plastic factory may develop severe thirst or hunger. She then drinks carbonated beverages or eats 'junk foods' until she sets up more addictive patterns taking more harmful substances into the body including medications and drugs in order to maintain her precarious balance. She develops a spreading phenomenon becoming sensitive to more chemicals as she adds to the body burden. As her load or burden increases, she becomes more and more sensitive to new foods and chemicals (Symington et al., 1981) which further derange body metabolism predisposing to severe PMS.
The final principle necessary to the understanding of the environmental aspects of gynaecological health and disease is that of individuality. Biochemical individuality is our uniqueness accounting for individual susceptibility. We have individually differing quantities of carbohydrates, fats, proteins, enzymes, vitamins, minerals, and immune parameters with which to respond to environmental factors. This individuality allows us to clear the body of noxious substances or to contribute to our own body burden. Biochemical individuality is dependent on at least three factors: genetics, state of fetus's nutritional health and toxic body burden during pregnancy, and the individual's present toxic body burden in relation to her present nutritional state at the time of exposure, e.g. some individuals are born with significantly less quantities of a specific enzyme (may be 25 per cent, 50 per cent or even 75 per cent). While she may be able to respond to an environmental stimulant, her response is often considerably less than that of the individual who was born with 100 per cent of the expected detoxifying enzyme and immune parameters. The over 2000 genetic metabolic defects already described in the literature appear to be 'time bombs' awaiting environmental triggers to elicit their expression. It is likely that any given individual may have one or more genetic defects. A common example, of the 'time bomb' effect is the children with phenylketonuria who do well as long as they do not take in phenylalanines although they have a genetic enzyme defect. Smith (1986) has shown that a group of individuals exist in the general population (approximately 25 per cent) who are slow sulphoxidisors. When they are exposed to a substance such as succinyl cysteine they will slowly metabolize it and become ill during the process. He also found another group (about 10 per cent) of the general population, who had genetic deficiency through the cytochrome P-450 system, who could not tolerate debrisoquine compounds. Monro (1986) studying a select group of chemically sensitive people showed as many as 60 per cent of the patients to have defects in these systems. It should be emphasized that many different toxic chemicals, additives, preservatives, pesticides, and chlorinated hydrocarbons may cause vitamin, amino acid, lipid, enzyme, and mineral depletion resulting in a selectively depleted individual. This may be due to in-utero depletion in the fetus which is due to bioconcentration of toxic chemicals, direct toxic effects of chemicals on nutrients, competitive inhibition; (e.g. some drugs like hydralazine are selectively absorbed in preference to vitamin B6), over utilization of the detoxification systems with depletion of their fuel sources (vitamins, etc.), or selective nutrient malabsorption due to toxic damage to intestinal walls or flora. An individual whose immune and enzyme detoxification systems are depleted is unable to respond as well to more toxic environmental exposures which are normally received in routine living. This cycle appears to occur in the PMS patient.
Food can influence the PMS process in many ways. This can be due to the nutritive quality, toxic effects of the food itself, sensitivity to the food, and sensitivity to its additives and preservatives. Many women on monotonous diets tend to get nutrient deficiencies because of limited variety of intake or poor nutritional quality.
There appears to be a decrease in the quality of foods raised on soils which have been regularly treated with pesticides and herbicides, and also soils that are naturally depleted of minerals (Pottigener, 1936; Hill, 1983). In addition processing is known to destroy nutrients, e.g. vitamin D is lost in the pasteurization of milk. Individuals who eat the so-called ultra-processed and preserved 'junk food' will tend to have more vitamin and mineral depletion. Vitamin B6 and magnesium depletion especially seem to occur with this type of diet. Also, selenium, zinc, and calcium intake may not be appropriate. Vitamins such as the other B vitamins, C, A and E may also be deficient in some diets. Fatty acids may also be deficient especially if there is a lack of fish and non-heated polyunsaturated oils or high amounts of animal protein. Diets high in simple rather than complex carbohydrates, or high in refined sugars, increase the need for the B-complex vitamins. Also, excessive total carbohydrate intake seems to be a problem in many PMS patients.
Toxic Effects of Foods
Many foods contain their own toxins. If these are ingested in large quantities or repetitively problems can arise. Toxins involved in food processing and storage include carcinogens such as nitrosamines, bleaching agents such as methionine sulphoximine, solvent extraction by trichloroethylene and fumigation with ethylene oxide. Natural toxins from plants may be both endogenous and exogenous. Cabbage and related vegetables contain glucosinolates which have goitrogenic activity although clinical symptoms are unlikely. Sweet potatoes or legumes may produce cyanogens thus producing neuropathy and mental confusion. Datura stramonium may produce atropine with resultant hallucinations. Bananas may produce pressor amines thus causing headache and hypertension. Solanine may be found in potatoes, especially when badly stored, which may result in headaches, incoherence, hallucination and dizziness. Exogenous sources include peanuts and grains which may contain aflatoxins if contaminated with certain moulds. Aflatoxins can cause encephalopathy, hallucinations, and hepatic disease. Nitrites originating from endogenous nitrates may be present in some green vegetables including spinach with potential risk of headache, hepatic disease and methaemoglobinaemia. Conversion to nitrosamines results in potential risk of carcinogenic activity. Naturally occurring toxins from animals occur. Endogenous examples include fish which contain certain lipoproteins which may result in symptoms of vomiting, headache, and dizziness. Other examples include cheese which contains tyramine which can give headache and elevated blood pressure in susceptible individuals. Saxitoxin originating from dinoflagellates may be found in fish or shellfish possibly giving symptoms of dyspnoea, paralysis, or haemorrhage.
These have been shown to cause mild to severe problems causing abnormal smooth muscle reactions. This occurs more in the uterus, tubes, and ovaries than previously thought and reactions occur especially in the blood vessels. This means that the ovaries, tubes and uterus could be a double target organ with the vessels contained in them and the intrinsic muscles themselves becoming sensitized. The mechanism of these sensitivities can be through IgE, but probably more often occurs via Type II, III, and IV mechanisms or even from direct non-immune triggering (Rea and Brown, 1986). Avoidance for four days with rechallenge usually allows the diagnosis of food sensitivity. The most common offenders for the tubes, ovaries, and uterus are coffee, tea, cane sugar, wheat, corn, milk, beef, eggs, chicken, and pork. Many of the accessory signs and symptoms such as headache, depression, and agitation of the PMS patient occur or may be accentuated as a result of sensitivity to these and other foods.
These consist of preservatives, colourings, pesticides, herbicides, and flavourings (Rea and Brown, 1986). All commercial foods in the USA now have pesticides and herbicides in them. This is probably so in the UK also. Reactivity in the PMS patient can occur from these and may well be one of the major reasons that menstrual cycles become disordered. Aldehydes are used in some foods as flavouring and when coupled with formaldehyde used as preservatives in others can trigger reactions of the gynaecological system. Sulphites, monosodium glutamate, benzoic acids, and tartrazine dyes can also trigger reactions. Many heavy metals like lead, cadmium and mercury may be found in foods and may trigger severe metabolic reactions especially through the glutathione pathway with resultant gynecological dysfunction. All of the food parameters tend to increase total body burdens in the PMS patient.
Water contains minerals, toxic organic and inorganic chemicals, particulates, and radiation. Mineral content has an effect on the vascular and other smooth muscles. Water with high calcium and magnesium content tends to have a soothing effect on the smooth muscle of blood vessels and probably the gynaecological organs. We have seen the immediate cessation of severe premenstrual cramps with the administration of magnesium intravenously. Those waters with a high sodium content tend to accentuate the frequent oedema problems of PMS. Most public water supplies are not only contaminated by the chlorination process, but also at the source of the water. Drinking and bathing water sources are from lakes, wells, and ponds. Most of this water comes from:
Radiation occurs naturally in some water due to the emission from the earth. The content varies depending on where and which type of stone the water comes from. External radiation can come from rain run-off from nuclear plants as seen dramatically in the Chernobyl accident.
In 1965, a serious drinking water problem existed in one in 25 patients hospitalized in the Environmental Control Unit. Today it is up to 80 per cent. Patients susceptible to water contaminants usually exhibit multiple sensitivities with advanced chemical susceptibility problems especially to airborne chemicals; 50 per cent of these menstruating females admitted to the Environmental Control Unit have severe PMS problems. They often experience some PMS symptoms which are triggered by water contaminant problems and cannot clear until this aspect is eliminated by using one of the less contaminated waters such as spring, distilled, or charcoal filtered. The water also must be contained in glass or steel rather than plastic in order to avoid recontamination.
Air pollution has long been known to enhance disease processes. There are basically two types, outdoor and indoor.
Outdoor Air Pollution
According to Environmental Protection Agency studies (Gilpin, 1978), there has been no fresh air in the USA in 20 years. This probably holds true for the UK and Europe as well. Air pollution can arise from natural sources such as volcanoes, forest fires, marshes, and animal emanations which account for 55 per cent of the world air pollution. However, 45 per cent comes from man-made sources such as factory, automobile, beating and electrical generating plant emissions. Of course, around urban areas major sources are manmade far exceeding the natural sources. Smog, the combination of fog and man-made pollution can be devastating as was seen in London earlier in the century and Los Angeles at the present. Weather conditions and terrain can markedly change air pollution, while cities now generate their own autogenous heat islands and local weather. Worse case situations occur due to subsidence and radiation inversions where there is a cap of stable pollution topping the city to accentuate more pollution from a layer coming from the lower levels. This is the worst of all possible conditions and can increase the pollutant gradient thousands of times. Inversions will make living more hazardous and often accentuates the PMS in already susceptible people. The major outdoor air pollutants include sulphur dioxide, nitrous oxide, carbon monoxide, ozone, particulates (pollens, moulds, hydrocarbons), lead with other heavy metals and chlorinated compounds and cyanides. Most of these pollutants have been shown to trigger various detoxification systems by the generation of free radicals. Many PMS patients find that when they go to areas of less polluted air their syndrome disappears only to return when they get back to areas of higher air pollution.
Indoor Air Pollution
Indoor air is now the most polluted place in our environment. This is due to the sealing of buildings to prevent heat and cold loss, and the stocking of homes with rapidly disintegrating synthetics. The most common cause of problems in the new homes less than three years of age are the stains, dyes, solvents, paints, and formaldehyde-impregnated plywood, pressboard, and gypsum board. Alkanes, alkabenzenes, and terpenes are also present. In addition older homes contain petroleum alcohols and moulds. Gas, oil or coal stoves and heaters are the most common offenders that increase total body burden in the home environment. These are followed by routine use of pesticide. Other significant contaminants are foam stuffed furniture and mattresses, synthetic fabrics, termite proofing, Scotch gard finishes, dry cleaned clothes, washing detergents, chlorinated compounds, and other solvents.
Blood levels of pesticides and volatile organic hydrocarbons in patients with environmentally influenced PMS usually contain numerous pollutants found all around us in the air, water, and food (Figure 1 and Table 1). These and their relatives apparently are a significant part of total body load disturbing both the immune and enzyme detoxification systems. Then disturbed metabolism occurs with the resultant PMS.
EHC-Dallas has seen 200 patients with severe PMS, who had to radically alter their home environments in removing pollutants just described in order to decrease their syndrome, e.g. they often reported that after the heating came on or spraying was done that they had a severe increase in their PMS and removal of these pollutants decreased their problems.
Applicability of Environmental Precepts to PMS
A less polluted environment in an isolated wing of the hospital was created. Other areas were sealed from all inlets. Double doors with air locks were used in order to prevent entry of contaminants. Air depollution devices were installed and no smoking, perfumes, or synthetics were allowed in order to decrease pollutants. Floors and walls were all ceramic. All food was grown in a less chemically contaminated environment in the relative absence of pesticides and herbicides. Less contaminated water includes spring, distilled, or charcoal filtered, all bottled in glass. Air analysis by particulate counters, gas chromatography, and mass spectroscopy was done daily inside and outside the unit revealing 80-100 per cent reduction of pollutants in the unit. The unit is free of formaldehyde and pesticides. Reports on several series of patients suffering from arthritis (Kroker et al., 1984), phlebitis (Rea et al., 1981), vasculitis (Rea, 1977), cardiac arrhythmias (Rea, 1980), asthma and recurrent sinusitis (Rea and Mitchell, 1982) have shown clearing with manipulation of environmental incitants without use of medication. Improvement of numerous laboratory parameters were seen including eosinophils, C-reactive protein, total and fractions of serum complements, T and B lymphocytes and immunoglobulins other than IgE, pesticide levels, volatile organic hydrocarbon levels, and brain functions in over 2000 environmentally sensitive patients. The patient can be taken off medications and not fed for two to seven days until she is deadapted in this less polluted environment. Challenge with (oral) water contaminants, food, food contaminants, and (inhaled) air can be carried out. The above principles, facts, and procedures were used as a scientific basis for evaluating the PMS patient.
Several characteristics seen in some PMS patients suggest environmental triggers; e.g. headache, cyclic oedema, drug sensitivity, inability to tolerate oral contraception, bloating, periorbital oedema, increased sinus congestion, post nasal drip, asthma, flare of skin problems, worse after each pregnancy, spontaneous bruising, petechiae, purpura, cold sensitivity, history of threatened abortion, inability to tolerate most medications, weather sensitivity, anaesthetic sensitivity, decreased tolerance for alcohol, food or alcohol craves, history of hypertension or pre-eclampsia. Severe odour sensitivity to perfumes, hairsprays, deodorants, gasoline, car exhaust fumes, pesticides, or formaldehyde is almost pathognomonic of environmental overload and is often seen in PMS patients.
Once a PMS patient is suspected of having environmental triggers, a symptom score sheet is done (Figure 2). Tracking of symptoms throughout a cycle is then easily accomplished. Patients are then evaluated to see if they have hormone sensitivity. Sensitivity to the hormones (luteinizing hormone, progesterone, and oestrogen) is assessed by the provocation neutralization technique either sublingually or intradermally. This is done by using 1:5 progressive serial dilution of each hormone individually, provoking and then relieving the symptoms and/or the wheal. One can frequently find a dose that will immediately stop symptoms. The first report of endocrine susceptibility demonstrated with skin testing was by Zondek and Bromberg in 1947. Heckel in 1953 treated by injection and cleared numerous patients. G. Fricke (personal communication) using the Lee-Miller method found immediate results with the intradermal provocation neutralization technique in PMS. Mabray et al. (1982) studied a large series of women with progesterone related symptoms (Table 2).
His technique of managing sensitivities by optimum-dose (provocative neutralization) testing and treatment using aqueous progesterone has been studied in 132 women having progesterone-related symptoms due to the menstrual cycle, pregnancy, or exogenous hormone administration. When extremely small doses of progesterone (0.0016 mg or below, up to a maximum of 2.5 mg) were administered following determination of specific dose requirement by skin testing, rapid and effective clearing of symptoms was observed (Table 3). With these individualized doses, symptoms cleared completely or almost completely within 30 min in the majority of patients. A single-blind technique was employed to rule out placebo effect (Mabray et al., 1982). Some common problems found to respond well to the procedure were nausea and vomiting during pregnancy (1 00 per cent), PMS (96 per cent), and dysmenorrhoea (84 per cent) (Table 3). Hormone sensitivities are then treated with the optimum dose therapy 0.05 ml of the appropriate dose which will either control the sensitivity and/or balance the hormonal dysfunction. The following schedule is used once this symptom neutralizing dose is found.
2. Progesterone: the prescribed dose, usually 0.05 ml of appropriate dilution (injection or sublingual), is taken daily with onset of premenstrual symptoms. Dosage may be taken up to four times a day to relieve symptoms. The dose on the day menstruation is expected should be held until onset of menses occurs. Then progesterone may be resumed if needed to control menstrual symptoms.
3. Luteinizing hormone: the prescribed dose, usually 0.05 ml of appropriate dilution (injection or sublingual), is taken daily one to two weeks prior to onset of menses when symptoms occur and are not neutralized by oestrogen and progesterone. Dosage may be repeated up to four times a day.
Many PMS patients have symptoms related to an overgrowth of the vaginal and/or gastrointestinal tracts with yeast (especially Candida albicans) and other fungi. In these cases yeast and high sugar containing foods such as cheese, vinegar, alcohol, sweets, and breads are discouraged. Also local and systemic anti-fungal therapy are applied. Nystatin 500 000 units twice daily for two to three months may be needed. Ketoconazole 200 mg daily for one to two weeks can be used or oral amphotericin-B 250 mg, three times a day, for two weeks may be used. Oral douches of chlotrimazole may be used up to four times a day for one month plus vaginal douches daily.
Correction of nutritional deficits is important when trying to correct vascular or other smooth muscle pollutant damage.
b-Carotene and vitamin A are used as potent antioxidants, being shown to affect free radicals, adversely. They also fight bacteria and other infections, maintain healthy epithelial tissue, and are essential for a normal menstrual cycle in the female. Up to 5000 i.u. daily for one to two months has been used in our centre without side effects. b-Carotene is preferable because it is less prone to rancidity and thus will trigger fewer free radicals. The patients with vascular acne-like lesions sometimes will respond to vitamin A-cis-retenoic acid. Care has to be taken here due to the multiple potential side effects (Pfeiffer, 1975). Careful monitoring of vitamin A compounds should be carried out to avoid liver damage. Vitamin A has been shown to blunt the effects of radiation probably through its free radical scavenger effect. It should not be taken for a long period of time without attempting to find the triggering agents. Vitamin A toxicity is rare but is characterized by irritability, headaches, skin desquamation, vomiting and loss of appetite.
PABA (para-aminobenzoic acid) will decrease the toxicity of ozone by neutralizing the free radical formation of lipid peroxidation (Goldstein et al., 1972). Deficiencies in thiamine, riboflavin, niacin, and pyridoxine enhance the toxicity of PCBS. Pyridoxine is a cofactor in many reactions in intermediary metabolism and has been shown to be of value in relieving the symptoms of PMS. Doses of up to 100 mg daily may be given. Care should be taken to be sure that adequate absorption occurs since some pollutant sensitive patients have selective malabsorption. Pyridoxine also helps to maintain the sodium balance. Many of the PMS patients can also have their central nervous system symptoms improved by the administration of thiamine, riboflavin and niacin in addition to vitamin B12. Vitamin B5 (pantothenic acid) is a component of co-enzyme A which serves in metabolic reactions involving transfer of acetyl groups. Symptoms of deficiency are headache, nausea, occasional vomiting and abdominal cramps.
Vitamin C can be depleted with chemical exposures particularly to substances like benzene (Forsman and Frykholm 1947), carbon monoxide (Zaffiri et al., 1971), ethanol (Yunice and Lindeman, 1979), smoking (Pelletier, 1975), nitrous compounds (Varghese et al., 1978), vinyl chloride (Gedigk et al., 1975), heavy metals (Samitz et al., 1968) and pesticides (Chakraborty et al., 1978). Amorphous ground substance of the vessel wall is somewhat dependent on vitamin C. Vitamin C supplements can be used to not only strengthen the blood vessel wall but also used as a free radical scavenger and antioxidant. Usually a range of 1-10 g day-1 of powdered vitamin C has been used in patients with vascular and PMS dysfunction. One must be careful of the source of carbohydrate excipients in vitamin C tablets since many individuals become intolerant of the food of origin, such as corn, sago palm, potato, and carrot, as well as the excipients of talc, silica, etc. The powder is much safer. Excessive use of vitamin C may cause gas and diarrhoea.
Vitamin D is needed to help regulate calcium metabolism. Those who live in northern climates have more difficulty generating vitamin D due to less exposure time to the sun. It has been shown that those persons living where the oxidant pollutant levels are high may have a concomitant decrease in vitamin D accumulations by as much as 15 per cent over a 25 year period. Pasteurization also eliminates vitamin D. Supplementation must be carefully monitored in order to avoid toxicity. Excess leads to hypercalcaemia. The safest therapy is exposure to sunlight.
Vitamin E has been used in some vascular and PMS patients. It is particularly important in maintenance of lipid membrane integrity and the preservation of tissue polyunsaturated fatty acid content. Deficiency results in more inflammation in animals while oral Vitamin E has been shown to stop lipid peroxidation (Menzel, 1976). Clearly vitamin E is not only a free radical scavenger but also a stabilizer of the cellular membranes. It has been shown to be an effective anti-pollutant. From 400 to 1400 units per day have been used.
Calcium is clearly a mineral that is necessary for membrane stability and thus vascular wall tone. It also is a co-factor in many metabolic steps. Calcium has been found to be inversely proportional to radiostrontium thus it would be of use in protecting a patient against this pollutant (Nordin et al., 1967). Doses of 1-3 g of calcium have been given daily to patients with vascular disease and PMS and have been found to stabilize cell membranes. It has reduced the damage caused by carbon tetrachloride ingestion in animals.
Magnesium is a membrane stabilizer. It is complexed with ATP and ADP and therefore is a mandatory co-factor for all kinases and other enzymes containing magnesium. The daily dose is 500 to 1000 mg.
Surgery on the PMS Patient
EHC - Dallas has eight patients who were severely incapacitated with their PMS after all of the aforementioned modalities. They were all in their late 30s and wished to have no more children. Oophorectomy was preferred with satisfactory results in this highly selected group. Each was able to tolerate hormone supplementation where she previously could not. Follow-up from one to eight years has shown continued improvement.
Stress management may be needed in many of these patients including the family. This lifestyle change may be accomplished in many ways. Biofeedback, relaxation therapy, imagery, and tension awareness as well as individual and group psychotherapy are used in our centre.
In conclusion it may be said that there are some new methods which have promise for the effective treatment of PMS. Today, however, the best mode of treatment and prevention of most PMS symptoms is avoidance of incitants, replacement of nutrients, and hormone neutralization and replacement.
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Parts-per-billion in serum
Parts-per-billion in serum
Figure 1. General volatile screening test (GVST)-an example
Table 1. Chlorinated pesticide screening test (CPST) - an example
Results Frequency Arithmetic
Compound (ng ml-1 ppb) per 100 mean
Aldrin <0.1 5.0 <0.1
Dieldrin <0.1 61.9 0.2
a-BHC <0.1 9.8 <0.1
ß-BHC <0.1 67.9 0.8
y-BHC <0.1 2.2 <0.1
s-BHC <0.1 0.3 <0.1
DDT <0.1 46.3 0.2
DDE <0.1 98.2 4.2
DDD <0.1 1.7 <0.1
a-Chlordane <0.1 0.7 <0.1
y-Chlordane <0.1 1.1 <0.1
Heptachlor <0.1 0.5 <0.1
Heptachlor epoxide <0.1 80.8 0.6
trans-Nonachlor <0.1 83.3 0.2
Endosulphan I <0.1 6.3 <0.1
Endosulphan II <0.1 0.7 <0.1
HCB <0.1 94.9 0.5
Endrin <0.1 2.3 <0.1
Base study group Blind study group
(N = 100) (N = 32) Total (N = 132)
覧覧覧覧 覧覧覧覧 覧覧覧覧
Marked or Marked or Marked or
complete complete complete
No. relief % No. relief % No. relief %
Dysmenorrhoea 37 32 86 6 4 67 43 36 84
Headache 29 26 90 10 10 100 39 36 92
Backache 14 13 93 11 10 91 25 23 92
Abdominal pain 11 10 91 9 8 89 20 18 90
bloating 2 2 100 4 4 100 6 6 100
Neck, leg, and hip pain 4 3 75 6 5 83 10 8 80
Breast pain 2 2 100 5 5 100 7 7 100
Nausea 18 16 89 2 2 100 20 18 90
depression 26 25 96 18 17 94 44 42 95
Vertigo, dizziness 6 6 100 6 6 100
Fatigue, weakness 3 3 100 7 6 86 10 9 90
Flushing, hot flashes 1 1 100 3 2 67 4 3 75
Urticaria of pregnancy 1 1 100 1 1 100
Tinnitus 1 1 100 1 1
Many patients presented with more than one complaint. Mabray et al., 1982.
Hormone Hormone Concentrate
Oestrone Oestrone 2 mg ml -1
Progesterone Progesterone 50 mg ml -1
Luteinizing Luteinizing 20 000 USP units vial (10 ml vial)
Dilution (mg) Symptoms Wheal
No. 1 0.25 ml3 1/5 2.5 Provoked 11 x 11
No. 2 0.05 ml3 1/25 0.5 Same 9 x 9
No. 3 0.05 ml3 1/25 0.1 Relieved 7 x 7
No. 4 0.05 ml3 1/625 0.02
No. 5 0.05 ml3 1/3125 0.004
Examples of intradermal injection for method of determining correct dose by the Lee-Miller method for hormonal treatment for relief of PMS symptoms. If no symptoms provoked the first dose that gives a 7 x 7 wheal will usually be the neutralizing dose.
(sublingual or injection) menstrual symptoms. May
repeat up to four times a
Luteinizing 0.05 CM3 of appropriate dilution Daily one to two weeks
hormone (sublingual or injection) prior to onset of menses.
May repeat up to four
times a day.