Reprinted from THE JOURNAL OF REPRODUCTIVE MEDICINE, Vol. 32 No. 6, June 1987
The clinical, biochemical and endocrine effects of a total dietary program were evaluated in patients with the premenstrual tension syndromes (PMTS). The program consisted of dietary guidelines and nutritional supplementation. Open trials suggested that an initial dosage of the supplement consisting of six tablets daily gave the best symptomatic relief during the first three to six months. Double-blind studies confirmed that a daily average of six tablets decreased PMTS symptom scores to significantly lower levels than did the placebo. A significantly higher percentage of PMTS patients reported feeling better on the dietary program than did those on the placebo. Although significant changes were observed in some liver function tests, the values were within the normal ranges. The dietary program, implemented for three to six months, decreased serum estradiol 17-β and increased serum progesterone levels during the midluteal phase in PMTS patients. Nonresponders using the program should be reevaluated and treated according to the results of the reevaluation and the PMTS symptoms.
In a recent survey of 502 U.S. physicians,81 90% said that they provided and 60% said that they recommended diet and nutritional supplements in the management of the premenstrual tension syndromes (PMTS). However, the kind of dietary recommendations made by those physicians and the rationale for the recommendations were not given. There is no general agreement on the nutritional program best suited to PMTS patients. We have proposed dietary recommendations based on PMTS symptom subgroups.5-7 Our purpose here is to define the PMTS subgroups and our nutritional program and to evaluate the clinical, biochemical and endocrine effects of this regimen on PMTS patients.
Although 150 symptoms have been added to the list of PMTS symptoms since Frank’s original publication88, 120 on the subject, most are not common and usually represent an exacerbation of a preexisting condition. The most common symptoms for which PMTS patients seek medical advice and relief can be divided into four subgroups.6 Each subgroup may exist alone or in combination with other subgroups.
The chief complaints of patients in the PMT-A category are anxiety, irritability and nervous tension, occurring as early as the midcycle, becoming progressively worse during the luteal phase, sometimes followed by mild to moderate depression and improving with menses. This PMTS subgroup is the most common one. Stieglitz and Kimble 116 found it in 68% of PMTS patients evaluated; Morton,90, 91 in 100%; Rees110 in 73-80%; and Mukherjee,93 in 77%. We found a prevalence of 66% in 702 PMTS patients evaluated.61
The PMT-H subgroup is characterized by a premenstrual sensation of weight gain, abdominal bloating and tenderness, breast congestion and mastalgia, and occasionally edema of the face and extremities. The actual premenstrual weight gain is <3 lb except in severe PMT-H, in which a premenstrual weight gain >5 lb is observed. With increased age, the weight gain is not completely lost with menses, and problems with overweight occur.
This subgroup is the second-most-common PMTS subgroup and occurs in 60-66% of PMTS patients. Mukherjee found a 60-66% incidence of PMT-H in his PMTS patients. Sutherland and Stewart118 observed a PMT-H prevalence of 63%. We found PMT-H in 65% of PMTS patients.61
The PMT-C subgroup is characterized by an increased premenstrual appetite and craving for sweets (mainly chocolate), with subsequent ingestion of large amounts of refined sugar, followed a few hours later by fainting spells, fatigue, palpitation and headache. This indulgence in eating sweets occurs during stressful situations, or at least in situations perceived by the patient as stressful. Smith and Saunder115 found a positive correlation between a premenstrual craving for sweets and a feeling of tension. Liebowitz and Klein79 postulated that the craving for chocolate is due to its high content of phenylethylamine and that these patients are deficient in central nervous system phenylethylamine, a psychotropic substance believed to act by stimulating dopamine release. Morton observed PMT-C symptomatology in 44% of PMT sufferers. We have found a prevalence of 24% in women suffering from PMTS symptomatology
In PMT-D patients, the PMTS is characterized by premenstrual depression, withdrawal and suicidal ideation followed by a suicide attempt. PMT-D patients complain of being lethargic, confused and incoherent and of having difficulty verbalizing. They usually do not seek medical care on their own but are brought to a psychiatrist by concerned friends or relatives. This PMTS subgroup, in the absence of PMT-A, requires psychiatric consultation. Tonks120 observed that suicide attempts and suicides occur premenstrually mote often in PMT-D patients who do not complain of experiencing PMT-A symptomatology than in PMT-D patients who do.
Fortunately, PMT-D frequently follows PMT-A and rarely occurs alone. Stieglitz116 reported depression to occur in 36% of 67 PMTS patients but stated that the depression was associated with irritability. Mukherjee93 found depression in 13.5% of 74 patients evaluated, but PMT-D was the prominent symptomatology in only 1.3% of the patients. We found a 1.7% prevalence of pure PMT-D and a 23% prevalence of combined PMT-A and PMT-D.61
A menstrual symptom questionnaire (MSQ) and a menstrual symptom diary (MSD) were developed for screening and evaluating PMTS.6 The criteria for PMTS classification require that there be a symptom-free interval for at least one subgroup during the week following the end of menses and a worsening during the luteal phase, with symptoms rated premenstrually as moderate to severe.
The postulated pathophysiology of the PMTS sub groups has been described.5-8
Prior to initiation of the nutritional program, the possibility of serious medical problems and life threatening diseases should be ruled out with a careful history, complete physical examination and routine hematology, urinalysis and blood chemistry.6 Psychologic testing during the follicular phase of the menstrual cycle will assist in detecting any underlying psychiatric problems. A nutritional survey is warranted in every PMTS patient prior to treatment since any dietary recommendation must take into account prior dietary habits and life-style. Because the intake of calories, fats, carbohydrates and proteins fluctuates during the menstrual cycle, with significant increases premenstrually, 9, 43 the nutritional survey should be performed during both phases of the menstrual cycle. There is also a significant increase in energy expenditure premenstrually127that could explain discrepancies in the reported caloric requirements of healthy women.98
PMTS patients should be checked carefully for alcoholism. It has been estimated that there are 2 million alcoholic women in the reproductive-age group in the United States.42 Sixty-seven percent of alcoholic women relate their drinking to the menstrual cycle, and drinking bouts occur almost always during the premenstruum, supposedly to relieve anxiety and nervous tension.22
A careful breast examination is warranted, not only to detect mammary dysplasia but also to screen for breast cancer. Patients with PMTS, mainly those scoring high for PMT-A, have a luteal phase deficiency.10, 19, 32, 94 One prospective study of 1,083 infertile patients revealed that the risk of breast cancer was 5.4 times greater in women with a luteal phase (progesterone [P]) deficiency than in those with a normal luteal phase and normal P levels.36 Therefore, PMT A patients should be considered at high risk for breast cancer. The prognosis seems to be better when breast cancer is detected during a routine examination by a physician than when discovered accidentally.30
Determination of serum prolactin and thyrotropin releasing hormone and a thyroid hormone evaluation are indicated in PMTS patients with galactorrhea to rule out pituitary and thyroid abnormalities.62, 71 Serum P and estradiol-17β (E2 during the midluteal phase may assist in assessing an adequate luteal phase in PMTS patients with unexplained infertility and may serve as a guideline before and during different treatment modalities.14 The role of serum and red blood cell magnesium is still at the research stage, and more clinical studies are needed to assess the mineral’s usefulness in the evaluation and treatment of PMTS.2-12
In PMTS patients with hirsutism, an adrenal suppression test is indicated to rule out life-threatening pathology of the adrenal cortex and ovary, to locate the source of the androgen excess and to guide therapy.13 Some PMT-D patients with hirsutism respond very well to the suppression of adrenal androgens. Increased peripheral E2 and a concomitant clinical improvement in depression are observed in such cases.7
Hyperandrogenized PMTS patients do not respond well to the nutritional program unless it is combined with androgen suppression of the ovary and/or the adrenal cortex.3
The nutritional program we recommend is based on dietary surveys of normal women and PMTS patients,55 the postulated pathophysiology of PMTS6 and the most recently published data on the role of nutrients and their end products on PMTS-related symptomatology.3-6
A nutritional survey of 14 normal women and 39 PMTS patients revealed a significant difference in the consumption of some macronutrients.55 The PMTS patients consumed more refined sugar, refined carbohydrates and dairy products than did the normal women. Women with PMT-A symptoms consumed more protein, more dairy products and more refined sugar than did PMTS patients without PMT-A.2 Although the percentage of calories from fats and proteins was not significantly different between PMTS patients and normal women, the sources of fats and proteins were predominantly vegetable products in normal women and animal in PMTS patients. Dietary fiber intake was twice as high in normal women, with an average of 12 g/d in PMTS patients (Table I).
The dietary recommendations for macronutrients displayed in Table I can be translated into some acceptable menus with the help of a dietician or nutritionist. Food preferences and allergies should be taken into consideration when preparing such menus.
Carbohydrates. Carbohydrates can be divided into complex (starch, glycogen, fiber) and simple sugars (monosaccharides and disaccharides).25 Complex carbohydrates can be divided into digestible (calorigenic) and nondigestible carbohydrates (fiber).
Dietary fiber plays an important role in the digestion and absorption of macronutrients and micro- nutrients, the metabolism of toxins and steroid hormones, and colonic functioning.38, 47, 56, 72, 111, 124 Although an adequate fiber intake is important for good health, an excess intake may be detrimental to the absorption of certain trace elements.95 A daily intake of 20-40 g of dietary fiber is recommended for PMTS patients.
Patients with PMT-A symptomatology have elevated serum estrogen levels.5-25 Food fiber increases the intestinal clearance of estrogen. A recent study analyzed peripheral and fecal estrogen and fiber in take in ten vegetarian and ten omnivorous women who were menstruating regularly.56 The omnivorous women consumed 11-13 g of fiber per day as compared to 25-33 g per day for vegetarian women. A significant negative correlation between fiber intake and blood estrogens and a positive correlation between fiber intake and fecal estrogen suggest that food fiber increases the clearance and fecal excretion of estrogen. Blood estrogen levels were significantly lower in the vegetarian women than in the omnivorous ones. Since women with breast cancer consumed significantly less fiber than vegetarian controls,15-64 and since women with severe constipation from a lower fiber diet have a high prevalence of precancerous lesions of the breast,101 this finding has physiologic and clinical significance.
We recommend that 15% or less of the total calories be derived from simple carbohydrates and that complex vegetable carbohydrates represent at least 40% of the calories consumed.
Simple carbohydrates ingested in large quantities have deleterious effects on all PMTS subgroups. In PMT-C patients, complex carbohydrates are preferred over simple sugars because they stimulate insulin release in a less abrupt and more sustained manner. A comparison of solid and liquid forms of sugar revealed that sugar ingested in solution has a greater effect on insulin release than when ingested in solid form.114
An increased consumption of simple carbohydrates favors the transfer of tryptophan from plasma to the central nervous system.132 It will result in a central nervous system (CNS) serotonin dominance, mainly if plasma free tryptophan is elevated from a meat-containing diet. The increase in CNS serotonin results in nervous tension, drowsiness, an inability to concentrate and water retention.6
Ketoacid formation occurs when insulin is low and the ingestion of simple carbohydrates minimal.7 After the ingestion of large amounts of sugar, the insulin level increases abruptly, suppressing ketoacid formation and thereby causing sodium and water retention, extracellular fluid volume expansion and PMT-H symptoms. Sodium retention following the ingestion of sugar is resistant to aldosterone inhibitors and shows little correlation with the aldosterone secretion rate.50 Insulin-induced sodium retention plays a significant role in some PMT-H patients. In such cases, PMT-H may be present in spite of normal and low aldosterone levels. By one to two days, weight gain follows the overconsumption of sweets. Besides the ketoacid mechanism of sodium retention by sugar-triggered insulin release, there are two other possibilities: the hypoglycemic episodes89, 90 in PMT-C could trigger aldosterone secretion via ACTH release63 or cause water retention via vasopressin release.21
Lipids. PMTS patients derive 40% of their calories from dietary lipids, consuming twice as much animal fats as vegetable oils.52 The dietary goals for these patients are a decrease to 30% of calories from fat and a saturated:unsaturated ratio of 0.5, with monounsaturates and polyunsaturates equally distributed (Table I). The monounsaturates and polyunsaturates should come predominantly from vegetable oils in order to emphasize oleic, cis-linoleic and a-linolenic acid. Good sources of these unsaturated fatty acids are, respectively, olive, safflower and linseed oil. The ingestion of animal fats and hydrogenated vegetable oils should be curtailed in order to minimize the in take of arachidonic acid, saturated fatty acids and transunsaturated fatty acids.
Explaining the rationale for the above recommendations requires a review of the role of certain essential fatty acids as precursors of prostaglandins84 and other compounds that have important physiologic effects (Figure 1). Arachidonic acid, present in animal fats, is the precursor of the series 2 prostaglandins, PGE2 and PGF2a; the leukotrienes; and other compounds (Figure 1). Besides causing inflammation of the breast and other tissues, the leukotrienes, in minute amounts, elicit severe bronchospasm in humans128 and could play an important role in the premenstrual exacerbation of asthma.52
Cis-linoleic acid, present in most vegetable oils in large quantities, is the precursor of the series 1 prostaglandins, PGE1 and PGF1α. As we previously reported, the series 1 prostaglandins have beneficial effects and series 2 have deleterious effects on PMTS symptoms.6 The conversion of cis-linoleic acid to arachidonic acid is very limited in adult humans.27 The yield of series 2 prostaglandins from arachidonic acid is 71%, whereas that of series 1 prostaglandins from cis-linoleic acid is <5%.27 The fatty acid dihomogammalinolenic acid (DGLA) is not available in the diet in significant quantities but is derived from the metabolism of cis-linoleic acid with the help of magnesium,28 niacinamide and vitamin B6 (Figure 1). The yield of series 1 prostaglandins from DGLA is 68%,27 therefore equivalent to the yield of series 2 prostaglandins from arachidonic acid. For the above reasons, the dietary ratio of cis-linoleic to arachidonic acid must be very high (at least 100:1) in order to maintain the proper balance between the series 1 and 2 prostaglandins. Intake of saturated and hydrogenated transfatty acid blocks the conversion of cis-linoleic acid to DGLA.75 Margarine, for example, is 10-65% transfatty acid and is consumed in large amount by young U.S. women.123 This dietary pattern would be detrimental to the synthesis of series 1 prostaglandins. Limiting the intake of these fats would increase the yield of series 1 prostaglandins from cis-linoleic acid.70
Oleic acid is preferentially oxidized and used as a source of calories as compared to cis-linoleic acid. Therefore, oleic acid has a sparing effect on linoleic acid, which then can be utilized as a precursor of series 1 prostaglandins. The fatty acid a-linolenic acid is the precursor of series 3 prostaglandins and eicosapentanoic acid (EPA) and has a modulating effect on the synthesis of series 1 prostaglandins.83 The fatty acid EPA suppresses the synthesis and release of arachidonic acid and its further metabolism to the series 2 prostaglandins and leukotrienes.27, 107
Both arachidonic acid and DGLA are stored in the cell membrane as phospholipids.46 The fatty acid composition of cell membranes, the main sources of prostaglandin precursors, change within one week to reflect the fatty acid content of the diet.46 Therefore, the effect of dietary modification on prostaglandin synthesis is relatively rapid. The enzyme phospholipase A2 releases these fatty acids for prostaglandin synthesis.77 The physiologic and clinical effects of phospholipase A2 stimulation would depend on the type of fatty acids present in the phospholipids of the cell membrane and also on the fatty acid composition of the diet consumed during the previous week. Since phospholipase A2 activity is influenced by zinc, magnesium and vitamin E,6, 39, 58, 99 the clinical effects of these micronutrients would depend on the diet of PMTS patients consuming these micronutrients. Besides its effect on phospholipase A2, vitamin E blocks lypoxygenase activity and therefore suppresses leukotriene formation.59
Another mechanism by which fatty acids influence PMTS-related symptomatology is by their effects on estrogen metabolism. A recent study compared blood and fecal estrogen levels in 10 white and 12 east Asian premenopausal women.57 The white women consumed 40% of their calories as fats, whereas only 22% of the calories consumed by the Asian women came from fats. The Asians consumed twice as much unsaturated as saturated fatty acids, where as the whites ingested equal amounts of saturated and unsaturated fats. The fecal estrogen level was significantly higher and blood estrogen level significantly lower in the Asian women. Since elevated peripheral estrogens are associated with PMT-A symptoms,5-7 decreasing the intake of fats may improve PMT-A symptoms. The authors57 found no correlation between blood estrogens and polyunsaturates but a highly significant and positive correlation between blood estrogen levels and saturated fats. Therefore, the emphasis should be on increasing the unsaturated:saturated ratio while lowering the total fats consumed.
Proteins. As a group, PMTS patients consume 30% more proteins than normal women do.55 There is a significant and positive correlation between the consumption of proteins and dairy products on the one hand and the severity of PMT-A symptomatology on the other.12 In 39 PMTS patients evaluated, the daily consumption (of protein, expressed as percentage of Recommended Daily Allowance (RDA), and dairy products, expressed as servings, was, respectively: no PMT-A = 140±15 and 1.33±0.41, moderate PMT-A = 239±28 and 2.8±0.5, and severe PMT-A = 376±59 and 5.7±0.88.12 The PMT-A patients consumed three times more animal protein than vegetable protein, whereas 14 normal women consumed on the average twice as much vegetable protein as animal protein. However, both normal women and PMTS patients consumed protein much in excess of the RDA. Daily protein intake in the U.S. has been fairly constant over the past 70 years, roughly 200% of the RDA, but the sources have changed. The percentage of protein from vegetables decreased from 48% in 1909 to 31% in 1970, while the percentage of protein from animal sources, including dairy products, increased from 52% in 1909 to 69% in 1970.102
Excessive intake of animal protein stimulates prolactin,31 insulin67 and luteinizing hormone (LH) secretions.66 Elevated prolactin causes luteolysis, predisposing to PMT-A symptoms.5 Hyperinsulinism increases glucose tolerance and predisposes to PMTC.6 Elevated LH levels increase the ovarian secretion of androgens,121 which suppress estrogen synthesis and predispose to PMT-D.4,7
Recent studies have suggested a significant effect of animal proteins on the length of the menstrual cycle.65, 66 Women who ate a vegetarian (meatless) diet had a shorter follicular phase and shorter menstrual cycle than when they ate a daily meat supplement, with a mean cycle length of 27 and 29 days, respectively, for the vegetarian and meat-containing diets.66 The basal LH levels were higher during the follicular and luteal phases of the menstrual cycle when the subjects ate a meat-containing diet. Isocaloric protein supplementation with soybean proteins, instead of meat, failed to modify the gonadotropin levels or the duration of the menstrual cycle. Women who ate a meat-containing diet had higher plasma-free tryptophan levels throughout the menstrual cycle than when they ate a soybean protein supplement.53 Since plasma free tryptophan is an active precursor of CNS serotonin levels53 and CNS serotonin has a stimulating effect on LH release,126 the increased CNS serotonin level following meat consumption could explain the effects of meat consumption on the menstrual cycle.
When two groups of healthy, menstruating women were placed on a diet of 1,000 calories per day for six weeks, with one group on a vegetarian diet and the other on a meat-containing diet, daily mood ratings on a visual analog scale were significantly higher in the women eating the meat-containing diet.105
Based on data obtained by Janiger68 regarding the prevalence of PMTS symptoms in the U.S., Japan and Greece (Table II) and data from the World Health Organization on the sources of proteins consumed by various nationalities (Table III), we compiled and plotted these two variables on x-y axes for three countries (Figure 2). The data, although limited in number, suggest an inverse relationship between the prevalence of PMTS symptoms and the vegetable:animal ratio of proteins consumed. If this relationship is valid, one would expect to find a low prevalence of PMTS in countries consuming proteins with a vegetable:animal ratio >2 and a high prevalence in countries where the ratio is <1.
Our recommendation is to lower total protein in take from 20% to 15% of calories consumed, with a vegetable:animal ratio of 2.
Although dietary surveys give an accurate index of the macronutrient intake, that is not the case for micronutrients since soil characteristics, methods of farming and processing affect the micronutrient con tent of foods. For this reason, supplementation of micronutrients is often required to increase the nutrient density of the food consumed.
A dietary survey of normal women and PMTS patients55 revealed that only two of the normal women were not ingesting nutritional supplements and that these two women were on a purely vegetarian diet at the time of the study. In comparison, 33 of the 39 PMTS patients did not consume nutritional supplements on a regular basis. The intake of B vitamins, iron, zinc and manganese was significantly higher in the normal women.
Vitamins. Some vitamins have been tested in PMTS patients, in open trials and under controlled conditions.104 Vitamin A, at daily doses of 100,000-300,000 IU for the last two weeks of the menstrual cycle, improved PMT-H symptoms in 87-93% of the cases but was less effective for PMT-A symptoms.17,26 The dosages of vitamin A found to be useful in PMT-H averaged 50,000-150,000 IU daily.17, 26, 104 The lowest dosage of vitamin A reported to cause toxicity in adults is 40,000 IU taken daily for many years.118, 48, 92 The recommended dosages of vitamin A in PMT-H patients are potentially in the toxic range. Zinc increases the mobilization of vitamin A from the liver, and vitamin E prevents the oxidation of vitamin A.1 Therefore, these two nutrients may lower the effective dose of vitamin A.
Vitamin E, at a daily dosage of 150 IU, improves PMT-A symptoms but has no effect on PMT-H, PMT-C or PMT-D. At a daily dosage of 600 IU it worsens PMT-A symptoms but improves PMT-C and PMT-D symptoms.80 Since selenium has synergistic effects with vitamin E,119 selenium supplementation may lower the effective dose of vitamin E in PMTS patients.
In an open trial, vitamin B6 at a daily dosage of 40-100 mg was found effective in 50-60% of 70 PMTS patients.74 In two control studies in which dosages of 100-500mg of B6 were used,11, 131 response rates of 82-84% were observed, and the placebo effect in both studies was significantly lower than the response to the vitamin.
Since vitamin C decreases the estrogen clearance rate29 and increases the biologic activity of estrogens, megadoses may be useful in PMT-D patients.
Minerals. PMTS patients consume a daily average of 100 mg of magnesium less and 200% more sodium than do normal women.55 The mean daily intakes of potassium and calcium have not been found to be significantly different between normal women and PMTS patients.
Low red cell magnesium levels have been found in PMTS patients.2, 12 In an open trial of 192 PMTS patients, magnesium supplementation during the week preceding menses significantly improved nervous tension, mastalgia and weight gain in 89-96% of the patients.96
PMT-A patients consume excessive amounts of calcium, mainly from dairy products.2 Since calcium interferes with the absorption and utilization of magnesium and other nutrients6, 130 and the main source of calcium in PMTS patients is dairy products, our dietary goal is to lower the intake of dairy products and increase the magnesium and potassium intake from vegetable sources. Limitation, but not restriction, of sodium is also advised.6
Trace Elements. Normal women consume twice as much iron and zinc and four times as much manganese as PMTS patients do. The intake of copper, selenium and chromium is not different between the two groups.55 So far there has been no published study on the effect of selected trace elements on PMTS symptoms.
We observed a significant and positive correlation between PMTS and premenstrual acne in 325 young women (X, M±SE = 25±2.5 years) attending a well-woman clinic (Table IV). Zinc deficiency has been found in acne patients,106 and zinc supplementation improved the acne score under double-blind conditions. PMTS patients with acne may benefit from zinc supplementation. At a daily dosage of 50 mg, zinc suppresses prolactin levels in hyperprolactinemic women without pituitary tumors.113 Since elevated prolactin levels suppress P secretion by the ovary104 and low P predisposes to PMT-A symptoms,7 zinc supplementation may be indicated in PMT-A patients with elevated prolactin not due to pituitary tumors. Increased urinary chromium excretion has been demonstrated in women following a glucose load.16 However, daily supplementation with 200 µg of trivalent chromium prevented glucose-stimulated chromium excretion. Since PMT-C patients consume excess amounts of refined sugar,55 chromium supplementation may be of value.
After ruling out serious medical problems, implementation of the nutritional program is warranted for a period of at least three months: our previous experience indicated that the best responses in PMTS patients were observed between three and six months on the program.49, 54
The assistance of a dietician or nutritionist is needed to formulate a menu appropriate in macronutrient content and proportions (Table I). Food allergies and preferences are important considerations in pre paring such a menu. In addition to the recommendations in Table I, patients should be advised that tobacco smoking suppresses estrogen levels,20, 82 predisposing to PMT-D,3 premature menopause69 and osteoporosis.44 For these reasons, patients should be advised against tobacco inhalation or chewing. Methylxanthine-containing foods should be limited because of their deleterious effects on breast cysts and mastalgia.86 ,87 Alcohol inhibits gluconeogenesis and promotes a distinct fall in plasma glucose,108 thereby predisposing to PMT-C symptoms. Alcohol intake should be limited to 5% or less of the calories consumed. We also recommend regular and moderate exercise in the form of a fast walk for three to five miles, five days a week.
For some of the micronutrients, we favor the use of supplements in order to guarantee a minimum intake and also to increase the nutrient density of the foods consumed.
As previously discussed,3,6 several micronutrients are required for the synthesis of prostaglandins from essential fatty acids and for the synthesis of CNS biogenic amines and neuropeptides from amino acids. A deficiency in some micronutrients may have a profound effect on the synthesis of these neuroactive substances. For example, iron deficiency decreases the synthesis of tyrosine from phenylalanine by 50%.78 Tyrosine is an important precursor of CNS cathecolamines109 (vide infra), such as dopamine, in which PMT-H patients are deficient.76 A mild copper deficiency has a significant effect on brain levels of endorphins, enkephalins and cathecolamines23 (vide infra).
Single-nutrient supplementation, although useful in PMTS patients when tested for a few months only,11, 80, 96, 130 may not be effective and safe when administered chronically.3
On the basis of published information regarding the role of certain micronutrients in PMTS-related symptoms, one of us (G.E.A.) formulated a nutritional supplement (Optivite, hereafter referred to as the PMTS supplement) high in vitamin B6 and magnesium and also containing other known micronutrients in quantities and proportions to meet or exceed the RDAs for these nutrients.103
The nutritional program consists of the guidelines detailed in Table I for macronutrients and administration of micronutrients orally (PMTS supplement). The dosages of micronutrients are adjusted within safe limits, according to the clinical responses obtained and side effects experienced by the patients.
The nutrients that are potentially toxic at the dosages used in the PMTS supplement are vitamin A1 and vitamin B6.40, 100, 112 The maximum recommended daily dosage of the PMTS supplement is 12 tablets containing 25,000 IU of vitamin A and 600 mg of vitamin B6.
Daily dosages of retinyl palmitate (vitamin A) ranging from 10,000 to 36,000 IU for a period of six months increase serum vitamin A levels significantly but do not place them in the toxic range.125 The supplement used in our program contains 25,000 IU of retinyl palmitate in 12 tablets, the maximum recommended daily dosage. Retinyl palmitate is preferred over carotene as a source of vitamin A because of serious side effects reported with hypercarotenemia —hypothalamic amenorrhea, leukopenia and neutropenia.73, 122
Vitamin B6 administration at daily dosages of 200—6,000 mg is associated with peripheral neuropathy in some women.99, 112 We have observed that when vitamin B6 is given alone (without other supplements), some women tend to develop B6 tolerance within six months and require an increased B6 dosage to produce the same symptomatic relief. We therefore do not recommend megadosages of vitamin B6 without the concomitant use of other important micronutrients.
Pyridoxine, the form of vitamin B6 used in the supplement, is biologically inactive. Two enzymatic steps are required for the conversion of pyridoxine to pyridoxal phosphate (PLP), the active form: phosphorilation of pyridoxine, which requires magnesium, and oxidation of pyridoxine phosphate, which requires riboflavin. The alternate pathway is oxidation of pyridoxine to pyridoxic acid, which is excreted in the urine.3 This alternate pathway is used when there is a block in the conversion of pyridoxine to PLP. If pyridoxine is the toxic form of vitamin B6, inefficient metabolism to PLP could be an important factor in B6 toxicity. We recently found an increased excretion of pyridoxic acid during the luteal phase of the menstrual cycle,1 suggesting a block in the conversion of pyridoxine to PLP during that phase.
Aldosterone increases the urinary excretion of magnesium and augments the formation of flavin nucleotides from riboflavin.3 Aldosterone levels are elevated during the luteal phase.3 Therefore, the hyperaldosteronism of the luteal phase could explain the block in the conversion of pyridoxine to PLP, due to depletion of magnesium and riboflavin. Since progesterone increases aldosterone secretion,97, 117 progesterone administration could predispose to vitamin B6 neurotoxicity. It is of interest in this regard that Dalton reported the largest series of B6 neurotoxicity to occur with a dosage of B6 as low as 50 mg per day.41 She prescribes extremely large dosages of progesterone to her PMTS patients.40
To minimize the side effects of vitamin B6 therapy, other micronutrients, mainly magnesium and other B vitamins, should be given together with vitamin B6. The dosage of the micronutrients should be adjusted every three months in order to use the minimum effective dosage.
Our nutritional program for PMTS has been recommended by physicians nationwide for several years. With an estimated 100,000 users, not a single case of hypervitaminosis A or B6 has been reported, due in part to the fact that the dosage of the PMTS supplement can be decreased within six months of use since the severity of PMTS symptoms improves significantly within that time.34, 49, 54
Effect of Nutritional Program on PMTS Symptomatology
The effects of the nutritional program on PMTS symptoms have been studied in open trials and con trolled studies.
Open trials are useful in assessing minimum effective dosages and possible side effects. In two uncontrolled studies involving 47 PMTS patients who were on the program for one to six months, the best responses were observed at a daily dosage of six tablets. Some patients required an increased dosage premenstrually, ingesting up to 12 tablets daily during the seven to ten days of the menstrual cycle, mainly when the MSQ score for the week before was > 30.49, 54 Symptom scores were lowest after three to six months on this regimen. Gastrointestinal side effects were observed occasionally at dosages greater than six tablets daily.54
In another open trial of the nutritional program, we assessed the importance of diet alone, PMTS supplementation alone and a combination of diet and PMTS supplementation in the management of PMTS. Four groups of patients were studied, with in formed consent, and each completed the MSQ for one control and three treatment cycles. Group I received no treatment except for a one-a-day vitamin. Patients with the lowest MSQ scores were placed in that group. Group II patients were only advised about the dietary recommendations, and no supplement was given. Group III patients received the PMTS supplement only at a daily dosage of six tablets, but no dietary recommendations were made. Group IV received both the PMTS supplement and dietary recommendations. Patients with the highest MSQ scores were placed in groups III and IV. Following three months on the one-a-day vitamins, the mean premenstrual MSQ scores were not significantly different from the mean scores in the control cycle (group I, Table V). The MSQ scores decreased more rapidly with the PMTS supplement alone than with diet alone. After three months, the differences between the pretreatment and posttreatment MSQ scores were significantly greater with the PMTS supplement than with diet alone (P< .05). When the data for each PMTS subgroup were evaluated, there was no significant difference between the effects of diet alone and PMTS supplementation alone on PMT-A and PMT-C symptoms. However, the PMTS supplement alone had a significantly greater effect (P< .01) than diet alone on PMT-H and PMT-D symptoms. Diet plus the PMTS supplement (group IV) gave results similar to those of the PMTS supplement alone. This study demonstrated that the carefully formulated nutritional supplement, tailored to PMTS patients, was effective in lowering PMTS symptomatology whereas a one-a-day vitamin had no significant effect. No side effects were reported.
The impact of PMTS on the social, familial and work performance of 313 women suffering from PMTS was self-assessed using a postal survey. The subjects were also asked to complete the MSQ. Following 2-60 months on the nutritional program, the above parameters were again evaluated (Tables VI and VII). When the degree of impairment caused by PMTS on social, familial and work performance was compared with the premenstrual MSQ scores, there was a significant (P< .01-.005) and positive correlation between the MSQ scores and the degree of interference on all three aspects of performance evaluated (Table VIII).
Following the nutritional program, there was a significant (P<.01-.005) and positive correlation between the initial MSQ scores and the degree of improvement in performance in all three parameters. There was a significant (P< .05) and negative correlation between the posttreatment MSQ scores and the beneficial effect of the program on performance in these three parameters (Table IX).
The subjects who assessed PMTS as having the most disruptive effect on their lives and who had the highest MSQ scores prior to the nutritional program and the lowest MSQ scores while on the program reported the greatest improvement, by self-assessment, in performance at home, at work and during social activities following dietary modification and nutritional supplementation. From the data in Table IX it is clear that the pre-post differences in MSQ scores have a positive relationship with degree of improvement observed: with a decrease in MSQ scores averaging 10 points or less, no effect or a slight improvement was reported; with a 15-point drop, a moderate improvement; and with 20 points, a marked improvement. Although the MSQ scores did not detect subtle changes in the quality of life, the MSQ appears to be a reliable index of the degree of disruption caused by PMTS and of the beneficial effect of PMTS management on familial, social and work performance as assessed by the PMTS sufferers.
The mean daily intake of the PMTS supplement decreased over time: 5.2 ± 0.36 tablets between 2 and 6 months, 4.8 ± 0.6 tablets between 7 and 12 months, 4.3 ± 0.48 tablets between 13 and 24 months and 3.2 ± 0.34 tablets over 24 months. Twenty-two subjects experienced side effects while on the program: 20 had gastrointestinal symptoms, and 2 experienced increased diuresis, which they considered and unpleasant side effect. Such an increase in diuresis would be expected in patients with PMTH symptoms following the program. The gastrointestinal side effects were gastric upset and nausea (13), loose stools (5) and constipation (2). The gastrointestinal side effects could be controlled with dosage adjustments and patient education on the importance of ingesting the PMTS supplement with meals.
Based on three double-blind studies of 254 PMTS patients (Table X), a dosage averaging six tablets daily lowered PMTS symptoms significantly as compared to placebo, but at a daily average dosage of three tablets, the effect of the PMTS supplement was not greater than that of the placebo. These studies were performed during a three- to four-month period, and at present we do not have controlled studies over a prolonged period to assess the minimum effective dosage over time. No side effect was reported with a daily dosage averaging up to six tablets in studies performed in the U.S., but in the two controlled studies by Stewart on British women (Table X), some 10% of the subjects ingesting the PMTS supplement at a dosage of three to six tablets daily experienced mild headache and diarrhea.
Biochemical and Endocrine Effects of the Nutritional Program
The effect of the nutritional program on blood chemistry was assessed in 16 PMTS patients with moderate to severe symptoms ingesting 6-12 tablets of the PMTS supplement daily.49 Blood samples were obtained prior to treatment and after three and six months on the program. There was a significant increase in serum fasting glucose, albumin, alkaline phosphatase, SGOT, SGPT and serum potassium. None of these parameters was above the normal range, however. There was a nearly significant drop in free bilirubin levels (P= .06). In six PMT-C patients with low fasting glucose levels, the levels in creased to normal following six months of nutritional therapy. Overall, improved liver function tests were observed in women on the program.
The effect of the nutritional program on the serum levels of E2,P, aldosterone and dehydroepiandrosterone sulfate (DHEA-S) during the midluteal phase was evaluated in 13 of the 16 PMTS patients.49 The mean E2 values were higher than normal during the control cycles. Following three to six months on the program, the mean serum E2 levels decreased significantly and reached normal values (Figure 3). Midluteal P levels were lower than normal prior to initiation of the nutritional regimen and increased significantly to normal levels after three to six months (Figure 4). There was a nonsignificant drop in serum aldosterone levels and no significant change in DHEA-S levels following three to six months of nutritional therapy.49
PMTS patients should be reevaluated as nonresponders in the nutritional program if, after three to six months of implementation, there is a less-than-moderate improvement in PMTS symptoms according to the MSQ and MSD scores (a decrease of <15 points in premenstrual MSQ scores from the control scores) and a less-than-moderate improvement in the negative effects of PMTS on the patient’s familial, social and work performance according to self- assessment. A reasonable trial period for PMTS patients with moderate symptoms (premenstrual MSQ score of < 30 points) is three months and for those with symptoms (premenstrual MSQ score >30), six months.
The algorithm in Figure 5 outlines the management of nonresponders in each PMTS subgroup.
When symptoms resistant to the nutritional program are in the PMT-.A subgroup, hyperthyroidism should be ruled out. The possibility of caffeinism due to an increased intake of caffeine-containing substances during the luteal phase should be assessed. If serum P:E2 ratio is low prior to and following three to six months on the program, P administration would be indicated using the smallest effective dose. We favor oral micronized P in a sustained-release form over vaginal or rectal suppositories, injections or implants because of better patient compliance6 and because it is the only mode of P administration shown to be effective in decreasing PMTS symptomatology under controlled conditions.33, 45
If the low midluteal P:E2 ratio is due to markedly elevated E2 levels (>300 pg/mL of serum), it is important to rule out ovarian tumors and cysts and other causes of increased E2 production. Potential causes of hyperestrogenemia in PMT-A patients are: (1) an increased production rate (increased ovarian secretion rate [ cyst, polycystic ovary syndrome, estrogen secreting ovarian tumors] or increased peripheral aromatization of androgens by adipose tissue [obesity]) and (2) a decreased clearance rate (decreased hepatic clearance from decreased blood flow [ vascular diseases, strenuous exercises] or decreased liver function, such as organic diseases [ cyrrhosis] and decreased enzymatic activity, including glucuronyl transferase and sulfokinase] or decreased intestinal clearance (decreased binding of estrogens in the intestinal tract, such as from a low-fiber diet or increased hydrolysis of conjugated estrogens by intestinal flora, such as from a high intake of animal fats]).3 E2 elevation from an increased E2 production rate does not respond well to nutritional therapy alone. A weight loss program is indicated in obese patients in order to decrease the aromatization of androgens by adipose tissue. Psychiatric consultation should be obtained if the above measures fail.
When symptoms not responding to nutritional therapy belong to the PMT-H subgroup, a careful charting of them over a period of one or more menstrual cycles should be performed to rule out idiopathic cyclic edema,74 in which the cyclicity of the symptoms is not related to the menstrual cycle.
A potassium-sparing diuretic may be tried for one to three cycles.33 Bromocriptine may be effective for breast-related symptoms. If in doubt about the possible etiology, the primary care physician should obtain an internal medicine consultation. Midfollicular and midluteal serum aldosterone levels may be used as an index of zona glomerulosa function and to rule out aldosterone-secreting adrenal tumors.
In PMT-C nonresponders, alcoholism should be ruled out by a careful reevaluation of life-style and alcohol intake.6 Large doses of P may aggravate PMT-C because of P’s hypoglycemic effects.6 Some PMT-C patients may be under the care of several clinicians, receiving different medications, including large doses of P. If this is the case, the P should be discontinued or the dose decreased to 300 mg a day, preferably using the oral form.
If headache is the predominant symptom, a neurologic consultation is indicated to rule out brain tumors.
If the midluteal P:E2 ratio is high due to low E2 levels, both prior to and following three to six months on the program, estrogen administration at a low dosage during the luteal phase is warranted in PMT-D nonresponders.7 In the presence of hypotyrosinemia, 3-6 g of L-tyrosine in the morning may be effective.5, 6 In cases of insomnia, 0.5-1.0 g of L-tryptophan at bed time may be of value.5, 35 If hirsutism is present, evaluation of hyperandrogenism of the adrenal and/or ovary is indicated.13 Saturnism should be ruled out by a careful evaluation of lead exposure at home, at work and from the environment6,60; if a positive history is obtained, blood and urine lead and red cell protoporphyrin levels are indicated. Psychiatric consultation should be obtained in patients with severe PMT-D.
The authors acknowledge the assistance of Kim Irvine, Dianne Tartaglini and Harriet Porter in the implementation and compilation of data from some of the studies described. The assistance of Wayne Dederick in statistical evaluation is also acknowledged.
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From Optimox, Inc., Torrance, California, and the Student Health Department, University of Colorado, Fort Collins.
Dr. Abraham is Medical Director, Optimox, Inc.
Dr. Rumley was Physician in Charge, Student Health Department, University of Colorado, Fort Collins, and is now retired.
Address reprint requests to: Guy E. Abraham, 2720 Monterey Street, Suite 406, Torrance, CA 90503.
This page was first uploaded to The Magnesium Web Site on July 19, 2002