The premenstrual tension syndromes (PMTS) represent a group of syndromes occurring premenstrually in a large percentage of women . The most common PMTS subgroup is PMT-A, characterized by a premenstrual increase in anxiety, nervous tension, irritability and mood swings . We will review recent data supporting an important role of certain nutrients on PMT-A symptomatology and propose some applications of this knowledge to the nutritional management of PMT-A.
Estrogens are central nervous system (CNS) stimulants and progesterone is a CNS depressant . Patients with severe PMT-A have elevated blood estrogens and/or decreased blood progesterone during the luteal phase of the menstrual cycle . The low progesterone/estradiol-17B ratio (P/E2 ratio) is the most consistent finding.
The mechanism by which estrogens and progesterone influence moods is not well defined. Estrogens and progesterone influence monoamine oxydase (MAO) activity. These enzymes are involved in the oxydation of biogenic amines, such as norepinephrine, epinephrine, serotonin, dopamine and phenylethylamine. These biogenic amines affect moods [5-10]. For example, epinephrine triggers anxiety; norepinephrine, hostility and irritability; serotonin at high levels creates nervous tension, drowsiness, palpitation, water retention and inability to concentrate and perform. Dopamine is believed to balance out the effects of these three amines by inducing relaxation and increasing mental alertness . There are two types of MAO: type A, which deactivates the first four biogenic amines mentioned above, and type B, which deactivates only dopamine and phenylethylamine . Estrogens suppress type A and increase type B-MAO activities, if whereas progesterone increases type A and suppresses type B-MAO activities [13-16]. Therefore, under estrogen stimulation, the deactivation of biogenic amines would be reduced mainly for type-A-MAO-sensitive amines, causing a relative imbalance, with excess serotonin, norepinephrine and epinephrine and a relative deficiency of dopamine. This imbalance would then trigger PMT-A symptoms.
In table I are outlined the dietary precursors of some neurotransmitters and the effects of these neurotransmitters on mood and behavior. A very important enzyme in the conversion of some dietary precursors to the corresponding neurotransmitters is decarboxylase. The active form of vitamin B-6, pyridoxal phosphate (PLP), is a required cofactor for the activity of this enzyme. Under chronic stress, decarboxylase may become the rate limiting step in the synthesis of these neurotransmitters . Three enzymatic steps are required for the synthesis of norepinephrine from the amino acid tyrosine: thyrosine hydroxylase, dopa decarboxylase and dopamine B-hydroxylase (fig. 1). Under chronic stress, tyrosine hydroxylase and dopamine-B-hydroxylase increase significantly without any change in dopa decarboxylase, making this latter enzyme rate-limiting. Such a condition would eventually result in a relative dopamine deficiency.
Fig. 1. Effect of chronic stress on the synthesis of CNS cathecolamines. Reproduced from Abraham .
Independent of estrogen and progesterone effects, magnesium deficiency may be involved directly in CNS dopamine deficiency. Although not yet confirmed in humans, studies performed in laboratory animals revealed that magnesium deficiency causes a specific depletion of brain dopamine without affecting brain serotonin and norepinephrine .
High intake of refined sugar favors the transfer of tryptophan from blood to the central nervous system where it is converted to serotonin . This dietary habit may therefore result in a CNS serotonin dominance and relative dopamine deficiency.
The increased blood E2 levels in PMT-A patients may be due to increased production rate or decreased clearance rate. Table II summarizes the factors possibly involved in the hyperestrogenemia of PMT-A patients. The increased E2 production rate could be the result of increased secretion rate by the ovary due to ovarian tumors, functional ovarian cysts and the polycystic ovary syndrome. PMT-A patients with increased E2 secretion rate do not respond well to nutritional therapy alone and require either surgery or ovarian suppression in order to respond to the nutritional approach.
Decreased clearance rate of estrogens by the liver could be due to organic lesions such as cyrrhosis. Pyridoxine requires phosphorylation to become active, and this phosphate transfer reaction is magnesium dependent. A magnesium deficiency may cause a relative B-vitamin deficiency. The Biskinds have demonstrated an important role of the B vitamins in the hepatic metabolism of estrogens [20-23]. Magnesium deficiency may therefore affect estrogen metabolism by decreasing the biological activity of the B vitamins. Vitamin B-6 increases cell membrane transfer and utilization of magnesium . By increasing utilization of magnesium, B6 may play a role in the metabolism of estrogens. Besides its effects on activation of the B vitamins, magnesium influences estrogens conjugation directly by increasing glucuronyl transferase activity , an enzyme involved in the hepatic glucuronidation of estrogens.
Another nutritional factor involved in decreased clearance of estrogens is the role of the intestinal tract in binding and excreting conjugated estrogens. Whereas food fiber increases binding and excretion of estrogens , animal fats stimulate the growth of intestinal bacteria, which are capable of hydrolyzing conjugated estrogens into biologically active free estrogens [27, 28]. These estrogens are then reabsorbed and contribute to the hyperestrogenemia of PMT-A patients. A recent study compared peripheral and fecal estrogens with fiber intake in 10 vegetarian and 10 omnivorous women who were menstruating regularly . The omnivorous women consumed 11-13 g of fiber/day compared to 25-33 g/day for vegetarian women. A significant negative correlation between fiber intake and blood estrogens; and positive correlation between fiber intake and fecal estrogens suggest that food fiber increases the clearance and fecal excretion of estrogens. Blood estrogen levels were significantly lower in the vegetarian women than in the omnivorous subjects. Since women with breast cancer consumed significantly less fiber than vegetarian controls , and women with severe constipation, due to a lower fiber diet, have a high prevalence of precancerous lesions of the breast , this is of physiological and clinical significance.
The low peripheral progesterone observed in some PMT-A patients could be explained by either decreased production rate and/or increased clearance rate (table III).
As previously discussed, nutritional deficiencies in B vitamins and magnesium lower the hepatic clearance rate of estrogens, with resultant hyperestrogenemia. The luteolytic effect of elevated estrogens could result in hypoprogesteronemia . Two other factors possibly involved in decreased progesterone production rate and independent from estrogen effect are precursor availability for the synthesis of progesterone and inhibition of this synthesis by the prostaglandin PGF2a. The corpus luteum depends almost exclusively on peripheral cholesterol for steroidogenesis . Low-density-lipoprotein-carried cholesterol (LDL-cholesterol) is the preferred substrate . Therefore, factors interfering with this mechanism could affect progesterone synthesis. Data available from recent studies by London et al. suggest that high doses of vitamin E may be luteolytic, probably by lowering LDL-cholesterol ( and vide infra).
An evaluation of the data available in London’s publications reveals that although a daily dose of 150 IU vitamin E raises midluteal serum P levels by 50% (luteotrophic effect), 300 and 600 LU daily were associated with lower P levels than control levels (fig. 2). Although such decreases in P levels were not significant, it is likely that dosage of vitamin E greater than 600 LU will result in greater P suppression. This may be the explanation for the worsening of PMT-A symptoms with 600 1U of vitamin E whereas 150 IU showed an improvement of PMT-A symptoms . The improvement of PMT-D symptoms by the administration of 600 IU of vitamin E  is also consistent with this explanation.
PGF2a is luteolytic in women . The precursor of PGF2a is arachidonic acid, present in animal fats. Consumption of excess animal fats increases precursor availability for the synthesis of PGF2a and therefore may cause luteal deficiency. This could be the mechanism by which an increased intake of animal fats predisposes to breast cancer , that is, by causing luteal deficiency, a high risk factor for breast cancer . The luteotrophic effect of small doses of vitamin F (150 IU or less) could be due to the inhibitory effect of vitamin Eon the release of arachidonic acid from storage pool, in this manner decreasing the availability of PGF2a precursors. The net effect of vitamin F on P synthesis would depend on the response of LDL-cholesterol and arachidonate release from storage pools to various dosages of vitamin E. It is possible that blockage of arachidonate release is more sensitive to vitamin E than suppression of LDL-cholesterol, such that low dose of vitamin E would decrease precursor availability for PGF2a synthesis (a luteotrophic effect) and high dose of vitamin E would suppress LDL cholesterol (a luteolytic effect).
As previously discussed, moods and behavior are influenced by biogenic amines present in the CNS. Some biogenic amines are excitatory and others are inhibitory.
Since PMT-A symptomatology represents an excitatory state of the CNS; the aim of the nutritional approach is to lower excitatory biogenic amines and to increase inhibitory biogenic amines. Vitamin B-6 is unique in its ability to perform this function. Not only does vitamin B-6 increase CNS levels of the inhibitory neurotransmitter dopamine, it also increases the conversion of CNS-active excitatory aminoacids to the corresponding inhibitory aminoacids. Certain diacidic aminoacids are CNS excitatory, but upon decarboxylation, the corresponding monoacidic, monobasic aminoacids have CNS-inhibitory effects . Vitamin B-6 is a required cofactor in this decarboxylation reaction (fig. 3). Therefore, the overall effect of vitamin B-6 on the CNS is an increased ratio of inhibitory/excitatory amino acids. Such an effect would result in sedation. Indeed, we have reported a significant effect of vitamin B-6 on PMT-A symptomatology, under double blind conditions . The daily dosage of 500 mg, however, was in the potentially toxic range. Recent publications have suggested that vitamin B-6 administration at a daily dose of 2000-6,000 mg results in peripheral neuropathy [39, 40]. We have also observed that when vitamin B-6 is given alone without other supplements, some women tend to develop a B-6 tolerance within 6 months, and require increased B-6 dosage to produce the same symptomatic relief. We therefore do not recommend prescribing megadose of vitamin B-6 alone.
Pyridoxine, the form of vitamin B-6 used in 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 oxydation of pyridoxine phosphate, which requires riboflavin (fig. 4). The alternate pathway is oxydation of pyridoxine to pyridoxic acid which is excreted in the urine . 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 B-6, inefficient metabolism to PLP could be an important factor in B-6 toxicity. We have recently reported an increased excretion of pyridoxic acid during the luteal phase of the menstrual cycle , suggesting a block in the conversion of pyridoxine to PLP during that phase of the menstrual cycle. Aldosterone levels are higher during the luteal phase . Aldosterone increases urinary excretion of magnesium and augments the formation of flavin nucleotides from riboflavin . 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 [44, 45] progesterone administration could predispose to vitamin B-6 neurotoxicity (fig. 5).
To minimize side effects of vitamin B-6 therapy, other micronutrients should be given together with vitamin B-6, mainly magnesium and the B-vitamins. Based on available data in the literature regarding dietary status of PMTS patients, an OTC nutritional supplement (Optivite) was formulated for use in the nutritional management of PMTS [30, 46]. Under double blind conditions, this supplement significantly decreased PMT-A symptomatology compared to placebo, when given at a daily dose of 6 tablets containing 300 mg of vitamin B-6 . Decreased serum estradiol-17B and increased serum progesterone levels were observed during the midiluteal phase of PMTS patients following 3-6 months of Optivite administration at daily dosage containing 300-600 mg of pyridoxine .There has been so far no reported case of peripheral neuropathy following this supplement, even though it has been prescribed by physicians nationwide for PMTS patients over the past 6 years, at daily doses tablets which contain 100-600 mg pyridoxine.
In terms of macronutrients, the following recommendations are in order in PMT-A patients: (1) Limit intake of simple carbohydrates to 15% of calories because they increase CNS serotonin, a biogenic amine involved in nervous tension . (2) Caffeine-containing foods and drinks should be curtailed since caffeine is a CNS stimulant. (3) Limit intake of dairy products to 2 servings a day, because they block magnesium absorption and increase urinary excretion of magnesium . (4) Limit total fats to 30% of calories, with twice as much vegetable as animal fats. As we have discussed above, animal fats cause hyperestrogenemia, and suppresses ovarian secretion of progesterone. (5) Limit daily intake of vegetable proteins to 1 g/kg body weight, and animal proteins to 0.5 g/kg body weight. Preliminary data suggests that a vegetable/animal ratio of protein consumed equal to or greater than two decreases the prevalence of PMTS symptomatology . (6) Increase dietary fiber intake to 20-40 g a day. Food fiber helps the bowel eliminate estrogens .
The PMTS problem presents a unique opportunity to study the relationship between nutrients and brain functions. This is a great challenge for multidisciplinary research with tremendous clinical applications.
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39 Schaumburg, H.; Kaplan, J.; Windebank, A.: Sensory neuropathy from pyridoxine abuse. New Engl. J. Med. 309: 445 (1983).
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43 Oelkers, W.; Schoneshofer, M.; Blumel, A.: Effects of progesterone and four synthetic progestagens on sodium balance and the renin-aldosterone system in man. J. clin. Endocr. Metab. 39: 882 (1974).
44 Sundsfjord, J.: Plasma renin activity and aldosterone excretion during prolonged progesterone administration. Acta endocr. 67: 483 (1971).
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46 Chakmakjian, Z.H.; Higgins, C.E.; Abraham, G.E.: the effect of a nutritional supplement, optivite for women, on premenstrual tension syndromes. Effect on symptomatology, using a double-blind cross-over design. J. appl. Nutr. 37: 12 (1985).
47 Fuchs, N.; Hakim, M.; Abraham, G.E.: The effect of a nutritional supplement, optivite for women, on premenstrual tension syndromes. Effect on blood chemistry and serum steroid levels during the midluteal phase. J. appl. Nutr. 37: 1(1985).
48 Wurtman, R.J.: Control of neurotransmitter synthesis by precursor availability and food consumption; in Naftolin, Ryan, Davies, Subcellular mechanisms in reproductive neuroendocrinology, pp. 149-166 (Elsevier, New York 1975).
49 Abraham, G.E.: Nutrition and the premenstrual tension syndromes. J. appl. Nutr. 36: 103-124 (1984).
Guy E. Abraham, MD, Optimox, Inc., 2720 Monterey Street No. 406, Torrance, CA 90503 (USA)
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