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In Journal of the American College of Nutrition, Vol. 12, NO. 4, 442-458 (1993)

INTERRELATIONSHIP OF MAGNESIUM AND ESTROGEN IN CARDIOVASCULAR AND BONE DISORDERS, ECLAMPSIA, AND PREMENSTRUAL SYNDROME

Mildred S. Seelig, M.D., M.P.H., F.A.C.N.,

Adjunct Professor: Community and Preventive Medicine, New York Medical College, Valhalla, New York, and Nutrition, School of Public Health, University of North Carolina, Chapel Hill


The section headers of this paper are as follows:


ABSTRACT

The anticonvulsive and antihypertensive values of magnesium (Mg) in eclampsia, and its antiarrhythmic applications in a variety of cardiac diseases, have caused Mg to be considered only for parenteral administration by many physicians. In contrast, nutritionists have long recognized Mg as an essential nutrient, because severe deficiencies elicit neuromuscular manifestations similar to those justifying its use in eclampsia. More recently, this element has been used to favorably influence latent tetany with and without thrombotic complications, to delay preterm birth, to influence premenstrual syndrome, and to ameliorate migraine headaches. Most of these disorders exclusively or largely afflict women. The lesions of arteries and heart caused by experimental Mg deficiency have been well documented and may contribute to human cardiovascular disease. Estrogen's enhancement of Mg utilization and uptake by soft tissues and bone may explain resistance of young women to heart disease and osteoporosis, as well as increased prevalence of these diseases when estrogen secretion ceases. However, estrogen-induced shifts of Mg can be deleterious when estrogen levels are high and Mg intake is suboptimal. The resultant lowering of blood Mg can increase the CA/Mg ratio, thus favoring coagulation. With Ca supplementation in the face of commonly low Mg intake, risk of thrombosis increases.


Abbreviations:

AMI=acute myocardial infarction Ca=calcium cAMP-cyclic adenosine monophosphate DM=diabetes mellitus EDRF=endothelial derived relaxing factor HDL=high density lipoprotein IHD=ischemic heart disease i.v.=intravenous IUGR=intrauterine growth retardation LDL=low density lipoprotein MAP=mean arterial pressure Mg=magnesium mmol=millimole OCA=oral contraceptive agent PGI=prostacyclin potassium=K PMS=premenstrual syndrome PTH=parathyroid hormone RDA=recommended dietary allowances TBX=thromboxane VLDL=very low density lipoprotein


INTRODUCTION

In physiologic amounts, estrogen protects against cardiovascular and bone diseases. In excess, especially in those with marginal or deficient magnesium (Mg) intake, estrogen may create problems. The observation that young women retaining Mg better than do young men has led to speculation that this might contribute to the sex difference in prevalence of ischemic heart disease (IHD). Lower dietary Mg intake in the West compared to the East may contribute to the relatively higher prevalence of IHD in Western populations [1]. Experimental and epidemiologic evidence implicating Mg deficiency in arteriosclerosis and IHD has been reviewed elsewhere [2-8]. The much greater prevalence of IHD in postmenopausal compared to young women, approaching that of men, reflects the protective effect of estrogen. The benefits of estrogen may be mediated in part by its effects on Mg distribution [9-11]. Estrogen replacement therapy during menopause is usually accompanied by increased intakes of calcium (Ca). Rarely considered is fact that Mg increases bone elasticity through formation and maintenance of bone matrix [5,9,12]. Development of osteoporosis in conditions of Mg malabsorption or urinary wasting provides evidence that Mg deficiency can be contributory to this disease [9].

Estrogen is deleterious at high levels. Thromboembolic events have complicated synthetic estrogen treatment of prostatic carcinoma [13], use as an oral contraceptive agent (OCA) [9,14,15] and use to inhibit lactation [9,16,17]. High estrogen secretion has been implicated in complications of pregnancy, for which parenteral Mg is effective and protective [18-34]. Correction of underlying Mg deficiency, and pharmacologic effects of Mg contribute to usefulness of Mg in cardiovascular disease and eclampsia. Mg deficiency is associated with thrombogenesis and arterioconstriction, which are pathogenic and complicating factors in both conditions. At pharmacologic levels, the anti-arrhythmic effects, formation of antiplatelet-aggregating, vasodilating factors: prostacycline (PGI) and endothelial derived relaxing factor (EDRF), and inhibition of formation of platelet-aggregating, vasoconstricting factors: thromboxane (TXB) and endothelin, were cited as justification of its use in a large study to test Mg's efficacy in reducing mortality in acute myocardial infarction (AMI) [35] . When estrogen is used to prevent osteoporosis, and Mg intake is marginal or low, high dosage Ca, which increases Mg needs [2-6], can keep the pro-coagulative effects of Ca from being countered by the normal anticoagulative effect of Mg in the circulation [5,9].


THERAPEUTIC USE OF MAGNESIUM IN COMPLICATED PREGNANCIES

Preeclampsia, Eclampsia and Preterm Labor

Treating toxemic pregnancy with intravenous (i.v.) Mg was reported in 1925 [36]. In 1932, i.v. Mg was found to control bovine hypocalcemic postpartum convulsions, to correct arrhythmia caused by i.v.Ca, and to prevent or cure neuromuscular irritability terminating in convulsions of lactating cows consuming forage poor in Mg and rich in potassium (K) [37]. Diuretics and anti-convulsants displaced Mg for a time, in treatment of eclampsia, until it was shown, in 1965, that Mg treatment achieved better fetal salvage than did the new drugs [38]. Accordingly, the position of parenteral Mg as treatment of choice, has endured [39]. Mg is used now, as adjunct to tocolytic therapy, or alone, to prevent premature uterine contractions and preterm births (40-49).


Hypomagnesemia and Coagulopathy

Increased blood coagulability causes complications of toxemic pregnancies: embolic events, phlebothrombosis, and microthrombosis of glomeruli, and placental scarring that interferes with fetal blood supply, thus resulting in intrauterine growth retardation [IUGR]) [5,9,50-53]. Pulmonary embolism may cause death during pregnancy and postpartum [51], which suggests that naturally high estrogen secretion increases intravascular coagulation. The latter may be mediated by estrogen-induced shift of Mg from the blood into cells in the face of marginal or low intake [9-11]. Hypomagnesemic pregnant ewes had three-fold more platelets clumping than did normal ewes [27]. In another study [54], hypomagnesemic cows and ewes exhibited abnormal platelet activation. It has been postulated that Mg deficiency in pregnant women increases coagulability. Therefore use of Mg in eclampsia may reduce fetal and infant complications [22,27,54].


Prostanoids

The production of glomerular microthrombi and lowered platelet counts in pregnant Mg deficient ewes developing preeclampsia called attention to the lowered ratio of PGI (vasodilator and anti-platelet-aggregating prostanoid) to thromboxane (vasoconstrictive, platelet-aggregating prostanoid) [27], that is seen in Mg deficiency [27,55,56, infra vide] and implicated in toxemias of pregnancy [57]. Furthermore, Mg increases formation of PGI by human umbilical endothelial cells [58] and cord vessel preparations [59]; endothelial cells from eclamptic patients who had received Mg treatment produced 2-5 times more PGI than did those not so treated [58]. Another potent circulating, naturally occurring vasoconstrictor (endothelin), produced by vascular endothelium, is more elevated in preeclamptic women before than after Mg treatment. Umbilical venous endothelin of toxemic patients was 10 times higher than in normal pregnant women [60]. Thus, not only has the use of Mg in eclampsia been scientifically justified, there is now laboratory evidence that Mg deficiency enhances intravascular blood coagulation and increases hypertension, both directly and indirectly via resultant increase in TXB and endothelin and decreases in EDRF and PGI.


Prophylaxis for Preeclampsia, Eclampsia and Preterm Birth

Several investigators have suggested that low Mg intake and tissue stores may contribute to eclampsia [18-34,41-46,61]. Mg supplements have prevented premature uterine contractions and reduced occurrence of calf cramps and sensations of numbness [25,30,42]. A double-blind study disclosed fewer complications in normal pregnant women given supplemental Mg than in controls [29]. Mg deficiency, alone, caused preeclamptic hypertension in pregnant triplet-bearing ewes [27]. Mg supplementation during pregnancy also was not only associated with fewer preterm deliveries, but fewer cases of IUGR [23,25,29-31,34,44,61]. In Hungary, where the prevalence of preterm deliveries is very high, a significant correlation was discerned between preterm delivery rates and Mg concentration in drinking water [62]. Two groups of pregnant women were randomly selected for a double blind study concerning prophylactic Mg supplementation [63]. Among 255 expectant mothers who received 300 mg/day from diagnosis of pregnancy to delivery, the preterm birth rate was 8.5%.; among 280 mothers given placebo but similarly managed prenatally, the preterm birth rate was 10.9%, a significant difference. There were too few spontaneous abortions to statistically evaluate the difference observed (1.6% in Mg-group; 3.6% in controls). However, supporting the premise that low Mg can contribute to spontaneous abortion was the observation from Italy that significantly lower Mg levels (and higher Ca/Mg ratios) were found in women whose pregnancies had aborted than in those whose pregnancies came to term [64]. Although a study in the United States has not confirmed the protection afforded by Mg against adverse outcomes of pregnancy [65]. routine Mg supplementation of pregnant women, is increasingly being recommended overseas [23,25,29-31,34,44,61].


MAGNESIUM DEFICIENCY DURING PREGNANCY

With the foregoing data that support the premise that the efficacy of high dose Mg treatment in complications of pregnancy might be explained by repair of gestational Mg deficiency, as well as by its pharmacologic activity, what evidence is there that pregnant women are likely to be Mg deficient?

Metabolic Balance Evidence

We must rely principally on the early long-term metabolic balance studies to estimate the amount of Mg required by pregnant women for formation of new maternal and fetal tissue [66-69]. These extensive studies suggested that at least 450 mg/day was required to maintain the strong positive balance needed for maternal and fetal health. Of particular interest are data from a multipara who had had repeated uncomplicated pregnancies and healthy infants [68]. Intakes as high as 600 mg/day during the last half of her pregnancy resulted in cumulative retentions of 15.5 grams. Daily Mg intakes below 300 mg resulted in negative balance or bare equilibrium in an adolescent primipara [69]. Only two Mg balance studies of pregnant women have been found, since the studies of the 1930s [66-69]. One, a study of Ca requirements during pregnancy, showed that three teen-age primiparas, on Ca intakes of 2 g/day, had Mg balances of -14, +1 and +24, with mean urinary Mg output of 124 mg/day in a six day balance period [70]. The only long-term metabolic balance study during pregnancy, to provide data on Mg, was conducted in 10 healthy pregnant white, middle class women [71]. With a mean Mg intake of 269 +/- 55 mg, they had positive Mg balance in only 3 of 47 balance periods. Their mean Mg balance was -40 +/- 50 mg; their mean urinary loss was 94 +/- 28 mg, reflecting failure of renal conservation.


Renal Magnesium Excretion Studies

To examine whether inadequate Mg intake is related to toxemia of pregnancy [72], the urinary Mg output (in mEq/g creatinine) from 117 white, middle class women (aged 14-39 yrs, 10-42 weeks gestation) was compared with their mean arterial pressure (MAP: 2 x diastolic pressure + systolic pressure divided by 3; normal = about 90). There was significant negative correlation between MAP and Mg excretion when it was less than 7.0 mEq/g creatinine, both in 25 multiparous mothers and 32 primiparas. Four women had values less than 2.0 mEq/g creatinine; all had hypertension, with MAP > 105. In this study, those with the poorest Mg status had the highest blood pressure. Percentage retention of Mg loads, by measuring urinary Mg before and 24 hours after a parenteral Mg load, is a practical means of determining Mg status; retention of >20-25% has long been accepted as an index of Mg deficiency [5,73]. Three studies have employed this test to demonstrate Mg deficiency in normal pregnancies, and in those complicated by hypertension or diabetes [21,74,75].


Dietary Surveys and Estimates

Dietary surveys of American pregnant women show that their Mg intakes generally fall far short of needs. A 1976 report of the Mg intake of pregnant women, estimated from food record diaries from the fifth month of pregnancy until delivery [76] showed the average intake to be 204 mg +- 54 (S.D.) mg/d (103 to 333 mg). Almost 80% consumed less than 248 mg Mg in their normal diets. There was a positive correlation between Mg intake and birthweight of infants. Dietary estimates from 24-hour recall of low income pregnant women indicated Mg intakes of 102, and 124 mg/1000 kcal for adolescent and older women; 97.3 and 92.1% of the younger and older women, respectively, had Mg intakes less than 100% of the 1980 RDA [77]. A 1987 review of mean dietary Mg of pregnant women showed intakes to be 35-58% of the amount deemed desirable: 450 mg/day [78]. Low income women consumed 97-100 mg Mg/1000 kcal; higher income women consumed an average of 120 mg Mg/1000 kcal, not taking into account the Mg in drinking water. A 1991 report of 212 pregnant women and their infants showed that maternal Mg intake was inversely related to six month infant systolic pressure [79].


Recommended Dietary Allowances for Magnesium

The 9th edition of the RDA [80] lists 450 mg/day as the requirement of pregnant women, i.e. 150 mg/day is added to the amount recommended for non-pregnant women. The current edition [81] lowered the base daily requirement to 4.5 mg/kg/day, discounting the extensive metabolic studies showing negative Mg balances during most periods on intakes of less than 5 mg/kg/day [1,82]. This also ignores a more recent study of young women on controlled diets providing 265-305 mg/day of Mg (4-5 mg/kg/day), who remained in strong negative Mg balance over three consecutive 20-day balance periods [83]. The current RDA of only 40 mg of Mg more per day during pregnancy than the amount for girls 15-18 (300 mg) or those 19-24 (280 mg) is inappropriate and possibly dangerous. This is especially true for pregnant adolescents, whose requirements for growth and development may compete with those of the fetus. The current RDA for Mg was based in part on the erroneous assumption that half the ingested Mg is absorbed and that renal conservation can prevent deficiency, a conclusion not substantiated by the metabolic studies. Accordingly, the increased need of Mg for anabolic processes of gestation seems to justify prophylactic Mg administration to pregnant women to lower the risk of maternal and infant complications, while awaiting results of further investigation. [84,85].


MAGNESIUM AND THE MIGRAINE-ECLAMPSIA RELATIONSHIP

The interrelationship between Mg and estrogen may be the basis for a strong association of migraine and eclampsia [86-88]. Migraine has been found to occur far more frequently in women who have had preeclampsia than in those who have not, and 2.5 times as often in patients with preeclampsia before the 34th week of pregnancy, than in those with normal pregnancy [88]. Favorable results have been reported in 80% of 3,000 women, given 200 mg/day of Mg for prophylaxis of eclampsia and migraine, when they were taking OCA or were pregnant [56,87]. The higher incidence of migraine among those prone to hypomagnesemia [25,89] and the influence of Mg on prostanoids and thrombogenesis, support the premise that Mg deficiency is involved in the pathogenesis of migraine [56,87,89].

Additional factors that may be involved in the role played by Mg deficiency in migraine relate, not only to prostaglandin metabolism [90], but to serotonin release and vascular reactivity to serotonin. In vitro studies have shown that platelets from migraine sufferers release more serotonin than normal, which may contribute to cerebral vasospasms [91]. Spasms of canine cerebral arteries induced by serotonin have been reduced by Mg [92]. Release of serotonin from platelets is enhanced by Ca and inhibited by Mg [93]. Serotonin levels are increased in Mg deficient animals [24,94]. Ca-channel blockers are effective in prophylaxis of migraine [95], and Mg is a physiologic Ca-channel blocker [96]. The latter further supports Mg treatment for migraine [97].


MAGNESIUM AND PREMENSTRUAL SYNDROME

Mg deficiency has been associated with the premenstrual syndrome (PMS) alone [98-101], or in combination with inadequacies of zinc, linoleic acid and B vitamin (predominantly pyridoxine) [102-104] and high Ca intake [103]. The condition has been reported to respond to Mg supplements alone [101,104,105] or in combination with trace minerals and vitamins [106,107]. Mechanisms that may explain the explain the development of PMS, and its response to nutritional therapy, entail interrelations of Mg with estrogen and B vitamins in prostanoid, catecholamine, and serotonin synthesis and release [102].


MAGNESIUM IN PREVENTION AND TREATMENT OF POSTMENOPAUSAL CARDIOVASCULAR DISEASE

Arrhythmia

Disturbances in cardiac rhythm caused by Mg deficiency were first described in rats in 1932 and 1938 [108, 109]. The nature of electrocardiogram changes caused by severe acute Mg deficiency was related to K deficiency in rats [110] and dogs [111], and then extended to longer-term subacute Mg deficiencies in dogs and monkeys [112-115]. Additional details of experimental evidence of the nature of Mg deficiency-induced dysrhythmias in cows and in humans have been presented elsewhere [3,5,8]. Additional evidence of Mg deficiency induced dysrhythmias in cows and humans has been presented elsewhere [3,5,8]. In addition, the therapeutic efficacy of i.v Mg was reported in cows with complications from i.v. Ca treatment) [37]. In the 1930 arrhythmias were also recognized as a risk of rapid i.v. Ca injections, used as an adjunct to digitalis treatment or to measure circulation time [116]. In contrast, i.v. Mg was recommended for circulation time determinations as it was relatively free of deleterious effect on the heart [117].

The efficacy of i.v Mg in controlling a variety of arrhythmias was shown in both men and women in 1935 [118], but received little attention until the 1975 evaluation of the role of Mg deficiency and replacement in cardiac rhythmicity [119]. The antiarrhythmic activity of Mg has since received widespread attention. Cited here are only a few key papers that consider prior Mg depletion as a pathogenic factor [120-123]. Use of Mg in victims of acute myocardial infarction (AMI), has been clearly demonstrated worldwide to improve survival [124-138]. The anti-arrhythmic effect of Mg is credited here; in the improved survival of AMI patients treated with Mg infusions; however its anti-thrombotic and anti-vasoconstrictive effects may also participate in the favorable outcome [5,8,35].


Ischemic Heart Disease

It has been recognized for many years that, with the menopause, the death rate from ischemic heart disease (IHD) increases, gradually rising by the seventh decade to about that of men (Table 1 [139].

Estrogen Table 1


However, low dosage estrogen replacement therapy has decreased the incidence of IHD in elderly women [140-143]. In a 1978 report, female to male ratios for pulmonary embolism death rates were higher from 20 to about 40 years of age; thereafter they were approximately the same [144]. A good question is whether the higher female:male ratio of this coagulative disorder reflects the use of OCA. OCA contained higher doses of estrogen 20 years ago. Thrombophlebitic events in women on high dosage estrogen-containing OCA [14-16], and in women given estrogen to inhibit lactation [16,17], led to studies examining whether estrogen increased coagulation. Synthetic estrogens, especially in high doses, but not low dose conjugated estrogens were shown to enhance blood coagulability [145-148]. In this regard, OCAs have been found to lower serum Mg levels [149-151] and Mg prophylaxis has been deemed protective for women on these agents [152].

Regarding eclampsia, intravascular coagulation that is seen with high levels of estrogen is described above. Men treated with estrogens for prostatic carcinoma had more thrombosis-associated cardiac disease than those not so treated [13] although the degree of atherosclerosis seems not to have been affected [153]. OCA users who smoke have increased platelet aggregation and decreased prostacyclin levels [154]. The interrelationships of Mg with PGI provide an additional mechanism through which estrogen may affect blood coagulation. It has been advised that during long-term estrogen therapy, Mg status should be monitored and deficits corrected to reduce the risk of phlebothrombosis [9,155].


MAGNESIUM DEFICIENCY AND THROMBOSES

Marginal Clinical Magnesium Deficiency

Women are more subject than men to latent tetany of marginal Mg deficiency. Many developed thromboses and emboli with this condition, yet new events have been prevented by Mg supplementation. However, these conditions often recurred when supplements were discontinued [152,156-158].


Magnesium/Calcium in Blood Coagulation

That Mg antagonizes activation Ca-induced blood clotting has been known since 1944 [159]. By many steps, Ca leads to fibrin formation and polymerization in clot formation has been defined [160,161]. Interestingly, Mg counteracts Ca stimulation of coagulation and enhances fibrinolysis [162,163] (Table 2).

Estrogen Table 2


Platelet aggregation requires both Mg and Ca, but is largely Ca-dependent. Mg is needed for deaggregation and to maintenance of platelet shape [9,164-167]. Aggregating platelets release serotonin, which participates in vasoconstriction (supra vide). The release is dependent on Ca and inhibited by Mg [93,168]. Serotonin-induced vascular muscle contraction is also inhibited by Mg [92,169,170].

Partial thromboplastin and thrombin clotting times were significantly shortened in Mg deficient calves, but prothrombin time, platelet counts and aggregation were unaffected [171]. Increasing serum Mg only to 2.1 mEq before partial occlusion (by suture) of coronary arteries of animals markedly diminished platelet aggregation at the site of injury and distal to it. This finding suggests that Mg might protect against thrombosis formation on atherosclerotic plaques and against formation of microthrombi associated with arteriospasms [172].


Magnesium and Experimental Lipidemic, Atherogenic, and Thrombogenic Diets

High blood levels of Ca increase risk of arrhythmias, and enhance blood coagulability (supra vide). Increased Mg levels counter both. Animal experiments demonstrating the anticoagulative, cardiovascular and renal protective effects of adding Mg to diets designed to be thrombogenic, hyperlipidemic, or infarctoid [3-5,173-175]. High-fat diets also have also been shown to increase Mg requirements. The atherogenicity of high fat diets is increased when the diets are also low in Mg [175-179]. How mechanisms involved in Mg/lipid interactions affect coagulation and vascular disease are being elucidated [180-186]. Of significance, in relating the effects of Mg on blood lipids to interrelationships with the effect of estrogen, is that both estrogen and Mg function to maintain levels of high-density lipoproteins (HDL).


Magnesium and Clinical Thrombotic Diseases

Ischemic Heart Disease. Increased platelet adhesiveness has long been recognized in patients with IHD [187] or AMI [188]. Adhesiveness is known to be intensified by hyperlipemia caused by high intake of saturated fatty acids [189-191]. As long recognized as the adverse effects of saturated fats on blood coagulation in patients with IHD, was the favorable response to Mg treatment of several hundred patients with IHD with and without recent AMI [192,193]. Their reduction in angina persisted as long as the Mg treatment was maintained, and tended to recur when it was discontinued. A 1959 report on patients with IHD correlated the efficacy of Mg with changes in blood lipids and coagulation factors and thrombolysis [194]. A recent double-blind study [195] of 47 IHD and MI patients compared the effects of 3 months of treatment with oral Mg (15 mmol/d) with placebo. Those receiving Mg had a 13% increase in molar ratio of apolipoprotein A1 to apolipoprotein B, vs a 2% increase in the placebo group. Triglycerides and very low density lipoproteins (VLDL) decreased by 27% after Mg treatment (from 2.41 to 1.76 mmol/L, and from 1.1 to 0.79 mmol/L, respectively). Decrements were much smaller with placebo. There was also a trend toward increased HDL and HDL/LDL/VLDLC ratio after Mg.

Magnesium, Prostacycline and Thromboxane. It has been hypothesized that the accelerated platelet-clumping produced by platelet-active collagen from damaged vascular intima in Mg deficient lambs is mediated by diminished production of PGI [196]. The release of more arachidonic acid, the precursor of prostanoids, from thymocytes of Mg deficient rats [197], led to study of the effect of Mg deficiency on these derivatives of phospholipid metabolism [198]. PGI, as measured by its stable metabolite 6-keto-PGFa1, increased 2-fold; PGE2 increased 3-fold, but TXB2 increased more than 10-fold. These increases were attributed to increased Ca levels of Mg deficient rats, since the enzyme responsible for liberation of arachidonic acid is Ca-activated phospholipase A2 [199]. The depression of cyclic adenosine monophosphate (cAMP) seen in Mg deficiency, also may participate directly in the markedly increased TXB2 synthesis of Mg deficiency, since cAMP inhibits TXB2 production by platelets [200]. Mg deficiency alters fatty acid metabolism, with arachidonic acid production diminished as a result of slowed conversion of linoleic acid to arachidonic acid [201]. This finding is pertinent to the role of prostanoids in blood coagulation. Dietary Mg depletion of humans has been shown to increase platelet aggregation and TXB2 release; effects that were reversed by Mg infusion [202].


MAGNESIUM IN POSTMENOPAUSAL OSTEOPOROSIS

Magnesium Deficiency and Decreased Bone Magnesium

Since osteoporosis is associated with disorders in which Mg loss occurs, estrogen deficiency may cause loss of tissue Mg. Postmenopausal osteoporosis is the most common form of this bone-wasting disease. Estrogen also interacts with other hormones that influence mineral utilization (infra vide) - both directly and possibly through its effects on Mg [9].

Evidence suggests a low Mg state in post menopausal women with osteoporosis. Significant retention of Mg after a parenteral Mg load - a practical means to detect Mg deficiency [5,9,73-75] has been found in postmenopausal patients with osteoporosis [203,204]. Serum Mg of 10 elderly osteoporotic women was marginally low (1.64 mEq/L) vs osteoporosis-free age-matched women (1.74 mEq/L). Biopsied bone Mg of the osteoporotic women (1.54 +- 0.29 mg/g) was lower than necropsy specimens from sudden death victims (1.75 +- 0.25) (205). Mg malabsorption was diagnosed in 12 of 20 post-menopausal osteoporotics [206]. Loss of trabecular bone (in which the bone crystals are abnormal [203,206]), is associated with decreased trabecular bone Mg in postmenopausal and senile osteoporosis [203,204,206,207], in alcohol-associated osteoporosis [208], and in diabetic osteoporosis (208,209]. Interestingly, the same abnormalities were not seen in estrogen treated women [203]. Patients with non-alcoholic cirrhosis (without osteoporosis), had low Mg in bone cortex rather than in trabecular bone [210]. The acidity of bone extracellular fluid, postulated to fall when Mg deficiency depresses the Mg-dependent adenosine triphosphatase H+-K+ pump in osteocytes, may result in decline in octacalcium phosphate formation in bone. The latter may explain the mechanism through which long-term Mg deficiency causes osteoporosis [[211].


Conditions that Increase Magnesium Needs in Osteoporosis

Magnesium Malabsorption and Renal Wasting. Patients with malabsorption caused by sprue, steatorrhea, inflammatory bowel disease, intestinal resections or genetic isolated Mg malabsorption manifest low bone Mg and low bone Mg/Ca ratios, as well as negative Mg balance [212-220]. Malabsorption was associated with slight generalized bone thinning in a 67 year old man [215], and with evidence of demineralization in a 56 year old black woman [219]. Vertebral osteoporosis was seen in a young man with Mg deficiency secondary to intestinal resection [213]. Juvenile osteoporosis has been reported in Bartter's syndrome, a genetic renal Mg wasting condition [220]. Malabsorption of Mg [207] and renal Mg wasting [221] have been diagnosed in postmenopausal osteoporosis.

Alcoholism. Many reasons exist for alcoholics to be hypomagnesemic. The chronic alcoholic has poor food intake and malabsorption. Alcohol causes a diuresis which increases urinary Mg output (seen even when consumed in moderate amounts [222-224]), and which can cause severe enough Mg deficiency leading to tremors, hallucinations, convulsions and arrhythmia, all of which respond to Mg therapy [224-226]. Accordingly, chronic Mg deficiency of alcoholism may contribute to development of osteoporosis [208].

Pregnancy. Pregnancy increases the need for both Mg and Ca [2,5,9,227, supra vide]. Therefore osteoporosis can be a risk among women who have experienced multiple pregnancies. In such women, repeated drains on Mg, as well as on Ca, may contribute to hyperparathyroidism of pregnancy (infra vide) This state is so common as to be termed "physiologic" [5,9,228].

Diabetes Mellitus. Mg depletion has long been associated with decompensated diabetes mellitus (DM) [229]. Osteoporosis is a frequent complication of insulin-dependent DM [203,230]. Subnormal serum Mg levels have been shown in juvenile diabetics [231,232]. Contributory to Mg deficiency is glycosuria, which increases Mg output in the urine even in normal subjects given glucose loads [224,233]. Because insulin is important in cellular uptake of Mg [234,235], chronic deficiency of this hormone may diminish tissue Mg, including bone. In fact, low bone Mg has been detected in diabetics [203,209], and low free ionic Mg has been detected in erythrocytes of DM patients [236].

Old Age. The elderly, who are prone to involutional osteoporosis, often have reduced food intake [237,238], impaired intestinal Mg absorption [207,239] and increased urinary Mg excretion [240], all factors that increase the likelihood of Mg deficiency. Also their hormonal changes can contribute to Mg loss [5,9,238]. Previously a dietary Ca/Mg ratio of 2/1, but with the frequently advised intake of 1200 mg/day of Ca or more, for the elderly, the ratio may be at least 4/1.


Calcium/Magnesium Imbalances

Effect of Increased Calcium Intakes on Magnesium. To compensate for the loss of Ca from osteoporotic bones, oral treatment with Ca is common. Rarely considered is the effect of high Ca intakes on Mg requirements [5-7], or the importance of Mg in maintaining normal bone matrix [5,9,12]. High dietary Ca/Mg ratios interfere with Mg absorption (Figure 1),

Estrogen Figure 1


partially because Ca and Mg share a common intestinal absorption pathway [217,241,242]. Metabolic studies have shown interference by high dietary Ca with Mg retention of normal young women [1,82], and of patients with osteopathies (Figure 2) [217,243-245].

Estrogen Figure 2


Moderately high Ca intake (1270 to 2360 mg/day) had little effect on the Mg balance of elderly men [246]. Similarly, increasing the Ca intake of young men from 700 to 1600 mg of Ca had little effect on Mg balance [247]. However, plasma Mg levels fell in the young men even though Mg balance was not affected when they were given up to 2 g/day of Ca [248].

Early experimental studies of Mg deficiency in rats employed diets with high Ca/Mg dietary ratios that were rich in vitamin D, resulting in hypermineralized, brittle bones [249-251]. This may be pertinent to the current encouragement of women to consume substantial amounts of Ca; regard is not given to probable low dietary Mg, as indicated by dietary surveys [252-258] and the inadequate current RDA for Mg [81].

Effect of Magnesium Deficiency and Calcium Supplementation. Diets low in Mg, or hypomagnesemia from other causes [259-263] have resulted in Mg-responsive hypocalcemia. Increasing Mg intake increased Ca absorption in normal young men on adequate Ca intake [264]. Refractoriness of hypocalcemia associated with Mg deficiency to Ca replacement, can be caused by impaired release of parathyroid hormone (PTH) and by resistance of target organs (bone and kidneys) to PTH [265-270], and/or by failure of to form hormonally active metabolites of vitamin D [271,272]. Treatment with Mg has long been known to restore responsiveness to vitamin D and PTH, and to correct hypocalcemia and hypomagnesemia [214,216,243].


Magnesium/Estrogen Interactions with Parathyroid Hormone and Vitamin D

Loss of estrogen's antagonism of PTH activity can be inferred by the development of postmenopausal hyperparathyroidism [273,274], and greater severity of osteoporosis in hyper- than in hypoparathyroid women [275]. Estrogen antagonizes PTH-induced bone resorption [276,277], and bone of ovariectomized rats has increased sensitivity to PTH as measured by Ca and hydroxyproline content and decreased bone thickness [278]. Loss of estrogen, which adversely affects Mg utilization [supra vide], is associated with greater bone responsiveness to the Ca-mobilizing effect of PTH, and with decreased formation of calcitriol. Both effects enhance Ca loss [279,280]. Thus, estrogen may protect bone via its influence on PTH release and its demineralization effects [5,9]. Whether estrogen's influence on the parathyroids might be mediated by Mg is not clear. As pointed out above, response to the PTH is impaired with severe Mg deficiency, and repair deficiency restores normal function. Paradoxically, deficiencies of Mg insufficient to suppress release of PTH or response of the target organs, have resulted in parathyroid hyperplasia and bone damage typical of hyperparathyroidism in normocalcemic calves [281] and increased PTH secretion by goat and sheep parathyroids perfused with hypomagnesemic, normocalcemic solutions [282-284].

Low calcitriol levels, and low activity of enzymes involved in its formation, are associated with old age and with involutional osteoporosis [285-290]. Nevertheless, response of the disease to its administration is inconsistent [289]. The need for more parathyroid stimulation for normal vitamin D metabolism by women with osteoporosis, and the lesser response of the elderly to calcitriol [290], has been correlated with possible Mg deficiency [291]. Calcitriol concentration has been raised during physiologically increased estrogen, during pregnancy [292], and during use of estrogen [293]. It has been suggested that impaired activation of 1-alpha-hydroxylase might be responsible for the estrogen deficiency-induced decreased formation of the active vitamin D metabolite [294]. On the grounds that low levels of the active form of vitamin D were found in Mg deficiency [295], that Mg administration (for 20 days) raised the level of PTH (the trophic hormone for alpha-hydroxylation [296], and that estrogen increases Mg retention (supra vide), estrogen-induced increase of calcitriol formation might be mediated by increased tissue Mg.


CONCLUSION

It is proposed that interrelationships between estrogen and Mg influence both women's resistance and vulnerability to certain diseases. When present in physiologic amounts, estrogen enhances Mg utilization, favoring its uptake by soft and hard tissues. Since there is substantial evidence that Mg is protective against cardiovascular disease, it is plausible that a contributory factor to the sex difference in prevalence of IHD in countries where the Mg intake is marginal or low might be estrogen's maintenance of adequate Mg levels in heart and arteries. On the other hand, high estrogen levels - whether secreted as in pregnancy, administered to prevent conception or lactation, or used in the treatment of prostatic cancer - have caused thrombotic complications. Ironically, hypercoagulability may also be a consequence of estrogen's shift of Mg from one compartment to another - in this case, lowering blood Mg in those with suboptimal Mg intakes. This results in diminution of counteraction by Mg of Ca-stimulating steps in the coagulation cascade. Lowered blood Mg also functions to increase levels of TXB and endothelin, and to decrease levels of PGI and EDRF. Calcemic prophylactic therapy of osteoporosis further increases the Ca/Mg ratio, creating a greater risk of thrombogenesis and arterial spasms.

Mg inadequacy may play a role in migraine and premenstrual tension, with and without participation of high estrogen levels. That estrogen is needed for maintenance of normal bone Mg levels is indicated by low bone Mg in post-menopausal osteoporotic bone. Mg is needed for maintenance of normal bone structure, both directly for matrix formation and indirectly for mineralization through its requirement for normal parathyroid and vitamin D metabolism. Estrogen also interacts with PTH and vitamin D, possibly in part through its effect on Mg. Development of osteoporosis in diseases associated with Mg loss is additional evidence of the importance of Mg in postmenopausal women.


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(This article has been placed on this web site with the permission of the Journal of the American College of Nutrition. We thank Dr. Mildred S. Seelig for providing us the information on a diskette.)


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