Key words: estrogen, Women's Health Initiative (WHI), heart attacks, strokes, thrombophlebitis, pulmonary emboli, osteoporosis, cognitive loss, Alzheimer's disease, magnesium-intake, calcium-intake, coagulation cascade, platelet aggregation
Because cardiovascular disease ( CVD), which is far less common in young women than in men, but increases in prevalence in the postmenopausal years to that of men, estrogen repletion therapy (ERT) or combined hormone replacement therapy (HRT), has been widely used to protect against development of both CVD and osteoporosis, and possibly to delay or prevent cognitive loss or Alzheimer's disease (AD). To test the validity of favorable findings in many small-scale studies, and in clinical practice, a large-scale trial: the Women's Health Initiative (WHI) was undertaken by the National Institutes of Health (NIH), a trial that was prematurely ended because of increased CVD complications, despite some lessening of hip fractures. This paper suggests that the customary high intake of calcium (Ca)— advised to protect against osteoporosis, and the marginal magnesium (Mg) intake in the USA, might well be contributory to the adverse CV effects, that were all thromboembolic in nature. The procoagulant effect of estrogen is intensified by Ca; Mg — which counteracts many steps in the coagulation cascade and inhibits platelet aggregation and adhesion — is commonly consumed in sub-optimal amounts. The high American dietary Ca/Mg ratio might also be contributory to the WHI failure to confirm ERT's favorable mental effects. Discussed are mechanisms by which Mg enhances estrogen's central nervous system protective effects. Mg's improvement of cerebral blood flow, which improves brain metabolism, can also enhance removal of the beta amyloid peptide, accumulation of which is implicated in AD.
Key teaching points:
The long accepted premise that postmenopausal sex hormone replacement therapy (HRT) protects against diseases that complicate the aging process in women: increased cardiovascular disease rate, bone loss, and impaired mental acuity—extending in some to the dementia of Alzheimer's disease has been tested in the Women's Health Initiative (WHI and WHIM) of the National Institutes of Health (NIH). That large scale study was planned in 1991, to be run through 2007, to test the validity of the benefit shown in many smaller controlled health programs, rating benefits to risks . Included in the description of the planned investigations of matched groups given conjugated estrogen alone (ERT) or with a synthetic progestin (HRT), controlled by those given a placebo, were two groups also with dietary modifications: one with lowered fat intake, and one supplemented with 1 g of calcium and 400 I.U. of vitamin D daily. Mixed results were reported after five years of the WHI trial [2,3].
A 1999 preliminary paper reported that HRT did not reduce the incidence of ischemic heart disease, and that there was a three-fold increase in thromboembolism . After five years, in 2002, the data and safety monitoring board recommended terminating the HRT trial because the women in that group had suffered eight more stroke (to a total of 212) and peripheral emboli (to 101), and seven more coronary events (to 286) than were experienced by those in the placebo group . The adverse embolic effects were also noted in the WHIM phase of the WHI, which evaluated the mental status of women in receiving HRT or ERT, undertaken because many studies of estrogen treated postmenopausal women suggested sustained cognition, as well as the lesser occurrence of dementia than in those not estrogen-repleted. Benefit of HRT in osteoporosis was confirmed, with slightly fewer hip fractures in the HRT group than in the placebo group. There was also slightly reduced incidence of endometrial and colorectal cancers, but there were eight more invasive breast cancers than in the placebo group. Because the benefit to risk ratio was not acceptable, the HRT phase of the study was terminated.
Considered in this two part paper, is evidence that the prevalent imbalance between calcium and magnesium intakes might well have contributed to the increased complications caused by enhanced intravascular coagulation. Evidence is also presented supporting the premise that increasing the magnesium/calcium intake ratio might have favorable influenced the anticipated benefits of female sex hormone replacement in postmenopausal women.
Estrogen and Magnesium/Calcium Interrelations Affecting the Cardiovascular System
Sex and Age Difference in Cardiovascular Disease (CVD). Male and female death rates from the major forms of cardiovascular disease were approximately equal through the 1920s, but the male/female ratio in fatal ischemic heart disease (IHD) rose sharply thereafter until the 1960s [4,5]. Data tabulated early in the sixth decade of the twentieth century, giving sex and age differences in ischemic heart disease (IHD) (Table 1)  at the time when heart disease rates in men, peaked.
A comparison of the IHD death rates in men and women showed a sharp increase of such deaths among men in 1961 (then almost three times the incidence in women), which contrasted with the only slightly greater male/female IHD mortality in 1926 (Table 2) .
|Deaths in Men||Deaths in Women|
|From||IHD/Other Cause||IHD/Other Cause|
Epidemiologic studies, reviewed in 1990, confirmed that coronary artery disease (CAD) is far more prevalent in young to middle-aged men than in women at comparable ages, with a consistent 2/1 male to female ratio . During the early 1960s, the years that cardiovascular disease (CVD) rates for young-middle aged men reached their highest levels, the rates did not rise in women to levels nearing those of men until their elderly years — suggesting a protective effect of estrogen. Thus, studies of ERT with estradiol or conjugated estrogen, (some with progesterone or a synthetic derivative), were undertaken, to determine whether replacing female sex hormones in postmenopausal women would protect them from advancing cardiovascular disease. Because the studies were not uniformly favorable, the large scale WHI studies were undertaken, to test the validity of the premise that female sex hormone repletion is protective against the common disorders of the post-menopausal years. Participants in the HRT part of the WHI had more adverse effects associated with embolic events than did those getting placebo (Table 3), which demonstrating the risk created by increasing blood coagulation.
Such findings are not new. When estrogen was given to men with CAD, in hope of achieving the lesser susceptibility to infarction of young women, the increased incidence of heart attacks and strokes necessitated ending, in 1973, The Coronary Drug Project . The limitation to only low doses of stilbesterol in men with newly diagnosed prostatic cancer, to avoid embolic accidents such as are caused by higher dose female sex hormone treatment, was indicated, first in 1970  and then in a summary report of the results of three major randomized clinical trials (from 1960 to 1975) , At the same time that estrogen was found to increase thromboembolic events in men [8-10], high dosage estrogen, used for oral contraception in women, was observed to more than double their death rate from venous thromboembolic disease [11-13].
Estrogen-Induced Factors in its Cardiovascular Protection. Apart from adverse effects attributed to the increase in coagulation factors noted in early oral contraceptive agent users, more recent studies have addressed mechanisms to explain how estrogen protects against manifestations of CAD reported in some of the postmenopausal HRT or ERT studies. Credited have been its improvement of the lipid profile, its increase of nitric oxide secretion, dilation of coronary arteries, as well as endothelial and anti-inflammatory effects [14-19].
However, the recent reports of thromboembolic effects in postmenopausal patients receiving sex hormone replacement have again called attention to the effect of ERT and HRT on risk of increased blood coagulation [17-21]. Pertinent to the WHI study of HRT, is the fact that the progesterone derivative used was the synthetic progestin, medroxy-progesterone acetate, which three investigative groups, one by the Geriatric Research Center of the NIH in the USA , one in Australia , and one in France , have shown to counteract estrogen's favorable effects on the arterial wall.
Effect of Estrogen, Calcium and Magnesium on Blood Coagulation. Coagulation studies of the influence of estrogen and the additive effect of calcium, that is counteracted by magnesium, on coagulation factors and on platelet aggregation and adhesiveness (Table 4) provide insight into the failure of the broad scale studies undertaken in the WHI to confirm the benefit of many of the smaller investigations. Noted in 1967 was the lowering of serum magnesium levels in users of oral contraceptives , an observation made at intervals thereafter [23-25]. As early as 1970, the significance of magnesium's anti-coagulative effect was applied to preventing the thrombotic effect of oral contraceptive users . Evidence that estrogen repletion of postmenopausal women increases urinary magnesium loss and alters its internal distribution — lowering its levels in blood — was reviewed in two papers dealing with postmenopausal and earlier female disorders in 1990  and 1993 . Relevance of administered estrogen's lowering of serum magnesium to induction of thrombophlebitic events is the evidence that magnesium inhibits several pro-coagulant factors, and that the coagulation cascade is activated by calcium.
|506 Women on HRT||8102 Women on Placebo|
|Myocardial Infarction (MI) — Manifest or Silent (with ECG and Enzyme Changes, Angina); Death|
|164 (0.37% had CAD||122 (0.30% had CAD|
|Non-fatal MI: 133 (0.30%)||Non-fatal MI: 96 (0.23%)|
|Fatal CAD: 33 (0.07%)||Fatal CAD: 13 (0.06%)|
|Strokes, Pulmonary Embolism, Deep Vein Thrombosis|
|Strokes in 127 (0.29%)||Strokes in 85 (0.21%)|
|Non Fatal: 94 (0.21%)||Non Fatal: 16 (0.04%)|
|Fatal: 13 (0.03%)||Fatal: 59 (0.14%)|
|Pulmonary Emboli in 70 (0.16%)||Pulmonary Emboli in 31 (0.08%)|
|Venous Thrombosis in 15 (0.26%)||Venous Thrombosis in 52 (0.08%)|
|Factor VIII Activation||Increased||Dependent||?|
|Factor IX Activation||Dependent||Decreased with high Mg|
|Prothrombin --> Thrombin||Dependent||Inhibited|
|Fibrinogin --> Fibrin||Increased||Increased||Decreased|
|Platelet Aggregation||Decreased (in vitro)|
|Serotonin Release (Increases Platelet Clumping)||Increased||Decreased|
Recent studies have shed light on how the sex hormones affect both magnesium and calcium during the normal menstrual cycle , and provide insight into how combined estrogen and progesterone repletion, after the menopause, affect these cations. Ionized and total magnesium were shown to be inversely related to the serum estrogen level, their levels were lowest when serum progesterone peaked, and serum levels of ionized calcium were significantly higher in menopausal than in young women [30,31], furthermore, as progesterone levels rose in the blood, the Ca++/Mg++ ratio increased . The sex hormone induced changes in magnesium and calcium were deemed sufficient to affect the vasculature directly, particularly in women who are marginally magnesium deficient .
It is likely that the volunteers in the WHI studies were aware of recommendations for high calcium intakes (to prevent osteoporosis), and since the American magnesium intake is low, might well have been on low magnesium/calcium intakes. This might have been intensified in the subgroup supplemented with extra calcium and vitamin D [I]. The disparity between intakes of magnesium and calcium — which affects blood coagulation — might well have intensified the hormone-induced adverse thromboembolic effects in the WHI, that led to its termination [2,3]. Not included in the protocols for the WHI studies, were investigation of levels of magnesium, nor advice to increase its intake .
Upper Limit Mg 
Cardiovascular Disease Risk Increased by Decreased Magnesium/Calcium Ratio
Changes in magnesium/calcium intakes over the years that CAD incidence rose (Table 5) [32-35] and the greater tolerance by young women of marginally low magnesium intakes [32,33] provide an explanatory clue to the jump in IHD death rates in men, but not in women, in the 1960s. During the years inclusive of the 1920s, the dietary magnesium/calcium ratio was 1/2, which had been found to be optimal for retention of each in extensive balance studies in young men and women [32,33]. Analysis of the metabolic balance data in young adults on marginally low magnesium intakes in 1962  disclosed that young women required less magnesium than did young men to remain in positive metabolic magnesium balance . At that time (1964) the author correlated the higher CVD death rate of men than of women to the greater negative magnesium balance in men on marginal magnesium intakes — noting that in the Orient, where the magnesium intake was much higher than in the West, the CVD death rate in men was much lower . Dietary surveys have disclosed declining intakes of magnesium, from the 1920s to the 1960s, and increases in calcium intake, that resulted by the sixth decade of the twentieth century in a Mg/Ca ratio of about 1/3 . Since then, the magnesium/ calcium ratio has fallen further to less than 1/3 to 1/4 (the amounts given by the Food and Nutrition Board as the Dietary Reference Intake [DRI]) or as much as 1/6 at the Upper Limits (maximum allowable intake) .
The falling magnesium and rising calcium intakes in the USA through the 1960s — when the male IHD death rate had risen sharply, had less impact on young women on marginal intakes, who retained magnesium better than they did on young men [32,33]. That estrogen secretion is responsible for the better magnesium utilization of magnesium by young women, and that the estrogen-induced increase of intracellular magnesium — in the cardiovascular tissue — has been largely ignored by clinicians in recent years. In the First International Magnesium Symposium, in 1971, evidence of estrogen's protective effective in several animal models of heart damage was related to its increase of cardiac magnesium content . Drawing on experiments with animal and in vitro models, evidence was also presented that loss of magnesium from myocardial mitochondria was characteristic of diverse forms of cardiac damage . In 1974, experimental and epidemiologic literature on the role of magnesium in protecting against cardiovascular damage, including that of IHD in humans was considered . The roles of magnesium in protecting against arterial damage caused by a number of toxic agents in experimental models, and in maintaining normal arterial dilatation and normal sodium, potassium and calcium levels was presented in the Second International Magnesium Symposium in 1976 [39,40]. The author wrote several papers on clinical manifestations of magnesium activities, in the next decade, as they affect potassium retention and arrhythmias, and management of other cardiovascular diseases [41-43].
Since estrogen increases intracellular levels of magnesium, the major cardiovascular benefits of estrogen treatment derive from activities that are shared with magnesium. Possibly, they might be implemented by estrogen-mediated shift of magnesium from plasma to cells [27,28,44]. As cited in the design paper for the WHI-HRT trial , treatment with estrogen improves the lipoprotein profile of postmenopausal women; it elevates the high density to low density lipoprotein cholesterol ratio. That increased magnesium blood levels can lower blood cholesterol levels was first reported in 1956, in South Africa — in recovering MI patients whose elevated beta-lipoprotein levels (LDL-C) levels were lowered by parenterally administered magnesium , a finding that was confirmed in Australia three years later . Orally administered magnesium was first shown, in 1984, to lower LDL-C and VLDL-C levels and to raise HDL-C levels in hyperlipidemic patients . More recently, a double-blind placebo-controlled study of IHD patients with and without acute MI, showed that three months of oral magnesium therapy decreased VLDL-C and triglycerides by 27%, and increased HDL-C somewhat less . Oral magnesium supplementation of hyperlipidemic Type II diabetic patients was shown to lower LDL-C and triglyceride levels, while raising HDL-C . Assessment of plasma ionized Mg (iMg++), total serum Mg (tMg), and lipoproteins in elderly men with insulin resistance but otherwise healthy, disclosed that plasma iMg++ was inversely correlated with serum VLDL-C, LDL-C, and the triglycerides, whereas the relationship with tMg was less significant .
Enzyme studies of severely magnesium deficient rats, when they were repleted, provides insight into the mechanism by which magnesium raises the HDL-C/LDL-C ratio. Magnesium treatment was shown to activate the enzyme (lecithin-cholesterol acyltransferase, or LCAT) that converts the LDL to HDL-C, and also increases cholesterol esterification, and lowers the triglyceride level in dyslipidemic, magnesium depleted rats [51,52]. A clinical study in Japan showed that several weeks of magnesium supplementation activates LCAT in human subjects, and that as a result the HDL-C level rises . Still another effect of magnesium on lipids is mediated by its modulation of the rate-limiting enzyme, adenosine triphosphatase that controls cholesterol biosynthesis by deactivating the HMG-CoA reductase which is responsible for converting mevalonate to cholesterol .
Bone Loss of Natural Estrogen Deficiency, or after Discontinuing ERT or HRT
Estrogen Deficiency Induced Osteoporosis. Osteoporosis is second to CVD in postmenopausal women, among their causes of chronic disease and death (Table 6).
Loss of estrogen secretion has long been implicated in bone loss of women after the menopause. An analysis of changes in incidence of hip fracture associated with moderate trauma, the sort usually attributed to post-menopausal osteoporosis, demonstrated rising age-adjusted rates from 1928 through 1982, with leveling of occurrence of female hip fractures from the mid 1950s . Might the rising calcium/magnesium intake (Table 5) relate to the increased incidence of hip fractures in women up to the mid 1950s, as well as to the increasing CVD in men? By 1993, such fractures were found to affect one in four post-menopausal white women, and fewer men or women of other races . About half of the 1.66 million hip fractures worldwide in 1990 occurred in Europe and North America At that time, in the U.S.A., alone, a quarter of a million hip fractures annually cost over $8 billion, mostly for acute medical care and nursing home services [56,57]. Current costs are probably more, because of the aging of the population.
|The Current Emphasis on High Calcium Intake to Increase Bone Hardness|
|Ignores the low magnesium intake|
|Disregards risks to arteries & heart|
|Arteries harden & are subject to thrombosis with low Mg/Ca intake|
|Disregards Mg need of organic bone matrix|
|Estrogen + magnesium needed for matrix that provides bone flexibility|
|Hypermineralized, matrix-poor bone are at increased fracture-risk|
The WHI study was modestly confirmatory of the favorable effect of HRT on risk of hip fractures . However, women in the HRT phase of the study, despite their slightly fewer hip fractures, had the sex hormone therapy discontinued because of increased risk of thrombophlebitic complications. Among those with already manifest osteoporosis, there is probable apprehension that more bone loss will occur when the hormone therapy stopped. A clinical study of women whose long-term ERT had been discontinued for two years showed accelerated bone loss similar to that seen within the first two postmenopausal years in untreated women . Beyond that two-year time period, the annual rate of bone loss decreased similarly to the rate observed following the menopause in untreated women . Two additional papers that provided data on loss of bone mineral density (BMD) a year after cessation of ERT did not find that BMD loss was accelerated beyond that usually occurring postmenopausally [59,60]. In a paper on discontinuation of two years of treatment with a biphosphonate or ERT, or a combination of these modalities, accelerated bone loss was seen only after withdrawal of ERT as the sole intervention .
Bone loss is usually measured as reduced BMD. Using a technic that determines structural geometry, and thus bone strength, it was found that current, but not past, use of ERT in elderly women seems to increase mechanical strength of the proximal femur by improving its geometric properties. These effects are not evident from changes in femoral neck BMD .
Magnesium Deficiency, Hyperparathyroidism, Vitamin D Metabolism and Postmenopausal Osteoporosis
Impaired Bone Strength in Magnesium Deficiency. Discussed in relation to CVD, is the significance of estrogen's shift of magnesium from serum to cells, altering its internal distribution [27,28,44] and increasing risk of intravascular coagulation (Table 4). As early as 1960, the decreased mineralization of postmenopausal osteoporosis was attributed to defective bone matrix, that was proposed to be due to both estrogen deficiency and magnesium deficiency, and that hypothesized magnesium deficiency as contributory to the osteoporosis . Thereafter, studies with magnesium deficient rats demonstrated the nature of the resultant bone abnormalities. In 1975, it was shown that rats kept on magnesium deficient diets had defective bone matrix, and brittle bones . In the 1990s magnesium deficient rats were found to have significantly impaired resistance to bending of their bones, altered apatite metaphyseal crystal size and perfection , and diminished elasticity of their femurs, fractures occurring at less stress . The importance of the crystalline mineral structures in the organic matrix was summed up as providing the ultimate strength, support, and other mechanical properties of a calcified tissue . Over a decade earlier, the magnesium crystals were described as abnormal — being larger and more perfect in shape than normal, a change that was correlated with lower serum magnesium, but higher bone magnesium, indicating change in internal distribution of magnesium in postmenopausal osteoporosis . A more recent study of response to magnesium supplementation of ovariectomized rats (as a model of postmenopausal women) showed that adequate magnesium prevented bone resorption and increased the dynamic strength of their bones .
Low Bone Magnesium in Osteoporosis. Except for the study reporting increased bone magnesium in osteoporotic women , most of the studies reviewed indicate decreased magnesium content of osteoporotic bones. The idea that loss of bone magnesium might be a factor in osteoporosis of estrogen deficiency, is supported by the development of osteoporosis, with low magnesium bone content, and lessened bone strength in conditions with magnesium deficiency . Well known examples are diabetes and alcoholism. Magnesium loss has long been known to be associated with decompensated diabetes mellitus . That this loss is a factor in the osteopenia of diabetic children, in whom their hypoparathyroidism and abnormal vitamin D metabolism was correctable by magnesium supplements, is indicated by the magnesium reversal of the bone loss . Bone loss and low magnesium content of bone is also seen Type II diabetes, as well as in the Type I of the juvenile form [68,72]. In both forms, it is associated with some hypoparathyroidism [71-74]. Chronic alcoholism also causes magnesium depletion, subnormal bone magnesium content and osteoporosis [75,76].
Magnesium Deficiency, Estrogen Deficiency and Parathyroid Function. The relationship of magnesium to calciotropic hormones: parathyroid hormone (PTH) and calcitriol (the hormone derived from vitamin D) is complex (Table 7) [77-92]. Serious magnesium deficiency causes hypocalcemia secondary to interference with parathyroid release [77-81], and failure to activate conversion of vitamin D to its hormonal derivatives [80-81]. Less severe magnesium deficiency has caused hyperparathyroidism, such as is seen in postmenopausal women  and has long been implicated in their osteoporosis [83,84]. The functional link between magnesium, PTH and calcitriol entails magnesium's role in maintaining normal PTH release and activity on target tissues, and in converting vitamin D to its hormonal derivative metabolites [77-86]. In contrast, like increased calcium, increased magnesium level, or its administration to those with hyperparathyroidism, inhibits PTH release [82-85].
|Impairs vitamin D metabolism: synthesis of 1,25(OH)2-D is decreased|
|Interferes with PTH release and with renal & bone response to D & PTH|
|Interferes with regulation of Ca homeostasis|
Postmenopausal bone loss is commonly attributed to hyperparathyroidism developing as a result of loss of estrogen's inhibition of parathyroid hormone (PTH) activity, or of its secretion. For example, postmenopausal women given exogenous PTH displayed greater skeletal sensitivity to that hormone, as expressed by increased serum calcium levels and urinary hydroxyproline levels . Although administration of HRT reduced urinary calcium excretion, it had little effect on serum calcium levels, but most importantly it suppressed PTH induced bone turnover and increased BMD throughout the skeleton in postmenopausal women with mildly elevated PTH . Comparison of levels of PTH and of bone resorption markers in women before and after menopause, who were not estrogen repleted, disclosed that mean serum PTH values were 33% higher in estrogen-deficient postmenopausal women than in premenopausal women and bone resorption markers were 50% higher. However, neither PTH values nor markers of bone resorption differed in postmenopausal women receiving ERT from those in premenopausal women . Among the greatest risks of bone fracture in a large European study of postmenopausal women were low estrogen and high PTH levels .
Since estrogen increases bone magnesium uptake, some of the protective effects of estrogen might well be via the influence of magnesium on bone. One of the demonstrated mechanisms is via magnesium activation of adenylate cyclase (which is inhibited by calcium) in generation of cyclic adenosine monophosphate (cAMP) in renal tissue, parathyroid and bone [81,91,92]. PTH both stimulates osteoclastic bone resorption and inhibits osteoblastic collagen synthesis. Estrogen inhibits PTH-stimulated osteoclast-like cell formation by indirectly acting on them via osteoblasts, possibly mediated by blocking the cAMP-dependent protein kinase pathway . Several publications have reported that magnesium supplementation of women prone to osteoporosis has resulted in improved bone density [93-98]. Furthermore, a large Swedish study found that providing calcium did not protect against hip fracture as well as did adding magnesium, iron and vitamin C . That magnesium, added to calcium, can be further improved upon for building healthy bones, is indicated by the benefit reported for boron [57,99,100], and vitamins K and C . Nutrients needed for protein synthesis, and thus for bone matrix formation, additional to magnesium, are zinc and potassium, and vitamins C and A . Some of the explanation of the concentration on calcium might stem from surveys querying vulnerable patients on their calcium intake, but not considering the other nutrients. One large study  found that intakes of protein, saturated fatty acids, vitamin D, magnesium and phosphorus were significantly higher in subjects whose calcium intake was high than in those consuming diets of low and mid calcium-intakes. In both men and women, alcohol intake (which wastes magnesium) was significantly lower in those with high calcium intakes than in those with low calcium . Diets rich in vegetables and fruits — which provide many nutrients other than calcium — also resulted in good bone density [104,105].
Clinical Trials and Mechanism of Action of Estrogen Alone or with Progesterone
WHIM Study. The third devastating problem, after the rising prevalence of CVD and osteoporosis, that is confronted by many women in their postmenopausal years is cognitive loss, extending in some to the dementia of Alzheimer's disease (AD). Female sex hormone replacement therapy has been utilized to counteract both, but the results have been controversial. Because some of the studies were inadequately controlled, have shown little or no improvement, and/or have caused untoward effects [106-112], the NIH undertook an extension of the WHI investigation, in a section termed WHIM (M for memory) to clarify whether sex hormone replacement can prevent impairment of mental acuity, and prevent AD dementia [113,114]. The HRT phase of these NIH studies was terminated in 2002, after just over five years, not only because of embolic complications (supra vide) , but because the mental benefit seen in some of the smaller studies was not confirmed in WHIM . In fact, there was a greater percentage mental decline among the 2,132 HRT patients than among the 2,215 patients receiving placebo, and twice as many developed dementia (Table 8).
|HRT: 2132 Women||Placebo: 2215 Women|
|Declines of mental scores of 2 S. D. in 6.7%||Declines of mental scores of 2 S. D. in 4.8%|
|Global Cognition: Worse in Some|
|40 Developed Dementia*||20 Developed Dementia|
|Silent brain infarct might have been contributory|
|* Meta-Analysis of Estrogen User Studies indicated 29% Had Decreased Dementia |
The decision to end the HRT phase of the WHIM study [3,114] which has resulted in a more general practice of ceasing hormone replacement therapy, has created profound anxiety in postmenopausal women who have been relying on hormone supplementation to maintain their health and mental capacity. Most apprehensive about stopping their hormone therapy are those with early signs of dementia or who have had victims of AD in their families, Their fear may well be justified because there is disproportionate representation of AD in postmenopausal women, and because of the evidence that dementia occurs less frequently in women taking estrogen than in those not so protected (Table 9) [109,115-127].
The magnitude of the problem — both financial and social — presented by loss of acuity and particularly by AD, and the, probable exacerbation of the problem now that the WHIM study results indicate that the most relied upon medication to control diminution of mentation seems unsafe, it is important to explore how best to confront the situation. It has been estimated that three to four million Americans have been struck by AD, at an annual cost in this country of about one hundred billion dollars . Furthermore, as the elderly woman's mental acuity diminishes, social and family problems eventuate. In view of the aging of our population, and the withholding of HRT, the problem can only grow. Thus, we must evaluate how estrogen exerts its protective effects on the brain, and what can be done to increase its efficacy and safety.
Estrogen's Mode of Action on the Brain. Estrogen has been termed "Nature's psychoprotectant"  because of its favorable influence on mood, mental state and memory — seen in women being treated with estrogen, in contrast to postmenopausal women without replacement therapy. Recent advances in knowledge of estrogen action in the brain and of estrogen, receptors, both nuclear and membrane, are considered in regard to their relevancy to unique requirements of the brain for estrogen, and its use in replacement therapy for cognitive health throughout the post-menopausal years .
ERT has been found to maintain many, but not all aspects of cognition in dementia-free women [115,127]. It acts on transmitter mechanisms in the brain, increasing monoamine and neuropeptide transmitters and their receptors, it modulates synaptogenesis, and binding sites in brain areas that control emotion, behavior, and cognition — involving verbal memory and learning capacity (Table 10) [116,119,122,124,125,127,129-140]. Cessation of estrogen secretion, whether induced surgically, or occurring spontaneously at menopause, or termination of its repletion has been reported to cause diminution of brain functional capacity, expressed by losses in learning, memory, mental control, and balance [124,130,137-143], although one large study questions whether ovariectomy necessarily causes cognitive loss . Depending on the area of the brain affected, different manifestations develop [14l]. Data from animal models suggest that estrogen deficiency selectively increases vulnerability of estrogen-responsive neural elements:
|ERT significantly protected against higher cognitive deterioration of senile dementia (in a 1 year study of >3000) |
|Estrogen preserves neurotransmitter paths involved in learning, memory, and balance |
|Diminution of dementia in AD — due to cholinergic. neurotrophic and neuroprotective effects of estrogen [115-127,129-143]|
|Estrogen modulates brain function and aging; reduces rate of cognitive decline in non-demented women|
|Effects on Neurones & Transmission|
|Estrogen modulates neurotransmission|
|Transmitters: acetyl-choline, serotonin, dopamine, NMDA via their release & receptors|
|Estrogen promotes neuronal circuitry and synaptic plasticity, and is neuroprotective|
|Estrogen preserves/regenerates eurones|
|There are brain receptors for estrogen|
cholinergic neurons of the basal forebrain and hippocampus [116,130,133]. That vulnerability might be mediated by reduced expression of neurotrophic factors, decreased clearance of the amyloid protein — a factor in AD and/or reduced cerebral blood flow associated with estrogen deficiency. Many investigators have observed estrogen deficiency related reduced cerebral blood flow [117,121,124,130,135,141]. ERT dilates cerebral arterioles, thereby protecting against ischemia of the brain, and possibly contributory to the decreased clearance of beta-amyloid (as in rodent models of AD) . In addition, estrogen's favorable effect on blood lipids (supra vide) slows progression of atherosclerosis throughout the body, including the brain. Estrogen-related increase in blood flow during the resting state has been documented in healthy elderly women, elderly women with CVD, and middle-aged postmenopausal women with early menopause . The adverse effect of estrogen on blood coagulation (Table 4), however, presents the risk of brain infarction.
The brain's ability to adapt to neuronal loss by stimulating axonal & synaptic regeneration is impaired by estrogen deficiency, as suggested by estrogen's ability to restore synaptic density of lesioned brains of ovariectomized animals . Increasing experimental and clinical evidence has established the role of estrogen in regeneration and preservation of neuronal elements — protecting against inflammatory reactions and apoptosis, and contributing anti-oxidant activity within the brain [16-18,122,123,145]. Furthermore, postmenopausal estrogen deficiency has been shown to accelerate aging of the brain and to increase risk of its degenerative processes [118,119,123,124,129,138].
The epidemiologic evidence of better cognition of estrogen-treated postmenopausal women than in those not receiving hormone replacement, is now supported by experimental findings that have shown which mental functions are most improved. Estrogen therapy has been associated with changes in brain activation patterns in middle-aged and elderly postmenopausal women during performance of verbal and figural memory tasks, providing biological support for the view that estrogen protects against age-associated changes in cognition and lowers the risk of AD [120,121,135,136]. Women receiving ERT were found to perform significantly better on measures of verbal learning and memory than did those who had never received hormones; specific aspects of memory performance, including also encoding, retrieval, reasoning, and other higher cognitive functions were superior among women receiving estrogen.
Possible Mitigation of Estrogen's Benefit by Progesterone or Progestin. The brain is a target for the sex hormones, of which estrogen has the most profound impact on brain function . For those who still subscribe to the menopause-is-natural philosophy, this question has been posed, "why does the brain naturally have sex hormone (i.e. estrogen) receptors if they are not necessary?" . Progesterone, in contrast, seems to have minor or even adverse effect [146-148]. In combination with estrogen, progestrogens have been found to modify estrogen's beneficial effect on the endothelium and on platelets . In the case of progestins (i.e. the synthetic progestin medroxyprogesterone acetate used in WHY-WHIM) inhibits the beneficial effects of estrogen on the arterial wall [15,16,19] whereas natural progesterone does not. A study of the influence of endogenous sex hormones during the normal menstrual cycle on mental acuity, has indicated that estrogen levels, rather than progesterone levels, correlated positively with verbal fluency .
Since much of the cardiovascular benefits of estrogen treatment might derive from its increase of intracellular levels of magnesium [27,28,44], the effect of changes in concentrations of estrogen and progesterone occurring at different phases of the menstrual cycle on central nervous system manifestations that are associated with low magnesium, such as migraine, cerebrovascular spasms, and stroke risk  might be germane, also, to mental acuity, and to nerve degeneration. Physiological concentrations of both estrogen and progesterone help cerebral vascular smooth cells sustain normal magnesium ion concentrations, which are beneficial to vascular function. High levels of progesterone, such as occurs in the late luteal phase (in premenstrual tension), were shown to lower magnesium in cultured (canine) cerebral vascular smooth muscle cells .
Magnesium's anti-spasmotic effect on the smooth muscles of arteries, which is manifested in dilation of blood vessels, allowing for increased regional blood supply — including that of the brain, has long been recognized [150-155]. The earliest recognized mechanism by which this effect is achieved is by its calcium blocking activity in animals [156-158] and humans . Thereby, magnesium enhances blood flow, counteracting ischemia, as well as by increasing prostacycline secretion  and exerting anticonstrictor effects against vascular mediators . Magnesium's antagonism of calcium [156-159] is linked to its protection against the damaging effect of calcium uptake in the cytoplasm, mitochondria or endoplasmic reticulum of the brain that occurs after brain damage — whether due to trauma or ischemia [161-163]. Massive influx of calcium ions into mitochondria is believed to produce free radicals, to open the mitochondrial permeability transition (MPT) pore and to disturb energy metabolism of the brain (Table 11) [163-167]. The mitochondrial permeability transition pore is an inducer of cell death, which occurs after mitochondrial calcium accumulation and formation of free radicals [164-167]. Biochemical cascades initiated by oxidative stress and elevated intracellular calcium lead to mitochondrial dysfunction . The importance of magnesium in maintaining mitochondrial integrity is suggested by its deficiency in brain mitochondria of patients with mitochondrial disease . These reactions are pertinent to the pathologic processes in AD, and magnesium has the important effect of delaying the onset of mitochondrial permeability transition, which is mediated by beta amyloid's production of free radicals .
The neurotoxic effects of beta-amyloid — pathogenic factor in AD — entail many of the processes associated with ischemia and trauma [169-172]. Magnesium's neuroprotective effects include its blockage of the calcium ion carrying channel which is opened by beta-amyloid , and its antioxidant activity [171,172], which counteracts beta-amyloid's increased production of free oxygen radicals . The antioxidant activity of magnesium is reflected both by the oxidative effect induced by its deficiency [173-179], and the direct evidence that its administration has antioxidant activity and reduces free radical production in experimental models [180-182]. Magnesium's limitation of the size of experimental myocardial and cerebral infarction has been attributed both to its action against free radicals and calcium uptake [180,181]. Its administration has reduced damage in animal models of cerebral emboli and extended the therapeutic window for neuroprotection to as long as six hours, reducing the brain infarct volume . Among the many mechanisms of magnesium's neuroprotection against the damage of brain ischemia is preservation of cellular energy metabolism . Significant correlation was found between cerebrospinal ion magnesium levels, the size of brain infarct (determined by computed tomography), and the extent of the neurologic deficit in 96 stroke victims in the first 48 hours after the cerebral artery occlusion . Neuroprotective effects of
|Mitochondrial (Mt) permeability transition (mPT) pore|
|Implicated in excitotoxicity and apoptosis of neural cells — associated with high Ca concentrations and free radical release [164-167]|
|High Ca/Mg and oxidative stress in mitochondria of neurons --> Mt dysfunction & neuronal cell death|
|Mg Deficiency --> neuronal mitochondrial (Mt) pathology|
|Mg delays onset of Mt permeability transition — pertinent to neurotoxic betapeptide opening of mPT in AD|
magnesium treatment are being applied to stroke victims [161,162], and have been demonstrated in animals with brain trauma [184-190]. Human brain trauma is associated with loss of magnesium [191-193]. The rationale for administering magnesium to limit brain damage after stress and trauma is based on its multiple roles for functioning of key enzymes involved in energy metabolism, protein synthesis and nucleic acid metabolism, in maintaining the stability and normal function of cell membranes of excitable tissues, and in blocking calcium, which enters damaged nerve tissue. The cellular disruption of brain trauma initiates complex, secondary neurochemical changes which include free radical production, membrane phospholipid breakdown, altered neurotransmitter release and energy failure — in all of which magnesium is protective.
Largely ignored, in prophylactic or therapeutic approaches to preventing the devastating complications that commonly develop in the post-menopausal period, are interrelations between estrogen and magnesium (Table 12).
Since estrogen shifts magnesium from the circulation' to the soft and hard tissues, its protective effects in the cardiovascular and skeletal systems parallel the effects of magnesium. However, that shift lowers the serum magnesium concentration, removing the anticoagulant and anti-platelet aggregation effect, that protects against the procoagulant effect of sex hormone repletion, which is enhanced by high calcium/magnesium intakes
Considering the widely recommended high calcium intake to avoid bone demineralization in post-menopausal (and even young) women, the calcium-blocking effect of magnesium is useful, with and without estrogen repletion. In view of the diminished cerebral blood flow that cessation of estrogen secretion induces, and the evidence that magnesium levels tend to be lower and calcium levels higher in postmenopausal women, the effect of magnesium administration can be expected to counteract both — by increasing cerebral blood flow and blocking calcium. Additionally, ischemia-resulting from degrees of blood flow impairment, also results in uptake of calcium, and is protected against by magnesium. There is also evidence that magnesium-low cerebral tissues, as reflected by low cerebrospinal levels are more vulnerable to ischemia than are magnesium replete tissues. This brings us back to brain damage of estrogen deficiency, that is associated with impaired cerebral circulation (which magnesium can help to correct), and with resultant cognitive loss, extending to dementia. Indirect links to the putative role of magnesium in protecting against the processes leading to Alzheimer's disease, are magnesium's use in recovery (measured by improvement in learning tests) of brain traumatized animals, and its favorable effect on upregulation of beta amyloid precursor protein in brain injured patients. Direct association of loss of cognition with low magnesium levels is the evidence that cognitive impairment was likelier in hypertensive patients with low serum magnesium than in normomagnesemic hypertensives . Patients with the chronic fatigue syndrome, associated with latent tetany of magnesium deficiency, commonly have cognitive impairment, that is responsive to magnesium repletion .
Of the deficiencies implicated in postmenopausal osteoporosis, two: estrogen and calcium are well recognized and have been used in its therapy. The use of female sex hormones has been discouraged, as a result of WHI disappointment with HRT. Risks of the current dietary high calcium and low magnesium intakes are summarized in Table 6. Disregard of the inadequacy of magnesium intake, in conjunction with the high calcium intake does not only present a risk of intensifying cardiovascular and skeletal complications, but also increases the likelihood of loss of cognition and dementia of the postmenopausal years.
|Estrogen Affects Distribution of Mg/Ca|
|Inhibits Ca Influx||Physiologic Ca-Blocker|
|Increases Mg Influx||Increases Tissue Mg|
|High Intracellular Ca/Mg with Injury in Cerebral Vascular Smooth Muscle & Brain|
|Increased Ca in Mitochondria --> Free Radicals; Oxidative|
|Cerebral Vasodilation Prevents Brain Ischemia|
|Ca Constricts Arteries||Mg Dilates Arteries|
|Decreases Serum Mg||Increases Mg Level|
|Transmission, Receptors Taken Up by Brain-Estrogen-Receptors||Against Brain Damage from Ischemia, Alcohol, Trauma|
|Enhances Neuronal Regeneration||Mg Maintains Stability, Function of Nerve Membranes|
|Lowers Beta Amyloid|
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Received August 5, 2004.
Address reprint requests to: Dr. Mildred Seelig, Department of Nutrition, University of North Carolina Medical Center, Chapel Hill, NC. E-mail: firstname.lastname@example.org. (Deceased)
Journal of the American College of Nutrition, Vol. 23, No.5, 482S-496S (2004) Published by the American College of Nutrition
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