Review
Benefits and Risks of Sex Hormone Replacement in
Postmenopausal Women
Mildred S. Seelig, MD, Burton M. Altura, PhD, Bella T.
Altura, PhD
Department of Nutrition, University of North Carolina
Medical Center, Chapel Hill, NC (M.S.S.), Department of
Physiology and Pharmacology, State University of New York,
Downstate Medical Center, Brooklyn, New York (B.M.A.,
B.T.A.)
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:
Part 1
- Failure of large test (Women's Health Initiative: WHI) to
confirm cardiovascular (CV) benefit of estrogen repletion
therapy (ERT) can be attributed in large part to high dietary
Ca/Mg. The increased CV adverse reactions in WHI participants
were due predominantly to thromboembolic complications:
cardiac and brain infarctions, pulmonary emboli, and venous
thromboses.
- Thromboembolic phenomena are known to have been increased
by use of estrogen — as oral contraceptives in women
and to suppress prostatic cancer in men.
- The current high dietary Ca/Mg ratio in the USA, Ca
increasing coagulation cascade steps, and Mg inhibiting them
and decreasing platelet aggregation, might well have
intensified pro-coagulant effects caused by estrogen.
- The results of the WHI confirmed the benefit of estrogen
and I high Ca intake — commonly advised to counteract
postmenopausal osteoporosis — in decreasing hip
fracture prevalence.
Part 2
- A subgroup of the WHI study (WHIM) tested the controversy
as to whether estrogen, with and without a progestogen can
delay postmenopausal loss of cognition and development of
Alzheimer's disease (AD).
- The results, particularly with combined hormone
replacement therapy (HRT), were not conclusive, although the
HRT group showed more decline of mental scores, and twice as
many developed dementia as did women on placebo.
- The possibility was considered that some of the dementia
might have stemmed from silent brain
infarcta—contributed to by increased blood
coagulability.
- The better results in mental status reported by smaller
studies with ERT: estrogen replacement therapy can be
attributed to neurotrophic and neuroprotective effects of
estrogen, which has beneficial effects on neurotransmission,
as well as to its cerebral arterial vasodilatory effect that
counteracts ischemia.
- Evidence is presented that correcting the marginal Mg
intake of most American women could protect against, not only
vulnerability to CV complications of use of HRT, but —
by several cited mechanisms — can improve the mental
benefit of ERT in postmenopausal women.
INTRODUCTION
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 [1].
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 [2]. 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 [3]. 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.
PART 1. CARDIOVASCULAR AND SKELETAL BENEFITS AND
COMPLICATIONS OF ERT
THROMBOPHLEBITIC COMPLICA TIONS CAUSED BY INTENSIFYING
PRO-COAGULATIVE EFFECT OF ESTROGEN BY LOW MAGNESIUM/HIGH
CALCIUM INTAKES VERSUS CARDIOVASCULAR BENEFITS OF ERT
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) [6] 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) [4].
Table 1. Sex and Age Differences in
Mortality Rates from Arteriosclerotic Heart Disease per
100,000 White Population [6]
|
Age
|
Men
|
Women
|
Men/Women
|
| 25-29 |
4.3 |
1.0 |
4.3/1 |
| 40-44 |
24.2 |
19.4 |
6.4/1 |
| 45-49 |
254.9 |
40.8 |
6.2/1 |
| Post-Menopausal Years |
| 50-59 |
719.0 |
183.6 |
3.9/1 |
| 60-64 |
1,119.1 |
384.4 |
2.9/1 |
| Elderly |
| 70-74 |
2,291.1 |
1,211.0 |
1.9/1 |
| 75-79 |
3,243.2 |
2,053.9 |
1.5/1 |
| 80-84 |
4,802.5 |
3,508.1 |
1.3/1 |
| over 84 |
7,248.7 |
6,233.7 |
1.2/1 |
Table 2. Before the Menopause, Women Are
Much More Resistant, Than Are Men, To Cardiovascular
Disease: Ischemic Heart Disease Prevalence in 1961 at Peak
of Incidence Compared to Lower 1926 Rates [4]
| |
Deaths in Men |
Deaths in Women |
| From |
IHD/Other Cause |
IHD/Other Cause |
| 1961 |
|
|
| 1961 |
560/55 |
190/55 |
| 1926 |
200/90 |
175/60 |
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 [7]. 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 [8]. 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 [9]
and then in a summary report of the results of three major
randomized clinical trials (from 1960 to 1975) [10], 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 [16], one in Australia [15], and
one in France [19], 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 [22], 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 [26]. 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 [27] and
1993 [28]. 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.
Table 3. Participants on HRT Had More
Adverse Reactions Than Did Those on Placebo
| 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%) |
Table 4. Estrogen, Calcium, Magnesium
Effects on Coagulation
| |
Estrogen |
Calcium |
Magnesium |
| Factor VII |
Increased |
Dependent |
|
| Factor VIII Activation |
Increased |
Dependent |
? |
| Factor IX Activation |
|
Dependent |
Decreased with high Mg |
| Factor X |
Increased |
|
|
| Prothrombin --> Thrombin |
|
Dependent |
Inhibited |
| Prothrombin Time |
|
Shortened |
Lengthened |
| Prothrombin Consumption |
|
Increased |
Decreased |
| Thrombin Generation |
Increased |
Accelerated |
Delayed |
| Fibrinogin --> Fibrin |
Increased |
Increased |
Decreased |
| Fibrinolytic Potential |
|
Decreased |
|
| Platelet Aggregation |
Decreased (in vitro) |
|
|
| Adhesiveness |
Increased |
Increased |
Decreased |
| Serotonin Release (Increases Platelet Clumping) |
|
Increased |
Decreased |
| Fibrinolysis |
Decreased |
? |
Increased |
| Fibrinolysis-Inhibition |
Increased |
? |
Decreased |
Recent studies have shed light on how the sex hormones
affect both magnesium and calcium during the normal menstrual
cycle [29], 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 [31]. 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 [30].
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 [1].
Table 5. Rising Dietary American Ca/Mg
Ratios during 20th Century From Early Balance Data [32,33]
and Dietary Surveys Reviewed in 2001 [34]
| |
1901-1939 |
1960-1967 |
2000 |
| DRI |
Upper Limit Mg [35]
|
| Mg: mg/d |
400 |
300 |
310 |
400 |
| Ca: mg/d |
800 |
1000 |
1000-1300 |
2500 |
| Ca/Mg Ratio |
2/1 |
>3/1 |
>3/1->4/1 |
>6/1 |
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 [33] disclosed that young women
required less magnesium than did young men to remain in
positive metabolic magnesium balance [32]. 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 [32]. 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 [34]. 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) [35].
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 [36]. 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 [37]. In 1974, experimental and
epidemiologic literature on the role of magnesium in protecting
against cardiovascular damage, including that of IHD in humans
was considered [38]. 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 [1], 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 [45], a finding that was confirmed in Australia three
years later [46]. 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 [47]. 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 [48]. Oral magnesium
supplementation of hyperlipidemic Type II diabetic patients was
shown to lower LDL-C and triglyceride levels, while raising
HDL-C [49]. 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 [50].
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 [53]. 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 [54].
ESTROGEN, CALCIUM REGULATORY HORMONES, AND MAGNESIUM IN
POSTMENOPAUSAL BONE HEALTH
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 [55]. 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 [56]. 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.
Table 6. High Ca/Mg Intake, Added to HRT
or ERT Increases Killers of Aging & the Major
Cripplers: Heart Disease and Osteoporosis
| 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 [3]. 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 [58]. Beyond that two-year time
period, the annual rate of bone loss decreased similarly to the
rate observed following the menopause in untreated women [58].
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 [61].
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
[62].
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 [63]. 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 [64]. 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 [65], and diminished elasticity of their femurs,
fractures occurring at less stress [66]. 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 [67]. 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 [68].
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 [69].
Low Bone Magnesium in Osteoporosis. Except
for the study reporting increased bone magnesium in
osteoporotic women [68], 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 [70].
Well known examples are diabetes and alcoholism. Magnesium loss
has long been known to be associated with decompensated
diabetes mellitus [71]. 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 [72]. 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 [82] 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].
Table 7. Magnesium Needed to Maintain
Calciotropic Hormones: Synthesis and Release [77-92]
| Mg Depletion |
| 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 [87]. 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 [88].
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 [89]. Among the greatest risks of
bone fracture in a large European study of postmenopausal women
were low estrogen and high PTH levels [90].
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 [92]. 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 [99]. 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 [101]. Nutrients
needed for protein synthesis, and thus for bone matrix
formation, additional to magnesium, are zinc and potassium, and
vitamins C and A [102]. 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 [103] 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
[103]. Diets rich in vegetables and fruits — which
provide many nutrients other than calcium — also resulted
in good bone density [104,105].
PART 2: MENTAL BENEFITS OF ESTROGEN REPLACEMENT WITH ADDED
MAGNESIUM AFTER MENOPAUSE
ESTROGEN'S PROTECTION AGAINST DIMINISHED COGNITION OF
MENOPAUSE
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)
[3], but because the mental benefit seen in some of the smaller
studies was not confirmed in WHIM [114]. 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).
Table 8. WHIM Study of HRT versus
Placebo; Comparative Cognnition
| 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 [107] |
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 [128]. 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" [129]
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
[119].
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 [144].
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:
Table 9. Estrogen Effects on Cognition
& Dementia from Pre-WHIMS Studies
| ERT significantly protected against higher cognitive
deterioration of senile dementia (in a 1 year study of
>3000) [142] |
| Estrogen preserves neurotransmitter paths involved in
learning, memory, and balance [115] |
| 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 |
Table 10. Mechanisms by Which Estrogen
Influences Brain Function in Areas Affecting Memory,
Learning, Emotion [106]
| 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) [130]. 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 [136]. 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
[130]. 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 [138]. 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?" [138].
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 [146]. 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 [148].
MAGNESIUM ENHANCEMENT OF ESTROGEN'S PROTECTION OF THE
BRAIN
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 [149]
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 [149].
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 [159]. Thereby, magnesium enhances blood flow,
counteracting ischemia, as well as by increasing prostacycline
secretion [160] and exerting anticonstrictor effects against
vascular mediators [161]. 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 [167]. The importance of magnesium in maintaining
mitochondrial integrity is suggested by its deficiency in brain
mitochondria of patients with mitochondrial disease [168].
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
[169].
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 [170], and its
antioxidant activity [171,172], which counteracts
beta-amyloid's increased production of free oxygen radicals
[169]. 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 [181]. Among the many mechanisms of
magnesium's neuroprotection against the damage of brain
ischemia is preservation of cellular energy metabolism [182].
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 [183]. Neuroprotective effects of
Table 11. Impaired Mitochondrial &
Neuronal Function & Cell Death Is Associated with High
Cellular Ca/Mg
| 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.
CONCLUDING COMMENTS
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 [194]. Patients with the
chronic fatigue syndrome, associated with latent tetany of
magnesium deficiency, commonly have cognitive impairment, that
is responsive to magnesium repletion [195].
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.
Table 12. Interplay of Estrogen-Magnesium:
Effects on the Brain
| |
Estrogen Affects Distribution of Mg/Ca |
|
| Estrogen |
|
Magnesium |
| Inhibits Ca Influx |
|
Physiologic Ca-Blocker |
| Increases Mg Influx |
|
Increases Tissue Mg |
| |
|
Is Anti-Oxidant |
| |
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 |
| Pro-Coagulalnt |
|
Anti-Coagulant |
| |
Neuronal Protection |
|
| 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 |
| |
Improves Cognition |
|
| |
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: mgseelig@comcast.net.
(Deceased)
Journal of the American College of Nutrition, Vol. 23, No.5,
482S-496S (2004) Published by the American College of
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