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<strong><span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: large"
>Hot flashes, energy, and aging</span></span></span></strong>
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<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Around the time that menstruation and fertility are ending, certain biological problems are more
likely to occur. Between the ages of 50 and 55, about 60% of women experience repeated episodes
of flushing and sweating. Asthma, migraine, epilepsy, arthritis, varicose veins, aneurysms,
urticaria, reduced lung function, hypertension, strokes, and interstitial colitis are some of
the other problems that often begin or get worse at the menopause, but that normally aren't
considered to be causally related to it.</span></span></span>
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<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Recently, hot flashes are being taken more seriously, because of their association with increased
inflammation, heart disease, and risk of dementia. Around the same age, late 40s to mid-50s, men
begin to have a sudden increase of some of the same health problems, including night sweats,
anxiety, and insomnia. In both sexes, the high incidence of depression in this age group has
usually been explained "psychologically," rather than biologically.</span></span></span>
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<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>When the estrogen industry began concentrating on women of menopausal age (after the disastrous
years of selling it as a fertility drug), "estrogen replacement" therapy was promoted as a cure
for the problems associated with menopause, including hot flashes, which were explained as the
result of a deficiency of estrogen. However, in recent years, the phrase "estrogen deficiency"
has begun to be replaced by the phrase "estrogen withdrawal," because it has been found that
women with hot flashes don't necessarily have less estrogen in their blood stream than women who
don't have hot flashes.</span></span></span>
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<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Associated with this change of terminology, there has been a recognition that changes in the
temperature regulating system in the brain, rather than changes in the amount of estrogen, are
responsible for the hot flashes, but mainstream medicine has carefully avoided the investigation
of this subject. The effects of estrogen on the thermoregulatory system are very clear, but the
standard medical view is that the physiology of hot flashes simply isn't understood.</span
></span></span>
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<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Since the medical literature boldly describes the mechanisms of the circulatory system and the
causes of major problems such as heart attacks, high blood pressure, and strokes, it's odd that
it doesn't have an explanation for "hot flashes."</span></span></span>
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<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>But looking at this historically, I think this selective ignorance is necessary, for the protection
of some doctrines that have become very important for conventional medicine.</span></span></span
>
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<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>When doctors are talking about diseases of the heart and circulatory system, it's common for them
to say that estrogen is protective, because it causes blood vessels to relax and dilate,
improving circulation and preventing hypertension. The fact that estrogen increases the
formation of nitric oxide, a vasodilator, is often mentioned as one of its beneficial effects.
But in the case of hot flashes, dilation of the blood vessels is exactly the problem, and
estrogen is commonly prescribed to prevent the episodic dilation of blood vessels that
constitutes the hot flash. Nitric oxide increases in women in association with the menopause
(Watanabe, et al., 2000), and it is increased by inflammation, and hot flushes are associated
with various mediators of inflammation, but, as far as I can tell, no one has measured the
production of nitric oxide during a hot flash. Inhibitors of nitric oxide formation reduce
vasodilation during hot flushes (Hubing, et al., 2010).</span></span></span>
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<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Starting in the 1940s, the doctrine that menopause is the result of changes in the ovaries,
involving a depletion of eggs and an associated loss of estrogen production, was widely taught
to medical students. By the 1970s, the taboo against discussing menopause publicly was fading,
and the mass media began teaching the public that hot flashes are the result of an estrogen
deficiency, and that "estrogen replacement" is the most appropriate and effective treatment, and
in the next 20 years almost half the women in the US began taking it around the time of
menopause. This practice became routine at a time when "evidence based medicine" was being
promoted as a new standard, but there was no evidence that women experiencing hot flashes were
deficient in estrogen (in fact, there was evidence that they weren't), and there was evidence
that hot flashes began when the first menstrual period was missed, which coincided with, and
resulted from, a failure to produce a functional corpus luteum, preventing the production of a
normal amount of progesterone. But the silly old doctrine of deficiency is often restated by
professors, as if there was no doubt about it (for example, Rance, 2009; Bhattacharya and
Keating, 2012).</span></span></span>
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<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>This extremely persistent disregard for important evidence about the nature of menopause and its
symptoms was guided by the estrogen industry, which began in the 1930s to call estrogen "the
female hormone," disregarding the facts about the biological roles of estrogen and progesterone,
because chemicals with estrogenic effects were numerous and cheap, while progesterone was
expensive, and had no synthetic equivalents. At the time the pharmaceutical industry began
promoting estrogen as the female hormone to prevent miscarriage, it was already well known that
it could produce abortion, as well as causing inflammation and cancer, and some of the most
famous estrogen researchers were warning of its multiple dangers in the 1930s.</span></span
></span>
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<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Menopause is a major landmark of aging, and if its meaning is radically misunderstood, a coherent
understanding of aging is unlikely, and without an understanding of the loss of functions with
age, we won't really understand life. More specifically, the real causes of the many serious
problems occurring in association with the menopause will be ignored. Finding the causes of the
seemingly trivial hot flash will affect the way we understand aging and its diseases.</span
></span></span>
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<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>If a common occurrence is thought to have some importance in itself, or to relate closely to
something of importance, it will be described carefully, and its general features will become
part of the common understanding. It's clear that our medical culture hasn't considered the hot
flash to be important, because there are still physicians who believe that the hot flash
represents a rise of body temperature caused by a sudden increase of heat production, which they
sometimes explain as an upward fluctuation of thyroid gland activity. Measurement of body
temperature before and during hot flashes has shown clearly that the internal temperature is
lowered slightly by the hot flash, as heat is lost from the skin, as a result of vasodilation.
Physiologists have been studying the differences in temperature regulation between men and
women, and the effects of hormones on temperature regulation, for more than 70 years, but the
medical profession in the United States showed almost no interest in the subject for about 50
years.</span></span></span>
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<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>August Weismann's doctrine of "mortal soma, immortal germ line," led people to postulate that
"primordial germ" cells migrated into the ovary (consisting of "somatic" cells) during embryonic
development, and that the baby was born with a supply of germ cells that was used up during the
reproductive lifetime, accounting for the decline of fertility with aging. The fact that
menstrual cycles ended around the time that fertility ended was explained by the idea that
ovulation caused the release of estrogen, and that the absence of eggs caused a failure to
produce estrogen, and that the absence of estrogen led to the failure of the cyclical uterine
changes. It was all deduced from a mistaken ideology about the nature of life. </span
></span></span>
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<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Cancer of the endometrium (lining) of the uterus and breast cancer were known to be the first and
second cancers, respectively, produced by uninterrupted exposure to estrogen (for example,
Lipshutz, 1950). Investigation of the causes of endometrial cancer showed that women with
anovulatory cycles, that failed to produce progesterone, or who had a reduced production of
progesterone, developed overgrowth of the endometrium, and that these were the women who were
later most likely to develop cancer of the endometrium. The peak incidence of endometrial cancer
is in the postmenopausal years, resulting from prolonged exposure to estrogen, unopposed by
progesterone. The medical belief* that "ovulation produces estrogen," and that the absence of
menstruation means an absence of estrogen, has been very harmful to women's health.</span></span
></span>
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<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Several laboratories, from the 1950s through the 1980s, investigated the causes of age-related
infertility. A.L. Soderwall, among others, demonstrated that an excess of estrogen makes it
impossible for the uterus to maintain a pregnancy. </span></span></span>
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<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Subsequently, his lab showed that neither changes in the eggs nor changes in the uterus could
explain age related infertility. Altered pituitary hormone cycles, resulting from changes in the
brain, could account for the major changes in the ovaries and uterus.</span></span></span>
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<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Other experimenters, including P.M. Wise, V.M. Sopelak and R.L. Butcher (1982), P. Ascheim (1983),
and D.C. Desjardins (1995) have clarified the interactions between the ovaries and the brain.
For example, when the ovaries of an old animal are transplanted into a young animal, they are
able to function in response to the new environment, but when the ovaries of a young animal are
transplanted into an old animal, they fail to cycle. However, if the ovaries are removed from an
animal when it's young, so that it lives to the normal age of infertility without being
regularly exposed to surges of estrogen, it will then be able to support normal cycles when
young ovaries are transplanted into it. But if it received estrogen supplements throughout its
life, transplanted young ovaries will fail to cycle.</span></span></span>
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<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>The work of Desjardins and others has demonstrated that free radicals generated by interactions of
estrogen and iron with unsaturated fatty acids are responsible for damage to brain cells
(Desjardins, et al., 1992). The damaged inhibitory nerve cells allow the pituitary to remain in
a chronically active state; in old rats, this can produce a state of constant estrus. Several
groups (Powers, et al., 2006; Everitt, et al., 1980; Telford, et al., 1986) have shown that
removal of the pituitary gland can greatly extend lifespan, if thyroid hormone is
supplemented.</span></span></span>
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<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>One of the animal "models" used to study hot flashes is morphine withdrawal. The model seems
relevant to human hot flashes, because estrogen can stop the morphine withdrawal flushing, and
estrogen's acute and chronic effects on the brain-pituitary-ovary system involve the endorphins
and the opioidergic nerves (Merchenthaler, et al., 1998; Holinka, et al., 2008).</span></span
></span>
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<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>In young rats, sudden morphine withdrawal caused by injecting the anti-opiate naloxone, causes the
tail skin to flush, with a temperature increase of a few degrees, and causes the core body
temperature to fall slightly. However, old animals respond to the withdrawal in two different
ways. One group responded to the naloxone with an exaggerated flushing and decrease of core
temperature. The other group of old rats, which already had a lower body temperature, didn't
flush at all (Simpkins, 1994). I think this provides an insight into the reason that menopausal
treatment with estrogen can relieve some hot flashes--estrogen treatment might create a flush
resistant state similar to that of the cooler old animals in Simpkins' experiment.</span></span
></span>
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<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>It has been known for a long time, from studies in animals and people, that estrogen lowers body
temperature, and that this involves a tendency to increase blood flow to the skin in response to
a given environmental temperature, that is, the temperature "set-point" is lowered by estrogen.
Besides increasing heat loss, estrogen decreases heat production. These physiological effects of
estrogen can be seen in the normal menstrual cycle, with progesterone having the opposite effect
of estrogen on metabolic rate, skin circulation, body temperature, and heat loss. This causes
the familiar rise in temperature when ovulation occurs. Occasionally, young women will
experience hot flashes during the luteal phase of their menstrual cycle because of insufficient
progesterone production, or at menstruation, when the corpus luteus stops producing
progesterone.</span></span></span>
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<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Estrogen increases the free fatty acids circulating in the blood, and this shifts metabolism away
from oxidation of glucose to oxidation of fat, and it also reduces oxidative metabolism, for
example by lowering thyroid function (Vandorpe and Kühn, 1989). These changes are analogous to
those of fasting, in which metabolism shifts to the oxidation of fatty acids for energy, causes
decreased body temperature, and in some animals leads to a state of torpor or hibernation.</span
></span></span>
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<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Despite decreasing oxidative metabolism, estrogen stimulates the adrenal cortex, both directly and
indirectly through the brain and pituitary, increasing the production of cortisol. Cortisol, by
increasing protein turnover, can increase heat production, but this effect isn't necessarily
sufficient to maintain a normal body temperature. It increases blood glucose, mainly by blocking
its use for energy production, but the glucose is derived from the breakdown of muscle protein.
It allows some glucose to be stored as fat. Sudden increases in the amount of glucose can lower
adrenaline, and chronically excessive cortisol tends to suppress adrenaline. Cushing's syndrome
(produced by excessive cortisol) commonly involves flushing and depression, both of which are
likely to be related to the decreased action of adrenaline.</span></span></span>
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<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>While the biological changes occurring at menopause and during hot flashes are very similar to some
of the direct actions of estrogen, and although the menopause itself is the result of prolonged
exposure to estrogen, very large doses of estrogen can, in many women (as well as in morphine
addicted rats), stop the flushing. In some of the published animal experiments, effective doses
of estrogen were about 2000 times normal, and in some human studies, the dose was 30 times
normal. By blocking the production of heat, the estrogen treatments might be creating conditions
similar to those in Simpkin's cooler old rats, which failed to flush during morphine withdrawal.
Menopausal estrogen treatment is known to lower temperature (Brooks, et al., 1994).</span></span
></span>
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<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Since the Women's Health Initiative publicized the dangers of estrogen, there has been some
interest in alternative treatments for hot flashes. Since a reduced production of progesterone
has been associated with hot flushes for several decades, it isn't surprising that it is now
being tested as an alternative to estrogen. Recently, 300 mg of oral progesterone was found to
be effective for decreasing hot flashes, and a month after discontinuing it, the hot flushes
were still less frequent than before using it (Prior and Hitchcock, 2012). Previously,
transdermal progesterone was found to be effective (Leonetti, et al., 1999).</span></span></span
>
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<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>One of the things progesterone does is to stabilize blood sugar. In one experiment, hot flashes
were found to be increased by lowering blood sugar, and decreased by moderately increasing blood
sugar (Dormire and Reame, 2003).</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Hypoglycemia increases the brain hormone, corticotropin release hormone, CRH (Widmaier, et al.,
1988), which increases ACTH and cortisol. CRH causes vasodilation (Clifton, et al., 2005), and
is more active in the presence of estrogen. Menopausal women are more responsive to its effects,
and those with the most severe hot flushes are the most responsive (Yakubo, et al., 1990).</span
></span></span>
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<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>The first reaction to a decrease of blood glucose, at least in healthy individuals, is to increase
the activity of the sympathetic nervous system, with an increase of adrenaline, which causes the
liver to release glucose from its glycogen stores. The effect of adrenaline on the liver is very
quick, but adrenaline also acts on the brain, stimulating CRH, which causes the pituitary to
secrete ACTH, which stimulates the adrenal cortex to release cortisol, which by various means
causes blood sugar to increase, consequently causing the sympathetic nervous activity to
decrease. Even when the liver's glycogen stores are adequate, the system cycles rhythmically,
usually repeating about every 90 minutes throughout the day.</span></span></span>
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<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Sympathetic nervous activity typically causes vasoconstriction in the skin and extremities,
reducing heat loss, but the small cycles in the system normally aren't noticed, except as small
changes in alertness or appetite. With advancing age, most tissues become less sensitive to
adrenaline and the sympathetic nervous stimulation, and the body relies increasingly on the
production of cortisol to maintain blood glucose. Many of the changes occurring around the
menopause, such as the rise of free fatty acids and decrease of glucose availability, increase
the sensitivity of the CRH nerves, causing the fluctuations of the adrenergic system to cause
larger increases of ACTH and cortisol. Estrogen is another factor that increases the sensitivity
of the CRH nerves, and unsaturated fatty acids (Widmaier, et al. 1995) and serotonin
(Buckingham, et al., 1982) are other factors stimulating it. Serotonin, like noradrenalin, rises
with hypoglycemia (Vahabzadeh, et al., 1995), and estrogen contributes to hypoglycemia, by
impairing the counterregulatory system (Cheng and Mobbs, 2009).</span></span></span>
</blockquote>
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<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>With the reduced vasoconstrictive effects of the sympathetic nerves, and the increased activity of
CRH, cyclic vasodilation under the influence of cortisol will become more noticeable. With the
onset of menopause, and in proportion to the number and intensity of symptoms (on the Greene
Climacteric Scale), the daily secretion of cortisol was increased (Cagnacci, et al.,
2011).</span></span></span>
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<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Once the ideologically based doctrine of menopause as estrogen deficiency is discarded, it's
possible to see its features as clues to the ways in which "stress" contributes to the
age-related degeneration of the various systems of the body--not just the reproductive system,
but also the immune system, the nutritive, growth, and repair processes, and the motivational,
emotional, and cognitive processes of the nervous systems. The changes around menopause aren't
the same for all women, but the ways in which they vary can be understood in terms of the basic
biological principles of energy and adaptation that are universal.</span></span></span>
</blockquote>
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<blockquote>
<span style="color: #222222"> <span style="font-family: georgia, times, serif"><span
style="font-size: medium"
><span style="font-style: normal"><span style="font-weight: normal"
>Each type of cell and organ is subject to injury, and in some cases these injuries are
cumulative. In the healthy liver, which stores glycogen, toxins can be inactivated, for
example by combining with glucuronic acid, derived from the stored glucose. With injury,
such as alcoholism combined with a diet containing polyunsaturated fats, the liver's
detoxifying ability is reduced. Even at an early stage, before there is a significant
amount of fibrosis, the reduced activity of the liver causes estrogen to accumulate in
the body. Estrogen's valuable actions are, in health, exerted briefly, and then the
synthesis of estrogen is stopped, and its excretion reduces its activity, but when the
liver's function is impaired, estrogen's activity continues, causing further
deterioration of liver function, as well as injury of nerves such as Desjardins
described, and the systemic energy shifts and stress activations mentioned above.</span
></span></span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Besides lowering the liver's detoxifying ability, stress, hypoglycemia, malnutrition,
hypothyroidism, and aging can cause estrogen to be synthesized inappropriately and continuously.
With aging, estrogen begins to be produced throughout the body--in fat, muscles, skin, bones,
brain, liver, breast, uterus, etc. Polyunsaturated fats are a major factor in the induction and
activation of the aromatase enzyme, which synthesizes estrogen.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Increased synthesis of estrogen, with aromatase, and decreased excretion of it, by the liver and
kidneys, are only two of the processes that affect the influence of estrogen during aging.
Cellular stress (chemical, mechanical, hypoxemic, hypoglycemic [Clere, et al., 2012; Aguirre, et
al., 2007, Zaman, et al., 2006, Saxon, et al., 2007; Tamir, et al., 2002; Briski, et al., 2010])
increases estrogen receptors (which activate CRH and the stress response). The presence of
estrogen receptors means that estrogen will be bound inside cells, where it acts to modify those
cells. Before estrogen can reach the liver to be inactivated, it must be released from cells.
Ordinarily, the cyclic production of progesterone has that function, by destroying the
estrogen-binding proteins. Progesterone also inhibits the aromatase which synthesizes estrogen,
and shifts the activities of other enzymes, including sulfatases and dehydrogenates, in a
comprehensive process of eliminating the presence and activity of estrogen. At menopause, when
the ovary fails to produce the cyclic progesterone, all of these processes of estrogen
inactivation fail. In the absence of progesterone, cortisol becomes more active, increasing
aromatase activity, which now becomes chronic and progressive. The decrease of progesterone
causes many other changes, including the increased conversion of polyunsaturated fatty acids to
prostaglandins, and the formation of nitric oxide, all of which contribute to the tendency to
flush.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"> <span style="font-family: georgia, times, serif"><span
style="font-size: medium"
><span style="font-style: normal"><span style="font-weight: normal"><hr /></span></span></span
></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>*The limits of the belief system or consciousness of US medicine are nicely defined by the topics
included in the Index Medicus, which was published from 1879 to 2004, by the Surgeon General's
Office of the U.S. Army, the American Medical Association, and the National Library of Medicine,
at different times. If you look up any important topic in physiology or biochemistry in an index
of scientific publications such as Biological Abstracts or Chemical Abstracts, and then look for
the same subject in the Index Medicus, you will find some startling differences--long delays and
antagonistic attitudes. At first the discrepancies seem ludicrous and hard to account for, but I
think they can be explained by recognizing that the editors of medical journals consider science
to be their enemy.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"> <span
style="font-family: georgia, times, serif"
><span style="font-size: medium"><span style="font-style: normal"><span style="font-weight: normal"><h3>
REFERENCES
</h3></span></span></span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>J Biol Chem. 2007 Aug 31;282(35):25501-8. A novel ligand-independent function of the estrogen
receptor is essential for osteocyte and osteoblast mechanotransduction. Aguirre JI, Plotkin LI,
Gortazar AR, Millan MM, O'Brien CA, Manolagas SC, Bellido T.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Prog Clin Biol Res. 1981;67:161-77. Metabolic adaptations to starvation, semistarvation, and
carbohydrate restriction. Aoki TT.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Ascheim, P. (1983). Relation of neuroendocrine system to reproductive decline in female rats. In
"Neuroendocrinology of Aging" (J. Meittes, ed.), 73-101, Plenum, NY.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>J Neuroendocrinol. 2010 Jun;22(6):599-607. Effects of hypoglycaemia on neurotransmitter and hormone
receptor gene expression in laser-dissected arcuate neuropeptide Y/agouti-related peptide
neurones. Briski KP, Nedungadi TP, Koshy Cherian A.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>J Appl Physiol. 1997 Aug;83(2):477-84. Chronic hormone replacement therapy alters thermoregulatory
and vasomotor function in postmenopausal women. Brooks EM, Morgan AL, Pierzga JM, Wladkowski SL,
O'Gorman JT, Derr JA, Kenney WL.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Thorax. 2002 Apr;57(4):361-3. Caffeine decreases exhaled nitric oxide. Bruce C, Yates DH, Thomas
PS.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>J Endocrinol. 1982 Apr;93(1):123-32. Effects of adrenocortical and gonadal steroids on the
secretion in vitro of corticotrophin and its hypothalamic releasing factor. Buckingham JC.</span
></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>L. B. Butareva, et al., "Pathogenetic mechanisms of the development of 'hot flushes' in patients
with climacteric disorders of the sympathetic-adrenal type," Akush. Ginekol. (Mosk.) 10, 30-33,
1989. (Besides activation of the sympathoadrenal system associated with hot flushes,
thyrotrophic hormone also increased.)</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Eur J Endocrinol. 1995 Dec;133(6):691-5. Melatonin enhances cortisol levels in aged but not young
women. Cagnacci A, Soldani R, Yen SS.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>R. F. Casper, et al., "Objective measurement of hot flushes associated with the premenstrual
syndrome," Fertil. Steril. 47(2), 341-344, 1987. ("These physiologic changes are identical
to those seen during menopausal flushes and suggest that PMS may be associated with
neuroendocrine events typical of estrogen withdrawal.")</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Zhonghua Fu Chan Ke Za Zhi. 2002 Dec;37(12):726-8. Changes of plasma serotonin precursor metabolite
concentrations in postmenopausal women with hot flushes. Chen Y, Lu X, Huang Y, Xin X, Ye
X.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Brain Res. 2009 Jul 14;1280:77-83. Epub 2009 May 13. Estradiol impairs hypothalamic molecular
responses to hypoglycemia. Cheng H, Isoda F, Mobbs CV.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Angiogenesis. 2012 Jul 25. Estrogen receptor alpha as a key target of organochlorines to promote
angiogenesis. Clere N, Lauret E, Malthiery Y, Andriantsitohaina R, Faure S.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>J Endocrinol. 2005 Jul;186(1):69-76. Microvascular effects of corticotropin-releasing hormone in
human skin vary in relation to estrogen concentration during the menstrual cycle. Clifton VL,
Crompton R, Read MA, Gibson PG, Smith R, Wright IM.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Pharmacol Biochem Behav 2000 May;66(1):39-45. Caffeine-induced increases in the brain and plasma
concentrations of neuroactive steroids in the rat. Concas A, Porcu P, Sogliano C, Serra M, Purdy
RH, Biggio G.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"> <span style="font-family: georgia, times, serif"><span
style="font-size: medium"
><span style="font-style: normal"><span style="font-weight: normal"
>Acta Anat (Basel), 1995, 152:1, 28-32. Immunohistochemical and radioimmunological
assessment of thyrotrophs in the pituitary of aging rats. Cónsole GM; Gómez Dumm CL;
Goya RG</span></span></span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Endocrinology. 1992 Nov;131(5):2482-4. Vitamin E protects hypothalamic beta-endorphin neurons from
estradiol neurotoxicity. Desjardins GC, Beaudet A, Schipper HM, Brawer JR.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Med Chem. 2007 Nov;3(6):546-50. A salicylic acid-based analogue discovered from virtual screening
as a potent inhibitor of human 20alpha-hydroxysteroid dehydrogenase. Dhagat U, Carbone V, Chung
RP, Matsunaga T, Endo S, Hara A, El-Kabbani O.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Nurs Res. 2003 Sep-Oct;52(5):338-43. Menopausal hot flash frequency changes in response
to experimental manipulation of blood glucose. Dormire SL, Reame NK.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>J Endocrinol. 1995 Sep;146(3):403-10. Ovulation rate and the concentrations of gonadotrophins and
metabolic hormones in ewes infused with glucose during the late luteal phase of the oestrous
cycle. Downing JA, Joss J, Scaramuzzi RJ.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>J Endocrinol. 1999 Dec;163(3):531-41. The effect of a direct arterial infusion of insulin and
glucose on the ovarian secretion rates of androstenedione and oestradiol in ewes with an
autotransplanted ovary. Downing JA, Joss J, Scaramuzzi RJ.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Biogerontology. 2003;4(1):47-50. Food restriction, pituitary hormones and ageing. Everitt AV.</span
></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Neuropharmacology. 2000 Aug 23;39(11):2205-13. Effects of caffeine and paracetamol alone or in
combination with acetylsalicylic acid on prostaglandin E(2) synthesis in rat microglial cells.
Fiebich BL. Lieb K, Hull M, Aicher B, van Ryn J, Pairet M, Engelhardt G.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Anim Reprod Sci. 2011 Sep;127(3-4):154-63. The infusion of glucose in ewes during the luteal phase
increases the number of follicles but reduces oestradiol production and some correlates of
metabolic function in the large follicles. Gallet C, Dupont J, Campbell BK, Monniaux D,
Guillaume D, Scaramuzzi RJ.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Endocrinology. 2011 Oct;152(10):3905-16. Unsaturated fatty acids stimulate LH secretion via novel
PKCepsilon and -theta in gonadotrope cells and inhibit GnRH-induced LH release. Garrel G, Simon
V, Denoyelle C, Cruciani-Guglielmacci C, Migrenne S, Counis R, Magnan C, Cohen-Tannoudji
J.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>J Neurochem. 2009 Sep;110(6):1796-805. Hypothalamic neuronal histamine signaling in the estrogen
deficiency-induced obesity. Gotoh K, Masaki T, Chiba S, Higuchi K, Kakuma T, Shimizu H, Mori M,
Sakata T, Yoshimatsu H.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Climacteric. 2008;11 Suppl 1:15-21. Preventive effect of oral estetrol in a menopausal hot
flush model. Holinka CF, Brincat M, Coelingh Bennink HJ.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Menopause. 2010 Sep-Oct;17(5):978-82. Nitric oxide synthase inhibition attenuates cutaneous
vasodilation during postmenopausal hot flash episodes. Hubing KA, Wingo JE, Brothers RM, Del
Coso J, Low DA, Crandall CG.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"> <span style="font-family: georgia, times, serif"><span
style="font-size: medium"
><span style="font-style: normal"><span style="font-weight: normal"
>Cancer Epidemiol Biomarkers Prev. 2008 Mar;17(3):680-7. Nonsteroidal anti-inflammatory drug
use and serum total estradiol in postmenopausal women. Hudson AG, Gierach GL, Modugno F,
Simpson J, Wilson JW, Evans RW, Vogel VG, Weissfeld JL.</span></span></span></span
></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Horm Metab Res. 1991 Oct;23(10):499-503. Studies on facial temperature rise and involvement of
serotonin in the respiratory stimulation by CRH. Krause U, Nink M, Brauer A, Huber I, Velten A,
Lehnert H, Beyer J. (Both serotonin and CRH cause facial flushing.)</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Obstet Gynecol 1999 Aug;94(2):225-8. Transdermal progesterone cream for vasomotor symptoms
and postmenopausal bone loss. Leonetti HB, Longo S, Anasti JN.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Chem Res Toxicol. 2002 Apr;15(4):512-0. Oxidative DNA damage induced by equine estrogen
metabolites: role of estrogen receptor alpha. Liu X, Yao J, Pisha E, Yang Y, Hua Y, van Breemen
RB, Bolton JL.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Maturitas. 1998 Nov 16;30(3):307-16. The effect of estrogens and antiestrogens in a rat model for
hot flush. Merchenthaler I, Funkhouser JM, Carver JM, Lundeen SG, Ghosh K, Winneker RC.</span
></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Menopause. 2005 Mar;12(2):210-5. Adipose aromatase gene expression is greater in older women and is
unaffected by postmenopausal estrogen therapy. Misso ML, Jang C, Adams J, Tran J, Murata Y, Bell
R, Boon WC, Simpson ER, Davis SR.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Menopause. 2010 Jul;17(4):860-73. Estrogen treatment impairs cognitive performance after
psychosocial stress and monoamine depletion in postmenopausal women. Newhouse PA, Dumas J,
Wilkins H, Coderre E, Sites CK, Naylor M, Benkelfat C, Young SN. ["E2-treated compared with
placebo-treated participants exhibited significant worsening of cognitive performance on tasks
measuring attentional performance and psychomotor speed."]</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Mol Cell Biochem. 2003 Feb;244(1-2):125-8. Effect of caffeine on metabolism of L-arginine in the
brain. Nikolic J, Bjelakovic G, Stojanovic I.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Maturitas, 2002 Jan 30;41(1):69-77. Androgens and estrogens in relation to hot flushes during the
menopausal transition. Overlie I, Moen MH, Holte A, Finset A.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>J Endocrinol. 1988 Nov;119(2):275-80. Increases in plasma concentrations of steroids in the rat
after the administration of caffeine: comparison with plasma disposition of caffeine. Pollard
I.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Mech Ageing Dev. 2006 Aug;127(8):658-9. Pituitary removal in adult mice increases life span. Powers
RW 3rd, Harrison DE, Flurkey K.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Gynecol Endocrinol. 2012 Aug 1. Progesterone for hot flush and night sweat treatment -
effectiveness for severe vasomotor symptoms and lack of withdrawal rebound. Prior JC, Hitchcock
CL.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Front Biosci (Schol Ed). 2011 Jan 1;3:474-86. The endocrinology of perimenopause: need for a
paradigm shift. Prior JC, Hitchcock CL.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Biol Reprod. 1976 Sep;15(2):153-7. Sex steroids in reproductive tract tissues: regulation of
estradiol concentrations by progesterone. Resko JA, Boling JL, Brenner RM, Blandau RJ.</span
></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Am J Physiol Endocrinol Metab. 2007 Aug;293(2):E484-91. The skeletal responsiveness to mechanical
loading is enhanced in mice with a null mutation in estrogen receptor-beta. Saxon LK, Robling
AG, Castillo AB, Mohan S, Turner CH.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>J Appl Physiol. 2000 May;88(5):1643-9. Estrogen modifies the temperature effects of progesterone.
Stachenfeld NS, Silva C, Keefe DL.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Life Sciences 32(17), 1957-1966, 1983.Similarities between morphine withdrawal in the rat and the
menopausal hot flush, J. W. Simpkins, et al. (Accelerated heart rate and hypersecretion of
luteinizing hormone preceded the increase in tail skin temperature.)</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Biol Reprod. 1982 Aug;27(1):29-37. Contribution of the ovary versus hypothalamus-pituitary to
termination of estrous cycles in aging rats using ovarian transplants. Sopelak VM, Butcher
RL.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Neuroendocrinology, 1986, 43:2, 135-42. The increase of anterior pituitary dopamine in aging
C57BL/6J female mice is caused by ovarian steroids, not intrinsic pituitary aging. Telford N;
Mobbs CV; Sinha YN; Finch CE.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Eur J Neurosci 1995 Feb 1;7(2):175-9. Effects of changes in rat brain glucose on serotonergic and
noradrenergic neurons, Vahabzadeh A, Boutelle MG, Fillenz M.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>J Clin Invest 1993; 92(4):1896-1902. Evidence of direct estrogenic regulation of human
corticotropin-releasing hormone gene expression. Potential implications for the sexual
dimorphism of the stress response and immune/inflammatory reaction. Vamvakopoulos NC and
Chrousos GP.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Gen Comp Endocrinol. 1989 Dec;76(3):341-5. Estradiol-17 beta silastic implants in female Rana
ridibunda depress thyroid hormone concentrations in plasma and the in vitro 5'-monodeiodination
activity of kidney homogenates. Vandorpe G, Kühn ER.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Gerontologia, 1966, 12:1, 48-56. The role of the pituitary in the aging of collagen. Verzár F;
Spichtin H</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Clin Chim Acta. 2000 Nov;301(1-2):169-79. Influence of sex and age on serum nitrite/nitrate
concentration in healthy subjects. Watanabe T, Akishita M, Toba K, Kozaki K, Eto M, Sugimoto N,
Kiuchi T, Hashimoto M, Shirakawa W, Ouchi Y.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Am J Physiol. 1988 Sep;255(3 Pt 1):E287-92. Regulation of corticotropin-releasing factor secretion
in vitro by glucose. Widmaier EP, Plotsky PM, Sutton SW, Vale WW.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Pharmacol Biochem Behav. 1988 Feb;29(2):433-41. Adenosine antagonists as potential therapeutic
agents. Williams M, Jarvis MF.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Am J Physiol. 1999 Dec;277(6 Pt 1):E965-70. Neuroendocrine modulation of the "menopause": insights
into the aging brain. Wise PM.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Rec Progr Hormone Res 52: 279-305, 1997. Aging of the female reproductive system: a window into
brain aging. Wise PM, Kashon ML, Krajnak KM, Rosewell KL, Cai A, Scarbrough K, Harney JP,
McShane T, Lloyd J, Weiland NG</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Nihon Sanka Fujinka Gakkai Zasshi. 1990 Jun;42(6):553-60. [Endocrinological analysis of climacteric
symptoms and gonadal dysfunction by CRF test]. [Article in Japanese] Yakubo K, Makino T,
Takayama S, Sakai A, Iizuka R.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>J Bone Miner Res. 2006 Aug;21(8):1297-306. Osteocytes use estrogen receptor alpha to respond to
strain but their ERalpha content is regulated by estrogen. Zaman G, Jessop HL, Muzylak M, De
Souza RL, Pitsillides AA, Price JS, Lanyon LL.</span></span></span>
</blockquote>
<p> </p>
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