Subject: Re: estrogen
From: Raymond Peat <[email-masked]>
To: "Earl Conroy" <[email-masked]>
Date: Wed, 28 Apr 1999 18:17:31 -0700

There was nothing enclosed with your letter, but since estrogen activates
lipid peroxidation, glutamate and calcium excitotoxicity, and DNA damage,
it isn't likely; women have, at middle age, 2.8 times the incidence of
Alzheimer's disease as men do, and in extreme old age, the ratio is over
six to one.  The cause of menopause is nerve damage produced by estrogen.
Here's an upcoming newsletter (not for distribution for about two moonths).

	Estrogen and brain aging in men and women: Depression, energy, stress 
		***********************************************************
			          THE CONTEXT:
   Estrogen is essential to masculinization of the young animal.  In aging
men its level increases progressively, while the opposing hormones
decrease, and during sickness or stress its level increases.
   Estrogen's masculinizing effects are seen occasionally in maturity, in
the polycystic ovary syndrome, in which hyperestrogenism causes hirsutism.
Women have higher progesterone levels than men do, and progesterone's
antiestrogen action can prevent masculinzation by estrogen and
testosterone.  It is mainly the influence of progesterone which accounts
for women's greater longevity and biological adaptability.
   In all mammals studied, estrogen generally increases with age.   In
women, its concentration increases throughout the reproductive years.  With
reduced progesterone function at menopause, estrogen's effects are
intensified.
   Estrogen's direct cumulative effect on brain cells causes menopause.
   Estrogen promotes the formation of histamine, serotonin, nitric oxide,
and carbon monoxide, all of which interfere with mitochondrial energy
production.
Estrogen, like other factors which interfere with the use of oxygen to
produce energy, stimulates the hormones of the stress reaction, including
pituitary ACTH and adrenal cortisol.
   The hormones of stress are associated with heart disease,
immunodeficiency, memory loss, osteoporosis, decreased energy metabolism in
the brain, and death of brain cells.
Estrogen promotes the hormonal pattern of diabetes, including elevations of
free fatty acids and growth hormone.
   Estrogen's effects on nerve cells are instantaneous, cumulative, and
inheritable.
Progesterone, thyroid, nutrition and other factors can correct both the
immediate and the long-range toxic effects of estrogen.
                 ********************************************

	Although the incidence of Alzheimer's disease is much higher among women
than among men, there is a major campaign under way to convince the public
that taking estrogen supplements will prevent the disease.  Estrogen is now
mainly promoted to prevent osteoporosis (another problem that is more
common in women) and heart disease (which is more common in men).  
	This substance, which came into medical use as "the female hormone" for
the treatment of "female problems," especially for improving fertility, and
then for preventing fertility as the oral contraceptive, is now being aimed
primarily at the post-reproductive population, for problems that are
essentially unrelated to femininity.  It is, in fact, being presented to
the public as something to prevent major age-related conditions.
	Brain degeneration, like osteoporosis, takes years to develop.  Analysis
of letters written by young women, for example, showed limited mental
functioning in those who many years later developed Alzheimer's disease,
and young women who have small bones are the ones most likely to develop
osteoporosis later.  It seems clear that the course of degenerative aging
processes is set in young adulthood (or even earlier), and that it is never
too early to be concerned with correcting processes that are going in the
wrong direction.  (See Walker, et al., 1988, and Smith, et al., 1992.) 
	In "The Biological Generality of Progesterone" (1979) I proposed that the
life-long trajectory of energy production and longevity was strongly
influenced by prenatal nutrition and progesterone.  This idea was based on
work by people such as Marion Diamond, who showed that prenatal
progesterone enlarges the cortex of the brain, and that estrogen makes it
smaller, and Leonell Strong, who showed that a treatment that lowered the
estrogen function in a young mouse could produce cancer-free offspring for
several generations.  Strong's work was very encouraging, because it showed
that biological problems that had been "bred in" over many generations
could be corrected by some simple metabolic treatments.
	Seeing these profoundly toxic long-range effects of estrogen, which shaped
the animal's growth, development, function, and even its heredity, made it
important to learn how estrogen works, because such fundamental changes
covering the whole range of biology, produced by a simple little molecule,
promised to reveal interesting things about the nature of life.

	Aging is an energy problem, and in the brain, which has extremely high
energy requirements, interference with the energy supply quickly causes
cells to die.
I believe that estrogen's "principle," in all of its actions, is to
interfere with the respiratory mode of energy production.  This is an
integrating principle that explains estrogen's immediate, direct effects on
cells and organisms, which aren't explained by the idea that it acts on the
genes through a specific "estrogen receptor."  (It's hard to imagine, for
example, how the "estrogen receptor" doctrine could explain the fact that a
single injection of estrogen can kill a large portion of brain cells.)  It
explains why estrogen causes cells to take up water, allowing calcium to
enter, activating various enzymes and cell division.  On the organismic
level, it explains why estrogen mimics "shock," releasing histamine and
activating the nervous and glandular stress response system.  The
inefficiency of metabolism which doesn't use oxygen in the normal way
causes glucose to be used rapidly, and this in itself is enough to trigger
the release of pituitary ACTH and adrenal cortisol.  The ACTH, and related
hormones, liberate free fatty acids, which cells take up instead of
glucose, and this (in the so-called Randall cycle) further limits the
body's ability to oxidize glucose.

	People have spoken of "cascades" in relation to the adrenal
glucocorticoids (e.g., cortisol) and estrogen, leading to cell damage, but
really both of these hormonal cascades have to be seen as part of a more
general collapse of adaptive systems, as a result of both chronic and
immediate inadequacies of energy production.

	Estrogen activates the adrenal stress reaction by way of the hypothalamus
and pituitary, by direct actions on the adrenal glands, and by a variety of
indirect effects, such as the increase of free fatty acids.  It activates
the excitotoxic glutamic acid pathway, and interferes with protective
adenosine inhibition of nerves.  It has both direct and indirect ways of
promoting the formation of nitric oxide and carbon monoxide.  These, and
other estrogen-promoted factors, quickly and seriously interfere with
mitochondrial respiration.  Many of these effects contribute to increased
intracellular calcium and free radical production, contributing to both the
excitatory excess and the energy deficit.

	The biochemical details of these cascades are mainly interesting because
they show how many different kinds of stress converge on a few
physiological processess--mitochondrial energy production, cellular
excitation, and intercellular communication--which, when damaged thousands
of times, lead to the familiar states of old age.  These few functions,
damaged by an infinite variety of stresses, have their own complexly
adaptive ways of deteriorating, producing the various degenerative diseases.
This perspective brings dementia, heart failure, autoimmunity,
immunodeficiency and other diseases of aging together, in ways that allow
generalized therapeutic and preventive approaches.
	The antistress, antiestrogen approaches become fundamental to prevention
of aging.  
	The pro-estrogenic nature of the unsaturated fatty acids is probably the
biggest barrier to the radical elimination of degenerative diseases.
Various saturated fatty acids, including butyric, octanoic, and palmitic,
have protective effects on mitochondrial respiration.
	Progesterone is the basic brain-protective antiestrogen.  It works to
protect the brain at many levels (preventing lipid peroxidation,
exitotoxicity, nitric oxide damage, energy deficit, edema, etc.) and it
promotes repair and recovery. 
Progesterone in most cases has effects opposite to estrogen's, improving
mitochondrial energy production while preventing excessive excitation.
Along with pregnenolone, progesterone is recognized as a neurosteroid with
anti-excitotoxic actions, with the ability to promote repair and
regeneration of the nervous system. (Roof, Stein, Faden; Schumacher, et
al.; Baulieu.) 
	The use of aspirin, which reduces inflammation and inhibits the formation
of neurotoxic prostaglandins, is known to be associated with a lower
incidence of Alzheimer's disease, and in other contexts, it offers
protection against estrogen.  Naloxone, the antiendorphin, has been found
to reverse some of the cumulative effects of stress, restoring some
pituitary and ovarian function, and it promotes recovery after brain
injury; in a variety of ways, it corrects some of estrogen's toxic effects. 
Adenosine helps to maintain brain glycogen stores, which are lost in stress
and aging.  Vitamin B12 protects against nitric oxide, and improves
alertness.  
	Pyruvic acid has brain-protective effects, apparently through its
decarboxylation (producing carbon dioxide) rather than through its use as
an energy source, since other ketoacids are similarly protective.  (The
ketoacids occur in some natural foods.) The directly brain-protective
effect of carbon dioxide offers many clues that should be interpreted in
relation to estrogen's toxicity, since many of their effects on nerves are
opposite.  Estrogen blocks the production of energy while it stimulates
nerve cells to use energy more rapidly, and carbon dioxide promotes the
production of energy, while restraining the excitation which expends
energy.   The presence of carbon dioxide is an indicator of proper
mitochondrial respiratory functioning.
	Pharmaceutical blockers of glutamic acid transmission, and of calcium and
sodium uptake, prevent some deterioration following brain injury, but the
most physiological way to protect against those toxic processes is to
maintain metabolic energy at a high level.  Magnesium, which is protective
against excitatory damage and is a calcium antagonist, tends to be retained
in proportion to the activity of thyroid hormone.
As I have discussed previously, progesterone alone has brought people out
of post-epileptic dementia and senile dementia, but it is reasonable to use
a combined physiological approach, including thyroid.
	Besides providing new insights into biological energy and aging, the
recognition that estrogen activates the stress hormone system--the
pituitary-adrenal system--also provides clear insights into other problems,
such as the polycystic ovary syndrome, hirsutism, adrenal hyperplasia,
Cushing's disease, etc.

				     REFERENCES
[The references are clustered into groups, showing estrogen's indirect
toxicity through its activation of the adrenal hormones, its direct
brain-toxicity, and some of the interactions between these and fats, nitric
oxide, etc.]
.
Stress 1996 Jul;1(1):1-19  Stress, Glucocorticoids, and Damage to the
Nervous System: The Current State of Confusion. Sapolsky RM Department of
Biological Sciences, Stanford University, Stanford, CA 94305. An extensive
literature demonstrates that glucocorticoids (GCs), the adrenal steroids
secreted during stress, can have a broad range of deleterious effects in
the brain. The actions occur predominately, but not exclusively, in the
hippocampus, a structure rich in corticosteroid receptors and particularly
sensitive to GCs. The first half of this review considers three types of GC
effects: a) GC-induced atrophy, in which a few weeks' exposure to high GC
concentrations or to stress causes reversible atrophy of dendritic
processes in the hippocampus; b) GC neurotoxicity where, over the course of
months, GC exposure kills hippocampal neurons; c) GC neuroendangerment, in
which elevated GC concentrations at the time of a neurological insult such
as a stroke or seizure impairs the ability of neurons to survive the
insult. The second half considers the rather confusing literature as to the
possible mechanisms underlying these deleterious GC actions. Five broad
themes are discerned: a) that GCs induce a metabolic vulnerability in
neurons due to inhibition of glucose uptake; b) that GCs exacerbate various
steps in a damaging cascade of glutamate excess, calcium mobilization and
oxygen radical generation. In a review a number of years ago, I concluded
that these two components accounted for the deleterious GC effects.
Specifically, the energetic vulnerability induced by GCs left neurons
metabolically compromised, and less able to carry out the costly task of
containing glutamate, calcium and oxygen radicals. More recent work has
shown this conclusion to be simplistic, and GC actions are shown to
probably involve at least three additional components: c) that GCs impair a
variety of neuronal defenses against neurologic insults; d) that GCs
disrupt the mobilization of neurotrophins; e) that GCs have a variety of
electrophysiological effects which can damage neurons. The relevance of
each of those mechanisms to GC-induced atrophy, neurotoxicity and
neuroendangerment is considered, as are the likely interactions among them. 
J Clin Endocrinol Metab 1996 Oct;81(10):3639-43 Short-term estradiol
treatment enhances pituitary-adrenal axis and sympathetic responses to
psychosocial stress in healthy young men. Kirschbaum C, Schommer N,
Federenko I, Gaab J, Neumann O, Oellers M, Rohleder N, Untiedt A, Hanker J,
Pirke KM, Hellhammer DH Center for Psychobiological, University of Trier,
Germany.  Evidence from animal studies and clinical observations suggest
that the activity of the pituitary-adrenal axis is under significant
influence of sex steroids. The present study investigated how a short term
elevation of estradiol levels affects ACTH, cortisol, norepinephrine, and
heart rate responses to mental stress in healthy men. In a double blind
study, 16 men received a patch delivering 0.1 mg estradiol/day
transdermally, and age- and body mass index-matched control subjects
received a placebo patch. Twenty-four to 48 h later, they were exposed to a
brief psychosocial stressor (free speech and mental arithmetic in front of
an audience). In response to the psychosocial stressor, ACTH, cortisol,
norepinephrine, and heart rate were increased in both experimental groups
(all P < 0.0001). However, the estradiol-treated subjects showed
exaggerated peak ACTH (P < 0.001) and cortisol (P < 0.002) responses
compared to the placebo group. Also, the norepinephrine area under the
response curve was greater in the estradiol group (P < 0.05). Although
heart rate responses differences failed to reach statistical significance,
they, too, tended to be larger in the estradiol group. Neither mood ratings
before or after the stressor, nor ratings of the perception of the stressor
could explain the observed endocrine response differences. In conclusion,
short term estradiol administration resulted in hyperresponses of the
pituitary-adrenal axis and norepinephrine to psychosocial stress in healthy
young men independent of psychological effects, as assessed in this study.   
J Appl Physiol 1996 Mar;80(3):931-9  Treadmill exercise training and
estradiol increase plasma ACTH and prolactin after novel footshock.
White-Welkley JE, Warren GL, Bunnell BN, Mougey EH, Meyerhoff JL, Dishman
RK  "We examined whether rats that were treadmill exercise trained (Tr) or
chronically immobilized (CI) had similar responses by the
hypothalamic-pituitary-adrenal (HPA) cortical axis to acute stress and
whether the HPA responses interacted with the
hypothalamic-pituitary-gonadal (HPG) axis." "[ACTH] and [prolactin] after
footshock were higher in Tr rats with E2 compared with CI and sedentary
rats without E2; recovery levels for sedentary animals were higher after
Run compared with Im. The elevation in [corticosterone] from minute 1 to 15
of recovery was higher after the familiar Run and Im conditions. Our
findings are consistent with an increased responsiveness of the HPA axis to
novel footshock after treadmill exercise training that is additionally
modulated by the HPG axis." 
Endocrinology 1992 Sep;131(3):1261-9. Chronic estrogen-induced alterations
in adrenocorticotropin and corticosterone secretion, and glucocorticoid
receptor-mediated functions in female rats. Burgess LH, Handa RJ "The
effect of estrogen (E) on the hypothalamic-pituitary-adrenal axis was
investigated in female Sprague-Dawley rats." "...the ACTH and CORT
secretory responses to ether stress could be suppressed by exogenous RU
28362 (a specific glucocorticoid receptor agonist; 40 micrograms/100 g BW
for 4 days) in OVX controls (P less than 0.05), but not in E-treated
animals. These data suggest that E can impair glucocorticoid
receptor-mediated delayed or slow negative feedback." "Thus, E treatment
results in a loss of the glucocorticoid receptor's ability to autoregulate;
this suggests that E may cause a functional impairment of the
glucocorticoid receptor even though receptor binding appears normal. These
findings suggest that hyperactivation of the hypothalamic-pituitary-adrenal
axis after stress in E-treated rats is due in part to impaired
glucocorticoid receptor-mediated slow negative feedback." 
Am J Physiol 1994 Jul;267(1 Pt 1):E32-8  Lesions of hypothalamic
paraventricular nuclei do not prevent the effect of estradiol on energy and
fat balance. Dagnault A, Richard D.  "Plasma levels of corticosterone and
ACTH were higher in E2-treated rats than in animals receiving the placebo
treatment. The present results provide evidence that the hypothalamic PVH
is not an essential neuroanatomical structure in the effects of E2 on
energy and fat balances." 
Fertil Steril 1994 Oct;62(4):738-43  Ovarian suppression reduces clinical
and endocrine expression of late-onset congenital adrenal hyperplasia due
to 21-hydroxylase deficiency. Carmina E, Lobo RA "OBJECTIVE: To determine
the effectiveness of GnRH-agonist (GnRH-a) treatment in women with late
onset congenital adrenal hyperplasia." "CONCLUSIONS: Suppression of the
ovary with GnRH-a treatment was beneficial in these patients with
late-onset congenital adrenal hyperplasia. An ovarian influence on the
clinical and biochemical findings of the disorder is suggested." 
Life Sci 1995;57(9):833-7.  Effects of sex hormones on the steroidogenic
activity of dispersed adrenocortical cells of the rat adrenal cortex. Nowak
KW, Neri G, Nussdorfer GG, Malendowicz LK  "The effect of 17 beta-estradiol
and testosterone on glucocorticoid secretion were studied in vitro by using
dispersed inner adrenocortical cells obtained from gonadectomized female
and male rats. Independently of the sex of animals, estradiol enhanced
basal, but not ACTH-stimulated corticosterone (B) secretion; conversely,
testosterone inhibited ACTH-stimulated, but not basal B output."
"Testosterone inhibited by about 30% ACTH-stimulated PREG production and by
about 54% total post-PREG secretion (B was decreased to 56% of the control
value, and other steroid hormones were below the limit of sensitivity of
our assay system). These findings indicate that sex hormones directly
affect rat adrenocortical secretion, mainly by acting on the rate-limiting
step of steroidogenesis (i.e. the conversion of cholesterol to PREG);
moreover, they suggest that testosterone is also able depress the activity
of the enzymes operating distally to cholesterol side-chain cleavage." 
J Endocrinol 1995 Feb;144(2):311-21  The influence of ovarian steroids on
hypothalamic-pituitary-adrenal regulation in the female rat. Carey MP,
Deterd CH, de Koning J, Helmerhorst F, de Kloet ER  "The present study
examined the association between hypothalamic- pituitary-adrenal (HPA) and
hypothalamic-pituitary-ovarian axes. HPA activity determined by plasma
levels of adrenocorticotropin (ACTH) and corticosterone (B) was assessed in
intact female rats as a function of oestrous cycle stage under resting
conditions and after exposure to a 20 min restraint stress. To delineate
the roles of oestradiol and progesterone in HPA axis modulation, plasma
concentrations of ACTH and B were determined in ovariectomised (OVX)
animals treated with oestradiol and/or progesterone under resting
conditions and during exposure to the stress of a novel environment. The
effects of these steroid treatments on the transcription and/or binding
properties of the two corticosteroid receptors, the mineralocorticoid (MR)
and glucocorticoid (GR) receptors, were also examined in hippocampal
tissue, (i) Fluctuations in basal and stress-induced plasma ACTH and B
concentrations were found during the oestrous cycle with highest levels at
late pro-oestrus. (ii) In OVX steroid-replaced animals, basal and
stress-induced activity was enhanced in oestradiol and oestradiol plus
progesterone-treated animals compared with OVX controls." "In conclusion,
we find that sex steroids modulate HPA activity and suggest that the
observed effects of these steroids on hippocampal MR may underlie their
concerted mechanism of action in inducing an enhanced activity at the
period of late pro-oestrus." 
 J Clin Endocrinol Metab 1995 Feb;80(2):603-7 The impact of estrogen on
adrenal androgen sensitivity and secretion in polycystic ovary syndrome.
Ditkoff EC, Fruzzetti F, Chang L, Stancyzk FZ, Lobo RA  "Adrenal
hyperandrogenism is a common feature of patients with polycystic ovary
syndrome (PCO). This may be due to enhanced adrenal sensitivity to ACTH.
Because enhanced ovarian androgen secretion does not appear to explain this
phenomenon, we explored the role of estrogen in inducing enhanced adrenal
sensitivity, in that a state of relative hyperestrogenism exists in PCO."
"Steroid ratio responses to oCRH suggested that 17,20-desmolase activity
(delta maximum change in the ratio of A4/17-hydroxyprogesterone) was
lowered with estrogen suppression and increased again after transdermal E2
administration." "In conclusion, these data provide evidence that estrogen
is at least one factor that influences adrenal androgen sensitivity in PCO
and may help explain the frequent finding of adrenal hyperandrogenism in
this syndrome." 
Endocrinology 1993 Nov;133(5):2284-91 Estrogen and hydroxysteroid
sulfotransferases in guinea pig adrenal cortex: cellular and subcellular
distributions. Whitnall MH, Driscoll WJ, Lee YC, Strott CA  "The high
concentration of EST immunoreactivity in nuclei suggests that EST may play
a role in modulating the ability of active estrogens to regulate gene
expression in ACTH-responsive cells. The distribution of HST labeling
suggests that sulfonation of adrenocortical 3-hydroxysteroids takes place
largely within smooth endoplasmic reticulum in the zona reticularis in
adult guinea pigs." 
J Clin Endocrinol Metab 1993 Sep;77(3):754-8. Interaction of insulin-like
growth factor-II and estradiol directs steroidogenesis in the human fetal
adrenal toward dehydroepiandrosterone sulfate production. Mesiano S, Jaffe
RB  
J Clin Endocrinol Metab 1993 Aug;77(2):494-7. Estradiol stimulates cortisol
production by adrenal cells in estrogen-dependent primary adrenocortical
nodular dysplasia. Caticha O, Odell WD, Wilson DE, Dowdell LA, Noth RH,
Swislocki AL, Lamothe JJ, Barrow R. Adrenal glands from a patient with
ACTH-independent Cushing's syndrome, whose symptoms worsened during
pregnancy and oral contraceptive use, were cultured in different
concentrations of estradiol. Estradiol stimulated cortisol secretion in a
dose-response manner in the absence of ACTH." . "This is the first
description of estradiol stimulation of cortisol production by cultured
adrenal cells in ACTH-independent Cushing's syndrome." 
Endocrinology 1992 Nov;131(5):2430-6  Effects of gonadectomy and sex
hormone therapy on the endotoxin-stimulated hypothalamo-pituitary-adrenal
axis: evidence for a neuroendocrine-immunological sexual dimorphism.
Spinedi E, Suescun MO, Hadid R, Daneva T, Gaillard RC  "Bacterial
lipopolysaccharide (LPS) stimulates the hypothalamo-pituitary-adrenal axis
by a mechanism involving the release of cytokines, which activate the
CRH-ACTH system and, as a result, increase glucocorticoid secretion. In the
present study we investigated the possibility that endogenous sex hormones
modulate the in vivo endotoxin-stimulated adrenal and immune responses in
adult BALB/c mice." "Our results indicate that 1) randomly cycling female
mice have significantly more pronounced corticosterone secretion than males
2 h after endotoxin injection, although the tumor necrosis factor responses
were similar....". 
J Neurosci Res 1995 Oct 1;42(2):228-35  Activation of the
hypothalamo-anterior pituitary corticotropin- releasing hormone,
adrenocorticotropin hormone and beta-endorphin systems during the estradiol
17 beta-induced plasma LH surge in the ovariectomized monkey. Kerdelhue B,
Jones GS, Gordon K, Seltman H, Lenoir V, Melik Parsadaniantz S, Williams
RF, Hodgen GD.  "These results suggest that there may be a marked
activation of the hypothalamo-anterior pituitary-adrenal axis during the
negative and positive feedback phases of the E2B-induced LH surge in the
ovariectomized monkey."  
Biol Reprod 1995 Nov;53(5):996-1002 Activation of the baboon fetal
pituitary-adrenocortical axis at midgestation by estrogen: responsivity of
the fetal adrenal gland to adrenocorticotropic hormone in vitro. Berghorn
KA, Albrecht ED, Pepe G.J.  
Fertil Steril 1996 May;65(5):950-3  Ovarian hyperstimulation augments
adrenal dehydro- epiandrosterone sulfate secretion. Casson PR, Kristiansen
SB, Umstot E, Carson SA, Buster JE.
Hinyokika Kiyo 1997 Apr;43(4):275-8  [A case of concurrent bilateral
adrenocortical adenoma causing Cushing's syndrome].  Koga F, Sumi S, Umeda
H, Maeda S, Honda M, Hosoya Y, Yano M, Konita A, Suzuki S, Yoshida K. "All
14 previously reported cases of bilateral adrenocortical adenoma (BAA)
causing Cushing's syndrome as well as the present case were concurrent and
dominant in females of reproductive age. This suggests that some cofactors
other than ACTH, such as estrogen, contribute to the pathogenesis of BAA." 
Endocrinology 1991 Nov;129(5):2503-11  Variations in the
hypothalamic-pituitary-adrenal response to stress during the estrous cycle
in the rat. Viau V, Meaney MJ. "In cycling rats, we found significantly
higher peak ACTH (P less than 0.01) and B (P less than 0.05) responses to
stress during proestrus compared to the estrous and diestrous phases." "In
response to stress, ACTH levels were higher (P less than 0.01) in the E'
group compared to the EP' and O' groups. Although the peak B response was
similar in all groups, the E' and EP' groups secreted more B after the
termination of stress than did the O' group. Within the 20 min stress
period, ACTH levels in the E' group were significantly (P less than 0.05)
higher at 5, 10, and 15 min after the onset of stress, compared to the EP'
and O' groups. Plasma B levels were significantly higher in the E' group at
5 and 10 min (P less than 0.05 and P less than 0.01, respectively) compared
to the EP' and O' group. beta-endorphin-like immunoreactive responses to
restraint stress were also significantly higher in the E' group compared to
the EP' (P less than 0.05) and O' (P less than 0.01) groups. In contrast to
the effect seen at 24 h, ACTH responses to stress 48 h after E2 injection
in the E' group were comparable to O' animals. There was no effect of E2 on
ACTH clearance, whereas B clearance was enhanced in E' treated animals vs.
O'-treated animals. These results indicate that the HPA axis in the female
rat is most sensitive to stress during proestrous. Such enhanced HPA
responses to stress are limited to the early portion of proestrous, as
progesterone appears to inhibit the facilitatory effects of estrogen on
ACTH release during stress. Taken together, these results suggest an
ovarian influence on both activational and inhibitory components of HPA
activity." 
Semin Reprod Endocrinol 1997 May;15(2):137-57 Adrenal involvement in
polycystic ovary syndrome. Gonzalez F.  "Whereas 17,20 lyase hyperactivity
diagnosed by defined criteria in response to pharmacological ACTH may be an
intrinsic genetic defect, increases in 17,20 lyase activity and adrenal
androgen hyper-responsiveness to ACTH in response to physiological ACTH may
be promoted by the functional elevation of estrogen of ovarian origin in
PCOS. The latest in vitro data suggest the estrogen may elicit its effect
on the adrenal cortex through a receptor mediated mechanism."
Metabolism 1997 Aug;46(8):902-7. Mild adrenal and ovarian steroidogenic
abnormalities in hirsute women without hyperandrogenemia: does idiopathic
hirsutism exist? Escobar-Morreale HF, Serrano-Gotarredona J, Garcia-Robles
R, Sancho J, Varela C "Basal and ACTH-stimulated 17OHP and delta 4-A, and
stimulated DHEA concentrations were reduced with ovarian suppression, but
their net increment and ratio to the increase of F in response to ACTH
remained unchanged, reflecting the ovarian contribution to the secretion of
these steroids.". 
Am J Physiol 1997 Apr;272(4 Pt 2):R1128-34.  Modulation of ovine fetal
adrenocorticotropin secretion by androstenedione and 17beta-estradiol.
Saoud CJ, Wood CE  "Parturition in sheep is initiated by increases in
activity of the fetal hypothalamic-pituitary-adrenal axis. We have
previously reported that cortisol negative feedback efficacy is decreased
at the end of gestation. The present study was designed to test the
hypothesis that increasing plasma estrogen and/or androgen concentrations
in the fetus might increase plasma adrenocorticotropic hormone (ACTH)
concentration, either by stimulating ACTH secretion or by altering the
negative feedback effect of cortisol on ACTH." "We conclude that increased
fetal cortisol and ACTH secretion at the end of gestation may be due to the
combined effects of the gonadal steroids in that estradiol increases basal
plasma ACTH secretion while androstenedione reduces cortisol negative
feedback efficacy." 
J Clin Endocrinol Metab 1998 Sep;83(9):3083-8.  Menstrual abnormalities in
women with Cushing's disease are correlated with hypercortisolemia rather
than raised circulating androgen levels. Lado-Abeal J, Rodriguez-Arnao J,
Newell-Price JD, Perry LA, Grossman AB, Besser GM, Trainer PJ.
Eur J Endocrinol 1998 Apr;138(4):430-5. Hypothalamo-pituitary-adrenal axis
and adrenal function before and after ovariectomy in premenopausal women.
De Leo V, la Marca A, Talluri B, D'Antona D, Morgante G  The
hypothalamo-pituitary-adrenal (HPA) axis is modulated by sex hormones. Few
data exist on the relation between acute estrogen deficit and HPA axis
response to corticotropin-releasing hormone (CRH). The effects of a sudden
drop in estradiol levels on basal and CRH-stimulated levels of ACTH,
cortisol, testosterone, androstenedione and 17-hydroxyprogesterone (17-OHP)
were assessed in nine premenopausal women (44-48 years of age), before and
after ovariectomy. The CRH test was performed before and 8 days after
ovariectomy. A significant reduction in ACTH and adrenal steroids but not
in cortisol response to CRH was observed after ovariectomy. The ratio of
deltamax androstenedione/17-OHP after CRH stimulation was substantially the
same before and after ovariectomy, whereas deltamax 17-OHP/cortisol was
significantly lower in ovariectomized women showing increased 21- and
11beta-hydroxylase activity. The results show that the acute estrogen
deficit induces changes in the HPA xis characterized by reduced stimulated
secretion of ACTH and steroids but normal stimulated cortisol production. 
Biokhimiia 1987 Sep;52(9):1501-11  [Activation of lipolysis and ketogenesis
in tumor-bearing animals as a reflection of chronic stress states].
[Article in Russian] Chekulaev VA, Shelepov VP, Pasha-zade GR, Shapot VS In
order to elucidate the peculiarities of brain metabolism in tumour-bearing
organisms, the arterio-venous (A-V) content of glucose, acetoacetate
(Ac-Ac), beta-hydroxybutyrate (beta-HB) and non-esterified fatty acids
(NEFA) in growing Zajdela ascite hepatoma (ZAH) and solid hepatoma 27
(H-27) was compared. Analysis of metabolic patterns of healthy, starving
and fed recipients (ZAH and H-27) revealed the inadequacy of the concepts
on anorexia as being the cause of carbohydrate-lipid metabolic
disturbances. In tumour-bearing organisms lipolysis and ketogenesis reflect
the tumour-induced chronic stress.  Absorption of beta-HB and release of
Ac-Ac by brain were observed at all stages of malignant growth.  This is
probably due to a partial switch-over of brain metabolism to
non-carbohydrate energy sources. Besides, certain stages of tumour growth
are associated with active assimilation of NEFA by brain. A correlation
between the A-V difference with respect to glucose and Ac-Ac as well as
between the glucose and NEFA contents was established. It was assumed that
the A-V difference in glucose is the main regulator of ketone body
metabolism. 
R. Sanchez Olea, et al., "Inhibition by polyunsaturated fatty acids of cell
volume regulation and osmolyte fluxes in astrocytes," Amer. J. of
Physiology--cell physiology 38(1), C96-C102, 1995.  "...potent blockers of
regulatory volume decrease and of the swelling-activated efflux of taurine,
D-aspartate, inositol, and I-125 (used as marker of Cl).  ...oleic and
ricinoleic acids and saturated fatty acids were ineffective."
"...polyunsaturated fatty acids directly inhibit the permeability pathways
correcting cell volume after swelling in cultured astrocytes."
	P. H. Chan and R. A. Fishman, "Brain edema:  Induction in cortical slices
by polyunsaturated fatty acids," Science 201, 358-369, 1978.  "This
cellular edema was specific, since neither saturated fatty acids nor a
fatty acid containing a single double bond had such effect."  
	Endocrinology 1992 Aug;131(2):662-8  Estradiol selectively regulates
agonist binding sites on the N-methyl-D-aspartate receptor complex in the
CA1 region of the hippocampus. Weiland NG. Laboratory of
Neuroendocrinology, Rockefeller University.  "Estradiol alters cognitive
function and lowers the threshold for seizures in women and laboratory
animals. Both of these activities are modulated by the excitatory
neurotransmitter glutamate in the hippocampus. To assess the hypothesis
that estradiol increases the sensitivity of the hippocampus to glutamate
activation by increasing glutamate binding sites, the densities of
N-methyl-D-aspartate (NMDA) agonist sites...." "Two days of estradiol
treatment increased the density of NMDA agonist, but not of competitive nor
noncompetitive NMDA antagonist binding sites exclusively in the CA1 region
of the hippocampus." "The increase in NMDA agonist sites with ovarian
hormone treatment should result in an increase in the sensitivity of the
hippocampus to glutamate activation which may mediate some of the effects
of estradiol on learning and epileptic seizure activity."
J Neurochem 1994 Sep;63(3):953-62  Corticosterone regulates heme
oxygenase-2 and NO synthase transcription and protein expression in rat
brain. Weber CM, Eke BC, Maines MD."We suggest that glucocorticoid-mediated
deficits in hippocampal functions may reflect their negative effect on
messenger-generating systems." 
    Gen Pharmacol 1993 Nov;24(6):1383-6  Changes in microtubular tau
protein after estrogen in a cultured human neuroblastoma cell line. Lew GM.
"4. The estrogen (10(-7) M) also caused a 31% reduction in the total number
of cells."
Rodriguez, P; Fernandez-Galaz, C; Tejero, A.  Controlled neonatal exposure
to estrogens: A suitable tool for reproductive aging studies in the female
rat. Biology of Reproduction, v.49, n.2, (1993): 387-392.
 O'Rourke, M T; Lipson, S F; Ellison, P T. Ovarian function in the latter
half of the reproductive lifespan.  American Journal of Human Biology, v.8,
n.6, (1996): 751-759.  
Schumacher, M; Robel, P; Baulieu, E-E.  Development and regeneration of the
nervous system: A role for neurosteroids.  Developmental Neuroscience,
v.18, n.1-2, (1996): 6-21. 
Life Sci 1996;58(17):1461-7  The endogenous estrogen metabolite
2-methoxyestradiol induces apoptotic neuronal cell death in vitro.
Nakagawa-Yagi Y, Ogane N, Inoki Y, Kitoh N.  "We examined the effects of
2-methoxyestradiol, a metabolite of estradiol, on cell death in retinoic
acid (RA)-differentiated neuroblastoma SH-SY5Y cell cultures. Cell death
was induced by 2-methoxyestradiol in a concentration- dependent manner."
[Provides evidence] "...for an endogenous neuroactive steroid metabolite in
the etiology of some neurodegenerative diseases."
Recent Prog Horm Res 1997;52:279-303 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 JM, Weiland NG "The
menopause marks the permanent end of fertility in women. It was once
thought that the exhaustion of ovarian follicles was the single, most
important explanation for the transition to the menopause. Over the past
decade, this perception has gradually changed with the realization that
there are multiple pacemakers of reproductive senescence. We will present
evidence that lends credence to the hypothesis that the central nervous
system is a critical pacemaker of reproductive aging and that changes at
this level contribute to the timing of the menopause." 
Neuroendocrinology 1989 Nov;50(5):605-612 N-methyl-aspartic acid lesions of
the arcuate nucleus in adult C57BL/6J mice: a new model for age-related
lengthening of the estrous cycle.  May PC, Kohama SG, Finch CE. "We report
a new effect of the excitotoxin N-methyl-aspartic acid (NMA) on adult mice.
Besides confirming cell loss in the arcuate nucleus of animals treated as
adults, we also observed lengthened estrous cycles. Cycling female C57BL/6J
mice were treated with subcutaneous injections of NMA and estrous cycles
monitored for 30 days. NMA treatment lengthened average estrous cycle
length by 1 day, to 5.6 days." "Consistent with the regional pattern of
cell loss, little specific binding of any glutamatergic ligand was observed
in the VMN. NMA caused weight gain in all age groups." "The transition from
4-day to 5- and 6-day estrous cycles produced by NMA treatment mimics the
early age-related changes in estrous cycle patterns in rodents." This new
model will be useful in analyzing the contributions of neuroendocrine
changes in the arcuate nucleus to reproductive senescence." 
Pathologic effect of estradiol on the hypothalamus. Brawer JR; Beaudet A;
Desjardins GC; Schipper HM.  Biol Reprod, 1993 Oct, 49:4, 647-52.  "In
addition to its multiple physiological actions, we have shown that
estradiol is also selectively cytotoxic to beta-endorphin neurons in the
hypothalamic arcuate nucleus. The mechanism underlying this neurotoxic
action appears to involve the conversion of estradiol to catechol estrogen
and subsequent oxidation to o-semiquinone free radicals. The
estradiol-induced loss of beta-endorphin neurons engenders a compensatory
increment in mu opioid binding in the medial preoptic area rendering this
region supersensitive to residual beta-endorphin or to other endogenous
opioids. The consequent persistent opioid inhibition results in a cascade
of neuroendocrine deficits that are ultimately expressed as a chronically
attenuated plasma LH pattern to which the ovaries respond by becoming
anovulatory and polycystic. This neurotoxic action of estradiol may
contribute to a number of reproductive disorders in humans and in animals
in which aberrant hypothalamic function is a major component." 
Vitamin E protects hypothalamic beta-endorphin neurons from estradiol
neurotoxicity.  Desjardins GC; Beaudet A; Schipper HM; Brawer JR.
Endocrinology, 1992 Nov, 131:5, 2482-4 "Estradiol valerate (EV) treatment
has been shown to result in the destruction of 60% of beta-endorphin
neurons in the hypothalamic arcuate nucleus." 
Estrogen-induced hypothalamic beta-endorphin neuron loss: a possible model
of hypothalamic aging.  Desjardins GC; Beaudet A; Meaney MJ; Brawer JR.
Exp Gerontol, 1995 May-Aug, 30:3-4, 253-67  Over the course of normal
aging, all female mammals with regular cycles display an irreversible
arrest of cyclicity at mid-life. Males, in contrast, exhibit gametogenesis
until death. Although it is widely accepted that exposure to estradiol
throughout life contributes to reproductive aging, a unified hypothesis of
the role of estradiol in reproductive senescence has yet to emerge. Recent
evidence derived from a rodent model of chronic estradiol-mediated
accelerated reproductive senescence now suggests such a hypothesis. It has
been shown that chronic estradiol exposure results in the destruction of
greater than 60% of all beta-endorphin neurons in the arcuate nucleus while
leaving other neuronal populations spared. This loss of opioid neurons is
prevented by treatment with antioxidants indicating that it results from
estradiol-induced formation of free radicals. Furthermore, we have shown
that this beta-endorphin cell loss is followed by a compensatory
upregulation of mu opioid receptors in the vicinity of LHRH cell bodies.
The increment in mu opioid receptors presumably renders the opioid target
cells supersensitive to either residual beta-endorphin or other endogenous
mu ligands, such as met-enkephalin, thus resulting in chronic opioid
suppression of the pattern of LHRH release, and subsequently that of LH.
Indeed, prevention of the neuroendocrine effects of estradiol by
antioxidant treatment also prevents the cascade of neuroendocrine
aberrations resulting in anovulatory acyclicity. The loss of beta-endorphin
neurons along with the paradoxical opioid supersensitivity which ensues,
provides a unifying framework in which to interpret the diverse features
that characterize the reproductively senescent female. 
The 21-aminosteroid antioxidant, U74389F, prevents estradiol-induced
depletion of hypothalamic beta-endorphin in adult female rats. Schipper HM;
Desjardins GC; Beaudet A; Brawer JR.  Brain Res, 1994 Jul 25, 652:1, 161-3
"A single intramuscular injection of 2 mg estradiol valerate (EV) results
in neuronal degeneration and beta-endorphin depletion in the hypothalamic
arcuate nucleus of adult female rats."
J Neurochem 1998 Sep;71(3):1187-93  Energy dependency of glucocorticoid
exacerbation of gp120 neurotoxicity. Brooke SM, Howard SA, Sapolsky RM
"The HIV envelope glycoprotein, gp120, a well documented neurotoxin, may be
involved in AIDS-related dementia complex. gp120 works through an NMDA
receptor- and calcium-dependent mechanism to damage neurons. We have
previously demonstrated that both natural and synthetic glucocorticoids
(GCs) exacerbate gp120-induced neurotoxicity and calcium mobilization in
hippocampal mixed cultures. GCs, steroid hormones secreted during stress,
are now shown to work in conjunction with gp120 to decrease ATP levels and
to work synergistically with gp120 to decrease the mitochondrial potential
in hippocampal cultures. Furthermore, energy supplementation blocked the
ability of GCs to worsen gp120's effects on neuronal survival and calcium
mobilization. A GC-induced reduction in glucose transport in hippocampal
neurons, as previously documented, may contribute to this energetic
dependency. These results may have clinical significance, considering the
common treatment of severe cases of Pneumocystis carinii pneumonia, typical
of HIV infection, with large doses of synthetic GCs." 
Acta Otolaryngol Suppl (Stockh) 1990;476:32-6. Glutamate neurotoxicity in
the cochlea: a possible consequence of ischaemic or anoxic conditions
occurring in ageing. Pujol R, Rebillard G, Puel JL, Lenoir M, Eybalin M,
Recasens M. 
Br J Pharmacol 1996 Jan;117(1):189-95. Metabotropic glutamate receptors,
transmitter output and fatty acids: studies in rat brain slices. Lombardi
G, Leonardi P, Moroni F. "The requirement of both unsaturated fatty acids
and 1S,3R-ACPD in the facilitation of transmitter exocytosis may play an
important role in the regulation of synaptic plasticity." 
Adv Exp Med Biol 1992;318:147-58 A role for the arachidonic acid cascade in
fast synaptic modulation: ion channels and transmitter uptake systems as
target proteins. Volterra A, Trotti D, Cassutti P, Tromba C, Galimberti R,
Lecchi P, Racagni G.  "Recent evidence indicates that arachidonic acid (AA)
and its metabolites play a fast messenger role in synaptic modulation in
the CNS." "Other types of K+ channels in vertebrate excitable cells have
been found to be sensitive to arachidonic acid, lipoxygenase products, and
polyunsaturated fatty acids (PUFA). In the mammalian CNS, arachidonic acid
is released upon stimulation of N-methyl-D-aspartate (NMDA)-type glutamate
receptors." "Polyunsaturated fatty acids mimic arachidonate with a rank of
potency parallel to the degree of unsaturation. Since the effect of
glutamate on the synapses is terminated by diffusion and uptake, a slowing
of the termination process may potentiate glutamate synaptic efficacy.
However, excessive extracellular accumulation of glutamate may lead to
neurotoxicity." 
J Neurochem 1999 Jan;72(1):129-38.  Transient inhibition of glutamate
uptake in vivo induces neurodegeneration when energy metabolism is
impaired. Sanchez-Carbente MR, Massieu L. "Impairment of glutamate
transport during ischemia might be related to the elevation of the
extracellular concentration of glutamate and ischemic neuronal damage.
Additionally, impairment of energy metabolism in vivo leads to
neurodegeneration apparently mediated by a secondary excitotoxic mechanism.
In vitro observations show that glucose deprivation and inhibition of
energy metabolism exacerbate the toxic effects of glutamate."  "Our results
show that glutamate uptake inhibition leads to marked neuronal damage in
energy-deficient rats but not in intact animals...."
J Neurochem 1998 Nov;71(5):1993-2005.  Glia modulate NMDA-mediated
signaling in primary cultures of cerebellar granule cells. Beaman-Hall CM,
Leahy JC, Benmansour S, Vallano ML "Nordihydroguaiaretic acid, a
lipoxygenase inhibitor, blocked NMDA-mediated toxicity in astrocyte-poor
cultures, raising the possibility that glia effectively reduce the
accumulation of highly diffusible and toxic arachidonic acid metabolites in
neurons. Alternatively, glia may alter neuronal development/phenotype in a
manner that selectively reduces susceptibility to NR-mediated toxicity." 
J Neurosci 1997 Dec 1;17(23):9060-7.  Pyruvate protects neurons against
hydrogen peroxide-induced toxicity. Desagher S, Glowinski J, Premont J.
"Pyruvate strongly protected neurons against both H2O2 added to the
external medium and H2O2 endogenously produced through the redox cycling of
the experimental quinone menadione. The neuroprotective effect of pyruvate
appeared to result rather from the ability of alpha-ketoacids to undergo
nonenzymatic decarboxylation in the presence of H2O2 than from an
improvement of energy metabolism. Indeed, several other alpha-ketoacids,
including alpha-ketobutyrate, which is not an energy substrate, reproduced
the neuroprotective effect of pyruvate. In contrast, lactate, a neuronal
energy substrate, did not protect neurons from H2O2." "Together, these
results indicate that pyruvate efficiently protects neurons against both
exogenous and endogenous H2O2. Its low toxicity and its capacity to cross
the blood-brain barrier open a new therapeutic perspective in brain
pathologies in which H2O2 is involved."  
J Neurosci 1998 Jan 1;18(1):156-63.  Neuroprotective effects of creatine
and cyclocreatine in animal models of Huntington's disease. Matthews RT,
Yang L, Jenkins BG, Ferrante RJ, Rosen BR, Kaddurah-Daouk R, Beal MF .  
M. C. Diamond, Enriching Heredity:  The Importance of the Environment on
the Anatomy of the Brain.  Free Press, N.Y., 1988.
C. Finch and L. Hayflick, Handbook of the Biology of Aging.  Van Nostrand
Reinhold, N.Y., 1977.
Swanson RA  Physiologic coupling of glial glycogen metabolism to neuronal
activity in brain.   Can J Physiol Pharmacol, 1992, 70 Suppl:, S138-44.
Brain glycogen is localized almost exclusively to glia, where it undergoes
continuous utilization and resynthesis. We have shown that glycogen
utilization increases during tactile stimulation of the rat face and
vibrissae.  Conversely, decreased neuronal activity during hibernation and
anesthesia is accompanied by a marked increase in brain glycogen content.
These observations support a link between neuronal activity and glial
glycogen metabolism. The energetics of glycogen metabolism suggest that
glial glycogen is mobilized to meet increased metabolic demands of glia
rather than to serve as a substrate for neuronal activity. An advantage to
the use of glycogen may be the potentially faster generation of ATP from
glycogen than from glucose. Alternatively, glycogen could be utilized if
glucose supply is transiently insufficient during the onset of increased
metabolic activity. Brain glycogen may have a dynamic role as a buffer
between the abrupt increases in focal metabolic demands that occur during
normal brain activity and the compensatory changes in focal cerebral blood
flow or oxidative metabolism. 
"Free fatty acids activate the hypothalamic-pituitary-adrenocortical axis
in rats."  Widmaier EP; Rosen K; Abbott B. Endocrinology, 1992 Nov, 131:5,
2313-8. "Intravenous administration of Intralipid 10% increases blood
levels of essential free fatty acids." "Since corticosterone, the final
secretory product of the rat hypothalamic-pituitary-adrenocortical (HPA)
axis, is also lipolytic, we tested the hypothesis that FFA would inhibit
the HPA axis." "At 60 min, plasma ACTH levels were significantly elevated
to over 1500 pg/ml in Intralipid-infused rats, but were unchanged in saline
controls. This dose of Intralipid increased corticosterone levels by nearly
20-fold at 120 min. At 180 min, corticosterone levels were still
significantly greater than those in saline controls. Lower doses of
Intralipid also significantly elevated both FFA and corticosterone levels,
but by 180 min, levels of both were similar to those in controls." "The
results suggest that high circulating FFA levels activate, rather than
inhibit, the HPA axis in rats. Since stress activates glucocorticoid
production and increases FFA levels due to lipolysis, it is possible that
FFA and the HPA axis constitute a previously unrecognized positive feedback
loop."
"Impairment of glucose disposal by infusion of triglycerides in humans:
role of glycemia," Felley CP; Felley EM; van Melle GD; Frascarolo P;
Jéquier E; Felber JP, Am J Physiol, 1989 Jun, 256:6 Pt 1, E747-52. "These
results suggest the existence of physiological regulatory mechanisms by
which 1) the rise in plasma free fatty acid inhibits both oxidative and
nonoxidative glucose disposal, and 2) the rise in glycemia stimulates
predominantly nonoxidative glucose disposal."
Nature 1998 Jan 15;391(6664):281-5. Prostaglandins stimulate
calcium-dependent glutamate release in astrocytes. Bezzi P, Carmignoto G,
Pasti L, Vesce S, Rossi D, Rizzini BL, Pozzan T, Volterra A.  Astrocytes in
the brain form an intimately associated network with neurons. They respond
to neuronal activity and synaptically released glutamate by raising
intracellular calcium concentration ([Ca2+]i), which could represent the
start of back-signalling to neurons. Here we show that coactivation of the
AMPA/kainate and metabotropic glutamate receptors (mGluRs) on astrocytes
stimulates these cells to release glutamate through a Ca2+-dependent
process mediated by prostaglandins. Pharmacological inhibition of
prostaglandin synthesis prevents glutamate release, whereas application of
prostaglandins (in particular PGE2) mimics and occludes the releasing
action of GluR agonists. PGE2 promotes Ca2+-dependent glutamate release
from cultured astrocytes and also from acute brain slices under conditions
that suppress neuronal exocytotic release. When applied to the CA1
hippocampal region, PGE2 induces increases in [Ca2+]i both in astrocytes
and in neurons. The [Ca2+]i increase in neurons is mediated by glutamate
released from astrocytes, because it is abolished by GluR antagonists. Our
results reveal a new pathway of regulated transmitter release from
astrocytes and outline the existence of an integrated glutamatergic
cross-talk between neurons and astrocytes in situ that may play critical
roles in synaptic plasticity and in neurotoxicity. 
Prog Neurobiol 1998 Jan;54(1):99-125. Microglia as effector cells in brain
damage and repair: focus on prostanoids and nitric oxide.  Minghetti L,
Levi G.  "The present article deals with two classes of compounds that
activated microglial cells can produce in large amounts: prostanoids (that
derive from arachidonic acid through the cyclooxygenase pathway), and
nitric oxide (that is synthesized from arginine by nitric oxide synthase).
Prostanoids and nitric oxide have a number of common targets, on which they
may exert similar or opposite actions, and have a crucial role in the
regulation of inflammation, immune responses and cell viability. Their
synthesis can massively increase when the inducible isoforms of
cyclooxygenase and nitric oxide synthase are expressed." 
In Vitro Cell Dev Biol Anim 1998 Mar;34(3):265-74. Prostaglandins act as
neurotoxin for differentiated neuroblastoma cells in culture and increase
levels of ubiquitin and beta-amyloid. Prasad KN, La Rosa FG, Prasad JE.
"Although chronic inflammatory reactions have been proposed to cause
neuronal degeneration associated with Alzheimer's disease (AD), the role of
prostaglandins (PGs), one of the secretory products of inflammatory
reactions, in degeneration of nerve cells has not been studied. Our initial
observation that PGE1-induced differentiated neuroblastoma (NB) cells
degenerate in vitro more rapidly than those inducedby RO20-1724, an
inhibitor of cyclic nucleotide phosphodiesterase, has led us to postulate
that PGs act as a neurotoxin. This study has further investigated the
effects of PGs on differentiated NB cells in culture. Results showed that
PGA1 was more effective than PGE1 in causing degeneration of differentiated
NB cells as shown by the cytoplasmic vacuolation and fragmentation of soma,
nuclei, and neurites. Because increased levels of ubiquitin and
beta-amyloid have been implicated in causing neuronal degeneration, we
studied the effects of PGs on the levels of these proteins during
degeneration of NB cells in vitro...." "Results showed that PGs increased
the intracellular levels of ubiquitin and beta-amyloid prior to
degeneration, whereas the degenerated NB cells had negligible levels of
these proteins. These data suggest that PGs act as external neurotoxic
signals which increase levels of ubiquitin and beta-amyloid that represent
one of the intracellular signals for initiating degeneration of nerve cells." 
Brain Res Bull 1998 Apr;45(6):637-40. The fatty acid composition of
maternal diet affects the response to excitotoxic neural injury in neonatal
rat pups.Valencia P, Carver JD, Wyble LE, Benford VJ, Gilbert-Barness E,
Wiener DA, Phelps C  Fatty acids and their derivatives play a role in the
response to neural injury. The effects of prenatal and postnatal dietary
fatty acid composition on excitotoxic neural injury were investigated in
neonatal rat pups."
Proc Soc Exp Biol Med 1998 Nov;219(2):120-5. Prostaglandins as putative
neurotoxins in Alzheimer's disease. Prasad KN, Hovland AR, La Rosa FG,
Hovland PG.  "Chronic inflammatory reactions in the brain appear to be one
of the primary etiological factors in the pathogenesis of Alzheimer's
disease (AD). This is supported by the fact that the secretory products of
inflammatory reactions, which include cytokines, complement proteins,
adhesion molecules, and free radicals, are neurotoxic. We have recently
reported that prostaglandins (PGs), which are also released during
inflammatory reactions, cause rapid degenerative changes in differentiated
murine neuroblastoma cells (NB) in culture." "The mechanisms underlying
Abeta-induced neuronal degeneration have been under intense investigation,
and several mechanisms of action have been proposed. We postulate that
PG-induced elevation of Abeta may lead to an increased binding of Abeta to
the 20S proteasome, resulting in a reduction of 20S proteasome-mediated
degradation of ubiquitin-conjugated proteins. This is predicted to lead to
an increase in an accumulation of abnormal proteins, which ultimately
contribute to neuronal degeneration and death.  Based on our hypothesis and
on studies published by others, we propose that a combination of
nonsteroidal anti-inflammatory drugs, which inhibit the synthesis of PGs,
and antioxidant vitamins, which quench free radicals and both of which have
been recently reported to be of some value in AD treatment when
used-individually, may be much more effective in the prevention and
treatment of AD than the individual agents alone." 
Mol Chem Neuropathol 1998 May;34(1):79-101.  Effects of EGb 761 on fatty
acid reincorporation during reperfusion following ischemia in the brain of
the awake gerbil. Rabin O, Drieu K, Grange E, Chang MC, Rapoport SI, Purdon
AD. 
Regulation of arcuate nucleus synaptology by estrogen. Leedom L; Lewis C;
Garcia-Segura LM; Naftolin F.  Ann N Y Acad Sci, 1994 Nov 14, 743:, 61-71
"Estrogen modulates the synaptology of the hypothalamic arcuate nucleus
during sexual differentiation of the rat brain in both males and females.
In males, testosterone of gonadal origin is converted to estrogen in the
brain by an enzyme, aromatase, which is also present in females. The
exposure of the male's hypothalamus to relatively high levels of estrogen
(following a perinatal testosterone surge) leads to the development of a
pattern of synaptogenesis which does not support an estrogen-induced
gonadotrophin surge in the adult.  In female rats, hypothalamic development
occurs with permissively low levels of estrogen, enabling a midcycle
estrogen-induced gonadotrophin surge and ovulation in adulthood. During
adult reproductive life in female rats, circulating estrogen modulates the
synaptology of the arcuate nucleus. The most physiological example of this
is the 30-50% loss of axosomatic synapses following the preovulatory
estrogen surge on diestrus-proestrus. Studies on post-synaptic membranes of
the arcuate nucleus reveal sex differences in membrane organization and
protein content which are estrogen-dependent.  Estrogen apparently
stimulates endocytosis of areas of post-synaptic membrane that are dense
with small intramembranous protein particles, resulting in a reduction in
the number of small intramembranous particles. This also appears to be the
physiologic mechanism of neuronal changes in females during the estrus
cycle. Repeated exposure to preovulatory levels of estrogen may lead to an
age-related decline in reproductive capacity in female rats.  Aging females
lose the estrogen-induced gonadotrophin surge responsible for ovulation.
This loss of function may result from a cumulative estrogen effect during
the repeated ovarian cycles which results in a reorganization of the
synaptology on which regulates the estrogen-induced gonadotrophin surge."
". . .recent research has shown that GABA, the monoamines, and several
neuropeptides are participants in the estrogen-sensitive network which
regulates GNRH secretion. In this regard, present work shows
estrogen-induced changes in GABA and dopamine synapses in the arcuate
nucleus."
17 beta Estradiol-induced increase in brain dopamine D-2 receptor:
antagonism by MIF-1.  Rajakumar G; Chiu P; Chiu S; Johnson RL; Mishra RK
Department of Psychiatry, Faculty of Health Sciences, McMaster University,
Hamilton, Ontario, Canada. Peptides, 1987 Nov-Dec, 8:6, 997-1002  Animal
behavioral and neurochemical studies implicate dopaminergic systems in the
neurological sequelae induced by estrogen. In the present study, we
demonstrated for the first time that MIF-1, a neuropeptide unrelated to
classical dopamine agonists, when given prior to, concurrently with, and
after 17 beta-estradiol, antagonized significantly the estrogen-induced
increase in the density of dopamine D-2 receptor both in the striatum and
the mesolimbic area of male rat brain. The current findings have
implications for the prophylactic and therapeutic potential for MIF-1 in
extrapyramidal motor disorders caused by estrogen imbalance in humans.
Eur J Clin Invest 1984 Dec;14(6):431-4  Effect of ovulation on haem
metabolism in rabbits.  Lindahl J, Werner B, Lerner R. "To investigate the
origin of the cyclic changes in the rate of endogenous carbon-monoxide
production (nCO) during the menstrual cycle, haem turnover was determined
before and after chorion gonadotropic hormone-induced ovulation in six
female rabbits. 14C-labelled delta-aminolevulinic acid and glycine were
administered and the excretion rate of 14CO (A14CO) was measured for
determination of hepatic and bone-marrow haem turnover, respectively."  ".
. . nCO was increased 34% (P less than 0.05) during the post-ovulation
period. As the increase in 'unassigned' haem turnover was small and may be
unaccompanied by a contemporary increase in bilirubin/CO production, it was
concluded that the increase in nCO during the post-ovulation period
essentially depends on increased destruction of circulating red cells in
the rabbit."
J Neurotrauma 1993 Winter;10(4):373-84. Beneficial effect of the
nonselective opiate antagonist naloxone hydrochloride and the
thyrotropin-releasing hormone (TRH) analog YM-14673 on long-term
neurobehavioral outcome following experimental brain injury in the rat.
McIntosh TK, Fernyak S, Hayes RL, Faden AI
J Neurosci 1990 Nov;10(11):3524-30. Opiate antagonist nalmefene improves
intracellular free Mg2+, bioenergetic state, and neurologic outcome
following traumatic brain injury in rats. Vink R, McIntosh TK, Rhomhanyi R,
Faden AI. "Treatment of CNS trauma with the opiate antagonist naloxone
improves outcome, though the mechanisms of action remain speculative."
Brain Res 1989 Mar 20;482(2):252-60. Magnesium protects against
neurological deficit after brain injury. McIntosh TK, Vink R, Yamakami I,
Faden AI.
Adv Neurol 1988;47:531-46. Role of thyrotropin-releasing hormone and opiate
receptor antagonists in limiting central nervous system injury. Faden AI.
"Opiate antagonists, including receptor antagonists and physiologic
antagonists, have been shown to produce beneficial effects in a variety of
models of CNS injury and in a variety of species. Opiate antagonists
improve spinal cord blood flow, electrical conduction of the spinal cord,
pathological changes, and motor recovery following traumatic spinal cord
injury in cats. TRH appears to be superior to naloxone in this regard,
although direct comparisons between receptor-selective opiate receptor
antagonists and TRH have not been made."     
Exp Neurol 1994 Sep;129(1):64-9.Progesterone facilitates cognitive recovery
and reduces secondary neuronal loss caused by cortical contusion injury in
male rats. Roof RL, Duvdevani R, Braswell L, Stein DG.
Exp Neurol 1996 Apr;138(2):246-51. Progesterone rapidly decreases brain
edema: treatment delayed up to 24 hours is still effective. Roof RL,
Duvdevani R, Heyburn JW, Stein DG.
Mol Chem Neuropathol 1997 May;31(1):1-11. Progesterone protects against
lipid peroxidation following traumatic brain injury in rats. Roof RL,
Hoffman SW, Stein DG.
Jiang N, et al. Progesterone is neuroprotective after transient middle
cerebral artery occlusion in male rats.  Brain Res. 1996 Sep 30;735(1):101-7. 
Roof RL, et al. Progesterone rapidly decreases brain edema: treatment
delayed up to 24 hours is still effective.      Exp Neurol. 1996
Apr;138(2):246-51. 
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At 11:52 AM 4/29/99 +1200, you wrote:
>Dear Ray:
>heres a bit of data that should be of interest to you.
>Do you feel that the data is correct??
>Can estrogen actually protect brain tissue?
>best wishes,
>Earl
>