Tissue-bound Estrogen in Aging

			        ******************************

The "Estrogen Replacement" industry is based on the doctrine that a woman's
tissues are depleted of estrogen after menopause. This doctrine is false.
The concentration of a hormone in the blood doesn't directly represent the
concentration in the various organs.

The amount of estrogen in tissue is decreased when progesterone is
abundant. In the absence of progesterone, tissues retain estrogen even when
there is little estrogen circulating in the blood.

Many things suggest an increased estrogenic activity at menopause. For
example, melatonin decreases sharply at puberty when estrogen increases,
and then it decreases again at menopause. Prolactin (stimulated by
estrogen) increases around puberty, and instead of decreasing at menopause,
it often increases, and its increase is associated with osteoporosis and
other age-related symptoms. 

Estrogen is produced in many tissues by the enzyme aromatase, even in the
breast and endometrium, although these are considered "target tissues"
rather than endocrine glands. Aromatase increases with aging.

Estrogen is inactivated, mainly in the liver and brain, by being made water
soluble by the attachment of glucuronic acid and/or sulfuric acid. 

Estrogen's concentration in a particular tissue depends on many things,
including its affinity or binding strength for components of that tissue,
relative to its affinity for the blood; the activity in that tissue of the
aromatase enzyme, which converts androgens to estrogen; the activity of the
glucuronidase enzyme, that converts water-soluble estrogen glucuronides
into the oil soluble active forms of estrogen; and the sulfatases and
several other enzymes that modify the activity and solubility of the
estrogens. The "estrogen receptors," proteins which bind estrogens in
cells, are inactivated by progesterone, and activated by many physical and
chemical conditions.

Inflammation activates beta-glucuronidase, and antiinflammatory substances
such as aspirin reduce many of estrogen's effects. 

			******************************

Doctrines are admitted into the "scientific canon" by those who have the
power of censorship. In astronomy, Halton Arp's discovery of "anomalous"
galactic red-shifts is practically unknown, because the journal editors say
the observations are "just anomalies," or that the theories which could
explain them are unconventional; but the actual problem is that they are
strong evidence against The Big Bang, Hubble's Law, and the Expanding
Universe. American science, since the 1940s, has probably been the most
censored and doctrinaire in the world. 

Gilbert Ling's revolution in cell biology remains outside the canon,
despite the profound influence of MRI, which grew directly out of his view
of the cell, because his work provided conclusive evidence that cells are
not regulated by "semipermeable membranes and membrane pumps." Every field
of science is ruled by a doctrinaire establishment. 

Charles E. Brown-Séquard (1817-94) was a physiologist who pioneered
scientific endocrinology, but who was ridiculed because of his claim that
extracts of animal glands had an invigorating effect when injected. His
place in the scientific canon is mainly as an object of ridicule, and the
details of his case are perfectly representative of the way our "canon" has
been constructed. The argument for dismissing his observations was that he
used a water extract of testicles, and, according to the 20th century
American biologists, testosterone is not water soluble, and so the water
extract would have "contained no hormone." The argument is foolish, because
living organs contain innumerable substances that will solublize oily
molecules, but also because Brown-Sequard was describing an effect that
wasn't necessarily limited to a single chemical substance. (The
transplanting of living cells to repair tissues is finally being accepted,
but the pioneers in promoting tissue regeneration or repair with the
transplantation of living, dead, or stressed cells--V. Filatov, L.V.
Polezhaev, W.T. Summerlin, for example--were simply written out of history.)
If Brown-Séquard's extract couldn't work because testosterone isn't soluble
in water, then what are we to think of the thousands of medical
publications that talk about "free hormones" as the only active hormones?
("Free hormone" is defined as the hormone that isn't bound to a
transporting protein, with the more or less explicit idea that it is
dissolved in the water of the plasma or extracellular fluid.)

Brown-Séquard's tissue extracts would have contained solublizing substances
including proteins and phospholipids, so the oily hormones would certainly
be present (and active) in his extracts. But the thousands of people who
ridiculed him committed themselves to the fact that steroid hormones are
insoluble in water. By their own standard, they are selling an
impossibility when they do calculations to reveal the amount of "free
hormone," as something distinct from the protein bound hormone, in the
patient's blood.

The immense Hormone Replacement Therapy industry--which Brown-Séquard's
experiments foreshadowed--is based on the fact that the concentrations of
some hormones in the blood serum decrease with aging.
At first, it was assumed that the amount of the hormone in the blood
corresponded to the effectiveness of that hormone. Whatever was in the
blood was being delivered to the "target tissues." But as the idea of
measuring "protein bound iodine" (PBI) to determine thyroid function came
into disrepute (because it never had a scientific basis at all), new ideas
of measuring "active hormones" came into the marketplace, and currently the
doctrine is that the "bound" hormones are inactive, and the active hormones
are "free." The "free" hormones are supposed to be the only ones that can
get into the cells to deliver their signals, but the problem is that "free
hormones" exist only in the imagination of people who interpret certain lab
tests, as I discussed in the newsletter on thyroid tests (May, 2000).

In the 1960s and 1970s, when the PBI test was disappearing, there was
intense interest in--a kind of mania regarding--the role of "membranes" in
regulating cell functions, and the membrane was still seen by most
biologists as the "semipermeable membrane" which, "obviously," would
exclude molecules as large as albumin and the other proteins that carry
thyroid and other hormones in the blood. (In reality, and experimental
observations, albumin and other proteins enter cells more or less freely,
depending on prevailing conditions.) The membrane doctrine led directly to
the "free hormone" doctrine. 

This issue, of arguing about which form of a hormone is the "active" form,
has to do with explaining how much of the blood-carried hormone is going to
get into the "target tissues." If the membrane is a "semipermeable" barrier
to molecules such as hormones, then specific receptors and transporters
will be needed. If the concentration of a hormone inside the cell is higher
than that in the blood, a "pump" will usually be invoked, to produce an
"active transport" of the hormone against its concentration gradient.

But if the membrane regulates the passage of hormones from blood to tissue
cells, and especially if pumps are needed to move the hormone into the
cell, how relevant is the measurement of hormones in the blood?

Within the blood, progesterone and thyroid hormone (T3) are much more
concentrated in the red blood cells than in the serum. Since it isn't
likely that red blood cells are "targets" for the sex hormones, or for
progesterone or even thyroid, their concentration "against their gradient"
in these cells suggests that a simple distribution by solubility is
involved. Oily substances just naturally tend to concentrate inside cells
because of their insolubility in the watery environment of the plasma and
extracellular fluid. Proteins that have "oily" regions effectively bind
oily molecules, such as fats and steroids. Even red blood cells have such
proteins.

In the case of oil soluble molecules, such as progesterone and estrogen,
it's important to explain that most of their "binding" to proteins or other
oil-loving molecules is really the nearly passive consequence of the
molecules' being forced away from the watery phase--they are hydrophobic,
and although it would take a great amount of energy to make these insoluble
substances enter the watery phase, the attractive force between them and
the cell is usually small. This means that they can be freely mobile, while
"bound" or concentrated within the cell. The oxygen atoms, and especially
the phenolic group of estrogen, slightly reduce the hormones' affinity for
simple oils, but they interact with other polar or aromatic groups, giving
estrogen the ability to bind more strongly and specifically with some
proteins and other molecules. Enzymes which catalyze estrogen's
oxidation-reduction actions are among the specific estrogen-binding proteins.
Many proteins and lipoproteins bind steroids, but some intracellular
proteins bind them so strongly that they have been--in a very teleological,
if not anthropomorphic, way--considered as the switch by which the hormone
turns on the cellular response. In the popular doctrine of the Estrogen
Receptor, a few molecules of estrogen bind to the receptors, which carry
them to the nucleus of the cell, where the activated receptors turn on the
genes in charge of the female response. (Or the male response, or the
growth response, or the atrophy response, or whatever genetic response
estrogen is producing.) Once the switch has been thrown, the estrogen
molecules have fulfilled their hormonal duty, and must get lost, so that
the response isn't perpetuated indefinitely by a few molecules.

Although the Estrogen Receptor doctrine is worse than silly, there are real
proteins which bind estrogen, and some of these are called receptors. The
uterus, breast, and brain, which are very responsive to estrogen, bind, or
concentrate, estrogen molecules.

When I was working on my dissertation, I tried to extract estrogens from
hamster uteri, but the chemical techniques I was using to measure estrogen
weren't accurate for such small quantities. A few years later, S. Batra was
able to extract the estrogen from human tissue in quantities large enough
for accurate analysis by radioimmunoassay. (Batra, 1976.)

His crucial observation was that the difference in estrogen concentration
between tissue and blood was lowest in the luteal phase, when progesterone
is high: 

"The tissue/plasma ratio of E2 [estradiol] ranged from 1.45 to 20.36 with
very high values in early follicular phase and the lowest in mid-luteal
phase." This means that progesterone prevents the tissue from concentrating
estrogen. He made similar observations during pregnancy, with tissue
estrogen decreasing as blood progesterone increased, so that there is less
estrogen in the tissue than in the plasma. But in women who aren't
pregnant, and when their progesterone is low, the tissues may contain 20 to
30 times more estrogen than the plasma (in equal volumes).

In aging, the sharply decreased progesterone production creates a situation
resembling the follicular phase of the menstrual cycle, allowing tissues to
concentrate estrogen even when the serum estrogen may be low.
"In postmenopausal women, the tissue concentration of E2 was not
significantly lower than in menstruating women in follicular phase. . . ."
(Akerlund, et al., 1981.)

Besides the relatively direct actions of progesterone on the estrogen
receptors, keeping their concentration low, and its indirect action by
preventing prolactin from stimulating the formation of estrogen receptors,
there are many other processes that can increase or decrease the tissue
concentration of estrogen, and many of these influences change with aging.

There are two kinds of enzyme that produce estrogen. Aromatase converts
male hormones into estrogen. Beta-glucuronidase converts the inactive
estrogen-glucuronides into active estrogen. The healthy liver inactivates
practically all the estrogen that reaches it, mostly by combining it with
the "sugar acid," glucuronic acid. This makes the estrogen water soluble,
and it is quickly eliminated in the urine. But when it passes through
inflamed tissue, these tissues contain large amounts of beta-glucuronidase,
which will remove the glucuronic acid, leaving the pure estrogen to
accumulate in the tissue.

Many kinds of liver impairment decrease its ability to excrete estrogen,
and estrogen contributes to a variety of liver diseases. The work of the
Biskinds in the 1940s showed that a dietary protein deficiency prevented
the liver from detoxifying estrogen. Hypothyroidism prevents the liver from
attaching glucuronic acid to estrogen, and so increases the body's
retention of estrogen, which in turn impairs the thyroid gland's ability to
secrete thyroid hormone. Hypothyroidism often results from nutritional
protein deficiency.

Although we commonly think of the ovaries as the main source of estrogen,
the enzyme which makes it can be found in all parts of the body.
Surprisingly, in rhesus monkeys, aromatase in the arms accounts for a very
large part of estrogen production. Fat and the skin are major sources of
estrogen, especially in older people. The activity of aromatase increases
with aging, and under the influence of prolactin, cortisol, prostaglandin,
and the pituitary hormones, FSH (follicle stimulating hormone) and growth
hormone. It is inhibited by progesterone, thyroid, aspirin, and high
altitude. Aromatase can produce estrogen in fat cells, fibroblasts, smooth
muscle cells, breast and uterine tissue, pancreas, liver, brain, bone,
skin, etc. Its action in breast cancer, endometriosis, uterine cancer,
lupus, gynecomastia, and many other diseases is especially important.
Aromatase in mammary tissue appears to increase estrogen receptors and
cause breast neoplasia, independently of ovarian estrogen (Tekmal, et al.,
1999).

Women who have had their ovaries removed are usually told that they need to
take estrogen, but animal experiments consistently show that removal of the
gonads causes the tissue aromatases to increase. The loss of progesterone
and ovarian androgens is probably responsible for this generalized increase
in the formation of estrogen. In the brain, aromatase increases under the
influence of estrogen treatment.

Sulfatase is another enzyme that releases estrogen in tissues, and its
activity is inhibited by antiestrogenic hormones. 

In at least some tissues, progesterone inhibits the release or activation
of beta-glucuronidase (which, according to Cristofalo and Kabakjian, 1975,
increases with aging). Glucaric acid, which inhibits this enzyme, is being
used to treat breast cancer, and glucuronic acid also tends to inhibit the
intracellular release of estrogen by beta-glucuronidase.

Although there is clearly a trend toward the rational use of antiestrogenic
treatments for breast cancer, in other diseases the myth of estrogen
deficiency still prevents even rudimentary approaches.

Ever since Lipshutz' work in the 1940s, it has been established that the
uninterrupted effect of a little estrogen is more harmful than larger but
intermittent exposures. But after menopause, when progesterone stops its
cyclic displacement of estrogen from the tissues, the tissues retain large
amounts of estrogen continuously.

The menopause itself is produced by the prolonged exposure to estrogen
beginning in puberty, in spite of the monthly protection of the
progesterone produced by cycling ovaries. The unopposed action of the high
concentration of tissue-bound estrogen after menopause must be even more
harmful.

The decline of the antiestrogenic factors in aging, combined with the
increase of pro-estrogenic factors such as cortisol and prolactin and FSH,
occurs in both men and women. During the reproductive years, women's cyclic
production of large amounts of progesterone probably retards their aging
enough to account for their greater longevity. Childbearing also has a
residual antiestrogenic effect and is associated with increased longevity.
Being aware of this pervasive increase in estrogen exposure with aging
should make it possible to marshal a comprehensive set of methods for
opposing that trend toward degeneration.

Raymond Peat, Ph.D.
Copyright 2000
All Rights Reserved
raypeat@efn.org
www.efn.org/~raypeat

REFERENCES

Contraception 1981 Apr;23(4):447-55. Comparison of plasma and myometrial
tissue concentrations of estradiol-17 beta and progesterone in nonpregnant
women. Akerlund M, Batra S, Helm G Plasma and myometrial tissue
concentrations of estradiol (E2) and progesterone (P) were measured by
radioimmunoassay techniques in samples obtained from women with regular
menstrual cycles and from women in pre- or postmenopausal age. In women
with regular cycles, the tissue concentration of E2 ranged from 0.13 to
1.06 ng/g wet weight, with significantly higher levels around ovulation
than in follicular or luteal phases of the cycle. The tissue concentration
of P ranged from 2.06 to 14.85 ng/g wet weight with significantly higher
level in luteal phase than in follicular phase. The tissue/plasma ratio of
E2 ranged from 1.45 to 20.36 with very high values in early follicular
phase and the lowest in mid-luteal phase. The ratio for P ranged from 0.54
to 23.7 and was significantly lower in the luteal phase than in other
phases of the cycle. One woman in premenopausal age with an ovarian cyst
was the only case with a tissue/plasma ratio of E2 Less Than 1, since her
plasma E2 levels were exceptionally high. In postmenopausal women, the
tissue concentration of E2 was not significantly lower than in menstruating
women in follicular phase, and the tissue concentration of P was not
significantly lower than in fertile women in any of the phases. Neither in
these women nor in menstruating women was there a close correlation between
tissue and plasma levels. The present data indicate that the myometrial
uptake capacity for ovarian steroids may be saturated, and also that a
certain amount of these steroids is bound to tissue even if plasma levels
are low.

Biokhimiia 1984 Aug;49(8):1350-6. [The nature of thyroid hormone receptors.
Translocation of thyroid hormones through plasma membranes]. Azimova ShS,
Umarova GD, Petrova OS, Tukhtaev KR, Abdukarimov A The in vivo
translocation of thyroxine-binding blood serum prealbumin (TBPA) was
studied. It was found that the TBPA-hormone complex penetrates-through the
plasma membrane into the cytoplasm of target cells. Electron microscopic
autoradiography revealed that blood serum TBPA is localized in ribosomes of
target cells as well as in mitochondria, lipid droplets and Golgi complex.
Negligible amounts of the translocated TBPA is localized in lysosomes of
the cells insensitive to thyroid hormones (spleen macrophages). Study of
T4- and T3-binding proteins from rat liver cytoplasm demonstrated that one
of them has the antigenic determinants common with those of TBPA. It was
shown autoimmunoradiographically that the structure of TBPA is not altered
during its translocation. 

 Biokhimiia 1985 Nov;50(11):1926-32. [The nature of thyroid hormone
receptors. Intracellular functions of thyroxine-binding prealbumin] Azimova
ShS; Normatov K; Umarova GD; Kalontarov AI; Makhmudova AA  The effect of
tyroxin-binding prealbumin (TBPA) of blood serum on the template activity
of chromatin was studied. It was found that the values of binding constants
of TBPA for T3 and T4 are 2 X 10(-11) M and 5 X 10(-10) M, respectively.
The receptors isolated from 0.4 M KCl extract of chromatin and mitochondria
as well as hormone-bound TBPA cause similar effects on the template
activity of chromatin. Based on experimental results and the previously
published comparative data on the structure of TBPA, nuclear, cytoplasmic
and mitochondrial receptors of thyroid hormones as well as on translocation
across the plasma membrane and intracellular transport of TBPA, a
conclusion was drawn, which suggested that TBPA is the "core" of the true
thyroid hormone receptor. It was shown that T3-bound TBPA caused histone
H1-dependent conformational changes in chromatin. Based on the studies with
the interaction of the TBPA-T3 complex with spin-labeled chromatin, a
scheme of functioning of the thyroid hormone nuclear receptor was proposed.

Biokhimiia 1984 Sep;49(9):1478-85[The nature of thyroid hormone receptors.
Thyroxine- and triiodothyronine-binding proteins of mitochondria] Azimova
ShS; Umarova GD; Petrova OS; Tukhtaev KR; Abdukarimov A. T4- and T3-binding
proteins of rat liver were studied. It was found that the external
mitochondrial membranes and matrix contain a protein whose electrophoretic
mobility is similar to that of thyroxine-binding blood serum prealbumin
(TBPA) and which binds either T4 or T3. This protein is precipitated by
monospecific antibodies against TBPA. The internal mitochondrial membrane
has two proteins able to bind thyroid hormones, one of which is localized
in the cathode part of the gel and binds only T3, while the second one
capable of binding T4 rather than T3 and possessing the electrophoretic
mobility similar to that of TBPA. Radioimmunoprecipitation with
monospecific antibodies against TBPA revealed that this protein also the
antigenic determinants common with those of TBPA. The in vivo translocation
of 125I-TBPA into submitochondrial fractions was studied. The analysis of
densitograms of submitochondrial protein fraction showed that both TBPA and
hormones are localized in the same protein fractions. Electron microscopic
autoradiography demonstrated that 125I-TBPA enters the cytoplasm through
the external membrane and is localized on the internal mitochondrial
membrane and matrix. 

Biokhimiia 1984 Aug;49(8):1350-6. [The nature of thyroid hormone receptors.
Translocation of thyroid hormones through plasma membranes] Azimova ShS;
Umarova GD; Petrova OS; Tukhtaev KR; Abdukarimov A The in vivo
translocation of thyroxine-binding blood serum prealbumin (TBPA) was
studied. It was found that the TBPA-hormone complex penetrates-through the
plasma membrane into the cytoplasm of target cells. Electron microscopic
autoradiography revealed that blood serum TBPA is localized in ribosomes of
target cells as well as in mitochondria, lipid droplets and Golgi complex.
Negligible amounts of the translocated TBPA is localized in lysosomes of
the cells insensitive to thyroid hormones (spleen macrophages). Study of
T4- and T3-binding proteins from rat liver cytoplasm demonstrated that one
of them has the antigenic determinants common with those of TBPA. It was
shown autoimmunoradiographically that the structure of TBPA is not altered
during its translocation.

Probl Endokrinol (Mosk), 1981 Mar-Apr, 27:2, 48-52. [Blood estradiol level
and G2-chalone content in the vaginal mucosa in rats of different ages]
Anisimov VN; Okulov VB. "17 beta-Estradiol level was higher in the blood
serum of rats aged 14 to 16 months with regular estral cycles during all
the phases as compared to that in 3- to 4-month-old female rats. The latter
ones had a higher vaginal mucosa G2-chalone concentration. The level of the
vaginal mucosa G2-chalone decreased in young rats 12 hours after
subcutaneous benzoate-estradiol injection. . . .". "Possible role of
age-associated disturbances of the regulatory cell proliferation stimulant
(estrogen) and its inhibitor (chalone) interactions in neoplastic target
tissue transformation is discussed."

Clin Endocrinol (Oxf) 1979 Dec;11(6):603-10. Interrelations between plasma
and tissue concentrations of 17 beta-oestradiol and progesterone during
human pregnancy. Batra S, Bengtsson LP, Sjoberg NO Oestradiol and
progesterone concentration in plasma, decidua, myometrium and placenta
obtained from women undergoing Caesarian section at term and abortion at
weeks 16-22 of pregnancy were determined. There was a significant increase
in oestradiol concentration (per g wet wt) both in placenta, decidua and
myometrium from mid-term to term. Both at mid-term and term oestradiol
concentrations in decidua and myometrium were much smaller than those in
the plasma (per ml). Progesterone concentration in placenta and in
myometrium did not increase from mid-term to term where it increased
significantly in decidua.  Decidual and myometrial progesterone
concentrations at mid-term were 2-3 times higher than those in plasma, but
at term the concentrations in both these tissues were lower than in plasma.
The ratio progesterone/oestradiol in plasma, decidua, myometrium and
placenta at mid-term was 8.7, 112.2, 61.4 and 370.0, respectively, and it
decreased significantly in the myometrium and placenta but was nearly
unchanged in plasma and decidua at term. The general conclusion to be drawn
from the present study is the lack of correspondence between the plasma
concentrations and the tissue concentrations of female sex steroids during
pregnancy.

Endocrinology 1976 Nov; 99(5): 1178-81. Unconjugated estradiol in the
myometrium of pregnancy. Batra S. By chemically digesting myometrium in a
mixture of NaOH and sodium dodecyl sulphate, estradiol could be recovered
almost completely by extraction with ethyl acetate. The concentration of
estradiol-17beta (E2) in the extracted samples could reliably be determined
by radioimmunoassay. Compared to its concentration in the plasma, E2 in the
pregnant human myometrium was very low, and as a result, the tissue/plasma
estradiol concentration ratio was less than 0.5. In the pseudopregnant
rabbit, this ratio ranged between 16 and 20.

J Steroid Biochem 1989 Jan;32(1A):35-9. Tissue specific effects of
progesterone on progesterone and estrogen receptors in the female
urogenital tract. Batra S, Iosif CS. The effect of progesterone
administration on progesterone and estrogen receptors in the uterus, vagina
and urethra of rabbits was studied. After 24 h of progesterone treatment
the concentration of cytosolic progesterone receptors decreased to about
25% of the control value in the uterus, whereas no significant change in
receptor concentration was observed in the vagina or the urethra. The
concentration of the nuclear progesterone receptor did not change in any of
the three tissues studied. The apparent dissociation constant (Kd) of
nuclear progesterone receptor increased after progesterone treatment in all
three tissues. Although the Kd of the cytosolic progesterone receptor also
increased in all tissues, the difference was significant for only the
vagina and urethra. The concentration of cytosolic estrogen receptors in
the uterus decreased significantly (P less than 0.001) after progesterone
treatment whereas the Kd value increased slightly (P less than 0.05). In
vagina or the urethra, there was no change in either estrogen receptor
concentration or Kd values after progesterone treatment. These data clearly
showed that the reduction by progesterone of progesterone and estrogen
receptor concentrations occurs only in the uterus and not in the vagina or
the urethra.

Am J Obstet Gynecol 1980 Apr 15;136(8):986-91. Female sex steroid
concentrations in the ampullary and isthmic regions of the human fallopian
tube and their relationship to plasma concentrations during the menstrual
cycle. Batra S, Helm G, Owman C, Sjoberg NO, Walles B. The concentrations
of estradiol-17 beta (E2) and progesterone (P) were measured in the
ampullary and isthmic portions of the fallopian tube of nonpregnant
menstruating women and the cyclic fluctuations were related to the
concentrations of these hormones in plasma. The steroid concentrations were
determined by radioimmunoassays. There was no significant difference in the
isthmic and ampullary concentrations of either steroid in any of the
menstrual phases. The mean value for E2 was highest in the ovulatory phase
and for P during the luteal phase. The tissue (per gm)/plasma (per ml)
ratio for the steroid concentrations was above unity in all measurements.
The ratio for E2 was highest (isthmus:12, ampulla:8) in the follicular
phase and for P (isthmus:26, ampulla:18) during ovulation. Since these
highest ratios were attained when plasma steroid concentrations were
relatively low they were interpreted as reflections of a maximal receptor
contribution.

Biol Reprod 1980 Apr;22(3):430-7. Sex steroids in plasma and reproductive
tissues of the female guinea pig. Batra S, Sjoberg NO, Thorbert G.

J Steroid Biochem Mol Biol 1997 Apr;61(3-6):323-39. Steroid control and
sexual differentiation of brain aromatase. Balthazart J. "Together, these
data indicate that the removal of estrogens caused by steroidal inhibitors
decreases the synthesis of ARO, presumably at the transcriptional level."

Science, Vol. 94, No. 2446 (Nov. 1941), p. 462. Diminution in Ability of
the Liver to Inactivate Estrone in Vitamin B Complex Deficiency, Biskind,
M.S., and G. R. Biskind.

Am. Jour. Clin. Path., Vol. 16 (1946), No. 12, pages 737-45. The
Nutritional Aspects of Certain Endocrine Disturbances, Biskind, G. R., and
M. S. Biskind. 

Biol Reprod, 1993 Oct, 49:4, 647-52. Pathologic effect of estradiol on the
hypothalamus.  Brawer JR; Beaudet A; Desjardins GC; Schipper HM. Estradiol
provides physiological signals to the brain throughout life that are
indispensable for the development and regulation of reproductive function.
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. 

Mech Ageing Dev, 1991 May, 58:2-3, 207-20. Exposure to estradiol impairs
luteinizing hormone function during aging. Collins TJ; Parkening TA
Department of Anatomy and Neurosciences, University of Texas Medical
Branch, Galveston 77550. "This work evaluated the anterior pituitary (AP)
component of the H-P axis by determining the ability of perifused AP to
release LH following sustained but pulsatile LHRH stimulation. The normal
dual discharge profile of LH was affected by age." "The role of estradiol
(E2) in AP aging was further tested as AP from ovariectomized (OVXed) mice,
deprived of E2 since puberty, responded as well as the mature proestrous
group. In contrast, aged mice subjected to long-term E2 exposure (cycling
or OVXed plus E2 replacement) failed to produce the dual response pattern."
"Furthermore, E2 is a major factor in altering LH function and appears to
act before middle age."

Mech Ageing Dev 1975 Jan-Feb;4(1):19-28. Lysosomal enzymes and aging in
vitro: subcellular enzyme distribution and effect of hydrocortisone on cell
life-span. Cristofalo VJ, Kabakjian J. "The acid phosphatase and beta
glucuronidase activities of four subcellular fractions (nuclear,
mitochondrial-lysosomal, microsomal, supernatant) of WI-38 cells were
compared during in vitro aging. All of the fractions showed an
age-associated increase in activity."

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. Estradiol valerate (EV) treatment has been shown
to result in the destruction of 60% of beta-endorphin neurons in the
hypothalamic arcuate nucleus. Evidence suggests that the mechanism of
EV-induced neurotoxicity involves the conversion of estradiol to catechol
estrogen and subsequent oxidation to free radicals in local
peroxidase-positive astrocytes. In this study, we examined whether
treatment with the antioxidant, vitamin E, protects beta-endorphin neurons
from the neurotoxic action of estradiol. Our results demonstrate that
chronic vitamin E treatment prevents the decrement in hypothalamic
beta-endorphin concentrations resulting from arcuate beta-endorphin cell
loss, suggesting that the latter is mediated by free radicals. Vitamin E
treatment also prevented the onset of persistent vaginal cornification and
polycystic ovarian condition which have been shown to result from the
EV-induced hypothalamic pathology.

Exp Gerontol, 1995 May-Aug, 30:3-4, 253-67. Estrogen-induced hypothalamic
beta-endorphin neuron loss: a possible model of hypothalamic aging.
Desjardins GC; Beaudet A; Meaney MJ; Brawer JR. 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.

Geburtshilfe Frauenheilkd 1994 Jun; 54(6):321-31. Hormonprofile bei
hochbetagten Frauen und potentielle Einflussfaktoren. Eggert-Kruse W; Kruse
W; Rohr G; Muller S; Kreissler-Haag D; Klinga K; Runnebaum B. [Hormone
profile of elderly women and potential modifiers]. Eggert-Kruse W, Kruse W,
Rohr G, Muller S, Kreissler-Haag D, Klinga K, Runnebaum B. "In 136 women
with a median age of 78 (60-98) years the serum concentrations of FSH, LH,
prolactin, estradiol-17 beta, testosterone and DHEA-S were determined
completed by GnRH and ACTH stimulation tests in a subgroup. This resulted
in median values for FSH of 15.8 ng/ml, LH 6.4 ng/ml, prolactin 6.9 ng/ml,
estradiol 16 pg/ml, testosterone 270 pg/ml and 306 ng/ml for DHEA-S. No
correlation with age in this population was found for gonadotropins as well
as the other hormones for an age level of up to 98 years." 

Acta Physiol Hung 1985;65(4):473-8. Peripheral blood concentrations of
progesterone and oestradiol during human pregnancy and delivery. Kauppila
A, Jarvinen PA To evaluate the significance of progesterone and estradiol
in human uterine activity during pregnancy and delivery the blood
concentrations of these hormones were monitored weekly during the last
trimester of pregnancy and at the onset of labour in 15 women, and before
and 3 hours after the induction of term delivery in 83 parturients. Neither
plasma concentrations of progesterone or estradiol nor the ratio of
progesterone to estradiol changed significantly during the last trimester
of pregnancy or at the onset of delivery. After the induction of delivery
parturients with initial progesterone dominance (ratio of progesterone to
estradiol higher than 5 before induction) demonstrated a significant fall
in serum concentration of progesterone and in the ratio of progesterone to
estradiol while estradiol concentration rose significantly. In estrogen
dominant women (progesterone to estradiol ratio equal to or lower than 5)
the serum concentration of progesterone and the ratio of progesterone to
estradiol rose significantly during the 3 hours after the induction of
delivery. Our results suggest that the peripheral blood levels of
progesterone and estradiol do not correlate with the tissue biochemical
changes which prepare the uterine cervix and myometrium for delivery. The
observation that the ratio of progesterone to estradiol decreased in
progesterone-dominant and increased in estrogen-dominant women stresses the
importance of a well balanced equilibrium of these hormones for
prostaglandin metabolism during human delivery.

Am J Obstet Gynecol 1984 Nov 1;150(5 Pt 1):501-5. Estrogen and progesterone
receptor and hormone levels in human myometrium and placenta in term
pregnancy. Khan-Dawood FS, Dawood MY. Estradiol and progesterone receptors
in the myometrium, decidua, placenta, chorion, and amnion of eight women
who underwent elective cesarean section at term were determined by means of
an exchange assay. The hormone levels in the peripheral plasma and cytosol
of these tissues were measured by radioimmunoassays. Maternal plasma and
the placenta had high concentrations of estradiol and progesterone, with
the placenta having 12 times more progesterone than in maternal plasma but
only half the concentrations of estradiol in maternal plasma. The decidua
and placenta had detectable levels of cytosol and nuclear estradiol
receptors, but the myometrium had no measurable cytosol estradiol
receptors, whereas the chorion and amnion had neither cytosol nor nuclear
estradiol receptors. However, the chorion and amnion had significantly
higher concentrations of estradiol in the cytosol than those in the decidua
and myometrium. Only the decidua and myometrium had cytosol and nuclear
progesterone receptors, but the placenta, amnion, and chorion had neither
cytosol nor nuclear progesterone receptors. In contrast, progesterone
hormone levels were significantly higher in the placenta, amnion, and
chorion than in the decidua and myometrium. The findings indicate that, in
the term pregnant uterus, (1) the placenta, amnion, and chorion are rich in
progesterone, estradiol, and nuclear estradiol receptors but have no
progesterone receptors, (2) the decidua and myometrium have nuclear
estradiol and progesterone receptors, and (3) the myometrium has a higher
progesterone/estradiol ratio than that of the peripheral plasma, thus
suggesting a highly progesterone-dominated uterus.

Biochem Biophys Res Commun 1982 Jan 29;104(2):570-6. Progesterone-induced
inactivation of nuclear estrogen receptor in the hamster uterus is mediated
by acid phosphatase. MacDonald RG, Okulicz WC, Leavitt, W.W.

Steroids 1982 Oct;40(4):465-73. Progesterone-induced estrogen
receptor-regulatory factor is not 17 beta-hydroxysteroid dehydrogenase.
MacDonald RG, Gianferrari EA, Leavitt WW These studies were done to
determine if the progesterone-induced estrogen receptor-regulatory factor
(ReRF) in hamster uterus is 17 beta-hydroxysteroid dehydrogenase (17
beta-HSD), i.e. that rapid loss of nuclear estrogen receptor (Re) might be
due to enhanced estradiol oxidation to estrone catalyzed by 17 beta-HSD.
Treatment of proestrous hamsters with progesterone (approximately 25 mg/kg
BW) for either 2 h or 4 h had no effect on 17 beta-HSD activity measured as
the rate of conversion of [6,7-3H]estradiol to [3H]estrone by whole uterine
homogenates at 35 degrees C. During this same time interval, progesterone
treatment increased the rate of inactivation of the occupied form of
nuclear Re as determined during a 30 min incubation of uterine nuclear
extract in vitro at 36 degrees C. Since we previously demonstrated that
such in vitro Re-inactivating activity represents ReRF, the present studies
show that ReRF is not 17 beta-HSD or a modifier of that enzyme.

Am J Obstet Gynecol 1987 Aug; 157(2):312-317. Age-related changes in the
female hormonal environment during reproductive life. Musey VC, Collins DC,
Musey PI, Martino-Saltzman D, Preedy JR Previous studies have indicated
that serum levels of follicle-stimulating hormone rise with age during the
female reproductive life, but the effect on other hormones is not clear. We
studied the effects of age, independent of pregnancy, by comparing serum\par hormone levels in two groups of nulliparous, premenopausal women aged 18 to
23 and 29 to 40 years. We found that increased age during reproductive life
is accompanied by a significant rise in both basal and stimulated serum
follicle-stimulating hormone levels. This was accompanied by an increase in
the serum level of estradiol-17 beta and the urine levels of estradiol-17
beta and 17 beta-estradiol-17-glucosiduronate. The serum level of estrone
sulfate decreased with age. Serum and urine levels of other estrogens were
unchanged. The basal and stimulated levels of luteinizing hormone were also
unchanged. There was a significant decrease in basal and stimulated serum
prolactin levels. Serum levels of dehydroepiandrosterone and
dehydroepiandrosterone sulfate decreased with age, but serum testosterone
was unchanged. It is concluded that significant age-related changes in the
female hormonal environment occur during the reproductive years.

Endocrinology 1981 Dec;109(6):2273-5. Progesterone-induced estrogen
receptor-regulatory factor in hamster uterine nuclei: preliminary
characterization in a cell-free system. Okulicz WC, MacDonald RG, Leavitt
WW. "In vitro studies have demonstrated a progesterone-induced activity
associated with the uterine nuclear fraction which resulted in the loss of
nuclear estrogen receptor." "This progesterone-dependent stimulation of
estrogen receptor loss was absent when nuclear extract was prepared in
phosphate buffer rather than Tris buffer. In addition, sodium molybdate and
sodium metavanadate (both at 10 mM) inhibited this activity in nuclear
extract. These observations support the hypothesis that progesterone
modulation of estrogen action may be accomplished by induction (or
activation) of an estrogen receptor-regulatory factor (Re-RF), and this
factor may in turn act to eliminate the occupied form of estrogen receptor
from the nucleus, perhaps through a hypothetical
dephosphorylation-inactivation mechanism."

American Journal of Human Biology, v.8, n.6, (1996): 751-759. Ovarian
function in the latter half of the reproductive lifespan. O'Rourke, M T;
Lipson, S F; Ellison, P T. "Thus, ovarian endocrine function over the
course of reproductive life represents a process of change, but not one of
generalized functional decline." 

J Gerontol, 1978 Mar, 33:2, 191-6. Circulating plasma levels of
pregnenolone, progesterone, estrogen, luteinizing hormone, and follicle
stimulating hormone in young and aged C57BL/6 mice during various stages of
pregnancy.  Parkening TA; Lau IF; Saksena SK; Chang MC Young (3-5 mo of
age) and senescent (12-15 mo of age) multiparous C57BL/6 mice were mated
with young males (3-6 mo of age) and the numbers of preimplantation embryos
and implantation sites determined on days 1 (day of plug), 4, 9, and 16 of
pregnancy. The numbers of viable embryos were significantly lower (p less
than 0.02 to p less than 0.001) in senescent females compared with young
females on all days except day 1 of pregnancy. Plasma samples tested by
radioimmunoassay indicated circulating estradiol-17B was significantly
lower (P less than 0.05) on day 1 and higher (p less than 0.05) on day 4 in
older females, whereas FSH was higher on days 4, 9, and 16 (p less than
0.02 to p less than 0.001) in senescent females when compared with samples
from young females. Levels of pregnenolone, progesterone, estrone, and LH
were not significantly different at any stage of pregnancy in the two age
groups. From the hormonal data it did not appear that degenerating corpora
lutea were responsible for the declining litter size in this strain of aged
mouse. 

Biol Reprod, 1985 Jun, 32:5, 989-97. Orthotopic ovarian transplantations in
young and aged C57BL/6J mice. Parkening TA; Collins TJ; Elder FF.
"Orthotopic ovarian transplantations were done between young (6-wk-old) and
aged (17-mo-old) C57BL/6J mice. The percentages of mice mating following
surgery from the four possible ovarian transfer combinations were as
follows: young into young, 83%; young into aged, 46%; aged into young, 83%;
and aged into aged, 36%." "The only statistical differences found between
the transfer groups occurred in FSH concentrations. Plasma FSH was markedly
elevated (P less than 0.005) in young recipients with ovaries transplanted
from aged donors, in comparison to young recipients with ovaries from young
donors. These data indicate that the aging ovary and uterus play a
secondary role in reproductive failure and that the aging
hypothalamic-hypophyseal complex is primarily responsible for the loss of
fecundity in older female C57BL/6J mice." 

 J Endocrinol, 1978 Jul, 78:1, 147-8. Postovulatory levels of progestogens,
oestrogens, luteinizing hormone and follicle-stimulating hormone in the
plasma of aged golden hamsters exhibiting a delay in fertilization.
Parkening TA; Saksena SK; Lau IF.

Biology of Reproduction, v.49, n.2, (1993): 387-392. Controlled neonatal
exposure to estrogens: A suitable tool for reproductive aging studies in
the female rat. Rodriguez, P; Fernandez-Galaz, C; Tejero, A. "The present
study was designed to determine whether the modification of exposure time
to large doses of estrogens provided a reliable model for early changes in
reproductive aging." "Premature occurrence of vaginal opening was observed
in all three estrogenized groups independently of EB exposure. However,
females bearing implants for 24 h had first estrus at the same age as their
controls and cycled regularly, and neither histological nor gonadal
alterations could be observed at 75 days. Interestingly, they failed to
cycle regularly at 5 mo whereas controls continued to cycle." "On the other
hand, the increase of EB exposure (Ei5, EI) resulted in a gradual and
significant delay in the onset of first estrus and in a high number of
estrous phases, as frequently observed during reproductive decline. At 75
days, the ovaries of these last two groups showed a reduced number of
corpora lutea and an increased number of large follicles. According to this
histological pattern, ovarian weight and progesterone (P) content gradually
decreased whereas both groups showed higher estradiol (E-2) content than
controls. This resulted in a higher E-2:P ratio, comparable to that
observed in normal aging rats. The results allow us to conclude that the
exposure time to large doses of  estrogens is critical to the gradual
enhancement of reproductive decline. Furthermore, exposures as brief as 24
h led to a potential early model for aging studies that will be useful to
verify whether neuroendocrine  changes precede gonadal impairment."

J Clin Endocrinol Metab 1996 Apr;81(4):1495-501. Characterization of
reproductive hormonal dynamics in the perimenopause. Santoro N, Brown JR,
Adel T, Skurnick JH. "Overall mean estrone conjugate excretion was greater
in the perimenopausal women compared to that in the younger women [76.9
ng/mg Cr (range, 13.1-135) vs. 40.7 ng/mg Cr (range, 22.8-60.3); P = 0.023]
and was similarly elevated in both follicular and luteal phases. Luteal
phase pregnanediol excretion was diminished in the perimenopausal women
compared to that in younger normal subjects (range for integrated
pregnanediol, 1.0-8.4 vs. 1.6-12.7 microg/mg Cr/luteal phase; P = 0.015)."
"We conclude that altered ovarian function in the perimenopause can be
observed as early as age 43 yr and include hyperestrogenism,
hypergonadotropism, and decreased luteal phase progesterone excretion.
These hormonal alterations may well be responsible for the increased
gynecological morbidity that characterizes this period of life." 

Brain Res, 1994 Jul 25, 652:1, 161-3. 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. "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." "The present findings
support the hypothesis that the toxic effect of estradiol on hypothalamic
beta-endorphin neurons is mediated by free radicals." 

Clin Exp Obstet Gynecol 2000;27(1):54-6. Hormonal reproductive status of
women at menopausal transition compared to that observed in a group of
midreproductive-aged women. Sengos C, Iatrakis G, Andreakos C, Xygakis A,
Papapetrou P. CONCLUSION: The reproductive hormonal patterns in
perimenopausal women favor a relatively hypergonadotropic hyper-estrogenic
milieu.

Endocr Relat Cancer 1999 Jun;6(2):307-14. Aromatase overexpression and
breast hyperplasia, an in vivo model--continued overexpression of aromatase
is sufficient to maintain hyperplasia without circulating estrogens, and
aromatase inhibitors abrogate these preneoplastic changes in mammary
glands. Tekmal RR, Kirma N, Gill K, Fowler K "To test directly the role of
breast-tissue estrogen in initiation of breast cancer, we have developed
the aromatase-transgenic mouse model and demonstrated for the first time
that increased mammary estrogens resulting from the overexpression of
aromatase in mammary glands lead to the induction of various preneoplastic
and neoplastic changes that are similar to early breast cancer." "Our
current studies show aromatase overexpression is sufficient to induce and
maintain early preneoplastic and neoplastic changes in female mice without
circulating ovarian estrogen. Preneoplastic and neoplastic changes induced
in mammary glands as a result of aromatase overexpression can be completely
abrogated with the administration of the aromatase inhibitor, letrozole.
Consistent with complete reduction in hyperplasia, we have also seen
downregulation of estrogen receptor and a decrease in cell proliferation
markers, suggesting aromatase-induced hyperplasia can be treated with
aromatase inhibitors. Our studies demonstrate that aromatase overexpression
alone, without circulating estrogen, is responsible for the induction of
breast hyperplasia and these changes can be abrogated using aromatase
inhibitors."

J Steroid Biochem Mol Biol 2000 Jun;73(3-4):141-5. Elevated steroid
sulfatase expression in breast cancers. Utsumi T, Yoshimura N, Takeuchi S,
Maruta M, Maeda K, Harada N. In situ estrogen synthesis makes an important
contribution to the high estrogen concentration found in breast cancer
tissues. Steroid sulfatase which hydrolyzes several sulfated steroids such
as estrone sulfate, dehydroepiandrosterone sulfate, and cholesterol sulfate
may be involved. In the present study, we therefore, assessed steroid
sulfatase mRNA levels in breast malignancies and background tissues from 38
patients by reverse transcription and polymerase chain reaction. The levels
in breast cancer tissues were significantly increased at 1458.4+/-2119.7
attomoles/mg RNA (mean +/- SD) as compared with 535.6+/-663.4 attomoles/mg
RNA for non-malignant tissues (P<0.001). Thus, increased steroid sulfatase
expression may be partly responsible for local overproduction of estrogen
and provide a growth advantage for tumor cells.

Ann N Y Acad Sci 1986;464:106-16. Uptake and concentration of steroid
hormones in mammary tissues. Thijssen JH, van Landeghem AA, Poortman J In
order to exert their biological effects, steroid hormones must enter the
cells of target tissues and after binding to specific receptor molecules
must remain for a prolonged period of time in the nucleus. Therefore the
endogenous levels and the subcellular distribution of estradiol, estrone,
DHEAS, DHEA ad 5-Adiol were measured in normal breast tissues and in
malignant and nonmalignant breast tumors from pre- and postmenopausal
women. For estradiol the highest tissue levels were found in the malignant
samples. No differences were seen in these levels between pre- and
postmenopausal women despite the largely different peripheral blood levels.
For estrone no differences were found between the tissues studied. Although
the estradiol concentration was higher in the estradiol-receptor-positive
than in the receptor-negative tumors, no correlation was calculated between
the estradiol and the receptor consent. Striking differences were seen
between the breast and uterine tissues for the total tissue concentration
of estradiol, the ratio between estradiol and estrone, and the subcellular
distribution of both estrogens. At similar receptor concentrations in the
tissues these differences cannot easily be explained. Regarding the
androgens, the tissue/plasma gradient was higher for DHEA than for 5-Adiol,
and for DHEAS there was very probably a much lower tissue gradient. The
highly significant correlation between the androgens suggests an
intracellular metabolism of DHEAS to DHEA and 5-Adiol. Lower concentrations
of DHEAS and DHEA were observed in the malignant tissues compared with the
normal ones and the benign lesions. For 5-Adiol no differences were found
and therefore these data do not support our original hypothesis on the role
of this androgen in the etiology of breast abnormalities. Hence the way in
which adrenal androgens express their influence on the breast cells remains
unclear.

Clin Endocrinol (Oxf) 1978 Jul;9(1):59-66. Sex hormone concentrations in
post-menopausal women. Vermeulen A, Verdonck L. "Plasma sex hormone
concentrations (testosterone, (T), androstenedione (A), oestrone (E1) and
oestradiol (E2) were measured in forty post-menopausal women more than 4
years post-normal menopause." "Sex hormone concentrations in this group of
postmenopausal women (greater than 4YPM) did not show any variation as a
function of age, with the possible exception of E2 which showed a tendency
to decrease in the late post-menopause. E1 and to a lesser extent E2 as
well as the E1/A ratio were significantly corelated with degree of obesity
or fat mass, suggesting a possible role of fat tissue in the aromatization
of androgens. Neither the T/A nor the E2/E1 ratios were correlated with fat
mass, suggesting that the reduction of 17 oxo-group does not occur in fat
tissue. The E1/A ratio was significantly higher than the reported
conversion rate of A in E1."

J Steroid Biochem 1984 Nov;21(5):607-12. The endogenous concentration of
estradiol and estrone in normal human postmenopausal endometrium.
Vermeulen-Meiners C, Jaszmann LJ, Haspels AA, Poortman J, Thijssen JH The
endogenous estrone (E1) and estradiol (E2) levels (pg/g tissue) were
measured in 54 postmenopausal, atrophic endometria and compared with the E1
and E2 levels in plasma (pg/ml). The results from the tissue levels of both
steroids showed large variations and there was no significant correlation
with their plasma levels. The mean E2 concentration in tissue was 420 pg/g,
50 times higher than in plasma and the E1 concentration of 270 pg/g was 9
times higher. The E2/E1 ratio in tissue of 1.6, was higher than the
corresponding E2/E1 ratio in plasma, being 0.3. We conclude that normal
postmenopausal atrophic endometria contain relatively high concentrations
of estradiol and somewhat lower estrone levels. These tissue levels do not
lead to histological effects.

J Clin Endocrinol Metab 1998 Dec; 83(12):4474-80. Deficient
17beta-hydroxysteroid dehydrogenase type 2 expression in endometriosis:
failure to metabolize 17beta-estradiol. Zeitoun K, Takayama K, Sasano H,
Suzuki T, Moghrabi N, Andersson S, Johns A, Meng L, Putman M, Carr B, Bulun
SE. "Aberrant aromatase expression in stromal cells of endometriosis gives
rise to conversion of circulating androstenedione to estrone in this
tissue, whereas aromatase expression is absent in the eutopic endometrium.
In this study, we initially demonstrated by Northern blotting transcripts
of the reductive 17beta-hydroxysteroid dehydrogenase (17betaHSD) type 1,
which catalyzes the conversion of estrone to 17beta-estradiol, in both
eutopic endometrium and endometriosis. Thus, it follows that the product of
the aromatase reaction, namely estrone, that is weakly estrogenic can be
converted to the potent estrogen, 17beta-estradiol, in endometriotic
tissues. It was previously demonstrated that progesterone stimulates the
inactivation of 17beta-estradiol through conversion to estrone in eutopic
endometrial epithelial cells." "In conclusion, inactivation of
17beta-estradiol is impaired in endometriotic tissues due to deficient
expression of 17betaHSD-2, which is normally expressed in eutopic
endometrium in response to progesterone."
Biochem Biophys Res Commun 1999 Aug 2;261(2):499-503. Piceatannol, a
stilbene phytochemical, inhibits mitochondrial F0F1-ATPase activity by
targeting the F1 complex. Zheng J, Ramirez VD.

Eur J Pharmacol 1999 Feb 26;368(1):95-102. Rapid inhibition of rat brain
mitochondrial proton F0F1-ATPase activity by estrogens: comparison with
Na+, K+ -ATPase of porcine cortex. Zheng J, Ramirez VD. "The data indicate
that the ubiquitous mitochondrial F0F1-ATPase is a specific target site for
estradiol and related estrogenic compounds; however, under this in vitro
condition, the effect seems to require pharmacological concentrations."

J Steroid Biochem Mol Biol 1999 Jan;68(1-2):65-75. Purification and
identification of an estrogen binding protein from rat brain: oligomycin
sensitivity-conferring protein (OSCP), a subunit of mitochondrial F0F1-ATP
synthase/ATPase. Zheng J, Ramirez VD. "This finding opens up the
possibility that estradiol, and probably other compounds with similar
structures, in addition to their classical genomic mechanism, may interact
with ATP synthase/ATPase by binding to OSCP, and thereby modulating
cellular energy metabolism."