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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.
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,
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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 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-glucosidurona
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.”
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