865 lines
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865 lines
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<head><title>Tissue-bound estrogen in aging</title></head>
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<body>
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<h1>
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Tissue-bound estrogen in aging
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</h1>
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<em><p>
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The "Estrogen Replacement" industry is based on the doctrine that a woman's tissues are depleted of
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estrogen after menopause. This doctrine is false.
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</p>
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<p>
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The concentration of a hormone in the blood doesn't directly represent the concentration in the various
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organs.
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</p>
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<p>
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The amount of estrogen in tissue is decreased when progesterone is abundant. In the absence of
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progesterone, tissues retain estrogen even when there is little estrogen circulating in the blood.
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</p>
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<p>
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Many things suggest an increased estrogenic activity at menopause. For example, melatonin decreases
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sharply at puberty when estrogen increases, and then it decreases again at menopause. Prolactin
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(stimulated by estrogen) increases around puberty, and instead of decreasing at menopause, it often
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increases, and its increase is associated with osteoporosis and other age-related symptoms.
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</p>
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<p>
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Estrogen is produced in many tissues by the enzyme aromatase, even in the breast and endometrium,
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although these are considered "target tissues" rather than endocrine glands. Aromatase increases with
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aging.
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</p>
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<p>
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Estrogen is inactivated, mainly in the liver and brain, by being made water soluble by the attachment of
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glucuronic acid and/or sulfuric acid.
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</p>
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<p>
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Estrogen's concentration in a particular tissue depends on many things, including its affinity or
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binding strength for components of that tissue, relative to its affinity for the blood; the activity in
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that tissue of the aromatase enzyme, which converts androgens to estrogen; the activity of the
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glucuronidase enzyme, that converts water-soluble estrogen glucuronides into the oil soluble active
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forms of estrogen; and the sulfatases and several other enzymes that modify the activity and solubility
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of the estrogens. The "estrogen receptors," proteins which bind estrogens in cells, are inactivated by
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progesterone, and activated by many physical and chemical conditions.
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</p>
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<p>
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Inflammation activates beta-glucuronidase, and antiinflammatory substances such as aspirin reduce many
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of estrogen's effects.
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</p></em>
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<hr />
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<p>
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Doctrines are admitted into the "scientific canon" by those who have the power of censorship. In astronomy,
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Halton Arp's discovery of "anomalous" galactic red-shifts is practically unknown, because the journal
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editors say the observations are "just anomalies," or that the theories which could explain them are
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unconventional; but the actual problem is that they are strong evidence against The Big Bang, Hubble's Law,
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and the Expanding Universe. American science, since the 1940s, has probably been the most censored and
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doctrinaire in the world.
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</p>
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<p>
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Gilbert Ling's revolution in cell biology remains outside the canon, despite the profound influence of MRI,
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which grew directly out of his view of the cell, because his work provided conclusive evidence that cells
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are not regulated by "semipermeable membranes and membrane pumps." Every field of science is ruled by a
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doctrinaire establishment.
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</p>
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<p>
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Charles E. Brown-S"quard (1817-94) was a physiologist who pioneered scientific endocrinology, but who was
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ridiculed because of his claim that extracts of animal glands had an invigorating effect when injected. His
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place in the scientific canon is mainly as an object of ridicule, and the details of his case are perfectly
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representative of the way our "canon" has been constructed. The argument for dismissing his observations was
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that he used a water extract of testicles, and, according to the 20th century American biologists,
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testosterone is not water soluble, and so the water extract would have "contained no hormone." The argument
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is foolish, because living organs contain innumerable substances that will solublize oily molecules, but
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also because Brown-Sequard was describing an effect that wasn"t necessarily limited to a single chemical
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substance. (The transplanting of living cells to repair tissues is finally being accepted, but the pioneers
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in promoting tissue regeneration or repair with the transplantation of living, dead, or stressed cells--V.
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Filatov, L.V. Polezhaev, W.T. Summerlin, for example--were simply written out of history.)
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</p>
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<p>
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If Brown-S"quard"s extract couldn"t work because testosterone isn"t soluble in water, then what are we to
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think of the thousands of medical publications that talk about "free hormones" as the only active hormones?
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("Free hormone" is defined as the hormone that isn"t bound to a transporting protein, with the more or less
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explicit idea that it is dissolved in the water of the plasma or extracellular fluid.) Brown-S"quard"s
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tissue extracts would have contained solublizing substances including proteins and phospholipids, so the
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oily hormones would certainly be present (and active) in his extracts. But the thousands of people who
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ridiculed him committed themselves to the fact that steroid hormones are insoluble in water. By their own
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standard, they are selling an impossibility when they do calculations to reveal the amount of "free
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hormone," as something distinct from the protein bound hormone, in the patient"s blood.
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</p>
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<p>
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The immense Hormone Replacement Therapy industry--which Brown-S"quard"s experiments foreshadowed--is based
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on the fact that the concentrations of some hormones in the blood serum decrease with aging.
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</p>
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<p>
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At first, it was assumed that the amount of the hormone in the blood corresponded to the effectiveness of
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that hormone. Whatever was in the blood was being delivered to the "target tissues." But as the idea of
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measuring "protein bound iodine" (PBI) to determine thyroid function came into disrepute (because it never
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had a scientific basis at all), new ideas of measuring "active hormones" came into the marketplace, and
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currently the doctrine is that the "bound" hormones are inactive, and the active hormones are "free." The
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"free" hormones are supposed to be the only ones that can get into the cells to deliver their signals, but
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the problem is that "free hormones" exist only in the imagination of people who interpret certain lab tests,
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as I discussed in the newsletter on thyroid tests (May, 2000).
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</p>
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<p>
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In the 1960s and 1970s, when the PBI test was disappearing, there was intense interest in--a kind of mania
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regarding--the role of "membranes" in regulating cell functions, and the membrane was still seen by most
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biologists as the "semipermeable membrane" which, "obviously," would exclude molecules as large as albumin
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and the other proteins that carry thyroid and other hormones in the blood. (In reality, and experimental
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observations, albumin and other proteins enter cells more or less freely, depending on prevailing
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conditions.) The membrane doctrine led directly to the "free hormone" doctrine.
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</p>
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<p>
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This issue, of arguing about which form of a hormone is the "active" form, has to do with explaining how
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much of the blood-carried hormone is going to get into the "target tissues." If the membrane is a
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"semipermeable" barrier to molecules such as hormones, then specific receptors and transporters will be
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needed. If the concentration of a hormone inside the cell is higher than that in the blood, a "pump" will
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usually be invoked, to produce an "active transport" of the hormone against its concentration gradient.
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</p>
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<p>
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<strong>But if the membrane regulates the passage of hormones from blood to tissue cells, and especially if
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pumps are needed to move the hormone into the cell, how relevant is the measurement of hormones in the
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blood?</strong>
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</p>
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<p>
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Within the blood, progesterone and thyroid hormone (T3) are much more concentrated in the red blood cells
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than in the serum. Since it isn"t likely that red blood cells are "targets" for the sex hormones, or for
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progesterone or even thyroid, their concentration "against their gradient" in these cells suggests that a
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simple distribution by solubility is involved. Oily substances just naturally tend to concentrate inside
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cells because of their insolubility in the watery environment of the plasma and extracellular fluid.
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Proteins that have "oily" regions effectively bind oily molecules, such as fats and steroids. Even red blood
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cells have such proteins.
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</p>
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<p>
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In the case of oil soluble molecules, such as progesterone and estrogen, it"s important to explain that most
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of their "binding" to proteins or other oil-loving molecules is really the nearly passive consequence of the
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molecules" being forced away from the watery phase--they are hydrophobic, and although it would take a great
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amount of energy to make these insoluble substances enter the watery phase, the attractive force between
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them and the cell is usually small. This means that they can be freely mobile, while "bound" or concentrated
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within the cell. The oxygen atoms, and especially the phenolic group of estrogen, slightly reduce the
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hormones" affinity for simple oils, but they interact with other polar or aromatic groups, giving estrogen
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the ability to bind more strongly and specifically with some proteins and other molecules. Enzymes which
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catalyze estrogen"s oxidation-reduction actions are among the specific estrogen-binding proteins.
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</p>
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<p>
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Many proteins and lipoproteins bind steroids, but some intracellular proteins bind them so strongly that
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they have been--in a very teleological, if not anthropomorphic, way--considered as the switch by which the
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hormone turns on the cellular response. In the popular doctrine of the Estrogen Receptor, a few molecules of
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estrogen bind to the receptors, which carry them to the nucleus of the cell, where the activated receptors
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turn on the genes in charge of the female response. (Or the male response, or the growth response, or the
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atrophy response, or whatever genetic response estrogen is producing.) Once the switch has been thrown, the
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estrogen molecules have fulfilled their hormonal duty, and must get lost, so that the response isn"t
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perpetuated indefinitely by a few molecules.
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</p>
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<p>
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Although the Estrogen Receptor doctrine is worse than silly, there are real proteins which bind estrogen,
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and some of these are called receptors. The uterus, breast, and brain, which are very responsive to
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estrogen, bind, or concentrate, estrogen molecules.
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</p>
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<p>
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When I was working on my dissertation, I tried to extract estrogens from hamster uteri, but the chemical
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techniques I was using to measure estrogen weren"t accurate for such small quantities. A few years later, S.
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Batra was able to extract the estrogen from human tissue in quantities large enough for accurate analysis by
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radioimmunoassay. (Batra, 1976.)
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</p>
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<p>
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His crucial observation was that the difference in estrogen concentration between tissue and blood was
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lowest in the luteal phase, when progesterone is high:
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</p>
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<p>
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<strong>"The tissue/plasma ratio of E2 [estradiol] ranged from</strong>
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<strong>1.45 to 20.36 with very high values in early follicular phase and the lowest in mid-luteal
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phase."</strong> This means that progesterone prevents the tissue from concentrating estrogen. He made
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similar observations during pregnancy, <strong>
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with tissue estrogen decreasing as blood progesterone increased, so that</strong>
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<strong>there is less estrogen in the tissue than in the plasma.</strong>
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But in women who aren"t pregnant, and when their progesterone is low, the tissues may contain 20 to 30 times
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more estrogen than the plasma (in equal volumes).
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</p>
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<p>
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In aging, the sharply decreased progesterone production creates a situation resembling the follicular phase
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of the menstrual cycle, allowing tissues to concentrate estrogen even when the serum estrogen may be low.
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</p>
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<p>
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"<strong>In postmenopausal women, the tissue concentration of E2 was not significantly lower than in
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menstruating women in follicular phase. . . .</strong>" (Akerlund, et al., 1981.)
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</p>
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<p>
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Besides the relatively direct actions of progesterone on the estrogen receptors, keeping their concentration
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low, and its indirect action by preventing prolactin from stimulating the formation of estrogen receptors,
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there are many other processes that can increase or decrease the tissue concentration of estrogen, and many
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of these influences change with aging.
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</p>
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<p>
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There are two kinds of enzyme that produce estrogen. Aromatase converts male hormones into estrogen.
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Beta-glucuronidase converts the inactive estrogen-glucuronides into active estrogen. The healthy liver
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inactivates practically all the estrogen that reaches it, mostly by combining it with the "sugar acid,"
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glucuronic acid. This makes the estrogen water soluble, and it is quickly eliminated in the urine. But when
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it passes through inflamed tissue, these tissues contain large amounts of beta-glucuronidase, which will
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remove the glucuronic acid, leaving the pure estrogen to accumulate in the tissue.
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</p>
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<p>
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Many kinds of liver impairment decrease its ability to excrete estrogen, and estrogen contributes to a
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variety of liver diseases. The work of the Biskinds in the 1940s showed that a dietary protein deficiency
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prevented the liver from detoxifying estrogen. Hypothyroidism prevents the liver from attaching glucuronic
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acid to estrogen, and so increases the body"s retention of estrogen, which in turn impairs the thyroid
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gland"s ability to secrete thyroid hormone. Hypothyroidism often results from nutritional protein
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deficiency.
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</p>
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<p>
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Although we commonly think of the ovaries as the main source of estrogen, the enzyme which makes it can be
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found in all parts of the body. Surprisingly, in rhesus monkeys, aromatase in the arms accounts for a very
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large part of estrogen production. Fat and the skin are major sources of estrogen, especially in older
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people. <strong>The activity of aromatase increases with aging, and under the influence of prolactin,
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cortisol, prostaglandin, and the pituitary hormones, FSH (follicle stimulating hormone) and growth
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hormone.</strong>
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<strong>It is inhibited by progesterone, thyroid, aspirin, and high altitude.</strong>
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Aromatase can produce estrogen in fat cells, fibroblasts, smooth muscle cells, breast and uterine tissue,
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pancreas, liver, brain, bone, skin, etc. Its action in breast cancer, endometriosis, uterine cancer, lupus,
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gynecomastia, and many other diseases is especially important. Aromatase in mammary tissue appears to
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increase estrogen receptors and cause breast neoplasia, independently of ovarian estrogen (Tekmal, et al.,
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1999).
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</p>
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<p>
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Women who have had their ovaries removed are usually told that they need to take estrogen, but animal
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experiments consistently show that removal of the gonads causes the tissue aromatases to increase. The loss
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of progesterone and ovarian androgens is probably responsible for this generalized increase in the formation
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of estrogen. In the brain, aromatase increases under the influence of estrogen treatment.
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</p>
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<p>
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Sulfatase is another enzyme that releases estrogen in tissues, and its activity is inhibited by
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antiestrogenic hormones.
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</p>
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<p>
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In at least some tissues, progesterone inhibits the release or activation of beta-glucuronidase (which,
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according to Cristofalo and Kabakjian, 1975, increases with aging). Glucaric acid, which inhibits this
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enzyme, is being used to treat breast cancer, and glucuronic acid also tends to inhibit the intracellular
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release of estrogen by beta-glucuronidase.
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</p>
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<p>
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Although there is clearly a trend toward the rational use of antiestrogenic treatments for breast cancer, in
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other diseases the myth of estrogen deficiency still prevents even rudimentary approaches.
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</p>
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<p>
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Ever since Lipshutz" work in the 1940s, it has been established that the <strong><em>
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uninterrupted</em></strong> effect of a little estrogen is more harmful than larger but intermittent
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exposures. But after menopause, when progesterone stops its cyclic displacement of estrogen from the
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tissues, the tissues retain large amounts of estrogen continuously.
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</p>
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<p>
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The menopause itself is produced by the prolonged exposure to estrogen beginning in puberty, in spite of the
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monthly protection of the progesterone produced by cycling ovaries. The unopposed action of the high
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concentration of tissue-bound estrogen after menopause must be even more harmful.
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</p>
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<p>
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The decline of the antiestrogenic factors in aging, combined with the increase of pro-estrogenic factors
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such as cortisol and prolactin and FSH, occurs in both men and women. During the reproductive years, women"s
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cyclic production of large amounts of progesterone probably retards their aging enough to account for their
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greater longevity. Childbearing also has a residual antiestrogenic effect and is associated with increased
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longevity.
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</p>
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<p>
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Being aware of this pervasive increase in estrogen exposure with aging should make it possible to marshal a
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comprehensive set of methods for opposing that trend toward degeneration.
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</p>
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<p>
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<strong><h3>REFERENCES</h3></strong>
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</p>
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<p>
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Contraception 1981 Apr;23(4):447-55. <strong>Comparison of plasma and myometrial tissue concentrations of
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estradiol-17 beta and progesterone in nonpregnant women.</strong> Akerlund M, Batra S, Helm G Plasma and
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myometrial tissue concentrations of estradiol (E2) and progesterone (P) were measured by radioimmunoassay
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techniques in samples obtained from women with regular menstrual cycles and from women in pre- <strong>or
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postmenopausal age.</strong> In women with regular cycles, the tissue concentration of E2 ranged from
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0.13 to 1.06 ng/g wet weight, with significantly higher levels around ovulation than in follicular or luteal
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phases of the cycle. The tissue concentration of P ranged from 2.06 to 14.85 ng/g wet weight with
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significantly higher level in luteal phase than in follicular phase. The tissue/plasma ratio of E2 ranged
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from <strong>1.45 to 20.36 with very high values in early follicular phase and the lowest in mid-luteal
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phase.</strong> The ratio for P ranged from 0.54 to 23.7 and was significantly lower in the luteal phase
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than in other phases of the cycle. One woman in premenopausal age with an ovarian cyst was the only case
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with<strong>
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a tissue/plasma ratio of E2 Less Than 1, since her plasma E2 levels were exceptionally high. In
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</strong>
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<strong>postmenopausal women, the tissue concentration of E2 was not significantly lower than in
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menstruating women in follicular phase, and the tissue concentration of P was not significantly lower
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than in fertile women in any of the phases.</strong> Neither in these women nor in menstruating women
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was there <strong>
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a close correlation between tissue and plasma levels.
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</strong>
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The present data indicate that the myometrial uptake capacity for ovarian steroids may be saturated, <strong
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>and also that a certain amount of these steroids is bound to tissue even if plasma levels are low.</strong>
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</p>
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<p>
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Biokhimiia 1984 Aug;49(8):1350-6. <strong>[The nature of thyroid hormone receptors. Translocation of thyroid
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hormones through plasma membranes].</strong> Azimova ShS, Umarova GD, Petrova OS, Tukhtaev KR,
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Abdukarimov A<strong>
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The in vivo translocation of thyroxine-binding blood serum prealbumin (TBPA) was studied. It was found
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that the TBPA-hormone complex penetrates-through the plasma membrane into the cytoplasm of target cells.
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Electron microscopic autoradiography revealed that blood serum TBPA is localized in ribosomes of target
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cells as well as in mitochondria, lipid droplets and Golgi complex. Negligible amounts of the
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translocated TBPA is localized in lysosomes of the cells insensitive to thyroid
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</strong>hormones (spleen macrophages). Study of T4- and T3-binding proteins from rat liver cytoplasm
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demonstrated that one of them has the antigenic determinants common with those of TBPA. It was shown
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autoimmunoradiographically that the structure of TBPA is not altered during its translocation.
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</p>
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<p>
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<strong> </strong>
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Biokhimiia 1985 Nov;50(11):1926-32.<strong>
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[The nature of thyroid hormone receptors. Intracellular functions of thyroxine-binding
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prealbumin</strong>] Azimova ShS; Normatov K; Umarova GD; Kalontarov AI; Makhmudova AA The effect of
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tyroxin-binding prealbumin (TBPA) of blood serum on the template activity of chromatin was studied. It was
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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,
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respectively. The receptors isolated from 0.4 M KCl extract <strong>of chromatin and mitochondria as well as
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hormone-bound TBPA cause similar effects</strong> on the template activity of chromatin. Based on
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experimental results and the previously published comparative data on the structure of TBPA, nuclear,
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cytoplasmic and mitochondrial receptors of thyroid hormones as well as on <strong>translocation across the
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plasma membrane and intracellular transport of TBPA, a conclusion was drawn, which suggested that TBPA
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is the "core" of the true thyroid hormone receptor. It was shown that T3-bound TBPA caused histone
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H1-dependent conformational changes in chromatin.</strong> Based on the studies with the interaction of
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the TBPA-T3 complex with spin-labeled chromatin, a scheme of functioning of the thyroid hormone nuclear
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receptor was proposed.
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</p>
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<p>
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Biokhimiia 1984 Sep;49(9):1478-85<strong>[The nature of thyroid hormone receptors. Thyroxine- and
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triiodothyronine-binding proteins of mitochondria]</strong>
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Azimova ShS; Umarova GD; Petrova OS; Tukhtaev KR; Abdukarimov A. T4- and T3-binding proteins of rat liver
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were studied. It was found that the external mitochondrial membranes and matrix contain a protein whose
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electrophoretic mobility is similar to that of thyroxine-binding blood serum prealbumin (TBPA) and which
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binds either T4 or T3. This protein is precipitated by monospecific antibodies against TBPA. The internal
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mitochondrial membrane has two proteins able to bind thyroid hormones, one of which is localized in the
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cathode part of the gel and binds only T3, while the second one capable of binding T4 rather than T3 and
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possessing the electrophoretic mobility similar to that of TBPA. Radioimmunoprecipitation with monospecific
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antibodies against TBPA revealed that this protein also the antigenic determinants common with those of
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TBPA. The in vivo translocation of 125I-TBPA into submitochondrial fractions was studied. The analysis of
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densitograms of submitochondrial protein fraction showed that both TBPA and hormones are localized in
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<strong>the same protein fractions. Electron microscopic autoradiography demonstrated that 125I-TBPA enters
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the cytoplasm through the external membrane and is localized on the internal mitochondrial membrane and
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matrix.
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</strong>
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</p>
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<p>
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Biokhimiia 1984 Aug;49(8):1350-6<strong>. [The nature of thyroid hormone receptors. Translocation of thyroid
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hormones through plasma membranes]</strong> Azimova ShS; Umarova GD; Petrova OS; Tukhtaev KR;
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Abdukarimov A The in vivo translocation of thyroxine-binding blood serum prealbumin (TBPA) was studied. It
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was found that the TBPA-hormone complex penetrates-through the plasma membrane into the cytoplasm of target
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cells. Electron microscopic autoradiography revealed that blood serum TBPA is localized in ribosomes of
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target cells as well as in mitochondria, lipid droplets and Golgi complex. Negligible amounts of the
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translocated TBPA is localized in lysosomes of the cells insensitive to thyroid hormones (spleen
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macrophages). Study of T4- and T3-binding proteins from rat liver cytoplasm demonstrated that one of them
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has the antigenic determinants common with those of TBPA. It was shown autoimmunoradiographically that the
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structure of TBPA is not altered during its translocation.
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</p>
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<p>
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Probl Endokrinol (Mosk), 1981 Mar-Apr, 27:2, 48-52.<strong>
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[Blood estradiol level and G2-chalone content in the vaginal mucosa in rats of different ages]</strong>
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Anisimov VN; Okulov VB. <strong>"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.
|
|
</strong>
|
|
|
|
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<strong>. . .
|
|
.</strong>". "Possible role of age-associated disturbances of the <strong>regulatory cell proliferation
|
|
stimulant (estrogen) and its inhibitor (chalone) interactions in neoplastic target tissue transformation
|
|
is discussed."</strong>
|
|
</p>
|
|
<p>
|
|
Clin Endocrinol (Oxf) 1979 Dec;11(6):603-10. <strong>Interrelations between plasma and tissue concentrations
|
|
of 17 beta-oestradiol and progesterone during human pregnancy.</strong> 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. <strong>Both at mid-term and term oestradiol concentrations in decidua and myometrium
|
|
were much smaller than those in the plasma (per ml).</strong>
|
|
Progesterone concentration in placenta and in myometrium did not increase from mid-term to term where it
|
|
increased significantly in decidua. <strong>
|
|
Decidual and myometrial progesterone concentrations at mid-term were 2-3 times higher than those in
|
|
plasma,
|
|
</strong>
|
|
|
|
but at term the concentrations in both these tissues were lower than in plasma. The ratio <strong
|
|
>progesterone/oestradiol in plasma, decidua, myometrium and placenta at mid-term was 8.7, 112.2, 61.4 and
|
|
370.0,</strong> 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
|
|
<strong>the lack of correspondence between the plasma concentrations and the tissue concentrations of female
|
|
sex steroids during pregnancy.</strong>
|
|
</p>
|
|
<p>
|
|
Endocrinology 1976 Nov; 99(5): 1178-81. <strong>Unconjugated estradiol in the myometrium of
|
|
pregnancy.</strong> 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.
|
|
</p>
|
|
<p>
|
|
J Steroid Biochem 1989 Jan;32(1A):35-9. <strong>Tissue specific effects of progesterone on progesterone and
|
|
estrogen receptors in the female urogenital tract.</strong> 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<strong>
|
|
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</strong> three tissues. Although the Kd of the cytosolic
|
|
progesterone receptor also increased in all tissues, the difference was significant for only the vagina
|
|
and<strong>
|
|
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,</strong>
|
|
|
|
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.
|
|
</p>
|
|
<p>
|
|
Am J Obstet Gynecol 1980 Apr 15;136(8):986-91. <strong>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.</strong>
|
|
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
|
|
<strong>
|
|
these highest ratios were attained when plasma steroid concentrations were relatively low they were
|
|
interpreted as reflections of a maximal receptor contribution.</strong>
|
|
</p>
|
|
<p>
|
|
Biol Reprod 1980 Apr;22(3):430-7.<strong>
|
|
Sex steroids in plasma and reproductive tissues of the female guinea pig.</strong> Batra S, Sjoberg NO,
|
|
Thorbert G.
|
|
</p>
|
|
|
|
<p>
|
|
J Steroid Biochem Mol Biol 1997 Apr;61(3-6):323-39.<strong>
|
|
Steroid control and sexual differentiation of brain aromatase.</strong> Balthazart J. "Together, these
|
|
data indicate that <strong>
|
|
the removal of estrogens caused by steroidal inhibitors decreases the synthesis of ARO,</strong>
|
|
presumably at the transcriptional level."
|
|
</p>
|
|
<p>
|
|
Science, Vol. 94, No. 2446 (Nov. 1941), p. 462. <strong>Diminution in Ability of the Liver to Inactivate
|
|
Estrone in Vitamin B Complex Deficiency,</strong> Biskind, M.S., and G. R. Biskind.
|
|
</p>
|
|
|
|
<p>
|
|
Am. Jour. Clin. Path., Vol. 16 (1946), No. 12, pages 737-45.<strong>
|
|
The Nutritional Aspects of Certain Endocrine Disturbances,</strong> Biskind, G. R., and M. S.
|
|
Biskind.<strong> </strong>
|
|
</p>
|
|
<p>
|
|
Biol Reprod, 1993 Oct, 49:4, 647-52<strong>. Pathologic effect of estradiol on the hypothalamus.</strong>
|
|
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.
|
|
</p>
|
|
<p>
|
|
Mech Ageing Dev, 1991 May, 58:2-3, 207-20. <strong>Exposure to estradiol impairs luteinizing hormone
|
|
function during aging.</strong> 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." <strong>"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
|
|
pa</strong>ttern." "Furthermore, <strong>E2 is a major factor in altering LH function and appears to act
|
|
before middle age."</strong>
|
|
</p>
|
|
<p>
|
|
Mech Ageing Dev 1975 Jan-Feb;4(1):19-28. <strong>Lysosomal enzymes and aging in vitro: subcellular enzyme
|
|
distribution and effect of hydrocortisone on cell life-span.</strong> 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.
|
|
A<strong>ll of the fractions showed an age-associated increase in activity.</strong>"
|
|
</p>
|
|
<p>
|
|
Endocrinology, 1992 Nov, 131:5, 2482-4.<strong>
|
|
Vitamin E protects hypothalamic beta-endorphin neurons from estradiol neurotoxicity.</strong> 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.
|
|
</p>
|
|
|
|
<p>
|
|
Exp Gerontol, 1995 May-Aug, 30:3-4, 253-67.<strong>
|
|
Estrogen-induced hypothalamic beta-endorphin neuron loss: a possible model of hypothalamic
|
|
aging.</strong>
|
|
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.<strong>
|
|
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.</strong> 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 <strong>destruction of greater than 60% of all beta-endorphin neurons in the arcuate nucleus
|
|
</strong>
|
|
while leaving other neuronal populations spared. This loss of opioid neurons is prevented by treatment with
|
|
antioxidants indicating that it results from <strong>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.</strong> 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 <strong>suppression of
|
|
the pattern of LHRH release, and subsequently that of LH.</strong> Indeed, prevention of the
|
|
neuroendocrine effects of estradiol by antioxidant treatment also <strong>prevents the cascade of
|
|
neuroendocrine aberrations resulting in anovulatory acyclicity.</strong> 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.
|
|
</p>
|
|
<p>
|
|
Geburtshilfe Frauenheilkd 1994 Jun; 54(6):321-31.<strong>
|
|
Hormonprofile bei hochbetagten Frauen und potentielle Einflussfaktoren.</strong> Eggert-Kruse W; Kruse
|
|
W; Rohr G; Muller S; Kreissler-Haag D; Klinga K; Runnebaum B. <strong>[Hormone profile of elderly women and
|
|
potential modifiers].
|
|
</strong>
|
|
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. <strong>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."</strong>
|
|
</p>
|
|
<p>
|
|
Acta Physiol Hung 1985;65(4):473-8. <strong>Peripheral blood concentrations of progesterone and oestradiol
|
|
during human pregnancy and delivery.</strong>
|
|
|
|
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<strong>
|
|
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</strong> 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.
|
|
</p>
|
|
<p>
|
|
Am J Obstet Gynecol 1984 Nov 1;150(5 Pt 1):501-5. <strong>Estrogen and progesterone receptor and hormone
|
|
levels in human myometrium and placenta in term pregnancy.</strong> 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<strong>
|
|
than in maternal plasma but only half the concentrations of estradiol in</strong> maternal plasma. The
|
|
decidua and placenta had detectable levels of cytosol and nuclear estradiol receptors, but the myometrium
|
|
had no measurable cytosol estradiol receptors, <strong>
|
|
whereas the chorion and amnion had neither cytosol nor nuclear estradiol receptors. However, the chorion
|
|
and amnion had significantly higher concentrations of estradiol</strong> 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) <strong
|
|
>the myometrium has a higher progesterone/estradiol ratio than that of the peripheral plasma, thus
|
|
suggesting a highly progesterone-dominated uterus.</strong>
|
|
</p>
|
|
<p>
|
|
Biochem Biophys Res Commun 1982 Jan 29;104(2):570-6. <strong>Progesterone-induced inactivation of nuclear
|
|
estrogen receptor in the hamster uterus is mediated by acid phosphatase.</strong> MacDonald RG, Okulicz
|
|
WC, Leavitt, W.W.
|
|
</p>
|
|
<p>
|
|
Steroids 1982 Oct;40(4):465-73. <strong>Progesterone-induced estrogen receptor-regulatory factor is not 17
|
|
beta-hydroxysteroid dehydrogenase.</strong> 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.
|
|
</p>
|
|
|
|
<p>
|
|
Am J Obstet Gynecol 1987 Aug; 157(2):312-317. <strong>Age-related changes in the female hormonal environment
|
|
during reproductive life.</strong> 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, <strong>
|
|
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
|
|
</strong>
|
|
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.
|
|
</p>
|
|
<p>
|
|
Endocrinology 1981 Dec;109(6):2273-5. <strong>Progesterone-induced estrogen receptor-regulatory factor in
|
|
hamster uterine nuclei: preliminary characterization in a cell-free system.</strong> Okulicz WC,
|
|
MacDonald RG, Leavitt WW.<strong>
|
|
"In vitro studies have demonstrated a progesterone-induced activity associated with the uterine nuclear
|
|
fraction which resulted in the loss of nuclear estrogen receptor."</strong> "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 <strong>act to eliminate the occupied form of estrogen receptor from
|
|
the nucleus,</strong> perhaps through a hypothetical dephosphorylation-inactivation mechanism."
|
|
</p>
|
|
|
|
<p>
|
|
American Journal of Human Biology, v.8, n.6, (1996): 751-759. <strong>Ovarian function in the latter half of
|
|
the reproductive lifespan.
|
|
</strong>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."
|
|
</p>
|
|
<p>
|
|
J Gerontol, 1978 Mar, 33:2, 191-6.<strong>
|
|
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.</strong>
|
|
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 <strong>higher (p less
|
|
than 0.05) on day 4
|
|
</strong>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.
|
|
</p>
|
|
<p>
|
|
Biol Reprod, 1985 Jun, 32:5, 989-97. <strong>Orthotopic ovarian transplantations in young and aged C57BL/6J
|
|
mice.</strong> 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%; <strong
|
|
>young into aged, 46%;</strong> aged into young, 83%; and aged into aged, 36%." <strong>"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.
|
|
</strong>
|
|
|
|
These data indicate that the aging ovary and uterus play a secondary role in <strong>reproductive failure
|
|
and that the aging hypothalamic-hypophyseal complex is primarily responsible for the loss of fecundity
|
|
in older female C57BL/6J mice."
|
|
</strong>
|
|
</p>
|
|
<p>
|
|
J Endocrinol, 1978 Jul, 78:1, 147-8. <strong>Postovulatory levels of progestogens, oestrogens, luteinizing
|
|
hormone and follicle-stimulating hormone in the plasma of aged golden hamsters exhibiting a delay in
|
|
fertilization.</strong> Parkening TA; Saksena SK; Lau IF.
|
|
</p>
|
|
<p>
|
|
Biology of Reproduction, v.49, n.2, (1993): 387-392. <strong>Controlled neonatal exposure to estrogens: A
|
|
suitable tool for reproductive aging studies in the female rat.</strong> 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 <strong>an increased number of
|
|
large follicles</strong>. 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 <strong>a higher E-2:P ratio, comparable to that observed in normal aging rats.</strong>
|
|
<strong>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."</strong>
|
|
</p>
|
|
|
|
<p>
|
|
J Clin Endocrinol Metab 1996 Apr;81(4):1495-501. <strong>Characterization of reproductive hormonal dynamics
|
|
in the perimenopause.</strong> Santoro N, Brown JR, Adel T, Skurnick JH. "<strong>Overall mean estrone
|
|
conjugate excretion was</strong>
|
|
<strong><hr /></strong>
|
|
<strong>and was similarly elevated in both follicular and luteal phases.</strong>
|
|
<strong>Luteal phase pregnanediol excretion was diminished in the perimenopausal women</strong> compared to
|
|
that in younger normal subjects (range for integrated pregnanediol,<strong> 1.0-8.4 vs. 1.6-12.7 </strong>
|
|
<hr />
|
|
<strong>
|
|
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."
|
|
</strong>
|
|
</p>
|
|
<p>
|
|
Brain Res, 1994 Jul 25, 652:1, 161-3.<strong>
|
|
The 21-aminosteroid antioxidant, U74389F, prevents estradiol-induced depletion of hypothalamic
|
|
beta-endorphin in adult female rats.</strong> Schipper HM; Desjardins GC; Beaudet A; Brawer JR.<strong>
|
|
"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."
|
|
</strong>
|
|
</p>
|
|
<p>
|
|
Clin Exp Obstet Gynecol 2000;27(1):54-6. <strong>Hormonal reproductive status of women at menopausal
|
|
transition compared to that observed in a group of midreproductive-aged women.</strong> Sengos C,
|
|
Iatrakis G, Andreakos C, Xygakis A, Papapetrou P. <strong>CONCLUSION: The reproductive hormonal patterns
|
|
in</strong>
|
|
<strong>perimenopausal women favor a relatively hypergonadotropic hyper-estrogenic milieu.</strong>
|
|
</p>
|
|
|
|
<p>
|
|
Endocr Relat Cancer 1999 Jun;6(2):307-14.<strong>
|
|
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.</strong> 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,<strong>
|
|
we have also seen downregulation of estrogen receptor and a decrease in cell proliferation</strong>
|
|
markers, suggesting aromatase-induced hyperplasia can be treated with aromatase inhibitors. Our studies
|
|
demonstrate that <strong>aromatase overexpression alone, without circulating estrogen, is responsible for
|
|
the induction of breast hyperplasia and these changes can be abrogated using aromatase
|
|
inhibitors."</strong>
|
|
</p>
|
|
<p>
|
|
J Steroid Biochem Mol Biol 2000 Jun;73(3-4):141-5. <strong>Elevated steroid sulfatase expression in breast
|
|
cancers.</strong> 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.
|
|
</p>
|
|
<p>
|
|
Ann N Y Acad Sci 1986;464:106-16. <strong>Uptake and concentration of steroid hormones in mammary
|
|
tissues.</strong> 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<strong>. No differences were seen in these
|
|
levels between pre- and postmenopausal women despite the largely different peripheral blood
|
|
levels.</strong> 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. <strong>At similar receptor
|
|
concentrations in the tissues these differences cannot easily be explained.</strong> 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. <strong>Lower concentrations of DHEAS and DHEA were
|
|
observed in the malignant tissues compared with the normal ones and the benign lesions.</strong> 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.
|
|
</p>
|
|
|
|
<p>
|
|
Clin Endocrinol (Oxf) 1978 Jul;9(1):59-66. <strong>Sex hormone concentrations in post-menopausal
|
|
women.</strong> 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." <strong>"Sex hormone concentrations in this group of postmenopausal
|
|
women (greater than 4YPM) did not show any variation as a function of age,</strong> 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."
|
|
</p>
|
|
<p>
|
|
J Steroid Biochem 1984 Nov;21(5):607-12. <strong>The endogenous concentration of estradiol and estrone in
|
|
normal human postmenopausal endometrium.</strong> 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<strong>
|
|
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.
|
|
</strong>The E2/E1 ratio in tissue of 1.6, was higher than the corresponding E2/E1 ratio in plasma, being
|
|
0.3. <strong>We conclude that normal postmenopausal atrophic endometria contain relatively high
|
|
concentrations of estradiol and somewhat lower estrone levels.</strong> These tissue levels do not lead
|
|
to histological effects.
|
|
</p>
|
|
|
|
<p>
|
|
J Clin Endocrinol Metab 1998 Dec; 83(12):4474-80. <strong>Deficient 17beta-hydroxysteroid dehydrogenase type
|
|
2 expression in endometriosis: failure to metabolize 17beta-estradiol.</strong> Zeitoun K, Takayama K,
|
|
Sasano H, Suzuki T, Moghrabi N, Andersson S, Johns A, Meng L, Putman M, Carr B, Bulun SE.<strong> </strong>
|
|
"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. <strong>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</strong>
|
|
<strong>
|
|
demonstrated that progesterone stimulates the inactivation of 17beta-estradiol</strong> through
|
|
conversion to estrone in eutopic endometrial epithelial cells." <strong>"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."</strong>
|
|
</p>
|
|
<p>
|
|
Biochem Biophys Res Commun 1999 Aug 2;261(2):499-503. <strong>Piceatannol, a stilbene phytochemical,
|
|
inhibits mitochondrial F0F1-ATPase activity by targeting the F1 complex.</strong> Zheng J, Ramirez VD.
|
|
</p>
|
|
<p>
|
|
Eur J Pharmacol 1999 Feb 26;368(1):95-102.<strong>
|
|
Rapid inhibition of rat brain mitochondrial proton F0F1-ATPase activity by estrogens: comparison with
|
|
Na+, K+ -ATPase of porcine cortex. Zheng J, Ramirez VD</strong>. "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."
|
|
</p>
|
|
<p>
|
|
J Steroid Biochem Mol Biol 1999 Jan;68(1-2):65-75. <strong>Purification and identification of an estrogen
|
|
binding protein from rat brain: oligomycin sensitivity-conferring protein (OSCP), a subunit of
|
|
mitochondrial F0F1-ATP synthase/ATPase.</strong> Zheng J, Ramirez VD. "This finding opens up the
|
|
possibility that estradiol, and probably other compounds with<strong>
|
|
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."</strong>
|
|
</p>
|
|
|
|
<p>© Ray Peat 2006. All Rights Reserved. www.RayPeat.com</p>
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