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Organ Donor and Transplantation – Effects of “EFA” Deficiency

Also see:
Protective “Essential Fatty Acid Deficiency”
“Curing” a High Metabolic Rate with Unsaturated Fats
Fat Deficient Animals – Activity of Cytochrome Oxidase
Anti-Inflammatory Omega -9 Mead Acid (Eicosapentaenoic acid)
Errors in Nutrition: Essential Fatty Acids
Arachidonic Acid’s Role in Stress and Shock
PUFA, Development, and Allergy Incidence
PUFA Accumulation & Aging
Metabolism, Brain Size, and Lifespan in Mammals
“Curing” a High Metabolic Rate with Unsaturated Fats
Glucocorticoids, Cytochrome Oxidase, and Metabolism
Fat Deficient Animals – Activity of Cytochrome Oxidase
Toxicity of Stored PUFA

Animals that have a diet free of polyunsaturated fats are good organ donors and recipients. -Ray Peat, PhD (personal correspondence)

Science. 1988 May 20;240(4855):1032-3.
Essential fatty acid depletion of renal allografts and prevention of rejection.
Schreiner GF, Flye W, Brunt E, Korber K, Lefkowith JB.
A central hypothesis in transplantation biology is that resident leukocytes expressing class II histocompatibility antigens may determine the immunogenicity of an organ. By means of a novel method to deplete the kidney of resident leukocytes, essential fatty acid deficiency (EFAD), this hypothesis was tested in an intact, vascular organ. Kidneys subjected to EFAD and thus depleted of resident Ia-positive macrophages survived and functioned when transplanted across a major histocompatibility antigen barrier in the absence of immunosuppression of the recipient. Control allografts were rejected promptly. Allografts from donors subjected to EFAD normalized their lipid composition and were repopulated with host macrophages by 5 days. Administration of Ia-positive cells at the time of transplantation established that the resident leukocyte depletion induced by EFAD was responsible for the protective effect. These observations may provide insights into the mechanisms underlying tissue immunogenicity and the population of normal tissues with resident leukocytes.

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Bowel Toxins Accelerate Aging

Also see:
Ray Peat, PhD on the Benefits of the Raw Carrot
Protective Cascara Sagrada and Emodin
Fermentable Carbohydrates, Anxiety, Aggression
Protective Bamboo Shoots
Endotoxin-lipoprotein Hypothesis
Endotoxin: Poisoning from the Inside Out
Protection from Endotoxin
PUFA Accumulation & Aging

Quotes by Ray Peat, PhD:
“Another process with potentially deadly results that increase with aging and stress, is the passage of bacteria from the intestines into the blood stream.”

“The intestine is source of toxins,, and some studies have found considerable life extension by keeping the intestine free of bacteria. At the beginning of the 20th century, Elie Metchnikof (The Nature of Man, 1894, Prolongation of Life; Optimistic Studies, 1907) believed, basing his ideas on comparative biology, that intestinal toxins caused aging by disrupting the immune and endocrine systems’ functions in tissue maintenance and renewal. He noticed that the intestine of short-lived herbivore such as rabbits had a strong odor of putrefaction and a great variety of bacterial species, but that the intestines of long-lived birds such as parrots and ravens had no unpleasant smell, even when he had fed the ravens with rotting meat, and contained only a few species of bacteria.

Metchnikof’s ideas about intestinal toxins as a source of sickness and aging were widely attacked in the US medical journals. In 1907 he wrote “Even at present there are critics who regard me as incapable of sane and logical reasoning.””

“The food industry is promoting the use of various gums and starches, which are convenient thickeners and stabilizers for increasing self-life, with the argument that the butyric acid produced when they are fermented by intestinal bacteria is protective. However, intestinal fermentation increases systemic and brain serotonin, and the short-chain fatty acids can produce a variety of inflammatory and cytotoxic effect. Considering the longevity and stress-resistance of germ-free animals, choosing foods (such as raw carrots or cooked bamboo shoots or cooked mushrooms) which accelerate peristalsis and speed transit through the bowel, which suppressing bacterial growth, seems like a convenient approach to increasing longevity.

In the years following the publication of Methnikof’s book in the US, there was a campaign in the medical journals to deny the validity of his idea of life-shortening “auto-intoxication” from the bowel. Warnings about the dangers of laxatives and enemas became common, and it was argued that a daily bowel movement wasn’t necessary. Max Gerson’s use of enemas in cacer therapy was ridiculed. Finally, the FDA banned the sale of cascara as a laxative. Recently, the kidney industry has been realizing that the bowel is the source of the major toxins of uremia, so there might be a gradual change of attitude toward the intestine in medicine generally.”

“Our innate immune system is perfectly competent for handling our normal stress induced exposures to bacterial endotoxin, but as we accumulate the unstable fats, each exposure to endotoxin creates additional inflammatory stress by liberating stored fats.”

“In aging, stress, and malnutrition, the barrier function of the intestine is weakened. Vitamin A and magnesium deficiencies allow macromolecules to enter the blood from the intestine.”

“Aging and stress increase some of the inflammatory mediators, tending to reduce the barrier function of the bowel, letting larger amounts of bacterial toxins enter the bloodstream, interfering with energy metabolism, creating inflammatory vicious circles of increasing leakiness and inflammation.”

“The gerontologist, V.V. Frolkis, recently found that mice lived 43% longer than animals on the standard diet when they periodically had activated charcoal added to their food. This is the clearest evidence I have seen that “bowel toxins” make a major contribution to the aging process.”

Biomater Artif Cells Artif Organs. 1989;17(3):341-51.
Effect of enterosorption on animal lifespan.
Frolkis VV, Nikolaev VG, Paramonova GI, Shchorbitskaya EV, Bogatskaya LN, Stupina AS, Kovtun AI, Sabko VE, Shaposhnikov VM, Muradian KK, et al.
Experiments were performed on Wistar male rats, starting from the 28th month of age. The effect of dietary sorbent (non coated nitrogen-containing carbon administered as 10 day courses at 1 month intervals in dosage of 10 ml/kg) on lifespan and a number of biological indices were studied. Enterosorption resulted in the increase of mean and maximal lifespan by 43 and 34% respectively. Analysis of the effect of enterosorption on activity of microsomal enzymes, intensity of total RNA and protein biosynthesis, lipid metabolism, formation of free radicals etc. showed that it produced a positive influence on the functional state of the studied systems and increased the organism’s adaptive capacities. Enterosorption was found to delay the rate of onset of age-related structural changes in the organs and tissues.

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Toxicity of Stored PUFA

Also see:
Fats, functions & malfunctions
Vitamin E Needs Increases with PUFA Consumption and Greater Unsaturation
Dietary PUFA Reflected in Human Subcutaneous Fat Tissue
Israeli Paradox: High Omega -6 Diet Promotes Disease
Thigh and Buttock Fat Depots more Unsaturated than Abdominal Fat Depots
PUFA Accumulation & Aging
PUFA Promote Stress Response; Saturated Fats Suppress Stress Response
Ray Peat, PhD on Low Blood Sugar & Stress Reaction
Low Blood Sugar Basics
Unsaturated Fats and Longevity
Arachidonic Acid’s Role in Stress and Shock
Protective “Essential Fatty Acid Deficiency”
Anti-Inflammatory Omega -9 Mead Acid (Eicosatrienoic acid)
“Curing” a High Metabolic Rate with Unsaturated Fats
Fat Deficient Animals – Activity of Cytochrome Oxidase
Ray Peat, PhD Quotes on Therapeutic Effects of Niacinamide
Benefits of Aspirin
Saturated and Monousaturated Fatty Acids Selectively Retained by Fat Cells
PUFA Promote Cancer
Your MUFA + PUFA Intakes Determine Your True Vitamin E Requirements – N-3s are the Worst Offenders + Even MUFAs Need Buffering | Tool to Calculate Your Individual Needs
The Dangers of Fat Metabolism and PUFA: Why You Don’t Want to be a Fat Burner

Quotes by Ray Peat, PhD
“The half-life of fats in human adipose tissue is about 600 days, meaning that significant amounts of previously consumed oils will still be present up to four years after they have been removed from the diet.”

“Heavy drinking inhibits cellular respiration and sets up an inflammatory process, involving iron, which will still be harmful, but less so than in the presence of PUFA. If absolutely none of the dietary PUFA were in the body, no one really knows what that metabolic stress would do, maybe nothing cumulative.”

“When the polyunsaturated fats in the diet are reduced, the amount of them stored in the tissues decreases for about four years, making it progressively easier to keep the metabolic rate up, and stress hormones down.”

“The use of adequate protein and saturated fats during pregnancy will prevent many of the problems of pregnancy and infancy, but since the unsaturated fats remain stored in the tissues for many years, and are mobilized during stress, it’s important to eat correctly long before pregnancy. The requirement for vitamin E remains high for years after the diet has contained an excess of the polyunsatured fats. The diet which protects the developing fetus happens to be the diet that protects adults from all sorts of stress, and prevents many of the worst symptoms of aging.”

“The quantity of PUFA in the tissues strongly determines the susceptibility of the tissue to injury by radiation and other stresses. But a diet rich in PUFA will produce brain damage even without exceptional stressors, when there aren’t enough antioxidants, such as vitamin E and selenium, in the diet.”

“‎The larger the quantity of “toxic fat” stored in the body, the more careful the person must be about increasing metabolic and physical activity. Using more vitamin E, short-chain saturated fats, and other anti-lipid-peroxidation agents is important.”

“Although thyroid, progesterone, and a high quality protein diet will generally correct the epilepsy problem, it is important to mention that the involvement of unsaturated fats and free radicals in seizure physiology implies that we should minimize our consumption of the unsaturated fats. Even years after eliminating them from the diet, their release from tissue storage can prolong the problem, and during that time the use of vitamin E is likely to reduce the intensity and frequency of seizures.”

“But when tissues contain large amounts of polyunsaturated fats, every episode of fatigue and prolonged excitation leaves a residue of oxidative damage, and the adaptive mechanisms become progressively less effective.”

“It’s the stored PUFA, released by stress or hunger, that slow metabolism. Niacinamide helps to lower free fatty acids, and good nutrition will allow the liver to slowly detoxify the PUFA, if it isn’t being flooded with large amounts of them. A small amount of coconut oil with each meal will increase the ability to oxidize fat, by momentarily stopping the antithyroid effect of the PUFA. Aspirin is another thing that reduces the stress-related increase of free fatty acids, stimulating metabolism. Taking a thyroid supplement is reasonable until the ratio of saturated fats to PUFA is about 2 to 1.”

“The saturated fats protect against the body’s stored PUFA, and keeping the blood sugar up keeps the stored fats from being mobilized.”

“It was the body’s load of polyunsaturated fats which made it very susceptible to inflammation, stress, trauma, infection, radiation, hormone imbalance, and other fundamental problems, and drugs like aspirin and cortisone, which limit the activation of the stored “essential fatty acids,” gain their remarkable range of beneficial effects partly by the restraint they impose on those stored toxins.”

“Since stored fats are usually mostly polyunsaturated, the thyroid gland will keep being suppressed as long as weight is being lost, since the PUFA are being released into the blood stream. If a person has enough cholesterol, thyroid, and vitamin A, and keeps estrogen low, progesterone supplements shouldn’t be needed, but since adipose tissue is a source of estrogen synthesis when there’s inflammation, stress, or low thyroid, the need for progesterone is likely to recur. Aspirin helps to inhibit estrogen synthesis.”

“People with a significant amount of fat in their body, who have in the past eaten foods containing vegetable oils, are likely to draw unsaturated fats out of storage, with toxic effects unless vitamin E, thyroid, and coconut oil are used protectively until tissue stores of unsaturated fats are depleted. Typically, body stores of fat take four years to completely reflect the change to a different type of dietary fat.”

“Eliminating polyunsaturated fats from the diet is essential if the bystander effect is eventually to be restrained. Aspirin and salicylic acid can block many of the carcinogenic effects of the PUFA. Saturated fats have a variety of antiinflammatory and anticancer actions. Some of those effects are direct, others are the result of blocking the toxic effects of the PUFA. Keeping the stored unsaturated fats from circulating in the blood is helpful, since it takes years to eliminate them from the tissues after the diet has changed. Niacinamide inhibits lipolysis. Avoiding overproduction of lipolytic adrenaline requires adequate thyroid hormone, and the adjustment of the diet to minimize fluctuations of blood sugar.”

“In a young person, good food, sunlight, and a high altitude can often overcome severe and progressive inflammatory conditions. In an older person, whose tissues contain larger amounts of polyunsaturated fats and their breakdown products, it takes more environmental support to get out of the inflammatory pattern.”

“Sugars, if they are consumed in quantities beyond the ability to metabolize them (and that easily happens in the presence of PUFA) are converted into saturated fatty acids, which have antistress, antiinflammatory effects. Many propaganda experiments are set up, feeding a grossly excessive amount of polyunsaturated fat, causing sugar to form fat, specifically so they can publish their silly diet recommendations, which supposedly explain the obesity epidemic, but the government figures I cited show that vegetable fat consumption has increased, sugar hasn’t. My articles have a lot of information on the mechanisms, such as the so-called ‘Randle cycle,’ in which fatty acids shut down the ability to oxidize sugar. Polyunsaturated fats do many things that increase blood sugar inappropriately, and my articles review several of the major mechanisms. Several years ago, medical people started talking about the harmful effects of insulin, such as stimulating fat production, so ‘insulin resistance’ which keeps a high level of insulin from producing obesity would seem to be a good thing, but the medical obesity culture really isn’t thinking very straight. One factor in the ‘insulin resistance’ created by PUFA involves estrogen—chronic accumulation of PUFA in the tissues increases the production of estrogen, and the polyunsaturated free fatty acids intensify the actions of estrogen, which acts in several ways to interfere with glucose oxidation.”

“Our innate immune system is perfectly competent for handling our normal stress induced exposures to bacterial endotoxin, but as we accumulate the unstable fats, each exposure to endotoxin creates additional inflammatory stress by liberating stored fats. The brain has a very high concentration of complex fats, and is highly susceptible to the effects of lipid peroxidative stress, which become progressively worse as the unstable fats accumulate during aging.”

“The polyunsaturated fatty acids differ from the saturated fats in many ways, besides their shape and their melting temperature, and each type of fatty acid is unique in its combination of properties. The polyunsaturated fatty acids, made by plants (in the case of fish oils, they are made by algae), are less stable than the saturated fats, and the omega-3 and omega-6 fats derived from them, are very susceptible to breaking down into toxins, especially in warm-blooded animals. Other differences between saturated and polyunsaturated fats are in their effects on surfaces (as surfactant), charges (dielectric effects), acidity, and their solubility in water relative to their solubility in oil. The polyunsaturated fatty acids are many times more water soluble than saturated fatty acids of the same length. This property probably explains why only palmitic acid functions as a surfactant in the lungs, allowing the air sacs to stay open, while unsaturated fats cause lung edema and respiratory failure.

The great difference in water/oil solubility affects the strength of binding between a fatty acid and the lipophilic, oil-like, parts of proteins. When a protein has a region with a high affinity for lipids that contain double bonds, polyunsaturated fatty acids will displace saturated fats, and they can sometimes displace hormones containing multiple double bonds, such as thyroxine and estrogen, from the proteins that have a high specificity for those hormones. Transthyretin (also called prealbumin) is important as a carrier of the thyroid hormone and vitamin A. The unsaturation of vitamin A and of thyroxin allow them to bind firmly with transthyretin and certain other proteins, but the unsaturated fatty acids are able to displace them, with an efficiency that increases with the number of double bonds, from linoleic (with two double bonds) through DHA (with six double bonds)…

Cells are lipophilic, and absorb molecules in proportion to their fattiness; this long ago led people to theorize that cells are coated with a fat membrane…

Since most people believe that cells are enclosed within a barrier membrane, a new industry has appeared to sell special products to “target” or “deliver” proteins into cells across the barrier. Combining anything with fat makes it more likely to enter cells. Stress (which increases free fatty acids and lowers cell energy) makes cells more permeable, admitting a broader range of substances, including those that are less lipophilic.

Linoleic acid and arachidonic acid, which are said to “make the lipid membrane more permeable,” in fact make the whole cell more permeable, by binding to the structural proteins throughout the cell, increasing their affinity for water, causing generalized swelling, as well as mitochondrial swelling (leading to reduced oxidative function or disintegration), allowing more calcium to enter the cell, activating excitatory processes, stimulating a redox shift away from oxidation and toward inflammation, leading to either (inappropriate) growth or death of the cell.

When we don’t eat for many hours, our glycogen stores decrease, and adrenaline secretion is increased, liberating more glucose as long as glycogen is available, but also liberating fatty acids from the fatty tissues. When the diet has chronically contained more polyunsaturated fats than can be oxidized immediately or detoxified by the liver, the fat stores will contain a disproportionate amount of them, since fat cells preferentially oxidize saturated fats for their own energy, and the greater water solubility of the PUFA causes them to be preferentially released into the bloodstream during stress.

Saturated fatty acids terminate the stress reactions, polyunsaturated fatty acids amplify them.

In good health, especially in children, the stress hormones are produced only in the amount needed, because of negative feedback from the free saturated fatty acids, which inhibit the production of adrenalin and adrenal steroids, and eating protein and carbohydrate will quickly end the stress. But when the fat stores contain mainly PUFA, the free fatty acids in the serum will be mostly linoleic acid and arachidonic acid, and smaller amounts of other unsaturated fatty acids. These PUFA stimulate the stress hormones, ACTH, cortisol, adrenaline, glucagon, and prolactin, which increase lipolysis, producing more fatty acids in a vicious circle. In the relative absence of PUFA, the stress reaction is self limiting, but under the influence of PUFA, the stress response becomes self-amplifying.

When stress is very intense, as in trauma or sepsis, the reaction of liberating fatty acids can become dangerously counter-productive, producing the state of shock. In shock, the liberation of free fatty acids interferes with the use of glucose for energy and causes cells to take up water and calcium (depleting blood volume and reducing circulation) and to leak ATP, enzymes, and other cell contents (Boudreault and Grygorczyk, 2008; Wolfe, et al., 1983; Selzner, et al, 2004; van der Wijk, 2003), in something like a systemic inflammatory state (Fabiano, et al., 2008) often leading to death.

The remarkable resistance of “essential fatty acid deficient” animals to shock (Cook, et al., 1981; Li et al., 1990; Autore, et al., 1994) shows that the polyunsaturated fats are centrally involved in the maladaptive reactions of shock. The cellular changes that occur in shock–calcium retention, leakiness, reduced energy production–are seen in aging and the degenerative diseases; the stress hormones and free fatty acids tend to be chronically higher in old age, and an outstanding feature of old age is the reduced ability to tolerate stress and to recover from injuries…

Since healthy cells are very lipophilic, saturated fatty acids would have a greater tendency to enter them than the more water soluble polyunsaturated fats, especially those with 4, 5, or 6 double bonds, but as cells become chronically stressed they more easily admit the unsaturated fats, which slow oxidative metabolism and create free radical damage. The free radicals are an effect of stress and aging, as well as a factor in its progression.”

Am J Clin Nutr. 1980 Jan;33(1):81-5.
A mathematical relationship between the fatty acid composition of the diet and that of the adipose tissue in man.
Beynen AC, Hermus RJ, Hautvast JG.

Based on literature data, the hypothesis is advanced that in human subjects a direct mathematical relationship exists between the average fatty acid composition of the habitual diet and that of the lipid stores of subcutaneous adipose tissue. Since the half-life of adipose tissue fatty acids in man is in the order of 600 days, the fatty acid pattern of depot fat provides a qualitative measure of the fat intake over a period of 2 to 3 years. It is concluded that in long-term experimental and epidemiological nutritional surveys the adipose tissue fatty acid pattern of the subjects is a useful index of the average composition of their habitual dietary fat.

Adv Nutr November 2015 Adv Nutr vol. 6: 660-664, 2015
Increase in Adipose Tissue Linoleic Acid of US Adults in the Last Half Century
Stephan J Guyenet and Susan E Carlson
Linoleic acid (LA) is a bioactive fatty acid with diverse effects on human physiology and pathophysiology. LA is a major dietary fatty acid, and also one of the most abundant fatty acids in adipose tissue, where its concentration reflects dietary intake. Over the last half century in the United States, dietary LA intake has greatly increased as dietary fat sources have shifted toward polyunsaturated seed oils such as soybean oil. We have conducted a systematic literature review of studies reporting the concentration of LA in subcutaneous adipose tissue of US cohorts. Our results indicate that adipose tissue LA has increased by 136% over the last half century and that this increase is highly correlated with an increase in dietary LA intake over the same period of time.

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Ray Peat, PhD on Aspirin

Also see:
Aspirin and Exercise
Benefits of Aspirin
PUFA Promote Cancer
Arachidonic Acid’s Role in Stress and Shock
Sunburn, PUFA, Prostaglandins, and Aspirin
Phospholipases, PUFA, and Inflammation
Dietary PUFA Reflected in Human Subcutaneous Fat Tissue
Toxicity of Stored PUFA
PUFA – Accumulation and Aging
Ray Peat, PhD Quotes on Therapeutic Effects of Niacinamide
Altitude Sickness: Therapeutic Effects of Acetazolamide and Carbon Dioxide
Carbonic Anhydrase Inhibitors as Cancer Therapy
Lab study: Daily aspirin could block growth of breast, other cancers

Screenshot 2016-01-22 at 6.22.56 AM

“When a drug such as caffeine or aspirin turns out to have a great variety of protective effects, it’s important to understand what it’s doing.

Because aspirin has been abused by pharmaceutical companies that have competing products to sell, as well as by the original efforts to promote aspirin itself, people can easily find reasons why they shouldn’t take it.

Early in the 20th century, people were told that fevers were very bad, and that aspirin should be used whenever there is a fever.

In the 1980s, there was a big publicity campaign warning parents that giving aspirin to a child with the flu could cause the potentially deadly Reye syndrome. Aspirin sales declined sharply, as sales of acetaminophen (Tylenol, etc.) increased tremendously. But in Australia, a study of Reye syndrome cases found that six times as many of them had been using acetaminophen as had used aspirin. (Orlowski, et al., 1987)

Until the 1950s and 1960s, when new products were being promoted, little was said about the possibility of stomach ulceration from aspirin. Lately, there has been more publicity about the damage it can do to the stomach and intestine, much of it in connection with the sale of the new “COX-2 inhibitors.” (These new drugs, rather than protecting the circulatory system as aspirin does, damage it.) Aspirin rapidly breaks down into acetic acid and salicylic acid (which is found in many fruits), and salicylic acid is protective to the stomach and intestine, and other organs. When aspirin was compared with the other common antiinflammatory drugs, it was found that the salicylic acid it releases protects against the damage done by another drug. (Takeuchi, et al, 2001; Ligumsky, et al., 1985.) Repeated use of aspirin protects the stomach against very strong irritants. The experiments in which aspirin produces stomach ulcers are designed to produce ulcers, not to realistically model the way aspirin is used.”

“Soon after vitamin E was discovered, tocopherol was defined as a brain-protective, pregnancy protective, male fertility protective, antithrombotic, antiestrogenic agent. But very soon, the estrogen industry made it impossible to present ideas that explained vitamin E, progesterone, vitamin A, or thyroid hormone in terms of the protection they provide against estrogenic substances. Since the polyunsaturated fats caused the same conditions that were caused by unopposed estrogen, vitamin E came to be known as an “antioxidant,” because it reduced their toxicity. (Vitamin E is now known to suppress COX-2, synergizing with aspirin and opposing estrogen.)”

“The competition between fatty acids and glucose, which has been called the “Randle cycle” for about 50 years, can be applied to the treatment of diabetes and other degenerative/stress problems by adjusting the diet, or by using supplements such as niacinamide and aspirin, which improve glucose oxidation by lowering the free fatty acids in the serum.”

“A few years later, aspirin was found to inactivate the enzyme that forms prostaglandins, by the transfer of the acetyl radical to the enzyme. This became the orthodox “explanation” for what aspirin does, though it neglected to explain that salicylic acid (lacking the acetyl radical) had been widely known in the previous century for its very useful antiinflammatory actions. The new theory did explain (at least to the satisfaction of editors of medical magazines) one of aspirin’s effects, but it distracted attention from all the other effects of aspirin and salicylic acid.

Aspirin is an antioxidant that protects against lipid peroxidation, but it also stimulates mitochondrial respiration. It can inhibit abnormal cell division, but promote normal cell division. It can facilitate learning, while preventing excitotoxic nerve injury. It reduces clotting, but it can decrease excessive menstrual bleeding. These, and many other strangely beneficial effects of aspirin, strongly suggest that it is acting on very basic biological processes, in a coherent way.

In explaining aspirin’s effects, as in explaining those of estrogen and progesterone, or polyunsaturated fats and vitamin E, I think we need concepts of a very broad sort, such as “stability and instability.””

“Aspirin activates both glycolysis and mitochondrial respiration, and this means that it shifts the mitochondria away from the oxidation of fats, toward the oxidation of glucose, resulting in the increased production of carbon dioxide. Its action on the glycolytic enzyme, GAPDH, is the opposite of estrogen’s.

The shift away from fat oxidation under the influence of aspirin doesn’t lead to an accumulation of free fatty acids in the circulation, since aspirin inhibits the release of fatty acids from both phospholipids and triglycerides. Estrogen has the opposite effects, increasing fat oxidation while increasing the level of circulating free fatty acids, since it activates lipolysis, as do several other stress-related hormones.

The polyunsaturated fatty acids, such as linolenic, linoleic, arachidonic, EPA, and DHA, have many directly toxic, antirespiratory actions, apart from the production of the prostaglandins or eicosanoids. Just by preventing the release of these fatty acids, aspirin would have broadly antiinflammatory effects.

Since the polyunsaturated fats and prostaglandins stimulate the expression of aromatase, the enzyme that synthesizes estrogen, aspirin decreases the production of estrogen. So many of aspirin’s effects oppose those of estrogen, it would be tempting to suggest that its “basic action” is the suppression of estrogen. But I think it’s more likely that both estrogen and aspirin are acting on some basic processes, in approximately opposite ways.

Bioelectrical functions, and the opposition between carbon dioxide and lactic acid, and the way water is handled in cells, are basic conditions that have a general or global effect on all of the other more specific biochemical and physiological processes. Originally, estrogen and progesterone were each thought to affect only one or a few biochemical events, but it has turned out that each has a multitude of different biochemical actions, which are integrated in globally meaningful ways. The salicylic acid molecule is much smaller and simpler than progesterone, but the range of its beneficial effects is similar. Because of aspirin’s medical antiquity, there has been no inclination to explain its actions in terms of an “aspirin receptor,” as for valium and the opiates, leaving its biochemistry, except for the inadequate idea of COX-inhibition, simply unexplained.”

“The competition between aspirin and salicylic acid, and other antiinflammatories, for the active site on the COX enzyme (Rao, et al., 1982), shows that the structural features of these molecules are in some ways analogous to those of the polyunsaturated fatty acids. Wherever there are phospholipids, free fatty acids, fatty acid esters, ethers, etc. (i.e., in mitochondria, chromosomes, cytoskeleton, collagen networks–essentially everywhere in and around the cell), the regulatory influence of specific fatty acids–or their surrogates–will be felt.

Although it would undoubtedly be best to grow up eating foods with relatively saturated fats, the use of aspirin preventively and therapeutically seems very reasonable under the present circumstances, in which, for example, clean and well ripened fruits are not generally available in abundance. Preventing blindness, degenerative brain diseases, heart and lung diseases, and cancer with aspirin should get as much support as the crazy public health recommendations are now getting from government and foundations and the medical businesses.

When people with cancer ask for my recommendations, they usually think I’m joking when I tell them to use aspirin, and very often they don’t take it, on the basis of what seems to be a very strong cultural prejudice. Several years ago, a woman whose doctors said it would be impossible to operate on her extremely painful “inflammatory breast cancer,” had overnight complete relief of the pain and swelling from taking a few aspirins. The recognized anti-metastatic effect of aspirin, and its ability to inhibit the development of new blood vessels that would support the tumor’s growth, make it an appropriate drug to use for pain control, even if it doesn’t shrink the tumor. In studies of many kinds of tumor, though, it does cause regression, or at least slows tumor growth. And it protects against many of the systemic consequences of cancer, including wasting (cachexia), immunosuppression, and strokes.

Opiates are the standard medical prescription for pain control in cancer, but they are usually prescribed in inadequate quantities, “to prevent addiction.” Biologically, they are the most inappropriate means of pain control, since they increase the release of histamine, which synergizes with the tumor-derived factors to suppress immunity and stimulate tumor growth.

It has recently become standard practice in most places to advise a person who is having a heart attack to immediately chew and swallow an aspirin tablet.

The same better-late-than-never philosophy can be applied to Alzheimer’s disease, Parkinson’s disease, and other degenerative nerve diseases. Aspirin protects against several kinds of toxicity, including excitotoxicity (glutamate), dopamine toxicity, and oxidative free radical toxicity. Since its effects on the mitochondria are similar to those of thyroid (T3), using both of them might improve brain energy production more than just thyroid. (By activating T3, aspirin can sometimes increase the temperature and pulse rate.) Magnesium, niacinamide, and other nerve protective substances work together.

In multiple organ failure, which can be caused by profound shock caused by trauma, infection, or other stress, aspirin is often helpful, but carbon dioxide and hypertonic glucose and sodium are more important.

Aspirin, like progesterone or vitamin E, can improve fertility, by suppressing a prostaglandin, and improving uterine circulation.

Although the animal studies that showed stomach damage from aspirin often used single doses equivalent to 10 or 100 aspirin tablets, the slight irritation produced by a normal dose of aspirin can be minimized by dissolving the aspirin in water. The stomach develops a tolerance for aspirin over a period of a few days, allowing the dose to be increased if necessary. And both aspirin and salicylic acid can be absorbed through the skin, so rheumatic problems have been treated by adding the drug to bath water.

The unsaturated (n-6 and n-3) fats that accumulate in our tissues, instead of being part of the system for reestablishing order and stability, tend to amplify the instability that is triggered by excitation, by estrogen, or by external stresses.

I think it’s important that we don’t allow the drug publicists to obscure the broad importance of substances such as aspirin, vitamin E, progesterone, and thyroid. For 60 years, a myth that was created to sell estrogen has harmed both science and the health of many people.”

“Aspirin protects against iron toxicity, clot formation, and reduces lipid peroxidation while blocking prostaglandin formation. Aspirin and other antiinflammatory drugs, taken for arthritis, have been clearly associated with a reduced incidence of Alzheimer’s disease. Aspirin reduces the formation of prostaglandins from arachidonic acid.”

“When I taught endocrinology, I annoyed my tidy-minded students by urging them to consider the potential hormone-like action of everything in the body, and to think of layers of control, ranging from sugar, salt, and carbon dioxide, through the “official hormones,” to complex nervous system actions such as expectancy, and biorhythms. Certain things that are active in very important processes deserve special attention as “signals,” but they still have to be understood in context. In this sense, we can think of Ca2+ as a signal substance, in its many contexts; it is strongly regulated by the cell’s energy charge. Magnesium and sodium antagonize it in certain situations. Linoleic acid, linolenic acid, arachidonic acid: Their toxicity is potentially prevented by the Mead acids, and their eicosanoid derivatives, which behave very differently from the familiar prostaglandins, as far as they have been compared; can be drastically reduced by dietary changes. Prostaglandins, prostacyclin, thromboxane: Formation is blocked by aspirin and other antiinflammatory drugs.”

“Aspirin’s antiinflammatory actions are generally important when the polyunsaturated fats are producing inflammatory and degenerative changes, and aspirin prevents many of the problems associated with diabetes, reducing vascular leakiness. It improves mitochondrial respiration (DeCristobal, et al., 2002) and helps to regulate blood sugar and lipids (Yuan, et al., 2001). Aspirin’s broad range of beneficial effects is probably analogous to vitamin E’s, being proportional to protection against the broad range of toxic effects of the polyunsaturated “essential” fatty acids.”

“Both preventively and therapeutically, the use of the antiinflammatory and antioxidative substances such as aspirin, caffeine, progesterone, and thyroid hormone would seem appropriate. Aspirin is coming to be widely accepted as an anticancer agent, and at moderate doses can cause cancer cells to die. It, like progesterone and thyroid, has a wide variety of anti-estrogenic effects. Especially when a tumor is painfully inflamed, aspirin’s effects can be quick and dramatic. However, people aren’t likely to be pleased if their cancer doctor tells them to “take aspirin and call me in six months.” Aspirin’s reputation for causing stomach bleeding causes people to avoid it, even when the alternative is something that’s seriously toxic to other organs, and it might just seem too ordinary to be considered as a powerful anticancer drug.”

“Aspirin protects against a variety of inflammatory processes, but it’s most famous for the inhibition of prostaglandins. While aspirin is often used to relieve pain in MS, and another inhibitor of prostaglandin synthesis, indomethacin, has been used therapeutically in MS, it would seem appropriate to investigate more carefully aspirin’s possible role in preventing or relieving MS.”

“Protein deficiency is an important cause of deranged calcium metabolism. Vitamins K, E, and A are important in regulating calcium metabolism, and preventing osteoporosis. Aspirin (with antiestrogenic and vitamin E-like actions) is protective against bone resorption and hypercalcemia.”

“If the physiology of shock has some relevance for eclampsia, so does the physiology of heart failure, since Meerson has shown that it is a consequence of uncompensated stress. The failing heart shifts from mainly glucose oxidation to the inefficient use of fatty acids, which are mobilized during stress, and with its decreased energy supply, it is unable to beat efficiently, since it remains in a partly contracted state. Estrogen (which is increased in men who have had heart attacks) is another factor which decreases the heart’s stroke volume, and estrogen is closely associated with the physiology of the free unsaturated fatty acids. The partly contracted state of the heart is effectively a continuation of the partly contracted state of the blood vessels that causes the hypertension, and reduced tissue perfusion seen in shock and eclampsia. Since shock can be seen as a generalized inflammatory state, and since aspirin has been helpful in protecting against heart disease, it’s reasonable that aspirin has been tried as a treatment in pre-eclampsia. It seems to protect the fetus against intrauterine growth retardation, an effect that I think relates to aspirin’s ability to protect in several ways against excesses of unsaturated fatty acids and of estrogen. But, since aspirin can interfere with blood clotting, its use around the time of childbirth can be risky, and it is best to correct the problem early enough that aspirin isn’t needed.”

“Some types of dementia, such as Alzheimer’s disease, involve a life-long process of degeneration of the brain, with an inflammatory component, that probably makes them comparable to osteoporosis and muscle-wasting. (In the brain, the microglia, which are similar to macrophages, and the astrocytes, can produce TNF.) The importance of the inflammatory process in Alzheimer’s disease was appreciated when it was noticed that people who used aspirin regularly had a low incidence of that dementia. Aspirin inhibits the formation of TNF, and aspirin has been found to retard bone loss. In the case of osteoporosis (A. Murrillo-Uribe, 1999), as in Alzheimer’s disease, the incidence is two or three times as high in women as in men. In both Alzheimer’s disease and osteoporosis, the estrogen industry is arguing that the problems are caused by a suddenly developing estrogen deficiency, rather than by prolonged exposure to estrogen.”

“Vitamin E, like progesterone and aspirin, acts within the cellular regulatory systems, to prevent
inflammation and inappropriate excitation. Since uncontrolled excitation causes destructive oxidations, these substances prevent those forms of oxidation.”

“Later, referring to the decades of hostility of the medical establishment to vitamin E, Dr. Shute said “…an obstetrician was unduly hardy and audacious to try it.” The spectrum of vitamin E’s protective effects (like those of aspirin) has been consistently misrepresented in the medical literature.”

“Abruptio placentae (premature detachment of the placenta) has often been blamed on the use of vitamin E, because of vitamin E’s reputation for preventing abnormal clotting, though the evidence tends to suggest instead that vitamin E (like aspirin) reduces the risk of pregnancy-related hemorrhaging.”

“But many very useful drugs that already existed, including cortisol and aspirin, were found to achieve some of their most important effects by inhibiting the formation of the prostaglandins. It was the body’s load of polyunsaturated fats which made it very susceptible to inflammation, stress, trauma, infection, radiation, hormone imbalance, and other fundamental problems, and drugs like aspirin and cortisone, which limit the activation of the stored “essential fatty acids,” gain their remarkable range of beneficial effects partly by the restraint they impose on those stored toxins.”

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

“Both the excitatory amino acids and a peptide that promotes inflammation, tumor necrosis factor (TNF), activate the enzyme which makes estrogen, aromatase. Estrogen, by activating NF kappaB, increases the formation of TNF, which in itself can promote the growth and metastasis of cancer. Various antiinflammatory agents, including aspirin, progesterone, testosterone, saturated fats, and glycine, can inhibit the production of NF kappaB.”

“The use of aspirin, which reduces inflammation and inhibits the formation of neurotoxic prostaglandins, is known to be associated with a lower incidence of Alzheimer’s disease, and in other contexts, it offers protection against estrogen. Naloxone, the antiendorphin, has been found to reverse some of the cumulative effects of stress, restoring some pituitary and ovarian function, and it promotes recovery after brain injury; in a variety of ways, it corrects some of estrogen’s toxic effects.”

“People who take aspirin, drink coffee, and use tobacco, have a much lower incidence of Alzheimer’s disease than people who don’t use those things. Caffeine inhibits brain phospholipase, making it neuroprotective in a wide spectrum of conditions. In recent tests, aspirin has been found to prevent the misfolding of the prion protein, and even to reverse the misfolded beta sheet conformation, restoring it to the harmless normal conformation. Nicotine might have a similar effect, preventing deposition of amyloid fibrils and disrupting those already formed (Ono, et al., 2002). Vitamin E, aspirin, progesterone, and nicotine also inhibit phospholipase, which contributes to their antiinflammatory action. Each of the amyloid-forming proteins probably has molecules that interfere with its toxic accumulation.”

“Aspirin protects cells in many ways, interrupting excitotoxic processes by blocking nitric oxide and prostaglandins, and consequently it inhibits cell proliferation, and in some cases inhibits glycolysis, but the fact that it can inhibit FAS (Beynen, et al., 1982) is very important in understanding its role in cancer.

There are several specific signals produced by lactate that can promote growth and other features of cancer, and it happens that aspirin antagonizes those: HIF, NF-kappaB, the kinase cascades, cyclin D1, and heme oxygenase.”

“The pituitary hormones, especially prolactin and TSH, are pro-inflammatory, and darkness increases TSH along with prolactin, so to compensate for a light deficiency, the pituitary should be well-suppressed by adequate thyroid. Armour thyroid or Thyrolar or Cynoplus, Cytomel, would probably be helpful. (Eye-drops containing T3 might be a way to restore metabolic activity more quickly.) Limiting water intake (or using salt generously) helps to inhibit prolactin secretion. The saturated fats protect against the body’s stored PUFA, and keeping the blood sugar up keeps the stored fats from being mobilized. Aspirin (or indomethacin) is generally protective to the retina, analogously to its protection against sunburn. Adequate vitamin E is extremely important. There are several prescription drugs that protect against serotonin excess, but thyroid and gelatin (or glycine, as in magnesium glycinate) are protective against the serotonin and melatonin toxicities.”

“In aspirin, it has been found that it is the acetyl group which (by a free radical action) blocks an enzyme involved in prostaglandin synthesis.”

“Carbon dioxide, high altitude, thyroid, progesterone, caffeine, aspirin, and decreased tryptophan consumption protect against excessive serotonin release. When sodium intake is restricted, there is a sharp increase in serotonin secretion. This accounts for some of the antiinflammatory and diuretic effects of increased sodium consumption–increasing sodium lowers both serotonin and adrenalin.”

“Aspirin, by inhibiting prostaglandin synthesis (and maybe other mechanisms) often lowers free radical production.”

“Antiinflammatory and anticoagulant things, especially aspirin and vitamin E, protect against the accelerated turnover of fibrinogen/fibrin caused by estrogen and the various inflammatory states.”

“I have known adults and children who were diagnosed as diabetic, and given insulin (and
indoctrinated with the idea that they had a terminal degenerative disease) on the strength of a single test showing excessive glucose. When I taught at the naturopathic medical school in Portland, I tried to make it clear that “diabetes” (a term referring to excessive urination) is a function, and that a high level of glucose in the blood or urine is also a function, and that the use of insulin should require a greater diagnostic justification than the use of aspirin for a headache does, because insulin use itself constitutes a serious health problem. (And we seldom hear the idea that “diabetes” might have a positive side [Robinson and Johnston], for example that it reduces the symptoms of asthma [Vianna and Garcialeme], which get worse when insulin is given. Normal pregnancy can be considered “diabetic” by some definitions based on blood sugar. I got interested in this when I talked to a healthy “diabetic” woman who had a two year old child whose IQ must have been over 200, judging by his spontaneous precocious hobbies. Old gynecologists told me that it was common knowledge that “diabetic” women had intellectually precocious children.)”

“Despite the nutritional value of those vitamins, fish oils are generally much more immunosuppressive than the seed oils, and the early effects of fish oil on the “immune system” include the suppression of prostaglandin synthesis, because the more highly unsaturated long chain fats interfere with the conversion of linoleic acid into arachidonic acid and prostaglandins. The prostaglandins are so problematic that their suppression is helpful, whether the inhibition is caused by aspirin or vitamin E, or by fish oil.”

“For a long time, gelatin’s therapeutic effect in arthritis was assumed to result from its use in repairing the cartilage or other connective tissues around joints, simply because those tissues contain so much collagen. (Marketers suggest that eating cartilage or gelatin will build cartilage or other collagenous tissue.) Some of the consumed gelatin does get incorporated into the joint cartilage, but that is a slow process, and the relief of pain and inflammation is likely to be almost immediate, resembling the antiinflammatory effect of cortisol or aspirin.”

“In aspirin, it has been found that it is the acetyl group which (by a free radical action) blocks an enzyme involved in prostaglandin synthesis.”

“(Chen, Y, et al., 1999: BRCA represses the actions of estrogen and its receptor, and, like progesterone, activates the p21 promoter, which inhibits cell proliferation. Aspirin and vitamin D also act through p21.)”

“Aspirin, which stimulates bone formation, has other thyroid-like actions, including activation of mitochondrial respiration and energy production, with an increase of cytochrome C oxidase (Cai, et al., 1996), and it lowers serotonin (Shen, et al., 2011). It also apparently protects against calcification of the soft tissues, (Vasudev, et al., 2000), \ though there has been surprisingly little investigation of that. “Aspirin can promote trabecular bone remodeling, improve three-dimensional structure of trabecular bone and increase bone density of cancellous in osteoporotic rats by stimulating bone formation. It may become a new drug for the treatment of osteoporosis,” Chen, et al., 2011.”

“Defensive aggression is probably a response intermediate between fearful giving up and confident achievement. When a rat is restrained, held down on its back, it quickly develops ulcers, but if it has a stick to bite, it is very resistant to the formation of the ulcers. The ability to do something with a defensive meaning prevents the excessive production of serotonin and its consequences, such as increased production of cortisol and other stress hormones, and disturbance of circulation and energy production. Endotoxin and prostaglandins activate these same systems, and progesterone and aspirin are among the protective factors that can oppose those effects.”

“In 1927, Bernstein and Elias found that rats eating a fat free diet had almost no spontaneous cancer, and many studies since then in animals and people have shown a close association between polyunsaturated fatty acids and cancer. The polyunsaturated fatty acids in themselves, and their breakdown products, are excitatory and destabilizing to normal cells, but by modifying the sensitivity and energy production of cells, they limit cells’ ability to respond to stimulation and destabilizing influences. Although they aren’t essential for wound healing (Porras-Reyes, et al., 1992), they and their metabolites, the prostaglandins, are very conspicuous in wounds and tumors, and their proportion generally increases with aging. The prostaglandins are involved in several vicious cycles, including that with HIF mentioned above. This makes the PUFA and prostaglandins important to consider in relation to optimizing wound healing, and decreasing cancerization. Aspirin’s protective and therapeutic effects in cancer are starting to be recognized, but there are several other things that can synergize with aspirin to reduce the circulation of free fatty acids and their conversion to prostaglandins. Niacinamide, progesterone, sugar, carbon dioxide, and red light protect against both free fatty acids and prostaglandins.”

“Increasing carbon dioxide lowers the intracellular pH, as well as inhibiting lactic acid formation, and restoring the oxidation of glucose increases CO2. Inhibiting carbonic anhydrase, to allow more CO2 to stay in the cell, contributes to intracellular acidification, and by systemically increasing carbon dioxide this inhibition has a broad range of protective anti-excitatory effects. The drug industry is now looking for chemicals that will specifically inhibit the carbonic anhydrase enzymes that are active in tumors. Existing carbonic anhydrase inhibitors, such as acetazolamide, will inhibit those enzymes, without harming other tissues. Aspirin has some effect as an inhibitor of carbonic anhydrase (Bayram, et al., 2008). Since histamine, serotonin (Vullo, et al., 2007), and estrogen (Barnett, et al., 2008; Garg, 1975) are carbonic anhydrase activators, their antagonists would help to acidify the hypoxic cells. Testosterone (Suzuki, et al., 1996) and progesterone are estrogen antagonists that inhibit carbonic anhydrase.”

“The foods that nourish the patient well enough to support healing while permitting energy reserves to be built up are also the foods that don’t interfere with the hormones, that don’t cause spurious excitation of the tissues. The polyunsaturated fats directly stimulate the stress hormones, activate the excitatory amino acid signals, and directly excite cells, while the saturated fats have opposite effects, and are anti-inflammatory, and also don’t interfere with mitochondrial function. When we eat more carbohydrate than can be oxidized, some of it will be turned into saturated fats and omega-9 fats, and these will support mitochondrial energy production. Carbohydrates in the diet also help to decrease the mobilization of fatty acids from storage; niacinamide and aspirin support that effect. Sugars are probably more favorable than starches for the immune system (Harris, et al., 1999), and failure of the immune system is a common feature of cancer. Polyunsaturated fats are generally known to suppress the immune system. Foods that provide generous amounts of sodium, calcium, magnesium, and potassium, help to minimize stress. Trace minerals and vitamins are important, but can be harmful if used excessively–iron excess is important to avoid.”

“While lactic acidosis causes bone loss, acidosis caused by increased carbonic acid doesn’t; low bicarbonate in the body fluids seems to remove carbonate from the bone (Bushinsky, et al., 1993), and also mineral phosphates (Bushinsky, et al., 2003). The parathyroid hormone, which removes calcium from bone, causes lactic acid to be formed by bone cells (Nijweide, et al., 1981; Lafeber, et al., 1986). Lactic acid produced by intense exercise causes calcium loss from bone (Ashizawa, et al., 1997), and sodium bicarbonate increases calcium retention by bone. Vitamin K2 (Yamaguchi, et al., 2003) blocks the removal of calcium from bone caused by parathyroid hormone and prostaglandin E2, by completely blocking their stimulation of lactic acid production by bone tissues. Aspirin, which, like vitamin K, supports cell respiration and inhibits lactic acid formation, also favors bone calcification. Vitamin K2 stimulates the formation of two important bone proteins, osteocalcin and osteonectin (Bunyaratavej, et al., 2009), and reduces the activity of estrogen by oxidizing estradiol (Otsuka, et al, 2005).”

“Aspirin, which is antilipolytic, decreasing the release of free fatty acids, as well as inhibiting their conversion to prostaglandins, lowers the production of stressed induced aldosterone, and helps to lower blood pressure, if it’s taken during the night. Aspirin increases insulin sensitivity.”

“Aspirin and vitamin E are protective against toxic radiation, and the consequent inflammatory processes.”

“Antioxidant, antiinflammatory, and antiestrogenic substances are protective against radiation damage. Aspirin, vitamin e, progesterone, saturated fats, and thyroid have these functions.”

“In recent years inflammation’s role in cancer and heart disease has been acknowledged to some extent, and simple antiinflammatory treatments such as aspirin have been more widely accepted in prevention and treatment of both heart disease and cancer. I think the next step is to recognize the importance of preventing all sorts of inflammation during the reproductive years, to protect the brains of the unborn, and the inheritance of future generations.”

“Aspirin and niacin help to prevent fatigue symptoms, and to prevent many of the harmful systemic oxidative after-effects. (Both are antilipolytic; aspirin uncouples mitochondria.)”

“Uncoupling of mitochondrial oxidative metabolism from ATP production helps to consume the sugar which otherwise would be diverted into lactic acid, and converts it into carbon dioxide instead…Aspirin and thyroid (T3) increase uncoupling. A drug that used to be used for weight reduction, DNP, also uncouples mitochondrial metabolism, and, surprisingly, it has some of the beneficial effects of thyroid and aspirin. It stimulates the consumption of lactic acid and the formation of carbon dioxide.”

“The “treatment” for intracellular fatigue consists of normalizing thyroid and steroid metabolism, and eating a diet including fruit juice, milk, some eggs, liver, and gelatin, assuring adequate calcium, potassium, sodium, and magnesium, and using supplements of niacinamide, aspirin, and carbon dioxide when necessary.”

“The excitatory metabolite glutamate, and nitric oxide, are both inhibited by aspirin (Moro, et al., 2000).”

“Aspirin and saturated fats can also be protective when applied topically.”

“Aspirin, increased levels of carbon dioxide (Ni Chonghaile, et aI., 2005), and progesterone (Deroo and Archer, 2002; Kelly, et al., 2001; Allport, et al., 2001; van der Burg and van der Saag, 1996; Caldenhoven, et aI., 1995) inhibit NF kappa-B, and NF kappa-B inhibits the synthesis of both testosterone (Hong, et aI., 2004) and progesterone (Allport, et aI., 2001).”

“Salicylic acid, which occurs naturally in many fruits, as well as in aspirin, is unlike the other antiinflammatory drugs so vaguely classified with it as “nonsteroidal,” in having a broad spectrum of antiinflammatory effects, inhibiting the prostaglandins and NF kappa-B, TNF, and IL-6, besides contributing to the inhibition of estrogen synthesis and actions.”

“Other things that protect against excessive polyamines are procaine and other local anesthetics (Yuspa, et al., 1980), magnesium, niacin, vitamin A, aspirin, and, in some circumstances, caffeine.”

“The amounts needed seem large if niacinamide is thought of as “vitamin B3,” but it should be considered as a factor that compensates for our unphysiological exposure to inappropriate fats. Aspirin and vitamin E are other natural substances that are therapeutic in “unnaturally” large amounts because of our continual exposure to the highly unsaturated plant-derived n-3 and n-6 fats.”

“Aspirin has a very broad spectrum of antiinflammatory actions, and is increasingly being recommended for preventing complications of diabetes. One of the consequences of inflammation is hyperglycemia, and aspirin helps to correct that (Yuan, et al., 2001), while protecting proteins against oxidative damage (Jafarnejad, et al, 2001).”

“The contractile ability of smooth muscle, that’s impaired by swelling and inflammation, can be restored by antiinflammatory agents, for example aspirin (or other inhibitor of prostaglandin synthesis) or antihistamines. This applies to the muscles of lymphatic vessels (Wu, et al., 2005, 2006; Gosling, 2000), that must function to reduce edema, as well as to the bowel muscles that cause peristalsis.”

“Another kind of adaptogen resembles the body’s intrinsic defensive substances, but isn’t produced in significant quantities in our bodies. This type includes caffeine and the anthraquinones (such as emodin) and aspirin and other protective substances from plants. These overlap in functions with some of our intrinsic regulatory substances, and can also complement each other’s effects.”

“This makes the PUFA and prostaglandins important to consider in relation to optimizing wound healing, and decreasing cancerization. Aspirin’s protective and therapeutic effects in cancer are starting to be recognized, but there are several other things that can synergize with aspirin to reduce the circulation of free fatty acids and their conversion to prostaglandins. Niacinamide, progesterone, sugar, carbon dioxide, and red light protect against both free fatty acids and prostaglandins.”

“The drug industry is now looking for chemicals that will specifically inhibit the carbonic anhydrase-enzymes that are active in tumors. Existing carbonic anhydrase inhibitors, such as acetazolamide, will inhibit those enzymes, without harming other tissues. Aspirin has some effect as an inhibitor of carbonic anhydrase (Bayram, et al., 2008).”

“When we eat more carbohydrate than can be oxidized, some of it will be turned into saturated fats and omega-9 fats, and these will support mitochondrial energy production. Carbohydrates in the diet also help to decrease the mobilization of fatty acids from storage; niacinamide and aspirin support that effect.”

“Many of the things that can be achieved by vaccination and treatment with safe antiinflammatories such as aspirin could be done better by long-term changes of diet, and by taking into account the interactions of the hormones, especially progesterone, estrogen, and thyroid, with nutrients and stressors. But much more than that is needed: The nature of the relationships between environmental factors and the body’s reactions has to be clarified, so that the processes of healing and regeneration can more closely resemble the prenatal condition, possibly even continuing in adulthood the “pedomorphic” process, realizing human potentials that haven’t previously been seen.”

“The continuing accumulation of polyunsaturated fats in the tissues is undoubtedly important in the changing relationship between the pancreas and the adrenal glands in aging. Aspirin, which is antilipolytic, decreasing the release of free fatty acids, as well as inhibiting their conversion to prostaglandins, lowers the production of stress induced aldosterone, and helps to lower blood pressure, if it’s taken in the evening, to prevent the increase of free fatty acids during the night. Aspirin increases insulin sensitivity. A low salt diet increases the free fatty acids, leading to insulin resistance, and contributing to atherosclerosis (Prada, et al., 2000; Mroka, et aI., 2000; Catanozi, et al., 2003; Garg, et al., 2011).”

“Recognizing causal connections between premature birth and respiratory distress and retinopathy of prematurity, it would be obvious that the greatest effort should be made to prevent the problems by improving the health of pregnant women. Hospitals, however, are invested in high technology systems for treating these problems, and even though their results are dismal, they can’t make money by getting pregnant women to eat enough protein to prevent preeclampsia, which is a major cause of premature birth, or by treating the problems with salt, magnesium, progesterone, thyroid, and aspirin when the women haven’t had a good diet.”

“The saturated fats protect against the body’s stored PUFA, and keeping the blood sugar up keeps the stored fats from being mobilized. Aspirin (or indomethacin) is generally protective to the retina, analogously to its protection against sunburn.”

“Since polyunsaturated fatty acids become integrated into all types of cell, and cause so many types of damage when they are released, everything which inhibits their release is protective. Niacinamide, Benadryl, aspirin (Yu, et aI., 2003), and procaine help to reduce the release of free fatty acids.”

“Aspirin’s similarity to benzoate and phenylacetate suggests that it might sometimes help to remove ammonia. The safest procedure is to use foods, such as fruit juices, that regulate nitrogen metabolism in varied ways.”

“Aspirin protects against some of the worst stressors, including the polyunsaturated fats, so despite its mild toxicity, long term studies usually show that it decreases sickness and mortality.”

“Aspirin, by inhibiting the production of estrogen, of carbon monoxide, and of several cytokines and toxic lipid products, and by supporting normal respiration, helping to correct hyperglycemia, and suppressing lactate production, is an especially valuable therapy. Sacca et aI., have recently (October, 2004) demonstrated that aspirin’s anticancer effect appears to involve the inhibition of heme oxygenase.”

“Caffeine, by inhibiting FAS and sparing glucose, and inhibiting many of the toxic lipid inflammatory mediators, additive effects when products and other should have at least combined with aspirin.

Vitamin D, by its antiestrogenic and antiinflammatory actions, and by suppressing FAS, parallels the effects of aspirin and caffeine in several ways.”

“The prostaglandins were discovered in prostatic fluid, where they occur in significant concentrations. They are so deeply involved with the development of cancers of all sorts that aspirin and other prostaglandin inhibitors should be considered as a basic part of cancer therapy.”

“The PUFA (especially the omega -3 fatty acids) spontaneously decompose into a variety of toxins, and arachidonate is also enzymically converted into prostaglandins, some of which exacerbate the excitatory damage (Pepicelli, et aI., 2005); aspirin’s neuroprotective effect (Riepe, et aI., 1997) is probably partly caused by inhibiting prostaglandin synthesis. Besides the prostaglandins, other mediators of inflammation including nitric oxide and interleukins are produced by excessive excitation, as cells lose their ability to retain magnesium, and to control excitatory intracellular calcium.”

“Inhibitors of estrogen synthesis are being considered for use in controlling epilepsy (Reddy, 2007), but aspirin and progesterone and thyroid can produce similar results.”

“It’s the stored PUFA, released by stress or hunger, that slow metabolism. Niacinamide helps to lower free fatty acids, and good nutrition will allow the liver to slowly detoxify the PUFA, if it isn’t being flooded with large amounts of them. A small amount of coconut oil with each meal will increase the ability to oxidize fat, by momentarily stopping the antithyroid effect of the PUFA. Aspirin is another thing that reduces the stress-related increase of free fatty acids, stimulating metabolism. Taking a thyroid supplement is reasonable until the ratio of saturated fats to PUFA is about 2 to 1.”

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Estrogen, Endotoxin, and Alcohol-Induced Liver Injury

Also See
Alcohol Consumption – Estrogen and Progesterone In Women
How does estrogen enhance endotoxin toxicity? Let me count the ways.
PUFA and Liver Toxicity; Protection by Saturated Fats
Endotoxin: Poisoning from the Inside Out
Estrogen and Liver Toxicity
Single Bout of Binge Drinking Linked to Immune System Effects

Estrogen makes the toxic-mediator-producing cells in the liver (Kupffer cells) hypersensitive to LPS–15 times more sensitive than normal (Ikejima, et al., 1998). One way estrogen increases the toxicity of endotoxin is probably by making the intestine more permeable (Enomoto, et al., 1999). -Ray Peat, PhD

AJP – GI April 1, 1998 vol. 274 no. 4 G669-G676
Estrogen increases sensitivity of hepatic Kupffer cells to endotoxin
Kenichi Ikejima1,2, Nobuyuki Enomoto1, Yuji Iimuro1, Ayako Ikejima2, Dawn Fang1, Juliana Xu1, Donald T. Forman3, David A. Brenner2, and Ronald G. Thurman1
The relationship among gender, lipopolysaccharide (LPS), and liver disease is complex. Accordingly, the effect of estrogen on activation of Kupffer cells by endotoxin was studied. All rats given estrogen intraperitoneally 24 h before an injection of a sublethal dose of LPS (5 mg/kg) died within 24 h, whereas none of the control rats died. Mortality was prevented totally by pretreatment with gadolinium chloride, a Kupffer cell toxicant. Peak serum tumor necrosis factor-α (TNF-α) values as well as TNF-α mRNA in the liver after LPS were twice as high in the estrogen-treated group as in the untreated controls. Plasma nitrite levels and inducible nitric oxide synthase in the liver were also elevated significantly in estrogen-treated rats 6 h after LPS. Furthermore, Kupffer cells isolated from estrogen-treated rats produced about twice as much TNF-α and nitrite as controls did in response to LPS. In addition, Kupffer cells from estrogen-treated rats required 15-fold lower amounts of LPS to increase intracellular Ca2+ than controls did, and Kupffer cells from estrogen-treated animals expressed more CD14, the receptor for LPS/LPS binding protein, than controls. Moreover, estrogen treatment increased LPS binding protein mRNA dramatically in liver in 6–24 h. It is concluded that estrogen treatment in vivo sensitizes Kupffer cells to LPS, leading to increased toxic mediator production by the liver.

Am J Physiol. 1999 Sep;277(3 Pt 1):G671-7.
Estriol sensitizes rat Kupffer cells via gut-derived endotoxin.
Enomoto N, Yamashina S, Schemmer P, Rivera CA, Bradford BU, Enomoto A, Brenner DA, Thurman RG.
The relationship between gender and alcohol-induced liver disease is complex; however, endotoxin is most likely involved. Recently, it was reported that estriol activated Kupffer cells by upregulation of the endotoxin receptor CD14. Therefore, the purpose of this work was to study how estriol sensitizes Kupffer cells. Rats were given estriol (20 mg/kg ip), and Kupffer cells were isolated 24 h later. After addition of lipopolysaccharide (LPS), intracellular Ca2+ concentration was measured using a microspectrofluorometer with the fluorescent indicator fura 2, and tumor necrosis factor-alpha was measured by ELISA. CD14 was evaluated by Western analysis. One-half of the rats given estriol intraperitoneally 24 h before an injection of a sublethal dose of LPS (5 mg/kg) died within 24 h, whereas none of the control rats died. Mortality was prevented totally by sterilization of the gut with antibiotics. A similar pattern was obtained with liver histology and serum transaminases. Translocation of horseradish peroxidase was increased about threefold in gut segments by treatment with estriol. This increase was not altered by treatment with nonabsorbable antibiotics. On the other hand, endotoxin levels were increased to 60-70 pg/ml in plasma of rats treated with estriol. As expected, this increase was prevented (<20 pg/ml) by antibiotics. In isolated Kupffer cells, LPS-induced increases in intracellular Ca2+ concentration, tumor necrosis factor-alpha production, and CD14 were increased, as previously reported. All these phenomena were blocked by antibiotics. Therefore, it is concluded that estriol treatment in vivo sensitizes Kupffer cells to LPS via mechanisms dependent on increases in CD14. This is most likely due to elevated portal blood endotoxin caused by increased gut permeability.

Hepatology. 2000 Jan;31(1):117-23.
Estrogen is involved in early alcohol-induced liver injury in a rat enteral feeding model.
Yin M, Ikejima K, Wheeler MD, Bradford BU, Seabra V, Forman DT, Sato N, Thurman
The aim of this study was to investigate whether reduction in blood estrogen by removal of the ovaries would decrease the sensitivity of female rats to early alcohol-induced liver injury using an enteral ethanol feeding model, and if so, whether estrogen replacement would compensate. Livers from ovariectomized rats with or without estrogen replacement after 4 weeks of continuous ethanol exposure were compared with nonovariectomized rats in the presence or absence of ethanol. Ethanol increased serum alanine transaminase (ALT) levels from 30 +/- 6 to 64 +/- 7 U/L. This effect was blocked by ovariectomy (31 +/- 7) and totally reversed by estrogen replacement (110 +/- 23). Ethanol increased liver weight and fat accumulation, an effect that was minimized by ovariectomy and reversed partially by estrogen replacement. Infiltrating leukocytes were increased 6. 7-fold by ethanol, an effect that was blunted significantly by ovariectomy and reversed by estrogen replacement. Likewise, a similar pattern of changes was observed in the number of necrotic hepatocytes. Blood endotoxin and hepatic levels of CD14 messenger RNA (mRNA) and protein were increased by ethanol. This effect was blocked in ovariectomized rats and elevated by estrogen replacement. Moreover, Kupffer cells isolated from ethanol-treated rats with estrogen replacement produced more tumor necrosis factor alpha (TNF-alpha) than those from control and ovariectomized rats. It is concluded, therefore, that the sensitivity of rat liver to alcohol-induced injury is directly related to estrogen, which increases endotoxin in the blood and CD14 expression in the liver, leading to increased TNF-alpha production.

Am J Physiol Gastrointest Liver Physiol. 2000 Apr;278(4):G652-61.
Gender differences in early alcohol-induced liver injury: role of CD14, NF-kappaB, and TNF-alpha.
Kono H, Wheeler MD, Rusyn I, Lin M, Seabra V, Rivera CA, Bradford BU, Forman DT, Thurman RG.
The purpose of this study was to determine whether early alcohol-induced liver injury (ALI) in females is associated with changes in CD14 on Kupffer cells, activation of hepatic nuclear factor (NF)-kappaB, and expression of tumor necrosis factor (TNF)-alpha mRNA. Male and female rats were given high-fat control or ethanol-containing diets for 4 wk using the intragastric enteral protocol. Physiological parameters were similar in both genders. Ethanol was increased as tolerance developed with higher blood levels than previously observed, resulting in a fourfold increase in aspartate aminotransferase (males 389 +/- 47 IU/l vs. females 727 +/- 66 IU/l). Hepatic pathology developed more rapidly and was nearly twofold greater and endotoxin levels were significantly higher in females after ethanol. Also, expression of CD14 on Kupffer cells was 1.5-fold greater and binding of transcription factor NF-kappaB in hepatic nuclear extracts and TNF-alpha mRNA expression were threefold greater in females. These data are consistent with the hypothesis that elevated endotoxin after ethanol triggers more activation of Kupffer cells via enhanced CD14 expression in females. NF-kappaB is activated in this process, leading to increases in TNF-alpha mRNA expression in the liver and more severe liver injury in females. It is concluded that gender differences in ALI are dependent on endotoxin and a signaling cascade leading to TNF-alpha.

World J Gastroenterol. 2010 Mar 21;16(11):1377-84.
Alcoholic liver injury: influence of gender and hormones.
Eagon PK.
This article discusses several subjects pertinent to a consideration of the role of gender and hormones in alcoholic liver injury (ALI). Beginning with an overview of factors involved in the pathogenesis of ALI, we review changes in sex hormone metabolism resulting from alcohol ingestion, summarize research that points to estrogen as a cofactor in ALI, consider evidence that gut injury is linked to liver injury in the setting of alcohol, and briefly review the limited evidence regarding sex hormones and gut barrier function. In both women and female animals, most studies reveal a propensity toward greater alcohol-induced liver injury due to female gender, although exact hormonal influences are not yet understood. Thus, women and their physicians should be alert to the dangers of excess alcohol consumption and the increased potential for liver injury in females.

Am J Physiol Gastrointest Liver Physiol. 2001 Dec;281(6):G1348-56.
Increased severity of alcoholic liver injury in female rats: role of oxidative stress, endotoxin, and chemokines.
Nanji AA, Jokelainen K, Fotouhinia M, Rahemtulla A, Thomas P, Tipoe GL, Su GL, Dannenberg AJ.
Alcoholic liver injury is more severe and rapidly developing in women than men. To evaluate the reason(s) for these gender-related differences, we determined whether pathogenic mechanisms important in alcoholic liver injury in male rats were further upregulated in female rats. Male and age-matched female rats (7/group) were fed ethanol and a diet containing fish oil for 4 wk by intragastric infusion. Dextrose isocalorically replaced ethanol in control rats. We analyzed liver histopathology, lipid peroxidation, cytochrome P-450 (CYP)2E1 activity, nonheme iron, endotoxin, nuclear factor-kappa B (NF-kappa B) activation, and mRNA levels of cyclooxygenase-1 (COX-1) and COX-2, tumor necrosis factor-alpha (TNF-alpha), monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein-2 (MIP-2). Alcohol-induced liver injury was more severe in female vs. male rats. Female rats had higher endotoxin, lipid peroxidation, and nonheme iron levels and increased NF-kappa B activation and upregulation of the chemokines MCP-1 and MIP-2. CYP2E1 activity and TNF-alpha and COX-2 levels were similar in male and female rats. Remarkably, female rats fed fish oil and dextrose also showed necrosis and inflammation. Our findings in ethanol-fed rats suggest that increased endotoxemia and lipid peroxidation in females stimulate NF-kappa B activation and chemokine production, enhancing liver injury. TNF-alpha and COX-2 upregulation are probably important in causing liver injury but do not explain gender-related differences.

J Hepatol. 2001 Jul;35(1):46-52.
The antiestrogen toremifene protects against alcoholic liver injury in female rats.
Järveläinen HA, Lukkari TA, Heinaro S, Sippel H, Lindros KO.
BACKGROUND/AIMS:
Females are generally considered to be more susceptible to alcohol-induced liver injury than males. To elucidate whether gonadal hormones are involved, female rats were chronically treated with ethanol and with an antiestrogen.
METHODS:
Ethanol was administered in a low-carbohydrate liquid diet. Estrogen action was blocked by daily intubation of toremifene, a non-hepatotoxic second generation estrogen receptor antagonist.
RESULTS:
The female rats consuming intoxicating amounts of ethanol diet for 6 weeks developed massive microvesicular/macrovesicular steatosis, frequent inflammatory foci and spotty necrosis. Serum alanine aminotransferase increased 7-fold. Toremifene treatment did not affect steatosis, but significantly reduced inflammation and necrosis. Ethanol increased the expression of CD14 and tumor necrosis factor- (TNF) alpha mRNA and also the production of TNF-alpha by isolated Kupffer cells, but toremifene had no significant counteracting effect. However, toremifene significantly alleviated both ethanol induction of the pro-oxidant enzyme CYP2E1 and ethanol reduction of the oxidant-protective enzyme Se-glutathione peroxidase.
CONCLUSIONS:
The partial protection by toremifene against ethanol-induced liver lesions suggests a pathogenic contribution of estrogens, possibly associated with an oxygen radical mediated mechanism.

Am J Physiol. 1997 May;272(5 Pt 1):G1186-94.
Female rats exhibit greater susceptibility to early alcohol-induced liver injury than males.
Iimuro Y, Frankenberg MV, Arteel GE, Bradford BU, Wall CA, Thurman RG.
It is known that women develop hepatic injury more rapidly and with exposure to less ethanol than men; however, mechanisms remain unclear. The purpose of this study was to determine if an enteral alcohol delivery model could be used to study susceptibility of females to alcohol-induced liver injury. Male and female Wistar rats (age- or weight-matched) were given ethanol (11-12 g.kg-1.day-1) continuously for up to 4 wk via intragastric feeding, and control rats received a high-fat diet without ethanol. There were no significant differences in body weight among the groups studied. Furthermore, mean ethanol concentrations, their cyclic pattern in urine, and rates of ethanol elimination were also not different between the genders under these conditions. Ethanol treatment elevated serum aspartate aminotransferase levels in male rats to 126 +/- 10 IU/l after 4 wk. In females, however, values increased more rapidly and reached significantly higher values at 4 wk (168 +/- 18 IU/l). Steatosis, inflammation, and necrosis assessed histologically also developed more rapidly and were more severe in females than males. Steatosis due to ethanol exposure, which was localized in centrilobular areas in males, was panlobular in the female. Moreover, endotoxin in plasma, intercellular adhesion molecule 1 expression in hepatic sinusoidal-lining cells, and the number of infiltrating inflammatory cells in the liver were 2-2.5-fold greater in females than males. These changes possibly account for increased hepatic injury due to ethanol in the female.

Can J Gastroenterol. 2000 Nov;14 Suppl D:129D-135D.
Sex-related liver injury due to alcohol involves activation of Kupffer cells by endotoxin.
Thurman RG.
Females have a greater susceptibility to ethanol-induced liver injury than males. Females who drink ethanol regularly and have been overweight for 10 years or more are at greater risk for both hepatitis and cirrhosis than males, and females develop ethanol-induced liver injury more rapidly and with less ethanol than males. Female rats on an enteral ethanol protocol exhibit injury more quickly than males and have widespread fatty changes over a larger portion of the liver lobule. Moreover, levels of plasma endotoxin, intracellular adhesion molecule-1, free radical adducts, infiltrating neutrophils and nuclear factor kappa B are doubled in female rat livers compared with male rat livers after enteral ethanol treatment. Additionally, estrogen treatment in vivo increases the sensitivity of hepatic macrophages or Kupffer cells to endotoxin. Evidence has been presented that Kupffer cells are pivotal in the development of ethanol-induced liver injury. Destroying Kupffer cells with gadolinium chloride or decreasing bacterial endotoxin by sterilizing the gut with antibiotics inhibits early inflammation due to ethanol. Similar results have been obtained with anti-tumour necrosis factor-alpha antibody. These data pointed to the hypothesis that ethanol-induced liver injury involves elevations in circulating endotoxin concentrations leading to activation of Kupffer cells, which causes a hypoxia-reoxygenation injury. This theory has been tested using pimonidazole, a 2-nitroimidazole marker, to quantify hypoxia in downstream, pericentral regions of the hepatic lobule. After chronic enteral ethanol treatment, pimonidazole binding doubles. Enteral ethanol also increases free radicals detected with electron spin resonance. Radical adducts, with coupling constants such as alpha-hydroxyethyl radical, have been shown to arise from ethanol. Importantly, hypoxia and radical production detected in bile are also decreased by the destruction of Kupffer cells with gadolinium chloride. These data support the hypothesis that Kupffer cells contribute to the vital sex differences in liver injury caused by ethanol.

J Gastroenterol Hepatol. 1998 Sep;13 Suppl:S39-50.
The role of gut-derived bacterial toxins and free radicals in alcohol-induced liver injury.
Thurman RG, Bradford BU, Iimuro Y, Knecht KT, Arteel GE, Yin M, Connor HD, Wall C, Raleigh JA, Frankenberg MV, Adachi Y, Forman DT, Brenner D, Kadiiska M, Mason RP.
Previous research from this laboratory using a continuous enteral ethanol (EtOH) administration model demonstrated that Kupffer cells are pivotal in the development of EtOH-induced liver injury. When Kupffer cells were destroyed using gadolinium chloride (GdCl3) or the gut was sterilized with polymyxin B and neomycin, early inflammation due to EtOH was blocked. Anti-tumour necrosis factor (TNF)-alpha antibody markedly decreased EtOH-induced liver injury and increased TNF-mRNA. These findings led to the hypothesis that EtOH-induced liver injury involves increases in circulating endotoxin leading to activation of Kupffer cells. Pimonidazole, a nitro-imidazole marker, was used to detect hypoxia in downstream pericentral regions of the lobule. Following one large dose of EtOH or chronic enteral EtOH for 1 month, pimonidazole binding was increased significantly in pericentral regions of the liver lobule, which was diminished with GdCl3. Enteral EtOH increased free radical generation detected with electron spin resonance (ESR). These radical species had coupling constants matching alpha-hydroxyethyl radical and were shown conclusively to arise from EtOH based on a doubling of the ESR lines when 13C-EtOH was given. Alpha-hydroxyethyl radical production was also blocked by the destruction of Kupffer cells with GdCl3. It is known that females develop more severe EtOH-induced liver injury more rapidly and with less EtOH than males. Female rats on the enteral protocol exhibited more rapid injury and more widespread fatty changes over a larger portion of the liver lobule than males. Plasma endotoxin, ICAM-1, free radical adducts, infiltrating neutrophils and transcription factor NFkappaB were approximately two-fold greater in livers from females than males after 4 weeks of enteral EtOH treatment. Furthermore, oestrogen treatment increased the sensitivity of Kupffer cells to endotoxin. These data are consistent with the hypothesis that Kupffer cells participate in important gender differences in liver injury caused by ethanol.

Journal of Hepatology 35 (2001) 130±133
Alcoholic liver disease: a matter of hormones?
Han Moshage

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Childhood conditions influence adult progesterone levels

Also see:
Nutrition and Brain Growth in Chick Embryos
PUFA, Estrogen, Obesity and Early Onset of Puberty

Quotes by Ray Peat, PhD:
“It seems clear that the course of degenerative aging processes is set in young adulthood (or even earlier), and that it is never too early to be concerned with correcting processes that are going in the wrong direction. (See Walker, et al., 1988, and Smith, et al., 1992.)

In “The Biological Generality of Progesterone” (1979) I proposed that the life-long trajectory of energy production and longevity was strongly influenced by prenatal nutrition and progesterone. This idea was based on work by people such as Marion Diamond, who showed that prenatal progesterone enlarges the cortex of the brain, and that estrogen makes it smaller, and Leonell Strong, who showed that a treatment that lowered the estrogen function in a young mouse could produce cancer-free offspring for several generations. Strong’s work was very encouraging, because it showed that biological problems that had been “bred in” over many generations could be corrected by some simple metabolic treatments.”

“Many factors, including poor nutrition, climate, emotional or physical stress (even excessive running) and toxins, can cause a progesterone deficiency. Use of estrogens, birth control pills and even IUDs can also bring about a deficiency. Animal studies and clinical experience suggests that the prenatal hormonal environment (a mother’s excess of estrogen during pregnancy) can incline a person toward a deficiency of progesterone relative to estrogen.”

PLoS Med. 2007 May;4(5):e167.
Childhood conditions influence adult progesterone levels.
Núñez-de la Mora A, Chatterton RT, Choudhury OA, Napolitano DA, Bentley GR.
BACKGROUND:
Average profiles of salivary progesterone in women vary significantly at the inter- and intrapopulation level as a function of age and acute energetic conditions related to energy intake, energy expenditure, or a combination of both. In addition to acute stressors, baseline progesterone levels differ among populations. The causes of such chronic differences are not well understood, but it has been hypothesised that they may result from varying tempos of growth and maturation and, by implication, from diverse environmental conditions encountered during childhood and adolescence.
METHODS AND FINDINGS:
To test this hypothesis, we conducted a migrant study among first- and second-generation Bangladeshi women aged 19-39 who migrated to London, UK at different points in the life-course, women still resident in Bangladesh, and women of European descent living in neighbourhoods similar to those of the migrants in London (total n = 227). Data collected included saliva samples for radioimmunoassay of progesterone, anthropometrics, and information from questionnaires on diet, lifestyle, and health. Results from multiple linear regression, controlled for anthropometric and reproductive variables, show that women who spend their childhood in conditions of low energy expenditure, stable energy intake, good sanitation, low immune challenges, and good health care in the UK have up to 103% higher levels of salivary progesterone and an earlier maturation than women who develop in less optimal conditions in Sylhet, Bangladesh (F9,178 = 5.05, p < 0.001, standard error of the mean = 0.32; adjusted R(2) = 0.16). Our results point to the period prior to puberty as a sensitive phase when changes in environmental conditions positively impact developmental tempos such as menarcheal age (F2,81 = 3.21, p = 0.03) and patterns of ovarian function as measured using salivary progesterone (F2,81 = 3.14, p = 0.04).
CONCLUSIONS:
This research demonstrates that human females use an extended period of the life cycle prior to reproductive maturation to monitor their environment and to modulate reproductive steroid levels in accordance with projected conditions they might encounter as adults. Given the prolonged investment of human pregnancy and lactation, such plasticity (extending beyond any intrauterine programming) enables a more flexible and finely tuned adjustment to the potential constraints or opportunities of the later adult environment. This research is the first, to our knowledge, to demonstrate a postuterine developmental component to variation in reproductive steroid levels in women.

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Exercise Induced Menstrual Disorders

Also See:
Exercise Induced Stress
Exercise and Effect on Thyroid Hormone
Potential Adverse Cardiovascular Effects from Excessive Endurance Exercise
Ray Peat, PhD: Quotes Relating to Exercise
Ray Peat, PhD and Concentric Exercise

“Sometimes progesterone seems to be chronically deficienct (leading to slight-though possibly prolonged-menstruation, or amenorrhea), in women who exercise hard. Since progesterone can be converted into cortisone to handle stress, this would explain why well trained athletes (who need lots of cortisone) so often miss periods. It seems to be a simple over-consumption of progesterone, which is probably a reasonable biological adaptation, preventing pregnancy during times of stress.” -Ray Peat, PhD

Proc Biol Sci. 1998 October 7; 265(1408): 1847–1851.
Physical work causes suppression of ovarian function in women.
G Jasieńska and P T Ellison
The suppression of reproductive function is known to occur in women engaging in activities that require high energetic expenses, such as sport participation and subsistence work. It is still unclear, however, if reproductive suppression is a response to high levels of energy expenditure, or only to the resulting state of negative energy balance. To our knowledge, this study provides the first evidence that work-related energy expenditure alone, without associated negative energy balance, can lead to the suppression of reproductive function in women. We document suppression of ovarian function expressed as lowered salivary progesterone levels in women from an agricultural community who work hard, but remain in neutral energy balance. We propose two alternative evolutionary explanations (the ‘pre-emptive ovarian suppression’ hypothesis and the ‘constrained down-regulation’ hypothesis) for the observed results.

Croat Med J. 2001 Feb;42(1):79-82.
Influence of high intensity training on menstrual cycle disorders in athletes.
Dusek T.
AIM:
To estimate the influence of intensive training on menstrual cycles in female athletes.
METHOD:
The questionnaire was used to determine the time of menarche, and the prevalence of primary and secondary amenorrhea and dysmenorrhea in 72 active female athletes from Zagreb (10 volleyball players, 18 basketball players, 10 ballet dancers, and 34 runners) aged between 15 and 21. The control group comprised 96 girls of the same age not engaged in any sports activity.
RESULTS:
The prevalence of secondary amenorrhea was three times higher in athletes than in the control group (p=0.037). The prevalence of primary amenorrhea was substantially higher in athletes than in the control group (6/72 vs. 0/96, p=0.014), whereas the prevalence of dysmenorrhea was twofold lower in athletes than in the control group (p<0.001). The highest prevalence of secondary amenorrhea was recorded in runners (14/31), particularly long-distance runners (11/17), whereas there was only one case of secondary amenorrhea among basketball players. Menarche was significantly delayed in the athletes who started physical activities before the onset of menstruation (13.8+1.4 vs. 12.6+1.0 years, p<0.001).
CONCLUSION:
High-intensity training before menarche postpones its onset. Type of training may be related to a significantly higher prevalence of secondary amenorrhea in runners than in basketball players.

Br J Sports Med. 2005 Mar;39(3):141-7.
Participation in leanness sports but not training volume is associated with menstrual dysfunction: a national survey of 1276 elite athletes and controls.
Torstveit MK, Sundgot-Borgen J.
OBJECTIVE:
To examine the prevalence of menstrual dysfunction in the total population of Norwegian elite female athletes and national representative controls in the same age group.
METHODS:
A detailed questionnaire that included questions on training and/or physical activity patterns, menstrual, dietary, and weight history, oral contraceptive use, and eating disorder inventory subtests was administered to all elite female athletes representing the country at the junior or senior level (aged 13-39 years, n = 938) and national representative controls in the same age group (n = 900). After exclusion, a total of 669 athletes (88.3%) and 607 controls (70.2%) completed the questionnaire satisfactorily.
RESULTS:
Age at menarche was significantly (p<0.001) later in athletes (13.4 (1.4) years) than in controls (13.0 (1.3) years), and differed among sport groups. A higher percentage of athletes (7.3%) than controls (2.0%) reported a history of primary amenorrhoea (p<0.001). A similar percentage of athletes (16.5%) and controls (15.2%) reported present menstrual dysfunction, but a higher percentage of athletes competing in leanness sports reported present menstrual dysfunction (24.8%) than athletes competing in non-leanness sports (13.1%) (p<0.01) and controls (p<0.05).
CONCLUSIONS:
These novel data include virtually all eligible elite athletes, and thus substantially extend previous studies. Age at menarche occurred later and the prevalence of primary amenorrhoea was higher in elite athletes than in controls. A higher percentage of athletes competing in sports that emphasise thinness and/or a specific weight reported present menstrual dysfunction than athletes competing in sports focusing less on such factors and controls. On the basis of a comparison with a previous study, the prevalence of menstrual dysfunction was lower in 2003 than in 1993.

Hum Reprod. 2010 Feb;25(2):491-503. Epub 2009 Nov 26.
High prevalence of subtle and severe menstrual disturbances in exercising women: confirmation using daily hormone measures.
De Souza MJ, Toombs RJ, Scheid JL, O’Donnell E, West SL, Williams NI.
BACKGROUND:
The identification of subtle menstrual cycle disturbances requires daily hormone assessments. In contrast, the identification of severe menstrual disturbances, such as amenorrhea and oligomenorrhea, can be established by clinical observation. The primary purpose of this study was to determine the frequency of subtle menstrual disturbances, defined as luteal phase defects (LPD) or anovulation, in exercising women, with menstrual cycles of 26-35 days, who engage in a variety of sports, both recreational and competitive. Secondly, the prevalence of oligomenorrhea and amenorrhea was also determined via measurement of daily urinary ovarian steroids rather than self report alone.
METHODS:
Menstrual status was documented by daily measurements of estrone and pregnanediol glucuronide and luteinizing hormone across two to three consecutive cycles and subsequently categorized as ovulatory (Ovul), LPD, anovulatory (Anov), oligomenorrheic (Oligo) and amenorrheic (Amen) in sedentary (Sed) and exercising (Ex) women.
RESULTS:
Sed (n = 20) and Ex women (n = 67) were of similar (P > 0.05) age (26.3 +/- 0.8 years), weight (59.3 +/- 1.8 kg), body mass index (22.0 +/- 0.6 kg/m2), age of menarche (12.8 +/- 0.3 years) and gynecological maturity (13.4 +/- 0.9 years). The Sed group exercised less (P < 0.001) (96.7 +/- 39.1 versus 457.1 +/- 30.5 min/week) and had a lower peak oxygen uptake (34.4 +/- 1.4 versus 44.3 +/- 0.6 ml/kg/min) than the Ex group. Among the menstrual cycles studied in the Sed group, the prevalence of subtle menstrual disturbances was only 4.2% (2/48); 95.8% (46/48) of the observed menstrual cycles were ovulatory. This finding stands in stark contrast to that observed in the Ex group where only 50% (60/120) of the observed menstrual cycles were ovulatory and as many as 50% (60/120) were abnormal. Of the abnormal cycles in the Ex group, 29.2% (35/120) were classified as LPD (short, inadequate or both) and 20.8% (25/120) were classified as Anov. Among the cycles of Ex women with severe menstrual disturbances, 3.5% (3/86) of the cycles were Oligo and 33.7% (29/86) were Amen. No cycles of Sed women (0/20) displayed either Oligo or Amen.
CONCLUSIONS:
This study suggests that approximately half of exercising women experience subtle menstrual disturbances, i.e. LPD and anovulation, and that one third of exercising women may be amenorrheic. Estimates of the prevalence of subtle menstrual disturbances in exercising women determined by the presence or absence of short or long cycles does not identify these disturbances. In light of known clinical consequences of menstrual disturbances, these findings underscore the lack of reliability of normal menstrual intervals and self report to infer menstrual status.

N Engl J Med. 1985 May 23;312(21):1349-53.
Induction of menstrual disorders by strenuous exercise in untrained women.
Bullen BA, Skrinar GS, Beitins IZ, von Mering G, Turnbull BA, McArthur JW.
We performed a prospective study of 28 initially untrained college women with documented ovulation and luteal adequacy to determine whether strenuous exercise spanning two menstrual cycles would induce menstrual disorders. To ascertain the influence, if any, that weight loss might exert, we randomly assigned the subjects to weight-loss and weight-maintenance groups. Subjects were expected to run 4 miles (6.4 km) per day, progressing to 10 miles (16.1 km) per day by the fifth week, and to engage daily in 3 1/2 hours of moderate-intensity sports. The normalcy of the menstrual cycles during the period of exercise was judged independently according to clinical and hormonal criteria, the latter comprising serial measurements of gonadotropin and sex-steroid excretion. A higher percentage of abnormalities proved to be detectable by hormonal means (P less than 0.02). Only four subjects (three in the weight-maintenance group) had a normal menstrual cycle during training. In the weight-loss group, the number of women who had luteal abnormalities as compared with those who lost the surge in luteinizing hormone altered significantly over time, the latter occurring more frequently (P less than 0.01) as training progressed. Within six months of termination of the study, all subjects were again experiencing normal menstrual cycles. We conclude that vigorous exercise, particularly if compounded by weight loss, can reversibly disturb reproductive function in women.

J Clin Endocrinol Metab. 1991 Jun;72(6):1350-8.
Exercise induces two types of human luteal dysfunction: confirmation by urinary free progesterone.
Beitins IZ, McArthur JW, Turnbull BA, Skrinar GS, Bullen BA.
We have previously reported that during 2 months of strenuous exercise, untrained young women with documented ovulatory menstrual cycles developed secondary oligoamenorrhea and luteal phase defects. In this study we tested the hypothesis that such abnormalities arise by altered neuroendocrine regulation of menstrual hormone secretion and that weight loss potentiates such effects. We supply a detailed analysis of the 20 cycles, of the total of 53, in which luteal phase abnormalities occurred. During the control month and 2 exercise months, all subjects collected daily overnight urine samples for the determination of LH, FSH, estriol (E3), and free progesterone (P) excretion by RIAs and creatinine by chemical assay. The characteristics of the abnormal luteal phase cycles were determined by comparing the excreted hormone levels and patterns during the control cycles with those of exercise cycles. The area under the curve (AUC) for each hormone was calculated for the follicular and luteal phases of each cycle. Six of the exercise cycles exhibited an inadequate luteal phase. This was characterized by a mean integrated P area of 202.4 (SEM, -61.8) nmol/day.nmol creatinine, compared with 331.7 (SEM, 64.7) during the corresponding control cycles, over a period of 9 or more days after the urinary LH peak to the onset of menses. Fourteen of the exercise cycles exhibited a short luteal phase. This was characterized by a mean integrated P area of 75.9 (30.9) nmol/day.nmol creatinine, compared to 267 (61.7) during the corresponding control cycles, over a span of 8 days or less from the urinary LH peak to the onset of menses. Additional abnormalities occurred only in the short luteal phase cycles. These included an increase in the length and AUC for E3 of the follicular phase and a decrease in the AUC of LH during the luteal phase. We conclude that the initiation of strenuous endurance training in previously ovulating untrained women frequently leads to corpus luteum dysfunction associated with insufficient P secretion and, in the case of short luteal phase cycles, decreased luteal phase length. That exercise may alter the neuroendocrine system is suggested by a delay in the ovulatory LH peak in spite of increased E3 excretion; moreover, less LH is excreted during the luteal phase. The lack of positive feedback to estrogens and decreased LH secretion during the luteal phase could compromise corpus luteum function. In contrast, decreased free P excretion was the sole abnormality noted in menstrual cycles with an inadequate luteal phase.

Annu Rev Med. 1988;39:443-51.
Exercise-induced menstrual dysfunction.
Henley K, Vaitukaitis JL.
Menstrual cycle changes associated with vigorous exercise can range widely. They may be only subtle abnormalities, ranging from delayed onset of spontaneous menses or anovulatory cycles to loss of spontaneous menses. They may be more serious, however. Significant adverse bone mineral changes, resulting in clinically significant osteoporosis and fractures, may occur concomitantly with exercise-induced menstrual dysfunction.

Sports Med. 1990 Oct;10(4):218-35.
Physical exercise and menstrual cycle alterations. What are the mechanisms?
Keizer HA, Rogol AD.
The prevalence of menstrual cycle alterations in athletes is considerably higher than in sedentary controls. There appears to be a multicausal aetiology, which makes it extremely difficult to dissociate the effects of physical exercise on the menstrual cycle from the other predisposing factors. From cross-sectional studies it appeared that physical training eventually might lead to shortening of the luteal phase and secondary amenorrhoea. Prospective studies in both trained and previously untrained women have shown that the amount and/or the intensity of exercise has to exceed a certain limit in order to elicit this phenomenon. We hypothesise, therefore, that apart from a certain predisposition, athletes with a training-induced altered menstrual cycle are overreached (short term overtraining, which is reversible in days to weeks after training reduction). Menstrual cycle alterations are most likely caused by subtle changes in the episodic secretion pattern of luteinising hormone (LH) as have been found in sedentary women with hypothalamic amenorrhoea as well as in athletes after very demanding training. The altered LH secretion then, might be caused by an increased corticotrophin-releasing hormone (CRH) secretion which inhibits the gonadotrophin-releasing hormone (GnRH) release. In addition, increased CRH tone will lead to increased beta-endorphin levels which will also inhibit the GnRH signaller. Finally, the continuous activation of the adrenals will result in a higher catecholamine production, which may be converted to catecholestrogens. These compounds are known to be potent inhibitors of GnRH secretion. In conclusion, menstrual cycle alterations are likely to occur after very demanding training, which causes an increase secretion of antireproductive hormones. These hormones can inhibit the normal pulsatile secretion pattern of the gonadotrophins.

Med Sci Sports Exerc. 2003 Sep;35(9):1553-63.
Menstrual disturbances in athletes: a focus on luteal phase defects.
De Souza MJ.
Subtle menstrual disturbances that affect the largest proportion of physically active women and athletes include luteal phase defects (LPD). Disorders of the luteal phase, characterized by poor endometrial maturation as a result of inadequate progesterone (P4) production and short luteal phases, are associated with infertility and habitual spontaneous abortions. In recreational athletes, the 3-month sample prevalence and incidence rate of LPD and anovulatory menstrual cycles is 48% and 79%, respectively. A high proportion of active women present with LPD cycles in an intermittent and inconsistent manner. These LPD cycles are characterized by reduced follicle-stimulating hormone (FSH) during the luteal-follicular transition, a somewhat blunted luteinizing hormone surge, decreased early follicular phase estradiol excretion, and decreased luteal phase P4 excretion both with and without a shortened luteal phase. LPD cycles in active women are associated with a metabolic hormone profile indicative of a hypometabolic state that is similar to that observed in amenorrheic athletes but not as comprehensive or severe. These metabolic alterations include decreased serum total triiodothyronine (T3), leptin, and insulin levels. Bone mineral density in these women is apparently not reduced, provided an adequate estradiol environment is maintained despite decreased P4. The high prevalence of LPD warrants further investigation to assess health risks and preventive strategies.

J Clin Endocrinol Metab. 2003 Jan;88(1):337-46.
Luteal phase deficiency in recreational runners: evidence for a hypometabolic state.
De Souza MJ, Van Heest J, Demers LM, Lasley BL.
Exercising women with amenorrhea exhibit a hypometabolic state. The purpose of this study was to evaluate the relationship of luteal phase deficient (LPD) menstrual cycles to metabolic hormones, including thyroid, insulin, human GH (hGH), leptin, and IGF-I and its binding protein levels in recreational runners. Menstrual cycle status was determined for three consecutive cycles in sedentary and moderately active women. Menstrual status was defined as ovulatory or LPD. Subjects were either sedentary (n = 10) or moderately active (n = 20) and were matched for age (27.7 +/- 1.2 yr), body mass (60.2 +/- 3.3 kg), menstrual cycle length (28.4 +/- 0.9 d), and reproductive age (14.4 +/- 1.2 yr). Daily urine samples for the determination of estrone conjugates, pregnanediol 3-glucuronide, and urinary levels of LH were collected. Blood was collected on a single day during the follicular phase (d 2-6) of each menstrual cycle for analysis of TSH, insulin, total T3, total T4, free T4, leptin, hGH, IGF-I, and IGF binding protein (IGFBP)-1 and IGFBP-3. Among the 10 sedentary subjects, 28 of 31 menstrual cycles were categorized as ovulatory (SedOvul). Among the 20 exercising subjects, 24 menstrual cycles were included in the ovulatory category (ExOvul), and 21 menstrual cycles were included in the LPD category (ExLPD). TSH, total T4, and free T4 levels were not significantly different among the three categories of cycles. Total T3 was suppressed (P = 0.035) in the ExLPD (1.63 +/- 0.07 nmol/liter) and the ExOvul categories of cycles (1.75 +/- 0.8 nmol/liter) compared with the SedOvul category of cycles (2.15 +/- 0.1 nmol/liter). Leptin levels were lower (P < 0.001) in both the ExOvul (5.2 +/- 0.4 microg/liter) and the ExLPD categories of cycles (5.1 +/- 0.4 microg/liter) when compared with the SedOvul category of cycles (13.7 +/- 1.7 microg/liter). Insulin was lower (P = 0.009) only in the ExLPD category of cycles (31.9 +/- 2.8 pmol/liter) compared with the SedOvul (60.4 +/- 8.3 pmol/liter) and ExOvul (61.8 +/- 10.4 pmol/liter) categories of cycles. IGF-I, IGFBP-1, IGFBP-3, IGF-I/IGFBP-1, IGF-I/IGFBP-3, and hGH were comparable among the different categories of cycles. These data suggest that exercising women with LPD menstrual cycles exhibit hormonal alterations consistent with a hypometabolic state that is similar to that observed in amenorrheic athletes and other energy-deprived states, although not as comprehensive. These alterations may represent a metabolic adaptation to an intermittent short-term negative energy balance.

J Clin Endocrinol Metab. 1998 Dec;83(12):4220-32.
High frequency of luteal phase deficiency and anovulation in recreational women runners: blunted elevation in follicle-stimulating hormone observed during luteal-follicular transition.
De Souza MJ, Miller BE, Loucks AB, Luciano AA, Pescatello LS, Campbell CG, Lasley BL.
The purposes of this investigation were to evaluate the characteristics of three consecutive menstrual cycles and to determine the frequency of luteal phase deficiency (LPD) and anovulation in a sample of sedentary and moderately exercising, regularly menstruating women. For three consecutive menstrual cycles, subjects collected daily urine samples for analysis of FSH, estrone conjugates (E1C), pregnanediol-3-glucuronide (PdG), and creatinine (Cr). Sedentary (n=11) and exercising (n=24) groups were similar in age (27.0+/-1.3 yr), weight (60.3+/-3.1 kg), gynecological age (13.8+/-1.2 yr), and menstrual cycle length (28.3+/-0.8 days). Menstrual cycles were classified by endocrine data as ovulatory, LPD, or anovulatory. No sedentary women (0%) had inconsistent menstrual cycle classifications from cycle to cycle, but 46% of the exercising women were inconsistent. The sample prevalence of LPD in the exercising women was 48%, and the 3-month sample incidence was 79%. In the sedentary women, 90% of all menstrual cycles were ovulatory (SedOvul; n=28), whereas in the exercising women only 45% were ovulatory (ExOvul; n=30); 43% were LPD (ExLPD; n=28), and 12% were anovulatory (ExAnov; n=8). In ExLPD cycles, the follicular phase was significantly longer (17.9+/-0.7 days), and the luteal phase was significantly shorter (8.2+/-0.5 days) compared to ExOvul (14.8+/-0.9 and 12.9+/-0.3 days) and SedOvul (15.9+/-0.6 and 12.9+/-0.4 days) cycles. Luteal phase PdG excretion was lower (P < 0.001) in ExLPD (2.9+/-0.3 microg/mg Cr) and ExAnov (0.8+/-0.1 microg/mg Cr) cycles compared to SedOvul cycles (5.0+/-0.4 microg/mg Cr). ExOvul cycles also had less (P < 0.01) PdG excretion during the luteal phase (3.7+/-0.3 microg/mg Cr) than the SedOvul cycles. E1C excretion during follicular phase days 2-5 was lower (P=0.05) in ExOvul, ExLPD, and ExAnov cycles compared to SedOvul cycles and remained lower (P < 0.02) in the ExLPD and ExAnov cycles during days 6-12. The elevation in FSH during the luteal-follicular transition was lower (P < 0.007) in ExLPD (0.7+/-0.1 ng/mg Cr) cycles compared to SedOvul and ExOvul cycles (1.0+/-0.1 and 1.1+/-0.1 ng/mg Cr, respectively). Energy balance and energy availability were lower (P < 0.05) in ExAnov cycles than in other menstrual cycle categories. The blunted elevation in FSH during the luteal-follicular transition in exercising women with LPD may explain their lower follicular estradiol levels. These alterations in FSH may act in concert with disrupted LH pulsatility as a primary and proximate factor in the high frequency of luteal phase and ovulatory disturbances in regularly menstruating, exercising women.

J Clin Endocrinol Metab. 1997 Sep;82(9):2867-76.
Bone health is not affected by luteal phase abnormalities and decreased ovarian progesterone production in female runners.
De Souza MJ, Miller BE, Sequenzia LC, Luciano AA, Ulreich S, Stier S, Prestwood K, Lasley BL.
The primary purpose of this study was to determine whether decreased ovarian progesterone production, associated with short and inadequate luteal phases in exercising women, was associated with decreased bone mineral density (BMD) and altered bone metabolism. Thirty-three eumenorrheic menstruating women participated in this study for 3 months. Subjects were required to collect daily urine samples for three consecutive menstrual cycles and have blood and urine collected weekly. Daily urine samples were analyzed for free LH, estrone conjugates (E1C), and pregnanediol 3-glucuronide (PdG), adjusted for creatinine, whereas weekly blood and urine samples were analyzed for bone markers, estradiol, progesterone, FSH, and LH. Based on the analyses of these samples, subjects were divided into three groups: sedentary ovulatory (SedOvul; n = 9), exercising ovulatory (ExOvul; n = 14), and exercising luteal phase defects (ExLPD; n = 10). The three groups were matched for age (27.6 +/- 1.0 yr), weight (60.6 +/- 1.9 cm), and reproductive maturity (14.5 +/- 1.0 yr), PdG production during the luteal phase was lower (P = 0.004) in the ExLPD women compared to that in the SedOvul group (2.4 +/- 0.4 vs. 5.1 +/- 0.6 ng/mL creatinine, respectively). The ExOvul group also had less (P < 0.01) PdG production during the luteal phase (3.5 +/- 0.3 ng/mL creatinine) compared to the SedOvul group. The total production of PdG, as assessed by area under the curve analysis, was also lower (P < 0.001) in the ExOvul and ExLPD groups compared to that in the SedOvul group. E1C production, however, was not different (P > 0.05) among the groups, except for E1C during the early follicular phase, which was lower (P = 0.043) in the ExLPD group than that in the SedOvul group. BMD and biochemical markers of bone metabolism were unaffected by and not associated with the compromised progesterone environment, but BMD values at the proximal femur (r = 0.354; P = 0.061) and total body (r = 0.359; P = 0.056) were associated with decreased early follicular E1C production. We conclude the following. 1) Luteal phase disturbances occur independent of training volume, and volume of training does not have to be severe to result in menstrual disturbances. 2) As a result of exercise, disturbance in progesterone production is not associated with decreased bone mass. 3) Long follicular phases are associated with reduced estrogen production during the early follicular phase, which are both associated with decreased bone mass. 4) Provided the estradiol status is adequately maintained, BMD is unaffected by decreased progesterone production associated with short and inadequte luteal phases in exercising women.

Clin Endocrinol (Oxf). 1990 Sep;33(3):345-53.
Luteinizing hormone and follicle stimulating hormone secretion patterns in female athletes with and without menstrual disturbances.
Pirke KM, Schweiger U, Broocks A, Tuschl RJ, Laessle RG.
Thirty-one young female athletes and 13 age-matched sedentary controls were studied throughout one menstrual cycle or over a 6 week period. Blood was sampled on 5 days per week. Episodic gonadotrophin secretion was measured in the early follicular phase and in the late luteal phase by blood sampling over a 12-h period at 15-min intervals. Eight athletes had anovulatory cycles, nine had impaired progesterone (P4) secretion during the luteal phase and 14 had normal cycles as judged from oestradiol (E2) and P4 plasma levels. Athletes with normal cycles had shorter cycles, lower E2 maxima at midcycle, and lower E2 and P4 concentrations during the luteal phase than had sedentary controls. Episodic luteinizing hormone (LH) secretion in the early follicular phase was significantly impaired in the anovulatory athletes: the average LH values over 12 h and the number of secretion episodes were significantly reduced. No significant changes were seen in follicle stimulating hormone secretion.

Br J Obstet Gynaecol. 1982 Jul;89(7):507-10.
Body weight, exercise and menstrual status among ballet dancers in training.
Abraham SF, Beumont PJ, Fraser IS, Llewellyn-Jones D.
A prospective study of the menstrual pattern and weight changes was made in the first year of training of 29 new female entrants to a professional ballet school. Seventy-nine per cent of the student girls had menstrual disturbances at entry: primary amenorrhoea, four; secondary amenorrhoea, 11; irregular menses, eight. The incidence of secondary amenorrhoea increase substantially by the end of the year (20), but was not associated with any significant change in body weight. Only three students menstruated regularly during the year. Menstrual regularity improved during periods of injury and long vacation and it appears that deterioration of the menstrual pattern during dancing periods was related to strenuous physical exercise rather than to any change in body weight.

Gynecol Endocrinol. 2006 Jan;22(1):31-5.
Influence of high-intensity training and of dietetic and anthropometric factors on menstrual cycle disorders in ballet dancers.
Castelo-Branco C, Reina F, Montivero AD, Colodrón M, Vanrell JA.
Background. Intensity of exercise and low energy consumption, specific type and amount of training, early age at initiation, previous menstrual dysfunctions, low body mass index (BMI) or percentage body fat, pathological feeding habits and psychological stress have been suggested as potential factors accountable for menstrual irregularities in female athletes.
Aim. To evaluate the influence of intensive training and of dietetic and anthropometric factors on menstrual cycles in female ballet dancers.
Method. A case-control study, in which a structured interview and physical examination were carried out in two groups of teenagers aged between 12 and 18 years. The study included a total of 115 adolescent girls distributed in two groups: dancers (group B, n = 38) and girls of the same age not engaged in any sports activity (group C, n = 77).
Results. Early starting high-intensity training delayed the onset of menarche ( p < 0.001). Dancers had a higher prevalence of oligomenorrhea and amenorrhea than control girls ( p = 0.004). Additionally, the dancers had lower scores in anthropometric variables: breast circumference 80 cm vs. 86.6 cm for controls ( p = 0.0001), low weight in 18% of dancers vs. 2.6% of controls ( p = 0.0001), and low height in 18% of dancers vs. 9% of controls ( p = 0.016). In addition, in dancers, low BMI was observed in 21% compared with 13% of controls ( p = 0.0001). Finally, 32% of the dancers were on a weight-control diet while this percentage decreased to 12% for the girls in control group (odds ratio = 3.49, 95% confidence interval = 1.31-9.25).
Conclusions. In ballet dancers, high-intensity training was associated with late onset of menarche, menstrual disorders, lower weight and height development, and abnormal feeding behaviors.

Clin Obstet Gynecol. 1983 Sep;26(3):728-35.
Exercise, sports, and menstrual dysfunction.
Hale RW.
With the increasing involvement of women in exercise programs, the physician is faced with more and more questions regarding the effect of exercise upon the reproductive system. Currently, it appears that premenarchal training may have the effect of delaying the onset of menses in some girls. There is no evidence that it delays the other stage of puberty or that it causes any harmful development by this delay. In the postmenarchal woman, strenuous exercise can definitely alter her bleeding pattern. The usual result is oligomenorrhea progressing toward amenorrhea as the exercise increases. This is not a universal phenomenon, however, and other factors such as percentage of body fat, stress, diet, and energy drain also play a role. The menses will usually resume its preexercise pattern after a period of rest.

Med Clin North Am. 1985 Jan;69(1):83-95.
Causes, evaluation, and management of athletic oligo-/amenorrhea.
Shangold MM.
Oligomenorrhea and amenorrhea are more common among athletes than among the general population. Although these conditions in athletes are often related to exercise and thinness, they may be caused by serious pathology too. All athletes with menstrual dysfunction deserve thorough evaluation and most need treatment.

Aust Fam Physician. 1984 Sep;13(9):659-63.
Oligomenorrhoea and amenorrhoea associated with exercise. A literature review.
Williams M.
Increasing numbers of women are embarking on more strenuous and constant exercise; their menstrual patterns are changing as a result. This review of the literature indicates that oligomenorrhoea and amenorrhoea in the physically active (particularly distance runners, gymnasts, ballet dancers and swimmers) are related to each woman’s physiological and psychological makeup.

Am Fam Physician. 1984 May;29(5):233-7.
The female athlete.
Wilkerson LA.
Anatomic considerations are the female athlete’s wider pelvis, shorter extremities and lower center of gravity. There is little qualitative difference in the muscle tissue of men and women; differences in strength stem from the amount of muscle mass. Amenorrhea/oligomenorrhea is common in runners, ballet dancers, cyclists, gymnasts, body builders, figure skaters and, to a lesser extent, swimmers. Pregnancy limits activity, but current evidence indicates that exercise during pregnancy is not harmful to either the mother or the fetus.

Int J Neurosci. 2006 Dec;116(12):1549-63.
Effects of menstrual cycle on sports performance.
Kishali NF, Imamoglu O, Katkat D, Atan T, Akyol P.
The aim of this study was to examine the effects of menstrual cycle on female athletes’ performance. Forty-eight teak-wondo athletes, 76 judoka, 81 volleyball, and 36 basketball players (total 241) elite athletes participated in the study. A questionnaire constituted from 21 questions about menstrual cycle applied. A one-way analysis of variance and scheffe tests were performed to assess differences between sport branches about physical and physiological characteristics. Chi square was used to evaluate the regularity of menstrual cycle, performance, and drug taking. The mean age of teak-wondo athletes, judokas, volleyball and basketball players were 20.71 +/- 0.41, 16.91 +/- 0.27, 21.22 +/- 0.26, and 21.03 +/- 0.63 years, respectively. The menarche ages of the athletes were 13.92, 13.22, 13.75, 13.86 years, respectively. 27.8% participated in regional competitions, 46.1% participated in just the national competitions, and 26.1% participated in the international competitions. Whereas the menstrual disorder was seen in 14.5% of the athletes in normal time, during the intensive exercise this ratio was increased to 20.7%. It was determined that during the competition 11.6% of the athletes used drug, 36.9% had a painful menstruation, 17.4% did not have a painful menstruation, 45.6% sometimes had a painful menstruation, and 63.1% of the athletes said that their pain decreased during the competition. First 14 days after the menstruation began, 71% of the athletes said that they felt themselves well. 71% of the athletes felt worst just before the menstruation period, 62.2% of the athletes said that their performance was same during the menstruation, and 21.2% said that their performance got worse. Both in general and during the training the menstruation period of the athletes was found to be regular (p < .01). Most of the athletes said that they have a painful menstruation period, and during the competition their pain decreased. As a result of the questionnaire, during the training and competition the number of athletes that did not use drugs were higher than the athletes that used drug (p < .01). The number of athletes that felt good before and during the menstruation were significantly higher (p < .05, p < .01). Between the menstruation periods the athletes said that they felt better in the first 14 days than the second 14 days (p < .01). When the non-menses period and menses period were compared the athletes said that their performance did not change (p < .01). It has been concluded that the menarche age was high in the athletes. It has found that the physical performance was not affected by the menstrual period and the pain decreased during the training and competition.

Am Fam Physician. 1989 Feb;39(2):213-21.
Exercise-induced amenorrhea.
Olson BR.
Strenuous exercise may cause menstrual abnormalities, including amenorrhea. The hypoestrogenemia that accompanies amenorrhea has been associated with a low bone mineral content and an increased incidence of stress fractures. With the resumption of menses, which usually occurs soon after female athletes decrease the intensity of their training or increase their body weight, bone mineral content increases and the incidence of stress fractures decreases.

Med Sci Sports Exerc. 1990 Jun;22(3):275-80.
Effects of exercise training on the menstrual cycle: existence and mechanisms.
Loucks AB.
This review evaluates the status of the evidence that exercise training affects the menstrual cycle beginning with evidence for the existence of delayed menarche, amenorrhea, and luteal suppression in athletes. A later age of menarche and a higher prevalence of amenorrhea and luteal suppression have been observed in athletes, but there is no experimental evidence that athletic training delays menarche, and alternative sociological and statistical explanations for delayed menarche have been offered. Cross-sectional studies of amenorrheic athletes have revealed abnormal reproductive hormone patterns, suggesting that the GnRH pulse generator in the hypothalamus is failing to initiate normal hypothalamic-pituitary-ovarian function. Longitudinal data show that the abrupt initiation of a high volume of aerobic training can disrupt the menstrual cycle in at least some women, but these women may be more susceptible to reproductive disruption than others, and some aspect of athletic training other than exercise (such as caloric deficiency) may be responsible for the observed disruption. Luteal suppression may be an intermediate condition between menstrual regularity and amenorrhea in athletes, or it may be the endpoint of a successful acclimation to exercise training. A potential endocrine mechanism of menstrual disruption in athletes involving the hypothalamic-pituitary-adrenal axis is discussed. Finally, promising future directions for research on this topic are described.

Appetite. 2010 Dec;55(3):379-87. Epub 2010 Aug 13.
Are female athletes at increased risk for disordered eating and its complications?
Coelho GM, Soares Ede A, Ribeiro BG.
The purpose of the study was to make a systematic review and describe and confront recent studies that compare the presence of disordered eating and its complications in young female athletes and controls subjects – PubMed, Scielo, Medline, ScienceDirect, WILEY InterScience, Lilacs and Cochrane were the databases used for this review. Out of 169 studies 22 were selected and 11,000 women from 68 sports were studied. The short version of the EAT was the most common instrument used to track disordered eating. Results showed that 55% found no significant difference in the percentage of disordered eating between athletes and controls. Also a higher percentage of studies reported higher frequency of menstrual dysfunction in athletes than controls and finally 50% of the studies found incidence of low bone mass in controls. Not all the studies that investigated all the conditions in the triad, but the authors concluded that it seemed that athletes were in more severe stage of this disorder. Due to the heterogeneity of the studies, a definitive conclusion about the groups and at highest risk for disordered eating and its complications remains to be elucidated.

Bone. 2009 Oct;45(4):760-7. Epub 2009 Jun 30.
History of amenorrhoea compromises some of the exercise-induced benefits in cortical and trabecular bone in the peripheral and axial skeleton: a study in retired elite gymnasts.
Ducher G, Eser P, Hill B, Bass S.
BACKGROUND:
Female gymnasts frequently present with overt signs of hypoestrogenism, such as late menarche or menstrual dysfunction. The objective was to investigate the impact of history of amenorrhoea on the exercise-induced skeletal benefits in bone geometry and volumetric density in retired elite gymnasts.
SUBJECTS AND METHODS:
24 retired artistic gymnasts, aged 17-36 years, who had been training for at least 15 h/week at the peak of their career and had been retired for 3-18 years were recruited. They had not been engaged in more than 2 h/week of regular physical activity since retirement. Former gymnasts who reported history of amenorrhoea (‘AME’, n=12: either primary or secondary amenorrhoea) were compared with former gymnasts (‘NO-AME’, n=12) and controls (‘C’, n=26) who did not report history of amenorrhoea. Bone mineral content (BMC), total bone area (ToA) and total volumetric density (ToD) were measured by pQCT at the radius and tibia (4% and 66%). Trabecular volumetric density (TrD) and bone strength index (BSI) were measured at the 4% sites. Cortical area (CoA), cortical thickness (CoTh), medullary area (MedA), cortical volumetric density (CoD), stress-strain index (SSI) and muscle and fat area were measured at the 66% sites. Spinal BMC, areal BMD and bone mineral apparent density (BMAD) were measured by DXA.
RESULTS:
Menarcheal age was delayed in AME when compared to NO-AME (16.4+/-0.5 years vs. 13.3+/-0.4 years, p<0.001). No differences were detected between AME and C for height-adjusted spinal BMC, aBMD and BMAD, TrD and BSI at the distal radius and tibia, CoA at the proximal radius, whereas these parameters were greater in NO-AME than C (p<0.05-0.005). AME had lower TrD and BSI at the distal radius, and lower spinal BMAD than NO-AME (p<0.05) but they had greater ToA at the distal radius (p<0.05).
CONCLUSION:
Greater spinal BMC, aBMD and BMAD as well as trabecular volumetric density and bone strength in the peripheral skeleton were found in former gymnasts without a history of menstrual dysfunction but not in those who reported either primary or secondary amenorrhoea. History of amenorrhoea may have compromised some of the skeletal benefits associated with high-impact gymnastics training.

J Clin Endocrinol Metab. 1980 Nov;51(5):1150-7.
The effects of exercise on pubertal progression and reproductive function in girls.
Warren MP.
To determine whether a significant energy drain during adolescence had a significant effect on puberty and normal reproductive function, 15 ballet dancers, aged 13–15 yr, who maintained a high level of physical activity from early adolescence were followed for 4.0 yr. Menarche was remarkably delayed in this group, occurring at a mean of 15.4 yr, significantly different (P < 0.01) from normal controls (12.5 yr) and normal music students (12.6 yr). In 2 dancers aged 18 yr, primary amenorrhea has persisted. While premenarchial, all of the dancers had varying breast development (Tanner stages 2–4) and low to low normal gonadotropin levels, normal PRL and T4 levels, and normal skull x-rays. The dancers’ mean body weight and calculated body fat were significantly less than in controls (P < 0.05). The progression of sexual development and the onset of menarche correlated in 10 or 15 subjects with a decrease in exercise and/or injury causing forced rest of at least 2-month duration. During this interval, weight gain was minimal or absent, with no significant change in body composition. A significant dichotomy in the order of pubertal development was also noted; while breast development and menarche were delayed, pubic hair development was not affected. Reversion to the amenorrheic state occurred in 11 of 13 patients with a return to exercise without a change in weight. In conclusion, energy drain may have an important modulatory effect on the hypothalamic pituitary set point at puberty and, in combination with low body weight, may prolong the prepubertal state and induce amenorrhea.

Clin Obstet Gynecol. 1985 Sep;28(3):573-9.
Body weight and the initiation of puberty.
Baker ER.
The onset and progression through the various stages of puberty are influenced by a number of factors (Fig. 2). In both animals and humans, the age of puberty appears to be related more to body weight than to chronologic age. Undernutrition and low body fat, or an altered ratio of lean mass to body fat, seem to delay the adolescent spurt and to retard the onset of menarche. According to Frisch, a minimum level of fatness (17% of body weight) is associated with menarche; however, a heavier minimum weight for height, representing an increased amount of body fat (22%), appears necessary for the onset and maintenance of regular menstrual cycles in girls over 16 years of age. This critical amount of body fat implies that a particular body composition, in addition to other environmental and psychosocial factors, is important in triggering and maintaining the pubertal process.
PIP:
Biological factors which influence the progression through female puberty stages are delineated, and an increase in the proportion of the body’s fat content is identified as a critical prerequisite for the onset and maintenance of regular ovulatory cycles. Excessive exercise or malnutrition may interfere with the normal increase in the proportion of body fat and retard the onset of menarche. Pubic hair growth and breast development begins in most American females between the ages of 8-13. Menarche follows 4.2 years later for 50% of the females, but of others, the time period ranges from 18 months to 6 mor years. Both males and females experience hormonal changes before the 1st physical signs of puberty are manifested. As sex hormones increase, changes in the body’s proportion of lean, fat, and skeletal mass occur. For females an increase in body fat begins at 7 years and continues through ages 16-18 years. Studies indicate that the body’s fat content must account for 17% of the body’s weight before menarche can occur and that, at age 18 years, the fat content must be at least 22% for the maintenance of regular menstrual cycles. Apparently, hypothalamic sensitivity to estrogens is decreased when the critical ratio of lean mass to body fat is reached, and changes in the hypothalamic and pituitary hormones promote pubertal progression and the establishment of reproductive functions. Poor nutrition alters the ratio of lean mass to body fat and delays the onset of menarche. In the US, the age at menarche decreased by 3 years since 1840 due to improvements in the population’s nutritional status. Underweight females generally experience menarche at later ages than normal weight females. In contrast overweight females often experience menarche earlier than the average weight female. Athletic females and ballet dancers frequently experience late menarche, and these delays may be due to the disruption in fat accumulation which results from excessive exercise. Physically, inactive adolescents, on the other hand, tend to experience menarche at an earlier age than normally active females. In conclusion, the body’s fat content along with a variety of environmental and psychosocial factors are responsible for the development and maintenance of female reproductive functions.

J Sports Med Phys Fitness. 1996 Mar;36(1):49-53.
Gymnasts, distance runners, anorexics body composition and menstrual status.
Bale P, Doust J, Dawson D.
Ten top class female distance runners, ten female anorexics and twenty female gymnasts of a similar age were compared for height, mass, %fat, fat mass, lean body mass, age of menarche and incidence of amenorrhoea. The mean age of the distance runners, anorexics, and gymnasts was 13.6 years, 14.7 years, and 13.3 years respectively. In comparison to normal data on females of a similar age they were shorter, lighter, had lower fat masses, and %fat, and the gymnasts and anorexics had lower lean body masses. However, the gymnasts and runners had higher lean body masses compared with the anorexic group. There were no significant differences in body composition by hydrostatic weighing but of these three groups the anorexics tended to have the highest total skinfold, %fat and fat masses. Only 20% of the gymnasts, 40% of the runners and 70% of the anorexics had started menstruating compared with 95% of girls of a similar age. Of the girls in our study who had started menstruating one gymnast, (25% of sub-group) two runners (50% of sub-group) and seven anorexics (100% of sub-group) had developed secondary amenorrhoea. The low body masses, low fat masses, delayed menarche and secondary amenorrhoea in athletes are discussed in relation to low caloric intake, stress, hormone levels, high training loads and genetic factors. Our data demonstrating no significant differences in body composition variables between the three groups of young girls, support the main contention that this type of physique may arise through different mechanisms leading to a common outcome, but without a proven causal link between anorexia and athletic performance.

Am Fam Physician. 1996 Mar;53(4):1185-94.
Evaluation of amenorrhea.
Kiningham RB, Apgar BS, Schwenk TL.
Pregnancy is the most common cause of amenorrhea and must be ruled out before proceeding with diagnostic evaluation. A careful history and physical examination may reveal evidence of androgen excess, estrogen deficiency or other endocrinopathies. Serum prolactin and thyroid-stimulating hormone (TSH) levels should be checked in all women who are not pregnant. Galactorrhea by history or on examination and/or an elevated prolactin level should be investigated with an imaging study to rule out a pituitary adenoma. If serum prolactin and TSH levels are normal, a progesterone challenge test should be performed to determine outflow tract patency and estrogen status. In women with hypoestrogenic amenorrhea, indicated by a negative challenge test and a competent outflow tract, serum gonadotropin, follicle-stimulating hormone and luteinizing hormone levels may be measured to determine whether amenorrhea represents ovarian failure or pituitary or hypothalamic dysfunction. Hypothalamic amenorrhea is common in women with a history of weight loss, stress or vigorous exercise. Amenorrheic women with adequate estrogen levels should receive cyclic progesterone. Hormonal therapy and calcium supplementation in hypoestrogenic amenorrhea.

Obstet Gynecol. 1979 Jul;54(1):47-53.
Menstrual dysfunction in distance runners.
Dale E, Gerlach DH, Wilhite AL.
The problem of menstrual dysfunction in women who engage in endurance training for participation in distance running events has been studied. Through survey, selected aspects of the personal, training, menstrual, and contraceptive histories of 168 women who were defined as runners, joggers, or controls were evaluated. In addition, defined subsets of the study subjects were evaluated for serum levels of pituitary and ovarian hormones and determination of percentage body fat. The data show significant differences among the 3 groups. It is concluded that menstrual dysfunction in distance runners is a real phenomenon. Presumably this is related to decreased percentage of body fat and/or minimal ovarian function secondary to diminished hypothalamic or pituitary hormone secretion.

Ugeskr Laeger. 1994 Nov 28;156(48):7219-23.
[Bone metabolism in female runners. Menstruation disorders are frequent among long-distance runners, but the bone mass is not influenced, with the exception of runners with amenorrhea].
[Article in Danish]
Hetland ML, Haarbo J, Christiansen C, Larsen T.
The purpose of the study was to investigate the prevalence of exercise-related menstrual and sex hormonal disturbances and the effect of exercise on bone mass and metabolism in female runners at various training levels. Two hundred and five premenopausal women (running 0-140 km a week) were recruited from a large population of female runners, who had responded to a questionnaire regarding exercise habits. Maximum oxygen uptake was determined by treadmill testing. Gynaecological status was assessed on entries in a menstrual calendar and by transvaginal ultrasonography; and sex hormonal status was measured three times with 10-day intervals. Bone mass was measured in the lumbar spine, proximal femurs and total body by dual energy x-ray absorptiometry, and in the forearm by single photon absorptiometry. Bone turnover was assessed by plasma osteocalcin, serum alkaline phosphatase, and urinary calcium and hydroxyproline. The results showed that sex hormonal disturbances were significantly related to training intensity. Compared with the normally active women, the baseline levels and fluctuations of oestradiol and progesterone in the elite runners were reduced by up to 25-44%, (0.01 < p < 0.05). The prevalence of amenorrhoea increased from 1% in the normally active to 11% in the elite runners. No statistically significant relation was found between running activity and bone mass or bone turnover. However, the group of amenorrhoeic runners had a 10% reduction in lumbar bone mass as compared to the normally menstruating runners (p < 0.05), but the bone turnover was similar.(ABSTRACT TRUNCATED AT 250 WORDS)

Am J Med. 1993 Jul;95(1):53-60.
Running induces menstrual disturbances but bone mass is unaffected, except in amenorrheic women.
Hetland ML, Haarbo J, Christiansen C, Larsen T.
PURPOSE:
To investigate the prevalence of exercise-related menstrual and sex hormonal disturbances and the effect of exercise on bone mass and metabolism in female runners at various training levels.
SUBJECTS AND METHODS:
Two hundred five premenopausal women (running 0 to 140 km a week) were recruited from a large population of female runners who had responded to a questionnaire regarding exercise habits. Maximum oxygen uptake was determined by treadmill testing. Gynecologic status was assessed on entries in a menstrual calendar and by transvaginal ultrasonography; sex hormonal status was measured three times with 10-day intervals. Bone mass was measured in the lumbar spine, proximal femurs, and total body by dual-energy x-ray absorptiometry, and in the forearm by single-photon absorptiometry. Bone turnover was assessed by measurement of plasma osteocalcin, serum alkaline phosphatase, and urinary calcium and hydroxyproline.
RESULTS:
Sex hormonal disturbances were significantly related to training intensity. Compared with the normally active women, the baseline levels and fluctuations of estradiol and progesterone in the elite runners were reduced by up to 25% to 44% (0.01 < p < 0.05). The prevalence of amenorrhea increased from 1% in the normally active subjects to 11% in the elite runners. No statistically significant relation was found between running activity and bone mineral measurements or bone turnover. However, the group of amenorrheic runners had a 10% reduction in lumbar bone density as compared with the normally menstruating runners (p < 0.05), but the bone turnover was similar. CONCLUSION: In the large majority of the female runners, no skeletal affection was found despite significant sex hormonal and menstrual disturbances. Only the runners with amenorrhea might be at increased risk of osteoporosis.

Fertil Steril. 1981 Dec;36(6):691-6.
Menstrual dysfunction and hormonal status in athletic women: a review.
Baker ER.
Since women have become more involved in physical fitness and competitive endurance sports, the incidence of menstrual dysfunction has increased. Long-distance running and other sports may lead to alterations in gonadotropins, androgens, estrogens, progesterone, or prolactin, which in some women may directly or indirectly result in amenorrhea or infertility. The effects of running and strenuous exercise on the menstrual cycle and reproductive hormones remain controversial. Reported incidences of menstrual dysfunction vary widely, and many factors have been implicated in the onset of this problem. Exercise associated menstrual dysfunction seems to occur more frequently in nulliparous athletes, in athletes with delayed menarche, and in athletes with low body fat. It is important to realize that disruption of the menstrual cycle, ranging from mild changes in flow to amenorrhea, is a relatively common problem for the female athlete engaged in strenuous endurance sports. Yet no evidence exists at present to indicate conclusively that this menstrual dysfunction is harmful to the female athlete’s reproductive system.

South Med J. 1983 May;76(5):619-24.
Athletic activity and menstruation.
Diddle AW.
Menstrual dysfunction characterized by delayed menarche, irregular menses, or secondary amenorrhea often affects women who compete in athletics over a prolonged time. Loss of body fat and emotional stress are important predisposing factors. Under these circumstances, hypoestrogenism, an altered ratio of follicle-stimulating hormone to luteinizing hormone, and elevation of serum testosterone, prolactin, catecholamines, and opioids are fairly common. There is controversy over whether the working capacity and performance of the average woman varies appreciably during various phases of the menstrual cycle. Apparently, those who suffer from premenstrual tension do have a diminution in working capacity. Generally, the causes of menstrual dysfunction are the same for athletes and nonathletes, and there are currently no data to forbid athletes’ training at any time during the menses. A gynecologic examination should be done before menstrual dysfunction is considered to be due to physical exercise. If this assumption is substantiated, and if amenorrhea persists for one year or more, a periodic estrogen-progesterone regimen should be offered to minimize vascular problems, osteoporosis, and stress fractures, and to protect the endometrium and ovarian function.

Br J Sports Med. 2005 Mar;39(3):141-7.
Participation in leanness sports but not training volume is associated with menstrual dysfunction: a national survey of 1276 elite athletes and controls.
Torstveit MK, Sundgot-Borgen J.
OBJECTIVE:
To examine the prevalence of menstrual dysfunction in the total population of Norwegian elite female athletes and national representative controls in the same age group.
METHODS:
A detailed questionnaire that included questions on training and/or physical activity patterns, menstrual, dietary, and weight history, oral contraceptive use, and eating disorder inventory subtests was administered to all elite female athletes representing the country at the junior or senior level (aged 13-39 years, n = 938) and national representative controls in the same age group (n = 900). After exclusion, a total of 669 athletes (88.3%) and 607 controls (70.2%) completed the questionnaire satisfactorily.
RESULTS:
Age at menarche was significantly (p<0.001) later in athletes (13.4 (1.4) years) than in controls (13.0 (1.3) years), and differed among sport groups. A higher percentage of athletes (7.3%) than controls (2.0%) reported a history of primary amenorrhoea (p<0.001). A similar percentage of athletes (16.5%) and controls (15.2%) reported present menstrual dysfunction, but a higher percentage of athletes competing in leanness sports reported present menstrual dysfunction (24.8%) than athletes competing in non-leanness sports (13.1%) (p<0.01) and controls (p<0.05).
CONCLUSIONS:
These novel data include virtually all eligible elite athletes, and thus substantially extend previous studies. Age at menarche occurred later and the prevalence of primary amenorrhoea was higher in elite athletes than in controls. A higher percentage of athletes competing in sports that emphasise thinness and/or a specific weight reported present menstrual dysfunction than athletes competing in sports focusing less on such factors and controls. On the basis of a comparison with a previous study, the prevalence of menstrual dysfunction was lower in 2003 than in 1993.

Gynecol Obstet Invest. 2000;49(1):41-6.
Women endurance runners with menstrual dysfunction have prolonged interruption of training due to injury.
Beckvid Henriksson G, Schnell C, Lindén Hirschberg A.
Strenuous exercise by women is associated with menstrual dysfunction, eating disorders and osteoporosis. Intensive training may also increase the susceptibility to infections. In this study, we investigated whether menstrual dysfunction was related to musculoskeletal injuries and/or upper respiratory tract infections in women middle/long-distance runners. A questionnaire was mailed to 127 Swedish female runners of whom 75% answered. This retrospective study showed a higher frequency of menstrual disorders (25%) in runners than in the general population. Furthermore, almost half of the athletes (46%) were classified as at risk of developing eating disorders. Women athletes with menstrual dysfunction were found to have had a longer interruption of training due to musculoskeletal injuries than those with regular cycles (34.1 +/- 3.0 vs. 9.0 +/- 9. 4 days, p < 0.05). However, no relation was found between susceptibility to infections and menstrual status.

Am J Obstet Gynecol. 1982 Aug 15;143(8):862-9.
The effect of marathon training upon menstrual function.
Shangold MM, Levine HS.
Detailed questionnaires were distributed to the 1,841 women who entered the 1979 New York City Marathon; the questions pertained to obstetric, gynecologic, and athletic histories, as well as height and weight. The incidence of oligomenorrhea/amenorrhea among the 394 respondents was 24% during training and 19% prior to training. The incidence of infertility among respondents was 10%. Of those women who had had regular menses prior to training, 93% continued to have regular menses during training. Amenorrheic women were significantly lighter (P less than 0.005) than regularly menstruating women and had significantly lower weight/height ratios (P less than. 0.0005). The best predictor of a women’s menstrual pattern during training was her pretraining menstrual pattern. Thinness was associated with amenorrhea, regardless of training.

Am J Physiol. 1994 Mar;266(3 Pt 2):R817-23.
Induction of low-T3 syndrome in exercising women occurs at a threshold of energy availability.
Loucks AB, Heath EM.
To investigate the relationship between energy availability (dietary energy intake minus energy expended during exercise) and thyroid metabolism, we studied 27 untrained, regularly menstruating women who performed approximately 30 kcal.kg lean body mass (LBM)-1.day-1 of supervised ergometer exercise at 70% of aerobic capacity for 4 days in the early follicular phase. A clinical dietary product was used to set energy availability in four groups (10.8, 19.0, 25.0, 40.4 kcal.kg LBM-1.day-1). For 9 days beginning 3 days before treatments, blood was sampled once daily at 8 A.M. Initially, thyroxine (T4) and free T4 (fT4), 3,5,3′-triiodothyronine (T3) and free T3 (fT3), and reverse T3 (rT3) were in the normal range for all subjects. Repeated-measures one-way analysis of variance followed by one-sided, two-sample post hoc Fischer’s least significant difference tests of changes by treatment day 4 revealed that reductions in T3 (16%, P < 0.00001) and fT3 (9%, P < 0.01) occurred abruptly between 19.0 and 25.0 kcal.kg LBM-1.day-1 and that increases in fT4 (11%, P < 0.05) and rT3 (22%, P < 0.01) occurred abruptly between 10.8 and 19.0 kcal.kg LBM-1.day-1. Changes in T4 could not be distinguished. If energy deficiency suppresses reproductive as well as thyroid function, athletic amenorrhea might be prevented or reversed by increasing energy availability through dietary reform to 25 kcal.kg LBM-1.day-1, without moderating the exercise regimen.

Am J Physiol. 1993 May;264(5 Pt 2):R924-30.
Induction and prevention of low-T3 syndrome in exercising women.
Loucks AB, Callister R.
To investigate the influence of exercise on thyroid metabolism, 46 healthy young regularly menstruating sedentary women were randomly assigned to a 3 x 2 experimental design of aerobic exercise and energy availability treatments. Energy availability was defined as dietary energy intake minus energy expenditure during exercise. After 4 days of treatments, low energy availability (8 vs. 30 kcal.kg body wt-1.day-1) had reduced 3,5,3′-triiodothyronine (T3) by 15% and free T3 (fT3) by 18% and had increased thyroxine (T4) by 7% and reverse T3 (rT3) by 24% (all P < 0.01), whereas free T4 (fT4) was unchanged (P = 0.08). Exercise quantity (0 vs. 1,300 kcal/day) and intensity (40 vs. 70% of aerobic capacity) did not affect any thyroid hormone (all P > 0.10). That is, low-T3 syndrome was induced by the energy cost of exercise and was prevented in exercising women by increasing dietary energy intake. Selective observation of low-T3 syndrome in amenorrheic and not in regularly menstruating athletes suggests that exercise may compromise the availability of energy for reproductive function in humans. If so, athletic amenorrhea might be prevented or reversed through dietary reform without reducing exercise quantity or intensity.

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Effect of luteal deficiency.

Acta Obstet Gynecol Scand. 1971;50(1):61-2.
Luteal insufficiency and pelvic adhesions.
Johansson ED, Persson BH, Gemzell C.
A young woman with a history of a septic abortion and left oophorectomy for a dermoid cyst was investigated before and after laparotomy with regard to the function of the corpus luteum. At laparotomy the remaining right ovary was surrounded and fixed by thick adhesions around the ovary. The adhesions were removed. During two regular menstrual cycles before operation, low plasma levels of progesterone were found during the luteal phase. After the removal of the adhesions normal plasma levels of progesterone were found. The urinary excretion of oestrogens also improved. Severe pelvic adhesions might be one cause of insufficient luteal function.

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Endotoxin-lipoprotein Hypothesis

Also see:
Ray Peat, PhD on the Benefits of the Raw Carrot
Endotoxin: Poisoning from the Inside Out
Protective Bamboo Shoots
The effect of raw carrot on serum lipids and colon function
Protection from Endotoxin
The Truth about Low Cholesterol

“The rate of cholesterol production, and the amount in circulation, tend to be inversely related to systemic inflammation. All of the types of lipoprotein absorb, bind, and help to eliminate endotoxin, for example.” -Ray Peat, PhD

“Cholesterol has a long history as a protectant against many toxins; I think this relates to the fact that people with very low cholesterol have such a high incidence of endotoxin-related symptoms.” -Ray Peat, PhD

Lancet. 2000 Sep 9;356(9233):930-3.
The endotoxin-lipoprotein hypothesis.
Rauchhaus M, Coats AJ, Anker SD.
The advent of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) has revolutionised the treatment of hypercholesterolaemia. Statin treatment, by lowering the atherogenic lipoprotein profile, reduces morbidity and mortality in patients with cardiovascular disease. Treatment with simvastatin causes a reduction of events of new-onset heart failure, but this may be attributable to properties other than its lipid-lowering effects. There is some evidence that lower serum cholesterol concentrations (as a surrogate for the totality of lipoproteins) relate to impaired survival in patients with chronic heart failure (CHF). Inflammation is a feature in patients with CHF and increased lipopolysaccharide may contribute substantially. We postulate that higher concentrations of total cholesterol are beneficial in these patients. This is potentially attributable to the property of lipoproteins to bind lipopolysaccharide, thereby preventing its detrimental effects. We hypothesise there is an optimum lipoprotein concentration below which lipid reduction would, on balance, be detrimental. We also propose that, in patients with CHF, a non-lipid-lowering statin (with ancillary properties such as immune modulatory and anti-inflammatory actions) could be as effective or even more beneficial than a lipid-lowering statin.

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Oral Contraceptives, Estrogen, and Clotting

Also see:
High Estrogen and Heart Disease in Men
Aldosterone and Thrombosis

In the 1970s, after reading Szent-Gyorgyi’s description of the antagonistic effect of progesterone and estrogen on the heart, I reviewed the studies that showed that progesterone protects against estrogen’s clotting effect. I experimented with progesterone, showing that it increases the muscle tone in the walls of veins, which is very closely related to the effects Szent-Gyorgyi described in the heart. And progesterone opposes estrogen’s ability to increase the amount of free fatty acids circulating in the blood. -Ray Peat, PhD

Br Med J. 1970 April 25; 2(5703): 203–209.
Thromboembolic Disease and the Steroidal Content of Oral Contraceptives. A Report to the Committee on Safety of Drugs
W. H. W. Inman, M. P. Vessey, Barbro Westerholm, and A. Engelund
Reports of thromboembolism following the use of oral contraceptives received by drug safety committees in the United Kingdom, Sweden, and Denmark have been analysed to investigate possible differences in the risks associated with the various preparations. For this purpose the numbers of reports of thromboembolism attributed to each product were compared with the distribution that would have been expected from market research estimates of sales, assuming that all products carried the same risk.

A positive correlation was found between the dose of oestrogen and the risk of pulmonary embolism, deep vein thrombosis, cerebral thrombosis, and coronary thrombosis in the United Kingdom. A similar association was found for venous thrombosis and pulmonary embolism in Sweden and Denmark.
No significant differences could be detected between sequential and combined preparations containing the same doses of oestrogen, nor between the two oestrogens, ethinyloestradiol and mestranol.

Certain discrepancies in the data suggest that the dose of oestrogen may not be the only factor related to the risk of thromboembolism; thus there was a significant deficit of reports associated with the combination of mestranol 100 μg. with norethynodrel 2·5 mg. and a significant excess of reports associated with the combination of ethinyloestradiol 50 μg. with megestrol acetate 4 mg. An excess of reports also occurred with other combined preparations containing megestrol acetate.

The data obtained in earlier epidemiological studies were re-examined and, though no trend was obvious in any one of them, the combined results showed an excess of cases of thromboembolism at the highest dose of oestrogen.

Lancet. 1976 Mar 6;1(7958):509-11.
Oral contraceptives, antithrombin- III activity, and postoperative deep-vein thrombosis.
Sagar S, Stamatakis JD, Thomas DP, Kakkar VV.
Deep-vein thrombosis (D.V.T.) was detected by the fibrinogen-uptake test in six out of a total of thirty-one young women undergoing emergency abdominal surgery who gave a history of recent oral contraceptive intake. In contrast, no D.V.T. developed in nineteen similar patients who were not on oral contraceptives (P less than 0.01). Plasma-antithrombin-III activity was significantly lower preoperatively in patients taking oral contraceptives; postoperative D.V.T. subsequently developed in three out of five patients with preoperative antithrombin-III activity below 50%. In seventy-eight dental patients undergoing molar extraction, antithrombin-III activity was measured before, during, and after operation. Activity fell in all patients during operation, but the fall was significantly greater in women taking oral contraceptives (P less than 0.01). The intra-operative fall in antithrombin-III activity was prevented by a small preoperative dose of subcutaneous heparin.

Am J Obstet Gynecol. 1975 Jul 15;122(6):688-92.
Conjugated estrogens and hypercoagulability.
von Kaulla E, Droegemueller W, von Kaulla KN.
A group of 11 menopausal women receiving 1.25 mg. of conjugated estrogens daily had coagulation tests to determine the development of hypercoagulability after taking 5 and 21 tablets. There was no essential change in thrombin generation or fibrinolytic activity as measured by euglobin lysis time. There was a shift toward hypercoagulability in all three parameters of the thrombelastograms. The decrease of the antithrombin III activity was not as pronounced following the administration of conjugated estrogens as had been the change associated with oral contraceptives. Fibrin monomers were observed in some women during the first week of Premarin therapy.

Arch Pathol. 1970 Jan;89(1):1-8.
Vascular lesions in women taking oral contraceptives.
Irey NS, Manion WC, Taylor HB.
Distinctive vascular lesions in association with thrombosis were found in arteries and veins in 20 relatively young women receiving oral contraceptives. These lesions were characterized by structural and histochemical changes in the intima and media. Occlusive thrombi were associated with relatively small, organized bases, the age of the latter measured in days to weeks. Nonocclusive and possibly earlier lesions were dominated by endothelial proliferation with minimal thrombus formation. It is postulated that this endothelial and intimal hyperplasia may be related to the steroids received and that it parallels similarly induced hyperplasias that have been found in cervical gland epithelium, in leiomyomas, and in a variety of mesenchymal derivatives under experimental conditions. Further control and experimental studies are required to clarify the possible relationship between these vascular lesions and oral contraceptives.

Br Med J. 1973 December 1; 4(5891): 507–512.
Cryptogenic Cerebral Embolism in Women Taking Oral Contraceptives
Karin Enzell and Gunnar Lindemalm
Fourteen women taking oral contraceptives were admitted during a five-year period because of acute cerebrovascular lesions. A diagnosis of major cerebral embolism was established in four of them. No source of embolism was found, and thorough investigation failed to reveal any predisposing illness. Cerebral embolism was a probable diagnosis in several of the remaining 10 patients. A comparison was made with the strokes occurring in women not taking contraceptive pills in corresponding age groups.

Lancet. 1973 Jun 23;1(7817):1399-404.
Oral contraceptives and venous thromboembolic disease, surgically confirmed gallbladder disease, and breast tumours. Report from the Boston Collaborative Drug Surveillance Programme.
[No authors listed]
A large survey of 24 hospitals was conducted to identify associations between commonly used drugs and various diseases. The results of 3 such studies–on venous thromboembolism, gall bladder disease, and breast tumors–are summarized in this article. Trained nurses in various hospital wards interviewed admissions, asking questions designed to determine smoking behavior, coffee and tea drinking, drug use, marital status, and parity and menopausal status, where appropriate. This report specifically centers on associations between oral contraceptive use and development of the 3 conditions under study. Women reported on in this portion of the study were aged 20-44 years. Compared with nonusers, the estimate of relative risk for thromboembolism in users was 11, and the estimated attack rate attributable to oral contraceptives was 60/100,000 users/year. For gall bladder disease (surgically confirmed) the corresponding relative risk estimate was 2.0, and the estimated annual attack rate was 79/100,000. The frequency of gall bladder disease in women under 35 years was significantly higher in oral contraceptive users of 6-12 months duration, compared with women who had taken the pills for longer periods. Breast cancer studies showed no evidence of a higher risk in oral contraceptive users relative to nonusers. In fact, a negative association between oral contraceptive use and breast tumors was found, and this was more pronounced in women with fibroadenoma of the breast. Most of the women surveyed for this report took low-dose estrogen formulations, but the role of dose to the above findings was not investigated.

The finding of a positive correlation between the dose of oestrogen and the risk of coronary thrombosis is of special interest since previous studies have failed to provide clear evidence of a relationship between oral contraceptives and this condition.

Am J Obstet Gynecol. 1987 Oct;157(4 Pt 2):1042-8.
Coagulation effects of oral contraception.
Bonnar J.
In Europe and North America, estrogen/progestogen oral contraception has been associated with an increase in venous thromboembolism, myocardial infarction, and stroke. These hazards are found mainly in smokers and in women over the age of 35. Venous thromboembolism appears to correlate with the estrogen dosage, and the arterial complications with both the estrogen and progestogen components. Blood coagulation and vascular thrombosis are intimately related. Estrogen/progestogen oral contraception affects blood clotting by increasing plasma fibrinogen and the activity of coagulation factors, especially factors VII and X; antithrombin III, the inhibitor of coagulation, is usually decreased. Platelet activity is also enhanced with acceleration of aggregation. These changes create a state of hypercoagulability that, to a large extent, appears to be counterbalanced by increased fibrinolytic activity. Studies of the oral contraceptives in current use show that the coagulation effects depend on the dosage of estrogen and the type of progestogen used in combination. Current research is aimed at finding the estrogen/progestogen formulations that induce the least changes in the coagulation system and other physiologic processes. In this respect, the new low-dose formulations are a major step forward and should reduce the risk of vascular thrombotic complications.

Lancet. 1980 May 24;1(8178):1097-101.
Oral contraceptives and thromboembolic disease: effects of lowering oestrogen content.
Böttiger LE, Boman G, Eklund G, Westerholm B.
The introduction of low-oestrogen oral contraceptives in Sweden and the concomitant disappearance of high-dose preparations did not result in a lowering of the mortality of fertile women from thromboembolic disease. Morbidity due to thromboembolism seems to have fallen, and the number of thromboembolic incidents reported to the Swedish Adverse Drug Reaction Committee decreased dramatically. The decrease was due exclusively to a reduction in venous thromboembolic disease: the frequency of arterial complications (cerebral and coronary) remained constant.

Estrogen has many pro-clotting effects, and one of them is a decreased activity of vascular plasminogen activator. K. E. Miller and S. V. Pizzo, “Venous and arterial thromboembolic disease in women using oral contraceptives,” Am. J. Obst. Gyn. 144, 824, 1982. -Ray Peat, PhD

Am J Obstet Gynecol. 1982 Dec 1;144(7):824-7.
Venous and arterial thromboembolic disease in women using oral contraceptives.
Miller KE, Pizzo SV.
Vascular plasminogen activator was measured by means of a new chromogenic assay in 24 women who had suffered from oral contraceptive-associated thrombotic disease and was compared to that in a control group of 78 premenopausal women. Vascular plasminogen activator levels were significantly reduced in the subjects who had venous thrombosis but not in the five women who had arterial thrombosis (0.04 +/- 0.03 versus 0.38 +/- 0.31, respectively) when compared to the levels in the control group (0.19 +/- 0.20). Since vascular activator levels distribute in a non-Gaussian manner, cases and controls were also stratified into deciles. Seventeen subjects who had suffered from venous thrombosis were stratified in the lowest three deciles, and two subjects, in the fourth and fifth deciles. Subjects who had suffered from arterial thrombosis were in the fourth or higher deciles. The conclusion is that, although there is a correlation between low levels of vascular plasminogen activator and venous thrombosis, no such correlation exists for arterial thrombosis.

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