Women, Estrogen, and Circulating DHA

Also see:
Fish Oil Toxicity
PUFA, Fish Oil, and Alzheimers
The Randle Cycle
Estrogen, Glutamate, & Free Fatty Acids
Menstrual Cycle Related Epilepsy (Catamenial Epilepsy
Estrogen’s Role in Seizures
Phospholipases, PUFA, and Inflammation

Quotes by Ray Peat, PhD:
“Women are known to have a greater susceptibility than men to lipolysis, with higher levels of free fatty acids in the serum and liver, because of the effects of estrogen and related hormones.

Women on average have more DHA circulating in the serum than men (Giltay, et al., 2004; McNamara, et al., 2008; Childs, et al., 2008). This high unsaturated fatty acid is the first to be released during stress, and biologically, the meaning of estrogen is to mimic stress. Estrogen and polyunsaturated fatty acids have similar actions on cells, increasing their water content and calcium uptake. Long before the Women’s Health Initiative reported in 2002 that the use of estrogen increased the risk of dementia, it was known that the incidence of Alzheimer‘s was 2 to 3 times higher in women than in men.”

“Under the influence of estrogen, or unsaturated fats, brain cells swell, and their shape and interactions are altered. Memory is impaired by an excess of estrogen. Estrogen and unsaturated fat and excess iron kill cells by lipid peroxidation, and this process is promoted by oxygen deficiency. The fetus and the very old have high levels of iron in the cells. Estrogen increases iron uptake. Estrogen treatment produces elevation of free fatty acids in the blood, and lipid peroxidation in tissues. This tends to accelerate the accumulation of lipofuscin, age-pigment. Lactic acid, the production of which is promoted by estrogen, lowers the availability of carbon dioxide, leading to impairment of blood supply to the brain.”

“One of estrogen’s effects is to chronically increase the circulation of free fatty acids, and to favor the long chain polyunsaturated fatty acids, such as EPA and DHA.”

“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.”

“Estrogen, which is promoted intensively as prevention or treatment for Alzheimer’s disease was finally shown to contribute to its development.”

“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.”

“Estrogen causes elevation of free fatty acids, and there are many interactions between the unsaturated fatty acids and estrogen, including their metabolism to prostaglandins, and their peroxidation.”

“Estrogen increases the free fatty acids circulating in the blood, and this shifts metabolism away from the oxidation of glucose to oxidation of fat, and it reduces oxidative metabolism for example by lowering thyroid function (Vandorpe and Kuhn, 1989)”

“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.

“For example, the brain toxic effects of estrogen were usually neglected, and the much higher incidence of Alzheimer’s disease in women was usually interpreted as evidence that the disease is caused by a deficiency of estrogen. The neurotoxic effects of lipid peroxides and prostaglandins were ignored, while fish oil was advocated to prevent and treat dementia. The toxic effects of serotonin and nitric oxide were seldom considered, whle drugs to increase those were advocated to treat Alzheimer’s.”

“Acrolein’s self-stimulating production from DHA is another factor that could account for the predominance of Alzheimer’s disease in women, since, under the influence of estrogen, women accumulate significantly more DHA than men (Giltay, et al., 2004), and similar effects can be seen in animal studies (McNamara, et al., 2008).”

Am J Clin Nutr. 2004 Nov;80(5):1167-74.
Docosahexaenoic acid concentrations are higher in women than in men because of estrogenic effects.
Giltay EJ, Gooren LJ, Toorians AW, Katan MB, Zock PL.
During pregnancy there is a high demand for docosahexaenoic acid (DHA), which is needed for formation of the fetal brain. Women who do not consume marine foods must synthesize DHA from fatty acid precursors in vegetable foods.
We studied sex differences in DHA status and the role of sex hormones.
First, DHA status was compared between 72 male and 103 female healthy volunteers who ate the same rigidly controlled diets. Second, the effects of sex hormones were studied in 56 male-to-female transsexual subjects, who were treated with cyproterone acetate alone or randomly assigned to receive oral ethinyl estradiol or transdermal 17beta-estradiol combined with cyproterone acetate, and in 61 female-to-male transsexual subjects, who were treated with testosterone esters or randomly assigned for treatment with the aromatase inhibitor anastrozole or placebo in addition to the testosterone regimen.
The proportion of DHA was 15 +/- 4% (x +/- SEM; P < 0.0005) higher in the women than in the men. Among the women, those taking oral contraceptives had 10 +/- 4% (P = 0.08) higher DHA concentrations than did those not taking oral contraceptives. Administration of oral ethinyl estradiol, but not transdermal 17beta-estradiol, increased DHA by 42 +/- 8% (P < 0.0005), whereas the antiandrogen cyproterone acetate did not affect DHA. Parenteral testosterone decreased DHA by 22 +/- 4% (P < 0.0005) in female-to-male transsexual subjects. Anastrozole decreased estradiol concentrations significantly and DHA concentrations nonsignificantly (9 +/- 6%; P = 0.09).
Estrogens cause higher DHA concentrations in women than in men, probably by upregulating synthesis of DHA from vegetable precursors.

Psychoneuroendocrinology. 2009 May;34(4):532-9. Epub 2008 Nov 28.
Gender differences in rat erythrocyte and brain docosahexaenoic acid composition: role of ovarian hormones and dietary omega-3 fatty acid composition.
McNamara RK, Able J, Jandacek R, Rider T, Tso P.
The two-fold higher prevalence rate of major depression in females may involve vulnerability to omega-3 fatty acid deficiency secondary to a dysregulation in ovarian hormones. However, the role of ovarian hormones in the regulation of brain omega-3 fatty acid composition has not been directly evaluated. Here we determined erythrocyte and regional brain docosahexaenoic acid (DHA, 22:6n-3) composition in intact male and female rats, and in chronically ovariectomized (OVX) rats with or without cyclic estradiol treatment (2 microg/4d). All groups were maintained on diets with or without the DHA precursor alpha-linolenic acid (ALA, 18:3n-3). We report that both male (-21%) and OVX (-19%) rats on ALA+ diet exhibited significantly lower erythrocyte DHA composition relative to female controls. Females on ALA+ diet exhibited lower DHA composition in the prefrontal cortex (PFC) relative males (-5%). OVX rats on ALA+ diet exhibited significantly lower DHA composition in the hippocampus (-6%), but not in the PFC, hypothalamus, or midbrain. Lower erythrocyte and hippocampus DHA composition in OVX rats was not prevented by estrogen replacement. All groups maintained on ALA- diet exhibited significantly lower erythrocyte and regional brain DHA composition relative to groups on ALA+ diet, and these reductions were greater in males but not in OVX rats. These preclinical data corroborate clinical evidence for gender differences in peripheral DHA composition (female>male), demonstrate gender differences in PFC DHA composition (male>female), and support a link between ovarian hormones and erythrocyte and region-specific brain DHA composition.

Proc Nutr Soc. 2008 Feb;67(1):19-27.
Gender differences in the n-3 fatty acid content of tissues.
Childs CE, Romeu-Nadal M, Burdge GC, Calder PC.
Dietary n-3 PUFA have many beneficial effects on cell and tissue function and on human health. In mammals the n-3 essential fatty acid alpha-linolenic acid (ALNA) can be converted into longer-chain (LC) n-3 PUFA such as EPA and DHA via a series of desaturase and elongase enzymes that are mainly active in the liver. Human studies have identified that males and females appear to differ in their ability to synthesise EPA and DHA from ALNA, with associated differences in circulating concentrations. Based on studies of women using the contraceptive pill or hormone-replacement therapy and of trans-sexual subjects it is suggested that sex hormones play a role in these differences. The rat has been used to investigate gender differences in n-3 PUFA status since this model allows greater dietary control than is possible in human subjects. Like human subjects, female rats have higher plasma DHA concentrations than males. Rats also respond to increased dietary ALNA in a way that is comparable with available human data. The concentrations of LC n-3 PUFA in rat plasma and tissues are positively associated with circulating concentrations of oestradiol and progesterone and negatively associated with circulating concentrations of testosterone. These findings suggest that sex hormones act to modify plasma and tissue n-3 PUFA content, possibly by altering the expression of desaturase and elongase enzymes in the liver, which is currently under investigation.

Am J Clin Nutr. 2006 Dec;84(6):1330-9.
Dietary fish intake and plasma phospholipid n-3 polyunsaturated fatty acid concentrations in men and women in the European Prospective Investigation into Cancer-Norfolk United Kingdom cohort.
Welch AA, Bingham SA, Ive J, Friesen MD, Wareham NJ, Riboli E, Khaw KT.
The n-3 polyunsaturated fatty acids (n-3 PUFAs) docosahexaenoic acid and eicosapentaenoic acid, found in fish and fish-oil supplements and also formed by conversion of alpha-linolenic acid in soy and rapeseed (canola) oils, are thought to have cardioprotective effects.
Because the relative feasibility and measurement error of dietary methods varies, this study compared fish and fish-oil intakes obtained from 4 dietary methods with plasma n-3 PUFAs in men and women in a general population.
The study participants were 4949 men and women aged 40-79 y from the European Prospective Investigation into Cancer-Norfolk United Kingdom cohort. Measurements of plasma phospholipid n-3 PUFA concentrations and fish intakes were made with the use of 4 dietary methods (food-frequency questionnaire, health and lifestyle questionnaire, 7-d diary, and first-day recall from the 7-d diary).
Amounts of fish consumed and relations with plasma phospholipid n-3 PUFAs were not substantially different between the 4 dietary methods. Plasma n-3 PUFA concentrations were significantly higher in women than in men, were 20% higher in fish-oil consumers than in non-fish-oil consumers, and were twice as high in fatty fish consumers as in total fish consumers. Only approximately 25% of the variation in plasma n-3 PUFA was explained by fish and fish-oil consumption.
This large study found no substantial differences between dietary methods and observed clear sex differences in plasma n-3 PUFAs. Because variation in n-3 PUFA was only partially determined by fish and fish-oil consumption, this could explain the inconsistent results of observational and intervention studies on coronary artery disease protection.

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