PUFA dangers part 5: Androgens, estrogen, prolactin & cortisol


PUFAs, when incorporated into cell membranes, cause the cells to become more fluid, are chaotropic, disorderly and reduce their function (1).

Steroids are made in the mitochondria and require lots of ATP (energy molecule of the cells) to synthesize steroid optimally. Low ATP = low steroidogenesis. Steroidogenesis requires cholesterol, vitamin A, thyroid hormones, NAD+, magnesium and ATP just to name a few necessary components. PUFAs inhibit thyroid function, vitamin A and thyroid hormone transport and shift tryptophan conversion away from NAD production.


Androgens (such as testosterone and DHEA) are synthesized in the gonads and in the adrenal glands. The hypothalamus releases luteinizing hormone releasing hormone (LHRH), which signals the pituitary to release luteinizing hormone (LH), which stimulates the testes to increase testosterone production. Cyclic adenosine monophosphate (cAMP) is a secondary signaling molecule that stimulates the testes to produce more testosterone. To produce testosterone, the body requires good cellular function, lots of NAD and ATP (high energy state), cholesterol, vitamin A and a proper functioning thyroid.

Androsterone backdoor pathway

PUFAs decrease sensitivity to cAMP, induce pituitary resistance to LHRH, and also raise LH (23). You might think this is a good thing, but elevated LH is associated with testicular failure and hypogonadism. PUFAs also reduce proper cellular function (by increasing fluidity and increasing water (cell swelling)), lower the NAD:NADH ratio, lower ATP, lower cholesterol, displace vitamin A and thyroid hormones from their carrier protein and antagonize thyroid on all levels.

In the mitochondria, cholesterol is converted to pregnenolone, which is then converted to progesterone and DHEA via 3-beta hydroxysteroid dehydrogenase (3β-HSD) and 17 alpha hydroxysteroid dehydrogenase (17α-HSD), respectively.

Inhibiting COX (the enzyme that converts arachidonic acid into inflammatory prostaglandins) and thromboxane A synthase (the enzyme that promotes thrombosis) increases StAR activity (the enzyme that transports cholesterol into the mitochondria for steroidogenesis) and also progesterone synthesis; this shows that PUFAs are a StAR and possibly a 3β-HSD inhibitor (4, 5, 6).

In this study, sesame seed ingestion, which consists predominantly of omega 6, showed to lower DHEA-S (the storage form of DHEA, indicating increased estrogen synthesis) (7). PUFAs are also a direct 17α-HSD (the enzyme that converts estradiol into its weaker metabolite – estrone) inhibitor and the potency increases with an increase in double bonds (8). And arachidonic acid, without even having to be converted by COX or LOX, is able to lower androgen synthesis, via the PKC pathway (9).

PUFAs are absolutely horrible for androgen production. In PUFA depleted animals, the conversion of acetate and cholesterol into testosterone and androstenedione is approximately double that from normal rats (10). This is because of the reduction in membrane permeability and improved mitochondrial function and ATP production due to low PUFA intake.

After PUFAs lower androgen synthesis, and inhibits 5-alpha reductase, it also inhibits the steroids from binding to its receptors (it’s an androgen receptor antagonist), except for the estrogen receptor, which it potentiates (11). This makes PUFAs both anti-androgenic and pro-estrogen.


PUFAs displace estrogen from albumin and SHBG (these two protein prevent estrogen entry into the cells), thus increasing free estrogen and allowing it greater access in the body, which can lead to more overall harm.

Estrogen in turn increases the activity of COX and LOX and promotes the synthesis of prostaglandins and leukotriene from arachidonic acid, thus promoting inflammation, asthma, vascular damage, tumor growth, cancer, etc.

In animals fed corn oil, which is rich in ω-6 PUFAs (primarily linoleic acid), estradiol increased ~2-fold compared to the low fat group. High intake of the PUFAs, linoleic acid and arachidonic acid, also inhibits the detoxification of estrogens by 2-hydroxylation and increases 16α-hydroxylation. This results in an accumulation of estrogenic metabolites that can undergo redox cycling and generate hydroxyl radicals (12).


PUFAs increase prolactin (13). Stimulation of phospholipase A2 (PLA2) is correlated with prolactin (14) as PLA2 releases arachidonic acid from cell membranes, which then lead to an increase in intracellular calcium, (which activates PKC and stimulates prolactin secretion (15)). Elevated intracellular calcium also creates leukotrienes (from PUFAs), which increases prolactin and elevates thyrotropin-releasing hormone (TRH), which also increases prolactin (16, 17).

Increase ACTH and cortisol

PUFAs increase cortisol production in the absence of ACTH (the hormone that stimulates the adrenaline glands to release cortisol), and also potentiates the effect of ACTH, whereas SFAs are inhibitory (181920).

PUFAs also increase liver mRNA levels for the enzyme HSD11B1 (the enzyme which converts cortisone to cortisol, the active form), which will lead to an increase in cortisol production at baseline (21).

Cortisol increases gluconeogenesis (the pathway that converts amino acids (mostly from muscle) into glucose) and fatty acid synthesis (formation of fat from glucose), causes hyperinsulinemia and insulin resistance, promotes fat storage in liver and adipose tissue and accelerates aging (22). The high insulin caused by cortisol will increase phospholipase A2, which releases more PUFAs from the cell membranes, which then increases cortisol and prolactin in a forward feedback loop.

Excess PUFA ingestion causes muscular dystrophy and creatinuria (23), possibly by the elevated cortisol and the decreased protein synthesis (24), whereas saturated fats are protective and are actually anabolic and androgenic.

Mice that didn’t have prostaglandin receptors, EP1 and EP3, (so that they weren’t affected by elevated toxic PUFA metabolites) had impaired adrenal activation during stress (in this case endotoxin stimulation), with a significant decrease in plasma levels of ACTH compared to normal mice (25). This would mean that, when there isn’t a lot of PUFAs in the body, the stress response would be much more blunted, so that the person would be able to stay calm under stress.

In conclusion

PUFAs inhibit androgen synthesis, increase the aromatase (via PGE2 stimulation), inhibit 5 alpha reductase, inhibit androgen receptors, potentiate estrogen receptors, increase prolactin and are catabolic by increasing cortisol (26, A, 27, 28, 29, 30).

It would be best to eat as little PUFAs as possible and preferably stay below 4g daily.

4 thoughts on “PUFA dangers part 5: Androgens, estrogen, prolactin & cortisol”

      • Thanks for answer. I know there are some rumours that PUFAs cause cancer and certainly high intake of PUFAs is not without risk.
        But I would rather rely on human studies, a lot of food people eat without any problems are harmful and toxic to animals.
        International Society for the Study of Fatty Acidsand Lipids made probably the best summary I’ve ever seen on PUFAs based on human studies, but I dont’ agree with what they say about DHA because high DHA is linked to prostate cancer even when adjusted to other factor. Here is it: https://www.issfal.org/assets/issfal%2003%20pufaintakereccomdfinalreport.pdf
        So intake below 4 grams is probably too low even though we can’t be sure. My intake is usually 10 grams which is probably too much…

      • Thanks for the link. They say the 2% requirement is based on minimizing Mead acid, which is not a good conclusion, because Mead acid is beneficial and anti-inflammatory. I’m not convinced that LA is necessary at all, but by eating a normal healthy diet, one is obviously going to consume some and should stress about it.
        PUFAs becomes more dangerous when the individual is exposed to stresses of all kinds, even when there is enough anti-oxidants like vitamin E present in the body as well.
        I’d say up to 10g is probably ok, but less is prefered. A goal of less that 4g per day can also be stressor in of itself for some people, so just being concious of avoid uphealthy high PUFA foods, like fried foods, dressings, baked goodies, nut butters, seeds, etc., will automatically keep PUFA on the low side and provide a good saturated to PUFA ratio.

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