How to lower your invisible (intracellular) cortisol

Your cortisol might not be where you think it is.

There are currently 3 major ways of measuring cortisol, which include, blood, urine, and saliva. All of those can show you something useful but isn’t the whole picture.

There is also intra and extracellular cortisol. Blood tests only measure extracellular cortisol.

The two enzymes, 11β-HSD1 and 11β-HSD2, control intracellular cortisol.

11β-HSD1 uses NADPH as a cofactor to convert cortisone to cortisol. It’s a bidirectional enzyme, so it can also convert cortisol into cortisone using NADP. This conversion is controlled by the redox state. Too much reduction (high NADPH) and you might have too much cortisol.

11β-HSD2 converts cortisol back into cortisone using NAD. This is one of the reasons why having high NAD levels is so important. Again, a reduced state (low NAD:NADH ratio) will lead to elevated cortisol.

Overactivation of 11β-HSD1 can cause issues, but under-expression of 11β-HSD2 can cause more severe issues.

11β-HSD dysregulation

11β-HSD1 & 2 are widely expressed in liver, adipose tissue, muscle, pancreatic islets, adult brain, inflammatory cells, skin, colon and gonads.

Elevated intracellular cortisol is trouble

Excess 11β-HSD1 and/or low 11β-HSD2 can lead to hypertension, hypokalemia (low potassium), insulin resistance, elevated fasting glucose, dyslipidemia, atherogenesis, low testosterone, reduced muscle mass and strength, periodontal disease, respiratory and central nervous systems disorders, depressive-like behavior (low 11β-HSD2 leads to elevated serotonin), etc. (R, R, R, R, R)

11β-HSD & testosterone

Compared with the whole testis, 11β-HSD2 mRNA is 6-fold higher in the Leydig cells.

11β-HSD2 inhibition increases the level of cortisol when then causes a decrease in testosterone production (R).

11β-HSD & muscle mass

Excess cortisol inhibits muscle protein synthesis and promotes protein breakdown. This can lead to muscle wasting and weakness. Inhibition of 11β-HSD1 helps to reverses this and increase muscle mass.

The 11β-HSD1 inhibitor, AZD4017, has been shown to increase lean mass and circulating androgens and lower lipid markers and liver enzymes (R).

Corticosterone (CORT) decreased myotube area, decreased protein synthesis, and increased protein degradation in murine myotubes. This was supported by decreased mRNA expression of insulin-like growth factor (IGF1), decreased activating phosphorylation of mammalian target of rapamycin (mTOR), decreased phosphorylation of 4E binding protein 1 (4E-BP1), and increased mRNA expression of key atrophy markers including: atrogin-1, forkhead box O3a (FOXO3a), myostatin (MSTN), and muscle-ring finger protein-1 (MuRF1).

Reference

Inflammation increase 11B-HSD, so chronic inflammation will lead to excess intracellular cortisol (R).

11β-HSD1 inhibitors

#1 Stress management

A single stress exposure produced a significant increase in the expression of corticosterone reactivator, 11-beta-hydroxysteroid dehydrogenase 1 (11β-Hsd1), while the 11β-Hsd2 isozyme and corticosteroid-binding globulin were down-regulated following stress, indicative of an elevated availability of active corticosterone.

Reference

Cortisol itself stimulates 11β-HSD1 expression in liver cells, fat cells and muscle cells. So it’s important to keep cortisol in check as well.

There are a variety of ways to manage stress, and I’d start with breathing (slow inhales and exhales and/or bag breathing) and supplements such as magnesium, aspirin, Tribulus Terrestris, etc.

• How to lower cortisol

#2 Improve insulin sensitivity

Insulin inhibits 11β-HSD1, and 11β-HSD1 can become upregulated if someone has insulin resistance.

…insulin opposes glucocorticoid action as shown by the fact that increased insulin sensitivity during intensive treatment for Type 2 diabetes decreases glucocorticoid receptor expression in skeletal muscle.

Reference

Switching from high GI refined starches (white bread, baked goodies, white rice, etc.) to fruit (whole or juice) can help improve insulin sensitivity. For example, eating just 1 apple before a high GI meal can reduce the insulin response by 50%.

Cinnamon, bitter melon, magnesium, zinc, aspirin, Pyrucet, etc., can all help to improve insulin sensitivity.

• Improve glucose oxidation
• How to improve insulin sensitivity

If you want to learn how much carbs you need per day, check out this youtube video of mine.

#3 Lower inflammation

Inflammatory cytokines, such as TNFα, IL-1β and IL-6 increase 11β-HSD1 expression at least in adipose stromal cells.

Exercise has also been shown to increase 11β-HSD1. This increase is thought to protect against the inflammation, since cortisol is anti-inflammatory. As you adapt to the exercise, the inflammatory response and 11β-HSD1 stays normal. But if you over-exercise, inflammation will be chronically elevated, and so will 11β-HSD1 and intracellular cortisol. If you struggle to build muscle, perhaps you’re doing too much volume.

Chronic physical exercise induces Nuclear Factor kappa B (NFkB) activation and increased transcription in adult males [19]. NFkB has been found to induce 11βHSD1 activity under hypoxic conditions [20].Increased cellular hypoxia can thus lead to increased 11βHSD1 activity.

Reference

The gut is another major source of inflammation, so it’s important to look after your gut. (The AthElite gut course is made for this)

#4 Lower estrogen

Estrogens can suppress 11β-HSD1 expression, leading to higher intracellular cortisol (R).

• How to block the aromatase: article 1, article 2
• How to block estrogen receptors
• How to detox estrogen: article 1, article 2

#5 Danshen

The Chinese herb Danshen is able to decrease the expression of inflammatory mediators such as 11β-HSD1 (R).

#6 Be wary of curcumin

Curcumin derivatives had high potencies for inhibition of human 11β-HSD1 (which is good) with selectivity against 11β-HSD2 (which is bad) (R). On one hand, it can inhibit cortisol synthesis, but on the other hand, it appears to inhibit cortisol breakdown more than it inhibits its synthesis.

#7 Vitamin A

Vitamin A supplementation significantly decreased body weight, visceral fat mass and 11β-HSD1 activity in visceral fat of WNIN/Ob obese rats. Hepatic 11β-HSD1 activity and gene expression were significantly reduced by vitamin A supplementation in both the phenotypes. CCAAT/enhancer binding protein α (C/EBPα), the main transcription factor essential for the expression of 11β-HSD1, decreased in liver of vitamin A fed-obese rats, but not in lean rats. Liver × receptor α (LXRα), a nuclear transcription factor which is known to downregulate 11β-HSD1 gene expression was significantly increased by vitamin A supplementation in both the phenotypes.

Reference

Reduced expression of 11β-hydroxysteroid dehydrogenase type 2 is associated with decreased PPARγ but increased PPARα expression (R). According to this study, knockdown of retinoid X nuclear receptor α (RXRα; the receptor for the active form of vitamin A) resulted in a loss of PPARγ effect but not PPARα effect on11β-HSD2. PPARγ agonists down-regulate 11β-HSD1 expression in adipose tissue and thereby decrease whole body cortisone to cortisol conversion in diabetic mice (R).

I like to get my vitamin A from beef liver, of which I consume 100-200g x1-2 per week.

#8 Emodin

Emodin is found in Cascara, Aloe and Rhubarb.

Emodin is a potent and selective 11β-HSD1 inhibitor with the IC₅₀ of 186 and 86 nM for human and mouse 11β-HSD1, respectively. Single oral administration of emodin inhibited 11β-HSD1 activity of liver and fat significantly in mice. Emodin reversed prednisone-induced insulin resistance in mice, whereas it did not affect dexamethasone-induced insulin resistance, which confirmed its inhibitory effect on 11β-HSD1 in vivo.

Reference

#9 Quercetin

Quercetin, the most active compound, was docked into the crystal structure of 11beta-HSD1. 

Reference

Quercetin is found in  apples, honey, raspberries, onions, red grapes, cherries, citrus fruits, etc.

#10 Phoradendron reichenbachianum

Phoradendron reichenbachianum (Loranthaceae), a medicinal plant used in Mexico for the treatment of diabetes. Morolic and moronic acids are the main constituents of the acetonic extract.

morolic and moronic acids have shown sustained antidiabetic and antihyperglycemic action possibly mediated by an insulin sensitization with consequent changes of glucose, cholesterol and triglycerides, in part mediated by inhibition of 11β-HSD 1 as indicated by in vitro and in silico studies.

Reference

#11 Vitamin D

All the more reason to get more sunlight exposure.

daily vitamin D supplementation may ameliorate CVD risk factors including a decrease in 11β-HSD 1 activity and improve exercise performance in healthy individuals

Reference

#12 Mango leaf extract

Methanolic leaf extract of Mangifera indica contains the well known gallotannin compound, 1,2,3,4,6 penta-O-galloyl-β-d-glucose (PGG).

…the PGG isolated from MEMI inhibits 11β-HSD-1 activity and ameliorates HFD-induced diabetes in male C57BL/6 mice.

Reference

#13 Aspirin

Aspirin is definitely one of my favorite supplements. This is one of the reasons why I use it regularly as part of my anti-serotonin stack.

In C57Bl/6 DIO mice, salicylate improved glucose tolerance and downregulated 11β-HSD1 mRNA and activity selectively in visceral adipose. DIO 11β-HSD1–deficient mice were resistant to these metabolic effects of salicylate. In men, salsalate reduced 11β-HSD1 expression in subcutaneous adipose, and in vitro salicylate treatment reduced adipocyte 11β-HSD1 expression and induced adiponectin expression only in the presence of 11β-HSD1 substrate.

Reference

11β-HSD2 promotors

#1 Boost NAD

Since 11β-HSD2 uses NAD as a cofactor, boosting NAD levels is just logical.

One of the best ways to boost NAD levels with to activate NQO1 with quinones and supplement vitamin B3.

My preferred combo for increasing NAD is:

• 500mg niacinamide once daily (this is basically a maintenance dose and it can be higher in a disease state)
• 500mg Pau d’ arco bark (contains beta-lapachone; a strong NQO1 activator)
• 1/2 tsp black cumin seed powder (contains thymoquinone)
• 10mg vitamin K2 (MK-4) daily (I also use it on my scrotum for testosterone production)
• 1mg methylene blue (a redox modulator that increases the NAD:NADH ratio)

#2 Increase DHEA

DHEAS is an inhibitor of 11βHSD1 enzyme in human adipocytes in vitro (R) and promotes 11βHSD2 (R)

#3 Increase IGF-1

IGF-1 inhibit 11B-HSD1, which is one of the reasons why it’s anabolic (R).

#4 Increase cAMP

Cyclic AMP helps to recycle AMP back into ATP, thus improving energy levels.

Intracellular cAMP increase 11B-HSD2 in osteocytes and osteoblasts (R) and caffeine and forskolin increases 11B-HSD2 (R).

#5 Try progesterone

Progesterone promotes 11β-HSD2 (R) and this could be because it’s antagonistic to estrogen and cortisol.

#6 Increase luteinizing hormone (LH)

LH promotes 11β-HSD2 (R). A few herbs such as Tribulus Terrestris, boron, dopaminergics, etc., can increase LH. Estrogen, serotonin, prolactin and opioids are the major inhibitors of LH secretion.

#7 Keep gut bacteria in check

In some cases, excess cortisone and its 5-alpha reduced metabolite, are excreted in the bile. Gut bacteria modify them into 11β-HSD1 and 11β-HSD2 inhibitors.

3alpha5alpha-tetrahydro-corticosterone, its derivative, 3alpha5alpha-tetrahydro-11beta-hydroxy-progesterone (produced by 21-deoxygenation of corticosterone in intestinal flora); 3alpha5alpha-tetrahydro-11beta-hydroxy-testosterone (produced by side chain cleavage of cortisol); are potent inhibitors of 11beta-HSD1 and 11beta-HSD2-dehydrogenase.

Reference

Neomycin, which destroys most gut bacteria, reduces these metabolites.

So it’s imperative not to get an overgrowth of gut bacteria. A major part of the Alpha Energy Nutrition Course is about optimizing the gut, gut bacteria, digestion and so much more.

#8 Avoid 11β-HSD2 inhibitors

• Dithiocarbamates – they are not only used in manufacturing cosmetics, rubber products and agricultural products, but also applicable in treating cancers (R). DTCs thiram and disulfiram appear to be the most potent inhibitors of 11β-HSD2. Thiram is environmentally degraded from DTC ziram. Ziram residues have been detected in food such as rice, beans, apple, banana, orange which are very common in our daily life. Ziram is known to cause endocrine disruption and immune and nervous system toxicity.
• Organotins – increased exposure results from a build-up through the marine food chain or from leaching of polyvinyl chloride from water pipes, food packaging material, fungicides and pesticides and antifouling agents (R).
• Butylated hydroxyanisole (BHA). BHA is a synthetic phenolic antioxidant widely used in food preservation (R).
• Perfluoroalkyl substances (PFASs). PFASs are used in a broad spectrum of consumer and industrial products including surfactants, adhesives, anticorrosion agents and insecticides and as reaction additives in various processes. They are resistant to environmental breakdown and also have very long half-lives in the human body. This is especially true for perfluorooctane sulfonate (PFOS), whose half-life is estimated to be as long as 8.5 years. Significant accumulations of PFASs, especially PFOS and perfluorooctanoic acid (PFOA), have been detected in human blood. There is a worrying fact that the IC50 of PFOS inhibition on human kidney microsome 11β-HSD2 falls into the range of average levels of PFOS worldwide (20–30ng PFOS/ml, 40–60nM). In other words PFOS exposure from environment is enough to cause inhibition on 11β-HSD2 (R).
• Bisphenol A (BPA). We all know that BPA is bad by now. BPA is used extensively in industry and commerce to manufacture polycarbonate plastics (which may be used in baby bottles, water storage tanks or supply pipes) and components of food packaging e.g. in the lining of food cans, among other applications. Bisphenol A (BPA) is an environmental endocrine disruptor which acts as an antiandrogen. This compound not only blocks several testosterone biosynthetic enzyme activities but also inhibits hydroxysteroid dehydrogenases
• Phthalates are synthetic compounds widely used as plasticizers and solvents in polyvinyl chloride products, children’s toys, cosmetics, soaps, shampoos, medical tubing, catheters and intravenous delivery sets (R).
• Zearalenone. Zearalenone is a mycotoxin produced by Fusarium spp which is found in a number of cereal crops such as wheat, maize, barley, oats, rice and sorghum. Coffee and cocoa are also two major sources of mycotoxins. A concerning fact regarding zearalenone is that it remains stable in foods even after heat processing. Zearalenone possesses weak estrogenic activity although it is structurally dissimilar to estradiol. Its estrogenic activity mainly targets the reproductive system (R).
• 2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE). Methoxychlor (MXC) is structurally similar to the famous insecticide Dichlorodiphenyltrichloroethane (DDT) and considered to be the preferred alternative to DDT due to its relatively low toxicity and lower persistence in the environment. MXC, as a pesticide, is sprayed on fruits, crops, vegetables and home gardens to prevent insect damage. After ingestion, MXC is predominantly metabolized into HPTE.
• Glycyrrhizin (GL) and its metabolites, found in licorice (R).
• Fluoxymesterone – a steroid (R).
• Gossypol found in cottonseeds as well as the oil (R). Gossypol was proposed as a drug for male contraception.

Defective 11B-HSD can lead to elevated cortisol, which activates the aldosterone receptors, which promote sodium retention and hypertension.

Summary

There is not a lot of marker that can show if 11β-HSD1 is elevated or if 11β-HSD2 is downregulated.

It’s been proposed that only in healthy subjects, 11β-HSD1 activity was associated with LDL. Also, there is some correlation between AST and 11β-HSD1 activity.

Fasting blood glucose after overnight 1 mg oral dexamethasone is a strong predictor of 11β-HSD1 activity, irrespective of the presence of type 2 diabetes (R).

But even if those markers aren’t elevated, it’s easy to consume some of these compounds mentioned above that will restore proper 11β-HSD1 and 11β-HSD2 function that will also have a lot of other benefits for your health.

My preferred ways of making sure these enzymes are functioning optimally are by:

• Keeping the gut clean and the intestine energized (as taught in the Alpha Energy Nutrition Course)
• Eating nutrient-dense foods (as taught in the Alpha Energy Nutrition Course)
• Optimizing my androgens (such as DHEA)
• Getting sunlight
• Maximizing my NAD:NADH ratio
  • 500mg niacinamide once daily (this is basically a maintenance dose and it can be higher in a disease state)
  • 500mg Pau d’ arco bark (contains beta-lapachone; a strong NQO1 activator)
  • 1/2 tsp black cumin seeds (contains thymoquinone) – chew them with 1 tbsp raw honey
  • 10mg vitamin K2 (MK-4) daily (I use Kuinone) (I also use it on my scrotum for testosterone production)
  • 1mg methylene blue (oxidal) (a redox modulator that increases the NAD:NADH ratio)

Check out the other articles I wrote about cortisol

• How to lower high cortisol
• How to interpret cortisol test results

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