Erectile dysfunction Part 3: nitric oxide, oxidative stress and insulin resistance

The cause of ED is rarely because of just one thing, but it’s often multifactorial, with lifestyle, neurologic (neurotransmitters and neural health), hormonal (testosterone, estrogen, DHT, prolactin, etc.), vascular, and psychological factors playing a role.

Welcome to part 3 of our erectile dysfunction series, where we’ll discuss nitric oxide, oxidative stress and inflammation and how to stop it.

Please check out part 1 and 2 of the series if you haven’t already. I’ll assure you that you’ll find it very interesting.

• Erectile dysfunction part 1: the solution to your neurotransmitters
• Erectile dysfunction part 2: which hormone to optimize and how
• Erectile dysfunction part 3 – the one you’re reading right now
• Erectile dysfunction part 4: which supplements to use
• Erectile dysfunction part 5: porn and masturbation 

In this article we’ll discuss:

• Nitric oxide
• Oxidative stress
  • Iron & copper
  • Polyunsaturated fat
  • Uncoupled eNOS
  • Hypertension
  • Lack of oxygen
  • Endotoxins
  • Sleep apnea
  • NAD:NADH ratio
  • Insulin resistance
  • Uric acid 
  • Kidney failure
• A few other causes of ED

Nitric oxide and erections

Let’s talk nitric oxide (NO). You probably can’t believe you had to wait till part 3 to hear about it? Isn’t NO the main erectogenic compound? Shouldn’t we have focused on that from the start?

First off, NO is important, but there are other erectogenic molecules as well, such as carbon monoxide (CO) and hydrogen sulfide (H2S). These would be considered NO-independent erectogenic.

Plus, about 30-40% of the people using NO boosters, such as Viagra, don’t get results, and this is increased even more in people with nerve damage, oxidative stress and insulin resistance.

Let’s start at the beginning.

NO basics

NO is created by nitric oxide synthase (NOS), of which there are three types, namely, endothelial NOS (eNOS), neuronal NOS (nNOS) and inducible NOS (iNOS).

All three can promote vasodilation and erection. iNOS is different from the other two, in that it can be induced. Once induced, iNOS can create a 1000 times more NO that the other 2 enzymes.

As seen in part 2, excess NO, induced by estrogen, promotes vascular leakage and can be detrimental to erections. In fact, recent data reveals more than 80% of ED has an organic basis, with vascular disease being the most common. Excess NO = vascular disease = ED.

Things that promote iNOS, include endotoxins (which are absorbed from the gut), infection and inflammation.

NO can be very harmful

When the body isn’t functioning optimally anymore, it’s producing an excess of free radicals (or reactive oxygen species (ROS)), specifically superoxide.

Excess superoxide has been shown to impair erectile function by inducing vascular damage, promoting inflammation and collagen formation (fibrosis of the penis) and a reduction in NO (R).

Superoxide reacts with NO to create the highly toxic peroxynitrite. So if you’re in a state of high ROS and NO, you’ll be creating a bunch of peroxynitrites and wreak havoc to your body including your crown jewels.

Peroxynitrite, in turn, uncouples eNOS to create superoxide instead of NO, which further contributes to the oxidative burden.

So the point should be to lower oxidative stress and iNOS, instead of getting eNOS to work properly again. Besides, pumping more arginine into the system will just be used by iNOS and eNOS to create more NO and superoxide respectively, and drive the peroxynitrite levels into outer space.

So here is our plan of action. We’re going to lower oxidative stress as well as iNOS and then upregulate eNOS again to restore proper erectile function

Here we go.

Oxidative stress

Oxidative stress is probably the biggest driver of disease, aging, neurological damage, erectile dysfunction and penile fibrosis.

Research shows that oxidative stress and inflammation are elevated in people with ED. Look to markers such as homocysteine and hsCRP, both of which are usually elevated in ED (R).

Physical symptoms, such as psoriasis, IBS, eczema, arthritis, etc., are also present together with ED (R).

Anti-oxidants, such as vitamin E, selenium, zinc, manganese, glycine, taurine, aspirin, etc., are able to reduce age-related erectile dysfunction (R).

A. Iron & copper excess creates ROS

Iron and copper are reactive metals that can react with a free radical, namely hydrogen peroxide (H2O2), in the process called the Fenton reaction. The reaction creates the hydroxyl radical (•OH) which can damage critical cell membranes in and around the penis leading to ED (R).

Getting iron tested can help determine if it should be a concern or not.

> What to get tested for an iron panel and how to interpret it

B. Polyunsaturated fats

Polyunsaturated fats (PUFAs) are another danger to the body. The many double bonds in its structure are highly sensitive to ROS and can easily be oxidized. The more unsaturated the fat, the easier it gets damaged. Fish oils, being the most unsaturated, can be the most harmful if consumed in large amounts due to being the most unstable.

Apart from being easily oxidized, PUFAs can also be used by the cyclooxygenase 1 and 2 (COX1 and 2) enzymes, which creates vasoconstrictive prostaglandin F2-alpha (PGF_2α), PGI₂ and thromboxane A₂ (R).

Aspirin, which is a very potent COX inhibitor has been tested for ED.

In a prospective randomized double-blind placebo-controlled study, Zeki Bayraktar, MD, and Selami Albayrak, MD, of Istanbul Medipol University in Turkey, found significant improvements in erectile function when given 100 mg/day of aspirin for 6 weeks (R).

C. Uncoupled eNOS

As mentioned above, eNOS can uncouple and produce superoxide, a free radical, instead of NO.

eNOS uses arginine as a substrate and BH4, vitamin B2 and iron as a cofactor. BH4 can also act as an anti-oxidant, and oxidative stress lowers BH4 levels. 

Supplementing BH4 does not restore (re-couple) eNOS function, but it does help to prevent additional oxidative stress (R). Additional BH4 supplementation can be a good thing because BH4 is also used in the synthesis of dopamine and serotonin. Oxidative stress can lower serotonin and dopamine synthesis and supplementing BH4 can restore their synthesis.

Providing more arginine when eNOS is uncoupled doesn’t restore proper eNOS function, but can support additional iNOS function.

There is research that shows that by inhibiting arginase, the enzyme that competes with eNOS for arginine, can restore eNOS function.

Arginase I is found in the urea cycle which converts arginine into ornithine and urea. Too much arginase and you can have low NO and high uric acid. Low arginase activity, on the other hand, can lead to ammonia build-up.

Arginase inducers are endotoxins, inflammation, peroxynitrite, hyperglycemia, nitric oxide, angiotensin II, intracellular calcium (induced by EMF and low magnesium) and cortisol.

A few good arginase inhibitors include ginger, saffron, cocoa, Panax ginseng, moringa, African basil (R), Tongkat ali (R), Cylicodiscus gabunensis (R), turmeric (R), cocoa powder, coffee, onion and pomegranates.

Of the compounds found in these foods, these are the most potent; in descending order: Chlorogenic acid (most potent) < piceatannol < Epicatechin < dihydroquercetin (taxifolin) < quercetin (R)

In my opinion, supplementing arginine or trying to boost NO to restore endothelial function is not a wise approach, unless iNOS is inhibited and oxidative stress lowered. Agmatine might be a good supplement to use as it inhibits iNOS, re-couples eNOS (restores it proper function) and lowers oxidative stress.

Viagra, which significantly increases NO levels, contributes to eye degeneration, headache, heartburn, facial flushing, nasal congestion, visual disturbances, myalgia (muscle pains), low blood pressure, auditory changes (hearing loss and tinnitus), etc. (R) Excess NO is not a good thing. Check out my other article on excess NO:

> Nitric oxide: more than just a vasodilator

D. Angiotensin II – hypertension

As previously discussed, stress, estrogen, oxidative stress, serotonin, etc., can increase the renin-angiotensin-aldosterone system. To recap on this system, check out part 2 again.

Angiotensin-converting enzyme 1 (ACE1) converts angiotensin 1 into angiotensin 2. Angiotensin 2 has inflammatory and vasoconstrictive properties and can lead to penile fibrosis (R).

Losartan, an inhibitor of ACE1, lowers angiotensin 2 and reduces inflammation and hypertension.

Exercise and treatment with angiotensin II type 1 (AT₁) receptor antagonists (such as Losartan) improve erectile function.

It’s not necessarily hypertension itself that contributes to ED, but it’s the decreased elasticity (due to fibrosis) due to inflammation induced by angiotensin 2.

E. Lack of oxygen (hypoxia)

Low hemoglobin, low CO2, excess nitric oxide, hyperventilation, breathing in air pollution, free serotonin in the blood, inflammation, etc., can all induce a hypoxic state in the body.

Hypoxia means that the tissue is not getting enough oxygen. Hyperventilating, to increase the intake of oxygen, only makes this worse. This is because hyperventilation blows off most of your carbon dioxide (CO2), and CO2 is needed to push the oxygen into the tissue (Bohr effect).

Hypoxia in the penis leads to an increase in fibrosis, which will decrease blood flow, erection capacity as well as penis size (R).

Rhodiola Rosea, vitamin B1 (R), vitamin B2 (R), niacinamide (R) and methylene blue (R), oppose hypoxia and lessens the damage induced by hypoxia (R).

F. Endotoxins

Endotoxins or lipopolysaccharides, found in the cell membrane of gram-negative bacteria in the gut can be highly toxic to the body when absorbed in large quantities.

Small amounts of endotoxins are normally absorbed and the liver just detoxes it. However, when you have leaky gut, when you exercise in the heat, when blood sugar drops too low or when there is inflammation in the gut, large amounts of endotoxins are absorbed. This overwhelms the detox capacity of the liver and then these endotoxins go and create damage and inflammation everywhere in the body.

Endotoxins bind to the toll-like receptor 4 (TLR4) in order to induce inflammation. TLR4 overactivation impairs the ability of the smooth muscle of the penis to relax for an erection to occur, by:

• increasing inflammation
• increasing ROCK, which inhibits relaxation. Testosterone inhibits ROCK.
• reducing NO bioavailability

All of this leads to vascular and structural dysfunction of the penis and contributes to ED and eventually fibrosis (R).

The fastest way to get rid of endotoxins is to lower excess gram-negative bacteria in the gut with anti-bacterial substances, such as monolaurin, oregano -, cinnamon -, clove -, thyme essential oil, olive leaf extract, flowers of sulfur, CamphoSal, etc.

Then to bind that dead bacteria to something and excrete it from the body, you can use activated charcoal, bentonite clay, grated carrot, cooked white button mushrooms, etc.

G. Sleep apnea

Sleep apnea is a significant contributor to tissue hypoxia and oxidative stress. Sleep apnea can greatly contribute to ED (R, R, R).

A CPAP mask is most commonly used with great success to resolve sleep apnea, but taping your mouth shut can also greatly help.

If your nose is blocked, use an H1 histamine antagonist, vitamin B1 (100-500mg) and a tat (∼1mg) of methylene blue before bed to unblock your nose.

H. NAD:NADH ratio

The NAD:NADH ratio is the best indicator of the redox balance, meaning, how effective the metabolism is working.

Although you can’t test it directly, you can test the acetoacetate to hydroxybutyrate ratio, which reflects the NAD:NADH ratio pretty closely. You want a very high NAD:NADH (acetoacetate:hydroxybutyrate) ratio.

NAD is converted to NADH during the breakdown of glucose and fats and is used in the electron transport chain to create energy. When the electron transport chain isn’t working that great (complex I specifically), then NADH builds up and creates ROS. Vitamin B1, B2 and choline support complex I function. Alternatively, NADH can also donate its hydrogen to methylene blue, vitamin C and CoQ10, thus increasing the NAD:NADH ratio and lowering ROS.

Another process that rapidly uses NAD and lowers the NAD:NADH ratio is the PARP enzymes. The PARP enzymes are needed to repair DNA damage, but when they become overactivated, they deplete the NAD and lower the NAD:NADH ratio, which increases ROS and oxidative stress.

Overactivation of the PARP pathway in the penis contributes to vascular damage and a drop in the NO/cGMP pathway resulting in ED (R).

Inhibitors of the PARP enzymes include (R, R):

• niacinamide
• myricetin (found in fruits (oranges and berries) and vegetables)
• tricetin (found in the pollen of Eucalyptus trees)
• gossypetin (found in the Roselle plant)
• delphinidin (found in grapes, cranberries, pomegranates and bilberries)
• quercetin (found in radish leaves, carob, dill, cilantro, onion, watercress, kale, apples, etc)
• fisetin (found in strawberries, apples, persimmons, onions and cucumbers)
• caffeine metabolites (found in coffee obviously)
• theobromine (found in cocoa powder)
• theophylline (found in cocoa powder and some teas)

I. Insulin resistance

According to this paper, the prevalence of diabetes (type 2 diabetes and type 1 diabetes) will increase by 54% to more than 54.9 million Americans between 2015 and 2030 (R). And that is just in America alone.

According to Dr. Paul Saladino, more than 80% of people have some sort of metabolic disorder that is effecting insulin sensitivity aversely.

In clinics that treat ED, about ∼50% of people who have ED also have diabetes (R).  However, about 100% of people with diabetic neuropathy have ED.

In diabetics, triglycerides, free fatty acids, fasting glucose, fasting insulin, uric acid, oxidized cholesterol, etc., are elevated. With that in mind, some “gurus” would like to say that hyperglycemia is the bad guy that’s causing all the issues.

What causes hyperglycemia? Carbs? Wrong!

It’s fats. Fat contributes to insulin resistance and inhibits the oxidation of glucose and this leads to insulin resistance. Blocking elevated lipolysis dramatically improves insulin sensitivity and glucose disposal (R). Magic!

The pharma companies even made a synthetic analog of niacin, called Acipimox, to inhibit lipolysis and improve insulin sensitivity. But you don’t necessarily need to take drugs to inhibit lipolysis.

Aspirin, niacin, curcumin (R), tyramine, berberine (R) and many other compounds found in herbs, fruits and vegetables are able to inhibit excess lipolysis.

Visceral fat and inflammation (induced by all the things discussed up to now) are major drivers of lipolysis and insulin resistance.

Cortisol and insulin resistance is the biggest contributors to visceral fat gain. So the fastest way to get rid of visceral fat is to lower cortisol and inflammation and lose fat.

Additionally, insulin inhibits the breakdown of dopamine, and in an insulin resistant state, dopamine breakdown is increased. And we know by now how important dopamine is for libido and erections. If you haven’t checked out part 1 already where I talk about this, please check it out after completing this article.

J. Uric acid

People with ED also have a much higher chance of having/getting gout (R). For each 1mg/dl increase in serum uric acid level, the risk of ED increases twofold. However, according to this study, uric acid is a marker of ED but only if there are also vascular complications present as well (R).

This could mean that uric acid isn’t directly harmful and does not contribute to ED, but could rather indicate that uric acid is found to be high when ED is present. Association doesn’t equal causation.

Interestingly, uric acid is actually an anti-oxidant and has anti-inflammatory and arthroprotective (protects against the formation of atherosclerosis) effects (R).

Some papers do show that uric acid can actually deactivate NO and contribute to hypertension (R). But this only occurs in the presence of low glutathione.

So what is the cause of elevated uric acid and should we be concerned?

If you have digestive issues and inflammation in the body with low glutathione levels, then uric acid could contribute to ED by deactivating NO. But on the other hand, uric acid acts as an anti-oxidant. So do we want to focus on lowering uric acid or do we want to fix what is causing it to be elevated in the first place?

I vote the latter.

iNOS, elevated arginase and lactate can increase uric acid in the body. Lowering endotoxins can help lower iNOS. I already discussed a few things that can inhibit arginase. In terms of the lactate, tissue hypoxia causes glucose to be wasted to lactate, so fixing that should lower the lactate and then the uric acid. Vitamin B1 inhibits the conversion of pyruvate to lactate so that could be a good addition.

K. Kidney failure

Kidney function directly correlates with erectile function. Kidney deficiency is believed to be the cause of impotency in Chinese literature. Poor kidney function can lead to erectile dysfunction and this blocking activity is inversely correlated with glomerular filtration rate (GFR). The ED causing effect of poor kidney function is almost entirely eliminated after kidney transplantation (R).

Kidney function is essential for health. The kidney is responsible for:

• regulating blood pressure
• maintaining fluid balance
• regulating/balancing minerals in the blood
• the synthesis of erythropoietin. Erythropoietin stimulates nerve regeneration. Remember, nerve degeneration leads to ED.
• the excretion of toxins and metabolic byproducts
• activating vitamin D
• regulation of pH
• etc…

Poor kidney function can be caused by:

• oxidative stress
• excess dietary phosphate (R) – found in high amounts in grains, legumes, nuts, seeds, beans and meat. Phosphorus is a significant predictor of ED and a strong factor that can be modified in the middle-age (R).
• elevated parathyroid hormone (PTH) – due to low vitamin D and calcium intake and high phosphorus intake.
• excess omega 6 (R). The 12/15-lipoxygenase enzymes appear to create pro-resolving lipid mediators that improve kidney function. Aspirin has been shown to increase resolvins (R, R).
• low vitamin K2 levels (R)

Olive leaf extract (R), rosemary (R), glycine (R), vitamin K2, coffee (R, R), etc., are beneficial to the kidney and can improve kidney function.

A word on hydrogen sulfide (H2S)

H2S has vasodilatory properties by boosting cyclic guanosine monophosphate (cGMP) by inhibiting phosphodiesterase 5 (PDE5), amplify the bioactivity of NO and increasing eNOS activity. 

eNOS, in turn, can also increase the expression of the enzyme that creates H2S, namely, cystathionine γ-lyase (CSE), thus increasing H2S synthesis. Perhaps it is appropriate to view NO and H2S as teammates that work together in complementary ways to promote cardiovascular health (R). H2S, contrary to NO, does not promote vascular leakage and disease but is highly protective to the vascular system.

A few things that can increase H2S include:

• taurine (R) – 500mg-1.5g
• Vitamin D (R)
• Aspirin (R, R) – 81mg-1600mg. The large dose has been found to significantly increase testosterone levels.
• N-acetylcysteine (NAC) by providing L-cysteine.
• Sulfur rich food such as garlic, onion and egg whites
• Meat for methionine & cysteine
• Vitamin B6 as it’s a cofactor for the enzymes that create H2S

A few other causes of ED

Infections

Infection, such as HIV, periodontitis, etc., can increase the risk of ED (R, R). Excess endotoxins in the gut can also contribute to infections, so it’s highly recommended to look after your gut.

Weed

Research suggests that ED is twice as high in cannabis users compared to non-users (R). This could be because the compounds in weed, THC and CBD (although CBD is not as potent as THC) lowers testosterone and energy production while increasing serotonin. If you don’t know why that is bad, please take a look at the serotonin section in part 1.

Second-hand smoke

Second-hand smoke induces oxidative stress, lowers testosterone and can contribute to ED (R). It doesn’t have to be only second-hand smoke, but smoking, in general, can negatively affect your erectile quality.

Conclusion

Excess oxidative stress and inflammation are no joke so don’t let it get out of hand. The most important things to pay attention to are your diet, lifestyle (sleep and activity level), stress levels, environmental toxins (mold, air pollution, poor water quality, excess EMF exposure, etc.) and gut health. Optimizing those should greatly help to reduce oxidative stress and inflammation.

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