Dr. Vliet’s Health Tip: Sex Hormones and Nitric Oxide Power Couple: Symbiotic Secret to Optimal Health and Desire

So what is this “power couple” doctors overlook?  It is the synergistic interaction between our sex hormones and the master molecule, nitric oxide. Testosterone for men and for women the powerful premenopausal estrogen, 17-beta estradiol, have a critical synergistic relationship with nitric oxide, mutually enhancing one another to regulate vascular health and sexual function. Testosterone and estrogen serve as vital triggers that increase the production of nitric oxide, which subsequently relaxes blood vessels and improves circulation and delivery of oxygen, nutrients and hormones (including testosterone and estrogen) throughout the body.

Nitric oxide is a key messenger that enables hormones to produce physical effects; without enough of it, hormonal signals may not function. This bi-directional signaling ensures that the brain and body can effectively interpret and act upon hormonal commands. Research has shown that maintaining a balance of testosterone and estradiol along with nitric oxide precursors, such as L-arginine or food sources such as beets, creates an optimal environment for many benefits we all need: sexual health, brain function, optimal cardiovascular function, and ability to improve muscle strength and overall energy.  But, before we dive too deep into this power couple’s relationship, let’s do a quick review of what nitric oxide is and what it does in our bodies.

KEY FUNCTIONS OF NITRIC OXIDE:

Nitric oxide (NO) is known as the master molecule and optimizer of blood flow to the whole body. The main function of this amazing little molecule is to dilate blood vessels and improve blood flow throughout the body, enabling delivering essential nutrients, hormones and removing toxic waste products to maintain and optimize health. Nitric oxide also stimulates formation of new blood vessels for tissue repair and wound healing, and to regulates platelet aggregation and reduce the risk of blood clots. Nitric oxide is truly nature’s super optimizer of health!   Some of nitric oxide (NO) functions include:

1. Vasodilation – relaxing and widening of blood vessels to help blood flow, to better deliver oxygen and nutrients to muscles and organs, and regulating blood pressure. Nitric oxide causes vasodilation by inhibiting smooth muscle contraction. Increased blood flow results in increased nutrient and glucose utilization in muscle, especially during exercise.
2. Mitochondrial regulation – Modulates mitochondrial respiration and energy production in cells by acting as a molecular switch that activates PGC-1α, the master regulator of mitochondrial biogenesis and energy metabolism.
3. Neurotransmission – Serves as a signaling molecule for the nervous system and helps improve cognitive function.
4. Platelet function – Helps to regulate platelet aggregation to prevent blood clots and maintain heart health.
5. Relaxation of smooth muscle tissue in gastrointestinal system, airways, urinary bladder, and uterus to regulate the processes of digestion, breathing, urination, menstruation and pregnancy, for example.
6. Immune response – Helps to regulate inflammation and immune cells to kill bacteria, viruses and parasites.
7. Gene expression regulation – Nitric oxide acts as a signaling molecule within cells to regulate gene expression and other cellular processes including cell proliferation (cell growth and division), differentiation (cell specialization), and apoptosis (programmed cell death).
8. Angiogenesis – the formation of new blood vessels important for tissue repair and wound healing.

Unfortunately, most people don’t realize that nitric oxide declines as we age in part from hormone decline, dietary imbalances and stress that decrease nitric oxide production and impair health! I first wrote about this molecule and its role in women’s health in my 1994 book, Screaming to Be Heard: Hormone Connections Women Suspect and Doctor’s Ignore (2001 edition available on Amazon). At the time, nitric oxide was called endothelium-derived releasing factor or EDRF. Then in 1998, three scientists discovered the endothelium-derived releasing factor molecule was actually nitric oxide, which led to their receiving a Nobel Prize.  The simple but powerful molecule we now know as Nitric oxide (nitrogen monoxide) is composed of one nitrogen atom and one oxygen atom. At room temperature, it is an odorless and colorless gas. It used to be thought of as simply the “foundation of heart health” until we realized it’s “master” effects on blood vessels throughout the brain and body as a vasodilator controlling blood flow to help support healthy blood flow pressure and endothelium health (the inner lining of blood vessels). In today’s health tip I dig deeper into the bi-directional relationship of nitric oxide and our sexual hormones (testosterone and estrogen) for men and women and discuss some newer research into the benefits of nitric oxide in gut health with strategies to help restore and maintain optimal levels of nitric oxide as we age.

Male Hormones, Erectile Dysfunction and Nitric Oxide (NO)

• Testosterone can positively regulate nitric oxide production, while nitric oxide also influences testosterone secretion. Each one influences the other’s levels and effects, particularly in the context of sexual health and endothelial function.
• Erectile Dysfunction – Nitric oxide is a key mediator of penile erection by stimulating the relaxation of smooth muscle cells in the erectile tissue leading to increased blood flow for the attainment of erection.
• Testosterone promotes production of Nitric oxide, especially in the corpus cavernosum (the tissue responsible for penile erection) through various mechanisms, including activation of endothelial nitric oxide synthase enzyme, which is crucial for Nitric oxide production.
• Sexual Excitation – Both testosterone and Nitric oxide levels increase during sexual arousal, and there is a strong correlation between our hormone and nitric oxide levels and sexual response in both men and women.
• NOTE: Nitric Oxide can have a dual effect on testosterone secretion. At low concentrations, Nitric oxide can stimulate testosterone production when levels are in the physiological range.  At excessively high concentrations, however, it can inhibit it. So beware, supraphysiological dosing is not recommended.

Female Hormones, Sexual Function and Nitric Oxide

• Estrogen (in particular, 17-beta estradiol, the primary pre-menopausal estrogen) and nitric oxide work together to maintain healthy blood vessels, reducing risk of stroke, protecting the brain and cognitive function, and maintaining healthy blood pressure. Estradiol decline in menopause also leads to decline in Nitric oxide production.  That means the combination of estradiol decline and decrease in nitric oxide is a main cause for menopausal women to have higher blood pressure, and loss of memory, low mood, disrupted sleep and impaired concentration.
• Increased Nitric oxide production – using 17β-estradiol boosts the expression and activity of nitric oxide synthase, the enzyme responsible for NO production.
• Sexual Function – Nitric oxide is involved in sexual arousal and function, with links to improved blood flow to the genital area.

Boosting Nitric Oxide Levels

L-arginine acts as the linchpin in the bi-directional relationship between sex hormones and nitric oxide as described below and in the following graphic.

• The Conversion Process: The enzyme endothelial nitric oxide synthase is responsible for converting L-arginine into nitric oxide within your blood vessels.
• Both testosterone and estradiol directly enhance the expression and activation of this endothelial nitric oxide synthase enzyme. By doing so, these hormones increase the body’s demand for and utilization of L-arginine to create nitric oxide.
• L-arginine as the Critical Effector: Nitric oxide acts as the “messenger system” that allows testosterone and estradiol to fully express their benefits. If you have an arginine deficiency, the resulting low Nitric oxide means that even normal levels of testosterone or estrogen will produce weaker functional effects, such as reduced vasodilation or weaker erections.
• Optimization and Stacking: Using L-arginine for supplementation helps maintain a “robust Nitric oxide environment”. Supporting the Nitric oxide pathway with arginine not only ensures that your sex hormones work better at the tissue level, but it also helps reduce inflammation and oxidative stress, indirectly maintaining a more favorable hormonal environment overall.
• As you can see in the diagram below, Nitric oxide is synthesized in the body through a process of converting L-arginine (a “semi-essential” amino acid) into nitric oxide and citrulline. Once synthesized, Nitric oxide is released to diffuse freely across cell membranes to exert its effects throughout the body.

Nitric oxide plays a multifaceted role in brain function, acting as a signaling molecule with both neuroprotective and neurotoxic effects. It’s involved in regulating cerebral blood flow, synaptic plasticity, learning, memory, and even has positive influence on our sleep-wake cycle. Nitric oxide is essential for normal brain function, contributing to neurovascular coupling, synaptic plasticity, and other vital processes.

• Neurovascular Coupling – Nitric oxide helps regulate blood flow in the brain, ensuring that blood supply matches neuronal activity. This is crucial for providing neurons with the necessary oxygen and glucose for proper function.
• Synaptic Plasticity – Nitric oxide acts as a retrograde neurotransmitter, influencing synaptic transmission and contributing to processes like long-term potentiation (LTP), which is important for learning and memory.
• Neuroprotection – In appropriate concentrations, Nitric oxide can protect neurons from damage by influencing various cellular processes like protein modification, dendritic spine growth, and myelination.  In various diseases, such as stroke, traumatic brain injury, and neurodegenerative disorders, NO can become dysregulated, contributing to neuronal damage and disease progression.
• Neurotransmitters – Nitric oxide can modulate the release and reuptake of neurotransmitters like dopamine, influencing their availability in the synapse.
• Treating secondary brain injury after trauma—Targeting the NO pathway is a potential therapeutic strategy for various neurological conditions. For example, Nitric oxide donors (chemical compounds that release nitric oxide) have shown promise in treating secondary brain injury after trauma.
• Neurodegeneration – It is important to avoid excess nitric oxide since excess nitric oxide can actually contribute to unwanted neurodegeneration. Excessive Nitric oxide production can lead to oxidative stress, neuronal damage, and neurodegeneration. This is observed in conditions like Alzheimer’s disease and other neurodegenerative disorders.

Post Traumatic Stress Disorder (PTSD):

• Nitric oxide plays a significant role in the development and progression of PTSD, particularly in the context of fear and memory. Studies suggest that alterations in NO signaling, especially involving the enzyme neuronal nitric oxide synthase, are linked to PTSD symptoms and related behaviors. Furthermore, manipulating Nitric oxide levels, such as through nitrous oxide inhalation has shown promise as a potential therapeutic approach for some individuals with PTSD.
• The “global arginine bioavailability ratio” (GABR), reflects Nitric oxide synthesis capacity, is decreased in veterans with PTSD. Increasing Nitric oxide bioavailability through nutritional interventions (e.g., increasing arginine intake) helps reduce PTSD symptom severity.
• In my medical experience, PTSD treatment adding proper testosterone therapy for men and optimal estradiol therapy for women has a synergistic effect to improve Nitric oxide levels, improve sleep and reduce PTSD anxiety and depressed mood.

Heart Health

• Nitric oxide plays an important role in protection against the onset and progression of cardiovascular disease. The heart protective roles of Nitric oxide include blood pressure regulation, vascular tone, inhibiting platelet aggregation and leukocyte adhesion, and prevention of smooth muscle cell proliferation.
• Low Nitric oxide levels are linked to hypertension, atherosclerosis, cardiomyopathy, congestive heart failure and heart attacks fundamentally via endothelial dysfunction, impaired blood flow and oxygen delivery to heart and lungs.

Diabetes

• Nitric oxide is a critical molecule in glucose metabolism. In diabetes, dysregulation of nitric oxide pathways can contribute to complications like kidney disease and blindness.
• Nitric oxide deficiency impairs blood vessel function and also lowers insulin sensitivity.
• Nitric oxide excess can be detrimental. High glucose levels in diabetes can lead to increased production of Reactive Oxygen species which that in turn inactivate Nitric oxide and contribute to oxidative stress and tissue damage.
• Medications that release nitric oxide are being explored as potential therapies for improving insulin sensitivity and glucose control in diabetes.

COPD

• Studies show L-arginine metabolism is disturbed in individuals with COPD. With less L-arginine available for nitric oxide synthase (NOS) activity, less nitric oxide is produced.
• A recent randomized controlled trial published in the European Journal of Internal Medicine has shown that supplementing with L- arginine and liposomal vitamin C improves self-reported shortness of breath and the ability to perform daily activities in individuals’ chronic obstructive pulmonary disease.

ADDITIONAL Nitric Oxide BENEFITS:

• Hair and skin health, repair and even protection from sun damage.
• Improved exercise performance, including endurance, delayed fatigue, better muscle recovery and growth, less muscle soreness.
• Reduced inflammation throughout the body.
• Improved immune function.

FACTORS THAT DECREASE NITRIC OXIDE:

• Aging: As we get older, Nitric oxide production declines, which is a big reason to consider supplements that increase Nitric oxide levels, as I will describe further below. Age effects are due to several factors: reduced synthesis, increased breakdown, and impaired signaling.
• Endothelium damage with age: impairs blood vessel lining’s ability to synthesize Nitric oxide because nitric oxide synthase, the enzyme responsible for producing Nitric oxide declines with age. There is also an increase in levels of reactive oxygen species (ROS) that react with Nitric oxide forming peroxynitrite that inactivates Nitric oxide.
• Older people also have diminished levels of nitrate-reducing bacteria in the mouth, and impaired Nitric oxide transport pathways to name a few of age-related changes in the body that reduce levels of Nitric oxide.
• Hypothalamic hypogonadism – i.e. stress-induced ovarian suppression in women and testicular suppression in men. MANY factors cause this in younger men and women: competitive athletics, anorexia, bulimia, use of psychotropic medicines (especially SSRIs, SNRIs, and atypical antipsychotics such as for PTSD, depression, anxiety, etc), marijuana/alcohol/narcotic use, nutritional deficiencies, COVID vaccines, COVID and other infectious illnesses (especially if chronic and subclinical residual effects).
• Menopause (natural or surgical) that leads to decline in estradiol
• Male Andropause and decline in testosterone
• Prescription medicines (via several mechanisms): big culprits are SSRIs, SNRIs, atypical antipsychotics, narcotics, beta blockers, chemotherapy drugs.
• Stress, COVID injections, severe illnesses and major surgeries also decrease Nitric oxide production and increase inflammation that damages vascular pathways and immune function.

ACTION STEPS TO RAISE NITRIC OXIDE LEVELS:

• Regular exercise
• Stress management
• Eat a balanced diet rich in vegetables and focus on those foods that increase Nitric oxide production: leafy greens, spinach, arugula, kale, beets and beet root juice, ginger, and celery.
• Add more fruits that increase nitric oxide: citrus, pomegranate, and watermelon all contain citrulline that is converted into arginine.
• Dark chocolate contains flavonoids that increase Nitric oxide production.

SUPPLEMENTS TO BOOST NITRIC OXIDE LEVELS:

1. Nitric Oxide supplements contain precursors for the body to make more Nitric oxide.  L-arginine is the most common supplement used to increase nitric oxide. Age and stress increase the need for L-arginine to make Nitric oxide.  L-citrulline is another supplement option that helps improve nitric oxide. These two supplements DO NOT contain actual nitric oxide gas.
2. Several factors, listed above in action steps, work together to affect L-arginine being utilized effectively to boost nitric oxide production, improve overall health and help the body’s natural L-arginine saturate the enzyme Nitric oxide synthetase.  Just taking extra L-arginine alone may not be enough to significantly increase Nitric oxide production.
3. L-arginine supplements have additional benefits beyond increasing Nitric oxide: protein synthesis, ammonia detoxification, hormone secretion, and immune function. Athletes often use L-arginine to increase “muscle pump” during a workout and for several hours afterward, and to increase in overall workout capacity (muscular endurance) and an increase in post-exercise recovery.

Optimizing Benefits of L-Arginine Supplementation:

•  recommend our TruNitricOxide SR™ which has a unique patented extended-release form of L-arginine to prolong bioavailability of L-arginine to make Nitric oxide.
• TruNitricOxide SR™ also contains ACTINOS2, a mixture of both high- and low-molecular weight fractions of proteins and peptides that activate NOS to boost nitric oxide production, enhance transcription of the NOS gene and support its role in reducing the negative feedback mechanism for Nitric oxide production.
• Studies found ACTINOS2 increases Nitric oxide production in human endothelial cells in vitro from 9.5 to 12.7 times compared to a control.

I also selected our TruNitricOxide SR™ product because it is manufactured in the United States using the highest purity (>98.0%) of commercially available L-arginine alpha ketoglutarate.  This formulation is designed to deliver L-arginine alpha ketoglutarate in a controlled manner over a period of approximately 4-6 hours.

CAUTIONS:
Nitric oxide is dose dependent as with many medications, drugs or supplements. Too little (deficiency) can cause many unwanted health effects, and lead to chronic fatigue and chronic illness. But too much can cause unwanted side effects also. Some of the side effects of excessive Nitric oxide include inflammation and oxidative stress, hypotension, headaches, bleeding risk, worsening of respiratory conditions like asthma, respiratory distress, lung damage and even death in rare cases of nitric oxide toxicity usually only in occupational settings.
Nitric oxide can also interact with other drugs and medications and enhance their effects, which could possibly lead to unwanted results. Check with your physician before combining ANY Nitric Oxide supplement when you take these RX medicines:

• Blood pressure medications. Adding NO can lower blood pressure further, which means your doctor may need to lower your Rx dose to avoid dropping blood pressure too much.
• Erectile Dysfunction drugs – Viagra, Cialis, Levitra.
• Anticoagulants and antiplatelet drugs -warfarin, heparin, aspirin, clopidogrel.
• Alpha-blockers used to treat benign prostatic hyperplasia (BPH) and hypertension.
• Any Rx medicines that affect cytochrome P450 enzymes.

I encourage you to consider our other natural medicines with our top quality, cGMP-compliant professional formulas: TruMitochondrial™ Boost,  TruNAC™, Tru BioD3, Tru B™ Complex Full Spectrum, TruZinc™, TruC with BioFlavonoids  (Natural sourced Vitamin C with complete Bioflavonoids), and TruProBiotic™ Daily to replenish critical bifidobacteria depleted by COVID shots, viral illnesses, and antibiotic therapy.

All Truth for Health Foundation Products Meet or Exceed cGMP Quality Standards, the highest quality standard for supplements sold in the USA. For more information, references from studies are listed in the Product Data Sheets for each product, available on our website.  Check us out at www.TruthforHealth.org Click on tab for Store.  OR www.shopTruthforHealth.com

CAUTION: As always, we urge you to avoid supplements without checking knowledgeable sources to evaluate your medical situation, proper lab tests to verify what is needed, and to make sure to avoid adverse interactions with prescription medicines and other supplements you take.  Under medical practice regulations, we are unable to answer individual medical questions or make specific individual supplement recommendations for people who are not established patients of Dr. Vliet’s independent medical practice (www.ViveLifeCenter.com).

To Your good health and improving resilience!
Elizabeth Lee Vliet, MD