Nitric Oxide: The Magic Midlife Molecule

From fatigue to hot flashes to heart disease, why every midlife woman needs to learn about the effects of declining nitric oxide levels.

In a million years, I never would have guessed the places researching this book would take me. I thought I’d find the info and just relay it to you. Easy, right?

Instead, I found myself digging for hours, creating theories and connecting the dots. This happened for two reasons. First, midlife is not a defined developmental/lifecycle stage in nutrition and health. And because of that (and second), there are many gaps in the research.

It’s no wonder a book like mine has not been written yet and why most of the focus is on perimenopause and menopause. That’s where the info, attention, and research is.

Don’t get me wrong, we need more awareness about menopause. But we also desperately need to learn more about how the body changes at midlife. Having this info could also change the course of menopause and its potential adverse effects.

My biggest aha yet: Nitric Oxide

When I first started researching midlife health, I stumbled across this article about nitric oxide. I was surprised by this molecule’s importance, after checking the research. But even more surprising was how little people knew about it.

Nitric oxide is a vital signaling molecule responsible for vasodilation, increasing blood flow, and maintaining vascular function. It was first identified in research studies in the 80s, and three researchers received the Nobel Peace prize for it in 1998.

Nitric oxide is a key biological messenger within the body. When released by the cells lining your arteries, it makes the walls of the arteries relax, allowing more blood to flow. - Michael Gregor, MD

It’s a simple molecule with one atom each of oxygen and nitrogen (NO) — with a second’s short half-life. That’s why the body needs to constantly produce it.

I have since followed the work of Dr. Nathan Bryan, nitric oxide expert who promotes nitric oxide’s role in human health and disease prevention. I interviewed him for the podcast a while ago but it his side didn’t record. It’s one of my biggest regrets.

According to Bryan, it takes about 17 years for new discoveries to make its way into the mainstream, so that may be why the word just isn’t out yet on NO.

The body generates most NO from two key pathways. First, NO is produced from the inner cells that line blood vessels called the endothelium through the nitric oxide synthase enzyme (eNOS). And second, is through the diet. Yet both aging and declining ovarian hormones cause the first pathway of NO to diminish.

For instance, according to Bryan, by the time a person is in their 40s, they produce half the nitric oxide they did from when they were in their early 20s. In other words, young arteries have tons of NO, but as we age, not so much (although my book will contain lots of ways to combat this).

And estrogen and progesterone help stimulate nitric oxide, too. It makes sense. In fertile women every month, the body is preparing for a potential pregnancy, so increasing blood flow is important.

As nitric oxide declines the endothelium suffers which is referred to as “endothelial dysfunction.” The arteries become more narrow and prone to plaque forming. Endothelial dysfunction is the silent, initial stage of heart disease. It goes unnoticed because clinical signs aren’t apparent yet.

Read: Heart Health for Women over 40 Comes Down to This

This is what makes second pathway that is generated from diet so important. This is called the “nitrate-nitrite-nitric oxide” pathway shown in the figure below from Kurtz et al 2018 Journal of Cardiology.

After ingesting nitrates from food (excellent sources: leafy greens, celery, and beets) bacteria reduces nitrate to nitrite. Acid in the stomach further reduces nitrite to NO, where it then goes into circulation.

For instance, a woman who has had low blood pressure may see it inch up after 40. She may think: “why is this happening, I’ve always had low blood pressure and haven't changed anything.”

Not getting adequate nitrates from her diet makes matter worse. But it may take years before blood pressure rises for some women. Yet many of us will feel tired and lethargic due to lower levels of NO and declining blood flow.

Another hidden culprit is the use of mouthwash which kills bacteria that reduces nitrate to nitrite. Then there’s over the counter antacids or prescribed proton pump inhibitors which decrease stomach acid needed in the final step of the Nitrate-Nitrite-NO pathway.

Someone may not feel the effects of using mouthwash until they are older and produce less NO. Crazy right?

Could NO play a role in the development of hot flashes?

As I kept digging, I found that nitric oxide is involved in more than the cardiovascular system. NO also plays potential roles in sleep, healthy aging, the GI system, immunity, insulin sensitivity, mitochondria function, nervous system maintenance, red blood cell health, and even menopause symptoms.

When I ran across a few studies, I made the connection between NO and hot flashes. This study explains the theory and this study was done with nitroglycerin patches, the organic form of nitrates. Post-menopausal women who wore nitroglycerin patches had a 69% decline in modest to severe hot flashes after four weeks.

A recent follow up study was just published but it lasted longer, 12 weeks. There was no difference in hot flashes in the women who wore nitroglycerin patches and those who didn’t.

The problem with organic nitrates found in nitroglycerin is the body develops a tolerance for it and actually produces less NO, which is why it’s not a long-term therapy. The theory behind the study is that NO vasodilation occurs during hot flashes, so let’s cut off NO? No!!

Why don’t we study the effects of inorganic nitrates in vegetables and/or nitric oxide supplements like beetroot juice and hot flashes? After all, this 2022 study in Menopause showed a plant-based diet with soybeans led to a 88% reduction in hot flashes. Could it be the nitrates?

Also, declining nitric oxide is one of the key reasons menopause is associated with increased risk of heart disease. The figure below is from a 2012 study showing how FMD declined from just about 10% to under 6% across the menopause transition. And severe hot flashes increase heart disease risk and are linked with lower FMD.

This also may be why certain herbal remedies help with hot flashes. For instance, two popular herbs used for menopausal symptoms —maca root and Pycenogenol —increase nitric oxide.

So let’s connect the dots. Nitric oxide declines significantly by the time a woman is 40. Her “NO pool” dips even lower as she hits peri-menopause. This is about the time disturbed sleep, hot flashes, and other symptoms increase, all of which are linked to increased risk of heart disease. We know giving both estrogen and progesterone help with these symptoms (one way to increase NO). Could restoring NO in other ways also help?

I also must add that this issue of depleted nitric oxide also happens to men and is a prime reason for erectile dysfunction. After all, Viagra is a PDE5 inhibitor which increases nitric oxide, allowing for increased blood flow to the penis.

Does NO have to decline with aging?

I’ve also discovered other ways to increase nitric oxide in addition to diet, which is why I’ve become a big proponent of breathing. According to The Buteyko Clinic International, after 40, people are six times more likely to start breathing through their mouth at least 50% of the time during sleep. When we breathe through our nose we take in NO because it lines our nasal sinuses.

Lung function declines significantly with the menopause transition and diaphragm and intercostal muscles becomes weaker with aging. This puts us all at risk for intermittent hypoxia due to inability to take in adequate oxygen. And guess what? This increases oxidative stress, which decreases the body’s ability to make nitric oxide.

But what if we keep our breathing muscles strong?

That’s why this 2021 study in the Journal of the American Medical Association was so amazing. Just 5 minutes a day of high resistance inspiratory muscle strength training (IMST) produced increased in nitric oxide bioavailability, lower CRP, and decreases in blood pressure (9 points!). Not only that, FMD increased 45% from 4.5% to 7% in women. The researchers write:

Collectively, these findings provide support for high‐resistance IMST as a novel lifestyle intervention for lowering SBP and improving vascular endothelial function in both midlife/older men and postmenopausal women, with favorable adherence compared with other healthy lifestyle interventions.

Could IMST be another way to prevent or decrease hot flashes and heart disease?

I’ll stop there but suffice it to say, this is a very interesting area. As I keep learning, I’m adding the variety of ways midlife women can keep their nitric oxide levels up.

I personally have noticed a huge difference focusing on boosting nitric oxide. Great sleep, good energy levels and besides vaginal symptoms, no hot flashes yet and I’m in late perimenopause.

In the book, I use the analogy of money. We all need money to live and there are different reasons we don’t have enough. Some spend a lot; others don’t make much, and many have unexpected expenses. Regardless of the reason for a lack of money, the result is the same.

This is the same for nitric oxide and midlife health. There are a variety of reasons we may be running low as we age. If we can get to the core reason(s) for its decline, we are well on our way to a healthier and better quality of life.

And it also means as women, we don’t have to rely on our hormones to keep blood flowing.

Does this nitric oxide stuff make sense to you?