Sleep Apnea, Adrenal Fatigue and Insulin Resistance

Paul L. Reller L.Ac. / Last Updated: August 03, 2017

Sleep apnea is a very prevalent disorder with rising incidence in the United States. Estimates of incidence vary widely, but it is estimated that greater than 6 percent of women and 4 percent of men suffer from sleep apnea, or the temporary stopping of breath during sleep. This may be an underestimation, as persons with mild sleep apnea usually will not seek a medical diagnosis. Recent studies (The Wisconsin Cohort) of the general population showed that 3-7 percent of men and 4-6 percent of women met the criteria for a clinical diagnosis of Obstructive Sleep Apnea Hypopnea Syndrome (OSAHS), but that 24 percent of men and 9 percent of women had abnormal AHI indices (apnea hypopnea index, or greater than 5 cessations of breathing per hour in sleep).

An apnea episode is defined by at least a ten second interval between breaths, with either a momentary neurological arousal from sleep, or a blood oxygen desaturation resulting. Hypopnea is defined as a partial cessation of breathing, with normal breathing but a partial reduction of ventilation by at least 50 percent from baseline. These episodes are normal in sleep, especially in people that snore, but create a serious disorder when there are greater than five episodes per hour during sleep, and are clinically designated as needing therapeutic measures when there are over twenty episodes per hour in sleep. Clinical diagnosis is achieved with an overnight sleep study called a polysomnogram. State of the art clinics are now using a device that is sent home with the patient called an at-home device with web-based diagnostics, created by Watermark Medical, which accumulates the polysomnogram data with less expense and patient inconvenience. A polysomnogram measures the extent of deep sleep, or REM, by monitoring brain function with EEG, rapid eye movements, muscle firing with EMG, and heart rhythm with ECG. All of these important bodily functions coordinate with breathing and blood oxygen levels, and when breathing is disrupted too often in deep sleep states, or when deep sleep states are interrupted or decreased in frequency, health problems may occur over time. Obviously, different testing devices could record a variety of data that could be complicated to assess. For tests that record just the number of apnea plus hypopnea episodes, but do not correlate these other health parameters, especially changes in blood oxygen saturation (SaO2), the need for standard CPAP therapy could be exaggerated. The challenge to understanding this complex disorder for the patient is one of understanding the entire health mechanism responsible, and the implications that this whole, complex disorder has on your health.

When you are diagnosed with sleep apnea, you should realize that this is almost always signifying a complex health problem that you should learn about and treat with a more holistic approach than standard allopathic medicine generally prescribes. The Complementary Medicine physician, or Licensed Acupuncturist and herbalist, can help you understand this problem and address the variety of health issues that you may need to correct. Recent studies at UCSF have shown that the risks of developing cognitive impairment and neurodegenerative disorders are doubled after 5 years of sleep apnea. Simply depending on a continuous airway pressure device (CPAP) to control apnea will not remove the underlying health problems or serious health implications of these underlying problems and the chronic airway obstruction.

Chronic sleep apnea may present a wide spectrum of health concerns. The implications of sleep apnea are foremost a lack of deep sleep and a sense of fatigue, but there is a high association with cardiovascular disease, metabolic syndrome, gout, adrenal fatigue, hormonal imbalance, weight gain, ovarian cysts, neuroendocrine imbalance, hypertension and depression/anxiety disorders. Recent evidence also shows a strong relationship to neurodegenerative states and cognitive impairment, perhaps due to decreased oxygen causing buildup of beta amyloid plaques or increasing inflammation and oxidative damage (Yaffe, UCSF 2011). While each patient presents uniquely in such a complicated scenario, a diagnosis of sleep apnea should be a sign to the patient that a holistic assessment of their health is in order. Allopathic medicine tends to oversimplify the implications of sleep apnea, ignoring the underlying causative imbalance and utilizing treatment to control symptoms, while suggesting that weight loss is in order. This approach will not address the various systemic imbalances that led to the onset of sleep apnea, and underly this diagnosis, and patients with an underlying metabolic disorder and insulin resistance will have much trouble losing weight with normal exercise and dieting. While many patients with sleep apnea may need to utilize an airway machine, mouthpiece, or even surgery, these treatments do not address the underlying causes of sleep apnea, and probably do not significantly reduce the associated risks if these underlying disorders are not addressed. For many patients, sleep apnea may be a warning sign that serious underlying health problems now need to be assessed and dealth with.

As the incidence of sleep apnea has grown in the United States, so has the scientific understanding of the mechanisms that create this condition. Of course, we have looked for the simplest explanation, but the truth is that for many patients with sleep apnea, a simple explanation has not produced a clear understanding of the pathology. Research into the pathology of sleep apnea has instead revealed an increasingly complex set of causes and effects. Since modern allopathic medicine has little to offer therapeutically to correct this complex set of physiological causes, a simplistic explanation is usually offered the patient, more to fit the treatment than to address the actual individual health problems. The truth is that for most patients with a serious sleep apnea there is complex set of obstructive and neurohormonal causes.

There are three categories of sleep apnea, central, obstructive, and complex (a combination of central and obstructive). There is ample evidence now that most cases are a complex disorder, although if there is no obvious serious hormonal disease, standard medicine is reluctant to diagnose the patient with a central sleep apnea. Central sleep apnea implies that the origin of the apnea episodes is in the central nervous system, and is usually associated with a neurohormonal disorder. Since we now know that many neurohormonal disorders are subclinical, meaning that they do not fit the prior definitions of serious clinical disease presentation, this aspect is still not addressed properly with standard diagnostic assessment in many hospitals and clinics. With findings of central biomarkers that are heavily correlated with the severity of sleep apnea, such as nesfatin-1, a hypothalamic neuropeptide associated with adaptation to stress, gastric hypofunction, and insulin resistance, this attitude must change. Obstructive sleep apnea is still the most prevalent diagnosis in standard medicine, although most experts in this realm now agree that a majority of disorders fit the complex category, and are a combination of obstructive and central nervous system health problems. Proper holistic assessment of subclinical endocrine and metabolic disorders, as well as adaptive stress responses, excitotoxicity affecting the sleep cycle, chronic inflammation and oxidative stress, and GI health may be the key to reversal and cure of sleep apnea for most patients. While this seems like a daunting task, an intelligent step-by-step approach will guarantee an eventual restoration of homeostatic health.

Diagnosis of Obstructive Sleep Apnea Hypopnea Syndrome (OSAHS) must include not only positive sleep study data, which frequently varies from night to night or over time, but also symptoms related to sleep apnea, such as daytime sleepiness and somnolence, fatigue, difficulty with concentration, non-restful sleep, and even night sweats or lowered libido. Physical signs include obesity, enlarged tissues at the neck or throat, and hypertension. Diagnostic markers for sleep apnea also imply that a majority of cases involve some obstructive causes, such as abnormal tissue growth or hardening, as well as central causes. For instance, the most used blood markers for sleep apnea are levels of oxidants (ROS, or reactive oxygen species), advanced oxidation protein products, AGEs (advanced glycation endproducts), or thiobarbituric acid (malondialdehyde reagent), a common marker of cell toxicity with oxidative stress. All of these may contribue to obstructive tissue growth. Studies have shown that the use of the CPAP has little significant effect on most of these markers of disease. There are a number of researched protocols to reduce oxidative stress, malondialdehyde, peptide fibrins, and AGEs with Complementary Medicine, yet these are not routinely integrated into the therapy. There are no pharmacological treatments to achieve these goals. The more we learn about sleep apnea, and the complexity of the disease, the more we should consider integrating Complementary Medicine into the overall strategy, but the opposite is occurring. Often, sleep studies, or polysomnograms, actually do no show oxygen desaturation, just a higher than normal number of short breaks in the breathing, and it is uncertain whether the CPAP is necessary, or doing any real physiological good, other than decreasing snoring and episodes of apnea or hypopnea. The real health problems need to be analyzed and treated.

While standard medicine continues to diagnose most cases of sleep apnea as an obstructive type, the obstructive causes are complex, with airway obstruction related to unnatural relaxation of the muscles around the soft palate, or base of the tongue, enlarged structures in the upper throat, such as the tonsils and uvula, increased fatty tissues around the pharynx, and sleep posture. Even nasal polyps and nasal septum deviation have been implicated in some cases. The standard area of airway obstruction is the pharynx, and apnea and hypopnea occurs on inspiration in breathing. Assessment often is determined by the specialist favoring a surgical or pharmacological approach, and since these treatments have a poor rate of success, control of symptoms rather than treatment of causes is by far the most prevalent approach in standard medicine. By far, though, in research, the most prevalent assessment of sleep apnea concerns changes in the tissues related to weight gain with metabolic syndrome, insulin resistance and hormonal imbalance. These issues may also be related to neurohormonal imbalances that affect the nervous system's response to changes in the oxygen and carbon dioxide content in the blood, oxygen content of the red blood cells, and changes in regulatory responses of respiration related to serotonin and norepinephrine diurnal levels. Poor function of the hypothalamus in relation to corticotropin releasing hormone neurons and adrenal stress appear to central to the underlying cause of sleep apnea (see the article cited below). The subject of sleep apnea has thus become another prevalent disorder that is difficult to understand, and thus difficult to treat. The proactive patient is taking the time to both better understand the disorder, and to seek out the knowledgeable Complementary Medicine physician to help deal with these dysfunction with a holistic approach.

Standard therapy for obstructive sleep apnea is still centered on cumbersome means of allowing the patient to achieve decreased incidence of apnea, with the use of a machine and mask to push increased air flow into the lung, and custom made mouth pieces that hold the airway open. The machine is called a continuous positive airway pressure device (CPAP), and is recommended when the respiratory disturbance index exceeds 20 episodes per hour, or 160 episodes per an 8-hour study. The noncompliance rate for this therapy, though, is very high, with complaints of excess noise, dry nose and throat, increased allergy symptoms, mask discomfort, cold or warm sensations disturbing the sleep, disturbance from the tubing with sleep movements, excess air in the stomach, and problems with reconnecting the device when waking to urinate and being too sleepy to reconnect. Many patients also report that these discomforts prompt them to remove the mask during the night in their sleep, or in a sleepy state. Often, the prescribing M.D. will also prescribe various medications to counter the increased allergy symptoms expected, sleep medications, etc. There are few studies that examine compliance and effectiveness of the machine and mask in the general population, although, studies in a controlled environment prove effectiveness in reduction of apnea. In other words, we know that CPAP is effective in the clinic, but we don't really know if it is effective at home. For this reason, many patients opt for a custom fitted mouthpiece to decrease sleep apnea and maintain an open airway. Satisfaction with custom made mouthpieces are high, but often these prove to decrease snoring but have not been proven to have enough effect to significantly reduce serious sleep apnea, and therefore are generally prescribed for mild to moderate obstructive sleep apnea. For many patients, a surgical approach is also recommended, with removal of enlarged tonsils as well as reduction in the enlarged tissues of the soft palate. If the underlying cause of excess expression of growth factors related to neurohormonal and immunological imbalance is not addressed, though, it is likely that these enlarged tissues will regrow after surgical excision.

As is often the case, standard therapeutic methods often lack a complete solution for many patients, and these patients often look to Complementary and Integrative Medicine (CIM) to both enhance the effectiveness of therapies to control sleep apnea, as well as to address the underlying causes, and decrease the serious health risks that are associated with the disease.

The standard treatment for sleep apnea involves just the use of a CPAP (continuous positive airway pressure) device. The drawbacks to this therapy are extreme, and consequently a strong system of selling the therapy to patients has occurred. One of the claims in recent years was that use of a CPAP actually resulted in improvement in the lipid profile of the patient, reducing cardiovascular risk, and perhaps accumulation of plagues and tangles in the brain associated with future neurodegeneration and Alzheimer's disease. In 2014, a multicenter randomized human clinical trial at the University of Pennsylvania in the U.S.A. and the University of Iceland, involving the Center for Sleep and Circadian Neurobiology, and the Department of Respiratory Medicine and Sleep at the National University Hospital of Iceland, showed that the use of the CPAP produced no changes in the lipid profile of patients over 2 years of use (PMID: 24833762). While the use of the CPAP may reduce episodes of sleep apnea and snoring, it does not address the multifactorial underlying health problems that both cause sleep apnea, and create the serious associated health risks that arise in patients with sleep apnea.

What is still lacking from this equation in standard medicine is the treatment for the underlying causes of obstructive sleep apnea, which include metabolic syndrome, insulin resistance, weight gain, hormonal changes, andrenal fatique, poor hypothalamic function, and possibly subclinical hypothyroid conditions. Also, the prevalence of jumping to the conclusion that the disorder is completely an obstructive sleep apnea often means that the patient is not sufficiently assessed for a diagnosis of central sleep apnea. The term central sleep apnea, as stated, implies that a disorder in the central nervous system, or regulatory brain centers, is involved in the apnea process. Central sleep apnea could explain the scientific findings of unnatural relaxation of the muscles around the soft palate, that may relate to altered dopamine metabolism in the part of the brain called the substantia nigra, which controls muscle coordination. Patients and physicians should always consider that the problem of sleep apnea that occurs during the premenopausal to postmenopausal states, when hormonal and metabolic imbalances are common, are probably complex. Patients with sleep apnea and obesity, or metabolic syndrome, should also realize that the apnea is a complex type, even if signs of obstructive changes are evident. By failing to address the implications of central sleep apnea in the complex syndrome, the patient and physician may be making a mistake that has serious consequences in the future.

While the patient naturally seeks a simple solution to sleep apnea, these simple solutions are usually inadequate to address the health risks associated and restore the patient fully to an optimum state. Even surgical approaches usually do not achieve the success hoped for. This is often accounted for by an assumption that there is more tissue obstruction present than is treated by the surgery, but in reality, the underlying causes probably are significant in many of these cases, contributing to the sleep apnea. In addition, surgical approaches do not stop the physiological mechanism that created the enlarged tissues in the first place, and there is an expectation that this enlarged airway tissue will regrow. The patient that undergoes tissue reduction should also consider a more comprehensive and integrated protocol to reduce the underlying causes to prevent this regrowth of obstructive tissue.

There is often no magic pill, or simple solution, to sleep apnea and the associated symptoms of fatique, weight gain, anxious depression, hypertension, cognitive impairment and neurodegeneration, etc. The wise patient seeks to better understand this complex disorder, and take a proactive step-by-step approach to correcting it, utilizing an integrated team and Complementary Medicine. Simple decrease in the symptoms of fatique and less waking during the night do not mean that all of the negative health issues are now resolved. This article, and other articles on the website, such as those addressing Metabolic Syndrome, seek to help the patient better understand sleep apnea and the related syndrome of health problems. Of course, as you read the article, you must understand that each patient is unique, and not all of these health problems are seen in each individual. You need to apply the information to your specific array of health issues when formulating a better proactive approach to help solve the problem and decrease the future health risks.

The Relationship between Snoring and Sleep Apnea

Simple snoring, until recently considered just a nuisance, not a real health problem, has now been well studied, as sleep apnea and the array of associated health problems has become an issue of concern. It is assumed that the great majority of patients with sleep apnea snore, although many do not realize that they snore. Simple snoring is considered one end of a spectrum of the problems with upper airway obstruction and central regulation of breathing at night, often proceeding to mild apnea, or upper airway obstruction, and finally to moderate to severe sleep apnea.

This study of snoring has revealed that the same underlying health problems are apparent in syndromes of snoring as with syndromes of sleep apnea. These include Metabolic Syndrome, Obesity, neurohormonal problems, and cardiovascular risk, as well as neurodegenerative risk. Obviously, the time to start treatment to prevent sleep apnea, and the health problems associated with sleep apnea, is early in the course of worsening snoring. Most syndromes of chronic and habitual snoring will worsen with aging, unless the underlying health problems are addressed comprehensively. An array of treatment protocols in Complementary Medicine can help with this broad syndrome of dysfunction, including acupuncture, electroacupuncture, herbal and nutrient medicine, and changes in behavior and diet.

Experts believe that over 40 percent of adults are habitual snorers, but that a smaller percentage are chronic snorers. About 5 percent of patients with habitual snoring in studies show that they have additional sleep disordered breathing. Sleep fragmentation, or the disruption of the normal progression in the sleep cycle, is common, leading to impaired daytime function and increased cardiovascular risk. The reasons for these problems and risks is that snoring is a sign that there is abnormal coordination between key control centers in the brain, especially the thalamus, various areas of the temporal, parietal and frontal lobes of the cerebrum, and the hippocampus, which is closely tied to autonomic regulation of the heart rate. In addition, airway tissue problems, such as inflammatory problems, nasal polyps, and allergies may contribute to abnormal tissue growths, narrowing the airways. Snoring is caused by upper airway muscle relaxation in deep sleep, narrowed respiratory passages, sleep position affecting the tongue and throat, and reactions in the brain to the balance between oxygen and carbon dioxide. During deep sleep, or REM stages of the sleep cycle, patients with snoring and sleep apnea show a diminished regulation of the centers in the brain that react to oxygen and carbon dioxide balance, and acidity in the body, measured by the amount of plasma carbon dioxide, may also affect this regulation. Sleep apnea is characterized by repetitive oxyhemoglobin desaturations during stages of the sleep cycle.

A comprehensive protocol and routine may be needed to reverse the chronic snoring pattern, and prevent the potential neurodegeneration that often occurs. Habits such as sleeping on your side, avoiding restless sleep and rolling onto your back, avoiding alcohol and medications that can disrupt your sleep cycle, such as pharmaceuticals that treat insomnia, antihistamines and muscle relaxants, and using small risers under the head of the bed to provide a slight imperceptible tilt, may all help. Wearing a mouthpiece that holds your airway open, or a nasal strip, may also help, but will not correct the underlying problems. Standard medicine urges patients with more serious problems to try a surgical correction, or use laser or radiofrequency ablation of excess tissue growth. If the underlying neurohormonal triggers of this excess tissue growth are not resolved, though, the tissue will grow back. While adopting a more comprehensive protocol with Complementary Medicine is not as simple as getting laser surgery, the end result may be more lasting and much healthier overall. Acupuncture stimulations have been proven to aid function in specific areas of the brain, as well as open the airways, and herbal/nutrient medicine offers a variety of studied medicines to improve sleep function and quality, help the body clear fibrins and proteins fragments or peptides in tissues, inhibit growth factors and VEGF, as well as aid correction of underlying problems such as Metabolic Syndrome and hormonal imbalance. The array of tools in Complementary Medicine is pretty big to address these many factors associated with snoring.

The relationship between obstructive sleep apnea, insulin resistance, and Metabolic Syndrome

It is widely acknowledged that increased accumulation of fatty tissue in the upper airway tissues is responsible for obstructive sleep apnea. While utilization of machines to force more air through these airways, mouthpieces that open the airways more, and even surgical correction to reduce these tissues may indeed temporarily open the airways and relieve symptoms, the thinking patient wonders what has actually led to this condition. Fatty tissue accumulation is regulated by our hormonal system, or endocrine function, which needs to be in balance for us to maintain optimal health. By separating sleep apnea from the associated hormonal and metabolic imbalances that underlie the condition, we ignore serious health risks that threaten our health as we age.

The control of fatty tissues in our bodies is a complex issue, but is tied to the hormonal regulation by insulin, and affected by a host of other hormones. The pioneer of bioidentical hormone therapy, Dr. John Lee, found that progesterone deficiency was often intricately tied to insulin resistance, which is a hallmark of metabolic syndrome. This is one piece of the puzzle when looking at this problem holistically. In Metabolic Syndrome and obesity, insulin resistance, or resistance to the effects of insulin hormone at cell receptors, which is due to a variety of factors, is the focal issue. This insulin resistance creates an episodic excess response of insulin secretion. Insulin is a steroid hormone secreted by the pancreas that affects our sugar and fat metabolism in a complex manner, and has a host of effects in our bodies. Hormones are simple molecules that do nothing on their own, but act by affecting a wide variety of cell receptors. Insulin does have a direct impact on the regulation of fatty tissue accumulation, and insulin resistance does have the effect of increasing the density of fat cells and tissues to compensate, which is central to the pathology of obstructive sleep apnea. In addition, a number of other hormones have a strong synergistic relationship to insulin in the regulation of fat metabolism, and tissue changes, and some of this physiology is explained below. Abnormalities of adiponectin metabolism have been directly linked to fatty tissue accumulation in muscle, as well as in organ tissues. A 2009 study (cited below) at the Prince of Wales Hospital Research Laboratories in Sydney, Australia, found that fat mass and high molecular weight, or altered, steroid hormones, as well as insulin resistance were directly related to adiponectin metabolism. The researchers found that insulin resistance was higher with imbalances of fat mass, estradiol (the most active estrogen) and progesterone, and lower when adequate adiponectin was observed. The researchers concluded that there were strong negative associations between circulating adiponectin, and some of its high molecular weight isoforms (variations), and progesterone, and that progesterone and estrogens are likely to affect insulin sensitivity through modulation of adiponectin and body fat.

Adiponectin is the hormonal molecule found to be the link between abnormal fatty accumulation in tissues, insulin resistance, and the steroid hormones, especially progesterone and the balance between progesterone and estrogen, with relative estrogen dominance. Adiponectin is a protein hormone that modulates a number of metabolic processes, including glucose regulation and fatty acid breakdown (catabolism). Adiponectin is secreted from fat cells and is usually found in abundance in circulating blood, where is must stay in balance with other circulating hormones, such as leptin and ghrelin, to achieve correct homeostasis of the fatty metabolism. Adiponectin has been found to play a major role in the body in suppression of metabolic imbalances, including metabolic syndrome (type 2 diabetes), obesity, fatty liver disease, and atherosclerosis. Like all hormones, this molecule is simple, and the activity generated from adipose is related not to the molecule itself, but to the hormonal receptors that it stimulates. Expression of these receptors is correlated with insulin levels, and has been found to be reduced when there is diabetes or metabolic syndrome present, either with reduced glucose tolerance, or insulin resistance at the receptors.

Insulin sensitivity and the homeostasis of blood sugar regulation are negatively impacted by both intermittent hypoxia (decreased blood oxygen) and sleep disruption. This presents a viscious cycle in sleep apnea. Some scientific studies have also linked insulin resistance and metabolic syndrome to complex sleep apnea independent of obesity. Patients that are not visibly overweight are not exempt from problems of sleep apnea related to metabolic dysfunction and insulin resistance. These studies have shown that insulin levels and the immune mediator cytokines interleukin-6 (IL-6) and TNFalpha are elevated in sleep apnea syndromes independently from obesity. Insulin is a hormone secreted by the pancreas that does more than just regulate blood sugar, and is also important for maintenance of cells and tissues in the brain. Insulin, TNFalpha, IL-6, and isoproterenol have all been found to effect the regulation of fatty tissue creation and degradation by downregulating the enzyme activity of adipose triglyceride lipase in fat cells. The depression of the normal enzyme function results in increased accumulation of fatty tissue in the upper airway structures. In addition, sleep apnea and intermittent hypoxia, with increased pro-inflammatory cytokines such as TNF-alpha and IL-6, may significantly contribute to chronic inflammatory problems in the body. We see from such analysis that a variety of factors may work synergistically to create the tissue growths in obstructive sleep apnea. Addressing both the hormonal and inflammatory dysfunctions is integral to the holistic treatment.

To better understand how insulin dysfunction is related to abnormal tissue growth in obstructive sleep apnea, we may look at the immune dysfunctions, to adrenal stress and fatique syndromes, and potentially to the use of medications, to see how an array of problems might be involved in this airway tissue hypertrophy. Isoproterenol is a synthetic sympathomimetic beta adrenergic agonist, meaning that it is a drug that acts like an andrenal hormone and affects the body like a sympathetic neurotransmitter. This drug is used mainly to treat racing heart (tachycardia), fibrillation, and hypertension, but is now also used to treat asthma, bronchitis and emphysema (COPD), often in combination with other drugs. Studies like the one cited above show clearly how chronic adrenal stimulation, inflammatory conditions, and metabolic imbalance can directly work together to create the fatty tissue growths seen in obstructive sleep apnea. It is widely accepted in the last few years that this combination of adrenal stress syndrome, chronic inflammatory dysfunction, and metabolic syndrome are probably responsible for the rising incidence we see in obstructive or complex sleep apnea. We see that this scenario could form a vicious cycle, with decreased intermittent blood oxygen negatively impacting insulin sensitivity, and changes in insulin sensitivity disrupting the normal regulation of fatty tissue accumulation, or in other words, insulin resistance and metabolic disorder eventually causing sleep apnea, with sleep apnea worsening the insulin resistance and metabolic syndrome.

Hormonal imbalances may also change the sleep cycle and create added stress on the regulation of breathing at night and apnea. In pregnancy, a number of hormones are secreted at much higher levels, and these hormonal effects have been well studied. Increased estrogens may inhibit REM sleep, and increased progesterones may promote more non-REM sleep time. Cortisol, an adrenal hormone, may also modify sleep patterns, and increases in hormones stimulated by the hypothalamus and secreted by the pituitary, such as prolactin and oxytocin, may also alter the sleep cycle. Prolactin increases prolong the duration of REM sleep time, and oxytocin may lead to excessive sleepiness. Studies of increased hormone levels in pregnancy also show that increases in estogen secretion may cause mucosal edema and upper airway resistance. Estrogen drives the weight gain and tissue growths in pregnancy, and often the pregnant woman develops snoring patterns and may then develop obstructive sleep apnea. Increased progesterone secretion in pregnancy may also act on the brain respiratory control centers (ventrolateral medulla) to reduce blood CO2, which may contribute to sleep apnea onset. These studies in pregnancy may be applied to the general population as well. When changes in the levels of estrogens and progesterone occur, both the sleep cycle and tissue growth and edema may be affected, as well as respiratory regulation. Especially in perimenopausal and menopausal states, levels of estrogens and progesterones change, and this is the time when many women experience the onset of sleep apnea. Throughout life, especially for women, subclinical hormonal pathologies may occur, causing premenstrual symptoms, infertility, polycystic ovarian syndrome, subclinical hypothyroidism, and hypothalamic dysfunction. Sleep apnea occurs most frequently in the female population, and these subclinical hormonal changes and stresses may play a significant role in the pathology.

Most patients acquire the health problems that lead to sleep apnea gradually, but when faced with the consequences to their health, such as the now noticeable fatique that results from unrecognized sleep apnea, they look to the physician for a quick and easy fix to the problem. For the acupuncturist, the patient may ask if it is possible to cure their sleep apnea with a few acupuncture sessions. Obviously, the patient and the physician should look further than the surface with this problem and correct the underlying conditions, and well as the problems with general health that both worsen the sleep apnea, and as the sleep apnea worsens, the underlying health problems. While standard medicine is helpful to decrease the incidence of sleep apnea with devices or surgery, it does not adequately address these chronic underlying health problems that will perpetuate the condition and add to future health risks. This is why the patient must try to gain some understanding of the problem and work with an integrated team of physicians, utiizing Complementary Medicine to regain a healthy homeostasis and stop the problems that cause and worsen the condition of obstructive or complex sleep apnea.

Numerous sleep studies have investigated the connection between increased weight, increased fatty tissues in the airway that lead to obstructive sleep apnea, and metabolic changes. A study cited below shows that sleep deprivation consistently leads to reduced leptin and elevated ghrelin, resulting in poor appetite control, excess appetite, craving for simple carbohydrates, and increases in BMI (body mass index), or fatty tissues. Leptin is a protein hormone that is created by fat cells to control appetite, affecting the regulatory centers in the brain, especially the hypothalamus, and is integral to insulin resistance and Metabolic Syndrome. Much research has now been conducted concerning leptin, and animal studies indicate that leptin is a stimulant of ventilation, as well as a role player in tissue development of the respiratory system. Leptin is being investigated not only as an important regulatory hormone affected by sleep deprivation, but as a potential causative factor in the pathology of sleep apnea when leptin deficiency or leptin resistance is evident. The Curie Institute in France has studied the subject of obesity thoroughly and concluded that chronic inflammatory dysfunction appears to be at the heart of this problem, the inability of the body to use stored fats in the metabolism, thus creating weight gain that is impossible to reduce, or a high BMI index. When this occurs, the white fat cells, which produce most of our leptin, become dysfunctional, resisting the insulin signals, and not producing sufficient leptin. We see how a number of factors work together, or holistically, to create this bad situation. Allopathic medicine looks to one step in this cycle to alter to correct the problem. An intelligent analysis concludes that we must affect the whole cycle of metabolic and inflammatory dysfunction to achieve real success.

Ghrelin is a hormone that is produced in the stomach lining, as well as the pancreas, that has a wide variety of effects. Chiefly, ghrelin is produced to stimulate appetite when we need food, but excess secretion of the hormone would drive appetite unnaturally, as well as affect mental function, memory, increase the concentration of the neurotransmitter dopamine in parts of the brain, promote intestinal wall cell proliferation and increase bowel motility, and affect the immune responses in the intestines. Chronically elevated ghrelin may be associated with GI dysfunction, such as irritable bowel syndrome, increased colon and pancreatic cancer risk, and poor short term memory, as well as having effects on mood. Stomach dysfunction may play a part in ghrelin imbalance, as well as increased oxidative states and inflamamtory dysfunction. Once again, a holistic approach to health in treating sleep apnea may work to resolve these various health problems in each individual case to restore balance and homeostasis, eventually decreasing fatty tissue accumulation and obstructive sleep apnea. This approach will work with long-term improvement in overall health, and the Complementary Medicine physician can help the patient improve these various aspects of their health to eventually cure the underlying cause of sleep apnea.

Metabolic Syndrome is a complex problem that is more fully explored in another article on this website. When this metabolic imbalance worsens in the body, increased stress is created on the metabolic processes, and insulin resistance, weight gain at the midsection, and poor liver metabolic function may result. If the liver is too stressed, triglyceride levels will be abnormal on blood tests, and cholesterol and lipoprotein levels, as well as circulating blood sugars may also be off. Insulin is a steroid hormone, and thus is part of the endocrine system and affected by other hormonal irregularities. This is perhaps one reason we see a higher incidence in women of sleep apnea, especially during the period of perimenopause to postmenopause. Restoration of hormonal balance with holistic treatment may have a very positive effect in the long term on sleep apnea disorder.

Metabolic syndrome is highly associated with estrogen dominance and relative deficiency of progesterone. Research in recent years has found that estrogen dominance with progesterone deficiency is highly associated with metabolic syndrome and insulin resistance. This problem may be worsened with the use of synthetic estradiol and progestins (see research cited below), with a high association between excess circulating estradiol and metabolic syndrome. These drugs may also affect the regulation of inflammation in the body, which could have a direct relationship to tissue hypertrophy in the airways. Studies have found that synthetic progestins exert a negative effect on the level of circulating adiponectin, and disequilibrium between proinflammatory cytokines (high interleukin-6/C-reactive protein) and the anti-inflammatory adipokine (low adiponectin). Since this inflammatory modulation is important in low-grade inflammatory states of fatty tissues, such an imbalance could promote tissue hypertrophy, leading to obstruction airways. The link between these various problems is becoming more and more evident over time.

Researchers in 2014 may have found another biochemical connection between this array of factors associated with sleep apnea. Nesfatin-1 is a neuropeptide produced in the hypothalamus of the brain, the command center of the neuroendocrine system, and has been inversely correlated with severity of sleep apnea in a number of studies.

This molecule is a key regulator of insulin secretion, appetite, and metabolism, and is also expressed in the pancreatic beta cells, gastric endocrine cells, fat cells and brainstem. Nesfatin-1 is also associated with immunoreactivity, is activated by ghrelin, co-expressed with melanin, and has been associated with autonomic regulation, mood, stres responses, cognition and sleep. In the hypothalamus, nesfatin-1 is believed to be produced by peroxisome proliferator-activated receptors (PPARs), which play essential roles in the regulation of metabolism and tissue growth. PPARs are activated by inflammatory mediators, such as prostaglandin-2 (PG2), and modified by free fatty acids and eicosanoids (inflammatory modulators such EPA in omega-3 essential fatty acids, arachidonic acid, an omega-6, and linolenic acid, an omega-6). PPARs are also affected by oxidative stress. We see from such study that the link between these various underlying conditions associated with sleep apnea may be found in this neuropeptide, nesfatin-1. We will probably see a concerted effort by the pharmaceutical industry to allopathically affect the nesfatin-1 expression to treat sleep apnea in the future, but this of course will come with many potential unwanted side effects. In holistic medicine, the goal is to normalize the expression of nesplatin-1 and to modulate the negative health factors that contribute to its deficient expression, such as chronic inflammation, oxidative stress, metabolic stress, and hormonal imbalance. By working on all of these factors, and aiding hypothalamic health, Complementary Medicine can achieve a homeostatic normalization and end to sleep apnea over time.

Nesplatin-1, a neuropeptide derived from the prohormone peptide precursor NUCB2, or nucleobindin 2, has been linked to a chronic emotional adaptive stress response in the human brain. Nesfatin-1 levels have been found to correlate with a number of chronic diseases, such as obesity, osteoarthritis, cancer, anxiety and depressive mood disorders, supraventricular tachycardia, autoimmune thyroid disease, diabetes and Metabolic Syndrome. While this information seems daunting in relation to finding a simple treatment response, it does explain many of the correlations seen in a majority of cases of sleep apnea to these chronic health problems, and does point to the real need to approach the problem holistically, identifying in each individual the various related health problems, and not only treating these problems in an individualized manner, but also working to understand and improve the cognitive and behavioral aspects of the adaptive stress response and underlying emotional stressors. From a biochemical perspective, the nesplatin-1/NUCB2 response is linked to the biochemical pathway of mTOR signaling and STAT3, or phophatidylinositol 3-kinase mammalian target of rapamycin (mTOR), and the signal transduction and activator of DNA transription (STAT3).

While this seems overly complicated, we do see that this pathway of cell expression is linked to gastric hypofunction and overexpression of nesfatin-1 by gastric endocrine cells, which easily crosses the blood-brain barrier and lead to a feedback mechanism of decreased nesplatin-1 expression in the hypothalamus. In response to weight gain, periods of fasting lead to the inhibition of gastric mTOR to restore energy balance and increase ghrelin, reducing the this expression of nesfatin-1 in gastric endocrine cells. A clear link between fluctuating dietary responses, and binge dieting, and this imbalance of nesfatin-1 is implicated. The answer to normalization of the homeostatic system is to adopt sound and consistent dietary habits, normalize and improve gastric function, and achieve gradual control of body weight through a consistent protocol of improved health and overall metabolic and hormonal health. Unfortunately, we live in a society that promotes the idea of quick fixes, binge dieting, treating chronic gastric dysfunction by taking gastric acid inhibitors, and treating dysfunction in the adaptive stress responses by taking anti-anxiety and anti-depression drugs. Obviously, these strategies do not address the need to restore the healthy homeostatic mechanisms our bodies need to stop the progression of related diseases, such as sleep apnea.

Countering the health risks associated with chronic sleep apnea

Besides reducing sleep apnea and working to correct the underlying health problems that cause the central and obstructive sleep apnea, the patient with sleep apnea should consider a holistic regimen to protect against the serious health problems associated with the disorder.

Cardiovascular risk is the main concern. Much research has uncovered the mechanisms by which increased cardiovascular risk is generated by sleep apnea disorders, and the smart patient seeks to understand the connection and do what is necessary to decrease the risk. Study at Columbia University (cited below) has concluded that obstructive sleep apnea (OSA) directly affects the vascular epithelium (lining of the arteries) by promoting inflammation and oxidative stress while decreasing nitric oxide (a vasodilator) availability and repair capacity of the blood vessels. Expression of the inflammatory mediators COX-2 (cyclooxygenase enzyme) and nitrotyrosine was found to be five-fold greater in sleep apnea patients in study, and nitric oxide synthase was found to be 56% greater in OSA patients than in control subjects. This contributes greatly to the poor health of the arteries, and to accumulation of plaque, or atherosclerosis.

A variety of therapies in Complementary Medicine offer the patient safe and effective therapies to increase antioxidant effects, increase healthy inflammatory regulation, inhibit COX-2, increase nitric oxide bioavailability, and modulate the systems responsible for maintenance and repair of vascular endothelium. Often, these various effects are combined in an herbal formula. Herbs contain a variety of medicinal chemicals, and a formula of herbs contains a wide variety of medicinal chemicals to achieve a complex goal. These chemicals have been well documented and studied, and comprise the modern science of herbal medicine and phytopharmacology. Naturopathic medicine also provides a wealth of research that is ongoing that addresses therapeutic protocol with nutrient medicines. While these therapies can be complex, they generally work to achieve the goal of reestablishing a healthy mechanisms within the body, and restore the homeostatis that protects against cardiovascular risk, and do not require chronic use of the herbs and supplements like pharmaceutical medicines.

Another focus of research into the cardiovascular negative effects seen in obstructive sleep apnea patients is the reduction of blood flow in the brain and increased reactivity to lowered blood pressure, which increases the risk of an eventual stroke, especially in the aging population. Sleep apnea is highly associated with increased stroke risk, and not only the decrease in healthy maintenance of the arterial vessels, but also neurochemical imbalances created in sleep apnea, either as a result of sleep apnea, or perhaps as part of the cause of sleep apnea, are implicated in the increases stroke risk. A study at Yale Center for Sleep Medicine, Yale University School of Medicine, found that there was a consistent decrease in cerebral blood flow velocity in sleep apnea patients during the waking hours, with an slower cerebrovascular response to hypotension. This slow response to hypotension was not attributed to a slow response to increased CO2 in the blood, which occurs when apnea results in decreased oxygenation and increased clearing of carbon dioxide by decreased breathing. The cause of the slow reactivity to hypotension and subsequent exagerrated response occurred because of other chemical imbalances associated with the sleep apnea disorder.

Nitric oxide (NO) is a potent vasodilator and important modulator of cardiovascular health and blood pressure. NO balance is intricately tied to the balance of oxygen and carbon dioxide in the body, as well as to oxygen radicals, or oxidants. Sleep apnea therefore has a clear effect on this oxygen metabolic balance. Red blood cells take up and carry oxygen, and sleep apnea has been shown to affect the oxygen concentration in red blood cells, mainly because of the imbalance of these various oxygen gases. A number of chemicals in the body are important as bioreactants and precursors to nitric oxide metabolism. These include glutathione, our main antioxidant and detox chemical, Cysteine, nitrates that are absorbed from food in our small intestine, L-arginine, and the various Vitamin B3 metabolites, or niacin molecules. As stated, there is a stress on the body in sleep apnea that leads to poor bioavailability of nitric oxide and increased nitric oxide synthase as a response. Nutrient and herbal medicine offers sound research and treatment to address such concerns.

Serotonin and Other Neurotransmitters: the role of chemical imbalance in the pathology of complex sleep apnea and natural correction of this imbalance

The neurotransmitters serotonin and norepinephrine (adrenaline) play an important role in the body and mind, and imbalance of these chemicals has been associated with sleep apnea and various negative health consequences of this disorder. Many anti-depressant and anti-anxiety medications have been created to achieve a higher level of these neurotransmitters in the brain tissues, such as Prozac, Cymbalta, Effexor etc. Many patients fear that chronic use of these SSNRIs have preceded the onset of sleep apnea, and are associated with the central pathology. Health experts have countered that SSNRIs could not cause sleep apnea because they actually reduce REM time, or deep sleep, the period that sleep apnea occurs. The analysis of central sleep apnea is still confounding researchers, though, and such simplistic reasoning is being questioned. There is a big problem with the limited effectiveness of the anti-depressants, as well as a big problem with an addictive cycle, as patients often have severe symptoms when trying to go off of these drugs. Many psychopharmacologists are also concerned that chronic use of SSNRIs are creating a greater usage of available serotonin and norepinephrine in the brain by blocking reuptake, but do not address the deficiencies and imbalances. Many doctors are now prescribing 5HTP and other nutrient and herbal supplements along with the drugs to try to reestablish a greater bioavailability and feedback balance of neurotransmitters in the brain.

Serotonin is created in the cells of the body, throughout the body and brain, from the amino acid tryptophan. L-tryptophan is an essential amino acid, meaning that it must be obtained from the diet and cannot be adequately manufactured in the body. Use of L-tryptophan by physicians has achieved great success in the treatment of depression and anxiety, and is used by many psychiatrists when their patients prove resistant to the serotonin reuptake inhibitors commonly prescribed. Serotonin, dopamine and norepinephrine are neurotransmitters that may also play a significant role in the mechanisms of central and complex sleep apnea disorders. Serotonin, tryptophan, and the precursor 5HTP (5-dydroxytryptophan precursor), are part of a metabolic mechanism associated with maintaining the right levels of the neurohormone melatonin. While melatonin was associated mainly with the sleep cycle in the past, research in recent years has uncovered its powerful effects throughout the body, its potent antioxidant activity in the brain, and its relationship to the diurnal hormonal metabolism.

High levels of circulating catecholamines, or neurohormonal mediators secreted by the adrenal gland, are associated with sleep apnea. Chronic stress may induce a condition called adrenal fatique, and levels of adrenal mediators, called adrenaline in the past, and now referred to mainly as norepinephrine and cortisol, are not maintained at proper levels in a diurnal cycle (night/day). Sluggish adrenal response will often create a situation of excess cortisol during the night, causing insomnia, non-restful sleep, and anxiety, and depressed cortisol levels during the day, causing sluggishness, fatique, and slow mental response. This upset of the diurnal neurohormonal balance may have a direct as well as indirect effect on sleep apnea. Clinical adrenal pathology, such as pheochromocytomas, produce excess catecholamines and are highly associated with sleep apnea. In a similar way, subclinical adrenal fatique syndromes may also be integral to the complex pathology.

Research in 2007, cited below, revealed that excessive catecholamines have been noted in patients prescribed antidepressants. Tricyclic antidepressants and phenoxybenzamine are most implicated, but selective serotonin and norepinephrine reuptake inhibitors (SNRIs) have now also been implicated in cases of medication induced high catecholamine levels, which are noticed as false positives on tests for phiochromocytomas. 40% of these false positive results of tests for adrenal tumors are attributed to these drugs. The implications are that chronic use of these antidepressants may be indirectly associated with sleep apnea disorders, and that imbalances related to serotonin, norepinephrine, and melatonin may be central to the causative mechanisms of sleep apnea. Restoration of a natural balance of catecholamines may have a positive effect on sleep apnea. Use of natural precursors and other chemicals that help achieve a bioavailability of these neurotransmitters is an alternative to synthetic drugs that block reuptake etc. Many patients have found success by holistic restoration of health and by establising a health bioavailability of the chemistry needed for your system to achieve proper balance.

One novel therapeutic supplement now being used is a low dose combination of Vitamin B6, 5HTP, St. John's Wort, and melatonin. These four supplements act synergistically to allow your brain to better regulate the diurnal and feedback levels of neurohormones and neurotransmitters in the brain. The goal of such therapy is to eventually restablish a healthy balance and homeostasis.

Some novel therapeutic aids used to reestablish a healthy bioavailability of neurotransmitters are listed here:

  • Vitamin B6, or the active metabolite P5P, is needed to produce serotonin.
  • 5HTP (hydroxytryptophan precursor) from griffonia seed is a precursor to L-tryptophan and is able to cross the blood brain barrier to enter the brain tissue.
  • Tryptophan is found in the foods oats (steel cut unprocessed), bananas, dried dates, milk, yoghurt, cottage cheese, red meat, eggs, fish, poultry, sesame seed, chickpeas, sunflower seeds, pumpkin seeds, spirulina and peanuts. It may also be taken as an amino acid supplement, as L-Tryptophan, or the tryptophan precursor 5HTP (extracted from griffonia seeds) may be taken to increase bioavailability in the brain.
  • Tryptophan is a complex carbohydrate with nitric oxide added. Increased or decreased nitric oxide may have implications on the bioavailability of tryptophan amino acid as an available precursor to serotonin or melatonin in the brain. One way to supply a balanced cycle of the precursors for these important neurotransmitters is to take a combination of 5HTP, melatonin, P5P (B6), and St. John's Wort extract at a low dosage. This combination is available as a supplement called Positrol.
  • L-Arginine is an amino acid that is a precursor to the healthy formation and bioavailability of nitric oxide. The steady-state bioavailability of nitric oxide is determined by both its rate of formation and its rate of decomposition, and a number of chemicals contribute to a better nitic oxide metabolism in the brain and arterial tissues. Antioxidants such as superoxide dismutase have been shown to protect nitric oxide availability in the arterial endothelium, and increased concentration of free radical oxidants has been shown to decrease the nitric oxide availability. Niacin and niacin metabolites (B3) have been shown to aid nitric oxide bioavailability, and thus have been a benefit to cardiovascular health as well. The combination of L-Arginine, P5P (to increase amino acid bioavailability), and inositol hexacotinate or niacinamide (forms of B3), may improve nitric oxide metabolism.
  • Melatonin is a hormone that is related to serotonin and is secreted in the diurnal cycle (day-night) to affect sleep cycles and hormonal balance in the diurnal cycle. There is a strong system of balance, or homeostasis, that the brain tries to maintain, and to promote this healthy balance, a number of factors may need to be addressed with nutrient and herbal medicine. The neurohormones GABA and dopamine are also related in this balanced equation. In addition, melatonin is a key antioxidant in the brain. Dopaminergic herbs and the right supply of GABA precursor may positively affect the melatonin and serotonin balance as well, with L-Glutamine, P5P and inositol hexacotinate supplying the building blocks for glutamate neurotransmitter and GABA.
  • Leptin X: high viscosity polysaccharides from the acacia tree gum, and esterified fatty acids, were found in human clinical trials at the University of Minnesota to significantly modulate leptin and adiponectin levels in circulation. Insulin resistance with higher insulin levels result in higher levels of leptin and lower levels of adiponectin, eventually resulting in leptin resistance, significantly affecting the regulation of sleep, and associated with sleep apnea and sleep cycle dysfunction. Normalization of leptin, adiponectin and insulin will eventually play a significant role in balancing neurohormonal regulation of sleep and a decrease in the accumulation of fatty tissues causing airway obstruction via inflammatory dysregulation and increased growth factors. While such strategies are not likely to have an immediate impact, a prolonged course of therapy within a holistic protocol may reverse the underlying mechanisms that cause sleep apnea.

New research is revealing how the body regulates fatty accumulation in muscles, and will lead to a more specific targets for herbal and nutrient medicine

Increased fatty accumulation and tissue growth is the most direct cause of obstructive sleep apnea. What causes this fatty accumulation and growth is rarely discussed with the patient, but this is a key consideration when trying to reverse chronic sleep apnea. Besides insulin and adiponectin, there are a variety of growth factors that are related to such tissue hypertrophy.

A study completed by the Swedish medical university Karolinska Institutet in 2010, and published in the scientific journal Nature, shows that hormonal signalling from muscles via the VEGF-B protein hormone (vascular endothelial growth factor) allows increased fatty acids to be transported throught the blood vessel membranes to be utilized by the muscles for energy. VEGF-B signalling created more fatty acid transport proteins in the blood vessel walls, and normally these fatty acids would be utilized by the muscles for energy. In animal studies, subjects that lacked VEGF-B expression in the muscles or VEGF-B receptors in the blood vessel walls had difficulty transporting fatty acids to the muscles and instead these fatty acids accumulated in white adipose tissues, the fat cells that are implicated in insulin resistance. VEGF expression in the muscles increases when the muscle is not receiving sufficient oxygen, triggering increased blood vessel formation. VEGF-B is a member of this family of molecules that does not respond to oxygen insufficiency, or hypoxia, directly, but is affected by VEGF stimulation. Binding of VEGF-B to the receptors on the blood vessel walls triggers a response that is also shared by the inflammatory mediators in the body, the tyrosine kinase pathway, and there is a close relationship between various inflammatory mediators, that also respond to hypoxia, and VEGF, as well as a protein hormone called platelet-derived growth factor. As research continues into this complex cascade of chemicals, we will gain an increased understanding of the holistic mechanisms that result in the accumulation of fatty tissues in airway muscles. All of this research reveals the complex workings of the body, and the need to target multiple systems and holistically promote a healthier homeostatic metabolism.

Another VEGF protein has been the subject of much research in cancer studies. VEGF-A is linked to tumor growth and the stimulation of increased blood vessel formation in tumors to meet the high energy needs. A number of pharmaceuticals have been created to inhibit VEGF formation, including Avastin. Naturopathic medicine has researched natural nutrient chemicals to achieve, or help achieve these goals, without side effects. This research may be important in the treatment of pathological fatty accumulation in muscle tissue. IP6 is one of these therapeutic nutrient medicines studied. Inositol hexaphosphate is found in high fiber foods, and has been proven in scientific studies to inhibit tumor growth via inhibition of VEGF production, as well as exerting strong antioxidant effects. Such effects will probably be found to also affect VEGF-B overexpression, and may be an effective addition to holistic and integrative therapy to reduce fatty accumulation in obstructive sleep apnea.

Another area of naturopathic research that may relate directly to inhibition of fatty accumulation in muscles is the subject of advanced glycation endproducts, or AGEs, that are implicated in the poor health of blood vessel walls and the accumulation of plaque and development of atherosclerosis. AGEs are also implicated in the physiological dysfunctions related to insulin resistance and metabolic syndrome, and the A1C index is now highly utilized in the diagnosis of diabetes type 2, or metabolic syndrome. AGEs could be implicated in the problems with VEGF-B signalling in the blood vessel walls, resulting in increased fatty acids transported to white adipose tissues rather than muscles for conversion to glucose energy. A number of nutrients have been studied in relation to improved fatty acid metabolism and clearing of AGEs. One company, Vitamin Research, has combined these nutrients and herbs into a product that includes R-Lipoic Acid, P5P, L-Carnosine, L-Histidine, N-Acetyl-Cysteine, Benfotiamine, and Guava and Yerba Mate leaf extracts. While this prescription is recommended for arterial health, macular degeneration and neurodegenerative conditions, future research may find this nutrient medicine formula very helpful in fatty tissue accumulation in obstructive sleep apnea in the future.

VEGF-B is also related to various inflammatory mediators, both in pathways that stimulate expression, and in sharing of receptors. Chronic low-grade inflammatory states may eventually have much to do with dysfunction of the VEGF-B metabolism and pathway. VEGF and interleukin-8 (IL-8) have been linked in studies, and problems with VEGF expression or receptor function could relate to excess IL-8, which is a pro-inflammatory mediator in epithelial and endothelial cells, and secreted by neutrophils and lymphocytes. Allergic responses in the airway could be related to eventual dysfunction of the VEGF-B pathway, as well as chronic tissue inflammation related to myofascial problems. A thorough approach to treatment of obstructive sleep apnea may include therapy that resolves myofascial problems, clears tissues of irritants and fibrin accumulations, and stimulates an improved immune response. When a number of interrelated health problems may work together to create an eventual complex pathology, such as fatty tissue accumulation in the airway creating obstructive sleep apnea, the therapeutic protocol must sometimes address these problems in a more complex manner. Complementary Medicine offers such holistic and intensive approaches with relatively inexpensive therapy. The end result of such therapy may be the eventual resolution of the causes of sleep apnea, as well as much improvement in overall health.

Information Resources and Additional Information with Links to Scientific Studies

  1. A 2014 report from Northumbria University, and Newcastle University, Centre for Sleep Research, found that simple snoring, often a precursor to sleep apnea, is not such a simple health problem, but a health problem that often worsens into a continuum that includes Upper Airway Resistance Syndrome and Obstructive Sleep Apnea, and is associated with Metabolic Syndrome, cardiovascular disease, and daytime drowsiness, like sleep apnea. The best time to treat may be when simple snoring becomes habitual, improving tissue health, hormonal balance, and metabolic function : http://www.ncbi.nlm.nih.gov/pubmed/24888523
  2. A 2010 article in the Journal of Clinical Endocrinological Metabolism, supported by research at the Hospital de Bicetre in France, found that endocrine and metabolic disorders have a high association with sleep apnea, and that in some cases, the sleep apnea was cured or improved by treatment of the endocrine disorder, and that an approach with Complementary Medicine integrating various therapeutic protocols is recommended: http://www.ncbi.nlm.nih.gov/pubmed/20061419?dopt=Abstract
  3. A 2008 article published in Diabetes Care, and supported by research at the Sleep Lab, Meyer Children'a Hospital, Haifa, Israel, finds that obstructive sleep apnea and metabolic syndrome are intimately linked, with each worsening the other, and highly associated with insulin resistance and autonomic imbalance: http://www.ncbi.nlm.nih.gov/pubmed/18227501
  4. A 2008 article published in the Archives of Physiology and Biochemistry, researched by the Sleep Research and Treatment Center in Hershey, Pennsylvania, found that insulin resistance and elevated insulin was associated with sleep apnea independent of obesity, and that subclinical hypothalamic function deficiency plays a major role in the pathogenesis of sleep apnea: http://www.ncbi.nlm.nih.gov/pubmed/18946782
  5. A 2014 long-term multicenter randomized controlled human clinical study at the University of Pennsylvania and the University of Iceland showed that the use of a CPAP (continuous positive airway pressure) device did not normalize the lipid imbalances associated with both chronic sleep apnea and cardiovascular disease. Obviously, a more holistic approach to therapy is needed to address these concerns : http://www.ncbi.nlm.nih.gov/pubmed/24833762
  6. A 2015 study at the University of Liverpool, United Kingdom, found that while sleep quality and blood pressure improved somewhat with the use of CPAP for obese patients with sleep apnea, measures of other cardiovascular problems, such as hardening of the arteries, were not improved with the use of CPAP, and that a broader and more integrative approach should be used to address cardiovascular health in these patients: http://www.ncbi.nlm.nih.gov/pubmed/25655633
  7. A 2009 case study of sleep apnea shows that this diagnosis is often undiagnosed until discovered in relation to other health problems. In this case the related condition was gout, for which subsequent studies have shown a high relationship. This patient was able to resolve his sleep apnea and not depend on a CPAP by sleep position, slight elevation of the head of the bed and other health improvements, and his attacks of gout then ceased: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2654829/
  8. A 2013 report from experts at Keele University, at Keele, United Kingdom, explains that there is a high association between sleep apnea and gout, both of which are associated with Metabolic Syndrome, obesity and diabetes, and that the connection seems to be between hypoxia and nucleotide turnover generating purines that are metabolized to uric acid: http://www.biomedcentral.com/1471-2474/14/119
  9. A 2013 study at the China Academy of Chinese Medical Sciences, in Beijing, China, found that obstructive sleep apnea syndrome is highly associated with hypertension and systemic inflammation, providing increased guidance of the integration of Complementary Medicine in the treatment protocol. Markers of inflammation that are increasingly shown to be highly associated with sleep apnea and hyptertension include C-reactive protein, interleukin-6, nuclear factor kappa B, TNF-alpha, interleukin-8 (IL-8) and MAPK-dependent pathways that can be modulated with both acupuncture and herbal medicine: http://www.ncbi.nlm.nih.gov/pubmed/23674113
  10. A 2016 study at Arizona State University and the Mayo Clinic, in Scottsdale, Arizona, U.S.A. noted that current treatment for obstructive sleep apnea, with the CPAP machine, did not address underlying causes, and ha many patients are intolerant of or noncompliant with this therapy. This meta-review of clinical human studies showed that exercise routines as a sole intervention improved clinical outcomes: http://www.ncbi.nlm.nih.gov/pu...http://www.ncbi.nlm.nih.gov/pubmed/27296826
  11. A 2006 study at the Center for Clinical and Basic Research, Ballerup, Denmark, found that metabolic syndrome and insulin resistance was linked to estrogen/progesterone imbalance, and that prescription of synthetic estradiol and progestins should only be prescribed when necessary for these patients; progestins have been shown to decrease circulating adiponectin, which is linked to inflammatory dysfunction that could be responsible for tissue hypertrophy, low grade chronic inflammation, and thus obstructive sleep apnea due to tissue growth: http://www.ncbi.nlm.nih.gov/pubmed/16766431
  12. A 1998 study at the Clinical Pharmacology and Metabolic Research Unit, University of Vermont, found that synthetic hormone replacement therapy was responsible for many cases of increased midsection fat accumulation, as in metabolic syndrome. The association with these fat metabolism changes and the fatty growth of tissues in obstructive sleep apnea are now well documented: http://www.ncbi.nlm.nih.gov/pubmed/9847982
  13. A 2002 study at the University of Wisconsin School of Medicine and Public Health found that chronic use of inhaled corticosteroid, such as asthma med inhalers, had a high association with risk of acquiring obstructive sleep apnea: http://chestjournal.chestpubs.org/content/135/5/1125.abstract
  14. A 2007 study at the Royal Bournemouth Hospital in England found that antidepressant medications may be implicated in many cases of elevated adrenal neurohormones, or catecholamines, which have a high association with central sleep apnea: http://www.endocrine-abstracts.org/ea/0014/ea0014P482.htm
  15. A 2016 study at the Finders University of South Australia noted that numerous studies show a clear link between opioid pain medication use and sleep disordered breathing such as apnea. Opioid use is highly linked to central sleep apnea, more than obstructive, and indicates that it may be a causative factor in complex sleep apnea syndromes: http://www.ncbi.nlm.nih.gov/pu...http://www.ncbi.nlm.nih.gov/pubmed/27262224
  16. Study at Penn State University College of Medicine found a high association between obstructive sleep apnea, insulin resistance, hypercytokinemia (hypersensitive immune response), polycystic ovary syndrome, and the hormonal imbalances associated with the premenopausal state, independent of obesity: http://www.ncbi.nlm.nih.gov/pubmed/11158002?dopt=Abstract
  17. A 2012 study at Cardiff University in the United Kingdom noted the connection between polycystic ovarian syndrome (PCOS), high insulin expression and insulin resistance, and chronic sympathetic nervous system activity relative to parasympathetic responses. These researchers noted that studies prove that low-frequency electroacupuncture modulates sympathetic nervous system excitotoxicity and should be integrated into the treatment protocol for PCOS and sleep apnea: http://www.ncbi.nlm.nih.gov/pubmed/?term=central+sleep+apnea+acupuncture
  18. A 2015 study at the University of Ovledo School of Medicine, in Ovledo, Spain, showed that reduced innervation in the human pharynx is a hallmark of obstructive sleep apnea, helping to elucidate this still unexplained etiopathology. Stimulation with acupuncture could play an important role in reversing this neural degeneration, and obviously a more holistic and restorative treatment protocol is needed: http://www.ncbi.nlm.nih.gov/pu...http://www.ncbi.nlm.nih.gov/pubmed/25663466
  19. A 2014 study at the University of Western Sydney, the University of Sydney and UCLA Schools of Medicine, in Australia and the United States, showed that elevated sympathetic nerve responses in obstructive sleep apnea are related to structural changes in the brain, with significant increases in grey matter of the insula and hippocampus, and decreased size in the amygdala and cerebellum. Restoration of homeostasis could help bring these areas into normalcy over time, and reduce associated cardioavascular pathology: http://www.ncbi.nlm.nih.gov/pu...http://www.ncbi.nlm.nih.gov/pubmed/25379440
  20. A 2010 randomized controlled human clinical study of acupuncture as part of a treatment protocol for sleep apnea, at the Federal University of Sao Paolo, Brazil, found that a single session of electroacupuncture had an acute effect of reducing the Apnea-Hypopnea Index as well as reduction of the number of nocturnal respiratory events in patients with moderate obstructive sleep apnea. The use of 10 Hz stimulation at appropriate points was found most effective: http://www.ncbi.nlm.nih.gov/pubmed/20615853
  21. A 2007 randomized controlled human clinical trial of acupuncture in the treatment of sleep apnea, at the Federal University of Sao Paolo, Brazil, showed that acupuncture was effective and significantly more effective than sham acupuncture in the treatment: http://www.ncbi.nlm.nih.gov/pubmed/17023212
  22. A 2009 study at the Shanghai University of TCM, in China, found that acupuncture showed a significant effectiveness on alleviating measures of anoxia in sleep apnea in more than 23 percent of patients. The study of 30 patients used DU16, 15, GB20 and the point Shanglianquan: http://www.ncbi.nlm.nih.gov/pubmed/19186731
  23. A meta-review of all published randomized controlled human clinical trials of acupuncture and electraacupuncture in the treatment of obstructive sleep apnea, at the Huazhong University of Science and Technology, in Wuhan, China, found that both manual and electroacupuncture was effective and could improve the apnea hypopnea index. Integration of short courses of acupuncture could improve outcomes significantly, and a more holistic and individualized TCM clinical treatment could address underlying causes and comorbid health conditions: http://www.ncbi.nlm.nih.gov/pu...http://www.ncbi.nlm.nih.gov/pubmed/27127530
  24. A 2013 study by the Sleep Disorders Unit and the University of Crete School of Medicine, in Crete, Greece, found that a prescription of high dose thiamine, Co-Q10, Vitamin C, E, and acetyl L-carnitine improved symptoms of sleep apnea at the University General Hospital. The recommendation that such therapy could be applied in early stages of sleep apnea to prevent worsening of the disorder, safely and relatively inexpensively in holistic medicine, was made. The acknowledgement in standard medicine that such diseases present a multi-organ involvement and thus may need a more holistic treatment approach is significant: http://www.ncbi.nlm.nih.gov/pubmed/23389837
  25. The strong connection between childhood sleep apneas and central adrenal insufficiency in Prader-Willi syndrome implies that there is a connection between adult sleep apnea and adrenal fatique and hormonal imbalance: http://www.ncbi.nlm.nih.gov/pubmed/19383777
  26. Adrenal fatique is explained clearly in this articel published by Complementary Prescriptions: http://www.cpmedical.net/articles.aspx?page=LIST&ProdID=6627&zTYPE=2
  27. Studies at Stanford and the University of Wisconsin show that sleep deprivation consistently resulted in hormonal changes (reduced leptin with increased ghrelin) that resulted in poor appetite control and weight gain: http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0010062
  28. An article in Respiratory and Critical Care Medicine from 2004, states unequivocably that sleep apnea and metabolic syndrome are strongly associated independently from obesity: http://ajrccm.atsjournals.org/cgi/content/full/169/2/139
  29. In 2009, research in Australia found that progesterone/estrogen balance affects insulin sensitivity (resistance) through modulation of adiponectin and body fat, and that fatty tissue accumulation (as we see in obstructive sleep apnea) is controlled by adiponectin hormone in balance with other hormonal mechanisms: http://www.ncbi.nlm.nih.gov/pubmed/19154958
  30. A 2008 study at the Columbia University College of Physicians and Surgeons and Tulane University School of Medicine found that sleep apnea is associated with high cardiovascular risk by promoting inflammation and oxidative stress while decreasing nitric oxide availability and vessel reapair capability: http://circ.ahajournals.org/cgi/content/short/CIRCULATIONAHA.107.741512v1
  31. A study at the Yale Universisty School of Medicine Center for Sleep Medicine found that sleep apnea patients had decrease waking cerebral blood flow and slow response to hypotension that could account for the increased risk of stroke: http://jap.physiology.org/cgi/content/full/105/6/1852
  32. A study at the Karolinska Institue in Sweden in 2010 found that pathological fatty accumulation in muscles, such as we see in obstructive sleep apnea, is related to a hormonal protein called VEGF-B (vascular endothelial growth factor), and that with insulin resistance and metabolic syndrome, a dysfunction is created that uncouples fatty acid burning in the muscle to meet energy needs, and the signals for transport, creating accumulation of fatty acids in the white fat cells that goes unused: http://www.nature.com/scibx/journal/v3/n13/full/scibx.2010.394.html
  33. An article in the Clinical Cancer Research journal in 2001 explored the research that has found a strong link between inflammatory mediators and the expression of VEGF, pointing to the complex holistic relationship between immune modulation and hormonal control of fatty tissue metabolism: http://clincancerres.aacrjournals.org/content/7/2/435.full
  34. The key focal biochemical pathway in sleep apnea may be the expression of a neuropeptide in the hypothalamus called nesfatin-1, which is inversely correlated with severity of sleep apnea, and is linked to adaptive stress response, insulin resistance, chronic inflammation, oxidative stress, and other associated underlying health factors linked to sleep apnea. Here, experts at the University of Cordoba, Spain, explain the research findings with nesfatin-1 in 2010: http://jme.endocrinology-journals.org/content/45/5/281.full.pdf
  35. Research in 2014, in China, found that there was a consistent inverse relationship between levels of nesfatin-1 and severity in sleep apnea: http://www.ncbi.nlm.nih.gov/pubmed/25056666
  36. Research in 2013, at Charite University School of Medicine, Berlin, Germany, found that the hypothalamic neuropeptide nesfatin-1/NUCB2 is also highly associated with anxiety in obese female patients, but not correlated with BMI, indicating that this biomarker of oxidative and metabolic stress, and adaptive stress response, may be a key to the relationship between emotional regulation and mood and obesity: http://www.ncbi.nlm.nih.gov/pubmed/23796625
  37. Research in 2010, at the Jichi Medical University School of Medicine, in Tochigi, Japan, found that the neuropeptide nesflatin-1, localized in the hypothalamus and brainstem, is co-localized and correlated with various biochemical related to stress response, such as noradrenalin, 5HT (serotonin), proopiomelanocortin, oxytocin, and corticotropin-releasing hormone, and that this central nesfatin-1 system is stimulated by chronic restraint stress and activates these stress biochemicals in the hypothalamic-adrenal axis. These findings clearly indicate that a deficient nesflatin-1 expression associated with sleep apnea is most likely related to an adrenal fatigue syndrome and chronic restraint stress: http://www.ncbi.nlm.nih.gov/pubmed/20966530
  38. Meta-research in 2012, at the Radboud University Nijmegen Donders Institute for Brain Cognition and Behaviour, in Nijmegen, The Netherlands, found that the neuropeptide nesfatin-1, derived from the peptide prohormone precursor NUCB2, is an important regulator of adaptive stress response : http://www.ncbi.nlm.nih.gov/pubmed/23537084
  39. Research in 2014, also in China, at Weifang Medical University, found that an inflammatory biomarker called serum S100A12 was also highly correlated with severity of obstructive sleep apnea, showing that chronic inflammatory stress was integral to the pathology: http://www.ncbi.nlm.nih.gov/pubmed/23868710
  40. Research in 2012, at the Federal University of Pernambuco, in Brazil, showed that markers of oxidative stress were also highly correlated with obstructive sleep apnea: http://www.ncbi.nlm.nih.gov/pubmed/22402994