Erectile Dysfunction as a Cardiovascular Impairment

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Chapter 1

Introduction

This chapter defines erectile dysfunction (ED) by the criteria in the Diagnostic and Statistical Manual of the American Psychiatric Association (DSM-IV-TR, 2000), and proposes the future inclusion of a medical cause diagnostic category corresponding to systemic as well as penile vascular impairment, purportedly the most common presentation of ED. The chapter further distinguishes between sexual dysfunction and low or absent sexual desire relating vasculogenic ED also to common cardiovascular (CV) health hazards that rarely affect desire. The chapter details the nature and the role of the vascular endothelium and the role of nitric oxide (NO) in the sequence of events in sexual arousal leading to penile erection—the ACh/NO/cGMP pathway. It ends by detailing the progressive age-related impairment in endothelium function and loss of sufficient formation of NO for attaining and sustaining penile erection.

Keywords

Acetycholine (ACh); Aging; Atherosclerosis; Cyclic Guanosine Monophosphate (cGMP); Erectile Dysfunction (ED); Endothelium; Heart Disease; Hypertension; L-Arginine; Nitric Oxide (NO); Penis; Phosphodiesterase Type-5 (PDE5); Sexual Arousal; Sexual Performance; Vasa Vasorum; Vasculogenic Erectile Dysfunction; Vasodilation; VIAGRA®

If we do not change our direction, we are likely to end up where we are headed.

—Ancient Chinese proverb

1.1 Erectile Dysfunction—as Presently Defined

The common term erectile dysfunction (ED) is Male Erectile Disorder in the current Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association. It is said to be a persistent or recurrent inability to attain or to maintain an adequate erection to completion of the sexual activity. It is a disturbance causing marked distress or interpersonal difficulty, an ED not better accounted for by any other diagnostic categories except mental retardation and personality disorder, and one that is not due exclusively to the direct physiological effects of a substance, e.g. a drug abused, a medication, or a general medical condition (APA—DSM-IV-TR, 2000).¹ The definition assigns etiology to other than medical causes thus seemingly excluding vascular/vasculogenic ED, now considered to be the most common form found among American men.

By no means is each and every case of chronic ED vasculogenic, but the overwhelming majority of cases that appear to develop in adults—estimated at about 90 percent in American men—and to follow an age-related timeline, fit that definition. There are, of course, other causes of ED, some due to hormonal imbalance, and others with an emotional basis, but they are not the concern of this monograph.

The recommendation to include diagnostic criteria for a medical basis of ED in subsequent editions of the DSM is made in the Journal of Sexual Medicine,² and it is consistent with the theme of this monograph. In fact it is essential to make both the medical and the mental health services community aware of that medical basis so as to improve health care delivery beyond simply treatment of ED per se.

1.2 The Aim and Scope of this Monograph

This monograph will make the general case and document the research and clinical evidence that ED is indeed caused by a medical condition: impaired vascular endothelium resulting in reduced bioavailability of nitric oxide (NO). NO is a biologically active gas, the link between sexual arousal and erection. It is derived in the body principally from the amino acid L-arginine and from dietary nitrates. NO mediates between the arousal-triggered release of acetylcholine (ACh), and the formation of the vasodilator, cyclic guanosine monophosphate (cGMP), in the ACh/NO/cGMP pathway to penis cavernosal relaxation, engorgement, and erection.

The advent of phosphodiesterase type-5 (PDE5) inhibitors including VIAGRA®, Cialis®, and Levitra®, have made the medical and psychiatric/psychological community aware that there are medical treatments for the most common form of ED, but it is not clear to most practicing clinicians how and why they work except in the most vague terms that they somehow influence blood flow and thus erection. Not being familiar with the ACh/NO/cGMP pathway, many suspect that these meds might just treat the psychological basis for ED.

There are precedents in medicine to parallel the disjunction between emotional disorder and medication treatment. For instance, bipolar disorder is a mood disorder that is treatable with medications. Thus, there is an understanding that medications can affect mood without most practitioners understanding the brain physiology basis for the mood, or the disorder, except in vague terms such as neurotransmitter biosynthesis that only specialists really know. Thus, it is not unreasonable to figure that meds can treat ED even if one holds that ED is basically an emotional disorder.

The reason for this information gap is that the clinical and basic research leading to our understanding of the ACh/NO/cGMP pathway to cavernosal relaxation and penis engorgement and erection, and related physiology, is found in thousands of scientific reports in hundreds of different journals straddling many dozens of different subspecialties, published over the past three decades. It would be an impossible task for any practicing clinician to keep up with this avalanche of data.

For example, there is an estimated 850,000 licensed physicians in the US. Less than half that number (about 300,000) subscribe to the Journal of the American Medical Association (JAMA). The New England Journal of Medicine (NEJM) has about 200,000 subscribers, and Annals of Internal Medicine has about 110,250 subscribers. These are major journals. Even so, basic research and clinical trials relevant to the present concerns appear in specialty journals such as Archives of Biochemistry and Biophysics, Ultrasound Medicine and Biology, and Vascular Physiology, where researchers basically talk to each other; and also in better known journals with a narrow-focus regular readership such as Diabetes Care, Hypertension, and the Journal of the American college of Cardiology, to name just a few. The information often doesn’t filter down to the rank and file practitioners who really most need it to serve patients well.

This monograph synthesizes information from a wide range of subspecialties, and in most cases indicates the source by naming the journal where cited reports were published. Naming the source is especially important here because it establishes the credibility of information drawn from a wide range of research subspecialties, each providing what amounts to a handful of tiles to form the overall mosaic: ED as a cardiovascular impairment. Furthermore, naming the journal sources also gives the reader insight into the complexity of contemporary research: The simple days are pretty much a thing of the past when, for instance, penicillin was discovered when an in vitro bacterial culture was inadvertently destroyed by a contaminating spore (penicillium) in Dr. Alexander Fleming’s lab, or the treatment of diabetes when Dr. Frederick Banting injected pancreatic extract into a patient, or when Dr. Barry Marshall established the cause of most ulcers by downing an infectious broth holding Helicobacter pylori.

1.3 The Prevalence of Erectile Dysfunction

According to a 2007 report from the Johns Hopkins Bloomberg School of Public Health, more than 18 million American men 20 years old, or older, experience some degree of ED, from mild-episodic to severe-sustained ED.³ The report pointed to causes ranging from cardiovascular and heart disease to diabetes. Advances in medical science are now shifting the attention of many clinicians from treating the mind to treating the body.

There is now overwhelming evidence that most men with ED can attribute this calamity to cardiovascular and metabolic disorders including hypertension, atherosclerosis, CHD, type-2 diabetes, and metabolic syndrome. It is also now known that the progress of this assortment of medical disorders is further enhanced by oxidative stress, by the progressive age-related decline of androgenic hormones, and by changes in energy storage and marshaling control-hormones.

For better or for worse, the timeline of these progressive age-related calamities for each one of us is pretty strictly subject to the dictates of genetics. It is pretty well established, and scientific proof abounds to show that we have little power to retard it. However, with the help of poor nutrition and an unhealthy life style we can readily accelerate it.

We are frequently cautioned by health authorities via media and other sources that unhealthy nutrition and sedentary lifestyle are at the very core of the cardiovascular afflictions that thwart vigorous and enduring erectile function. These reports bolster the idea that when it comes to lovemaking, our diet can either make us or unmake us because our diet is principally responsible for these medical disorders that result in ED. In fact, our diet by itself is not at fault. The most recent scientific findings teach us that:

• High blood pressure, atherosclerosis, insulin resistance, visceral adiposity (metabolic syndrome), and ED are natural, progressive, age-related cardiovascular conditions with a timeline determined principally by our genes.

• The progress timeline of these conditions can be accelerated by a diet that is poor in certain nutrients and micronutrients, and either too poor or, paradoxically, too rich in antioxidants.

• High blood pressure, atherosclerosis, and insulin resistance, leading to cardiovascular and heart diseases, diabetes, metabolic syndrome, and the ensuing ED, may not be diseases as we understand that term, but the presenting clinical symptoms of an underlying natural process of systematic degradation and ultimate dysfunction of the endothelium, the cell-layer lining the blood vessels throughout the body.

• Endothelium dysfunction adversely impacting the ACh/NO/cGMP pathway is causally linked to high blood pressure, atherosclerosis, insulin resistance, oxidative stress, metabolic syndrome, declining testosterone, changes in sensitivity/resistance of appetitive control hormones, and ultimately, ED, by interference with the formation of endothelium-derived NO.

• The endothelium serves a vital physiological control function that is undermined in part by oxidative stress and is in part linked to a diet that fails to supply certain essential nutrients and micronutrients that support the proper balance of endogenous and exogenous antioxidants.

• Endothelium impairment is now recognized as the primary cause of most cases of ED, and in fact, prescription medications such as VIAGRA are used to bolster its flagging function.

• While even the healthiest diet and lifestyle may not stop progressive aging, they can significantly keep it to its natural individual dictates, whereas poor diet and sedentary lifestyle can speed up endothelial aging as noted by rapidly progressing hypertension, atherosclerosis, and insulin resistance.

These findings may seem outside the mainstream of current intuition regarding what leads to what, that leads to ED. Nevertheless, while perhaps not widely known yet, these assertions constitute the consensus of contemporary scientists spanning those subspecialties examining the clinical and the laboratory links between cardiovascular risk factors and ED.

The epidemiological derivative of the links of cardiovascular disorders and ED to endothelium impairment gives rise to a formulation of their interrelationship that strongly suggests that they are all, in fact, symptoms of underlying blood vessel disease. Many investigators worldwide now hold that view. Thus, this book proposes no unconventional theory of the cause of ED, and no unconventional theory of its treatment outside the mainstream of up-to-date medical research. The ideas and assertions are those of the rank and file in medical laboratory and clinical research whose journal publications are abstracted, paraphrased, and cited here. Their individual research forms fractions of a whole, and the synthesis of these disparate findings into that coherent whole is, however, my main contribution to understanding what leads to what, that leads to ED, and how best to treat it.

1.4 It is more complicated than the Standard American Diet

The Standard American Diet (SAD) is often accorded the lion’s share of blame for the common cardiovascular disorders that befall Americans. The prevention and treatment of ED would be greatly simplified and facilitated were it just a matter of nutritional intervention. The fact is that this is not the case. Unhealthy diet alone does not cause ED. ED results from the complex interaction of diet, heredity, endocrine function, natural progressive aging, and cardiovascular hazards.

This is not to say that nutrition is tangential. To the contrary, it plays a significant role in accelerating the progression of the factors that lead to ED, and it can play a significant role in strategies that correct the factors that speed up that time line. For example: If left to its natural dictates, and in the absence of certain nutrient supplements, the time course of hypertension, atherosclerosis, and insulin resistance will result in a predictable age-related prevalence of ED. This time course is detailed later in the book. However, nutritional intervention can stretch and extend that time line for any given individual, mostly by preventing it from accelerating.

For that reason, elements of nutrition, both what we consume and what we fail to consume, are examined in some detail later in different sections of this monograph. The selection of these nutrients is based on what their active constituents teach us about endothelial function and dysfunction. No attempt at a comprehensive survey is made here: samples serve as examples.

1.5 The Standard American Diet

The SAD is high in animal fats, high in saturated, hydrogenated fats, low in fiber, high in processed foods, low in complex carbohydrates, low in fruits and greens. The daily intake of important micronutrients (vitamins, minerals, etc.) is impossible to gauge with any degree of certainty. Were one to wish to meet the Required Daily Allowance (RDA) of vitamins and minerals as set by the US Food and Drug Administration (FDA), minimal levels at best, certainly the SAD, is not likely to provide it.

As an alternative to the SAD, and in order to forestall these health hazards that impair response to sexual arousal in both men and women, my co-author and I proposed Three Food Factors in our earlier book Great Food, Great Sex:⁴ two factors to supply the body with adequate amounts of the amino acid L-arginine, and dietary nitrates, from which we derive the NO, proven by 1998 Nobel Prize in Medicine research to be the key to penis erection in men and clitoral engorgement and vaginal lubrication in women. The other factor is intended to reduce oxidative stress and inflammation by providing sufficient NO and antioxidants to keep our heart and blood vessels in tip-top condition as recommended by the National Heart Lung and Blood Institute (NHLBI) of the National Institutes of Health (NIH). Many of the recipes for success in that book were provided by the NHBLI studies promoting cardiovascular and heart health.⁵

This book will also explain that what is not consumed will also undermine sexual vitality: The effects of a lifetime of SAD that most can see beginning to downsize sexual performance were shown scientifically in many cases to be reversible by the dietary micronutrients and other supplements detailed in later chapters. Conventional medical research now focuses on what was once thought to be unconventional approaches to treatment of ED by zeroing in on the molecular basis of endothelial function support. For instance, a clinical study appearing in the New England Journal of Medicine reported on the salutary effect of coupling statin therapy with niacin (vitamin B3) in patients with low high-density lipoprotein cholesterol (HDL-C) levels.⁶

1.6 An Important Note to the Reader

In the following sections, and indeed in subsequent chapters, there will be numerous medical science studies that are paraphrased and summarized. In some instances, there are direct quotations. These summaries will always include:

• AIM of the study—what the researcher intended to accomplish with the treatment(s); a description of

• PARTICIPANTS in the treatment plan, including age, gender, health status, etc;

• METHOD, i.e. procedure and protocols used in carrying out the treatment, including diagnostic laboratory and other test procedures used to evaluate pre-trial to post-treatment changes; and the researcher’s

• RESULTS & CONCLUSION(S) about statistically significant findings.

Background information providing context for the studies is conventionally found in the INTRODUCTION in journal articles. It has been omitted here as the book itself provides that. In addition, things such as number of participants, the types of statistical analysis used, and the significance level have been omitted from the summaries. Their absence is neither an oversight nor an effort to obfuscate. Here, I exercise my editorial skills to determine what does, and what does not, explain or enlighten. The information omitted is usually science or statistics jargon intended to convince the editors of a given medical journal to which a study is submitted for publication that the research methodology is valid and sound, and that the data and conclusions are reliable and valid. Having passed their accepted-for-publication test, there is in most cases no further need for that sort of information. That the margin of error (significance level) is 1%, 2%, or 5% is trivial. The reader may rest assured that no study in this monograph is cited that did not meet criteria for statistical significance at a conventionally acceptable level.

The aim of this editing is to help to focus on the issues without the distraction of minutiae that contribute nothing to understanding what the study was about and what we can learn from it. For most readers, the aim of each study cited and the outcome and conclusion will be clear and comprehensible in context. Furthermore, each assertion and each study is carefully referenced in the text directly to the source on the Internet or in a library to support its credibility. The actual references can be found in the reference list at the end of each chapter.

1.7 What Impairs Sexual Vitality?

This book does not address issues concerning dysfunctional sexual desire because there is no need to do that. Contrary to long held belief, ED is very rarely due to lack of desire, but rather to blood vessel dysfunction. The PDE5 inhibitor meds do not correct low or absent desire. There is no need for that: If men with ED had no desire, it would be difficult to explain how just VIAGRA saw sales of $2 billion in 2011. Lacking desire, who would buy it?

Most men experience occasional temporary loss of sexual desire and/or fluctuation in the strength of desire. They may also experience temporary inability to erect, and fluctuations in latency and strength of erection. Infrequent such events are not abnormal, although they cause alarm. The desire to explain consistent inability to attain erection has led to psychological hypotheses that assign these events to inhibiting subconscious motives.

The advent of the PDE5 inhibitors has shown that desire and performance are two separate, albeit overlapping, functions; desire is affected by the available level of testosterone in men, and in women, whereas performance is determined by the capacity of the endothelium to form NO when prodded to do so by sexual arousal.

It should be noted that the ontological development of sexual activity may depend on maturation-related testosterone levels, but its continuation in adulthood may not. Castration after puberty has, in most cases, relatively little impact on sexual activity in various animal species, as well as in men.⁷ This suggests that in consistently sexually active men, declining available testosterone levels do not go very far to explain ED in such a vast proportion of the adult population.

1.8 Sexual Arousal and Performance

There have been, over the years, many theories to explain to the patients whose arousal fails to result in erection that, barring hormone insufficiency, the problem is either psychological or stress. There is now rarely mention of stress as a cause of ED as we have learned that stress does not cause erectile failure. In fact, erectile failure causes stress. Stress and anxiety actually heighten sexual