Managing Erectile Dysfunction—When Viagra Doesn’t

by Lara Pizzorno, MDiv, MA, LMT

Phosphodiasterase-5 (PDE-5) inhibitors, e.g., sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis), are ineffective in 30-40% of men diagnosed with erectile dysfunction (ED).  New studies show that erectile function can be restored in these men, without resorting to intracavernous injections or a penile prosthesis, by using natural agents (including NO-producing substrates such as N-hydroxyarginine [OH-arginine]) in combination with the PDE-5 inhibitors.1

In ~70% of impotent men, ED is due to cardiovascular disease, MetS, diabetes mellitus, hypogonadism, and/or use of prescription and non-prescription drugs (e.g., antihypertensive agents including diuretics and betablockers; psychotropic drugs including neuroleptics, and SSRIs and other antidepressants; anti-arrhythmics, anti-androgens, steroids, nicotine [smoking] and alcohol).2 3 4 Identifying and treating the individual’s underlying cause(s) of ED will not only rejuvenate his sexual performance but significantly enhance his overall health and longevity.5

Just say NO to ED

In the vast majority of individuals with ED, the dysfunction is nitric oxide-related. In the healthy male, in response to sexual stimulation, nitric oxide (NO) is released in the corpus cavernosum, the cylinder of erectile tissue forming the dorsal part of the body of the penis, and binds to receptors on the enzyme guanylate cyclase, which results in production of cyclic guanosine monophosphate (cGMP), leading to smooth muscle relaxation (vasodilation) of the intimal cushions of the helicine arteries, increased inflow of blood and an erection.

By selectively blocking the normal hydrolysis of cGMP, the PDE-5 inhibitors promote cGMP accumulation, thus partially reversing deficiencies in the NO/cGMP pathway. The key word here, however, is “partially,” since decreased expression or activity of endothelial NO synthase (eNOS), impaired NO release, and/or rapid NO destruction will preclude sufficient cGMP formation to enable benefit from a PDE-5 inhibitor. Thus, to make possible PDE-5 efficacy in men unresponsive to these drugs, the amount of available NO must be increased in penile tissue.1 This can be accomplished safely and without the risk of inducing adverse side effects with the use of natural agents that have been shown in the peer-reviewed research to enhance NO synthesis, facilitate NO release, and/or inhibit NO breakdown.

Enhancing NO Synthesis

L-arginine: NO is generated via the activity of NOS, which catalyzes the oxidation of L-arginine with NADPH and molecular oxygen to yield L-citrulline and NO. L-arginine, as substrate for this reaction, is its key limiting factor. (For a full discussion of L-arginine metabolism and NO production, please see “Longevity Medicine Strategies for Cardiovascular Disease: Closing the Statin Gap in Endothelial Dysfunction and Insulin Resistance Naturally, with L-Arginine and Citrulline”.

Supplemental L-arginine is readily absorbed and well tolerated in single doses of 3-6 grams.6   When larger doses are desirable, adverse gastrointestinal effects can be avoided with multiple daily doses of <6 grams.7   However, optimizing L-arginine delivery for NO production is not as straightforward as this since L-arginine may be co-opted for a number of other uses in the body.

~50% of ingested L-arginine is rapidly converted in the body to ornithine, primarily by the enzyme arginase, whose expression and activity is upregulated in the presence of oxidized LDL and conditions associated with endothelial dysfunction, including—in addition to ED—hypertension, heart failure, atherosclerosis, and diabetic vascular disease—co-morbidities  so frequently seen in men with ED that a growing number of studies recognize ED as a reliable marker not only for overt cardiovascular disease, but also one that serves as an early indicator of subclinical systemic vascular disease.8 9   In the man with ED, arginase is highly likely to be upregulated, which translates to a need for higher than typical doses of supplemental L-arginine to produce benefit.

Furthermore, L-arginine, in addition to its roles as substrate for NOS and arginase, is also a precursor for the synthesis of proteins, urea, creatine, vasopressin, and agmatine. In addition to NOS, L-arginine that escapes metabolism by arginase is targeted by three other enzymes: arginine:glycine amidinotransferase (to become creatine); arginine decarboxylase (to become agmatine); and arginyl-tRNA synthetase (to become arginyl-tRNA, a precursor to protein synthesis).12

Sustained-release preparations of L-arginine have been suggested as a means of helping to maintain blood levels over time, yet arginase’s substantial intestinal and hepatic metabolism of L-arginine to ornithine and urea, combined with L-arginine’s use for other functions in the body, lessen the likelihood of optimal improvement in NO production from oral supplements of L-arginine.10   L-citrulline or hydroxyl-arginine (OH-arginine) may provide a better option.

L-citrulline is readily absorbed and efficiently converted to L-arginine, but since the conversion occurs in the kidneys, vascular endothelium and other tissues, and not in the liver and intestine where arginase is concentrated, the formation of L-arginine from supplemental L-citrulline does not induce arginase activity, increasing the amount of L-arginine available for NO production.  Published data also indicates that L-citrulline has relatively better absorption and systemic bioavailability than L-arginine.12 13

N-hydroxy-arginine (OH-arginine) is a stable intermediate product formed during the synthesis of NO. Arginine is first oxidized into OH-arginine, which carries an atom of oxygen bonded to the guanidine group of L-arginine, and then further oxidized to citrulline concomitant with the release of NO. Thus, when OH-arginine is provided as substrate, NOS requires one less step and a lesser amount of oxygen and NADPH to produce NO. As a result, OH-arginine is a highly potent competitive inhibitor of arginase.14 15   In rabbit corpus cavernosum, OH-arginine, but not L-arginine, was found to promote NO-mediated relaxation and cGMP accumulation, and OH-arginine has also been shown to improve NO generation in hypoxic and aged tissues.1 16   During the last decade, a great number of compounds have been synthesized and studied as possible NO-producing substrates for NOS. OH-arginine, although not yet available as a supplement, is one of the very few found capable of promoting significant formation of NO. 17

Conversion of L-arginine to NO

OH-arginine – a more reliable indicator of NOS activity. Levels of OH-arginine have been found to be significantly reduced in patients with MetS compared to healthy controls, while these men showed no significant differences in concentrations of the NO precursor, L-arginine, or the end product of NO synthesis, L-citrulline. OH-arginine may therefore also serve as a more reliable marker of reduced NO formation and cardiovascular risk in men with MetS, ED and its other co-morbidities than L-citrulline, nitrite and nitrate, the compounds that have been commonly used to evaluate CVD risk. Because NO is very unstable, techniques to measure its formation in vivo have concentrated on measuring NO decomposition products, i.e., citrulline and the electron oxidation products of NO, nitrite and nitrate. But these compounds are also produced by other enzymes, while only NOS produces OH-arginine. For this reason, plasma OH-arginine concentration has been suggested as a more accurate indicator of NOS activity.18

When lab testing reveals low plasma levels of OH-arginine, this must either be due to decreased eNOS activity or increased breakdown of OH-arginine by oxidants, e.g., superoxide and peroxynitrite. Both oxidants indicate increased need for the cofactors in NO metabolism, i.e., tetrahydrobiopterin (BH4) [and its recycling partner, vitamin C], and the methylating factors, B6, B12 and folate. (For a full discussion of these issues, please see “Longevity Medicine Strategies for Cardiovascular Disease: Closing the Statin Gap in Endothelial Dysfunction and Insulin Resistance Naturally, with L-Arginine and Citrulline, Part II”).

Ginseng has also demonstrated efficacy in enhancing NO synthesis and improving erectile function in men with ED.19  Ginseng, specifically an extract of Panax ginseng containing the ginsenoside Rg1, has been shown to increase phosphorylation of eNOS, leading to enhanced production of NO and of vascular endothelial growth factor, which also increases production of eNOS, and thus, NO synthesis.20 21 22 In a double-blind, placebo-controlled 8-week study involving 143 men with ED, scores on the International Index of Erectile Function (IIEF) questionnaire were significantly higher, and erectile function significantly improved, in subjects given extract from Panax ginseng extract (1,000 mg b.i.d.), while no improvement was experienced by those receiving placebo.23   At least one mechanism through which ginseng exerts its beneficial effects was identified in a recently published rat study in which Rg1 increased serum testosterone concentration, and enhanced NO release and cGMP accumulation in the corpus cavernosum both in vivo and in vitro. Within 16 days, Rg1 (10 mg/kg) significantly increased mounting, pelvic thrusting frequency and intromission by male mice.24

Facilitating NO Release

Yohimbine, an α-2 antagonist, inhibits activation of the nitrergic nerves in the penile arteries and corpus cavernosum tissue, thus promoting nitrergic relaxation and NO release.1 2 16 Although controlled, randomized human studies involving yohimbine are few, meta-analyses of the available research have consistently shown an advantage of yohimbine over placebo.25   The most recent was a double-blind, placebo-controlled, three-way crossover, randomized clinical trial, conducted by the Urology Department at the Hopital Foch, Suresnes, France, that involved 45 men with mild to moderate ED and compared the efficacy of a combination of 6g of L-arginine glutamate and 6 mg of yohimbine hydrochloride with that of 6 mg of yohimbine hydrochloride alone or placebo. Capsules were administered orally one to two hours before intended sexual intercourse. At the end of each treatment period, scores on the IIEF were 17.2+/-7.17, 15.4+/-6.49 and 14.1+/-6.56, for the combination of arginine and yohimbine, yohimbine alone, and placebo respectively, with the difference between the arginine plus yohimbine combination achieving statistical significance. According to both investigator and participant assessments, erectile function was significantly improved by yohimbine, which the paper describes as a promising addition to first-line therapy for ED.26

Further recent evidence of yohimbine’s potential benefit for men with ED was noted in a study conducted in 18 non-smoking men (since tobacco has been thought to affect yohimbine’s efficacy more than other risk factors for ED); 50% of subjects were successful in completing intercourse in more than 75% of attempts. Yohimbine responders did have less severe ED (as manifested by improved increased rigidity on RigiScan testing, higher Florida Sexual Health Questionnaire scores, and slightly higher levels of testosterone).27   A review of the clinical, pharmacological and therapeutic profiles of yohimbine concluded that, as monotherapy, yohimbine exerts only modest efficacy in ED patients, but increasing evidence indicates concomitant administration of yohimbine with other agents that augment NO release or action in the corpus cavernosum significantly improves erectile function.28

Thermal therapy. Systemic thermal therapy, such as taking a warm-water bath or sauna (60 degrees C / 140 degrees F for 15 minutes, followed by bed rest with a blanket for 30 minutes), induces systemic vasodilation and has been shown to improve vascular endothelial dysfunction within 2 weeks in patients with congestive heart failure, hypertension, hyperlipidemia, diabetes mellitus, obesity, and compromised endothelial function due to smoking.29 30 In experiments with cardiomyopathic hamsters with heart failure, sauna therapy increased expression of eNOS mRNA and aortic eNOS protein expression. Far-infared sauna therapy has been shown to significantly increase hindlimb eNOS  expression and capillary density in apoE-deficient mice with hindlimb ischemia. No improvement was seen in animals given a NOS inhibitor [N(G)-nitro-L-arginine methyl ester], confirming benefit was due to eNOS/NO activity.31

In obese patients, body weight and fat—contributing factors to all the lifestyle-related diseases typically present in men with ED—significantly decreased after 2 weeks of sauna therapy with no increase in plasma ghrelin concentrations.3032 

Not only does regular thermal therapy, using saunas or hot baths, boost expression of eNOS, but it may promote insulin sensitivity, whose importance, given the number of men with ED for whom MetS or type 2 diabetes is a contributing factor, should not be underestimated. And thermal therapy’s beneficial effects on eNOS expression are not slight, but comparable to those of regular aerobic exercise.33  Several recent animal studies provide evidence that thermal induction of heat shock protein 72 (Hsp72) can counter insulin resistance induced by a high-fat diet by suppressing activation of Nterminal-Jun kinase (JNK) in skeletal muscle. Hsp72 is clearly an inhibitor of the fat-mediated activation of JNK, which leads to phosphorylation of Ser307. Serine 307 is a major site of JNK phosphorylation in insulin receptor substrate-1 [IRS-1] whose phosphorylation causes inhibition of IRS-1’s function in insulin signaling.3435  IRS-1 is now believed to be a key mediator of fat-induced insulin resistance in skeletal muscle. This may be the mechanism through which glycemic control improves in type 2 diabetic patients receiving regular hot tub treatments. Skeletal muscle expression of hsp72 mRNA tends to be decreased in patients with type 2 diabetes as compared to healthy age-matched controls, and a polymorphism of hsp72 has been linked to increased diabetes risk.

Thus, thermal therapy may be of special benefit for diabetic and/or obese men with ED who find it difficult to participate in significant aerobic activity. However, thermal therapy does produce physiological stress and is therefore contraindicated in men with unstable angina, recent myocardial infarction, decompensated heart failure, cardiac arrhythmias, uncontrolled hypertension, and severe aortic stenosis.33

Testosterone. Approximately one-third of men with ED have low serum testosterone levels.3637 A number of human clinical trials have demonstrated that testosterone replacement therapy improves erectile function and the response to PDE-5 inhibitors in hypogonadal patients with ED—even in hypogonadal men who previously failed to respond to PDE-5 inhibitors alone.37  Testosterone acts as a vasodilator in the penis via its potent stimulation of NOS protein expression and activity. In one study of castrated rats, testosterone fully restored penile NOS activity, which had been reduced by 45%.38  In humans, bioavailable testosterone’s direct relationship with cavernous vasodilation was demonstrated in a retrospective, double-blind correlation analysis of 52 impotent men who had no confounding risk factors for ED. Low free testosterone correlated independently of age with impaired relaxation of cavernous endothelial and corporeal smooth muscle cells in response to a vasoactive challenge, confirming the importance of androgens in regulating smooth muscle function in the penis.39 

Testosterone – the Structure-Function Connection

In addition to stimulating NOS expression and activity, testosterone also plays a key role in maintaining penile structural integrity. Recent studies indicate that androgens are necessary for the maintenance of the anatomical and physiological substrate of erections, and that the beneficial effects of PDE-5 inhibitors can only be optimally expressed in the eugonadal male.40  Experimental animal models have demonstrated that androgens beneficially affect structural components in the corpus cavernosum, including the smooth muscle fibers and connective tissue necessary for the structural and functional integrity of penile erection. Androgen deprivation promotes differentiation of progenitor stroma cells in the corpus cavernosum into adipocytes; clearly, replacement of muscle and connective tissue with fat cells will impair erectile function.41  The diameter of the dorsal nerve and nerve fibers in the rat corpus cavernosum are also dependent on androgens, evidenced by their shrinking in diameter in castrated rats.4243  In both animals and humans, the penile corpus cavernosum is a vascular bed; androgen insufficiency-related alterations to its structure will produce vascular dysfunction.44  In recognition of these factors, European guidelines now recommend that testosterone concentrations be measured in all men presenting with ED.37

Inhibiting NO breakdown

As discussed in “Longevity Medicine Strategies for Cardiovascular Disease: Closing the Statin Gap in Endothelial Dysfunction and Insulin Resistance Naturally, with L-Arginine and Citrulline: Part II,” oxidative inactivation of NO caused by the increased levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the vasculature that accompany cardiovascular disease, MetS and diabetes, are a significant contributing factor to NO insufficiency. As noted in a review titled, Oxygen free radicals and the penis, “evidence from basic scientific studies indicates that oxidative stress mediated through the superoxide radical and other reactive oxygen species (ROS) may be central to impaired cavernosal function in erectile dysfunction.” 45

Tetrahydrobiopterin (BH4). RNS are of special concern since peroxynitrites oxidize tetrahydrobiopterin (BH4), the cofactor for eNOS, and once uncoupled, eNOS itself will produce superoxide radical by reducing oxygen. This promotes a vicious cycle in which levels of reactive species build, causing further eNOS uncoupling, insufficient NO production, and vascular oxidative damage. BH4 levels can be preserved by supplementation with ascorbate and 5-methyltetrahydrofolate (5-MTHF), the circulating form of folate. Ascorbate does not fully protect BH4 from oxidation by perxoynitrite, but effectively recycles BH3 radical back to BH4.464748  5-MTHF is a strong peroxynitrite scavenger, which has been shown to increase vascular BH4 and the BH4/total biopterin ratio.49 

Methylating Factors. Approximately 10-fold more L-arginine is metabolized to creatine than is used for NO synthesis,50  and an intermediary compound formed during creatine synthesis is homocysteine. Thus, in addition to 5-MTHF, the other key nutrients needed for the metabolism of homocysteine, namely the other B vitamins needed for methylation, B6 and B12, are also required to prevent the accumulation of homocysteine, which lessens NO production both by promoting increased ROS production, and also by inhibiting dimethylarginine dimethylaminohydrolase (DDAH), the enzyme that metabolizes the potent NOS inhibitor, asymmetric dimethylarginine (ADMA) to L-citrulline.5152

Alpha-lipoic acid (ALA). A potent water- and fat-soluble antioxidant, ALA has also been shown to improve endothelial function by ameliorating the age-related decrease in the phosphorylation of NOS.53  When given to diabetic rats exhibiting a 41% reduction in endothelium-dependent NO-mediated relaxation in the corpus cavernosum, ALA reversed this reduction by 65%.1

In research using rats with diabetes-induced ED, ALA was found to decrease inducible macrophage-type NOS (iNOS), while increasing eNOS and neuronal NOS (nNOS).54   nNOS is expressed in penile neurons innervating the corpus cavernosum, while eNOS protein expression has been identified primarily in both cavernosal smooth muscle and endothelium.55   Vasodilatation of penile arteries and large veins during erection is mediated by nNOS. The subsequent increased arterial inflow to the cavernosal sinoids and shear stress on the endothelium lining the penile arteries triggers Akt phosphorylation of eNOS and NO production.16  iNOS induction during aging has been hypothesized to cause neurotoxicity in critical related regions of the hypothalamus during senescence and to be a major cause in the net loss of trabecular smooth muscle in the corpus cavernosum through apoptosis.56

Ascorbic acid.  In addition to recycling BH3 radical back to BH4, L-ascorbic acid’s ability to enhance impaired endothelium-dependent vasodilation is likely attributable to its antioxidant actions, including scavenging intracellular superoxide, direct reduction of nitrite to NO, and recycling of vitamin E.5758

Alpha tocopherol. In studies of hypertensive rats, alpha tocopherol decreased oxidant levels, while increasing the activity of superoxide dismutase and corpus cavernosum relaxation, and improving erectile function.59   When given concurrently with PDE-5 inhibitors to 89 men with ED (average age 61.6) who had failed to respond to PDE-5 inhibitors, administration of alpha-tocopherol (300 mg/day for 1 month) resulted in an increase in the average IIEF score from 13.8 to 17.1. 60

Thermal Therapy. In addition to increasing expression of eNOS mRNA (discussed above), sauna treatments have been shown to increase production of BH4, thus also protecting eNOS from ROS and increasing NO availability by lessening eNOS uncoupling. Sauna therapy increases BH4 availability via two distinct pathways. Increased blood flow in heated surface tissues results in increased vascular shear stress, thus inducing increased activity of GTP cyclohydrolase I (GTPCH-I, the rate-limiting enzyme involved in de novo biosynthesis of BH4) in those vascular tissues. Even modest heating of mammalian tissues also induces heat shock protein 90 (Hsp90), which interacts with GTPCH-I, increasing its activity by lowering its degradation. Increased BH4 synthesis in surface tissues of the body will result in increased circulating BH4, providing BH4 to other body tissues, e.g., penile tissue, which may be BH4 deficient.61

Conclusion

ED, like diabetes, should be considered a “cardiovascular equivalent.”62  ED unresponsive to PDE-5 inhibitors should definitely be a red flag for risk of serious endothelial dysfunction. As the relationship among cardiovascular disease, MetS/type 2 diabetes, and ED clearly indicates, first line therapy in the treatment of ED should be promotion of the diet and lifestyle choices now shown in hundreds of studies to improve cardiovascular health and restore insulin sensitivity: a Mediterranean-style diet including frequent consumption of omega-3-rich fish, regular aerobic and resistance exercise, and 6-8 hours nightly sleep.

Aging itself is already associated with increased oxidative stress, but the process is greatly accelerated by MetS, type 2 diabetes and obesity, all of which promote CVD and reduced production of NO, which in turn suppresses the NO-cGMP pathway, resulting in ED unresponsive to PDE-5 inhibitors. Addressing the underlying causes of endothelial dysfunction is a necessary prerequisite for PDE-5 efficacy.

NO production lessens slightly even in the healthiest of aging males, and PDE-5 inhibitors can help extend the years in which to enjoy an active sex life. Even in healthy, younger men, these cGMP-conserving drugs can bolster sexual function, enabling a stronger erection and enhanced ability to engage in sexual intercourse. The ideal outcome for the aging male is for PDE-5 inhibitors to be optional—to be able to function with—or without—these performance enhancing drugs.  The natural therapies discussed in this article provide this option, increasing not only a man’s potential for healthy erectile function but his overall health and longevity.
 

©2017 Smart Publications. All Rights Reserved. www.lmreview.com