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Latest Advancements in the Integrative Treatment of Erectile Dysfunction and Sexual Dysfunction in Men

Steve Parcell, ND

Erectile dysfunction and low libido are common problems here in my Boulder practice. Should low testosterone be identified as the problem, testosterone administration would be indicated, assuming there are no contraindications such as prostate cancer and there are no obvious neurologic explanations for a lack of sensation such as multiple sclerosis.

This is because the integrity of the dorsal nerve is androgen dependent. If the patient is on a selective serotonin reuptake inhibitor (SSRI) anti-depressant or another medication known to inhibit ejaculation such as a sympatholytic agent, discussion should ensue with the prescribing physician to seek an alternative class of drug.

Dopamine agonist therapy may be helpful to men with erectile dysfunction (ED) including low sexual interest (HSDD) and orgasm problems. This is a particularly helpful treatment for men who suffer from depression, have been treated for cancer or have high levels of prolactin. Sexual behavior is modulated by a number of central nervous system neurotransmitters including dopamine.

Dopamine agonists have been reported to improve sexual function. It is postulated that the increased levels of dopamine in the brain from dopamine agonists facilitate sexual functions including sexual interest and orgasm. These changes are induced, in part, by the action of sex steroids (estrogen, testosterone, progesterone) and by the central neurotransmitter dopamine that may play a critical intermediary role in the central regulation of sexual arousal and excitation, mood, and incentive-related sexual behavior.

Bupropion is a dopamine agonist anti-depressant with fewer reported adverse sexual effects than traditional selective serotonin reuptake inhibitors and therefore clinically useful as an antidote to anti-depressant-associated sexual dysfunction. Researchers assessed the effectiveness of management strategies for sexual dysfunction caused by anti-depressant medications. Compared with serotonin reuptake inhibitors, the dopamine agonist bupropion has revealed less desire dysfunction and less orgasm dysfunction and superior overall satisfaction with sexual functioning while no differences were found in self-reported sexual function, number of erections, total erection time or penile rigidity in healthy subjects taking bupropion compared with those taking placebo or baseline. Treatment with a dopamine agonist such as cabergoline, a potent and long-lasting dopamine agonist is of particular benefit in certain men, especially those with high levels of prolactin.

In one study of hyperprolactinemic men, 6 months of treatment with cabergoline normalized testosterone levels, thus restoring and maintaining the capability of normal sexual activity. In another study, investigators compared the effects of chronic treatment with cabergoline and bromocriptine on sexual function in hyperprolactinemic males and found in men with prolactinomas that cabergoline normalized prolactin levels and improved sexual function earlier than bromocriptine treatment. Nickel and colleagues studied men with psychogenic ED and no elevations in prolactin. Cabergoline treatment resulted in improvement in erectile function, sexual desire, orgasmic function, and the patient’s and the partner’s sexual satisfaction. Safarinejad reported that cabergoline is effective in salvage therapy for sildenafil non-responders.

In men who have androgen insufficiency syndrome or testosterone deficiency who failed PDE5 therapy, many studies have shown that treatment with testosterone for 3 months results in increases in PDE5 facilitated erection. The presumed explanation is the increase in synthesis of the vasodilator neurotransmitter, nitric oxide synthase. Furthermore, aging men followed over 17 years who have low total testosterone values showed a much higher rate of cardiovascular disease and cardiovascular death than those men who, during aging, had normal total testosterone values. The role of testosterone in facilitating erection and PDE5 response is no longer considered controversial.

Assuming the patient meets the criteria for testosterone insufficiency syndrome (“calculated free testosterone” of less than 5 and symptoms) there are several testosterone therapies including testosterone gels, testosterone intramuscular injections and subcutaneous testosterone pellets. Concerning testosterone gels the typical dose is one tube or packet or four pumps per day. Testosterone gel is typically rubbed on the upper chest, shoulders and arms in the morning after a shower. Concerning intramuscular testosterone, low volumes of testosterone cypionate or enanthate such as 0.25 ml (200 mg/ml) can be administered by the patient into the anterolateral aspect of the thigh on a weekly basis. Concerning testosterone pellets they are implanted every 4 – 6 months. After therapy is started androgen blood levels should be measured every 3 months until they reach normal physiologic levels, then every 6 months. Measuring blood values of total testosterone and SHBG to determine calculated free testosterone allows the physician to help the patient maintain normal androgen levels (>5 ng/dl). Measurement of LH, FSH, estradiol, prolactin and dihydrotestosterone may also be performed in follow up.

Currently administration of testosterone is contraindicated in men with a known history of prostate cancer. A PSA blood test must be obtained prior to initiating treatment, and PSA levels should be followed closely during treatment as there is concern that testosterone may cause an existing prostate cancer to grow more rapidly. This is, however, highly controversial. If the physician is concerned about the PSA value, it may be necessary to perform a prostate needle biopsy. It is appropriate to also obtain a hematocrit, liver function tests and cholesterol blood tests prior to starting treatment and to be repeated annually while on androgen therapy.

The side effects associated with androgen therapy include acne, hair loss on the scalp, hair growth on the face, and testicular atrophy. An alternative to testosterone is clomophine citrate (clomid), which is especially useful in younger men with testosterone deficiency with FSH and LH blood tests in the low or normal range. Use of clomiphene can raise testosterone blood test values and avoid potential testicular atrophy and infertility. Another strategy to raise testosterone, especially in men with high estradiol, is to give an aromatase inhibitor such as anastazole.

While long-term testosterone therapy was less common in the past, a large number of aging men now include testosterone therapy as part of their daily regimen. Dehydroepiandrosterone (DHEA) is synthesized at a much greater amount than testosterone. DHEA has many actions in a man’s body, especially including acting on vascular smooth muscle DHEA receptors inducing smooth muscle relaxation. Low DHEA values herald vascular disease in aging men. A typical dose to replace DHEA is 25 – 50 mg/day.

A new report shows that yohimbine hydrochloride taken on an empty stomach at doses of 20 – 40 mg one to two hours prior to sexual activity has the ability to restore ejaculation capabilities in some men. Aromatase inhibitor therapy may be helpful for some men with erectile dysfunction (ED). Aromatase is an enzyme, especially found in the liver, ovary and adipose tissue, required for the conversion of androgens to estrogens. Specifically, aromatase is responsible for the conversion of the androgens androstenedione and testosterone into the estrogens estrone (E1) and estradiol (E2), respectively. In women, the great majority of testosterone is converted to estradiol and estrone, whereas in men, most of the testosterone stays as testosterone, and only a small percentage is converted to estradiol and estrone.

Aromatase inhibitors prevent the action of the enzyme aromatase. Thus, in the presence of an aromatase inhibitor, the body produces less estradiol (E2) and estrone (E1) and maintains a higher level of testosterone. Aromatase inhibitors have been traditionally used as second-line therapy (after tamoxifen) for the treatment of breast cancer, tumors that usually depend on estrogen for growth.

In men, the effect of 2.5 mg of the aromatase inhibior letrozole suppressed plasma estradiol to concentrations less than 50% of pretreatment values after 2 days, with recovery to approximately pretreatment values after 6 days. These decreases were accompanied by increased gonadotrophin (luteininzing hormone – LH and follicle stimulating hormone – FSH) concentrations, with resultant increases of approximately 50% in plasma testosterone.

In men, aromatase activity appears to increase with age. This is particularly so in men with a high body mass index. Increased aromatase activity in men results in conversion of testosterone into higher levels of estradiol. This is especially a problem if men are taking exogenous testosterone (intramuscular testosterone enanthate or cypionate, or topical 1% testosterone as a hydroalcolic gel) for treatment of hypogonadism. Under such conditions, raising the testosterone in a man with a high aromatase level will elevate the serum estradiol. It is controversial but several investigators believe that elevated estradiol values in men are responsible, in part, for causing persistence of many of the symptoms of “androgen insufficiency”, despite receiving testosterone treatment. Some investigators also believe that higher estradiol values are associated with prostate enlargement and there is increasing discussion of the role of estrogen in abnormal prostate tissue growth. High levels of estrogen are also thought to result in male hair loss.

Thus there appears to be a role (“off-label” as it concerns FDA government indications) in the use of aromatase inhibitors in some men with sexual dysfunction and elevated estradiol values. Approximately 20 30 million men may be affected with erectile dysfunction (ED) in the United States. The recent development of effective oral medications to treat erectile dysfunction has raised awareness of various pharmacologic and non-pharmacologic sexual medicine treatment options. Can lifestyle changes, such as an increase in physical activity, improved dietary control and engaging in measures to prevent cardiovascular disease and diabetes prevent a decrease in erectile function?

Metabolic syndrome affects sexual health, therefore a change in eating habits, in particular to the Mediterranean diet that improves endothelial health, can positively influence the sexual health of men. The Mediterranean diet consists of a high consumption of fruits, vegetables, potatoes, beans, nuts, seeds, breads, and other cereals relying on local, seasonal fresh produce. The contemporary Mediterranean diet utilizes olive oil widely for cooking and dressings, with a low to moderate amount of full fat cheese and yogurt. There is a modest consumption of wine, usually with meals, as well as a moderate amount of fish but little meat. An adequate intake of water must be maintained.

Men, in general, have decreased their physical activity and increased ingestion of processed foods, resulting in increased metabolic syndrome, obesity, hypertension, high cholesterol, high blood levels of glucose, and diabetes. For vascular health, matching our genetic information with our ancestral diet is the real life and health match. The Mediterranean diet has been shown to lower endothelial inflammation, reduce the prevalence of metabolic syndrome, and potentially contribute to the prevention of vascular diseases such as coronary heart disease. Men with metabolic syndrome and sexual dysfunction have lower total sexual function scores, lower sexual satisfaction scores, and higher markers of endothelial inflammation compared with the general population. A study of men with metabolic syndrome and erectile dysfunction, when put on the Mediterranean diet, showed an improvement in the endothelial function score, inflammatory markers such as C-reactive protein, and sexual function. Endothelial function can be tested and covered by insurance! Call the clinic for details.

Exercise affects sexual health as well. A study of over 40,000 men examined erectile function and the intensity of participants exercise, as measured by metabolic energy transfer units or METS. This is one of the largest studies to show that the more exercise a man performs, the less likely he is to get erectile dysfunction. It is suggested that a change in exercise habits can positively influence a man’s sexual health by improving cardiovascular and endothelial health. Further, when exercising, individuals make healthy lifestyle choices, increase stamina, improve body image and elevate mood. There is one caveat. Exercise by bicycle riding can have deleterious sexual health consequences. Multiple studies show that bicycle riders have a higher propensity to neurovascular injury, resulting in lower sensation in the perineum or even pain in the perineum, as well as reduced blood flow and erectile dysfunction to the penis. Avoid use of bicycle saddles that force weight bearing on the perineum. Use wide bicycle seats that encourage weight bearing on the sit bones. Get off the saddle frequently and allow perineal and genital blood flow to return.

In a study published in the February 2007 issue of The American Journal of Medicine, researchers analyzed data from 2126 men who participated in the 2001-2002 National Health and Nutrition Examination Survey. These investigators reported that erectile dysfunction was significantly associated with age, cardiovascular disease, diabetes, and lack of physical activity. There was an especially high prevalence of erectile dysfunction among men with hypertension and diabetes, suggesting that screening for erectile dysfunction in these patients may be warranted. In this study, 18% of men reported erectile dysfunction, defined as “sometimes able” or “never able” to get and keep an erection. There was an association between erectile dysfunction and lack of physical activity. These data suggest that lifestyle changes, especially increasing exercise level, may be effective non-pharmacological treatments for men with ED. Data suggest that physical activity and other measures for the prevention of cardiovascular disease and diabetes may prevent a decrease in erectile function.

Changing medications may be helpful for some men with erectile dysfunction (ED) taking anti-depressants or SSRI’s, with low or high levels of dihydrotestosterone (DHT), with high levels of estrogen or with venous leak. A physiologic penile erection requires the complex sequencing of initiating, blood filling and blood storing. The sequence begins in the brain and the intricate events of initiation result in nerve impulses being passed via parasympathetic nerves fibers to the arterial and lacunar smooth muscles of the penis. Following smooth muscle relaxation, arterial inflow will result in an intracavernosal pressure elevation in part dictated by the perfusion pressure of the cavernosal arteries. Blood storage or corporal veno-occlsuion will result if the expandable erectile tissue is able to develop sufficient compression pressure on the subtunical venules under the tunica albuginea. Erectile dysfunction can occur when any of these physiologic processes are disrupted. Interference to the initiation, filling and storing processes, often as a result of medication use, is a common cause of erectile dysfunction. Many common medicines, such as blood pressure drugs, antihistamines, antidepressants, tranquilizers, appetite suppressants, and cimetidine can produce erectile dysfunction as a side effect.

For example, medicines that reduce the central nervous system availability of testosterone, estrogen and progesterone levels or block its effects peripherally are likely to reduce sex drive. Libido is also affected by general emotional and physical health. Medicines that affect any of these aspects, even indirectly by causing drowsiness, lethargy, weight gain or confusion, have the potential to reduce sex drive. Medicines that have an adverse physical effect on the blood vessels in the penis, those that act on the brain or interfere with the transmission of nerve messages, can all cause erectile dysfunction. Medicines that block alpha receptors can interfere with ejaculation. Medicines that interfere with the increased alpha receptor activation closing the bladder neck, facilitating the normal flow of semen out of the penis will results in retrograde ejaculation. The most widely prescribed centrally-acting agents that affect ejaculation are selective serotonin re-uptake inhibitor (SSRI) antidepressants. These medicines adversely affect orgasm and ejaculation by increasing the central nervous system inhibitory neurotransmitter serotonin. Blood pressure lowering (antihypertensive) medicines are also involved since they act to lower the cavernosal artery perfusion pressure.

The following medicines have been reported to be associated with sexual side-effects:
• Antidepressants: MAOI antidepressants (eg moclobemide, phenelzine); SSRI antidepressants (eg fluoxetine); Tricyclic antidepressants (eg amitryptiline)
• Antiepileptics: Carbamazepine
• Antihypertensives: ACE inhibitors (eg enalapril, lisinopril); Alpha blockers (eg prazosin, doxazosin); Beta blockers (eg atenolol, propranolol and including timolol eye drops); Calcium channel blockers (eg verapamil, nifedipine); Clonidine; Methyldopa; Thiazide diuretics (eg bendroflumethiazide)
• Antipsychotics: Phenothiazines (eg chlorpromazine, thioridazine); Risperidone
• Cholesterol lowering medicines: Fibrates (eg clofibrate, gemfibrozil); Statins (eg simvastatin)
• Other: Benzodiazepines; Cimetidine; Cyproterone acetate; Disulfiram; Finasteride; Metoclopramide; Omeprazole; Opioid painkillers; Prochlorperazine; Propantheline; Spironolactone

In summary, dopamine agonist pharmacologic agents such as bupropion, bromocriptine, cabergoline, apomorphine, and Parkinson-type drugs such as L-dopa, pergolide, pramipexole, and ropinrole may be helpful in men with sexual dysfunction. Mucuna is a plant extract that contains L -Dopa.
Androgen therapy may be helpful for men with erectile dysfunction (ED) including low desire (HSDD) and problems with orgasm, androgen insufficiency syndrome, diabetes or metabolic syndrome, venous leak, high levels of sex hormone binding globuin (SHBG) or who have been treated for cancer. Androgens, primarily testosterone, have repeatedly been shown to be critical for structure and function of multiple organs including genital tissues. Testosterone is required at puberty for penile and genital development. Testosterone has been shown to regulate penile stem cells towards smooth muscle growth and differentiation. Absence of testosterone stimulates growth and accumulation of adipose tissue in the penis leading to erectile dysfunction. Testosterone is also critical for dorsal nerve and autonomic cavernosal nerve structure and function. Finally, testosterone has been repeatedly shown to be responsible for the synthesis of the enzyme which facilitates release of the critical neurotransmitter of blood vessel relaxation (nitric oxide synthase), which is not only involved in the process of erection, but the process of increasing blood flow to all organs such as the heart and brain.