Advances in the Diagnosis and Management of Impotence

Advances in the Diagnosis and Management of Impotence
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In the last few years, great advances have been made in our under- standing of the normal physiology of erection that have translated into new ideas about the pathophysiology of erectile dysfunction and, impor- tantly, new treatment options for patients with erectile dysfunction. The definition of erectile dysfunction is the consistent inability to attain and maintain a penile erection sufficient to permit satisfactory sexual intercourse as outlined by the National Institutes of Health Consensus Development Panel on Impotence.’ Erectile dysfunction is a significant health problem affecting 30 million men in the United States.2 The inci- dence of impotence in men increases with age, with estimates as low as 5% at age 40 to 25% at age 65.2 Subpopulations of men are at greater risk, including those with diabetes mellitus and vascular disease. Although not life threatening, the impact of erectile dysfunction is signif- icant, and our recent ability to intervene with safe treatment options makes evaluation and treatment of the disorder imperativ
Epidemiology of Impotence-Impact of Age and Comorbid Conditions 

Several studies show that erectile dysfunction increases with age. The Massachusetts Male Aging Study studied (by questionnaires) 1704 men aged 40 to 70 in a community setting.2 Of the 1290 responders, 52% of the men reported impotence, with 10% having complete, 25% having moderate, and 17% having minimal dysfunction. In 1985,525,OOO outpa- tient visits (0.2% of all ambulatory visits) were for erectile dysfunction.3 The incidence is increased in subsets of aging men in a Veteran Administration setting, where 33% of the men reported erectile dysfunc- tion.394 An increased risk of impotence was correlated in many studies with the following co-morbidities: a diagnosis of diabetes, cardiovascular disease, or hypertension. 2,4 Baseline laboratory data that were associated with an increased risk of erectile dysfunction included a low high-density lipoprotein concentration. 2 The use of medications for the associated systemic diseases was also predictive of an increased prevalence of impo- tence.2 Finally, on psychological profile a high level of depression or

anger and low degrees of dominance were associated with erectile dysfunction.2 Although historically it was thought that erectile dysfunction was primarily a psychogenic disorder, most studies suggest an organic cause in the majority of patients. 1 Thus our approach to an impotent patient involves an investigation of five major causes of erectile dysfunction- vascular, neurogenic, hormonal, psychogenic, and iatrogenic (medication related)-with many men having multifactorial impotence. To understand the most appropriate manner in which to evaluate and treat patients with erectile dysfunction, it is important to understand the new advances in our comprehension of the normal physiology of erectile dysfunction.

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Physiology of Erection

Changes in both the vasculature and nervous system play an integral role in a normal erection.4-7 Hemodynamically, in the flaccid state the smooth muscle of the penile vessels is contracted. Together with an unre- stricted venous outflow system, this increased resistance to arterial inflow is what maintains the flaccid state. Two key events take place during erection: first, dilation of resistance in the arterial bed to enhance blood flow and pressure, and second, relaxation of trabecular smooth muscle to allow expansion of the lacunar spaces and trapping of the blood by compression of the peripheral draining venules. Neurologically, contraction of corporal tissue is caused by the activation of adrenergic receptors by norepinephrine from sympathetic nerve terminals. The auto- nomic nerves serve as modulators of the sympathetic activation of contraction to maintain flaccidity. Although the parasympathetic system was initially thought to be critical in erection because acetylcholine evokes endothelial-dependent relaxation of corpora cavernosal tissue to allow increased blood flow, more recent data show that erection is not dependent on acetylcholine because atropine has no effect on erection when injected intracavernosally.7 Other studies have focused on the role of the nonadrenergic, noncholin- ergic system (NANC) in erection. 7-10 Nitric oxide (NO) synthetase is an enzyme initially described in the lung, vasculature, and brain that is now known to be present in endothelial cells lining blood vessels in the penis and also in nerve endings within the cavernosa.” Its action is to release NO from L-arginine. In other systems, NO serves a role in endothelial vasodilatation.* In the brain, NO plays a role in N-methyl-D- aspartate-induced glutamate toxicity in stroke, but it has also been shown to be important in synaptic plasticity and long-term potentiation o confirm its role as an important neurotransmitter in the penis, inves- tigators demonstrated that NO is formed from L-arginine through the activation of NO synthetase in endothelial cells and NANC nerves in the corpora cavernosa. lo Nitric oxide triggers the relaxation of smooth muscle through the activation of guanylate cyclase and the production of cyclic guanine monophosphate (cGMP) to induce an erection. Administration of NO was shown to mimic the effects of stimulating these nerves. In addition, blockade of NO results in blockade of the effects of nerve stimulation.1° Nitric oxide belongs to a new class of neurotransmitters in that it is a cytoplasmic protein and not localized to synaptic vessels or membrane. It is made locally and diffuses short distances to have its effect. Additional studies have shown that acetylcholine and substance P can also diffuse from adventitial nerves and activate endothelial N0.7 However, because an erection can occur in the absence of endothelial cells, it is suggested that the primary role of NO is that of a neurotrans- mitter.7-*0 Thus NO is the product of the NANC nerves that is respon- sible for endothelial and smooth muscle relaxation during tumescence

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Treatment Options

 The treatment of erectile dysfunction has been revolutionized over the past 10 years with the use of intracavemosal injection of various agents and the availability of reliable and relatively affordable vacuum erection devices Psychotherapy and Behavioral Therapy Although a psychological component of the disorder is present to a greater or lesser extent in all patients, no data suggest whether coun- seling or other interventions will have an impact on the disorder.’ Obviously, patient and spousal education and reassurance are important parts of the treatment paradigm. 

Medical Therapy 

Initial efforts are made to treat reversible causes of erectile dysfunc- tion, ie, treatment of hypogonadism, hypothyroidism, or hyperpro- lactinemia. Medications are reviewed and changed if possible without adversely affecting other medical problems. Therapy for androgen deficiency has changed dramatically over the past 10 years.22 The gold standard of androgen replacement has been the use of depot formulations of testosterone (testosterone cypionate or enanthate) in doses of 200 to 300 mg IM every 2 to 3 weeks. These regi- mens do not recapitulate the normal diurnal variation in testosterone levels. The first several days are associated with supraphysiologic levels of testosterone, which has clinical sequelae and increases the risk of polycythemia, worsening of sleep apnea, and prostatic hypertrophy. The end of the cycle is often associated with subphysiologic androgen levels, which is often distressing to the patient. This form of therapy, however

 is still the most widely prescribed and is relatively inexpensive. All men should be screened for prostate cancer before initiating therapy, and trough testosterone levels should be checked before the fourth injection to aim for a low normal testosterone level to adjust the dose or timing interval in the individual patient. We monitor trough testosterone levels and hematocrit levels (to watch for polycythemia) and perform prostate examinations every 6 to 12 months during therapy. Oral androgens are hepatotoxic and are not to be prescribed for hypogonadism. In the last few years, the availability of testosterone patch delivery systems has allowed us to more closely mimic the normal androgen levels in a 24-hour period. 22 Two systems are currently available. The first, Testoderm, is a scrotal patch available in 4- or 6-mg sizes that is applied nightly. It has the advantage that the patch can be cut to adjust the total androgen dose in an individual patient:It has the disadvantage of difficulty adhering to the scrotal skin and a hypothetical disadvantage of selectively increasing dihydrotestosterone (DHT) levels. Testosterone is a prohormone that is converted to either estradiol or DHT, the more potent androgen. Certain tissues such as the prostate are especially sensi- tive to the actions of DHT, and there is a theoretical risk of increasing prostatic hypertrophy. All short-term studies to date, however, have not shown any deleterious effect of this product on the prostate. A second formulation, Androderm, is available in 2.5- or 5.0-mg patches that are applied to the body. 22 These patches have the advantage of convenience and acceptability. Disadvantages include a nonadjustable dosing regimen and a high incidence of contact dermatitis caused by either the adhesive or the ethyl alcohol vehicle. This side effect can be modified by the application of a small amount of topical steroid cream on the patch area as it is removed nightly. Both of these patch systems are expensive relative to injectable testosterone. In patients without hypogonadism, therapies for erectile dysfunction are expanding in recent years. In the past, oral therapy for impotence was limited to yohimbine hydrochloride, an a2-adrenergic antagonist with both central and peripheral actions. 23 It has been shown to be effec- tive only in psychogenic impotence (20% above placebo) at a dose of 5.4 mg three times daily. 23 Recent studies suggest that the effectiveness of yohimbine may be improved by combining it with the serotonin agonist trazodone.24

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New Treatment Options 

Recently, new advances in the treatment of impotence have been based on a better understanding of the mechanism of normal erectile function. In the field of injection therapy, a combination of vasoactive intestinal peptide (VIP) and phentolamine (Invicorp) is in the pipeline for FDA review in 1998.35 Vasoactive intestinal peptide and phentolamine are smooth muscle relaxants, with VIP thought to increase NO production. In the last year, the first of the oral agents for erectile dysfunction, sildenafil (Viagra), was approved by the FDA. Sildenatil is a specific type V phosphodiesterase enzyme inhibitor.36,37 The drug works by preventing the breakdown of the NO second messenger, cyclic guanosine monophosphate (cGMP), in cavernosal smooth muscle cells, thus prolonging the NO signal. It has no effect on libido. In published studies to date,38 the medication was effective in organic and nonorganic impo- tence (further breakdown of classification was not given). Doses in the range of 25 to 100 mg have been effective. The published studies and package information suggest up to an 80% response versus a placebo response of 24%. However, on more careful analysis of different popula- tions, the response in patients with hypertension was 68%; with diabetes, 57%; following transurethral resection of the prostate, 61%; and after radical prostatectomy, only 43%. Headache, flushing, and dyspepsia were the most common side effects in the published studies, occurring in 6% to 18% of men completing the study. Investigators have also noted a decrease in blood pressure with sildenafil that could potentially syner- gize with the hypotensive effects of nitrates; thus, it is contraindicated in any patient receiving any nitrate-containing medication. In addition, many medications interact with the clearance of sildenafil and might potentiate its side effects. Thus, the starting dose should be 25 mg, rather than 50 mg, in patients over 65 or with decreased creatinine clearance (< 30 mL/min) or liver disease or concominant cimetidine, erythromycin, itraconazole, potassium-sparing diuretics, or nonselective beta blockers. Further studies will be necessary to clarify the response rates of different populations to this new medication and its ultimate risk/benefit profile. The impact of the cost of new oral agents for erectile dysfunction in terms of health care resources is being actively debated in the media and by the insurance industry. At present, oral apo 

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 REFERENCES

 Impotence. JAMA 1993;270:83-90. Feldman HA, Goldstein I, Hatzichristal DG, et al. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. .I Urol 1994;151:54-61. Jtinemann K-P Pharmacotherapy of impotence: where are we going? In: Lue TF, editor. World book of impotence. London: Smith-Gordon; 1992. p. 181-98. Krane RJ, Goldstein I, Saenz de Tejada I. Medical progress: impotence. N Engl J Med 1989;321:1648-59. Lemer SE, Melman A, Christ GJ. A review of erectile dysfunction: new insights and more questions. J Urol 1993;149:1246-55. Korenman SG. Sexual dysfunction. In: Williams RH, Wilson JD, editors. Williams textbook of endocrinology. Philadelphia: WR Saunders; 1992. p. 1033-48. Ignarro LJ. Nitric oxide as the physiological mediator of penile erection. J NIH Res 1992;4:59-62. 18 DM, January 1999 REFERENCES
8. 9. 10. 11. 12. 13. 14. 1.5. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. Snyder SH. Nitric oxide: first in a new class of neurotransmitters. Science 1992;257:494-6. Burnett AL, Lowenstein CJ, Bredt DS, et al. Nitric oxide: a physiologic mediator of penile erection. Science 1992;257:401-3. Rajfer J, Aronson WJ, Bush PA, et al. Nitric oxide as a mediator of relaxation of the corpus cavemosum in response to nonadrenergic, noncholinergic neurotrans- mission. N Engl J Med 1992;326:90-4. Saenz de Tejada I, Goldstein I, Azadzoi K, et al. Impaired neurogenic and endothe- lium-mediated relaxation of penile smooth muscle from diabetic men with impo- tence. N Engl J Med 1989;320: 1025-30. Kim N, Vardi Y, Padma-Nathan H, et al. Oxygen tension regulates the nitric oxide pathway: physiological role in penile erection. J Clin Invest 1993;91:437-42. Morley JE. Management of impotence: diagnostic considerations and therapeutic options. Postgrad Med 1993;93:65-72. Montejo-Gonzales AL, Llorca G, Izquierdo JA, et al. SSRI-induced sexual dysfunction: fluoxetine, paroxetine, sertraline, and fluvoxamine in a prospective, multicenter, and descriptive clinical study of 344 patients. J Sex Marital Ther 1997;23: 176-94. Buvat J, Lemaire A. Endocrine screening in 1,022 men with erectile dysfunction: clinical significance and cost-effective strategy. J Urol 1997;158: 1764-7. Mahoney J, Bruder JM, Balanoff A, et al. Effectiveness of laboratory assessment of the pituitary-gonadal axis in patients with impotence [abstract 00381. Clin Res 1994;42:250. Korenman SG, Morley JE, Mooradian AD, et al. Secondary hypogonadism in older men: its relation to impotence. J Clin Endocrinol Metab 1990;71:963-9. Welt CK, Hall JE. Gonadotropin deficiency: differential diagnosis and treatment. In: Wierman ME, editor. Diseases of the pituitary: diagnosis and treatment. Totowa (NJ): Humana Press; 1997. p. 221-46. Nachtigall B, Boepple PA, Pralong FP, et al. Adult-onset idiopathic hypogo- nadotropic hypogonadism-a treatable form of male infertility. N Engl J Med 1997;336:410-5. McDermott MT. Infiltrative diseases of the pituitary gland. In: Wierman ME, editor. Diseases of the pituitary: diagnosis and treatment. Totowa (NJ): Humana Press; 1997. p. 305-22. Lee EJ, Jameson JL. Gonadotropin (FSH and LH) pituitary tumors: differential diagnosis and treatment. In: Wierman ME, editor. Diseases of the pituitary: diag- nosis and treatment. Totowa (NJ): Humana Press; 1997. p. 247-72. Bagatell CJ, Bremner WJ. Androgens in men-uses and abuses. N Engl J Med 1996;334:707-14. Reid K, Surridge DH, Morales A, et al. Double blind trial of yohimbine in the treatment of psychogenic impotence. Lancet 1987;2:421-3. Montorsi F, Strambi L, Guazzoni G, et al. Effect of yohimbine-trazodone in psychogenic impotence: a randomized double blind, placebo-controlled study. Urology 1994;44:732-6. Lue TF. Intracavemous drug administration: its role in diagnosis and treatment of impotence. Semin Urol 1990;8:100-6. Dunsmuir WD, Holmes SA. The aetiology and management of erectile, ejaculatory, and fertility problems in men with diabetes mellitus. Diabet Med 1996;13:7