Sexual Dysfunction in Men and Women. Stanley Zaslau

Chapter 4. Medical Therapies for Erectile Dysfunction

Adam Luchey, MD

■ Stanley Zaslau, MD, MBA, FACS


 When considering treatment for sexual dysfunction, management is grouped into:

 Erectile dysfunction

 Decreased libido

 Premature ejaculation

 This chapter will evaluate the different pharmaceutical regimens for the above conditions.

 As always, a thorough history and physical examination (including psychological history affecting sexual function) is critical.

 Erectile Dysfunction

 Erectile dysfunction is defined by the National Institutes of Health as an erection insufficient for sexual function.1

 Medical optimization of systemic comorbidities should be controlled and/or eliminated. These include:


• Hyperlipidemia

 Diabetes mellitus

• Alcoholism


• Smoking

 Other medications can have a detrimental effect on libido and/or achieving a satisfactory erection. These include:


 Antidepressants (TCA, SSRI)



 Antihypertensives (alpha/beta-blockers and thiazides)

 First-line therapy should include phosphodiesterase (PDE-5) inhibitors, unless contraindicated. There has been no consensus about which is best, sildenafil, varden- afil, or tadalafil.

Sildenafil (Viagra)

 Administer 25—100 mg PO one hour before sexual stimulation; effects last four hours.

 This was the first drug approved for treatment of erectile dysfunction.

 Goldstein compared the effects of sildenafil to that of a placebo in people with varying forms of erectile dysfunction (organic, psychogenic, or mixed). He discovered that sexual intercourse was achievable in 69% of patients taking sildenafil as compared to placebo.2

 10 tablets of 100 mg cost $155.99.*

Vardenafil (Levitra)

 Administer 5—20mg PO one hour before sexual stimulation; effects last four hours.

 Hellstrom, and colleagues found vardenafil to be as effective as sildenafil at successfully overcoming erectile dysfunction as per the International Index of Erectile Function.

 It should be noted that in this study, vardenafil was not compared directly to sildenafil.

 This was a double-blind, 26-week placebo-controlled study.3

 Success was defined as achieving penetration and maintaining an erection.

 10 tablets of 20 mg cost $153.99.*

Tadalafil (Cialis)

 Administer 5—20 mg PO before sexual stimulation (effects last 12 to 36 hours) or 2.5—5 mg PO per day.

 This drug is not affected by alcohol.

 Brock et al. evaluated 1112 patients with an average age of 59 years who were assigned to either placebo or tadalafil groups (daily doses of 2.5 mg, 5 mg, 10 mg, or 20 mg).

 Patients receiving 20 mg a day of tadalafil noted 81% improvement in erections, compared to 35% in the control group.4

 10 tablets of 20 mg cost $171.99.*

 A recent meta-analysis completed by Tsertsvadze and associates indicated that all three phosphodiesterase inhibitors were beneficial at increasing success of sexual intercourse when compared to placebo (69% to 35%).5

 The most common adverse effect of the above medications has been reported to be headache, with between 8 and 18% of patients reporting this effect, followed by flushing, reported by 6—13%. This is because all three medications cause peripheral dilation. Other reported side effects include dyspepsia and altered vision.6

 Do not use any of the PDE-5 inhibitors if the patient:

 Is taking nitrates

 Has a prior heart history (without medical clearance from cardiology)

 Has QT prolongation (as with vardenafil).

 Care should be taken to hepatically dose those with liver dysfunction will all three PDE-5 medications.

 If a patient fails treatment with one particular PDE-5, it is reasonable to attempt treatment with another PDE-5. If the second attempt fails to produce adequate results, progress to other treatments (as outlined as follows).

Yohimbine (Aphrodyne)

 This medication originates from the yohimbe tree.

 It is often a component in male enhancement medications.

 It works as an alpha 2—adrenergic inhibitor.

 It is not recommended in the 2005 American Urological Association guidelines for the treatment of erectile dysfunction.

 Weiner associated yohimbine with such adverse effects as:

 Increased blood pressure

 Increased heart rate


 Kunelius failed to show an improvement in erectile dysfunction when compared to placebo.8

Vacuum Erection Device (VED)

 This device is used in conjunction with an occlusive ring at the base of the penis.

 A cylindrical pump is applied to the penis, causing a “vacuum” effect of blood flowing to the penis. The occlusive ring is then applied to maintain the erection.

 A study conducted in Singapore by Tay and Kim evaluated VED with 18 men using questionnaires over a six- month period,

 After one week, 13 patients (72.2%) reported being confident in using the device, and 88.9% of patients reported achieving satisfactory erections.9

 There have been publications of unique complications with this method:

 Urethral bleeding

 Capture of scrotal tunica within the penile shaft

 Cystic mass formation

 Peyronie’s disease

 All patients who reported these effects ceased using VED after treatment for the aforementioned effects.10

 One of the larger studies on VED was performed by Opsomer et al., who studied VED in 110 patients between the ages of 36 and 75 over a three-year period.11

Medicated Urethral System for Erection (MUSE)

 This is a special form of Alprostadil that is inserted into the urethra.

 It promotes erectile function by increasing the concentration of cAMP, which decreases intracellular calcium, resulting in erection due to relaxation of smooth muscle and dilation of cavernosal arteries.

 Contraindications to its use include, but are not limited to:

 Peyronie’s disease




 Guay et al. studied 277 patients who were administered dosages of Alprostadil between 500 micrograms and 1000 micrograms.

 In this study, 56% of patients reported having satisfactory completion of sexual intercourse in more than 66% of attempts.12

 Padma-Nathan and colleagues used MUSE in a doubleblind, placebo-controlled study of 1511 patients.

 Each patient was instructed in the correct application in office and then was assigned 125, 250, 500, or 1000 micrograms per day of either Alprostadil or placebo for three months at home.

 Researchers reported the efficacy of this drug in achieving erections sufficient for intercourse in 64.9%, compared to 18.6% in placebo, with painful erections being the most reported side effect.

 Of the men who responded to the treatment, 70% were able to engage in sexual intercourse.13

 After administration of the medication, it is important to instruct the patient to massage his penis to make sure the medication is distributed throughout the cavernosal bodies.

 Also instruct the patient not to use more than two applications per 24 hours (with a maximal dose of 1000 micrograms).

 Inform the patient that he may experience:





 Potential other side effects

Intracavernosal Injections

 This is the most effective nonsurgical treatment of erectile dysfunction.

 There are three possible medications that can be injected intracavernosally:

 Papaverine (PDE inhibitor)

 Phentolamine (alpha-adrenergic receptor inhibitor, needs to be used in conjunction with either papaverine or alprostadil because its function is to prevent detumescence and not to cause an erection in itself)

 Alprostadil (function is to increase cAMP)

 The first administration should be performed by the urologist in order to educate the patient and to determine the efficacy of the treatment.

 Each of the above medications carries with it the risk of certain adverse effects.

 When alprostadil is compared to papaverine, alprostadil shows lower rates of priapism and penile fibrosis.

 Kulmala and Tamella believe that erections lasting longer than 36 hours should be treated with puncture and administration of alpha-adrenergic drugs. If present for longer than 48 hours, a shunt is needed.14

 In the men who required shunts, fibrosis of the cavernosal muscle was the end result (no fibrosis was seen in erections lasting less than 36 hours).

 However, the majority of patients could continue to use the intracavernosal injection after successful treatment of the priapism.


 Trazadone was hypothesized by Fink et al. to improve erectile dysfunction by inhibiting alpha 2—adrenergic receptors, leading to enhanced arterial flow.

 However, no benefit was shown when compared to placebo.15

According to the American Urological Association update by Montague et al., this drug should not be used for the treatment of erectile dysfunction.16

Decreased Libido

 “Loss of libido refers to reduction in sexual interest, initiative, frequency and intensity of responses to internal or external erotic stimuli . . . factors include psychogenic, CNS disease, androgen deficiency and resistance, and side effects from medications.”17

 Common medications/agents producing these effects are alcohol, blood pressure medications, and psychotropics.

 The differential diagnosis for decreased libido should include chronic fatigue syndrome, hypogonadism, hy- pothryoidism, and psychological conditions.18

 Morning testosterone is used for evaluation of sexual dysfunction. If testosterone is low, further work-up should entail FSH, LH, prolactin, and a repeat testosterone.

 The goals of testosterone replacement therapy include:

 Restoring normal sexual function and sexual drive

 Optimizing bone density

 Prevention of osteoporosis

 Improving energy and well-being

 Improving mood and cognition

 Improving fertility in those with hypogonadotrophic hypogonadism

 Possible reduction in the risk of cardiovascular disease

 There are various testosterone formulations available for use and include: intramuscular injections, subcutaneous implants, and topical agents.

 Intramuscular injectible agents can be self-administered and often dosed weekly or biweekly. Their disadvantages include the need for a deep intramuscular injection of a large volume of material. Serum testosterone levels may fluctuate and, thus, symptoms may wax and wane.

 Subcutaneous injections can be in a pellet form and have the advantage of having a long duration of action (up to six months). Disadvantages include the need for a minor

surgical procedure for implantation, infection and extrusion of the pellets.

 Topical agents can include topical gels, transdermal patches that can be placed on the skin of the scrotum, non scrotal skin or in the buccal mucosa.

 Topical gels are well tolerated and easy to use. However, they must be applied daily. There is potential for the gel to rub off, which may limit efficacy, and they can be expensive.

 Transdermal patches can be applied to the scrotum or nonscrotal skin. These are easy to apply. Side effects include skin irritation and can be expensive.

 Buccal mucosal systems are also available and considered to be a form of transdermal testosterone. Side effects include mouth and gum irritation as well as alteration of taste. These may require twice daily application for best efficacy. It is possible to swallow the small patch. This therapy can be cost limiting in some.

 Rhoden and Morgentaler looked at testosterone replacement therapy in hypogonadal men at high risk for prostate cancer. In a study of 75 hypogonadal men that were followed for 12 months with testosterone replacement with prostate biopsies prior were found not to have a greater increase in PSA or significant increase risk of developing prostate cancer.19

Premature Ejaculation

 The 2004 AUA guidelines reports that premature ejaculation is “ejaculation that occurs sooner than desired, either before or shortly after penetration, causing distress to either one or both partners.”20 History and physical is always important but obtaining information from the partner is imperative.

 Premature ejaculation can be a lifelong problem that is characterized by ejaculation that occurs too early at nearly every intercourse with nearly every woman. Most males with this condition ejaculate within 60 seconds of penetration.

 Acquired premature ejaculation implies that the individual had normal ejaculation prior to the start of his

complaints. This condition may be due to an underlying physical problem such as ED, prostatitis, thyroid dysfunction or an underlying psychologic disturbance. This condition may be assuaged by treatment of the underlying cause. For example, treatment of the patient with prostatitis who has premature ejaculation may be helped by treatment of the prostatitis with antibiotics and antiinflammatory agents.

 Natural variable premature ejaculation can occur coincidentally and/or situationally. This may be due to a normal variation in the male sexual response cycle. Patients complain of early ejaculations that are inconsistent and irregular with interspersed normal sexual intercourse.

 Premature-like ejaculatory dysfunction is usually not due to an underlying medical reason. Patients subjectively perceive rapid ejaculation and become preoccupied by this. These patients likely have a normal intravaginal ejaculatory latency time of between 5 and 25 minutes.

 Often times there is a combination of premature ejaculation and erectile dysfunction, in those circumstances the physician should try and correct the erectile dysfunction first. After this, antidepressants are often the treatment of choice, SSRIs (Fluoxetine [5—20 mg daily], Paroxetine [10—40 mg daily], Sertraline [25—200 mg daily]), or Clomipramine (25—50 mg daily). If the patient wished not to take a daily antidepressant, the previous medications could be taken, on average, four hours prior to intercourse to achieve the desired effect. In a doubleblind, randomized, placebo-controlled study with fluoxetine, fluvoxamine, paroxetine, and Sertraline, intravaginal ejaculation latency time increased on average from 20 seconds to 110 seconds, with the best results using Paroxetine. The results were conducted through surveys in approximately 60 men over a six week period.21


 There are several oral agents used to treat erectile dysfunction. Each has been shown to be effective versus

placebo in controlled trials. The agents appear to be similarly effective in the treatment of ED.

 The Vacuum Erection Device, Intracavernosal injection agents, and MUSE are considered to be second line agents in the treatment of ED.

 It is important to recognize low libido states and premature ejaculation and differentiate these conditions from erectile dysfunction. The treatment of these conditions, as shown in this chapter, are different from the treatment of ED.

 Finally, it is important to consider that ED, premature ejaculation and low libido states may occur in the same patient. Thus, treatment may involve several treatments in selected patients.

■ References

1. Impotence. NIH consensus statement. 1992;10:1.

2. Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA. Oral sildenafil in the treatment of erectile dysfunction. N Engl J Med. 1998;338:1997.

3. Hellstrom W, Gittelman M, Karlin G, et al. Sustained efficacy and tolerability of vardenafil, a highly potent selective phosphodiesterase type 5 inhibitor, in men with erectile dysfunction: results of a randomized, double-blind, 26-week placebo-controlled pivotal trial. Urology. 2004;61:8-14.

4. Brock G, McMahon C, Point P, et al. Efficacy and safety of tadalafil for the treatment of erectile dysfunction: result of integrated analyses. J Urol. 2005;173:664.

5. Tsertsvadze A, Fink H, Yazdi F, et al. Oral phosphodiesterase-5 inhibitors and hormonal treatments for erectile dysfunction: a systematic review and meta-analysis. Ann Intern Med. 2009;151(9):650-661.

6. Ellsworth P, Kirshenbaum E. Current concepts in the evaluation and management of erectile dysfunction. Urol Nurs. 2008;28:357-369.

7. Weiner N. Drugs that inhibit adrenergic nerves and block adrenergic receptors. In: Gilman AG, Goodman LS, Rall TW, Murad F, eds. Goodman and Gilman's The Pharmacological Basis of Therapeutics, 7th ed. New York, NY: MacMillan; 1985:181-214

8. Kunelius P, Hakkinen J, Lukkarinen O. Is high-dose yohimbine hydrochloride effective in the treatment of mixed-type impotence? A prospective, randomized, controlled doubleblind crossover study. Urology. 1997;49:441.

9. Tay K, Lim P. A prospective trial with vacuum-assisted erection devices. Ann Acad Med Singapore. 1997;24:705-707.

10. Ganem J, Lucey D, Janosko E, Carson C. Unusual complications of the vacuum erection device. Urology. 1998;51(4):627—631.

11. Opsomer R, Wese F, De Groote P, Van Cangh P. The external vacuum device in the management of erectile dysfunction. Acta Urol Belg. 1997;65:13-16.

12. Guay AT, Perez JB, Velasquez E, Newton RA, Jacobson JP. Clinical experience with intraurethral alprostadil (MUSE) in the treatment of men with erectile dysfunction. A retrospective study. Medicated Urethral System for Erection. Eur Urol. 2000;38:671-676.

13. Padma-Nathan H, Hellstrom WJ, Kaiser F, et al. Treatment of men with erectile dysfunction with transurethral alprosta- dil. Medicated Urethral System for Erection (MUSE) Study Group. N Engl J Med. 1997;336:1-7.

14. Kumala R, Tamella T. Effects of priapism lasting 24 hours or longer caused by intracavernosal injection of vasoactive drugs. Int J Impot Res. 1995;7:131.

15. Fink HA, MacDonald R, Rutks, IR, and Wilt TJ. Trazadone for erectile dysfunction: a systematic review and metaanalysis. Br J Urol. 2006;92:441.

16. Montague D, Jarrow JP, Broderick GA, Dmochowski RR, Heaton JP, Lue TF, et al. Chapter 1: the management of erectile dysfunction: an AUA update. J Urol. 2005;174:230-239.

17. Swerdloff RS, Wang C. The testis and male sexual function. In: Goldman L, Ausiello D, eds. Cecil Medicine, 23rd ed. Philadelphia, Pa: Saunders Elsevier; 2007:chap 252.

18. Heidelbaugh JJ. Management of erectile dysfunction. Am Fam Physician. 2010;81:305-312.

19. Rhoden EL, Morgentaler A. Testosterone replacement therapy in hypogonadal men at high risk for prostate cancer: results of 1 year of treatment in men with prostate intraepithelial neoplasia. J Urol. 2003;170:2348-2351.

20. Montague K, Jarrow J, Broderick GA, et al. AUA guidelines on the pharmacologic management of premature ejaculation. J Urol. 2004;172(1):290-294.

21. Waldinger MD, Hengeveld MW, Zwinderman AH, Olivier £дB. Effect of SSI antidepressants on ejaculation: a double- cxd blind, randomized, placebo-controlled study with fluox- sp, etine, fluvoxamine, paroxetine, and sertraline. J Clin ok? Psychopharmacol. 2001;21:241-242.

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