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Erectile Dysfunction: New Paradigms in Treatment
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Ranjith RamasamySeguir
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Erectile Dysfunction: New Paradigms in Treatment
9 de Oct de 2016•0 recomendaciones•2,615 vistas
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1. Discuss diagnosis of erectile dysfunction 2. Treatments of ED using Viagra, Cialis, Trimix (intracavernosal injections) 3. Evaluate penile prosthesis and implant as ED surgical therapy options
Ranjith RamasamySeguir
Assistant Professor at University of Miami, Miller School of Medicine en University of Miami, Miller School of MedicinePublicidad
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Erectile Dysfunction: New Paradigms in Treatment
- Erectile Dysfunction: New Paradigms in Treatment Ranjith Ramasamy, MD Director, Male Reproductive Urology University of Miami ramasamy@miami.edu
- Epidemiologic Survey: Prevalence of ED* No erectile dysfunction (48%) Erectile dysfunction (52%) Men aged 40 to 70 years (N=1290) Minimal (17%) Complete (10%) Moderate (25%) *Massachusetts Male Aging Study. Adapted from Feldman HA, et al. J Urol. 1994;151:54-61.
- • Erections are a complex event, requiring – Intact arterial and venous system – Normal innervation – Normal hormonal factors – Functioning erectile tissue (the penis) Physiology of Normal Erections Abnormalities in any or all of these will lead to ED.
- ON Breakdown by PDE5cGMP Vascular smooth muscle relaxation Inflow to corpus cavernosum Sexual stimulation NANC Mechanism of Erections: Chemical Pathway cGMP=cyclic guanosine monophosphates. NO=nitric oxide. PDE5=phosphodiesterase type 5.
- Erect PenisFlaccid Penis Mechanism of Erections: Cross Section Cavernosal artery Tunica albuginea UrethraCorpus spongiosum Dorsal nerve Dorsal vein Dorsal artery Corpora cavernosa National Erectile Dysfunction Foundation. Understanding Erectile Dysfunction. 1998.
- Pathophysiologic Mechanism of ED: The Common Link Dzau VJ, et al. Am J Cardiol. 1997;80:33I-39I. NIH Consensus Development Panel on Impotence. JAMA. 1993;270:83-90. Oxidative stress Endothelial cell injury Diabetes ED Thrombosis Atherosclerosis Tobacco Dyslipidemia Precursors Outcomes Hypertension Vasoconstriction
- The Link Between ED and Other Conditions May Be Endothelial Dysfunction 0 0.01 0.02 0.03 0.04 0.05 0 10 20 30 40 50 60 70 80 ED Control Kaiser DR. J Am Coll Cardiol. 2004;43:179-184. Flow-mediatedvasodilation(%) Time (s) Brachial Artery Flow-Mediated Vasodilation P=0.014
- ED May Be Clinically Evident Prior to CAD Symptoms Among 300 patients with CAD and angina • Prevalence of ED among patients was 49% • Mean time between onset of ED symptoms and onset of CAD is 38.8 months (range 1-168) • All patients with type 1 diabetes had ED prior to CAD 0 10 20 30 40 50 60 All ED Severe ED ED symptoms prior to CAD CAD=coronary artery disease Montorsi F. Eur Urol. 2003;44:360-364. Percent
- Relationship of ED to Silent MI in Type 2 Diabetes • 133 men with type 2 diabetes and documented asymptomatic CAD were compared with 127 men with type 2 diabetes and negative cardiac evaluation • ED was highly correlated with the presence of asymptomatic silent MI and CAD • Men with type 2 diabetes who present with ED and no cardiac history need cardiac evaluation Gazzaruso C, et al. Circulation. 2004;110:22-26.
- ED as Prognostic Indicator in Young Men Inman et al. A population-based, longitudinal study of erectile dysfunction and future coronary artery disease. Mayo Clin Proc. 2009; 84: 108–113 -1400 community- dwelling men - Incidence densities of CAD were calculated after adjustment for age and potential confounders - ED in younger men is associated with a marked increase in the risk of future cardiac events
- It doesn’t take much for a man with testosterone to become aroused
- The Interpersonal Dilemma
- • Reluctance to discuss ED because of embarrassment, shame, or ignorance about normal sexual functioning • Cultural beliefs about discussing sexuality • Discomfort • Fear of offending patient or causing discomfort • Lack of confidence in diagnosing and treating ED • Interpersonal differences with patient (cultural, religious, ethnic) • Concern with appearing “overly interested” in patient’s sex life PhysicianPatient Barriers to Identifying Erectile Dysfunction (ED) Humphery S, Nazareth I. Fam Pract. 2001;18:516-518.
- ED Treatment-Seeking Behavior in Urology Offices No ED 56% ED 44% 0 10 20 30 40 50 60 70 80 Embarrassed ED part of aging Unaware urologists treat ED ED not important Prevalence of previously unreported ED among 500 men (aged ≥50) visiting for non-ED complaint Reasons for Failure to Discuss ED With Urologist Baldwin K, et al. Int J Impot Res. 2003;15:87-89. Percentage
- Diagnosing ED • Basic evaluation of sexual dysfunction – Sexual, medical, and psychosocial history • Focused physical examination • Recommended diagnostic tests including – Glucose, lipids, serum chemistries, testosterone, prostate-specific antigen (PSA), and complete blood count Empiric trials of therapy are discouraged without this basic evaluation. The Process of Care Consensus Panel. Int J Impot Res. 1999;11:59-70. Meuleman E, et al. In: Jardin A, et al, eds. Erectile Dysfunction. Plymouth, United Kingdom: Plymbridge Distributors; 2000:115-138.
- Classification of ED: Psychogenic or Organic? Psychogenic Organic Sudden onset Gradual onset Complete immediate loss Incremental progression AM erections present Lack of AM erections Varies with partner and circumstance Lack of erections under most sexually stimulating circumstances Ralph D, et al. BMJ. 2000;321:499-503. With permission from the BMJ Publishing Group.
- Erectile Dysfunction: Management
- Interventions • Lifestyle/drug therapy modification • Psychosocial counseling and education • Androgen replacement therapy • Oral therapy Recommendations of the 1st International Consultation on Erectile Dysfunction. In: Jardin A, et al, eds. Erectile Dysfunction. Plymouth, UK: Health Publication, Ltd; 2000:711-726.
- First-Line Intervention: Drug Therapy Modifications • Modify drug regimens associated with ED1 – Antihypertensives/diuretics2 – Selective serotonin reuptake inhibitors3 – Hormonal agents (eg, antiandrogens)4,5 – Histamine-2-receptor antagonists6 1. Lue TF. N Engl J Med. 2000;342:1802-1813. 2. Grimm RH Jr, et al. Hypertension. 1997;29:8-14. 3. Rosen RC, et al. J Clin Psychopharmacol. 1999;19:67-85. 4. Jackson G, et al. Int J Clin Pract. 1999;53:445-451. 5. Ralph D, et al. BMJ. 2000;321:499-503. 6. Lundberg PO, Biriell C. Int J Impot Res. 1993;5:237-239.
- Evaluating for hypogonadism: ED and Testosterone • The chemical mechanism for normal erections seems to be testosterone dependent • Men with low testosterone have a diminished response to PDE5i • Improvement of other health problems, including low testosterone, → improved response rates with PDE5i 2*2*
- Diagnostic Testosterone Testing: Initial Tests • Serum Total Testosterone (free plus protein-bound) Morning sample recommended in young men Reasonable screening tool • Serum Free Testosterone (nonprotein-bound) Better in older/obese men • Serum Bioavailable T (free plus albumin-bound) Measures albumin-bound and free testosterone Best test, most expensive . Tenover J.L..Tenover J.L.. Endocrinol Metab Clin North Am.Endocrinol Metab Clin North Am. 1998;27:969-987.1998;27:969-987. Braunstein G.D.. In:Braunstein G.D.. In: Basic & Clinical EndocrinologyBasic & Clinical Endocrinology. 5th ed. Stamford, Conn: Appleton & Lange; 1997:403.. 5th ed. Stamford, Conn: Appleton & Lange; 1997:403.
- DM: Hypogonadism and ED • Both ED and Hypogonadism (low T) are increased in the diabetic patient • There does not appear to be a common pathophysiology – ED peripheral neuropathy, small vessel→ angiopathy and endothelial dysfunction – HypoT obesity, metabolic syndrome or→ dysfunctional adipocytes • Each abnormal state needs to be diagnosed and treated as with any other patient
- • Men with DM are 2X as likely to have low T levels than they are to have normal T levels • DM independently predicts low levels of testosterone • Patients with DM had even greater declines in Testosterone than those with Metabolic Syndrome (MetS) Corona G, et al,Corona G, et al, J Sex MedJ Sex Med, 272-283, 2011., 272-283, 2011. DM: Hypogonadism and ED
- Hypogonadism and ED: Intervention • Intervention with TRT in hypogonadal men has shown improvement in: – Individual body weight – Waist circumference – Lipid profiles – MetS complete reversal→ 1 • Randomized, double blind trial intramuscular TU for 12 months improved MetS parameters, waist circumference and fat mass2 1.1. Haider A, et al,Haider A, et al, German Soc EndocrGerman Soc Endocr, 118:167-171, 2010., 118:167-171, 2010. .. AversaAversa A, et al,A, et al, J Endocr InvestJ Endocr Invest, 33:776-783, 2010., 33:776-783, 2010.
- Guidelines on Testosterone and ED • AUA Recs: Testosterone therapy is not indicated for the treatment of erectile dysfunction in the patient with a normal serum testosterone level. • EUA Recs: Laboratory testing must be tailored to the patient’s complaints and risk factors. Hormonal tests include a morning sample of total testosterone.
- Testosterone level and ED Zitzmann M, et alith serum testosterone in older men. J Clin Endocrinol Metab. 2006 Nov;91(11):4335-43. Epub 2006 Aug 22. -In erectile dysfunction hard to tease out contribution of metabolic risk factors, smoking, etc - concentrations below 8 nmol/liter (230ng/dl) consistently contributed to ED
- Androgen Replacement Oral TabletsOral Tablets IntramuscularIntramuscular InjectionsInjections Pellet ImplantsPellet Implants TransdermalTransdermal GelsGels TransdermalTransdermal PatchesPatches
- TRT Formulation-Specific Adverse Effects Oral tablets – Effects on liver and cholesterol (methyltestosterone) Intramuscular injections of testosterone enanthate or cypionate – Fluctuation in mood or libido – Pain at injection site – Excessive erythrocytosis (especially in older patients) Transdermal patches – Skin reactions at application site Transdermal gel – Potential risk for testosterone transference to partner Pellet implants – Infection, expulsion of pellet Bhasin S, et al.Bhasin S, et al. J Clin Endocrinol MetabJ Clin Endocrinol Metab, 91:1995-2010, 2006., 91:1995-2010, 2006. 5*5*
- First-Line Therapy: Oral Agents • US Food and Drug Administration (FDA)- approved phosphodiesterase type 5 (PDE5) inhibitors – Sildenafil citrate –1998 – Vardenafil –2003 – Tadalafil –2003 – Avanafil-2012 • Investigational oral agents – Yohimbine and L-arginine Goldstein I. Int J Impot Res. 2000;12(suppl 1):S75-S80. Greiner KA, Weigel JW. Am Fam Physician. 1996;54:1675-1682. Klotz T, et al. Urol Int. 1999;63:220-223. Lue TF. N Engl J Med. 2000;342: 1802-1813. Padma-Nathan H, Giuliano F. Urol Clin North Am. 2001;28:321-334.
- PDE5 Inhibitors: Onset and Duration of Activity PDE5 inhibitor Onset (min) Duration (h) Sildenafil1,2 30-60* 4* Tadalafil3-5 120 36‡ Vardenafil6-8 25* 4 Avanafil 7 35-45 5 1. Viagra® (sildenafil) prescribing information, September 2002. 2. Boolell M, et al. Int J Impot Res. 1996;8:47-52. 3. Padma-Nathan H. J Urol. 2001;165(suppl):224. Abstract 923. 4. Porst H. J Urol. 2002;167(suppl):176. Abstract 709. 5. Brock GB, et al. J Urol. 2002;168:1332-1336. 6. Vivanza (vardenafil) EU prescribing information, March 2003. 7. Klotz T, et al. World J Urol. 2001;19:32-39. 8. Stark S, et al. Eur Urol. 2001;40:181-188. 7. Kedia G et al Avanafil for the treatment of erectile dysfunction: initial data and clinical key properties. Ther Adv Urol. 2013 Feb;5(1):35-41
- When to refer a patient to a Urologist? • PDE5i treatment failure • Daily Cialis 5mg + Viagra 100mg PRN
- Your Patient Has Failed Phosphodiesterase Type 5 (PDE5) Inhibitor Therapy . . . What Now? • Reeducate and rechallenge with same agent • Switch to another PDE5 inhibitor • Try different therapeutic approach – Vacuum erection devices – Prostaglandin E1(PGE1) injections – Implants
- Evaluation of Penile Blood Flow • Duplex Ultrasonography – Penile blood flow study (CIS & blood flow measurement by US) is most reliable & least invasive evidence based assessment of ED • Red = towards probe • Blue = away from probe – Can visualize dorsal & cavernous arteries in real time
- 2nd line - Ultrasound • Technique – Measure flow velocities 5-10 min after injection – Rate erectile quality – Look at both cavernous arteries
- 2nd line - Ultrasound • Peak Systolic Velocity (PSV) – PSV < 25 correlates with abnormal pudendal arteriography – Severe unilateral arterial insufficiency >10 cm/s asymmetry – Severe vascular ED, diameter increase is <75%, diameter rarely exceeds 0.7 mm
- 2nd line - Ultrasound • Veno-occlusive Dysfuntion – Need to trap blood & limit venous outflow – Venogenic impotence • High systolic flow (>25 cm/s) • Persistent end-diastolic flow (EDV) (>5 cm/s) – Resistive Index (RI) • RI = PSV – EDV/PSV – Measure 20 min after injection & stimulation • RI > 0.9 normal • RI < 0.75 venous leakage
- Recommendations on US • Intracavernosal injection with color duplex Doppler ultrasound – Most informative diagnostic test – Least invasive for vascular ED, high vs. low flow priapism, Peyronie’s plaque – Useful measurements • PSV, cavernous artery diameter, EDV, RI • PSV <25 = severe cavernous artery insufficiency • PSV >35 = normal inflow • Negative relationship between age & PSV
- Vacuum Erection Devices
- Second-Line Therapy: Vacuum Erection Devices (VEDs) • Lack of interest in drug therapy • Specific contraindications to drug therapy • Patient preference Jardin A, et al, eds. Erectile Dysfunction. Plymouth, United Kingdom: Health Publication, Ltd; 2000:357-404.
- VED: Basic Principles • Externally applied device mechanically effects penile blood engorgement • Cylinder/pump placed over penis creates closed chamber; pump creates vacuum, drawing blood into corpora cavernosa • Constrictive elastic ring then placed at base of penis to restrict flow of suctioned blood Levine LA, Dimitriou RJ. Urol Clin North Am. 2001;28:335-341. Montague DK, et al, for the AUA Clinical Guidelines Panel on Erectile Dysfunction. J Urol. 1996;156:2007-2011.
- Medicated Urethral System for Erection (MUSE)
- Second-Line Therapy: Transurethral System • Lack of response to oral therapy1 • Contraindications to specific oral drugs1 • Adverse reactions/intolerance to oral drugs1 • Rapid, predictable erection • Failed penile prostheses2 • Failed intracavernosal therapy3 • Patient preference 1. Recommendations of the 1st International Consultation on Erectile Dysfunction. In: Jardin A, et al, eds. Erectile Dysfunction. Plymouth, United Kingdom: Health Publication, Ltd; 2000:711- 726. 2. Benevides MD, Carson CC. J Urol. 2000;163:785-787. 3. Engel JD, McVary KT. Urology. 1998;51:687-692.
- Transurethral Alprostadil (MUSE) Smooth muscle–relaxing urethra suppository mimics physiology of erection (PGE1)
- Transurethral Medications • Method of application: 2-mm pellet into urethra • Mechanism of action: urethral absorption and distribution into cavernosal tissue → smooth muscle relaxation • Study results – 66% of 1511 patients had erections in office – Of these, 65% had successful intercourse at home vs 18.6% with placebo – Treatment efficacy was similar regardless of age or cause of ED (vascular, diabetes, surgery, or trauma) • Overall success reported was 30% to 60% Alprostadil: MUSE Padma-Nathan H, et al. N Engl J Med. 1997;336:1-7.
- Intracavernosal Injection
- Smooth muscle–relaxing medication injected directly into the penis (papaverine, phentolamine, PGE1) Penile Injection Therapy
- Second-Line Therapy: Intracavernosal Injection • Lack of response to oral therapy1,2 • Contraindications to specific oral drugs1 • Adverse reactions/intolerance to oral drugs1 • More reliable, instant, predictable erection • Patient preference 1. Recommendations of the 1st International Consultation on Erectile Dysfunction. In: Jardin A, et al, eds. Erectile Dysfunction. Plymouth, United Kingdom: Health Publication, Ltd; 2000:711-726. 2. Shabsigh R, et al. Urology. 2000;55:477-480.
- Penile Injection Therapy: Advantages • Highly effective • Mimics natural physiology of erection • No effect on sensation, ejaculation, fertility • Higher level of discretion, thus spontaneity
- Penile Injection Therapy: Disadvantages • Poor long-term tolerability (dropout rate >60%) • Bruising, prolonged erection, cavernosal fibrosis, pain at injection site, penile deformity (rare) • Cumbersome, especially for patients with poor manual dexterity/vision or severe obesity • Requires training, follow-up, and dosing adjustments • May be risky with heart disease, previous strokes, or liver or blood disorders • May not be covered by insurance
- Low Intensity Shockwave Therapy • Not incorporated into AUA guidelines yet • Shockwaves at 1/10th the dose of traditional ESWL for stones Vardi Y, et al.. Can low-intensity extracorporeal shockwave therapy improve erectile function? European Urology. 2010;58: 243-48
- Low Intensity Shockwave Therapy • Meta-analysis: combined improvement in IIEF-EF score isMeta-analysis: combined improvement in IIEF-EF score is 4.284.28 • Greater than theGreater than the minimal clinically important difference (MCID) of 4 IIEF points as described by Rosen et al. • Zero adverse effects
- Should We Doing Implants Earlier? Clavijo RI, et al Time course and predictors of use of erectile dysfunction treatment in a Veterans Affairs medical center. Int J Impot Res. 2016 May 19.
- Penile Prosthesis Implantation
- Types of Prostheses • Malleable/semirigid (AMS, Mentor) • Mechanical rod (Duraphase) • Inflatable – 2-piece (Ambicor) – 3-piece – AMS (CX, CXM) – Coloplast ( Titan )
- www.amselabeling.com
- Penile Implant Indications • Oral drug (PDE5 inhibitor) failure – Radical prostatectomy – Diabetes mellitus • Scarred penis – Priapism – Previous implant – Trauma • Peyronie’s disease • Severe venous leak
- Issues Regarding Informed Consent • Size of penis—stretched penile length • Possible need for revision surgery – Infection – Malfunction – Tissue damage • Sensation • Ejaculation • Discuss alternative treatments, eg, vacuum constriction device (VCD), Medicated Urethral System for Erections (MUSE), etc • Variety of prostheses • Reduced erectile function if device removed
- Reliability—Device Survival Montague Ultrex 78% 5 years Levine Ambicor 93% 3-5 years Choi CXM 90% 5 years Carson CX 86% 5 years Montorsi AMS700 96% 5 years Wilson Mentor Alpha-1 93% 5 years Govier AMS 91% 3 years Dhabuwala Mentor 96% 5 years AMS 84% 5 years
- Penile Implant -Satisfaction • In contemporaryIn contemporary series,series, satisfaction issatisfaction is >80%>80% Bernal, R et al. Adv in Uro. 2012
- Reasons for Dissatisfaction With Penile Implant • Loss of penile length • Reduced sexual spontaneity • Unrealistic expectations • Malfunction • Infection- 1-4%
- Implant Surgical Technique • Infrapubic approach – Familiar surgical approach for urologists – Easy placement of reservoir – Potential injury to dorsal penile nerve • Penoscrotal approach – Easy dissection and corporal dilation – Penile nerves not in surgical field – Blind placement of reservoir sometimes difficult
- Post-Op Care: • Foley catheter for 24 hours • Bed rest from 48 hours • Cylinder straight, up and deflated • Warm baths bid starting on post-op day #3 • Prosthesis cycling at 6 to 8 weeks
- Keys to Successful IPP Surgery: • Dedicated set of instruments • Penile pack • Full inventory of devices • Strategy to decrease skin bacteria flora • Strategy to prevent contact with the skin during the procedure
- Conclusions • ED can be identified and managed in the primary care setting—detection is key! • Effective treatments are available • Treatment efficacy can be optimized by establishing its proper usage and pursuing risk-factor modification and vascular disease treatment
- Thank @ranjithramamd ramasamy@miami.edu
Notas del editor
- To
- Against common believe, older Men are still sexually very active, even in the older age group 70-79 Sexual activity here was defined as intercourse, masturbation and any activity that the participant considered “sexual”.
- Self reported impotence to some degree affected 52% of 40–70-year-old men Prevalence increased with age, complete impotence rising from 5–15% between 40–70 years Impotence was strongly associated with treated heart disease (quadrupling), diabetes (tripling) and smoking (doubling prevalence in association with chronic disease) Impotence correlated with increasing expression or suppression of anger and with increasing depression
- Normal Male Sexual Response Since the publication of Masters and Johnson’s work on the human sexual response, we have made great progress in elucidating the physiology of normal male sexual response. Exactly how is a “normal” male sexual response defined? William Masters and Virginia Johnson divided the sexual response into a cycle of 4 phases, identified as excitement or arousal, plateau, orgasm and ejaculation, and resolution. Dysfunction may occur in one or more of these phases, and the clinician evaluating the problem must clarify which phase is primarily responsible for the patient’s symptoms. The graph on this slide depicts the 4 phases as described by Masters and Johnson. The solid line depicts normal sexual response. During the excitement or arousal phase, the pelvis becomes engorged with blood and the penis becomes erect. Engorgement and erection are accompanied by increases in muscle tension, heart and respiratory rates, and blood pressure. The duration of these effects can range from minutes to hours, and are sustained through the plateau phase. When stimulation reaches a critical point, orgasm, or waves of rhythmic contractions of pelvic voluntary and involuntary musculature, occurs. Usually, semen is ejaculated. During the resolution phase, muscle tension diminishes gradually, and relaxation and drowsiness usually occur. Dilation of blood vessels drains the pelvic and genital engorgement.1 Good overall health and healthy interpersonal relationships are also necessary for normal sexual response.2 1. Masters WH, Johnson VE. Human Sexual Inadequacy. Boston, Mass: Little, Brown and Co; 1970. 2. Maurice WL. Sexual Medicine in Primary Care. St Louis, Mo: Mosby; 1999:170-176.
- Physiology of Normal Erections Blood is supplied to the penis corporal bodies by pudendal arteries. Venous drainage is via a complex network of pelvic veins. Autonomic innervation to corporal bodies arises from pelvic plexus and travels in close proximity to the prostate. Testosterone facilitates this process.
- Mechanism of Erections: Chemical Pathway The relaxation of the smooth muscle of the corpora cavernosa is mediated by nitric oxide, a nonadrenergic, noncholinergic neurotransmitter released by the cavernosal nerves and endothelial cells in response to sexual stimulation.1,2 Nitric oxide activates guanylate cyclase, an enzyme that instructs muscle cells to produce cyclic guanosine monophosphate. This second messenger of nitric oxide provides the signal for smooth-muscle relaxation via a decrease in intracellular calcium.1 To prevent a permanent erection, the enzyme phosphodiesterase type 5 (PDE5), present in cavernosal tissue, breaks down cyclic guanosine monophosphate (cGMP). This causes the smooth muscle cells to contract, and the penis returns to the flaccid state.1 1. Boolell M, et al. Int J Impot Res. 1996;8:47-52. 2. The Process of Care Consensus Panel. Int J Impot Res. 1999;11:59-74.
- AUTHOR INFORMATION George F. Lasker, Edward A. Pankey, and Philip J. Kadowitz Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana [email_address] Author contributions: G.L., E.A.P., and P.J.K. prepared figures; G.L., E.A.P., and P.J.K. drafted manuscript; G.L., E.A.P., and P.J.K. edited and revised manuscript; G.L., E.A.P., and P.J.K. approved final version of manuscript. View Full Text
- Mechanism of Erections: Cross Section The 2 structural compartments of the penis, the paired corpora cavernosa and the corpus spongiosum, are interspersed with a complex network of endothelial cell–lined lacunae, helicine arteries, and nerve terminals. The organ is innervated by somatic and autonomic nerve fibers.1 The tunica albuginea is the dense, fibrous, elastic covering of the corpora cavernosa in the penis. During an erection, small penile blood vessels are compressed against the tunica albuginea, trapping blood in the penis and causing it to stay rigid.1 Achieving an erection is a complex process. In a flaccid penis, there is a balance between blood flow in and out of the erection chambers. When a man becomes aroused, blood flow to the penis increases significantly. As the penis expands and hardens, veins that normally carry blood away from the penis are compressed. This limits the amount of blood that can flow out of the penis. With more blood flowing in and less blood flowing out, the penis enlarges and becomes fully erect.2 1. Kandeel FR, et al. Endocr Rev. 2001;22:342-388. 2. Andersson KE, Wagner G. Physiol Rev. 1995;75:191-236.
- Pathophysiologic Mechanism of ED: The Common Link The most common cause of ED is vascular disease. Vascular insufficiency can lead to insufficient blood flow to the penis during an erection. Screening for ED may lead to a diagnosis of cardiovascular disease (CVD), including atherosclerosis, in otherwise asymptomatic individuals. ED can also be an early warning sign for conditions leading to heart disease and stroke.
- The Link Between ED and Other Conditions May Be Endothelial Dysfunction Evidence that ED may be related to endothelial dysfunction was demonstrated in this study of brachial artery vasodilation. There is a statistically significant decrease in flow-mediated dilation between subjects who had ED versus those who did not.
- ED May Be Clinically Evident Prior to CAD Symptoms According to Montorsi, ED symptoms may precede symptoms of coronary artery disease (CAD). Among 300 patients with CAD and angina, almost half reported some degree of ED, and one third reported that symptoms of ED appeared before CAD symptoms. (mean age 62:5 8 years; range 33–86) plaining the difference noted in prevalence rates. The present study assessed the prevalence and the time of ED onset in a large group (n ¼ 300) of patients with ACS and angiographically documented CAD. We confirmed the high prevalence (147/300, 49%) of ED in CAD patients. Also, among those with concomitant ED, 67% reported that they had become impotent well before the onset of CAD symptoms, with a mean time interval of more than 3 years. This finding, while from one side, does not mean that the majority of patients with ED will ultimately develop CAD during the follow-up, from the other side, highlights the role of isolated ED as a potential marker of sub-clinical vascular disease. Interestingly, in this patient subgroup, the first manifestation of CAD was an ACS in 40/99 (40%). Although a cardiological evaluation at the time of the initial ED diagnosis was not performed in most of these patients, it is likely that common screening tests for CAD would have failed to show an abnormal response at that time. Thus, a systematic and standardized cardiological work-up should be considered in patients with ED, multiple risk factors and no symptoms or signs of CAD. We, as others [1,3–5], found common risk factors for atherosclerosis as being well represented and equally distributed between patients with or without ED (see Table 1) except for type 1 diabetes, which was significantly more prevalent in patients with ED. Thus
- ED as a Predictor of Heart Attack ED is associated with coronary events. In this study, more than 12,500 men with self-reported ED were compared with a similar number of men without ED. Men reporting ED had almost twice the risk of heart attack. Men over the age of 40 with ED had 3 to 4 times the heart attack risk than younger men without ED.
- Inman et al14 studied a random sample of more than 1400 community-dwelling men who had regular sexual partners and no known CAD. Over a 10-year follow-up period, the men were biennially screened for the presence of ED. Incidence densities of CAD were calculated after age stratification and adjusted for potential confounders by time-dependent Cox proportional hazards models. Prevalences of ED were 2%, 6%, 17%, and 39% for men 40 to 49 years, 50 to 59 years, 60 to 69 years, and ≥70 years of age, respectively.14 The CAD incidence densities per 1000 person-years for men without ED were 0.94 (40−49 years old), 5.09 (50−59 years old), 10.72 (60−69 years old), and 23.30 (≥70 years old). For men with ED, CAD incidence densities increased to 48.52 (40−49 years old), 27.15 (50−59 years old), 23.97 (60−69 years old), and 29.63 (≥70 years old) (Figure).14 These data suggest that ED in younger men is associated with a marked increase in the risk of future cardiac events, whereas in older men, the prognostic importance of ED is diminished.14
- Number of Patients Seeking Treatment for ED Is Low Even patients who visit their urologist can be reluctant to discuss ED. Of 500 men over age 50 who visited their urologist for a complaint unrelated to ED, 218 (44%) had some degree of ED; they were then asked to complete a questionnaire. The most important reason for under-reporting was embarrassment (cited by 74% of the 218 men with ED); far fewer men cited a belief that ED was a natural consequence of age or unawareness that urologists treat ED. Only 5% did not consider ED worthy of attention (not shown). Only 48 of the 218 men with ED had discussed it with their primary care physician (PCP). Of the 170 who had not, 82% (140/170) wanted their physician to initiate the conversation. Baldwin K, et al. Int J Impot Res. 2003;15:87-89.
- Diagnosing ED A comprehensive clinical history and physical examination that addresses sexual, medical, and psychosocial components help identify the medical status of the patient and uncover risk factors associated with ED that may support the diagnosis and facilitate treatment. The physician must obtain a sexual, medical, and psychosocial history from the patient, and conduct a complete physical examination. Certain laboratory tests may reveal underlying medical conditions and are therefore an important part of the systematic diagnostic process for ED. These tests include evaluation of blood chemistries (specifically, glucose, lipids, and creatinine) and assessment of testosterone levels. A complete blood count is also done. Each of these elements of the diagnostic process is detailed in subsequent slides. Importantly, initiating patients on empiric trials of therapy is not recommended without a basic workup. The Process of Care Consensus Panel. Int J Impot Res. 1999;11:59-70. Meuleman E, et al. In: Jardin A, Wagner G, Khoury S, Giuliano F, Padma-Nathan H, Rosen R, eds. Erectile Dysfunction. Plymouth, United Kingdom: Plymbridge Distributors; 2000:115-138.
- Classification of ED: Psychogenic or Organic? In most cases, the sexual history provided by the patient can suggest whether the primary cause is psychogenic or organic. ED primarily of psychogenic origin is characterized by a sudden onset, and complete and immediate loss of sexual function. However, morning erections are present. In addition, the condition seems to vary according to the partner and circumstances in which sexual relations are attempted. ED primarily of organic origin typically has a gradual onset and progresses incrementally. A characteristic finding is a lack of morning erections and lack of erections under sexually stimulating circumstances. Ralph D, et al. BMJ. 2000; 321:499-503.
- Why Use Patient Questionnaires? Patient questionnaires can help the clinician facilitate dialogue1 and establish the diagnosis of ED.2 Many clinicians use a questionnaire to introduce the patient to the subject of ED prior to a face-to-face interview.1 Because ED may be a topic that the patient has not discussed even with his sexual partner, going through the questionnaire and educational materials will help increase the patient’s level of comfort with the topic.1 The Sexual Health Inventory for Men (SHIM), a validated, self-administered questionnaire, is an abridged version of the International Index of Erectile Function (IIEF).2,3 1.Chun J, Carson CC III. Urol Clin North Am. 2001;28:249-258. 2.Rosen RC, et al. Int J Impot Res. 1999;11:319-326. 3.Rosen RC, et al. Urology. 1997;49:822-830.
- SHIM SHIM, or IIEF-5, is a valid and reliable self-administered questionnaire for the assessment of ED and treatment effectiveness. It is an abbreviated version of the IIEF. SHIM has been shown to remain valid when patient cultural and language differences are taken into account. The questionnaire can be administered at the initial or follow-up visit to facilitate patient-physician communication about erectile function or sexual satisfaction. Rosen RC, et al. Int J Impot Res. 1999;11:319-326.
- First-Line Therapy Components of first-line therapy include Lifestyle and drug therapy modifications that may impact ED Psychosocial counseling and education about sexual techniques and normal age-related changes Androgen replacement therapy if a documented deficiency is present Oral therapy Recommendations of the 1st International Consultation on Erectile Dysfunction. In: Jardin A, Wagner G, Khoury S, Giuliano F, Padma-Nathan H, Rosen R, eds. Erectile Dysfunction. Plymouth, United Kingdom: Health Publication, Ltd; 2000:711-726.
- First-Line Therapy: Drug Therapy Modifications A number of prescription and over-the-counter (OTC) medications have been linked to ED. Antihypertensive agents, mainly thiazides and thiazide-like diuretics,1-7 and, to a lesser extent, beta-blockers5,6 and calcium-channel blockers6,7 have been reported to adversely affect sexual function. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers are less likely to affect sexual function.8 The selective serotonin reuptake inhibitors (SSRIs) are another category of drugs commonly associated with sexual side effects, such as delayed ejaculation and absent or delayed orgasm. Less common sexual side effects include decreased libido and problems with arousal, although a specific association between these complaints and SSRIs has not been found consistently.9 Hormonal chemotherapeutics, particularly the antiandrogens, also increase the risk of ED.10,11 Other drugs that interfere with the endocrine system, such as the histamine-2-receptor antagonists, contribute to ED. The histamine-2-receptor antagonist most often associated with ED is cimetidine, which binds to androgen receptors.7 There have been few reports of ED with the newer proton-pump inhibitors.7 If a patient receiving treatment with any of these agents complains of ED, he should be switched to an alternative therapeutic regimen whenever possible. Grimm RH Jr, et al. Arch Intern Med. 1985;145:1191-1199. Chang SW, et al. Arch Intern Med. 1991;151:2402-2408. Curb JD, et al. JAMA. 1985;253:3263-3268. Wassertheil-Smoller S, et al. Arch Intern Med. 1991;114:613-620. Grimm RH Jr, et al. Hypertension. 1997;29:8-14. Suzuki H, et al. J Hypertens. 1988;6(suppl):S649-S651. Lundberg PO, Biriell C. Int J Impot Res. 1993;5:237-239. Rosas RE, et al. Kidney Int. 2001;59:2259-2266. Rosen RC, et al. J Clin Psychopharmacol. 1999;19:67-85. Ralph D, et al. BMJ. 2000;321:499-503. Jackson G, et al. Int J Clin Pract. 1999;53:445-451. Cardiovascular Therapeutics Explore this journal &gt; Previous article in issue: Inflammatory Signaling in Pulmonary Arterial Hypertension: The Controversial Role of CRP, and the Search for New Therapies Next article in issue: Atorvastatin Decreases C-Reactive Protein-Induced Inflammatory Response in Pulmonary Artery Smooth Muscle Cells by Inhibiting Nuclear Factor-κB Pathway View issue TOCVolume 28, Issue 1February 2010 Pages 5–7 Hypertensive Medication and Erectile Dysfunction Authors Dr Geoff Hackett First published: 11 January 2010Full publication history DOI: 10.1111/j.1755-5922.2009.00130.xView/save citation Cited by: 3 articlesCitation tools Patients frequently blame the medication for their ED, particularly if there seems to be a temporal relationship and it is mentioned within the product insert. Stopping the offending drug is rarely effective, unless an early therapy switch is made when a definite relationship is found [4]. Thiazides and nonselective beta-blockers have been shown in a number of studies to be associated with ED and the summary of product characteristics (SPCs) of both classes of drug state these warnings. The mechanism is felt to be through an associated elevation of angiotensin II, a potent vasoconstrictor within the penile vascular bed [5]. In a recent study, atenolol was associated with fewer sexual attempts, lower level of serum testosterone after 16 weeks, and a rate of ED of 18% compared with 0% with the angiotensin II inhibitor valsartan [6]. Angiotensin converting enzyme inhibitors (ACEIs) and calcium channel blockers, in normal doses, are unlikely to be a major contributory factor to the development of ED [7] but angiotensin receptor blockers (ARBs) are the only class of antihypertensive not to list ED as a side-effect in the product insert. An increasing number of trials suggest that angiotensin II inhibitors may actually improve sexual function [6,2] and may be the drug of choice in the ED patient newly diagnosed with hypertension [4]. There is evidence to support Valsartan, Losartan, Irbesartan, and Telmisartan. [8–10] with a comparative study between Telmisartan and Ramipril (ON TARGET- TRANSCEND) ongoing [11]. Dusing et al. [9] found that, by 6 months, 20% of previously treated and newly diagnosed patients returned to normal function as compared with baseline. The mechanism of action is likely to be through the potent inhibition of angiotensin II and subsequent enhancement of smooth muscle relaxation. These patients would not have required ED therapy to perform and we need to be aware that taking a tablet before each negotiated sexual contact is not viewed as a satisfactory outcome for many couples. Prescribing cheaper drugs is usually less cost effective if more expensive therapy is required to reverse the sexual adverse event. We also know that only 70–75% of hypertensive patients respond to PDE5 inhibitors and, based on these studies, a change of therapy to ARB is likely to enhance the response to the ED medication, reducing the number of patients requiring less satisfactory second and third line ED therapies. Recent studies have suggested some other clinical benefits of ARBs over ACEIs, namely a reduced incidence of stroke (around 8%) [12] and a better profile in patients with chronic kidney disease (CKD) [13]. Cough is also troublesome in up to 20%, particularly in women. It is interesting that most prescribing guidelines allow complete clinical freedom to switch patients from an ACEI to an ARB on the basis of cough but not on the basis of ED. There is also evidence that the same mechanisms of endothelial dysfunction affect the pelvic vascular bed in women with hypertension, diabetes, and dyslipidaemia, leading to decreased sexual arousal. There is one published study comparing the ARB Valsartan with Carvedilol [14] showing improved arousal, desire and increased sexual frequency. This suggests that the choice of antihypertensive drug may be important in women&apos;s sexual function. There are special populations, such as the afro-caribean population, where ACEIs and ARBs appear less effective and, in such cases, the optimal hypertensive therapy to reduce cardiovascular complications should be used, but these issues around sexual function should still be discussed with the patient. Eur J Clin Pharmacol. 2002 Jun;58(3):177-80. Epub 2002 May 1. Effect of antihypertensive treatment with valsartan or atenolol on sexual activity and plasma testosterone in hypertensive men. Fogari R1, Preti P, Derosa G, Marasi G, Zoppi A, Rinaldi A, Mugellini A. Author information Abstract OBJECTIVE: To compare the effects of valsartan and atenolol on sexual activity and plasma testosterone in newly diagnosed, previously untreated, essential hypertensive male subjects. METHODS: One hundred and ten hypertensive men, aged 40-49 years, homogeneous for marital status and without any previous sexual dysfunction were randomly treated with valsartan 80 mg daily (o.d.) or atenolol 50 mg o.d. for 16 weeks according to a double-blind, parallel-arm study design. After 8 weeks the dose was doubled in the non-responders (diastolic blood pressure &gt; 90 mmHg). Clinical evaluation was performed after 8 weeks and 16 weeks of treatment and included blood pressure and plasma testosterone measurements and the compilation of a questionnaire about sexual activity (sexual intercourse episodes/month). RESULTS: Despite similar blood pressure lowering, atenolol significantly reduced sexual activity (from 6.0 sexual intercourse episodes/month to 4.2 sexual intercourse episodes/month, P &lt; 0.01 vs placebo), whereas valsartan increased it, although not significantly (from 5.8 sexual intercourse episodes/month to 7.4 sexual intercourse episodes/month, P = 0.058), compared with placebo, but significantly compared with the atenolol group ( P &lt; 0.05). Testosterone was reduced by atenolol (from 18.2 nmol/l to 13.8 nmol/l, P &lt; 0.01 vs baseline) but was not affected by valsartan (from 17.6 nmol/l to 18.3 nmol/l). CONCLUSIONS: These results suggest that atenolol induces a worsening of sexual activity and a reduction of testosterone, whereas valsartan does not worsen sexual activity and does not change testosterone levels. PMID: 12107602 DOI: 10.1007/s00228-002-0456-3 J Clin Psychopharmacol. 1999 Feb;19(1):67-85. Effects of SSRIs on sexual function: a critical review. Rosen RC1, Lane RM, Menza M. Author information Abstract Sexual problems are highly prevalent in both men and women and are affected by, among other factors, mood state, interpersonal functioning, and psychotropic medications. The incidence of antidepressant-induced sexual dysfunction is difficult to estimate because of the potentially confounding effects of the illness itself, social and interpersonal comorbidities, medication effects, and design and assessment problems in most studies. Estimates of sexual dysfunction vary from a small percentage to more than 80%. This article reviews current evidence regarding sexual side effects of selective serotonin reuptake inhibitors (SSRIs). Among the sexual side effects most commonly associated with SSRIs are delayed ejaculation and absent or delayed orgasm. Sexual desire (libido) and arousal difficulties are also frequently reported, although the specific association of these disorders to SSRI use has not been consistently shown. The effects of SSRIs on sexual functioning seem strongly dose-related and may vary among the group according to serotonin and dopamine reuptake mechanisms, induction of prolactin release, anticholinergic effects, inhibition of nitric oxide synthetase, and propensity for accumulation over time. A variety of strategies have been reported in the management of SSRI-induced sexual dysfunction, including waiting for tolerance to develop, dosage reduction, drug holidays, substitution of another antidepressant drug, and various augmentation strategies with 5-hydroxytryptamine-2 (5-HT2), 5-HT3, and alpha2 adrenergic receptor antagonists, 5-HT1A and dopamine receptor agonists, and phosphodiesterase (PDE5) enzyme inhibitors. Sexual side effects of SSRIs should not be viewed as entirely negative; some studies have shown improved control of premature ejaculation in men. The impacts of sexual side effects of SSRIs on treatment compliance and on patients&apos; quality of life are important clinical considerations. Br J Urol. 1995 Feb;75(2):220-4. The role of histamine in human penile erection. Cará AM1, Lopes-Martins RA, Antunes E, Nahoum CR, De Nucci G. Author information Abstract OBJECTIVE: To investigate the relaxant action of histamine on human corpus cavernosum in vitro and the erectile response caused by the intracavernous injection of histamine in patients with psychogenic impotence. PATIENTS AND METHODS: Human corpus cavernosum (HCC) tissue was cut into strips of approximately 2 cm and suspended in a cascade bioassay. The strips were then superfused with oxygenated and warmed Krebs solution and precontracted with noradrenaline (3 microM). Glyceryl trinitrate, acetylcholine and histamine were injected as a single bolus in the absence or in the presence of mepyramine and cimetidine. For the in vivo studies, histamine (30-60 micrograms) was injected intracavernously as a single bolus into the right corpus cavernosum 1 cm from the balamo-preputial sulcus. Similar protocols were carried out for papaverine (50 mg). The erectile response was divided into four grades: no response, tumescence, partial and full erection. RESULTS: In vitro studies demonstrated that histamine (3-100 micrograms) caused dose-dependent relaxation of the HCC strips which was significantly inhibited by cimetidine (5-10 microM). The histamine H1 receptor antagonist mepyramine (1 microM) potentiated histamine-induced relaxation. The co-infusion of both mepyramine and cimetidine did not abolish histamine-induced relaxation. When injected intracavernously in humans, histamine (30 micrograms) caused full erection in 13% of the patients, whereas 87% had partial erection or tumescence. A higher dose of histamine (60 micrograms) caused full erection in 26% of the patients and 74% had partial erection or tumescence. Papaverine induced full erection in the majority of patients (66%). In contrast to papaverine, the duration of erection induced by histamine was markedly shorter (mean 200 and 6.5 min, respectively). The penile erections induced by papaverine were associated with complications such as pain, haematoma and priapism. Histamine did not induce any complications. Treatment of eight male patients with psychogenic impotence with the histamine H1 receptor antagonist astemizol (10 mg orally once daily for 1 week) did not affect histamine-induced erectile responses. CONCLUSION: These results indicate that histamine may play a role in human penile erection. The erection-promoting action of histamine is probably due to H2 receptor activation, although another histamine receptor, possibly H3, also seems to be involved. This study suggests that histamine could be a valuable tool in the diagnosis of erectile dysfunction. PMID: 7850330
- BJU Int. 2007 May;99(5):988-92. Epub 2007 Feb 19. Effects of testosterone on erectile function: implications for the therapy of erectile dysfunction. Saad F1, Grahl AS, Aversa A, Yassin AA, Kadioglu A, Moncada I, Eardley I. Author information In adults, testosterone and DHT are needed to maintain intact libido and potency, muscle mass and strength, fat distribution, bone mass, erythropoiesis, prostate growth, male hair growth, and spermatogenesis. Testosterone seems to have a major role in modulating erectile function [17,18]. It determines the frequency of nocturnal penile tumescence and has a regulatory action within the CNS through apomorphine-like effects [19]. There is a normal decline of testosterone levels with age; the age-dependent down-regulation of testosterone level is paralleled by increase in its serum-binding counterpart, sex hormonebinding globulin (SHBG). This condition is commonly referred to as late
- A commonly used test to evaluate for hypogonadism is a morning serum total testosterone level, which measures free testosterone plus protein-bound testosterone.1 This test is a reliable and inexpensive testosterone assay.1 A morning sample is recommended because testosterone levels demonstrate a diurnal variation in which a maximum level is reached in the early morning.2 In older men, however, this circadian rhythm may be blunted.1 Testosterone values &lt;300 ng/dL (10.4 nmol/L) suggest hypogonadism and should be confirmed by a second determination.2 Note that the range of testosterone values indicating hypogonadism may vary according to laboratory. Many clinicians will also order a free testosterone assay. This test measures serum testosterone unbound by sex hormone-binding globulin (SHBG). Although this test is more expensive, it measures the amount of physiological testosterone available in the bloodstream. This is important because age-related increases in SHBG concentration can lower bioavailable testosterone, even though total testosterone concentrations may test within the normal range. Free testosterone levels &lt;50 pg/mL suggest hypogonadism.2 Serum bioavailable (weakly bound) testosterone, also known as non-SHBG-bound, is that portion of the total testosterone that is not protein bound, ie, free plus that portion that is bound to albumin.
- 2.2.1.3 Laboratory testing Laboratory testing must be tailored to the patient’s complaints and risk factors. Patients may need a fasting glucose or HbA1c and lipid profile if not recently assessed. Hormonal tests include a morning sample of total testosterone. If indicated bioavailable or calculated-free testosterone may be needed to corroborate total testosterone measurements. However, the threshold of testosterone to maintain ED is low and ED is usually a symptom of more severe cases of hypogonadism (7). For levels &gt; 8 nmol/l the relationship between circulating testosterone and sexual function is very low (7,8). Additional laboratory tests may be considered in selected patients, for example, prostate-specific antigen (PSA) for detection, or suspicion, of prostate cancer (9). Additional hormonal tests, for example, prolactin, and luteinizing hormone, are performed when low testosterone levels are detected. If any abnormality is observed, referral to an endocrinologist may be indicated (10,11). Although physical examination and laboratory evaluation of most men with ED may not reveal the exact diagnosis, these opportunities to identify critical comorbid conditions should not be missed (12). Reference 7: J Clin Endocrinol Metab. 2006 Nov;91(11):4335-43. Epub 2006 Aug 22. Association of specific symptoms and metabolic risks with serum testosterone in older men. Zitzmann M1, Faber S, Nieschlag E. Author information Abstract CONTEXT: Although attention and concern about health disorders in aging men have been growing, the structure of psychological and somatic complaints of actual patients, not population-based cohorts, has not been elucidated in relation to sex hormone patterns and metabolism. OBJECTIVE: The objective of the study was investigation of factors influencing complaint structures in aging male patients. DESIGN: This was a cross-sectional cohort study. SETTING: The study was conducted in an andrological outpatient department. PATIENTS: Subjects included 434 consecutive male patients aged 50-86 yr. MAIN OUTCOME MEASURES: The following hypotheses were measured: 1) psychosomatic complaints and metabolic factors in aging male patients are related to sex hormone levels in a symptom-specific manner, and 2) patients form subcohorts. RESULTS: A clear-cut threshold for late-onset hypogonadism was not found; rather, prevalence of psychosomatic symptoms and metabolic risk factors accumulated with decreasing androgen levels. For example, androgen-induced prevalence of loss of libido or vigor increased below testosterone concentrations of 15 nmol/liter (P &lt; 0.001), whereas depression and diabetes mellitus type 2 (also in nonobese men) were significantly more present in men with testosterone concentrations below 10 nmol/liter (P &lt; 0.001). Erectile dysfunction was identified as a composite pathology of metabolic risk factors, smoking, and depressivity, whereas only testosterone concentrations below 8 nmol/liter contributed to that symptom (P = 0.003). Cluster analysis revealed aging men to present within three independent groups characterized by psychosomatic complaints, metabolic disorders, and sexual health problems. These subgroups of patients exhibit distinct features in terms of androgen levels, age, and body mass index. CONCLUSIONS: There is no evidence that a uniform structure of testosterone concentrations and complaints exists within the cohort of elderly male patients. Rather, in aging male patients, psychosomatic complaints and metabolic risk relate to testosterone in a symptom-specific manner.
- Context: Although attention and concern about health disorders in aging men have been growing, the structure of psychological and somatic complaints of actual patients, not population-based cohorts, has not been elucidated in relation to sex hormone patterns and metabolism. Objective: The objective of the study was investigation of factors influencing complaint structures in aging male patients. Design: This was a cross-sectional cohort study. Setting: The study was conducted in an andrological outpatient department. Patients: Subjects included 434 consecutive male patients aged 50–86 yr. Main Outcome Measures: The following hypotheses were measured: 1) psychosomatic complaints and metabolic factors in aging male patients are related to sex hormone levels in a symptom-specific manner, and 2) patients form subcohorts. Results: A clear-cut threshold for late-onset hypogonadism was not found; rather, prevalence of psychosomatic symptoms and metabolic risk factors accumulated with decreasing androgen levels. For example, androgen-induced prevalence of loss of libido or vigor increased below testosterone concentrations of 15 nmol/liter (P 0.001), whereas depression and diabetes mellitus type 2 (also in nonobese men) were significantly more present in men with testosterone concentrations below 10 nmol/liter (P 0.001). Erectile dysfunction was identified as a composite pathology of metabolic risk factors, smoking, and depressivity, whereas only testosterone concentrations below 8 nmol/liter contributed to that symptom (P 0.003). Cluster analysis revealed aging men to present within three independent groups characterized by psychosomatic complaints, metabolic disorders, and sexual health problems. These subgroups of patients exhibit distinct features in terms of androgen levels, age, and body mass index. Conclusions: There is no evidence that a uniform structure of testosterone concentrations and complaints exists within the cohort of elderly male patients. Rather, in aging male patients, psychosomatic complaints and metabolic risk relate to testosterone in a symptomspecific manner. (J Clin Endocrinol Metab 91: 4335–4343, 2006 Erectile dysfunction. The specific question was: did you have problems achieving an erection during the last 6 months, which caused you subjective disturbances in general sexual well-being? The patient was categorized with erectile dysfunction if this question was answered with yes. This is in good agreement with the one-question procedure applied in the MMAS (12) and the Australian MATeS study (1).
- First-Line Therapy: Androgen Replacement Although androgens were advocated in the past to enhance male sexual function, more effective treatments are available today. Use of testosterone should be discouraged when ED is not associated with hypogonadism. For men with a documented deficiency (eg, androgen deficiency and hypogonadism), hormone replacement therapy is appropriate. However, androgen replacement therapy may not necessarily improve ED, and the long-term health risks of such therapy, particularly with regard to cardiovascular disease (CVD) and prostate disease, are not known.1 The most widely used form of testosterone replacement therapy in the United States is the transdermal gel, which can be applied daily to the shoulder, upper arm, or abdomen.2 The gel delivers a continuous amount of testosterone for 24 hours. A recent comparative trial in 227 hypogonadal men showed that the testosterone gel improved sexual function and mood, increased lean mass and muscle strength, and was associated with less skin irritation and fewer discontinuations than a permeation-enhanced testosterone patch.3 There are 2 transdermal testosterone patches for daily application to various nonscrotal body sites.4,5 One formulation provides continuous release of testosterone.4 The other has a central drug-delivery reservoir that delivers physiologic amounts of testosterone so that circulating levels of hormone mimic the normal circadian rhythm of healthy young men.4 Long-acting testosterone pellets for subcutaneous implantation have recently become available.6 Each pellet contains 75 mg of testosterone and provides a slow release of hormone for 3 to 6 months. The usual subcutaneous dosage for replacement in androgen deficiency is 150 mg to 450 mg.6 Until recently, the standard treatment for androgen deficiency was a depot intramuscular (IM) injection of testosterone enanthate or cypionate (200 mg or 300 mg, respectively) every 2 or 3 weeks.1 Because smaller dosages and more frequent injections (50 mg to 150 mg IM at 7- to 14-day intervals) maintain normal levels of circulating testosterone more effectively, the current approach is to administer 100 mg on days 1, 11, and 21 of each month.1 Oral testosterone preparations are contraindicated for use in the United States because of hepatotoxicity (cholestasis, hepatitis, benign or malignant tumors).7 AACE Clinical Practice Guidelines. Available at: http://www.aace.com/clin/guides/sexualdysfunction.html. AndroGel® prescribing information. Physicians’ Desk Reference. 56th ed. Montvale, NJ:Medical Economics Company; 2002:3322-3325. Wang C, et al. J Clin Endocrinol Metab. 2000;85:2839-2853. Testoderm® prescribing information. Physicians’ Desk Reference. 56th ed. Montvale, NJ: Medical Economics Company; 2002:574-576. Androderm® prescribing information. Physicians’ Desk Reference. 56th ed. Montvale, NJ:Medical Economics Company; 2002:3377-3380. Testopel™ prescribing information. Physicians’ Desk Reference. 56th ed. Montvale, NJ: Medical Economics Company; 2002:3610-3611. Lue TF. N Engl J Med. 2000;342:1802-1813.
- The Endocrine Society Guidelines recommend evaluation for signs and symptoms of formulation-specific adverse events at each visit. There is potential for liver toxicity in some oral tablet formulations. Pellet implants may extrude spontaneously or cause infection. Physicians should inquire about fluctuations in mood or libido in patients treated with intramuscular injections of testosterone enanthate or cypionate and evaluate hemocrit to detect excessive erythrocytosis, especially in older patients. In patients treated with transdermal patches, physicians should look for signs of skin reaction at the application site. Patients treated with transdermal gels should be advised to cover the application site with clothing and wash the skin before having skin-to-skin contact, because gels leave a residue of testosterone on the skin. In patients receiving buccal tablets, guidelines suggest that physicians inquire about alterations in taste and examine gums and the oral mucosa for irritation. Reference Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in adult men with androgen deficiency syndromes: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2006;91:1995-2010.
- First-Line Therapy: Oral Agents The older oral therapies include yohimbine, trazodone, and L-arginine. Placebo-controlled trials have not demonstrated any clear benefit in taking these medications.1-4 Phentolamine is an oral -adrenergic receptor blocker. Clinical trials for phentolamine were put on hold in the United States because of the development of soft tissue tumors in experimental animals.5 Apomorphine was submitted to the FDA for approval and then had its submission withdrawn in June of 2000 pending further studies.6 In a phase 3 clinical trial of apomorphine, up to 50% of men had a firm enough erection for intercourse. Dose titration was recommended to reduce some of the side effects associated with this medication, which included nausea in about 15% of men at the 2- and 4-mg doses. Less than 2% required an antiemetic because of more severe nausea, and the nausea does seem to decrease with time.5,7,8 Syncope is one of the major warnings that drew concern by the FDA, resulting in the temporary withdrawal of the FDA submission.5,9 Apomorphine was approved in Europe. A combination of yohimbine and L-arginine (NitroMed, Boston, MA) is in early Phase 3 development.9 Other phosphodiesterase type 5 (PDE5) inhibitors are undergoing preclinical and clinical trials. The two PDE5 inhibitors in the latest stage of development are tadalafil (Cialis®, Lilly ICOS, Indianapolis) and vardenafil (Levitra®, Bayer, New Haven, CT).10 These new agents have a mechanism of action similar to that of sildenafil but may have slightly greater specificity. In clinical trials, the drugs significantly improved ED and were well tolerated.10-12 Greiner KA, Weigel JW. Am Fam Physician. 1996;54:1675-1682 Lue TF. N Engl J Med. 2000;342:1802-1813. Klotz T, et al. Urol Int. 1999;63:220-223. DeWire DM. Am Fam Physician. 1996;53:2101-2108. Mulcahy JJ. Available at: http://www.hisandherhealth.com/Drug_Therapies_for_Treatment_of_Erectile_Dysfunction.shtm. Accessed April 25, 2001. Abbott Laboratories. TAP Pharmaceutical Products Inc. withdraws NDA for UPRIMA® (apomorphine HCL tablets) sublingual [press release]. June 30, 2000. Available at: http://www.abbott.com/ai/news/news.cfm?id=151. Accessed April 25, 2001. Dula E, et al. Urology. 2000;56:130-135. Lewis R, et al. Abstract presented at: Annual Meeting of the American Urological Association; May 1-6, 1999; Dallas, Tex. Abstract 1508. Padma-Nathan H, Giuliano F. Urol Clin North Am. 2001;28:321-334. Padma-Nathan H, et al. Int J Impot Res. 2001;13:2-9. Klotz T, et al. World J Urol. 2001;19:32-39. Bischoff E, et al. J Urol. 2001;165:1316-1318.
- Role of NO and cGMP in Erections PDE5 inhibitors work by enhancing nitric oxide (NO)-mediated vasodilation. The relaxation of the smooth muscle of the corpora cavernosa is mediated by NO and nonadrenergic, noncholinergic neurons (NANC), which is a nonadrenergic, noncholinergic neurotransmitter that is released by cavernosal nerves and endothelial cells in response to sexual stimulation. NO activates guanylate cyclase, an enzyme that instructs muscle cells to produce cyclic guanosine monophosphate (cGMP). This second messenger of NO provides the signal for smooth-muscle relaxation via a decrease in intracellular calcium. Relaxation of the smooth muscle of the corpus cavernosum ultimately results in penile erection. cGMP breakdown is catalyzed primarily by phosphodiesterase type 5 (PDE5), an enzyme highly concentrated in the corpus cavernosum. Sildenafil and vardenafil are selective inhibitors of PDE5. By blocking the actions of this enzyme, these inhibitors facilitate higher levels of cGMP in the corpus cavernosum, which helps to improve erectile function. Rajfer J, et al. N Engl J Med. 1992;326:90-94.
- Distribution of PDE Isoenzymes Unlike most other PDEs, the distribution of PDE5 and PDE6 in body tissues is relatively limited.1 PDE5 is referred to as the cGMP-binding, cGMP-specific PDE. This makes use of agents that selectively target PDE5 and its related physiologic processes more feasible.1 PDE5 is found in cavernosal smooth muscle2 and is the main isoenzyme involved in the NO-cGMP cascade that is key to penile erection. The distribution of PDE6 is restricted to the rods and cones of the retina. Thus, PDE inhibitors with a fairly high affinity for the PDE6 isoenzyme relative to the PDE5 isoenzyme have the potential for visual abnormalities.3 Francis SH, et al. In: Progress in Nucleic Acid Research and Molecular Biology. Academic Press. 2001;65:1-52. Ballard SA, et al. J Urol. 1998;159:2164-2171. Viagra® (sildenafil) prescribing information, January 2000.
- Distribution of PDE Isoenzymes (cont’d) PDE8 and PDE9 are broadly distributed throughout the body. PDE8 displays high affinity and specificity for cyclic adenosine monophosphate (cAMP), whereas PDE9 has a very high affinity and specificity for cGMP. The tissue distribution of PDE10 has not been reported.1 PDE11, which affects both cAMP and cGMP, was recently reported to be present in penile smooth muscle and corpus cavernosum,2 and is also thought to be present in the testes, pituitary, prostate, and heart.3 Francis SH, et al. In: Progress in Nucleic Acid Research and Molecular Biology. New York, NY: Academic Press; 2001;65:1-52. Baxendale RW, et al. J Urol. 2001;165(suppl):223-224. Abstract 922. Corbin JP, et al. Int J Clin Pract. 2002;56:453-459.
- PDE5 Inhibitors: Onset and Duration of Activity RigiScan® evaluations during sexual stimulation provide an objective measurement of hardness and duration of erection as well as onset. With sildenafil, the onset of penile tumescence in 10 patients who took part in a pilot study was approximately 30 to 40 minutes after administration of a 25- or 50-mg dose, corresponding approximately to the peak plasma concentration of drug.1 In 8 double-blind, placebo-controlled, crossover studies of patients with either psychogenic or organic ED, the erectile response generally was assessed approximately 60 minutes postdose. Sexual stimulation resulted in improved erections after sildenafil administration compared with placebo. In one study, the drug effect persisted for up to 4 hours, although the response was less than that at 2 hours.2 The time of onset and period of responsiveness to tadalafil were assessed in two Phase 2 studies, one using RigiScan® measurements and the other using stopwatch measurements in the home setting.3 In the pilot, double-blind, crossover RigiScan® study in 61 ED patients, a response trend was noted 30 minutes after a 10-mg dose of tadalafil, and a statistically significant response compared with placebo occurred at 45 minutes (P= 0.034) and 24 hours (P&lt; 0.001). In the 20-mg dose group, the elapsed time from dosing to attainment of the first erection resulting in successful intercourse, measured by participants using a stopwatch, was as short as 16 minutes after dosing. Thus, the results of the 2 tadalafil studies indicate that, after a 20-mg dose, an erection can be achieved as early as 16 minutes and responsiveness lasts for up to 24 hours, enabling a man and his partner to have sex whenever they choose within a 24-hour period. Although a RigiScan® study of vardenafil (20 and 40 mg) was conducted in 21 patients with ED, time to onset and duration of activity were not reported.4 Boolell M, et al. Int J Impot Res. 1996;8:47-52. Viagra® (sildenafil) prescribing information, January 2000. Padma-Nathan H. J Urol. 2001;165(suppl):224. Abstract 923. Sorbera LA, et al. Drugs Future. 2001;26:141-144.
- Tadalafil: Efficacy Evaluation in Men With Diabetes The objective of this 12-week, multicenter, randomized, double-blind, parallel-group, phase 3 study (N=216) was to assess the efficacy and safety of tadalafil in men with diabetes and mild-to-severe ED. All study subjects had received a clinical diagnosis of type 1 or 2 diabetes, were at least 18 years of age, and had experienced ED due to psychogenic, organic, or mixed etiology for at least 3 months. Subjects took tadalafil 10 mg or 20 mg or placebo as needed at any time before sexual activity, without regard to food consumption. Efficacy measures were the GAQ, the EF domain of the IIEF, and the SEP. Both the 10- and 20-mg dosages of tadalafil were superior to placebo when taken as needed for the treatment of ED. Based on responses to SEP question 3 (ie, positive attempts at successful intercourse), the percentage of patients achieving more than a 25% increase in “yes” responses was 44% and 51% for those receiving tadalafil 10 mg and 20 mg, respectively, compared with 16% for the placebo group. Tadalafil led to improvement in IIEF domain scores regardless of diabetes type, current diabetic therapy, initial level of glycemic control, or presence of microvascular complications. Saenz de Tejada I, et al. Eur Urol. 2001;39(suppl):16. Abstract 56.
- J Sex Med. 2014 Mar;11(3):820-30. doi: 10.1111/jsm.12253. Epub 2013 Jul 10. A return to normal erectile function with tadalafil once daily after an incomplete response to as-needed PDE5 inhibitor therapy. Kim ED1, Seftel AD, Goldfischer ER, Ni X, Burns PR. Author information Abstract INTRODUCTION: An optimal outcome of an erectile dysfunction (ED) treatment is to enable a return to normal erectile function (as defined by an International Index of Erectile Function-Erectile Function [IIEF-EF] domain score ≥ 26). As-needed (PRN) phosphodiesterase type 5 (PDE5) inhibitor treatment does not always result in a return-to-normal erectile function. AIM: The combined studies evaluated whether treatment with tadalafil once daily would allow men to return to normal erectile function who had less than normal IIEF-EF domain scores while using a maximum dose of a PRN PDE5 inhibitor treatment. METHODS: Men were ≥ 18 years of age, sexually active, reported a ≥ 3-month history of ED, and had been taking the maximum dose of sildenafil citrate, vardenafil, or tadalafil PRN. Randomization to once-daily therapy with tadalafil 2.5 mg to 5 mg (N = 207), tadalafil 5 mg (N = 207), or placebo (N = 209) for 12 weeks followed a 4-week maximum dose PRN PDE5 treatment and 4-week nondrug lead periods. Two identical double-blind, randomized, placebo-controlled studies were conducted; combined results are reported. MAIN OUTCOME MEASURE: The main outcome measure was the percentage of subjects with a return-to-normal erectile function (IIEF-EF domain score ≥ 26) when treated with tadalafil once daily compared with placebo. RESULTS: In subjects not achieving normal erectile function with the maximum dose of a PRN PDE5 inhibitor, a higher percentage of subjects treated with tadalafil had an IIEF-EF domain score ≥ 26 at end point (tadalafil 2.5- to 5-mg group [39%]; tadalafil 5-mg group [40%]) compared with the placebo group (12.1%; P &lt; 0.001). Tadalafil was generally well tolerated and adverse events observed were consistent with previous reports of tadalafil once daily. CONCLUSIONS: Treatment with tadalafil once daily significantly improved erectile function in men with mild to mild-moderate impairments in erectile function following PRN PDE5 inhibitor treatment.
- Diagnosis and Evaluation of PD A history of trauma during sexual activity has been considered the most common etiology triggering the excessive fibrotic process. Sudden onset has been reported in up to 20% of patients although the actual onset is unlikely to be over night, the deformity may be something which is suddenly recognized and accounts for the so-called rapid onset of this disorder. A useful question to ask during initial consultation is “If your penis were straight and you had the same rigidity, would it be adequate for sexual activity?” This question provides useful information when considering future surgical options. The physical examination should be a general urological one with a detailed examination of the penis. Penile length, which may be best measured by placing the penis on stretch and pressing down on the pubic fat pad to the pubic bone and then measuring dorsally to the corona or the meatus, should be recorded. Plaque location is useful to note, but plaque size is difficult to accurately measure and probably has little value. Biothesiometry, a measure of vibratory sensation, may be the best indirect measure of penile sexual sensory integrity. It is also useful to discuss the patient’s goals, as an inappropriate expectation by the patient should trigger consultation by a sex therapist. Patients with PD should know that the penis and erections they had prior to developing this disease are unlikely to be recovered. Duplex ultrasound with vasoactive drug injection is considered the best approach to assess penile vascular integrity and allow objective measurement of deformity and plaque calcification. Gholami SS, et al. J Urol. 2004;169:1234-1241. Levine LA, et al. Int J Impot Res. 2003;15(suppl 5):S113-S120.
- Utilization of intracavernosal injections by investigators reveals varied initial dosing and titration regimens. In one study, titration with alprostadil (prostaglandin E1) was started at the 5 mcg dose and increased by intervals of 5 mcg with most of the men responding to the 2.5 to 15 mcg range (Brock, Tu, & Linet, 2001). Montorsi et al. (2002) also began with an initial dose of 5 mcgs and titrated to an effective dose of prostaglandin. Another investigator used a 5 mcg starting dose initially and switched to 10 mcgs in subsequent studies as a starting dose with titration of medication up to 40 mcg (Goldstein et al., 2000). Richter et al. (2001) used a starting dose of 5 mcg with all patients, titrating up by 5 mcg to achieve an erection sufficient for sexual relations with a maximum dose of 30 mcg. Typically trimix (papaverine 30 mg, phentolamine 1 mg, and prostaglandin E1 10 mcg) and bimix (papaverine 30 mg and phentolamine 1 mg) are started at a dose of 0.1 to 0.5 ml in my clinic depending on the patient&apos;s age and concomitant problems for ED. Investigators have utilized dose volumes of trimix (papaverine 30 mg, phentolamine 1 mg, and prostaglandin E1 10 mcg per 1 ml) ranging from 0.18 to 1.0 ml in previous studies (Bennett, Carpenter, & Barada, 1991; Montorsi et al., 2002; Mulhall et al., 1999). One physician, who only sends post prostatectomy patients for referral, prefers only trimix with post radical prostatectomy patients related to the side effect of pain with monotherapy using prostaglandin E1. For this reason, this physician&apos;s patients are immediately started on dose titration of trimix, foregoing the monotherapy with prostaglandin E1/alprostadil.Continue Reading super trimix combination of the same papaverine 30 mg, while doubling both the phentolamine (to 2 mg) and the prostaglandin E1 (to 20 mg) in doses up to 1 ml maximum.
- Second-Line Therapy: Vacuum Erection Devices (VEDs) Vacuum erection devices (VEDs) are an option for men who are not interested in drug therapy or those who have specific contraindications to the available pharmacologic options. By applying negative pressure to the penis, VEDs draw blood into it. The blood is then retained by application of an elastic band to the base of the penis. Penile pain, numbness, bruising, and retarded ejaculation are the main side effects associated with VED therapy. Many patients prefer VED therapy because it is available for on-demand use, lacks contraindications, and is less costly over time than other treatment options. VED: Basic Principles VEDs are a useful noninvasive treatment for ED. They involve a cylindrical device that is placed over the penis. Many types of VEDs are now available, and it is recommended that only those available by prescription should be used.1,2 A VED, which mechanically creates penile blood engorgement, consists of a vacuum chamber or cylinder, a pump to produce negative pressure, and constriction rings.3 VEDs can be used to treat organic or psychogenic ED. Current reviews report successful results in men with a variety of organic etiologies, including spinal cord injuries, postprostatectomy, diabetes, and arterial insufficiency.3 After the penis and constriction rings are coated with water-soluble lubricant and the rings are loaded onto the cylinder base, the cylinder is placed over the penis with the base held firmly against the pubis to maintain a seal. The pump is then activated to slowly create negative pressure, or a vacuum, inside the cylinder, which draws blood into the corpora cavernosa, producing an erection.1,3 Once the penis is engorged, the constriction band is pulled from the cylinder onto the base of the penis. The negative pressure is released through a valve, and the cylinder is removed. It takes an average of 2 to 2½ minutes to create an erection through this procedure, according to recent reviews.3 The erectile state produced by VEDs differs from a normal erection: penile skin temperature is lower, the veins of the penis appear distended, and penile circumference is increased. In addition, the penis may pivot at the base, requiring the patient to stabilize the penis during intercourse.1 Montague DK, et al, for the AUA Guidelines Panel on Erectile Dysfunction. J Urol. 1996;156:2007-2011. Donatucci CF. In: Mulcahy JJ, ed. Male Sexual Function. Totowa, NJ: Humana Press Inc; 2001:253-261. Levine LA, Dimitriou RJ. Urol Clin North Am. 2001;28:335-341. Jardin A, et al, eds. Erectile Dysfunction. Plymouth, United Kingdom: Health Publication, Ltd; 2000:357-404.
- VED: Basic Principles VEDs are a useful noninvasive treatment for ED. They involve a cylindrical device that is placed over the penis. Many types of VEDs are now available, and it is recommended that only those available by prescription should be used.1,2 A VED, which mechanically creates penile blood engorgement, consists of a vacuum chamber or cylinder, a pump to produce negative pressure, and constriction rings.3 VEDs can be used to treat organic or psychogenic ED. Current reviews report successful results in men with a variety of organic etiologies, including spinal cord injuries, postprostatectomy, diabetes, and arterial insufficiency.3 After the penis and constriction rings are coated with water-soluble lubricant and the rings are loaded onto the cylinder base, the cylinder is placed over the penis with the base held firmly against the pubis to maintain a seal. The pump is then activated to slowly create negative pressure, or a vacuum, inside the cylinder, which draws blood into the corpora cavernosa, producing an erection.1,3 Once the penis is engorged, the constriction band is pulled from the cylinder onto the base of the penis. The negative pressure is released through a valve, and the cylinder is removed. It takes an average of 2 to 2½ minutes to create an erection through this procedure, according to recent reviews.3 The erectile state produced by VEDs differs from a normal erection: penile skin temperature is lower, the veins of the penis appear distended, and penile circumference is increased. In addition, the penis may pivot at the base, requiring the patient to stabilize the penis during intercourse.1 Montague DK, et al, for the AUA Guidelines Panel on Erectile Dysfunction. J Urol. 1996;156:2007-2011. Donatucci CF. In: Mulcahy JJ, ed. Male Sexual Function. Totowa, NJ: Humana Press Inc; 2001:253-261. Levine LA, Dimitriou RJ. Urol Clin North Am. 2001;28:335-341.
- VED: Practical Aspects Several practical aspects of the use of VEDs should be considered. First, given the number and nature of the steps involved in using these devices, it is clear that the patient must have a certain amount of manual dexterity in order to use them effectively. Second, individual instruction must be provided when VEDs are prescribed. This instruction must include a visual component, whether a one-on-one demonstration in the office or by means of an instructional video.1 Because penile vascular stasis and a state of relative ischemia exist during a VED-produced erection, the constriction bands cannot be left in place for a prolonged period.1 It is recommended that the bands be removed after no more than 30 minutes.2 Petechiae, bruising, and hematoma formation may occur with the use of VEDs. These hematologic adverse effects are more likely to occur in men taking aspirin or other anticoagulant therapy or who have easy bruisability.1,2 Finally, as previously noted, it has been demonstrated that higher VED success rates are achieved by men who are in stable relationships with motivated, understanding partners.2 Montague DK, et al, for the AUA Guidelines Panel on Erectile Dysfunction. J Urol. 1996;156:2007-2011. Levine LA, Dimitriou RJ. Urol Clin North Am. 2001;28:335-341.
- VED: Profile VEDs are nearly uniformly effective in producing an erection. Erections sufficient for vaginal penetration are obtained in more than 90% of patients, according to recent reviews.1 Reported satisfaction rates are somewhat lower, however, at approximately 55% after 2 years of use.2 VEDs offer several advantages. In addition to the fact that they can be used on demand, the devices are very safe. Although serious complications are possible—cases of penile skin necrosis and Peyronie’s disease have been reported, related primarily to misuse of the devices—such problems are quite rare. Most complications resulting from the use of VEDs are minor and localized.1,3 VEDs are relatively inexpensive.3 However, patients should be cautioned about the use of devices that are available over the counter. VEDs are not without disadvantages. Although side effects are generally not serious, several may occur. Petechiae and ecchymosis are not uncommon; recent reviews report that petechiae occur in 25% to 39% of users, while penile bruising occurs in 6% to 20%.1 The most common adverse effect, however, is pain, which may occur during the suction process in 20% to 40% of users, especially during the early period. Up to 45% of users complain of pain at the constriction ring site, and 3% to 16% complain of pain upon ejaculation. Further, inability to ejaculate has been reported in 12% to 30% of users, according to recent reviews.1 Numbness may also occur. Finally, the penis may pivot, or “hinge,” at the point of constriction, which some patients or partners may find disconcerting.1 Levine LA, Dimitriou RJ. Urol Clin North Am. 2001;28:335-341. Jarow JP, et al. J Urol. 1996;155:1609-1612. Donatucci CF. In: Mulcahy JJ, ed. Male Sexual Function. Totowa, NJ: Humana Press Inc; 2001:253-261.
- Second-Line Therapy: Transurethral System An alternative to injection therapy is transurethral application of alprostadil with or without a penile constriction device.1,2 Like injection therapy, transurethral alprostadil is appropriate for those who are intolerant of or who fail to respond to oral therapy, who have adverse reactions to specific oral drugs, or in whom specific oral drugs are contraindicated.1 It is also another option for men who have failed injection therapy3 or in whom a penile prosthesis has failed.4 Transurethral therapy is less invasive than injections and produces more rapid (5 to 10 minutes), predictable erections.5 However, it is significantly less effective than intracavernosal injection.1,2 Penile pain is a common complaint of patients who use transurethral alprostadil.1,2 In addition, symptomatic hypotension and syncope have been reported.5 Transurethral alprostadil is contraindicated in men with abnormal penile anatomy and sickle cell anemia.5 Recommendations of the 1st International Consultation on Erectile Dysfunction. In: Jardin A, et al, eds. Erectile Dysfunction. Plymouth, United Kingdom: Health Publication, Ltd; 2000:711-726. Shabsigh R, et al. Urology. 2000;55:477-480. Benevides MD, Carson CC. J Urol. 2000;163:785-787. Engel JD, McVary KT. Urology. 1998;51:687-692. MUSE® (alprostadil) urethral suppository prescribing information. Physicians’ Desk Reference. 56th ed. Montvale, NJ: Medical Economics Company; 2002:3335-3338.
- N Engl J Med. 1997 Jan 2;336(1):1-7. Treatment of men with erectile dysfunction with transurethral alprostadil. Medicated Urethral System for Erection (MUSE) Study Group. Padma-Nathan H1, Hellstrom WJ, Kaiser FE, Labasky RF, Lue TF, Nolten WE, Norwood PC, Peterson CA, Shabsigh R, Tam PY, Place VA, Gesundheit N. Author information Abstract BACKGROUND: Erectile dysfunction in men is common. We evaluated a system by which alprostadil (prostaglandin E1) is delivered transurethrally to treat this disorder. METHODS: Alprostadil was delivered transurethrally in a double-blind, placebo-controlled study of 1511 men, 27 to 88 years of age, who had chronic erectile dysfunction from various organic causes. The men were first tested in the clinic with up to four doses of the drug (125, 250, 500, and 1000 microg); those who had sufficient responses were randomly assigned to treatment with either the effective dose of alprostadil or placebo for three months at home. RESULTS: During in-clinic testing, 996 men (65.9 percent) had erections sufficient for intercourse. Of these men, 961 reported the results of at least one home treatment; 299 of the 461 treated with alprostadil (64.9 percent) had intercourse successfully at least once, as compared with 93 of the 500 who received placebo (18.6 percent, P&lt;0.001). On average, 7 of 10 alprostadil administrations were followed by intercourse in men responsive to treatment. The efficacy of alprostadil was similar regardless of age or the cause of erectile dysfunction, including vascular disease, diabetes, surgery, and trauma (P&lt;0.001 for all comparisons with placebo). The most common side effect was mild penile pain, which occurred after 10.8 percent of alprostadil treatments, but the pain rarely resulted in refusal to continue in the study. Hypotension occurred in the clinic in 3.3 percent of men receiving alprostadil. Hypotension-related symptoms were uncommon at home. No men had priapism or penile fibrosis. CONCLUSIONS: In men with erectile dysfunction, transurethral alprostadil therapy resulted in erections in the clinic and in intercourse at home. Comment in ACP J Club. 1997 Jul-Aug;127(1):7
- Second-Line Therapy: Intracavernosal Injection Intracavernosal injection therapy is the preferred second-line treatment option after oral therapy.1 It is appropriate for those who are intolerant of or who fail to respond to oral therapy, who have adverse reactions to specific oral drugs, or in whom specific oral drugs are contraindicated.1,2 An office trial of intracavernosal injection therapy is done initially to determine the patient’s responsiveness. After the patient has become comfortable with the injection technique, at-home therapy can be prescribed. A follow-up examination is scheduled several weeks after starting home therapy; subsequent follow-up visits are scheduled 2 or 3 times a year.3 Advantages of intracavernosal injection therapy are that it is relatively safe and highly effective, producing more reliable, rapid (5 to 20 minutes),1 and predictable erections.2 Intracavernosal injection is associated mainly with local side effects, including pain, priapism, and fibrotic changes (ie, palpable nodules or plaques) on or within the tunica albuginea.2,3 Intracavernosal therapy is contraindicated in patients with sickle cell anemia and other conditions that predispose to priapism.2 Shabsigh R, et al. Urology. 2000;55:477-480. Recommendations of the 1st International Consultation on Erectile Dysfunction. In: Jardin A, et al, eds. Erectile Dysfunction. Plymouth, United Kingdom: Health Publication Ltd; 2000:711-726. Leungwattanakij S, et al. Urol Clin North Am. 2001;28:343-354.
- Minimal clinically important differences in the erectile function domain of the International Index of Erectile Function scale. Rosen RC1, Allen KR, Ni X, Araujo AB. Author information Abstract BACKGROUND: Despite widespread adoption of the six-item erectile function (EF) domain of the International Index of Erectile Function (IIEF) as a clinical trial end point, there are currently no objective data on what constitutes a minimal clinically important difference (MCID) in the EF domain. OBJECTIVE: Estimate the MCID for the IIEF EF domain. DESIGN, SETTING, AND PARTICIPANTS: Anchor-based MCIDs were estimated using data from 17 randomized, double-blind, placebo-controlled, parallel-group clinical trials of the phosphodiesterase type 5 inhibitor (PDE5-I) tadalafil for 3345 patients treated for 12 wk. MEASUREMENTS: The anchor for the MCID is the minimal improvement measure calculated using change from baseline to 12 wk on IIEF question 7: &quot;Over the past 4 weeks, when you attempted sexual intercourse how often was it satisfactory for you?&quot; MCIDs were developed using analysis of variance (ANOVA)- and receiver operating characteristic (ROC)-based methods in a subset of studies (n=11) by comparing patients with and without minimal improvement (n=863). MCIDs were validated in the remaining six studies (n=377). RESULTS AND LIMITATIONS: The ROC-based MCID for the EF domain was 4, with estimated sensitivity and specificity of 0.74 and 0.73, respectively. MCIDs varied significantly (p&lt;0.0001) according to baseline ED severity (mild: 2; moderate: 5; severe: 7). MCIDs consistently distinguished between patients in the validation sample classified as no change or minimally improved overall and by geographic region, ED etiology, and age group. MCIDs did not differ by age group, geographic region, or ED etiology. Current analyses were based on 17 clinical trials of tadalafil. Results need to be replicated in studies using other PDE5-Is or in nonpharmacologic intervention studies. CONCLUSIONS: The contextualization of treatment-related changes in terms of clinically relevant improvement is essential to understanding treatment efficacy, to interpreting results across studies, and to managing patients effectively. This analysis provides, for the first time, anchor-based estimates of MCIDs in the EF domain score of the IIEF.
- eview Article Contemporary Patient Satisfaction Rates for Three-Piece Inflatable Penile Prostheses Raymond M. Bernal1 and Gerard D. Henry2 1Division of Urology, Department of Surgery, Duke University Medical Center, Box 3274, Durham, NC 27710, USA2Regional Urology, 255 Bert Kouns Industrial Loop, Shreveport, LA 71106, USA Received 28 February 2012; Accepted 30 May 2012 Academic Editor: Rafael Carrion Copyright © 2012 Raymond M. Bernal and Gerard D. Henry. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Among the many treatments for erectile dysfunction, implantation of a penile prosthesis has been associated with high patient satisfaction rates. Specifically, the placement of a three-piece inflatable penile prosthesis (IPP) confers the highest rates of satisfaction. We reviewed the literature over the past 20 years regarding satisfaction rates for penile prostheses, with a focus on patients who had undergone an initial IPP implantation for erectile dysfunction. In all, 194 articles were reviewed, and of these, nine met inclusion criteria for analysis and data collation. We determined contemporary satisfaction rates to reflect patients’ experiences with newer products and surgical approaches. Of importance, we noted that varied metrics were used to determine patient satisfaction, and overall satisfaction could not be precisely determined. Nevertheless, we found that patients in general were quite satisfied with their three-piece IPPs and restoration of sexual function. We also identified reasons for patient dissatisfaction and reviewed the literature to find ways by which satisfaction could be improved. Given the various means by which patient satisfaction was determined, future efforts should include standardized and validated questionnaires.
- J Urol. 2012 Sep;188(3):899-903. doi: 10.1016/j.juro.2012.04.116. Epub 2012 Jul 20. Long-term infection outcomes of 3-piece antibiotic impregnated penile prostheses used in replacementimplant surgery. Nehra A1, Carson CC 3rd, Chapin AK, Ginkel AM. Author information Abstract PURPOSE: Patients who undergo device revision surgery are at higher risk for infection than virgin implant recipients. The revision rate due to virgin implant infection is statistically significantly lower for minocycline/rifampin impregnated than for nonimpregnated inflatable penile prostheses. We determined whether the frequency of infection revision events after device replacement surgery would also be lower for minocycline/rifampin impregnated inflatable penile prostheses. MATERIALS AND METHODS: Patient information forms voluntarily submitted to AMS® after replacement inflatable penile prosthesis implantation between 2001 and 2007 were retrospectively reviewed to compare secondary infection related revision events for antibiotic impregnated vs nonimpregnated implants. Only men who received an inflatable penile prosthesis at a first recorded operation to replace a previously implantedpenile prosthesis were included in the study. Life table survival analysis was done between the groups to compare infection related events resulting in a second surgical revision after replacement implantation. Survival function extrapolation was based on parametric analysis using the Weibull distribution model. RESULTS: On life table survival analysis secondary revision due to infection was significantly less common in the minocycline/rifampin impregnated group than in the nonimpregnated group (log rank p = 0.0252). At up to 6.6 years of followup 2.5% of 9,300 men with vs 3.7% of 1,764 without an impregnated device underwent secondary revision due to infection. ========================== Eur Urol. 2011 Jul;60(1):167-72. doi: 10.1016/j.eururo.2011.01.046. Epub 2011 Feb 4. Long-term infection rates in diabetic patients implanted with antibiotic-impregnated versus nonimpregnated inflatable penile prostheses: 7-year outcomes. Mulcahy JJ1, Carson CC 3rd. Author information 1Division of Urology, University of Arizona, Tucson, AZ, USA. johnmulc@gmail.com Abstract BACKGROUND: Diabetic patients may be more prone to penile-implant infections than other men. OBJECTIVE: We sought to determine whether revision surgeries due to infection were less common in diabetic men after implantation of an inflatable penile prosthesis (IPP) impregnated with minocycline and rifampin (M/R) versus a nonimpregnated prosthesis. DESIGN, SETTING, AND PARTICIPANTS: Infection-related revisions for M/R-impregnated and nonimpregnated implants were compared during a retrospective review of patient-implant and removal data recorded in the manufacturer&apos;s database. The data set included men with diabetes as an etiology of erectile dysfunction and who were implanted with their first IPPs between 2001 and 2008. INTERVENTION: All men received three-piece IPPs. MEASUREMENTS: The number of first revisions due to infection reported at any time during the study period were summarized for each group. Freedom from infection-related revisions for initial M/R-impregnated implants were compared to nonimpregnated implants with ≤ 84 mo of follow-up using life-table survival analysis. Infection-free survival was also compared for diabetics versus nondiabetics. RESULTS AND LIMITATIONS: Mean age was 59.1 yr for the 6071 diabetic men in the M/R-impregnated group. The nonimpregnated group included 624 diabetics with a mean age of 57.6 yr. Initial revisions due to infection were reported for 1.47% of M/R-impregnated versus 4.17% of nonimpregnated implants. At 7 yr, the rate of infection-related revisions was significantly lower for M/R-impregnated (1.62%) than for nonimpregnated implants (4.24%; log-rank p &lt; 0.0001). Diabetic men had a significantly higher rate of revisions due to infection at 7 yr (1.88%) than men without diabetes (1.53%; log-rank p = 0.0052). CONCLUSIONS: This long-term evidence from the largest known database of diabetic IPP recipients establishes that the use of an antibiotic-impregnated IPP can decrease revisions due to infection. Reducing the incidence of this devastating complication represents a significant medical advance in erectile restoration for diabetic patients.
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