ISSUES IN ANDROLOGY
From the New York University Postgraduate Medical School Symposium on Surgical, Pharmacological, and Technological
Advances in Adult and Pediatric Urology: State-of-the Art
| PHOSPHODIESTERASE TYPE 5 (PDE-5) INHIBITORS FOR ERECTILE DYSFUNCTION (ED): ARE THEY ALL
THE SAME ?—Stephen M. Auerbach, MD, Medical Director of California Professional Research, and Staff Member,
Hoag Memorial Hospital Presbyterian, Newport Beach, CA
|
| Erectile dysfunction: potential problems—emotional issue, ie, patient too embarrassed to discuss situation; patient’s
physician may not consider ED to be real disease; disease may be warning sign for cardiovascular (CV) disease;
causes—age-related changes; diabetes mellitus; heart disease; hyperlipidemia; hypertension; prostate cancer treatment;
couple-related factors—age-related problems, eg, arthritis; issues of concern to women (eg, poor communication, postmenopausal
changes), and differences in level of sexual desire
|
| Basic evaluation: avoids “doorknob close” statement from patient, ie, “Can you write me a prescription for sildenafil
(eg, Viagra), vardenafil (Levitra), or tadalafil (Cialis)?”; ask patient whether he has any—erection problems (question
requires yes or no answer); new illnesses or takes new medications; laboratory evaluation—obtain serum and free testosterone
levels in morning; basic blood work-up; CV evaluation—necessary when concerned about physical exertion
during sex; indicated for men who have trouble walking up stairs or pain with exercise; metabolic equivalent table (MET)
facilitates assessment of exertion level from various physical activities
|
| Comparison of phosphodiesterase type 5 inhibitors (ie, sildenafil, tadalafil, and vardenafil): drug selection
depends on preference of patient and physician
|
 | Factors to consider: effectiveness—all 3 drugs work well; determine which drug works best in particular patient; early
onset of action—all 3 drugs work within 15 min; some patients expect drugs to work before they have achieved maximum
levels of effectiveness; absorption times—sildenafil (1 hr); vardenafil (0.8 hr); tadalafil (2 hr); onset of action
with food—sildenafil (2 hr); vardenafil (absorption delayed 18%-50% by high-fat meals); tadalafil (absorption unaffected);
half-life—sildenafil (3.7 hr); vardenafil (4.6 hr); tadalafil (17.5 hr); point—some men report better erections
on morning after taking sildenafil or vardenafil; this experience may influence drug preference; side effects—
headache, dyspepsia, and nasal congestion with all 3 drugs; flushing with sildenafil and vardenafil; backache and myalgia
with tadalafil; blue vision in small percentage of men taking sildenafil
|
| Cardiac safety: PDE-5 inhibitors—never use in combination with nitrates (risk for hypotension); do not increase risk
for myocardial infarction (MI) or death (eg, sildenafil can be used in men with pulmonary hypertension); considered safe
with multiple blood pressure medications; can be used after angioplasty or coronary bypass surgery when cardiologist
clears patient for sexual activity; with cardiac emergency—nitrates can be administered 24 hr after administration of
sildenafil or vardenafil and 48 hr after administration of tadalafil; all emergency facilities have protocols for administering
alternative medications to patients taking PDE-5 inhibitors
|
| Additional pointers to facilitate management: patients should—try specific drug on ≥5 occasions before switching
to another drug (compensates for anxiety and worry generated by ED); try all PDE-5 inhibitors before making final
selection (one drug may be more effective or have fewer side effects than others); determine copayment for each drug; to
maximize therapeutic efficacy—sexual stimulation necessary; multiple attempts and dosage adjustments may be required;
testosterone therapy may improve therapeutic response in hypogonadal men; involve partner in process; options
when oral therapy fails—vacuum erection; penile injections; penile implants
|
| PDE-5 INHIBITORS IN THE MANAGEMENT OF LOWER URINARY TRACT SYMPTOMS (LUTS) AND ED —
Arthur L. Burnett II, MD, Professor of Urology, Johns Hopkins University School of Medicine, Baltimore, MD
|
| Lower urinary tract symptoms and ED: epidemiologic data suggest—association may exist between ED and
LUTS; men with LUTS may face increased risk of developing ED; quality of erectile function can vary inversely with severity
of LUTS symptoms (such activity may occur independently of age); risk factors of interest—aging; androgens;
benign prostatic hyperplasia (ie, local paracrine factors have been associated with progression of BPH); regulatory factors
for ED, including neurotransmitters, hormonal factors, and local paracrine factors in genitalia; trophic mechanisms;
genetic involvement; concept—ED, BPH, and LUTS may describe symptoms of associated underlying disease; proposed
pathogenic links—nitric oxide (NO) pathway; autonomic hyperactivity or metabolic syndrome (ie, involvement of
sympathetic nervous system); endothelins and rho-kinase pathways (thought to be vasoconstrictive component of various
smooth muscle tissue states involving vasculature, penis, and lower urinary tract); pelvic atherosclerosis
|
| NO pathway: relaxation of smooth muscle tissue occurs in response to release of NO via cholinergic nerve activity and
other endothelial sources
|
| Activity within smooth muscle cell: NO binds to iron within heme moiety of guanine cyclase; cyclic guanosine monophosphate
(cGMP)—potent second-messenger molecule; forms when enzyme interacts with guanosine triphosphate;
activates protein kinase G, which changes calcium levels within tissue and elicits tissue relaxation; point—PDE-5 inhibitors
promote cGMP effect; data—suggest BPH potentially associated with low NO release; show decrease in nitric
oxide synthase (NOS)-containing nerves in BPH tissue; indicate NO relevant factor in contractility of prostate tissue
|
| Phosphodiesterases: data suggest—mechanisms besides NO pathway may play role in tissue response of prostate and
urinary outlet; nitrates administered to men with obstructive BPH seem to exert favorable effect on urinary flow rates,
international prostate symptom scores (IPSS), and urinary volumes; PDE-4 and PDE-5 active in human prostate and
play role in tissue contractility; sildenafil potentiated NO cGMP effect (ie, IPSS and sexual function improved)
|
| Clinical trial data: when compared to placebo, men receiving tadalafil (5-mg dose administered at 6 wk increased to 20
mg at 12 wk)—experienced improved quality of life (QOL) or IPSS by 12 wk; derived significant benefit as shown by
BPH impact index at 12 wk; demonstrated no significant difference in urinary flow rates or residual urine volumes;
men with ED and BPH-related LUTS who received sildenafil had—no change in urinary flow rates; improved erectile-function,
relationship, and IPSS scores; improved BPH and QOL parameters; combination of sildenafil and alfuzosin
(α-blocker)—dramatically improved IPSS scores and urinary flow rates; may provide greatest therapeutic
benefit
|
| PDE-5 inhibition in men with BPH and LUTS: data suggest—long-term use of PDE-5 inhibitors may improve voiding
and erectile function in men with concomitant ED and LUTS; combination of α-blocker and PDE-5 inhibitor may be
most effective intervention; points—biologic mechanism of effect elusive for PDE-5 inhibition; animal data suggest
PDE-5 inhibitors may activate endothelial NO release in vascular mechanism
|
| Conclusions: relationship between LUTS and ED—demonstrated by epidemiologic studies; may involve commonality
of risk factors and some molecular mechanisms; PDE-5 inhibitor therapy—potential therapeutic relevance for ED and
LUTS suggests pathogenic link for both conditions; therapeutic benefit may be matter of smooth muscle relaxation and
reconditioning effect involving endothelial NO
|
| PREMATURE EJACULATION: BACK TO THE DRAWING BOARD —Andrew R. McCullough, MD, Associate Professor
of Urology, Director of Sexual Health and Fertility, New York University School of Medicine, New York, NY
|
| Premature ejaculation (PE): defined by American Urological Association (AUA) as ejaculation occurring sooner
than desired, either before or shortly after penetration, and causing distress to one or both partners; intravaginal ejaculation
latency time (IELT)—data suggest mean IELT lasts <3 min in men with PE and >9 min in men with “normal” ejaculatory
function; in reality, considerable overlap exists, with normal IELT still undetermined, ie, some men consider their
normal IELT to be abnormal; prevalence of—ED increases with age; PE remains constant in men ≤59 yr of age (men
>59 yr of age, develop form of PE associated with ED); PE can adversely affect—sexual performance and satisfaction;
social life; psychologic well being, ie, decreased self confidence and anxiety about having sex; PE can affect couple’s
relationship—while some men feel they cannot fulfill partner’s needs, others are satisfied with being able to achieve
ejaculation; in some cases, concerned woman seeks help for unconcerned partner with PE
|
| Etiology of PE: multifactorial; biologic basis—in animal models, low serotonin levels produce situation similar to PE;
in humans, biologic PE may be caused by hypersensitivity and/or hyposensitivity of serotonin receptors located at synaptic
cleft (large number of receptors may create multifactorial problem and explain why some selective serotonin reuptake
inhibitors [SSRIs] work better than others); psychologic basis—usually acquired; may involve problem with one partner;
usually associated with anxiety or early sexual experiences; can be related to frequency of sexual activity, complicated
psychodynamics, or evolution; points—primary PE probably has strong biogenic component; acquired PE more likely
psychogenic problem and can be associated with ED or use of medications
|
| AUA guidelines for diagnosing PE: sexual history should determine—frequency and duration of PE; relationship to
partner; frequency and nature of sexual activity; aggravating or alleviating factors; effect of PE on sexual activity, relationships,
and QOL; relationship to drug use or abuse; ask patient whether he usually ejaculates too soon—if yes, problem
exists; if no, man does not have PE; key point—50% of patients not bothered by their PE
|
| Management: self-help—multiple condoms; masturbation prior to intercourse (approach delays IELT of secondary
erection; less effective as men age and secondary erections become more difficult to achieve); mental exercises during
sex; psychologic intervention (poor results long term); vacuum erection devices and penile injections—cumbersome;
constrict base of penis and create nonejaculation situation; topical therapy—combination of lidocaine and prilocaine (increased
average IELT from 1 min 24 sec to 11 min; can cause vaginal numbness); SS cream (proprietary; not available in
United States; efficacy unconfirmed)
|
| PDE-5 inhibitors: off-label use; allow erections to occur with less stimulation; decrease refractory period for erection,
enabling patient to resume intercourse within refractory period for orgasm, ie, patient with mild ED can regain erectile
function of younger man and achieve second orgasm that takes longer to achieve; sildenafil—helps older men with PE
and associated ED recover erections more quickly; on-demand sildenafil proved superior to alternative techniques (eg,
pause-squeeze technique ) for ejaculatory latency and patient satisfaction; in men with mixed PE and ED, PDE-5
inhibitors—may be ideal therapeutic option; avoid use of SSRIS and associated mania/cycling; may be used in addition
to SSRIs in refractory cases; mechanism of action unclear
|
| SSRIs: off-label use; activate 5-HT2c receptors and increase set point of ejaculatory threshold; paroxetine—initial 10-mg
dose can be increased to 20 mg; patient requiring higher doses should be referred to mental health professional; several
weeks of continuous therapy required to improve mean IELT; side effects significant problem for men who, theoretically,
must take drug for life; limitations of SSRIs—long-term dosing; unpredictability of therapeutic response; delayed
onset of action and long half-life not conducive to on-demand therapy; side effects (dry mouth; nervousness;
gastrointestinal upset; headaches; drowsiness; decreased libido and erectile function with long-term dosing)
|
| Points: ideal drug for PE must be fast acting, have short half-life, and be capable of activating selected serotonin receptors;
initial SSRI developed for PE not approved for use by Food and Drug Administration (problem probably associated
with risk for depressive symptoms and suicidal ideation associated with withdrawal of short-acting SSRIs);
dapoxetine—evaluated at 30-mg and 60-mg doses; peak serum level at ≈1 hr; eliminated from body ≤24 hr; 30-mg
dose achieved 3-fold increase in IELT (increase slightly higher with 60-mg dose); achieved high level of patient satisfaction,
even though side effects could be problematic; side effects include—nausea at higher doses (fairly well tolerated);
decreased libido and ED in subset of men
|
| ANDROGEN REPLACEMENT AND PROSTATE CANCER —Dr. Burnett
|
| Androgen deficiency in aging male (ADAM): common problem; refers to documented decline in levels of bioeffective
testosterone in men >50 yr of age; symptom cluster includes—decrease in libido and sexual function, muscle mass
and strength, and cognitive ability; loss of secondary sexual characteristics; point—androgen supply may be important in
preserving sexual function and overall health in men; hypogonadism in ADAM—may involve central mechanism, ie, men
demonstrate abnormal secretion of gonadotropin-releasing hormone and failure to increase leuteinizing hormone; in addition,
as men age, increased levels of sex hormone–binding globulin may decrease levels of free testosterone or testosterone
that can be released immediately from albumin
|
| Testosterone replacement therapy: favored by many men eager to preserve sense of well-being; contraindicated in
men with prostate and breast cancers; data suggest approach may help—address deficiencies in sexual function; restore
psychologic well being; improve overall body function, bone mass, and strength; decrease CV risk; can potentially increase
risk for—hepatotoxicity (risk contraindicates use of oral testosterone supplements); prostate cancer; edema; exacerbating
preexisting cardiac, renal, or hepatic disease; gynecomastia; sleep-related complications
|
| Risk for prostate cancer in men receiving testosterone administration: factors suggesting potential risk—
prostate gland relies on androgens for growth (testosterone replacement therapy can increase prostate size and prostate
specific antigen [PSA] levels in hypogonadal men); role of androgen ablation in managing advanced prostate cancer (testosterone
supplementation may exert opposite effect); literature survey provides no evidence that—normal testosterone
levels promote carcinogenesis; testosterone replacement initiates or promotes de novo or preexisting prostate cancer; utility
of testosterone replacement therapy—remains open question; larger randomized trials with appropriate follow-up may
clarify issue
|
| Recommendations: candidates for testosterone replacement—must be screened routinely; should not have high-risk
profile based on routine evaluation; when patients undergo replacement therapy—monitor with digital rectal examination
(DRE) and PSA evaluation; maintain low threshold for biopsy, ie, >1 ng/mL increase in serum PSA ≤6 mo after start
of therapy or >0.4 ng/mL increase at ≥6 mo; in men who have undergone radical prostatectomy—administer lowest
dose of testosterone necessary to achieve eugonadal state; continue therapy only if signs and symptoms of hypogonadism
improve; if patient’s status does not improve, further treatment may not be appropriate; perform DRE and PSA evaluation
every 1 to 2 mo during first year and every 5 to 6 mo thereafter; with any increases in PSA, discontinue therapy and
look for cancer recurrence
|
Suggested Reading
Andersson KE et al: Phosphodiesterases (PDEs) and PDE inhibitor for treatment of LUTS. Neurourol Urodyn 26:928,
2007; Barqawi A, Crawford ED: Testosterone replacement therapy and the risk of prostate cancer. Is there a link? Int
J Impot Res 18:323, 2006; Burnett AL: Phosphodiesterase 5 mechanisms and therapeutic applications. Am J Cardiol
96:29M, 2005; Hellstrom WJ: Current and future pharmacotherapies of premature ejaculation. J Sex Med 332:41, 2006;
Sharlip ID: Guidelines for the diagnosis and management of premature ejaculation. J Sex Mod 4:309, 2006; Young JM
et al: Tadalafil improved erectile function at twenty-four and thirty-six hours after dosing in men with erectile dysfunction:
US trial. J Androl 26:310, 2005.
Educational Objectives
| The goal of this program is to improve management of issues related to andrology. After hearing and assimilating this program,
the clinician will be better able to:
|
| 1. Evaluate and treat men presenting with erectile dysfunction (ED).
|
| 2. Compare the relative clinical merits of phosphodiesterase type 5 (PDE-5) inhibitors in the management of ED.
|
| 3. Determine the potential role of PDE-5 inhibitors in the management of lower urinary tract symptoms .
|
| 4. Review current techniques for managing and treating premature ejaculation.
|
| 5. Assess the potential risk for prostate cancer in men undergoing testosterone replacement therapy.
|
Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and planning committee
members to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of
interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and
not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Auerbach is affiliated
with Eli Lilly & Co, Pfizer Inc, and Schering-Plough Corp; Dr. Burnett is affiliated with Pfizer Inc and Lilly ICOS;
Dr. McCullough is affiliated with Allergan, Alza/Johnson & Johnson, Astellas Pharma Inc, Auxilium, Bayer GSK, Guilford/Symphony
Neurodevelopment, Ion Channel, Lilly ICOS, Merck, MGI Pharma, Nexmed, Oscient Pharmaceuticals,
Pfizer Inc, Schwarz Pharma, Solvay Pharmaceuticals, Threshold Pharmaceuticals, VIOptix Inc, and Vivus. The planning
committee reported nothing to disclose.
Acknowledgements
Drs. Auerbach, Burnett, and McCullough gave their lectures at Surgical, Pharmacological, and Technological Advances in
Adult and Pediatric Urology: State-of-the Art, presented December 7-9, 2006, in New York, NY, by New York University
Postgraduate Medical School. The Audio-Digest Foundation thanks the speakers and the sponsor for their cooperation in
the production of this program.
|
