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ED, EjD, and Hypogonadism in Diabetic Males Steven N. Gange, MD, FACS 4252 S. Highland Drive • • • • • • Lane Childs, MD Peter Fisher, MD Steven Gange, MD Scott Hopkins, MD Regan Brooks, PA-C Elizabeth Darling, PA-C This is a talk about sex, and contains potentially offensive images… Men’s Health Statistics Reality bites… With Respect to American Women, Men… • Die 7 years younger (1 year younger in 1920) • Die more often from all 15 leading causes of death (except Alzheimer’s) • Greater risk of serious chronic diseases, and suffer from them at an earlier age • Are twice as likely to die from heart disease (3 of 4 heart attack deaths under 65 are men) With Respect to American Women, Men… • More likely to be drug abusers, pathological gamblers, alcoholics, and smokers… With Respect to American Women, Men… • Are responsible for 8 of 10 car accidents! Men Avoid Doctors • Twice as many men than women have no regular source of medical care • Men comprise 70% of those who haven’t seen a doctor in the past 5 years • 25% of men would wait “as long as possible” to see a doctor And, yet… • What universally gets a man’s attention: Older Men Are Still Sexually Active 100% 83% 92% 83% 65% 80% 60% 40% 20% 0% Total 50-59 60-69 70-79 Sexual activity = Intercourse, masturbation and any activity that the participant considered “sexual” Rosen R. Multinational Survey of the Aging Male (MSAM-7). Presented at the Annual Meeting of the AUA ; May 26, 2002; Orlando, Fla. Age Massachusetts Male Aging Study: Prevalence of Erectile Dysfunction (ED) • In 2005, 30 million men are affected worldwide • By 2025, over 300 million men will have ED Feldman HA et al. J Urol. 1994;151:54-61. Major Risk Factors for ED: Aging Age-Adjusted Progression of ED 80 67 70 57 60 48 50 Prevalence (%) 40 40 30 20 10 0 40 Severe ED Moderate ED Mild ED 50 60 Age (y) Feldman HA, Goldstein I, Hatzichristou DG et al. Impotence and its medical and psychosocial correlates: results from the Massachusetts Male Aging Study. J Urol. 1994;151(1):54-61. 70 Major Risk Factors for ED • Aging • Chronic diseases – Hypertension – Diabetes – Depression – Cardiovascular disease • Medications – Antihypertensives • Thiazide diuretics • Beta-blockers • Lifestyle – Stress – Alcohol abuse – Smoking Feldman HA et al. J Urol. 1994;151:54-61. ED and Endothelial Injury Precursors Diabetes Hypertension Dyslipidemia Oxidative Stress Tobacco Endothelial Cell Injury Vasoconstriction Atherosclerosis Erectile Dysfunction Thrombosis Outcomes Dzau et al. Am J Cardiol. 1997;80:33I-39I Cooke, Dzau. Annu Rev of Med. 1997;48:489-509 Solomon et al. Heart. 2003;89:251-254. Anatomy of an Erection Anatomy of an Erection Anatomy of an Erection How Inflow Affects Outflow Biochemistry of an Erection: The Nitric Oxide (NO) Story • Prior to 1990: an air pollutant • Named “Molecule of the Year” by Science magazine in 1992 • Nobel Prize in Medicine 1998 to 3 PhDs responsible for discovery Phosphodiesterases • Main role: termination of cyclic nucleotide second messenger signal, often cGMP • 11 PDE groups (PDE 1-11) • PDE-5 breaks down cGMP (the second messenger of Nitric Oxide—NO), reversing the musclerelaxant effect of NO • PDE-5 is found in corpus cavernosum, vascular and visceral muscles, and in platelets N.O. Release Increases Penile Bloodflow Lue,T. NEJM 2000. 342:1802 PDE-5 Terminates the Process and Slows Blood Flow Norepinephrine released Lue,T. NEJM 2000. 342:1802 Ejaculation and Orgasm Ejaculatory Anatomy Components of Ejaculation • Seminal emission: semen is delivered into the posterior urethra • Propulsion of semen from the posterior urethra outside, involving muscular contractions of the epididymus, vas deferens, seminal vesicles, and prostate • Simultaneous bladder neck closure • Orgasm is the sensation that accompanies ejaculation in the male (it is rare for one to occur without the other) Erection and Ejaculation Necessities • • • • • • • • Libido Intact neural pathway Adequate blood inflow Expandable penis Compressible veins Continued stimulation Prostate and seminal vesicles Competent bladder neck Erection and Ejaculation Necessities • • • • • • • • Libido Intact neural pathway Adequate blood inflow Expandable penis Compressible veins Continued stimulation Prostate and seminal vesicles Competent bladder neck It doesn’t take much for a man with testosterone to become aroused Male Hypogonadism (symptomatic low testosterone level) Hypothalamus GnRH Production and Regulation of Testosterone Pituitary Testosterone LH FSH Free T 2% Albuminbound T 38% SHBG-bound T 60% Testis 40% of serum testosterone is “bioavailable” Testosterone Sperm Adapted from Bagatell C.J., Bremner W.J.. N Engl J Med. 1996;334:707-715. Adapted from Braunstein G.D.. In: Basic & Clinical Endocrinology. 5th ed. Stamford, Conn: Appleton & Lange; 1997:403-433. Testosterone At Work Dihydrotestosterone (DHT) is the primary end-organ androgen Hypogonadism in the Aging Man • All components of testosterone decline with normal aging • Decline in Leydig cell count and function • Increase SHBG, lowers bioavailable T • Not all men with low testosterone have symptoms or need treatment Tenover J.L. Endocrinol Metab Clin North Am. 1998;27:969-987. Swerdoff, R.S. Summary of the Consensus Session from the 1st Annual Andropause Consensus Meeting. The Endocrine Society, April 2000. Age-Related Changes in Testosterone Testosterone (nmol/L) 20 (177) 18 (144) (151) 16 (109) 14 (43) (158) 12 10 30 40 50 60 Age (Years) Adapted from Harman S.M., et al. J Clin Endocrinol Metab. 2001;86:724-731. 70 80 90 Rates of Low T in Selected Conditions Prevalance of Low Testosterone 1 50% Hypertension Type 2 Diabetes Obesity 42% 40% Hyperlipidemia 52% Other Areas of Concern HIV/AIDS 30% of HIV-infected men and 50% of men with AIDS have low testosterone.2 Chronic Pain 74% of men consuming sustained-action oral opioids have low testosterone.3 1. Mulligan, et al. Int J Clin Pract 2006 Jul;60(7):762–769 2. Dobs A.S. Clin Endocrinol Metab 1998;12:379-370 3. Daniell HW. J Pain 2002 Oct;3(5):377-84 Potential Effects of Hypogonadism Long-term complications • Decline in libido and erectile function • Increased body fat mass • Decreased muscle mass, bone mass, and strength • Possibly: fatigue, mood / cognitive changes • Increased incidence of osteoporosis Tenover J.L.. Endocrinol Metab Clin North Am. 1998;27:969-987. Petak S.M., et al. AACE Clinical Practice Guidelines. Available at: http://www.aace.com/clin/guidelines/hypogonadism.html. Hormones and Osteoporosis Annual Fracture Incidence Donaldson L..F, et al. J Epidemiol Community Health. 1990;44:241-245. Testosterone and Sex • ED exclusively related to hypogonadism is rare (5%) • In hypogonadal men with ED, return to low level of normal testosterone range is adequate • Libido is most likely to improve with treatment • Spermatogenesis is greatly reduced with testosterone replacement, and may not be reversible with cessation Bhasis, S., Mayo Clin Proc 2000; 75: S70. Leungwattanakij, S., et al, Mediguide to Urology, 2000; 13:1. 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.. Endocrinol Metab Clin North Am. 1998;27:969-987. Braunstein G.D.. In: Basic & Clinical Endocrinology. 5th ed. Stamford, Conn: Appleton & Lange; 1997:403. Diagnostic Testosterone Testing: Additional Tests • LH and FSH • Serum Prolactin • Baseline PSA, Hematocrit Tenover J.L.. Endocrinol Metab Clin North Am. 1998;27:969-987. Risks of Testosterone Replacement Therapy (TRT) • Hepatic adverse effects with oral therapy • Polycythemia • Edema • Gynecomastia • Precipitation or worsening of sleep apnea • Infertility • Acceleration of BPH or Prostate Cancer Petak S.M., et al. AACE Clinical Practice Guidelines. Available at: http://www.aace.com/clin/guidelines/hypogonadism.html. S.Leungwattanakij, et al. Mediguide to Urology 2000; 13:1. Absolute Contraindications of TRT • Male breast cancer • Known or suspected prostate cancer • Hematocrit > 55% • Known or suspected sensitivity to ingredients used in testosterone therapy systems Petak S.M., et al. AACE Clinical Practice Guidelines. Available at: http://www.aace.com/clin/guidelines/hypogonadism.html. Cunningham, G.R. Summary of the Consensus Session from the 2nd Annual Andropause Consensus Meeting. The Endocrine Society, April 2001. Testosterone Delivery Systems • Oral and transmucosal tablets • Injectables • Transdermal patches • Transdermal gel Petak S.M., et al. AACE Clinical Practice Guidelines. Available at: http://www.aace.com/clin/guidelines/hypogonadism.html. Bals-Pratsch M./, et al. Acta Endocrinol (Copenh). 1988;118:7-13. Arver S., et al. J Urol. 1996;155:1604-1608. Oral Testosterone • Oral free- and methyl-testosterone: 98% first pass effect in liver; hepatotoxic • Transmucosal delivery (Striant): - twice a day - doesn’t fully dissolve Leungwattanakij, S. et al, Mediguide to Urology, 2000; 13:1. Injectable Delivery Systems • Testosterone enanthate and cipionate (t1/2 = 4.5 d) 200 mg injection dosed every 14 to 21 days 100 mg every week minimizes troughs • Testosterone proprionate (t1/2 = 0.8 d) must inject every 2-3 days Leungwattanakij, S. et al, Mediguide to Urology, 200; 13:1. Testosterone Enanthate 250 mg Administered IM Every 3 Weeks Behre HM, et al. In: Testosterone: Action, Deficiency, Substitution. Berlin, Germany: Springer-Verlag; 1998:329-348. Transdermal Patches • Androderm 5 mg/d, applied to back, abdomen, etc High rate of skin irritation Leungwattanakij, S. et al, Mediguide to Urology, 200; 13:1. AndroGel® and Testim™ • Most physiologic application method • Testosterone gel 1% Recommended starting dose: 5 g / day to deliver 5 mg testosterone Can be titrated up to 10 g per day Wait 5-6 hrs after dosing to swim/shower Avoid partner contact with area Wang C, et al. J Clin Endocrinol Metab. 2000;85:2839-2853. AndroGel vs. Androderm Mean Steady-state Concentrations 24-Hour Concentrations on Day 90 of Therapy Upper limit of Normal Range T Gel 1% 5 g T Gel 1% 10 g T Patch 5 mg Lower limit of Normal Range Wang C, et al. J Clin Endocrinol Metab. 2000;85:2839-2853. TRT Efficacy and Cost • Efficacy: Gel = Patch > Shots • Side Effects: Shots > Patch > Gel • Cost: Gel > Patch > Shots • Testosterone enanthate Androderm 5gm AndroGel 5gm Testim 50mg Harmon’s Pharmacy 8/07 $21/mo $178/mo $197/mo $181/mo Evaluation of ED: Tests • • • • • • AM Testosterone, if low libido Glucose (fasting or at least dipstick) Thyroid tests Fasting lipid profile Total PSA if age-appropriate Others, selectively: - Nocturnal tumescence testing - Penile doppler studies How Strenuous is Sex? Sexual Activity Requires the Same Effort as Gardening Estimated METs Description 2 Sitting Physical Activities Reading, watching TV 3 Very light exertion Moderate sexual activity with longterm partner, office work, strolling in park 4-5 Moderate exertion Vigorous sexual activity, normal walking, golfing on foot, gardening 5-6 Vigorous to heavy exertion Running, racquetball, fast biking, heavy snow-shoveling METs = metabolic equivalents of oxygen consumption Adapted from DeBusk et al. Am J Cardiol. 2000;86:175-181. Patient Preferences for ED Treatment Options 100 Oral therapies are the preferred treatment option by patients with ED Percent 80 60 40 20 0 Oral Intraurethral therapy Braun et al. Int J Imp Res. 2000;12:305. Injection therapy Vacuum Surgery Prosthesis Mechanism of Action of PDE5 Inhibitors Lue, T NEJM 2000. 342:1802 PDE5 Inhibitors: Pharmacokinetics T1/2, h Tmax, h* Metabolism 1Klotz Tadalafil (Cialis) Vardenafil (Levitra) 20mg 17.5 20mg 4.6 Sildenafil (Viagra) 100mg 3.7 2.0 (0.5-12) 0.8 (0.3-2.0) 1 (0.5-2) CYP3A4 CYP3A4 CYP3A5 CYP2C9 CYP3A4 CYP2C9 et al. ACCP. 2002;2 As reported in Kim et al. Formulary. 2002;37. *Median (range). My Take on PDE-5 Inhibitors • • • • • All three are excellent drugs for ED All work best with practice All work least well in post-prostatectomy patients Can’t use ANY with nitrates Some patients prefer “spontaneity” of tadalafil Patient Preferences for ED Treatment Options 100 Oral therapies are the preferred treatment option by patients with ED Percent 80 60 …but 100,000 men fail oral ED therapy PER MONTH! 40 20 0 Oral Intraurethral therapy Braun et al. Int J Imp Res. 2000;12:305. Injection therapy Vacuum Surgery Prosthesis Vacuum Devices MUSE (Medicated Urethral System for Erection) Intracavernosal Injections Penile Prosthesis Surgery • 1936: human rib cartilage inserted into corpora • Silicone prostheses implanted successfully since 1973: - 29,000 in 1991 - 8,000 in 1998 - 17,000 in 2001 - 23,000 in 2009 - 90,000 breasts; 600,000 hips/knees - penile prostheses have lower infection and revision rates than breast and orthopedic implants - well-controlled diabetics do well, no higher infection rate • An EXCELLENT option Hinged Penile Prosthesis Inflatable Penile Prosthesis AMS 700 Penile Prosthesis with InhibiZone™ • InhibiZone™ is the first FDA approved permanent implant with an antibiotic surface treatment • InhibiZone™ is a combination of rifampin and minocycline HCl impregnated into the outer silicone surface of the device Coloplast Titan • Girth enhancement vs AMS • Hydrophilic coating which absorbs antibiotic fluid (R10/G1) Step-Care Approach to ED Management Therapeutic Options Second-Line Therapy Vacuum constriction device Intracavernosal injection or Transurethral therapy First-Line Therapy Third-Line Therapy Lifestyle / drug therapy modification Penile Prosthesis Psychosocial counseling Androgen replacement therapy Oral therapy Recommendations of the 1st International Consultation on Erectile Dysfunction. In: Erectile Dysfunction; Jardin A, et al, eds. Plymouth, UK: Health Publication Ltd; 2000:725 Its never so “broke” that a Urologist can’t fix it Ejaculatory Dysfunction • Anejaculation • Retrograde Ejaculation • Premature (Rapid) Ejaculation Anejaculation • Different than “anorgasmia” (usually psychogenic) • Medical Causes: – Anatomical/Surgical: Obstruction of the ejaculatory duct; Radical Prostatectomy (for cancer) – Neurogenic (“sympathectomy”): severe lumbar disk disease or surgery; retroperitoneal lymph node dissection for testis cancer; spinal cord injury – Medications: certain alpha-blockers for benign prostatic hyperplasia (BPH)—e.g., tamsulosin (Flomax®); SSRIs – Inflammatory: prostatitis can inhibit ejaculatory function Retrograde Ejaculation • Medical Causes: – Anatomical/Surgical: TURP (resection of the bladder neck) – Medications: certain alpha-blockers for benign prostatic hyperplasia (BPH)—e.g., tamsulosin (Flomax®) Premature Ejaculation • Ejaculation which occurs within 15 seconds of beginning of intercourse (ICD-10) • Ejaculation occurs with minimal sexual stimulation before, on, or shortly after penetration…before the person wishes (DSM-IV) • Recent reviews place prevalence between 22-38% • Etiology: psychogenic (anxiety, frequency, conflicts, etc), pelvic nerve damage, prostatitis, withdrawl from narcotics, possibly genetic, penile hypersensitivity… Premature Ejaculation Treatment • Psychological: - Squeeze technique (Masters and Johnson) - Sensate focus - “Quiet vagina” • Self Help: multiple condoms, desensitizing creams, distraction, etc • Pharmacologic treatment - MAO-inhibitors - Tricyclic antidepressants - SSRIs (especially sertraline and clomipramine) Dapoxetine for Premature Ejaculation • Oral tablet (Alza; Johnson & Johnson) in Ph III trials • Inhibits seratonin reuptake at multiple levels • Rapid onset of action, quickly eliminated: prn use and fewer side effects (rare nausea, nervousness) ED and EjD: Summary • ED is very common, particularly in diabetics, and fairly easy to evaluate • Many (not all) patients respond to PDE-5 inhibitors; urologists can help the rest • Anejaculation is rare but may be treatable • Retrograde ejaculation is almost never treatable • Options for premature ejaculation are improving Questions? 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