Transcript Document

ED, EjD, and Hypogonadism
in Diabetic Males
Steven N. Gange, MD, FACS
4252 S. Highland Drive
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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.
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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
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Libido
Intact neural pathway
Adequate blood inflow
Expandable penis
Compressible veins
Continued stimulation
Prostate and seminal vesicles
Competent bladder neck
Erection and Ejaculation Necessities
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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.
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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
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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
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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
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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?
[email protected]