Peter J. Burrows MD FACS
Transcript of Peter J. Burrows MD FACS
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Testosterone Supplementation, Prostate Cancer Screening and Vitamins
Peter J. Burrows MD FACS
Clinical Assistant Professor of UrologyUniversity of Arizona, College of Medicine
Adjunct Assistant Professor of UrologyUSC Department of Urology, USC/Keck School of Medicine
International Center for Vasectomy ReversalArizona Center for Vasectomy and Urology
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Testosterone
Key information on Testosterone and it’s impact on Men’s Health
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SkinHair growth, balding, sebum production
LiverSynthesis of serum proteins
Male sexual organsPenile growth, spermatogenesis, prostate growth and function
BrainLibido, mood
MuscleIncrease in strength and volume
KidneyStimulation of erythropoietin production
Bone marrowStimulation of stem cells
BoneAccelerated linear growth, closure of epiphyses
Morley JE, et al. Morley JE, et al. MetabMetab 2000;49:12392000;49:1239--1242.1242.AACE Hypogonadism Task Force AACE Hypogonadism Task Force Endocrinol PractEndocrinol Pract 2002;8:4392002;8:439--456456
Testosterone’s impact on the Male Body
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Age related Changes in Testo
• Total and Free T decline with age• By 75 ys, T (total) is 2/3 T at age 20 and Free T
drops by 40%• Circadian rhythms of T drop as age• DHT and Estradiol levels remain the same with
age.
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ANDROGENS AND BODY COMPOSITION
•Androgen replacement in hypogonadal men leads to:– Decreased % body fat – Increased lean body mass– Reduced bone remodeling– Increased trabecular bone density
Bhasin et al., Issues in Testosterone Replacement in Older Men, J. Clin Endocrin. Metab., 1998.
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The prevalence of Low Testosterone increases with age (<300 ng/dL)
45 to 54 55 to 64 65 to 74 75 to 84 85+ Total0
10
20
30
40
50
60
70
38.7(36.6–40.7)
50.0(32.7–67.3)
45.5 (39.0–52.1)39.9
(35.4–44.4)40.2
36.6–43.8)34.0
(30.6–37.4)
Patient Age Range
Prev
alen
ce o
f Low
T in
All
Enro
lled
Patie
nts
(%, 9
5%C
I)
Mulligan, et al. Int J Clin Pract. 2006 Jul;60(7):762–769.
The relative risk was greater with each 10-year increase in age.
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UNITED STATES AGE DEMOGRAPHICS
# m
en >
65
year
s old
(m
illio
ns)
1900 2000 2030
3
30
70
Year
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LONGITUDINAL CHANGES IN SERUM TESTOSTERONE LEVELS IN 4 AGE COHORTS
Adapted from Morley JE et al, Metabolism 46:410, 1997.
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Male Brain
Benefits and Risks of TRT
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EFFECTS OF AGING ON THE MALE
• Decline in testosterone production1
–Decreased testosterone levels• Long-term complications due to low
testosterone levels1
– Increased body fat mass–Decreased muscle mass –Decreased bone mass– Increased incidence of osteoporosis–Decline in libido, erectile function
1. Tenover JL. Endocrinol Metab Clin North Am. 1998;27:969-987.
NOT FOR DISTRIBUTION. Amory, et al. Amory, et al. J Clin Endocrinol MetabJ Clin Endocrinol Metab 2004; 89: 5032004; 89: 503--510510
BMD
(% C
hang
e)
Study Month
Placebo
T+F
T only
0
141210
-2
8642
-40 10 20 30 40
Mean +/- SEM
* Testosterone (T) and finasteride (F)
Other Effects of TRT: Changes inBone Mineral Density
Changes in Lumbar Spine Bone Mineral Density
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VIAGRA® AND TESTOSTERONE DEFICIENCY
• Viagra is not a treatment for testosterone deficiency
• Viagra does not improve libido
• Testosterone deficiency should be treated before Viagra is prescribed
• Viagra and testosterone replacement may have beneficial effects in men who have testosterone deficiency and vascular disease
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PATHOPHYSIOLOGY OF ERECTILE DYSFUNCTION
• Insufficient arterial flow• Venous leakage• Neurologic damage (autonomic, sensory)• Testosterone deficiency• Medications• Psychogenic (depression, anxiety)
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Management of ED:Lifestyle Modification
• Stop smoking1,2
• Limit or avoid alcohol1
• Follow healthy diet2
• Exercise regularly3
1. 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. 2. Feldman HA et al. Prev Med. 2000;30:328-338. 3. Derby CA et al. Urology. 2000;56:302-306.
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IDENTIFICATION AND DIAGNOSIS OF LOW T
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SYMPTOMS/CONSEQUENCES OF TESTOSTERONE DEFICIENCY
• Adolescent (prepubertal)– Nonvirilization, decreased bone density, eunuchoidal proportions,
psychosocial problems• Adult (postpubertal)– Decreased libido, fatigue, erectile dysfunction, depressed mood, hot
flashes• Aging men– Decreased strength/muscle mass/body hair, osteoporosis, increased
abdominal fat• Miscellaneous– Autoimmune problems, mild anemia
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Conditions in which Low T is significantly more likely to occur
Odds Ratio (95% CI)Condition
1.29 (1.03–1.62)Prostatic disease/disorder1.40 (1.04–1.86)Asthma/COPD1.47 (1.23–1.76)Hyperlipidemia1.84 (1.53–2.22)Hypertension2.08 (1.70–2.58)Diabetes2.38 (1.93–2.93)Obesity
Mulligan, et al. Mulligan, et al. Int J Clin PractInt J Clin Pract 2006 Jul;60(7):7622006 Jul;60(7):762––769.769.
A prospective analysis of 2162 men over 45 years of age demonstrated that men with these conditions were significantly more likely to have testosterone levels below 300 ng/dL than in men without these conditions
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Prevalence of Low Testosterone in Other Conditions
74
52 50 50
42 40
19
0
10
20
30
40
50
60
70
80
(%)
Ob
esi
ty
Dia
bete
s
Hyp
ert
en
sio
n
Hyp
erl
ipid
em
ia
Ch
ron
ic O
pio
idU
se
AID
S
Other ConditionsHIV = 30%.ED = erectile dysfunction.Bodie J, et al. J Urol. 2003;169:2262–2264; Daniell HW. J Pain. 2002;3:377-384; Dobs AS. Baillière’s ClinEndocrinol Metab. 1998;12:379-390; Grinspoon S, et al. Ann Intern Med. 1998;129:18-26; Mulligan T, et al. Int J Clin Pract. 2006;60:762–769.
ED
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Percentage rates of Low Testosterone in selected conditions
Prevalance of Low Testosterone 1
52% 50%42% 40%
Other Areas of Concern
HIV/AIDS30% of HIV-infected men and 50% of men with AIDS may have low testosterone.2
Chronic Pain74% of men consuming sustained-action oral opioids may have low testosterone.3
1. 1. Mulligan, et al. Mulligan, et al. IntInt J J ClinClin PractPract 2006 Jul;60(7):7622006 Jul;60(7):762––7697692. Dobs A.S. 2. Dobs A.S. Clin Endocrinol MetabClin Endocrinol Metab 1998;12:3791998;12:379--370370
3. Daniell HW. 3. Daniell HW. J PainJ Pain 2002 Oct;3(5):3772002 Oct;3(5):377--8484
Obe
sity
Dia
bete
s
Hyp
erte
nsio
n
Hyp
erlip
idem
ia
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Mechanism of drug-induced hypogonadism1-3
Increase prolactinPhenothiazines, H2 blockers
Inhibits gonadal steroid production
Cyclophosphamide
Inhibits gonadal steroid production
Ketoconazole
Reduce gonadotropic secretionGlucorticoids and anabolic steroids
Inhibit gonadotropin-releasing hormone
Opiate compounds
11 Glass, Glass, J J ClinClin EndocrinolEndocrinol MetabMetab.. 1986;63:11211986;63:1121--5522 GrinspoonGrinspoon. . ClinClin EndocrinolEndocrinol MetabMetab 1994;79:9231994;79:923--3131
33 HofbauerHofbauer. . Medicine Medicine 1996;75:2621996;75:262--7878
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Low Testosterone and Body Composition
Associated with• Increase in body fat• Decrease in lean
body mass (muscle)• Decrease in bone
mineral density (BMD)
Hijazi RA, et al. Annu Rev Med. 2005;56:117-137; Szulc P, et al. Am J Clin Nutr. 2004;80:496-503.
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Testosterone and Metabolic Syndrome Connection
• Metabolic Syndrome defined as: 1. Insulin resistance2. HTN3. Dyslipidemia4. Central Obesity
Leads to endothelial dysfunction and Oxidative stress.
Obesity is likely the common link. Adipose cells produce Leptin, which decreases T
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Low T levels may predict future onset of Type II Diabetes or Metabolic Syndrome
Low total testosterone and low serum SHBG are associated with increased risk of developing MetS over time, particularly non-overweight, middle-aged men (BMI<25)
40 –70
1709Kupelian, et al J Clin Endocrinol Metab2006: 98(13):843-850
Levels of testosterone and SHBG were inversely associated with metabolic syndrome and insulin resistance
Each unit increase (1 SD or 5.3 nmol/L) in total testosterone level reduced the risk of metabolic syndrome by 57%
40 –80
400Muller, et alJ Clin Endocrinol Metab2005: 90(5):2618-2623
Men with low testosterone were significantly more likely to develop either metabolic syndrome or diabetes
Among men monitored for 11 years, those in the lowest testosterone quartile had a 2.3-fold higher risk of both outcomes
42 –60
702Laaksonen, et alDiabetes Care2004: 27(5): 1036-1041
Results/ConclusionsAgeNAuthor / Publication
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Testosterone and Mortality
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VA database 2006
• Subject Group: 858 veterans older than 40 years with repeated T levels obtained from October 1, 1994 to December 31, 1999 and without diagnosed prostate cancer
• Low testosterone level = total testosterone less than 250 ng/dLor a free T level of less than 0.75 ng/dL
– Low: 166 (19.3%)– Equivocal*: 240 (28.0%)– Normal: 452 (45.7%)
* Equivocal levels indicated equal number of low and normal levels
Shores M., et al. Shores M., et al. Arch Intern Med.Arch Intern Med. 2006; 166: 16602006; 166: 1660--1665.1665.
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Study Results
Shores M., et al. Shores M., et al. Arch Intern Med.Arch Intern Med. 2006; 166: 16602006; 166: 1660--1665.1665.
34.9%
24.6%
20.1%
Mortality 95% CITestosterone Level
28.5-41.4%Low
19.2-30.0%Equivocal
16.2 -24.1%Normal
After adjusting for age, medical morbidity and other clinical covariates, low testosterone levels continued to be associated with increased mortality.
Hazard Ratio: 1.8895% CI: 1.34-2.63P < 0.001
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Testo less than 200ng/dl associated with serious health risks (2005 Mass Aging Study)
• Over 17 years of T less than 200 vs men with T above 400– 2x risk of death– 3x risk of cancer death– 2x risk of CV death
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• Why are men with these comorbid conditions NOT being screened and diagnosed for low T?
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TESTOSTERONE SCREENING CONSIDERATIONS
• Mass screening for hypogonadism with serum testosterone is costly
• Screen only if considering replacement
• Swerdloff RS et al: Summary of the Consensus Session from the 1st Annual Andropause Consensus 2000 Meeting. The Endocrine Society, April 2000.
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Measuring Testosterone
• Morning lab draw.
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What Is Considered a Low Serum T-Level?
• Total Testosterone <300 ng/dL*
• FT <50 pg/mL
• Bioavailable Testosterone <70 ng/dL
*Most frequently used lab test for the diagnosis of hypogonadism.
AACE Hypogonadism Task Force. Endocrinol Pract. 2002;8:439-456; Bhasin S, et al. J Clin EndocrinolMetab. 1997;82:3-8.
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What labs are relevant
• Total T= SHBG T +AlbuminT +free T• ½ T bound to SHBG- this T is functionally unaval.• Free T = Albumin bound T and unbound T• Older men have more SHBG, thus less Free T• No true threshold of “hypogonadal” cutoff• Guidelines that if Total <300 = hypogonadal or
Total > 400 is not hypogonadal. Rest is up for interpretation and trial
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Contraindications for TRT
Androgens are contraindicated in men with known or suspected carcinoma of the prostate or carcinoma of the breast.
Androgens are “not indicated” for use in women
Obstructive Sleep Anpea
Optimal spermatogenesis
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Known Adverse Effects of TRT and Dogma
KNOWNErythorcytosis
More common with IM administration (44% vs 5% of transdermal preparations)
Gynecomastia (T E)BPH- 15% increase in prostate volume but minimal change on AUA
Sx score
DOGMA:Lipids- no adverse effects!Liver- not with IM or dermal Cardiac- Protective!
Better angina free exercise when replacedInjection of T into coronaries- dilation and improved blood flow
Endocrine Society Guidelines. Endocrine Society Guidelines. July 2006July 2006
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Prostate volume and male hormones
• No significant differences in prostate events betw T replacement and placebo
• Typically no change in AUA Sx score while on T replacement
• Men with severe AUA Sx scores (>21) should avoid any additional prostate growth
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PSA on TRT
• Normal rise of PSA on TRT= 0.2 while T increased from 265 566
• Small prostate volumes had greater relative rise of PSA vs larger glands
• Younger men had greater PSA increase than older men
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Monitoring Men while on Testosterone Replacement
• Maximal PSA elevation is achieved at T at the lower end of normal
• Higher doses of T should not increase PSA after initial elevation
• Therefore, increase of PSA more than 1.0, regardless of starting point is concerning
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Low Testo is a risk factor for prostate cancer
• Men with severely reduced testosterone levels had a significantly higher prostate cancer rate of 20%.
1. 1. MorgentalerMorgentaler A, et al. A, et al. JAMA. JAMA. 1996;276:19041996;276:1904--1906.1906.2. Rhoden EL, 2. Rhoden EL, MorgentalerMorgentaler A. A. J J UrolUrol.. 2003;169:S119.2003;169:S119.
3. Thompson IM, et al. 3. Thompson IM, et al. N N EnglEngl J Med.J Med. 2004;350(22):22392004;350(22):2239--2246.2246.
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TRT and prostate cancer
• TRT in men with PIN did not have increased development of PCA
• Maximal prostatic saturation of T reached within the prostate at low levels of T
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Post-prostatectomy and TRT (Baylor 2007)
• Qualifications: Negative surgical margins. PSA undetectable
• None (N=21) had PSA increase from undetectable over 5 ys when receiving Testoreplacement
TREATMENT OPTIONS
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OBJECTIVES OF TESTOSTERONE REPLACEMENT THERAPY IN MEN
• Provide physiological amounts of testosterone on a daily, consistent basis
• Restore serum levels of testosterone and active metabolites, DHT and E2, to normal physiologic ranges
• Be safe and well tolerated by patient and partner
• Be comfortable to administer and convenient to use
TESTOSTERONE REPLACEMENT:CURRENT THERAPIES
• Oral: 3 - 4 times daily• IM injection: every 1-2 weeks• Patch: once daily• Absorbable Gels: once daily• Bucal: Twice daily
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CURRENT TREATMENT OPTIONS (LISTED IN CHRONOLOGICAL ORDER)
• Intramuscular depot testosterone esters (enanthate and cypionate)
• Orally active testosterone derivatives (alkylated and esterifiedcompounds*)
• Testosterone patch (Androderm®)
• Transdermal testosterone gel (AndroGel®, Tetsim®)
• Buccal pellet (Striant®)
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IM TESTOSTERONE
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Patch or Gel InjectionNormal Range
Adapted from Bhasin S, et al. J Clin Endocrinol Metab. 1997;82:3-8; Testosterone gel (AndroGel 1%) Unimed Pharmaceuticals and Solvay Pharmaceuticals, 2007.
Time (d)
0
200
400
600
800
1000
1200
1400
0 3 5 7 12 17 21 30 34
T n
g/d
L No
rmal
ran
ge
Testosterone Levels After Replacement With Gel, Patch, or Injection
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INTRAMUSCULAR INJECTION OF TESTOSTERONE ESTERS
• Supraphysiological levels of T, BT , DHT and E2
• “Roller-coaster” effects on libido, energy, and mood
• Gynecomastia common
• Abnormal elevations in hematocritare common
• No diurnal cycle*
• Painful administration
• Large clinical experience
• Infrequent administration
• Not visible to others
• Low cost
Positives Negatives
*Clinical significance of diurnal cycle is unknown
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ORALLY ACTIVE TESTOSTERONE DERIVATIVES(ALKYLATED AND ESTERIFIED*)
• Alkylated (eg, methyl T)• Potentially hepatotoxic
• Markedly lowers HDL
• Not metabolized to T
• Esterified* (eg, undecanoate)• Low bioavailability, T levels
• TID, QID dosing
• No diurnal cycle†
• Oral administration
• Not visible to others
*Not approved in US
Positives Negatives
NOT FOR DISTRIBUTION. Marbury et al.Marbury et al. Biopharm Drug Dispos Biopharm Drug Dispos 2003;24:1152003;24:115--120 120
Uniquely formulatedOnly 3 common ingredients with
AndroGel.
Not bioequivalentThe FDA has classified TESTIM as
not bioequivalent with AndroGel.
In the only head to head PK study, Testim patients demonstrated 47% higher free testosterone and 30% higher total testosterone
Non-substitutableTESTIM cannot be substituted without physician approval.
Testim® and AndroGel®:Key Points of Differentiation
AndroGelTestim
XSodium Chloride
XIsopropyl Myristate
XCarbomer 940
XXTestosterone
XXPurified Water
XXAlcohol
XTromethamine
XPropylene glycol
XPolyethylene glycol
XPentadecalactone
XGlycerin
XCarbopol
XAcrylates
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Recommendations for Monitoring Older Men During Testosterone Replacement
• Baseline Evaluation• Follow-up at 3, 6, 12 mo and then annually– DRE– PSA, Testo, CBC– AUA Sx score
Bhasin et al. 2003
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Indications for Urologic Evaluation
• PSA >4.0• Increase of PSA >1.0 after 3 or 6 months of T
therapy• PSA velocity >.4ng/ml/yr after 6 months of T
therapy• Change of DRE• AUA Sx score >21
Bhasin et al. 2003
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Prostate Cancer
• Screening• Prevention• Treatment options
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Prostate Cancer Screening in Men Over 75
• Recent recommendation to stop screening at age 75– Cancers found at this age are insignificant! – Testing/biopsy and treatment more harmful than ignoring
cancer
Maybe reasonable if mens’ life expectancy remained that is was 40 ys ago (life expectancy = 72)
Just an ignorant, “cost saving” ill-advised RETRACTED
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Prostate Cancer Screening
• 244,000 new cases a year with 38,000 deaths a year
• Death rate down 25% since mass screening with PSA in 1980’s
• PSA blood test– Raw numbers less important than rate of change.
PSA velocity is the most important– So what does a PSA more than 4.0 mean?
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PSA Screening
• Screening began 1986• High PSA still best predictor for cancer• PSA detects cancer 5-10 ys before exam• Most cancer found by PSA is curable• Regular PSA tests eliminates dying of advanced
prostate cancer.
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Prostate Cancer Screening
1in 4 men found to have cancer with elevated PSA (25%)PSA not specific for prostate cancer and predicts benign
growth more accuratelyDNA markers are the next wave:
EPCA-2. Blood test. Not yet avaliable.PCA-3:
Urine marker. 55% predictive if (+)78% negative if (-)
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Prostate Cancer Prevention
• Prostate Cancer Rate not the same between races in USA– White: 101 per 100,000– Black: 137 per 100,00– Asian: 40 per 100,000
Cancer rates are different from nation to nation and from region to region within this nation
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Dietary Fat and Prostate Cancer
• American diet: 30-40% fat– Associated with lower intake of fruits and vegies,
no soy, little fish• Japanese diet: 15% fat– Higher Omega-3 fats (anti-inflammatory)
Soy products, fish NOT meat
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Fruits and Vegetables
• 28 servings of veg/wk 35% reduction of prostate cancer
• Soy products:– Increase estradiol: testo
• Lycopene: effective antioxidant• Best source: Cruciferous vegetables:– Broccoli, cabbage– Men who ate 3 or more servings of crucif veg has
41% reduction of prostate cancer
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Vitamins and Prostate Cancer
• Calcium– High calcium INCREASED prostate cancer 2x– Rec no more than 500mg/day
• Vitamin D (sunlight)– Protective
15 min a day without sunscreen400 IU/day vit D
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Exercise and obesity
• For men over 65 ys: 70% reductive effect with vigorous exercise
• Diet with more than 2400Kcal/day 4x risk of prostate cancer
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SUMMARY: TESTOSTERONE DEFICIENCY
• Testosterone deficiency may affect as many as 8 million men in the US of all ages
• Testosterone deficiency is observed in men with diabetes, HIV infection, renal failure, cancer and obesity
• Erectile dysfunction may be a symptom of testosterone deficiency
• Viagra® is not a treatment for testosterone deficiency
• A variety of modalities for treating testosterone deficiency are currently available in the US
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CONCLUSIONS
• Testosterone replacement therapy can increase hormone levels to normal ranges and improve these symptoms
• Transdermal formulations provide testosterone at more natural levels and rhythms compared with oral and intramuscular formulations
• Careful follow-up of PSA levels and hematocrit is an important component of testosterone replacement
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ANDROGEN REPLACEMENT: Conclusions: Gestalt
• Replacement has wide benefits for men with TDS– Improved: Mood, behavior, muscle mass, fat distribution,
bone density, cardiovascular risk, sexual response.
Testim has 30% better absorption than other topical options and can salvage “non-responders”
15% of men will not absorb either gel due to skin enzymatic breakdown and will require IM shots.
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Female Brain
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THANK YOU!
Peter Burrows, MDE-mail: [email protected]: 520-731-0600
www.dadsagain.comwww.vasectomytucson.com
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Which condition(s) has been assocaited with Low testosterone?
• A) Obesity
• B) Elevated Cholesterol
• C) Diabetes
• D) Chronic Pain
• E) All of the above
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What is the main difference between the American diet and Japanese
• A) Greater calories
• B) More carbohydrate calories
• C) Greater Fat calories
• D) More Alcohol