Download The Truth About Low Testosterone

The “Truth” About Low Testosterone
To treat or Not to Treat???
C. W. Spellman, DO, PhD
Professor Medicine & Dir MCH Diabetes Center
Department Internal Medicine, Div. Endocrinology
Texas Tech University Health Science Center
Odessa, Texas
Hypogonadism or Life Style?
“Low T:” Causes of Hypogonadism
Klinefelter syndrome
Kallmann syndrome
Infiltrative diseases
Pituitary disorder
Autoimmune syndromes
Radiation
Tumors, head trauma
Defects in androgen
synthesis or action
Cryptorchidism
Testicular trauma
Aging
Obesity
Type 2 Diabetes
Medications:
Opioids
Glucocorticoids
Ketoconazoles
Petak SM, et al, 2002 update. Endocr Pract. 2002;8(6):440-456
Seftel A. et al, Int J Impot Res. 2006;18(3):223-228
Conditions Associated with Hypogonadism
HIV-associated wasting
End-stage renal disease
COPD
Infertility
Osteoporosis
Anemia
Coronary artery disease
Prostate cancer
1. Orwoll E, et al. Arch Intern Med 2006;166:2124–2131
2. Amin S, et al. Am J Med 2006;119:426–433
3. Ferrucci L, Maggio M, Arch Intern Med 2006;166:1380–1388
4. Ding EL, Song Y, JAMA 2006;295:1288–1299
5. Shores MM, et al. Arch Gen Psychiatry 2004; 61:162–167
6. Moffat SD, Zonderman AB, J Clin Endocrinol Metab 2002;87:5001–5007
7. Hak AE, Witteman JC, J Clin Endocrinol Metab 2002;87:3632–3639
8. Bhasin et al. J Clin Endocrinol Metab 2006;91:1995-2010
Symptoms of Low Testosterone

Decreased energy or vitality, increased fatigue

Reduced libido and sexual activity

Erectile dysfunction

Reduced muscle mass and strength

Increased Fat mass

Low bone mass

Depression
Bhasin S, et al. J Clin Endocrinol Metab. 2006;91(6):1995-2010
Observations
Prevalence of hypogonadism in men ≥45 yr is
estimated at 12-38%1,2
Hypogonadism increases with3
Age
Obesity
Diabetes
1Mulligan
T, et al. Intl J Clin Practice. Jul 2006;60(7):762-769.
SM, et al. J clin endocrinol metab. Feb 2001;86(2):724-731.
3Dhindsa S, et al. Diabetes care. Jun 2010;33(6):1186-1192.
2Harman
Observations
Testosterone replacement decreases1-5
TC:HDL ratio
Weight
Waist circumference
Insulin levels
Insulin resistance
CRP
1Baillargeon
J, et al. Ann pharmacotherapy. Jul 2 2014;48(9):1138-1144.
2Jones TH, et al. Diabetes care. Apr 2011;34(4):828-837.
3Kalinchenko SY, et al. Clin Endocrinolo. Nov 2010;73(5):602-612.
4Svartberg J, et al. J Int. Med. Jun 2006;259(6):576-582.
5Aversa A, et al. J Sex. Med Oct 2010;7(10):3495-3503.
Background…..
Over the last 10 years there has been a great increase
In the number of men treated with testosterone for
hypogonadism
Rx have increased 500% s/p TV ads about “Low-T”
So, now the FDA issues warnings about testosterone
therapy…What’s the data?
Is it safe?
Who should be treated?
Goal: Review the studies on testosterone replacement
therapy and cardiovascular outcomes
Setting the Stage for the Current FDA
Recommendations
“Testosterone in Older Men with Mobility Limitations”
was a randomized control study1
Qu: Will testosterone therapy improve leg strength in
elderly, frail men with hypogonadism and multiple
comorbidities (diabetes, obesity, HTN, lipids)
Enrollment never completed because there was a
suspicion of increased adverse cardiovascular “like”
events in the testosterone-treated group
Basaria, S., et al. N Engl J Med 2010;363:109-122.
Setting the Stage for the Current FDA
Recommendations
Examination 55,593 insurance claims by Finkle et al.1
Qu: What is the incidence of MI at 90 days after the
initial Rx for testosterone?
Results: Increased risk non-fatal MI men <65 with
preexisting heart disease
Problems:
No control group
No data on testosterone levels pre- or post Rx
No data on cardiac risk factors in treated men
3 months is inadequate for a cardiovascular study
1Finkle
WD, et al. 2014. PLoS ONE 9(1): e85805. DOI:10.1371/journal.pone.0085805
Longitudinal Observations
There are no randomized control trials that address
the question:
Does testosterone replacement therapy
change cardiovascular outcomes?
However, there are many studies reporting the
association of hypogonadism with increased cardiovascular events1-7
1Mulligan
T, et al. Intl J Clin Practice. Jul 2006;60(7):762-769.
SM, et al. J clin endocrinol metab. Feb 2001;86(2):724-731.
3Dhindsa S, et al. Diabetes care. Jun 2010;33(6):1186-1192.
4Laughlin GA, et al. J Clin Endocrinol Metabol Jan 2008;93(1):68-75.
5Tivesten A, et al. J Clin Endocrinol Metab Jul 2009;94(7):2482-2488.
6Yeap BB, et al. J Clin Endocrinol Metab . Jul 2009;94(7):2353-2359.
7Malkin CJ, et Heart. Nov 2010;96(22):1821-1825.
2Harman
Association of Low Testosterone with
Cardiovascular Events &/or All-Cause Mortality
Author
Sample
Age
Duration
size
(average)
yrs
T level
(ng/dL)
HR death or
Risk death
Laughlin1
794
50-90
(74)
20
240
1.4
Tivesten2
3014
(75)
4.5
25%’ile
65% †
Yeap3
3443
>70
3.5
25%’ile
1.99
Haring4
1954
20-79
7.5
<250
2.3
1Laughlin
GA, et al. J Clin Endocrinol Metab. Jan 2008;93(1):68-75.
2Tivesten A, et al. J Clin Endocrinol Metab. Jul 2009;94(7):2482-2488.
3Yeap BB, et al. J Clin Endocrinol Metab. Jul 2009;94(7):2353-2359.
4Haring R, et al. Euro Heart Journ. Jun 2010;31(12):1494-1501.
Association of Low Testosterone and Mortality
In Men with Heart disease and/or Diabetes
Author
Sample size
Ponikowska1
153
65 +/-9
Malkin2
930
61 +/-9
T level
(ng/dL)
HR death or
Risk death
2
240
140% †
6.9
<230
127% C
Age
Duration
(average)
yrs
Araujo3
16,181
61 yrs
Meta-analysis, (all cause †) 11 studies
average 300-600 Increasing †
9.7
as T declines
Araujo3
Meta-analysis,
11,831
(CV †)
average 300-600 Increasing †
9.7
as T declines
Corona4
70 meta
analyses
1Ponikowska
61 yrs
7 studies
Increasing †
as T declines
B, et al. Intl J Cardiol. Sep 3 2010;143(3):343-348.
CJ, et al. Heart. Nov 2010;96(22):1821-1825.
3Araujo AB, et al. J Clin Endocriol Metab Oct 2011;96(10):3007-3019.
4Corona G, et al. Eur J Endocrinol /Eur Fed of Endo Soc. Nov 2011;165(5):687-701.
2Malkin
Low Testosterone and Artherosclerosis
Low testosterone is associated with increased
atherosclerosis elderly men1
Low free testosterone is associated with increased
carotid intimal-medial thickness2
Low total testosterone is associated with increased
with age-adjusted carotid intimal-medial thickness3
1Hak
AE, et al (Rotterdam Study Group) J Clin Endocrinol Metab Aug 2002;87(8):3632-3639.
2Fukui M, et al. Diabetes care. Jun 2003;26(6):1869-1873.
3Farias JM et al. J Clin Endocrinol Metab 2014 Dec;99(12):4698-4703
Randomized Trials of Testosterone Therapy
No difference in cardiovascular events was reported in
two small randomized control studies on testosterone
Therapy (topical gel or intramuscular injection) to
increase muscle strength and body composition1-4
Note: These studies addressed the effects of
replacement therapy on muscle strength and
body composition
These studies were not powered to determine if
testosterone causes adverse cardiovascular
outcomes
1Srinivas-Shankar,
U., et al. J Clin Endocrinol Metab 2010;95:639-650.
2Snyder, P.J., et al. J Clin Endocrinol Metab 1999;84:2647-2653.
3Jones TH, et al. Diabetes care. Apr 2011;34(4):828-837.
4Gianatti, E.J. et al. Diabetes Care 2014;37(8):2098-2107.
Retrospective Studies on Testosterone Therapy
Mortality in middle age and elderly men1
Mortality @ 3 yr
Testosterone therapy (n=398)
10.3%
No therapy
(n=633)
20.7%
Mortality in men with diabetes2
Testosterone therapy (n=64)
No therapy
(n=174)
8.4%
19.2%
Medicare review3
Outcome
Testosterone therapy (n=6,355) No increased
No therapy
(n=19,065)
risk MI
1Shores
MM, et al. J Clin Endocrinol Metab Jun 2012;97(6):2050-2058.
2Muraleedharan V, et al. Euro J Endocrinol / Euro Fed Endo Soc. Dec 2013;169(6):725-733.
3Baillargeon
J, et al. Ann Pharmacotherapy. Jul 2 2014;48(9):1138-1144.
Meta-analyses on Testosterone Therapy
Corona et al1 completed a meta-analyses of 75
randomized, placebo-controlled studies
Qu: What is the incidence of major CV events?
Result: No difference in CV events between
testosterone and placebo therapy
Similar results have been reported by other
Investigators2-5
1Corona
G, et al. Expert Opin Drug Saf 2014;13:1327-1351.
2Calof, et al. J Gerontol A Biol Sci Med Sci 2005 60:1451-1457.
3Haddad, R.M. et al. Mayo Clin Proc 2007;82:29-39.
4Fernandez-Balsells, et al. J Clin Endocrinol Metab 2010;95:2560-2575.
5Xu, L., et al. BMC Med 2013;11:108.
Does Testosterone Replacement Therapy
Increase Cardiovascular Events?
We will find out…..Testosterone Trial is underway!
Funded by National Institutes of Health
Hypothesis:
Testosterone replacement therapy in men >65 yr
with documented low testosterone, compared to
placebo, will:
improve physical, sexual and cognitive function
improve vitality, low hemoglobin
Decrease cardiovascular disease and diabetes
1ABOUT
THE TESTOSTERONE TRIAL. http://rt5.cceb.upenn.edu/portal/page/portal/TTrial%20Portal/T-Trial%20Public%20Page%20-%20About
What’s New?
2015 ENDO Endocrine Society

No increased risk venous thrombosis in
hypogonadal men treated with testosterone
(n=102,650) versus no testosterone (n=102,650)

No major adverse cardiovascular events in men
treated with testosterone with documented
coronary disease or recent ACS
2015 American College Cardiology

No increased cardiovascular risk among
testosterone users…. actually testosterone was
cardioprotective
Clinical Recommendations
Who are Candidates for Testosterone
Replacement Therapy?
FDA:
Testosterone is approved to treat hypogonadism
due to testicular, pituitary or other CNS conditions
leading to hypogonadism
Testosterone is not approved to treat age-related
declines in testosterone
Testosterone is not approved to treat conditions like:
Obesity, sexual dysfunction, depression
Endocrine Society:
Do not treat without biological evidence of low
testosterone
What is Biochemical Evidence for
Testosterone Replacement Therapy?
Lab
Order total and free testosterone by “LC/MS”
LC= liquid chromatography
MS=mass spectroscopy
Need sequential 2 morning (7-10 AM) studies
demonstrating low testosterone on both tests
Interpretation:
Use the normal ranges indicated by the lab
Our lab: total testosterone is 350 -1198
free testosterone is 52- 208
In our clinics we use the free testosterone value for Dx
Universal Screening of Testosterone
Levels is Not Recommended

Endocrine Society does not recommend routine
laboratory screening for low testosterone

Serum testosterone should be measured in men with
signs and symptoms of androgen deficiency
History
Proven stud, trauma, diabetes, autoimmune
disease, infection, etc.
Physical Examination
Development, 2nd sex features, testicular
volume/consistency, etc
ADAM question survey symptoms1
1Morley
JE, et al Metabolism 2000;49(9):1239-1242
Low Testosterone: To Treat or Not to Treat?
Rule out reversible causes of low testosterone
Examples:
Obesity?
For every 5% decrease in weight,
testosterone increases ~50 ng/dL
Opiates?
Vicodin, Lortab, morphine… all narcotics
suppress testosterone to low levels!
Low T: Are Other Studies Needed?
Qu: Measure prolactin?
Should an MRI be obtained?
Evaluate all anterior pituitary hormones?
Is a DEXA scan needed?
Ans:
OK to measure PRL
IF total testosterone is 150 ng/dL
Get MRI
Check anterior pituitary hormones
Do DEXA scan
Goals for Testosterone Therapy
Therapeutic target should be a T level in mid-normal
for healthy young men
Total Testosterone ~550-750ng/dL
Free Testosterone >52
Also important is the ratio of testosterone to estrogen
Males often increase their dose…. Wrong!
Too high testosterone levels decrease libido, etc
If total testosterone is ~700, estrogen should be ~30
AACE Clinical Practice Guidelines. Available at:
http://www.aace.com/clin/guidelines/hypogonadism.pdf.
How Much Testosterone1?
FDA
200 to 800 mg IM per month
200 mg IM every 10-14 days
(300 mg every 3 weeks?)
Something to consider…
Sometimes more frequent lower doses are
more effective (that T:E ratio)....
100 mg IM q wk
40mg IM twice-weekly?
FYI: Therapeutic replacement doses do not cause
gynecomastia
1Testosterone
cypionate IM injection
What to Monitor?
Testosterone level
Hct
PSA
DRE
Dex
Baseline
X
X
X
X
X
3 month
X
X
X
annual
X
X
(X)
(X)
When to be Concerned…
Hct >54
PSA velocity change >0.4/yr
Sleep apnea
OSA
Cardiovascular changes
CHF, etc
AACE Clinical Practice Guidelines. Available at:
http://www.aace.com/clin/guidelines/hypogonadism.pdf.
How Does Testosterone Affect
PSA and Prostate?
Testosterone replacement increases PSA about
30% or back to normal levels
Testosterone replacement will increase prostate
volume about 15%
Testosterone replacement does not cause prostate
cancer
(It can accelerate metastatic prostate cancer)
Case
54 yr old man presents with CC of fatigue, loss libido, erectile
dysfunction with an unsatisfactory response to sildenafil 100 mg
PMHx: T2D, HTN
Meds: Lisinopril 10 mg bid
Metformin 1500 mg HS
Simvastatin 40 mg QOD
PE
VS: BP 145/90 BMI 34
No gynecomastia
Testicular vol 20 ml, normal DRE
Lab
Normal CMP, CBC, non-HDL 98
A1C 6.9%
T 220 ng/dL (280-1000) FT 33 pg/ml (35-155)
LH 4.5 IU/L (2-12)
FSH 6.3 IU/L (1-12)
What is the next step in this patient’s evaluation?
Questions….
1. Is this patient hypogonadal?
2. Would you treatment with testosterone?
3. Should Prolactin be measured?
4. Should other anterior pituitary hormones be
measured?
5. Should MRI of pituitary be done ?
6. Should bone mineral density be measured?
Just for FYI: What About High Testosterone?
Interesting Facts


A pro bodybuilder spends $2,000 to $5,000 a
week on drugs during a competition cycle.
Health issues and deaths associated with
bodybuilders are related not to steroids, but:
a. Recreational drug use
b. Diuretics and insulin
Moderate and High Dose
Steroid Regimens
How to “Juice”
Week
01-10 Testosterone enanthate IM
Moderate
750mg/wk
High
1000-1200
01-10 Boldenone undeclynate IM
01-10 Trenbolone enanthate IM
800mg/wk
600mg/wk
1000
800
50mg/d
100
01-08 Dianabol
PO, IM
10-16 Testosterone prop
IM
100mg/qod
100mg/d
10-16 Trenbolone Acetate
IM
100 mg/qod
100mg/d
10-16 Masteron propionate
IM
50mg/qod
100mg/d
10-16 Winstrol
PO, IM
50 mg/d
08-16 Cytomel
12-16 Halotestin
PO
PO
25mcg/d
10mg/d
30mg
Relative Activities of Steroids








Dihydrotestosterone
Testosterone
Boldenone undeclynate
Trembolone
Dianabol
Masteron
Winstrol
Halotestin
Androgenic
500
100
50
500
40
25
30
850
Anabolic
500
100
100
500
200
60
350
1900
Major Steroids for Juicing

Boldenone undeclynate (AKA EQ, Ganabol)
Originally vet drug used to treat horses (anemia)
Now available only from South america
Testosterone derivative: double bond C1-2:
Not aromatized: no gynecomastia,
no virilization
Juicers use it to build bulk

Trenbolone acetate and enanthate
As potent as DHT
Vet product (pellet) implanted in cattle
Goal: Bigger, Leaner Steaks!
Major Steroids for Juicing

Trenbolone acetate and enanthate, cont.
#1 Favorite anabolic steroid!
19-nortestosterone: Double bond C9-11
Increases androgen receptor binding
Inhibits aromatizing
Increases IGF-1
Juicers use it to build bulk, build strength
Side effects:
Acne, hair loss, low testosterone
Low HDL, high LDL
Major Steroids for Juicing

Dianabol
2nd steroid synthesized (testosterone was 1st)
17 alpha alkyl derivative of testosterone:
Oral or injection
Rapid onset 6 hrs
Juicers use it for “cutting”
(i.e. cut fat, preserve muscle)
PROBLEM: Hepatoxic, HTN
Major Steroids for Juicing


Masteron (Drostanolone)
Original use was for treating breast cancer
Effective with temoxifen
Only anabolic with anti-estrogen properties
Juicers use it to “cut”
Winstrol (Stanozolol)
17-alkyl derivative of testosterone: Anabolic
PROBLEM: Liver Toxicity
Originally used to treat anemia (increases Hct)
Increases appetite, bone density
Weak conversion to estrogen
Juicers use it for “cutting”
Major Steroids for Juicing

Halotestin
Most powerful anabolic and andogenic steroid
Testosterone derivative: Oral drug 5 mg tablets
Original use:
Induce puberty in teen males
Tissue/burn repair
Bone fractures and osteoporosis
Malnutrition, glucocorticoid wasting, anemia
Breast cancer (anti-estrogen effects)
Juicers use it for cutting: High fat loss!
PROBLEM: “Only steroid that can cause death”
“Aggression Drug”
Extra Juice for the “Big Boys”

Insulin
Pre-workout
Beginning dose
10 units + Plazma (drink)
“Crazy juicers”
100 units insulin + 10,000 calories p.o. intake

GH
Beginning dose
6-12 units every day weeks 1-16
“Crazy juicers”
30 units every day
Credits
Literature review on atherosclerosis, mortality, cardiovascular
risk and meta-analyses
Hans S. Sartaj MD1
Sandeep Dhindsa, MD2
William C. Little, MD3
Rama Chemitiganti, MD4
1,3Division
2,4Division
Cardiology, Dept Medicine, Univ Mississippi Med Ctr, Jackson MS
Endocrinology and Metabolism, Dept Medicine, Texas Tech University Health
Sciences Center-Permian Basin, Odessa TX