hypogonadism in men
TRANSCRIPT
James Voirin, DO FAAFP
Physicians Associates
Orlando Heath
Hypogonadism in Men
A Best Practice Approach
This is Controversial
“Many American men have embarked on a perilous course of overtreatment”
“Testosterone is now being prescribed to men who are simply reluctant to
accept the fact that they are getting older”
“Drug companies have shamelessly pushed the notion”
“Dangers of seeking a quick fix for aging”
New York Times Editorial Board. February 5, 2014
Best Practices Pearls
Utilize lab testing in appropriate patients who have complaints consistent
with the often subtle signs and symptoms of hypogonadism
Select testosterone replacement therapy based on patient preference and
safety in patients with hypogonadism
Monitor the effectiveness and side effects of testosterone replacement
therapy in your patients being treated for hypogonadism with testosterone
replacement therapy
How is Hypogonadism Defined by Endocrine Society?
A clinical syndrome that results from failure of the testis to produce
physiological levels of testosterone (androgen deficiency) and the normal
number of spermatozoa caused by the disruption of one or more levels of
the hypothalamic-pituitary-testicular (HPT) axis
Bhasin S, et al. J Clin Endocrinol Metab. 2010;95(6):2536-2559.
Why Do We Need Testosterone?
The Myth of Testosterone
The Reality of Testosterone
Physiological Effects of Testosterone in Male Adults
Maintains reproductive tissues
Stimulates spermatogenesis
Stimulates and maintains sexual function
Increases body weight and nitrogen retention
Increases lean body mass
Maintains bone mass
Promotes sebum production, and axillary and body hair growth
Stimulates erythropoiesis
Bagatell CJ, Brenner WJ. N Eng J Med. 1996;334:707- 714.
Hypogonadism Is Underdiagnosed and Undertreated
Baltimore Longitudinal Study
on Aging1
Low testosterone in 19% of men 60 years
and older
Hypogonadism in Males Study2
Low testosterone in 39% of men 45 years and older
Boston Area Community Health
Survey3
24% of men age 39-79 years had
biochemical hypogonadism
5.6% of men were symptomatic
Only 5%-35% of hypogonadal males
actually receive treatment4,5
1 Harman SM, et al. J Clin Endocrinol Metab. 2001;86:724-731. 2 Mulligan T, et al. Int J Clin Pract. 2006;60:762-769. 3 Araujo AB, et al. J Clin Endocrinol
Metab. 2007;92:4241-4247. 4 Seftel AD. Int J Impot Res. 2006;18:115-110. 5 Gooren LJ, et al. Aging Male 2007;10:173-181.
34%
40% 40%
46%
50%
39%
0%
10%
20%
30%
40%
50%
60%
45-54 55-64 65-74 75-84 85+ Total
Prevalence of Low Testosterone (<300 ng/dL) Increases with Age
Pre
vale
nce o
f L
ow
Testo
ste
ron
e (
%)
Adapted from: Mulligan T, et al. Int J Clin Pract. 2006;60(7):762-769.
Patient Age Range (years)
The Dilemma Is That Low Testosterone Levels Are Associated with an Increased Mortality
VA Puget Sound 8-year study of 858 men
Low T <250 ng/dL or a free T <0.75 ng/dL
All-cause mortality was 34.9% in men with low T and 20.1% in men
with normal T
Shores MM, et al. Arch Intern Med. 2006;166(15):1660-1665.
Improved Survival in Men with Coronary Heart Disease
BAT = bioavailable testosterone.
Malkin CJ, et al. Heart. 2010;96:1821-1825.
0.85
0.9
0.95
1
0 500 1000 1500 2000 2500 3000 3500
Cu
mu
lati
ve S
urv
ival
Survival Time (days)
BAT <2.6 nmol/L
(n=194)
BAT >2.6 nmol/L
(n=736)
Log rank, P=.007, HR 2.2 (1.2-3.9)
The Dilemma
Natural process?
Medically significant condition resulting in detriment to quality of life and
adversely affecting the function of multiple organ systems?
Chemical marker of generalized disease?
Nonconclusive evidence that these diseases are helped with testosterone
Surampudi PN, et al. Int J Endocrinol. 2012; [Epub ahead of print].
Who Should Be Screened for Low Testosterone?
The Endocrine Society recommends screening for androgen deficiency only in men who present with consistent signs and symptoms of low testosterone levels
Subjects with the following conditions should be screened:
● Sellar mass, radiation to the sellar region, or other diseases of the sellar region
● Treatment with medications that affect testosterone production or metabolism, such as glucocorticoids and opioids
● HIV-associated weight loss
● End-stage renal disease and maintenance hemodialysis
● Moderate to severe COPD
● Infertility
● Osteoporosis or low-trauma fracture, especially in a young man
● T2DM
COPD = chronic obstructive pulmonary disease. HIV = human immunodeficiency virus.
Bhasin S, et al. J Clin Endocrinol Metab. 2010;95(6):2536-2559.
Patient Presentation
Harvey, a 58-year-old Caucasian man, presents with a chief complaint of
fatigue
He reports that he often wakes up in the middle of the night and is unable to
go back to sleep
He feels depressed and finds it difficult to concentrate at work
Patient Evaluation and Medical History
Harvey has been married for 37 years and has 2 adult children
He works long hours at his accounting firm and frequently eats fast food for
lack of time. He has no time to exercise and has been sleeping poorly
Medical history:
● T2DM
● Hypertension
● Dyslipidemia
Current Medications
Metformin 500 mg twice daily
Linagliptin 5 mg daily
Enalapril 10 mg daily
Atorvastatin 10 mg daily
Physical Examination
Neck: No thyromegaly
Lungs: Clear
Cor S1S2S4
Genital: testes descended, no masses, no varicocele,
normal size (15-18 g); no prostate nodule palpated
Feet: no ulcers
Neurologic: mild decreased sensation to 10-g
monofilament; no visual field cuts
Skin/hair: normal beard, normal male pattern hair in
genital axilla
No gynecomastia
• Height: 5’ 9”
• Weight: 217 lbs
• BMI: 32 kg/m2
• BP: 140/80 mmHg
BMI = body mass index.
Laboratory Results
A1C: 6.8% at his last check-up 6 months ago
Cr: 1.3 mg/dL
PSA: 1.7 ng/mL
TC: 210 mg/dL
LDL-C: 110 mg/dL
HDL-C: 35 mg/dL
TG: 250 mg/dL
Microalbumin: undetectable
GFR: 50 mL/min
A1C = glycated hemoglobin. Cr = creatinine. GFR = glomerular filtration rate. HDL-C = high-density lipoprotein cholesterol.
LDL-C = low-density lipoprotein cholesterol. PSA = prostate-specific antigen. TC = total cholesterol. TG = triglyceride.
Patient Presentation
Harvey, a 58-year-old Caucasian man, presents with a chief complaint
of fatigue
He reports that he often wakes up in the middle of the night and is unable to
go back to sleep
He feels depressed and finds it difficult to concentrate at work
Patient Evaluation and Medical History
Harvey has been married for 37 years and has 2 children
He works long hours at his accounting firm and frequently eats fast food for
lack of time. He has no time to exercise and has been sleeping poorly
Medical history:
● T2DM
● Hypertension
● Dyslipidemia
Symptoms and Signs Suggestive of Hypogonadism: FACTS
No symptoms are unique to hypogonadism
Screening with testosterone level is appropriate when presented with
symptoms
Diagnosis of hypogonadism is made when one or more symptoms are
combined with low testosterone concentration
Dandona P, Rosenberg MT. Int J Clin Pract. 2010;64(6):682-696.
Symptoms and Signs Suggestive of Hypogonadism
BMD = bone mineral density.
Bhasin S, et al. J Clin Endocrinol Metab. 2010;95(6):2536-2559.
More-specific Symptoms and Signs
• Incomplete of delayed sexual development
• Reduced libido
• Decreased spontaneous erections
• Breast discomfort, gynecomastia
• Loss of body hair (axillary or pubic), reduced shaving
• Very small (< 5mL) or shrinking testis
• Inability to father children (azoospermia, oligospermia)
• Height loss, osteoporosis, low trauma fracture, low BMD
• Hot flushes, sweats
Symptoms and Signs Suggestive of Hypogonadism (cont’d)
Less-specific Symptoms and Signs
• Decreased energy, motivation, initiative, and self-confidence
• Feeling sad or blue, depressed mood, dysthymia
• Poor concentration and memory
• Sleep disturbance, increased sleepiness
• Mild anemia (normochromic, normocytic, in the female range)
• Reduced muscle bulk and strength
• Increased body fat, BMI
• Diminished physical or work performance
Bhasin S, et al. J Clin Endocrinol Metab. 2010;95(6):2536-2559.
Chronic Illness Lowers Testosterone Levels
T2DM, metabolic syndrome, hypertension, obesity
Steroid use
Moderate-to-severe COPD
Sellar mass, radiation to the sellar region, or other diseases of the
sellar region
End-stage renal disease, maintenance hemodialysis
HIV-associated weight loss
Dandona P, Rosenberg MT. Int J Clin Pract. 2010;64(6):682-696. Bhasin S, et al. J Clin Endocrinol Metab. 2010;95(6):2536-2559.
Hypogonadism and Chronic Opioid Use
Up to 86% of men treated with chronic opioids may have hypogonadism
Chronic opioid use affects the endocrine system, increasing the risk of
testicular hypogonadism, hypothyroidism, and osteoporosis
Men requiring chronic opioid therapy:
● Should be assisted in eliminating chronic use of opioids unless absolutely
necessary and supervised by an appropriate healthcare provider
● Require routine testosterone, thyroid hormone levels, and BMD assessments
● May benefit from TRT if serum levels are decreased
TRT = testosterone replacement therapy.
Reddy RG, et al. BMJ. 2010;341:c4462. Woody GM, et al. NIDA Res Monogr. 1988;81:216-223.
Common Comorbidities of Hypogonadism
Mulligan T, et al. Int J Clin Pract. 2006;60:762-769.
Condition Odds Ratio
Obesity 2.38
Diabetes 2.09
Hypertension 1.84
Hyperlipidemia 1.47
Osteoporosis 1.41
Asthma/COPD 1.40
Screening for Low Testosterone
The patient may have low
testosterone if the answer is “yes” to
question 1 or 7, or at least 3 of the
other questions
Aging Male Symptoms questionnaire
is a similar questionnaire3
These questionnaires have limited
sensitivity in detecting actual
androgen deficiency; further physical
examinations and hormonal
measurements should be obtained in
patients with suspected low
testosterone
1 Dandona P, Rosenberg MT. Int J Clin Pract. 2010;64:682-696. 2 Morley JE. Metabolism. 2000;49:1239-1242. 3 Chueh KS, et al. J Androl. 2012;33:817-823.
ADAM Questionnaire
1. Do you have a decrease in
libido (sex drive)? 6. Are you sad and/or grumpy?
2. Do you have a lack of
energy?
7. Are your erections less
strong?
3. Do you have a decrease in
strength and/or endurance?
8. Have you noticed a recent
deterioration in your ability to
play sports?
4. Have you lost height? 9. Are you falling asleep after
dinner?
5. Have you noticed a
decreased enjoyment of life?
10. Has there been a recent
deterioration in your work
performance?
Making the Lab Diagnosis
The Hypothalamic-Pituitary-Testicular Axis
FSH = follicle-stimulating hormone. GnRH = gonadotropin-releasing hormone. LH = luteinizing hormone.
Dandona P, Rosenberg MT. Int J Clin Pract. 2010;64(6):682-696.
HYPOTHALAMUS
ANTERIOR PITUITARY
Sertoli cells Leydig cells
TESTIS
Spermatozoa Testosterone
GnRH
Seminiferous tubules
FSH LH
Testosterone in the Blood
Testosterone bound to SHBG
Testosterone bound to albumin
Free Testosterone
SHBG = sex hormone-binding globulin.
Dandona P, Rosenberg MT. Int J Clin Pract. 2010;64(6):682-696.
Not All Testosterone is Available
Free Bound to
Albumin BAT
Bound to
SHBG
Not
Available
Dandona P, Rosenberg MT. Int J Clin Pract. 2010;64(6):682-696.
What Is Considered to Be a Low Serum Testosterone Level?
Total testosterone <300 ng/dL*
Free testosterone <50 pg/mL
Bioavailable testosterone <70 ng/dL
*Total testosterone is the most frequently used lab test for the
diagnosis of hypogonadism in the medical literature
Brawer MK. Rev Urol. 2004;6:S9-S15. AACE Hypogonadism Task Force. Endocrinol Pract. 2002;8:439-456.
Making the Diagnosis
TT = total testosterone.
Dandona P, Rosenberg MT. Int J Clin Pract. 2010;64(6):682-696. Bhasin S, et al. J Clin Endocrinol Metab. 2006;91(6):1995-2010. Arver S, et al. Front
Horm Res. 2009;37:5-20. ASA Position Statement. J Androl. 2006;27(2):133-134. Rosner W, et al. J Clin Endocrinol Metab. 2007;92(2):405-413.
Normal
TT
Remeasure
morning TT
Refer to
endocrinologist
Diagnosis of
hypogonadism
Low
TT
Seek other
causes Normal
TT
Symptoms
History and
physical exam
Patient
with
suspected
low T
Measure
morning
TT Levels
Low
TT
>300 ng/dL
<300 ng/dL >300 ng/dL
<300 ng/dL
Primary Hypogonadism: Hypergonadotropic Hypogonadism
What occurs?
● Testicular dysfunction
● Normal hypothalamic/pituitary function
What results are seen?
● Low testosterone levels
● Impairment of spermatogenesis
● Elevated gonadotropin levels
Possible cause?
● Karyotype to rule out Klinefelter’s
Seftel A. Int J Impot Res. 2006;18(3):223-228. Bhasin S, et al. J Clin Endocrinol Metab. 2010;95(6):2536-2559. Surampudi PN, et al. Int J Endocrinol.
2012;2012:625434.
Secondary Hypogonadism: Hypogonadotropic Hypogonadism (cont’d)
What occurs?
● Normal testicular function
● Hypothalamic/pituitary dysfunction
What results are seen?
● Low testosterone levels
● Impairment of spermatogenesis
● Low or low-normal gonadotropin levels
Possible cause?
● Infiltrative disease (eg, check iron, TIBC)
● Age-related androgen deficiency
TIBC = total iron-binding capacity.
Seftel A. Int J Impot Res. 2006;18(3):223-228. Bhasin S, et al. J Clin Endocrinol Metab. 2010;95(6):2536-2559. Surampudi PN, et al. Int J Endocrinol.
2012;2012:625434.
Combined Primary and Secondary Mixed Hypogonadism
What occurs?
● Testicular dysfunction
● Hypothalamic/pituitary dysfunction
What results are seen?
● Low testosterone levels
● Impairment of spermatogenesis
● Low or low-normal gonadotropin levels (variable)
Possible causes:
● Age-related androgen deficiency, alcohol. Glucocorticoids, chronic infections
(HIV), hemochromatosis, systemic disease
Seftel A. Int J Impot Res. 2006;18(3):223-228. Bhasin S, et al. J Clin Endocrinol Metab. 2010;95(6):2536-2559. Surampudi PN, et al. Int J Endocrinol.
2012;2012:625434.
Harvey’s Laboratory Results
First TT: 230 ng/dL
Second TT: 243ng/dL
LH: 7.2 IU
Summary of 2010 Endocrine Guidelines
Bhasin S, et al. J Clin Endocrinol Metab. 2010;95(6):2536-2559.
Diagnose
• Only in men with consistent signs and unequivocally low serum
testosterone levels
• Do not screen in general population; however, consider
measurement in disease conditions with high prevalence
Measure • Morning total testosterone level
• Confirm abnormal level and, if in question, assess free or
bioavailable testosterone
Treatment
Goals
• Induce and maintain secondary sex characteristics as well as
sexual function
• Improve sense of well-being
• Improve muscle mass and strength, and BMD
“Therapeutic Trial” Concept
In the presence of a clinical picture of androgen deficiency and borderline
serum total or free testosterone levels, a short (eg, 3 months) therapeutic trial
may be justified
Consider discontinuing testosterone treatment if no clinical improvement
Wang C, et al. J Andrology. 2009;30(1):1-9.
Contraindications in Using Testosterone
Male breast cancer
Prostate cancer: but not absolute
Known allergic reactions or sensitivities to substrates used in all types of TRT
Bhasin S, et al. J Clin Endocrinol Metab. 2006;91(6):1995-2010.
Precautions in Using Testosterone
BPH or LUTS
Edema in patients with preexisting cardiac, renal, or hepatic disease
Gynecomastia
Precipitation or worsening of sleep apnea
Azoospermia; testicular atrophy
Erythrocytosis
BPH = benign prostatic hyperplasia. LUTS = lower urinary tract symptoms.
Bhasin S, et al. J Clin Endocrinol Metab. 2006;91(6):1995-2010. Seftel A. Int J Impot Res. 2006;18(3):223-228. Surampudi PN, et al. Int J Endocrinol.
2012; [Epub ahead of print].
Results of Therapy: FACTS
Restore sexual functioning and libido
Restore sense of well-being
Prevent loss or improve bone density
Restore muscle mass and strength
Improves mood
Dandona P, Rosenberg MT. Int J Clin Pract. 2010;64(6):682-696.
Results of Therapy: Expert Opinion, Not Expert Evidence
Improvement in insulin resistance
Decrease abdominal fat
Decrease cardiovascular risk factors
Decrease overall mortality
Mårin P, et al. Eur J Med. 1992;1(6):329-336. Kapoor D, et al. Eur J Endocrinol. 2006;154(6):899-906. Dandona P, Rosenberg MT. Int J Clin Pract. 2010;64(6):682-696. Bhasin S, et al. J Clin Endocrinol Metab. 2010;95(6):2536-2559. Shores MM, et al. J Clin Endocrinol Metab. 2012 ;97(6):2050-2058.
Common Sense in Initiating Testosterone
Joint decision of informed patient and provider
Short-acting preparations are better in the beginning to assess tolerability
Start low and go slow
Bhasin S, et al. J Clin Endocrinol Metab. 2006;91(6):1995-2010.
Treatment Options
Intramuscular injections
Transdermal patches
Transdermal gels
Buccal tablets
Subcutaneous pellets
Dandona P, Rosenberg MT. Int J Clin Pract. 2010;64(6):682-696.
Intramuscular Injections
Pros Cons
History (available for 50 years) Pain
Self administration Frequency of injections
(every 2-4 weeks)
Inexpensive
Symptomatic peaks and troughs
resulting in variations in breast
tenderness, libido, emotional
stability, energy
Flexibility of dosing
Dandona P, Rosenberg MT. Int J Clin Pract. 2010;64(6):682-696.
Transdermal Patches
Pros Cons
Non-scrotal patches Scrotal patches
Night-time application results in
good approximation of normal
circadian plasma testosterone levels
Skin irritation
Flexibility of dosing
Dandona P, Rosenberg MT. Int J Clin Pract. 2010;64(6):682-696.
Transdermal Gels
Dandona P, Rosenberg MT. Int J Clin Pract. 2010;64(6):682-696.
Pros Cons
Application sites
(upper arms, shoulder, axilla)
Transfer to others
(risk is minimized with high-dose,
low-volume preparations)
Low skin irritation Low skin irritation
Invisibility of application
Flexibility of dosing
Various concentrations
Buccal Tablets
Dandona P, Rosenberg MT. Int J Clin Pract. 2010;64(6):682-696.
Pros Cons
Application site Application site
Relative invisibility Inadvertent loss of tablet
Bypass first-pass hepatic
metabolism
Gum and buccal irritation, alteration
in taste
Slow release Twice-daily dosing
No dose titration
Subcutaneous Pellets
Dandona P, Rosenberg MT. Int J Clin Pract. 2010;64(6):682-696. Bhasin S, et al. J Clin Endocrinol Metab. 2010;95(6):2536-2559.
Pros Cons
History (started in 1940s) Painful application
Relative invisibility Surgical procedure unlikely to be
used by primary care physician
Long acting Long acting
Slow release Inconvenient removal
No dose titration
Procedure can result in infection,
fibrosis, or pellet extrusion
Monitoring Therapy (Part 1)
Bhasin S, et al. J Clin Endocrinol Metab. 2010;95(6):2536-2559.
Symptoms • Evaluate response 3-6 months after treatment initiation and
then annually
Measuring
Testosterone
• 3-6 months after initiation
• Aim to raise level into mid-normal range
• Monitoring guidelines depend on chosen therapy
Hematocrit • Check at 3-6 months, then annually
Osteoporosis • Measure BMD after 1-2 years
Monitoring Therapy (Part 2)
Prostate • DRE at 3 months, then yearly
• In men >40 years, check baseline PSA,
at 3-6 months and then in accordance with guidelines
Urologic
Consultation
• PSA increase >1.4 ng/mL in any 12-month period
• PSA velocity of >0.4 ng/mL-yr after 6 months of therapy
• Detection of abnormality on DRE
• AUA/IPSS score of >19
Adverse
Effects • At each visit
• Can be formulation specific
AUA = American Urological Association. DRE = digital rectal examination. IPSS = International Prostatic Symptom Score.
Bhasin S, et al. J Clin Endocrinol Metab. 2010;95(6):2536-2559.
Measuring Testosterone: When to Check
Injectable Testosterone –
Enanthate or Cypionate • Measure level midway between injections
Transdermal Patches • Assess level 3-12 hours after application
Buccal Tablets • Assess immediately before or after application
of fresh system
Transdermal Gels • Any time after patient has been on for a week
Testosterone Pellets • Measure at end of dosing interval
• Adjust pellets or interval
Bhasin S, et al. J Clin Endocrinol Metab. 2010;95(6):2536-2559.
Potential Urologic Adverse Effects of Testosterone Replacement
Worsening of LUTS
Rise in PSA
Testicular atrophy/infertility
Progression of undiagnosed prostate cancer
Bhasin S, et al. J Endocrinol Metab. 2010;95(6):2536-2559.
Potential Systemic Adverse Effects of Testosterone Replacement
Erythrocytosis
Acne and oily skin
Gynecomastia
Male pattern balding (familial)
Growth of breast cancer
Induction or worsening of obstructive sleep apnea
Edema in patients with preexisting cardiac, renal, or hepatic disease
Bhasin S, et al. J Endocrinol Metab. 2010;95(6):2536-2559.
Prostate Cancer and Testosterone Therapy: FACTS
Fear of causing prostate cancer leaves many appropriate patients untreated
No evidence of causality of testosterone use and development of
prostate cancer
Testosterone will stimulate growth of existing prostate cancers
Obtain consult for any concern:
● PSA abnormal per guidelines
● Abnormal prostate exam
Gooren LJ, et al. Aging Male. 2007;10(4):173-181. Rhoden EL, Morgentaler A. N Engl J Med. 2004;350(5):482-492. Raynaud JP. J Steroid Biochem Mol
Biol. 2006;102(1-5):261-266. Wang C, et al. J Androl. 2009;30(1):1-9. Carroll P, et al. Urology. 2001;57(2):217-224.
BPH and Testosterone Therapy: FACTS
Patients with BPH treated with testosterone are at increased risk of
worsening signs or symptoms
Correlation of voiding volume to prostate size is poor
Prostate size may increase in first 6 months, but generally to normal volume
seen in eugonadal men
Monitoring is strongly advised
Bhasin S, et al. J Clin Endocrinol Metab. 2006;91(6):1995-2010. Wang C, et al. J Androl. 2009;30(1):1-9. Hijazi RA, et al. Annu Rev Med. 2005;56:117-
137. Miner MM, et al. Cleve Clin J Med. 2007;74:S38-S46. Rhoden EL, Morgentaler A. N Engl J Med. 2004;350(5):482-492.
Testosterone Deficiency and Cardiovascular Disease
Testosterone and CV Risk in Men: A Systemic Review and
Meta-analysis of Randomized Placebo — Controlled Trials
Authors point out that many of the studies had limitations: limited reporting of
methods; few patients; brief duration – only 4 trials followed patients ≥1 year,
9% loss to follow-up; trials failing to report data on measured outcomes
Results: exogenous testosterone given to men with low T levels had
insignificant changes in blood pressure, glycemia, and lipid parameters
Odds ratio between testosterone therapy and any cardiovascular event was
1.82 (95% CI = 0.78-4.23) but not statistically significant
Conclusion of Authors
“Testosterone was not associated with important CV events
… patients and clinicians need large randomized trials of men at risk for CV
disease to better inform the safety of long-term testosterone use”
CI = confidence interval. CV = cardiovascular.
Hadda RM, et al. Mayo Clin Proc. 2007;82:29-39.
Testosterone Therapy Effects: Systematic Review and Meta-analysis
Meta-analysis of 51 studies
Follow-up ranged from 3 months to 3 years
No significant effect on mortality, prostate, or CV outcomes
Testosterone treatment was associated with:
● Significant increase in hemoglobin (WMD, 0.80 g/dL; 95% CI),
0.45 to 1.14] and hematocrit (WMD, 3.18%; 95% CI, 1.35 to 5.01).
● Decrease in HDL (WMD, -0.49 mg/dl; 95% CI, -0.85 to -0.13).
These findings are of unknown clinical significance
Current evidence about the safety of testosterone treatment in men in terms
of patient-important outcomes is of low quality and is hampered by the brief
study follow-up WMD = weighted mean difference. OR = odds ratio.
Fernández-Balsells MM, et al. J Clin Endocrinol Metab. 2010;95(6):2560-2575.
Survival of Treated vs Untreated Testosterone-deficient Men in VA Population: Does TRT Improve Mortality?
1031 men aged >40 years,
testosterone <250 ng/dL
Mortality: 10.3% treated,
20.7% untreated (P<.0001)
Su
rviv
al
by T
esto
ste
ron
e
Tre
atm
en
t, %
Log rank P=.029
1.0
0
0.9
0
0.8
0
0 12 24 36 48
Time Since Testosterone Test Date (months)
15 301 321 323 146
1016 639 557 496 193 Untreated
Treated
At risk, n
Untreated
Treated
VA = US Department of Veterans Affairs.
Shores MM, et al. J Clin Endocrinol Metab. 2012 ;97(6):2050-8.
TOM Trial: Study Design
Effect of testosterone therapy on lower-extremity strength and physical function in
older, hypogonadal men with limitations in mobility
Men aged ≥65 y (mean, 74 y) with serum TT 100-350 ng/dL or FT <50 pg/mL
209 participants randomized to receive testosterone gel or placebo for 12 months
Testosterone gel titrated from 50 to 150 mg/d, based on serum testosterone level
After dose adjustment, 16 men received 150 mg/d, 61 received 100 mg/d, and 29
received 50 mg/d
Mean serum testosterone levels achieved were 574 (403) ng/dL in treatment group
and 292 (160) ng/dL in placebo group
Both groups had high prevalence of hypertension, obesity, diabetes, hyperlipidemia,
and CVD
CVD = cardiovascular disease. FT = free testosterone.
Basaria S et al. N Engl J Med. 2010;363(2):109-122.
TOM Trial: Outcomes Show Benefit
Unloaded stair climb
Chest-press strength
Treatment Effect, SD Units
−0.2 0 0.2 0.4 0.6
Lift and lower
Loaded stair climb
Loaded gait speed
Unloaded gait speed
Grip strength
ALST
Total lean mass
Chest-press power
Leg-press power
Leg-press strength
Testosterone preferred
Absolute treatment differences (testosterone vs placebo arms) are plotted for primary and secondary outcomes in units normalized to baseline standard deviation of measurement. Data are point estimates with 95% confidence intervals.
ALST = appendicular lean soft tissue. SD = standard deviation.
Adapted from: Travison TG, et al. J Gerontol A Biol Sci Med Sci. 2011;66(10):1090-1099.
TOM Trial: Safety
In treatment arm, hematocrit and hemoglobin levels increased significantly,
and HDL and LDL levels decreased
TOM trial reported more cardiovascular AEs
● 23 men receiving testosterone vs 5 receiving placebo
Cardiovascular AEs had variable clinical importance
Based on significantly increased incidence of cardiovascular AEs in
treatment arm, data and safety monitoring board recommended cessation of
enrollment and testosterone therapy:
● Termination of study in December 2009
AE = adverse event.
Basaria S, et al. N Engl J Med. 2010;363(2):109-122.
Association of TRT with Mortality, MI, and Stroke
MI = myocardial infarction.
Vigen R, et al. J Am Med Assoc. 2013;310(17):1829-1836.
Study Design • Retrospective VA study of men with low testosterone levels (<300 ng/dL) who
underwent coronary angiography
Population • 1223 patients started testosterone after a median of 531 days following
angiography
• 7486 patients received no testosterone
Results
• 3 years after coronary arteriography, the Kaplan-Meier estimated cumulative
percentages with events were 19.9% in the control group vs 25.7% in the
TRT group
• Absolute risk difference of 5.8% at 3 years after coronary angiography
• No difference in effect among those with and without coronary artery disease
10.1
15.4
19.9
11.3
18.5
25.7
0
5
10
15
20
25
30
at 1 year at 2 years at 3 years
no TRT TRT
Proportion of All Events after Statistical Modeling: VIGEN Study
Vigen R, et al. J Am Med Assoc. 2013;310(17):1829-1836.
Pro
po
rtio
n o
f even
ts (
%)
9.1
5.6
6.5
5.5
1.9
2.7
0
2
4
6
8
10
Death MI Stroke
No TRT
TRT21.2
10.1
0
5
10
15
20
25
All Events
Vigen R, et al. J Am Med Assoc. 2013;310(17):1829-1836.
Proportion of All Events in Patients with Hypogonadism (%) with or Without TRT: VIGEN Study
Pro
po
rtio
n o
f e
ven
ts (
%)
Pro
po
rtio
n o
f e
ven
ts (
%)
Increased Risk of Non-fatal MI Following Testosterone Prescription
PDE5 = phosphodiesterase type 5.
Frinkle WD, et al. PLoS One. 2014 Jan 29;9:e85805.
Study Design • Retrospective cohort study of the risk of acute non-fatal MI in
the 90 days following testosterone prescription
Population • 55,593 patients started testosterone compared to 167,279
prescribed PDE5 inhibitors
Results
• In men <65 years, excess risk was confined to those with prior
heart history, relative risk (RR) of 2.9 (1.49. 5.62)
• In men >65 years, the 2-fold increased risk was associated
with testosterone prescription regardless of CV history
Endocrine Society Statement Regarding Cardiovascular Risk
Longer, large-scale prospective randomized controlled trials on testosterone
therapy are needed
Physicians and patients should have a conversation about the risks and
benefits of using testosterone
It may be prudent “not to administer testosterone therapy to men who have
had a cardiovascular event (MI, stroke, or acute coronary syndrome) in the
preceding 6 months.”
Medscape Medical News. Available at: http://www.medscape.com/viewarticle/820383. Accessed April 18, 2014.
Testosterone Deficiency and Diabetes
Effects on Insulin Resistance From Testosterone Therapy
IIEF = International Index of Erectile Function.
Jones TH, et al. Diabetes Care. 2011;34(4):828-837.
Study Design • A 12-month, multicenter, prospective, randomized,
double-blind, placebo-controlled study
Population • 220 men with hypogonadism with T2DM and
metabolic syndrome
Results
• Significantly improved insulin resistance in all patients
(by 15.2% at 6 months and by 16.4% at 12 months)
• Significantly improved HDL (-0.049 mmol/L) and
LDL-C (-0.210 mmol/L), lipoprotein a (-0.31 mmol/L) in selected
groups
• Significantly improved sexual health (increase of 4.8 on IIEF)
Effects on A1C from Testosterone Therapy: BLAST Study
Hackett G, et al. J Sex Med. 2013;10:1612-1627.
Study Design • 30-week double-blind, placebo-controlled study of long-acting
testosterone undecanoate
Population • 211 males with T2DM
Results
• Significantly improved A1C at 6 and 18 weeks
• Significant reduction in waist circumference, weight and BMI
related to achieving adequate serum testosterone levels
• Significance not reached in patients with depression
Conclusions
Conclusions
Hypogonadism is very prevalent, underdiagnosed
and undertreated
Hypogonadism is associated with major illnesses such as metabolic
syndrome, T2DM, and increased mortality
Indications for referral include change in DRE or PSA, HCT, worsening of
voiding symptoms or infertility
There is no increased risk of prostate cancer from TRT
Abraham Morgentaler, MD Journal Mayo Clinic Proceedings June 4, 2015
Found no evidence that testosterone therapy
increases cardiovascular risk. On the contrary the
weight of evidence accumulated by researches
around the world over several decades clearly
indicate that higher levels of testosterone are
associated with amelioration of cardiovascular risk
factor and reduced risk of mortality.
Best Practices Pearls
Utilize lab testing in appropriate patients who have complaints consistent
with the often subtle signs and symptoms of hypogonadism
Select testosterone replacement therapy based on patient preference and
safety in patients with hypogonadism
Monitor the effectiveness and side effects of testosterone replacement
therapy in your patients being treated for hypogonadism with testosterone
replacement therapy