Treatment of The
Hypogonadal Male
William Abeyta MD
Associate Professor of Medicine
AVAH/UNM SOM
OBJECTIVES
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Understand the clinical features of male
hypogonadism.
Discuss possible causes.
Interpret laboratory tests and how to order them
in different clinical scenarios.
Review and describe the hypothalamic-pituitarytesticular axis.
Understand general principles of treatment
OBJECTIVES
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Describe the various testosterone preparations.
Understand the monitoring required when using
testosterone replacement.
Identify complications of treatment.
Roles of Testosterone
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In men, testosterone plays a key role in the
development of male reproductive tissues such
as the testis and prostate as well as promoting
secondary sexual characteristics such as
increased muscle, bone mass, and the growth of
body hair. In addition, testosterone is essential
for health and well-being as well as the
prevention of osteoporosis.
HISTORY
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Testosterone first used clinically in 1937, only 2
years after it’s Nobel Prize-winning discovery.
Annual prescriptions for testosterone increasd
by more than 5-fold from 2000-2011 reaching
5.3 million prescriptions.
Testosterone prescribing has created a nearly $2
billion annual market.
Surging off-label use (anti-aging, sexual tonic,
bodybuilding or doping.
HYPOGONADISM
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Defined as the failure of the testes to produce
androgen, sperm, or both.
Testosterone production decreases with
advancing age: 20% of men older than 60 and
30-40% of men older than 80 have serum
testosterone levels that would be subnormal in
their younger male counterparts.
Hypogonadism
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Low levels of testosterone along with other
specific signs and sxs. (diminished libido, ED,
reduced muscle mass/bone density, depression,
anemia)
Affects 2-4 million males in the US.
Hypogonadism
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Only 5% of men currently receive rx
Recent interest in rx d/t media attention,
marketing of new preparations, “desire of baby
boomers” to maintain vigor and health into their
more mature years.
Considerable controversy regarding indications
for testosterone supplementation in aging males.
Hypogonadism
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No large-scale, long-term studies available to assess
risks and benefits of testosterone-replacement rx in part
d/t theoretical risk of possible stimulation of prostate
cancer by testosterone.
It is estimated that a study would need to include 6000
elderly hypogonadal men randomly assigned to receive
testosterone or placebo for 6 years in order to
determine whether rx increases risk of prostate cancer
by 30%.
Snyder.Hypogonadism in Elderly Men-What To
Until the Evidence Comes.N Engl J Med 2004;350:440-442
The Testes
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60% of testicular volume accounted for by
seminiferous tubules.
Prepubertal testis 2cm in length and 2ml in
volume.
Testes average 4.6cm in length in adults but
range from 3.5-5.5 cm according to Harrisons
Textbook of Medicine.
4-7cm in UpToDate.
Testes
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Advanced age does not influence testicular size.
(therefore significance of small testes is the same
at all ages of the adult)
Testis size varies among ethnic groups.
Asian men have smaller testes than western
Europeans, independent of differences in body
size.
Serum Testosterone Levels
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Diurnal rhythm.
Values are 30% higher near 8am vs later in the
day.
Normal range varies among laboratories.
Usual range for young men is 300-1000ng/d.
In general values < 220-250 are clearly low in
most laboratories.
Values 250-350 should be considered borderline
low.
TABLE 2. Conditions associated with alterations in SHBG concentrations
Conditions associated with decreased SHBG concentrations
• Moderate obesity1
• Nephrotic syndrome1
• Hypothyroidism
• Use of glucocorticoids, progestins, and androgenic steroids1
Conditions associated with increased SHBG concentrations
• Aging1
• Hepatic cirrhosis1
• Hyperthyroidism
• Use of anticonvulsants1
• Use of estrogens
common
conditions associated with alterations in SHBG concentrations.
• HIV
infection
1Particularly
Signs and Symptoms of
Hypogonadism
1.
2.
3.
4.
5.
Diminished libido
Erectile dysfunction
Difficulty achieving orgasm
Diminished intensity of orgasmic experience
Diminished sexual penile sensation
Signs and Symptoms of
Hypogonadism
Other
1. Diminished energy/sense of well being
2. Increased fatigue
3. Depressed mood
4. Anemia
5. Diminished bone density/muscle mass
Risks of Testosterone Therapy
Coronary Artery Disease:
“Adverse Events Associated with Testosterone
Administration” TOM Trial. NEJM July 8, 2010.
-209 community-dwelling men 65 years of age or older,
with limitations of mobility.
-total serum testosterone level of 100-350ng/dl or a free
testosterone level of <50pg/ml
-Randomly assigned to receive placebo gel or testosterone
gel daily for 6 months.
1.
Results
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Trial terminated early because of a significantly higher
rate of adverse CV events in the testosterone group
than in the placebo group.
Higher rates of cardiac, respiratory, dermatologic
events in the testosterone treated group.
23 subjects in testosterone group as compared with 5 in
the placebo group had cardiovascular-related adverse
events.
Testosterone group had significantly greater
improvements in leg press and chest press strength and
in stair-climbing while carrying a load.
Risks of Testosterone-Replacement
Therapy
“Association of Testosterone Therapy With
Mortality, Myocardial Infarction, and Stroke in
Men With Low Testosterone Levels”
JAMA 11-6-2013 Volume 310
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Retrospective national cohort study of men with
low testosterone levels (<300ng/dl) who
underwent coronary angiography in the VA
system between 2005-2011.
Primary outcome was a composite of all-cause
mortality, MI, and ischemic stroke.
Results
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At 3 years after coronary angiography
cummulative percentages with events were
19.9% in the no-testosterone therapy group vs
25.7% in the testosterone therapy
group…absolute risk difference of 5.8%.
Limitations in the Study
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Observational
Select group of patients in VA system
undergoing angiography.
Length of follow-up.
Risks of Testosterone-Replacement
Therapy
2. Lipid Profiles: Available data inconsistent
(supraphysiologic doses appear to lower HDL).
Some variability may be explained by dosage.
Present data taken together suggest that
testosterone replacement therapy within the
physiologic range is not associated with
worsening of the lipid profile.
Rhoden, et al. Risks of Testosterone-Replacement
Therapy and Recommendations for Monitoring
N Engl J Med 2004; 350:482-492
Risks of Testosterone-Replacement
Therapy
3. Polycythemia: Higher testosterone levels act as
a stimulus for erythropoiesis. Injections appear
to be associated with a greater risk than topical
preparations.
No testosterone-associated thromboembolic
events have been reported to date.
Risks of Testosterone-Replacement
Therapy
4. BPH: Prostate volume DOES increase significantly
during testosterone-replacement therapy (determined
by ultrasonography) mainly during the first 6 months.
Poor correlation between prostate volume and urinary sxs.
Multiple studies fail to demonstrate exacerbation of
voiding sxs attributed to BPH during testosterone
supplementation.
Risks of Testosterone-Replacement
Therapy
5. Prostate Cancer: Prospective studies have
demonstrated a low frequency of prostate cancer in
association with testosterone-replacement rx.
Occult prostate cancer in men with low testosterone levels
appears to be substantial with higher grade prostate
cancers.
No compelling evidence to suggest men with higher
testosterone levels are at a greater risk or that treating
men who have hypogonadism with exogenous
androgens increases this risk.
Rhoden, et al. Risks of Testosterone-Replacement
Therapy and Recommendations for Monitoring
N Engl J Med 2004; 350:482-492
*Prostate cancer becomes more
prevalent at the time of a man’s
life when testosterone levels
decline.
Risks of Testosterone-Replacement
Therapy
6. PSA: Studies have inconsistently shown a rise in
PSA in testosterone treated patients (0.30.4ng/ml)
A substantial rise in PSA should arouse suspicion
that a prostate cancer has developed.
Risks of Testosterone-Replacement
Therapy
7. Hepatic Effects: Oral preparations of
testosterone reported to lead to hepatotoxic
effects and neoplasia, including benign and
malignant tumors.
IM injections and topical preparations of
testosterone do not appear to be associated with
hepatic dysfunction and routine monitoring of
LFTs is unnecessary for men on these forms of
replacement rx.
Risks of Testosterone-Replacement
Therapy
8. Sleep Apnea: Testosterone-replacement
therapy has been associated with the
exacerbation of sleep apnea or with the
development of sleep apnea (Seen in men
treated with higher doses of parenteral
testosterone and have other risk factors for sleep
apnea). Probably by central mechanisms rather
than by anatomical changes in the airway.
Miscellaneous Effects of
Testosterone
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Breast tenderness and swelling
Testicular size and consistency diminish
Fertility is diminished
Skin reactions with topicals
Pain, bruising, soreness, furuncles with testosterone
injections
Fluid retention
Acne, oily skin
No data to suggest acceleration of male-pattern
baldness.
Evaluation of the Possible
Hypogonadal Male
Physical exam: focus on whether or not sexual
development is consistent with the patient’s age.
 Testicular size: 4-7cm in length.
 Normal musculature
 Dense pubic hair and in a diamond pattern.
 Beard should be full and dense
 Chest and other body hair should be present.
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Endocrine Society Guideline
Who To Treat With TestosteroneReplacement Therapy?
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Testosterone should be given ONLY to a male
who is hypogonadal as evidenced by a low
testosterone level.
There is insufficient evidence that testosterone
benefits elderly males without clearly abnormally
low testosterone levels.
Baseline Exam/Tests Before
Beginning Treatment With
Testosterone
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Voiding history
History of sleep apnea
Perform DRE
Baseline PSA and HCT/hemoglobin
GU referral if PSA over 4.0 or abnormal
prostate exam
Testosterone Preparations
Testosterone Esters: injectable testosterone
2. Transdermal:
Nonscrotal patch
Testosterone Gel
Ointment
Solution
3. Buccal tablet
4. Pellet (Testopel Implant)
1.
Testosterone Esters
Testosterone Esters: Injectable testosterone
 Testosterone enanthate and cypionate used for
years in treatment of testosterone deficiency.
 Begin with 200mg IM every 2 weeks.
 Can change to 100mg every week if fluctuations
in libido, mood, energy.
Testosterone Esters: Injectable
testosterone
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Measure testosterone midway between injections
and value should be mid-normal (350750ng/ml)
Reduce dose if higher values obtained.
Disadvantage is fluctuations in mood, energy
and libido in many patients
Nonscrotal Patch
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One body patch is available (Androderm)
Worn on arm, torso, or thigh
Start with 4mg patch
Check level 3-12 hours after application of
patch.
Testosterone Gel
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Apply once per day
Takes a month to reach normal levels and
remain steady throughout 24 hours.
Can check serum level at any time of day
Buccal Tablet
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Approved by FDA June, 2003 (Striant)
Applied and adheres to a depression in the gum
above the upper incisors and releases
testosterone across the buccal mucosa
Check level immediately before or after
application of new system.
Follow-up of The TestosteroneReplaced Male
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Follow-up visit in 3-6 months for efficacy evaluation
and adverse effects.
Assess urinary sxs/sleep apnea
Perform DRE at ~3-6 months and see below PSA rec.
Testosterone level at 3-6 months.(aim for mid-normal
range 350-750 ng/dl.)
PSA at 3-6months and thereafter in accordance with
guidelines for screening depending on age and race of
patient.
HCT at 3-6 months and than yearly(discontinue
treatment if >54%)
Obtain Urologic Consultation if
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Increase in PSA >1.4ng/ml within any 12
month period of testosterone rx.
PSA velocity of >0.4ng/ml using PSA level after
6 months of testosterone administration as the
reference (if PSA data are available for a period
exceeding 2 years)
Abnl DRE
AUA prostate sxs score >19.
Case I
82 yo male presented to his new PCP with a
chief complaint of back pain.
The pain began suddenly when he helped
move a pool table at the senior center one
month prior to this visit.
Despite worsening pain to the point that he
could no longer walk very well, he had refused
to come in for evaluation.
He had no neurologic/bowel/bladder complaints
Case I
Meds: APAP, viagra.
Tobacco: 1PPD x 65 years
ETOH: none x 5 years, formerly heavy use
PMH:
1. Right hip fracture with ORIF 2 years ago
2. Esophageal stricture with multiple
dilations in the past.
FH: neg for osteoporosis that he was aware of.
Case I
PE: normal vitals
Neck: no nodes or thyromegaly
Lungs: decreased BSs throughout
CV: RRR without M/R/G
Abd: soft without hepatosplenomegaly or masses
Back: Marked thoracic kyphosis with tenderness
at T12 and L1
Testicles: 5cm bilat, normal pubic hair
CXR: Hyperinflation
Thoracic and lumbar spine films: compression
fractures of T12 and L1 appearing acute.
Lab:
Hct 38, MCV 95, nl WBC/plts
Calcium 9.2
SPEP neg for paraprotein
PSA <.03
Normal TSH/prolactin
Free testosterone 0.3 (11-25)
Total testosterone 32 (241-827)
LH 14.1 (1-7)
FSH 61.2(1.4-15)
PTH normal
DXA: >4SD hip&spine
Case II
66 year-old male presented to his resident MD
for general medical f/u. He had been on
testosterone injections for 2 years for primary
hypogonadism. His last Hct was one year prior
and had been 50. The patient complained of
fatigue, headaches, and dizziness.
On exam his face appeared very flushed. Lab
testing showed a Hct of 62%.