Free
C
contInuIng educatIon Lesson
OBJECTIVES
Upon successfully completing this lesson, the
pharmacist will be able to:
1. Define testosterone deficiency or
hypogonadism and describe its common
symptoms.
2. Identify patient populations that are at
increased risk for experiencing testosterone
deficiency.
3. Describe the advantages and disadvantages
of the different treatment options for
testosterone therapy.
4. Discuss the potential side effects and risks
associated with testosterone therapy.
5. Develop a monitoring plan to evaluate
efficacy, safety and adherence with
testosterone therapy.
INSTRUCTIONS
1. After carefully reading this lesson, study
each question and select the one answer
you believe to be correct. Circle the
appropriate letter on the attached reply
card.
2. To pass this lesson, a grade of 70% (14 out
of 20) is required. If you pass, your CEU(s)
will be recorded with the relevant provincial
authority(ies). (Note: some provinces require
individual pharmacists to notify them.)
ansWerIng optIons
A. For immediate results, answer online
at www.pharmacygateway.ca.
B. Mail or fax the printed answer card
to (416) 764-3937. Your reply
card will be marked and you will be
advised of your results within six to
eight weeks in a letter from Rogers
Publishing.
This CE lesson is published by Rogers Publishing
Limited (Pharmacy Group), One Mount Pleasant
Rd., Toronto, Ont. M4Y 2Y5. Tel.: (416) 764-3916
Fax: (416) 764-3931. No part of this CE lesson
may be reproduced, in whole or in part, without
the written permission of the publisher. ©2007
approVed for
1.25 ce unIts
approved for 1.25 ce units by the canadian council
on continuing education in pharmacy. file #506-1206.
not valid for ce credits after January 15, 2010.
Testosterone deficiency in
aging men and its treatment:
Your questions answered
By Christine Folia, BScPhm, PharmD
March 2007
The author, expert reviewer Mario de Lemos and Rogers Publishing magazine have each declared
that there is no real or potential conflict of interest with the sponsor of this lesson. Expert reviewer
Randy McFadyen discloses that he has authored a CE lesson on andropause for the sponsor.
IntroductIon
The topic of testosterone deficiency and
its treatment, especially in the aging male,
continues to draw a great deal of interest
and controversy. While the “perfect” studies, designed to answer all of the outstanding
questions in this field do not exist, it is clear
that a proportion of men with testosterone
deficiency are significantly impacted by their
symptoms and may benefit from treatment.
This lesson provides answers to some of the
common questions pharmacists and their patients may have regarding testosterone deficiency in the aging male and its treatment.
What Is testosterone defIcIency or
hypogonadIsm? Is thIs dIfferent
from “andropause”?
Medical dictionaries define hypogonadism
as “inadequate gonadal function, as manifested by deficiencies in gametogenesis and/
or the secretion of gonadal hormones”.1,2
In practice, hypogonadism (or testosterone
deficiency) is typically defined as a clinical
syndrome characterized by low serum testosterone (Total T) levels (<10.4 nmol/L or 300
ng/dL) along with one or more clinical signs
or symptoms (Table 1).3,4
Hypogonadism can generally be divided
into two main types or categories: primary
hypogonadism and secondary hypogonadism
(Table 2).5 Age-related declines in testosterone production result from defects in both
testicular (primary) and hypothalamic-pituitary (secondary) function.5 Unlike women
who will all undergo a relatively rapid decline
in estrogen production with menopause, the
decline in testosterone production in aging
men is much more gradual (average decline
of 1-2% per year). Only a subset of aging
men will have levels below the lower limit of
normal and experience symptoms.5
Age-related hypogonadism has previously
been identified by several names, including
andropause, male climacteric, androgen decline in the aging male (ADAM), and symptomatic late-onset hypogonadism (SLOH).8
However, many feel these terms poorly reflect the specific hormone deficiency state
involved,8,9 and as a result, the terms testosterone deficiency syndrome8 or simply male
hypogonadism10 are preferred.
hypogonadIsm – hoW common Is It?
The prevalence of hypogonadism in Canada
is unknown. Various estimates of prevalence
in the United States have been published,
however these estimates vary with the patient population studied and the definition
of hypogonadism used. For example, several
studies have shown that the percentage of
men with low levels of testosterone increases
SUPPORTED BY AN EDUCATIONAL GRANT FROM
TaBLE 1: Signs and symptoms of
hypogonadism
3,5,6
Physical
• Low overall energy, fatigue
• Increased visceral (abdominal) fat
•Reduced bone mineral density (BMD),
osteoporosis, loss of height, bone aches
• Reduced muscle mass and strength
•Diminished athletic ability or physical
performance
•Loss of facial, axillary and pubic hair,
reduced shaving
• Hot flushes, night sweats
Sexual
• Diminished sexual desire (low libido)
• Decreased nocturnal erections
Psychological
•Frequent sadness, depressed mood (not
“clinical depression”)
• Moodiness and/or irritability
•Low self-esteem, decreased self-confidence
• Diminished sense of well-being
• Difficulty concentrating
• Impaired work performance
• Decreased motivation
with age (Figure 1). However not all men
with low testosterone levels are symptomatic.
It is estimated that nearly 40% of American
men over age 40 have low testosterone levels (Total T) and approximately 12-25% of
these men will report one or more symptoms
of hypogonadism.11,12
Despite the significant prevalence of hypogonadism, it has been estimated that only
5-9% of affected men are currently receiving treatment.11,13 This may be due to the
under-reporting of symptoms by patients or
a lack of physician awareness or recognition
Table 2: Classification of hypogonadism3,7
Primary Hypogonadism Secondary Hypogonadism
Abnormality
•Problem or defect in the •Problem or defect in the hypothalamus testicles or pituitary (Impaired production of hormones necessary for controlling
testosterone production and release)
Causes / Examples* •Genetic conditions (i.e., •Hyperprolactinemia
Klinefelter’s syndrome) •Pituitary or hypothalamic tumor
•AIDS •Surgery or radiation to the pituitary
•Sickle cell disease
•Adrenal or testicular tumor
•Infection (i.e., mumps orchitis) •Obesity
•Testicular injury or trauma
•Hypothyroidism
•Disruption of testicular blood •AIDS
flow during surgery
•Medications
•Testicular radiation
•Aging
•Chemotherapy
•Medications
•Alcohol abuse
•Aging
*not a complete list
of hypogonadism in aging men.3,6 Ongoing
debate regarding the validity of a diagnosis of
age-related hypogonadism and controversies
over treatment efficacy and safety in this patient group may also influence the low treatment rates.4
What are the signs and symptoms
of testosterone deficiency?
Testosterone is metabolized to dihydrotestosterone (DHT), and estradiol.14 As a result,
several organs in the body are affected by the
presence (or absence) of testosterone and its
metabolites (Figure 2). Men with age-related testosterone deficiency may experience
a variety of symptoms that can generally be
FIGURE 1: P revalence of low levels of testosterone
as an index of male hypogonadism
according to decade of life.4
Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and
recommendations for monitoring. N Engl J Med 2004;350:482-92. Copyright ©
2004 Massachusetts Medical Society.
| Testosterone deficiency in aging men and its treatment
classified as physical, sexual and psychological (Table 1). The symptoms of testosterone
deficiency also overlap with several other
medical conditions, which must be considered and ruled out before a diagnosis of hypogonadism can be made.5,6
Testosterone deficiency may have indirect
effects on health and lifestyle as well. Symptoms of anger, irritability and reduced libido
can have a negative impact on personal relationships.15 Similarly, symptoms of reduced
energy, motivation and strength can lead to
impaired work performance and reduced
participation in fitness and leisure activities.15 Low testosterone levels have also been
shown to be associated with a higher risk of
Figure 2: Target Organs for Testosterone in the
Body
Reproduced with permission from Organon Canada Ltd.
Answer online at www.pharmacygateway.ca | March 2007
Figure 3: ADAM Questionnaire20
positive answer to questions 1 or 7, or to any three questions, would justify a referral to the
A
physician for further investigation.
Yes
No
1. Do you have a decrease in libido (sex drive)?
o
o
2. Do you have a lack of energy?
o
o
3. Do you have a decrease in strength and/or endurance?
o
o
4. Have you lost height?
o
o
5. Have you noticed a decreased “enjoyment of life”?
o
o
6. Are you sad and/or grumpy?
o
o
7. Are your erections less strong?
o
o
8. Have you noticed a recent deterioration in your ability to play sports?
o
o
9. Are you falling asleep after dinner?
o
o
10. Has there been a recent deterioration in your work performance?
o
o
Reproduced with permission from Organon Canada Ltd.
falls16 and increased mortality.17
In addition to symptoms, laboratory findings must be considered before making a diagnosis of hypogonadism. A Total T below
the lower limit of normal in a symptomatic
patient is often suggestive of hypogonadism.5
However, additional biochemical changes
that occur with aging may make Total T a
less accurate measure of testosterone deficiency in aging men.
Testosterone is known to bind quite
strongly to a protein called sex hormone
binding globulin (SHBG) and SHBG levels
commonly increase with aging. Once bound
to SHBG, testosterone becomes unavailable
to the tissues. Testosterone that is not bound
to SHBG is available for use by the tissues
and is described as bioavailable testosterone
(Bio T). Testosterone not bound to any pro-
teins (including albumin) is described as free
testosterone (Free T).5 Assessment of the Bio
T or Free T is generally a more accurate measure of testosterone deficiency than Total T
in the aging male.3,18
It is not uncommon for aging men to experience changes with aging and wonder if
these changes are a “normal” part of aging
or if they are a symptom of a problem that
could benefit from treatment. The ADAM
(androgen deficiency in aging males) questionnaire is a validated screening tool that
can be used to identify male patients who
may benefit from further discussion and investigation of their symptoms by their doctor
(Figure 3).20
Table 4: Medications associated with reduced testosterone levels*5,21,24
Mechanism
Examples
Decreased testosterone production
•Alcohol
•Ketoconazole
•Chronic use of opioids (morphine, methadone,
heroin)
•LHRH agonists (buserelin, goserelin, leuprolide)
Testosterone antagonists
•Cimetidine
•Spironolactone
•Antiandrogens (bicalutamide, flutamide,
nilutamide)
Increased prolactin levels (which lead to decreased testosterone levels)
•Phenothiazines
•Metoclopramide
•Domperidone
•Methyldopa
•Reserpine
Increased SHBG levels (reduced Bio T)
•Barbiturates
•Some anticonvulsants (carbamazepine)
Decreased DHT levels
•Finasteride
•Saw palmetto
* not a complete list
Bio T: bioavailable testosterone, DHT: dihydrotestosterone, SHBG: sex hormone binding globulin
Note: Dose-response effects of medications on testosterone levels are poorly documented in the literature. Some
medications may not necessarily be an independent cause of hyogonadism but may be a contributing factor in
men at risk.
March 2007 | Answer online at www.pharmacygateway.ca
TaBLE 3: Factors associated with
increased risk of hypogonadism
Patient populations with a higher
prevalence of hypogonadism5
• Diabetes (Type 2)
• HIV/AIDS
• Hypothyroidism21
• End-stage renal disease or hemodialysis
•Moderate to severe chronic obstructive
lung disease
• Osteoporosis or low-trauma fracture
Concomitant conditions with overlapping
symptoms (hypogonadism may be
overlooked)
•Erectile dysfunction (ED) and PDE5
inhibitor failure22
• Depression and antidepressant failure22
•Parkinson’s disease and refractory
nonmotor symptoms23
Contributing factors (may further
reduce testosterone levels)
• Stress21
• Obesity6
• Lack of exercise21
• Excessive alcohol consumption21
• Medications5,21,24
Who is at risk for symptomatic
hypogonadism or testosterone
deficiency?
Men with reduced testosterone levels due
to primary or secondary causes (Table 2),
including men with age-related declines in
testosterone production, are at risk for experiencing symptoms of hypogonadism. Additional factors that may assist in identifying
men at risk of symptomatic hypogonadism
are summarized in Table 3. Medications may
also have an impact on testosterone levels
(Table 4). Pharmacists should be aware of
these potential risk factors and refer symptomatic patients for physician assessment
where appropriate.
A variety of treatment options exist for
symptomatic men with documented testosterone deficiency (Table 5). Each treatment
option has its own set of advantages and
disadvantages. The choice of agent is often
dependent on patient factors such as convenience, sensitivity to side effects, preference
for a particular dosage form, and drug plan
coverage.
Intramuscular (IM) injections of testosterone (testosterone cypionate, testosterone
enanthate) have been available for many
years and their effects are well recognized.9
Without considering physician or nurse time
for dose administration, IM testosterone is
the least expensive treatment option.5 However, the injections are long-acting, making
it difficult to rapidly interrupt treatment if
intolerable side effects or contraindications
emerge.22 Doses are given every 2-4 weeks,
and patients may experience peaks and valleys in testosterone levels, resulting in fluctuating periods of side effects and breakthrough
Testosterone deficiency in aging men and its treatment | FIGURE 4: A bsorption (serum levels) of testosterone undecanoate when
taken with and without food28
Reproduced with permission from Organon Canada Ltd.28
symptoms (commonly referred to as “roller
coaster” effects).5,9 These effects can be minimized by more frequent administration of
smaller doses, however this may be less convenient. Intramuscular injections should also
be used with caution in patients with an increased risk of bleeding (bleeding disorders,
anticoagulant or antiplatelet use, etc.).
Testosterone undecanoate is the only oral
testosterone formulation currently available
in Canada. Since testosterone undecanoate
is lymphatically absorbed, it avoids first-pass
inactivation in the liver. Each dose must be
taken with a meal in order to enhance absorption (Figure 4). According to the manufacturer, a meal containing 18 g of fat (i.e.,
3.5 oz of meat, 1 oz of nuts, 2 oz of cheese)
Tip: Hypogonadism is considered a major risk
factor for osteoporosis. Men with low testosterone levels should be referred for bone mineral
density testing.19
will ensure optimal absorption of an 80 mg
dose.26 Some physicians report good results
when the dose is taken with 20 mL of Extra
Light Tasting Olive Oil.27 Although doses
Table 5: Canadian testosterone therapy options25
Treatment Options
Supplied format
Dose
Oral
Testosterone undecanoate 40 mg capsule
(Andriol®)
Up to 80 mg BID with meals
Intramuscular Injection
Testosterone cypionate 100 mg/ml injection
(Depo-testosterone)
(contains cottonseed oil)
200 mg - 400 mg every 3-4 weeks (100 mg
per week or 200 mg every 2 weeks has
also been recommended)5
Testosterone enanthate 200 mg/ml injection
(Delatestryl®)
(cottains sesame oil)
200 mg - 400 mg every 2-4 weeks (100 mg
per week or 200 mg every 2 weeks has
also been recommended)5
Topical
Testosterone gel (AndroGel®)
Foil packets: 2.5 g, 5 g
Pump: 1.25 g/pump
5 g - 10 g applied once daily
Testosterone patch (Androderm®)
12.2 g (2.5 mg/24 hr)
24.3 g (5 mg/24 hr)
5 mg - 7/5 mg applied nightly
(worn for 24 hours)
| Testosterone deficiency in aging men and its treatment
of up to 160 mg (in divided doses) are recommended,28 the availability of the 40 mg
capsule facilitates dose titration to meet patient-specific requirements. This product has
been reformulated in recent years so that it
maintains its stability when stored at room
temperature. No refrigeration is required
by either pharmacists or patients.28 Unlike
other oral androgens (i.e., oral alkylated androgens) testosterone undecanoate is free of
significant liver toxicity.9,22
Testosterone gel is supplied as single-dose
foil packets, as well as a metered-dose pump,
allowing for flexible dosing to meet patientspecific requirements.5 The gel is colourless
and odourless, making it a more discrete option than the patch. It also has a lower risk
of skin reactions compared to the patch.4
The dose should be applied each morning to
the shoulders, upper arms and/or abdomen,
however to ensure adequate absorption, it is
recommended that patients avoid showering
or swimming for 5-6 hours after application.25 (Occasional showering or swimming
within one hour of application is not expected to significantly impact the effects.)25
Although prolonged or vigorous direct skinto-skin contact with another person should
be avoided due to the risk of drug transfer,
this can be completely prevented by covering
the application site with a shirt.25
Testosterone transdermal patches should
be applied once daily in the evening and worn
for 24 hours.25 The application site should be
rotated daily and the same site should not be
used within a 7-day period, to minimize the
risk of skin reactions.25 In addition, patches
should not be applied to pressure areas (i.e.,
shoulders, elbows, etc.) to avoid skin reactions.25 Patches may be applied to the back,
abdomen, upper arms or thighs. They should
not be applied to the scrotum. Potential disadvantages include the size and “visibility”
of the patches, which may be of concern for
patients requiring more than one patch for
their dose. Pharmacists should ensure that
patients apply the patch properly and are not
experiencing problems with adhesion. (Occasionally, adhesion may be poor if applied
to skin that is hairy, oily or perspires excessively.) As with all transdermal medication
patches, patients should be advised on their
safe disposal.
Although some older publications discuss
the use of oral alkylated androgens (methyltestosterone, fluoxymesterone), these products are not available in Canada and are considered obsolete. They are not recommended
for the treatment of hypogonadism due to
their risk of liver toxicity and sub-optimal
clinical response.5,22
Answer online at www.pharmacygateway.ca | March 2007
Figure 5: Sample treatment journal (The Aging Males’ Symptoms Rating Scale)
31
Evaluate how you’re feeling on a scale of 1 to 5:
1=None 2=Mild 3=Moderate 4=Sever 5=Extremely Severe
Which of the following symptoms apply to you at this time?
SymptomsPre-Treatment: Date:
________________
________________
1.Decline in your feeling of general well-being (general state of health)
1
2
3
4
5
1
2
3
4
5
2. Joint pain and muscle ache (lower
back, pain in a limb, general back
ache)
1
2
3
4
5
1
2
3
4
5
3. Excessive sweating (sudden episodes 1
of sweating, hot flushes independent
of strain)
2
3
4
5
1
2
3
4
5
4. Sleep problems (difficulty in falling asleep, difficulty sleeping through
the night, waking up early)
1
2
3
4
5
1
2
3
4
5
5. Increased need for sleep, often feeling 1
tired
2
3
4
5
1
2
3
4
5
6. Irritability (feeling aggressive, easily 1
upset about little things, moody)
2
3
4
5
1
2
3
4
5
7. Nervousness (inner tension,
restlessness, feeling fidgety)
1
2
3
4
5
1
2
3
4
5
8. Anxiety (feeling panicky)
1
2
3
4
5
1
2
3
4
5
9. Physical exhaustion/lacking vitality (general decrease in performance,
reduced leisure activity)
1
2
3
4
5
1
2
3
4
5
10.Decrease in muscular strength (feeling of weakness)
1
2
3
4
5
1
2
3
4
5
11.Depressive mood (feeling down, sad, 1
lack of drive, mood swings)
2
3
4
5
1
2
3
4
5
12.Feeling that you have passed your peak
1
2
3
4
5
1
2
3
4
5
13.Feeling burnt out, having hit
rock-bottom
1
2
3
4
5
1
2
3
4
5
14. Decrease in beard growth
1
2
3
4
5
1
2
3
4
5
15.Decrease in ability/frequency to perform sexually
1
2
3
4
5
1
2
3
4
5
16.Decrease in number of morning erections
1
2
3
4
5
1
2
3
4
5
17. Decrease in sexual desire/libido (lacking pleasure in sex, lacking
desire for sexual intercourse)
1
2
3
4
5
1
2
3
4
5
Total
_________________
_________________
Heinemann LAJ, Saad F, Thiele K, Wood-Dauphinee S. The Aging Male 2001; 4:14-22. Adapted with permission.
What potential benefits may a
patient expect from testosterone
therapy?
Potential benefits of testosterone therapy
can be classified as sexual, physical or psychological, as well as biochemical. However,
since the symptom spectrum and response
to therapy will vary from patient to patient,
treatment with testosterone therapy may result in clinical benefits in some, all or none
of these areas.4
Sexual: Several studies have shown testosMarch 2007 | Answer online at www.pharmacygateway.ca
terone therapy to improve libido and sexual
desire.5,22 Testosterone therapy has not been
shown to independently improve erectile
dysfunction,5 however recent studies have
demonstrated significant improvements in
erectile function in hypogonadal men who
have not responded to therapy with phosphodiesterase-5 (PDE5) inhibitors alone.22
Physical: Several studies have documented
the effects of testosterone therapy on muscle
mass, muscle strength and body composition.22 Individual studies have shown an in-
crease in lean muscle mass, decrease in body
fat, and increases in strength (hand grip, leg
press, leg power).22 Results of a recent metaanalysis30 and systematic review5 suggest that
testosterone therapy may increase lean muscle mass by 1.6-2.7 kg and reduce body fat
by 1.6-2 kg, however the effects on muscle
strength were heterogeneous. The effects of
testosterone therapy on bone mineral density (BMD) have been evaluated in several
studies, however the results have been inconsistent.5,22 A meta-analysis demonstrated
an increase in BMD of 3.7% at the lumbar
spine, but the effects on the femoral neck
(hip) were inconsistent.30 Studies have not
been conducted to assess the impact of testosterone therapy on fracture rates.5
Psychological: Several studies have documented the association between low testosterone levels and cognitive function, memory
and visuospatial function, however the effect
of testosterone therapy on cognition remains
uncertain.5,22 While some studies have shown
improvement in some measures of cognitive
function, others have not.5,22 Testosterone
therapy has been shown to improve mood
(i.e., reduced anger, irritability, sadness, tiredness and nervousness, and improved energy,
motivation, confidence and well-being).22
Although low testosterone levels are not a
direct cause or risk factor for major depression, testosterone supplementation has been
shown to be an effective add-on therapy in
hypogonadal men with treatment refractory
depression.22
Biochemical: Testosterone therapy is
known to improve insulin sensitivity.22 A
recent study of hypogonadal men with Type
2 diabetes (treated with oral hypoglycemics
and/or insulin) demonstrated an improvement in glucose tolerance, fasting blood glucose and hemoglobin A1c in patients treated
with testosterone therapy when compared to
placebo.22 The effects of testosterone therapy
on insulin sensitivity and the metabolic syndrome are still considered investigational. It
is recommended that diabetes be evaluated
and adequately treated before considering
the role of testosterone in hypogonadal men
with diabetes.22
Pharmacists can play an important role in
managing patient expectations for testosterone therapy. It is important for patients to
know when they should see the initial benefits of therapy and how much of an improvement is expected. Improvements in mood
and sexual function are typically seen after 13 months, however improvements in muscle
mass, strength, body composition and bone
density are observed after 6-12 months or
longer.
Since many of the symptoms of hypogonadism are vague and non-specific, patients
Testosterone deficiency in aging men and its treatment | Table 6: Potential risks associated with testosterone therapy4
Table 7: P otential drug interactions
with testosterone therapy25
Potential RiskComments
Cardiovascular disease Existing evidence suggests a neutral or possible beneficial effect
Lipid alterations
Most studies show no change with physiologic replacement doses
Erythrocytosis
(polycythemia)
Wide range of risk, depending on mode of administration: 3-18% with
transdermal administration, up to 44% with injection; Requires monitoring;
May need to reduce dose, withhold testosterone, or consider therapeutic
phlebotomy.
Fluid retention
Rarely of clinical significance
Benign prostatic hyperplasia (BPH)
Rarely of clinical significance
Prostate cancer
Controversial; Unknown level of risk; Requires long-term monitoring
Hepatotoxicity
Limited to oral alkylated androgens (methyltestosterone, fluoxymesterone)
Sleep apnea
Infrequent
Gynecomastia
Rare, usually reversible
Skin reactions
High incidence with patch (up to 66%), low incidence with gel (5%),
rare with injections
Acne or oily skin
Infrequent
Testicular atrophy or infertility
Common, especially in young men; Usually reversible with cessation of
treatment
Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl
J Med 2004;350:482-92. Copyright © 2004 Massachusetts Medical Society. Adapted with permission 2006.
should be encouraged to keep a log or diary of their symptoms to allow for a more
objective evaluation of response to therapy.
Patients may evaluate their symptoms at
baseline (pre-treatment) and regularly during
therapy, and should be encouraged to discuss
their progress with their doctor and pharmacist. The Aging Males’ Symptoms Rating
Scale, which is a validated tool, may also be
used (Figure 5).31
Tip: Men with ED who fail to respond to PDE5
inhibitors might benefit from a referral to
their doctor for an assessment of their testosterone levels.29
What potential risks and side effects should patients treated with
testosterone therapy be aware of?
Contraindications to testosterone therapy
include prostate cancer, breast cancer, erythrocytosis (hematocrit >50%), severe obstructive benign prostatic hyperplasia (BPH) and
unstable severe congestive heart failure (class
III or IV).5,22
A summary of the potential risks and side
effects associated with testosterone therapy is
provided in Table 6 and potential drug interactions are listed in Table 7. The effects
of testosterone on prostate health (mainly
BPH symptoms and risk of prostate cancer)
deserve special attention however, since these
issues are often of greatest concern to patients
considering therapy.14
BPH: Hypogonadal men usually have
reduced prostate size. Prostate volume has
been shown to increase during the first six
| Testosterone deficiency in aging men and its treatment
months of therapy, to a level comparable to
men without hypogonadism.4 However, several studies evaluating testosterone therapy
have failed to show any worsening of voiding symptoms due to BPH compared to placebo.4 No significant changes in urine flow
rates, residual urine volumes, urine retention
or prostate voiding symptoms have been observed.4 Testosterone therapy is not expected
to worsen symptoms of BPH, however since
individual men may occasionally have increased voiding symptoms, use in men with
severe BPH should be avoided.
Prostate cancer: Although it is well
known that reducing or eliminating testosterone may cause prostate cancer to regress,
the inverse association (i.e., raising testosterone levels may increase the risk of developing prostate cancer) has not been proven. A
systematic review demonstrated an increased
risk of “prostate events” with testosterone
compared to placebo, however, no significant
difference in the individual prostate events
(rates of prostate cancer, PSA >4 ng/mL,
prostate biopsies) were observed.5,32 In addition, a collection of studies demonstrated a
low risk of prostate cancer (1.1% of treated
Tip: Consider patient comfort if a large volume IM injection is required. Large injection
volumes (i.e., greater than 2.5 - 3.0 mL) can
be divided into two separate injections. Another alternative is to recommend a more
concentrated formulation. Testosterone enanthate (200 mg/mL) can supply a similar
dose with a smaller volume than testosterone
cypionate (100 mg/mL).
DrugEffect and
recommended management
Warfarin
•Testosterone may increase anticoagulant effect
•Monitor INR whenever testosterone therapy is started or stopped
•Dose adjustments may benecessary
Insulin •Testosterone may Oral hypogly- decrease blood glucose cemics levels
•Monitor for signs of hypoglycemia
•Dose adjustments may be necessary
Cyclosporine
•Testosterone may inhibit hepatic metabolism and increase levels of cyclosporine
•Monitor and adjust dose if necessary
Table 8: R ecommendations for
pharmacist monitoring
of testosterone therapy
Efficacy
•Set realistic goals at onset of therapy and
follow-up with each refill. Encourage the
use of a treatment journal. (see Figure 5)
•Encourage persistence with lifestyle
changes such as diet, exercise, weight loss,
stress reduction, etc.
•Assess for improvement in symptoms:
uPsychological and sexual symptoms after 1-3
months.
uPhysical symptoms after 6-12 months or
longer. Assessment of bone density every 1-2
years is advised.5,29
•In absence of benefit, therapy should be
discontinued and further investigation for
other causes is recommended.29
Safety
•Verify mandatory baseline PSA, DRE, hemoglobin and hematocrit before initiating
therapy.22,29
•Assess for and address side effects with
each prescription refill. (see Table 6)
•Reinforce the importance of physician
follow-up:
u DRE, PSA, hemoglobin, hematocrit every 3
months for first year, then annually.4,22,29
u Liver enzymes and lipids annually (optional)4
Adherence
•Review and confirm appropriate use:
uTestosterone undecanoate administration twice
daily with meals, adequate fat intake, etc.
uTechnique for application of testosterone gel
or patch.
•Ensure reasonable expectations (i.e., expected degree of benefit, onset of effects,
limits of therapy, role of lifestyle, etc.).
•Review importance of continued use
and commitment to regular follow-up to
ensure ongoing benefit and safety.22
DRE: digital rectal exam.
PSA: prostate specific antigen.
Answer online at www.pharmacygateway.ca | March 2007
Table 9: Useful websites
Andropause.ca www.andropause.ca
Canadian Society for the Study of the Aging Male (CSSAM) www.cssam.com
Canoe Health (C-Health) – special section for men’s health http://chealth.canoe.ca
The Mayo Clinic Mens Health Centre http://mayoclinic.com/health/mens-health/MC99999
The National Library of Medicine’s special section for men
http://www.nlm.nih.gov/medlineplus/menshealthissues.html
men followed for 6-36 months) and only
small increases in PSA (0.3-0.43 ng/mL) in
men receiving testosterone therapy.4 (PSA
increases greater than 1.0-2.0 ng/mL usually
trigger the need for a prostate biopsy.4,5)
Testosterone therapy can stimulate the
growth of an existing cancer, therefore prostate cancer is an absolute contraindication.
In contrast, there is no strong evidence to
suggest that treating hypogonadal men with
testosterone increases their risk of developing prostate cancer.4 However, due to the
lack of sufficiently powered and long-range
studies to definitively answer this clinical question, an on-going commitment to
closely monitor men receiving testosterone
therapy (i.e., PSA and digital rectal exam)
is required.14
Table 8 provides a summary of key monitoring points for pharmacists involved with the
care of men receiving testosterone therapy.
Where can male patients find more
information about testosterone
deficiency and other men’s health
topics?
Male patients may sometimes find it difficult to ask questions or express concerns
regarding their health, especially when they
refer to gender-related health issues such as
hypogonadism and sexual function. Therefore it is important for pharmacists to proactively learn about men’s health issues and
the various tools and resources that can be
used to meet the information needs of male
patients. Several websites on the topic of tes-
tosterone deficiency are available (Table 9),
and multidisciplinary societies, such as the
Canadian Society for the Study of the Aging
Male (CSSAM), support the development
of information resources and educational
events designed to raise awareness and encourage research in this growing field.
References
1.
Stedman’s Medical Dictionary. 26th edition ed. Baltimore:
Williams & Wilkins, 1995.
2.
American Association of Clinical Endocrinologists Medical
Guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients--2002 update. Endocr Pract 2002;
8:440-56.
3.
Seftel A. Male hypogonadism. Part II: Etiology, pathophysiology, and diagnosis. Int J Impot Res 2006; 18:223-8.
4.
Rhoden EL, Morgentaler A. Risks of testosterone-replacement
therapy and recommendations for monitoring. N Engl J Med 2004;
350:482-92.
5.
Androgen Deficiency Syndromes in Men Guideline Task Force:
Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ,
Swerdloff RS et al. Testosterone therapy in adult men with androgen
deficiency syndromes: An endocrine society clinical practice guideline. J Clin Endocrinol Metab 2006; 91:1995-2010.
6.
Little D. Andropause: Identifying, treating, and following the
patient. Geriatrics & Aging 2004; 7:13-8.
7.
Tenover JL. Male hormone replacement therapy including “andropause”. Endocrinol Metab Clin North Am 1998; 27:969-87
8.
Morales A, Schulman C, Tostain J, Wu FCW. Selecting the correct terminology for testosterone deficiency. Available at http://jcem.
endojournals.org/cgi/eletters/91/6/1995. Accessed August 9, 2006.
9.
Morales A, Lunenfeld B. Investigation, treatment and monitoring of late-onset hypogonadism in males. Official recommendations
of ISSAM. International Society for the Study of the Aging Male.
Aging Male 2002; 5:74-86.
10. Canadian Society for the Study of the Aging Male. Issue analysis: Regulatory issues surrounding testosterone therapy in aging males.
Position statement of the Canadian Society for the Study of the Aging
Male. Submitted to the “Journal of Sexual Medicine” for publication.
2006.
11. Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter
C. Prevalence of hypogonadism in males aged at least 45 years: the
HIM study. Int J Clin Pract 2006; 60:762-9.
12. Araujo AB, O’Donnell AB, Brambilla DJ, Simpson WB, Longcope C, Matsumoto AM et al. Prevalence and incidence of andro-
gen deficiency in middle-aged and older men: estimates from the
Massachusetts Male Aging Study. J Clin Endocrinol Metab 2004;
89:5920-6.
13. Updates. Rockville, Md.: Food and Drug Administration,
1996. Available at: http://www.fda.gov/fdac/departs/196_upd.
html. Accessed November 8, 2006.
14. Morales A. Testosterone and prostate safety. Geriatrics & Aging
2004; 7:6-12.
15. Novak A, Brod M, Elbers J. Andropause and quality of life: findings
from patient focus groups and clinical experts. Maturitas 2002; 43:2317.
16. Orwoll E, Lambert LC, Marshall LM, Blank J, Barrett-Connor
E, Cauley J et al. Endogenous testosterone levels, physical performance, and fall risk in older men. Arch Intern Med 2006; 166:212431.
17. Shores MM, Matsumoto AM, Sloan KL, Kivlahan DR. Low
serum testosterone and mortality in male veterans. Arch Intern Med
2006; 166:1660-5.
18. Lue TF, Giuliano F, Montorsi F, Rosen RC, Andersson KE,
Althof S et al. Summary of the recommendations on sexual dysfunctions in men. J Sex Med 2004; 1:6-23.
19. Brown JP, Josse RG. 2002 clinical practice guidelines for the
diagnosis and management of osteoporosis in Canada. CMAJ 2002;
167:S1-S34.
20. Morley JE, Charlton E, Patrick P, Kaiser FE, Cadeau P, McCready D et al. Validation of a screening questionnaire for androgen
deficiency in aging males. Metabolism 2000; 49:1239-42.
21. Carruthers M. A multifactorial approach to understanding andropause. J Sex Reprod Med 2001; 1:69-74.
22. Lunenfeld B, Saad F, Hoesl CE. ISA, ISSAM and EAU recommendations for the investigation, treatment and monitoring of lateonset hypogonadism in males: scientific background and rationale.
Aging Male 2005; 8:59-74.
23. Okun MS, McDonald WM, DeLong MR. Refractory nonmotor symptoms in male patients with Parkinson disease due to testosterone deficiency: A common unrecognized comorbidity. Arch Neurol
2002; 59:807-11.
24. Killinger D. Biosynthesis, metabolism & physiology of testosterone. In: Bain J, editor. Mechanisms in Andropause. Concord, ON:
Mechanisms in Medicine, 2003.
25. Compendium of pharmaceuticals and specialties. Ottawa, Ontario: Canadian Pharmacists Association, 2006.
26. Organon Canada Ltd. Data on file. 2006.
27. Personal communication. Dr. L. Komer, Burlington, ON. Nov.
2006.
28. Organon Canada Ltd. Andriol® Product Monograph. March
10, 2004.
29. Nieschlag E, Swerdloff R, Behre HM, Gooren LJ, Kaufman
JM, Legros JJ et al. Investigation, treatment and monitoring of lateonset hypogonadism in males. Aging Male 2005; 8:56-8.
30. Isidori AM, Giannetta E, Greco EA, Gianfrilli D, Bonifacio V,
Isidori A et al. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis.
Clin Endocrinol (Oxf ) 2005; 63:280-93.
31. Heinemann LAJ, Saad F, Thiele K, Wood-Dauphinee S. The
aging males’ symptoms rating scale: cultural and linguistic validation
into english. The Aging Male 2001; 4:14-22.
32. Calof OM, Singh AB, Lee ML, Kenny AM, Urban RJ, Tenover
JL et al. Adverse events associated with testosterone replacement in
middle-aged and older men: a meta-analysis of randomized, placebocontrolled trials. J Gerontol A Biol Sci Med Sci 2005; 60:1451-7.
QUESTIONS
1. Men with clinically relevant testosterone
deficiency or hypogonadism have:
a)Low testosterone levels (testosterone
levels below the lower limit of normal)
b) Symptoms of hypogonadism
c)Low testosterone levels OR symptoms of
hypogonadism
d)Low testosterone levels AND symptoms of
hypogonadism
2. W
hich statement about testosterone
deficiency is TRUE?
a)All men will develop low (below normal)
testosterone levels as they age.
b)All men with low testosterone levels will
experience symptoms.
March 2007 | Answer online at www.pharmacygateway.ca
c)Age-related declines in testosterone are
due to defects in the testes and the brain.
d)Testosterone levels decline dramatically in
men after age 50, similar to menopause in
women.
3. Which organ(s) is/are not influenced by
testosterone?
a) Stomach
b) Bone
c) Male sexual organs
d) Skin
4. What are metabolites of testosterone?
a) Estradiol, dihydrotestosterone (DHT)
b)Estradiol, DHT, sex hormone binding
globulin (SHBG)
c)Estradiol, DHT, prostate specific antigen
(PSA)
d) Bio T, Free T
5. Which condition is not a symptom of
testosterone deficiency?
a) Depression
b) Low libido
c) Reduced energy
d) Reduced muscle mass
6. Which medication does not reduce testosterone levels?
a) Spironolactone
b) Morphine
Testosterone deficiency in aging men and its treatment | QUESTIONS continued
c) Warfarin
d) Alcohol
Case Study #1: Joe is a 65-year-old male who
is frustrated with the lack of response he has
had with sildenafil. He wonders if he should go
back to his doctor and ask for an alternative or
if he should just “give up”, because he’s never
really in the mood for sex anymore. His wife
is upset with him as well, because he’s always
irritable and tired. In addition to having erectile
dysfunction, he is obese, has Type 2 diabetes
and hypertension.
7. Which characteristic is not associated with
an increased risk of hypogonadism?
a) Increasing age
b) Obesity
c) Type 2 diabetes
d) Hypertension
8. W
hich recommendation would be most
appropriate for Joe?
a)Consider an alternate PDE5 inhibitor since
he is not responding to sildenafil.
b)Before giving up on sildenafil, he should
return to his doctor for a complete physical, including an assessment of testosterone levels.
c)He should learn to accept these changes,
since they are a normal part of aging.
d)Consider going for marital counselling
with his wife.
9. The ADAM questionnaire could be used to
diagnose testosterone deficiency in Joe.
a) True
b) False
10. Which statement is TRUE?
a)Sildenafil can cause hypogonadism in men
with diabetes.
b)Testosterone is a first-line alternative for
the treatment of ED.
c)Men with ED who do not respond to PDE5
inhibitors may be hypogonadal.
d)There is a drug interaction between testosterone and sildenafil.
11. Which lifestyle intervention is unlikely
to affect Joe’s testosterone levels?
a) Decrease caffeine intake
b) Decrease alcohol intake
c) Exercise regularly
d) Reduce weight
12. After seeing his doctor, Joe returns with
a prescription for testosterone undecanoate. Your counselling includes all of the
following EXCEPT:
a)The capsules should be taken with meals
to increase absorption.
b)He should start noticing some benefits
within 1-3 months.
c)He should monitor his blood glucose
more frequently, since testosterone may
decrease blood glucose levels.
d)Testosterone undecanoate capsules should
be refrigerated.
Case Study #2: Doug (age 71 years) presents
with a new prescription for testosterone enanthate injection after being told by his doctor that
his Total T and Bio T levels are low. He appears
thin and frail and no longer needs to shave daily.
Doug complains that his energy and mood are
low and that he is not looking forward to having
to see the doctor every 2 weeks for an injection.
13. What would you say to Doug?
a)He should ask his doctor if he could have
his bone density tested, since hypogonadism increases his risk for osteoporosis.
b)Testosterone is most effective when it is
administered by injection.
c)Testosterone enanthate can be given less
often (every 4-6 weeks), for improved
convenience.
d)Testosterone therapy will decrease his risk
of fractures.
14. Which statement(s) about age-related
hypogonadism is/are TRUE?
a)It is associated with an increased rate of
mortality.
b)It is associated with an increased risk of
falls.
c)It can have a negative impact on relationships and work performance.
d) All of the above.
15. Some of the potential side effects of
testosterone injections include all of the
following EXCEPT:
a) Hepatotoxicity
b) Gynecomastia
c)“Roller coaster” effects (fluctuating side
effects and breakthrough symptoms)
d) Acne
16. Which test is NOT required at baseline
and then every 3 months for the first
year of testosterone therapy?
a) Hematocrit and hemoglobin
b)Liver function tests and cholesterol levels
c) Prostate Specific Antigen (PSA)
d) Digital rectal exam (DRE)
17. What should be recommended if Doug
experiences polycythemia while receiving
treatment?
a)Lower the dose or change to a different
dosage form with a lower risk of polycythemia
b) Stop testosterone therapy
c) Phlebotomy
d) Any of the above
18. Doug asks about some of the other
formulations of testosterone. Which
statement is FALSE?
a)Patients using testosterone gel should
avoid vigorous skin-to-skin contact at the
application site due to the risk of drug
transfer.
b)The most common side effect with testosterone patches is skin irritation or rash.
c)Testosterone undecanoate is associated
with the same risk of hepatotoxicity as
oral alkylated androgens.
d)Testosterone undecanoate is poorly absorbed if not taken regularly with meals.
19. What is a contraindication to testosterone therapy?
a) Prostate cancer
b) Mild-moderate obstructive BPH
c) Congestive heart failure (class I or II)
d) All of the above
20. Which statement is false?
a)Improvements in libido, mood, muscle
strength and bone density are usually
seen early in therapy (within 1-3 months).
b)The Aging Males’ Symptoms Rating Scale
can be used to objectively assess response
to testosterone therapy.
c)Patients receiving testosterone therapy
must commit to long-term monitoring of
efficacy and safety, including regular PSA
and DRE.
d)Patients should be encouraged to adopt
healthy lifestyle habits that may improve
their general well-being and may help to
improve testosterone levels.
FACULTY:
About the author
Christine Folia is a clinical pharmacist at the
Hamilton Health Sciences Corporation. She has
been involved in the development and delivery
of numerous education programs for healthcare professionals and patients in a variety of
therapeutic areas including
| Testosterone deficiency in aging men and its treatment
hypogonadism, erectile dysfunction, prostate cancer
and prostatitis. Christine is also a member of the
Ontario College of Pharmacists and the Canadian
College of Clinical Pharmacy.
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