1. health and fitness
2. disease

pplement to
Su
DE
CEM
01
BER 2
1
Testosterone Deficiency in Men
© Alfred Pasieka / Photo Researchers, Inc
More Common Than You Think
CPE grading online at www.cealliance.org/testing/CAE76711
This activity is supported by an educational grant from Abbott Laboratories and Lilly USA, LLC.
u.s. pharmacist
December 2011
CONTINUING
EDUCATION
Target Audience: Pharmacists
Release date: December 1, 2011
Expiration date: December 1, 2013
Type of Activity: Knowledge
This activity is supported by an educational grant from Abbott
Laboratories and Lilly USA, LLC.
Program Description: Testosterone deficiency is a highly prevalent
condition among aging men, particularly among those who are obese and
those with metabolic syndrome and type 2 diabetes. Increasingly
recognized as more than a marker of sexual function, testosterone is an
integral component of many metabolic pathways associated with body
composition, cardiometabolic risk profile, and general well-being. Recently
developed options in testosterone replacement therapy (TRT) are
improving tolerability and safety, allowing patients to replace testosterone
at near-normal physiologic levels with a low risk of adverse events. New
developments in TRT include higher-potency, lower volume transdermal
formulations that carry a lower risk of transference to partners.
Successful treatment depends on matching the patient’s needs, lifestyle,
and preferences with specific formulations. Pharmacists play an essential
role in educating patients about the value of TRT, explaining potential
complications associated with its use, and setting treatment expectations to
improve adherence and satisfaction with therapy.
Faculty Disclosure: All faculty and planners participating in continuing
education activities sponsored by Continuing Education Alliance are
expected to disclose to the audience any significant support or substantial
relationship(s) with providers of commercial products and/or devices
discussed in this activity and/or with any commercial supporters of the
activity. In addition, all faculty are expected to openly disclose any offlabel, experimental, or investigational use of drugs or devices discussed in
this activity. The faculty and planning committee have been advised that
this activity must be free from commercial bias, and based upon all the
available scientifically rigorous data from research that conforms to
accepted standards of experimental design, data collection, and analysis.
Dr E. Knezevich has nothing to disclose with regard to commercial
interests.
Dr J. Knezevich has nothing to disclose with regard to commercial
interests.
FACULTY
Emily L. Knezevich, PharmD, BCPS, CDE
Assistant Professor
Department of Pharmacy Practice
Creighton University School of Pharmacy and Health Professions
Omaha, Nebraska
The Planning Committee for this activity included Ruth Cohen and
Margaret Inman of Continuing Education Alliance. The members of the
Planning Committee have no significant relationships to disclose.
Disclaimer: The opinions or views expressed in this CPE activity do not
Jon T. Knezevich, PharmD, BCPS
Assistant Professor
Department of Pharmacy Practice
Creighton University School of Pharmacy and Health Professions
Omaha, Nebraska
necessarily reflect the opinions or recommendations of Continuing
Education Alliance, U.S. Pharmacist, Abbott Laboratories, or Lilly USA,
LLC.
How to Receive Credit:
Participants wishing to earn CPE credit must:
• Read the supplement.
• Relate the content material to the learning objectives.
• Complete the self-assessment questions and evaluation form online at:
www.cealliance.org/testing/CAE76711
ACCREDITATION
Continuing Education Alliance is accredited by the
Accreditation Council for Pharmacy Education as a
provider of continuing pharmacy education. This
program is approved for 2.0 contact hours (0.2 CEUs).
Universal Activity Number 0270-0000-11-002-H01-P.
After login, please enter the code: CAE76711
Successful completion of the self-assessment is required to earn CPE
credit. Successful completion is defined as a cumulative score of at least
70%. A certificate of credit will be automatically generated upon
successful completion of the activity.
The providers of this program have waived the processing fees.
The estimated time to complete this activity is 2 hours.
U.S.
INFORMATION
PHARMACIST
CONTINUING
EDUCATION
Goals: To educate pharmacists about national and international standards for screening, evaluation, and treatment of testosterone deficiency, to delineate common comorbidities, to describe treatment options for TRT, and to provide strategies for patient education.
Learning Objectives: After completing this activity, participants should be better able to:
• Discuss the important association of low testosterone with other comorbidities, including type 2 diabetes and metabolic syndrome
• Identify potential secondary causes of low testosterone levels using patient medication records
• Educate patients on the application/administration of TRT
Copyright 2011 by Jobson Medical Information LLC, 100 Avenue of the Americas, New York, NY 10013-1678. No part of this publication may be reproduced or transmitted by
any means, electronic or mechanical, or stored in any storage and retrieval system, without permission in writing from the publisher. U.S. PHARMACIST (ISSN 01484818;
USPS No. 333-490) is published monthly by Jobson Medical Information LLC, 100 Avenue of the Americas, New York, NY 10013-1678. Periodicals postage paid at New York,
NY and additional mailing offices. Acceptance of advertising in U.S. PHARMACIST does not constitute endorsement of the advertiser, its products or services. The opinions,
statements, and views expressed within this publication do not necessarily reflect those of Jobson Medical Information LLC or the editors of U.S. PHARMACIST.
PHS1102
u.s. pharmacist
1
December 2011
Testosterone Deficiency in Men
© Alfred Pasieka / Photo Researchers, Inc
More Common Than You Think
POPQUIZ
INTRODUCTION
Testosterone deficiency, or hypogonadism, is defined
by low levels of serum total testosterone (TT) and the
presence of associated signs and symptoms.1
Hypogonadism is almost always a chronic and irreversible disorder that, left untreated, can compromise sexual function, body composition, cardiometabolic profile,
and healthy aging.2 Testosterone replacement therapy
(TRT) can restore serum testosterone to normal physiologic levels and ameliorate many of the symptoms of
hypogonadism. Pharmacists play an important role in
the management of testosterone deficiency through
patient education and counseling, screening for drug
interactions and adverse events, and monitoring for
adherence and therapeutic response.
The biochemical definition of hypogonadism is controversial because there is no clear threshold for serum testosterone that distinguishes testosterone deficiency from
normal levels. Moreover, endogenous serum testosterone
levels vary widely as the result of circadian rhythms, episodic secretion, and fluctuations in sex hormone-binding globulin (SHBG) levels. Bioavailable or free testosterone (FT) appears to be a better indicator of testosterone status, but FT is more difficult to measure with current assays.3
In the absence of a more conclusive diagnostic test
for hypogonadism, the Endocrine Society defines the
lower limit of normal TT as ~300 ng/dL (10.4
nmol/L).1 As techniques for measuring serum testosterone improve, the threshold for normal may change. For
example, in a recent analysis of data from the
Framingham Heart Study, investigators used liquid
chromatography tandem mass spectrometry to measure
TT and FT in healthy nonobese men aged 19 to 40
years.4 Values below the 2.5th percentile of TT (348.3
Emily L. Knezevich, PharmD, BCPS, CDE
Creighton University School of Pharmacy
and Health Professions
Department of Pharmacy Practice
Omaha, Nebraska
Jon T. Knezevich, PharmD, BCPS
Creighton University School of Pharmacy
and Health Professions
Department of Pharmacy Practice
Omaha, Nebraska
u.s. pharmacist
Testosterone deficiency is defined by:
A. TT levels
B. Signs and symptoms
C. Both of the above
2
December 2011
ng/dL) and FT (70 pg/mL) were considered low. When
applied to cohorts from the Framingham Heart Study,
European Male Aging Study, and Osteoporotic Fractures
in Men Study, these TT and FT thresholds correctly
identified men with a higher prevalence of sexual dysfunction, physical dysfunction, and diabetes.4
POPQUIZ
PATHOPHYSIOLOGY
Testosterone production is regulated by the hypothalamic-pituitary-testicular (HPT) axis. Testosterone deficiency
can result from a disease of the testes (primary hypogonadism), defects of the pituitary or hypothalamus (secondary hypogonadism), or a combination of primary and
secondary causes.1 Measuring leuteinizing hormone (LH)
and follicle-stimulating hormone (FSH) levels can distinguish between these etiologies.1 Men with primary hypogonadism are expected to have low testosterone in association with elevated LH and FSH levels. By comparison,
men with secondary hypogonadism—also called hypogonadotropic hypogonadism—will have low testosterone
and low or normal LH and FSH levels.1
Testosterone levels may be adversely affected by acute
illness, nutritional deficiency, excessive exercise, and certain medications, including opiates and glucocorticoids.
Therefore, evaluation for testosterone deficiency should
exclude conditions that cause transient fluctuations in testosterone.1 For men with an initial TT measurement in
the mildly hypogonadal range, a repeat TT measurement
is necessary to confirm a low testosterone concentration.1
Clinicians should also consider the potential effects of
chronic health conditions and medications on a patient’s
testosterone level.1,9 In addition, aging, obesity, diabetes,
and other factors can alter SHBG and TT levels. In cases
of suspected hypogonadism and borderline TT level,
measuring or calculating bioavailable testosterone can
clarify the diagnosis.1,9
Additional diagnostic testing may be necessary to identify the cause of hypothalamic and/or pituitary dysfunction in men with secondary hypogonadism. These may
include hyperprolactinemia, hemochromatosis, pituitary
neoplasia, obstructive sleep apnea, and genetic diseases
associated with gonadotropin deficiency.1 For men with
primary testicular failure of unknown etiology, genetic
testing can exclude Klinefelter syndrome.1
The prevalence of testosterone deficiency:
A. Is highest in middle age
B. Increases with common comorbidities
such as obesity
C. Is higher in ethnic minorities in the
United States
POPQUIZ
POPQUIZ
In the Hypogonadism in Males (HIM) study of men
treated in the primary care setting, 38.7% of men aged
≥45 years tested positive for hypogonadism (TT <300 ng/
dL).5 Applied to U. S. census data, these findings suggest
that 13.8 million American men aged ≥45 years may be
testosterone-deficient.5 Furthermore, the prevalence of
testosterone deficiency increases with age, reaching 50%
for men aged ≥85 years.5 As the population ages, the burden of testosterone deficiency is expected to grow.6 The
prevalence of low testosterone also increases in men with
common comorbidities, such as obesity, diabetes, and
metabolic syndrome.7
Despite the availability of effective treatment, few
patients with hypogonadism receive appropriate therapy. In
the HIM study, <10% of men with biochemical hypogonadism were being treated with TRT.5 Therefore, according
to current estimates, 12.5 million American men aged ≥45
years have untreated testosterone deficiency.5
Many factors contribute to poor recognition of
hypogonadism. The symptoms of testosterone deficiency are nonspecific and may be attributed to other conditions. Patients may be reluctant to disclose sexual
symptoms—one of the most common presenting
symptoms of low testosterone—and physicians may be
reluctant to ask. Clinicians also face diagnostic barriers
that limit the timely recognition of hypogonadism,
including lack of consensus on the biochemical definition of testosterone deficiency and unreliability of
serum testosterone assays.8
Primary vs secondary hypogonadism can
be distinguished by:
A. TT and FT levels
B. Leuteinizing hormone and folliclestimulating hormone levels
C. Neither of the above
u.s. pharmacist
What is the most common symptom
associated with testosterone deficiency?
A. Erectile dysfunction
B. Loss of body hair
C. Low libido
D. Reduced vigor
CLINICAL PRESENTATION
Testosterone deficiency is associated with a spectrum of
clinical signs and symptoms. Given uncertainty about
the optimal biochemical threshold for hypogonadism,
symptoms play an important role in determining the
3
December 2011
presence and severity of testosterone deficiency.3 The
Endocrine Society recommends measuring serum testosterone levels in men with clinical manifestations of low
testosterone (TABLE 1) and in men with comorbid conditions associated with a high prevalence of androgen
deficiency (TABLE 2 ).1
Low libido is the most common presenting symptom of
hypogonadism.9 The association between hypogonadism
and sexual dysfunction is well documented. Up to 35% of
men with erectile dysfunction (ED) have low testosterone
levels, which contribute to the underlying pathophysiology
of ED.10 Testosterone regulates nitric oxide and phosphodiesterase-5 (PDE5) levels, which are important for normal
erectile function.10 Normal testosterone levels also are
important for other aspects of sexual function such as
orgasm and ejaculatory volume.11 Because of the mulitplicity of etiologies for ED, TRT does not always completely
reverse symptoms of this disorder.
Testosterone deficiency is also associated with a reduc-
POPQUIZ
tion in bone mineral density (BMD) in older (≥65 years)
men. The Osteoporotic Fractures in Men Study Group
reported that a comparison of osteoporotic men with
men with normal BMD showed the prevalence of TT
deficiency was 6.9% and 3.2% (P = .01).12 Other changes in body composition, including decreased muscle mass
and strength and increased body fat, also are symptoms of
testosterone deficiency.1
Memory, energy, and physical functioning also are
impaired in men with testosterone deficiency, leading to
an erosion in quality of life.13 In addition, hypogonadism
also adversely effects vitality, mood, and cognition, particularly in older men.14
Table1.SignsandSymptomsAssociated
WithTestosteroneDeficiency
Which is a common comorbidity
of testosterone deficiency?
A. Metabolic syndrome
B. Rheumatoid arthritis
C. Asthma
D. Overactive bladder
COMORBIDITIES
Growing beyond its role as a sex hormone, testosterone
is recognized increasingly as an important regulator of
metabolic homeostasis. Testosterone deficiency is associated with an interrelated array of adverse metabolic
parameters, including obesity, insulin resistance, hyperglycemia, hypertension, and dyslipidemia.3,15 Low testosterone levels also are associated with increased inflammation and endothelial dysfunction, which are major
risk factors for cardiovascular disease (CVD).3 Evidence
Measureserumtestosteroneinmenwith
thesesignsandsymptoms
• Incomplete sexual development, eunuchoidism,
aspermia
• Reduced libido and sexual activity
• Decreased spontaneous erections, poor morning
erection
• Erectile dysfunction
• Reduced muscle bulk and strength
• Low BMD, height loss, low-trauma fracture
• Breast discomfort, gynecomastia
• Loss of body (axillary and pubic) hair, reduced
shaving
• Very small or shrinking testes (especially <5 cm)
• Inability to father children, low or zero sperm counts
• Hot flushes, sweats
Table2.ComorbidConditionsAssociated
WithElevatedRiskofHypogonadism
• S
ellar mass, radiation to the sellar region, or other
diseases of the sellar region
• T reatment with medications that affect testosterone
production or metabolism, such as glucocorticoids,
ketoconazole, and opioids
Consideralsomeasuringinmenwith
• R
educed vigor: decreased energy, motivation,
initiative, aggressiveness, self-confidence
• Diminished physical or work performance
• Depressed mood: feeling sad or blue, dysthymia
• Poor concentration and memory
• Sleep disturbance, increased sleepiness
• Mild anemia (normochromic, normocytic, in the
female range)
• Increased body fat or BMI
• HIV-associated weight loss
BMD: bone mineral density; BMI: body mass index.
Source: Reference 1.
HIV: human immunodeficiency virus; T2DM: type 2 diabetes mellitus.
Source: Reference 1.
u.s. pharmacist
• E
nd-stage renal disease and maintenance
hemodialysis
• Moderate to severe chronic obstructive lung disease
• T2DM
• Metabolic syndrome
• Obesity
• Hemochromatosis
4
December 2011
metabolic syndrome, with each log-ng/mL increase in
bioavailable testosterone reducing cardiovascular mortality by 28% during the median follow-up of 15.6 years
(HR, 0.72; P = .03).19
linking testosterone deficiency to a multitude of comorbidities and adverse outcomes mandates a comprehensive screening and workup that includes testosterone
measurement in patients with these comorbidities. This
should improve the under-recognition and undertreatment of testosterone deficiency.
Diabetes
Type 2 diabetes mellitus (T2DM) affects one-third of
men aged ≥65 years, and the prevalence is expected to
increase 69% over the next 2 decades.17 Observational
studies consistently show that men with diabetes have
lower TT levels than nondiabetic controls.17 At least 25%
of men with T2DM have evidence of secondary hypogonadism, and an additional 4% have primary hypogonadism.20 Given the strong correlation between diabetes and
testosterone deficiency, the Endocrine Society recommends the routine measurement of testosterone in
patients with T2DM.20
The relationship between testosterone and T2DM is
complex and likely mediated by obesity.20 Still, several
studies suggest men with low testosterone are at a greater
risk of developing T2DM, and low testosterone may even
predict the onset of diabetes.21-27 In a meta-analysis of 43
diabetes studies including 6427 men, men with TT levels
449.6 to 605.2 ng/dL had a 42% lower risk of T2DM
compared with men with lower serum TT levels (RR,
0.58; 95% CI, 0.39-0.87) independent of adiposity.28
Furthermore, testosterone deficiency appears to worsen
cardiovascular outcomes in men with T2DM.29
Muraleedharan and colleagues recently evaluated the relationship between TT and cardiovascular mortality in a
study of men with T2DM (N = 587).30 At baseline, the
mean age of patients was 61 years, and 42% had serum
TT levels <300 ng/dL. Compared with normal TT levels,
testosterone deficiency more than doubled the risk of cardiovascular death during the 6-year follow-up period,
independent of age, BMI, HbA1c, pre-existing CVD,
smoking status, and use of angiotensin-converting
enzyme inhibitors or angiotensin-receptor blockers (HR,
2.2; P = .001).30
Obesity
Several measures of obesity correlate strongly with testosterone deficiency in men. In the National Health and
Nutrition Examination Survey (NHANES) III, TT and
FT decreased significantly with increasing body mass index
(BMI) (P <.05), waist circumference (P <.05), and body
fat percentage (P <.05).16 In the HIM study, obese men
were more than twice as likely as nonobese men to have
low testosterone levels (odds ratio [OR], 2.38).5 Obesity,
particularly the accumulation of excess visceral fat, appears
to activate a self-perpetuating cycle of insulin resistance,
systemic inflammation, and other metabolic derangements,
including decreased testosterone.17
Metabolic Syndrome
Metabolic syndrome describes a cluster of related cardiometabolic risk factors, including visceral obesity, insulin
resistance, hypertriglyceridemia, and hypertension. A
recent meta-analysis of 20 testosterone studies evaluated
the inverse relationship between metabolic syndrome and
testosterone deficiency.18 Controlling for age and BMI,
metabolic syndrome was an independent risk factor for
hypogonadism (P <.05). Low testosterone also predicted
metabolic syndrome: baseline TT levels were significantly
lower for men with new-onset metabolic syndrome than
for controls (2.17 nmol/L; P <.0001).18
Mechanisms underlying the interplay between testosterone and metabolic syndrome are not well understood.
Testosterone deficiency may be a downstream consequence of obesity, or it may drive accumulation of visceral fat and reduction of insulin-sensitive muscle
mass.18 Whatever the mechanism, metabolic syndrome
and testosterone deficiency are a particularly dangerous
combination. In an analysis of men aged ≥40 years in
the NHANES III study, Lin et al evaluated the effect of
low testosterone—defined as a calculated bioavailable
testosterone level <3.54 ng/mL (354 ng/dL)—in men
with and without metabolic syndrome.19 Men with metabolic syndrome and testosterone deficiency had nearly
twice the risk of cardiovascular mortality (hazard ratio
[HR], 1.90; P = .02) than men with metabolic syndrome alone (HR, 0.82; P = .95). Higher testosterone
protected against cardiovascular death in patients with
u.s. pharmacist
Cardiovascular Disease
Testosterone concentrations decline with aging, obesity,
and other risk factors for cardiovascular morbidity and
mortality. Low testosterone increases the risk of cardiovascular death in men with pre-existing metabolic syndrome and diabetes.19,30 However, whether testosterone
deficiency is itself a risk factor for CVD is not clear.
Testosterone deficiency may be a marker of underlying
disease processes associated with CVD rather than an
independent predictor of adverse outcomes.31
5
December 2011
nadism are observed is not known. For most symptoms, the lower threshold of normal is approximately
300 ng/dL (10.4 nmol/L).1
The Endocrine Society recommends TRT to restore
serum testosterone levels to within a range that is midnormal for healthy young men (400-700 ng/dL).1 Some
evidence suggests older hypogonadal men may need higher levels of testosterone, owing to age-related changes in
the sensitivity of target tissues to serum testosterone.2
Therefore, rather than aiming for specific biochemical
goals, treatment should be designed to improve serum
testosterone to levels sufficient to relieve the signs and
symptoms of testosterone deficiency.2
Although TRT was introduced into clinical practice to
improve sexual function in hypogonadal men, there is
increasing interest in the use of TRT to address the array
of adverse metabolic issues associated with testosterone
deficiency. Given the physiologic importance of testosterone to insulin sensitivity, inflammation, vasodilation, and
endothelial function, restoring optimal testosterone levels
has many potential benefits for men with hypogonadism.
Few trials have been powered to examine the relationship between testosterone and CVD, and results of metaanalyses have been inconsistent. In 2011, Ruige and colleagues evaluated testosterone levels in 19 prospective
studies of men who were at least 45 years of age and generally healthy at enrollment. Serum TT had a modest
protective benefit against incident CVD, but only in men
>70 years of age (RR, 0.84 for each standard deviation of
TT; 95% CI, 0.76-0.92). There was no apparent link
between testosterone deficiency and incident CVD in
men <70 years (RR, 1.01; 95% CI, 0.95-1.08). In another meta-analysis, Corona et al examined 70 studies enrolling patients with and without established CVD. Men
with any CVD had significantly lower mean serum TT
levels than men without CVD (−2.55 nmol/L; P
<.0001).32 Testosterone deficiency also was associated
with overall and cardiovascular mortality. Baseline TT
levels were significantly lower in men who died from any
cause (−1.53 nmol/L; 95% CI, −2.69 to −0.37) and in
those who died from cardiovascular causes (−0.97
nmol/L; 95% CI, −1.55 to −0.40).32
In the Corona meta-analysis, certain comorbidities such
as diabetes, obesity, and hypertension resulted in a more pronounced difference in TT levels between men with and
without CVD.32 Investigators also examined the role of obesity as a potential mediator of testosterone-related cardiovascular risk in a study of 1687 men with ED.33 In this population, there was a significant interaction between hypogonadism and BMI as risk factors for major cardiovascular adverse
events (MACE). Whereas testosterone deficiency significantly increased the risk of MACE in normal-weight men (HR,
6.361; P = .048), hypogonadism was paradoxically protective against MACE in obese men (HR, 0.097; P = .032).33
These findings underscore the complexity of interactions
among testosterone, obesity, and other pathways that contribute to cardiovascular risk, and the importance of tailoring
treatment to individual patient needs.
Lifestyle interventions aimed at weight loss are beneficial
for patients with hypogonadism, particularly those with
comorbid conditions that are exacerbated by obesity. In a
study of obese men with hypogonadism, metabolic syndrome, and T2DM, a 52-week program of diet and exercise resulted in significant increase in serum testosterone
level (P <.001) and improved glycemic control.33
Additional lifestyle interventions, including smoking cessation and avoidance of excess alcohol intake, also correlated with higher TT levels.34
POPQUIZ
POPQUIZ
Lifestyle Interventions
What is the goal of TRT?
A. Ameliorate symptoms of hypogonadism
B. Raise serum testosterone to normal
physiologic levels
C. Both a and b
TRT Administration
Native testosterone is challenging to administer orally or
parenterally because it is metabolized rapidly during first
hepatic passage. To overcome this barrier, certain chemical modifications to the molecular structure of testosterone have been introduced to slow the rate of absorption
and hepatic clearance (FIGURE).35
• Alkylation at the 17α position protects the testosterone molecule from being metabolized by the liver.
TREATMENT OF TESTOSTERONE DEFICIENCY
The goal of TRT is to ameliorate the symptoms of
hypogonadism by restoring serum testosterone to normal physiologic levels. The optimal biochemical target,
however, is controversial because the lower threshold of
serum testosterone below which symptoms of hypogo-
u.s. pharmacist
Formulations of TRT in the United States
include all of the following except:
A. Oral (swallowed)
B. Oral (transbuccal)
C. Transdermal (patch)
D. Pellets
6
December 2011
Testosterone
1α-alkylation retards hepatic
catabolism
2
O
3
1
19 11
10
4
5
18
12
9
6
8
7
OH
17
13
14
Esterification of 17β-hydroxil
improves lipophilicity, enabling
parental use
16
15
17α-alkylation retards hepatic
catabolism
Figure. Structural modifications associated with improved bioavailability and pharmacokinetics of testosterone.
Source: Reference 35.
normal endogenous production (3-10 mg/day)
• Reproduce testosterone fluctuations that match the
circadian rhythm
• Deliver serum testosterone that can be converted to its
metabolites at the desired concentrations, including
conversion to dihydrotestosterone (DHT) by 5-alpha
reductase activity (30-80 ng/dL) and to 17β-estradiol
by aromatase activity (20-50 pg/mL)
• Induce little or no negative effects on the prostate,
liver, or cardiovascular system
• Represent a convenient treatment option that hypogonadal men can manage autonomously
However, this modification increases the risk of liver
toxicity. Therefore, 17α-alkylated testosterone preparations such as methyltestosterone should be avoided35
• Alkylation at position 1 prevents premature metabolism without the risk of liver toxicity. Mesterolone is a
1-alkylated testosterone analogue available for oral
administration35
• Esterification of the 17β-hydroxyl group prevents
premature liver metabolism without the risk of liver
toxicity. This modification also improves the lipophilicity of testosterone, enabling intramuscular administration in an oil solution. However, because the resulting analogue has the same short half-life of native testosterone, it must be delivered via a delayed-release
depot injection to prolong its therapeutic effect.
Several 17β-hydroxyl-ester preparations are available
for intramuscular injection, including testosterone
enanthate, testosterone cypionate, testosterone propionate, and testosterone undecanoate (TU)35
OPTIONS FOR TRT
Transdermal Formulations
Transdermal testosterone preparations, including patches,
gels, and sprays, are used daily to provide stable serum
testosterone levels during treatment.
Patches: Testosterone patches can deliver testosterone to
the systemic circulation, increase testosterone levels to the
normal physiologic range, and mimic the normal circadian rhythm of serum testosterone levels. Scrotal patches,
which took advantage of rapid absorption through highly
vascularized scrotal skin, were first introduced in the
1990s. More recently, nonscrotal patches were introduced
and scrotal patches are no longer available. Nonscrotal
patches require an alcohol base to enhance skin absorption. The use of transdermal patches is limited by adverse
skin reactions at the patch site, including skin irritation
in approximately 32% of patients and allergic contact
dermatitis in 12%.44 Pretreatment with triamcinolone
Desirable Attributes of TRT
Testosterone therapy is available in various formulations
and delivery systems, each with advantages and disadvantages related to convenience, bioavailability, and tolerability (TABLE 3).1,35-43 In 2011, Giagulli and colleagues
described the ideal clinical and biochemical characteristics
of TRT.2 While no formulation fulfills all criteria, these
properties provide a useful framework for evaluating
available options.2 Ideally, TRT should:
• Raise circulating testosterone levels to strictly normal
physiologic ranges
• Provide a daily release of testosterone that is similar to
u.s. pharmacist
7
December 2011
Other advantages of testosterone gels include ease of use,
invisibility of application, and flexible dosing. Gels are
the most widely prescribed form of TRT for adult men in
the United States, reflecting the favorable efficacy, safety,
and tolerability of this testosterone delivery system.39
Until recently, the standard formulation for testosterone gel contained 1% testosterone, and the gel was
acetonide 0.1% under the patch can improve local tolerability.44 However, skin irritation, as well as the obtrusive
presence of patches on the skin, may reduce the acceptability of skin patches for many patients.
Topical gel: Testosterone gel provides a transdermal sys-
tem that avoids skin irritation associated with patches.
Table3.TRTFormulations
Formulation
Frequencyof
Administration Dose
Advantages
Disadvantages,
SideEffects,Precautions
Transdermal
gel
Daily
• Serum TT
• Need for daily administration
• Risk of transfer to partners and
5-10 g of a 1%-2%
testosterone
gel applied
to shoulders,
upper arms,
abdomen,
or upper and
inner thighs,
depending
on product
maintained
within normal
range
• Flexible dosing
• Less risk of
skin irritation
compared with
transdermal
patches
•
•
Transdermal
spray
Daily
1 pump actuation
of 30-mg
testosterone
to each axilla
Transdermal
patch
Every night
Buccal tablet
Every 12 h
One 5-mg, or one
5-mg plus one
2.5-mg patch(es)
applied over the
skin of the back,
thigh, or upper
arm, avoiding
pressure points
One 30-mg bioadhesive tablet
applied to buccal
mucosa
Subcutaneous
pellets
Intramuscular
injection
Every 3-6 mo
Every 1-2 wk
Implanted; dose
and regimen vary
with formulation
used, patient age,
diagnosis
75-100 mg,
testosterone
enanthate or
cypionate weekly
or 150-200 mg
every 2 wk
• Higher potency,
smaller surface
area
• Less “messy”;
applicator; does
not touch hands
• Mimics circadian
rhythm of
testosterone
release
• Simple
administration
• Serum TT
maintained
within normal
range
• Treatment only
twice per year
• Low cost
• Need for daily administration
• Skin reactions at the application
site: pruritus, 37%; burnlike
blister, 12%; erythema, 7%;
vesicles, 6%; burning, 3%;
induration, 3%
• Need for twice daily administration
• Gum or mouth irritation, 9.2%;
•
•
•
•
•
•
TT: total testosterone.
Source: References 1, 35-43.
u.s. pharmacist
•
•
8
December 2011
children via skin-to-skin contact
(risk diminished by newer, highpotency formulations applied to
smaller skin area)
Patients should wash hands after
applying gel, cover skin with
clothing, and wash skin before
skin contact to minimize risk of
secondary testosterone exposure
Rate of application-site reactions
varies from 2%-5% depending on
product and dosage
Need for daily administration
Absorption limited by small
surface area
gum pain, 3.1%; gum tenderness,
3.1%; gum edema, 2%; bitter taste,
4.1%; taste perversion, 2%.
Invasive placement
Inflammation and pain at
site of implantation
Infection
Expulsion of pellet
Associated with supraphysiologic
testosterone levels that fall to
hypogonadal range by end of
dosing interval
Fluctuations in mood, libido;
erythrocytosis (especially in older
men); pain at injection site
applied to the shoulders, upper arms, or abdomen,
depending on formulation and target dosage. The major
limitation of testosterone gel is the risk of testosterone
transfer from the patient to others via skin contact.45
Men treated with testosterone gel should be advised to
wash their hands after applying gel, cover medicated areas
with clothing, and wash before skin contact to minimize
risk of secondary testosterone exposure.37,42
Newer formulations of transdermal testosterone diminish the risk of transfer by reducing the surface area of skin
that must be treated or by targeting a more discreet application site. In 2011, the US Food and Drug
Administration (FDA) approved a new formulation of
1.62% testosterone gel. With increased viscosity and permeation, the concentrated formulation delivers the
desired testosterone dose within a lower volume of gel,
reducing the total mass of gel applied per day from 5.0 to
10.0 g with 1.0% gel to 1.25 g and 5.0 g with 1.62%
gel.39 The 1.62% concentration testosterone decreases the
overall surface area required for application.
Another new transdermal formulation, a 2% testosterone gel, is applied directly to the front and inner thighs
rather than the upper body.40 The gel is supplied in a 60-g
canister that uses a metered-dose pump to deliver 10 mg of
testosterone per pump actuation. Doses can be adjusted
between 10 mg (1 actuation) and 70 mg (7 actuations),
with a recommended starting dose of 40 mg applied to the
front and inner thighs once daily in the morning.40
are absorbed through the oral mucosa, avoiding intestinal
absorption and hepatic clearance. The sustained-release,
mucoadhesive tablets are applied twice daily to the upper
gums, where they soften, mold to the shape of the gum,
and gradually release unmodified testosterone with a halflife of 12 hours.35 The most common side effects include
gum or mouth irritation, pain, tenderness, and swelling;
bitter taste; and taste perversion.41
Underarm spray: Another recent addition to the transdermal arsenal is a 2% testosterone underarm spray,
approved for the treatment of hypogonadism in 2010 and
specifically designed to reduce the risk of testosterone
transfer.38 The delivery system uses a metered-dose pump
with a no-touch applicator to titrate the testosterone dose
from 30 mg (1 pump) to 120 mg (4 pumps). The recommended starting dose is 30 mg applied to each underarm
(60 mg total) at the same time each morning, with or
without prior use of deodorants or antiperspirants, and
no shaving requirement. As with other topical testosterone products, the underarm spray carries a boxed warning
regarding the potential for virilization in children with
secondary exposure to treated skin. Patients who use the
testosterone underarm spray should wash their hands
immediately after application, and avoid skin-to-skin contact with the unwashed or unclothed application sites
with others.38
Intramuscular Injection
Subcutaneous Testosterone Pellets
Subcutaneous testosterone pellets have been available
since the 1940s, and although no longer frequently used,
they remain the only long-acting testosterone treatment
available in the United States. In the typical procedure, 8
to 12 testosterone 75-mg pellets (total dose, 450-900 mg)
are implanted under the skin of the lower abdomen,
where they provide sustained release of unmodified testosterone for up to 6 months.46 Testosterone pellets are associated with possible inflammation and pain at site of
implantation,43 infection, and expulsion of pellets.1
Testosterone pellets are not the best choice for first-line
testosterone therapy, given their long-lasting effects and the
inconvenience of removing them. It may be preferable to
reserve them for patients who have shown response to and
tolerate TRT.47 Testosterone pellets may be an appropriate
alternative to testosterone gels for men who have a high
risk of secondary testosterone exposure to young children,
such as grandfathers who play a prominent caregiving role.
Intramuscular injection of testosterone esters may be an
appropriate option for some patients, particularly when
cost is an issue. Testosterone injections typically are
given every 2 weeks, beginning with a lower dose and
titrating upward. Testosterone injections are associated
with fluctuating serum levels over time—rising initially
to supraphysiologic levels and declining gradually to
hypogonadal levels by the end of the dosing interval—
leading to fluctuations in mood, libido, and general
well-being. Although these fluctuations can be reduced
by compressing the dosing interval to once a week, it
may not be possible to achieve stable testosterone concentrations without unacceptably frequent injections of
small doses of testosterone. In addition, the viscosity of
the testosterone formulation used for intramuscular
administration requires long (1.5 inch) and large-gauge
(usually 21 or 23 G) needles that may cause pain at the
injection site. An additional side effect includes erythrocytosis (especially in older men).1
An investigational, long-acting depot formulation of
Transbuccal Testosterone Tablets
Unlike traditional oral preparations, transbuccal systems
u.s. pharmacist
9
December 2011
when deciding whether testosterone therapy is appropriate, as this will help determine which patients will benefit
the most from treatment.
injectable testosterone undecanoate (TU) may be an
option for avoiding frequent testosterone injections.
After 2 initial loading doses, TU requires only 4 injections per year, compared with 26 injections for standard
twice-weekly intramuscular testosterone. A recent longterm study demonstrated the sustained efficacy and safety of TU injections given every 10 weeks over 21
months.48 If approved by the FDA, TU will be the first
intramuscular testosterone formulation available for
injection every 3 months.
Patient Preference
Successful TRT depends on matching the patient’s lifestyle and treatment expectations with an appropriate
method of delivery. Patients may have concerns about
specific delivery options, such as an aversion to needles
or gel odor. For some patients, cost may be an important factor, while others prioritize convenience. The
patient’s experiences with TRT or other therapies also
may influence current preferences and priorities.
Oral Testosterone Preparations
Oral TU is available in many countries and is under
review in the United States. Oral testosterone bypasses
hepatic clearance through lymphatic absorption to deliver
testosterone to the systemic circulation. Lymphatic
absorption of TU is highly dependent on the lipid content of the diet, however, and it must be taken with at
least 20 g of fat. Oral TU has been available in capsule
form dissolved in oleic acid since the 1970s and was
recently reformulated in a mixture of castor oil and propylene glycol laureate. The half-life of TU is approximately 4 hours, requiring 2 to 3 daily doses that result in an
irregular pattern of serum testosterone throughout the
day.35 A new formulation of oral TU, using a self-emulsifying drug delivery system (SEDDS) that promotes intestinal lymphatic absorption, is in development. In a phase
2 study, most hypogonadal men achieved stable testosterone levels in the normal physiologic range after 7 days of
treatment with a SEDDS formulation of oral TU 200 mg
twice daily, with no evidence of liver toxicity.49
Alkylated oral testosterone derivatives such as methyltestosterone and oxandrolone are associated with liver
toxicity and are not safe for long-term use. Novel formulations of non–alkylated testosterone may provide a safer
alternative for oral dosing. An investigational formulation
of slow-release oral testosterone is in development. In a
phase 1 study of healthy men with experimentally
induced hypogonadism, treatment with slow-release oral
testosterone 300 mg 3 times daily normalized serum testosterone levels after 9 days.9
Risk of Transference
For patients who are considering transdermal testosterone, it is important to assess and manage risk of transference. Compared with traditional 1% testosterone gel formulations, new transdermal formulations reduce risk of
transference by enabling patients to use a smaller volume
of gel and/or apply gel to discreet application sites such as
the underarms and upper and inner thighs.39,40 All
patients who initiate treatment with transdermal testosterone gel should be advised of the risk of transference
and trained in appropriate safety precautions as described
on product labeling.
Adherence
Poor medication adherence is a widespread problem in
patients with chronic conditions. Nonadherence decreases
therapeutic efficacy, leading to poor outcomes.
Pharmacists can encourage adherence by explaining the
value of treatment, keeping the regimen uncomplicated,
and customizing treatment to fit the patient’s lifestyle.
Counseling patients on the correct usage of testosterone
patches, gels, buccal tablets, and other delivery systems
can increase the likelihood of successful treatment.
Pharmacists can educate patients about expected side
effects and options for managing adverse events.
Adherence usually is better when the patient understands
that treatment is important, perceives that the regimen is
convenient, and is prepared to manage potential side
effects of treatment.50
TREATMENT CONSIDERATIONS
No TRT formulation perfectly replicates the daily endogenous production of testosterone. Treatment selection
therefore depends on patient preference, cost, factors that
may influence adherence, potential adverse effects, and
other considerations.1 The potential clinical benefits of
TRT should be weighed against risks. In addition, the
severity of testosterone deficiency should be considered
Contraindications
Men should be screened for absolute and relative contraindications before initiating TRT (TABLE 4).1 Repeat
screening is recommended throughout the treatment
course, as new conditions can arise that warrant treatment
modification or discontinuation. TRT is contraindicated
10
u.s. pharmacist
December 2011
TRT has a range of potential beneficial effects in men
with testosterone deficiency, including improved libido,
erectile function, body composition (reduced fat mass,
increased lean body mass), bone density, and mood.51-56
Patients should understand these potential benefits
when considering TRT.
associated with significant improvements in the total
BMSFI score (P <.001) and in each of the individual
domains of sex drive/libido, erectile function, ejaculatory
function, and level of bother. Importantly, treatment with
TRT significantly improved sexual function in the subgroup of men who were also taking PDE5 inhibitors (P
<.001). Therefore, findings from TRiUS demonstrate the
beneficial effects of 12 months of TRT on sexual function
in hypogonadal men, including men receiving concomitant treatment for ED.57
For some men with testosterone deficiency and
comorbid vascular disease, TRT alone may not be sufficient to improve sexual function. For instance, in obese
hypogonadal men with T2DM, TRT improves libido
but does not universally improve ED. Additional treatment with PDE5 inhibitors may be necessary to fully
restore sexual function.47
Sexual Function
Body Composition
Restoring testosterone levels improves overall sexual function in men with testosterone deficiency. The Testim
Registry in the United States (TRiUS) included 849 men
with hypogonadism who were treated with testosterone
1% transdermal gel.57 Sexual function was measured at
baseline and during the 12-month follow-up by the selfreported Brief Male Sexual Function Inventory (BMSFI).
With TRT, patients saw significant improvements in TT
and FT levels (P <.001), with TT reaching a mean of
500.6 ng/dL after 1 year. Testosterone normalization was
Treatment with TRT is associated with an overall
improvement in body composition, including a decrease
in fat mass and an increase in lean body mass and muscle strength.1 Normalization of testosterone levels also
appears to improve BMD in men with hypogonadism.1
Improvements in body composition are observed in men
of all ages. The Hormonal Regulators of Muscle and
Metabolism in Aging (HORMA) study evaluated testosterone supplementation in 122 older community-dwelling men (mean age 70.8 years).58 After 16 weeks of
treatment with transdermal testosterone, patients had a
significant increase in total lean body mass and appendicular lean tissue, as well as a significant decrease in
total fat mass and abdominal fat. Moreover, composite
upper and lower body muscle strength increased, as did
aerobic endurance.58 In a follow-up analysis of the
HORMA study, patients who made the greatest gains in
muscle strength and endurance during short-term treatment with TRT retained these benefits 3 months after
treatment was discontinued.59
in men with hormone-dependent cancers, including
breast cancer or metastatic prostate cancer, which may be
stimulated during testosterone treatment.1 The Endocrine
Society also cautions against TRT in men with a moderate-to-high risk of adverse events, including men with an
elevated risk of prostate cancer, erythrocytosis, untreated
obstructive sleep apnea, severe lower urinary tract symptoms, uncontrolled/untreated severe heart failure, or men
who wish to maintain their fertility.1
BENEFITS OF TRT
Table4.Contraindications
andPrecautionsforTRT
Highriskofseriousadverseevents
• Male breast cancer
• Metastatic prostate cancer
Moderate-to-highriskofadverseevents
• U
nevaluated prostate nodule or induration
• PSA >4 ng/mL for most men, or >3 ng/mL in men
with a high risk of prostate cancer (eg, African
American men and men with a first-degree relative
with prostate cancer)
• Hematocrit >50%
• Severe lower urinary tract symptoms (AUA/IPSS
score >19)
• Untreated obstructive sleep apnea
• Uncontrolled or poorly controlled congestive heart
failure
Cardiometabolic Profile
Several studies have identified favorable changes in lipid
parameters and other markers of cardiometabolic risk in
hypogonadal men undergoing treatment with TRT. One
meta-analysis showed treatment with TRT corrected
many components of metabolic syndrome, resulting in
loss of visceral fat, improved glucose tolerance, and an
increase in HDL.18 However, while these markers of cardiovascular risk change favorably, whether these changes
result in improved outcomes is being studied.
AUA: American Urological Association; IPSS: International Prostate
Symptom Score; PSA: prostate-specific antigen.
Source: Reference 1.
11
u.s. pharmacist
December 2011
The Testosterone Replacement in Hypogonadal Men
With Type 2 Diabetes and/or Metabolic Syndrome
(TIMES2) study evaluated the effects of TRT on insulin
resistance and cardiovascular risk factors in 220 hypogonadal men with T2DM or metabolic syndrome.60
Patients were randomly assigned to treatment with 3-g
metered-dose 2% transdermal testosterone gel (60 mg testosterone) or placebo gel once daily for 1 year. Many
patients also were taking concomitant oral antidiabetes
drugs such as metformin. Main findings from the
TIMES2 study included the following:
• Transdermal testosterone was associated with a reduction in insulin resistance of 15.2% at 6 months (P =
.006) and 16.4% at 12 months (P = .006) compared
with placebo
• In the subgroup of patients with diabetes, those in
the TRT arm had significantly better glycemic control at 9 months, as measured by a greater reduction
in mean HbA1c compared with placebo (−0.446%;
P = .035)
• TRT improved several lipid parameters in patients
with metabolic syndrome, leading to greater reductions
in lipoprotein a (−0.31 µmol/I; P = .008), total cholesterol (−0.336 mmol/L; P = .003), and low-density
lipoprotein cholesterol (LDL-C) (−0.210 mmol/L; P =
.012) compared with placebo. However, in the overall
study population, TRT decreased high-density lipoprotein cholesterol (HDL-C) compared with placebo
(−.049 mmol/L; P = .032).
Improvements in lipid profiles among men treated
with TRT may result from improvements in body composition, particularly loss of overall fat mass and reduction in abdominal obesity. However, beneficial changes
in cardiometabolic profile also have been observed in
patients who did not experience any significant changes
in body composition.60 Other studies of men undergoing treatment with TRT have found no changes in any
lipid parameters, including total cholesterol, HDL,
LDL, or triglyceride levels, between, before, and after
TRT.61 Another meta-analysis of TRT and cardiovascular safety found a modest decrease in HDL (−.49 mg/
dL; 95% CI, −.85 to −.13 mg/dL), but no other
adverse cardiovascular outcomes associated with testosterone therapy.62
TRTandProstateCancer:
CommonFearsvsClinicalEvidence
Some patients may ask about TRT and risk of prostate
cancer. In a recent meta-analysis from the Endogenous
Hormones and Prostate Cancer Collaborative Group,
there was no evidence of a link between serum
testosterone levels and prostate cancer risk.68 In
another recent meta-analysis of patients who received
TRT for 3 months to 3 years, there was no relationship
between testosterone therapy and prostate cancer, the
need for prostate biopsy, or other prostatic and urologic
outcomes, including PSA and lower urinary tract
symptoms.62
Protecting prostate health is an important
component of TRT monitoring. The risk of prostate
cancer must be assessed before starting TRT, and
treatment should not be started without further urologic
evaluation in patients with prostate cancer, a palpable
prostate nodule or induration, or a PSA level >3 ng/
mL.50 The Endocrine Society recommends PSA
surveillance at baseline and again after 3 to 6 months
in men aged ≥40 years with a baseline PSA >0.6 ng/
mL. Beyond 6 months of TRT, clinicians monitor prostate
health according to current prostate cancer screening
guidelines for the patient’s age and race. Although the
Endocrine Society suggests performing DRE as well as
measuring PSA to monitor for prostate cancer, some
experts disagree with this recommendation.69 Patients
should be referred for a urology consult if1:
• P
SA concentration rises by >1.4 ng/mL within any
12-month period during TRT
• P
SA velocity exceeds 0.4 ng/mL/y, using a PSA level
after 6 months of TRT as a reference and based on
>2 years of PSA measurements
• D
RE reveals a prostatic abnormality
• S
evere lower urinary tract symptoms are present
Researchers continue to examine the relationship
between testosterone deficiency and prostate health.
The Registry of Hypogonadism in Men (RHYME) is an
international registry of men with treated and untreated
testosterone deficiency.70 The registry will recruit 1000
men with primary hypogonadism, secondary
hypogonadism, and late-onset hypogonadism receiving
care in primary care and specialty practices. Patients
will undergo clinical and laboratory evaluation at
baseline, 3 to 6 months, 12 months, and 24 months.
The primary end point of the RHYME registry study is
the rate of positive prostate biopsy results in
hypogonadal men. Secondary end points will include
other measures of prostate health, such as benign
prostatic hyperplasia (BPH), as well as sexual function,
quality of life, and cardiovascular outcomes. Findings
from the RHYME registry study will provide important
information on the natural history of testosterone
deficiency and the safety and efficacy of TRT in
hypogonadal men.70
POPQUIZ
12
u.s. pharmacist
Risks of TRT include:
A. Erythrocytosis
B. Hypersomnia
C. Migraine headache
D. Osteoporosis
December 2011
disease, including hypertension, diabetes, hyperlipidemia, and obesity.65 Compared with men in the placebo
group, men in the TRT group had significantly greater
increases in leg-press strength, chest-press strength, and
stair-climbing power while carrying a load. However,
during the 6-month study period, 23 men in the testosterone group had cardiovascular-related adverse events,
including hypertension and MI, compared with 5 men
in the placebo group. The finding of excess cardiovascular risk in the TRT group mandated that the TOM
study be discontinued early.65 The study authors cautioned against extrapolating these findings to other
patient populations, particularly to younger men with
testosterone deficiency without established CVD or limitations in mobility.65
POTENTIAL RISKS OF TRT
Erythrocytosis
Increases in hemoglobin and hematocrit are the most frequent adverse events observed with TRT. In a meta-analysis of 51 trials, TRT was associated with an increase in
mean hemoglobin (0.80 g/dL, 95% CI, 0.45-1.14 g/dL)
and hematocrit (3.18%, 95% CI, 1.35%-5.01%) compared with placebo.62 TRT also increased the risk of
erythrocytosis compared with placebo (RR, 3.15; 95%
CI, 1.56-6.35), although this effect is dose-related and is
often managed with dose reduction.62 The clinical significance of these findings on patient outcomes is unclear.
Cardiovascular Risk
The role of TRT in men with cardiovascular disease
remains contentious. It appears to reduce risk in
advanced cardiac failure.63 Adverse cardiovascular
events, however, have been reported, including myocardial infarction (MI) and depressed ventricular function. These events typically occur in patients who take
supraphysiologic testosterone doses, such as anabolic
steroid users.63 In general, it appears that testosterone
can be used safely in hypogonadal men with established CVD.63,64 Patients should be monitored during
TRT to ensure that testosterone levels remain in physiologic ranges.63
TRT may increase cardiovascular risk factors in certain high-risk populations. The Testosterone in Older
Men with Mobility Limitations (TOM) trial evaluated
safety and efficacy of treatment with 1% testosterone gel
in a population of 209 older men (mean age, 74 years)
with limited mobility and a high prevalence of chronic
Other Adverse Events
Testosterone injections are associated with peak and
trough serum testosterone concentrations, increasing the
risk of mood swings. This may be an important consideration for patients with comorbid psychiatric illness.
Hepatotoxicity is a concern with oral testosterone formulations, which are not available in the United States.
Other adverse events include acne and reduced sperm
production.1
MONITORING RECOMMENDATIONS
Monitoring Testosterone Levels
The Endocrine Society recommends measuring testosterone levels 3 to 6 months after initiating therapy.1
Endogenous testosterone levels follow a circadian
rhythm, with highest levels in the morning. Therefore,
Table5.TRTMonitoringStrategies
Parameter
Schedule
Comments
Testosterone level
After 3-6 mo
TRT should aim to raise serum testosterone to mid-normal range
Hematocrit
Baseline, after
3-6 mo, then annually
If hematocrit is >54%, discontinue TRT until hematocrit
decreases to safe level; exclude hypoxia or sleep apnea; resume
TRT with a reduced dose
BMD
After 1-2 y
Measure in hypogonadal men with osteoporosis
or low trauma fracture
PSA and DRE
Baseline, after 3-6 mo, then
in accordance with standard
screening guidelines
Measure in men aged ≥40 y with baseline PSA >0.6 ng/mL
Adverse events
Every office visit
Monitor for formula-specific adverse events, such as skin
reactions (patch) or changes in taste (buccal tablets)
BMD: bone mineral density; DRE: digital rectal examination; PSA: prostate-specific antigen; TRT: testosterone replacement therapy.
Source: Reference 1.
13
u.s. pharmacist
December 2011
testosterone should be measured in a nonfasting blood
sample taken between 7:00 am and 11:00 am, or within
a few hours of waking in nightshift workers and others
with nontraditional sleep/wake schedules.1
Need for Referral
In collaborative care settings, multidisciplinary healthcare
providers work together to select appropriate therapy and
assess therapeutic outcomes. Collaborative-care models that
include pharmacists have improved outcomes in a range of
complex chronic conditions, including mental health disorders and chronic kidney disease.66,67 As central members of
the care team, pharmacists provide guidance on initiating,
modifying, and discontinuing drug therapy; provide
patient counseling and education; and identify and resolve
potential and actual drug-related problems. Pharmacists
can refer patients to other healthcare providers as warranted. Patients who fail to respond to treatment, lose response
after an initial benefit, or have adverse events may need to
be re-evaluated for a change in underlying disease status. In
particular, patients in whom new prostate or urinary symptoms develop should be assessed by a urologist.1
Other Monitoring Recommendations
Patients should receive ongoing assessments of response
and adherence to treatment with TRT (TABLE 5). This
includes an evaluation of formulation-specific adverse
effects at every office visit.1
The patient’s hematocrit should be measured at 3 to 6
months after treatment initiation and then annually, and
TRT should be stopped if hematocrit exceeds 54%.1 If
the hematocrit later decreases to normal levels and evaluation reveals no contraindication such as hypoxia or sleep
apnea, TRT may be resumed at a reduced dose.1 In men
with osteoporosis or a history of low-trauma fracture,
BMD should be measured at the lumbar spine, femoral
neck, and hip 1 to 2 years after TRT initiation.1 Prostatespecific antigen (PSA) test and digital rectal exam (DRE)
should be assessed at baseline, after 3 to 6 months, and
then in accordance with standard prostate cancer screening guidelines.1
CONCLUSIONS
Testosterone deficiency is a highly prevalent condition
among aging men, particularly among men who are
obese and in those with metabolic syndrome, T2DM,
and other chronic conditions. Increasingly recognized as
more than a marker of sexual function, testosterone is
now understood to be an integral component of many
metabolic pathways associated with body composition,
cardiometabolic risk profile, and general well-being.
New and emerging options for TRT may improve tolerability and treatment adherence, allowing patients to
replace testosterone at near-normal physiologic levels
with a low risk of adverse events. Successful treatment
depends on matching the patient’s needs, lifestyle, and
preferences with specific formulations. Pharmacists play
an essential role in educating patients about the value of
TRT, explaining potential complications associated with
its use, and setting treatment expectations to improve
adherence and satisfaction with therapy.
Treatment Modification
For the patient who does not achieve an adequate
response to TRT within 3 to 6 months of starting therapy, an additional workup may be required to identify
other factors contributing to the clinical presentation.
This may include a shift in the relative contribution of
primary and secondary hypogonadism that warrants a
change in treatment plan. Treatment adherence also
should be assessed. For patients with poor adherence to
TRT, a change in formulation may improve treatment
success. Changes in dosing also may be needed, keeping
in mind that serum testosterone levels should not exceed
the normal physiologic range.
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14
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December 2011
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NOTES
This Continuing Education article is supported by an educational grant from Abbott Laboratories and Lilly USA, LLC.