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Clinical Guidelines
Disclaimer: Clinical Practice Guidelines are developed to be of assistance to endocrinologists and other health
care professionals by providing guidance and recommendations for particular areas of practice. The Guidelines
should not be considered inclusive of all proper approaches or methods, or exclusive of others. The Guidelines
cannot guarantee any specific outcome, nor do they establish a standard of care. The Guidelines are not
intended to dictate the treatment of a particular patient. Treatment decisions must be made based on the inde-
pendent judgment of health care providers and each patient’s individual circumstances.
Testosterone Therapy in Adult Men
The Endocrine Society makes no warranty, express or implied, regarding the Guidelines and specifically
with Androgen Deficiency Syndromes:
excludes any warranties of merchantability and fitness for a particular use or purpose. The Society shall not be
liable for direct, indirect, special, incidental, or consequential damages related to the use of the information An Endocrine Society Clinical Practice Guideline
contained herein.
First published in Journal of Clinical Endocrinology & Metabolism, June 2010, Vol. 95(6):2536–2559.
This revised guideline replaces the previous version published in 2006: Bhasin S, Cunningham GR, Hayes FJ,
Matsumoto AM, Snyder PJ, Swerdloff RS, Montori, VM 2006 Testosterone Therapy in Adult Men with Androgen
Deficiency Syndromes: An Endocrine Society Clinical Practice Guideline (J Clin Endocrinol Metab 91:1995–
2101l doi: 10.1210/jc.2005–2847)
Clinical Guidelines
Summary of Recommendations.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Diagnosis of Hypogonadism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Order Form. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Objective: To update the guidelines for the evalua- Conclusions: We recommend making a diagnosis of
tion and treatment of androgen deficiency syndromes androgen deficiency only in men with consistent
in adult men published previously in 2006. symptoms and signs and unequivocally low serum
testosterone levels. We suggest the measurement of
Participants: The Androgens in Men Guideline Task morning total testosterone level by a reliable assay as
Force was composed of a chair, selected by the Clin- the initial diagnostic test. We recommend confirma-
ical Guidelines Subcommittee of The Endocrine tion of the diagnosis by repeating the measurement of
Society, five additional experts, a methodologist, and morning total testosterone and in some men in whom
a medical writer. The Task Force received no corpo- total testosterone is near the lower limit of normal or
rate funding or remuneration. in whom sex hormone binding globulin (SHBG)
abnormality is suspected by measurement of free or
Evidence: This evidence-based guideline was devel-
bioavailable testosterone level, using validated assays.
oped using the Grading of Recommendations, Assess-
We recommend testosterone therapy for men with
ment, Development, and Evaluation (GRADE)
symptomatic androgen deficiency to induce and main-
system to describe the strength of recommendations
tain secondary sex characteristics and to improve
and the quality of evidence.
their sexual function, sense of well-being, muscle mass
Consensus Process: Consensus of this guideline was and strength, and bone mineral density. We recom-
guided by systematic reviews of evidence and discus- mend against starting testosterone therapy in patients
3
In men with primary testicular failure of unknown
SUMMARY OF etiology, we suggest obtaining a karyotype to exclude
Klinefelter syndrome, especially in those with testic-
RECOMMENDATIONS ular volume less than 6 ml. (2| )
We suggest measurement of bone mineral density
1.1. DIAGNOSIS AND EVALUATION by using dual-energy x-ray absorptiometry (DXA)
OF PATIENTS WITH SUSPECTED scanning in men with severe androgen deficiency or
ANDROGEN DEFICIENCY low trauma fracture. (2| )
4
We recommend against testosterone therapy in to a safe level, evaluate the patient for hypoxia and
patients with hematocrit above 50%, untreated severe sleep apnea, and reinitiate therapy at a reduced dose.
obstructive sleep apnea, severe lower urinary tract (1| )
symptoms [American Urological Association (AUA)/ We suggest repeating bone mineral density of the
International Prostate Symptom Score (IPSS) 19], or lumbar spine, femoral neck, and hip after 1 to 2 years
uncontrolled or poorly controlled heart failure, or in of testosterone therapy in hypogonadal men with
those desiring fertility. (1| ) osteoporosis or low trauma fracture. (2| )
We suggest initiating testosterone therapy with In men 40 years of age or older who have a base-
any of the following regimens, chosen on the basis of line PSA > 0.6 ng/ml, we recommend digital exami-
the patient’s preference, consideration of pharmacoki- nation of the prostate and PSA measurement before
netics, treatment burden, and cost. (2| ) initiating treatment, at 3 to 6 months, and then in
• 75–100 mg of testosterone enanthate or cypio- accordance with evidence-based guidelines for pros-
nate administered intramuscularly (IM) weekly, tate cancer screening, depending on the age and race
or 150–200 mg administered every 2 weeks. of the patient. (1| )
• One or two 5-mg nongenital, testosterone patches We recommend that clinicians obtain urological
applied nightly over the skin of the back, thigh, consultation if there is: (1| )
or upper arm, away from pressure areas. • An increase in serum or plasma PSA concentra-
• 5–10 g of a 1% testosterone gel applied daily over tion greater than 1.4 ng/ml within any 12-month
a covered area of nongenital skin (patients should period of testosterone treatment.
wash hands after application). • A PSA velocity of more than 0.4 ng/ml·yr using
• 30 mg of a bioadhesive buccal testosterone tablet the PSA level after 6 months of testosterone
applied to buccal mucosa every 12 hours. administration as the reference. PSA velocity
• Testosterone pellets implanted subcutaneously at should be used only if there are longitudinal PSA
intervals of 3 to 6 months; the dose and regimen data for more than 2 years.
vary with the formulation used. • Detection of a prostatic abnormality on digital
• Oral testosterone undecanoate, injectable testos- rectal examination.
terone undecanoate, testosterone-in-adhesive • AUA/IPSS score > 19.
5
2.2. TESTOSTERONE THERAPY IN MEN
WITH SEXUAL DYSFUNCTION Method of Development
We suggest that clinicians offer testosterone therapy of Evidence-Based Clinical
to men with low testosterone levels and low libido to
Practice Guidelines
improve libido (2| ) and to men with erectile
dysfunction (ED) who have low testosterone levels
after evaluation of underlying causes of ED and The Clinical Guidelines Subcommittee of The
consideration of established therapies for ED. Endocrine Society deemed testosterone therapy in
(2| ) androgen-deficient men a priority area in need of
practice guidelines and appointed a Task Force to
2.3. OLDER MEN WITH LOW SERUM formulate evidence-based recommendations. The
TESTOSTERONE CONCENTRATION Task Force elected to use the approach recommended
by the Grading of Recommendations, Assessment,
We recommend against a general policy of offering Development, and Evaluation (GRADE) workgroup,
testosterone therapy to all older men with low testos- an international group with expertise in development
terone levels. (1| ) and implementation of evidence-based guidelines (1).
We suggest that clinicians consider offering
testosterone therapy on an individualized basis to The Task Force used systematic reviews of available
older men with low testosterone levels on more than evidence and two commissioned systematic reviews
one occasion and clinically significant symptoms of (2–4) to inform its key recommendations and consis-
androgen deficiency, after explicit discussion of the tent language. The Task Force also used consistent
uncertainty about the risks and benefits of testos- language and graphical descriptions of both the strength
terone therapy. (2| ) of a recommendation and the quality of evidence. The
strength of a recommendation is indicated by the
number 1 (strong recommendation, associated with the
2.4. PATIENTS WITH CHRONIC ILLNESS
phrase “we recommend”) or 2 (weak recommendation,
AND LOW TESTOSTERONE LEVELS
associated with the phrase “we suggest”). The quality of
We suggest that clinicians consider short-term testos- the evidence is indicated by cross-filled circles, such that
terone therapy as an adjunctive therapy in HIV- denotes very low quality evidence; ,
infected men with low testosterone levels and weight low quality; , moderate quality; and ,
loss to promote weight maintenance and gains in lean high quality. The Task Force has confidence that persons
body mass (LBM) and muscle strength. (2| ) who receive care according to the strong recommenda-
An Endocrine Society Clinical Practice Guideline
6
The age-related decline in testosterone levels,
1.0. DIAGNOSIS OF confirmed in several cross-sectional and longitudinal
studies (7–9), results from defects in both testicular
HYPOGONADISM and hypothalamic-pituitary function. The average
decline in serum testosterone levels with aging in men
Definition of hypogonadism. Hypogonadism in men is 1–2% per year (7, 8). A significant fraction of older
is a clinical syndrome that results from failure of the men have levels below the lower limit of the normal
testis to produce physiological levels of testosterone range for healthy, young men (8, 9).
(androgen deficiency) and a normal number of sper-
matozoa due to disruption of one or more levels of the 1.1. DIAGNOSIS AND EVALUATION
hypothalamic-pituitary-testicular (HPT) axis. OF PATIENTS WITH SUSPECTED
ANDROGEN DEFICIENCY
Classification of hypogonadism. Abnormalities of
the HPT axis at the testicular level cause primary
1.1.A. Recommendations
testicular failure, whereas central defects of the
hypothalamus or pituitary cause secondary testicular We recommend making a diagnosis of androgen defi-
failure. Hypogonadism also can reflect dual defects ciency only in men with consistent symptoms and signs
that affect both the testis and the pituitary. and unequivocally low serum testosterone levels.
(1| )
• Primary testicular failure results in low testos-
terone levels, impairment of spermatogenesis, We suggest that clinicians measure serum testosterone
and elevated gonadotropin levels. level in patients with clinical manifestations shown in
• Secondary testicular failure results in low testos- Table 1. We suggest that clinicians also consider
terone levels, impairment of spermatogenesis, measuring serum testosterone level when patients report
and low or low-normal gonadotropin levels. the less specific symptoms and signs listed in Table 1.
• Combined primary and secondary testicular (2| )
failure results in low testosterone levels, impair-
We suggest the measurement of morning total testos-
ment of spermatogenesis, and variable gonado-
7
TABLE 1. Symptoms and signs suggestive of androgen In population-based surveys of community-dwelling
deficiency in men middle-aged and older men, low libido, ED and hot
flushes, as well as less specific symptoms such as fatigue
A. More specific symptoms and signs or loss of vigor, irritability or depressed mood, poor
concentration, reduced physical performance, or sleep
• Incomplete or delayed sexual development,
eunuchoidism disturbance, were associated with low testosterone
• Reduced sexual desire (libido) and activity levels (10–12). In these surveys, the crude prevalence
• Decreased spontaneous erections of symptomatic androgen deficiency was ~6% in the
• Breast discomfort, gynecomastia population of middle-aged to older men and increased
• Loss of body (axillary and pubic) hair, reduced shaving with age, waist circumference, and poor self-reported
• Very small (especially <5 ml) or shrinking testes health status, but was unrelated to race and ethnicity
• Inability to father children, low or zero sperm count (12). In other population-based studies, the preva-
• Height loss, low trauma fracture, low bone lence of low testosterone irrespective of symptoms
mineral density
was associated with age, obesity, diabetes, and comor-
• Hot flushes, sweats
bidities or health status (9, 12, 13). The overall
B. Other less specific symptoms and signs prevalence of low testosterone was found to be higher
• Decreased energy, motivation, initiative, and
in a primary care practice–based population of patients
self-confidence than that reported in populations of community-
• Feeling sad or blue, depressed mood, dysthymia dwelling men (14).
• Poor concentration and memory
• Sleep disturbance, increased sleepiness The threshold testosterone level below which symp-
• Mild anemia (normochromic, normocytic, in the toms of androgen deficiency and adverse health
female range) outcomes occur and testosterone administration
• Reduced muscle bulk and strength improves outcomes in the general population is not
• Increased body fat, body mass index known. However, in healthy men as well as in referral
• Diminished physical or work performance
patient populations, the threshold of testosterone
levels varied for various symptoms of androgen defi-
substantially different from that resulting from onset ciency and target organs, and among individuals
in the fetal or prepubertal period. In contrast to men (11, 12, 15). For most symptoms, the average testos-
whose hypogonadism is of postpubertal onset, men terone threshold corresponded to the lower limit of
whose hypogonadism is of prepubertal onset and who the normal range for young men, i.e., ~300 ng/dl
were not adequately treated will exhibit eunuchoid (10.4 nmol/l) with a greater likelihood of having
proportions, delayed development of secondary sex symptoms below this threshold than above it (11, 15).
An Endocrine Society Clinical Practice Guideline
8
measurement for the diagnosis of androgen deficiency TABLE 2. Conditions associated with alterations in
should be performed in the morning. It has been SHBG concentrations
argued that morning testosterone measurements are
not needed in older men in whom the circadian Conditions associated with decreased SHBG
concentrations
rhythm is blunted. However, a substantial fraction of
• Moderate obesity*
older men, 65 to 80 years of age, has low serum testos-
• Nephrotic syndrome*
terone levels in the afternoon will have normal testos-
• Hypothyroidism
terone concentrations in the morning (17). • Use of glucocorticoids, progestins, and androgenic
steroids*
It is important to confirm low testosterone concentra- • Acromegaly
tions in men with an initial testosterone level in the • Diabetes mellitus*
mildly hypogonadal range, because 30% of such men
may have a normal testosterone level on repeat Conditions associated with increased SHBG
measurement (17). Also, 15% of healthy young men concentrations
may have a testosterone level below the normal range • Aging*
9
The normative ranges for total and free testosterone 1.1.1. FURTHER EVALUATION OF MEN
levels in healthy young men vary among laboratories DEEMED ANDROGEN DEFICIENT
and assays (18). In some laboratories, the lower limit (FIG. 1)
of the normal range for total testosterone level in
healthy young men is 280-300 ng/dl (9.8-10.4 nmol/l). 1.1.1.A. Recommendations
Similarly, in some reference laboratories, the lower We recommend measurement of serum LH and FSH
limit of the normal range for serum free testosterone levels to distinguish between primary (testicular) and
level, measured by the equilibrium dialysis method, is secondary (pituitary-hypothalamic) hypogonadism.
5–9 pg/ml (0.17-0.31 nmol/l). The clinicians should (1| )
use the lower limit of normal range for healthy young
men established in their laboratory. In men with secondary hypogonadism, we suggest further
evaluation to identify the etiology of hypothalamic and/
The assessment of men for androgen deficiency should or pituitary dysfunction. This evaluation may include
include a general health evaluation to exclude systemic measurements of serum prolactin and iron saturation,
illness, use of certain medications (e.g., opiates or pituitary function testing, and magnetic resonance
high-dose glucocorticoid therapy) and recreational imaging of the sella turcica. (2| )
drugs that affect testosterone production or metabo-
lism, eating disorders, and excessive exercise because In men with primary testicular failure of unknown
these conditions can lower testosterone levels tran- etiology, we suggest obtaining a karyotype to exclude
siently (5). Long-acting opioid analgesics suppress the Klinefelter syndrome, especially in those with testicular
hypothalamic-pituitary-gonadal (HPG) axis in men, volume less than 6 ml. (2| )
produce symptomatic androgen deficiency, and are
associated with increased risk of osteoporosis (22, 23). In men being evaluated for infertility, we recommend
The suppression of testosterone is particularly profound obtaining at least two seminal fluid analyses. (1| )
in men on methadone maintenance therapy because of
We suggest measurement of bone mineral density by
its long duration of action; buprenorphine suppresses
using dual-energy x-ray absorptiometry (DXA) scanning
plasma testosterone to a lesser extent than methadone
in men with severe androgen deficiency or low trauma
(24). Androgen deprivation therapy using gonado-
fracture. (2| )
tropin-releasing hormone (GnRH) analogs in men
with prostate cancer has emerged as an important
1.1.1.B. Evidence
cause of therapeutically induced androgen deficiency
that is associated with increased risk of sexual dysfunc- Measurement of LH and FSH concentrations can
tion, fatigue, fractures, cardiovascular disease, and help distinguish between primary and secondary
An Endocrine Society Clinical Practice Guideline
diabetes (25). The diagnosis of androgen deficiency hypogonadism. Men with primary hypogonadism
should not be made during an acute illness. have low testosterone levels in association with
elevated LH and FSH levels, while men with
1.1.C. Values secondary hypogonadism have low testosterone levels
in association with low or inappropriately normal LH
Our proposed diagnostic strategy reflects our prefer-
levels. Because LH is secreted in a pulsatile manner by
ence to avoid labeling men with low testosterone
the pituitary, serum LH levels in men with secondary
levels due to SHBG abnormalities, natural variations
hypogonadism may be below the normal range or in
in testosterone levels, or transient disorders as
low-normal range but clearly inappropriate in relation
requiring testosterone therapy. Our strategy also
to the low testosterone concentrations. In individuals
reflects our preference to avoid treatment in men
with complete idiopathic hypogonadotropic hypogo-
without unequivocally low testosterone levels and
nadism (e.g., Kallmann syndrome) and severe gonad-
symptoms in whom the benefits and risks of testos-
aotropin suppression or deficiency, LH pulsatility may
terone therapy remain unclear.
be absent or markedly suppressed and these men
10
FIG. 1. An approach for the diagnostic evaluation of adult men suspected of having androgen deficiency. FSH = follicle-
stimulating hormone; LH = luteinizing hormone; MRI=magnetic resonance imaging; SFA,=seminal fluid analysis; SHBG =
sex hormone-binding globulin; T = testosterone
Low T # Follow up
usually have very low testosterone and LH levels. In obstructive sleep apnea, and genetic disorders associ-
most clinical laboratories, LH levels are measured ated with gonadotropin deficiency. The measurement
using nonradioactive immunometric assays that have of serum prolactin and iron saturation can help deter-
sufficient sensitivity to distinguish between normal mine the presence of hyperprolactinemia and hemo-
and low levels. chromatosis, respectively. Assessment of anterior
pituitary function, if clinically indicated or in the
In men deemed to have secondary hypogonadism, presence of severe secondary hypogonadism (testos-
additional diagnostic evaluation may be needed to terone level <150 ng/dl [<5.2 nmol/l]), can uncover
exclude pituitary neoplasia, hyperprolactinemia, other pituitary hormone deficiencies. A diagnosis of
hemochromatosis and other infiltrative diseases,
11
idiopathic hypogonadotropic hypogonadism is made separated by an interval of several weeks should be
after excluding other causes of hypogonadotropic performed on semen samples collected within 1 hour
hypogonadism. Patients with hypogonadotropic of ejaculation after at least 48 hours of abstinence.
hypogonadism should be examined for dysmorphic
features—such as extreme obesity (e.g., Prader-Willi The cost-effectiveness of these diagnostic strategies
Syndrome), polydactyly, anosmia (e.g., Kallmann has not been evaluated in clinical trials.
syndrome), short stature (e.g., contiguous gene dele-
tions of chromosome X), or kidney abnormalities 1.1.1.C. Values
(e.g., Kallmann syndrome)—to facilitate recognition Our recommended diagnostic strategy places a rela-
of specific syndromes by pattern recognition. tively higher value in detecting conditions (e.g.,
pituitary neoplasia or other treatable pituitary disor-
In the evaluation of men with secondary hypogo- ders) for which effective treatment or counseling is
nadism, the cost-effectiveness of pituitary imaging available. This strategy places a relatively lower
MRI to exclude pituitary and/or hypothalamic tumor value in avoiding the burden and cost of tests with
is unknown. Surveys of men with secondary hypogo- unknown yield.
nadism and sexual dysfunction have revealed a low
prevalence of hypothalamic-pituitary abnormalities
(26, 27). The diagnostic yield of pituitary imaging to 1.2. SCREENING FOR ANDROGEN
exclude pituitary and/or hypothalamic tumor can be DEFICIENCY
improved by performing this procedure in men with
serum testosterone below 150 ng/dl (26), panhypopi- 1.2.1. Screening in the general population
tuitarism, persistent hyperprolactinemia, or symptoms
of tumor mass effect (headache, visual impairment, or 1.2.1.A. Recommendation
visual field defect). We recommend against screening for androgen deficiency
in the general population. (1| )
Karyotype can be useful in excluding Klinefelter
syndrome ─ a common identifiable cause of primary 1.2.1.B. Evidence
testicular failure ─ in men with primary testicular
Because of the lack of consensus on a case definition
failure, especially in those with testicular volume less
and the extent to which androgen deficiency is an
than 6 ml, although men with mosaic Klinefelter
important health problem, as well as the lack of data
syndrome may have larger testicular volumes. The
on the performance characteristics of candidate
karyotype obtained from peripheral blood lympho-
screening tools, the usefulness of population
cytes may be normal (46, XY) in men with Klinefelter
screening cannot be evaluated at present. The long-
An Endocrine Society Clinical Practice Guideline
12
it. No clinical trials have assessed the effectiveness TABLE 3. Conditions in which there is a high
of screening strategies. prevalence of low testosterone levels and for which we
suggest measurement of serum testosterone levels
1.2.1.C. Values
• Sellar mass, radiation to the sellar region, or other
The recommendation not to screen men in the diseases of the sellar region
general population places a high value on avoiding • Treatment with medications that affect testosterone
labeling and medicalization of otherwise healthy men production or metabolism, such as glucocorticoids and
opioids
for whom testing, treatment, and monitoring would
• HIV-associated weight loss
represent a burden with unclear benefit. This recom-
• End-stage renal disease and maintenance hemodialysis
mendation also places a high value on avoiding inter-
• Moderate to severe chronic obstructive lung disease
ventions with unclear outcomes. It places a low value
• Infertility
on the potential benefits of early detection and treat- • Osteoporosis or low trauma fracture, especially in a
ment of androgen deficiency in men who have not young man
sought medical attention. • Type 2 diabetes mellitus
1.2.2. Case Finding of Androgen Deficiency In men with chronic diseases such as diabetes mellitus,
end-stage renal disease, chronic obstructive lung disease,
measurement of testosterone may be indicated by
1.2.2.A. Recommendations symptoms such as sexual dysfunction, unexplained weight
We suggest that clinicians not use the available case- loss, weakness, or mobility limitation. In men with some
other conditions, such as a pituitary mass, HIV-associated
finding instruments for detection of androgen deficiency weight loss, low trauma fracture, or treatment with
in men receiving health care for unrelated reasons. medications that affect testosterone production, measure-
(2| ) ment of testosterone may be indicated regardless of
symptoms.
13
tate and PSA measurement before initiating treatment, at
2.0. TREATMENT OF 3 to 6 months, and then in accordance with evidence-based
guidelines for prostate cancer screening, depending on the
ANDROGEN DEFICIENCY age and race of the patient. (1| )
WITH TESTOSTERONE
2.1.B. Evidence
IPSS score > 19), or uncontrolled or poorly controlled the negative aspects of mood (60, 61). Uncontrolled
heart failure, or in those desiring fertility. (1| ) studies report improvements in energy and sense of
well-being after testosterone therapy (62). In a small
We suggest that when clinicians prescribe testosterone open-label trial, testosterone therapy has been reported
therapy, the therapeutic target should be to raise serum to improve some quality-of-life measures such as sexual
testosterone levels into a range that is mid-normal for function, well-being, and mood in men with opioid-
healthy, young men. (2| ) induced androgen deficiency (22). The effects of
testosterone on cognitive function are poorly under-
In men receiving testosterone enanthate or cypionate, stood; some studies report small effects on visuospatial
serum testosterone levels vary during the dosing interval; cognition and verbal memory and fluency (63, 64).
we suggest aiming for testosterone levels between 400
and 700 ng/dl midway between injections. (2| ) Data on the impact of testosterone replacement on
insulin sensitivity have yielded conflicting results.
In men 40 years of age or older who have a baseline PSA > Some studies have demonstrated favorable effects in
0.6 ng/ml, we recommend digital examination of the pros-
14
men with obesity (65, 66) or type 2 diabetes (67), and should include consideration of additional risk factors,
in healthy older men (68). In contrast, other studies such as age, family history (greater risk in men having
have shown no changes in insulin sensitivity following a first-degree relative with prostate cancer), race
androgen administration to healthy young (69) and (greater risk in African Americans), prior biopsy
older men (70). history, comorbidities, and PSA velocity and density
(75, 76). We suggest estimating prostate cancer risk
Testosterone therapy may be associated with using the prostate cancer risk calculator (http://
increased risk of serious adverse effects in men with deb.uthscsa.edu/URORiskCalc/Pages/calcs.jsp),
some disorders (Table 4). Metastatic prostate cancer which takes into consideration age, ethnicity, PSA,
and breast cancer are hormone-dependent cancers findings of digital rectal examination, family history,
that may be stimulated to grow during testosterone the use of a 5-α reductase inhibitor, and prior biopsy
treatment (71); testosterone should not be adminis- history. Men in the placebo arm of the Prostate
tered to men with these cancers. Although some Cancer Prevention Trial were observed to have
clinicians have suggested that patients with organ- increased risk of an occult prostate cancer even if
confined prostate cancer who have undergone radical their PSA was < 4.0 ng/ml, and the risk increased as
prostatectomy and have been disease-free 2 or more the PSA increased above 0.5 ng/ml (75). The prostate
years after radical prostatectomy and who have unde- cancer risk calculator provides a means for evaluating
tectable PSA levels may be considered for testos- prostate cancer risk in men who are considering
terone replacement on an individualized basis testosterone treatment (76), but it can only be used
(72–74), but the lack of data from randomized trials for men 55 to 95 years of age (76). In men deemed to
precludes a general recommendation. be at high risk for prostate cancer, such as African
Americans and men with first-degree relatives with
A prostate nodule or induration or a PSA > 4.0 ng/ml
prostate cancer, a PSA level > 3 ng/ml should prompt
may indicate a previously unrecognized prostate cancer.
a urological consultation before consideration of
In addition to PSA and digital rectal examination
testosterone therapy. Furthermore, in men with hema-
(DRE) results, the assessment of prostate cancer risk
tocrit >50%, untreated obstructive sleep apnea, severe
lower urinary tract symptoms, or severe congestive
TABLE 4. Conditions in which testosterone
Very high risk of serious adverse outcomes Open-label studies in young, hypogonadal men have
• Metastatic prostate cancer found a low frequency of adverse events with replace-
• Breast cancer ment doses of testosterone. Common drug-related
adverse events include increase in hematocrit, acne,
Moderate to high risk of adverse outcomes oiliness of skin, and breast tenderness (Table 5). The
• Unevaluated prostate nodule or induration
frequency of breast enlargement, sleep apnea, and
• PSA > 4 ng/ml (>3 ng/ml in individuals at high risk
for prostate cancer, such as African Americans or men
prostate events is low in trials of young, hypogonadal
with first-degree relatives who have prostate cancer) men. A systematic review of testosterone therapy in
• Hematocrit >50% men with low or low normal testosterone levels
• Severe lower urinary tract symptoms associated with included 37 randomized controlled testosterone trials
benign prostatic hypertrophy as indicated by AUA/ in hypogonadal men, healthy older men, men with
IPSS score >19
sexual dysfunction, HIV-infected men with weight
• Uncontrolled or poorly controlled congestive heart
failure
loss, and in men with a variety of other conditions
(2). This meta-analysis of low quality evidence, mostly
AUA/IPSS = American Urological Association/International Prostate because of large loss to follow-up and inconsistent
Symptom Score
results across studies, found that testosterone therapy
15
was associated with greater increases in hemoglobin, TABLE 5. Potential adverse effects of testosterone
hematocrit, and PSA, and a greater decrease in high- replacement
density lipoprotein (HDL) cholesterol level than Adverse events for which there is evidence of association
placebo (2). These effects were most marked in studies with testosterone administration
enrolling older patients with low testosterone levels • Erythrocytosis
using intramuscular testosterone preparations. Overall • Acne and oily skin
mortality, cardiovascular event rates, prostate cancer, • Detection of subclinical prostate cancer
lower urinary tract symptom scores, and systolic and • Growth of metastatic prostate cancer
diastolic blood pressure did not differ among testos- • Reduced sperm production and fertility
terone- and placebo-treated men (2). Uncommon adverse events for which there is weak
evidence of association with testosterone administration
• Gynecomastia
2.1.2. Placebo-controlled, randomized trials.
• Male pattern balding (familial)
A systematic review found no randomized, placebo- • Growth of breast cancer
controlled trials of the effect of testosterone therapy • Induction or worsening of obstructive sleep apnea
on depression, cognition, fragility fractures, quality of
Formulation-specific adverse effects
life, or cardiovascular outcomes in young, hypogo- • Intramuscular injections of testosterone enanthate,
nadal men (3). In trials that reported the effect of cypionate or undecanoate
testosterone on libido (3, 4, 46, 78–80) and erectile – Fluctuation in mood or libido
function (81–87) in hypogonadal men, testosterone – Pain at injection site
therapy was associated with greater improvements in – Excessive erythrocytosis (especially in older patients)
libido (difference between testosterone and placebo – Coughing episodes immediately after the
groups 1.2; 95% confidence interval [CI], 0.3, 2.2) but intramuscular injection*
no significant improvements in self-reported erectile • Transdermal patches
function (0.8; 95% CI, –0.05, 1.6.) compared with – Frequent skin reactions at application site
placebo (4). In a systematic review of testosterone • Transdermal gel
trials that were published before October 2004 and – Potential risk for testosterone transfer to partner or
that enrolled men with low testosterone levels (4), another person who is in close contact (need to
remind patient to cover application sites with clothing
testosterone therapy was associated with a moderate and to wash skin and hands with soap before
nonsignificant and inconsistent effect on satisfaction having skin-to-skin contact with another person)
with erectile function (random effects pooled effect – Skin irritation
size, 0.80; 95% CI –0.10, 1.60), a large effect on libido • Buccal testosterone tablets
(pooled effect size, 1.31, 95% CI, 0.40, 2.25), and no – Alterations in taste
significant effect on overall sexual satisfaction (4).
An Endocrine Society Clinical Practice Guideline
– Irritation of gums
Trials that enrolled patients with low or low-normal • Pellet implants
testosterone levels at baseline showed a small effect – Infection, expulsion of pellet
on satisfaction with erectile function (pooled effect • Oral tablets
size, 0.34; 95% CI, 0.03, 0.65), moderate nonsignifi- – Effects on liver and cholesterol (methyltestosterone)†
cant effect on libido (pooled effect size, 0.41; 95% CI,
* The mechanism of cough, which has been reported rarely after
–0.01, 0.83), and no significant effect on overall intramuscular injections of testosterone undecanoate and even
sexual satisfaction. The inconsistency across trials and more rarely after testosterone enanthate and cypionate, is
unknown, but it has been attributed to oil embolization.
imprecision of pooled estimates weaken these infer-
† Liver toxicity has been reported mostly with oral 17-alpha
ences (4). The trials of the effects of testosterone alkylated androgens. The frequency of skin reactions is higher
with the testosterone patch than with the transdermal gels.
therapy on erectile response to selective phosphodies-
terase 5 (PDE-5) inhibitors have been inconclusive
(87–93).
16
Most studies of testosterone therapy in young, Monitoring androgen-deficient men receiving
hypogonadal men have been open label and did not testosterone therapy. Androgen-deficient men
include a placebo group. The observations from receiving testosterone therapy who are > 40 years of
these open-label studies are consistent with the sparse age with a baseline PSA > 0.6 ng/ml should be
data from randomized trials and with the experience followed using a standardized, monitoring plan
of the panelists. (Quality of evidence: ) (Table 8) to facilitate early detection of adverse
events and to prevent unnecessary prostate biopsies
2.1.C . Values that might lead to detection of subclinical prostate
The recommendation to offer testosterone therapy to cancer (77, 98). A difficult issue in the follow-up of
healthy, hypogonadal men with classic androgen-defi- hypogonadal men receiving testosterone therapy
ciency syndromes places a relatively higher value on relates to the criteria that should be used to guide
alleviating hypogonadal symptoms and other benefits the decision to perform prostate biopsy. PSA
of testosterone therapy and a relatively lower value on measurements have considerable test-retest vari-
avoiding the potential burden of long-term treatment, ability (99). Transient PSA elevations may be due
monitoring, cost, and its unclear long-term safety. to other prostatic disorders. PSA levels may be
increased by prostatitis, benign prostatic hyper-
2.1.D. Remarks plasia, prostate trauma, urinary tract infections,
prostate cancer, and assay variability. If prostatitis is
Table 6 summarizes the clinical pharmacology of the
suspected, appropriate antibiotic treatment has
available testosterone formulations. When clinicians
been reported to decrease PSA by approximately
recommend testosterone therapy, we suggest aiming at
30% (100, 101). Therefore, we recommend that
achieving testosterone levels in a range that is
PSA elevations be confirmed by repeating the test.
midnormal for healthy, young men. In men receiving
testosterone enanthate or cypionate, serum testos- The 90% confidence limit for the change in PSA
terone levels vary during the dosing interval; we suggest levels between two tests performed 3 to 6 months
aiming for testosterone levels between 350 and 750 ng/ apart in a study of men with benign prostatic hyper-
dl one week after the injection. Testosterone therapy plasia was 1.4 ng/ml (102). In a systematic review, the
can be initiated with any of the suggested regimens in average PSA increase after initiation of testosterone
17
TABLE 6. Clinical pharmacology of some testosterone formulations
Pharmacokinetic
Formulation Regimen DHT and E2 Advantages Disadvantages
profile
T enanthate 150–200 mg IM q 2 After a single IM DHT and E2 levels rise Corrects symptoms of Requires IM injection;
or cypionate wk or 75–100 mg/wk injection, serum T levels in proportion to the androgen deficiency; peaks and valleys in
rise into the supraphysi- increase in T levels; relatively inexpensive, serum T levels
ological range, then T:DHT and T:E2 ratios if self-administered;
decline gradually do not change flexibility of dosing
into the hypogonadal
range by the end of
the dosing interval
1% Testosterone Available in sachets, Restores serum T Serum DHT levels are Corrects symptoms of Potential of transfer to
gel tubes and pumps 5–10 and E2 levels to higher and T:DHT ratios androgen deficiency, a female partner or
g T gel containing the physiological are lower in provides flexibility child by direct
50–100 mg T q d male range hypogonadal men of dosing, ease of skin-to-skin contact; skin
treated with the T gel application, good skin irritation in a small
than in healthy tolerability proportion of treated
eugonadal men men; moderately high
DHT levels
Transdermal 1 or 2 patches, Restores serum T, T:DHT and T:E2 levels Ease of application, Serum T levels in some
testosterone patch designed to nominally DHT, and E2 levels are in the physiological corrects symptoms of androgen-deficient
deliver 5–10 mg T over to the physiological male range androgen deficiency men may be in the
24 h applied q d on male range low-normal range;
nonpressure areas these men may need
application of 2
patches daily; skin
irritation at the
application site occurs
frequently in many
patients
Buccal, 30 mg controlled Absorbed from the Normalizes serum T Corrects symptoms Gum-related adverse
bioadhesive, release, bioadhesive buccal mucosa and DHT levels in of androgen deficiency events in 16% of
T tablets tablets bid hypogonadal men in healthy, hypogo- treated men
nadal men
T pellets 3-6 pellets implanted Serum T peaks at 1 mo T:DHT and T:E2 ratios Corrects symptoms of Requires surgical
sc; dose and regimen and then is sustained do not change androgen deficiency incision for insertions;
vary with formulation in normal range for pellets may extrude
3–6 mo, depending spontaneously
on formulation
17-α methyl T This 17-α alkylated Orally active Clinical responses are
compound should variable; potential for
not be used because liver toxicity; should not
of potential for liver be used for treatment of
toxicity. androgen deficiency
Oral T 40 to 80 mg po bid When administered High DHT with T ratio Convenience of oral Not approved in the
undecanoate* or tid with meals in oleic acid, T administration USA;variable clinical
An Endocrine Society Clinical Practice Guideline
Injectable European regimen When administered DHT and E2 levels rise Corrects symptoms of Requires IM injection
long-acting 1000 mg IM, followed at a dose of 750 to in proportion to the androgen deficiency; of a large volume
T undecanoate by 1000 mg at 6 wk, 1000 mg IM, serum T increase in T levels; requires infrequent (4 ml); cough reported
in oil* and 1000 mg q levels are maintained in T:DHT and T:E2 ratios administration. immediately after
10–14 wk the normal range in a do not change injection in a very small
majority of treated men number of men
Testosterone 2 X 60 cm2 patches Restores serum T, T:DHT and T:E2 are Lasts 2 d Some skin irritation
in-adhesive delivering approxi- DHT and E2 to the in the physiological
matrix patch* mately 4.8 mg T/d physiological range range
18
TABLE 7. Some recommended regimens* for before consideration of testosterone therapy. Men
testosterone replacement therapy receiving testosterone therapy should have hemato-
crit measured at baseline and 3 to 6 months after initi-
• 150 to 200 mg administered every 2 wk, or 75–100 ation of testosterone therapy.
mg of testosterone enanthate or cypionate administered
IM weekly
• One or two 5-mg testosterone patches applied nightly
2.2. TESTOSTERONE THERAPY IN MEN
over the skin of the back, thigh, or upper arm, away
from pressure areas WITH SEXUAL DYSFUNCTION
• 5 to 10 g of testosterone gel applied daily over a
covered area of skin 2.2.A. Recommendation
• 30 mg of a bioadhesive, buccal testosterone tablet We suggest that clinicians offer testosterone therapy to
applied to buccal mucosa twice daily men with low testosterone levels and low libido to
• Testosterone pellets (dose and regimen vary with the improve libido (2| ) and to men with ED who
formulation used)
have low testosterone levels after evaluation of under-
* Formulations available in other countries but not in the United lying causes of ED and consideration of established ther-
States include: 1) oral testosterone undecanoate (typically used apies for ED. (2| )
at a dose of 40 to 80 mg orally two or three times daily with
meals); 2) two testosterone matrix patches 30, 45, or 60 cm2
applied every 2 days; 3); Injectable testosterone undecanoate 2.2.B. Evidence
1000 mg followed by a second 1000 mg injection 6 weeks
later, and then 1000 mg every 10 to 14 weeks. Physicians in Spontaneous and experimentally induced androgen
those countries where these formulations are available should
follow the approved drug regimens. See Tables 6 and 8 for deficiency is associated with a decreased frequency of
additional safety and pharmacokinetics information.
sexual thoughts and fantasies, nighttime erections.
overall sexual activity, and attentiveness to erotic
stimuli (4, 46–53, 59, 78–83). Androgen deficiency is
Best Practice Statement (2009) (104) recommends
an important cause of hypoactive sexual desire
obtaining a baseline PSA at age 40, and then to deter-
disorder. However, androgen deficiency and ED are
mine future screening intervals based on this value.
two independently distributed clinical disorders with
Men at least 40 years of age who have a baseline PSA distinct pathophysiology; the two disorders may
19
TABLE 8. Monitoring men receiving testosterone therapy
1. Evaluate the patient 3 to 6 months after treatment initiation and then annually to assess whether symptoms have responded
to treatment and whether the patient is suffering from any adverse effects.
3. Check hematocrit at baseline, at 3 to 6 months, and then annually. If hematocrit is >54%, stop therapy until hematocrit
decreases to a safe level; evaluate the patient for hypoxia and sleep apnea; reinitiate therapy with a reduced dose.
4. Measure bone mineral density of lumbar spine and/or femoral neck after 1–2 yr of testosterone therapy in hypogonadal men
with osteoporosis or low trauma fracture, consistent with regional standard of care.
5. In men 40 years of age or older with baseline PSA greater than 0.6 ng/ml, perform digital rectal examination and check
PSA level before initiating treatment, at 3 to 6 months, and then in accordance with guidelines for prostate cancer screening
depending on the age and race of the patient.
• Injectable testosterone esters (enanthate, cypionate, and undecanoate): Ask about fluctuations in mood or libido, and
rarely cough after injections.
• Testosterone patches: Look for skin reaction at the application site.
• Testosterone gels: Advise patients to cover the application sites with a shirt and to wash the skin with soap and water
before having skin-to-skin contact, because testosterone gels leave a testosterone residue on the skin that can be transferred
to a woman or child who might come in close contact. Serum testosterone levels are maintained when the application site
is washed 4–6 h after application of the testosterone gel.
• Testosterone pellets: Look for signs of infection, fibrosis, or pellet extrusion.
was not significant (0.4 SD units; 95% CI, –0.01, 0.8) Erectile dysfunction. A meta-analysis by Jain et al.
(76). Lack of precision around this estimate weakens (85) evaluated the effects of testosterone therapy in
this inference. (Quality of evidence: ) men with ED. Among 16 published studies (85), 57%
20
of subjects experienced an improvement in erectile 2.2.D. Remarks
function. In a later systematic review of randomized Diagnostic and treatment recommendations are the
placebo-controlled trials that enrolled patients with same as for patients with classical androgen deficiency
total testosterone < 300 ng/dl (10.4 nmol/l) (4), two (Sections 1.1. and 2.1.). Men with sexual dysfunction
parallel trials and two crossover trials reported effects should be evaluated for the underlying causes,
on erectile function. The results were inconsistent including low testosterone levels.
across trials, and the pooled estimate was not signifi-
cant (0.8 SD units; 95% CI, –0.1, 1.6) (4). (Quality
of evidence: ) 2.3. OLDER MEN WITH LOW SERUM
TESTOSTERONE CONCENTRATION
Among trials that enrolled men with total testos-
terone > 300 ng/dl (10.4 nmol/l), several parallel trials 2.3.A. Recommendation
enrolled men with ED in whom sildenafil had failed We recommend against a general policy of offering testos-
(87–93) and three crossover trials in men with either terone therapy to all older men with low testosterone
low libido or ED (112, 113). These trials reported levels. (1| )
inconsistent and nonsignificant effects on erectile
function (0.3 SD units; 95% CI, –0.03, 0.65) (4). The We suggest that clinicians consider offering testosterone
inconsistency across trials and the imprecision of the therapy on an individualized basis to older men with low
pooled estimate weaken our inferences. (Quality of testosterone levels on more than one occasion and clini-
evidence: ) cally significant symptoms of androgen deficiency, after
explicit discussion of the uncertainty about the risks and
Other sexual outcomes. Several studies have evaluated benefits of testosterone therapy. (2| )
the effects of testosterone treatment in men who failed
to respond to a PDE5 inhibitor (87–93). Some of these The panelists disagreed on serum testosterone levels
studies were not placebo controlled, and the degree of below which testosterone therapy should be offered to
testosterone deficiency varied among trials (87–93, older men with symptoms. Depending on the severity
112, 113). Several trials reported on the impact of of clinical manifestations, some panelists favored
testosterone therapy on other sexual outcomes, namely, treating symptomatic older men with a testosterone
21
2.3.B. Evidence did not differ significantly between groups (–0.6 kg;
Several cross-sectional and longitudinal studies 95% CI, –2.0, 0.8) (125 ).
demonstrate that serum total and free testosterone
Muscle strength and physical function. Testosterone
concentrations in men fall with increasing age (7–9,
therapy was associated with a greater improvement in
84, 103, 104, 114, 115). Although the fall is gradual,
grip strength than placebo (3.3 kg; 95% CI, 0.7, 5.8)
by the eighth decade, according to one study, 30% of
(125). Changes in lower-extremity muscle strength
men had total testosterone values in the hypogonadal
and measures of physical function were reported in
range, and 50% had low free testosterone values (8).
only a few studies and were inconsistent. Some studies
The rate of age-related decline in serum testosterone
reported no changes in performance-based measures
levels varies in different individuals and is affected
of physical function (68, 119, 121), whereas one study
by chronic disease, adiposity, and medications (7, 9,
reported improvement in a composite measure of
114–117).
physical function (121). Most of the studies included
Testosterone trials in older men. In randomized, men who had no functional limitations and used
placebo-controlled trials of 3 months to 3 years in measures of physical function that had a low ceiling.
older men with low-normal to low testosterone
Sexual function. Two placebo-controlled trials yielded
concentrations, testosterone administration was asso-
imprecise results regarding the effect of testosterone
ciated with varying degrees of elevation in testos-
on overall sexual satisfaction (0.2 SD units; 95% CI,
terone levels (68, 119–131). Overall, testosterone
–0.02, 0.57) (4).
trials in older men were characterized by small sample
size, inclusion of healthy older men with low or low- Quality of life. Four placebo-controlled randomized
normal testosterone levels who were asymptomatic, trials reported on testosterone’s effect on quality of
variable dosing regimens, and the use of surrogate life (119, 129, 133, 134). The results were inconsis-
outcomes; these studies did not have sufficient power tent across trials and imprecise. However, testos-
to detect either meaningful gains in patient-impor- terone therapy was associated with significantly
tant outcomes or changes in prostate and cardiovas- greater improvement in the physical function domain
cular event rates (68, 119–131). score than was placebo (0.5 SD units; 95% CI, 0.03,
0.9) (125 ).
Bone mineral density. We did not find any trials
reporting the effect of testosterone on bone fractures. Depression. The effects of testosterone therapy on
A systematic review of randomized, placebo- depression have been inconsistent across trials. A
controlled trials of 1- to 3-year’s duration that evalu- recent systematic review of randomized trials reported
ated effects on bone mineral density and were significantly greater improvements in depression
An Endocrine Society Clinical Practice Guideline
published before March 2005 yielded inconsistent and scores in testosterone-treated men than in placebo-
imprecise results (118, 120, 122, 132); these trials treated men (135). However, several randomized
showed a moderate treatment effect on lumbar bone trials have found no significant effects of testosterone
mineral density (0.4 SD units; 95% CI, 0.1, 0.7), therapy on depression in older men with low or
equivalent to an increase in lumbar bone density of low-normal testosterone levels (127–133). The
2% (95% CI, 0.5, 3.3) (132). These trials ruled out a inconsistent and imprecise results limit the inferential
moderate-to-large testosterone effect on femoral neck strength.
bone density (0.0 SD units; 95% CI, –0.3, 0.3).
Cognition. Three placebo-controlled randomized
Body composition. In our systematic review, testos- trials (130, 133, 136), one of which studied patients
terone therapy was associated with a significantly with Alzheimer’s dementia and low testosterone
greater increase in LBM (2.7 kg; 95% CI, 1.6, 3.7) and levels (136), reported imprecise effects on several
a greater reduction in fat mass (–2.0 kg; 95% CI, –3.1, dimensions of cognition, none of which was signifi-
–0.8) than placebo (125). The body weight change cant after pooling.
22
Adverse outcomes associated with testosterone patients choose testosterone therapy, we suggest that
therapy. In a systematic review of 19 randomized trials clinicians aim at achieving total testosterone levels in
to determine the risks of adverse events associated the lower part of the normal range of young men
with testosterone therapy in older men (77), the (400–500 ng/dl [14.0–17.5 nmol/l]).
combined rate of all prostate events was significantly
greater in testosterone-treated men than in placebo-
2.4. PATIENTS WITH CHRONIC ILLNESS
treated men (odds ratio, 1.78; 95% CI, 1.07, 2.95).
AND LOW TESTOSTERONE LEVELS
Rates of prostate cancer, PSA greater than 4 ng/ml,
and prostate biopsies were higher in the testosterone
2.4.1. HIV-infected men with weight loss
group than in the placebo group, although differences
between groups were not statistically significant (77).
2.4.1.A. Recommendation
Testosterone-treated men were nearly four times more
likely than placebo-treated men to experience hema- We suggest that clinicians consider short-term testos-
tocrit > 50% (odds ratio, 3.69; 95% CI, 1.82, 7.51). terone therapy as an adjunctive therapy in HIV-infected
The frequency of cardiovascular events, sleep apnea, men with low testosterone levels and weight loss to
or death did not differ significantly between groups. promote weight maintenance and gains in lean body
Thus, testosterone therapy of older men was associ- mass and muscle strength. (2| )
ated with a higher risk of detecting prostate events
and hematocrit above 50% than was placebo (77). 2.4.1.B. Evidence
There is a high prevalence of low testosterone levels
A meta-analysis by Haddad et al. (3) of studies found in HIV-infected men (37, 38, 137): 20– 25% of HIV-
through October 2004 enrolling older men with low infected men on highly active antiretroviral therapy
testosterone levels yielded insignificant changes in have low testosterone levels (137). Low testosterone
major lipid fractions (total cholesterol standardized levels are associated with weight loss, progression to
mean difference [SMD] -0.22 (-0.71 to 0.27) ; LDL AIDS (138), wasting (139), depression, and loss of
cholesterol SMD 0.06 [-0.30 to 0.42]; HDL choles- muscle mass and exercise capacity (139).
terol SMD 0.04 [-0.39 to 0.40]; triglycerides SMD,
-0.27 [-0.61 to 0.08]). Body weight and LBM. In a systematic review of
23
sion limit the strength of inferences. Overall, testos- 2.4.2.B. Evidence
terone therapy had a moderate effect on depression Testosterone levels are lower in glucocorticoid-treated
(–0.6 SD units; 95% CI, –1.0, –0.2). There were no men than in age-matched controls (39). There is a
significant testosterone effects on quality of life. high prevalence of low testosterone levels in gluco-
corticoid-treated men due to glucocorticoid-induced
Adverse outcomes. The adverse event rates did not differ
suppression of all components of the hypothalamic-
significantly between placebo and testosterone groups.
pituitary-testicular axis. Typically, administration of
Changes in CD4+ T lymphocyte counts, HIV viral load,
more than 5–7.5 mg/d of prednisone or its equivalent
PSA, and plasma high-density lipoprotein cholesterol
increases the risk of gonadotropin and testosterone
were not significantly different between groups.
suppression and alterations in muscle and bone
There was considerable heterogeneity across trials mass (149).
(varying degrees of weight loss, disease severity, testos-
In two placebo-controlled trials (150, 151), testos-
terone regimens, treatment duration, and methods to
terone therapy of men receiving glucocorticoid treat-
assess body composition). There are no data on testos-
ment for bronchial asthma or chronic obstructive
terone’s effects on physical function, risk of disability,
pulmonary disease was associated with a greater gain
or long-term safety. Overall, short-term (3- to
in LBM (2.3 kg; 95% CI, 2.0, 3.6) and a greater
6-month) testosterone use in HIV-infected men with
decrease in fat mass (–3.1 kg; 95% CI, –3.5, –2.8)
low testosterone levels and weight loss can lead to
than was placebo. These two trials reported significant
small gains in body weight and LBM with minimal
increase in lumbar bone mineral density in associa-
change in quality of life and mood. This inference is
tion with testosterone therapy (4%; 95% CI, 2, 7%);
weakened by inconsistent results across trials.
the effect on femoral bone mineral density was incon-
sistent and not significant. There are no bone fracture
2.4.1.C. Values
data in this population.
The recommendation to offer short-term testosterone
therapy to HIV-infected men with low testosterone Testosterone administration was associated with a low
levels and weight loss places a relatively higher value frequency of adverse events. However, these infer-
on gaining LBM and muscle strength and a relatively ences are weakened by the small size of these studies,
lower value on avoiding the potential for testosterone- their short duration, and their inconsistent results.
related adverse effects, cost, and unclear long-term
safety. Patients with a different value structure may 2.4.2.C. Values
decide to avoid testosterone therapy. Our recommendation to offer testosterone therapy to
glucocorticoid-treated men with low testosterone
An Endocrine Society Clinical Practice Guideline
24
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Acknowledgments
The members of the Task Force thank The Endocrine Society’s Clinical Guidelines Subcommittee, Clinical Affairs
Core Committee and Council for their careful, critical review of earlier versions of this manuscript and their
helpful comments and suggestions. We also thank the staff at the Society office for their helpful support during the
development of this guideline.
* Evidence-based reviews for this guideline were prepared under contract with The Endocrine Society.
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