Compliance with the provisions in this policy may be monitored and addressed
through post payment data analysis and subsequent medical review audits.

**Covered Indications**

Treatment with testosterone is medically reasonable and necessary when
prescribed for:

  * Symptomatic hypogonadism (congenital or acquired) due to a disorder of the testicles, pituitary gland, or brain
  * Delayed male puberty
  * Gender dysphoria in a member who is able to make an informed decision to engage in hormone therapy

This A/B MAC expects that the establishment of a diagnosis of primary
hypogonadism will be undertaken with at least 2 separate fasting serum
testosterone levels, taken on 2 different days, drawn prior to 10 AM, and
obtained from identical laboratories. A single luteinizing hormone (LH) or
follicle stimulating hormone (FSH) level will also be drawn. Elevated LH/FSH
confirms primary hypogonadism and the potential need for replacement hormone.
If the 2 testosterone determinations are low AND the LH/FSH level(s) are also
low, pituitary disease (including a serum prolactin) or chronic diseases
should be assessed. ONLY secondary hypogonadism that is due to a medical
disorder of the testicles, pituitary gland, or brain will be considered
reasonable and necessary for treatment with testosterone. Prescribing and
monitoring parameters will include:

  * Prostate-specific antigen (PSA) testing must be done within the last 12 months prior to prescribing testosterone AND there will be ongoing monitoring throughout therapy.
  * Hematocrit must be evaluated prior to prescribing testosterone AND there will be ongoing monitoring throughout therapy.
  * Digital prostate exam must be done within the last 12 months prior to prescribing testosterone AND there will be ongoing monitoring throughout therapy. 
  * Where replacement is indicated, the dose of replacement therapy should be the least amount necessary to obtain a serum testosterone in the low normal range. There will be ongoing monitoring of testosterone levels throughout therapy.
  * Testosterone replacement can be administered by many routes. The current preferred routes are by transdermal preparations. 
  * Due to United States (U.S.) Food and Drug Administration (FDA) listed warnings about possible thromboembolic disease, increase in erythrocythemia, cardiovascular risk, and stroke, the clinical records shall reflect that these issues were discussed with the patient before initiating therapy. 
  * Documentation of the symptoms, signs, physical examination, and required laboratory tests must be available in the chart if requested.

**Limitations**

The following uses of testosterone are considered NOT medically reasonable and
necessary:

  * Patients with hypogonadism due to aging also known as late-onset hypogonadism (LOH)
  * Idiopathic hypogonadism not due to disorder of the testicles, pituitary gland, or brain
  * Male menopause
  * Patients with a breast cancer diagnosis 
  * Patients with a prostate cancer diagnosis unless previously undergone a radical prostatectomy and disease free for at least 2 years
  * Patients with thrombophilia or patients who have had a myocardial infarction (MI), cardiac revascularization, or a stroke within the past 6 months
  * Patients with a prostate nodule or induration, a PSA > 4 ng/mL or > 3 ng/mL in men at increased risk of prostate cancer (e.g., African American men or those who have a first-degree relative with diagnosed prostate cancer)
  * Patients with a hematocrit > 48% 
  * Patients interested in reproduction

**Notice:** Services performed for any given diagnosis must meet all of the
indications and limitations stated in this policy, the general requirements
for medical necessity as stated in CMS payment policy manuals, any and all
existing CMS National Coverage Determinations (NCDs), and all Medicare payment
rules.

The redetermination process may be utilized for consideration of services
performed outside of the reasonable and necessary requirements in this Local
Coverage Determination (LCD).

**Background**

Testosterone is the main androgen secreted by the testes, and the testes are
the major source of circulating androgens in males. Testosterone is present in
the body in 3 forms: free testosterone (FT), albumin bound testosterone, and
testosterone bound to serum hormone binding globulin (SHBG). Albumin bound
testosterone readily dissociates to FT. SHBG tightly binds the testosterone it
carries and this form is not bioavailable. Testosterone levels are controlled
by interaction of the testicular-pituitary-hypothalamic axis. Primary
hypogonadism is failure of the testes to produce testosterone and is
accompanied by elevated LH and/or FSH. Causes of primary hypogonadism include,
but are not limited to, Klinefelter syndrome (KS), cryptorchidism, some types
of chemotherapy, radiation to the testes, trauma, torsion, infectious
orchitis, human immunodeficiency virus (HIV) infection, anorchia syndrome, and
myotonic dystrophy. Secondary hypogonadism is disruption of the testicular-
pituitary-hypothalamic pathway. These patients will typically have low or
normal LH and FSH levels. Causes of secondary hypogonadism include
hyperprolactinemia; severe obesity; iron overload syndromes; the use of
opioids, glucocorticoids, or androgen-deprivation therapy with gonadotropin-
releasing hormone agonists; androgenic-anabolic steroid (AAS) withdrawal
syndrome; idiopathic hypogonadotropic hypogonadism; hypothalamic or pituitary
tumors or infiltrative disease; head trauma; and pituitary surgery or
radiation. In other cases, the decline in gonadal function, as may occur
gradually with aging, may not be a clearly pathological process. This process
is known as LOH.1 As men age, their serum concentrations of total testosterone
(TT) gradually decrease. Furthermore, SHBG increases with age, thus the normal
course of aging is to further decrease the total bioavailable testosterone.

Testosterone products have been approved by the FDA for replacement therapy in
men with primary or secondary hypogonadism caused by specific, well-recognized
medical conditions. On the basis of this replacement use, the FDA has required
only that testosterone products reliably bring low serum testosterone
concentrations into the normal range, defined as the concentrations seen in
healthy young men. The FDA has not mandated that clinical trials show
improvements in signs or symptoms of hypogonadism in order for a testosterone
product to be approved.2

Testosterone prescriptions for men have increased substantially in recent
years. One study found that in 2011, 3.7% of the men 60 years or older were
taking some form of testosterone.3 Yet, as many as 25% of the 11 million men
over the age of 40 who were prescribed such treatment had not undergone
testosterone testing in the 12 months prior to beginning an androgen.4 This
increase in prescribing may be due to direct to consumer marketing for "low
testosterone syndrome" as well as conflicting prescribing guidelines.5

**Prevalence**

The actual prevalence of low serum testosterone in aging men is not known with
certainty. Important cross-sectional and longitudinal studies have reported
different prevalence rates of hypogonadism in men. The differences may be in
part due to different definitions of hypogonadism adopted by these studies.
Variables include low testosterone level definition, clinical symptoms used
for the diagnosis of hypogonadism, the population studied, and the inclusion
or exclusion of comorbid conditions in older men.6

The Hypogonadism in Males (HIM) study estimated the prevalence of hypogonadism
[TT < 300 ng/dl] in men aged  45 years visiting primary care practices in the
U.S. Of 2162 patients, 836 were hypogonadal, rendering a prevalence rate of
38.7%. Odds ratios for having hypogonadism were significantly higher in men
with hypertension (1.84), hyperlipidemia (1.47), diabetes (2.09), obesity
(2.38), prostate disease (1.29), and asthma or chronic obstructive pulmonary
disease (1.40) than in men without these conditions.7

In a report from the European Male Aging Study (EMAS), 2966 men aged 40 to 79
were evaluated to determine if men with a low serum testosterone concentration
for no apparent reason other than age develop the typical signs and symptoms
of male hypogonadism.8 The combination of low serum testosterone (< 317 ng/dL)
and 3 sexual symptoms, was seen in only 2.1% of men (n=63). More severe
hypogonadism (serum testosterone concentration < 230 ng/dL) was seen in 27 of
the 63 (0.9%) hypogonadal men. The hypogonadal men tended to be older and more
obese, and in proportion to their testosterone deficiency they had
significantly lower: hemoglobin, heel bone mineral density, muscle mass, and
poorer general health. Severe hypogonadism was also associated with insulin
resistance and the metabolic syndrome. The associations were stronger when the
serum testosterone concentration was < 230 ng/dL than when it was in the 230
to 317 ng/dL range. This data supports the concept of a low testosterone
syndrome in middle-aged and older men, but only in a small percentage of men.

**Symptoms**

Symptoms of testosterone deficiency are varied and can occur with a myriad of
other illnesses. Symptoms and signs suggestive of androgen deficiency include
low libido, decreased morning erections, loss of body hair, low bone density,
gynecomastia, and small testes. Symptoms and signs such as fatigue,
depression, loss of motivation, decline in cognitive function, anemia, reduced
muscle strength, and increased fat mass are not specific to, and not directly
correlated to, specific levels of testosterone. **** It is difficult to
ascertain which condition caused the other. For example, obesity is strongly
associated with a decrease in testosterone. This relationship is complex and
likely to be bidirectional. Obesity can give rise to low testosterone, insulin
resistance, the metabolic syndrome, and cardiovascular changes. Hypogonadism
can also promote fat accumulation, insulin resistance, the metabolic syndrome,
and cardiovascular changes. While treatment with testosterone has been
reported to improve some of these conditions, it is equally valid that weight
loss will not only improve the comorbidities but will also increase the serum
testosterone. The appropriate treatment for such functional declines in serum
testosterone is not testosterone therapy but reversing the underlying
condition. The most logical approach is lifestyle modification, weight
reduction, and good treatment of comorbid diseases.9,10

**Testing Limitations**

The laboratory diagnosis of testosterone deficiency is a challenge. Serum
testosterone levels are subject to variation-- diurnal, seasonal, and age-
related. Illness and certain medications, such as opiates and glucocorticoids,
can temporarily affect testosterone concentrations through central and
peripheral effects.11 When low testosterone is suspected, serum TT is
initially measured, sometimes followed by measurement of FT. Additional
laboratory tests may be required to characterize the etiology of hypogonadism
as primary or secondary. In certain clinical situations, genetic testing is
also appropriate to identify etiology.

Contemporary assay techniques to assess TT include immunoassays (IA) and mass
spectrometry (MS). Currently, the most accurate method for determining the TT
to differentiate eugonadal from hypogonadal males is liquid chromatography-
tandem MS. Despite the recognition of MS as a reference technique, the
reliability of results depends upon regular calibration maintenance, which is
labor intensive and limits the ability to achieve consistently high
throughputs without deterioration. Few studies discussing testosterone
supplementation report details on specifics of the testing modality itself.12

FT is measured either through direct assays or indirectly via several
different published calculations. The equilibrium dialysis is the gold
standard for the direct measurement of FT concentrations. This method is very
complex and is typically only available in reference laboratories. Universally
accepted methods of calculating FT do not exist. The calculations of FT are
limited by assumptions made for the equilibrium dissociation constants for the
binding of SHBG and testosterone, and albumin and testosterone. In addition,
there is no agreed standard for determining the SHBG.

Furthermore, results of testosterone measurements are affected by patient
factors, such as glucose intake, triglyceride (TG) levels, medications taken,
and initial processing of a sample. Pre-analytical factors include various
technical factors, such as types of collection tubes used to obtain samples,
sample centrifugations, intermediate storage, and environmental conditions of
sample transport. For example, storage of serum or plasma in collection tubes
following centrifugation can affect the results of measured testosterone after
processing; storage in ethylenediaminetetraacetic acid (EDTA) can adversely
affect SHBG measurement and thereby affect the calculation of FT.

All of the above makes analysis of testosterone deficiency treatment very
difficult. From a clinical aspect, the same result should be obtained if blood
was drawn from the same patient, at the same time, and sent to different
laboratories, a scenario that is not common at present.12

**Definition of Low Testosterone**

In healthy males, the circadian rhythm causes testosterone levels to change
throughout the day. Testosterone levels are highest in the morning and start
to decline by 10 am. Because levels are suppressed by glucose ingestion,13 the
evaluation of primary hypogonadism should be undertaken with a fasting TT
level performed in the morning before 10 am. Clinicians should use an accurate
and reliable method, optimally, an assay that has been certified by an
accuracy-based standardization or quality control program [e.g., Centers for
Disease Control and Prevention (CDC) Hormone Standardization Program for
Testosterone]. If this level is below 280 ng/ml further testing is warranted,
with at least 2 separate serum testosterone levels taken on 2 different days
at least 1 month apart, preferably using the same laboratory with the same
method/instrumentation for measurement. It is important to confirm low TT
concentrations, because 30% of men with an initial TT concentration in the
hypogonadal range have a normal TT concentration on repeat measurement.14 Some
have suggested establishing age-adjusted normal values and recommend not
defining hypogonadism in older men until serum levels are below 200 ng/dL,
rather than 280 ng/dL. In men with 200-300 ng/dL and who have a condition that
alters sex hormone binding globulin (obesity, type 2 diabetes mellitus), FT
should be obtained using either equilibrium dialysis or estimating it using an
accurate formula. If the FT is normal there is no need for testosterone
therapy.15

Medications such as glucocorticoids and opioids can affect testosterone
levels, as can acute or subacute illness. Therefore, testosterone levels
should not be measured while a patient is receiving these medications, and
testing should wait until a patient has recovered from being ill. If a low
testosterone level is confirmed on 2 occasions, testing of LH and FSH should
be performed.14 Elevated LH/FSH confirms primary hypogonadism and the
potential need for replacement hormone. Two testosterone determinations which
are low, along with normal or low LH and FSH levels, confirms secondary
hypogonadism. Only patients with low testosterone associated significant
symptoms should be considered for treatment.15

Potentially reversible pituitary disease or chronic diseases such as
hemochromatosis, should be assessed with further testing. A comprehensive
examination should evaluate for medications or chronic diseases known to cause
decreased energy, memory problems, impotence, and mental health problems as
these issues should be treated first. For example, Viana Jr., et al.16
conducted a small retrospective review of 153 non obese men with obstructive
sleep apnea (OSA) and found a significant association between OSA severity,
oxygen desaturation index (ODI), and a reduced testosterone level in 3 men >
age 50. The significant association of low TT levels with high apnea-hypopnea
index (AHI) values suggest that gonadal dysfunction is a consequence of OSA
rather than a primary condition independent of the hypothalamic-pituitary-
gonadal axis.

**Benefits and Risks**

****

March 2015, at the joint meeting of the Bone, Reproductive, and Urologic Drugs
Advisory Committee and the Drug Safety and Risk Management Advisory Committee
of the U.S. FDA, experts mandated that package labeling for testosterone must
state that "the efficacy and safety for testosterone therapy in age-related
hypogonadism have not been established," and that there is biological
plausibility for so-far weak cardiovascular safety signals and "the potential
signal for increased cardiovascular and stroke risk". They reiterated the
original FDA approval which indicated that testosterone is approved as
replacement therapy only for men who have confirmed low testosterone due to
disorders of the testicles, pituitary gland, or brain that cause a condition
called hypogonadism. The benefit and safety of these medications have not been
established for the treatment of low testosterone levels due to aging, even if
a man's symptoms seem related to low testosterone. This FDA instruction has
specifically made testosterone treatment of aging-related, idiopathic and
metabolic hypogonadism "off-label".2

****

The multicenter Testosterone Trials (TTrials),17 published in 2016, were a
coordinated set of 7 double-blind placebo-controlled trials at 12 U.S.
academic centers to assess the 1-year efficacy of testosterone versus placebo
gel in 788 men, 65 years or older with hypogonadism who had self-reported and
objective impairment of sexual and physical function and/or vitality, and an
average of 2 morning serum testosterone concentrations < 275 ng/dL. The
initial dose of the gel (5 g daily) was adjusted at months 1, 2, 3, 6, and 9,
to keep the serum testosterone concentration within the normal range for young
men. To allow the results to be widely applicable to older men with low
testosterone, they included men with comorbid conditions, unless those
conditions might have exposed the men to excessive risk. Thus, they excluded
men with a history of prostate cancer and those whose risk (using the Prostate
Cancer Risk Calculator) of any prostate cancer was > 35% and that of high-
grade prostate cancer was > 7%. They also excluded men whose lower urinary
tract symptoms were moderately severe, as judged by an International Prostate
Symptom Score > 19\. They excluded men with any cancer and those with severe
cardiac, renal, or hepatic disease. The enrollees participated in 1 or more of
3 main trials (the **Sexual Function Trial** [n = 470], the **Physical
Function Trial** [n = 390], and the **Vitality Trial** [n = 474]). They could
also participate in any of the other trials for which they qualified.17

Significantly, over 51,000 men were screened to enroll the 790 men who met
inclusion criteria (only 1.5% of those screened). The median pretreatment
testosterone concentration was 232 ng/dL. After 1 year of testosterone gel
therapy, average serum testosterone concentrations increased into the mid-
normal range (approximately 500 ng/dL) for men ages 19 to 40 years. The median
serum testosterone concentration of the men treated with testosterone
increased from unequivocally low at baseline to mid-normal for young men by
month 3 and remained at that level during the 12 months of treatment. Of the
394 men in the testosterone arm, 301 required 504 adjustments of the dose at
months 3, 6, and/or 9 to maintain the testosterone level within the target
range. The levels of TT did not change in the men who used placebo gel. Of the
788 enrollees, 689 participated in more than 1 of the 3 main trials, and many
also participated in 1 or more of the other trials.

Inclusion in the **Sexual Function Trial** required self-reported decreased
libido, a score of 20 or less on the sexual desire domain range (0-33) of the
Derogatis Interview for Sexual Functioning in Men-II, and a partner willing to
have intercourse at least twice a month. Primary outcome was change in
baseline in the score for sexual activity with secondary outcomes of erectile
function and sexual desire. Testosterone therapy was associated with a
moderate improvement in sexual function, including sexual activity, sexual
desire (libido), and, to a lesser extent, erectile function. Sexual activity
was assessed by the Psychosexual Daily Questionnaire which assesses 12 types
of sexual activity, from flirting to intercourse. Testosterone treatment,
compared with placebo, substantially increased sexual activity, of all types,
about 4 times a week. The clinical significance of the effect of testosterone
on libido was judged by the responses to the Patient Global Impression of
Change question, in which 20% of men treated with testosterone reported that
their sexual desire was "much better" than before treatment compared with 10%
of men treated with placebo. These results are also consistent with another 16
week placebo-controlled study of a different testosterone gel in 751 men with
a mean age of 55 years who had low testosterone levels.18

Testosterone has long been recognized to stimulate the growth of muscles and
increase muscle strength, resulting in greater muscle development during
puberty in men than in women. Administration of testosterone to older men also
increases muscle mass and, in some studies, increases muscle strength.19
Inclusion in the **Physical Function Trial** required self-reported difficulty
in walking or climbing stairs and a gait speed of at least 1.2 m per second on
the 6 minute walk test. Men who were not ambulatory were excluded. Primary
outcome was increased distance in the 6 minute walk test. There was no
significant difference between the testosterone- versus placebo-treated groups
in walking distance on a 6 minute walk test in the 390 men who were enrolled
in the physical function trial, but testosterone did improve walking distance
by a small amount when all 788 men were included. In 2 trials reported while
the TTrials were in progress, testosterone treatment of moderately frail older
men improved muscle strength but did not clearly or consistently improve
physical performance.19-21

Many physicians believe that testosterone improves mood, although data is
inconsistent because few trials used validated questionnaires. Low certainty
evidence demonstrated a small improvement in quality of life as measured by
the Aging Males' Symptoms (AMS) scale, however, this change might have been
driven solely by improvement in sexual function which is an AMS subscale.8,22
The **Vitality Trial** enrolled men who had self-reported low energy and
scored less than 40 on the Functional Assessment of Chronic Illness Therapy
(FACIT)-Fatigue scale. This questionnaire has been validated for assessing
energy vs. fatigue in many different diseases. Testosterone, compared with
placebo, did not substantially increase vitality, as determined by an increase
of  4 points on the FACIT-Fatigue scale for the 474 men enrolled in this
trial (the primary outcome), although it was statistically significant for all
788 TTrials men. The effect of testosterone on mood (determined using the
positive and negative affect scales), and depressive symptoms (determined
using the Patient Health Questionnaire) was statistically significant. The
magnitude of each of these effects, however, was small.

Testosterone has long been known to stimulate erythropoiesis, which explains
why normal men have higher hemoglobin levels than normal women. Before the
availability of erythropoietin, testosterone was actually used to treat anemia
**.** The goal of the **Anemia Trial** was to determine whether testosterone
treatment for older men with low testosterone and unexplained mild anemia
(hemoglobin < 12.7 g/dL) would increase their hemoglobin by  1.0 g/dL and
correct the anemia. Those with severe anemia (hemoglobin < 10.0 g/dL) were
excluded. Of the 788 men enrolled in the TTrials, 126 were anemic at baseline.
Of these, 64 were found to have a known cause of the anemia, such as iron,
B12, or folate deficiencies or inflammation. The other 62 were considered to
have unexplained anemia of aging. In the men with unexplained anemia,
testosterone treatment, compared with placebo, substantially increased the
hemoglobin concentration by  1.0 g/dL (54% vs. 15% of men) and corrected the
anemia (58.3% vs. 22.2% of men). In the men with anemia of known cause,
testosterone also substantially increased the hemoglobin concentration by  1
g/dL (52% vs. 19%) and corrected the anemia (60% vs. 14.8%). The magnitude of
the effect was modest, with a mean increase in hemoglobin to greater than
baseline of 0.8 to 1.1 mg/dL at months 6 to 12. Testosterone-treated men were
nearly 4 times as likely to have hematocrit > 50% as placebo-treated men (OR =
3.69, 95% CI, 1.82-7.51).

With this benefit, comes a risk, particularly with testosterone ester
injections. More men in the testosterone group experienced erythrocytosis
(hemoglobin  17.5 g/dL) (7 versus 0). This is of concern because the risk of
venous thromboembolic disease is directly related to hematocrit. Standard
labeling of testosterone products in the U.S. has information about the risk
of venous thromboembolism (VTE) as a consequence of the erythrocytosis. In a
meta-analysis of 3 placebo-controlled clinical trials that enrolled a total of
1543 participants, erythrocytosis occurred in 16 men in the testosterone arms
compared with 1 man in the placebo arms.

Previous studies of the effect of testosterone on bone in men who were
severely hypogonadal showed marked increases in areal bone mineral density
(aBMD) by dual energy x-ray absorptiometry and estimated bone strength using
magnetic resonance imaging (MRI). The 211 men in the **Bone Trial** underwent
assessment of volumetric bone mineral density (vBMD) and bone strength by
quantitative computed tomography (QCT) scanning at baseline and 12 months.
After 12 months, testosterone significantly increased mean lumbar spine
trabecular vBMD by 8.5% more than placebo (P  0.001; (7.5% versus 0.8%)), as
well as lumbar peripheral and hip trabecular and peripheral vBMD and mean
estimated strength of spine trabecular bone (11% versus 2.4%).23

Overall men with low TT levels may be at increased risk for cardiovascular
disease as seen by elevated cardiovascular risk markers, but studies often
lack clinical data indicating presence or absence of preexisting
cardiovascular disease or other cardiovascular risk factors.24 Furthermore, it
is not known whether improving the testosterone level to that of a healthy
male, improves or worsens cardiovascular disease risk. A retrospective
national cohort study of 8709 men with low testosterone (< 300 ng/dL) who
underwent coronary angiography in the Veterans Affair (VA) system between 2005
and 2011, found an increased risk of MI and stroke in the patients receiving
testosterone therapy. Among 1223 patients receiving testosterone therapy, 67
died, 23 had MIs, and 33 had strokes. At 3 years after coronary angiography,
the Kaplan-Meier estimated cumulative percentages with events were 19.9% in
the no testosterone therapy group vs. 25.7% in the testosterone therapy group,
with an absolute risk difference of 5.8% (95% CI, 1.4% to 13.1%).25 A
systematic review and meta-analysis of 27 placebo-controlled randomized trials
of testosterone therapy among men lasting 12+ weeks reporting cardiovascular-
related events found the effect of testosterone therapy varied with source of
funding. Overall in trials not funded by the pharmaceutical industry,
exogenous testosterone increased the risk of cardiovascular-related events.26
The **Cardiovascular Trial** performed serial coronary computed tomographic
angiography (CCTA) on 165 men at baseline and after 12 months of therapy. The
primary trial endpoint was % change in noncalcified coronary plaque volume
over the 12-month treatment period. In addition to the entry requirements to
the TTrial itself, participants had to have a normal baseline renal function
[estimated glomerular filtration rate (eGFR) > 60 ml/min/1.73 m2]. Men were
excluded if their weights were greater than 300 pounds, they had known allergy
to iodinated contrast medium, they were unable to breath-hold for 10 seconds,
they had a prior diagnosis of tachycardia or irregular heart rhythm, or they
had undergone coronary artery bypass graft surgery. Total noncalcified plaque
at baseline showed a slight but nonsignificant trend toward lower plaque
volume with higher serum testosterone concentrations (P = 0.12). One year of
testosterone therapy was associated with a greater increase than placebo in
noncalcified coronary artery plaque volume, as measured by CCTA, although
there was no change in the coronary calcification score in either group.
Several cardiovascular biomarkers were also evaluated (total cholesterol, high
density lipoprotein (HDL), TG, low density lipoprotein (LDL), glucose,
insulin, hemoglobin A1C (HbA1c), D-dimer, C-reactive protein (CRP), Troponin)
at baseline, 3 months, and 12 months. Testosterone treatment, compared to
placebo, significantly decreased total cholesterol, HDL, and LDL from baseline
to month 12. Testosterone also slightly but significantly decreased fasting
insulin. Testosterone did not change TG, D-dimer, CRP, glucose, or HbA1c more
than placebo.27 Major limitations of the study were the use of CCTA (a
surrogate outcome for atherosclerosis) and the small size and short duration
of the trial. Testosterone treatment of 1 year for older men with low
testosterone was not associated with more cardiovascular events; however, the
number of men and the duration of treatment were not sufficient to draw
definitive conclusions about the risks.28

Tao, et al.,29 conducted a review of 8 published clinical trials of 170
patients in the testosterone supplementation group to determine whether
testosterone treatment would benefit patients with congestive heart failure
(CHF). Information on exercise capacity, hemodynamic parameters,
electrocardiogram indicators, muscle strength, echocardiography guidelines,
and laboratory indexes were collected to assess clinical outcomes. They found
that testosterone did not significantly improve exercise capacity, ejection
fraction, systolic blood pressure, diastolic blood pressure, or high
sensitivity CRP in men with CHF.

Finkle, et al.,30 conducted a cohort study of the risk of acute non-fatal MI
following an initial testosterone prescription (N = 55,593) in a large health-
care database. They compared the incidence rate of MI in the 90 days following
the initial prescription (post-prescription interval) with the rate in the 1
year prior to the initial prescription (pre-prescription interval) (post/pre).
Among men aged 65 years and older, they observed a 2-fold increase in the risk
of MI in the 90 days after filling an initial testosterone prescription. The
risk declined to baseline in the 91 to 180 days after initial testosterone
prescription among those who did not refill their prescription. Among younger
men with a history of heart disease, they observed a 2 to 3-fold increased
risk of MI in the 90 days following an initial testosterone prescription and
no excess risk in younger men without such a history. Among older men, the
2-fold increased risk was associated with testosterone prescription regardless
of cardiovascular disease history, although this analysis was based on
relatively small numbers of MI cases in each subgroup. Taken together, the
evidence supports an association between testosterone therapy and risk of
serious, adverse cardiovascular related events-including non-fatal MI.

While several studies have investigated the association between testosterone
and the risk of arterial thrombosis, limited information is available
regarding its risk of VTE, outside of the known increased risk of VTE due to
testosterone induced erythrocytosis. A systematic review of randomized
clinical trials (RCTs) looked at this question. In all, 2636 men were
randomized to testosterone, and 2414 men to placebo. Sample sizes ranged from
101 to 790 men, and testosterone duration from 3 to 36 months. Five studies
had a high risk of bias, largely driven by unclear randomization and outcome
assessment. When data were pooled across RCTs, testosterone therapy was not
associated with VTE compared with placebo (RR: 1.03, 95% CI: 0.49-2.14; I(2):
0%; low-quality evidence). Similar estimates were obtained for deep vein
thrombosis and pulmonary embolism outcomes. Their systematic review suggests
that testosterone is not associated with an increased risk of VTE. However,
estimates were accompanied by a wide 95% CIs, and a clinically important
increased risk cannot be ruled out.31

Prostate volumes and PSA increase in response to testosterone treatment.
Because benign prostatic hypertrophy (BPH) is a testosterone dependent
disease, there are theoretical concerns that testosterone treatment may
increase the incidence of BPH and worsen urinary outflow obstruction. Calof,
et al.,32 performed a meta-analysis of RCTs to determine the risks of adverse
events associated with testosterone replacement in older men. Of the 417
studies identified, 19 met the inclusion criteria: testosterone replacement
for at least 90 days, men  45 years old with low or low-normal testosterone
level, RCT, and medically stable men. In the 19 studies, 651 men were treated
with testosterone and 433 with placebo. The combined rate of all prostate
events was significantly greater in testosterone-treated men than in placebo-
treated men (OR = 1.78, 95% confidence interval [CI], 1.07-2.95). Rates of
prostate cancer, PSA > 4 ng/ml, and prostate biopsies were numerically higher
in the testosterone group than in the placebo group, although differences
between the groups were not individually statistically significant.

During the TTrials, serum testosterone and PSA along with digital prostate
exam were monitored at screening, 3, and 12 months. Testosterone treatment was
associated with a small but substantially greater increase (P < 0.001) in PSA
levels than placebo treatment. Serum PSA levels increased from 1.14  0.86
ng/mL (mean 6 SD) at baseline by 0.47  1.1 ng/mL at 12 months in the
testosterone group and from 1.25  0.86 ng/mL by 0.06  0.72 ng/mL in the
placebo group. Five percent of men treated with testosterone had an increase 
1.7 ng/mL and 2.5% of men had an increase of  3.4 ng/ml. A confirmed absolute
PSA > 4.0 ng/mL at 12 months was observed in 1.9% of men in the testosterone
group and 0.3% in the placebo group. Four men were diagnosed with prostate
cancer. These trials had too little statistical power nor were they carried
out for a long enough time period to adequately evaluate whether testosterone
treatment increases the risk of prostate cancer. Overall, when hypogonadal
older men with normal baseline PSA are treated with testosterone, 5% had an
increase in PSA  1.7 ng/mL, and 2.5% had an increase  3.4 ng/mL.33

In 2 previous epidemiologic studies, low testosterone levels were associated
with cognitive impairment.34,35 A subgroup of 493 men in the TTrials met
criteria for age-associated memory impairment (AAMI), based on subjective
memory complaints and objective memory performance lower than younger men.
They participated in the **Cognitive Function Trial** and were evaluated by
delayed paragraph recall, as determined by the Wechsler Memory Scale, Revised,
Logical Memory II. The primary outcome was the mean change from baseline to 6
months and 12 months for delayed paragraph recall (score range, 0 to 50) among
men with AAMI. Secondary outcomes were mean changes in visual memory (Benton
Visual Retention Test; score range, 0 to 26), executive function (Trail-
Making Test B minus A; range, 290 to 290), and spatial ability (Card Rotation
Test; score range, 80 to 80) among men with AAMI. Tests were administered at
baseline, 6 months, and 12 months. There was no significant mean change from
baseline to 6 and 12 months in delayed paragraph recall score among men with
AAMI in the testosterone and placebo groups (adjusted estimated difference,
0.07 [95% CI, 0.92 to 0.79]; P = 0.88). Mean scores for delayed paragraph
recall were 14.0 at baseline, 16.0 at 6 months, and 16.2 at 12 months in the
testosterone group and 14.4 at baseline, 16.0 at 6 months, and 16.5 at 12
months in the placebo group. Testosterone was also not associated with
significant differences in visual memory (0.28 [95% CI, 0.76 to 0.19]; P =
0.24), executive function (5.51 [95% CI, 12.91 to 1.88]; P = 0.14), or
spatial ability (0.12 [95% CI, 1.89 to 1.65]; P = 0.89). After 6 and 12
months, there were no differences in changes from baseline in testosterone-
and placebo-treated men in test scores for memory and other cognitive
functions (delayed paragraph recall, visual memory, executive function, or
spatial ability).36

Serum testosterone levels and insulin sensitivity both decrease with age.
Severe testosterone deficiency is associated with the development of insulin
resistance. The Testosterone Effects on Atherosclerosis in Aging Men Trial was
a placebo-controlled, randomized, double-blind trial. The participants were
308 community-dwelling men,  60 years old, with TT 100 to 400 ng/dL or FT <
50 pg/mL. A subset of 134 nondiabetic men (mean age, 66.7 +/- 5.1 years)
underwent an octreotide insulin suppression test at baseline and at 3 and 36
months after randomization to measure insulin sensitivity. Testosterone
administration for 36 months in older men with low or low-normal testosterone
levels did not improve insulin sensitivity.37

The TTrials, in short, demonstrated that testosterone treatment of symptomatic
older men with low testosterone levels is efficacious in improving sexual
function, anemia, and bone density, all to modest degrees. Testosterone
therapy was not efficacious in vitality, cognitive function, metabolic
syndrome, or cardiovascular disease. Furthermore, testosterone therapy is
associated with an increased risk in erythrocytosis, sleep apnea, and acne.
Although testosterone was not associated with more cardiovascular or prostate
adverse events than placebo, a trial of a much larger and longer trial would
be necessary to assess these risks with greater certainty.23,38

**Treatment Options**

Where replacement is indicated, the dose of replacement therapy should be the
least amount necessary to obtain a serum testosterone in the low normal range.
Choice of testosterone regimen requires an understanding of their
pharmacokinetics. Native testosterone is absorbed well from the intestine, but
it is metabolized so rapidly by the liver that it is virtually impossible to
maintain a normal serum testosterone concentration in a hypogonadal man with
oral testosterone. The solutions to this dilemma involve modifying the
testosterone molecule, changing the method of testosterone delivery, or both.

Several 17-alpha alkylated androgens (e.g., methyltestosterone) have been
available for oral use for many years. Many endocrinologists who treat male
hypogonadism think that these preparations are not fully effective in
producing virilization, although no studies have tested these observations. In
addition, several reports have described hepatic side effects with these
preparations, including cholestatic jaundice, a hepatic cystic disease called
peliosis hepatis, and hepatoma. For both of these reasons and because better
preparations are available, the 17-alpha alkylated androgens should generally
not be used to treat testosterone deficiency.39

An oral form of testosterone undecanoate (Jatenzo) was approved by the FDA in
March 2019. This is an oral softgel that is taken twice daily. Because
subjects in the original trial exhibited an increase in mean systolic blood
pressure, there is a boxed warning label advising monitoring for new onset
hypertension or exacerbation of pre-existing hypertension.40

A nasal testosterone gel (Natesto) is approved in the U.S. for the treatment
of male hypogonadism. The gel is administered into the nostrils via a metered-
dose pump applicator. One pump actuation delivers 5.5 mg of testosterone; the
recommended dose is 11 mg (2 pump actuations, 1 in each nostril), 3 times
daily (total 33 mg/day). One advantage over other formulations is the minimal
risk of gel transfer to a partner or child. On the other hand, some men may
find the 3 times daily regimen inconvenient, and men with allergies or
underlying nasal or sinus pathology may have trouble tolerating the
formulation as  3% of subjects in clinical trials experienced rhinorrhea,
epistaxis, nasopharyngitis, sinusitis, and nasal scab.15

Testosterone enanthate and testosterone cypionate are esters of testosterone
that have been used for many years for the treatment of testosterone
deficiency. Intramuscular (IM) injection of testosterone esters results in
their storage in and gradual release from the oil-based vehicle in which they
are administered, thereby prolonging the presence of testosterone in the
blood. An advantage of these products to some men is freedom from daily
administration. The disadvantages are the need for deep IM administration of
an oily solution every 1 to 3 weeks and fluctuations in the serum testosterone
concentration, which results in fluctuations in energy, mood, and libido in
many patients. These fluctuations are more pronounced as the dosing interval
is increased.41

An extra-long lasting IM formulation of another ester of testosterone,
testosterone undecanoate, is available. The dosing is 750 mg in 3 mL of oil
injected only into the buttocks. The initial dose is followed by a second dose
4 weeks later and by subsequent doses every 10 weeks. Data provided by the
manufacturer demonstrate that, after the third injection, the average peak
serum testosterone value occurs approximately 1 week after an injection and is
followed by a gradual decline until the next injection. The serum testosterone
concentration at approximately 5 weeks would provide an approximate average
for the interdosing period. The extra-long acting preparations have been
associated with rare cases of pulmonary oil microembolism (POME) and
anaphylaxis (1.5 and 0.4 cases per 10,000 injections, respectively). In the
U.S., the drug is available only through a restricted program called the AVEED
Risk Evaluation and Mitigation Strategy (REMS) Program. All injections must be
administered in an office or hospital setting by a trained and registered
health care provider and monitored for 30 minutes afterwards for adverse
reactions.42

A formulation of testosterone enanthate for subcutaneous injection by
autoinjector (Xyosted) once a week is now available. A total of 150 patients
in a single arm dose blinded 52 week study found 92.7% of patients achieved an
average TT concentration of 300 to 1,100 ng/dl (mean  SD 553.3  127.29) at
week 12. Of the patients more than 95% reported no injection related pain. The
most frequently reported treatment emergent adverse events were increased
hematocrit, hypertension, and increased PSA, which led to discontinuation in
30 men. The dose adjusted subcutaneous testosterone enanthate auto-injector
demonstrated a steady serum TT pharmacokinetic profile with small peak and
trough fluctuations. The device was safe, well tolerated and virtually
painless, indicating that this subcutaneous testosterone enanthate auto-
injector offers a testosterone delivery system that is a convenient weekly
option to treat testosterone deficiency.43

The skin and oral mucosa are also considered favorable routes for the delivery
of testosterone. One transdermal patch (Androderm) is available in the U.S.
It relies upon chemical means to increase the absorption of testosterone
across nongenital skin, and it is meant to be worn on the arm or torso. It
delivers approximately 2 or 4 mg of testosterone per 24 hours and results in
normal serum testosterone concentrations in the majority of hypogonadal men.
Skin tolerability problems affects compliance with transdermal patches and can
be ameliorated by pretreating the skin with cortisone cream.

Topical agents are administered daily in a low dose such that the risk of
supraphysiological or subtherapeutic levels is minimized. Four testosterone
gels (Androgel, Testim, Vogelxo, and Fortesta) and 1 solution (Axiron)
are available. Generic versions of most gels are also now available. Indeed,
in series examining the toxicity of topical agents, adverse events are nearly
nonexistent when administered by these routes.41 The main disadvantage of the
topical agents are their high cost ($100 to $150 per month), as well as the
potential risk of inadvertent transfer of hormone to women or children through
skin contact. The possibility of skin transfer to another person is very low
if the patient follows the package insert directions that include washing
hands thoroughly after application and avoiding skin contact until the gel has
dried completely.

A subcutaneous testosterone pellet (Testopel) is available. The manufacturer
recommends 3 to 6, 75 mg testosterone pellets every 3 to 6 months. The pellets
are surgically implanted into the subdermal fat of the buttocks, lower
abdominal wall, or thigh with a trocar under sterile conditions and a local
anesthetic. Testosterone pellet implants release testosterone at a steady rate
of 1.3 mg/200 mg implant/day (95% CI).44 Adverse events include pellet
extrusion, hematoma formation at injection site, infection, and fibrosis.
Handelman, et al.,45 conducted a retrospective review of the past 13 years
with 973 implant procedures in 221 men. Overall rate of adverse events
(108/973, 11.1%) was significantly related to increased numbers of implants
(4.20.1 vs. 4.00.03, P = 0.031) and higher levels of physical activity at
work (P = 0.030). The most common adverse effect was extrusion (83/973, 8.5%)
which was related to occupational classification (P = 0.033) and increasing
work activity (P = 0.044) and occurred more frequently than by chance in
multiple (16 vs. 3.3 expected) rather than single (65 vs. 76.1 expected)
episodes. Bleeding (22/973, 2.3%) was significantly associated with an
increased number of implants (4.50.2 vs. 4.00.03, P = 0.020) but even in the
worst cases (3/22) it was of minor clinical importance. Infection was rare
(6/973, 0.6%) but occurred more among thinner men.

The annual cost in 2016 per beneficiary for testosterone was $2135.32 for the
transdermal and $156.24 for the IM formulation, according to paid
pharmaceutical claims provided in the 2016 Medicare Part D Drug Claims data.22
The annual cost for Testopel with insertion is approximately $3133.

Guidelines for the diagnosis of male hypogonadism as well as testosterone
treatment and contraindications to testosterone have been developed by the
American College of Physicians (ACP) and endorsed by the American Academy of
Family Physicians.22 Similar recommendations have been made by the Endocrine
Society15 as well as the American Urological Association.14 Testosterone
therapy impairs fertility by suppressing pituitary LH secretion (essential for
spermatogenesis), as well as shrinks testicular tissue. It is contraindicated
in those interested in reproduction.22 Given the possible increase in
cardiovascular risk, patients who have had an MI, cardiac revascularization,
or a stroke within the past 6 months are not good candidates for replacement
therapy. Testosterone is contraindicated in men with thrombophilia. It is
prudent to make sure that traditional cardiovascular disease risk factors
including smoking, hypertension, hyperlipidemia, and diabetes have been
assessed and are appropriately managed in men prescribed testosterone
replacement. Because testosterone is aromatized to estradiol, it is
contraindicated in men with breast cancer. A man who has a history of prostate
cancer should not be treated with testosterone. A possible exception is a
hypogonadal man who had a radical prostatectomy for cancer confined to the
prostate and has been free of disease and has had an undetectable PSA for at
least 2 years. Testosterone treatment should not be initiated if the patient
has a prostate nodule or induration, a PSA > 4 ng/mL or > 3 ng/mL in men at
increased risk of prostate cancer (e.g., African American men or those who
have a first-degree relative with diagnosed prostate cancer), a hematocrit >
48%, untreated severe OSA, or severe lower urinary tract symptoms.15

Due to the risk of erythrocytosis, all patients should undergo a baseline
measurement of hemoglobin/hematocrit prior to commencing testosterone therapy.
If the hematocrit exceeds 50%, clinicians should withhold testosterone therapy
until the etiology is formally investigated. While on testosterone therapy, a
hematocrit  54% warrants intervention, such as dose reduction or temporary
discontinuation.15

PSA should be measured prior to the commencement of testosterone therapy in
patients over 40 years of age in order to minimize the risk of prescribing
testosterone therapy to men with occult prostate cancer. For patients who have
an elevated PSA at baseline, a second PSA test is recommended to rule out a
spurious elevation. In patients who have 2 PSA levels at baseline that raise
suspicion for the presence of prostate cancer, a more formal evaluation,
potentially including a prostate biopsy with/without MRI, should be considered
before initiating testosterone therapy. Men over age 50 years (or 40 years if
they are at high risk) who begin testosterone treatment should be reevaluated
for prostate cancer 3 months and 1 year after beginning treatment and
thereafter according to the standard of care. PSA should be repeated 3 to 6
months after initiation of testosterone treatment to determine if it has
increased more than 1.4 ng/mL above baseline or to > 4 ng/mL. If the increase
is reproducible, testosterone should be stopped and the patient referred for
urologic evaluation.15

Patients who are treated with testosterone must be monitored to determine that
normal serum testosterone concentrations are being achieved. Monitoring should
be done 2 to 3 months after initiation of treatment and after changing a dose.
The therapeutic goal should be a testosterone value well within the normal
range (400 to 700 ng/dL) to lower the risk of testosterone-dependent diseases.

The timing of serum testosterone measurements varies with the preparation that
is used:

  * Serum testosterone should be measured midway between injections in men who are receiving testosterone enanthate or cypionate.
  * The serum testosterone can be measured at any time in men who are using the transdermal patch, with the recognition that the peak values occur 6 to 8 hours after application of the patch.
  * Serum testosterone concentrations vary substantially when a gel is used but not in a predictable way. Multiple dose adjustments are needed to maintain serum testosterone. Therefore, the Endocrine Society suggests 2 serum testosterone measurements before making dose adjustments.

After therapeutic levels have been achieved, all patients on testosterone
therapy should have serum testosterone levels checked every 6-12 months to
ensure maintenance of target levels.14 Clinicians should discuss the cessation
of testosterone therapy 3 to 6 months after commencement of treatment in
patients who experience normalization of TT levels but fail to achieve symptom
or sign improvement. The American Urologic Association nor the Endocrine
Society make any recommendations as to ideal type of therapy. Evidence from
indirect comparisons suggests no substantial differences in clinical
effectiveness, benefits, or harms between IM and transdermal testosterone
applications, although very little evidence exists from direct comparisons of
the 2 formulations. Because the 2 formulations are similar in terms of
benefits and harms but the IM formulation is substantially cheaper ($156.32
vs. $2135.32 per person per year for the transdermal option), the IM
application is the preferred testosterone treatment by the American College of
Physicians.22 There is no preference stated in guidance from the AUA or
Endocrine Society.14,15

The incidence of hypogonadism in the U.S. when defined as at least 3 sexual
symptoms with a TT level < 320 ng/dL, is most likely in the range of 1.5-2.5%.
Uncertainty exists as to whether nonspecific signs and symptoms associated
with age-related low testosterone, such as sexual dysfunction, decreases in
energy and muscle mass, mood disturbances, changes in bone mineral density,
cardiovascular disease, depression, decreased libido, erectile dysfunction,
decreased volume of ejaculate, loss of body and facial hair, weakness, and
mortality, are a consequence of age-related low testosterone or whether they
are a result of other factors, such as chronic illnesses or concomitant
medications.

Good evidence suggests that testosterone treatment in older men with low
testosterone improves sexual function, anemia, vertebral and femoral BMD, and
possibly walking distance. Compared to placebo, testosterone does not improve
cognitive function, depressive symptoms, energy, vitality or physical
function. Testosterone does not improve glycemic control. Testosterone
treatment slightly increases non-calcified and total plaque volume; while
concerning, the clinical significance of this finding is not clear.
Testosterone treatment also increases PSA levels and referral for urological
evaluation and causes erythrocytosis in some men. Most studies included in the
evidence review followed patients for 12 months or less. Larger and longer-
term placebo-controlled clinical trials are needed to assess the long-term
benefits and risks of testosterone treatment on clinical outcomes such as
frailty, depression, fractures, prostate cancer, and cardiovascular events.

Testosterone products are FDA-approved only for use in men who lack or have
low testosterone levels in conjunction with an associated medical condition.
Examples of these conditions include failure of the testicles to produce
testosterone because of reasons such as genetic problems or chemotherapy.
Other examples include problems with brain structures, called the hypothalamus
and pituitary, that control the production of testosterone by the testicles.
None of the FDA-approved testosterone products are approved for use in men
with low testosterone levels who lack an associated medical condition. All
testosterone medications are required to have a black box warning to reflect
the possible increased risk of heart attacks and strokes associated with
usage.