CAM 50123

Testosterone Replacement Therapies

Category:Prescription Drug   Last Reviewed:April 2019
Department(s):Medical Affairs   Next Review:April 2020
Original Date:April 2014    

Description
Testosterone replacement therapy is the primary treatment for androgen deficiency in men. Testosterone replacement is intended to counter the adverse effects of low testosterone levels. A variety of testosterone preparations are available for clinical use.

For individuals who have androgen deficiency and clinical symptoms of hypogonadism who receive testosterone replacement therapy, the evidence includes randomized controlled trials (RCTs) and systematic reviews. Relevant outcomes are overall survival, symptoms, morbid events, functional outcomes, and quality of life. For men with low testosterone levels and sexual dysfunction, the evidence has been fairly consistent in demonstrating a beneficial effect on increased libido. Other sexual function symptoms (eg, erectile dysfunction) are also likely to be improved, but the evidence is less strong. For other symptoms, there is evidence that lean body mass is increased, body fat is decreased, and bone mineral density is increased with testosterone therapy. However, the impact of these changes on functional status and fractures is less clear. For outcomes such as decreased energy, depression, quality of life, and cognition, the evidence is limited and inconsistent in reporting benefits of replacement therapy. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have androgen deficiency and HIV infection who receive testosterone replacement therapy, the evidence includes RCTs and systematic reviews. Relevant outcomes are overall survival, symptoms, morbid events, functional outcomes, and quality of life. A limited number of trials have included patients with HIV infection and weight loss. These trials have reported improvements in body weight, lean body mass, and a decrease in body fat, which indicates that testosterone replacement is likely to ameliorate weight loss associated with HIV infection. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have androgen deficiency on chronic steroid treatment who receive testosterone replacement therapy, the evidence includes RCTs and systematic reviews. Relevant outcomes are overall survival, symptoms, morbid events, functional outcomes, and quality of life. A limited number of trials have included patients with androgen deficiency on chronic steroid treatment. These trials have reported improvements in body weight, lean body mass, and a decrease in body fat, which are likely to ameliorate the effects of chronic steroids on these parameters. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have androgen deficiency and type 2 diabetes who receive testosterone replacement therapy, the evidence includes RCTs and systematic reviews. Relevant outcomes are overall survival, symptoms, morbid events, functional outcomes, and quality of life. The available RCTs have reported that testosterone replacement leads to modest improvements in glucose control (eg, hemoglobin A1c levels, insulin sensitivity). There is a lack of trials reporting on clinical outcomes, and the small benefits may be outweighed by the adverse events of treatment. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals (older men) with low testosterone levels without definite hypogonadism who receive testosterone replacement therapy, the evidence includes RCTs and systematic reviews. Relevant outcomes are overall survival, symptoms, morbid events, functional outcomes, and quality of life. The available RCTs are mostly small and have reported on a limited range of clinical outcomes. For most outcomes, there was no benefit for testosterone replacement. Some studies have reported improvements in lean body mass and decreased body fat, and a recent RCT found improved sexual function. However, these studies did not report improvements in functional status or muscle strength. Although the adverse event profile of testosterone therapy is not well-defined, there are concerns about increased adverse prostate-related outcomes and cardiovascular outcomes. This uncertainty in the adverse event profile creates challenges in determining the risk-benefit profile of treatment in otherwise healthy men. The evidence is insufficient to determine the effects of the technology on health outcomes.

Background 
TESTOSTERONE AND TESTOSTERONE LEVELS
Testosterone is produced in males, primarily by the testes, in response to stimuli from the hypothalamic and pituitary glands. Low testosterone is caused by deficient production of the hormone and is also known as androgen deficiency. Primary androgen deficiency results from failure of testosterone production at the testicular level in the presence of normal hypothalamic and pituitary function. Secondary androgen deficiency results from failure of the pituitary gland to produce androgen-stimulating hormones (luteinizing hormone, follicle-stimulating hormone). It can be caused by dysfunction at the hypothalamic or pituitary level.

HYPOGONADISM
Diagnosis
Hypogonadism is the clinical syndrome associated with androgen deficiency. The signs and symptoms of hypogonadism depend on the age of onset. In prepubertal males, the hallmark of androgen deficiency is the failure to develop secondary male sex characteristics. In adults, the signs and symptoms are nonspecific, with the most specific symptoms related to sexual functioning such as decreased libido and erectile dysfunction. Symptoms are dependent on age, the severity of androgen deficiency, duration of androgen deficiency, sensitivity to androgen, and comorbid illness.1 Symptoms and signs other than sexual dysfunction include loss of body hair, hot flashes or sweats, decreased energy, depression, sleep disturbance, reduced muscle massand strength, and/or increased body fat. All can occur in the absence of androgen deficiency and, therefore, the diagnosis of hypogonadism can be challenging. A 2014 systematic review by Zarotsky et al (2014) reported on risk factors, comorbidities, and consequences of male hypogonadism and identified multiple comorbid conditions consistently risk factors for hypogonadism, including advanced age, obesity, metabolic syndrome, and poor general health status.2 Multiple other conditions, including diabetes, coronary heart disease, hypertension, stroke, and peripheral artery disease, correlated with the presence of hypogonadism, although were not identified as risk factors.

Testosterone levels decrease with age, beginning in the fourth or fifth decade of a person’s life, and this decrease is sometimes referred to as male “andropause.” In the European Male Aging Study of 3220 men, there was a decline in serum testosterone levels of 0.4% per year between the ages of 40 and 70.3 Because this decline is gradual and modest, the clinical impact is uncertain. While there are also parallel decreases in androgen-dependent factors with age, such as sexual function, lean body mass, and bone mineral density, the degree to which these changes are due to decreasing testosterone has not been determined with certainty.

Because of the decline in testosterone levels with age, more elderly males will have lower levels than younger men. Using a cutoff of 325 ng/dL as the lower limit of normal testosterone levels, Travison et al (2007) estimated based on a prospective cohort of 890 men that the rate of low testosterone is 20% for men in their 60s; 30% for men in their 70s; and 50% for men in their 80s.In this study, other factors were associated with decreased testosterone, such as obesity and severe emotional stress. A much lower percentage of men have a combination of low testosterone levels and definite symptoms of hypogonadism. In the European Male Aging Study, this was estimated to be present in 2.3% of men when using a cutoff of at least 3 symptoms potentially related to androgen deficiency.

Another factor that makes the diagnosis of hypogonadism challenging is the measurement of testosterone levels. Testosterone levels fluctuate substantially due to various factors. There is a diurnal variation, which is more pronounced in younger men, with peak levels occurring in the early morning. This makes the timing of measurement important and requires repeated measurement before making a determination that testosterone is consistently low. Also, there is a wide range of levels seen in healthy men and assigning the proper age-appropriate cutoff is controversial. Some men exhibit clear symptoms of hypogonadism with testosterone levels that are in the low-normal range, while other men with low levels do not experience any symptoms.

Treatment
There are numerous Food and Drug Administration (FDA)-approved testosterone formulations available for replacement therapy. For most delivery preparations, approval was based on the ability to increase levels to the normal range, not to demonstrate beneficial clinical outcomes.5

Oral Testosterone
The most common forms of oral testosterone in clinical use are testosterone enanthate and testosterone cypionate, which are generally dosed twice daily. Oral testosterone is readily absorbed from the intestine and is rapidly metabolized by the liver. The rapid metabolism in the liver limits its clinical utility because it is difficult to maintain steady serum levels. In addition, the first pass through the liver may increase the probability of liver toxicity.

Intramuscular Testosterone
Testosterone undecanoate is an intramuscular depot preparation that is slowly absorbed into the circulation. It is administered by deep intramuscular injection every 10 to 14 weeks and thus has the advantage of infrequent dosing. Disadvantages of this preparation include the intramuscular injection route, which can be painful, and also inconsistent rates of absorption. Inconsistent absorption can lead to fluctuating testosterone levels and related clinical symptoms.

Topical Patch
Topical testosterone patches can be applied to nongenital skin areas. Patches are generally dosed once per day and result in stable testosterone levels over time. A limiting factor of patch use is the development of skin irritation at the patch site in a high percentage of users.

Topical Gels
A number of topical testosterone gel preparations are commercially available. They range in strength from 1% to 2% and provide stable serum levels. The gel is applied daily to nongenital skin areas. Precautions need to be taken to avoid transmission of the drug to others by direct contact. Therefore it is recommended that the gel is placed on coveredskin and that handwashing is performed after application.

Buccal Tablets
Buccal tablets are commercially available and applied twice per day to the gums over the upper incisors. Testosterone is absorbed through the buccal mucosa into the systemic circulation.

Subcutaneous Pellets
Another depot formulation is a subcutaneous testosterone pellet. The pellets are placed subcutaneously in the buttocks, abdominal wall, or thigh under local anesthesia. They are replaced every 3 to 6 months. Limitations include the need for minor surgical procedures, and local reactions at the implantation site (eg, infections, fibrosis).

Regulatory Status 
Numerous preparations of testosterone have been approved by the U.S. Food and Drug Administration (FDA) for use in testosterone replacement therapy. They include intramuscular, oral, topical, subcutaneous, and buccal preparations. 

In January 2014, FDA announced its plan to investigate the risk of stroke, heart attack, and death in men taking FDA-approved testosterone products based on increased risks reported in several studies.6 In September 2014, at a meeting of the FDA’s Bone, Reproductive and Urologic Drugs Advisory Committee, the committee reported that FDA had concluded that FDA-approved testosterone treatment does not increase the risk of stroke, heart attack, and death. However, the Advisory Committee voted in favor of changing the current FDA labeling for indications for testosterone therapies, with committee members stating that the indication for testosterone therapy should be limited to men with classical hypogonadism.7

Policy
Testosterone replacement therapy may be considered MEDICALLY NECESSARY under the following conditions: 

  • An established diagnosis of hypogonadism with androgen deficiency (see Policy Guidelines) that includes:
    • Persistently low testosterone levels, AND
    • Multiple symptoms of hypogonadism including at least one “more specific” symptom. (see Policy Guidelines)
  • HIV-infected men with low testosterone levels and weight loss; or
  • Men on chronic steroid treatment with low testosterone levels (see Policy Guidelines section).
  • Testosterone replacement therapy is considered INVESTIGATIONAL in all other situations in which the above criteria are not met, including, but not limited to, older men with low testosterone levels in the absence of clinical signs and symptoms of hypogonadism. 
  • Testosterone implants will only be considered Medically Necessary as a second-line replacement therapy when oral, topical or intra-muscular testosterone replacement was ineffective.

Policy Guidelines
This policy addresses only testosterone replacement therapy and therefore does not apply to those undergoing treatments for gender transition.

Diagnosis of Androgen Deficiency
An established diagnosis of hypogonadism with androgen deficiency includes appropriate evaluation and diagnostic workup of a man who presents with symptoms of hypogonadism. Clinical practice guidelines recommend measuring serum testosterone only in men with consistent clinical manifestations of hypogonadism. Screening in asymptomatic populations is not recommended. Measurement of serum total testosterone is initially used; serum-free testosterone levels can be measured when total testosterone is in the low-normal range, and alterations of serum hormone-binding globulin are suspected Bhasin et al [2018]). Once a persistently low testosterone level has been established, diagnostic testing of the hypothalamic-pituitary axis should be performed to distinguish primary hypogonadism from secondary hypogonadism. When secondary hypogonadism is identified, the underlying etiology should be identified and any reversible causes treated appropriately before consideration of testosterone replacement.

Men on chronic steroid treatment would be receiving ongoing treatment for a chronic condition as opposed to episodic treatment for an acute condition or acute flare of a chronic condition. The length of acute episodic steroid treatment may vary from several days to several months, but, in most cases, will be less than 4 to 6 weeks.

Persistently low testosterone levels refer to serum levels below the lower limit of normal on at least 2 occasions when measured in the early morning (≈8:00 a.m.). The threshold lower limit for serum testosterone levels is not standardized. The Endocrine Society has recommended a lower limit for normal levels of 300 ng/dL for total testosterone and 9.0 ng/dL for free testosterone (Bhasin et al [2018]). Joint guidelines from several European and American specialty societies have recommended that replacement therapy be considered at serum total testosterone levels less than 350 ng/dL.

“More specific” symptoms of hypogonadism, as classified by the Endocrine Society, include the following (Bhasin et al [2018]):

  • Incomplete or delayed sexual development 
  • Decreased libido 
  • Decreased spontaneous erections 
  • Breast discomfort, gynecomastia 
  • Loss of axillar and/or pubic body hair 
  • Very small (<5 mL) or shrinking testes 
  • Infertility due to low sperm count 
  • Height loss due to vertebral fractures, low trauma fractures, low bone density 
  • Hot flushes, sweats 

Testosterone Dosage Guidelines
Dosing of testosterone varies, depending on age, baseline testosterone levels, comorbid disease, response to initial replacement levels, and adverse reactions. General dosing guidelines are provided by Endocrine Society (see Practice Guidelines and Position Statements section). Specific dosing guidelines for a few of the more commonly used preparations, taken from the product prescribing information, follow:

  • Androgel® (1.62%): The recommended starting dose is 40.5 mg/d, corresponding to 2 pumps applied topically. The recommended dose range is between 20.25 mg (1 pump) and 81 mg (4 pumps) per day. 
  • Androderm® patch: The suggested starting dosing for Androderm patch is one 4-mg patch applied daily. The usual range of dosing required to achieve and maintain normal levels is between 2 mg/d and 6 mg/d.
  • Testopel®: The recommended dosing range for Testopel is 150 to 450 mg every 3 to 6 months. For 75-mg pellets, this would correspond to implant of 2 to 6 pellets every 3 to 6 months. The dosing interval is individualized, as some patients will require redosing as early as every 3 months while others may not require redosing for up to 6 months. 

Monitoring of testosterone replacement should be performed beginning 3 to 6 months after replacement is initiated to ascertain whether serum levels are restored to the normal range, to determine whether clinical symptoms have improved, and to monitor for adverse events. The goal of testosterone replacement is to raise levels into the mid-normal range. Higher replacement levels are unlikely to improve symptoms further and may increase the incidence and/or severity of adverse events. 

Monitoring Strategies for Patients on Testosterone Therapy
Recommendations for monitoring for testosterone-related adverse events have been provided by Endocrine Society guidelines on testosterone therapy in men with androgen deficiency (see Practice Guidelines and Position Statements section) (Bhasin et al [2018]). These recommendations include:

  • Determine a hematocrit at baseline, at 3 to 6 months, and then annually. If the hematocrit is above 54%, stop therapy until the hematocrit decreases to a safe level, evaluate the patient for hypoxia and sleep apnea, and reinitiate therapy at a reduced dose. 
  • Repeating bone mineral density of the lumbar spine, femoral neck, and hip after 1 to 2 years of testosterone therapy in hypogonadal men with osteoporosis or low trauma fracture. 
  • For men 55 to 69 years of age, and for men 40 to 69 years of age who are at increased risk for prostate cancer, conduct a digital examination of the prostate and prostate-specific antigen (PSA) measurement before initiating treatment, at 3 to 2 months after initiating treatment, and then in accordance with evidence-based guidelines for prostate cancer screening, depending on the age and race of the patient.
  • Obtain urological consultation if there is:
    • An increase in serum or plasma PSA concentration greater than 1.4 ng/mL within 12-month period of initiating testosterone treatment. 
    • A confirmed PSA of more than 4 ng/mL at any time. 
    • Detection of a prostatic abnormality on digital rectal examination. 
    •  Substantial worsening of lower urinary tract symptoms. 

Benefit Application
Blue Card/National Account Issues
State or federal mandates (eg, FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational, and thus these devices may be assessed only on the basis of their medical necessity.

Rationale
Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function---including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical uses of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

There is a large body of literature that evaluates the efficacy of testosterone replacement therapy. This body of evidence is primarily characterized by small- to medium-sized trials of short duration. There is a high degree of variability in the patient populations, dosing and delivery methods for testosterone replacement, and outcomes measured. There are also numerous systematic reviews of the available evidence. This review focuses on the impact of testosterone on specific symptoms for adults with androgen deficiency and clinical symptoms of hypogonadism, and on the benefit for specific subpopulations. The discussion emphasizes the available systematic reviews and larger individual RCTs.

Androgen Deficiency and Clinical Symptoms of Hypogonadism
Clinical Context and Therapy Purpose
The purpose of testosterone replacement therapy in patients with androgen deficiency and clinical symptoms of hypogonadism is to provide a treatment option that results in improvement in the net health outcome compared with no testosterone replacement therapy.

The question addressed in this evidence review is: Does testosterone replacement therapy in patients with androgen deficiency and clinical symptoms of hypogonadism improves the net health outcome?

The following PICOTS were used to select literature to inform this review.

Patients
The relevant population of interest is patients with androgen deficiency and clinical symptoms of hypogonadism.

Interventions
The therapy being considered is testosterone replacement therapy.

Comparators
The following practice is currently being used: no testosterone replacement therapy.

Outcomes
The general outcomes of interest are overall survival (OS), symptoms, morbid events, functional outcomes, and quality of life. The potential beneficial outcomes of primary interest would be improvements in specific outcomes such as libido, erectile function, sexual activity, sexual satisfaction, energy, and mood.

Timing
The interest is in whether testosterone replacement therapies improve symptoms that occur as a result of androgen deficiency and whether long-term testosterone replacement therapy is safe. For the former, outcomes at 1 year are relevant; for latter, outcomes at 5 years are relevant.

Setting
Patients requiring testosterone replacement therapies are managed by urologists and endocrinologists in an outpatient setting.

Systematic Reviews
A large number of systematic reviews that assess only RCTs or RCTs and non-RCTs have been published over the last 2 decades and reported on outcomes such as sexual function,7-9 body composition,10,11 and bone mineral density12 while individual RCTs have evaluated the impact of testosterone on depression13-15 and cognition.16 These are not detailed here because they are outdated and/or include results of non-RCTs. A more recent systematic review that only included data from RCTs with low bias is discussed next.

The Endocrine Society commissioned a systematic review and meta-analysis, conducted by Ponce et al (2018), to determine whether testosterone replacement therapy (1) improves sexual function, physical function, fatigue, mood, cognition, anemia, and bone mineral density in men with hypogonadism and (2) is associated with an increased risk of lower urinary tract symptoms and erythrocytosis in men with hypogonadism.17 The systematic review evaluated only placebo-controlled randomized trials (4 RCTs; total N=1779 patients) that assigned men with symptomatic hypogonadism with total testosterone level less than 300 ng/dL at screening. The systematic review characteristics and results are summarized in Tables 1 and 2. Results reported that testosterone replacement therapy was associated with a small but statistically significant improvement in libido, erectile function, sexual activity, and sexual satisfaction compared with placebo but no differences in energy levels or mood. Compared with placebo, testosterone treatment was associated with a significantly higher frequency of erythrocytosis but there was no significant difference in the change in lower urinary tract symptoms. Strengths of this review were inclusion of only RCTs that were low risk of bias, participants who met criteria for the diagnosis of hypogonadism (testosterone level ≤300 ng/dL, and presence of ≥1 symptoms or signs of hypogonadism), and reported outcomes were deemed clinically relevant and important to patients and ascertained using validated instruments. Limitations included the heterogeneity of instruments used to ascertain outcomes across trials, hypogonadism of multiple etiologies and lack of individual patient data meta-analysis to ascertain the relation between symptoms improvement and testosterone levels. Further, none of the trials selected in the systematic review were long enough or large enough to have sufficient statistical power to ascertain safety outcomes (prostate cancer, cardiovascular events, bone fractures).

Table 1. Systematic Review Characteristics  

Study

Dates

Trials

Participants

N (Range)

Design

Duration, wk

Ponce et al (2018)17

To 2017

4

Symptomatic hypogonadism with total testosterone level <300 ng/dL at screening

1779 (NR)

RCT

12-52

NR: not reported; RCT: randomized controlled trial.

Table 2. Systematic Review Results  

Study

Libido

Erectile Function

Sexual Activity

Sexual Satisfaction

Energy

Mood

Erythrocytosis

LUTS

Ponce et al (2018)17

 

 

 

 

 

 

 

 

n

1383

1344

1486

676

1503

1179

1579

866

SMD, RR, or MD (95% CI)

0.17a

(0.01 to 0.34)

0.16a

(0.06 to 0.27)

0.23a

(0.13 to 0.33)

0.16a

(0.01 to 0.31)

0.08a

(-0.02 to 0.18)

0.08a

(-0.03 to 0.20)

8.14b

(1.87 to 35.40)

0.38c (20.67 to 1.43)

CI: confidence interval; SMD: standardized mean difference; LUTS: lower urinary tract symptoms; MD: mean difference; RR: relative risk; SMD: standardized mean difference.

SMD.
b RR.
c MD.

Randomized Controlled Trials
The National Institutes of Health sponsored 7 double-blind, placebo-controlled randomized trials that evaluated whether testosterone treatment of elderly men with low serum testosterone concentrations and symptoms and objective evidence of impaired mobility and/or diminished libido and/or reduced vitality would be efficacious in improving mobility (Physical Function Trial), sexual function (Sexual Function Trial), fatigue (Vitality Trial), cognitive function (Cognitive Function Trial), hemoglobin (Anemia Trial), bone density (Bone Trial), and coronary artery plaque volume (Cardiovascular Trial).18 The major consideration in participant selection in these trials was a requirement of serum testosterone low enough to ensure that the men were unequivocally testosterone deficient, but not so low as to preclude sufficient enrollment or eventual generalizability of the results. Men were randomized to 12 months of testosterone gel (1%) or to placebo gel. General eligibility criteria for all trials age 65 years or older with serum testosterone levels averaging less than 275 ng/dL. Exclusion criteria were a history of prostate cancer, at high risk of prostate cancer, International Prostate Symptom Score (IPSS) greater than 19, a condition known to cause hypogonadism, or at high cardiovascular risk. There were also trial-specific eligibility criteria. The Sexual Function Trial required decreased libido and a partner willing to have intercourse twice a month. The Physical Function Trial required difficulty walking or climbing stairs and gait speed of less than 1.2 m/s on the 6-minute walk test. The Vitality Trial required low vitality (self-report and indicated by the score on a validated test). Results are summarized in Table 3. Briefly, testosterone treatment resulted in substantial benefit for sexual function, anemia, and bone density outcomes but had a small impact on physical function and vitality and no effect on cognition. Although testosterone treatment was associated with an increase in coronary artery noncalcified plaque volume, the number of cardiovascular or prostate adverse events were comparable with the placebo arm. The major limitation of these trials is that the results apply only to men ages 65 years and older with confirmed testosterone concentrations less than 275 ng/dL and durability of treatment effect beyond a year has not been demonstrated.19

Table 3. Results From the Primary Outcomes of the 7 NIH-Sponsored Testosterone Trials  

Trial and Outcomes

N

Mean Difference or OR (95% CI)a

Effect Size (95% CI)b

p

Sexual Function Trial

 

 

 

 

PDQ-Q4 scorec

459

0.58 (0.38 to 0.78)

0.45 (0.30 to 0.60)

<0.001

Sexual desire, DISF-M-II score

470

2.93 (2.13 to 3.74)

0.44 (0.32 to 0.56)

<0.001

Erectile function, IIEF score

470

2.64 (1.68 to 3.61)

0.32 (0.20 to 0.44)

<0.001

Physical Function Trial

 

 

 

 

Men with ≥50 m increase in 6MWD test, %c

387

1.42 (0.83 to 2.45)

Not reported

0.20

6MWD, m

387

4.09 (-3.00 to 11.8))

0.06 (0.004 to 0.16)

0.28

Men whose PF-10 score increased ≥8, %

365

1.34 (0.90 to 2.00)

Not reported

0.15

PF-10 score

365

2.75 (0.20 to 5.29)

0.13 (0.01 to 0.26)

0.03

Vitality Trial

 

 

 

 

Energy, increase ≥4 in FACIT-Fatigue score, %c

474

1.23 (0.83 to 1.84)

Not reported

0.30

Energy, FACIT-Fatigue score

471

1.21 (-0.04 to 2.46)

0.19 (-0.01 to 0.38)

0.03

SF-36 vitality score

404

2.41 (0.31 to 4.50)

0.18 (0.02 to 0.34)

0.03

Positive affect, PANAS score

463

0.47 (0.02 to 0.92)

0.14 (0.01 to 0.27)

0.04

Negative affect, PANAS score

463

-0.49 (-0.79 to -0.19)

-0.18 (-0.29 to -0.06)

<0.001

Depression, PHQ-9 score

464

-0.72 (-1.20 to -0.23)

-0.18 (-0.30 to -0.06)

0.004

Cognitive Function Trial

 

 

 

 

Verbal memory; delayed paragraph recallc

493

-0.07 (-0.92 to 0.79)

-0.01 (-0.14 to 0.12)

0.88

Visual memory; Benton Visual Retention Test

492

-0.28 (-0.76 to 0.19)

-0.09 (-0.24 to 0.06)

0.24

Spatial ability; card rotation test

488

-0.12 (-1.89 to 1.65)

-0.01 (-0.13 to 0.11)

0.89

Executive function; Trail Making Test B-A, sd

490

-5.51 (-12.91 to 1.88)

-0.09 (-0.22 to 0.03)

0.14

Anemia Trial

 

 

 

 

Hemoglobin increase from baseline ≥1.0 g/dL, %c,e

62

31.5 (3.7 to 277.8)

Not reported

0.002

Hemoglobin, g/dLe

62

0.83 (0.48 to 1.39)

1.30 (0.75 to 2.18)

0.001

Hemoglobin increase from baseline ≥1.0 g/dL, %f

64

8.2 (2.1 to 31.9)

Not reported

0.003

Hemoglobin, g/dLf

64

0.64 (0.12 to 1.17)

0.90 (0.17 to 1.65)

0.018

Bone Trial

 

 

 

 

Spine trabecular BMD, % change from baselinec

207

6.8 (4.8 to 8.7)

0.23 (0.17 to 0.29)

0.001

Spine whole bone BMD, % change from baselined

207

4.2 (3.2 to 5.3)

0.12 (0.09 to 0.15)

0.001

Hip trabecular BMD, % change from baseline

191

1.5 (0.9 to 2.0)

0.04 (0.03 to 0.06)

0.001

Hip whole bone BMD, % change from baseline

191

1.3 (0.8 to 1.7)

0.03 (0.02 to 0.04)

0.001

Cardiovascular Trial

 

 

 

 

Noncalcified coronary artery plaque volume,c mm3

138

41 (14 to 67)

0.11 (0.04 to 0.19)

0.003

Total coronary artery plaque volume, mm3

138

47 (13 to 80)

0.09 (0.02 to 0.15)

0.006

Coronary artery calcium score, Agatston units

138

-27 (-80 to 26)

-0.03 (-0.07 to 0.02)

0.31

Adapted from Snyder et al (2018).19

BMD: bone mineral density; CI: confidence interval; DISF-M-II: Derogatis Inventory of Sexual Function-Men-II, sexual desire domain (range, 0-33); FACIT-Fatigue: Functional Assessment of Chronic Illness Therapy-Fatigue (range, 0-52, higher scores indicate less fatigue); IIEF: International Index of Erectile Function, erectile function domain (range, 0-30); NIH: National Institutes of Health; OR: odds ratio; PANAS: Positive and Negative Affect Scale (range, 5-50); PDQ-Q4: Psychosexual Daily Questionnaire (range, 0-12, higher scores indicate greater number of activities); PF-10, physical function scale of the Medical Outcomes Short Form Health Survey (range, 0-100); PHQ-9: Patient Health Questionnaire 9 (range, 0-27; higher scores indicate greaterdegree of depressive symptoms); SF-36, 36-item Short-Form Survey (range, 0-100); 6MWD: 6-minute walk distance.

a Treatment effect: for continuous outcomes, the treatment effect was the mean change in men allocated to testosterone minus the mean change in men allocated to placebo, adjusted for balancing factors: baseline total testosterone level (≤200 or >200 ng/dL), age (≤75 or >75 years), trial site, participation in the main trials, use or nonuse of antidepressants, use or nonuse of phosphodiesterase type 5 inhibitors, and baseline value of the outcome variable; for binary outcomes, the adjusted OR was the ratio of the outcome in men allocated to testosterone to the outcome in men allocated to placebo, adjusted for the same balancing factors.
The effect size for continuous outcomes was calculated from the mean difference divided by the baseline standard deviation pooled across treatment arms; an effect size of 0.2 is considered a small effect, 0.5 a medium effect, and 0.8 a large effect.
Primary outcome measure.
Lower scores reflect better function.
e Among men with unexplained anemia
f Among men with anemia of known cause.

Section Summary: Androgen Deficiency and Clinical Symptoms of Hypogonadism
For men with low testosterone levels and sexual dysfunction, evidence from RCTs and meta-analyses has demonstrated a beneficial effect on increased libido. Other sexual symptoms (eg,erectile dysfunction) are also likely to be improved, but the evidence is less strong. For nonsexual symptoms, there is evidence that lean body mass increased, body fat decreased, and bone mineral density (BMD) increased with testosterone therapy. However, the impact of these changes on functional status and fractures is less clear. For outcomes such as decreased energy, depression, quality of life, and cognition, the evidence is limited and inconsistent in reporting benefits of replacement therapy.

Androgen Deficiency and HIV Infection
There is a high prevalence of androgen deficiency in patients with HIV infection who are on antiviral treatment, with up to 25% of this population having low testosterone levels. Men with low levels of testosterone have worse outcomes of HIV disease, including faster disease progression, greater loss of muscle mass, and larger declines in physical functioning.1

Clinical Context and Therapy Purpose
The purpose of testosterone replacement therapy in patients with HIV infection and androgen deficiency is to provide a treatment option that results in improvement in net health outcome compared with no testosterone replacement therapy.

The questions addressed in this evidence review is: Does testosterone replacement therapy in patients withHIV infection and androgen deficiency improve the net health outcome?

The following PICOTS were used to select literature to inform this review.

Patients
The relevant population of interest is patients with HIV infection and androgen deficiency.

Interventions
The therapy being considered is testosterone replacement therapy.

Comparators
The following practice is currently being used: no testosterone replacement therapy.

Outcomes
The general outcomes of interest are OS, symptoms, morbid events, functional outcomes, and quality of life. The potential beneficial outcomes of primary interest would be an improvement in specific outcomes such as body weight, fat-free mass, and lean body mass.

Timing
The interest is in whether testosterone replacement therapies improve symptoms that occur as a result of androgen deficiency and whether long-term testosterone replacement therapy is safe. For the former, outcomes in 1 year are relevant; for latter, outcomes for 5 years are relevant.

Setting
Patients with HIV infection and androgen deficiency requiring testosterone replacement therapies are managed by physicians who provide HIV care in an outpatient setting.

Systematic Reviews
A systematic review of testosterone replacement in HIV-infected men with weight loss was performed by Bhasin et al (2006).20 They identified 8 trials of testosterone replacement in HIV-infected patients with weight loss. The trials were of variable quality and heterogeneous in their methodologies. Combined analysis of changes in body weight, fat-free mass, and lean body mass was performed. There was an estimated increase of 1.1 kg in body weight (95% CI, 0.2 to 2.0 kg), 1.4 kg in fat-free mass (95% CI, 0.7 to 2.1 kg), and 1.3 kg in lean body mass (95% CI, 0.4 to 2.2 kg) associated with testosterone replacement. Reviewers also assessed the outcomes of muscle strength and depression. Three trials reported on changes in muscle strength, with 2 of 3 reporting significant improvements with testosterone therapy. Four trials reported on changes in depression, with combined analysis showing a modest improvement in depression scores for testosterone-treated patients. There were no significant changes in parameters of HIV infection (eg, T lymphocyte or viral load for patients treated with testosterone).

Section Summary: Androgen Deficiency and With HIV Infection
RCTs of patients with HIV infection and weight loss, included in a systematic review, found that testosterone replacement was associated with an increase in body weight and lean body mass and a decrease in body fat. Findings from these trials would suggest that testosterone replacement is likely to ameliorate the weight loss associated with HIV infection.

Androgen Deficiency and Chronic Steroid Treatment
Patients treated with chronic steroid therapy have lower levels of testosterone compared with age-matched patients not on steroids. This effect of steroids is thought to suppress the hypothalamic-pituitary axis as well as testosterone production in the testes. This hormonal suppression contributes to the increase in abdominal fat and a decrease in BMD seen in patients treated chronically with steroids.

Clinical Context and Therapy Purpose
The purpose of testosterone replacement therapy in patients who receive chronic steroid treatment and have androgen deficiency is to provide a treatment option that results in improvement in the net health outcome compared with no testosterone replacement therapy.

The questions addressed in this evidence review is: Does testosterone replacement therapy in patients who receive chronic steroid treatment and have androgen deficiency improve net health outcome?

The following PICOTS were used to select literature to inform this review.

Patients
The relevant population of interest is patients treated with chronic steroid treatment who have androgen deficiency.

Interventions
The therapy being considered is testosterone replacement therapy.

Comparators
The following practice is currently being used: no testosterone replacement therapy.

Outcomes
The general outcomes of interest are OS, symptoms, morbid events, functional outcomes, and quality of life. The potential beneficial outcomes of primary interest would be an improvement in specific outcomes such as body weight, fat-free mass, and lean body mass.

Timing
The interest is in whether testosterone replacement therapies improve symptoms that occur as a result of androgen deficiency and whether long-term testosterone replacement therapy is safe. For the former, outcomes in 1 year are relevant; for latter, outcomes for 5 years are relevant.

Setting
Patients who receive chronic steroid treatment, have androgen deficiency, and require testosterone replacement therapies are managed by general physicians as well as multiple specialties in an outpatient setting.

Systematic Reviews
The systematic review by Bhasin et al (2006; discussed previously) identified 2 placebo-controlled randomized trials of testosterone replacement in patients on chronic steroid treatment for asthma or chronic obstructive pulmonary disease.20 The trials were limited by small sample sizes and short duration of follow-ups. Pooled analysis of the 2 trials showed a significant increase in lean body mass of 2.3 kg (95% CI, 2.0 to 3.6 kg) and a significant decrease in fat mass of 3.1 kg (95% CI, -2.8 to -3.5 kg). There was also a significant improvement in lumbar bone density of 4% (95% CI, 2% to 7%), although there was no significant improvement in BMD of the femoral neck.

Section Summary: Androgen Deficiency and Chronic Steroid Treatment
A meta-analysis of 2 RCTs in men receiving chronic steroid treatment found a significant increase in lean body mass and a significant decrease in fat mass in patients receiving testosterone therapy vs placebo. Thus, the evidence would suggest that testosterone is likely to ameliorate adverse events related to chronic steroid use on these parameters.

Androgen Deficiency and Type 2 Diabetes
Clinical Context and Therapy Purpose
The purpose of testosterone replacement therapy in patients with type 2 diabetes and androgen deficiency is to provide a treatment option that results in improvement in the net health outcome compared with no testosterone replacement therapy.

The questions addressed in this evidence review is: Does testosterone replacement therapy in patients with type 2 diabetes and androgen deficiency improve the net health outcome?

The following PICOTS were used to select literature to inform this review.

Patients
The relevant population of interest is patients with type 2 diabetes and androgen deficiency.

Interventions
The therapy being considered is testosterone replacement therapy.

Comparators
The following practice is currently being used: no testosterone replacement therapy.

Outcomes
The general outcomes of interest are OS, symptoms, morbid events, functional outcomes, and quality of life. The potential beneficial outcomes of primary interest would be metabolic measures for diabetes (eg, glucose and hemoglobin A1c (HbA1c) levels.

Timing
The interest is in whether testosterone replacement therapies improve symptoms that occur as a result of androgen deficiency and whether long-term testosterone replacement therapy is safe. For the former, outcomes in 1 year are relevant; for latter, outcomes for 5 years are relevant.

Setting
Patients with type 2 diabetes, androgen deficiency, and require testosterone replacement therapies are managed by general physicians and endocrinologists.

Systematic Reviews
Cai et al (2014) reported on the results of a systematic review and meta-analysis of RCTs that evaluated the effect of testosterone therapy on metabolic parameters in patients with type 2 diabetes and hypogonadism.21 Five RCTs (total N=351 subjects) identified met eligibility criteria, 3 of which were double-blind, placebo-controlled trials and 2 of which were open-label and single-blind, no-treatment controlled trials. In pooled analysis, testosterone was associated with reduced fasting plasma glucose levels (MD = -1.10; 95% CI, -1.88 to -0.31), fasting insulin levels (MD = -2.73; 95% CI, -3.63 to -1.84), HbA1c level (MD = -0.87; 95% CI, -1.32 to -0.42), and triglyceride levels (MD = -0.35; 95% CI, -0.62 to -0.07). Reviewers noted that both trials were limited by relatively few participants and discussion of methods.

Randomized Controlled Trials
One of the larger RCTs in the Cai meta-analysis, conducted by Jones et al (2011), enrolled 220 patients with type 2 diabetes and/or metabolic syndrome and hypogonadism.22 Treatment in the testosterone group was with daily transdermal testosterone 60 mg. The primary outcome was the change in insulin resistance, as measured by the homeostasis model of insulin resistance, and secondary outcomes were changes in body composition, glycemic control, lipid levels, and sexual dysfunction. There was a 16% reduction in the homeostasis model of insulin resistance at the 6-month follow-up (p<0.02), and this difference persisted at 12-month follow-up. Other outcomes were reported at the 6-month follow-up. There were statistically significant improvements for the overall group in International Index of Erectile Function scores for the testosterone group, but no significant improvement in the HbA1c or fasting glucose levels. There were no differences for the overall group on measures of body composition or lipid levels. On subgroup analysis, there was an improvement for patients with metabolic syndrome in their mean low-density lipoprotein levels.

In an RCT not included in the Cai meta-analysis, Hackett et al (2014) randomized 211 patients with type 2 diabetes and hypogonadism to parenteral testosterone (testosterone undecanoate 1000 mg at weeks 0, 6, and 18) or to placebo; they were followed for 30 weeks.23 For the trial’s primary outcome (change in HbA1c level), testosterone treatment was associated with a significant reduction in HbA1c levels at 6 weeks of therapy (from 7.74% to 7.50%). At 18 weeks of therapy, the MD between treatment and control group, after adjusting for covariates, was -0.20 (95% CI, -0.34 to -0.05; p=0.007). There were significant reductions in waist circumference, weight, and body mass index in men without depression. Hackett et al (2016) reported on a secondary study outcome, sexual function outcomes.24 Sexual function was assessed with the 15-item International Index of Erectile Function. In men with mild hypogonadism, there were no significant differences in sexual function scores in the testosterone and placebo groups. In men with severe hypogonadism, at 30 weeks, there was a significant improvement in 3 of 4 International Index of Erectile Function sexual function domains compared with placebo. In the testosterone group, 116 adverse events were reported, 2 of which (injection pain) were definitely treatment-related and 19 of which were possibly treatment-related. There were 4 serious adverse events (2 in each group), but none was treatment-related. Trialists did not specify the nonserious adverse events.

Magnussen et al (2016) reported on the findings of a small RCT evaluating 39 patients with controlled type 2 diabetes.25 Men ages 50 to 70 years with bioavailable testosterone levels less than 7.3 nmol/L were randomized to testosterone gel (n=20) or to placebo (n=19) for 24 weeks. Treatment with testosterone improved body composition (increase lean body mass and decrease fat mass), but not glycemic control, peripheral insulin sensitivity, endogenous glucose production, or substrate metabolism.

Section Summary: Androgen Deficiency and Type 2 Diabetes
Several RCTs have assessed testosterone replacement in patients with hypogonadism and type 2 diabetes. A systematic review of five of these trials noted methodologic limitations (eg, lack of blinding, limited discussion of methods). Pooled analyses found testosterone replacement led to modest improvements in glucose control (eg, hemoglobin A1c levels, insulin sensitivity). There is a lack of trials reporting on clinical outcomes, and the small benefits with uncertain clinical significance might be outweighed by the adverse events of treatment.

Older Men With Low Testosterone Levels Without Definite Hypogonadism
Clinical Context and Therapy Purpose
The purpose of testosterone replacement therapy in older men with low testosterone levels without definite hypogonadism is to provide a treatment option that results in improvement in the net health outcome compared with no testosterone replacement therapy.

The questions addressed in this evidence review is: Does testosterone replacement therapy in older men with low testosterone levels without definite hypogonadism improve the net health outcome?

The following PICOTS were used to select literature to inform this review.

Patients
The relevant population of interest is older men with low testosterone levels without definite hypogonadism.

Interventions
The therapy being considered is testosterone replacement therapy.

Comparators
The following practice is currently being used: no testosterone replacement therapy.

Outcomes
The general outcomes of interest are OS, symptoms, morbid events, functional outcomes, and quality of life. The potential beneficial outcomes of primary interest would be an improvement in specific outcomes such as libido, erectile function, sexual activity,sexual satisfaction, energy, and mood.

Timing
The interest is in whether testosterone replacement therapies improve symptoms that occur as a result of androgen deficiency and whether long-term testosterone replacement therapy is safe. For the former, outcomes in 1 year are relevant; for latter, outcomes for 5 years are relevant.

Setting
In older men with low testosterone levels without definite hypogonadism requiring testosterone replacement therapies are managed by urologists and endocrinologists in an outpatient setting.

Randomized Controlled Trials
A few RCTs have evaluated the impact of testosterone replacement in elderly men with low testosterone levels, without definite evidence of hypogonadism. Most trials have been small and included only a limited range of outcomes. The largest RCTs are discussed next.

A large multicenter RCT, reported by Legros et al (2009) from Europe, enrolled 322 patients who were 50 years or older, with mild-to-moderate symptoms of hypogonadism and low testosterone levels.26, Patients were randomized to daily testosterone 80, 160, or 240 mg or to placebo, and the primary outcome was the change in the Aging Males Symptom scale at 6 months. There were no statistically significant differences on the total Aging Males Symptom score between groups at 6 months, although the scores in the testosterone group showed a greater numeric improvement. There was a statistically significant difference in the Aging Males Symptom sexual domain subscore for the 160-mg testosterone group, but not for the 80- and the 240-mg groups. There were no statistically significant differences in adverse events between groups, including the change in prostate-specific antigen (PSA) level.

A trial by Emmelot-Vonk et al (2008) enrolled 237 men between the ages of 60 and 80 years who had low testosterone levels but were otherwise healthy.27 Patients were randomized to oral testosterone 80 mg or to placebo and followed for 6 months. A range of outcome measures was reported, including functional mobility, body composition, muscle strength, cognitive function, bone mineral density, metabolic parameters, and quality of life. Safety outcomes were also included: PSA, prostate volume, renal function, liver function, and hematocrit levels. For most outcome measures, there was no improvement in the testosterone group compared with placebo therapy. There was an increase in lean body mass and a decrease in the percent body fat. However, these changes were not accompanied by improvements in functional capacity or muscle strength. There were no significant changes in cognitive function, BMD, or quality of life. There was worsening metabolic profile, though not statistically significant (p=0.07), with 47.8% of men in the testosterone group meeting the definition for metabolic syndrome at the end of the study compared with 35.5% of men in the placebo group. There was a significant, but small, increase in hematocrit concentration for men in the testosterone group, and an increase in creatinine levels that was of borderline significance. Otherwise, there were no group differences in the safety outcomes.

Several smaller RCTs have been published, ranging in size from 13 to 131 patients.28-32 The most consistent finding reported in these trials was an increase in lean body mass (4 studies) and a decrease in body fat (3 studies). The impact on strength was mixed, with 2 studies reporting an improvement in the testosterone group and 2 studies reporting no difference between groups. An increase in hemoglobin level and/or hematocrit concentration was reported in 1 study, and an increase in bone mineral density was reported in another. None of these RCTs reported on functional status, quality of life, or sexual performance.

Section Summary: Older Men With Low Testosterone Levels Without Definite Hypogonadism
Several RCTs have been published, and most have been small and reported on a limited range of clinical outcomes. For most outcomes reported, there was no significant benefit reported for testosterone replacement. Some studies have reported improvements in lean body mass and decreased body fat, and a recent RCT reported improvement in sexual function. However, these trials did not report improvements in functional status or muscle strength. The adverse event profile of testosterone therapy is not well-defined, and there have been concerns about increased adverse prostate-related outcomes and cardiovascular outcomes. This uncertainty in the adverse event profile creates challenges in determining the risk-benefit profile of treatment in otherwise healthy men.

Adverse Events of Testosterone Therapy
There is a long list of potential adverse events that with testosterone replacement, as follows5  

  • Prostate-related events, including development or worsening of prostate cancer, prostatic hypertrophy, increases in PSA levels, and symptoms of prostatism
  • Cardiovascular events
  • Adverse changes in lipid profile
  • Erythrocytosis and increases in hematocrit
  • Precipitation or worsening of sleep apnea
  • Liver toxicity
  • Suppression of spermatogenesis
  • Acne
  • Worsening of male pattern baldness
  • Gynecomastia.

The clinical significance of many of these potential adverse events is unclear. Several meta-analyses have studied adverse events expected to be more common. This review of adverse events will include both randomized and nonrandomized studies, with emphasis on systematic reviews and meta-analyses of the available studies.

Cardiovascular Events
Systematic Reviews
Albert and Morley (2016) reported the findings of a systematic review that included 45 trials with 5328 subjects with mean age of 63.3 years and a mean follow-up of 10.6 months.33 Over the duration of available follow-up, testosterone treatment was not associated with increased risk of cardiovascular events (RR=1.10; 95% CI, 0.86 to 1.41; p=0.45). However, there was an increase event rate during the first 12 months (RR=1.79; 95% CI, 1.13 to 2.83; p=0.012), predominantly among those 65 years or older (RR=2.90; 95% CI, 1.35 to 6.21; p=0.006).

Corona et al (2015) published an overview of previously published meta-analyses on the association between testosterone replacement therapy and cardiovascular risk.34 Reviewers included the 3 meta-analyses described below, as well as two others, all of which focused on RCT evidence. Reviewers reported that only one of the 5 meta-analyses supported an association between testosterone therapy and an increased cardiovascular risk. They stated that, in the single positive meta-analysis, cases of peripheral edema and self-reported syncope were included in the category of cardiovascular events, which might have overstated the number of clinically significant events. The other 4 meta-analyses did not find significant differences between testosterone and placebo groups in the incidence of overall cardiovascular events or specific events including cardiovascular death, fatal and nonfatal myocardial infarctions, and cerebrovascular events.

Fernandez-Balsells et al (2010) published a systematic review of randomized and nonrandomized comparative studies.35 They included 51 studies and examined the outcomes of mortality, cardiovascular events, cardiovascular risk factors, prostate events, and erythrocytosis. Patients treated with testosterone had increased hematocrit concentrations (weighted mean difference, 3.2%; 95% CI, 1.4% to 5.0%), and decreased high-density lipoprotein levels (weighted mean difference, 0.5 mg/dL; 95% CI, 0.13 to 0.85 mg/dL). No significant differences were reported in mortality, cardiovascular events, or prostate-related events.

Calof et al (2005) performed a meta-analysis of placebo-controlled randomized trials.36 Nineteen studies were selected (total N=1084 patients) and assessed the outcomes of mortality, prostate-related events, changes in hematocrit concentration, and sleep apnea. Patients treated with testosterone were more likely to have a hematocrit greater than 50% (OR=3.7; 95% CI, 1.8 to 7.5). There were no significant differences in mortality, cardiovascular events, or sleep apnea.

In another systematic review of placebo-controlled randomized trials, Haddad et al (2007) examined the rates of adverse cardiovascular events and changes in cardiovascular risk factors.37 This review included 30 trials (total N=1642 men). Total adverse cardiovascular events were numerically more frequent in testosterone-treated patients, but the difference compared with placebo was not statistically significant (OR=1.8; 95% CI, 0.8 to 4.2). There were small changes in blood pressure, lipid levels, and glucose, but none of these changes was statistically significant.

Cohort Studies
In addition to RCTs and meta-analyses of them, several large cohort studies have been published. Finkle et al (2014) conducted a large retrospective cohort study using administrative claims data to assess the relation between testosterone therapy and nonfatal myocardial infarction (MI).38 The authors generated a cohort of 55,593 men who filled their first prescription for one of several testosterone prescriptions between 2008 and 2010 from the Truven Health MarketScan Commercial Claims and Encounters Database, which includes diagnoses, procedures, and prescriptions for all enrollees of contributing health plans. Testosterone recipients were compared with a population of men who filled their first prescription for a phosphodiesterase type 5 inhibitor (sildenafil or tadalafil; N=167,279) during the same time period. For testosterone recipients, the rate ratio of MI in the post- compared with the pre-testosterone period was 1.36 (95% CI, 1.03 to 1.81). Compared with subjects in the phosphodiesterase type 5 inhibitor group, the rate ratio for MI risk for testosterone recipients was 1.90 (95% CI, 1.04 to 3.49). After stratifying by age, for testosterone recipients younger than age 55 years, the rate ratio for MI in the post-testosterone period was 0.95 (95% CI, 0.54 to 1.67); for testosterone recipients ages 75 and older, the rate ratio for MI in the post-testosterone period was 3.43 (95% CI, 1.54 to 7.56; p=0.03 for trend). No similar trend was seen for phosphodiesterase type 5 inhibitor recipients. Although this study suggested an association between testosterone use and nonfatal MI, it was limited by its retrospective design and the potential for confounding by measured and unmeasured variables.

Another large retrospective cohort study conducted by Baillargeon et al (2014) evaluated administrative claims data from Medicare to assess the relation between testosterone administered intramuscularlyand the risk of MI.39 The study included 6355 Medicare beneficiaries who received at least 1 testosterone injection between 1997 and 2005 and who were matched in a 1:3 ratio to 19,065 testosterone nonusers based on a composite MI prognostic score. After adjustment for demographic and clinical covariates, testosterone therapy was not associated with an increased risk of MI (adjusted hazard ratio, 0.84; 95% CI, 0.69 to 1.01). Testosterone therapy was associated with a reduced risk of MI in men with an MI prognostic score in the highest quartile (hazard ratio, 0.69; 95% CI, 0.53 to 0.92), while men in the lower 3 quartiles showed no difference in MI risk with testosterone therapy.

A large retrospective comparative cohort study, Vigen et al (2013) evaluated the risk of cardiovascular events in patients treated with testosterone replacement therapy.40 This study used data from the Veterans Administration Clinical Assessment Reporting and Tracking Program to identify all male patients who had both undergone coronary angiography and had a total testosterone level checked between 2005 and 2011. There were 8709 patients with a low testosterone level, defined as less than 300 ng/dL. The population had high levels of comorbidity, with 80% of patients having coronary artery disease, 50% diabetes, and 20% prior MI. There were 1223 patients treated with testosterone and 7486 who were not. After a mean follow-up of 27.5 months, the primary outcome of all-cause mortality, MI, or stroke was more frequent in the group treated with testosterone (hazard ratio, 1.29; 95% CI, 1.04 to 1.58; p=0.02).

A case-control study performed within a cohort of 934,283 men ages 45 to 80 years was published by Etminan et al (2015).41 It identified 30,066 cases of MI and matched each case with 4 controls. There was no evidence of increased current testosterone replacement therapy use in case patients (RR=1.01; 95% CI, 0.89 to 1.16). There was also no association between past testosterone replacement therapy use and MI or evidence of different risk level by type of preparation. A small increase in risk was reported for first-time testosterone replacement therapy users (RR=1.41; 95% CI, 1.06 to 1.87).

Effects on Prostate Gland
Several meta-analyses have specifically evaluated the relation between testosterone and prostate-related events. Cui et al (2013) conducted a systematic review of RCTs, which reported on the effect of testosterone replacement on prostate growth.42 Sixteen RCTs comparing testosterone replacement with placebo (total N=1030 patients) were included, 7 of which were short-term (<12 months) and 9 long-term (12-36 months). Seven studies evaluated transdermally administered testosterone, while 6 evaluated injected testosterone and 3 evaluated orally administered testosterone. In the short-term, transdermal, but not orally administered or injected, testosterone administration was significantly associated with changes in PSA levels (SMD=0.30; 95% CI, 0.07 to 0.54; p=0.002). However, there was no significant association between testosterone administration and PSA levels over the longer term. Testosterone administration by any method was not associated with significant differences in IPSS, prostate volume, or maximum urine flow rate.

In a separate publication, Cui et al (2014) conducted a systematic review of RCTs that reported on the effect of testosterone replacement therapy on prostate cancer risk.43 This analysis included 22 RCTs (total N=2351 patients), 11 of which reported short-term (<12 months) outcomes and 11 of which reported long-term (12-36 months) outcomes. Five studies evaluated injectable testosterone, one evaluated oral testosterone, and 5 studies evaluated transdermal testosterone over the short-term; there was no significant association between any administration method and prostate cancer, prostate biopsy, or prostate nodules. However, for the studies evaluating transdermal testosterone, there was a significant association between testosterone treatment and change in PSA level (SMD=0.33; 95% CI, 0.21 to 0.45; p<0.000). There was no association between testosterone therapy and abnormal PSA levels. For long-term administration, 3 studies evaluated injectable testosterone, 2 studies evaluated oral testosterone, and 6 studies evaluated transdermally administered testosterone. There was no significant association between testosterone administration by any method and prostate cancer, prostate biopsy, or prostate nodules. No significant association was found between testosterone administration over the long-term and change in PSA level.

A systematic review by Kohn et al (2016) identified 14 RCTs on testosterone therapy in aging men and assessed lower urinary tract symptoms with the IPSS.44 In a pooled analysis, there was no statistically significant difference in change in IPSS among men treated with testosterone vs placebo (p=0.11). Similarly, another systematic review, Kathrins et al (2016) identified 35 prospective studies and found that most trials did not demonstrate a correlation between testosterone therapy and enlarged prostate volume, de novo lower urinary tract symptoms, or worsening lower urinary tract symptoms.45

Venous Thromboembolism
A large case-control study by Baillargeon et al (2015) evaluated the risk of venous thromboembolism associated with testosterone replacement therapy.46 This study assessed 30,572 men ages 40 years and older. Subjects had a diagnosis of venous thromboembolism and were on an anticoagulant drug. Cases were matched with 3 controls on age, time of onset, location, diagnosis of hypogonadism, and the presence of a prothrombotic condition. There was no increased risk of testosterone replacement therapy in the venous thromboembolism group (OR=0.91; 95% CI, 0.38 to 2.16). The lack of an association persisted when different time frames of testosterone replacement therapy exposure were examined.

Summary of Evidence
For individuals who have androgen deficiency and clinical symptoms of hypogonadism who receive testosterone replacement therapy, the evidence includes RCTs and systematic reviews. Relevant outcomes are overall survival, symptoms, morbid events, functional outcomes, and quality of life. For men with low testosterone levels and sexual dysfunction, the evidence has been fairly consistent in demonstrating a beneficial effect on increased libido. Other sexual function symptoms (eg, erectile dysfunction) are also likely to be improved, but the evidence is less strong. For other symptoms, there is evidence that lean body mass is increased, body fat is decreased, and bone mineral density is increased with testosterone therapy. However, the impact of these changes on functional status and fractures is less clear. For outcomes such as decreased energy, depression, quality of life, and cognition, the evidence is limited and inconsistent in reporting benefits of replacement therapy. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have androgen deficiency and HIV infection who receive testosterone replacement therapy, the evidence includes RCTs and systematic reviews. Relevant outcomes are overall survival, symptoms, morbid events, functional outcomes, and quality of life. A limited number of trials have included patients with HIV infection and weight loss. These trials have reported improvements in body weight, lean body mass, and a decrease in body fat, which indicates that testosterone replacement is likely to ameliorate weight loss associated with HIV infection. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have androgen deficiency on chronic steroid treatment who receive testosterone replacement therapy, the evidence includes RCTs and systematic reviews. Relevant outcomes are overall survival, symptoms, morbid events, functional outcomes, and quality of life. A limited number of trials have included patients with androgen deficiency on chronic steroid treatment. These trials have reported improvements in body weight, lean body mass, and a decrease in body fat, which are likely to ameliorate the effects of chronic steroids on these parameters. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have androgen deficiency and type 2 diabetes who receive testosterone replacement therapy, the evidence includes RCTs and systematic reviews. Relevant outcomes are overall survival, symptoms, morbid events, functional outcomes, and quality of life. The available RCTs have reported that testosterone replacement leads to modest improvements in glucose control (eg, hemoglobin A1c levels, insulin sensitivity). There is a lack of trials reporting on clinical outcomes, and the small benefits may be outweighed by the adverse events of treatment. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals (older men) with low testosterone levels without definite hypogonadism who receive testosterone replacement therapy, the evidence includes RCTs and systematic reviews. Relevant outcomes are overall survival, symptoms, morbid events, functional outcomes, and quality of life. The available RCTs are mostly small and have reported on a limited range of clinical outcomes. For most outcomes, there was no benefit for testosterone replacement. Some studies have reported improvements in lean body mass and decreased body fat, and a recent RCT found improved sexual function. However, these studies did not report improvements in functional status or muscle strength. Although the adverse event profile of testosterone therapy is not well-defined, there are concerns about increased adverse prostate-related outcomes and cardiovascular outcomes. This uncertainty in the adverse event profile creates challenges in determining the risk-benefit profile of treatment in otherwise healthy men. The evidence is insufficient to determine the effects of the technology on health outcomes.

PRACTICE GUIDELINES AND POSITION STATEMENTS
Endocrine Society
The Endocrine Society published clinical practice guidelines on testosterone therapy in men with androgen deficiency in 2018 (see Table 4).

Table 4. Practice Guidelines on Testosterone Therapy in Men With Hypogonadism  

Recommendations

SOR

QOE

“We recommend testosterone therapy in hypogonadal men to induce and maintain secondary sex characteristics and correct symptoms of testosterone deficiency.”

Recommend

Moderate

“We recommend against testosterone therapy in men planning fertility in the near term or in men with breast or prostate cancer, a palpable prostate nodule or induration, a prostate-specific antigen level > 4 ng/mL, a prostate-specific antigen level > 3 ng/mL combined with a high risk of prostate cancer (without further urological evaluation), elevated hematocrit, untreated severe obstructive sleep apnea, severe lower urinary tract symptoms, uncontrolled heart failure, myocardial infarction or stroke within the last 6 months, or thrombophilia”

Recommend

Low

“In hypogonadal men 55 to 69 years old, who are being considered for testosterone therapy and have a life expectancy >10 years, we suggest discussing the potential benefits and risks of evaluating prostate cancer risk and prostate monitoring and engaging the patient in shared decision making regarding prostate cancer monitoring. For patients who choose monitoring, clinicians should assess prostate cancer risk before starting testosterone treatment and 3 to 12 months after starting testosterone.”

Suggest

Very low

“In hypogonadal men being considered for testosterone therapy who are 40 to 69 years old and at increased risk of prostate cancer (e.g., African Americans and men with a first-degree relative with diagnosed prostate cancer), we suggest discussing prostate cancer risk with the patient and offering monitoring options.”

Suggest

Very low

Adapted from Bhasin et al (2018).47
SOR: strength of recommendation; QOE: quality of evidence.

European Menopause and Andropause Society
A position statement was published by the European Menopause and Andropause Society in 2016 on testosterone replacement therapy in the aging male.48 The Society made the following relevant recommendations:  

  • “A general policy of offering TRT [testosterone replacement therapy] to all aging men with low testosterone concentrations is not recommended.”
  • “Physicians should consider offering TRT, on an individual basis, to aging men with low testosterone concentrations on more than one occasion and clinically significant symptoms of androgen deficiency.”
  • “Currently available percutaneous, transdermal, subcutaneous and buccal testosterone preparations are considered to be safe and effective.”
  • “There is no consensus on the beneficial effects of TRT with regard to obesity, metabolic syndrome, type 2 diabetes mellitus, sexual functionand osteoporosis.”
  • “Specific populations, such as older men with low testosterone concentrations and type 2 diabetes mellitus might benefit from TRT.”
  • “TRT is absolutely contraindicated in cases of metastatic prostate or breast cancer, unevaluated prostate nodule or induration, PSA [prostate-specific antigen] > 4 ng/ml, hematocrit >50%,severe lower urinary tract symptoms and/or uncontrolled congestive heart failure.”
  • “Risks and benefits of TRT should be very carefully weighed up in testosterone deficient aging men with or without pre-existing heart disease, until evidence from large randomized prospective trials regarding cardiovascular safety of TRT becomes available.”

U.S. PREVENTIVE SERVICES TASK FORCE RECOMMENDATIONS
Not applicable.

ONGOING AND UNPUBLISHED CLINICAL TRIALS
Some currently unpublished trials that might influence this review are listed in Table 5.

Table 5. Summary of Key Trials   

NCT No.

Trial Name

Planned Enrollment

Completion Date

Ongoing

 

 

 

NCT02712944

Testosterone Replacement in Renal Failure

44

Dec 2018

NCT02803073

Effect of Testosterone Replacement on Exercise Capacity in Hypogonadal Men After a Recent Myocardial Infarction

60

Dec 2019

NCT: national clinical trial.
a Denotes industry-sponsored or cosponsored trial.

References 

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  2. Zarotsky V, Huang MY, Carman W, et al. Systematic literature review of the risk factors, comorbidities, and consequences of hypogonadism in men. Andrology. Nov 2014;2(6):819-834. PMID 25269643
  3. Wu FC, Tajar A, Pye SR, et al. Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the European Male Aging Study. J Clin Endocrinol Metab. Jul 2008;93(7):2737-2745. PMID 18270261
  4. Travison TG, Araujo AB, Kupelian V, et al. The relative contributions of aging, health, and lifestyle factors to serum testosterone decline in men. J Clin Endocrinol Metab. Feb 2007;92(2):549-555. PMID 17148559
  5. Cunningham GR, Toma SM. Clinical review: Why is androgen replacement in males controversial? J Clin Endocrinol Metab. Jan 2011;96(1):38-52. PMID 20881265
  6. FDA Drug Safety Communication: FDA cautions about using testosterone products for low testosterone due to aging; requires labeling change to inform of possible increased risk of heart attack and stroke with use. https://www.fda.gov/Drugs/DrugSafety/ucm436259.htm. Accessed June 29, 2018.
  7. Bolona ER, Uraga MV, Haddad RM, et al. Testosterone use in men with sexual dysfunction: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc. Jan 2007;82(1):20-28. PMID 17285782
  8. Jain P, Rademaker AW, McVary KT. Testosterone supplementation for erectile dysfunction: results of a meta-analysis. J Urol. Aug 2000;164(2):371-375. PMID 10893588
  9. Corona G, Rastrelli G, Morgentaler A, et al. Meta-analysis of Results of Testosterone Therapy on Sexual Function Based on International Index of Erectile Function Scores. Eur Urol. Dec 2017;72(6):1000-1011. PMID 28434676
  10. Neto WK, Gama EF, Rocha LY, et al. Effects of testosterone on lean mass gain in elderly men: systematic review with meta-analysis of controlled and randomized studies. Age (Dordr). Feb 2015;37(1):9742. PMID 25637335
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  12. Tracz MJ, Sideras K, Bolona ER, et al. Testosterone use in men and its effects on bone health. A systematic review and meta-analysis of randomized placebo-controlled trials. J Clin Endocrinol Metab. Jun 2006;91(6):2011-2016. PMID 16720668
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  14. Shores MM, Kivlahan DR, Sadak TI, et al. A randomized, double-blind, placebo-controlled study of testosterone treatment in hypogonadal older men with subthreshold depression (dysthymia or minor depression). J Clin Psychiatry. Jul 2009;70(7):1009-1016. PMID 19653976
  15. Seidman SN, Orr G, Raviv G, et al. Effects of testosterone replacement in middle-aged men with dysthymia: a randomized, placebo-controlled clinical trial. J Clin Psychopharmacol. Jun 2009;29(3):216-221. PMID 19440073
  16. Borst SE, Yarrow JF, Fernandez C, et al. Cognitive effects of testosterone and finasteride administration in older hypogonadal men. Clin Interv Aging. Aug 2014;9:1327-1333. PMID 25143719
  17. Ponce OJ, Spencer-Bonilla G, Alvarez-Villalobos N, et al. The efficacy and adverse events of testosterone replacement therapy in hypogonadal men: A systematic review and meta-analysis of randomized, placebo-controlled trials. J Clin Endocrinol Metab. Mar 17 2018. PMID 29562341
  18. Snyder PJ, Ellenberg SS, Cunningham GR, et al. The Testosterone Trials: Seven coordinated trials of testosterone treatment in elderly men. Clin Trials. Jun 2014;11(3):362-375. PMID 24686158
  19. Snyder PJ, Bhasin S, Cunningham GR, et al. Lessons from the testosterone trials. Endocr Rev. Jun 1 2018;39(3):369-386. PMID 29522088
  20. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in adult men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. Jun 2006;91(6):1995-2010. PMID 16720669
  21. Cai X, Tian Y, Wu T, et al. Metabolic effects of testosterone replacement therapy on hypogonadal men with type 2 diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials. Asian J Androl. Jan-Feb 2014;16(1):146-152. PMID 24369149
  22. Jones TH, Arver S, Behre HM, et al. Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care. Apr 2011;34(4):828-837. PMID 21386088
  23. Hackett G, Cole N, Bhartia M, et al. Testosterone replacement therapy improves metabolic parameters in hypogonadal men with type 2 diabetes but not in men with coexisting depression: the BLAST study. J Sex Med. Mar 2014;11(3):840-856. PMID 24308723
  24. Hackett G, Cole N, Saghir A, et al. Testosterone undecanoate improves sexual function in men with type 2 diabetes and severe hypogonadism: results from a 30-week randomized placebo-controlled study. BJU Int. Nov 2016;118(5):804-813. PMID 27124889
  25. Magnussen LV, Glintborg D, Hermann P, et al. Effect of testosterone on insulin sensitivity, oxidative metabolism and body composition in aging men with type 2 diabetes on metformin monotherapy. Diabetes Obes Metab. Oct 2016;18(10):980-989. PMID 27265844
  26. Legros JJ, Meuleman EJ, Elbers JM, et al. Oral testosterone replacement in symptomatic late-onset hypogonadism: effects on rating scales and general safety in a randomized, placebo-controlled study. Eur J Endocrinol. May 2009;160(5):821-831. PMID 19211706
  27. Emmelot-Vonk MH, Verhaar HJ, Nakhai Pour HR, et al. Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial. JAMA. Jan 2 2008;299(1):39-52. PMID 18167405
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  31. Sih R, Morley JE, Kaiser FE, et al. Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab. Jun 1997;82(6):1661-1667. PMID 9177359
  32. Tenover JS. Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab. Oct 1992;75(4):1092-1098. PMID 1400877
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  36. Calof OM, Singh AB, Lee ML, et al. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J Gerontol A Biol Sci Med Sci. Nov 2005;60(11):1451-1457. PMID 16339333
  37. Haddad RM, Kennedy CC, Caples SM, et al. Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc. Jan 2007;82(1):29-39. PMID 17285783
  38. Finkle WD, Greenland S, Ridgeway GK, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One. Feb 2014;9(1):e85805. PMID 24489673
  39. Baillargeon J, Urban RJ, Kuo YF, et al. Myocardial infarction in older men receiving testosterone therapy. Ann Pharmacother. Jul 2 2014;48(9):1138-1144. PMID 24989174
  40. Vigen R, O'Donnell CI, Baron AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. Nov 6 2013;310(17):1829-1836. PMID 24193080
  41. Etminan M, Skeldon SC, Goldenberg SL, et al. Testosterone therapy and risk of myocardial infarction: a pharmacoepidemiologic study. Pharmacotherapy. Jan 2015;35(1):72-78. PMID 25582846
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  44. Kohn TP, Mata DA, Ramasamy R, et al. Effects of testosterone replacement therapy on lower urinary tract symptoms: a systematic review and meta-analysis. Eur Urol. Jun 2016;69(6):1083-1090. PMID 26874809
  45. Kathrins M, Doersch K, Nimeh T, et al. The relationship between testosterone-replacement therapy and lower urinary tract symptoms: a systematic review. Urology. Feb 2016;88:22-32. PMID 26616095
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 Coding Section

Codes Number Description
CPT 11980

Subcutaneous hormone pellet implantation (implantation of estradiol and/or testosterone pellets beneath the skin)

  96372

Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular

ICD-9-CM Diagnosis 257.2

Other testicular hypofunction (includes defective biosynthesis of testicular androgen and testicular hypogonadism)

HCPCS J1070, J1080, J3120, J3130, J3140, J3150

Testosterone injectable products code list (J0900 and J1060 are combination products with estradiol) (codes deleted 12/31/14)

  J1071

Injection, testosterone cypionate, 1 mg (new code 01/01/15)

  J3121

Injection, testosterone enanthate, 1 mg (new code 01/01/15)

  J3145

Injection, testosterone undecanoate, long-acting, 1 mg (new code 01/01/15)

  S0189

Testosterone pellet, 75 mg

ICD-10-CM (effective 10/01/15) E29.1

Testicular hypofunction

ICD-10-PCS (effective 10/01/15)  

ICD-10-PCS codes are only used for inpatient services. There is no specific ICD-10-PCS code for this therapy.

  3E013VJ

Percutaneous administration of hormone

Type of Service    
Place of Service    

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology© American Medical Association.  All Rights Reserved" 

History From 2014 Forward     

04/10/2019 

Annual review, adding medical necessity criteria for HIV-infected members and chronic steroid treatment. Also updating description, background, guidelines, rationale and references. 

04/12/2018 

Annual review, no changes to policy intent. Updating background, rationale and references. 

04/04/2017 

Annual review, no change to policy intent. Updating background, description, regulatory status, rationale and references. 

04/11/2016 

Annual review, no change to policy intent. Updating background, description, rationale and references. 

04/28/2015 

Annual review, no change to policy intent. Updated background, description, regulatory status, guidelines, rationale and references. Added coding.

04/01/2014

New Policy


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