Clinical UM Guideline

 

Subject: Testosterone Injectable
Guideline #:  CG-DRUG-59 Publish Date:    02/28/2018
Status: Revised Last Review Date:    01/25/2018

Description

This document addresses indications for the intramuscular (IM) administration of testosterone injectables for the treatment of hormone deficient conditions. Testosterone is an androgen hormone responsible for normal growth and development of male sex characteristics. In certain medical conditions, such as hypogonadism, the endogenous level of testosterone falls below normal parameters. According to the Endocrine Society, use of testosterone injectable is contraindicated in persons with prostate cancer, cardiac disorders and other risk factors (also see the contraindications listed by the Food and Drug Administration within this document; 2015).

Note: This document addresses testosterone injectables for intramuscular administration only. This document does not address other formulations of testosterone, such as oral (pills and sublingual), topical (for example, gels), or subcutaneous (pellet implants) medication products.

Please see the following documents for information on related topics:

Clinical Indications

Medically Necessary:

Symptomatic Hypogonadism (Primary or Secondary) in Adults:

  1. Testosterone injection used for initiation of replacement therapy is considered medically necessary when ALL of the following  criteria are met (A, B, C, D and E):
    1. Individual is a male; and
    2. Individual is 18 years or older; and
    3. Prior to starting testosterone therapy, an initial and a repeat (at least 24 hours apart) morning total testosterone level is provided to confirm a low testosterone serum level indicating one of the following (1 or 2);
      1. Individual is 70 years of age or younger with a serum testosterone level of less than 300 ng/dL; or
      2. Individual is over 70 years of age with a serum testosterone level of less than 200 ng/dL; and
    4. Individual has a diagnosis of one of the following (1 or 2):
      1. Primary hypogonadism (congenital or acquired) (for example, bilateral torsion, cryptorchidism, chemotherapy, Klinefelter Syndrome, orchitis, orchiectomy, toxic damage from alcohol or heavy metals, Vanishing Testis Syndrome, idiopathic primary hypogonadism, age-related hypogonadism [also referred to as late-onset hypogonadism]);
        or
      2. Hypogonadotropic hypogonadism (congenital or acquired) (for example, idiopathic gonadotropic or luteinizing hormone-releasing hormone (LHRH) deficiency, pituitary- hypothalamic injury); and
    5. Individual presents with symptoms associated with hypogonadism, such as, but not limited, to at least one of the following (1 through 9):
      1. Reduced sexual desire (libido) and activity; or
      2. Decreased spontaneous erections; or
      3. Breast discomfort/gynecomastia; or
      4. Loss of body (axillary and pubic) hair, reduced need for shaving; or
      5. Very small (especially less than 5 mL) or shrinking testes; or
      6. Inability to father children or low/zero sperm count; or
      7. Height loss, low trauma fracture, low bone mineral density; or
      8. Hot flushes, sweats; or
      9. Other less specific signs and symptoms including decreased energy, depressed mood/dysthymia, irritability, sleep disturbance, poor concentration/memory, diminished physical or work performance.
  1. Testosterone injection used for continuation of replacement therapy is considered medically necessary when ALL the following criteria are met (A, B, and C):
    1. Individual met all diagnostic criteria for initial therapy; and
    2. Individual has had serum testosterone level measured in the previous 180 days; and
    3. Individual has obtained clinical benefits as noted by symptom improvement.

Delayed Puberty:

  1. Testosterone enanthate injections are considered medically necessary for treatment of delayed puberty when ALL the criteria below are met (A, B, and C):
    1. Individual is a male 14 years of age or older; and
    2. Individual is using to stimulate puberty; and
    3. Documentation is provided indicating few to no signs of puberty.

Breast Cancer:

  1. Testosterone enanthate injection are considered medically necessary for treatment of breast cancer when the criteria below are met (A and B or C):
    1. Female 1-5 years post-menopause; and
    2. Individual is using secondarily for advanced inoperable metastatic (skeletal) breast cancer;
      or
    3. Premenopausal female who has benefited from oophorectomy and is considered to have a hormone responsive tumor.

HIV-associated Weight Loss and Wasting:

  1. Testosterone enanthate or testosterone cypionate injections are considered medically necessary for the treatment of HIV-infected male adults with low testosterone and HIV-associated weight loss and wasting.

Gender Reassignment:

  1. Testosterone injection are considered medically necessary for transgender individuals who meet ALL the following criteria (A, B and C):
    1. Individual is 16 years of age or older; and
    2. Individual has a diagnosis of gender dysphoria/incongruence or gender identity disorder; and
    3. The goal of treatment is female-to-male gender reassignment.

Not Medically Necessary:

Testosterone injections are considered not medically necessary when criteria are not met and for all other indications.

Coding

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

HCPCS

 

J1071

  Injection, testosterone cypionate, 1 mg [Depo®-Testosterone]

J3121

Injection, testosterone enanthate, 1 mg [Delatestryl®]

J3145

Injection, testosterone undecanoate, 1 mg [Aveed®]

 

 

ICD-10 Diagnosis

 

 

All diagnoses

Discussion/General Information

There are a number of male conditions associated with testosterone deficiency. Primary hypogonadism includes conditions, such as testicular failure due to cryptorchidism, bilateral torsion, orchitis, or vanishing testis syndrome; bilateral orchidectomy; and inborn errors in the biosynthesis of testosterone. Secondary hypogonadism, also called hypogonadotropic hypogonadism (congenital or acquired), includes conditions, such as idiopathic gonadotropin or LHRH deficiency, or pituitary-hypothalamic injury from tumors, trauma, or radiation.

According to the American Association of Clinical Endocrinologists (AACE) medical guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult males (2002 update):

Hypogonadism may manifest with testosterone deficiency, infertility, or both conditions. Symptoms of hypogonadism depend primarily on the age of the male patient at the time of development of the condition. Hypogonadism is often unrecognized before the age of puberty unless it is associated with growth retardation or other anatomic or endocrine abnormalities. When hypogonadism develops before the age of puberty, the manifestations are those of impaired puberty (for example, gynecomastia; small testes, phallus and prostate; scant pubic and axillary hair; reduced male musculature; persistent high-pitched voice)… Post-pubertal loss of testicular function results in slowly evolving subtle clinical symptoms and signs…Adult males with hypogonadism may exhibit progressive loss of muscle mass; loss of libido; impotence; and oligospermia or azoospermia… In aging men, these symptoms and signs may be difficult to appreciate because they are often attributed to getting older… Hormonal and ancillary testing should be performed to allow pertinent treatment considerations. Testosterone replacement therapy can often enable the patient to function in a more normal manner and decrease the risk of future problems with fertility, mood disturbances, fatigue, impaired virilization, and osteoporosis. Further studies are needed to determine the influence of testosterone replacement therapy on cardiovascular risk… The ultimate goals are to improve not only the duration but also the quality of life and to allow people to reach their full potential regardless of age.

Testosterone enanthate and testosterone cypionate are long-acting testosterone esters suspended in oil to prolong absorption. Peak levels occur about 72 hours after intramuscular injection and are followed by a slow decline during the subsequent 1 to 2 weeks. For complete androgen replacement, the regimen should be between 50 and 100 mg of testosterone enanthate or cypionate administered intramuscularly every 7 to 10 days, which will achieve relatively normal levels of testosterone throughout the time interval between injections. Longer time intervals are more convenient but are associated with greater fluctuations in testosterone levels. Higher doses of testosterone produce longer-term effects but also higher peak levels and wider swings between peak and nadir circulating testosterone levels; the result is fluctuating symptoms in many patients (Petak, 2002).

The Endocrine Society published clinical practice guidelines on Testosterone Therapy in Men with Androgen Deficiency in 2006, with an update published in 2010 (Bhasin). The 2010 guidelines included the following statements for the diagnosis of androgen deficiency and therapy with testosterone replacement:

In 2015, the Endocrine Society added the following amended recommendations:

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. 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 prior to consideration of testosterone replacement.

Persistently low testosterone levels refers to serum levels that are below the lower limit of normal on at least two occasions when measured in the early morning. The threshold lower limit for serum testosterone levels is not standardized. The Endocrine Society recommends that a lower limit for normal levels is 300 ng/dL for total testosterone and 9.0 ng/dL for free testosterone…We suggest monitoring testosterone levels 3 to 6 months after initiation of testosterone therapy and then annually to assess whether symptoms have responded to treatment and whether the individual is suffering from any adverse effects. Therapy should aim to raise the serum testosterone level into the mid-normal range. For injectable testosterone enanthate or cypionate: measure serum testosterone level midway between injections. If testosterone is > 700 ng/dl (24.5 nmol/liter) or < 400 ng/dl (14.1 nmol/liter), adjust dose or frequency. For injectable testosterone undecanoate: measure serum testosterone level just prior to each subsequent injection and adjust the dosing interval to maintain serum testosterone in mid-normal range (Bhasin, 2010).

The Endocrine Society also provided the following list of specific symptoms of hypogonadism:

Regarding hypogonadism associated with male aging, in 2009 the International Society for the Study of Aging Male, the International Society of Andrology, the European Association of Urology, the European Academy of Andrology, and the American Society of Andrology issued joint guidelines on the treatment and monitoring of late-onset hypogonadism which provided the following:

The following preparations of testosterone have been approved by the U.S. Food and Drug Administration (FDA) for clinical use: (This document addresses testosterone injectables for intramuscular administration only).

On March 19, 2015 the FDA issued the following safety announcement which was updated January 16, 2016:

The Food and Drug Administration (FDA) has determined that there is a possible link between increased risk of heart attack and stroke and testosterone use. FDA is requiring that the manufacturers of all approved prescription testosterone products change their labeling to clarify the approved uses of these medications and add information about the elevated risk of heart attacks and strokes. FDA also cautions that prescription testosterone products are approved only for men who have low testosterone levels caused by certain medical conditions. Per FDA’s recommendation, prescriptions should only be provided to men with low testosterone levels caused by certain medical conditions and confirmed by laboratory tests. Health care professionals should make patients aware of this possible risk when deciding whether to start or continue a patient on testosterone therapy. We are also requiring manufacturers of approved testosterone products to conduct a well-designed clinical trial to more clearly address the question of whether an increased risk of heart attack or stroke exists among users of these products (FDA, 2016).

This FDA safety announcement also included the following information related to testosterone treatment for low testosterone associated with aging:

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. We are requiring that the manufacturers of all approved prescription testosterone products change their labeling to clarify the approved uses of these medications. Testosterone is FDA-approved as replacement therapy only for men who have low testosterone levels due to disorders of the testicles, pituitary gland, or brain that cause a condition called hypogonadism. Examples of these disorders include failure of the testicles to produce testosterone because of genetic problems, or damage from chemotherapy or infection. However, FDA has become aware that testosterone is being used extensively in attempts to relieve symptoms in men who have low testosterone for no apparent reason other than aging. The benefits and safety of this use have not been established (FDA, 2016).

The FDA announcement was criticized in an American Association of Clinical Endocrinologists and the American College of Endocrinology (AACE/ACE) 2015 Position Statement as being, “Too vague to be clinically meaningful.” The AACE/ACE recommends that, “The decision to replace testosterone therapy should be guided by the signs/symptoms and testosterone concentrations, rather than the underlying cause” advising practicing clinicians to “Be extra cautious in the symptomatic elderly with demonstrably low testosterone levels prior to embarking on replacement therapy and to avoid treatment of the frail elderly altogether.” (See: https://www.aace.com/files/position-statements/ep14434ps.pdf.)

There are multiple formulations of injectable testosterone for IM administration with approval from the FDA. On May 11, 2015 the FDA approved labeling for testosterone undecanoate (AVEED®) (Endo Pharmaceuticals, Inc., Malvern, PA) was updated as follows:

Aveed is indicated for testosterone replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone for:

Aveed should only be used in patients who require testosterone replacement therapy and in whom the benefits of the product outweigh the serious risks of pulmonary oil microembolism and anaphylaxis.

Limitations of use:

The FDA labeling for Aveed now contains the following updated Black Box warnings:

Serious Pulmonary Oil Microembolism (POME) Reactions and Anaphylaxis –

Delatestryl® (testosterone enanthate injection, USP) is another preparation of testosterone also manufactured by Endo Pharmaceuticals, Inc. with identical FDA approved indications for use in males but with the following additional indications and precautions:

The FDA label for Delatestryl also contains the following approved indication for females:

Metastatic mammary cancer – Delatestryl may be used secondarily in women with advancing inoperable metastatic (skeletal) mammary cancer who are one to five years postmenopausal. Primary goals of therapy in these women include ablation of the ovaries. Other methods of counteracting estrogen activity are adrenalectomy, hypophysectomy, and/or antiestrogen therapy. This treatment has also been used in premenopausal women with breast cancer who have benefited from oophorectomy and are considered to have a hormone-responsive tumor. Judgment concerning androgen therapy should be made by an oncologist with expertise in this field (FDA, 2015).

Another formulation with FDA approval is Depo®-Testosterone (testosterone cypionate injection, USP) (Pharmacia and Upjohn Company, division of Pfizer, Inc., New York, NY) which has approved indications that are identical to Aveed and Delatestryl for adult males with primary hypogonadism (congenital or acquired) and hypogonadotropic hypogonadism (congenital or acquired) and with the following additional information:

CONTRAINDICATIONS

  1. Known hypersensitivity to the drug;
  2. Males with carcinoma of the breast;
  3. Males with known or suspected carcinoma of the prostate gland;
  4. Women who are or who may become pregnant;
  5. Patients with serious cardiac, hepatic or renal disease (FDA, 2015).

In addition, both testosterone enanthate (Delatestryl) and testosterone cypionate (Depo-Testosterone) have been designated as orphan products for use in the treatment of weight loss in individuals with AIDS and HIV-associated wasting (DrugPoints, December 29, 2015; March 18, 2016; August 30, 2017).

Potential adverse events from testosterone therapy have been reported in multiple studies including systematic reviews and meta-analyses of randomized trials. These include, but are not limited to, the following:

On October 25, 2016 the FDA issued the following new warning and required labeling changes for all testosterone products:

The U.S. Food and Drug Administration (FDA) approved class-wide labeling changes for all prescription testosterone products, adding a new Warning and updating the Abuse and Dependence section to include new safety information from published literature and case reports regarding the risks associated with abuse and dependence of testosterone and other anabolic androgenic steroids (AAS). The Anabolic Steroids Control Act of 1990 placed AAS, including testosterone, in Schedule III of the Controlled Substances Act. Testosterone and other AAS are abused by adults and adolescents, including athletes and body builders. Abuse of testosterone, usually at doses higher than those typically prescribed and usually in conjunction with other AAS, is associated with serious safety risks affecting the heart, brain, liver, mental health, and endocrine system. Reported serious adverse outcomes include heart attack, heart failure, stroke, depression, hostility, aggression, liver toxicity, and male infertility. Individuals abusing high doses of testosterone have also reported withdrawal symptoms, such as depression, fatigue, irritability, loss of appetite, decreased libido, and insomnia… In addition to the new Warning, all testosterone labeling has been revised to include information in the Abuse and Dependence section about adverse outcomes reported in association with abuse and dependence of testosterone/AAS, and information in the Warning and Precautions section advising prescribers of the importance of measuring serum testosterone concentration if abuse is suspected (FDA, 2016).

A large number of randomized controlled trials (RCTs) have evaluated the effect of testosterone replacement on sexual function in men with hypogonadism and low or low-normal testosterone levels. In 2000, Jain and colleagues conducted a systematic review and meta-analysis of 16 randomized and non-randomized trials that examined the impact of testosterone therapy on erectile dysfunction. The overall response rate was 57%. In the nine series with response rate by etiology subjects with primary versus secondary testicular failure had a response rate of 64% versus 44% (p<0.001). Intramuscular and oral methods of delivery were equivalent with a response rate of 51.3% and 53.2%, respectively. However, the response to transdermal therapy was significantly different from that of intramuscular and oral treatment (80.9% versus 51.3% and 53.2%, respectively, p<0.001). The mean confidence level response for testosterone treatment was 16.7% in the placebo and 65.4% in the treated group (p<0.0001). The authors concluded that response rates for a primary etiology were improved over that for a secondary etiology.

Transdermal testosterone therapy was more effective than intramuscular or oral treatment, and intramuscular and oral treatments were equivalent. There was a statistically significant difference in favor of testosterone over placebo, indicating there is a role for supplementation in select groups (Jain, 2000).

Additional small studies have reported on the effects of testosterone therapy on outcomes, such as bone density, muscle mass, and sexual function/libido with limited but favorable results.  Regarding the impact of testosterone therapy on other conditions, such as androgen deficiency and weight loss due to HIV infection, the published evidence is adequate to demonstrate net health outcomes improvement (Bhasin, 2006).

The Endocrine Society Clinical Practice Guideline for Endocrine Treatment of Transsexual Persons recommends that adolescents who fulfill eligibility and readiness criteria for gender reassignment initially undergo treatment to suppress pubertal development which should be initiated at about the age of 16 years, using a gradually increasing dose schedule of cross-sex steroids (Hembree, 2009).

According to Newfield and colleagues:

Masculinizing hormone therapy (the administration of exogenous endocrine agents to induce masculinizing changes) is a medically necessary intervention for many transsexual, transgender, and gender nonconforming individuals with gender dysphoria… In FtM patients, the following physical changes are expected to occur: deepened voice, clitoral enlargement (variable), growth in facial and body hair, cessation of menses, atrophy of breast tissue, and decreased percentage of body fat compared to muscle mass (Newfield, 2006).

In 2017, the Endocrine Society updated its guideline for Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons (Hembree, 2017), in which the terminology was updated to “Gender Dysphoria/Gender Incongruence (GD/gender incongruence).” The following recommendations were made to amend to the earlier recommendations:

The updated Endocrine Society guidelines document contains additional information about long-term care and monitoring for adverse outcomes prevention and about surgical options when being considered:

We suggest that clinicians delay gender-affirming genital surgery involving gonadectomy and/or hysterectomy until the patient is at least 18 years old or legal age of majority in his or her country (Hembree, 2017).

In May 2013, the American Psychiatric Association published an update to their Diagnostic and Statistical Manual of Mental Disorders, Fifth edition (DSM-5). This update included a significant change to the nomenclature of conditions related to gender psychology. Specifically, the term "Gender Identify Disorder (GID)" was replaced with "Gender Dysphoria." Additionally, the DSM-5 provided updated diagnostic criteria for gender dysphoria for both children and adults. The new criteria are as follows:

Gender dysphoria in Children*

  1. A marked incongruence between one's experienced/expressed gender and assigned gender, of at least 6 months duration, as manifested by at least six of the following (one of which must be Criterion A1):
    1. A strong desire to be of the other gender or an insistence that one is the other gender (or some alternative gender, different from one's assigned gender).
    2. In boys (assigned gender), a strong preference for cross dressing or simulating female attire; or in girls (assigned gender), a strong preference for wearing only typical masculine clothing and a strong resistance to wearing of typical feminine clothing.
    3. A strong preference for cross-gender roles in make-believe play of fantasy play.
    4. A strong preference for toys, games, or activities stereotypically used or engaged in by the other gender.
    5. A strong preference for playmates of the other gender.
    6. In boys (assigned gender), a strong rejection of typically masculine toys, games and activities and a strong avoidance of rough and tumble play; or in girls (assigned gender), a strong rejection of typically feminine toys, games and activities.
    7. A strong dislike of one's sexual anatomy.
    8. A strong desire for the primary and/or secondary sex characteristics that match one's experienced gender.
  2. The condition is associated with clinically significant distress or impairment in social, school, or other important areas of functioning.

Specify if:

With a disorder of sex development (e.g., a congenital adrenogenital disorder such as 255.2 [E25.0] congenital adrenal hyperplasia or 259.0 [E34.50] androgen insensitivity syndrome).
Coding note: Code the disorder of sex development as well as gender dysphoria.

Gender dysphoria in Adolescents and Adults*

  1. A marked incongruence between one's experienced/expressed gender and assigned gender, of at least 6 months duration, as manifested by at least two of the following:
    1. A marked incongruence between one's experienced/expressed gender and primary and/or secondary sex characteristics (or in young adolescents, the anticipated secondary sex characteristics).
    2. A strong desire to be rid of one's primary and/or secondary sex characteristics because of a marked incongruence with one's experienced/expressed gender (or in young adolescents, a desire to prevent the development of the anticipated secondary sex characteristics).
    3. A strong desire for the primary and /or secondary sex characteristics of the other gender.
    4. A strong desire to be of the other gender (or some alternative gender different from one's assigned gender).
    5. A strong desire to be treated as the other gender (or some alternative gender different from one's assigned gender).
    6. A strong conviction that one has the typical feelings and reactions of the other gender (or some alternative gender different from one's assigned gender).
  2. The condition is associated with clinically significant distress or impairment in social, occupational, or other important areas of functioning.

Specify if:

With a disorder of sex development (e.g., a congenital adrenogenital disorder such as 255.2 [E25.0] congenital adrenal hyperplasia or 259.0 [E34.50] androgen insensitivity syndrome).
Coding note: Code the disorder of sex development as well as gender dysphoria.

Specify if:

Post transition: The individual has transitioned to full-time living in the desired gender (with or without legalization of gender change) and has undergone (or is preparing to have) at least one cross-sex medical procedure or treatment regimen- namely regular cross-sex treatment or gender reassignment surgery confirming the desired gender (e.g., penectomy, vaginoplasty in a natal male; mastectomy or phalloplasty in the natal female).

*From: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. DSM-5. American Psychiatric Association. Washington, DC. May 2013. pp. 451-459.

Definitions

Cryptorchidism: Failure of descent of the testes into the scrotum during fetal development.

Delayed Puberty: The absence or incomplete development of secondary sexual characteristics bounded by an age at which 95 percent of children of that sex and culture have initiated sexual maturation. In the United States, the upper 95th percentile for boys to initiate puberty is 14 (an increase in testicular size being the first sign) and for girls is 12.

Gender Dysphoria/Incongruence (formerly Gender Identity Disorder): Discomfort or distress that is caused by a discrepancy between a person’s gender identity and that person’s sex assigned at birth (and the associated gender role and/or primary and secondary sex characteristics).

Hypogonadism: Decreased functional activity of the gonads resulting in clinically low testosterone levels.

Hypogonadotropic Hypogonadism (congenital or acquired):  Idiopathic gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency, or pituitary-hypothalamic injury from tumors, trauma, or radiation.

Klinefelter's Syndrome (also known as 47XXY or XXY): The set of symptoms that result from two or more X chromosomes in males; the primary feature is sterility.

Orchiectomy: Surgical removal of the testes.

Orchitis (Epididymoorchitis): The most common complication of mumps infection in the adult male; it is characterized by the abrupt onset of fever from 39 to 41ºC and severe testicular pain, accompanied by swelling and erythema of the scrotum.

Primary Hypogonadism (congenital or acquired) also known as primary testicular failure: Common causes of primary hypogonadism include: bilateral torsion, cryptorchidism, chemotherapy, Klinefelter Syndrome, orchitis, orchiectomy, toxic damage from alcohol or heavy metals, Vanishing Testis Syndrome, idiopathic primary hypogonadism, and age-related hypogonadism (also referred to as late-onset hypogonadism).

Torsion, Bilateral: Refers to twisting of both testes which interrupts the blood supply.

Vanishing Testes Syndrome (also known as anorchia): A congenital genetic XY disorder of sex development during fetal growth in which the individual has one or both testes absent at birth. If the testes are present, the affected testicle is atrophied with loss of testicular function and low testosterone production.

MICROMEDEX Solutions Strength of Recommendations Scale:

Table 1. Strength Of Recommendation

Class I

Recommended

The given test or treatment has been proven to be useful, and should be performed or administered.

Class IIa

Recommended, In Most Cases

The given test, or treatment is generally considered to be useful, and is indicated in most cases.

Class IIb

Recommended, In Some Cases

The given test, or treatment may be useful, and is indicated in some, but not most, cases.

Class III

Not Recommended

The given test, or treatment is not useful, and should be avoided.

Class Indeterminate

Evidence Inconclusive
 

           

MICROMEDEX Solutions Strength of Evidence Scale:

Table 2. Strength Of Evidence

Category A

Category A evidence is based on data derived from: Meta-analyses of randomized controlled trials with homogeneity with regard to the directions and degrees of results between individual studies. Multiple, well-done randomized clinical trials involving large numbers of patients.

Category B

Category B evidence is based on data derived from: Meta-analyses of randomized controlled trials with conflicting conclusions with regard to the directions and degrees of results between individual studies. Randomized controlled trials that involved small numbers of patients or had significant methodological flaws (e.g., bias, drop-out rate, flawed analysis, etc.). Nonrandomized studies (e.g., cohort studies, case-control studies, observational studies).

Category C

Category C evidence is based on data derived from: Expert opinion or consensus, case reports or case series.

No Evidence

               

 

References

Peer Reviewed Publications:

  1. Baillargeon J, Urban RJ, Kuo YF, et al. Risk of myocardial infarction in older men receiving testosterone therapy. Ann Pharmacother. 2014; 48(9):1138-1144.
  2. Baillargeon J, Urban RJ, Morgentaler A, et al. Risk of venous thromboembolism in men receiving testosterone therapy. Mayo Clin Proc. 2015; 90(8):1038-1045.
  3. Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med. 2010; 363(2):109-122.
  4. 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. 2007; 82(1):20-28.
  5. 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. 2005; 60(11):1451-1457.
  6. Cheetham C, An J, Jacobsen SJ, et al. Association of testosterone replacement with cardiovascular outcomes among men with androgen deficiency. JAMA Intern Med. 2017; 177(4):491-499.
  7. Cui Y, Zhang Y. The effect of androgen-replacement therapy on prostate growth: a systematic review and meta-analysis. Eur Urol. 2013; 64(5):811-822.
  8. Cui Y, Zong H, Yan H, et al. The effect of testosterone replacement therapy on prostate cancer: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis. 2014; 17(2):132-143.
  9. Etminan M, Skeldon SC, Goldenberg SL, et al. Testosterone therapy and risk of myocardial infarction: a pharmacoepidemiologic study. Pharmacotherapy. 2015; 35(1):72-78.
  10. Fernandez-Balsells MM, Murad MH, Lane M, et al. Clinical review 1: Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2010; 95(6):2560-2575.
  11. Finkle WD, Greenland S, Ridgeway GK, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One. 2014; 9(1):e85805.
  12. Francomano D, Ilacqua A, Bruzziches R, et al. Effects of 5-year treatment with testosterone undecanoate on lower urinary tract symptoms in obese men with hypogonadism and metabolic syndrome. Urology. 2014; 83(1):167-173.
  13. Hackett G, Cole N, Bhartia M, et al. The response to testosterone undecanoate in men with type 2 diabetes is dependent on achieving threshold serum levels (the BLAST study). Int J Clin Pract. 2014; 68(2):203-215.
  14. 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. 2007; 82(1):29-39.
  15. Jain P, Rademaker AW, McVary KT. Testosterone supplementation for erectile dysfunction: results of a meta-analysis. J Urol. 2000; 164(2):371-375.
  16. Kang DY, Li HJ. The effect of testosterone replacement therapy on prostate-specific antigen (PSA) levels in men being treated for hypogonadism: a systematic review and meta-analysis. Medicine (Baltimore). 2015; 94(3):e410.
  17. Kaplan AL, Trinh QD, Sun M, et al. Testosterone replacement therapy following the diagnosis of prostate cancer: outcomes and utilization trends. J Sex Med. 2014; 11(4):1063-1070.
  18. Newfield E, Hart S, Dibble S, Kohler L. Female-to-male transgender quality of life. Quality of Life Research. 2006; 15(9):1447-1457.
  19. Pearl JA, Berhanu D, Francois N, et al. Testosterone supplementation does not worsen lower urinary tract symptoms. J Urol. 2013; 190(5):1828-1833.
  20. 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. 2013; 310(17):1829-1836.
  21. 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. 2008; 93(7):2737-2745.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. American Geriatrics Society 2015 Beers Criteria Update Expert Panel. American Geriatrics Society 2015 updated Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2015; 63(11):2227-2246.
  2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. 2013. Washington, DC. pp. 451-459.
  3. Aveed® (testosterone undecanoate injection) [Prescribing Information], Malvern, PA. Endo Pharmaceuticals, Inc. May 2015. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/022219s005lbl.pdf. Accessed on December 7, 2017.
  4. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010; 95(6):2536-1559. Available at: http://press.endocrine.org/doi/full/10.1210/jc.2009-2354. Accessed on December 7, 2017.
  5. 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. 2006; 91(6):1995-2010.
  6. Coleman E, Bockting W, Botzer M, et al. World Professional for Transgender Health (WPATH). Standards of Care for the Health of Transsexual, Transgender, and Gender-Nonconforming People, Version 7. Int J Transgen. 2012; 13:165-232. Available at: http://www.wpath.org/site_page.cfm?pk_association_webpage_menu=1351&pk_association_webpage=4655. Accessed on December 7, 2017.
  7. Delatestryl® (testosterone enanthate injection, USP) [Prescribing Information], Malvern, PA Endo Pharmaceuticals, Inc. May 2015. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/009165s033lbl.pdf. Accessed on December 7, 2017.
  8. Department of Health and Human Services (HHS). Proposed Rule on Nondiscrimination in Health Programs and Activities. §1557 of Affordable Care Act (ACA); Proposed 45 C.F.R. §92.206; 80 Fed. Reg. 54176-54177. RIN 0945-AA02. The Kaiser Commission on Medicaid and the Uninsured. Issue Brief. October 2015. Final Rule. Published May 18, 2016. Effective July 18, 2016. Available at: https://www.federalregister.gov/articles/2016/05/18/2016-11458/nondiscrimination-in-health-programs-and-activities. Accessed on December 7, 2017.
  9. Depo®-Testosterone (testosterone cypionate injection, USP) [Prescribing Information], New York, NY. Pharmacia & Upjohn Company, division of Pfizer, Inc. April 2015. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/085635s030lbl.pdf. Accessed on December 7, 2017.
  10. Dimopoulou C, Ceausu I, Depypere H, et al. European Menopause and Andropause Society (EMAS) position statement: Testosterone replacement therapy in the aging male. Maturitas. 2016; 84:94-99.
  11. Hembree WC. Guidelines for pubertal suspension and gender reassignment for transgender adolescents. Child Adolesc Psychiatr Clin N Am. 2011; 20(4):725-732.
  12. Hembree WC, Cohen-Kettenis P, Delemarre-van de Waal HA, et al. Endocrine Treatment of Transsexual Persons: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2009; 94(9):3132-3154. Available at: http://press.endocrine.org/doi/pdf/10.1210/jc.2009-0345. Accessed on December 7, 2017.
  13. Hembree WC, Cohen-Kettenis P, Gooren L, et al.; Endocrine Society. Endocrine Treatment of Gender Dysphoric/Gender Incongruent Persons. An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2017; 102(11):1-35.
  14. Morales A, Bebb RA, Manjoo P, et al. Diagnosis and management of testosterone deficiency syndrome in men: clinical practice guideline. CMAJ. 2015; 187(18):1369-1377.
  15. Petak SM, Nankin HR, Spark RF, et al. American Association of Clinical Endocrinologists (AACE) Medical Guidelines for Clinical Practice for the Evaluation and Treatment of Hypogonadism in Adult Male Patients. 2002 update. Available at: https://www.aace.com/files/hypo-gonadism.pdf. Accessed on December 7, 2017.
  16. Seftel AD, Kathrins M, Niederberger C. Critical update of the 2010 Endocrine Society clinical practice guidelines for male hypogonadism: a systematic analysis. Mayo Clin Proc. 2015; 90(8):1104-1115.
  17. Testosterone enanthate injection, USP (Delatestryl®) In: DrugPoints® System [electronic version]. Truven Health Analytics, Greenwood Village, CO. Updated December 19, 2015. Available at: http://www.micromedexsolutions.com. Accessed on December 7, 2017.
  18. Testosterone undecanoate injection, USP (Aveed®) In: DrugPoints® System [electronic version]. Truven health Analytics, Greenwood Village, CO. Updated January 26, 2016. Available at: http://www.micromedexsolutions.com. Accessed on December 7, 2017.
  19. Testosterone cypionate injection, USP (Depo®-Testosterone) In: DrugPoints® System [electronic version]. Truven Health Analytics, Greenwood Village, CO. Updated August 30, 2017. Available at: http://www.micromedexsolutions.com. Accessed on December 7, 2017.
  20. U.S. Food and Drug Administration (FDA). Safety alerts. Testosterone and Other Anabolic Androgenic Steroids (AAS): FDA Statement - Risks Associated With Abuse and Dependence. October 25, 2016. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm526206.htm. Accessed on December 7, 2017.
  21. U.S. Food and Drug Administration (FDA). FDA evaluating risk of stroke, heart attack and death with FDA-approved testosterone products. Drug Safety Communications 2014. Available at: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM383909.pdf. Accessed on December 7, 2017.
  22. U.S. Food and Drug Administration (FDA). FDA Drug Safety Communication: FDA cautions about using testosterone products for low testosterone due to aging. 2015. Available at: https://www.fda.gov/downloads/Drugs/DrugSafety/UCM436270.pdf. Accessed on December 7, 2017.
  23. Wang C, Nieschlag E, Swerdloff R, et al. International Society for the Study of Aging Male, the International Society of Andrology, the European Association of Urology, the European Academy of Andrology, and the American Society of Andrology (ISSAM/ISA/EAU/EAA/ASA). Investigation, treatment, and monitoring of late-onset hypogonadism in males: recommendations. Eur Urol. 2009; 55(1):121-130.
Websites for Additional Information
  1. American Association of Clinical Endocrinologists (AACE). Additional information and clinical practice guidelines available at: https://www.aace.com/publications/guidelines. Accessed on December 7, 2017.
  2. U.S. Food and Drug Administration (FDA). Drug safety information. Last updated January 16, 2016. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm436259.htm. Accessed on December 7, 2017.
Index

Aveed, testosterone undecanoate injection
Delatestryl, testosterone enanthate injection
Depo-Testosterone, testosterone cypionate injection
Testosterone cypionate injection
Testosterone enanthate injection
Testosterone undecanoate injection

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

History

Status

Date

Action

Revised

02/23/2018

Behavioral Health Subcommittee review. 

Revised

01/25/2018

Medical Policy & Technology Assessment Committee (MPTAC) review. The document header wording was updated from “Current Effective Date” to “Publish Date.” Added age-related hypogonadism (also referred to as late-onset hypogonadism) to the list of examples of medically necessary diagnoses for treatment in symptomatic primary hypogonadism (congenital or acquired). Clarified the formatting of the examples of hypogonadotropic hypogonadism. Added the term, “Gender Incongruence” to the Clinical Indications section for treatment in gender reassignment. Expanded the Discussion section with recommendations from the 2017 Endocrine Society updated guidelines for Endocrine Treatment of Gender Dysphoric/Gender Incongruent Persons. Added information from the APA DSM-5 related to gender psychology. The Discussion, Definitions and References sections were updated.

Revised

08/03/2017

MPTAC review. Reformatted the Clinical Indications section adding section headers for clarification. References were updated.  

 

11/16/2016

Updated the formatting in the Clinical Indications section. The Discussion section was expanded with updated FDA information about warnings and label changes for all testosterone products. References were updated.

New

08/04/2016

MPTAC review. Initial document development.