Description/Background
The steroid hormone testosterone plays a role in development and health. Production of testosterone is controlled by the pituitary gland, specifically by luteinizing hormone (LH), via negative feedback. Most of the testosterone circulating in blood is bound to sex-hormone binding globulin (SHBG), and a lesser amount is bound loosely to albumin, while a very small fraction occurs in the biologically active or "free" form. "Bioavailable" testosterone is considered to be the combination of that which is free and that which is bound to albumin in circulation.

Low testosterone can result in delayed puberty, and can indicate testicular failure. In adults, decreases in testosterone production occur normally with age, typically starting gradually in the mid-40s, and more pronounced after 60 years of age. Significant decreases may result in symptoms such as fatigue, decreased libido, erectile dysfunction, depression, muscle weakness, and others. Unfortunately, these symptoms are not specific to testosterone deficiency. Low testosterone levels are associated with diabetes, metabolic syndrome, cardiovascular disease, obesity, sleep apnea, and other disorders. Therefore, the evaluation of patients with symptoms of testosterone deficiency should not be limited to measurement of testosterone levels. Co-morbid conditions that may be the underlying cause of the low testosterone should be investigated as well. Association of low testosterone with increased risk of death from all causes has been noted, providing additional impetus for accurate assessment and treatment.

For symptomatic individuals who are testosterone deficient, and in whom the symptoms are directly caused by low testosterone, testosterone replacement therapy may relieve symptoms and improve quality of life. However, concurrent improvements in healthy living are also recommended.

Additionally, testosterone elevations are associated with serious conditions, including tumors, hyperthyroidism, genetic disorders, including congenital adrenal hyperplasia, and polycystic ovarian syndrome (PCOS).

Policy

1. Testing for serum total testosterone* (See Note 1) is considered MEDICALLY NECESSARY in patients that were male at birth being evaluated for androgen deficiency.
2. Repeat testing for serum total testosterone* (See Note 1) is considered MEDICALLY NECESSARY in individuals with low initial serum testosterone results. Sample collection should occur in early morning, after fasting, and at least one week after the initial test.
3. For individuals with hypogonadism, gynecomastia, and/or other forms of testicular hypofunction, measurement of serum free testosterone, sex hormone-binding globulin (SHBG), and/or albumin is considered MEDICALLY NECESSARY if total testosterone is confirmed as borderline or low.
4. Testing for serum total testosterone* (See Note 1) is considered MEDICALLY NECESSARY in symptomatic individuals being evaluated for conditions associated with androgen excess.
5. Measurement of serum free testosterone using a medically accepted algorithm based on total serum testosterone, SBHG, and/or albumin or bioavailable testosterone is consdered MEDICALLY NECESSARY in individuals suspected of having a disorder that is accompanied by increased or decreased SHBG levels* (See Notes 2 and 3).
6. Testing for serum total testosterone measurements* (See Note 1) is considered MEDICALLY NECESSARY in monitoring treatment response in individuals taking enzyme inhibitors for prostate cancer.
7. Testing for serum total testosterone* (See Note 1) is considered MEDICALLY NECESSARY in individuals receiving testosterone replacement therapy every 3 – 6 months for the first year after initiation of therapy, and annually thereafter.
8. Testing for serum total testosterone* (See Note 1) is considered MEDICALLY NECESSARY in gender-dysphoric/gender-incongruent persons at baseline, during the treatment and for the therapy monitoring.
9. For individuals with gynecomastia, serum estradiol testing is considered MEDICALLY NECESSARY ONCE in a lifetime prior to initiating testosterone therapy.
10. Testing for serum total testosterone* (See Note 1) is considered MEDICALLY NECESSARY in symptomatic individuals being evaluated for conditions associated with androgen excess (e.g., polycystic ovary syndrome and functional hypothalamic amenorrhea). The technology used for testing should be sensitive enough to detect the low concentrations normally found in females.
11. Testing for serum free testosterone and/or bioavailable testosterone as primary testing (i.e. in the absence of prior serum TOTAL testosterone testing) is considered NOT MEDICALLY NECESSARY.
12. Testing for serum total testosterone, free testosterone, and/or bioavailable testosterone is considered NOT MEDICALLY NECESSARY in asymptomatic individuals or in individuals with non-specific symptoms.
13. Testing for serum testosterone is considered NOT MEDICALLY NECESSARY for the identification of androgen deficiency in patients that were female at birth.

The following does not meet coverage criteria due to a lack of available published scientific literature confirming that the test(s) is/are required and beneficial for the diagnosis and treatment of a patient’s illness.

14. Salivary testing for testosterone is considered NOT MEDICALLY NECESSARY.
15. Measurement of serum dihydrotestosterone in individuals is consideredNOT MEDICALLY NECESSARY except in diagnosing 5-alpha reductase deficiency in individuals with ambiguous genitalia, hypospadias, or microphallus.

NOTE 1: Due to considerable variability in serum total testosterone testing, the Centers for Disease Control and Prevention (CDC) developed a standardization program for total testosterone assays (Hormone Standardization [HoSt]/Testosterone). An assay certified by the CDC’s HoSt/Testosterone program is standardized to within ± 6.4% of the CDC total testosterone reference standard. It is STRONGLY RECOMMENDED that serum total testosterone testing be performed on an assay that has been certified by the CDC HoSt/Testosterone program (Shalender Bhasin et al., 2018). A list of CDC-certified assays is available on the HoSt website (CDC, 2021).

NOTE 2:  Conditions associated with decreased SHBG concentrations according to the 2018 Endocrine Society Guidelines (Shalender Bhasin et al., 2018):

• Obesity
• Diabetes mellitus
• Use of glucocorticoids, progestins, and androgenic steroids
• Nephrotic syndrome
• Hypothyroidism
• Acromegaly
• Polymorphisms in the SHBG gene

NOTE 3: Conditions associated with increased SHBG concentrations according to the 2018 Endocrine Society Guidelines (Shalender Bhasin et al., 2018):

• Aging
• HIV disease
• Cirrhosis and hepatitis
• Hyperthyroidism
• Use of some anticonvulsants
• Use of estrogens
• Polymorphisms in the SHBG gene

Rationale 
The Endocrine Society recommends measurement of serum testosterone in individuals with specific symptoms such as incomplete or delayed sexual development, eunuchoidism, reduced libido, breast discomfort, shrinking testes, and others. They also recommend consideration of serum testosterone evaluation for individuals with non-specific symptoms such as fatigue, depression, poor concentration, sleep disturbance, and others. Additionally, The Endocrine Society suggests that androgen deficiency not be evaluated during acute or sub-acute illness.

The Endocrine Society recommends use of total testosterone measurement from a morning sample, with confirmation by repeat testing for results that are low or borderline, or in those suspected of abnormal SHBG levels. Repeat testing should also include measurement of free or bioavailable testosterone. They note that all testing should be performed with reliable, validated assays.

The Endocrine Society recommends against androgen deficiency screening in the general population.

For individuals receiving testosterone replacement therapy, the Endocrine Society recommends monitoring serum testosterone levels 3 to 6 months after initiation of therapy.

The American Association of Clinical Endocrinology (AACE) also recommends use of a morning sample for determination of serum total testosterone in individuals being evaluated for androgen deficiency. Additionally, AACE recommends repeat testosterone measurement and use of SHBG or free testosterone testing "if testosterone levels are low-normal and the symptoms and signs indicate hypogonadism."

For individuals receiving testosterone replacement therapy, AACE recommends measurement of serum testosterone levels every 3 – 4 months for the first year after initiation of therapy, as part of the overall monitoring of therapy effectiveness.

The British Columbia Medical Association also recommends against screening for testosterone deficiency in asymptomatic individuals, and indicates that presence of erectile dysfunction alone is not sufficient to warrant serum testosterone testing. They also recommend against serum testosterone testing in females for the purpose of identifying hypoandrogenism.

Relative to the diagnosis of PCOS, the Endocrine Society identifies three criteria that may be evaluated: androgen excess, ovulatory dysfunction, and polycystic ovaries. Two of the three criteria are sufficient for diagnosis, and if both clinical criteria are met, they do not recommend testing for androgen excess..

References 

1. "Androgen deficiency in older men: Indications, advantages, and pitfalls of testosterone replacement therapy." Retrieved on January 14, 2014 from http://www.ccjm.org/content/79/11/797.full.pdf
2. "The Role of Routine Serum Testosterone Testing: Routine Hormone Analysis Is Not Indicated as an Initial Screening Test in the Evaluation of Erectile Dysfunction." Retrieved on January 14, 2014 from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1472836/pdf/RIU006004_0203.pdf, 2014.
3. "Testosterone Therapy in Adult Men with Androgen Deficiency Syndromes: An Endocrine Society Clinical Practice Guideline." Journal of Clinical Endocrinology & Metabolism, June 2010, Vol. 95(6):2536–2559.
4. "American Association Of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Evaluation and Treatment of Hypogonadism in Adult Male Patients—2002 Update." Endocrine Practice, Vol. 8, No. 6, November/December 2002 439-456.
5. "Diagnosis and Treatment of Polycystic Ovary Syndrome: An Endocrine Society Clinical Practice Guideline." Journal of Clinical Endocrinology & Metabolism, December 2013.
6. "Testosterone Testing Protocol." British Columbia Medical Association, June, 2011. Accessed February, 2014 at www.BCGuidelines.ca

Coding Section 

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 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 2016 Forward