Medical Policy: 02.01.49
Original Effective Date: June 2012
Reviewed: February 2020
Revised: February 2020
This policy contains information which is clinical in nature. The policy is not medical advice. The information in this policy is used by Wellmark to make determinations whether medical treatment is covered under the terms of a Wellmark member's health benefit plan. Physicians and other health care providers are responsible for medical advice and treatment. If you have specific health care needs, you should consult an appropriate health care professional. If you would like to request an accessible version of this document, please contact customer service at 800-524-9242.
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based on contract, and individual member benefits must be verified. Wellmark determines medical
necessity only if the benefit exists and no contract exclusions are applicable. This medical
policy may not apply to FEP. Benefits are determined by the Federal Employee Program.
This Medical Policy document describes the status of medical technology at the time the document
was developed. Since that time, new technology may have emerged or new medical literature may
have been published. This Medical Policy will be reviewed regularly and be updated as scientific
and medical literature becomes available.
Menopause is a normal, natural sign of aging. There is a long list of physical changes that geno typical women may experience around menopause, which may be related to menopause or aging- or both. Some of these symptoms include hot flashes, sleep disturbances, night sweats and vaginal dryness and decreased sex drive.
Several prescription drugs are available to help relieve menopause-related symptoms. Hormone therapy has been shown to be the most effective intervention for management of these symptoms.
This policy is specifically related to subcutaneously implanted hormone pellets. The individual pellets are smaller than a grain of rice and are implanted into the subcutaneous tissue, where they provide a slow continuous release of hormone into the bloodstream. The pellets are implanted in the lower abdomen or buttocks. The procedure is done in a physician's office with the use of a local anesthetic and a small incision for insertion. The release of the drug continues over a 3-6 month period.
Subcutaneous implantable pellets made up of estradiol, estrogen, or testosterone in combination with estrogen or estradiol has been custom compounded by pharmacists according to physician specifications. However, none of these are FDA approved for U.S. distribution and their safety and efficacy has not been adequately demonstrated in well-designed clinical trials.
There is a long list of potential adverse effects that could occur with testosterone replacement, as follows:
- 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
- Worsening of male pattern baldness
European and American specialty societies recommend that replacement testosterone therapy be considered at serum total testosterone levels less than 300-350 ng/dL. The testing methods for testosterone vary, and the level of deficiency is not standard with providers.
The following principles should guide testosterone therapy:
- Testosterone should be administered only to a man who is hypogonadal, as evidenced by clinical symptoms and signs consistent with androgen deficiency and a distinctly subnormal serum testosterone concentration. In comparison, increasing the serum testosterone concentration in a man who has symptoms suggestive of hypogonadism, but whose testosterone concentration is already normal, will not relieve those symptoms.
- Symptoms and signs suggestive of androgen deficiency include low libido, decreased morning erections, loss of body hair, low bone mineral density, gynecomastia, and small testes. Symptoms and signs such as fatigue, depression, anemia, reduced muscle strength, and increased fat mass are less specific.
- Testosterone can be replaced satisfactorily whether the testosterone deficiency is due to primary or secondary hypogonadism.
- The principal goal of testosterone therapy is to restore the serum testosterone concentration to the normal range. It is not yet known if restoring the normal circadian rhythm of testosterone is important.
- The role of testosterone replacement to treat the decline in serum testosterone concentration that occurs with increasing frequency in men above age 60 years, in the absence of identifiable pituitary or hypothalamic disease, is uncertain.
- Testosterone therapy is indicated only for testosterone deficiency, not for impaired spermatogenesis. Testosterone therapy impairs spermatogenesis further by suppressing pituitary gonadotropin secretion.
The American College of Obstetricians and Gynecologists’ Committee on Gynecologic Practice and the Practice Committee of the American Society for Reproductive Medicine make the following conclusions and recommendations:
- Evidence is lacking to support superiority claims of compounded bioidentical hormones over conventional menopausal hormone therapy.
- Customized compounded hormones pose additional risks. These preparations have variable purity and potency and lack efficacy and safety data.
European Menopause and Andropause Society
A position statement was published by the European Menopause and Andropause Society (EMAS) in 2016 on testosterone replacement therapy in the aging male made the following relevant recommendations: “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.”
The Endocrine Society
In 2018, the Endocrine Society updated its guidelines for testosterone therapy with the following conclusions:
- We recommend making a diagnosis of hypogonadism only in men with symptoms and signs consistent with testosterone (T) deficiency and unequivocally and consistently low serum T concentrations.
- We recommend measuring fasting morning total T concentrations using an accurate and reliable assay as the initial diagnostic test.
- We recommend confirming the diagnosis by repeating the measurement of morning fasting total T concentrations.
- In men whose total T is near the lower limit of normal or who have a condition that alters sex hormone–binding globulin, we recommend obtaining a free T concentration using either equilibrium dialysis or estimating it using an accurate formula.
- In men determined to have androgen deficiency, we recommend additional diagnostic evaluation to ascertain the cause of androgen deficiency. We recommend T therapy for men with symptomatic T deficiency to induce and maintain secondary sex characteristics and correct symptoms of hypogonadism after discussing the potential benefits and risks of therapy and of monitoring therapy and involving the patient in decision making.
- We recommend against starting T therapy in patients who are planning fertility in the near term or have any of the following conditions: breast or prostate cancer, a palpable prostate nodule or induration, prostate-specific antigen level > 4 ng/mL, prostate-specific antigen > 3 ng/mL in men at increased risk of prostate cancer (e.g., African Americans and men with a first-degree relative with diagnosed 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.
- We suggest that when clinicians institute T therapy, they aim at achieving T concentrations in the mid-normal range during treatment with any of the approved formulations, taking into consideration patient preference, pharmacokinetics, formulation-specific adverse effects, treatment burden, and cost.
- Clinicians should monitor men receiving T therapy using a standardized plan that includes: evaluating symptoms, adverse effects, and compliance; measuring serum T and hematocrit concentrations; and evaluating prostate cancer risk during the first year after initiating T therapy
US Food and Drug Administration
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 hypogonadism (FDA, 2015). However, the 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, 2015).
The FDA advises that health care professionals should prescribe testosterone therapy only for men with low testosterone levels caused by certain medical conditions and confirmed by laboratory tests (FDA, 2015). Health care professionals should make patients aware of the possible increased cardiovascular risk when deciding whether to start or continue a patient on testosterone therapy. Patients using testosterone should seek medical attention immediately if symptoms of a heart attack or stroke are present, such as chest pain, shortness of breath or trouble breathing, weakness in one part or one side of the body, or slurred speech. The FDA is requiring that the manufacturers of all approved prescription testosterone products change their labeling to clarify the approved uses of these medications (FDA, 2015).
The FDA is also requiring these manufacturers to add information to the labeling about a possible increased risk of heart attacks and strokes in patients taking testosterone. The FDA cautions that prescription testosterone products are approved only for men who have low testosterone levels caused by certain medical conditions. 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 (FDA, 2015).
Based on the available evidence from studies and expert input from an FDA Advisory Committee meeting, the FDA has concluded that there is a possible increased cardiovascular risk associated with testosterone use (FDA, 2015).
Per the FDA (12/27/2017)
Some hormones for menopause are called “bio-identical” by their sellers because they claim they are identical to hormones made in a woman’s body. These hormones are made from plant estrogens and are said to be a natural form of Menopause Hormone Therapy with fewer risks. These products have not been approved by FDA.
- FDA is concerned that claims like these may mislead women and healthcare professionals. These claims may give them a false sense of assurance about using potentially dangerous hormone products.
- Be aware that natural doesn’t always mean safe.
Many “bio-identical” hormones are compounded in pharmacies. Compounding is generally a practice in which ingredients are combined, mixed, or altered to create a medication tailored to the needs of an individual patient.
- Don’t believe false claims that compounded “bio-identical” hormones are safer and more effective than FDA-approved Menopause Hormone Therapy drugs.
- Compounded “bio-identical” Menopause Hormones are not FDA approved and may carry additional risks.
Although the clinical observations described above suggest that the decline in testosterone with age may have several adverse consequences, the impact of testosterone replacement in older men with low serum testosterone and hypogonadal symptoms has been unclear. Trials have been limited by small sample size, inclusion of asymptomatic men with low-normal testosterone levels, and variable testosterone regimens. A committee of the Institute of Medicine of the National Academy of Sciences Committee reviewed available studies and concluded in 2002 that no beneficial effects of administering testosterone have been well established. The US Food and Drug Administration (FDA) reviewed the evidence and reached the same conclusion in 2015, and they directed manufacturers of testosterone products to state in their labels that these products are approved only for men with low testosterone due to known causes.
The American Urology Association (AUA)
The AUA recommends that testosterone therapy is not indicated for the treatment of erectile dysfunction in patients with a normal serum testosterone level. Also, the role of testosterone therapy in men with sexual dysfunction with low, borderline normal, and normal testosterone levels is not well defined.
Subcutaneous hormone pellets containing estrogen alone or estrogen combinations (including Estradiol and bioidentical hormone formulations) are considered investigational for all indications including, but not limited to, symptoms associated with female menopause, because there are no FDA-approved formulations of these products.
The use of testosterone pellets, specifically Testopel, in genotypical women is considered investigational as the FDA indications are only for the use in genotypical males. The literature does not support off-label use for menopausal symptoms or decreased libido.
Testopel use in genotypical males is considered medically necessary for men without a history of prostate cancer, in the office setting, in the following conditions:
- Delayed puberty in genotypical males greater than 14 years old with laboratory evidence of hypogonadism (only for a period of 1 year for this condition). It is unusual for a boy with constitutional delay of puberty to require more than two courses of androgen therapy before spontaneous puberty occurs; or
- Hypogonadotropic hypogonadism (congenital or acquired) with low serum testosterone: idiopathic gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency or pituitary-hypothalamic injury from tumors, trauma, or radiation; or
- Primary hypogonadism (congenital or acquired) (androgens) with low serum testosterone: testicular failure due to conditions such as cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy (also called orchidectomy)
The use of subcutaneous hormone pellets in genotypical men, outside of the use of Testopel, is considered investigational. Testopel is the only FDA approved subcutaneous pellet approved at this time.
Use for aging changes in males
Safety and efficacy of Testopel in genotypical men with "age-related hypogonadism" (also referred to as "late-onset hypogonadism") have not been established. The use of Testopel is considered investigational for genotypical male menopause, hypogonadism due to aging, erectile dysfunction, and for all other age related conditions not listed above.
Other uses of implantable testosterone pellets are considered investigational including, but not limited to, their use in the treatment of sexual dysfunction in both men (e.g., erectile dysfunction) and women (e.g., decreased libido), post-menopausal symptoms, depression and for the enhancement of athletic performance.
The use of Testopel dosage is limited to a maximum number of pellets per injection, based on labeling indications. Safety is of concern for pellet implantation beyond the labeling indications. The dosage guideline for the testosterone pellets for replacement therapy in androgen-deficient males, per product label, is 150mg to 450mg subcutaneously every 3 to 6 months. The dosing interval is individualized because some patients will require redosing as early as every 3 months while others may not require redosing for up to 6 months.
At the current time, there is lack of medical and scientific evidence to support the efficacy and safety of customized subcutaneous hormone replacement regimes utilizing bioidentical hormones. Well-designed and controlled clinical trials are needed to provide evidence of improved net health outcomes with compounded bioidentical hormone replacement, subcutaneously inserted over conventional hormone therapies. The FDA issued a safety communication in 2015, warning against the use of testosterone products for low testosterone due to aging.
Procedure Codes and Billing Guidelines:
To report provider services, use appropriate CPT* codes, Modifiers, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or diagnosis codes.
- 11980 Subcutaneous hormone pellet implantation (implantation of estradiol and/or testosterone pellets beneath the skin)
- J3490 Unclassified drugs
- S0189 Testosterone pellet, 75 mg
- North American Menopause Society. Bioidentical Hormone Therapy
- American College of Obstetricians and Gynecologists. ACOG Committee Opinion #532, November 2005 (Reaffirmed 2012): Compounded Bioidentical Menopausal Hormone Therapy
- Institute for Clinical Systems Improvement (ICSI). Health Care Guideline: Menopause and Hormone Therapy (HT): Collaborative Decision-Making and Management Ninth Edition, October 2008.
- Gallenberg, Mary. Mayo Foundation for Medical Education and Research (MFMER). Bioidentical hormones: Are they safer?. December 15, 2011.
- Goodman NF, Cobin RH, Ginzburg SB, Katz IA, Woode DE. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Diagnosis and Treatment of Menopause. Endocr Pract. November/December 2011; 17(Suppl 6).
- Position Statement: The 2012 Hormone Therapy Position Statement of the North American Menopause Society. Menopause. January 17, 2012; 19(3): pp. 257-271.
- FDA Consumer Health Information. Bio-Identicals: Sorting Myths from Facts. April 8, 2008. Accessed 3/25/2014.
- National Institutes of Health (NIH). Menopausal Hormone Therapy Information. Last reviewed September 15, 2011. Accessed 3/25/2014.
- Ruiz AD, Daniels KR, Barner JC, Carson JJ, Frei CR. Effectiveness of compounded bioidentical hormone replacement therapy: an observational cohort study. BMC Womens Health. 2011 Jun 8; 11: 27.
- Conaway E. Bioidentical hormones: an evidence-based review for primary care providers. J Am Osteopath Assoc. 2011 Mar;111(3):153-64.
- Sood R, Shuster L, Smith R, Vincent A, Jatoi A. Counseling postmenopausal women about bioidentical hormones: ten discussion points for practicing physicians. J Am Board Fam Med. 2011 Mar-Apr; 42(2):202-10.
- U.S. Food and Drug Administration. Compounded menopausal hormone therapy questions and answers.
- Wierman ME, Wiebke A, Basson R, et al. Androgen Therapy in Women: A Reappraisal: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2014:99;3489-3510.
- Boothby LA, Doering PL, Kipersztok S. Bioidentical hormone therapy: a review. Menopause 2004; 11:356.
- Takahashi K, Manabe A, Okada M, et al. Efficacy and safety of oral estriol for managing postmenopausal symptoms. Maturitas 2000; 34:169.
- Xu L, Freeman G, Cowling BJ, Schooling CM (2013).Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials BMC Med, 11, 108.
- Fda.gov. "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". N.p., 2015. Web. 8 May 2015.
- Wang C, Nieschlag E, Swerdloff R, et al. Investigation, treatment, and monitoring of lateâ€onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations. J Androl. 2008;159:507â€514.
- Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of testosterone treatment in older men. N Engl J Med. Feb 18 2016;374(7):611-624. PMID 26886521
- Dimopoulou C, Ceausu I, Depypere H, et al. EMAS position statement: Testosterone replacement therapy in the aging male. Maturitas. Feb 2016;84:94-99. PMID 26614257
- Morales A, Bebb RA, Manjoo P, et al. Diagnosis and management of testosterone deficiency syndrome in men: clinical practice guideline. CMAJ. Dec 8 2015;187(18):1369-1377. PMID 26504097
- Crowley, W., Pitteloud, N., et al. (2016) Diagnosis nad treatment of delayed puberty. UptoDate, updated 2/2016
- FDA.gov Womens Health Topics: Menopause. 12-27-2017.
- Albert SG, Morley JE. Testosterone therapy, association with age, initiation and mode of therapy with cardiovascular events: a systematic review. Clin Endocrinol (Oxf). Sep 2016;85(3):436-443. PMID 27124404
- 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
- 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. Apr 20 2017. PMID 28434676
- Snyder,P., Matsumoto, A., Schmader, K., Martin, K. Overview of testosterone deficiency in older men. UptoDate Jan 2018.
- Testosterone and aging: Clinical research directions, Liverman CT, Blazer DG (Eds), National Academies Press, Washington DC 2004.
- 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; 95:2536
- Bhasin et al.(2018) Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. The Journal of Clinical Endocrinology & Metabolism, Volume 103, Issue 5, 1 May 2018, Pages 1715–1744ï‚§
- McClintock, T., Valovske, M., Kwon, N. et al. (2019) Testosterone replacement therapy associated with an increased risk of urolithiasis. World Journal of Urology 37(12) 2737-2746.
- Kaminetsky JC, McCullough A, Hwang K, et al. A 52-Week Study of Dose Adjusted Subcutaneous Testosterone Enanthate in Oil Self-Administered via Disposable Auto-Injector. J Urol 2019; 201:587.
- February 2020 - Annual Review, Policy Revised
- February 2019 - Annual Review, Policy Revised
- February 2018 - Annual Review, Policy Revised
- February 2017 - Annual Review, Policy Revised
- February 2016 - Annual Review, Policy Revised
- March 2015 - Annual Review, Policy Revised
- April 2014 - Annual Review, Policy Revised
- May 2013 - Annual Review, Policy Revised
- June 2012 - New Policy
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