Medical Policy: 02.01.49 

Original Effective Date: June 2012 

Reviewed: February 2018 

Revised: February 2018 

 

Benefit Application:

Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary 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.

 

Description:

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
  • Acne
  • Worsening of male pattern baldness
  • Gynecomastia

 

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

  • We recommend making the diagnosis of androgen deficiency only in men with consistent symptoms and signs and unequivocally low serum testosterone levels. (Strong recommendation; very low quality of evidence);
  • We recommend testosterone therapy for symptomatic men with classical androgen deficiency syndromes aimed at inducing and maintaining secondary sex characteristics and at improving their sexual function, sense of well-being, and bone mineral density (Strong recommendation; low quality of evidence);
  • We recommend against testosterone therapy in patients with breast or prostate cancer. (Strong recommendation; quality of evidence very low for breast cancer, low for prostate cancer);
  • We recommend that clinicians assess prostate cancer risk in men being considered for testosterone therapy. (Strong recommendation; very low quality of evidence);
  • We suggest initiating testosterone therapy with any of the following regimens (75 to 100 mg of testosterone enanthate or cypionate administered IM weekly, or 150 to 200 mg administered every 2 weeks, injectable testosterone, also patches, gel, buccal tablets, implanted pellets) chosen on the basis of the patient's preference, consideration of pharmacokinetics, treatment burden, and cost. (Weak recommendation; strength of evidence low).

 

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

  • Men with metabolic syndrome, who were previously unexamined by the 2010 Endocrine Society Clinical Practice Guidelines, may benefit from testosterone replacement therapy (TRT) based on improvements in biometrics and insulin sensitivity. Effects of TRT on similar endpoints in men with type 2 diabetes mellitus remain unclear;
  • Effects of TRT on erectile function, even in men refractory to phosphodiesterase type 5 inhibitors, and on quality of life in men with erectile dysfunction remain inconclusive (Seftel, 2015).

 

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. Testosterone pellets, measure testosterone levels at the end of dosing intervals. Adjust the number of pellets and/or the dosing interval to achieve serum testosterone levels in the normal range. (Bhasin, 2010)

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

  • 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

 

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.

 

Prior Approval:

Not applicable

 

Policy:

Subcutaneous hormone pellets containing estrogen alone or estrogen combinations (including Estradiol and bioidentical hormone formulations) are considered INVESTIGATIVE 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 geno typical 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 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.
  • 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.

 

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.

  

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

 

Selected References:

  • 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
  • The Endocrine Society. Position Statement: Bioidentical Hormones. October 2006.
  • 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 late‐onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations. J Androl. 2008;159:507‐514.
  • 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

 

Policy History:

  • 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

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

 

*CPT® is a registered trademark of the American Medical Association.