Medical Policy: 02.01.49
Original Effective Date: June 2012
Reviewed: February 2018
Revised: February 2018
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.
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:
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:
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:
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. 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:
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).
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.
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.
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.
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:
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.
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