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Implantable Hormone Pellets

Number: 0345



Policy
  1. Estrogen

    Aetna considers implantable estradiol pellets experimental and investigational because they have been shown to produce unpredictable and fluctuating serum concentrations of estrogen.

  2. Testosterone

    Aetna considers implantable testosterone pellets (Testopel pellets) medically necessary for either of the following indications:

     
  3. Primary hypogonadism (congenital or acquired) (androgens) with low serum testosterone (see appendix): testicular failure due to conditions such as cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy,* Klinefelter's syndrome, chemotherapy, or toxic damage from alcohol or heavy metals; or
  4. Hypogonadotropic hypogonadism (congenital or acquired) with low serum testosterone (see appendix): idiopathic gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency or pituitary-hypothalamic injury from tumors, trauma, or radiation; or
  5. Delayed male puberty; or
  6. Female to male gender reassignment.
  7.  

    Aetna considers implantable testosterone pellets experimental and investigational for the treatment of symptoms associated with menopause as this use remains unlabeled and unsubstantiated.  Implantable testosterone pellets are considered experimental and investigational for male menopause, hypogonadism due to aging, idiopathic hypogonadism (not due to disorders of the testicles, pituitary gland or brain) and for all other indications because their effectiveness for indications other than the ones listed above has not been established.

    * Note: Documentation of low serum testosterone is not required for bilateral orchiectomy.

  8. Progestin/Progesterone

    Aetna considers progestin/progesterone pellets experimental and investigational for the treatment of dysmenorrhea and erythema nodosum because their effectiveness for these indications has not been established.

See also CPB 0501 - Gonadotropin-Releasing Hormone Analogs and Antagonists.

Background

While implantable estradiol pellets have been suggested as treatment for symptoms of menopause, there are no United States Food and Drug Administration (FDA)-approved, commercially available formulations of implantable estradiol pellets available in the United States.  These formulations of estradiol have been shown to produce unpredictable and fluctuating serum concentrations of estrogen.  The FDA's Fertility and Maternal Health Drugs Advisory Committee unanimously agreed to terminate compassionate investigative new drug (IND) programs for estrogen pellets as a last-resort treatment of menopausal disorder.  The Committee noted “the risk of bleeding and infection, the lack of information on release rates, difficulty in reversibility of the drug, increased feasibility of over-dosage of the drug, and increased risk of non-compliance with safety measures [such as] the addition of progestin.”

Implantable testosterone pellets may be indicated as second-line testosterone replacement therapy for males.  Testosterone implants (Testopel Pellets) are commercially available in the United States.  Androgens are primarily indicated in males as replacement therapy when congenital or acquired endogenous androgen absence or deficiency is associated with primary or secondary hypogonadism.  Primary hypogonadism includes conditions such as: testicular failure due to cryptorchidism, bilateral torsion, orchitis, or vanishing testis syndrome; inborn errors in testosterone biosynthesis; or bilateral orchidectomy.  Hypogonadotropic hypogonadism (secondary hypogonadism conditions include gonadotropin-releasing hormone (GnRH) deficiency or pituitary-hypothalamic injury as a result of surgery, tumors, trauma, or radiation, and are the most common forms of hypogonadism seen in older adults.

If testosterone implants are to be used for treatment of androgen deficiency due to primary or secondary hypogonadism, the usual adult dosage is 150 to 450 mg subcutaneously every 3 to 4 months, or, in some cases, as long as 6 months.  Dosage adjustment is needed to accomodate individual clinical requirements for such life changes as induction of puberty, development of secondary sexual characteristics, impotence due to testicular failure, or infertility due to oligospermia.

For treatment of delayed male puberty, a 6-month or shorter course of androgen is indicated for induction of puberty in patients with familial delayed puberty, a condition characterized by spontaneous, non-pathologic, late-onset puberty, if the patient does not respond to psychological treatment.  If subcutaneous testosterone implants are to be used, the usual dosage is to be determined by the physician.  Low-doses are used initially and increased gradually as puberty progresses. 

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). These studies included aging men treated with testosterone. Some studies reported an increased risk of heart attack, stroke, or death associated with testosterone treatment, while others did not (FDA, 2015).

Filho et al (2007) retrospectively reviewed the medical records of 258 post-menopausal patients using estradiol and testosterone implants as combined hormone therapy to evaluate the effects of testosterone on the endometrium after 2 years of continuous use.  Endometrial thickness was measured by ultrasonography.  Histology was performed on samples of thickened endometria obtained during hysteroscopy with biopsy.  In the 44 patients in whom endometrial thickening was greater than 5 mm at the end of the second year of implant use, the most frequent finding at hysteroscopy was polypoid lesion in 61.3 % of cases, followed by normal uterine cavity in 31.8 % of cases and submucous myoma in 6.8 %.  Histology of the endometrial samples confirmed endometrial polyp in 38.6 % of cases, a histologically normal endometrium in 31.8 % of cases, simple endometrial hyperplasia in 20.4 % of cases, and myoma and atrophic endometrium in 4.5 %.  It is possible that testosterone may exert its anti-proliferative effects on the endometrium but not on polyps in an action similar to that exerted by combined estrogen/progestin therapies.  A greater incidence of simple, low-grade endometrial hyperplasia was found in this study compared with studies using continuous estrogen/progestin regimens.  The use of progestins as the ideal endometrial protection should therefore be re-considered.

Fennell and colleagues (2010) compared the 2 long-acting depot testosterone (T) products -- subdermal T implants (TI) and injectable T undecanoate (TU) -- for maintenance of testosterone replacement therapy (TRT).  Men with organic androgen deficiency (n = 38) undergoing regular TRT were recruited for a 2-period, randomized sequence, cross-over clinical trial without intervening wash-out period of TRT maintenance.  For both depot T products, their pharmacokinetics and pharmacodynamics were evaluated using a range of androgen sensitive clinical, laboratory and quality of life measures as well as preference for ongoing treatment after experience of both products.  The 2 depot T products had distinct pharmacokinetics and were not bioequivalent.  However, there were no consistent clinical differences in a comprehensive range of pharmacodynamic measures reflecting androgen effects on biochemistry and hematology, muscle mass and strength, and quality of life, mood and sexual function.  The majority (91 %) of subjects chose TU over TI at study completion.  The authors concluded that despite significant pharmacokinetic differences, the 2 depot T products are clinically interchangeable allowing for choice dependent on patient and physician delivery preference in practice; but most patients preferred the injectable over the implantable form.

An UpToDate review on “Treatment of primary dysmenorrhea in adult women” (Smith and Kaunitz, 2014) does not mention the use of progestin pellet as a management option.

An UpToDate review on “Erythema nodosum” (Shojania, 2014) does not mention the use of progestin/progesterone as a management option.

Reis and Abdo (2014) stated that with advancing age, there is an increase in the complaints of a lack of a libido in women and erectile dysfunction in men.  The effectiveness of phosphodiesterase type 5 inhibitors (PDE5i), together with their minimal side effects and ease of administration, revolutionized the treatment of erectile dysfunction.  For women, testosterone administration is the principal treatment for hypoactive sexual desire disorder.  These investigators evaluated the use of androgens in the treatment of a lack of libido in women, comparing 2 periods, i.e., before and after the advent of the PDE5i.  These researchers also analyzed the risks and benefits of androgen administration.  They searched the Latin-American and Caribbean Health Sciences Literature, Cochrane Library, Excerpta Medica, Scientific Electronic Library Online, and Medline (PubMed) databases using the search terms disfunção sexual feminina/female sexual dysfunction, desejo sexual hipoativo/female hypoactive sexual desire disorder, testosterona/testosterone, terapia androgênica em mulheres/androgen therapy in women, and sexualidade/sexuality as well as combinations thereof.  They selected articles written in English, Portuguese, or Spanish.  The authors concluded that after the advent of PDE5i, there was a significant increase in the number of studies aimed at evaluating the use of testosterone in women with hypoactive sexual desire disorder.  However, they stated that the risks and benefits of testosterone administration have yet to be clarified.

Corona et al (2014) noted that the role of testosterone supplementation (TS) as a treatment for male sexual dysfunction remains questionable.  These researchers attempted a meta-analysis on the effect of TS on male sexual function and its synergism with the use of PDE5i.  An extensive Medline, Embase, and Cochrane search was performed.  All randomized controlled trials (RCTs) comparing the effect of TS versus placebo or the effect of TS as add on to PDE5is on sexual function were included.  Data extraction was performed independently by 2 of the authors, and conflicts resolved by the third investigator.  Out of 1,702 retrieved articles, 41 were included in the study.  In particular, 29 compared TS versus placebo, whereas 12 trials evaluated the effect of TS as add on to PDE5is.  Testosterone supplementation is able to significantly ameliorate erectile function and to improve other aspects of male sexual response in hypogonadal patients.  However, the presence of possible publication bias was detected.  After applying "trim and fill" method, the positive effect of TS on erectile function and libido components retained significance only in RCTs partially or completely supported by pharmaceutical companies (confidence interval [CI]: 0.04 to 0.53 and 0.12 to 0.52, respectively).  In addition, these researchers reported that TS could be associated with an improvement in PDE5i outcome.  These results were not confirmed in placebo-controlled studies.  The majority of studies, however, included mixed eugonadal/hypogonadal subjects, thus imparting uncertainty to the statistical analyses.  The authors concluded that TS plays positive effects on male sexual function in hypogonadal subjects.  The role of TS is uncertain in men who are not clearly hypogonadal.  The apparent difference between industry-supported and independent studies could depend on trial design more than on publication bias.  They stated that new RCTs exploring the effect of TS in selected cases of PDE5i failure that persistently retain low testosterone levels are advisable.

Fui et al (2014) stated that with increasing modernization and urbanization of Asia, much of the future focus of the obesity epidemic will be in the Asian region.  Low testosterone levels are frequently encountered in obese men who do not otherwise have a recognizable hypothalamic-pituitary-testicular (HPT) axis pathology.  Moderate obesity predominantly decreases total testosterone due to insulin resistance-associated reductions in sex hormone binding globulin.  More severe obesity is additionally associated with reductions in free testosterone levels due to suppression of the HPT axis.  Low testosterone by itself leads to increasing adiposity, creating a self-perpetuating cycle of metabolic complications.  Obesity-associated hypotestosteronemia is a functional, non-permanent state, which can be reversible, but this requires substantial weight loss.  While TRT can lead to moderate reductions in fat mass, obesity by itself, in the absence of symptomatic androgen deficiency, is not an established indication for TRT.  The authors concluded that TRT may lead to a worsening of untreated sleep apnea and compromise fertility.  Whether TRT augments diet- and exercise-induced weight loss requires evaluation in adequately designed RCTs.

Cai et al (2014) evaluated the metabolic effects of TRT on hypogonadal men with type 2 diabetes mellitus (T2DM). These investigators performed a literature search using the Cochrane Library, EMBASE and PubMed.  Only RCTs were included in the meta-analysis; 2 reviewers retrieved articles and evaluated the study quality using an appropriate scoring method.  Outcomes including glucose metabolism, lipid parameters, body fat and blood pressure were pooled using a random effects model and tested for heterogeneity.  These researchers used the Cochrane Collaboration's Review Manager 5.2 software for statistical analysis.  A total of 5 RCTs including 351 participants with a mean follow-up time of 6.5 months were identified that strictly met the eligibility criteria.  A meta-analysis of the extractable data showed that testosterone reduced fasting plasma glucose levels (mean difference (MD): -1.10; 95 % CI: -1.88 to -0.31), fasting serum insulin levels (MD: -2.73; 95 % CI: -3.62 to -1.84), HbA1c % (MD: -0.87; 95 % CI: -1.32 to -0.42) and triglyceride levels (MD: -0.35; 95 % CI: -0.62 to -0.07).  The testosterone and control groups demonstrated no significant difference for other outcomes.  The authors concluded that TRT can improve glycemic control and decrease triglyceride levels of hypogonadal men with T2DM.  However, they stated that considering the limited number of participants and the confounding factors in this systematic review; additional large, well-designed RCTs are needed to address the metabolic effects of TRT and its long-term influence on hypogonadal men with T2DM.

Appendix

n deficiency is indicated by either two consecutive low total (free plus protein-bound) fasting serum testosterone levels (below the testing laboratory's normal reference range or below 300 ng/dL), or for persons with low normal total fasting serum testosterone levels (above 300 ng/dL but below 400 ng/dL), two consecutive low free or bioavailable fasting serum testosterone levels (below the testing laboratory's normal reference range or less than 225 picomoles per liter (pmol/L) (6 ng/dL) if reference ranges are not available). Two consecutive fasting total serum testosterone levels are required to determine medical necessity of testosterone replacement, or two consecutive free or bioavailable fasting serum testosterone levels if total testosterone is in the low normal range. Two morning samples drawn between 7:00 a.m. and 10:00 a.m. obtained on different days are required. (One fasting total serum testosterone level is sufficient for persons with severe deficiency (less than 150 ng/dL.) Testosterone levels should not be measured during acute or subacute illness.

Note: Reference laboratories ranges should be used to document testosterone levels. A laboratory reference range is defined as the set of values 95 percent of the normal population falls within (that is, 95% prediction interval).

CPT Codes / HCPCS Codes / ICD-9 Codes
CPT codes covered if selection criteria are met:
11980 Subcutaneous hormone pellet implantation (implantation of estradiol and/or testosterone pellets beneath the skin) [covered for testosterone only - not estradiol]
CPT codes not covered if selection criteria are met:
11981 Insertion, non-biodegradable drug delivery implant [not covered when used to implant progestin/ progresterone pellets]
Other CPT codes related to the CPB:
80414 Chorionic gonadotropin stimulation panel; testosterone response
80415     estradiol response
84402 Testosterone; free
84403     total
HCPCS codes covered if selection criteria are met:
S0189 Testosterone pellet, 75mg
ICD-9 codes covered if selection criteria are met:
253.4 Pituitary hypogonadism [hypothalamic hypogonadism]
257.2 Testicular hypogonadism [primary] [not covered for androgen deficiency due to aging or idiopathic hypogonadism not due to disorders of the testicles, pituitary gland or brain]
259.0 Delay in sexual development and puberty, not elsewhere classified [congenital or acquired endogenous androgen absence or deficiency]
302.50 - 302.53 Trans-sexualism
302.85 Gender identity disorder in adolescents or adults
ICD-9 codes not covered for indications listed in CPB:
625.3 Dysmenorrhea
626.0 - 626.9 Disorders of menstruation and other abnormal bleeding from female genital tract
627.0 - 627.9 Menopausal and postmenopausal disorders
695.2 Erythema nodosum
Other ICD-9 codes related to the CPB:
194.3 Malignant neoplasm of pituitary gland and craniopharyngeal duct
227.3 Benign neoplasm of pituitary gland and craniopharyngeal duct (pouch)
604.0 - 604.99 Orchitis and epididymitis
608.20 - 608.24 Torsion of testis
608.3 Atrophy of testis
608.89 Other specified disorders of male genital organs [male menopause]
752.51 - 752.52 Undescended and retractile testicle
V10.47 Personal history of malignant neoplasm of testis
V45.77 Acquired absence of genital organs [testes]
CPT Codes / HCPCS Codes / ICD-10 Codes
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
ICD-10 codes will become effective as of October 1, 2015 :
CPT codes covered if selection criteria are met:
11980 Subcutaneous hormone pellet implantation (implantation of estradiol and/or testosterone pellets beneath the skin) [covered for testosterone only - not estradiol]
CPT codes not covered if selection criteria are met:
11981 Insertion, non-biodegradable drug delivery implant [not covered when used to implant progestin/ progresterone pellets]
Other CPT codes related to the CPB:
80414 Chorionic gonadotropin stimulation panel; testosterone response
80415     estradiol response
84402 Testosterone; free
84403     total
HCPCS codes covered if selection criteria are met:
S0189 Testosterone pellet, 75mg
ICD-10 codes covered if selection criteria are met:
E23.0 Hypopituitarism [hypothalamic hypogonadism] [not covered for androgen deficiency due to aging or idiopathic hypogonadism not due to disorders of the testicles, pituitary gland or brain]
E29.1 Testicular hypofunction [primary] [not covered for androgen deficiency due to aging or idiopathic hypogonadism not due to disorders of the testicles, pituitary gland or brain]
E30.0 Delayed puberty [congenital or acquired endogenous androgen absence or deficiency]
F64.1 Gender identity disorder in adolescence and adulthood
Z87.890 Personal history of sex reassignment
ICD-10 codes not covered for indications listed in CPB:
L52 Erythema nodosum
N50.8 Other specified disorders of male genital organs [male menopause]
N91.0 - N93.9 Disorders of menstruation and other abnormal bleeding
N94.4 - N94.6 Dysmenorrhea
N95.0 - N95.9 Menopausal and other perimenopausal disorders
Z85.43 Personal history of malignant neoplasm of ovary


The above policy is based on the following references:
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    24. Edelstein D, Sivanandy M, Shahani S, Basaria S. The latest options and future agents for treating male hypogonadism. Expert Opin Pharmacother. 2007;8(17):2991-3008.
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    26. McCullough AR, Khera M, Goldstein I, et al. A multi-institutional observational study of testosterone levels after testosterone pellet (Testopel(®)) insertion. J Sex Med. 2012;9(2):594-601.
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    31. Reis SL, Abdo CH. Benefits and risks of testosterone treatment for hypoactive sexual desire disorder in women: A critical review of studies published in the decades preceding and succeeding the advent of phosphodiesterase type 5 inhibitors. Clinics (Sao Paulo). 2014;69(4):294-303.
    32. Corona G, Isidori AM, Buvat J, et al. Testosterone supplementation and sexual function: A meta-analysis study. J Sex Med. 2014;11(6):1577-1592.
    33. Fui MN, Dupuis P, Grossmann M. Lowered testosterone in male obesity: Mechanisms, morbidity and management. Asian J Androl. 2014;16(2):223-231.
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