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Clinical Policy Bulletin:
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:

    1. As second-line testosterone replacement therapy in males with congenital or acquired endogenous androgen absence or deficiency associated with primary or secondary hypogonadism (see appendix) when oral, intra-muscular, or topical testosterone replacement therapy is ineffective or inappropriate; or 
    2. For treatment of delayed male puberty.

    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 all other indications because their effectiveness for indications other than the ones listed above has not been established.

  3. 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. 

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.

Appendix

The diagnosis and establishment of hypogonadism with any of the following combinations:

  • At least 1 low testosterone level (below the normal range for the laboratory) with elevated FSH and/or LH.
  • At least 2 testosterone levels, both of which are less than normal based upon the laboratory reference range.

 
CPT Codes / HCPCS Codes / ICD-9 Codes
CPT codes covered if selection criteria are met:
11980
CPT codes not covered if selection criteria are met:
11981
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
257.2 Testicular hypogonadism
259.0 Delay in sexual development and puberty, not elsewhere classified [congenital or acquired endogenous androgen absence or deficiency]
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
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]


The above policy is based on the following references:
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  2. Carmichael JM. Postmenopausal hormone replacement. US Pharmacist. 1992;:8-13.
  3. Guirgis RR. Oestradiol valerate. Lancet. 1987;2(8563):856.
  4. Stumpf PG. Pharmacokinetics of estrogen. Obstet Gynecol. 1990;75(4)Suppl:9S-17S.
  5. Kapetanakis E, Dmowski WP, Auletta F, et al. Endocrine and clinical effects of estradiol and testosterone pellets used in long-term replacement therapy. Int J Gynaecol Obstet. 1982;20(5):387-399.
  6. Lobo RA, March CM, Goebelsmann U, et al. The modulating role of obesity and 17 beta-estradiol (E2) on bound and unbound E2 and adrenal androgens in oophorectomized women. J Clin Endocrinol Metab. 1982;54(2):320-324.
  7. Handelsman DJ, Conway AJ, Boylan LM. Pharmacokinetics and pharmacodynamics of testosterone pellets in man. J Clin Endocrinol Metab. 1990;71:216-222.
  8. Garnett T, Studd J, Watson N. et al. A cross-sectional study of the effects of long-term percutaneous hormone replacement therapy on bone density. Obstet Gynecol. 1991;78(6):1002-1007.
  9. Jockenhovel F, Blum WF, Vogel E, et al. Testosterone substitution normalizes elevated serum leptin levels in hypogonadal men. J Clin Endocrinol Metab. 1997;82(8):2510-2513.
  10. United States Pharmacopeial Convention, Inc. USP Dispensing Information. Volume I -- Drug Information for the Health Care Professional. Greenwood Village, CO: Micromedex; 2007.
  11. American Society of Health-System Pharmacists, Inc. AHFS Drug Information 2009. Bethesda, MD: American Society of Health-System Pharmacists; 2009.
  12. Thomson Reuters. Physicians' Desk Reference. 63rd Ed. Montvale, NJ: Physicians' Desk Reference, Inc.; 2009.
  13. Vandekerckhove P, Lilford R, Vail A, Hughes E. Androgens versus placebo or no treatment for idiopathic oligo/asthenospermia. Cochrane Database Syst Rev. 1996;(4):CD000150. 
  14. Basson R. Androgen replacement for women. Can Fam Physician. 1999;45:2100-2107.
  15. Basaria S, Dobs AS. Hypogonadism and androgen replacement therapy in elderly men. Am J Med. 2001;110(7):563-572.
  16. Morley JE. Androgens and aging. Maturitas. 2001;38(1):61-73.
  17. F-D-C- Reports Inc. Estrogen pellets availability under compassionate INDs should be discontinued as a last resort treatment for menopausal symptoms -- FDA advisory committee. The Pink Sheet. 1988;50(4).
  18. Somboonporn W, Davis SR. Postmenopausal testosterone therapy and breast cancer risk. Maturitas. 2004;49(4):267-275.
  19. Alexander JL, Kotz K, Dennerstein L, et al. The effects of postmenopausal hormone therapies on female sexual functioning: A review of double-blind, randomized controlled trials. Menopause. 2004;11(6 Pt 2):749-765.
  20. Nieschlag E, Behre HM, Bouchard P, et al. Testosterone replacement therapy: Current trends and future directions. Hum Reprod Update. 2004;10(5):409-419.
  21. Nieschlag E. Testosterone treatment comes of age: New options for hypogonadal men. Clin Endocrinol (Oxf). 2006;65(3):275-281.
  22. Seftel A. Testosterone replacement therapy for male hypogonadism: Part III. Pharmacologic and clinical profiles, monitoring, safety issues, and potential future agents. Int J Impot Res. 2007;19(1):2-24.
  23. Filho AM, Barbosa IC, Maia H Jr, et al. Effects of subdermal implants of estradiol and testosterone on the endometrium of postmenopausal women. Gynecol Endocrinol. 2007;23(9):511-517.
  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.
  25. Fennell C, Sartorius G, Ly LP, et al. Randomized cross-over clinical trial of injectable vs. implantable depot testosterone for maintenance of testosterone replacement therapy in androgen deficient men. Clin Endocrinol (Oxf). 2010;73(1):102-109.
  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.
  27. Moskovic DJ, Freundlich RE, Yazdani P, et al. Subcutaneous implantable testosterone pellets overcome noncompliance in adolescents with Klinefelter syndrome. J Androl. 2012;33(4):570-573.
  28. Kovac JR, Rajanahally S, Smith RP, et al. Patient satisfaction with testosterone replacement therapies: The reasons behind the choices. J Sex Med. 2014;11(2):553-562.
  29. Smith RP, Kaunitz AM. Treatment of primary dysmenorrhea in adult women. Last reviewed January 2014. UpToDate Inc., Waltham, MA.
  30. Shojania KG. Erythema nodosum. Last reviewed January 2014. UpToDate Inc., Waltham, MA.


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Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial, general description of plan or program benefits and does not constitute a contract. Aetna 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 Aetna or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to change.
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