Description:
This policy addresses the use of subcutaneous hormone implants to replace hormones and treat conditions resulting from a decrease in naturally occurring hormones. The document does not address the use of hormone implants for other conditions, such as contraception, treatment of cancer or precocious puberty.

Policy:
Estrogen:
Implanted estrogen (including estradiol) pellets are considered INVESTIGATIONAL because they have been shown to produce unpredictable and fluctuating serum concentrations of estrogen. There are no FDA-approved, commercially available formulations of implantable estradiol pellets. The FDA warns that these products are "potentially" dangerous.

Testosterone:
Implantable testosterone pellets are considered INVESTIGATIONAL for the treatment of symptoms associated with menopause, as this use remains unlabeled and unsubstantiated.

Bioidentical Hormone Replacement Implants are considered to be INVESTIGATIONAL, as they are not FDA-approved. Therefore, they are not a covered benefit. 

Rationale:
Testosterone is an androgen hormone responsible for normal growth and development of male sex characteristics. In certain medical conditions, such as hypogonadism, the endogenous level of testosterone falls below normal levels. Primary hypogonadism includes conditions such as testicular failure due to cryptorchidism, bilateral torsion, orchitis or vanishing testis syndrome; bilateral orchidectomy; and inborn errors in the biosynthesis of testosterone. Secondary hypogonadism, also called hypogonadotropic hypogonadism, includes conditions such as gonadotropin-releasing hormone (GnRH) deficiency or pituitary-hypothalamic injury resulting from tumors, trauma, surgery or radiation.

Testosterone hormone replacement can be delivered by mouth, intramuscular injection, topically or subcutaneously by testosterone pellets. Testosterone pellets have been approved by the U.S. Food and Drug Administration for the treatment of congenital or acquired androgen deficiency as a result of primary or secondary hypogonadism.

Although secondary or tertiary hormonal treatments with androgens are indicated for palliation therapy in post-menopausal women with metastatic breast cancer, subcutaneous testosterone implants are not indicated for these uses and should not be used by females.

Estrogen
Estrogen is a hormone that occurs naturally, or is manufactured as a synthetic steroidal or nonsteroidal compound with estrogenic activity. Estrogen is used to treat moderate to severe symptoms of female menopause. Estrogen replacement therapy (ERT) indicates the use of estrogen hormone as a single agent. Estrogen in combination with progestin is called hormone replacement therapy (HRT).

While implantable estradiol pellets have been suggested as treatment for symptoms of menopause, there are no 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 U.S. Food and Drug Administration'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."

Several studies (Studd, 1994; Holland, 1995; Wahab, 1997) measured estrogen implant effect on bone density, which provided objective measurement. There have been relatively few studies in which delivery of estrogen replacement therapy using implants was directly compared with other methods of estrogen administration.

There are several randomized controlled studies and uncontrolled prospective clinical trials evaluating subcutaneous HRT. Subcutaneous HRT was compared with placebo and with oral and transdermal therapy. The studies had relatively few subjects, considering the large number of female candidates for HRT. None of the studies was completely blinded. Symptom relief was largely based on subjective and participant-reported results. These studies could be subject to bias based on placebo effect. Reported problems with subcutaneous HRT therapy include:

• Problems with pellet removal if the therapy has to be discontinued.
• Infection, extrusion and/or discomfort at the insertion site.
• Fluctuating blood levels of estrogen.
• Dosing is not easily adjusted
• Compliance with cyclical progesterone therapy in hysterectomized women.
• Cumulative effect of two to three times higher estrogen blood levels over several years not seen with the oral route.

HRT for menopause has been the subject of debate. Additional research is needed to determine the optimal dosage, treatment interval and benefit-to-risk ratio of hormone replacement therapy as a treatment for menopause. Estrogen compounded with testosterone for subcutaneous HRT is not FDA-approved. The published literature does not demonstrate safety and utility in short- and long-term therapy.

Background/Overview
Hormone therapy can be delivered subcutaneously by implantation of the drug in pellet form 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 three- to six-month period, eliminating individual compliance with dosing schedules. Since the drug bypasses the gastrointestinal system and most liver metabolism, bioavailability can be increased. Sustained release can mimic endogenous production, achieving therapeutic blood levels.

According to the American Association of Clinical Endocrinologists (AACE, 2002), men with decreased testosterone levels may experience a higher incidence of osteoporosis, sexual dysfunction, fatigue, cardiovascular disease and disturbances in mood.

Menopause occurs when the ovaries no longer produce estrogen, causing the reproductive system to shut down. The normal aging process is the usual reason for menopause. However, the loss of estrogen production may also be due to the surgical removal of the ovaries or as a result of treatment with chemotherapy.

According to the AACE (2006), although many women are asymptomatic in menopause, other women in the hypoestrogenic state may experience symptoms that may be severe and have a negative impact on quality of life. Symptoms of estrogen deficiency include hot flashes, sweating, insomnia and vaginal dryness and discomfort. Hormone replacement therapy goals are to alleviate menopause symptoms, and include estrogen alone, or estrogen in combination with testosterone. However, there are currently no implantable hormone pellets approved by the FDA for treatment of symptoms of menopause. 

References:

1. Anderson RA, Wallace AM, Sattar N, et al. Evidence for tissue selectivity of the synthetic androgen 7 alpha-methyl-19-nortestosterone in hypogonadal men. J Clin Endocrinol Metab. 2003; 88(6):2784-2793.
2. Buckler HM, Robertson WR, Wu FC. Which androgen replacement therapy for women? J Clin Endocrinol Metab. 1998; 83(11): 3920-3924.
3. del Carmen Cravioto M, Larrea F, Delgado NE, et al. Pharmacokinetics and pharmacodynamics of 25-mg estradiol implants in postmenopausal Mexican women. Menopause. 2001; 8(5): 353-360.
4. File SE, Heard JE, Rymer J. Trough oestradiol levels associated with cognitive impairment in post-menopausal women after 10 years of oestradiol implants. Psychopharmacology. 2002; 161(1): 107-112.
5. Holland EF, Leather AT, Studd JW. Increase in bone mass of older postmenopausal women with low mineral bone density after one year of percutaneous oestradiol implants. Br J Obstet Gynaecol. 1995; 102(3):238-242.
6. Howell S, Shalet S. Testosterone deficiency and replacement. Horm Res. 2001; 56 Suppl 1:86-92.
7. Kelleher S, Conway AJ, Handelsman DJ. Influence of implantation site and track geometry on the extrusion rate and pharmacology of testosterone implants. Clin Endocrinol. 2001; 55(4):531-536.
8. Kenemans P, van Unnik GA, Mijatovic V, van der Mooren MJ. Perspectives in hormone replacement therapy. Maturitas. 2001 15; 38 Suppl 1:S41-S48.
9. Stanczyk FZ, Shoupe D, Nunez V, et al. A randomized comparison of nonoral estradiol delivery in postmenopausal women. Am J Obstet Gynecol. 1988; 159:1540-1546.
10. Studd JWW, Holland EFN, Leather AT, Smith RNJ. The dose-response of percutaneous oestradiol implants on the skeletons of postmenopausal women. Br J Obstet Gynaecol. 1994; 101:787-791.
11. Studd JWW, Smith RNJ. Oestradiol and testosterone implants. Baillière's Clin Endocrinol Metabol. 1993; 7:203-223.
12. Suhonen SP, Allonen HO, Lähteenmäki P. Sustained-release estradiol implants and a levonorgestrel-releasing intrauterine device in hormone replacement therapy. Am J Obstet Gynecol. 1995; 172:562-567.
13. Templeman C, Quinn D, Hansen R, et al. An audit of oestrogen implant hormone replacement therapy. Aust NZ J Obstet Gynaecol. 1998; 38:455-460.
14. Vogelvang, TE et al. Neither long-term treatment with raloxifene nor hormone replacement therapy modulate cardiac function in healthy postmenopausal women: Two randomized, placebo-controlled, 2-year studies. Am J Obstet Gynecol. 2002; 186(4): 729-736.
15. Wahab M, Ballard P, Purdie DW, Cooper A, Willson JC. The effect of long-term oestradiol implantation on bone mineral density in postmenopausal women who have undergone hysterectomy and bilateral oophorectomy. Br J Obstet Gynaecol. 1997; 104(6):728-731

Coding Section

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

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