Implantable Hormone Pellets

Number: 0345

Table Of Contents

Applicable CPT / HCPCS / ICD-10 Codes


  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 Implantable Pellets

    Aetna considers testosterone propionate implant pellets (Testopel pellets) medically necessary for any of the following indications: 

    1. Delayed male puberty; or
    2. Gender dysphoria when all of the following are met:

      1. The member has a diagnosis of gender dysphoria; and
      2. The member is able to make an informed decision to engage in hormone therapy; and
      3. The member's comorbid conditions are reasonably controlled; and
      4. The member has been educated on any contraindications and side effects to therapy; and
      5. Before the start of therapy, the member has been informed of fertility preservation options; and
      6. For members less than 18 years of age, this medication will be prescribed by or in consultation with a provider specialized in the care of transgender youth (e.g., pediatric endocrinologist, family or internal medicine physician, obstetrician-gynecologist), that has collaborated care with a mental health care provider; and the member has reached, or has previously reached, Tanner stage 2 of puberty or greater; or
    3. Primary or hypogonadotropic hypogonadism, when the following criteria are met: 

      1. Before the start of testosterone therapy, the member has at least two confirmed low morning testosterone levels according to current practice guidelines or your standard lab reference values Footnotes*; or
      2. For continuation of testosterone therapy: before the member started testosterone therapy, the member had a confirmed low morning testosterone level according to current practice guidelines or your standard lab reference values.Footnotes*

    Aetna considers implantable testosterone pellets experimental and investigational for the following (not an all-inclusive list) because their effectiveness for indications other than the ones listed above has not been established:

    • Hypogonadism due to aging (also known as "age-related hypogonadism" or "late-onset hypogonadism") 
    • Idiopathic hypogonadism (not due to disorders of the testicles, pituitary gland or brain)
    • Male menopause
    • Pain management in women
    • Treatment of cancers (e.g., breast, kidney, and prostate)
    • Treatment of symptoms associated with menopause (as this use remains unlabeled and unsubstantiated)

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

  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.

  4. Related Policies

Dosage and Administration

Testosterone Propionate Implant Pellets (Testopel)

The suggested dosage for androgens varies depending on the age, and diagnosis of the individual. Dosage is adjusted according to the person's response and the appearance of adverse reactions. The dosage guideline for the testosterone pellets for replacement therapy in androgen-deficient males is 150 mg to 450 mg subcutaneously every 3 to 6 months. Various dosage regimens have been used to induce pubertal changes in hypogonadal males; some experts have advocated lower doses initially, gradually increasing the dose as puberty progresses, with or without a decrease in maintenance levels. Other experts emphasize that higher dosages are needed to induce pubertal changes and lower dosages can be used for maintenance after puberty. The chronological and skeletal ages must be taken into consideration, both in determining the initial dose and in adjusting the dose.

Dosages in delayed puberty generally are in the lower range of that listed above and, for a limited duration, for example 4 to 6 months.

The number of pellets to be implanted depends upon the minimal daily requirements of testosterone propionate determined by a gradual reduction of the amount administered parenterally. The usual dosage is as follows: implant two 75 mg pellets for each 25 mg testosterone propionate required weekly. Thus, when a person requires injections of 75 mg per week, it is usually necessary to implant 450 mg (6 pellets). With injections of 50 mg per week, implantation of 300 mg (4 pellets) may suffice for approximately three months. With lower requirements by injection, correspondingly lower amounts may be implanted. It has been found that approximately one-third of the material is absorbed in the first month, one-fourth in the second month and one-sixth in the third month. Adequate effect of the pellets ordinarily continues for three to four months, sometimes as long as six months.

Source: Endo Pharmaceuticals, 2018


CPT Codes / HCPCS Codes / ICD-10 Codes

Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

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]
+20700 Manual preparation and insertion of drug-delivery device(s), deep (eg, subfascial) (List separately in addition to code for primary procedure)

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
84410 Testosterone; bioavailable, direct measurement (eg, differential precipitation)

HCPCS codes covered if selection criteria are met:

S0189 Testosterone pellet, 75mg

ICD-10 codes covered if selection criteria are met:

E23.0 Hypopituitarism [hypogonadotropic 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]
F64.0 - F64.9 Gender identity disorders
Z87.890 Personal history of sex reassignment

ICD-10 codes not covered for indications listed in CPB:

C50.011 – C50.929 Malignant neoplasm of breast
C61 Malignant neoplasm of prostate
C64.1 – C64.9 Malignant neoplasm of kidney, except renal pelvis
L52 Erythema nodosum
N50.89 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


Implantable Estrogen

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.”

Testosterone Implantable Pellets

U.S. Food and Drug Administration (FDA)-Approved Indications of Testopel

  • Males - androgens are indicated for replacement therapy in conditions associated with a deficiency or absence of endogenous testosterone.
  • Primary hypogonadism (congenital or acquired) - testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testes syndrome; or orchiectomy.
  • Hypogonadotrophic hypogonadism (congenital or acquired) - gonadotropic LHRH deficiency, or pituitary- hypothalamic injury from tumors, trauma or radiation. If the above conditions occur prior to puberty, androgen replacement therapy will be needed during the adolescent years for development of secondary sex characteristics. Prolonged androgen treatment will be required to maintain sexual characteristics in these and other males who develop testosterone deficiency after puberty. Safety and efficacy of Testopel (testosterone pellets) in men with “age-related hypogonadism” (also referred to as “late-onset hypogonadism”) have not been established.
  • Androgens may be used to stimulate puberty in carefully selected males with clearly delayed puberty. These patients usually have a familial pattern of delayed puberty that is not secondary to a pathological disorder; puberty is expected to occur spontaneously at a relatively late date. Brief treatment with conservative doses may occasionally be justified in these patients if they do not respond to psychological support. The potential adverse effect on bone maturation should be discussed with the patient and parents prior to androgen administration. An X-ray of the hand and wrist to determine bone age should be taken every 6 months to assess the effect of treatment on epiphyseal centers.

Compendial Use of Testopel

  • Gender dysphoria

Testosterone is an endogenous androgen. Androgens are responsible for normal growth and development of male sex organs. Testosterone is involved in the growth and maturation of the prostate, seminal vesicles, penis, and scrotum; development of male hair distribution (e.g., beard, pubic, chest and axillary hair); laryngeal enlargement, vocal cord thickening, and alterations in body musculature and fat distribution. Low serum testosterone concentrations due to inadequate secretion of testosterone is associated with male hypogonadism. Symptoms include decreased sexual desire with or without impotence, fatigue, and mood disturbances.

Implantable testosterone pellets may be indicated as second-line testosterone replacement therapy for males.  Testosterone implants (Testopel Pellets; Endo Pharmaceuticals, Inc) are commercially available in the United States. Testopel (testosterone) is indicated for replacement therapy in males for conditions associated with a deficiency or absence of endogenous testosterone.

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.

Testosterone is available as Testopel in 78 mg pellets (75mg testosterone) for subcutaneous implantation. 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 in the lower range of that listed above.  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).

The label for Testopel include the following warnings (Endo Pharmaceuticals, 2018): 

  • May cause hypercalcemia by stimulating osteolysis in patients with breast cancer, androgen therapy. In this case, the drug should be discontinued
  • Prolonged use of high doses of androgens has been associated with the development of peliosis hepatis and hepatic neoplasms including hepatocellular carcinoma Peliosis hepatis can be a life-threatening or fatal complication
  • Men treated with androgens may be at an increased risk for the development of prostatic hypertrophy and prostatic carcinoma
  • There have been postmarketing reports of venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients using testosterone products, such as Testopel® (testosterone pellets)
  • Long term clinical safety trials have not been conducted to assess the cardiovascular outcomes of testosterone replacement therapy in men. To date, epidemiologic studies and randomized controlled trials have been inconclusive for determining the risk of major adverse cardiovascular events (MACE), such as non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death, with the use of testosterone compared to non-use. Some studies, but not all, have reported an increased risk of MACE in association with use of testosterone replacement therapy in men. Patients should be informed of this possible risk when deciding whether to use or to continue to use Testopel® (testosterone pellets)
  • Edema with or without congestive heart failure may be a serious complication in patients with preexisting cardiac, renal, or hepatic disease. In addition to discontinuation of the drug, diuretic therapy may be required
  • Gynecomastia frequently develops in patients and occasionally persists in patients being treated for hypogonadism
  • Androgen therapy should be used cautiously in healthy males with delayed puberty. The effect on bone maturation should be monitored by assessing bone age of the wrist and hand every 6 months. In children, androgen treatment may accelerate bone maturation without producing compensatory gain in linear growth. This adverse effect may result in compromised adult stature. The younger the child the greater the risk of compromising final mature height
  • Post-marketing cases associate TESTOPEL® pellet(s) insertion with implant site infection (cellulitis and abscess), and/or pellet extrusion at or near the implantation site. Infection and extrusion may occur concurrently or separately. Reported signs and symptoms of infection and/or extrusion at the implant site included induration, inflammation, fibrosis, bleeding, bruising, wound drainage, pain, itching, and pellet extrusion. Although cases of infection and/or extrusion may occur at any time, most reported cases occurred within the first month after TESTOPEL® implantation. Infection and/or extrusion may require further treatment
  • This drug has not been shown to be safe and effective for the enhancement of athletic performance. Because of the potential risk for serious adverse health effects, this drug should not be used for such purpose.

Testopel has potential for abuse (Schedule CIII). Testosterone has been subject to abuse, typically at doses higher than recommended for the approved indication and in combination with other anabolic steroids. Anabolic androgenic steroid abuse can lead to serious cardiovascular and psychiatric adverse reactions. If testosterone abuse is suspected, it is recommened that the healthcare provider check serum testosterone concentrations to ensure they are within therapeutic range. However, testosterone levels may be in the normal or subnormal range in men abusing synthetic testosterone derivatives. Patients should be counseled concerning the serious adverse reactions associated with abuse of testosterone and anabolic androgenic steroids. Conversely, consider the possibility of testosterone and anabolic androgenic steroid abuse in suspected patients who present with serious cardiovascular or psychiatric adverse events.

Testopel must not be used in women as testosterone exposure during pregnancy has been reported to be associated with fetal abnormalities.

Pellet implantation is much less flexible for dosage adjustment than is oral administration, intramuscular injections of oil solutions, or aqueous suspensions and, therefore, great care should be used when estimating the amount of testosterone needed.

The number of pellets to be implanted depends upon the minimal daily requirements of testosterone propionate determined by a gradual reduction of the amount administered parenterally. The usual dosage is as follows: implant two 75mg pellets for each 25mg testosterone propionate required weekly. Thus when a patient requires injections of 75mg per week, it is usually necessary to implant 450mg (6 pellets). With injections of 50mg per week, implantation of 300mg (4 pellets) may suffice for approximately three months. With lower requirements by injection, correspondingly lower amounts may be implanted. It has been found that approximately one‐third of the material is absorbed in the first month, one fourth in the second month, and one sixth in the third month. Adequate effect of the pellets ordinarily continues for three to four months, sometimes as long as six months.

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.

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.

Testosterone Implantable Pellets for the Prevention of Invasive Breast Cancer in Women

Glaser and colleagues (2019) stated that testosterone implants have been used for over 80 years to treat symptoms of hormone deficiency in pre- and post-menopausal women.  Evidence supports that androgens are breast-protective; however, there is a lack of data regarding the long-term effect of testosterone (T) therapy on the incidence of invasive breast cancer (IBC).  In a prospective, 10-year. cohort study, these investigators examined the incidence of IBC in pre- and post-menopausal women (presenting with symptoms of androgen deficiency) treated with subcutaneous T implants or T implants combined with anastrozole.  This trial was approved in March 2008 at which time recruitment was initiated; and recruitment was closed March 2013.  Pre- and post-menopausal women receiving at least 2 pellet insertions were eligible for analysis (n = 1,267).  Breast cancer incidence rates were reported as an unadjusted, un-weighted value of newly diagnosed cases divided by the sum of “person-time of observation” for the at-risk population.  Incidence rates on T therapy were compared to age-specific Surveillance Epidemiology and End Results (SEER) incidence rates and historical controls.  Bootstrap sampling distributions were constructed to verify comparisons and tests of significance that existed between these findings and SEER data.  As of March 2018, a total of 11 (versus 18 expected) cases of IBC were diagnosed in patients within 240-days following their last T insertion equating to an incidence rate of 165/100,000 person-years (p-y), which was significantly less than the age-matched SEER expected incidence rate of 271/100,000 p-y (p < 0.001) and historical controls.  The authors concluded that long-term subcutaneous T therapy, or T combined with anastrozole, did not increase the incidence of IBC.  These researchers stated that testosterone should be further examined for hormone therapy and breast cancer prevention. 

Donovitz and Cotton (2021) noted that T therapy has been shown to be breast-protective in both pre- and post-menopausal patients.  Furthermore estradiol (E) does not cause BC in the majority of the world's literatures.  These investigators examined the incidence of IBC in pre- and post-menopausal women treated with T therapy and T in combination with E (T/E).  Since January 2010, a total of 2,377 pre- and post-menopausal women were treated with T or T/E implants; and IBC rates were reported based on newly diagnosed IBC cases in the total study.  Total cases divided by the total sample size and years in study was expressed as an incidence per 100,000 p-y.  The BC incidence was compared with age-specific SEER incidence rates.  As of October 2020, 14 cases diagnosed with IBC have been found in 9,746 p-y of follow-up for an incidence of 144 cases per 100,000 p-y, substantially less than the age-specific SEER incidence rates (223/100,000), placebo arm of Women's Health Initiative Study (330/100,000), and never users of hormone therapy from the Million Women Study (312/100,000).  The authors concluded that T and/or T/E pellet implants significantly reduced the incidence of BC in pre- and post-menopausal women.  The addition of E did not increase the incidence over using T alone.  These investigators stated that this was the 2nd multi-year, long-term study demonstrating the benefits of T therapy in reducing the incidence of IBC.   This Trial (The Testosterone Therapy and Breast Cancer Incidence Study) was the largest long-term study to further demonstrate this benefit and showed a reduced incidence of IBC in women taking T/E sub-cutaneous hormone pellet therapy.

Testosterone for Pain Management in Women

Aloisi et al (2011) noted that in male patients suffering from chronic pain, opioid administration induces severe hypogonadism, leading to impaired physical and psychological conditions such as fatigue, anemia and depression.  Hormone replacement therapy is rarely considered for these hypogonadic patients, notwithstanding the various pharmacological solutions available.  To treat hypogonadism and to evaluate the consequent endocrine, physical and psychological changes in male chronic pain patients treated with morphine (epidural route), these researchers tested the administration of testosterone via a gel formulation for 1 year.  Hormonal (total testosterone, estradiol, free testosterone, DHT, cortisol), pain (VAS and other pain questionnaires), andrological (Ageing Males' Symptoms Scale-AMS) and psychological (POMS, CES-D and SF-36) parameters were evaluated at baseline (T0) and after 3, 6 and 12 months (T3, T6, T12 respectively).  The daily administration of testosterone increased total and free testosterone and DHT at T3, and the levels remained high until T12.  Pain rating indexes (QUID) progressively improved from T3 to T12 while the other pain parameters (VAS, Area%) remained unchanged.  The AMS sexual dimension and SF-36 Mental Index displayed a significant improvement over time.  The authors concluded that these findings suggested that a constant, long-term supply of testosterone could induce a general improvement of the male chronic pain patient's quality of life (QOL), an important clinical aspect of pain management.  These researchers stated that their results strongly suggested that this therapy can positively modulate the dimensions of pain.  This effect allowed them to propose the use of testosterone in clinics as an adjuvant, in combination with opioid therapy.  These preliminary findings need to be validated by well-designed studies.

Calabrese et al (2014) stated that diabetic neuropathy is associated with neuropathic pain in about 50 % of diabetic subjects.  Clinical management of neuropathic pain is complex and so far unsatisfactory.  These investigators analyzed the effects of the testosterone metabolites, dihydrotestosterone (DHT), and 3α-diol, on nociceptive and allodynia thresholds and on molecular and functional parameters related to pain modulation in the dorsal horns of the spinal cord and in the dorsal root ganglia of rats rendered diabetic by streptozotocin injection.  Furthermore, the levels of DHT and 3α-diol were analyzed in the spinal cord.  Diabetes resulted in a significant decrease in DHT levels in the spinal cord that was reverted by DHT or 3α-diol treatments.  In addition, 3α-diol treatment resulted in a significant increase in 3α-diol in the spinal cord compared with control values.  Both steroids showed analgesic properties on diabetic neuropathic pain, affecting different pain parameters and possibly by different mechanisms of action.  Indeed, DHT counteracted the effect of diabetes on the mechanical nociceptive threshold, pre- and post-synaptic components, glutamate release, astrocyte immunoreactivity, and expression of interleukin-1β (IL1β), while 3α-diol was effective on tactile allodynia threshold, glutamate release, astrocyte immunoreactivity and the expression of substance P, toll-like receptor 4, tumor necrosis factor-α, transforming growth factor β-1, IL1β, and translocator protein.  The authors concluded that these findings indicated that testosterone metabolites are potential agents for the treatment of diabetic neuropathic pain.

In a case-series study, Dubick et al (2015) examined the feasibility and safety of a novel method for the management of chronic lower back pain (LBP).  Injections of recombinant human growth hormone (rhGH) and testosterone to the painful and dysfunctional areas in individuals with chronic LBP were used.  In addition, subjects received manual therapies and exercise addressing physical impairments such as motor control, strength, endurance, pain, and loss of movement.  Pain ratings and self-rated functional outcomes were assessed.  This trial involved consecutive patients with chronic LBP who received the intervention of injections of recombinant human growth hormone and testosterone, and attended chiropractic and/or physical therapy.  Outcomes were measured at 12 months from the time of injection.  A total of 60 consecutive patients attending a pain management practice for chronic LBP were recruited for the experimental treatment.  Most subjects were private pay.  Subjects who provided informed consent and were determined not to have radicular pain received diagnostic blocks.  Those who responded favorably to the diagnostic blocks received injections of recombinant human growth hormone and testosterone in the areas treated with the blocks.  Subjects also received manipulation- and impairment-based exercises.  Outcomes were assessed at 12 months through pain ratings with the Mankowski Pain Scale and the Oswestry Disability Index (ODI).  Of the 60 patients recruited, 49 provided informed consent, and 39 completed all aspects of the study.  Those patients receiving the intervention reported a significant decrease in pain ratings (p < 0.01) and a significant improvement in self-rated ODI scores (p < 0.01).  In addition, in the ODI results, 41 % of the patients demonstrated a 50 % or greater change in their disability score.  Of the subjects who withdrew from the study, 1 was due to the pain created by the injections and 9 were for non-study factors.  The authors concluded that the intervention appeared to be safe and the results provided a reasonable expectation that the intervention would be beneficial for a population of individuals with chronic non-radicular LBP.  Moreover, these researchers stated that due to the design of the study, causality could not be inferred, but these findings did indicate that further study of the intervention may be needed.  These researchers stated that the results of this case series support the development of randomized controlled trials (RCTs) comparing the use of placebo injections versus rhGH and testosterone injection therapy, with and without impairment-specific rehabilitation.  This was a small (n = 39 subjects who completed the study); and its findings were confounded by the combined use of rhGH, testosterone, manual therapies and exercise.

Pogatzki-Zahn et al (2019) noted that the role of sex hormones on post-surgical pain perception is basically unclear.  These researchers examined the role of endogenous gonadal hormones for pain and hyperalgesia in human volunteers after experimental incision.  A 4-mm incision was made in the volar forearm of 15 female volunteers both in the follicular and the luteal phase (random block design).  Somatosensory profiles were assessed at baseline and 1 to 72 hours after incision by quantitative sensory testing (QST), compared between both cycle phases, and related to individual plasma levels of gonadal hormones.  Sensory testing at baseline revealed significantly lower pain thresholds (25 versus 46 mN, p < 0.005) and increased pain ratings to pinprick (0.96 versus 0.47, p < 0.0001) in the luteal phase; similarly, 1 hour after incision, pain intensity to incision (38 versus 21/100, p < 0.005), pinprick hyperalgesia by rating (p < 0.05), and area of secondary hyperalgesia (p < 0.001) were enhanced in the luteal phase.  Multiple regression analysis revealed that pinprick pain sensitivity at baseline was significantly predicted by progesterone (partial r = 0.67, p < 0.001), follicle-stimulating hormone (FSH) (partial r = 0.61, p < 0.005), and negatively by testosterone (partial r = -0.44, p < 0.05).  Likewise, incision-induced pain and pinprick hyperalgesia (rating and area) were significantly predicted by progesterone (partial r = 0.70, r = 0.46, and r = 0.47, respectively; p < 0.05 to 0.0001) and in part by FSH; the contribution of estrogen, however, was fully occluded by progesterone for all measures.  The authors concluded that pinprick pain and incision-induced pain and mechanical hyperalgesia were greater in the luteal phase and predicted by progesterone, suggesting a major role for progesterone.  Other hormones involved were testosterone (protective) and in part FSH.

Testosterone for the Treatment of Cancers

The Endocrine Society of Australia’s consensus guidelines for androgen prescribing (Conway et al, 2000) noted that androgen replacement therapy (ART) is usually life-long; and should only be started after androgen deficiency has been proven by hormone assays.  The objective is to maintain physiological testosterone levels.  Testosterone rather than synthetic androgens should be used.  Oral 17 alpha-alkylated androgens are hepato-toxic and should not be used for ART.  There is no indication for androgen therapy in male infertility.  Although androgen deficiency is an uncommon cause of erectile dysfunction (ED), all men presenting with ED should be examined for androgen deficiency.  If androgen deficiency is confirmed, investigation for the underlying pathological cause is needed.  Contraindications to androgen therapy are prostate and breast cancer.  Precautions include using lower starting doses for older men and induction of puberty.  Intra-muscular (IM) injections should be avoided in men with bleeding disorders.  Androgen-sensitive epilepsy, migraine, sleep apnea, polycythemia or fluid over-load need to be considered.  Competitive athletes should be warned regarding the risks of disqualification.  ART should be initiated with IM injections of testosterone esters, 250 mg every 2 weeks.  Maintenance requires tailoring treatment modality to the patient's convenience.  Modalities currently available include testosterone injections, implants, or capsules.  Choice depends on convenience, cost, availability and familiarity.  The authors concluded that there is no convincing evidence that, in the absence of proven androgen deficiency, androgen therapy is safe and effective for older men per se, in men with chronic non-gonadal disease, or for the treatment of non-specific symptoms.  These investigators stated that until further evidence is available, such treatment cannot be recommended.

Glaser and colleagues (2017) stated that hormone receptor-positive BCs respond favorably to subcutaneous T combined with an aromatase inhibitor; however, the effect of T combined with an aromatase inhibitor on tumor response to chemotherapy was unknown.  These investigators examined the effect of T-letrozole implants on BC tumor response before and during neoadjuvant chemotherapy.  A 51-year-old woman on T replacement therapy was diagnosed with hormone receptor-positive IBC.  Six weeks before starting neoadjuvant chemotherapy, the patient was treated with subcutaneous T-letrozole implants and instructed to follow a low-glycemic diet.  Clinical status was followed.  Tumor response to "T-letrozole" and subsequently, "T-letrozole with chemotherapy" was monitored using serial ultrasonography (US) and calculating tumor volume.  Response to therapy was determined by change in tumor volume.  There was a 43 % reduction in tumor volume 41 days after the insertion of T-letrozole implants, before starting chemotherapy.  After the initiation of concurrent chemotherapy, the tumor responded at an increased rate, resulting in a complete pathologic response.  Chemotherapy was tolerated; blood counts and weight remained stable.  There were no neurologic or cardiac complications from the chemotherapy.  The authors concluded that subcutaneous T-letrozole was an effective treatment for this patient's BC and did not interfere with chemotherapy.  These researchers stated that this novel combined T-letrozole implant has the potential to prevent side effects from chemotherapy, improve QOL, and warrants further investigation.

A National Cancer Institute’s webpage on “Hormone Therapy for Breast Cancer” (last updated: July 7, 2021) did not mention testosterone therapy as an option.

Furthermore, National Comprehensive Cancer Network’s clinical practice guidelines on “Breast cancer” (Version 2.2022), “Kidney cancer” (Version 4.2022) and “Prostate cancer” (Version 3.2022) do not mention testosterone as a management/therapeutic option.

Progesterone Pellets

An UpToDate review on "Dysmenorrhea in adult women: Treatment" (Smith and Kaunitz, 2021) does not mention use of progestin hormone "pellet" implant as a managment option.

An UpToDate review on "Erythema nodosum" (Kroshinsky, 2020) does not mention the use of progestin/progesterone as a management option.


Androgen deficiency is indicated by either 2 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), 2 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 2 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.


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

Consecutive testing of fasting serum testosterone levels refer to testing in succession; not consecutive days of testing.


The above policy is based on the following references:

  1. 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.
  2. Aloisi AM, Ceccarelli I, Carlucci M, et al. Hormone replacement therapy in morphine-induced hypogonadic male chronic pain patients. Reprod Biol Endocrinol. 2011;9:26.
  3. American College of Obstetricians and Gynecologists’ Committee on Gynecologic Practice; American College of Obstetricians and Gynecologists’ Committee on Health Care for Underserved Women. Health Care for Transgender and Gender Diverse Individuals: ACOG Committee Opinion, Number 823. Obstet Gynecol. 2021;137(3):e75-e88.
  4. American Society of Health-System Pharmacists, Inc. AHFS Drug Information. Bethesda, MD: American Society of Health-System Pharmacists; updated periodically.
  5. Auxilium Pharmaceuticals, Inc. Testopel Pellets [package insert]. Malvern, PA: Auxilium Pharmaceuticals; August 2018.
  6. Basaria S, Dobs AS. Hypogonadism and androgen replacement therapy in elderly men. Am J Med. 2001;110(7):563-572.
  7. Basson R. Androgen replacement for women. Can Fam Physician. 1999;45:2100-2107.
  8. Bhasin S, Cunningham G, Hayes F, et al. Testosterone therapy in adult men with androgen deficiency syndromes: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(5):1715-1744.
  9. Cai X, Tian Y, Wu T, et al. Metabolic effects of testosterone replacement therapy on hypogonadal men with type 2 diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials. Asian J Androl. 2014;16(1):146-152.
  10. Calabrese D, Giatti S, Romano S, et al. Diabetic neuropathic pain: A role for testosterone metabolites. J Endocrinol. 2014;221(1):1-13.
  11. Carmichael JM. Postmenopausal hormone replacement. US Pharmacist. 1992;:8-13.
  12. Coleman E, Bockting W, Botzer M, et al. Standards of care for the health of transsexual, transgender, and gender nonconforming people. Minneapolis, MN: World Professional Association for Transgender Health (WPATH); last updated 2012. Available at: Accessed February 3, 2021.
  13. Conway AJ, Handelsman DJ, Lording DW, et al. Use, misuse and abuse of androgens. The Endocrine Society of Australia consensus guidelines for androgen prescribing. Med J Aust. 2000;172(5):220-224.
  14. 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.
  15. Donovitz G, Cotten M. Breast cancer incidence reduction in women treated with subcutaneous testosterone: Testosterone therapy and breast cancer incidence study. Eur J Breast Health. 2021;17(2):150-156.
  16. Dubick MN, Ravin TH, Michel Y, Morrisette DC. Use of localized human growth hormone and testosterone injections in addition to manual therapy and exercise for lower back pain: A case series with 12-month follow-up. J Pain Res. 2015;8:295-302.
  17. 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.
  18. Endo Pharmaceuticals, Inc. Testopel (testosterone pellets). Prescribing Information. Malvern, PA: Endo Pharmaceuticals; revised August 2018.
  19. 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).
  20. 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.
  21. 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.
  22. Fui MN, Dupuis P, Grossmann M. Lowered testosterone in male obesity: Mechanisms, morbidity and management. Asian J Androl. 2014;16(2):223-231.
  23. 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.
  24. Glaser RL, York AE, Dimitrakakis C. Incidence of invasive breast cancer in women treated with testosterone implants: A prospective 10-year cohort study. BMC Cancer. 2019;19(1):1271.
  25. Glaser RL, York AE, Dimitrakakis C. Subcutaneous testosterone-letrozole therapy before and concurrent with neoadjuvant breast chemotherapy: clinical response and therapeutic implications. Menopause. 2017;24(7):859-864.
  26. Guirgis RR. Oestradiol valerate. Lancet. 1987;2(8563):856.
  27. Handelsman DJ, Conway AJ, Boylan LM. Pharmacokinetics and pharmacodynamics of testosterone pellets in man. J Clin Endocrinol Metab. 1990;71:216-222.
  28. Hembree WC, Cohen-Kettenis P, Delemarre-van de Waal HA, et al; Endocrine Society.  Endocrine treatment of gender dysphoric/gender-jncongruent persons:  An Endocrine Society Clinical Practice Guideline. J Clin Encorinol Metab. 2017;102(11):3869-3903.
  29. IBM Micromedex, DRUGDEX System [Internet database]. Armonk, NY: IBM Watson Health; updated periodically.
  30. 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.
  31. 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.
  32. Knezevich EL, Viereck LK, Drincic AT.  Medical management of adult transsexual persons. Pharmacotherapy. 2012;32(1):54-66.
  33. 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.
  34. Kroshinsky D. Erythema nodosum. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed January 2020.
  35. Lexicomp Online, AHFS DI (Adult and Pediatric) Online. Waltham, MA: UpToDate, Inc.; 2023; Accessed January 26, 2023.
  36. 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.
  37. 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.
  38. Morley JE. Androgens and aging. Maturitas. 2001;38(1):61-73.
  39. 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.
  40. National Comprehensive Cancer Network (NCCN). Breast cancer. NCCN Clinical Practice Guidelines in Oncology, Version 2.2022. Plymouth Meeting, PA: NCCN; December 20, 2021.
  41. National Comprehensive Cancer Network (NCCN). Kidney cancer. NCCN Clinical Practice Guidelines in Oncology, Version 4.2022. Plymouth Meeting, PA: NCCN; December 21, 2021.
  42. National Comprehensive Cancer Network (NCCN). Prostate cancer. NCCN Clinical Practice Guidelines in Oncology, Version 3.2022. Plymouth Meeting, PA: NCCN; January 10, 2022.
  43. National Institutes of Health (NIH), National Cancer Institute (NC). Hormone therapy for breast cancer [online]. Bethesda, MD: NIH; updated July 7, 2021. Available at: Accessed February 28, 2022.
  44. Nieschlag E, Behre HM, Bouchard P, et al. Testosterone replacement therapy: Current trends and future directions. Hum Reprod Update. 2004;10(5):409-419.
  45. Nieschlag E. Testosterone treatment comes of age: New options for hypogonadal men. Clin Endocrinol (Oxf). 2006;65(3):275-281.
  46. Pastuszak AW, Gomez LP, Scovell JM, et al. Comparison of the effects of testosterone gels, injections, and pellets on serum hormones, erythrocytosis, lipids, and prostate-specific antigen. Sex Med. 2015;3(3):165-173.
  47. Petak S, Nankin H, Spark R, et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Evaluation and Treatment of Hypogonadism in Adult Male Patients – 2002 update. Endocrine Practice. 2002;8(6):439-456.
  48. Physicians' Desk Reference (PDR). Montvale, NJ: Thomson PDR; updated periodically.
  49. Pogatzki-Zahn EM, Drescher C, Englbrecht JS, et al. Progesterone relates to enhanced incisional acute pain and pinprick hyperalgesia in the luteal phase of female volunteers. Pain. 2019;160(8):1781-1793.
  50. 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.
  51. Rotker KL, Alavian M, Nelson B, et al. Association of subcutaneous testosterone pellet therapy with developing secondary polycythemia. Asian J Androl. 2018;20(2):195-199.
  52. 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.
  53. Smith RP, Kaunitz AM. Dysmenorrhea in adult women: Treatment. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed January 2021.
  54. Somboonporn W, Davis SR. Postmenopausal testosterone therapy and breast cancer risk. Maturitas. 2004;49(4):267-275.
  55. Stumpf PG. Pharmacokinetics of estrogen. Obstet Gynecol. 1990;75(4)Suppl:9S-17S.
  56. Thom MH, Studd JW. Procedures in practice. Hormone implantation. Br Med J. 1980;280(6217):848-850.
  57. U.S. Food and Drug Administration (FDA). 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. Testosterone Products: Drug Safety Communication. Silver Spring, MD: FDA; March 3, 2015.
  58. 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. 
  59. Wang D , Steffi C , Wang Z, et al. Beta-cyclodextrin modified mesoporous bioactive glass nanoparticles/silk fibroin hybrid nanofibers as an implantable estradiol delivery system for the potential treatment of osteoporosis. Nanoscale. 2018;10(38):18341-18353.