Androgens and Anabolic Steroids

Number: 0528

Brand Selection for Medically Necessary Indications

As defined in Aetna commercial policies, health care services are not medically necessary when they are more costly than alternative services that are at least as likely to produce equivalent therapeutic or diagnostic results. Aveed (testosterone undecanoate) long-acting injectable anabolic-androgenic steroid is more costly to Aetna than other long-acting anabolic-androgenic steroids. There is a lack of reliable evidence that Aveed (testosterone undecanoate) is superior to the lower cost long-acting injectable anabolic-androgenic steroids, Depo-Testosterone (testosterone cypionate) and Delatestryl (testosterone enanthate). Therefore, Aetna considers Aveed (testosterone undecanoate) to be medically necessary only for members who have a contraindication, intolerance or ineffective response to the available equivalent alternative long-acting injectable anabolic-androgenic steroids: Depo-Testosterone (testosterone cypionate) and Delatestryl (testosterone enanthate).

Policy

Note: Requires Precertification.

Precertification of testosterone undecanoate (Aveed) is required of all Aetna participating providers and members in applicable plan designs.  For precertification of testosterone undecanoate (Aveed), call (866) 752-7021, or fax (866) 267-3277.

Note: Most policies specifically exclude coverage of steroids for performance enhancement.  For plans without this exclusion, androgens and anabolic steroids as well as other medical interventions for performance enhancement are not covered because performance enhancement of non-diseased individuals is not considered treatment of disease or injury.  Please check benefit plan descriptions for details.

1. Anabolic Steroids

   Aetna considers anabolic steroids medically necessary for any of the following indications:

   1. AIDS wasting syndrome; or
   2. Anemia accompanying chronic renal failure; or
   3. Bone marrow failure anemias (e.g., Fanconi's anemia); or
   4. Breast cancer; or
   5. Conditions associated with decreased fibrinolytic activity due to anti-thrombin III deficiency or fibrinogen excess (including cutaneous vasculitis, scleroderma of Raynaud's disease, vasculitis of Behcet's disease, complications of deep vein thrombosis such as venous lipodermatosclerosis, other vascular disorders associated with these forms of reduced fibrinolytic activity, and prevention of recurrent venous thrombosis associated with anti-thrombin III deficiency); or
   6. Constitutional delay in growth (androgenic anabolic steroids); or
   7. Delayed male puberty (androgenic anabolic steroids); or
   8. Endometrial carcinoma (megestrol acetate); or
   9. Endometrial stromal sarcoma (low-grade) (megestrol acetate); or
   10. Endometriosis (danazol) (see CPB 0327 - Infertility); or
   11. Female to male gender reassignment; or
   12. Fibrocystic breast disease or mastalgia (danazol) (see CPB 0512 - Premenstrual Syndrome and Premenstrual Dysphoric Disorder); or
   13. Growth failure in children with growth hormone deficiency (treatment adjunct); or
   14. Hereditary angioedema; or
   15. Hypospadias (testosterone injection as pre-surgical adjuvant hormonal therapy); or
   16. Microphallus (androgenic anabolic steroids); or
   17. Primary hypogonadism (congenital or acquired) (androgens) in men with low serum testosterone (see appendix): testicular failure due to conditions such as cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomyFootnote1*, Klinefelter's syndrome, chemotherapy, or toxic damage from alcohol or heavy metals; or
   18. Hypogonadotropic hypogonadism (congenital or acquired) in men 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
   19. Refractory red cell production anemias (including aplastic anemia, myelofibrosis, myelosclerosis, agnogenic myeloid metaplasia, hypoplastic anemias caused by malignancy or myelotoxic drugs); or
   20. Severe burn injury; or
   21. To offset protein catabolism (as adjunctive therapy) associated with prolonged administration of corticosteroids; or
   22. To promote weight gain after weight loss (as adjunctive therapy) following cancer chemotherapy, extensive surgery, chronic infections, or severe trauma; or
   23. Uterine leiomyosarcoma that is estrogen and progesterone receptor (ER/PR) positive.

   Footnote1* Documentation of low serum testosterone is not required for persons with bilateral orchiectomy.

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).  

2. Testosterone undecanoate (Aveed)

   1. Criteria for Initial Approval

      Aetna considers testosterone undecanoate (Aveed) medically necessary for the following indications:

      1. Primary hypogonadism or hypogonadotropic hypogonadism when all of the following criteria are met:

         1. Member is a biological male or a person that self identifies as male; and
         2. Member is at least 18 years of age; and
         3. Member has at least two confirmed low morning serum total testosterone concentrations based on the reference laboratory range or current practice guidelines.

      2. Gender dysphoria when the member is able to make an informed decision to engage in hormone therapy. 

      Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

   2. Continuation of Therapy

      Aetna considers continuation of testosterone undecanoate (Aveed) therapy medically necessary for the following indications:

      1. Primary hypogonadism or hypogonadotropic hypogonadism - For members who are not currently receiving Aveed therapy through samples or a manufacturer’s assistance program, and member is a biological male or a person that self identifies as male, and member is at least 18 years of age. All other members (including new members) must meet all inital authorization criteria.
      2. Gender dysphoria for all members (including new members) who meet all initial authorization criteria.

Dosage and Administration

Aveed is available for injection as 750 mg/3 mL (250 mg/mL) testosterone undecanoate sterile injectable solution, single use vial. Aveed is for intramuscular use only. Dosage titration is not necessary. 

Primary hypogonadism (congenital or acquired) or Hypogonadotropic hypogonadism (congenital or acquired):

For adult males, the recommended dose of Aveed is 3 mL (750 mg) injected intramuscularly, followed by 3 mL (750 mg) injected after 4 weeks, then 3 mL (750 mg) injected every 10 weeks thereafter. 

Note: 

1. Safety and efficacy of Aveed in men with “age-related hypogonadism” (also referred to as “late-onset hypogonadism”) have not been established.
2. Safety and efficacy of Aveed in males less than 18 years old have not been established. 

Source: Endo Pharmaceuticals, 2020.

Experimental and Investigational

Aetna considers injectable androgens experimental and investigational for the treatment of female menopause because of insufficient evidence in the peer-reviewed literature.

Aetna considers androgen therapy experimental and investigational to improve live birth outcome in poor responders undergoing in-vitro fertilization/intra-cytoplasmic sperm injection treatment because of insufficient evidence.

Aetna considers androgens and anabolic steroids experimental and investigational as a treatment option for the following indications (not an all-inclusive list) because of insufficient evidence in the peer-reviewed literature:

1. androgen deficiency due to aging
2. chronic obstructive pulmonary disease
3. chronic pressure ulcers
4. idiopathic hypogonadism (not due to disorders of the testicles, pituitary gland or brain)
5. menopause (female or male)
6. rehabilitation after hip fracture.

Aetna considers testosterone undecanoate (Aveed) experimental and investigational for use in age-related hypogonadism or late-onset hypogonadism. 

Aetna considers testosterone injections experimental and investigational for the following indications (not an all-inclusive list) because of insufficient evidence in the peer-reviewed literature:

1. female sexual dysfunction/hypoactive sexual desire disorder
2. heart failure 
3. improvement of cognitive function in aging men
4. treatment of amyotrophic lateral sclerosis.

Aetna considers testosterone gel experimental and investigational for the improvement of cognitive function in aging men because of insufficient evidence in the peer-reviewed literature.

Background

Androgens and anabolic steroids include:

• Danazol
• Fluoxymesterone
• Megesterol acetate
• Methyltestosterone
• Oxandrolone
• Oxymetholone
• Stanozolol
• Testosterone.

Depot (slow-release) forms of testosterone include testosterone cypionate and testosterone undecanoate.

Testosterone is an endogenous androgen that is responsible for normal growth and development of male sex organs and sexual characteristics. 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.

Anabolic steroids are synthetic versions of testosterone. Testosterone stimulates and maintains the male sexual organs. It also stimulates development of bones and muscle, promotes skin and hair growth, and can influence emotions and energy levels. The anabolic properties of these agents are used in the clinical setting to manage various conditions.

Testosterone is Food and Drug Administration (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).

Testosterone should be administered only to a man who is hypogonadal, as evidenced by clinical symptoms and signs consistent with androgen deficiency and a distinctly subnormal serum testosterone concentration (Snyder, 2013). In comparison, increasing the serum testosterone concentration in a man who has symptoms suggestive of hypogonadism but whose testosterone concentration is already normal will not relieve those symptoms. The principal goal of testosterone therapy is to restore the serum testosterone concentration to the normal range. The role of testosterone replacement to treat the decline in serum testosterone concentration that occurs with increasing frequency above age 60 in the absence of identifiable pituitary or hypothalamic disease is uncertain.

Measurement of the serum testosterone concentration is usually the most important single diagnostic test for male hypogonadism because a low value usually indicates hypogonadism. Measurement of the serum total (free plus protein-bound) testosterone concentration is usually an accurate reflection of testosterone secretion. Interpretation of serum testosterone measurements should take into consideration its diurnal fluctuation, which reaches a maximum at about 8 AM and a minimum, approximately 70 percent of the maximum, at about 8 PM. It is easier to distinguish subnormal from normal when normal is higher, so the measurements should always be made at 8 AM. If a single 8 AM value is well within the normal range, testosterone production can be assumed to be normal. If a single 8 AM value is low or borderline low or does not fit with the clinical findings, the measurement should be repeated once or twice before making the diagnosis of hypogonadism.

Testing during acute illness or during a time of decompensation of chronic illness is not advised since testosterone levels may be temporarily depressed during such times (Hayes, 2015). Relevant chronic illnesses include coronary artery disease, heart failure, and diabetes. The recommended target of testosterone therapy is the middle of a normal range for healthy young men. Food, especially glucose ingestion, also decreases the serum testosterone concentration, so the blood should also be drawn fasting (Snyder, 2013).

Guidelines recommend that free or bioavailable testosterone be measured when total testosterone levels are close to the lower limit of the normal range (less than 400 ng/dL) and when altered SHBG levels are suspected, as may be the case in older men and men with obesity, diabetes mellitus, cachexia, malnutrition, advanced cirrhosis, acromegaly, hypothyroidism, or nephrotic syndrome (Hayes, 2015; ASRM, 2006).  

Following a determination of abnormally low serum testosterone, best practice requires measurement of serum LH and FSH levels to distinguish between primary (testicular) and secondary (pituitaryhypothalamic)hypogonadism, as well as other tests for possible causes of primary or secondary hypogonadism (Hayes, 2015). Additional laboratory tests and/or imaging are recommended for cases of secondary hypogonadism in order to evaluate etiology and exclude diagnoses such as pituitary neoplasia, hyperprolactinemia, hemochromatosis, obstructive sleep apnea, and genetic disorders. A karyotype is recommended for cases of primary hypogonadism of unknown etiology to rule out Klinefelter's syndrome.

In symptomatic men, regardless of age, testosterone levels are assessed by comparing them with the normal range for young men, based on the known gradual decline of testosterone levels with aging, starting at approximately age 30 years (Hayes, 2015). The lower limit of normal for healthy young men is 280 to 300 ng/dL (9.7 to 10.4 nmol/L). The panel assembled for the current Endocrine Society guidelines was divided between 2 options for symptomatic older men (Bhasin et al., 2010; Hayes, 2015):

• Treat only when levels of total testosterone are < 300 ng/dL (10.4 nmol/L) because of the association between testosterone at those levels and typical symptoms of androgen deficiency;
• Treatment only when levels of total testosterone are < 200 ng/dL (6.9 nmol/L) because randomized trials have suggested that testosterone therapy is ineffective in men with pretreatment values of 300 ng/dL. 

Free and bioavailable testosterone can be calculated by various formulas on the basis of total testosterone and SHBG assays (Hayes, 2015). There is no consensus regarding cutoff values for free or bioavailable testosterone, but a level of > 225 picomoles per liter (pmol/L) (6 ng/dL) is generally considered normal.

Measurement of salivary testosterone has been proposed as an alternative to serum testosterone, but measurement of salivary testosterone is not a standard practice (Hayes, 2015). 

In a prospective, double-blind, placebo-controlled, 16-week study, Sharma et al (2008) examined the benefits of anabolic steroids in patients with severe chronic obstructive pulmonary disease (COPD) who did not participate in a structured rehabilitation program.  Biweekly intra-muscular injections of either the drug (nandrolone decanoate) or placebo were administered.  A total of 16 patients with severe COPD were randomized to either placebo or nandrolone decanoate.  The placebo group weighed 55.32 +/- 11.33 kg at baseline and 54.15 +/- 10.80 kg at 16 weeks; the treatment group weighed 68.80 +/- 6.58 kg at baseline and 67.92 +/- 6.73 kg at 16 weeks.  Lean body mass remained unchanged, 71 +/- 6 kg versus 71 +/- 7 kg in placebo group and 67 +/- 7 kg versus 67 +/- 7 kg in treatment group, at baseline and 16 weeks respectively.  The distance walked oin 6 mins was unchanged at baseline, 8 weeks, and 16 weeks in placebo (291.17 +/- 134.83 m, 282.42 +/- 115.39 m, 286.00 +/- 82.63 m) and treatment groups (336.13 +/- 127.59 m, 364.83 +/- 146.99 m, 327.00 +/- 173.73 m).  No improvement occurred in forced expiratory volume in 1 second, forced vital capacity, maximal inspiratory pressure, maximal expiratory pressure, VO(2) max or 6-min walk distance or health related quality of life.  The authors concluded that administration of anabolic steroids (nandrolone decanoate) outside a dedicated rehabilitation program did not lead to either weight gain, improvement in physiological function, or better quality of life in patients with severe COPD.

It is interesting to note that while testosterone treatment improved body composition and sexual function in men with COPD in a 6-month trial, no improvement in pulmonary function was found (Svartberg et al, 2004). 

Miller and Btaiche (2009) stated that severe thermal injury is associated with hyper-metabolism and hyper-catabolism, leading to skeletal muscle breakdown, lean body mass loss, weight loss, and negative nitrogen balance.  Muscle protein catabolism in patients with severe thermal injury is the result of stress-induced increased release of cytokines and counter-regulatory hormones.  Coupled with decreased serum anabolic hormone concentrations such as testosterone and growth hormone along with the presence of insulin resistance, anabolism in patients with severe thermal injury is inefficient or impossible during the acute post-burn period.  This causes difficulty in restoring lean body mass and regaining lost body weight, as well as poor healing of the burn wound and delayed patient recovery.  Oxandrolone, a synthetic derivative of testosterone, has been used in adult patients with severe thermal injury to enhance lean body mass accretion, restore body weight, and accelerate wound healing.  In clinical studies, oxandrolone 10 mg orally twice-daily improved wound healing, restored lean body mass, and accelerated body weight gain.  During the rehabilitation period, oxandrolone therapy with adequate nutrition and exercise improved lean body mass, increased muscle strength, and restored body weight.  However, most data on oxandrolone use in adult patients with severe thermal injury were derived from single-center studies, many of which enrolled a relatively small number of subjects and some of which had a poor design.  The authors stated that multi-center, prospective, randomized studies are needed to better define the optimal oxandrolone dosage and to confirm the safety and effectiveness of this drug in adult patients with severe thermal injury.

Woerdeman and de Ronde (2010) stated that a variety of clinical conditions/diseases are complicated by loss of weight and skeletal muscle, which may contribute to morbidity and mortality.  Anabolic androgenic steroids have been demonstrated to increase fat-free mass, muscle mass and strength in healthy men and women without major adverse events and therefore could be beneficial in these conditions.  The authors provided an overview of clinical trials with anabolic androgenic steroids in the treatment of chronic diseases including HIV-wasting, chronic renal failure, COPD, muscular disease, alcoholic liver disease, burn injuries and post-operative recovery.  Relevant studies were identified in PubMed (years 1950 to 2010), bibliographies of the identified studies and the Cochrane database.  Although the beneficial effects of anabolic androgenic steroids in chronic disorders are promising, clinically relevant endpoints such as quality of life, improved physical functioning and survival were mainly missing or not significant, except for burn injuries.  The authors concluded that more studies are needed to confirm their long-term safety and effectiveness.

Oxandrolone, an anabolic steroid used to treat muscle wasting in HIV patients, is associated with decreased loss of lean body mass, improved wound healing compared with placebo, and decreased hospital stay in severe burn injury (Wolf et al, 2006).  However, oxandrolone may prolong the need for mechanical ventilation in trauma patients and can elevate serum transaminase levels. Oxandrin (oxandrolone) is inidcated as adjunctive therapy to promote weight gain after weight loss following extensive surgery, chronic infections, or severe trauma. It is also used as adjunct therapy to offset the protein catabolism associated with prolonged administration of corticosteroids (Savient, 2005).

Makinen and Huhtaniemi (2011) stated that normal testicular function is essential for the maintenance of male physical strength and behavior irrespective of age.  A new term of late-onset hypogonadism (LOH) has been coined for the condition of decreased testosterone and hypogonadal symptoms in aging men.  The most important testicular hormone, testosterone, is responsible for the gender-specific androgenic-anabolic effects in men.  Testicular production of testosterone remains stable until around the age of 40 years after which it declines by 1 to 2 % annually.  Despite this age-related decline, serum testosterone levels in most older men remain within the reference range of younger men.  The decreasing androgen levels are paralleled by well-defined objective biological and non-specific subjective signs and symptoms of aging.  Because these symptoms are similar to those observed in young men with documented hypogonadism, androgen replacement therapy (ART) has been considered a logical way to treat them.  These researchers conducted a thorough review of the existing literature to evaluate the current concepts and controversies related to aging men and ART.  Although it is intuitively logical that the symptoms of LOH are due to the aging-related deficiency of testosterone, and that they can be reversed by ART, the evidence for this is still variable and often weak.  In particular, evidence-based information about long-term benefits and risks of ART in aging men is largely missing.  The authors concluded that despite widespread use, evidence-based proof for the objective benefits and side effects of ART of elderly men is still scanty, and such treatments should be considered experimental.

Shelton and Rajfer (2012) noted that androgen deficiency in aging men is common, and the potential sequelae are numerous.  In addition to low libido, erectile dysfunction, decreased bone density, depressed mood, and decline in cognition, studies suggest strong correlations between low testosterone, obesity, and the metabolic syndrome.  Because causation and its directionality remain uncertain, the functional and cardiovascular risks associated with androgen deficiency have led to intense investigation of testosterone replacement therapy in older men.  Although promising, evidence for definitive benefit or detriment is not conclusive, and treatment of LOH is complicated.

The British Committee for Standards in Haematology’s guideline on “The diagnosis and management of myelofibrosis” (Reilly et al, 2012) provided the following recommendations:

• Danazol should be considered as a therapeutic option to improve the hemoglobin concentration of patients with myelofibrosis and transfusion-dependent anaemia (Evidence level 2, Grade B).
• Recommended starting dose is 200 mg daily, with a gradual dose escalation, depending on tolerability and patient weight (to a maximum of 600 mg daily for patients less than80 kg and 800 mg for patients greater than 80 kg) (Evidence level 2, Grade B).
• Patients should be treated for a minimum period of 6 months.  Responding patients should be maintained for a further 6 months on 400 mg daily before titrating down the dose to the minimum required in order to maintain a response (Evidence level 2, Grade B).

Toma et al (2012) stated that low testosterone is an independent predictor of reduced exercise capacity and poor clinical outcomes in patients with heart failure (HF).  These investigators examined if testosterone therapy improves exercise capacity in patients with stable chronic HF.  They searched Medline, Embase, Web of Science, and Cochrane Central Register of Controlled Trials (1980 to 2010).  Eligible studies included randomized controlled trials (RCTs) reporting the effects of testosterone on exercise capacity in patients with HF.  Reviewers determined the methodological quality of studies and collected descriptive, quality, and outcome data.  A total of 4 trials (n = 198; men, 84 %; mean age of 67 years) were identified that reported the 6-minute walk test (2 RCTs), incremental shuttle walk test (2 RCTs), or peak oxygen consumption (2 RCTs) to assess exercise capacity after up to 52 weeks of treatment.  Testosterone therapy was associated with a significant improvement in exercise capacity compared with placebo.  The mean increase in the 6-minute walk test, incremental shuttle walk test, and peak oxygen consumption between the testosterone and placebo groups was 54.0 m (95 % confidence interval [CI]: 43.0 to 65.0 m), 46.7 m (95 % CI: 12.6 to 80.9 m), and 2.70 ml/kg per min (95 % CI: 2.68 to 2.72 mL/kg per min), respectively.  Testosterone therapy was associated with a significant increase in exercise capacity as measured by units of pooled SDs (net effect, 0.52 SD; 95 % CI: 0.10 to 0.94 SD).  No significant adverse cardiovascular events were noted.  The authors concluded that given the unmet clinical needs, testosterone appears to be a promising therapy to improve functional capacity in patients with HF.  They stated that adequately powered RCTs are required to assess the benefits of testosterone in this high-risk population with regard to quality of life, clinical events, and safety.

Testosterone Undecanoate (Aveed)

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

• Aveed is indicated for testosterone replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone:

  • Primary hypogonadism (congenital or acquired): testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter’s syndrome, chemotherapy, or toxic damage from alcohol or heavy metals. These men usually have low serum testosterone concentrations and gonadotropins (follicle-stimulating hormone [FSH], luteinizing hormone [LH]) above the normal range.
  • Hypogonadotropic hypogonadism (congenital or acquired): gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency, or pituitary-hypothalamic injury from tumors, trauma, or radiation. These men have low testosterone serum concentrations but have gonadotropins in the normal or low range.
    
    
• Aveed should only be used in patients who require testosterone replacement therapy and in whom the benefits of the product outweigh the serious risks of pulmonary oil microembolism and anaphylaxis.
• Limitations of use:
  
  
  • Safety and efficacy of Aveed in men with “age-related hypogonadism” (also referred to as “late-onset hypogonadism”) have not been established.
  • Safety and efficacy of Aveed in males less than 18 years old have not been established.

Compendial Use

• Gender dysphoria (also known as gender non-conforming or transgender persons).

On March 6, 2014, the FDA approved testosterone undecanoate injectable (Aveed, Endo Pharmaceuticals) for the treatment of men with hypogonadism.  Aveed is a long-acting depot formulation of testosterone in castor oil and benzyl benzoate.  It offers a novel dosing schedule, with a single 3-ml (750 mg) intra-muscular injection given once at initiation of therapy, at 4 weeks, and then every 10 weeks thereafter.  The approval follows 3 previous rejections of Aveed by the FDA for safety and risk/benefit concerns and comes just a month after the FDA announced that it is investigating cardiovascular safety data for all testosterone preparations.  The FDA is requiring that Aveed's label contain a boxed warning regarding the risks of serious pulmonary oil micro-embolism (POME) and anaphylaxis and is making the product available only through a restricted distribution scheme known as a risk evaluation and mitigation strategy (REMS) to ensure that it is used only in men for whom the benefits out-weigh the risks. 

According to the Prescribing Information, Aveed (testosterone undecanoate) injection is indicated for testosterone replacement therapy in adult males (18 years and older) for primary hypogonadism (congenital or acquired) and hypogonadotropic hypogonadism (congenital or acquired).  The most common side effects of Aveed include acne, difficulty sleeping, feeling tired, increased estradiol level, increased prostate specific antigen, increased red blood cell count, irritability, low testosterone level, mood swings, and pain at the injection. 

Aveed should only be used in patients who require testosterone replacement therapy and in whom the benefits of the product outweigh the serious risks of pulmonary oil microembolism (POME) and anaphylaxis.

Aveed contains testosterone, a Schedule III controlled substance as defined by the Anabolic Steroids Control Act.  Aveed is administered via deep intramuscular injection. 

Because of the risks of serious POME reactions and anaphylaxis, Aveed is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Aveed REMS Program. Healthcare settings must be certified with the REMS Program and have healthcare providers who are certified before ordering or dispensing Aveed. Healthcare settings must have on‐site access to equipment and personnel trained to manage serious POME and anaphylaxis.

Safety and efficacy of Aveed in men with “age‐related hypogonadism” have not been established.

Prior to initiating Aveed, confirm the diagnosis of hypogonadism by ensuring that serum testosterone has been measured in the morning on at least two separate days and that these concentrations are below the normal range.

The European Federation of Neurological Societies’ guidelines on the clinical management of amyotrophic lateral sclerosis (Andersen et al, 2012) did not recommend testosterone for the treatment of amyotrophic lateral sclerosis because of insufficient evidence of its effectiveness.

In a parallel-group, placebo-controlled, randomized trial, Bauman et al (2013) examined if oxandrolone increases the percentage of target pressure ulcers (TPUs) that heal compared with placebo and whether healed ulcers remain closed 8 weeks after treatment.  A total of 1,900 patients were prescreened, 779 screened, and 212 randomly assigned inpatients with spinal cord injury (SCI) and stage III or IV TPUs.  Oxandrolone, 20 mg/d (n = 108), or placebo (n = 104) until the TPU healed or 24 weeks.  The primary outcome was healed TPUs.  The secondary outcome was the percentage of TPUs that remained healed at 8-week follow-up.  A total of 24.1 % (95 % CI: 16.0 % to 32.1 %) of TPUs in oxandrolone recipients and 29.8 % (CI: 21.0 % to 38.6 %) in placebo recipients healed (difference, -5.7 percentage points [CI: -17.5 to 6.8 percentage points]; p = 0.40).  At 8-week follow-up, 16.7 % (CI: 9.6 % to 23.7 %) of oxandrolone recipients and 15.4 % (CI: 8.5 % to 22.3 %) of placebo recipients retained a healed TPU (difference, 1.3 percentage points [CI: -8.8 to 11.2 percentage points]; p = 0.70).  No serious adverse events were related to oxandrolone.  Liver enzyme levels were elevated in 32.4 % (CI: 23.6 % to 41.2 %) of oxandrolone recipients and 2.9 % (CI: 0.0 % to 6.1 %) of placebo recipients (p < 0.001).  The authors concluded that oxandrolone showed no benefit over placebo for improving healing or the percentage of TPUs that remained closed after 8 weeks of treatment.

Anabolic Steroids for the Treatment of Pressure Ulcers

Naing and Whittaker (2017) stated that pressure ulcers, also known as bed sores, pressure sores or decubitus ulcers develop as a result of a localized injury to the skin or underlying tissue, or both.  The ulcers usually arise over a bony prominence, and are recognized as a common medical problem affecting people confined to a bed or wheelchair for long periods of time.  Anabolic steroids are used as off-label and have been used as adjuvants to usual treatment with dressings, debridement, nutritional supplements, systemic antibiotics and antiseptics, which are considered to be supportive in healing of pressure ulcers.  Anabolic steroids are considered because of their ability to stimulate protein synthesis and build muscle mass.  Comprehensive evidence is required to facilitate decision-making, regarding the benefits and harms of using anabolic steroids.  In a Cochrane review, these investigators evaluated the effects of anabolic steroids for treating pressure ulcers.  In March 2017, these researchers searched the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid Medline (including In-Process & Other Non-Indexed Citations); Ovid Embase and EBSCO CINAHL Plus.  They also searched clinical trials registries for ongoing and un-published studies, and scanned reference lists of relevant included studies as well as reviews, meta-analyses and health technology reports to identify additional studies.  There were no restrictions with respect to language, date of publication or study setting.  Published or un-published RCTs comparing the effects of anabolic steroids with alternative treatments or different types of anabolic steroids in the treatment of pressure ulcers.  Two review authors independently carried out study selection, data extraction and risk of bias assessment.  The review contains only 1trial with a total of 212 participants, all with spinal cord injury and open pressure ulcers classed as stage III and IV.  The participants were mainly men (98.2 %, 106/108) with a mean age of 58.4 (standard deviation 10.4) years in the oxandrolone group and were all men (100 %, 104/104) with a mean age of 57.3 (standard deviation 11.6) years in the placebo group.  This trial compared oxandrolone (20 mg/day, administered orally) with a dose of placebo (an inactive substance consisting of 98 % starch and 2 % magnesium stearate) and reported data on complete healing of ulcers and adverse events (AEs).  There was very low-certainty evidence on the relative effect of oxandrolone on complete ulcer healing at the end of a 24-week treatment period (RR 0.81, 95 % CI: 0.52 to 1.26) (down-graded twice for imprecision due to an extremely wide 95 % CI, which spanned both benefit and harm, and once for indirectness, as the participants were mostly male spinal cord injury patients).  Thus, these researchers were uncertain whether oxandrolone improved or reduced the complete healing of pressure ulcers, as they assessed the certainty of the evidence as very low.  There was low-certainty evidence on the risk of non-serious AEs reported in participants treated with oxandrolone compared with placebo (RR 3.85, 95 % CI: 1.12 to 13.26) (down-graded once for imprecision and once for indirectness, as the participants were mostly male spinal cord injury patients).  Thus, the treatment with oxandrolone may increase the risk of non-serious AEs reported in participants.  There was very low-certainty evidence on the risk of serious AEs reported in participants treated with oxandrolone compared with placebo (RR 0.54, 95 % CI: 0.25 to 1.17) (down-graded twice for imprecision due to an extremely wide 95 % CI, which spanned both benefit and harm, and once for indirectness, as the participants were mostly male spinal cord injury patients).  Of the 5 serious AEs reported in the oxandrolone-treated group, none was classed by the trial teams as being related to treatment.  These investigators were uncertain whether oxandrolone increased or decreased the risk of serious AEs as they assessed the certainty of the evidence as very low.  Secondary outcomes such as pain, length of hospital stay, change in wound size or wound surface area, incidence of different type of infection, cost of treatment and quality of life were not reported in the included trial.  Overall the evidence in this study was of very low quality (down-graded for imprecision and indirectness).  This trial stopped early when the futility analysis (interim analysis) in the opinion of the study authors showed that oxandrolone had no benefit over placebo for improving ulcer healing.  The authors concluded that there was no high quality evidence to support the use of anabolic steroids in treating pressure ulcers.  Moreover, they stated that further well-designed, multi-center trials, at low risk of bias, are needed to evaluate the effect of anabolic steroids on treating pressure ulcers, but careful consideration of the current trial and its early termination are needed when planning future research.

Androgens and Anabolic Steroids for the Treatment for Female Menopause

Cappelletti and Wallen (2016) stated that both estradiol and testosterone have been implicated as the steroid critical for modulating women's sexual desire.  By contrast, in all other female mammals only estradiol has been shown to be critical for female sexual motivation and behavior.  Pharmaceutical companies have invested heavily in the development of androgen therapies for female sexual desire disorders, but today there are still no FDA approved androgen therapies for women.  Nonetheless, testosterone is currently, and frequently, prescribed off-label for the treatment of low sexual desire in women, and the idea of testosterone as a possible cure-all for female sexual dysfunction remains popular.  These investigators placed the ongoing debate concerning the hormonal modulation of women's sexual desire within a historical context, and reviewed controlled trials of estrogen and/or androgen therapies for low sexual desire in post-menopausal women.  These studies demonstrated that estrogen-only therapies that produce peri-ovulatory levels of circulating estradiol increase sexual desire in post-menopausal women.  Testosterone at supra-physiological, but not at physiological, levels enhances the effectiveness of low-dose estrogen therapies at increasing women's sexual desire; however, the mechanism by which supra-physiological testosterone increases women's sexual desire in combination with an estrogen remains unknown.  Because effective therapies require supra-physiological amounts of testosterone, it remains unclear whether endogenous testosterone contributes to the modulation of women's sexual desire.  The authors concluded that the likelihood that an androgen-only clinical treatment would meaningfully increase women's sexual desire is minimal, and the focus of pharmaceutical companies on the development of androgen therapies for the treatment of female sexual desire disorders is likely misplaced.

Zhao and colleagues (2018) noted that higher androgen and lower estrogen levels are associated with cardiovascular disease (CVD) risk factors in women.  However, studies on sex hormones and incident CVD events in women have yielded conflicting results.  These investigators evaluated the associations of sex hormone levels with incident CVD, coronary heart disease (CHD), and heart failure (HF) events among women without CVD at baseline.  These researchers studied 2,834 post-menopausal women participating in the MESA (Multi-Ethnic Study of Atherosclerosis) with testosterone, estradiol, dehydroepiandrosterone, and sex hormone binding globulin (SHBG) levels measured at baseline (2000 to 2002).  They used Cox hazard models to evaluate associations of sex hormones with each outcome, adjusting for demographics, CVD risk factors, and hormone therapy use.  The mean age was 64.9 ± 8.9 years.  During 12.1 years of follow-up, 283 CVD, 171 CHD, and 103 HF incident events occurred.  In multivariable-adjusted models, the hazard ratio (HR; 95 % CI) associated with 1 SD greater log-transformed sex hormone level for the respective outcomes of CVD, CHD, and HF were as follows: total testosterone: 1.14 (95 % CI: 1.01 to 1.29), 1.20 (95 % CI: 1.03 to 1.40), 1.09 (95 % CI: 0.90 to 1.34); estradiol: 0.94 (95 % CI: 0.80 to 1.11), 0.77 (95 % CI: 0.63 to 0.95), 0.78 (95 % CI: 0.60 to 1.02); and testosterone/estradiol ratio: 1.19 (95 % CI: 1.02 to 1.40), 1.45 (95 % CI: 1.19 to 1.78), 1.31 (95 % CI: 1.01 to 1.70).  Dehydroepiandrosterone and SHBG levels were not associated with these outcomes.  The authors concluded that among post-menopausal women, a higher testosterone/estradiol ratio was associated with an elevated risk for incident CVD, CHD, and HF events, higher levels of testosterone associated with increased CVD and CHD, whereas higher estradiol levels were associated with a lower CHD risk.  Sex hormone levels after menopause were associated with women's increased CVD risk later in life.

Furthermore, an UpToDate review on “Treatment of menopausal symptoms with hormone therapy” (Martin and Barbieri, 2018) states that “The known decrease in ovarian androgen production rates and serum androgen concentrations has caused concern that menopause might be associated with a decline in libido.  An age-associated decline in sexual desire has been observed in both men and women.  However, it is unclear whether the decline in libido in women is age or menopause related, since studies in women have not shown a significant correlation between libido and the serum estradiol or testosterone concentration.  Clinical trials of exogenous testosterone replacement suggest modest benefits of testosterone therapy in some postmenopausal women.  However, there are potential risks associated with androgen replacement, and the use of testosterone is limited by the lack of approved and commercially available products for women.  Until the beneficial effects of androgen replacement are better established, it cannot be routinely recommended to postmenopausal women”.

Androgens for Women Sexual Desire Disorders

Reis and Abdo (2014) 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 phosphodiesterase type 5 inhibitors.  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.  After the advent of phosphodiesterase type 5 inhibitors, 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, the risks and benefits of testosterone administration have yet to be clarified.

Cappelletti and Wallen (2016) noted that both estradiol and testosterone have been implicated as the steroid critical for modulating women's sexual desire.  By contrast, in all other female mammals only estradiol has been shown to be critical for female sexual motivation and behavior.  Pharmaceutical companies have invested heavily in the development of androgen therapies for female sexual desire disorders (FSDDs), but today there are still no FDA-approved androgen therapies for women.  Nonetheless, testosterone is currently, and frequently, prescribed off-label for the treatment of low sexual desire in women, and the idea of testosterone as a possible cure-all for female sexual dysfunction remains popular.  These researchers placed the ongoing debate concerning the hormonal modulation of women's sexual desire within a historical context, and reviewed controlled trials of estrogen and/or androgen therapies for low sexual desire in post-menopausal women.  They noted that available studies demonstrated that estrogen-only therapies that produce peri-ovulatory levels of circulating estradiol increase sexual desire in post-menopausal women.  Testosterone at supra-physiological, but not at physiological, levels enhances the effectiveness of low-dose estrogen therapies at increasing women's sexual desire; however, the mechanism by which supra-physiological testosterone increases women's sexual desire in combination with an estrogen remains unknown.  Because effective therapies require supra-physiological amounts of testosterone, it remains unclear whether endogenous testosterone contributes to the modulation of women's sexual desire.  The authors concluded that the likelihood that an androgen-only clinical treatment will meaningfully increase women's sexual desire is minimal, and the focus of pharmaceutical companies on the development of androgen therapies for the treatment of FSDDs is likely misplaced.

Rehabilitation after Hip Fracture

In a Cochrane review, Farooqi and colleagues (2014) examined the effects (primarily in terms of functional outcome and adverse events) of anabolic steroids after surgical treatment of hip fracture in older people. These investigators searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (10 September 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2013 Issue 8), MEDLINE (1946 to week 4 of August 2013), EMBASE (1974 to week 36 of 2013), trial registers, conference proceedings, and reference lists of relevant articles.  The search was run in September 2013; RCTs of anabolic steroids given after hip fracture surgery, in in-patient or out-patient settings, to improve physical functioning in older patients with hip fracture were selected for analysis.  Two review authors independently selected trials (based on pre-defined inclusion criteria), extracted data and assessed each study's risk of bias.  A 3rd review author moderated disagreements.  Only very limited pooling of data was possible.  The primary outcomes were function (e.g., independence in mobility and activities of daily living) and adverse events, including mortality.  These researchers screened 1,290 records and found only 3 trials involving 154 female participants, all of whom were aged above 65 years and had had hip fracture surgery.  All studies had methodological shortcomings that placed them at high or unclear risk of bias.  Because of this high risk of bias, imprecise results and likelihood of publication bias, the authors judged the quality of the evidence for all primary outcomes to be very low.  These trials tested 2 comparisons; 1 trial had 3 groups and contributed data to both comparisons.  None of the trials reported on patient acceptability of the intervention.  Two very different trials compared anabolic steroid versus control (no anabolic steroid or placebo).  One trial compared anabolic steroid injections (given weekly until discharge from hospital or 4 weeks, whichever came first) versus placebo injections in 29 "frail elderly females".  This found very low quality evidence of little difference between the 2 groups in the numbers discharged to a higher level of care or dead (1 person in the control group died) (8/15 versus 10/14; risk ratio (RR) 0.75, 95 % CI: 0.42 to 1.33; p = 0.32), time to independent mobilization or individual adverse events.  The 2nd trial compared anabolic steroid injections (every 3 weeks for 6 months) and daily protein supplementation versus daily protein supplementation alone in 40 "lean elderly women" who were followed-up for 1 year after surgery.  This trial provided very low quality evidence that anabolic steroid may result in less dependency, assessed in terms of being either dependent in at least 2 functions or dead (1 person in the control group died) at 6 and 12 months, but the result was also compatible with no difference or an increase in dependency (dependent in at least 2 levels of function or dead at 12 months: 1/17 versus 5/19; RR 0.22, 95 % CI: 0.03 to 1.73; p = 0.15).  The trial found no evidence of between-group differences in individual adverse events.  Two trials compared anabolic steroids combined with another nutritional intervention ('steroid plus') versus control (no 'steroid plus').  One trial compared anabolic steroid injections every 3 weeks for 12 months in combination with daily supplement of vitamin D and calcium versus calcium only in 63 women who were living independently at home.  The other trial compared anabolic steroid injections every 3 weeks for 6 months and daily protein supplementation versus control in 40 "lean elderly women".  Both trials found some evidence of better function in the steroid plus group.  One trial reported greater independence, higher Harris hip scores and gait speeds in the steroid plus group at 12 months.  The 2nd trial found fewer participants in the anabolic steroid group were either dependent in at least 2 functions, including bathing, or dead at 6 and 12 months (1 person in the control group died) (1/17 versus 7/18; RR 0.15, 95 % CI: 0.02 to 1.10; p = 0.06).  Pooled mortality data (2/51 versus 3/51) from the 2 trials showed no evidence of a difference between the 2 groups at 1 year.  Similarly, there was no evidence of between-group differences in individual adverse events; 3 participants in the steroid group of 1 trial reported side effects of hoarseness and increased facial hair.  The other trial reported better quality of life in the steroid plus group.  The authors concluded that the available evidence is insufficient to draw conclusions on the effects, primarily in terms of functional outcome and adverse events, of anabolic steroids, either separately or in combination with nutritional supplements, after surgical treatment of hip fracture in older people.  Given that the available data pointed to the potential for more promising outcomes with a combined anabolic steroid and nutritional supplement intervention, the authors suggested that future research should focus on evaluating this combination.

Testosterone for the Improvement of Cognitive Function in Aging Men

Hua and colleagues (2016) stated that endogenous testosterone in the aging man has been scrutinized extensively in regard to its effects on performance in many cognitive domains, especially verbal fluency, visuo-spatial and visuo-perceptual abilities, memory, and executive function.  Studies of testosterone supplementation have sought to identify potential cognitive improvements in men with and without baseline cognitive impairment, and have had a wide range of results.  The variability in outcomes is likely related, in part, to the lack of consensus on methods for testosterone measurement and supplementation and, in part, to the disparate measures of cognitive function used in RCTs.  Despite the limitations imposed by such inconsistent methods, promising associations have been found between cognition and testosterone supplementation in both eugonadal men and men with low testosterone levels, with and without baseline cognitive dysfunction.  These investigators highlighted the cognitive measures used in and the outcomes of existing studies of testosterone and cognition in aging men.  The authors concluded that that larger studies and a more standardized approach to assessment are needed before one can fully understand and realize sustained benefits from testosterone supplementation in the elderly male population, especially given the substantial increase in testosterone supplementation in clinical practice.

Resnick and associates (2017) examined if testosterone treatment compared with placebo is associated with improved verbal memory and other cognitive functions in older men with low testosterone and age-associated memory impairment (AAMI).  The Testosterone Trials (TTrials) were 7 trials to evaluate the effectiveness of testosterone treatment in older men with low testosterone levels.  The Cognitive Function Trial evaluated cognitive function in all TTrials participants.  In 12 US academic medical centers, a total of 788 men who were 65 years or older with a serum testosterone level less than 275 ng/ml and impaired sexual function, physical function, or vitality were allocated to testosterone treatment (n = 394) or placebo (n = 394).  A subgroup of 493 men met criteria for AAMI based on baseline subjective memory complaints and objective memory performance.  Enrollment in the TTrials began on June 24, 2010; the final participant completed treatment and assessment in June 2014.  Participants received testosterone gel (adjusted to maintain the testosterone level within the normal range for young men) or placebo gel for 1 year.  The primary outcome was the mean change from baseline to 6 months and 12 months for delayed paragraph recall (score range of 0 to 50) among men with AAMI.  Secondary outcomes were mean changes in visual memory (Benton Visual Retention Test; score range of 0 to -26), executive function (Trail-Making Test B minus A; range of -290 to 290), and spatial ability (Card Rotation Test; score range of -80 to 80) among men with AAMI.  Tests were administered at baseline, 6 months, and 12 months.  Among the 493 men with AAMI (mean age of 72.3 years [SD, 5.8]; mean baseline testosterone, 234 ng/dL [SD, 65.1]), 247 were assigned to receive testosterone and 246 to receive placebo.  Of these groups, 247 men in the testosterone group and 245 men in the placebo completed the memory study.  There was no significant mean change from baseline to 6 and 12 months in delayed paragraph recall score among men with AAMI in the testosterone and placebo groups (adjusted estimated difference, -0.07 [95 % CI: -0.92 to 0.79]; p = 0.88).  Mean scores for delayed paragraph recall were 14.0 at baseline, 16.0 at 6 months, and 16.2 at 12 months in the testosterone group and 14.4 at baseline, 16.0 at 6 months, and 16.5 at 12 months in the placebo group.  Testosterone was also not associated with significant differences in visual memory (-0.28 [95 % CI: -0.76 to 0.19]; p = 0.24), executive function (-5.51 [95 % CI: -12.91 to 1.88]; p = 0.14), or spatial ability (-0.12 [95 % CI: -1.89 to 1.65]; p = 0.89).  The authors concluded that among older men with low testosterone and age-associated memory impairment, treatment with testosterone for 1 year compared with placebo was not associated with improved memory or other cognitive functions.

Testosterone Treatment and Increases in Cardiovascular Risk

Budoff and colleagues (2017) stated that recent studies have yielded conflicting results as to whether testosterone treatment increases cardiovascular risk.  In a double-blinded, placebo-controlled, multi-center trial, these researchers tested the hypothesis that testosterone treatment of older men with low testosterone slows progression of non-calcified coronary artery plaque volume.  Participants were 170 of 788 men aged 65 years or older with an average of 2 serum testosterone levels lower than 275 ng/dL (82 men assigned to placebo, 88 to testosterone) and symptoms suggestive of hypogonadism who were enrolled in the Testosterone Trials between June 24, 2010, and June 9, 2014.  Testosterone gel, with the dose adjusted to maintain the testosterone level in the normal range for young men, or placebo gel for 12 months.  The primary outcome was non-calcified coronary artery plaque volume, as determined by coronary computed tomographic angiography; secondary outcomes included total coronary artery plaque volume and coronary artery calcium score (range of 0 to greater than 400 Agatston units, with higher values indicating more severe atherosclerosis).  Of 170 men who were enrolled, 138 (73 receiving testosterone treatment and 65 receiving placebo) completed the study and were available for the primary analysis.  Among the 138 men, the mean (SD) age was 71.2 (5.7) years, and 81 % were white.  At baseline, 70 men (50.7 %) had a coronary artery calcification score higher than 300 Agatston units, reflecting severe atherosclerosis.  For the primary outcome, testosterone treatment compared with placebo was associated with a significantly greater increase in non-calcified plaque volume from baseline to 12 months (from median values of 204 mm3 to 232 mm3 versus 317 mm3 to 325 mm3, respectively; estimated difference, 41 mm3; 95 % CI: 14 to 67 mm3; p = 0.003).  For the secondary outcomes, the median total plaque volume increased from baseline to 12 months from 272 mm3 to 318 mm3 in the testosterone group versus from 499 mm3 to 541 mm3 in the placebo group (estimated difference, 47 mm3; 95 % CI: 13 to 80 mm3; p = 0.006), and the median coronary artery calcification score changed from 255 to 244 Agatston units in the testosterone group versus 494 to 503 Agatston units in the placebo group (estimated difference, -27 Agatston units; 95 % CI: -80 to 26 Agatston units).  No major adverse cardiovascular events occurred in either group.  The authors concluded that among older men with symptomatic hypogonadism, treatment with testosterone gel for 1 year compared with placebo was associated with a significantly greater increase in coronary artery non-calcified plaque volume, as measured by coronary computed tomographic angiography.  Moreover, they stated that larger studies are needed to understand the clinical implications of this finding.

Women Undergoing Assisted Reproduction

Sunkara and colleagues (2011) noted that many trials have evaluated the use of androgen supplements and androgen-modulating agents to improve outcome of poor responders undergoingin-vitro fertilization (IVF) treatment.  These investigators performed a systematic review and meta-analysis of controlled trials of androgen adjuvants (testosterone, dehydroepiandrostereone) and the androgen-modulating agent (letrozole) in poor responders undergoing IVF treatment.  Searches were conducted on MEDLINE, EMBASE, Cochrane Library, ISRCTN Register and ISI proceedings.  All randomized and non-randomized controlled trials were included.  Study selection, quality appraisal and data extraction were performed independently and in duplicate.  The main outcome measure was clinical pregnancy rate.  The secondary outcome measures were dose and duration of gonadotrophin use, cycles cancelled before oocyte retrieval, oocytes retrieved and ongoing pregnancy rates.  A total of 2,481 cycles in women considered as poor responders undergoing IVF/intra-cytoplasmic sperm injection (ICSI) treatment were included in 9 controlled trials.  Meta-analyses of these studies did not show any significant difference in the number of oocytes retrieved and ongoing pregnancy/live-birth rates with androgen supplementation or modulation compared with the control groups.  The authors concluded that there is currently insufficient evidence from the few randomized controlled trials to support the use of androgen supplementation or modulation to improve live birth outcome in poor responders undergoing IVF/ICSI treatment.

Szymusik and co-workers (2015) noted that despite the vast experience in controlled ovarian hyper-stimulation, there are still women who respond poorly to gonadotropins, which results in few oocytes at retrieval, reduced number of embryos for transfer and consequently unsatisfactory pregnancy rates. Although such patients are quite common in IVF practice, the exact prevalence of so-called "poor responders" is difficult to estimate due to the variety of applied definitions.  The urgent need for an internationally accepted definition of poor ovarian response (POR) was addressed by an ESHRE Workshop held in Bologna in 2010, where the consensus was reached and criteria were finally established.  The application of this uniform definition may allow a correct estimate of POR prevalence and, what is more important, designing proper trials to assess and finally compare the interventions used in POR patients.  These investigators described the possible physiology of POR and patient characteristics, mentioned risk factors and laboratory tests of decreased ovarian reserve.  They reviewed the possible management of POR with different stimulation protocols in the light of EBM.  Basing on published meta-analyses, various additional alternatives (such as estradiol priming, the addition of rLH, growth hormone, androgens and androgen-modulating agents, aspirin) were also summarized.  The authors concluded that despite the 2 decades of trying, there is still no consensus on what is best for POR.  No single treatment can be recommended over another, as the evidence for all of them is insufficient.  They stated that it is obvious that interventions used in POR require properly designed large randomized studies, because until now there is no evidence-based treatment for that particular group of patients.

In a Cochrane review, Nagels and associates (2015) evaluated the safety and effectiveness and of dehydroepiandrosterone (DHEA) and testosterone (T) as pre- or co-treatments in sub-fertile women undergoing assisted reproduction. These investigators searched the following electronic databases, trial registers and websites up to March 12, 2015: the Cochrane Central Register of Controlled Trials (CENTRAL), the Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, MEDLINE, EMBASE, PsycINFO, CINAHL, electronic trial registers for ongoing and registered trials, citation indexes, conference abstracts in the Web of Science, PubMed and OpenSIGLE.  They also carried out hand-searches; there were no language restrictions.  These researchers included RCTs comparing DHEA or T as an adjunct treatment to any other active intervention, placebo, or no treatment in women undergoing assisted reproduction.  Two review authors independently selected studies, extracted relevant data and assessed them for risk of bias.  They pooled studies using fixed-effect models, and calculated odds ratios (ORs) for each dichotomous outcome.  Analyses were stratified by type of treatment; there were no data for the intended groupings by dose, mode of delivery or after 1/more than 1 cycle.  These researchers assessed the overall quality of the evidence for the main findings using the GRADE working group methods.  This analysis included 17 RCTs with a total of 1,496 participants.  Apart from 2 trials, the subjects were women identified as “poor responders” to standard IVF protocols.  The included trials compared either T or DHEA treatment with placebo or no treatment.  When DHEA was compared with placebo or no treatment, pre-treatment with DHEA was associated with higher rates of live-birth or ongoing pregnancy (OR 1.88, 95 % CI: 1.30 to 2.71; 8 RCTs, n = 878, I² statistic = 27 %, moderate quality evidence).  This suggested that in women with a 12 % chance of live-birth/ongoing pregnancy with placebo or no treatment, the live-birth/ongoing pregnancy rate in women using DHEA will be between 15 % and 26 %.  However, in a sensitivity analysis removing trials at high risk of performance bias, the effect size was reduced and no longer reached significance (OR 1.50, 95 % CI: 0.88 to 2.56; 5 RCTs, n = 306, I² statistic = 43 %).  There was no evidence of a difference in miscarriage rates (OR 0.58, 95 % CI: 0.29 to 1.17; 8 RCTs, n = 950, I² statistic = 0 %, moderate quality evidence).  Multiple pregnancy data were available for 5 trials, with 1 multiple pregnancy in the DHEA group of 1 trial (OR 3.23, 95 % CI: 0.13 to 81.01; 5 RCTs, n = 267, very low quality evidence).  When T was compared with placebo or no treatment, the authors found that pre-treatment with T was associated with higher live-birth rates (OR 2.60, 95 % CI: 1.30 to 5.20; 4 RCTs, n = 345, I² statistic = 0 %, moderate evidence).  This suggested that in women with an 8 % chance of live-birth with placebo or no treatment, the live-birth rate in women using T will be between 10 % and 32 %.  On removal of studies at high risk of performance bias in a sensitivity analysis, the remaining study showed no evidence of a difference between the groups (OR 2.00, 95 % CI: 0.17 to 23.49; 1 RCT, n = 53).  There was no evidence of a difference in miscarriage rates (OR 2.04, 95 % CI: 0.58 to 7.13; 4 RCTs, n = 345, I² = 0 %, low quality evidence).  Multiple pregnancy data were available for 3 trials, with 4 events in the T group and 1 in the placebo/no treatment group (OR 3.09, 95 % CI: 0.48 to 19.98; 3 RCTs, n = 292, very low quality evidence).  One study compared T with estradiol and reported no evidence of a difference in live-birth rates (OR 2.06, 95 % CI: 0.43 to 9.87; 1 RCT, n = 46, very low quality evidence) or miscarriage rates (OR 0.70, 95 % CI: 0.11 to 4.64; 1 RCT, n = 46, very low quality evidence).  The quality of the evidence was moderate, the main limitations being lack of blinding in the included trials, inadequate reporting of study methods, and low event and sample sizes in some trials.  The authors concluded that in women identified as poor responders undergoing ART, pre-treatment with DHEA or T may be associated with improved live-birth rates.  The overall quality of the evidence was moderate.  The authors stated that there is insufficient evidence to draw any conclusions about the safety of either androgen; definitive conclusions regarding the clinical role of either androgen awaits evidence from further well-designed studies.

Appendix

The following are required to document androgen deficiency in men with primary hypogonadism (congenital or acquired) or hypogonadotropic hypogonadism (congenital or acquired)::

• Low serum testosterone 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 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 for reporting 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).

Table: 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 "+":
Other CPT codes related to the CPB:
80414	Chorionic gonadotropin stimulation panel; testosterone response
84270	Sex hormone binding globulin (SHBG)
84402	Testosterone; free
84403	total
84410	Testosterone; bioavailable, direct measurement (eg, differential precipitation)
96372	Therapeutic prophylactic or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
99506	Home visit for intramuscular injection
HCPCS codes covered if selection criteria are met:
J1071	Injection, testosterone cypionate, 1 mg
J2320	Injection, nandrolone decanoate, up to 50 mg
J3121	Injection, testosterone enanthate, 1 mg
J3145	Injection, testosterone undecanoate, 1 mg
S0179	Megestrol acetate, oral, 20mg
Other HCPCS codes related to the CPB:
J0702	Injection, betamethasone acetate 3mg and betamethasone sodium phosphate 3mg
J1020	Injection, methylprednisolone acetate, 20 mg
J1030	Injection, methylprednisolone acetate, 40 mg
J1040	Injection, methylprednisolone acetate, 80 mg
J1094	Injection, dexamethasone acetate, 1 mg
J1100	Injection, dexamethasone sodium phosphate, 1mg
J1720	Injection, hydrocortisone sodium succinate, up to 100 mg
J3300	Injection, triamcinolone acetonide, preservative free, 1 mg
J3301	Injection, triamcinolone acetonide, not otherwise specified, 10 mg
J3302	Injection, triamcinolone diacetate, per 5mg
J3303	Injection, triamcinolone hexacetonide, per 5mg
ICD-10 codes covered if selection criteria are met:
B20	Human immunodeficiency virus [HIV] disease
C50.011 - C50.929	Malignant neoplasm of breast
C54.1	Malignant neoplasm of endometrium
D25.0 - D25.9	Leiomyoma of uterus
D46.0 - D46.9 D47.01 - D47.09	Neoplasm of uncertain behavior of other lymphatic and hematopoietic tissues (e.g., myelosclerosis with myeloid metaplasia)
D60.0 - D61.9	Aplastic anemias
D63.0	Anemia in neoplastic disease
D63.1	Anemia in chronic kidney disease
D68.2	Hereditary deficiency of other clotting factors
D68.59	Other primary thrombophilia [antithrombin III deficiency]
D84.1	Defects in the complement system
D89.1	Cryoglobulinemia
E23.0	Hypopituitarism [hypogonadotropic hypogonadism]
E23.6	Other disorders of pituitary gland [covered for hypothalamic hypogonadism; not covered for idiopathic hypogonadism (not due to disorders of the testicles, pituitary gland or brain)]
E29.1	Testicular hypofunction
E30.0	Delayed puberty
F64.0 - F64.9	Gender identity disorders
E89.5	Postprocedural testicular hypofunction
I73.00 - I73.01	Raynaud's syndrome
I77.6	Arteritis, unspecified
I82.0 - I82.91	Other venous embolism and thrombosis
L90.0	Lichen sclerosus et atrophicus
L94.0	Localized scleroderma [morphea]
L94.1	Linear scleroderma
L94.3	Sclerodactyly
M35.2	Behcet's disease
N60.11 - N60.19	Diffuse cystic mastopathy
N64.4	Mastodynia [mastalgia]
N80.0 - N80.9	Endometriosis
Q54.0 - Q54.9	Hypospadias
Q55.62	Hypoplasia of penis
Q98.0 - Q98.4	Klinefelter's syndrome
R62.0 - R62.59	Lack of expected normal physiological development in childhood and adults
R63.4	Abnormal weight loss
T86.00 - T86.09	Complications of bone marrow transplant (e.g., graft-versus-host disease (acute) (chronic))
Z17.0	Estrogen receptor positive status [ER+]
Z79.52	Long term (current) use of systemic steroids
Numerous options	Third degree burns [Codes not listed due to expanded specificity]
ICD-10 codes not covered for indications listed in the CPB:
E28.310 - E28.319	Premature menopause
F52.0 - F52.9	Sexual dysfunction not due to a substance or known physiological condition
G12.21	Amyotrophic lateral sclerosis
J40 - J47.9	Chronic lower respiratory diseases
L89.000 - L89.95	Pressure ulcer of skin
N46.0 - N46.9	Male infertility
N50.9	Disorder of male genital organs, unspecified [male menopause]
N95.0 - N95.9	Menopausal and other perimenopausal disorders
N97.0 - N97.9	Female Infertility
R37	Sexual dysfunction, unspecified
R41.81	Age-related cognitive decline [improvement of cognitive function in aging men]
S72.001S - S72.26XS	Fracture of femur, sequela
Z78.0	Asymptomatic menopausal state
Z79.890	Hormone replacement therapy (postmenopausal)
Symptoms and Signs Suggestive of Androgen Deficiency in Men (See appendix Table 1A):
ICD-10 codes covered if selection criteria are met:
D64.9	Anemia, unspecified
E29.1	Testicular hypofunction [eunuchoidism] [shrinking testes]
E66.0 - E66.9	Overweight and Obesity
F32.9	Major depressive disorder, single episode, unspecified
F34.1	Dysthymic disorder
F52.21	Male erectile disorder
G47.9	Sleep disorder, unspecified
L63.0 - L65.9	Nonscarring hair loss, unspecified [loss of body (axillary and pubic) hair] [reduced shaving]
M62.81	Muscle weakness (generalized) [reduced muscle bulk and strength]
M62.89	Other specified disorders of muscle [reduced muscle bulk and strength]
M81.0 - M81.8	Osteoporosis
M84.30x+ - M84.38x+	Stress fracture [low trauma]
M84.40 x+ - M84.68x+	Pathological fracture [low trauma]
M85.80 - M85.9	Other specified disorders of bone density and structure
N46.0 - N46.9	Male infertility
N52.9	Male erectile dysfunction, unspecified
N62	Hypertrophy of breast
N64.4	Mastodynia
Numerous Options	Fractures [low trauma]
Q55.0	Absence and aplasia of testis
Q55.1	Hypoplasia of testis and scrotum [very small testes]
R23.2	Flushing
R29.890	Loss of height
R41.3	Other amnesia
R41.840	Attention and concentration deficit
R53.83	Other fatigue [decreased energy] [sleepiness]
R61	Generalized hyperhidrosis [sweats]
R63.5	Abnormal weight gain
R68.82	Decreased libido
R86.8	Other abnormal finding in specimens from male genital organs [low sperm count]
Z87.81	Personal history of (healed) traumatic fracture [low trauma]
Z87.311	Personal history of (healed) other pathological fracture [low trauma]
Z87.312	Personal history of (healed) stress fracture [low trauma]

The above policy is based on the following references: