Testosterone Enanthate Injection

Number: 1015

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

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. Prescriber Specialties

   For gender dysphoria, the medication must 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 provider for members less than 18 years of age.

2. Criteria for Initial Approval

   Aetna considers intramuscular testosterone enanthate injection (generic Delatestryl) medically necessary for the following indications: (Note: The Delatestryl brand name has been discontinued in the U.S.; however, there is an FDA-approved generic equivalent available)

   1. Primary hypogonadism or hypogonadotropic hypogonadism when both of 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; and
      2. The requested drug is not being prescribed for age-related hypogonadism; or
         

   2. Gender dysphoria

      1. 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. The member has been informed of fertility preservation options; or
            

      2. In an adolescent member when all of the following criteria 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 has reached Tanner stage 2 of puberty or greater; and
         4. The member’s comorbid conditions are reasonably controlled; and
         5. The member has been educated on any contraindications and side effects to therapy; and
         6. The member has been informed of fertility preservation options.

   3. Inoperable metastatic breast cancer when both of the following criteria are met:

      1. Member is 1 to 5 years postmenopausal; and
      2. The member had an incomplete response to other therapy for metastatic breast cancer; or

   4. Premenopausal member with breast cancer when both of the following criteria are met:

      1. Member has benefited from oophorectomy; and 
      2. Member is considered to have a hormone-responsive tumor; or

   5. Delayed puberty.

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

3. Continuation of Therapy

   Aetna considers continuation of intramuscular testosterone enanthate injection therapy medically necessary for members with any of the following indications:

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

      1. Before the member started testosterone therapy, the member had a confirmed low morning testosterone level according to current practice guidelines or per standard lab reference values; and
      2. The requested drug is not being prescribed for age-related hypogonadism; or

   2. Gender dysphoria

      1. 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; or
            

      2. In adolescent members when all of the following criteria 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 has previously reached Tanner stage 2 of puberty or greater; and
         4. The member’s comorbid conditions are reasonably controlled; and
         5. The member has been educated on any contraindications and side effects to therapy; and
         6. Before the start of therapy, the member has been informed of fertility preservation options.

   3. For all other indications listed in Section II, member meets all initial selection criteria.

4. Related Policies

   For subcutaneous testosterone enanthate injection (Xyosted), see Pharmacy Clinical Policy Bulletin Testosterone - Testosterone Enanthate TGC PA Policy 1368-A.

   See also:

   1. CPB 0345 - Implantable Hormone Pellets
   2. CPB 0501 - Gonadotropin-Releasing Hormone Analogs and Antagonists
   3. CPB 0528 - Testosterone Undecanoate Injection (Aveed)
   4. CPB 0574 - Female Sexual Dysfunction (FSD)
   5. CPB 1014 - Testosterone Cypionate Injection (Depo-Testosterone).

Dosage and Administration

Testosterone Enanthate Injection, USP (generic Delatestryl) 200 mg/mL is available as 5 mL multiple dose vial, cartons of 1 vial, for deep gluteal intramuscular (IM) injection only. 

Primary or Hypogonadotropic Hypogonadism

Prior to initiating testosterone enanthate injection, diagnosis of hypogonadism should be confirmed by ensuring that serum testosterone concentrations have been measured in the morning on at least two separate days and that these serum testosterone concentrations are below the normal range.

Dosage and duration of therapy with testosterone enanthate injection will depend on age, sex, diagnosis, person's response to treatment, and appearance of adverse effects. 

In general, total doses above 400 mg per month are not required because of the prolonged action of the preparation. Injections more frequently than every two weeks are rarely indicated.

For replacement in the hypogonadal male, the recommended dose is 50 mg to 400 mg administered every 2 to 4 weeks.

Delayed Puberty

In males with delayed puberty: Various dosage regimens have been used; some call for lower dosages initially with gradual increases as puberty progresses, with or without a decrease to maintenance levels. Other regimens call for higher dosage to induce pubertal changes and lower dosage 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. Dosage is within the range of 50 to 200 mg every 2 to 4 weeks for a limited duration, for example, 4 to 6 months.

Palliation of Inoperable Mammary Cancer in Women

A dosage of 200 to 400 mg every 2 to 4 weeks is recommended. Women with metastatic breast carcinoma must be followed closely because androgen therapy occasionally appears to accelerate the disease.

Source: Hikma Pharmaceuticals, 2021

Experimental and Investigational 

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

• Age-related hypogonadism or late-onset hypogonadism
• Female sexual dysfunction / hypoactive sexual desire disorder
• Heart failure
• Improvement of cognitive function in aging men.

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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:
84402	Testosterone; free
84403	total
84410	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:
J3121	Injection, testosterone enanthate, 1 mg
ICD-10 codes covered if selection criteria are met:
C50.011 - C50.929	Malignant neoplasm of breast
E23.0	Hypopituitarism [Hypogonadotropic hypogonadism]
E29.1	Testicular hypofunction [not covered for age-related hypogonadism]
E30.0	Delayed puberty
F64.0 – F64.9	Gender identity disorders
ICD-10 codes not covered for indications listed in the CPB (not all inclusive):
F52.0	Hypoactive sexual desire disorder
F52.22	Female sexual arousal disorder
I50.1 – I50.9	Heart failure
R41.81	Age-related cognitive decline [improvement of cognitive function in aging men]

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Background

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

• Males

  • Testosterone Enanthate Injection (generic Delatestryl) is 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 testis syndrome, or orchiectomy.
    • Hypogonadotropic hypogonadism (congenital or acquired) - gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency, or pituitary-hypothalamic injury from tumors, trauma, or radiation. (Appropriate adrenal cortical and thyroid hormone replacement therapy are still necessary, however, and are actually of primary importance). If the above conditions occur prior to puberty, androgen replacement therapy will be needed during the adolescent years for development of secondary sexual 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 Delatestryl in men with “age-related hypogonadism” (also referred to as “late-onset hypogonadism”) have not been established.
    • Delayed puberty - Testosterone Enanthate Injection (generic Delatestryl) 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 obtained every six months to assess the effect of treatment on the epiphyseal centers.
      
      

• Females

  • Metastatic Mammary Cancer - Testosterone Enanthate Injection (generic Delatestryl) may be used secondarily in women with advancing inoperable metastatic (skeletal) mammary cancer who are one to five years postmenopausal. Primary goals of therapy in these women include ablation of the ovaries. Other methods of counteracting estrogen activity are adrenalectomy, hypophysectomy, and/or anti-estrogen therapy. This treatment has also been used in pre-menopausal women with breast cancer who have benefited from oophorectomy and are considered to a have a hormone-responsive tumor. Judgment concerning androgen therapy should be made by an oncologist with expertise in this field.

Compendial Uses 

• Gender dysphoria

Intramuscular Testosterone Enanthate Injection, USP (Hikma Pharmaceuticals USA Inc.), a Schedule III controlled substance, is an FDA-approved generic equivalent of Delatestryl. Delatestryl was discontinued in the United States; however, the branded generic remains available.  

Testosterone is an endogenous androgen which is responsible for normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include growth and maturation of the prostate, seminal vesicles, penis, and scrotum; the development of male hair distribution, such as facial, pubic, chest, and axillary hair; laryngeal enlargement, vocal cord thickening, 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. Male hypogonadism has two main etiologies, primary hypogonadism, which is caused by defects of the gonads, such as Klinefelter's Syndrome or Leydig cell aplasia, and secondary hypogonadism, which is the failure of the hypothalamus (or pituitary) to produce sufficient gonadotropins (FSH, LH).

Androgens are contraindicated in men with carcinomas of the breast or with known or suspected carcinomas of the prostate and in women who are or may become pregnant. When administered to pregnant women, androgens cause virilization of the external genitalia of the female fetus. This virilization includes clitoromegaly, abnormal vaginal development, and fusion of genital folds to form a scrotal-like structure. The degree of masculinization is related to the amount of drug given and the age of the fetus and is most likely to occur in the female fetus when the drugs are given in the first trimester. If the patient becomes pregnant while taking androgens, she should be apprised of the potential hazard to the fetus. This preparation is also contraindicated in patients with a history of hypersensitivity to any of its components (Hikma Pharmaceuticals, 2021).

Labeled warnings and precautions include the following:

• Hypercalcemia - In patients with breast cancer and in immobilized patients, androgen therapy may cause hypercalcemia by stimulating osteolysis. In patients with cancer, hypercalcemia may indicate progression of bony metastasis
• Development of peliosis hepatis and hepatic neoplasms including hepatocellular carcinoma with prolonged use of high doses of androgens. Peliosis hepatis can be a life-threatening or fatal complication.
• Lipid changes
• Geriatric patients treated with androgens may be at an increased risk for the development of prostatic hypertrophy and prostatic carcinoma
• Postmarketing reports of venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), have been reported in patients using testosterone products, such as testosterone enanthate injection.
• 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 testosterone enanthate injection.
• Abuse potential, typically at doses higher than recommended for the approved indication and in combination with other anabolic steroids. 
• Due to sodium and water retention, edema with or without congestive heart failure may be a serious complication in patients with preexisting cardiac, renal, or hepatic disease.
• Gynecomastia
• Adverse effects on bone maturation, may result in acceleration of bone age and premature closure of epiphyses in pediatric patients which may result in compromised adult stature. Monitor the effect on bone maturation by assessing bone age of the wrist and hand every 6 months.
• Women should be observed for signs of virilization (deepening of the voice, hirsutism, acne, clitoromegaly, and menstrual irregularities).

Male adolescent patients receiving androgens for delayed puberty should have bone development checked every six months.

The physician should instruct patients to report any of the following side effects of androgens:

• Adult or adolescent males: too frequent or persistent erections of the penis
• Women: hoarseness, acne, changes in menstrual periods, or more facial hair
• All patients: any nausea, vomiting, changes in skin color, or ankle swelling.

Geriatric patients: Clinical studies of testosterone enanthate did not include sufficient numbers of subjects, aged 65 and older, to determine whether they respond differently from younger subjects. Testosterone replacement is not indicated in geriatric patients who have age‑related hypogonadism only (“andropause”), because there is insufficient safety and efficacy information to support such use. Current studies do not assess whether testosterone use increases risks of prostate cancer, prostate hyperplasia, and cardiovascular disease in the geriatric population.

Nursing mothers: It is not known whether androgens are excreted in human milk.

Pediatric patients: Androgen therapy should be used very cautiously in pediatric patients and only by specialists who are aware of the adverse effects on bone maturation. Skeletal maturation must be monitored every six months by an X-ray of the hand and wrist.

The most common adverse reactions include the following:

• Endocrine and Urogenital, Female – amenorrhea and other menstrual irregularities, inhibition of gonadotropin secretion, and virilization, including deepening of the voice and clitoral enlargement. The latter usually is not reversible after androgens are discontinued. When administered to a pregnant woman, androgens cause virilization of the external genitalia of the female fetus.
• Male – Gynecomastia, and excessive frequency and duration of penile erections. Oligospermia may occur at high dosages.
• Skin and Appendages – Hirsutism, male pattern baldness, and acne.
• Cardiovascular Disorders – Myocardial infarction, stroke.
• Fluid and Electrolyte Disturbances – Retention of sodium, chloride, water, potassium, calcium, and inorganic phosphates.
• Gastrointestinal – Nausea, cholestatic jaundice, alterations in liver function tests; rarely, hepatocellular neoplasms, peliosis hepatis.
• Hematologic – Suppression of clotting factors II, V, VII, and X; bleeding in patients on concomitant anticoagulant therapy; polycythemia.
• Nervous System – Increased or decreased libido, headache, anxiety, depression, and generalized paresthesia.
• Metabolic – Increased serum cholesterol.
• Vascular Disorders – venous thromboembolism
• Miscellaneous – Rarely, anaphylactoid reactions; inflammation and pain at injection site.

Other Indications

Coronary Heart Disease / Heart Failure

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.

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.

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.

Female Sexual Dysfunction / Hypoactive Sexual Desire Disorder

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.

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.

Effects of Testosterone Treatment on Transgender Males

Korpaisarn et al (2021) noted that data regarding gender-affirming hormone therapy in the Asian population are sparse.  In a retrospective, single-center study, these investigators examined the safety and effectiveness of testosterone therapy in transgender men.  They carried out a chart review in a single university-based transgender clinic.  Transgender men aged 18 years or older who newly started testosterone therapy during January 2015 to October 2019 were recruited.  Physical changes, laboratory results, and adverse events (AEs), including cancer, thromboembolism, cardiovascular events, and death after masculinizing hormone therapy, were evaluated.  A total of 39 transgender men (mean age of 27.8 ± 6.0 years) were included.  All subjects were treated with intra-muscular testosterone injection with a mean follow-up of 25.2 ± 12.9 months.  The most common maintenance regimen was testosterone enanthate 250 mg every 4 weeks.  Masculinizing effects developed in all transgender men.  There were no changes in body weight, and systolic and diastolic blood pressure (SBP and DBP).  Hematocrit (Hct) levels were 12 % significantly increased from 39.9 % ± 3.3 % to 48.9 % ± 2 % (p < 0.001); 10 subjects (25.6 %) had Hct of greater than 50 %.  Significant changes were found in decreased fasting plasma glucose, increased creatinine, and increased uric acid levels.  A non-significant increase of alanine aminotransferase (ALT), increased low-density lipoprotein cholesterol (LDL-C), and decreased high-density lipoprotein cholesterol (HDL-C) were observed.  No thromboembolism, cancer, stroke, or coronary artery disease (CAD) occurred.  The authors concluded that gender-affirming hormone therapy was a safe and effective short-term treatment in Thai transgender men.  Apart from the standard recommendation, uric acid, plasma glucose, and creatinine level evaluation before and during masculinizing hormone therapy are rational practices.  An intra-muscular testosterone enanthate of 250 mg every 4 weeks was an alternative masculinizing regimen with decent safety and effectiveness profile.

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References