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Recently, the use of testosterone replacement therapy (TRT) has received a lot of media attention. Although its use is growing, there is much debate regarding TRT’s risks and benefits.

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From 2008 to 2012 in the United States, spending on TRT increased from $1 billion to $2 billion, and from 2003 to 2013 there was a fourfold increase in the rate of TRT in men aged 18 to 45 years old.

This article will discuss appropriate TRT use, available formulations and cost, side effects, trends, and the pharmacist’s role in patient education.

Physiology

Testosterone, which is essential for the development and maintenance of organs and physiological functions in males, has many biological effects. In males, this hormone is produced by Leydig cells in the testes in response to luteinizing hormone from the pituitary gland.

In females, testosterone is made in the ovaries and adrenal glands and is an essential precursor to estrogen; it is associated with mood, sexual function, and bone health.

Indications and Other Uses

TRT in males with low concentrations of testosterone is controversial because this condition is often a normal sign of aging; testosterone concentrations in men naturally begin to decline at age 40 years, at an average of 1% to 2% per year.

Clinical hypogonadism, however, is an approved indication for TRT and is the only FDA-approved indication for TRT in men. The American Association of Clinical Endocrinologists (AACE) defines male hypogonadism as a decrease in testicular function (sperm or testosterone production) accompanied by signs or symptoms.

In women, additional FDA-approved indications include vasomotor symptoms of menopause (using a combination of esterified estrogens and methyltestosterone) and breast cancer.

Despite having only the abovementioned FDA-approved indications, TRT is often recommended by prescribers — based on a presumption of low testosterone — for sexual function, bone density, body composition, muscle strength, mood, behavior, and cognition.

Two areas of use that are beyond the scope of this article are TRT in sports — an ongoing controversy —and in female-to-male transgender patients.

Diagnosis

The Endocrine Society recommends that men with symptoms or signs of testosterone deficiency and consistently low serum testosterone concentrations be tested for hypogonadism.

The healthcare provider should confirm that the patient has low testosterone concentrations on at least two occasions and should evaluate associated signs and symptoms via questionnaire. Commonly used assessments for diagnosis of clinical hypogonadism include the Androgen Deficiency in the Aging Male questionnaire and the Aging Males’ Symptoms scale.

Confirmatory diagnosis is made via total testosterone, luteinizing hormone, and follicle-stimulating hormone concentrations. Circulating testosterone concentrations vary throughout the day, peaking in the early morning; therefore, fasting concentrations should be obtained between 8 am and 10 am.

Hypogonadism and Benefits of TRT

Hypogonadism is classified as primary, secondary, or mixed. In males, primary hypogonadism results from dysfunction of the testes; secondary hypogonadism results from dysfunction of the pituitary or hypothalamus. See the table below for a summary of laboratory values, causes, and symptoms of hypogonadism.

Hypogonadism in Men

    
Primary ↓Serum testosterone
↑LH (Luteinizing hormone)
↑FSH (Follicle-stimulating hormone)
Chromosomal abnormalities,
FSH/LH receptor mutations,
chemotherapy, hypothyroidism.
Reduced libido, erectile
dysfunction, alopecia, infertility, patological fracture, depressed mood, fatigue, reduced muscle mass, sleep disturbance, increased body fat, IDA (Iron deficiency anemia).
Secondary ↓Serum testosterone
N/↓LH
N/↓FSH
Genetic abnormalities,
Chronic opioid use,
hyperprolactinemia, pituitary
tumors, trauma.
Mixed↓Serum testosterone
Variable LH
Variable FSH
Aging, cancer, DM (diabetes mellitus), chronic glucocorticoid use, COPD (Chronic obstructive pulmonary disease), CKD (Chronic kidney disease), HIV/AIDS, obesity.

Most laboratory reference ranges for males report total testosterone concentrations <300 ng/dL as diagnostic, with a reference range of 300 ng/dL to 1,000 ng/dL.

In women, menopause-associated vasomotor symptoms result from thermoregulatory dysfunction, the vasomotor symptoms of menopause (e.g., hot flashes) associated with poor sleep, irritability, poor concentration, and decreased quality of life.

Hormone therapy with estrogen and progesterone is recommended for symptom management; however, treatment failure can lead to the recommendation to add TRT.

In a systematic review of 47 studies assessing sexual function, 23 studies reported beneficial effects for TRT, and 24 studies found no improvement in any sexual-function endpoint. In the studies with positive outcomes, the effect of testosterone was smaller than with phosphodiesterase type 5 inhibitors.

The American Urological Association states that although TRT can increase sexual interest, it has no significant influence on erectile function in men with normal testosterone concentrations. TRT has been shown to be effective for improving libido, sexual desire, arousal, sexual frequency, and sexual satisfaction in women.

TRT is also used in men with poor bone density, body composition, and muscle strength. Although osteoporosis is less common in men than in women, more than 8 million men in the U.S. have osteopenia or osteoporosis.

A low testosterone concentration reduces bone density and changes body composition. In middle-aged men with low testosterone concentrations, TRT increases bone density in the lumbar spine. In older men, TRT increases bone density in the spine and hip.

A small number of studies have reported mixed results for improved mood, vitality, and quality of life in aging men receiving TRT. Most studies used standard questionnaires to assess these factors. TRT has been demonstrated to improve symptoms of depression in men with hypogonadism and HIV/AIDS.

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TRT has been linked to effects on cognitive skills. Several small studies have had mixed results for cognition, some of them finding benefit in men with mild cognitive deficits or memory disorders such as Alzheimer’s disease (AD).

Risks of TRT

Risks and side effects of TRT include development or acceleration of prostate or breast cancer, development or worsening of benign prostatic hyperplasia, increased risk of polycythemia, development or worsening of acne, alopecia, gynecomastia, worsening sleep apnea, increased lower urinary tract symptoms (LUTS), and liver toxicity.

However, risks are not associated with the compulsory occurrence of side effects. If a patient holds to the prescribed dosage and follows a doctor’s recommendations, the risks of TRT are minimal.

It is important to obtain a thorough history and physical examination prior to initiating TRT. Absolute contraindications include breast cancer, polycythemia, prostate cancer, prostate-specific antigen (PSA) >4 ng/mL, and nodules upon digital rectal examination (DRE).

Monitoring

The American Association of Clinical Endocrinology guidelines suggests that testing be performed before a patient starts using a testosterone product.

Although there are no specific recommendations, the consensus is that testosterone concentrations be targeted to the mid-normal range of 400 ng/dL to 700 ng/dL.

A history and physical examination—including DRE (digital rectal exam) — and total serum testosterone, CBC (complete blood count), and PSA (prostate-specific antigen) should be performed at baseline, 3 to 6 months after therapy initiation, and then annually if stable.

A bone-density scan should be obtained at baseline and then annually, in addition to an annual mammogram and endometrial ultrasonography in women.

Conclusion

There are many uses for TRT, some of them acceptable and others under debate. It is important for pharmacists to keep abreast of the available literature in order to provide the best education for patients.

If you need more information concerning the use of TRT and your personal indications, please get in touch with our experts to learn more for free.