HIV and Testosterone Replacement

Testosterone deficiency is frequently seen in both men and women with HIV. Endocrine abnormalities, which can affect testosterone production, have long been recognized as a complication of HIV since the earliest days of the pandemic (although it has generally been associated with late-stage disease).

However, recent research has shown that nearly one out of every five men with HIV has documented testosterone deficiency, irrespective of CD4 count, viral load, or treatment status. Similarly, testosterone deficiency is seen in one in four HIV-positive women, most often in the context of severe, unexplained weight loss (HIV wasting).

The Role of Testosterone

Testosterone is the steroid hormone which is central to the development of the testes (testicles) and prostate in men as well as the promotion of secondary male sexual characteristics (e.g., lean muscle mass, bone mass, hair growth). Testosterone is also important to women in maintaining normal muscle and bone mass, although at levels around 10% less than men.

In both men and women, testosterone is essential to a person's overall health and well-being, contributing to an individual's strength, energy levels, and libido.

By contrast, testosterone depletion is associated with:

• Loss of lean muscle mass
• Anemia
• Osteoporosis
• Insulin resistance
• Increased lipids (fat and/or cholesterol) in the blood
• Increased subcutaneous fat in the abdomen

Testosterone Deficiency

Testosterone deficiency in men with HIV is largely associated with an endocrine abnormality called male hypogonadism in which the function of the male gonads (testes) is impaired, resulting in the diminished production of sex hormones beyond what would be expected of a man's specific age.

In the general population, hypogonadism is known to occur in about one in 25 men between the ages of 30 and 50, increasing to one in 14 between the ages of 50 to 79. By contrast, the incidence among men with HIV is as much as five times greater.

Hypogonadism can be caused by either a defect in the testes themselves (primary) or a dysfunction occurring outside of the testes (secondary). In adult males with HIV:

• Primary hypogonadism accounts for some 25 percent of cases. It can be caused by damage to the testes due to an infection (including some opportunistic infections), testicular cancer, or by physical trauma to the testes (although damage to a single testicle doesn't necessarily correlate to diminished testosterone production).
• Secondary hypogonadism accounts for the other 75 percent and is most often related to neuroendocrine disturbances in which the interaction between the nervous system and endocrine system is significantly impaired. Although there are rare cases of HIV causing damage to the pituitary gland, HIV itself does not cause the impairment. Rather, hypogonadism is observed in presence of many chronic illnesses, with persistent inflammation and nonspecific weight loss seen to be associative factors.

Hypogonadism can also be caused by childhood mumps or the abuse of anabolic steroids. HIV medications have not been shown to contribute to hypogonadism.

Symptoms

Hypogonadism in adult males is characterized by low serum (blood) testosterone levels, as well as one or several of the following symptoms:

• Muscle wasting
• Reduced energy and stamina
• Depression, irritability, difficulty concentrating
• Enlargement of breast tissue (gynecomastia)
• Decreased facial and body hair
• Increase in abdominal fat
• Loss of bone mass (osteoporosis)
• Testicular shrinkage
• Sexual dysfunction (e.g. erectile dysfunction, reduced ejaculate, low libido, difficulty attaining orgasm)

Testing and Diagnosis

Diagnosis is made by measuring the amount of testosterone in the blood, of which there are three different subtypes. When a test is performed, the results will reveal both a person's total testosterone (all subtypes) and one of the three subtypes called free testosterone.

Free testosterone is simply a type of testosterone to which no protein is attached, allowing it to enter cells and activate receptors that other subtypes can't. It is considered the most accurate measure of testosterone deficiency, despite representing only 2-3% of the total population. On its own, total testosterone is considered less accurate since results can appear normal if other non-free subtypes are elevated.

Testing should be performed early in the morning since levels can fluctuate by up to 20% during the course of a day. "Normal" levels are simply those within the reference range of the lab. These ranges can vary, but, for illustrative purposes, are roughly between

• 250-800 ng/dL for total testosterone, and
• 50-200 pg/mL for free testosterone.

However, an assessment of "normal" cannot be made by numbers alone. Testosterone levels tend to drop by about 1-2% every year after the age of 40. Therefore, what may be "normal" for a 60-year-old male won't be the same for a 30-year-old. Assessments need to be made on an individual basis with your treating healthcare provider.

Treatment

If a diagnosis of hypogonadism is confirmed, testosterone replacement therapy may be indicated. Intramuscular (IM) testosterone injections are usually recommended, which may offer lower side effects than other dosage forms. FDA-approved IM options include Depo-testosterone (testosterone cypionate) and testosterone enanthate.

On average, injections are given every one to two weeks. To avoid the effects of fluctuating testosterone levels—which can sometimes cause dramatic swings in mood, energy, and sexual function—lower doses and shorter dosing intervals are often used.

Side effects of treatment can include:

• Acne and/or oily skin
• Hair loss or thinning of hair
• Swelling of feet, ankles or body
• Sleep apnea
• Development of breast tissue (gynecomastia)
• Blood clots
• Enlargement of the prostate

Testosterone replacement therapy can also cause the acceleration of pre-existing prostate cancer. Because of this, a patient's prostate-specific antigen (PSA) levels will be tested and monitored during the course of therapy.

All told, intramuscular injections offer a cost-effective option for treating hypogonadism, with associative increases in alertness, well-being, libido, lean muscle mass, and erection ability. Disadvantages include regular healthcare provider visits and dosing administration.

Other options include oral agents like Kyzatrex, Jatenzo, and Tlando (testosterone undecanoate), transdermal, and topical gels, which may be applicable in certain cases. Discuss these with your healthcare provider.

Hypogonadism in HIV-Positive Women

In women, testosterone is produced in the ovaries and adrenal glands. As with men, it is an important hormone for maintaining normal muscle and bone mass, as well as energy, strength, and libido.

While hypogonadism is far less common in women with HIV, it can occur and is most often in the context of HIV wasting and advanced disease. The implementation of ART can reverse wasting and the hypogonadal state in many cases.

There are currently no fixed guidelines for the treatment of female hypogonadism, and treatment options are limited. ​Hormone replacement therapy (HRT) may be appropriate for some, while the short-term use of testosterone may improve sex drive, lean muscle mass, and energy levels.

However, data is still incomplete on the use of testosterone to treat hypogonadism in pre-menopausal women with HIV. Speak with your healthcare provider about possible side effects. Testosterone is not recommended for women who are pregnant or wish to become pregnant.