Androgen replacement therapy

Androgen replacement therapy (ART), often referred to as testosterone replacement therapy (TRT), is a class of hormone replacement therapy in which androgens, often testosterone, are replaced. ART is often prescribed to counter the effects of male hypogonadism. It typically involves the administration of testosterone, either by injection or by use of testosterone skin creams or gels. ART may also be prescribed to lessen the effects or delay the onset of normal male aging. However, this is controversial and is the subject of ongoing clinical trials, assessing the benefits and harms of its use in otherwise healthy older men. As men enter middle age they may notice changes caused by a relative decline in testosterone: fewer erections, fatigue, thinning skin, declining muscle mass and strength, more body fat. This dissatisfaction with the changes of aging has led to the development of the idea of androgen replacement therapy. Androgen replacement therapy is also used for men who have lost testicular function to disease, cancer, or other causes. For men who have had prostate cancer or at elevated risk, androgen replacement therapy remains controversial because some studies have shown that it increases the risk for prostate cancer; others refute that risk. Nonetheless, as of September 2014, testosterone replacement therapy has been under review for appropriateness and safety by the Food and Drug Administration due to the "potential for adverse cardiovascular outcomes".

Medical uses

Androgen replacement has a role in the treatment of hypogonadism, and may improve associated features such as low red blood cells, and fatigue.

In addition, a number of other effects of testosterone have led to research into possible therapeutic roles in:

• erectile dysfunction
• osteoporosis
• diabetes mellitus
• chronic heart failure
• dementia, but the evidence base is small and the balance of benefit needs to be clarified
• hormone replacement therapy for transgender men

Diabetes and testosterone

The risks of diabetes and of testosterone deficiency in men over 45 (i.e., hypogonadism, specifically hypoandrogenism) are strongly correlated. Testosterone replacement therapies have been shown to improve blood glucose management. Still, "it is prudent not to start testosterone therapy in men with diabetes solely for the purpose of improving metabolic control if they show no signs and symptoms of hypogonadism."

Management guidelines for diabetes developed by expert groups in Europe and the United States are to some extent at odds with more recent Canadian consensus guidelines.

Adverse effects

See also: Testosterone § Adverse effects

The Food and Drug Administration (FDA) stated in 2015 that neither the benefits nor the safety of testosterone have been established for low testosterone levels due to aging. The FDA has required that testosterone labels include warning information about the possibility of an increased risk of heart attacks and stroke.

Heart disease

On January 31, 2014, reports of strokes, heart attacks, and deaths in men taking testosterone-replacement led the FDA to announce that it would be investigating this issue. The FDA's action followed three peer-reviewed studies of increased cardiovascular events and deaths. Due to an increased rate of adverse cardiovascular events compared to a placebo group, a randomized trial stopped early. Also, in November 2013, a study reported an increase in deaths and heart attacks in older men. Even after a correction was published, the "Androgen Study Group", a group with many members who have relationships with drug companies in the testosterone market, requested JAMA to retract the article as misleading due to substantial residual errors. Concerns have been raised that testosterone was being widely marketed ahead of large randomized controlled trials. As a result of the "potential for adverse cardiovascular outcomes", the FDA announced, in September 2014, a review of the appropriateness and safety of testosterone replacement therapy.

Other

Other significant adverse effects of testosterone supplementation include acceleration of pre-existing prostate cancer growth in individuals who have undergone androgen deprivation; increased hematocrit, which can require venipuncture in order to treat; and, exacerbation of sleep apnea. Adverse effects may also include minor side-effects such as acne and oily skin, as well as, significant hair loss and/or thinning of the hair, which may be prevented with 5-alpha reductase inhibitors ordinarily used for the treatment of benign prostatic hyperplasia, such as finasteride or dutasteride. Exogenous testosterone may also cause suppression of spermatogenesis, leading to, in some cases, infertility. It is recommended that physicians screen for prostate cancer with a digital rectal exam and prostate-specific antigen (PSA) level before starting therapy, and monitor PSA and hematocrit levels closely during therapy.

Athletic use

There is the possibility of abuse: some athletes may demand far higher levels of androgen than normal in order to out-perform others, other people may feel they require greater doses in order to achieve what they perceive as a feeling of greater well-being. A UK study in 2013 showed that prescriptions for testosterone replacement, particularly transdermal products, almost doubled between 2000 and 2010.

History

Male hormones are called androgens from Greek words andro meaning man, and gen meaning giving birth to. Primary among them is the natural hormone testosterone, which is produced in the testes, ovaries and adrenals. Females also produce testosterone in the adrenals and as a precursor to estrogen, but the amount of circulating testosterone is generally far less than in males. Both sexes also produce an androgen precursor called dihydroepiandrostene (DHEAS) from which the body can make androgens. Androgens cause the secondary sex characteristics of males: facial hair, thicker skin, low body fat, deeper voice, muscularity, penis and scrotal growth and darkening, broad shoulders, body hair, erection of the penis, etc. With increasing age, testosterone production declines, and many of these changes start to reverse.

The decline with age in the physical characteristics of men has given rise to a term, andropause, derived from the term menopause. Menopause is literally defined as the permanent pausing of menstruation, but "menopause" as a medical rather than a physiological condition marks the decline of estrogen and, as with andropause, has given rise to medical treatments to avert such a lowering of the female hormone. Another term used is "progressive androgen deficiency of the aging male" (PADAM).

There are several artificial androgens, including nandrolone and various other manipulations of the testosterone molecule. Androgen replacement is administered by patch, tablet, pill, cream or gel; or depot injections given into fat or muscle.