Testosterone Replacement Therapy: New Modalities and Emerging Clinical Issues

At a symposium held in conjunction with the American Association of Clinical Endocrinologists annual meeting in Chicago, Illinois, four leaders in testosterone research and therapy presented the latest research on testosterone replacement therapy. Topics included how testosterone functions in the body, its role in osteopenia/osteoporosis, its central actions, and the risks associated with testosterone replacement therapy.

This program was supported by an unrestricted educational grant from Solvay Pharmaceuticals, Inc.

Anabolic Applications of Testosterone in Older Men and in Men with Chronic Illness

It is estimated that 4-5 million men in the United States are currently testosterone deficient. Many of these men are elderly and/or have a chronic illness that would benefit from increased muscle mass and function associated with testosterone replacement therapy. Surprisingly, only 5% of these hypogonadal men are currently being treated with testosterone. This low percentage is largely due to a poor understanding of testosterone’s therapeutic value. To educate clinicians on the testosterone’s effects on muscle mass, Shalender Bhasin, MD, professor of medicine at UCLA School of Medicine and chief of the Division of Endocrinology and Molecular Medicine at Charles R. Drew University of Medicine and Science in Los Angeles, California provided the audience with an overview of testosterone’s effect on muscle tissue in elderly men and in men with chronic illnesses.

Testosterone and Muscle Mass
As people age, lower testosterone levels leads to a decrease in lean body mass and an increase in fat mass. By the time men reach the age of 80 years, half of them will have sarcopenia (decreased muscle mass) leading to falls, fractures, disability, and a poor quality of life. Sarcopenia also is extremely common “in chronic illnesses such as end stage renal disease, HIV infection, chronic obstructive lung disease, and many types of cancers,” said Dr. Bhasin.

Studies in young hypogonadal men have shown that testosterone replacement is associated with an increase in fat-free mass and an increase in muscle size and muscle strength. Testosterone may also affect fat mass, but its effects are variable, depending on the patient population, age, duration of treatment, and the pre-treatment body composition.

Testosterone increases muscle mass by stimulating muscle protein synthesis. Preliminary data indicates that testosterone promotes myogenesis, “by promoting the differentiation of muscle stem cells into satellite cells in the myogenic lineage and it inhibits the differentiation of the stem cells into the adipogenic lineage,” stated Dr. Bhasin.

Testosterone Use in Chronically Ill Patients
Many chronically ill patients have sarcopenia, and it is of interest to determine if testosterone replacement therapy is beneficial in these patients. In one study, a replacement dose of testosterone (100 mg weekly) given to HIV infected men with low testosterone levels and low body weight, was associated with an 2.5–3.0 kg increase in lean body mass and significant gains in muscle strength. Dr. Bhasin summarized the study by saying, “testosterone replacement in HIV infected men with weight loss can promote weight and lean body mass restitution.” Similar improvements have been seen in patients with chronic obstructive pulmonary disease (COPD).

Testosterone Use in the Elderly
Several studies have shown testosterone supplementation produces modest gains in fat- free mass and decreases fat mass in older men with low normal testosterone, but “the effects on muscle strength and physical function have not been clearly demonstrated,” according to Dr. Bhasin.

In one study, testosterone replacement was associated with greater improvements in functional independence measures and grip strength. Similarly, other studies have shown that testosterone replacement supplementation improves the patient’s self-perception and quality of life. Dr. Bhasin stated, however, that these studies are generally not designed to accurately measure improvements in overall physical function and that further studies are needed.

In conclusion, testosterone supplementation increases fat- free mass and muscle strength. In chronically ill patients with weight loss, testosterone replacement can promote weight maintenance and lean body mass restitution, improve sense of energy, and reduce fatigue. In older men testosterone also improves muscle mass but its effects on physical function as well as in other health related outcomes remain largely unknown.

Treatment Effects on Younger and Older Males

In men over 50 years of age, 3 %–6% (1–2 million men) have osteoporosis. Furthermore, another 28–47% of these men may have osteopenia. These percentages translate into the incidence of orthopedic fractures in men over 60 being 2.2%, at a staggering cost of about $2.8 billion.

The exact role of testosterone on bone mass is difficult to assess. During puberty, growth is associated with increased testosterone levels but there also are increases in estradiol and growth hormone levels that influence growth. Individuals who are androgen deficient, though, do have reduced bone density. “Testosterone, its metabolite estradiol, or the combination is clearly important in terms of skeletal mass,” stated Glenn Cunningham, MD, professor of medicine, professor of molecular and cell biology, and vice chairman for research, Department of Medicine at Baylor College of Medicine, and executive of research service line at the VA Medical Center in Houston, Texas.

There have been numerous studies examining the relationship between testosterone levels and changes in bone density during aging. In the Framingham study, testosterone levels were not found to correlate with bone density measures. In contrast, estradiol levels were highly correlated with bone density. From this and other studies, it has been estimated that approximately 70% of testosterone’s effect on maintaining bone density is mediated through its conversion to estrogen and 30% by a direct action on androgenic receptors.

Testosterone Replacement Therapy
In a one-year trial by Dr. Kenny, a transdermal body testosterone patch led to minimal increase in bone density at the hip and femoral neck. In the placebo group, however, there was a continued deterioration of bone density. In another study (J. Tenover, personal communication), men over 65 years of age with testosterone levels of 350 ng/dL or less were randomly assigned to placebo, testosterone enanthate, or testosterone enanthate plus finasteride, and it was found that both testosterone-treated groups had very significant increases in bone density at the lumbar spine. A third study by Dr. Snyder involving men with testosterone levels up to 475 ng/dL (i.e., includes both low and low-normal testosterone levels), it was found that treatment with a scrotal testosterone patch found in men with normal testosterone levels caused very little change in bone density; whereas, men with low testosterone levels at baseline had significant increases in lumbar spine bone density.

In conclusion, testosterone therapy can have a beneficial effect on increasing bone density for hypogonadal men. As our population continues to age and the incidence of osteoporosis continues to rise, it is imperative that more studies be performed to determine the safest and most effective regimen.

Testosterone Effects on Mood and Cognitive Function

Alvin Matsumoto, MD, professor of Medicine at the University of Washington School of Medicine and Associate Director of the Geriatric Research, Education and Clinical Center and director of the Clinical Research Unit at VA Puget Sound Health Care System in Seattle, Washington began his presentation by saying that testosterone is well recognized as a potent brain neuromodulator. In the brain, testosterone and its metabolite dihydrotestosterone can stimulate androgen receptors, and test-osterone’s conversion to estradiol can stimulate estrogen receptors. Dr. Matsumoto also pointed out that all of the conversion enzymes and receptors are highly concentrated in the cortex, the limbic system, medial temporal lobe, hippocampus and hypothalamus, areas of brain that are important in neuroendocrine control of reproductive function and regulation of mood and cognitive function.

Dr. Matsumoto divided testosterone’s central actions into permanent and modulatory effects. Permanent or organizational effects refer to the permanent brain structural effects that often occur early in development. These are responsible for structural and functional sexual dimorphism in the brains of men and women. During adulthood, however, changes in testosterone tend to be modulatory, or activational. For example, “if someone were to acquire testosterone deficiency as an adult, they may lose some brain function,” said Dr. Matsumoto, adding “and if you replace testosterone, the lost brain function would be improved.”

Testosterone and Mood
To date, there are very few studies that have examined the role of testosterone on mood. In patients with mild hypo-gonadism, common symptoms include dysphoria, increased irritability, as well as decreased libido, energy, vigor, concentration, confidence, and motivation. “There’s a body of thinking, at least in the psychiatric literature, that low testosterone is not associated with major depression but it is with milder depression or dysthymia,” stated Dr. Matsumoto. In a study examining the effect of testosterone in hypogonadal men it was found that testosterone increased positive moods (i.e., energy, well-being, friendliness, relationships) and decreased negative moods (i.e., irritability, anger, sadness). In contrast, in one controlled study, testosterone replacement therapy in hypogonadal men with major depression results in no significant changes in mood.

In elderly patients, the effect of testosterone on mood is inconclusive, but Dr. Matsumoto said that in general, testosterone appears to improve well- being and energy in hypogonadal elderly men. In an epidemiological study, testosterone levels correlated inversely with depression scores.

Testosterone and Cognition
Dr. Matsumoto acknowledged “there has been a positive correlation between testosterone levels and spatial abilities or spatial cognition,” but further stated, “at very high doses there appears to be a negative correlation.” In one large epidemiological study, testosterone levels were positively correlated with verbal memory, mental control, and visual spatial ability. In a preliminary study looking at the mechanism of action of testosterone on cognition it was found that when the aromatization of testosterone to estradiol was blocked, testosterone had no effect on verbal memory effects but did improve spatial memory. While data is limited, Dr. Matsumoto concluded that testosterone acting as an androgen affects spatial memory while testosterone’s conversion to estradiol affects verbal memory.

In conclusion, testosterone has beneficial effects on some aspects of mood. Testosterone also affects visual, spatial, and verbal cognition. While these studies are promising, more placebo-controlled trials are needed.

Potential Adverse Effects of TRT and Guidelines for Monitoring

Only 5% of men with hypogonadism actually undergo treatment. “In part, this is because many healthcare providers don’t know what the rules are — when is it safe to give testosterone and when is it not? And, there are a number of misconceptions in the medical community regarding testosterone usage,” said Abraham Morgentaler, MD, Director of the Men’s Health Boston and Associate Clinical Professor of Surgery (Urology) at Harvard Medical School in Boston, Massachusetts. Testosterone replacement therapy is indicated in a variety of clinical situations, the most common involving sexual dysfunction and diminished libido. Dr. Morgentaler is convinced that many men go untreated simply because physicians are not yet comfortable with testosterone replacement therapy and tend to err on the side of caution.

The Alleged Risks of Testosterone Replacement Therapy
Dr. Morgentaler provided the audience with a list of risks, both actual and fictitious, that are associated with testosterone therapy. He then proceeded to discuss each risk in detail to educate the audience on how each risk should be managed to safely and effectively use testosterone replacement therapy.

Liver toxicity
Most testosterone is given by intramuscular injections or by topical application. Liver toxicity does not occur with these regimens. Oral testosterone agents do carry a risk of hepatotoxicity and are also not recommended due to poor efficacy.

Lipids
Data on cholesterol are conflicting but it appears that testosterone does not increase cholesterol levels. “If anything, a small beneficial effect occurs, and if there’s a negative effect in the studies, those effects have been relatively mild,” said Dr. Morgentaler.

Cardiac
Much of the concern regarding possible cardiac problems and testosterone is based on the observation that men are at greater risk than women of suffering a myocardial infarction, with the implicit assumption that this must be related to higher testosterone levels in men. However, well-controlled trials have shown “there is no compelling data that testosterone itself directly contributes to cardiac disease or cardiac events in men,” stated Dr. Morgentaler.

Edema
Mild fluid retention may occur following testosterone therapy. Most of the time this is unnoticed but Dr. Morgentaler told the audience that testosterone should be used cautiously in men with renal problems.

Sleep apnea
Sleep apnea may be exacerbated with testosterone therapy.

Erythrocytosis
Testosterone is a growth factor for erythropoiesis. As such, testosterone therapy is helpful for anemic men with low testosterone. In men with normal hemocrits with low testosterone, a significant proportion of these men will develop elevated hematocrits. This is especially true if they are given intramuscular injections. If hemocrit levels are high, the best solution may be to simply ask the patient to donate blood or to undergo therapeutic phlebotomy. If not, treatment may be temporarily discontinued, or the dose reduced.

Benign prostate hyperplasia
In older men, testosterone can increase the size of the prostate. As a urologist, however, Dr. Morgentaler said that size does not matter, only symptoms. “We sometimes find men who have enormous prostates who have very little symptoms. We don’t treat them as long as we’re sure that they don’t have cancer,” acknowledged Dr. Morgentaler. Clinicians should discuss the symptoms of benign prostatic hyperplasia (i.e., increased frequency, slower stream) with their patients and should be alert to worsening symptoms with treatment.

Prostate cancer
The most common fear regarding testosterone therapy among clinicians is that treatment will ‘cause’ cancer. Testosterone does not cause cancer but a legitimate concern is that treatment may cause a hidden prostate cancer to grow. Therefore, it is important to adequately assess the prostate.

Prior to beginning testosterone therapy, Dr. Morgentaler said “monitor the men with PSAs and digital rectal exams and you have to have a low threshold for doing a biopsy.” If the patient shows abnormal PSA or abnormal digital rectal exam, a biopsy needs to be performed. Once testosterone therapy has begun, a biopsy should be done if there is any significant change in PSA or digital rectal exam.

Conclusion
Dr. Morgentaler concluded his presentation by stating, “the risks of testosterone replacement therapy are by and large known, and I think they’re really quite manageable. With proper monitoring I think testosterone treatment is a very safe and valuable modality.” Dr. Morgentaler also hoped that the presentations at this symposium were helpful to educate clinicians on the risks and benefits of testosterone therapy and asked the audience to “go back to your communities, to your hospitals, to your groups and be somebody who is comfortable with testosterone supplementation, who is aware of what the risks are and are not, and become a resource for your local area because your patients, 95 percent of them, aren’t getting treatment and you can change that.”

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