The Impact of Low Testosterone in Chronic Diseases

At an industry-sponsored seminar held in conjunction with the American Association of Clinical Endocrinologists’ 2003 Annual Meeting and Clinical Congress, three leaders in the diagnosis and treatment of testosterone disorders presented the latest information on the prevention or reversal of aspects of hypogonadism through testosterone replacement therapy. Topics included why there is a need to treat hypogonadism, the benefits of testosterone replacement on diabetes, lipids and cardiovascular disease and the possible connections between androgens, benign prostatic hyperplasia and prostate cancer.

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

Why Do We Need to Treat Hypogonadism?

It is estimated that 4 to 5 million men in the United States are hypogonadal, but only 5% of them have been identified and treated. The anticipated aging of the male population could mean even greater increases in these numbers during the next 30 years.

“Aging is associated with a progressive decline in the levels of total and free testosterone,” said Marc R. Blackman, MD, Scientific Director for Clinical Research, National Center on Complementary and Alternative Med-icine, National Institutes of Health, Bethesda, MD.

Dr. Blackman and colleagues evaluated circulating androgen levels, cross-sectionally and longitudinally, in nearly 900 healthy men evaluated for up to 33 years as part of the Baltimore Longitudinal Study on Aging. There was an age-invariant decline in total and free testosterone levels from age 30 through the 80s (Harman SM, et al. J Clin Endocrinol Metab. 2001; 86:724).

Between the seventh and ninth decades, the frequency of low testosterone in this particularly large cohort of healthy men rose from 20% to 50% while levels of low free testosterone rose from 40% to 90%.

“One of the concerns to be addressed from this information is the need to age-adjust both total and free testosterone levels,” Dr. Blackman. “Currently norms are derived from much younger men and should be recast in age appropriate terms.”

There are many age-related changes in physiological functioning that may be related to dropping testosterone levels. These include such things as changes in lean and fat body mass, bone density, cognition, mood, psychosexual functioning, strength and energy.

A morning total testosterone level <300 nanograms/deciliter is the value Dr. Blackman suggested as a cut-off for suspecting a man might be hypogonadal. Testosterone status can also be measured using free or bioavailable testosterone levels. However, due to many confounding factors, physicians and endocrinologists are looking at optimal methods for assessing total and free testosterone in aged men.

The next component of evaluation is to determine whether low testosterone results from primary (testis-related) or secondary (hypothalamic and/or pituitary) or combined deficiencies. This is accomplished by measuring the levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH and/or FHS tend to be elevated in primary and not elevated in secondary or combined hypogonadism. Measuring prolactin levels is often useful, because of the somewhat higher frequency of hyperpro- lactinemia in older men.

“The potential benefits of testosterone replacement therapy include maintenance and restoration of secondary sexual characteristics, positive changes in libido and erectile function, improvements in energy and mood as well as increased muscle and bone mass,” said Dr. Blackman. “The big question mark relates to the effects testosterone replacement on the incidence of fractures, cardiovascular disease, general functional status and safety, including development of prostate cancer.”

One of the problems with assessing response to these treatments is that most of the target symptoms are multi-factorial. For example, sexual activity problems can be related to vascular changes, depression, and reasons other than low testosterone.

Unpublished observations from Dr. Lisa Tenever looked at placebo versus intramuscular (IM) testosterone injections vs. IM injections plus finasteride over three years. At the end of the study, those men in the groups receiving testosterone had significant improvements in indices of sexual activity and general energy. Although interesting, these data have not yet been published in a peer-reviewed journal.

With advancing age, the frequency of frank depression increases. Elizabeth Barret-Connor has shown an inverse relationship between the Beck Depression Inventory (BDI) and testosterone levels in aged men. When men have low testosterone they have higher BDI scores and are more depressed (Barret-Connor E, et al. J Clin Endocrinol Metab. 1999;84: 573).

This led Drs. Swerdloff and Wang to undertake a number of studies. They have consistently shown that daily mood records of hypogonadal men show a mood-enhancing effect from testosterone replacement. In addition to the increase in indices of positive moods, there were decreases in negatives including anger (Swerdloff RS, et al. J Clin Endocrinol Metab. 1996:81:3578).

Cognitive function measures are not as consistent. It has been shown that serum testosterone or pre-testosterone correlates with various indices of cognitive function, especially spatial relations. Androgen replacement improved spatial ability but had no effect on memory or verbal fluency.

“It has been known for many years that as we advance in age, although weight doesn’t change much, the pie is sliced differently,” said Dr. Blackman. “It is not that the pie becomes larger, rather we lose lean body mass and gain fat.”

Low testosterone is related to an increase in total adiposity. A series of studies by Snyder, et al compared placebo and the Testoderm testosterone patch. Over three years, men who received testosterone had a substantial and progressive decrease in absolute and percent total fat as assessed by dual energy X-ray absorptiometry (DEXA) scans. These same men had an increase in the absolute and percent amount of lean body mass (Snyder P, et al.J Clin Endocrinol Metab. 1999;84:2647).

“We still do not know if testosterone supplementation actually improves physical functioning,” said Dr. Blackman. “We also don’t know if there are reductions in the risk of falls, fractures or other health-related outcomes.”

In men, as in women, aging is associated with a progressive decrease in bone mineral density (BMD). The age-specific changes in the risk for fractures differ between the two genders, with a shift of 10 years later in men.

Another study by Snyder and colleagues showed that a 36-month course of testosterone supplementation versus placebo had no treatment effect on BMD at the lumbar spine as measured by DEXA. However, when Dr. Snyder looked at the relationship between baseline testosterone and the likelihood of increasing BMD in the spine, pre-treatment levels of 200 nanograms/dl or less significantly increased spinal BMD. Those over that level did not show significant changes (Snyder PJ, et al. J Clin Endocrinol Metab.1999:84:1966).

Dr. Tenever’s unpublished study suggests that at the end of the first six months, and at every 180-day interval after that during the three-year follow-up, the men receiving testosterone had significant increases in BMD in the spine. This was across the spectrum and not just those with low baselines. In addition, there was a significant increase in bone marrow density in the hip.

“Our goal is to increase the number and quality of life of individuals in both the ‘young old’ and ‘old, old’ demographic classifications,” said Dr. Blackman.

Benefits of Testosterone Replacement on Diabetes, Lipids & Cardiovascular Disease

As men age, their physicians become more concerned about issues related to coronary artery disease (CAD). In those patients with testosterone deficiency, additional questions arise concerning the impact of testosterone deficiency or its treatment on the incidence of CAD.

“We know that men are more susceptible to CAD in an age-related fashion and the risks are between 2- to 4-fold above that seen in females over a wide age spectrum,” said Ronald L. Swerdloff, MD, Professor and Associate Chair of Medicine at the UCLA School of Medicine. “Since CAD is the primary cause of death in our population, it becomes reasonable to wonder if this is related to gender differences in hormone concentration.”

Epidemiological data do not help clear the picture, noted Dr. Swerdloff. A meta-analysis of published studies found roughly half suggested a decrease in testosterone results in an increased risk of CAD. There are as many others that show no relationship.

“There have been a number of prospective, cohort, nested case-control studies that failed to show that increased testosterone is a causal factor for CAD,” said Dr. Swerdloff. “Taken together, the epidemiological studies suggest that either testosterone is cardioprotective or neutral. Very few of the data suggest that testosterone is a cardiac risk factor.”

It is well established that testosterone replacement returns muscle and fat mass toward normal and that pharmacological doses have an even greater effect on body composition. It is also known that an increase in fat mass in a risk factor for CAD. The question then becomes: Does testosterone replacement impact on CAD?

To address this question Bhasin and colleagues treated a group of normal individuals with a gonadotropin releasing hormone (GnRH) agonist, suppressing testosterone to very low levels. They replaced the hormone using injectable testosterone over a very wide range of doses.

They found a dose-related increase in muscle mass. There was also a dose-related change in fat mass with a neutral effect at physiological replacement levels, less fat mass as doses increased and the opposite effect at lower doses (Bhasin S, et al. Am J Physiol Endocrinol Metab. 2001;281:E1172).

While pharmacological doses of testosterone will lower HDL cholesterol, the effects of testosterone replacement treatment are less clear for several reasons. One is that there are certain effects on various lipoproteins that may be beneficial. The hormone also lowers fibrinogen with positive effects on plasminogen activator. It is important to remember that studies of physiological replacement of testosterone in all age groups have not seen any significant changes in LDL cholesterol with the possible exception of a trend toward reduction.

“The issue of serum testosterone and diabetes is a very complicated one,” said Dr. Swerdloff. “Diabetic men in general have low serum testosterone values. There is little evidence to link testosterone to insulin secretion, insulin resistance and incidence of diabetes outside its known impacts on body composition.”

The effects of testosterone on vascular cells are separated into three categories: vascular responsiveness, atherosclerosis and smooth muscle proliferation. There are a number of possible triggers for these effects.

Testosterone can be metabolized to dihydrotestosterone or estradiol. These then act on either androgen or estrogen receptors, which influence vascular response in addition to smooth muscle and macrophage lipid accumulation. Animal studies, and some in human males, show that testosterone can increase coronary blood flow and there have been some reports of testosterone administration improving exercise-induced S-T segment depression.

“Testosterone’s effects on lipid transportation are also complicated,” said Dr. Swerdloff. “We know the hormone modulates lipid transportation and has mechanisms on macrophages but they seem to be opposing and therefore it is not quite clear what is the net benefit or risk. There does seem to be no effect on smooth muscle proliferation leaving us with no clear idea of where we stand.”

There are some secondary effects of testosterone that could be CAD risk factors. For example, a 36-week study by Drs. Wang and Swerdloff of patients being administered a testosterone gel demonstrated a 10% increase in hematocrit and hemoglobin levels (unpublished data).

Other studies have shown testosterone favors platelet aggregation. However, the impact of this on atherosclerotic obstructive events is not at all clear.
“Longer term, well controlled studies of testosterone treatment on CAD, and specifically cardiac morbidity and mortality, are badly needed,” said Dr. Swerdloff. “Because we have a significant number of individuals who are potential candidates for treatment, we need to know what the implications are for cardiovascular events in this group.”

Androgens, Benign Prostatic Hyperplasia & Prostate Cancer: Is There a Connection?

Dr. Charles Huggins won a Nobel Prize for his groundbreaking work on the role of castration in controlling the spread of prostate cancer. This experimental research, originally performed in dogs, was soon taken to the clinic where Huggins was able to demonstrate that if he castrated men with prostate cancer, they lived longer than those men with prostate cancer who were not.

“Thus a connection between having or not having a testicle and cancer survival was established,” said Richard F. Spark, MD, Associate Clinical Professor of Medicine at Harvard Medical School, Boston.

Since then the treatments have continued to evolve. Most recently GnRH agonists and antagonists have become the current standard of care.
One study by Bolla followed men who had radiotherapy as their primary treatment for prostate cancer. Some were given no additional treatment and others were treated with goserelin, a GnRH agonist that lowered the serum testosterone level in men with prostate cancer. Those with no follow-up treatment had 48% 10-year survival rates compared to 85% in those given the treatment designed to lower their serum cholesterol level (Bolla M, et al. NEJM. 1997;337: 295).

“There is no question that Huggins was right in his concept that in men with prostate cancer, getting rid of testosterone extends survival,” said Dr. Spark. “We don’t know if testosterone treatment of testosterone-deficient men are more at risk for BPH or prostate cancers.”

A three-year study by Jin evaluated hypogonadal men, who were and were not given testosterone replacement therapy. They were age-matched with controls and segregated into those over 40 years of age and those under. The untreated men had low central prostate volume (CPV) and very low testosterone levels. When hypogonadal men where given testosterone to increase their serum level to the normal range, CPV increased slightly. CPV also increased with age independent of treatment (Jin B, et al. Clin Endocrinol (Oxf.). 2001;54:437).

A study by Morgentaler measured testosterone levels in 77 men with sexual dysfunction. They found 11 (14%) had prostate cancer. He claimed that a high prevalence of biopsy-detectable prostate cancer was seen in men with low total or free testosterone despite normal prostate-specific antigen (PSA) and digital exams (Morgentaler A, et al. JAMA. 1996;276:1904).

“Looking closer at the data, there was no difference in the mean and total testosterone levels of the men who did and did not develop prostate cancer,” said Dr. Spark. “The only major difference between those who did and did not get cancer was age, men who developed prostate cancer were older. There is nothing about this study that would justify considering low testosterone a risk factor for prostate cancer and ordering biopsies.”

In a publication by Snyder, PSAlevels were measured in hypogonadal men over 65 who were treated with placebo or testosterone over three years. Transient increases in PSA were noted in the first six months of testosterone treatment. One man in the placebo and another in the testosterone treatment arm developed prostate nodules and one testosterone-treated man was found to have a prostate cancer (Snyder PJ, et al. JCEM. 1999;84: 1966).

“For years it has been known that all mammals have prostates, but only men, dogs and African lions develop disease,” said Dr. Spark. “Science has since given us the Norway brown rat and aromatase knock-out mouse (ARKO) to study.”

When rats were given testosterone and estradiol, they had 100% dorsal lateral prostate dysplasia (a precursor for malignant change) associated with high prolactin levels. When given bromocriptine to correct the excess prolactin, the dysplasia was diminished. This implies that something about the high prolactin levels invoked these changes. There is an investigational antiestrogen, ICI 182780, which totally prevents dysplasia in this rodent model. It also reverses a series of oncogenes generated when the rat is given testosterone (Banerjee PP, et al. Endocrinology. 2001; 142: 4066).

Like humans, androgen receptors in the Norway rat decline with age. The receptors decrease in the ventral prostate, which is not linked to dysplasias. However, the androgen receptor count was increased 2.7 and 1.3 times in the dorsal lateral and lateral prostate.

“The ARKO mouse is another interesting model,” said Dr. Spark. “Testosterone, dihydrotestosterone and prolactin increase hyperplasia in the ventral, dorsal lateral and posterior lobes. However, prostate malignancy does not occur in the absence of estradiol suggesting a possible role for estrogen in the development of prostate cancer in this rodent model.” (McPherson SJ, et al. Endocrinology. 2001;142:2458).

In summary, restoring normal testosterone levels in hypogonadal men does not appear to increase the risk of BPH or prostate cancer above that seen in age-matched controls who do not receive testosterone supplements.