May/June 2015

Andropause Isn't Menopause — But It's Real
By Dudley S. Danoff, MD, FACS
Today's Geriatric Medicine
Vol. 8 No. 3 P. 14

Physicians must recognize which patients are good candidates for testosterone replacement therapy along with the associated risks and benefits of the treatment.

Similar to what happens to women during menopause, testosterone levels begin to fall at an average of about 1.6% per year in men over the age of 40.1 Once serum testosterone levels fall below normal, symptoms of andropause ensue, including a reduction in vigor and sexual drive. For young men, testosterone helps build muscles and develop strong bones, boosts energy levels to allow all-nighters with ease, and propels foolish actions with the false belief that their youthful bodies can scale an unattainable mountaintop or perhaps leap from a helicopter without a parachute. But during the middle-age years and beyond, that all begins to change, and men in this age group may approach their physicians with concerns about those changes. This article addresses what physicians should know and share about andropause with their aging male patients.

As urologists learn more about the role of testosterone in the physical and mental development of young men in their prime, they are also studying the role of testosterone in the aging body. One result of this increased study is that testosterone replacement therapy (TRT) has increasingly been promoted in print media, on television, and especially via the Internet as the solution to the male equivalent of menopause, known as andropause.

TRT is intended to counter the effects of andropause with promises to improve a man's libido, increase muscle mass, eliminate cognitive deficiencies, elevate mood, and bolster bone density. Before prescribing TRT to a patient, however, a medical provider needs to know what makes a patient a good candidate for this treatment, as well as the associated risks and benefits.

Common Symptoms of Andropause and Hypogonadism
The progressive testosterone (androgen) deficiency that occurs during andropause in aging men can lead to a syndrome known as hypogonadism, which can manifest itself in osteoporosis (loss of bone density), decreased libido, erectile dysfunction, difficulty sleeping, and mood changes. In addition, hypogonadism causes muscle to become flabby and decrease in size, leaving men with the dreaded middle-age paunch. Because serum testosterone levels continue to decline about 1% per year, about one-half of men aged 80 and older will have a low serum testosterone and may experience the slow changes to the body listed above.

Who Needs TRT?
Hypogonadism has become widely recognized over the past 10 years. As a result, physicians have increased the number of testosterone replacement prescriptions at an enormous rate. Pharmaceutical studies indicate a 500% increase in the use of testosterone products in the elderly and middle-aged population over the last decade,2 promoting the hopes of turning pot bellies into six-packs, fragile bones into pillars of strength, and grumpy old men into enthusiastic Lotharios.

To determine whether a patient needs TRT, a physician must assess base levels of testosterone. Some important numbers should be kept in mind when measuring serum testosterone: the accepted low limit for normal men is a testosterone level of at least 200 ng/dL (nanograms per deciliter). If a man's serum testosterone is below 200 ng/dL, TRT is recommended. If a man's serum testosterone level falls between 200 and 400 ng/dL, the risk-to-benefit ratio of TRT and its potential hazards, which are discussed below, must be considered.

This range of testosterone levels is considered a gray zone for TRT. Therefore, physicians should discuss all of the potential risks of TRT with patients whose testosterone levels fall within that zone. For serum testosterone levels greater than 400 ng/dL, not only is there no benefit from TRT, but there is also considerable risk involved. TRT is absolutely contraindicated in men with normal serum testosterone levels. If given in this scenario, a patient is no better than a cheating jock attempting to get "juiced" to enhance physical performance. The results can be disastrous.

It is not uncommon to find low serum testosterone in patients with infertility. The testicles are the primary source for the production of testosterone, and the pituitary gland and the brain send signals to the testicles to regulate testosterone production. Low testosterone levels can result from problems either in the pituitary or in the testicles, but in the aging male, the most common cause is testicular dysfunction. Less common causes for low serum testosterone are testicular injury, undescended testicles, the result of radiation or chemotherapy, and mumps infection affecting the testicles. Other factors resulting in low serum testosterone can include inflammatory disease such as tuberculosis, HIV and AIDS, opiate use, obesity, and type 2 diabetes.

If a patient displays the most common side effects associated with low testosterone, usually manifest by a depressed mood, fatigue, anemia, cognitive problems, and hot flashes, a physician may consider the presumptive diagnosis of hypogonadism. The gold standard for diagnostic hypogonadism is to measure the total testosterone levels in the blood, using the guidelines above to determine whether the level is low. Blood for testing should be drawn in the morning when testosterone levels are typically the highest.

TRT and Prostate Cancer
Contrary to common thinking, TRT does not cause prostate cancer. However, if a small undiagnosed prostate cancer is present, TRT can accelerate the growth of the tumor. Older men with high levels of prostate-specific antigen (PSA) are not suitable candidates for TRT. Patients receiving exogenous testosterone need to have their serum testosterone and overall condition monitored on a regular basis. Patients who respond well to treatment should be monitored every three to four months during the first year of treatment. In men over the age of 50, a prostate examination (digital rectal exam) and PSA testing every six to 12 months is recommended.

Method of Treatment
Unfortunately, no simple pill exists that can be taken because the oral ingestion of testosterone is extremely toxic to the liver. However, men with confirmed low testosterone levels who choose to undergo treatment have a number of options, including injection therapy, wherein testosterone is admitted intramuscularly every two to three weeks. The disadvantage of injections is that they cause a strong surge in the level of serum testosterone shortly after the injection, and this level decreases dramatically by the end of the two- to three-week cycle. The good news is that several topical preparations are available. In this treatment method, the testosterone is applied to the skin and is absorbed into the bloodstream at a constant level. Several gels can be applied to the lower abdomen, upper arm, armpit, or shoulder. As the gel dries, the testosterone is absorbed through the skin. Physicians should advise patients using the gel not to wash the area and to avoid contact with children and female partners for several hours after applying the gel.

Risks Associated With TRT
No discussion of TRT would be complete without weighing the risks against the benefits. First, the long-term effects of TRT are not well defined. The main areas of concern are cardiovascular and prostate problems, both of which are common in men with diminished testosterone levels, particularly older males. Cardiologists have noted that the increased incidence of coronary artery disease in men, compared with women, may be testosterone-dependent. It has been found that aging men receiving long-term TRT have significant changes in their lipid profiles. These changes directly affect cardiovascular health. Unfortunately, TRT lowers the beneficial cholesterol (HDL) widely recognized for its role in protecting against coronary artery disease. The good news is that TRT also lowers the bad cholesterol (LDL) responsible for blocking coronary arteries. It is encouraging that these effects on the lipid profile may be minimal when TRT maintains a serum testosterone level below 400 ng/dL. However, the cardiac risks increase dramatically when TRT is taken to abusive or supraphysiological levels above 400 ng/dL.

Another effect of TRT is increased production of red blood cells. The increase causes a hypercoagulation of the blood, causing a thickening that may increase the potential for a stroke or heart attack. This is especially true in smokers, who already have an increased circulating red blood cell volume. Therefore, it is not recommended that physicians prescribe TRT that would raise serum testosterone above 400 ng/dL. Having a healthy heart and healthy arteries should not be compromised by the desire to attain a slender waistline or bigger muscles.

A practitioner who starts a patient on TRT should ensure that he does not exceed the recommended dosage in an attempt to radically change his physical appearance. To the aging man who longs for that youthful body that is beginning to disappear, a physician may recommend that he modify his diet, maintain a healthful exercise routine, and accept the realities of aging—a reality that sometimes brings with it a little paunch.

Another important issue to consider related to the risks of TRT is its impact on prostate disease. As mentioned previously, it is well known that TRT does not induce the development of prostate cancer. What it can do, however, is cause rapid and potentially catastrophic growth of an unrecognized prostate cancer. There is no evidence that TRT can create prostate cancers. However, if there is even a tiny focus of cancer cells in an otherwise benign prostate, TRT can encourage these cells to grow explosively. This can become life threatening. If a man is receiving TRT, his physician should meticulously monitor his prostate health with a semiannual digital rectal examination, cancer screening blood tests (PSA), and prostatic ultrasonography.

Prescribing TRT
With the overwhelming media blitz promoting treatment for male andropause and hypogonadism, patients express concerns about TRT's safety. Based on the evidence available, it is safe to use TRT, and it is clearly beneficial in symptomatic men with a serum testosterone level of less than 200 ng/dL. But remember that in men whose serum testosterone is greater than 400 ng/dL, it is unacceptable. The results of TRT for symptomatic men are quite remarkable and will improve many of the physical effects associated with the toughest part of life—getting older. TRT is the primary medical treatment available for andropause and, for the right patients, physicians should recommend TRT as appropriate.

A Note on the Placebo Effect
A final word to physicians with aging male patients: At the end of the day, a lot of the sexual dysfunction and issues related to aging male sexuality in general can be attributed to the placebo effect. Much of an aging male's sexuality can be defined as "99% between the ears and 1% between the legs." The unscrupulous marketers of non–FDA-approved products and supplements, who often make bold and false claims—that love, sex, size, desire, and performance will be enhanced—rely on this. Many well-controlled scientific studies across the board show about 40% of patients receiving a placebo report that they experience effects similar to patients receiving the real product or supplement. Male sexuality, being so intertwined with imagination, mental gymnastics, the power of suggestion, and the illusion of sex appeal, becomes the perfect foil for the wide distribution and enormous profitability of thousands of male enhancement products by companies capitalizing on the placebo effect or the power of suggestion.

The takeaway message is this: If your patient has legitimate symptoms of andropause, such as weakness, fatigue, loss of libido, increased abdominal girth, and mood change, test his serum testosterone level and, if deficient, prescribe an FDA-approved product and monitor the results of treatment for any ill effects.

— Dudley S. Danoff, MD, FACS, is president and founder of the Cedars-Sinai Tower Urology Group in Los Angeles, a diplomate of the American Board of Urology, a fellow of the American College of Surgeons, and author of two books on men's health.

References
1. Stanworth RD, Jones TH. Testosterone for the aging male; current evidence and recommended practice. Clin Interv Aging. 2008;3(1):25-44.

2. Silverman E. Low T or high risk? Testosterone treatments and heart attacks. Forbes website. http://www.forbes.com/sites/edsilverman/2014/01/29/low-t-or-high-risk-testosterone-treatments-and-heart-attacks/. January 29, 2014. Accessed March 9, 2015.

Most Men With Borderline Testosterone Levels May Have Depression
Men with borderline testosterone levels have higher rates of depression and depressive symptoms than the general population, according to new research. The results were presented in San Diego in March at ENDO 2015, the annual meeting of the Endocrine Society. "Over half of men referred for borderline testosterone levels have depression. This study found that men seeking management for borderline testosterone have a very high rate of depression, depressive symptoms, obesity, and physical inactivity," says principal study author Michael S. Irwig, MD, FACE, an associate professor of medicine and director of the Center for Andrology in the Division of Endocrinology at George Washington University in Washington, D.C. "Clinicians need to be aware of the clinical characteristics of this sample population and manage their comorbidities such as depression and obesity."

The number of men having their testosterone levels checked has increased dramatically. Studies of the possible association between depression and serum testosterone show inconsistent results, and few studies have been published about adult men referred for the management of borderline testosterone.

Irwig and his colleagues studied 200 adult men between the ages of 20 and 77 whose testosterone levels were borderline, that is, between 200 and 350 ng/dl. The researchers recorded the men's demographic information, medical histories, medication use, and signs and symptoms of hypogonadism.

They remeasured the men's total testosterone and assessed depression from their medical histories and depressive symptoms with the validated Patient Health Questionnaire 9 (PHQ-9).

Using a score of 10 or higher on the PHQ-9, 56% of the study participants had significant depressive symptoms, known diagnosis of depression, and/or use of an antidepressant.

Their rates of depressive symptoms were markedly higher than the 15% to 22% in an ethnically diverse sample of primary care patients and the 5.6% among overweight and obese adults in the United States. The population also had a high prevalence of overweight (39%), obesity (40%), and physical inactivity; 51% of the men did not engage in regular exercise other than walking. The most commonly reported symptoms were erectile dysfunction (78%), low libido (69%), and low energy (52%).

"This study underscores the utility of a validated instrument to screen for depression, especially as some subjects may deny signs and symptoms during the interview. Appropriate referrals should be made for formal evaluation and treatment of depression," Irwig says.

— SOURCE: THE ENDOCRINE SOCIETY