Androgen deficiency in older men: Indications, advantages, and pitfalls of testosterone replacement therapy
ABSTRACTThe decline in testosterone with age has been associated with specific physical changes that affect quality of life and life expectancy, although a cause-and-effect relationship is yet to be established. While female menopause is rapid and well described, “male menopause” or androgen decline in older men is gradual and marked by nonspecific symptoms. This makes diagnosis of true testosterone deficiency and prediction of response to testosterone replacement therapy (TRT) challenging. This article reviews androgen decline in men, focusing on those over age 40, and covers symptoms, indications, contraindications, diagnosis, treatments, and the risks and benefits of treatment.
KEY POINTS
- General health benefits and safety of TRT in asymptomatic patients are not clearly defined by current data.
- Treatment of low testosterone is discouraged in the absence of clinical symptoms.
- A morning serum testosterone should be obtained after ruling out other causes of symptoms. It should also be repeated to confirm androgen deficiency in older men.
- Androgen deficiency in older men is associated with metabolic syndrome, type 2 diabetes mellitus, obesity, osteoporosis, renal failure, anemia, and previous treatment with steroids or opiates.
- TRT in men with a history of prostate cancer remains controversial. The existing limited data suggest that TRT is safe after curative therapy for prostate cancer. Patients treated should be monitored closely and informed of the risks of cancer progression and recurrence while they are on TRT.
MONITORING PATIENTS ON TRT
Patients starting TRT will require clinical and biochemical monitoring to evaluate response to therapy as well as possible side effects. The first set of laboratory values should be obtained 6 to 12 weeks after initiation of therapy and then typically quarterly for 1 year, every 6 months for the second year, and annually thereafter. Laboratory values monitored should include total testosterone, PSA, and hematocrit.
Men on daily therapy (patch, gel, liquid) should have testosterone drawn approximately 2 hours after application. Current TRT regimen data lack an appropriate target testosterone value, and guidelines suggest a mid to lower young adult male testosterone level.8 Since this is not clearly delineated in the current literature, the authors recommend monitoring clinical symptoms along with testosterone levels when adjusting TRT. It is important to document that serum testosterone was actually increased to the normal range in treated men without clinical improvement.
A rise in PSA of up to 24% would be an acceptable response in a benign prostate gland, but a higher increase or increase above 4.0 ng/dL should prompt consideration of prostate biopsy. 39 Similarly, hemoglobin and hematocrit typically increase, but a hematocrit greater than 55% should prompt dose reduction or cessation.7 Transaminases do not need routine monitoring during parenteral or transdermal therapy. Bone mineral density should be monitored every 1 to 2 years.7,8
CLINICAL BENEFITS OF TRT
There are promising data regarding the clinical benefits of TRT in patients with metabolic syndrome and type 2 diabetes mellitus. A recent meta-analysis investigating the effect of TRT on metabolic syndrome revealed an improvement in fasting plasma glucose, homeostatic model assessment index, triglycerides, treadmill duration, high-density lipoprotein cholesterol, and waist circumference.40,41 TRT also decreased insulin resistance and improved glycemic control in type 2 diabetic hypogonadal men.42 Results from a randomized controlled trial comparing 12 weeks of intramuscular testosterone treatment vs placebo in men with metabolic syndrome revealed an improvement in mean waist circumference from 108 cm ± 8 cm to 105.5 cm ± 7.7 cm. Sixty percent of men initially diagnosed with metabolic syndrome and treated with testosterone no longer met diagnostic criteria for metabolic syndrome according to the National Cholesterol Education Program–Third Adult Treatment Panel (NCEP-ATP III) and the International Diabetes Federation (IDF) guidelines.43
Depression has also been associated with low testosterone, with free testosterone levels below 170 pmol/L associated with frank depressive symptoms and levels below 220 pmol/L predictive of future onset of depressive symptoms.15 Testosterone replacement therapy has been shown to improve depressive symptoms in hypogonadal men.16,17 Shores et al16 conducted a randomized placebo-controlled study of testosterone replacement in men older than 50 years with dysthymia or minor depression. Men treated with testosterone gel for 12 weeks showed an improvement of baseline total testosterone levels from 291 ng/dL to 449 ng/dL. Men treated with testosterone also had a 53% rate of depression remission compared with 19% in the placebo group.16
The evidence supporting improved sexual function with TRT is variable. Some studies indicate limited or transient improvement of sexual function after TRT in men with erectile dysfunction,18,19 while others report an improvement in sexual function after 3 months of TRT.44 Because of the multifactorial nature of erectile dysfunction, men with erectile dysfunction and ADAM may require TRT and a phosphodiesterase type 5 (PDE5) inhibitor, as TRT alone may be insufficient. In a prospective observational study of men with erectile dysfunction and an initial testosterone lower than 300 ng/dL, testosterone gel was administered for at least 1 year, and improvement in sexual function was seen. Results revealed a correlation between improvement in sexual function and concurrent therapy with a PDE5 inhibitor.45 In a recent multicenter placebo-controlled study of PDE5 inhibitor nonresponders, the addition of a testosterone gel to tadalafil (Cialis) improved sexual function, again suggesting a synergistic effect when treating erectile dysfunction with both TRT and a PDE5 inhibitor.46
ADVERSE EVENTS RELATED TO TRT
Despite the aforementioned benefits, it must be emphasized that TRT should be used for specific target symptoms related to hypogonadism in older men and that the general health benefits and safety of TRT in an asymptomatic man with a low measured testosterone alone remains unproven.
Cardiovascular events. In a recent study of 209 elderly men with low testosterone and limited mobility associated with other chronic illnesses, 6 months of TRT resulted in the development of cardiovascular-related adverse events in 23 patients compared with 5 men in the placebo group.47 This may have been related to how adverse events were reported, with cumulative adverse events reviewed every 6 months, ranging from peripheral edema, hypertension, arrhythmias, and electrocardiographic changes. Serious adverse events were reviewed as they occurred, including stroke and acute myocardial events.
Other studies41,43 have revealed a favorable effect of TRT on cardiovascular disease and its surrogate markers but have lacked detailed reports and close monitoring of adverse events. Thus, variation of outcome measurement and reporting may obfuscate the detection of adverse cardiovascular events. Outcomes may also depend on the testosterone formulation and the target serum concentration.43
Larger, long-term placebo-controlled trials are needed to elucidate cardiovascular risk as a primary outcome in older androgen-deficient men undergoing TRT.
Other adverse effects related to TRT include erythrocytosis, seen in 3% to 18% of patients with transdermal administration,48,49 and up to 44% of patients undergoing IM therapy.48 Gynecomastia can occur and is more likely to resolve after treatment cessation of transdermal testosterone treatment than IM injections.48 Other potential clinical side effects that should prompt dose-reduction or discontinuation are irritability, bothersome acne, fluid retention, testicular atrophy, worsening of lower urinary tract symptoms from an enlarged prostate, and new or worsening heart failure. Infrequently, obstructive sleep apnea may be worsened by TRT, although currently the data linking sleep apnea and TRT are limited.50
TRT AND PROSTATE CANCER
The relationship between prostate cancer growth and testosterone is well established, with androgen ablation remaining the cornerstone of treatment for metastatic disease. Since androgen deprivation leads to the regression of prostate cancer, there has been concern that TRT may lead to growth or de novo development of prostate cancer. TRT has thus been strongly prohibited in patients with prostate cancer.7 However, recent data challenge this paradigm.
In a retrospective study of 81 men (mean age 56.8 years) treated with TRT, only 4 men (4.9%) developed prostate cancer over a 5-year period.51 This is less than the estimated 16.7% probability of developing prostate cancer in the general US population.52
Recent accumulating data support the concept of testosterone reaching a saturation level when binding androgen receptors within the prostate at extremely low levels. Increases above this level with TRT as with ADAM do not increase the risk of development or progression of prostate cancer.53 In addition, large doses of dihydrotestosterone do not seem to alter PSA, prostate volume, or International Prostate Symptom Score.54 These findings may have implications in future androgen therapies in hypogonadal older men.
Pathologic studies suggest low testosterone is associated with a higher Gleason grade of prostate cancer,55 although this association remains unconfirmed.56
In men with erectile dysfunction after prostate cancer treatment, TRT appears safe after brachytherapy57 or radical prostatectomy.58 A small study of 15 hypogonadal men with castrate-resistant prostate cancer and minimal or no metastatic disease showed only 1 patient had symptomatic progression.59 Moreover, a recent small study of 13 men with known prostate cancer on active surveillance showed that TRT did not lead to local progression or metastatic disease in any of the patients.60
While these data are provocative, it should still be emphasized that the standard of care for prostate cancer screening should be followed in age-appropriate men with ADAM. In addition, hypogonadal men with prostate cancer should only be treated with testosterone in conjunction with careful counseling and ongoing monitoring.
TRT SHOULD NOT REPLACE HEALTHY LIFESTYLE CHANGES
There has been a dramatic increase in TRT initiation for nonspecific symptoms of low testosterone in older androgen-deficient men. With this increase in initiation of TRT, there is a significant risk of overtreating. While there are many encouraging associations between treatment of androgen deficiency and improvement in rates of of morbidity and mortality, much remains unknown about the overall long-term risks and benefits of TRT. It is important to emphasize that TRT should not replace healthy lifestyle changes including regular exercise, weight loss, and diet modifications, which may provide the patient symptom resolution. Thoughtful dialogue with the patient is critical prior to TRT initiation, including thorough disclosure of the risks and benefits of treatment, and the limitations of the data as it evolves.
