Testosterone and Andropause
By Dónal P. O’Mathúna, PhD
Alternative medicine always has included its share of anti-aging remedies. Supplements like DHEA, human growth hormone, melatonin, and other natural hormone therapies have been marketed as the elixir of youth. Testosterone is the latest addition to hormonal anti-aging remedies. Its use in older men has accompanied increased controversy over the existence of andropause, or male menopause, and if it exists, whether testosterone safely and effectively treats it. Given concerns about hormone replacement therapy in women, physicians likely will receive many questions about the safety of testosterone use from older male patients.
Interest in the effects of testosterone in older men is traced to 1889 when a 72-year-old French physiologist, Charles Brown-Séquard, presented a medical paper on an extract prepared from dog and guinea pig testicles. Injecting the extract gave dramatically improved physical strength and cognitive abilities. However, a very recent experiment failed to produce physiologically significant quantities of testosterone in extracts prepared using Brown-Séquard methodology.1 Nevertheless, testicular extracts were marketed widely until testosterone was identified in 1935 as the key male hormone.
As menopause results from reduced estrogen production, male symptoms that result from reduced testosterone levels have been labeled andropause, male menopause, viropause, male climacteric, or low-testosterone syndrome.2 The necessity of injecting testosterone limited its popularity, until patches and gels became available.3 The publicity has led to a doubling in the number of testosterone prescriptions between 1997 and 2001.4
Natural History and Pharmacology
Total testosterone levels decline gradually with age. At the same time, men report a variety of symptoms, which most commonly include a lack of energy, reduced muscle mass, loss of libido, erectile dysfunction, depression, and reduced cognitive function.
During menopause, estrogen levels decrease dramatically, but testosterone levels decline gradually in men, about 1% per year between ages 40 and 70.2 This reduction occurs in free testosterone (the biologically active fraction); total testosterone usually does not decline until after age 60.2 Individual variability is high, but testosterone production is estimated to be reduced by one-third at age 70 and by half at age 80.5 The overall prevalence of actual hypogonadism is low, with estimates ranging from 20-30% of older men.6 A common lower serum testosterone level on many assays is 350 ng/dL or 14 nmol/L.7
Testosterone levels are controlled by a complex interplay of several hormones, and are influenced by confounding factors, including smoking, obesity, alcohol use, lifestyle, and concomitant illnesses. Some argue that the symptoms of andropause are due more to declining health with age, rather than declining testosterone levels. All the symptoms of andropause could be caused by other diseases and conditions, yet many are improved by supplemental testosterone.8
Mechanism of Action
Reduced testosterone production in older men originally was believed to be due to testicular dysfunction (primary hypogonadism), but now is believed to be related more commonly to hypothalamic-pituitary dysfunction (secondary hypogonadism).5 Testosterone has powerful effects on libido and sexual arousal, and anabolic effects on muscle, bone, erythropoiesis, and the brain, affecting mood and cognition.8
Clinical studies have focused on the effects of testosterone replacement therapy on muscular strength and mass, sexual arousal, and general well-being. However, very few controlled studies exist, and those that have been conducted are small and of short duration. For example, 12 older men with serum testosterone levels less than 480 ng/dL were randomly assigned to receive biweekly injections of placebo or testosterone enanthate (doses adjusted to achieve normal physiological concentrations).9 After six months, those receiving testosterone had significantly increased lean body mass, muscle mass, and muscle strength.
Another study enrolled 67 healthy older men (mean 76 years) with low bioavailable testosterone levels (< 4.44 nmol/L).10 Subjects were assigned randomly to wear two 2.5 mg testosterone patches or placebo patches daily for one year. Only 44 subjects completed the study. Those using placebo patches suffered a 1.6% loss in femoral neck bone mineral density, while those using testosterone gained 0.3% (P = 0.015). The testosterone group had reduced body fat and increased lean body mass (P = 0.001). No significant differences were found in muscle strength, hematocrit, prostate-specific antigen (PSA), or signs of benign prostatic hyperplasia (BPH).
Very few controlled studies have examined sexual or cognitive changes with testosterone. A controlled study randomly assigned 227 hypogonadal men to either testosterone gel (either 50 or 100 mg/d) or testosterone patch (5 mg/d) for six months.11 Sexual function and mood improved significantly in all groups after one month, with no further improvement. Lean body mass and muscle strength also improved, with the largest improvement in the 100 mg gel group (P = 0.0002). Hematocrit and PSA levels increased in all groups.
In an uncontrolled study, 10 hypogonadal men used testosterone gel for 12 weeks.6 On average, total, LDL, and HDL cholesterol levels were each reduced 15% (P < 0.005), sexual arousal and spontaneous erections increased (P < 0.02), and mood and cognitive abilities improved (P < 0.05). In another uncontrolled study, five hypogonadal men (mean 277 ng/dL) with major depression refractory to selective serotonin reuptake inhibitor therapy received testosterone enanthate injections (400 mg biweekly) for 14 weeks. Four then received placebo injections. While taking testosterone, HAM-D depression scores dropped from 19.2 to 7.2 (P = 0.01). Within two weeks of placebo treatment, three subjects relapsed to a mean HAM-D score of 11.3 (P < 0.05).
The prostate is dependent on testosterone, but paradoxically, as testosterone levels drop with age, the prostate enlarges, leading to BPH in many older men,12 and the discomfort of urinary symptoms. The single largest concern with testosterone administration is its impact on the prostate. Existing prostate cancer is an absolute contraindication for testosterone administration.13 However, testosterone’s role in causing prostate cancer is less clear. Controlled studies have found high serum testosterone levels associated with a higher risk of prostate cancer; others have found no correlation; still others have found reduced risk.13 Testosterone administration in hypogonadal men can increase prostate volume and PSA levels, but within normal ranges. Some studies found that supplemental testosterone reduced prostate volume and PSA levels.12 Careful prostate monitoring is essential when administering testosterone.
Patients with several other conditions should be monitored carefully when taking testosterone.13 Those with liver disease should be cautious since the liver metabolizes testosterone, and high doses of testosterone can slow the liver’s metabolism and increase the risk of toxicity. Serum lipid profiles are affected by testosterone, requiring monitoring of those with cardiovascular diseases. Hematocrit changes may progress to polycythemia. In rare cases, testosterone may lead to gynecomastia and thus is contraindicated in men with breast cancer. Testicular atrophy and decreased spermatogenesis also have been reported with use.
Testosterone is available in various formulations.8 Intramuscular injections use testosterone cypionate or testosterone enanthate (200 mg biweekly). These injections are uncomfortable and lead to wide swings in physiological levels. Oral testosterone undecanoate (usually 160 mg/d) is better tolerated, but its absorption is highly variable. Testosterone patches better mimic physiological production, but have practical problems. Between 42% and 84% of users report adverse skin reactions, and are uncomfortable wearing the patch, especially when it is applied to the scrotum.6 Topically applied gels are available either commercially, though their potency is generally low, or through compounding pharmacies.6 Testosterone propionate is available as a generic preparation for topical application.
In June 2002 the National Institutes of Health and the Department of Veterans Affairs decided not to proceed with a large randomized controlled trial of testosterone replacement therapy, citing problems with designing a large enough study without subjecting many subjects to unknown risks.4
A growing number of symptoms associated with aging in men have been correlated with decreased levels of testosterone. Administration of testosterone, by injection, orally, or topically, reverses many of these symptoms. However, much remains to be learned about andropause and testosterone replacement. Great individuality exists among men in their production of testosterone and response to testosterone replacement. Normal ranges are broad, and laboratory tests vary widely. Most of the studies have, to date, been relatively small and of short duration, although one study found testosterone patches safe and well tolerated for 7-10 years.14
Although much remains to be learned about testo-sterone supplementation for the symptoms of andro-pause and reduced testosterone levels, studies to date have not revealed serious problems. PSA and hematocrit usually are increased, but their clinical significance remains unclear. The potential for testosterone to stimulate pre-existing but undetected prostate cancer is of greatest concern. In announcing a thorough review of testosterone replacement therapy, the National Institute on Aging and the Institute of Medicine cautioned that "testosterone supplementation remains a scientifically unproven method for preventing or relieving any physical and psychological changes that men with normal testosterone levels may experience."15
Clinicians are left in a difficult position, given the negative results of the Prempro trial last year, and the effectiveness of those hormones in controlling symptoms and (it was believed) in preventing cardiac disease. Men eager to find relief from their age-related symptoms already are asking clinicians hard-to-answer questions about testosterone replacement.
Men who have low testosterone levels may benefit from testosterone replacements with each formulation having its pros and cons. While using testosterone, patients should have their prostate and hematocrit closely monitored. Patients with prostate or breast cancer, and patients at high risk for either, should not be given testosterone.
Because most men’s testosterone levels remain within the normal range, the risk-benefit analysis for them is less clear. Since many age-related symptoms can have several origins, other potential causes should be explored before prescription.
Dr. O’Mathúna is Professor of Bioethics and Chemistry at Mount Carmel College of Nursing, Columbus, OH.
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15. National Institute on Aging. Scientific task force to examine usefulness of testosterone replacement therapy in older men. Press release, Nov. 6, 2002. Available at: www.nia.nih.gov/news/pr/2002/1106.htm. Accessed on Dec. 4, 2002.