Faculty Peer Reviewed
Women have long bemoaned menopause and its physiological, psychological, and sexual effects. Fortunately, hormone replacement therapy has provided relief for symptomatic women. Less attention is paid to men, who also experience declines in their sex hormones. Decreased testosterone may explain many symptoms experienced by elderly men, such as poor sexual function and libido, decreased bone mineral density, fatigue, and decreased muscle mass and strength. Should physicians treat elderly men with testosterone replacement therapy?
Late-onset hypogonadism, or “andropause,” is the gradual decline in testosterone levels in aging men. It differs from menopause in that it is a gradual process with a constant rate of androgen decline over decades, rather than years. Hypogonadism is defined as serum levels less than 280-300 ng/dL for total testosterone and 5-9 ng/dL for free testosterone, the lower limits of normal in healthy young men. Total testosterone (T) declines gradually with age at a relatively constant rate of 1-2% (3.2 ng/dL) per year, beginning in men’s 20s. Free T declines more rapidly than total T owing to an increase in sex hormone binding globulin (SHBG) with age. Declining levels of T with age are independent of other variables that are associated with low T, such as obesity, chronic illness, and chronic alcohol use. Of men older than 80 years old, 90% have free testosterone levels in the hypogondal range (less than 5 ng/dL) and 50% have total testosterone in the hypogonadal range (less than 320 ng/dL).
Primary hypogonadism is a result of testicular insufficiency, while secondary hypogonadism is a central problem arising from the hypothalamus or pituitary gland. Primary pathology presents with low testosterone and high levels of the gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Central hypogonadism is characterized by both low gonadotropins and testosterone.
Men with late-onset hypogonadism have increased FSH and LH; however these values are not high enough to indicate a primary (testicular) etiology alone. Instead, late-onset hypogonadism is attributed to both testicular and hypothalamic-pituitary dysfunction. Although we know that testosterone declines with age, much is still unconfirmed as to its nature—is this decline physiologic or pathologic?
Testosterone is known to have widespread effects on tissues throughout the body, including bone, muscle, bone marrow, brain, skin, hair, prostate, and external genitalia. Frank hypogonadism due to known testicular or pituitary disease causes decreases in libido, bone density, muscle mass and strength, and energy. Yet it remains unclear whether low T in elderly men has a physiologic benefit, and if replacement may exacerbate testosterone-dependent diseases such as prostate cancer, benign prostatic hyperplasia, erythrocytosis, and sleep apnea.
Testosterone deficiency has been associated with many symptoms in sexual, physical, and psychological domains, but most data on associated symptoms in elderly men are varied. A recent cross-sectional study examined 32 of these broad domains and concluded that only sexual symptoms have a strong association with decreasing T levels. These authors propose that at least 3 sexual symptoms–decreased frequency of morning erection, erectile dysfunction, and decreased frequency of sexual thoughts–are a necessary component for diagnosis.
To diagnose androgen deficiency, patients must have symptoms and low serum testosterone. Testosterone levels vary throughout the day and are most reliably measured in the morning when they are highest. Levels should be confirmed with a repeat measurement. Total and free T levels should be obtained in older men, since there is often SHBG alteration with age and comorbid conditions (diabetes, obesity, cirrhosis, and HIV). LH should be measured when low T is confirmed to assess for secondary hypogonadism, which, if indicated by a low LH value, should be worked up separately. Only after confirming hypogonadism due to age with clinically significant symptoms should patients begin to consider treatment.
The lack of high-quality, longitudinal, randomized trials assessing long-term effects of testosterone replacement therapy has led to disagreement among experts over treatment guidelines. The 2010 clinical practice guideline by the Endocrine Society recommends against general T replacement in older men with low T levels. Treatment should be discussed on an individual basis, and patients should have both clinically significant symptoms and confirmed low T levels. Some experts advise therapy when the total T level in symptomatic men is less than 280 ng/dL whereas others advise a more conservative approach, treating at a level of less than 200 ng/dL.
Current data from both longitudinal and cross-sectional studies reveal inconsistent and imprecise results for benefits in bone mineral density, physical function, sexual function, depression, cognition, and quality of life. Replacement in older men is associated with an increase in lean body mass and reduction in fat mass, as well as a modest trend toward increased bone density, but there is no clear evidence for improved libido, cognition, depression, or energy.
Patients and providers must be aware of the risks of T therapy. A 2010 randomized placebo-controlled trial of the effect of testosterone gel on muscle mass and strength in 209 elderly men (half of whom had pre-existing cardiac disease) was terminated early due to increased cardiovascular events in the treatment group. Studies have brought to light additional adverse effects associated with testosterone replacement, such as increased hemoglobin and hematocrit, decreased HDL cholesterol, and a higher rate of prostatic events in treated groups versus placebo groups.[6,7]
Patients must be made aware of the risks and benefits of testosterone therapy, as elderly men with low testosterone may have higher risks for cardiac and prostatic disease while on T therapy.[6,7] Additionally, before initiation of therapy patients should be screened for testosterone-dependent disease with a digital rectal exam, PSA, and hematocrit measurements. If treatment is initiated, serum T levels should be monitored with a target T level of the lower limit of normal for young men (400-500 ng/dL) to decrease the risk of testosterone-associated adverse effects. These patients should continue to be monitored for prostate disease throughout treatment.
Kylie Birnbaum is a 3rd year medical student at NYU School of Medicine
Peer reviewed by Robert Lind, MD, Medicine (Endocrinology), NYU Langone Medical Center
Image courtesy of Wikimedia Commons
1. Bhasin S, Cunningham GR, Hayes FJ, et al; Task Force, Endocrine Society. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(6):2536-2559. http://www.ncbi.nlm.nih.gov/pubmed/16720669
2. Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR; Baltimore Longitudinal Study of Aging. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. J Clin Endocrinol Metab. 2001;86(2):724-731. http://www.ncbi.nlm.nih.gov/pubmed/11158037
3. Morley JE, Kaiser FE, Perry HM 3rd, et al. Longitudinal changes in testosterone, luteinizing hormone, and follicle-simulating hormone in healthy older men. Metabolism. 1997;46(4):410-413. http://www.ncbi.nlm.nih.gov/pubmed/9109845
4. Wu FC, Tajar A, Beynon JM, et al. Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med. 2010;363(2):123-135.
5. Snyder PJ. Hypogonadism in elderly men–what to do until the evidence comes. N Engl J Med. 2004;350(5):440-442. http://www.ncbi.nlm.nih.gov/pubmed/14749451
6. Calof OM, Singh AB, Lee ML, et al. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J Gerontol A Biol Sci Med Sci. 2005;60(11):1451-1457. http://jcem.endojournals.org/content/95/6/2560.long
7. Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med. 2010;363(2):109-122. http://www.ncbi.nlm.nih.gov/pubmed/20592293