Key points are not available for this paper at this time.
The powerful demographic trend toward aging of populations in most countries has appropriately focused attention on the health problems of older men. Although there is agreement that serum total, bioavailable, and free testosterone concentrations decline with advancing age (Haffner et al, 1996; Kaufman and Vermeulen 1997; Morley et al, 1997; Zmuda et al, 1997; Smith et al, 2000; Harman et al, 2001), there is considerable uncertainty about the benefits and risks of testosterone replacement in older men with low testosterone concentrations (Bhasin and Buckwalter 2001; Matsumoto 2002). Initial randomized, placebo-controlled studies (Tenover 1992, 1998; Morley et al, 1993; Sih et al, 1997; Snyder et al, 1999a, b; Urban 1999; Kenny et al, 2001) have established the feasibility of testosterone replacement in older men for up to 3 years, and demonstrated that testosterone replacement increases fat-free mass, sense of well-being, and bone mineral density, and decreases fat mass in older men with low or low-normal testosterone concentrations. However, these initial studies (Tenover 1992, 1998; Morley et al, 1993; Sih et al, 1997; Snyder et al, 1999a, b; Urban 1999; Kenny et al, 2001) were neither designed to determine the effects of testosterone supplementation on health outcomes such as fracture rates, falls, physical function, disability, neurocognitive ability, and progression to dementia, nor powered to evaluate the effects of androgen administration on prostate and cardiovascular event rates. Long-term studies of 1 to 3 years in duration (Sih et al, 1997; Tenover 1998; Snyder et al, 1999a, b; Kenny et al, 2001) have generally reported a greater increase in hematocrit with testosterone administration than that associated with placebo administration. A few older men will develop hematocrits >55% during testosterone administration; increases in hematocrit to these high levels would increase blood viscosity, decrease blood flow rates, and might increase the risk of stroke. Androgen replacement may also worsen or induce sleep apnea, and cause edema, especially in older men with pre-existing heart disease. In the context of this uncertainty about the long-term risks of testosterone supplementation in older men, it is notable that testosterone prescription sales have increased 1700% in the last 9 years, and have grown 460% just in the last 3 years. Testosterone sales that had been stagnant at about 18 million until 1988 are projected to reach 400 million before the end of 2002 (IMS sales data, Philadelphia, Pa; BMC Corporation sales data, Minne-apolis, Minn). Whereas the greatest growth in testosterone sales appears to be in men with hypogonadism and younger than 65 years of age, testosterone use is also growing in older men. A growing interest in testosterone use is reflected in greater media and public attention that this topic has received. Although prostate event rates have not been significantly different between placebo- and testosterone-treated men in the previously published studies of testosterone replacement in older men (Sih et al, 1997; Tenover 1998; Snyder et al, 1999a, b), it is important to recognize that these studies did not have sufficient power to detect significant differences in prostate event rates between the 2 groups. It has been estimated that in order to detect a 30% difference in prostate cancer incidence rates between the placebo- and testosterone-treated groups, it would require randomization of approximately 6000 older men with low testosterone levels to the placebo and testosterone groups and treatment for an average of 5 years. Because such a randomized clinical trial would likely include relatively healthy older men with unequivocally low testosterone levels who do not have prostate cancer or prostate-specific antigen (PSA) levels >4 ng/mL, this would require screening a significantly larger number of older men in order to enroll 6000 eligible men. Accrual of sufficient numbers of men in such a clinical trial would be a challenging task. At this time, no study of this size has been funded; therefore, we will not know for several years whether testosterone replacement increases the incidence of clinically overt prostate cancer. Because the baseline prevalence of benign as well as malignant prostatic disorders is high (Berry et al, 1984; Carter et al, 1990; Sakr et al, 1994; Coley et al, 1995; Hsing et al, 2000; Jemal et al, 2002) in older men and the risks of prostate problems during testosterone administration remain undefined, there is understandable anxiety among health care providers who are facing increasing pressure from patients to consider hormone replacement. Therefore, the objectives of this commentary are to review the available data on the effects of testosterone replacement on the risk of prostatic disease in older men, and to present some recommendations for prostate monitoring during androgen administration in older men. This review should not be construed as our endorsement of testosterone replacement in older men with low testosterone concentrations. Our position is that at present, insufficient data exist to warrant a general recommendation for testosterone replacement of all older men with low testosterone concentrations, but that in some patients with unequivocally low testosterone levels and clinical and laboratory findings that can be attributed to androgen deficiency, individualized testosterone replacement might be justified after appropriate discussion of the benefits and risks with the patient, and institution of a standardized monitoring plan to maximize patient safety and minimize risk. Most but not all authorities believe that testosterone does not cause prostate cancer. Also, there is no consistent relationship between endogenous serum testosterone levels and the risk of prostate cancer. However, there are a number of areas of concern. Prostate cancer is a common, androgen—dependent tumor, and androgen administration promotes tumor growth in patients with metastatic prostate cancer (Fowler and Whitmore 1981; Manni et al, 1988; Santen et al, 1990). Therefore, testosterone administration is absolutely contraindicated in men with a clinical prostate cancer. PSA levels increase with age in men who do not have clinical prostate cancer (Oesterling et al, 1993), and levels are higher in blacks than in whites (Morgan et al, 1996). Some men with PSA 4 ng/mL should We recognize that some men with hypogonadism who have had a for prostate cancer and PSA levels for several years may be and may be for testosterone replacement Because testosterone administration the growth of replacement in this should be after and after a discussion of the replacement is to such men, PSA levels be with and to of than can be with testosterone replacement with of testosterone replacement PSA levels and of the prostate should be at and and 2001). and data from clinical have established that the increments in PSA levels after testosterone administration in men with hypogonadism in the at PSA levels are treatment would be to be associated with in PSA Therefore, increases in serum PSA levels after of testosterone replacement should be Our recommendations for a are in for testosterone replacement should also be for prostate the or the Testosterone should not be to men with in of should be 3 after testosterone replacement and increases in PSA or increases during treatment should to Although this review focused on related to prostate and monitoring during testosterone replacement of older men, a number of are related to the of testosterone have been in 2001; for and of in 2002 and Buckwalter 2001; Matsumoto of and but were not in this is no on of serum or free testosterone concentrations, should be to in older men. However, most authorities levels with in healthy men to or years of The effects of testosterone replacement in older men on outcomes are to be We do not know the of serum testosterone that should be during testosterone replacement and that would maximize benefits and minimize the risks of testosterone The of androgen and are available in health recommendations for prostate monitoring of men receiving or for testosterone replacement are not on data from long-term randomized, placebo-controlled reflect the of the that were the available data from studies of testosterone administration in and older men of up to 3 years of the and the on recommendations should be as an and are not to for clinical and
Bhasin et al. (Tue,) studied this question.