Managing the Risks of Prostate Disease During Testosterone Replacement Therapy in Older Men: Recommendations for a Standardized Monitoring Plan

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 <4.0 ng/mL will have or will develop clinical prostate cancer. The risk of developing a clinical prostate cancer is related to the baseline PSA value (Gann et al, 1995; Fang et al, 2001). Many older men have occult, microscopic foci of cancer in their prostates (Guileyardo et al, 1980; Carter et al, 1990; Sakr et al, 1994). We do not know whether testosterone administration will make these subclinical foci of cancer grow and become clinically overt. Older men with low testosterone levels may have occult or clinical prostate cancer (Morgentaler, 1996; Schatzl et al, 2001). Because PSA levels may be lower in men with androgen deficiency than in men with eugonadism, PSA levels in men with low testosterone levels may not accurately reflect the presence of prostate cancer. Serum PSA levels may be lower in men with testosterone deficiency and are restored to levels seen in age-matched controls following testosterone replacement (Sasagawa, 1990; Behre, 1994; Cooper et al, 1996; Meikle et al, 1997; Svetec et al, 1997). Therefore, in men receiving testosterone replacement, it is important to determine whether the increments in PSA levels are greater than what is after testosterone administration in men prostate cancer. PSA levels can be differences between PSA testosterone replacement, benign prostatic as well as prostate cancer. PSA levels in men with androgen deficiency and a testosterone replacement a from baseline or from a previously the consider of these before that the patient prostate PSA screening and of men receiving testosterone replacement might to greater numbers of prostate and of subclinical prostate that would have Therefore, it is important to for monitoring PSA during testosterone that use low for prostate to will likely in an number of with their associated and the that use high for prostate may to detect clinical prostate at an Many Prostate are demonstrated that metastatic prostate after androgen has been to induce in approximately of patients with metastatic prostate and has become a treatment for this et al, et al, 1990; et al, of testosterone concentrations, or or administration of a hormone or is the of of metastatic prostate cancer. a study (Fowler and Whitmore of patients with metastatic prostate cancer tumor progression in of patients who testosterone and disease had to testosterone androgen a in most men with and androgen supplementation metastatic prostate cancer to Many aging men with serum levels of testosterone will have occult prostate that become clinical prostate (Guileyardo et al, 1980; Carter et al, 1990; Sakr et al, 1994). The of men with occult prostate at increases with age and is in the of The prevalence of occult prostate cancer is in and men in et al, 1990). However, the incidence of clinical prostate cancer and in blacks and and in men in and 2001). data do not a significant difference in serum levels of testosterone among older men of different groups. It has been that greater of androgen to of the in 1 of the et al, 1996; et al, 1997; et al, 2001), or of androgen of of the 5 et al, 2000; Hsing et al, 2001), the prostatic 5 might to some of the increased risk of prostate cancer in some groups. to prostate cancer with age and most occult prostate do not become clinical prostate Many of the occult in men, it is not whether the androgen deficiency that is associated with aging the risk of an occult prostate cancer a clinical prostate cancer. It is that testosterone administration might cause these or occult prostate to grow and become clinically significant prostate cancer. we do not know the long-term effects of testosterone replacement on occult prostate In randomized and of clinical (Tenover 1992, 1998; Morley et al, 1993; Sih et al, 1997; Snyder et al, 1999a,b; Kenny et al, 2001), the number of prostate has not been greater in testosterone-treated men than in men. However, all of the published studies (Tenover 1992, 1998; Morley et al, 1993; Sih et al, 1997; Snyder et al, 1999a,b; Kenny et al, 2001) have than older men who had been for prostate cancer to treatment and It will require a clinical trial to the with testosterone supplementation might increase the of clinically overt prostate to detect a 30% difference in the incidence rates of prostate between testosterone-treated and men, approximately 6000 older men, years of age, with low testosterone will to be randomized to of the 2 treatment groups and a incidence of prostate in men of this age et al, 1998; et al, 1999; et al, the average treatment duration will have to be 5 years. A study of this and would require of and but is to this about the safety of testosterone administration in older men. studies have to a between prostate cancer risk and hormone levels et al, 1981; et al, 1981; Meikle and et al, et al, et al, 1988; Meikle et al, et al, 1990; et al, 1993; Hsing and 1993; et al, 1996; et al, 1996; et al, 1997; et al, 1997; et al, 1997; et al, 1997; et al, 1998; et al, 1999; et al, 2000; et al, 2000; et al, 2001; A of studies have no significant between serum testosterone or concentrations and the risk of prostate cancer. and reported a review of the data from studies and that there are no differences in between men who on to develop prostate cancer and who remain free of the disease. In a of studies et no difference between serum testosterone levels between men with prostate cancer and had lower testosterone and higher in 2 and studies et al, 1988; Hsing and 1993; et al, men with the higher of serum testosterone concentrations, after for age, mass and had the risk for prostate cancer than men in the The increased risk is attributed to study (Gann et al, in low levels were with high serum testosterone an that is not reported in It also should be that 2 studies of and older et al, and the et al, not a significant or a between serum testosterone concentrations and the risk of prostate cancer. of the studies that and higher levels of these in than in levels have also not been significantly different between and controls in a of studies with the of study (Gann et al, 1996). the available is and on whether high testosterone concentrations a higher risk of prostate cancer in men. In the hormone were on that were at different of the may have a The of data from studies is also the in study and for hormone The for controls and were not in some Many of the studies did not the effects of prostate cancer and on hormone in older men, and the high between concentrations of and of serum hormone levels does not the that concentrations of might not accurately reflect hormone or concentrations at the the randomized, study of for the of prostate cancer may important the of and concentrations in the of prostate cancer. The problems in studies have been the that after the of data from the on the effects of The data from this and randomized, have with the data from studies that had reported lower cardiovascular in The of the and the et al, the for randomized, placebo-controlled studies of testosterone supplementation in older men. et men with low testosterone or free testosterone a concentrations. men with a age of years had a of the a PSA of ng/mL, and of the of men were to have prostate cancer with of or Serum PSA concentrations, PSA density, prostate and or free testosterone concentrations were not significantly different between men who had cancer and who did This study did not have a and we do not know whether of age-matched controls with testosterone levels would a high incidence of cancer. In study of men age years and who had PSA levels to ng/mL and a benign prostate cancer in of the et al, 1997). In 2 were in of et al, and of men et al, 2001) with PSA levels between and ng/mL and a of the Therefore, the study et should not be to that there is an increased prevalence of prostate cancer in men with low free or testosterone or that prostate are in all men with low testosterone concentrations. a higher prevalence of prostate cancer in the and a higher prostate cancer in men with low testosterone levels et al, 2000; Schatzl et al, 2001). and patients with prostate of these men with low testosterone levels were older had a higher of that cancer and had a higher of with a of or greater of of study et al, 2001) reported that in men with prostate low testosterone levels are associated with prostate than in men with testosterone levels age, PSA and prostate were in the men with low and testosterone studies men who were with prostate cancer and the tumor on the of serum levels of of appropriate controls that are for and it to these data the to be about the risk of prostate cancer in men with low testosterone these data should not be to that low testosterone levels are a risk for prostate cancer. of serum testosterone concentrations of androgen in men with hypogonadism is associated with a decrease in serum PSA levels 1997). treatment of men with with a is associated with a significant of serum and prostatic PSA levels et al, several studies et al, 1993; and 1994; 1994; et al, 1995; et al, 1997; Meikle et al, 1997; et al, 1997; Svetec et al, 1997; et al, 1998; et al, 2000; et al, 2001; et al, 2001; et al, 2001; and 2002) of testosterone replacement in healthy men with hypogonadism have demonstrated a significant increase in serum PSA levels after testosterone administration some studies have reported no significant in PSA levels et al, 1996; et al, 1996; Snyder et al, In a review of published studies of testosterone replacement in men with we have the size to be with a of to is This that the average of testosterone replacement is to increase PSA levels about Because the average in this the of an average increase in serum PSA levels of about is considerable in the of in PSA after testosterone supplementation among these studies in to the of study of older men in some studies but not and differences in PSA In patients who were in these studies were likely receiving testosterone replacement we do not know whether the sufficient to PSA levels to Therefore, it is that of the increments in serum PSA levels after testosterone administration might have been evaluate whether older men a greater increase in PSA after testosterone we a review of data from placebo-controlled of testosterone supplementation in older men with low or low-normal testosterone concentrations (Tenover Morley et al, 1993; Urban et al, 1995; Sih et al, 1997; Snyder et al, Kenny et al, 2001). The size in studies of older men with a of to on older men a greater increase in serum PSA concentrations than populations of younger men. The average of testosterone replacement in older men is to increase PSA levels significant in the among these studies and the average 1 had a high et al, 2001). this the average in serum PSA levels after testosterone replacement in studies of older men In the randomized, placebo-controlled of testosterone supplementation in older men (Sih et al, 1997; Snyder et al, 1999a,b; Kenny et al, 2001), the in PSA levels in testosterone-treated men were not significantly different from that in men clinical of testosterone supplementation in older men (Tenover Urban did significant increments in PSA levels after testosterone the increments in PSA levels were serum PSA increased from to ng/mL in trial (Tenover and from to ng/mL in the trial In men with eugonadism, administration of of testosterone does not increase serum PSA levels (Bhasin et al, 1996; et al, 1996). data are consistent with studies in men (Bhasin et al, 2001) that that serum concentrations of PSA are at testosterone levels that are at the lower end of the higher testosterone concentrations are not associated with higher PSA data that the administration of replacement of testosterone in men with androgen deficiency can be to a in serum PSA in PSA levels after testosterone supplementation in men with androgen deficiency are generally than ng/mL, and increments in of ng/mL a are administration of testosterone to men with baseline PSA levels between and ng/mL will cause PSA levels to ng/mL in some men. in PSA levels ng/mL will a and of these men will be to prostate is considerable in PSA Some of this is to the and a significant of this is to and the of serum PSA levels in men prostate cancer. The of in serum PSA in of the men a up and had at a PSA increase ng/mL were larger with higher PSA is some that the is greater than 1 ng/mL in a significant of with the et al, is reported to be with the can be greater are in different that use et al, 1993; et al, The for the in PSA levels between 2 in the men in a study of in men with ng/mL or of baseline value et al, therefore, a of ng/mL in has been as a for in some clinical of et al, a the of of PSA on average has been reported to be et al, 1997). The of of the PSA should be the in PSA between at different or the PSA PSA in Some of prostatic such as prostatic and can significantly increase PSA such as and have on serum PSA levels and 1997). should be in the of PSA In patients in PSA are available for than 2 years, Carter and have the use of PSA to men at higher risk for prostate cancer. A PSA has not been in of the published clinical of testosterone on the of the data of men in the of Carter et demonstrated that the baseline PSA were between and ng/mL, a of of in PSA in men with benign prostatic disease. Because most men receiving testosterone replacement will have baseline PSA levels <4.0 ng/mL, the established for baseline PSA between and ng/mL are In a of data from the Fang et reported the PSA in men with prostate who have baseline PSA In these men with initial PSA of than ng/mL, the long-term that a for PSA of ng/mL had a of and a of for the of prostate cancer. the at ng/mL a of and a of findings to be it should be that in of the considerable in PSA levels in the for prostate that are lower than the would likely in a number of for The use of PSA is likely to be in men in PSA data are available years that the PSA baseline the an consider the of a with baseline PSA of ng/mL and PSA after 2 years of testosterone supplementation is 3 The in PSA of ng/mL a PSA of and the of Fang et However, this of ng/mL is than 2 the or it should be with and of PSA the than prostate It should be that the study Fang et a relatively number of men who prostate cancer a of In study a PSA of ng/mL or a of and a of in prostate cancer and 1994). from a prostate cancer study that men with baseline PSA levels of <4.0 ng/mL and who PSA men with PSA levels ng/mL prostate for up to 5 years. Carter and have that PSA should not be for of than 2 years. Also, of PSA PSA PSA is as the in PSA from baseline the in years. A PSA of does not that the patient has prostate nor should it be to prostate it a higher than average risk for developing prostate cancer during the Therefore, PSA can be during long-term of patients years. of than 3 years, we that PSA of should warrant a and for prostate cancer. 3 years, a PSA of is likely associated with a greater than average risk of prostate cancer and should warrant a of the of these PSA that we have has been for or in of testosterone should be as the on a relatively of Prostate size increases during the after of there is in prostate size until approximately years of years of age, prostate size to increase (Berry et al, is in men in their and and prevalence increases with age that age about of men have of of these men develop is no between serum androgen concentrations and prostate size in men. men age, the prostate serum and free testosterone concentrations Most but not all studies have that serum and levels remain relatively in men with advancing a between prostate and The study that baseline PSA and prostate are powerful of the risk of and the for et al, of serum testosterone concentrations administration of a or androgen effects administration of an is associated with a in prostate are associated with a in prostate of decreases serum and and associated with an average in prostate in a study et al, androgen is in prostate In men with prostate are lower than in age-matched and testosterone replacement increases prostate to that of age-matched controls 1994; 1997). However, treatment with replacement of testosterone does not increase prostate or the size for of is the of and prostate and are not In randomized, clinical of testosterone in older men with low or low-normal testosterone levels (Sih et al, 1997; Tenover 1998; Snyder et al, 1999a,b), there were no significant differences in the of prostate or between placebo and testosterone-treated men. Although 2 of the randomized clinical were of 3 years duration (Tenover 1998; Snyder et al, 1999a,b), of the studies powered to detect clinically differences in prostate event rates. did not a number of men for a to this Therefore, we do not know whether testosterone replacement will increase the for treatment of Testosterone replacement can be to men with who have to The of associated with can be the Prostate or the Because androgen replacement in men with androgen deficiency increases prostate (Sasagawa, 1990; Behre, 1994; Cooper et al, 1996; there is or no in prostate in most men with replacement of However, it is that in patients with of increases in prostate during testosterone administration may In these men, testosterone should not be or it should be with monitoring of their and after their prostatic has been The of of free and PSA for prostate cancer screening has been in several et al, 1999; et al, et al, these studies generally that free PSA the for prostate cancer in men with PSA between and However, these studies have not demonstrated higher value with the use of that and the of free to PSA that use and The have to the of free to PSA or PSA in screening for prostate cancer. Some studies have that a PSA of greater than may from prostate cancer than PSA the value and of such as an for screening of older men has not been in clinical The of PSA the of prostate the use of this significantly to the of In no data are available from testosterone to the use of free to PSA or PSA in prostate screening during testosterone Older men testosterone supplementation should of the of risk for prostate and for the or the and a baseline PSA a general men with a of prostate cancer should not be androgen and with of the prostate or PSA levels >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