Clinical experiences with testosterone therapy: prostate safety

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1 The Aging Male 2004;7: Clinical experiences with testosterone therapy: prostate safety T. EuromedClinic, Fürth, Germany Key words: TESTOSTERONE, PROSTATE CANCER, PROSTATE-SPECIFIC ANTIGEN, TESTOGEL 1, SYMPTOMATIC LATE-ONSET HYPOGONADISM, HYPOGONADISM ABSTRACT Due to a decrease in Leydig cell function, a considerable proportion of men over 50 years of age will develop hypogonadism. Consequently, loss of libido and several other testosterone-dependent symptoms may become evident. When decreased levels of biologically available testosterone are found, and corresponding symptoms are present, these men could be eligible for testosterone substitution therapy. Testosterone treatment in testosterone-deprived men has been shown to improve general well-being, osteoporosis, muscle atrophy, libido and if present anemia. Despite these positive effects, testosterone treatment has to be performed with caution. Although it has not been proven that elevation of the serum testosterone level to the normal range results in a greater risk of developing prostate cancer, the effects of testosterone on a prostate cancer already present are well established. Several studies have demonstrated that testosterone treatment does not result in a significant increase in serum levels of prostate-specific antigen (PSA) or prostate volume. The long-term effects, however, are currently unknown. For these reasons, testosterone treatment should be performed only when the presence of prostate cancer is unlikely; i.e. when PSA levels are within normal limits and digital rectal examination does not reveal any suspicious findings. These examinations may still miss some small prostate cancers that could be promoted by testosterone treatment. The determination of PSA levels under testosterone treatment is necessary every 3 months, at least for the first year. Steadily rising PSA levels require immediate cessation of testosterone administration and the initiation of further diagnostic procedures (prostate biopsy), to rule out prostate cancer. INTRODUCTION Testosterone is synthesized and secreted by the Leydig cells of the testes 1 and is regulated by a negative feedback system involving the hypothalamus and the pituitary gland. The testes produce between 5 and 7 mg/day testosterone 2, which is metabolized to dihydrotestosterone (DHT) the primary androgen in the prostate by the enzyme 5a-reductase 3. Approximately 60% of circulating testosterone is bound to sex hormone binding globulin (SHBG), with a further 38% being bound by albumin or other proteins; only about 2% of circulating testosterone is free and bioactive 4. Normal young men exhibit a circadian rhythm in serum testosterone, with highest levels around and lowest levels in the late afternoon and evening 5. It is now generally understood that men experience a slow but continuous decline in serum levels of total testosterone after about the age of 40 years; on average, the loss is 1 2% per Correspondence: Dr T., Europa-Alle 1, D Fürth, Germany ª 2004 Parthenon Publishing. A member of the Taylor & Francis Group DOI: / Received Accepted

2 year 6,7. Additionally, as men age, levels of SHBG rise, and thus the levels of free bioactive testosterone are reduced even further 8. In elderly men, the diurnal variation of testosterone is lost and levels remain similar to those of young men at 20.00, throughout the day 9. Declining levels of testosterone result in a considerable number of men over the age of 50 years developing hypogonadism. The causes of hypogonadism may be classified as primary (due to inadequate testicular Leydig cell function), secondary (due to inadequate pituitary stimulation of the testes by luteinizing hormone) or a combination of the two (common in older men) 10. While symptomatic late-onset hypogonadism (SLOH) presents with many signs and symptoms (Table 1) 10, arguably one of the most important testosterone-dependent symptoms affecting the quality of life of aging men is the decline in or loss of sexual function and/or libido. Such dysfunction can significantly impact on a man s sense of well-being and may contribute to lethargy, depression, increased irritability and mood swings associated with the condition, often referred to as the andropause 11. In the majority of men with age-related sexual decline, medical problems other than low levels of testosterone, such as impaired penile vasculature, depression and chronic illness, and pharmacotherapy, may have a contributory role. However, research has demonstrated that testosterone therapy can significantly enhance sexual desire and fantasy 12 and sexual functioning 13 in men with SLOH. Table 1 The signs and symptoms of hypogonadism when accompanied by low levels of serum testosterone Sexual symptoms diminished libido erectile dysfunction difficulty achieving orgasm diminished intensity of the experience of orgasm diminished sexual penile sensation Diminished energy, vitality, well-being Increased fatigue Depressed mood Impaired cognition Diminished muscle mass and strength Diminished bone density Anemia TESTOSTERONE TREATMENT FOR HYPOGONADISM Hypogonadism is defined as a clinical condition characterized by low serum testosterone levels occurring in association with any of the signs and symptoms listed in Table 1. When symptoms of hypogonadism and low levels of testosterone present together in the aging male, testosterone substitution may be suitable and may result in clinical benefits in some, all or none of these symptoms. If the total testosterone concentration is low, free testosterone levels should be obtained 3. Although testosterone therapy can provide important benefits, there is considerable uncertainty about the risks of such treatment in older men with low testosterone concentrations 14,15. While individualized testosterone therapy may be justified for some men, it is essential that all patients are informed at the outset of treatment of both the benefits to health and the potential risks 16. PROSTATE CANCER Prostate cancer is one of the most commonly diagnosed cancers in Western countries. Many elderly men (50%) will have microscopic prostate cancer by the age of 70 years, but progression to clinical disease is variable and linked to both genetic and environmental factors 17. Although there are no data to demonstrate that androgens enhance the progression of preclinical to clinical cancer, it is known that androgens stimulate the growth of clinically diagnosed cancer 18. For this reason, testosterone therapy is an absolute contraindication in men suspected of having cancer of the prostate. This includes those men with abnormal digital rectal examination (DRE) or PSA value in whom the diagnosis of cancer has not been proved unequivocally negative, and men who have been recently treated for prostate cancer 19. All men who receive testosterone therapy need close monitoring of PSA values, since these correlate to the probability of developing prostate cancer. The ability to test for PSA has resulted in significant improvements in the detection of prostate cancer at an earlier stage, compared with 30 years ago. Although many undetected prostate The Aging Male 305

3 cancers probably have limited invasive potential, the addition of exogenous androgen stimulation may theoretically lead to cancer growth and spread 20. While a tumor remains confined within the prostate, it is still curable, but, once it invades surrounding tissues, treatment may only be palliative. ENDOGENOUS TESTOSTERONE LEVELS AND PROSTATE CANCER Multiple studies have attempted to clarify whether there is a link between the endogenous levels of testosterone or its major metabolites, such as DHT, and the development of prostate cancer. However, the results have often proved conflicting and the evidence is not clear-cut. Using data from the Massachusetts Male Aging Study, Mohr and colleagues 21 determined that baseline testosterone levels were not predictive of prostate cancer risk in a sample of men aged years; they called into question whether serum hormones levels during mid-life are risk factors for prostate cancer. There is evidence suggesting that a normal or malignant prostate can produce inhibitory factors that may be capable of suppressing serum levels of testosterone, by negative feedback of the hypothalamus pituitary axis 22,23. In order to determine whether the presence of prostate cancer altered serum testosterone levels, Zhang and colleagues 23 assayed serum levels of total and free testosterone in three groups of patients before diagnostic core needle biopsies. On the basis of their biopsy specimens, the men were subsequently divided into three groups: those with grade 3 cancer (high grade, n = 18), those with grade 2 cancer (moderate grade, n = 146) and those without cancer (controls, n = 90). The results demonstrated that serum total and free testosterone levels were significantly lower in the group with grade 3 cancer (307 ng/dl and 1.14 ng/dl, respectively), compared with grade 2 cancer (452 ng/dl and 1.51 ng/dl, respectively) and no cancer (451 ng/dl and 1.55 ng/dl, respectively; p ) (Figure 1). Following prostatectomy for cancer in 79 of these patients, the serum levels of both total and free testosterone were found to be significantly elevated (511 ng/dl and 1.78 ng/dl, respectively), compared with their pre-surgical levels (450 ng/dl and 1.60 ng/dl, respectively; p ) (Figure 2). Such findings support the view that prostate cancer may inhibit serum testosterone levels. The enzyme 5a-reductase catalyzes the reduction of testosterone into the more potent androgen DHT, which has been implicated in causing prostate cancer 24,25. Finasteride is an inhibitor of 5a-reductase and thus inhibits the conversion of testosterone to DHT. Finasteride is widely used to shrink the prostate in cases of benign prostate hyperplasia (BPH), and may have a role in reducing the risk of prostate cancer. To investigate this further, the Prostate Cancer Prevention Trial randomly assigned nearly men over the age of 55 years with no evidence of prostate cancer (a normal DRE and a PSA level of 4 3 ng/ml) to treatment with finasteride (5 mg/day) or placebo for 7 years 26. It was anticipated that 60% of Figure 1 Levels of testosterone in men with and without prostate cancer The Aging Male

4 Figure 2 Levels of testosterone following prostatectomy 23. Based on a figure by Zhang PL, et al., Association between prostate cancer and serum testosterone levels. Prostate 2002;53: Copyright 2002 Wiley-Liss, Inc. Reprinted by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc. participants would have prostate cancer diagnosed during the study or would undergo biopsy at the end of the study. By the study end, prostate cancer had been detected in 18.4% of men in the finasteride group and 24.4% of men in the placebo group, which equated to a reduced risk of prostate cancer over 7 years of 24.8% with finasteride treatment, compared with placebo (p ). However, there was an increased prevalence of high-grade tumors in the group treated with finasteride (37%), compared with placebo (22.2%; p ) (Figure 3). The prevalence of high-grade tumors was 6.4% vs. 5.1% in the finasteride vs. placebo groups. These results suggest that finasteride can prevent or delay the onset of prostate cancer, indicating that DHT may be a causative factor in the development of prostate cancer. However, the potential benefits of finasteride treatment must be weighed against an increased risk that, if prostate cancer does develop, the tumors may be of high grade. In a meta-analysis of 25 studies 27, no correlation between serum testosterone and prostate cancer was found in 15 studies; four studies linked high serum testosterone with prostate cancer, and six linked low serum testosterone with prostate cancer. The authors point out that, although there is an association between the levels of DHT in the prostatic tissue at the time of puberty and an increased risk of prostate cancer in young men, it is less clear whether there is link between testosterone or its metabolites and the incidence of prostate cancer later in life. TESTOSTERONE TREATMENT Since the discovery of the androgen-dependent growth of prostate cancer 28, it has been known that the addition of exogenous testosterone to men in temporary remission from prostate cancer can cause the disease to flare. Unsurprisingly, the relationship between prostate cancer and androgens raises serious concerns over the use of testosterone treatment in aging men. Since PSA levels are dependent on testosterone levels, PSA levels are a recommended safety parameter to monitor when giving testosterone treatment 10. In order to study the effect of exogenous testosterone treatment on PSA levels and prostate cancer, Gerstenbluth and colleagues 20 assessed 54 hypogonadal men with erectile dysfunction who received intramuscular injections of testosterone cypionate ( mg) every 2 4 weeks for 30 months. To meet inclusion criteria, patients were required to have a normal baseline PSA level (5 4 ng/ml) with a normal DRE or a prostate biopsy negative for prostate cancer. As expected, post-treatment total testosterone levels increased significantly from a baseline mean of 1.89 ng/ml to a mean of 9.74 ng/ml during therapy (p ). Mean PSA levels rose from a baseline mean of 1.86 ng/ml to a mean of 2.82 ng/ml (p ), but, importantly, these levels remained well within the normal range (upper limit, 4 ng/ml) (Figure 4). Six men experienced a rise in PSA above 4 ng/ml and underwent biopsy. However, only one of these men (1.9%) developed prostate cancer, suggesting that the The Aging Male 307

5 Figure 3 Relative incidence of prostate cancer: finasteride group 26 Figure 4 Prostate-specific antigen (PSA) and testosterone levels following testosterone administration 20 unmasking of an occult prostate carcinoma in the immediate period after starting testosterone treatment is a rare event. Biopsies were performed on a subset of patients who had received testosterone treatment for a mean of 58.5 months. Of these 19 men, no patients were diagnosed with prostate cancer. This subset analysis represents one of the longest follow-up evaluations of hypogonadal men receiving testosterone treatment, and suggests that there is no increased risk of prostate cancer after 4 5 years of continuous therapy. PSA VELOCITY AND TESTOSTERONE TREATMENT The rate of the PSA rise (the velocity) is probably the most important measure that needs monitoring. It is recommended that a PSA velocity greater than 0.4 ng/ml/year, or greater than 1 ng/ml in the first 6 months of treatment, should result in treatment being stopped and further investigations being performed 17. Treatment with a 1% testosterone gel (Testogel 1, Schering AG, Berlin, Germany) has been assessed for its effect on PSA levels in hypogonadal men 29,30. After 3 years of treatment with testosterone gel 1%, there was a small increase of approximately 0.37 ng/ml in the mean PSA level. Importantly, this increase occurred within the first 6 months and remained stable thereafter. Although three men (1.8%) were shown to have elevated PSA and biopsy-proven cancer, it was impossible to determine if this incidence was above the background rate, and further studies are needed. However, a recent review compiled the results of published, prospective studies of testosterone replacement therapy and found no evidence of an increased prevalence rate of prostate cancer in a total of 461 patients followed for 6 36 months The Aging Male

6 PROSTATIC INTRAEPITHELIAL NEOPLASIA The relationship between prostate cancer and testosterone is not completely understood, particularly with regard to the promotion or development of new cancers; this applies especially to high-grade prostatic intraepithelial neoplasia (PIN), which is considered to be a precancerous condition. In a recent study, Rhoden and Morgentaler 31 evaluated the effects of testosterone treatment in men at high risk of developing prostate cancer. A total of 75 hypogonadal men enrolled in the study, and all underwent prostate biopsies prior to initiating treatment. Fifty-five men were found to have benign prostate biopsies (PIN-negative), and 20 had PIN without frank cancer (PIN-positive). PSA levels at baseline were statistically similar (Table 2). After 12 months of testosterone treatment, PSA levels had risen slightly from baseline in both groups, although the increases were statistically similar between the two groups (Table 2). Importantly, there was no statistical significance between baseline levels of PSA and those 1 year after treatment in either group. These results indicate that testosterone treatment may not be contraindicated in men with a history of PIN. However, although encouraging, these early data are only based on 12-month data, and longer studies of this nature are needed before such a conclusion can be reached with a high degree of certainty. BENIGN PROSTATIC HYPERPLASIA It is well recognized that the development of BPH requires the presence of androgens, and that a reduction in DHT can markedly reduce prostate volume. However, multiple studies have failed to demonstrate an exacerbation of voiding symptoms, indicating an increase in prostate size, attributed to BPH, during treatment with testosterone 10,32,33. Nevertheless, prostate volume should be monitored in hypogonadal men receiving testosterone treatment, particularly in cases where there is an increase in voiding symptoms. PRECAUTIONS BEFORE AND DURING TESTOSTERONE TREATMENT Before beginning testosterone therapy, there are clear contraindications for treatment. Testosterone therapy should not be given to any man who has proven or suspected prostate (or breast) cancer. In cases where a patient may be in remission from prostate cancer, for example after curative measures, further advice should be sought. Monitoring for signs of prostate cancer prior to initiating testosterone treatment is mandatory. There is general agreement that the baseline level of PSA should be below 4 ng/ml and a DRE should be normal 10. If either assessment proves abnormal, then a negative prostate biopsy must be documented before treatment can begin, as such men are at risk of developing prostate cancer. A rapid elevation of PSA, even at levels below 4 ng/ml, is associated with prostate cancer 10. Immediate cessation of treatment and referral for a possible prostate biopsy are recommended for patients with an increase in PSA of more than 1 ng/ml during the first 6 months of treatment, or more than 0.4 ng/ml/year thereafter 17. Patients receiving testosterone treatment should be offered regular tests throughout the first year of treatment. Although no guidelines currently exist, several recommendations for monitoring testosterone treatment are outlined in a recent publication by Rhoden and Mor- Table 2 Change in prostate-specific antigen (PSA) levels after testosterone therapy in men with and without prostatic intraepithelial neoplasia (PIN) PIN-negative (n = 55) PIN-positive (n = 20) p Value Baseline PSA (ng/ml) year post-treatment PSA (ng/ml) Change (ng/ml) The Aging Male 309

7 gentaler 10. In brief, PSA levels need to be measured every 3 months; if they remain stable during the first year, then longer intervals can be considered thereafter. Testosterone levels need to be measured until the normal range is attained, and less often thereafter. Prostate volume/residual volume and DRE need to be measured every 12 months. SUMMARY Testosterone levels steadily decline in men over the age of 40 years, leading to the development of SLOH in many men. Studies have shown that hypogonadism can respond well to treatment with testosterone; however, there are safety concerns with testosterone treatment. Although there is no evidence that testosterone therapy induces prostate cancer in aging men, it is a growth factor for an existing prostate cancer. Therefore, men need to be informed of the risks before initiating testosterone therapy, and levels of PSA must be carefully monitored; if levels increase by more than 0.4 ng/ml/year (or more than 1 ng/ml during the first 6 months), treatment must be stopped and further investigations performed. In most studies of testosterone treatment, PSA levels rise to normal at a velocity within the normal limits. In addition, testosterone treatment does not appear to cause a rapid increase in prostate size, suggesting it would not exacerbate BPH. Testosterone therapy is an effective treatment for men with SLOH, and does not negatively affect the prostate in men without prostate cancer 21. However, as with all androgen therapies, testosterone is contraindicated in patients with suspected or confirmed cancer, and close, regular monitoring of the prostate is mandatory. Conflict of interest The author presented this paper at a symposium sponsored by Schering AG at the XIXth Congress of the European Association of Urology, Vienna, March References 1. Jeffcoate SL, Brooks RV, Lim NY, et al. Androgen production in hypogonadal men. J Endocrinol 1967;37: Griffin JE, Wilson JD. Disorders of the testes and the male reproductive tract. In Wilson JD, Foster DW, eds. Williams Textbook of Endocrinology. 1992: Basaria S, Dobs AS. Risks versus benefits of testosterone therapy in elderly men. Drugs Aging 1999: Jockenhoevel F. Male Hypogonadism, 1st edn. Bremen: Uni-Med, 2004:18 5. Nieschlag E. Circadian rhythm of plasma testosterone. In Aschoff J, Halberg F, eds. Chronobiological Aspects of Endocrinology. Stuttgart, New York: Schattauer Verlag, Morley JE, Kaiser FE, Perry HM, et al. Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. Metabolism 1997;46: Gray A, Berlin JA, McKinlay JB, Longcope C. An examination of research design effects on the association of testosterone and male aging: results of a meta-analysis. J Clin Epidemiol 1991;44: Kley HK, Nieschlag E, Bidlingmaier F, Kruskemper HL. Possible age-dependent influence of estrogens on the binding of testosterone in plasma of adult men. Horm Metab Res 1974;6: Bremner WJ, Vitiello MV, Prinz PN. Loss of circadian rhythmicity in blood testosterone levels with aging in normal men. J Clin Endocrinol Metab 1983;56: Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med 2004;350: Schow DA, Redmon B, Pryor JL. Male menopause. how to define it, how to treat it. Postgrad Med 1997;101: Davidson JM, Camargo CA, Smith ER. Effects of androgen on sexual behavior in hypogonadal men. J Clin Endocrinol Metab 1979;48: Wang C, Swerdloff RS, Iranmanesh A, et al. Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. Testosterone Gel Study Group. J Clin Endocrinol Metab 2000;85: The Aging Male

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