DOI 10.1515/hmbci-2012-0032 Horm Mol Biol Clin Invest 2012; 11(3): 347–353
Mohit Khera*
Testosterone replacement in normal and pathologic prostate Abstract: The testosterone replacement therapy (TRT) market has grown rapidly over the past 5 years. Exogenous testosterone in various forms is now the fastestgrowing medication prescribed in the USA. From 2005 to 2009, spending on testosterone jumped 115.5%, and the number of prescriptions filled increased 64.5%. One of the main reasons for this rapid growth in the TRT market is decreased concern that TRT can lead to prostate cancer. Other reasons are decreased concerns that testosterone can lead to worsening of benign prostatic hyperplasia (BPH) symptoms. In fact, recent studies suggest that TRT may improve BPH symptoms. Although there have been marked increases in the treatment of low testosterone, lingering concerns about prostate cancer have hindered progress. There are many theories, such as the prostate saturation theory, that may help us understand why testosterone may be safely administered in men with hypogonadism with normal and pathologic prostatic disease. Keywords: androgen; BPH; cancer; prostate; testosterone.
*Corresponding author: Mohit Khera, MD, MBA, MPH, 6620 Main Street, Suite 1325, Houston, TX 77030, USA, E-mail: [email protected]
Introduction The testosterone replacement therapy (TRT) market has grown rapidly over the past 5 years. Exogenous testosterone in various forms is now the fastest-growing medication prescribed in the USA. From 2005 to 2009, spending on testosterone jumped 115.5%, and the number of prescriptions filled increased 64.5%. One of the main reasons for this rapid growth in the TRT market is decreased concern that TRT can lead to prostate cancer. Other reasons are decreased concerns that testosterone can lead to worsening of benign prostatic hyperplasia (BPH) symptoms. In fact, recent studies suggest that TRT may improve BPH symptoms. Although there have been marked increases in the treatment of low testosterone,
lingering concerns about prostate cancer have hindered progress. Gooren and Behre’s multinational survey of physicians suggested that amongst the most common concerns physicians expressed about testosterone therapy was the assumed risk of BPH and prostate cancer [1]. There are many theories, such as the prostate saturation theory, that may help us understand why testosterone may be safely administered in men with hypogonadism with normal and pathologic prostatic disease.
Testosterone replacement in normal prostate TRT and the risk of developing prostate cancer To date, there are no convincing data to support the theory that giving men testosterone increases their chances of developing prostate cancer. Calof et al. performed a meta-analysis of 19 placebo-controlled TRT trials in men with hypogonadism and found no higher risk of prostate cancer in men being treated with testosterone than in men receiving a placebo [2]. Roddam et al. studied sex hormone levels and the risk of developing prostate cancer in 3886 men with prostate cancer, with over 6438 men without prostate cancer serving as age-matched controls. They found no relationship between the risk of developing prostate cancer and serum concentrations of testosterone, free testosterone, and dihydrotestosterone (DHT) levels [3]. Shabsigh et al. conducted a systematic review of the literature, assessing the risk of prostate cancer in men being treated for hypogonadism with TRT [4]. They found 11 placebo-controlled randomized studies, 29 non-placebo-controlled studies of men with no history of prostate cancer, and four studies of men with hypogonadism with a history of prostate cancer. Of the studies that met inclusion criteria, none demonstrated that TRT in men with hypogonadism increased the risk of prostate cancer or increased the Gleason grade of cancer detected.
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348 Khera: Testosterone replacement in normal and pathologic prostate
Prostate saturation theory The prostate saturation theory is based on the relative activity of androgen receptors, which are stimulated by testosterone and directly regulate the gene for prostatespecific antigen (PSA) in the prostate. The theory suggests that PSA levels and prostate tissue growth are sensitive to changes in serum testosterone levels only when testosterone serum levels are low. At this low level, prostate androgen receptors lack bound testosterone and are inactive, the prostate shrinks, and PSA levels decrease. Conversely, when testosterone levels are normal, all available androgen receptors are saturated by hormone, and further increases in testosterone have no effect on prostate size or PSA levels (Figure 1). A study by Marks et al. on the effect of TRT on prostate tissue in men who had late-onset hypogonadism helps explain the prostate saturation theory [5]. In this randomized, double-blinded, controlled trial, 40 men with hypogonadism were treated with testosterone enanthate (150 mg) or placebo intramuscularly every 2 weeks. Prostate biopsies were performed at baseline and at the end of 6 months. Serum testosterone increased from 282 to 640 ng/dL in the treated men. In contrast, there was no significant change in testosterone levels within the
placebo-treated group (282–273 ng/dL). Testosterone and DHT concentrations within the prostate did not change significantly in either group. Treatment-related changes in prostate histology, PSA, tissue biomarkers, gene expression, or cancer incidence or severity were not evident. These data suggest that although 6 months of TRT normalizes serum androgen levels, it appears to have little effect on prostate tissue androgen levels and androgendependent cellular functions. One of the best models to support the prostate saturation theory is when men receive luteinizing hormonereleasing hormone (LHRH) agonists for the treatment of prostate cancer. Initially, when LHRH agonists are given, there is a large surge in testosterone. However, the PSA does not increase during this time. This is probably because the prostate receptors are saturated, and the additional testosterone to the prostate will have no further effect. As the testosterone levels begin to decline to low levels, the PSA then begins to decline toward low levels. In a study by Tomera and colleagues, they did not notice any increase in PSA level above baseline in men being treated for metastatic prostate cancer with LHRH agonists alone [6]. The testosterone flare did not result in any increase in PSA or prostate cancer growth despite the mean PSA starting at 500 ng/mL. These data also suggest that androgen
Prostate saturation model Saturation model of physiologic testosterone replacement
“Normal physiologic range” Prostate growth (PSA)
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d te ra tu a ns U
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Serum testosterone level, ng/dL Adapted from Morgentaler A, Traish AM. Eur Urol. 2008;55:310-320
Figure 1 Prostate saturation model demonstrating no change in PSA or prostate growth at higher levels of testosterone.
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receptors in prostate cancer cells may become saturated, and higher levels of serum testosterone may not result in any further increase in PSA levels. In further support of the prostate saturation theory, a study by Khera et al. evaluated changes in PSA levels in men being treated with testosterone for hypogonadism [7]. This was an observational registry study comprising 451 men who were divided into two groups: group A [total testosterone (TT) < 250 ng/dL, n = 197] and group B (TT ≥ 250 ng/dL, n = 254). The groups differed significantly in free testosterone (FT) and sex hormone-binding globulin (SHBG), but not age or PSA levels. In group A but not group B, PSA significantly correlated with TT (r = 0.20, p = 0.005), FT (r = 0.22, p = 0.03), and SHBG (r = 0.59, p = 0.002) at baseline. After 12 months of TRT, increased PSA was statistically significant in group A (+0.19 ± 0.61 ng/mL, p = 0.02) but not in group B. The average percent PSA increase from baseline was higher in group A (21.9%) than in group B (14.1%). Overall, the greatest PSA levels were observed after 1 month’s treatment and declined thereafter. Patients with baseline TT < 250 ng/dL were more likely to have increased PSA after TRT than patients with baseline TT ≥ 250 ng/dL, supporting the prostate saturation hypothesis.
Understanding testosterone’s effect on PSA and prostate volume in normal prostate tissue It is important to understand how testosterone affects prostate tissue growth and changes in PSA. In the past, several studies have demonstrated that there is no significant increase in PSA levels upon administration of testosterone [8]. Today, we know that there may be a slight rise in PSA after the initiation of TRT, especially in men who are more severely hypogonadal [7]. There is a belief that the higher one raises serum testosterone levels, the higher the PSA will rise. However, studies have demonstrated that even raising testosterone to supraphysiologic levels did not result in a significant increase in serum PSA levels. Bhasin et al. administered testosterone enanthate (600 mg) or placebo weekly for 10 weeks to 43 healthy young men [9]. Although testosterone levels > 2800 ng/dL were seen, there were no significant increases in PSA levels or prostate growth. Similarly, Cooper et al. randomized 31 young healthy men to receive 100, 250, or 500 mg of testosterone via intramuscular injection once a week for 15 weeks [10]. Supraphysiologic serum testosterone levels of 1138 and 1994 ng/dL were seen at doses of 250 and 500 mg, respectively. No significant change occurred in the
prostate volume or serum PSA levels at any dose of exogenous testosterone.
Testosterone replacement in the pathologic prostate Testosterone replacement in men with a history of prostate cancer Approximately 217,730 new cases of prostate cancer were diagnosed in 2010 in the USA, and approximately 32,050 men died of the disease [11]. Traditionally, these patients have been denied TRT. If we assume that 39% of men over the age of 45 years are hypogonadal and that most men being diagnosed and treated for prostate cancer are over the age of 45 years, this results in a significant number of patients with hypogonadism after prostate cancer treatment [12]. A decision to deprive these men of testosterone supplementation should be based on conclusive evidence that giving these men testosterone supplementation would increase the risk of prostate cancer progression and recurrence. This conclusive evidence has not been found. Several recent studies have examined the use of TRT following radical prostatectomy (RP) and have shown an improvement in testosterone levels without a corresponding increase in PSA. To date, there have only been three retrospective studies assessing the use of TRT after RP. Agarwal and Oefelein published a series of 10 patients with a history of RP for organ-confined prostate cancer who were treated with TRT for symptomatic hypogonadism [13]. At 19 months, the patients had improved testosterone levels and hypogonadal symptoms, and none had recurrence of their disease. Another study by Kaufman and Graydon examined the outcomes of seven symptomatic hypogonadal men treated with androgen replacement after curative RP in early-stage prostate cancer [14]. Results over a follow-up period of up to 12 years documents normal testosterone levels with symptomatic improvement without significant increase in PSA or biochemical recurrence of prostate cancer. Khera et al. further confirm no incidence of prostate cancer recurrence or significant increases in PSA in 57 post-retropubic RP men with an average of 13 months of TRT treatment [15]. These three studies comprise a total of 74 patients published in the literature who have received testosterone following RP. Clearly, we cannot state that TRT is safe on the basis of these small retrospective studies; large randomized placebo trials are needed to truly assess the
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350 Khera: Testosterone replacement in normal and pathologic prostate
safety of TRT following RP. Currently, an FDA-approved, randomized, placebo-controlled trial in hypogonadal men is currently investigating the effect of testosterone therapy initiated 3 months after RP. The inclusion criteria for this clinical trial are that patients must have undergone a bilateral nerve-sparing RP and had nadir PSA values ( < 0.01 ng/mL) on two consecutive occasions separated by 4 weeks at the start of treatment. Patients with total testosterone levels > 300 ng/dL, preoperative sexual health inventory for men (SHIM) score < 17, positive surgical margins or evidence of residual prostate cancer, clinically suspected advanced disease or evidence of metastatic prostate cancer, primary Gleason grade > 3, and secondary Gleason > 4 in final pathologic specimen are excluded [16]. The data on the use of TRT after XRT and brachytherapy for prostate cancer are even more limited. Sarosdy evaluated TRT in patients with prostate cancer who were treated with brachytherapy [17]. In this study, 31 men were followed for a median of 5 years after starting TRT. Although testosterone levels increased significantly, no patient stopped TRT because of cancer recurrence, and no patient experienced cancer progression. Morales et al. published a study of five patients with hypogonadism treated with TRT after external beam radiation for prostate cancer [18]. None of the patients in this series developed a biochemical recurrence even up to 27 months after treatment. When including all publications that have been published thus far of patients treated with testosterone after prostate cancer, the risk of recurrence is < 1%. This is far less than the expected natural recurrence of the disease. Although most patients with prostate cancer treated with local therapy are cured, approximately 15%–40% will experience a biochemical PSA recurrence [19]. The recurrence rates in these series of men being treated with TRT after treatment of prostate cancer are even lower than that in patients with favorable pathology after RP and not treated with testosterone [20].
Changes in testosterone levels after prostatectomy and external beam radiation therapy (XRT) Significant changes in serum testosterone levels have been reported after RP and XRT, even in the absence of androgen deprivation therapy. Studies have generally demonstrated that testosterone levels decline after XRT
and may increase after prostatectomy. However, few studies have reported no significant changes in serum testosterone after RP or XRT [21, 22]. One study found that men treated with XRT were more likely to become hypogonadal than men who underwent RP, with a 27.3% lower testosterone and 31.6% lower FT level in the XRT group [23]. Two additional studies reported testosterone levels that did not recover to pretreatment levels in 40% of men after XRT, with median decreases in testosterone of 17%–19% [24, 25]. Several studies have also reported drops in testosterone levels post-XRT, with subsequent normalization to pretreatment levels [26]. Finally, Miller et al. found that prostate cancer exerts an inhibitory effect on testosterone synthesis, with a significant increase in testosterone after an RP [27].
Could testosterone supplementation be protective against the development of prostate cancer? The significantly low rate of prostate cancer recurrence and progression in those men being treated with TRT after RP lends the question of whether testosterone supplementation could have a protective effect in men with a history of prostate cancer. As mentioned earlier, there are data to support the theory that men with lower testosterone levels are more likely to have prostate cancer and more aggressive prostate cancer. There are also data suggesting that androgens may have a beneficial effect on prostate cancer by promoting a less aggressive phenotype via the androgen receptor [28]. A study by Hatzoglou et al. found that activation of the membrane androgen receptor induced apoptotic regression of human prostate cancer cells in vitro and in vivo [29]. More studies are needed to further understand these findings.
TRT in men with untreated prostate cancer Every day, men with untreated “occult” prostate cancer are being treated with TRT. It is known that the risk of occult prostate cancer in the community is one in seven men [30]. Thus, every day, men with undiagnosed prostate cancer are being treated with testosterone. However, in every significant study, the incidence of prostate cancer
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in those men being treated with testosterone is identical to those in men not being treated with testosterone. In other words, testosterone is not further exacerbating the cancer already present in undiagnosed men. A recent study investigated the effect of testosterone therapy in men with untreated prostate cancer [31]. A total of 13 symptomatic testosterone-deficient men with untreated prostate cancer who were undergoing active surveillance received testosterone therapy for a median of 2.5 years (range, 1.0–8.1 years). Mean age was 58.8 years. Gleason score at initial biopsy was 6 in 12 men and 7 in 1. Mean number of follow-up biopsies was two. Mean serum concentration of total testosterone increased from 238 to 664 ng/dL (p = 0.001). Mean PSA did not change with testosterone therapy. Prostate volume was also unchanged. No cancer was found in 54% of follow-up biopsies. Although biopsies in two patients suggested upgrading of pathologic grade, follow-up revealed no upgrading of cancer stage. No local prostate cancer progression or distant disease was observed in this study. These results are consistent with the saturation model demonstrating that maximal prostate cancer growth is achieved at low androgen concentrations.
Low testosterone: a risk factor for prostate cancer For decades we have believed the “androgen hypothesis” that higher testosterone levels contribute to prostate cancer development and causes rapid growth, and that low testosterone is protective against development of prostate cancer, causing it to regress. However, current data have demonstrated that low testosterone levels are more likely to be associated with prostate cancer. Yamamoto and colleagues demonstrated that preoperative testosterone serum levels were an independent and significant predictor of PSA failure after RP in patients who had clinically localized prostate cancer [32]. In this study, the 5-year PSA failure-free survival rates of the patients with preoperative low testosterone levels were significantly lower than those with normal testosterone values (67.8% versus 84.9%, respectively; p < 0.035). A study published by García-Cruz et al. in BJU International found that low pretreatment testosterone levels are related to a poor prognosis in prostate cancer (PCa); patients with PCa and lower testosterone levels have higher tumor burden before treatment onset [33]. In fact, several studies have found that low testosterone levels were associated with more aggressive and higher-grade prostate cancer [34, 35]. These findings suggest that low
circulating testosterone levels may not have a protective effect against the development of prostate cancer.
Testosterone replacement in BPH For many years it has been believed that TRT exacerbates BPH/lower urinary tract symptoms (LUTS). In fact, most of the package inserts of testosterone therapies state that clinicians should monitor patients with BPH for worsening of signs and symptoms and that elderly patients treated with androgens may be at increased risk for BPH. However, recent data suggest that TRT may actually improve BPH/ LUTS and calls into question our conventional understanding between testosterone and BPH/LUTS. Because testosterone receptors are found in the urothelium, bladder, urethra, and prostate, testosterone potentially directly or indirectly impacts BPH/LUTS via several pathways including the autonomic nervous system, bladder smooth muscle, Rho/Rho kinase, nitric oxide/nitric oxide synthase, and phosphodiesterase 5 activities [36]. It is believed that hypogonadism results in bladder fibrosis and loss of tissue elasticity, which, in turn, may play a crucial role in explaining the apparent relationship between LUTS and metabolic syndrome [37, 38]. In a randomized controlled study of 52 hypogonadal men with BPH, Shigehara et al. evaluated the effects of testosterone on LUTS. At the 12-month visit, in the treatment arm, there was a significant decrease in International prostate symptom score (IPSS) when compared with baseline (p < 0.05), as well as maximum flow rate and voided volume (p < 0.05), whereas in the control group, no significant changes were observed. Post-void residual showed no significant changes in either group. In addition, the TRT group showed significant enhancement of mean muscle volume (p < 0.05), whereas no significant changes were seen in the controls. The authors concluded that TRT improves LUTS in men with mild BPH symptoms [36]. One randomized pilot study evaluated the effect of testosterone therapy in older men with symptomatic LUTS and low testosterone. Patients were randomized to receive testosterone gel (50 mg/day) for 3 months (n = 10) or testosterone undecanoate (1000 mg) for 26 weeks (n = 20). Both groups attained eugonadal plasma testosterone levels, and Aging Male Survey (AMS) and International Index of Erectile Function (IIEF-5) scores and IPSS improved significantly. Furthermore, there was no increase in prostate volume or PSA level [39]. Amano et al. evaluated patients with hypogonadism and concomitant LUTS (n = 41) treated with testosterone
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352 Khera: Testosterone replacement in normal and pathologic prostate
therapy daily for 3 months. Serum FT and scores from the AMS, Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), IIEF-5, and IPSS and its subscores (postvoiding, storage, voiding symptoms, and quality of life) were assessed pre- and posttreatment. Serum FT levels rose significantly (p = 0.0047; paired t-test), total AMS scores decreased, and scores for the three AMS domains (psychological, physiologic, and sexual disturbance) were significantly reduced. Six of the eight SF-36 domains and erectile function (p = 0.0001; paired t-test), as measured by IIEF-5, improved significantly. Total IPSS and all IPSS domains improved significantly, with marked improvement in voiding function. These authors concluded that TRT is considered to be effective in the improvement of not only ED and late-onset hypogonadism (LOH) symptoms but also LUTS (especially voiding disturbance) of patients with LOH [40]. Karazindiyanoğlu and Çayan prospectively evaluated 25 hypogonadal men presenting with sexual dysfunction and treated for 1 year with testosterone gel (50–100 mg/day). Before and after treatment, patients were evaluated with urodynamic studies (pressureflow analysis) and measurements of prostate volume, PSA, and free PSA. IPSS, AMS, and IIEF-5 scores were assessed. The mean AMS score significantly decreased from 40.4 to 28.8 (p = 0.001), and mean IIEF-5 score significantly increased from 8.84 to 14.36 (p = 0.001). The mean maximal bladder capacity and compliance significantly
increased (p = 0.007 and p = 0.032, respectively), and mean detrusor pressure at Qmax significantly decreased from pretreatment to posttreatment (p = 0.017). These authors concluded that in men with hypogonadism, testosterone therapy may improve LUTS/bladder function by increasing bladder capacity and compliance and decreasing detrusor pressure at maximal flow [41]. Although we have been conventionally taught that testosterone therapy given to hypogonadal men may exacerbate the risk of LUTS, or urinary retention, this belief needs further investigation. Current evidence suggests that TRT may in fact improve BPH and LUTS.
Conclusion Over the past 5 years the rapid growth of the TRT market has challenged us to once again reevaluate the role of TRT in benign and pathologic prostate conditions. Our conventional teaching that TRT causes prostate cancer and worsening of BPH has now come into question. There is a growing body of evidence to support that TRT does not cause prostate cancer and may actually improve BPH symptoms. Much of these findings can be explained by the prostate saturation theory.
Received August 8, 2012; accepted September 17, 2012
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Mohit Khera*
Testosterone replacement in normal and pathologic prostate Abstract: The testosterone replacement therapy (TRT) market has grown rapidly over the past 5 years. Exogenous testosterone in various forms is now the fastestgrowing medication prescribed in the USA. From 2005 to 2009, spending on testosterone jumped 115.5%, and the number of prescriptions filled increased 64.5%. One of the main reasons for this rapid growth in the TRT market is decreased concern that TRT can lead to prostate cancer. Other reasons are decreased concerns that testosterone can lead to worsening of benign prostatic hyperplasia (BPH) symptoms. In fact, recent studies suggest that TRT may improve BPH symptoms. Although there have been marked increases in the treatment of low testosterone, lingering concerns about prostate cancer have hindered progress. There are many theories, such as the prostate saturation theory, that may help us understand why testosterone may be safely administered in men with hypogonadism with normal and pathologic prostatic disease. Keywords: androgen; BPH; cancer; prostate; testosterone.
*Corresponding author: Mohit Khera, MD, MBA, MPH, 6620 Main Street, Suite 1325, Houston, TX 77030, USA, E-mail: [email protected]
Introduction The testosterone replacement therapy (TRT) market has grown rapidly over the past 5 years. Exogenous testosterone in various forms is now the fastest-growing medication prescribed in the USA. From 2005 to 2009, spending on testosterone jumped 115.5%, and the number of prescriptions filled increased 64.5%. One of the main reasons for this rapid growth in the TRT market is decreased concern that TRT can lead to prostate cancer. Other reasons are decreased concerns that testosterone can lead to worsening of benign prostatic hyperplasia (BPH) symptoms. In fact, recent studies suggest that TRT may improve BPH symptoms. Although there have been marked increases in the treatment of low testosterone,
lingering concerns about prostate cancer have hindered progress. Gooren and Behre’s multinational survey of physicians suggested that amongst the most common concerns physicians expressed about testosterone therapy was the assumed risk of BPH and prostate cancer [1]. There are many theories, such as the prostate saturation theory, that may help us understand why testosterone may be safely administered in men with hypogonadism with normal and pathologic prostatic disease.
Testosterone replacement in normal prostate TRT and the risk of developing prostate cancer To date, there are no convincing data to support the theory that giving men testosterone increases their chances of developing prostate cancer. Calof et al. performed a meta-analysis of 19 placebo-controlled TRT trials in men with hypogonadism and found no higher risk of prostate cancer in men being treated with testosterone than in men receiving a placebo [2]. Roddam et al. studied sex hormone levels and the risk of developing prostate cancer in 3886 men with prostate cancer, with over 6438 men without prostate cancer serving as age-matched controls. They found no relationship between the risk of developing prostate cancer and serum concentrations of testosterone, free testosterone, and dihydrotestosterone (DHT) levels [3]. Shabsigh et al. conducted a systematic review of the literature, assessing the risk of prostate cancer in men being treated for hypogonadism with TRT [4]. They found 11 placebo-controlled randomized studies, 29 non-placebo-controlled studies of men with no history of prostate cancer, and four studies of men with hypogonadism with a history of prostate cancer. Of the studies that met inclusion criteria, none demonstrated that TRT in men with hypogonadism increased the risk of prostate cancer or increased the Gleason grade of cancer detected.
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348 Khera: Testosterone replacement in normal and pathologic prostate
Prostate saturation theory The prostate saturation theory is based on the relative activity of androgen receptors, which are stimulated by testosterone and directly regulate the gene for prostatespecific antigen (PSA) in the prostate. The theory suggests that PSA levels and prostate tissue growth are sensitive to changes in serum testosterone levels only when testosterone serum levels are low. At this low level, prostate androgen receptors lack bound testosterone and are inactive, the prostate shrinks, and PSA levels decrease. Conversely, when testosterone levels are normal, all available androgen receptors are saturated by hormone, and further increases in testosterone have no effect on prostate size or PSA levels (Figure 1). A study by Marks et al. on the effect of TRT on prostate tissue in men who had late-onset hypogonadism helps explain the prostate saturation theory [5]. In this randomized, double-blinded, controlled trial, 40 men with hypogonadism were treated with testosterone enanthate (150 mg) or placebo intramuscularly every 2 weeks. Prostate biopsies were performed at baseline and at the end of 6 months. Serum testosterone increased from 282 to 640 ng/dL in the treated men. In contrast, there was no significant change in testosterone levels within the
placebo-treated group (282–273 ng/dL). Testosterone and DHT concentrations within the prostate did not change significantly in either group. Treatment-related changes in prostate histology, PSA, tissue biomarkers, gene expression, or cancer incidence or severity were not evident. These data suggest that although 6 months of TRT normalizes serum androgen levels, it appears to have little effect on prostate tissue androgen levels and androgendependent cellular functions. One of the best models to support the prostate saturation theory is when men receive luteinizing hormonereleasing hormone (LHRH) agonists for the treatment of prostate cancer. Initially, when LHRH agonists are given, there is a large surge in testosterone. However, the PSA does not increase during this time. This is probably because the prostate receptors are saturated, and the additional testosterone to the prostate will have no further effect. As the testosterone levels begin to decline to low levels, the PSA then begins to decline toward low levels. In a study by Tomera and colleagues, they did not notice any increase in PSA level above baseline in men being treated for metastatic prostate cancer with LHRH agonists alone [6]. The testosterone flare did not result in any increase in PSA or prostate cancer growth despite the mean PSA starting at 500 ng/mL. These data also suggest that androgen
Prostate saturation model Saturation model of physiologic testosterone replacement
“Normal physiologic range” Prostate growth (PSA)
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Figure 1 Prostate saturation model demonstrating no change in PSA or prostate growth at higher levels of testosterone.
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receptors in prostate cancer cells may become saturated, and higher levels of serum testosterone may not result in any further increase in PSA levels. In further support of the prostate saturation theory, a study by Khera et al. evaluated changes in PSA levels in men being treated with testosterone for hypogonadism [7]. This was an observational registry study comprising 451 men who were divided into two groups: group A [total testosterone (TT) < 250 ng/dL, n = 197] and group B (TT ≥ 250 ng/dL, n = 254). The groups differed significantly in free testosterone (FT) and sex hormone-binding globulin (SHBG), but not age or PSA levels. In group A but not group B, PSA significantly correlated with TT (r = 0.20, p = 0.005), FT (r = 0.22, p = 0.03), and SHBG (r = 0.59, p = 0.002) at baseline. After 12 months of TRT, increased PSA was statistically significant in group A (+0.19 ± 0.61 ng/mL, p = 0.02) but not in group B. The average percent PSA increase from baseline was higher in group A (21.9%) than in group B (14.1%). Overall, the greatest PSA levels were observed after 1 month’s treatment and declined thereafter. Patients with baseline TT < 250 ng/dL were more likely to have increased PSA after TRT than patients with baseline TT ≥ 250 ng/dL, supporting the prostate saturation hypothesis.
Understanding testosterone’s effect on PSA and prostate volume in normal prostate tissue It is important to understand how testosterone affects prostate tissue growth and changes in PSA. In the past, several studies have demonstrated that there is no significant increase in PSA levels upon administration of testosterone [8]. Today, we know that there may be a slight rise in PSA after the initiation of TRT, especially in men who are more severely hypogonadal [7]. There is a belief that the higher one raises serum testosterone levels, the higher the PSA will rise. However, studies have demonstrated that even raising testosterone to supraphysiologic levels did not result in a significant increase in serum PSA levels. Bhasin et al. administered testosterone enanthate (600 mg) or placebo weekly for 10 weeks to 43 healthy young men [9]. Although testosterone levels > 2800 ng/dL were seen, there were no significant increases in PSA levels or prostate growth. Similarly, Cooper et al. randomized 31 young healthy men to receive 100, 250, or 500 mg of testosterone via intramuscular injection once a week for 15 weeks [10]. Supraphysiologic serum testosterone levels of 1138 and 1994 ng/dL were seen at doses of 250 and 500 mg, respectively. No significant change occurred in the
prostate volume or serum PSA levels at any dose of exogenous testosterone.
Testosterone replacement in the pathologic prostate Testosterone replacement in men with a history of prostate cancer Approximately 217,730 new cases of prostate cancer were diagnosed in 2010 in the USA, and approximately 32,050 men died of the disease [11]. Traditionally, these patients have been denied TRT. If we assume that 39% of men over the age of 45 years are hypogonadal and that most men being diagnosed and treated for prostate cancer are over the age of 45 years, this results in a significant number of patients with hypogonadism after prostate cancer treatment [12]. A decision to deprive these men of testosterone supplementation should be based on conclusive evidence that giving these men testosterone supplementation would increase the risk of prostate cancer progression and recurrence. This conclusive evidence has not been found. Several recent studies have examined the use of TRT following radical prostatectomy (RP) and have shown an improvement in testosterone levels without a corresponding increase in PSA. To date, there have only been three retrospective studies assessing the use of TRT after RP. Agarwal and Oefelein published a series of 10 patients with a history of RP for organ-confined prostate cancer who were treated with TRT for symptomatic hypogonadism [13]. At 19 months, the patients had improved testosterone levels and hypogonadal symptoms, and none had recurrence of their disease. Another study by Kaufman and Graydon examined the outcomes of seven symptomatic hypogonadal men treated with androgen replacement after curative RP in early-stage prostate cancer [14]. Results over a follow-up period of up to 12 years documents normal testosterone levels with symptomatic improvement without significant increase in PSA or biochemical recurrence of prostate cancer. Khera et al. further confirm no incidence of prostate cancer recurrence or significant increases in PSA in 57 post-retropubic RP men with an average of 13 months of TRT treatment [15]. These three studies comprise a total of 74 patients published in the literature who have received testosterone following RP. Clearly, we cannot state that TRT is safe on the basis of these small retrospective studies; large randomized placebo trials are needed to truly assess the
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350 Khera: Testosterone replacement in normal and pathologic prostate
safety of TRT following RP. Currently, an FDA-approved, randomized, placebo-controlled trial in hypogonadal men is currently investigating the effect of testosterone therapy initiated 3 months after RP. The inclusion criteria for this clinical trial are that patients must have undergone a bilateral nerve-sparing RP and had nadir PSA values ( < 0.01 ng/mL) on two consecutive occasions separated by 4 weeks at the start of treatment. Patients with total testosterone levels > 300 ng/dL, preoperative sexual health inventory for men (SHIM) score < 17, positive surgical margins or evidence of residual prostate cancer, clinically suspected advanced disease or evidence of metastatic prostate cancer, primary Gleason grade > 3, and secondary Gleason > 4 in final pathologic specimen are excluded [16]. The data on the use of TRT after XRT and brachytherapy for prostate cancer are even more limited. Sarosdy evaluated TRT in patients with prostate cancer who were treated with brachytherapy [17]. In this study, 31 men were followed for a median of 5 years after starting TRT. Although testosterone levels increased significantly, no patient stopped TRT because of cancer recurrence, and no patient experienced cancer progression. Morales et al. published a study of five patients with hypogonadism treated with TRT after external beam radiation for prostate cancer [18]. None of the patients in this series developed a biochemical recurrence even up to 27 months after treatment. When including all publications that have been published thus far of patients treated with testosterone after prostate cancer, the risk of recurrence is < 1%. This is far less than the expected natural recurrence of the disease. Although most patients with prostate cancer treated with local therapy are cured, approximately 15%–40% will experience a biochemical PSA recurrence [19]. The recurrence rates in these series of men being treated with TRT after treatment of prostate cancer are even lower than that in patients with favorable pathology after RP and not treated with testosterone [20].
Changes in testosterone levels after prostatectomy and external beam radiation therapy (XRT) Significant changes in serum testosterone levels have been reported after RP and XRT, even in the absence of androgen deprivation therapy. Studies have generally demonstrated that testosterone levels decline after XRT
and may increase after prostatectomy. However, few studies have reported no significant changes in serum testosterone after RP or XRT [21, 22]. One study found that men treated with XRT were more likely to become hypogonadal than men who underwent RP, with a 27.3% lower testosterone and 31.6% lower FT level in the XRT group [23]. Two additional studies reported testosterone levels that did not recover to pretreatment levels in 40% of men after XRT, with median decreases in testosterone of 17%–19% [24, 25]. Several studies have also reported drops in testosterone levels post-XRT, with subsequent normalization to pretreatment levels [26]. Finally, Miller et al. found that prostate cancer exerts an inhibitory effect on testosterone synthesis, with a significant increase in testosterone after an RP [27].
Could testosterone supplementation be protective against the development of prostate cancer? The significantly low rate of prostate cancer recurrence and progression in those men being treated with TRT after RP lends the question of whether testosterone supplementation could have a protective effect in men with a history of prostate cancer. As mentioned earlier, there are data to support the theory that men with lower testosterone levels are more likely to have prostate cancer and more aggressive prostate cancer. There are also data suggesting that androgens may have a beneficial effect on prostate cancer by promoting a less aggressive phenotype via the androgen receptor [28]. A study by Hatzoglou et al. found that activation of the membrane androgen receptor induced apoptotic regression of human prostate cancer cells in vitro and in vivo [29]. More studies are needed to further understand these findings.
TRT in men with untreated prostate cancer Every day, men with untreated “occult” prostate cancer are being treated with TRT. It is known that the risk of occult prostate cancer in the community is one in seven men [30]. Thus, every day, men with undiagnosed prostate cancer are being treated with testosterone. However, in every significant study, the incidence of prostate cancer
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in those men being treated with testosterone is identical to those in men not being treated with testosterone. In other words, testosterone is not further exacerbating the cancer already present in undiagnosed men. A recent study investigated the effect of testosterone therapy in men with untreated prostate cancer [31]. A total of 13 symptomatic testosterone-deficient men with untreated prostate cancer who were undergoing active surveillance received testosterone therapy for a median of 2.5 years (range, 1.0–8.1 years). Mean age was 58.8 years. Gleason score at initial biopsy was 6 in 12 men and 7 in 1. Mean number of follow-up biopsies was two. Mean serum concentration of total testosterone increased from 238 to 664 ng/dL (p = 0.001). Mean PSA did not change with testosterone therapy. Prostate volume was also unchanged. No cancer was found in 54% of follow-up biopsies. Although biopsies in two patients suggested upgrading of pathologic grade, follow-up revealed no upgrading of cancer stage. No local prostate cancer progression or distant disease was observed in this study. These results are consistent with the saturation model demonstrating that maximal prostate cancer growth is achieved at low androgen concentrations.
Low testosterone: a risk factor for prostate cancer For decades we have believed the “androgen hypothesis” that higher testosterone levels contribute to prostate cancer development and causes rapid growth, and that low testosterone is protective against development of prostate cancer, causing it to regress. However, current data have demonstrated that low testosterone levels are more likely to be associated with prostate cancer. Yamamoto and colleagues demonstrated that preoperative testosterone serum levels were an independent and significant predictor of PSA failure after RP in patients who had clinically localized prostate cancer [32]. In this study, the 5-year PSA failure-free survival rates of the patients with preoperative low testosterone levels were significantly lower than those with normal testosterone values (67.8% versus 84.9%, respectively; p < 0.035). A study published by García-Cruz et al. in BJU International found that low pretreatment testosterone levels are related to a poor prognosis in prostate cancer (PCa); patients with PCa and lower testosterone levels have higher tumor burden before treatment onset [33]. In fact, several studies have found that low testosterone levels were associated with more aggressive and higher-grade prostate cancer [34, 35]. These findings suggest that low
circulating testosterone levels may not have a protective effect against the development of prostate cancer.
Testosterone replacement in BPH For many years it has been believed that TRT exacerbates BPH/lower urinary tract symptoms (LUTS). In fact, most of the package inserts of testosterone therapies state that clinicians should monitor patients with BPH for worsening of signs and symptoms and that elderly patients treated with androgens may be at increased risk for BPH. However, recent data suggest that TRT may actually improve BPH/ LUTS and calls into question our conventional understanding between testosterone and BPH/LUTS. Because testosterone receptors are found in the urothelium, bladder, urethra, and prostate, testosterone potentially directly or indirectly impacts BPH/LUTS via several pathways including the autonomic nervous system, bladder smooth muscle, Rho/Rho kinase, nitric oxide/nitric oxide synthase, and phosphodiesterase 5 activities [36]. It is believed that hypogonadism results in bladder fibrosis and loss of tissue elasticity, which, in turn, may play a crucial role in explaining the apparent relationship between LUTS and metabolic syndrome [37, 38]. In a randomized controlled study of 52 hypogonadal men with BPH, Shigehara et al. evaluated the effects of testosterone on LUTS. At the 12-month visit, in the treatment arm, there was a significant decrease in International prostate symptom score (IPSS) when compared with baseline (p < 0.05), as well as maximum flow rate and voided volume (p < 0.05), whereas in the control group, no significant changes were observed. Post-void residual showed no significant changes in either group. In addition, the TRT group showed significant enhancement of mean muscle volume (p < 0.05), whereas no significant changes were seen in the controls. The authors concluded that TRT improves LUTS in men with mild BPH symptoms [36]. One randomized pilot study evaluated the effect of testosterone therapy in older men with symptomatic LUTS and low testosterone. Patients were randomized to receive testosterone gel (50 mg/day) for 3 months (n = 10) or testosterone undecanoate (1000 mg) for 26 weeks (n = 20). Both groups attained eugonadal plasma testosterone levels, and Aging Male Survey (AMS) and International Index of Erectile Function (IIEF-5) scores and IPSS improved significantly. Furthermore, there was no increase in prostate volume or PSA level [39]. Amano et al. evaluated patients with hypogonadism and concomitant LUTS (n = 41) treated with testosterone
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352 Khera: Testosterone replacement in normal and pathologic prostate
therapy daily for 3 months. Serum FT and scores from the AMS, Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), IIEF-5, and IPSS and its subscores (postvoiding, storage, voiding symptoms, and quality of life) were assessed pre- and posttreatment. Serum FT levels rose significantly (p = 0.0047; paired t-test), total AMS scores decreased, and scores for the three AMS domains (psychological, physiologic, and sexual disturbance) were significantly reduced. Six of the eight SF-36 domains and erectile function (p = 0.0001; paired t-test), as measured by IIEF-5, improved significantly. Total IPSS and all IPSS domains improved significantly, with marked improvement in voiding function. These authors concluded that TRT is considered to be effective in the improvement of not only ED and late-onset hypogonadism (LOH) symptoms but also LUTS (especially voiding disturbance) of patients with LOH [40]. Karazindiyanoğlu and Çayan prospectively evaluated 25 hypogonadal men presenting with sexual dysfunction and treated for 1 year with testosterone gel (50–100 mg/day). Before and after treatment, patients were evaluated with urodynamic studies (pressureflow analysis) and measurements of prostate volume, PSA, and free PSA. IPSS, AMS, and IIEF-5 scores were assessed. The mean AMS score significantly decreased from 40.4 to 28.8 (p = 0.001), and mean IIEF-5 score significantly increased from 8.84 to 14.36 (p = 0.001). The mean maximal bladder capacity and compliance significantly
increased (p = 0.007 and p = 0.032, respectively), and mean detrusor pressure at Qmax significantly decreased from pretreatment to posttreatment (p = 0.017). These authors concluded that in men with hypogonadism, testosterone therapy may improve LUTS/bladder function by increasing bladder capacity and compliance and decreasing detrusor pressure at maximal flow [41]. Although we have been conventionally taught that testosterone therapy given to hypogonadal men may exacerbate the risk of LUTS, or urinary retention, this belief needs further investigation. Current evidence suggests that TRT may in fact improve BPH and LUTS.
Conclusion Over the past 5 years the rapid growth of the TRT market has challenged us to once again reevaluate the role of TRT in benign and pathologic prostate conditions. Our conventional teaching that TRT causes prostate cancer and worsening of BPH has now come into question. There is a growing body of evidence to support that TRT does not cause prostate cancer and may actually improve BPH symptoms. Much of these findings can be explained by the prostate saturation theory.
Received August 8, 2012; accepted September 17, 2012
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