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Keywords:

  • predictor;
  • prognosis;
  • prostate cancer;
  • risk;
  • testosterone

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Biosynthesis and metabolism of testosterone
  5. Epidemiological evidence
  6. Tissue-based studies
  7. Testosterone and prostate cancer risk
  8. Testosterone and prognosis for prostate cancer
  9. Testosterone replacement therapy and prostate cancer
  10. Conclusions
  11. References

Abstract:  Relationships between androgenic hormones and prostatic tissue growth are complex. It is certainly true that the prostate will not develop without androgens and the gland will atrophy if androgen support is withdrawn. The hormonal hypothesis remains one of the most important hypotheses in the etiology of prostate cancer (PCa), and efforts are continuing to improve the understanding of androgen actions in PCa. Although evidence from epidemiological studies of associations between circulating levels of androgens and PCa risk has been inconsistent, the traditional view that higher testosterone (T) levels represent a risk factor for PCa appears to have little evidentiary support. Reinvestigation of the relationship between T and PCa seems important and necessary if a new, clinically and scientifically rewarding concept is to be constructed. The present review considers the metabolism and intraprostatic action of T, epidemiological evidence, and the association between T and PCa risk.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Biosynthesis and metabolism of testosterone
  5. Epidemiological evidence
  6. Tissue-based studies
  7. Testosterone and prostate cancer risk
  8. Testosterone and prognosis for prostate cancer
  9. Testosterone replacement therapy and prostate cancer
  10. Conclusions
  11. References

Efforts are continuing to improve the understanding of androgen actions in prostate cancer (PCa). Androgenic hormones are widely accepted to regulate proliferation, apoptosis, angiogenesis, metastasis and differentiation in different ways. The relationships of androgenic hormones to prostatic tissue growth are complex. Certainly, the prostate will not develop without androgens and the gland will atrophy if androgen support is withdrawn.

The androgen-dependence of the prostate makes it appealing to search for a testosterone (T)-related approach to improve diagnostic accuracy for PCa. Multiple T trials of up to 36 months in duration have failed to demonstrate any dramatic acute increase in PCa, and at least 16 longitudinal studies, involving several hundred-thousand men, have consistently failed to show any long-term risk of PCa development from higher levels of endogenous T.1 The historical perspective reveals that there is not now, nor has there ever been, any scientific basis for the belief that T causes PCa growth.1 Discarding this modern myth will allow the exploration of alternative hypotheses regarding the relationship between T and PCa that may be clinically and scientifically rewarding. The present review is aimed at reinvestigating relationships between T and PCa to construct a new concept that finally fits the natural history of PCa.

Biosynthesis and metabolism of testosterone

  1. Top of page
  2. Abstract
  3. Introduction
  4. Biosynthesis and metabolism of testosterone
  5. Epidemiological evidence
  6. Tissue-based studies
  7. Testosterone and prostate cancer risk
  8. Testosterone and prognosis for prostate cancer
  9. Testosterone replacement therapy and prostate cancer
  10. Conclusions
  11. References

Testosterone and dihydrotestosterone (DHT) are the two most important androgens in adult men. Testosterone is the major male androgen in circulation, while DHT is the principal androgen in tissues. In healthy adult men, 90% of circulating levels of T is secreted by Leydig cells of the testes, with 5–10% coming from the adrenal glands. In the circulation, about 44% of T is bound firmly to sex hormone-binding globulin (SHBG), 54% is bound loosely to albumin, and only 1–2% is in a free state. Unlike testosterone, only 25% of DHT in the circulation is secreted by the testes, with most DHT (65–75%) arising from conversion of T in peripheral tissues (such as the prostate and skin) through the action of the enzyme 5a-reductase. Serum levels of total T, free T and DHT decrease with age, while serum levels of estradiol and SHBG increase.2–4

Concentrations of free T, biologically the most active form of T, are most accurately directly measured using the dialysis method, which has been used rather infrequently in epidemiological studies due to the requirements of large sample volumes and time-consuming methodology. However, such direct measurements have been shown to correlate well with indices of free T calculated from total T and SHBG levels.5–8

No consensus has been reached regarding the relative validity of serum free T measures derived from calculated indicators. Parsons et al. used both free T concentration, calculated by the mass action equation, and free T index (FTI).9 FTI was highly correlated with dialysis-measured serum free T, but was potentially less reliable for determining true levels among individuals.7,10 Compared with equilibrium dialysis (the gold standard for measuring serum free T), both the mass action equation and FTI have the potential for introducing error.

Epidemiological evidence

  1. Top of page
  2. Abstract
  3. Introduction
  4. Biosynthesis and metabolism of testosterone
  5. Epidemiological evidence
  6. Tissue-based studies
  7. Testosterone and prostate cancer risk
  8. Testosterone and prognosis for prostate cancer
  9. Testosterone replacement therapy and prostate cancer
  10. Conclusions
  11. References

A growing number of studies published over the past several years have suggested that low T is associated with worrisome features of PCa. For instance, low serum T has been associated with high-grade PCa11–13 (Table 1), more aggressive disease,14 advanced pathological stage at radical prostatectomy (RP)15–17 and shorter survival.18,19

Table 1.  Univariate analysis of relationship between pretreatment testosterone levels and clinical and pathological factors (Yano et al. 200713)
VariableTestosterone (ng/mL)P
MeanMedianRange
  • *

    Well-differentiated vs moderately differentiated, poorly differentiated, or both. DRE, digital rectal examination.

Diagnosis   0.090
 Cancer3.903.7250.90–12.7 
 Not cancer3.663.6500.10–8.56 
DRE   0.806
 Positive3.893.6700.09–8.56 
 Negative3.753.7350.16–12.7 
Pathological Gleason score   0.030
 ≤64.213.950.90–12.7 
 7–103.733.620.09–9.35 
Pathological differentiation   <0.010*
 Well-differentiated4.854.3551.39–12.7 
 Moderately differentiated3.803.680.90–9.35 
 Poorly differentiated3.713.540.09–7.74 

Several studies, but not all, have reported an association between low T and a high Gleason score (GS).1,20 Zhang et al. found lower total T levels in patients with high-grade tumors than in patients with moderate-grade tumors or without PCa.21 Schatzl et al. also reported a significant difference in mean GS between patients with partial androgen deficiency (T < 300 ng/dL) and patients without androgen deficiency (T ≥ 300 ng/dL),12 suggesting that PCa with a high GS shows lower pretreatment T levels. Of note is the fact that both metastatic and locally advanced PCa were included in their study cohort. Another study by Hoffman et al.11 demonstrated that patients with lower T were more likely to display a GS ≥8 along with a higher percentage of positive cores on biopsy. The authors indicated that lower serum-free T might represent a marker for more aggressive disease (any clinical stage with a high GS), but they noted no significant differences based on total T. This finding is unsurprising, as free T is considered the more biologically active form, and the discrepancy may also be attributable to the relatively small patient cohorts.

Other studies have described a relationship between lower T and more advanced disease. Recently, despite a small study cohort, Teloken et al.22 from Brazil reported a preoperative low T level as associated with positive surgical margins in radical prostatectomy (RP). Similar results have been found in a recent study of a large cohort of patients also treated with RP. Massengill et al.15 retrospectively analyzed a large cohort of 879 patients treated with RP from multiple institutions, following different parameters over several years. They showed significantly lower preoperative T levels in patients with non-organ-confined PCa than in those with organ-confined PCa, and the preoperative T level represented a significant predictor of extraprostatic disease in multivariate analysis. These findings have been confirmed in patients of differing ethnic backgrounds by two other investigators.23,24

Our previous study validates these results (Fig. 1).16 Similarly, Isom-Batz et al.17 reported that low preoperative total T was associated with an advanced pathological stage, but not with biochemical recurrence on multivariate analysis. No association between pretreatment T level and GS was shown in the reports of Massengill et al.,15 Imamoto et al.16 or Isom-Batz et al.,17 in which study populations were limited to patients with clinically localized PCa. However, Massengill et al. demonstrated that T level appeared inversely proportional to tumor grade.

image

Figure 1. High pretreatment total testosterone levels predict organ-confined disease in patients treated with radical prostatectomy (Imamoto et al. 200516).

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The limitations of these studies included retrospective designs and diurnal variations in androgen, which were not accounted for in these studies,17 however all were processed at the same laboratory. The precise reasons that led to the request for T measurement were unknown. Body mass index (BMI) and SHBG, which can affect T levels, were unavailable in these studies.16,17 Most investigators assessed sex steroid hormone concentrations at one time point in midlife, although the etiologically relevant time period is unknown. Nevertheless, Platz et al.20 showed a good correlation between two measures of each hormone in blood taken an average of 3 years apart in a subset of men in their cohort, suggesting that a single measurement is reasonably representative of circulating hormone levels in middle age.

The cause of the association between a high risk of PCa and low serum T remains under investigation. Several hypotheses have been suggested as to why the pathological stage is more advanced in men with lower T. T might be lower secondary to chronic disease or as a consequence of advanced disease.25 Alternatively, PCa may inhibit androgens through negative feedback of inhibin, prostate-specific antigen (PSA) or DHT.21,26 Another theory is that with low T, the hormonal milieu might be sufficiently altered to disrupt the normal growth and maintenance of prostatic tissue, while the compensatory hyperplasia that results when the prostate atrophies might lead to cell mutations and a consequent selection of androgen-independent, aggressive prostate cells.15,27

One explanation for the association between low T and PCa is the apparent suppression of T by PCa via the hypothalamic-pituitary axis. Miller et al.26 revealed that T and gonadotropin levels are significantly increased after RP. According to Lukkarinen et al.,28 these endocrine changes were not seen after simple prostatectomy for benign prostatic hypertrophy (BPH). Previous studies have shown that T, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels all rise following RP, but not after transurethral resection of the prostate (TURP).26,29 The authors speculated that the prostate itself (or the transition zone in BPH, at least) does not interfere with the hypothalamic-pituitary hormone axis as far as serum hormone levels are concerned.

These results suggest that one or more factors from a normal or malignant prostate can generate negative feedback in the hypothalamus-pituitary axis. Inhibin is considered a candidate for such an inhibitory factor. Miller et al.26 suggested that inhibin-a produced by PCa cells suppresses the hypothalamus-pituitary axis, resulting in a lowering of T levels. A decrease in prostatic inhibin production after RP could thus explain the endocrine changes seen after surgery. One study has shown decreased inhibin levels after simple prostatectomy.30 According to those data, this effect is specific for PCa, as serum endocrine levels did not change after TURP for BPH and correlated highly with tumor grade. In animal and cell culture models, inhibin produced in the testes and prostate can inhibit the production and secretion of pituitary gonadotropins.31,32 Gosh et al. noted that levels of T and enzymes involved in T production increased in rats after prostatectomy.33 Studies of inhibin have been limited to animal prostates, and the role of inhibin in human prostate tissue thus remains poorly defined. Moreover, Risbridger et al. evaluated tumor expression of inhibin-a in 174 RP specimens and concluded that elevated expression of inhibin-a is related to higher risk of PSA failure.34 Yamamoto et al. also noted an increase in T following RP, with a greater increase seen in the low T group than in the normal T group.35

Tissue-based studies

  1. Top of page
  2. Abstract
  3. Introduction
  4. Biosynthesis and metabolism of testosterone
  5. Epidemiological evidence
  6. Tissue-based studies
  7. Testosterone and prostate cancer risk
  8. Testosterone and prognosis for prostate cancer
  9. Testosterone replacement therapy and prostate cancer
  10. Conclusions
  11. References

Androgens stimulate PCa both in vitro and in vivo. In humans, an increased risk of PCa may depend on increases in testicular production of T, resulting in high levels of circulating androgens, and/or tissue-specific alterations within the prostate increasing androgen stimulation only in the prostate.36

DHT levels in tissue are several times higher than levels of T, but serum levels of DHT are only 10% of the serum levels of T, since most DHT is produced in tissues. Within the prostate, DHT binds to androgen receptor (AR) to form an intracellular DHT-AR complex (T binds to AR with much lower affinity).37 Notably, androgenic action within the prostate is determined by tissue DHT concentration along with several other factors, including the amount of T, the activity of several key enzymes, levels of AR protein and coactivators, levels of growth factors and associated receptors, and perhaps other factors yet to be identified.

A recent report found that men on finasteride, a 5a-reductase inhibitor that inhibits the conversion of T to DHT, displayed a lower overall rate of cancer, but increased risk of high-grade tumors.38 By decreasing intraprostatic T, finasteride might have created an environment for high-grade cancers that were less dependent on androgens for growth.39,40

In another study of interest, low serum T levels in men with newly diagnosed PCa were associated with higher tumor microvessel and AR density, as well as higher GS.41 Yet another study demonstrated that men with PCa have lower circulating androgen bioreactivity.42

Nishiyama et al. reported that intraprostatic DHT levels were significantly reduced in men with PCa and a GS 7–10 compared with men with a GS ≤6.43 This may represent the best explanation for the increased number of high GS cancers in the finasteride arm of the Prostate Cancer Prevention Trial (PCPT),38 since finasteride lowers prostatic concentrations of DHT. However, the emergence of higher-grade PCa in patients treated with finasteride may support the hypothesis that decreases in DHT are associated with more aggressive tumors.38 A wrongly pejorative interpretation of the GS was induced by finasteride, it has been suggested. Recent reports have shown that although finasteride might cause some alterations in the assignment of the GS, no consistent hormonal effect due to treatment has been observed.44,45

These findings suggest that biologically aggressive PCa can exist in a low-DHT environment. One hypothesis that stems from these studies is that PCa is stimulated to dedifferentiate in a T-deficient environment, leading to more aggressive tumors. Some of this dedifferentiation may be reflected by a higher GS, whereas other changes may not be histologically apparent or may not manifest due to higher PSA values.

Nishiyama et al. also found no correlation between serum T or DHT and prostate tissue concentrations of DHT.43 Moreover, Freedland et al.46 recently reported that T might not reflect intraprostatic androgenicity; so simply comparing outcomes between men with low and high T levels might not provide any meaningful insights into associations between low androgenicity and PCa aggressiveness.

Circulating androgen levels can be important for PCa development only if they accurately reflect intraprostatic androgen signaling, however whether they do remains extremely contentious. Humans produce two isoenzymes of 5a-reductase. Both type I and type II 5a-reductase catalyze the conversion of T to DHT. Type 1 enzyme (encoded by SRD5A1) is expressed mostly in skin and hair, while type 2 enzyme (encoded by SRD5A2) is located primarily in androgen target tissues, including genital skin and prostate.47,48 Administration of finasteride, an inhibitor of 5a-reductase type II, leads to a 60–70% reduction in circulating DHT.49,50 Intraprostatic androgen signaling may depend more on the rate of conversion of T by the 5a-reductase II enzyme to DHT, the most potent androgen in the prostate, and on the propensity for AR activation than on circulating androgen levels.36,51,52

Experimental studies have shown that in normal cells, the length of the polymorphic glutamine (CAG) trinucleotide repeat in the AR gene is related to transactivation of AR,53 thereby affecting androgenic action and the growth of prostate cells. Furthermore, variations in the length of CAG repeats in the AR affect DNA transcriptional activity and may also influence development of PCa.52,54,55 Conversely, Platz et al. demonstrated that the overall lack of association of PCa diagnosed in the PSA era with sex steroid hormones and AR gene CAG repeat length is consistent with the hypothesis that these factors do not substantially contribute to the development of early PCa in the PSA era.20 The published reports on sex steroid hormones, AR gene CAG repeat length and PCa has been inconsistent. A possible explanation for the apparent inconsistencies is differences among studies in the extent of early versus late-stage disease.

In future, measurement of both serum T and T in prostatic tissue might be required to further investigate associations between T levels and the prognosis for PCa. A better understanding of the hormonal milieu within the prostate and the relationship with circulating hormones is critical to interpret results from serum-based studies and to expand our knowledge of the role of androgens in PCa.

Testosterone and prostate cancer risk

  1. Top of page
  2. Abstract
  3. Introduction
  4. Biosynthesis and metabolism of testosterone
  5. Epidemiological evidence
  6. Tissue-based studies
  7. Testosterone and prostate cancer risk
  8. Testosterone and prognosis for prostate cancer
  9. Testosterone replacement therapy and prostate cancer
  10. Conclusions
  11. References

Prostatic development and growth depend on androgenic stimulation. In 1941, Huggins et al. published the first report on a relationship between serum T and PCa.56 However, evidence from epidemiological studies of an association between circulating levels of androgens and PCa risk has been inconsistent.

At least 10 modest-sized prospective studies have investigated the relationship, i.e. the association between circulating levels of androgens and PCa risk.57–59 Overall, results from these studies have been inconclusive. Some studies have shown a mildly increased risk,9,60–63 whereas others have demonstrated a mildly decreased risk,64,65 but none have shown any significant association between absolute levels of circulating T, the principal androgen in the circulation, and the risk of PCa.

The difficulties in demonstrating positive associations between serum levels of androgens and PCa in epidemiological settings can partly be explained by several methodological limitations, including limited statistical power in most studies, the relatively small number of incident cases in follow-up studies (<150 cases), the relatively small differences (10–15%) in mean serum levels of hormones between cases and controls, and the somewhat large (5–15%) laboratory variations in intra- and interassays of serum hormone.66

Similarly, several other factors, including body size, physical activity, diabetes and benign prostatic hyperplasia, that might impact serum levels of hormones and have been linked to PCa have not been adjusted for in previous nested case-control studies. In future studies, interrelations among serum hormones and several other factors should be evaluated prior to establishing a model to assess the independent or joint effects of serum androgens and related factors. More sophisticated approaches that incorporate both biological and statistical perspectives are thus needed to clarify the effects of serum androgens.

Recent reports that have discriminated between free and total T have indicated that a low serum level of free T can be associated with PCa compared with healthy men in the same age range. Eaton et al. reported the results from a meta-analysis in which no significant association between T and risk was found in an analysis of data from 8 prospective studies with a total number of 817 cases and 2107 controls.57 Similarly, data from all published prospective studies on circulating levels of total and free T do not support the hypothesis that high levels of circulating androgens are associated with an increased risk of PCa.58

A few studies have investigated associations between serum levels of free T and risk of PCa. No significant association was observed in any of the three studies in which free T was directly measured.63,65,67 However, a significant increase was observed in one study in which bioavailable T was calculated by linear regression adjustment of total T for SHBG.61 Finally, several studies have shown a moderate decrease in risk for high serum levels of SHBG.61,64,65,67 Furthermore, serum levels of T and SHBG are inversely correlated to obesity, which has been inconsistently associated with a weak increase in the risk of PCa.58,68,69 An obesity-induced decrease in SHBG levels decreases T levels through a feedback mechanism of free T on the hypothalamic-pituitary-gonadal axis.58 The fact that obesity is not a protective factor for PCa thus supports the idea that circulating T is not a major risk factor for PCa. The association of sex steroid hormones with PCa may be more evident in leaner men than in overweight and obese men,70 possibly because insulin metabolism and the balance of sex steroids are perturbed in these latter, obfuscating associations for androgens and estrogens.

PCa is one of the most common cancers among Western populations, and incidence is increasing in Asia. Epidemiological and biological differences in PCa are generally believed to exist between Western and Asian men. We therefore previously investigated clinical and laboratory data predicting the probability of a positive prostate biopsy in a Japanese population.13,71 Differences in hormone levels in various racial/ethnic groups have been suggested to account for part of the differences in prostate cancer risk. Racial/ethnic differences in the intraprostatic T/DHT conversion ratio would provide important support for the hypothesis that differences in the enzymatic activity of 5a-reductase within the prostate gland can explain most of the racial/ethnic differences in PCa risk.72,73

Statin et al. observed a modest but significant decrease in PCa risk for increasing levels of total T.5 Several studies have identified relationships between pretreatment serum T levels with clinical PCa stage and patient survival, suggesting that the pretreatment serum T level has potential as a prognostic factor for PCa. Low serum T has been postulated as a marker for PCa.74 Although the cause of the positive association between low T level and PCa risk is unclear, the results might be explained by the suppressive action of the presence of PCa on low T levels in the patient. In a retrospective study among 77 hypogonadal men with PSA <4.0 ng/mL and a normal prostate exam, PCa was found in 11 patients (14%).39 Mean age was only 58 years. At the time, this cancer rate was several-fold higher than any similar series.

In 2001, Hsing reviewed the 12 available prospective studies that had examined relationships between serum androgen levels and PCa.37 Only one study (the Physicians' Health Study), a nested case-control study, suggested any significant relationship between higher T levels and PCa.61 However, this study found no significant difference in the risk of cancer between men in the highest and lowest quartiles for serum T.

Recent reviews have failed to find any compelling evidence to support the notion that T causes PCa growth.75–77 Morgentaler et al. reported biopsy results in a large series of 345 hypogonadal men with PSA levels <4.0 ng/mL.78 The overall cancer rate was similar at 15%, but the most significant finding was that the risk of a positive biopsy increased with the severity of T deficiency. Men with a T level <250 ng/dL had a cancer rate of 21%, compared with 12% for men with a T level >250 ng/dL. In addition, the probability of cancer was more than doubled when men in the lowest tertile were compared to men in the highest tertile for both total T and free T. The combination of low T and a PSA value of 2.0–4.0 ng/mL was particularly worrisome, with a cancer rate of 30%. Although a 15% cancer rate for men with PSA <4.0 ng/mL was also found in the placebo arm of the PCPT,79 men in that series were a full decade younger. One way to look at these results, then, is that low T raises the risk of PCa to the level of men who are a decade older.

These results suggest that hypogonadism offers little protection against the development of biopsy-detectable PCa. Taken together, these various studies suggest that PCa is highly prevalent in men with T deficiency, and that low T confers an increased risk of a high GS and poor outcomes in men already diagnosed with PCa.

Does low T contribute to the development of PCa, or does PCa cause low T? The latter possibility is supported by the observation that levels of serum T increase after radical prostatectomy, suggesting that PCa itself may secrete an agent that suppresses T.21,26 However, the point during the natural history of PCa at which malignant tumors begin to impact on androgen biosynthesis and metabolism remains unknown, and no data comparing pre- and post-diagnostic serum levels of androgens within the same subject are available to provide any insight into the extent of changes in hormone levels in relation to malignant growth. Although such comparisons would be informative, methodological issues such as treatment effects, stress related to surgery and weight loss are considered related to malignancy, and may affect serum levels of hormones in post-diagnostic blood, thereby influencing the validity of the comparison between pre- and post-diagnostic serum androgens.

Testosterone and prognosis for prostate cancer

  1. Top of page
  2. Abstract
  3. Introduction
  4. Biosynthesis and metabolism of testosterone
  5. Epidemiological evidence
  6. Tissue-based studies
  7. Testosterone and prostate cancer risk
  8. Testosterone and prognosis for prostate cancer
  9. Testosterone replacement therapy and prostate cancer
  10. Conclusions
  11. References

Since the report by Morgentaler et al.,39 low pretreatment levels of T have been considered a potential marker for a worse prognosis in patients with PCa. Yamamoto et al.35 examined the predictive value of T for biochemical failure following RP. Among 272 men undergoing RP, 49 had T-values < 300 ng/dL, a commonly used threshold to indicate T deficiency. Ribeiro et al. demonstrated that low T, indicating androgen independence, and younger age, seem to result in a more aggressive disease and poorer prognosis in advanced PCa.14

We have previously reported that a higher pretreatment T level appears predictive of marker response to endocrine therapy, showing a positive prognostic value and indicating good prognosis in patients at the metastatic stage (Tables 2,3).18 However, a higher T level was associated with stage progression of the disease in this study. The suggestion was made that a preexisting low T level may induce growth of less androgen-sensitive cells, as these cells are already accustomed to a low-androgen environment.80 According to one hypothesis, PCa cells that develop in the presence of high-level T may contain a high level of AR, which would make these cells very sensitive to androgen ablation.19 Chen et al. also demonstrated poor responses to hormonal therapy for patients with low pretreatment T81 and, men with high T before androgen ablation presented better survival rates.19,25

Table 2.  Pretreatment plasma levels of testosterone in stage D2 patients classified according to tumor grade, extent of disease (EOD) grade, performance status and marker reaction to endocrine therapy (Imamoto et al. 200118)
  1. Pretreatment serum levels of testosterone (ng/mL) are expressed as mean ± SD. *CR vs**non-CR: P < 0.05. CR, complete response; EOD, extent of disease (bone metastases); Mod., moderately differentiated tumor; NC, no change; PD, progressive disease, Poor, poorly differentiated tumor; PR, partial response; Well, well-differentiated tumor.

Age (years)≤65>65 but ≤75>75 but ≤80>80 
(n = 14)(n = 30)(n = 14)(n = 16) 
Not significant4.48 ± 2.155.28 ± 2.604.20 ± 1.544.94 ± 1.78 
Tumor gradeWell (n = 1)Mod. (n = 35)Poor (n = 36)  
Not significant4.084.83 ± 2.484.88 ± 1.99  
EOD grade0 (n = 11)1 (n = 32)2 (n = 16)3 (n = 9)4 (n = 6)
Not significant5.77 ± 1.725.06 ± 1.783.58 ± 2.025.20 ± 3.204.91 ± 2.82
Performance status0 (n = 6)1 (n = 53)2 (n = 12)3 (n = 2)4 (n = 0)
Not significant6.31 ± 1.544.73 ± 2.134.62 ± 2.374.89 ± 4.79 
Marker responseCR (n = 42)*PR (n = 25)**NC (n = 4)**PD (n = 3)** 
**CR vs non-CR: P < 0.055.32 ± 1.654.21 ± 1.932.89 ± 2.976.20 ± 6.31 
Table 3.  Multivariate analysis of prognostic factors with progression-free survival according to the Cox regression model (Imamoto et al. 200118)
FactorsPRelative hazards ratio95% confidence interval
  1. CR, complete response, EOD, extent of disease (bone metastases); Mod., moderately differentiated tumor; Poor, poorly differentiated tumor; Well, well-differentiated tumor.

Age (>65 years vs≤65 years)0.5611.240.60–2.59
Performance status (2–4 vs 0–1)0.8450.930.43–1.99
Tumor grade (Poor/Well/Mod.)0.1601.590.83–3.06
EOD grade (3–4/0–2)0.0212.281.13–4.61
Marker response (CR/non-CR)0.0500.520.28–1.00
Testosterone (≥4.9/<4.9)0.0330.460.23–0.94

Other investigators have reported results opposite to ours, in which higher T correlated with increased metastatic risk. In a study of men treated with radiation, higher T, particularly levels >500 ng/dL, correlated with increased metastatic relapse, but not with PSA recurrence.82 An important difference compared with our study is that the group did not report the pathological stage. As a consequence, patients might have had more advanced disease than determined clinically, leading to abnormally high rates of disease progression and recurrence.

As reviewed nicely by Yamamoto et al.,35 low T has been shown to be associated with advanced stage at presentation, positive surgical margins, and worse overall survival. A significant postoperative rise in T level was noted, particularly in patients with a preoperatively low T level, suggesting that PCa cells in these patients might produce some substances that suppress T level.

As one of the causes of the positive association between a pretreatment low T level and poor prognosis, PCa cells in patients with a lower pretreatment T level were speculated to produce inhibin-a, resulting in a poorer prognosis. This paraneoplastic effect of PCa is an intriguing area for further investigation.

Testosterone replacement therapy and prostate cancer

  1. Top of page
  2. Abstract
  3. Introduction
  4. Biosynthesis and metabolism of testosterone
  5. Epidemiological evidence
  6. Tissue-based studies
  7. Testosterone and prostate cancer risk
  8. Testosterone and prognosis for prostate cancer
  9. Testosterone replacement therapy and prostate cancer
  10. Conclusions
  11. References

Over the past several years a growing number of studies have been published concerning quality of life in the management of PCa. One of the most important issues comes from the effect of androgen deprivation therapy.83,84 Androgen replacement therapy in the aging male with partial androgen deficiency improved quality of life. However, such treatment is prohibited for men with a preexisting PCa. Despite decades of research, no compelling evidence indicates a causative role for T in PCa.37,60,85–87 The relationship of T and other hormones to subsequent development of PCa has been studied in at least 16 population-based longitudinal studies,5,9,20,37,88–90 but none have shown any direct correlation between total T levels and PCa. Consequently, no support was found for the hypothesis that high levels of circulating androgens within a physiological range stimulate development and growth of PCa.

At the extreme low end of serum T concentration, PCa regression is clearly seen. Raising T levels in men with metastatic PCa who already display castrate T levels does indeed cause PCa growth, however it has been nearly impossible to show that raising T causes an incremental increase in PCa growth beyond the near-castrate range for T. In the review by Morgentaler referring to the association of PCa with testosterone deficiency, also termed hypogonadism, or more simply low T, the concept of saturation was suggested, in which maximal stimulation of PCa growth is achieved at some relatively low concentration of T.1 As T levels below the saturation point, PCa growth would be expected to vary with T concentration.

Strong evidence for this saturation effect comes from a recently published landmark study in which hypogonadal men receiving T therapy for 6 months failed to demonstrate any increase in prostatic concentrations of T or DHT, nor in markers of cellular proliferation, despite a substantial increase in serum T and DHT levels.91

To date, prospective studies have demonstrated a low frequency of PCa in association with T replacement therapy (TRT).92 A compilation of published prospective studies of TRT revealed only five cases of PCa among 461 men (1.1%) followed for 6–36 months, representing a prevalence rate similar to that in the general population.93–99 In the study by Cooper et al. despite significant elevations in serum total and free T, healthy young men did not demonstrate increased serum or semen PSA levels, or increased prostate volume in response to exogenous T injections.100 Rhoden et al. stated that TRT did not increase the risk of PCa growth or development, even in men with high-grade prostatic intraepithelial neoplasia (PIN)101 and that TRT causes only a mild increase in PSA in most hypogonadal men that does not appear to be influenced by mode of TRT, age or baseline levels of PSA or T.102 In a recent report of 31 men who were treated with T for a median of 4.5 years following brachytherapy for PCa, none developed evidence of cancer recurrence, 74% maintained PSA <0.1 ng/mL, and all showed PSA <1.0 ng/mL.103

Taken together, Morgentaler suggested that the old analogy that ‘T acts like food for a hungry tumor’ should be discarded, as higher T does not appear to cause greater PCa growth.104 Instead, the analogy should be: ‘T is like water for a thirsty tumor’, since once the tumor is no longer ‘thirsty’, additional amounts are treated as excess. Morgentaler also advocated dropping the traditional prohibition against offering T therapy to men with a prior history of PCa. Consequently, continued recommendation of prostate biopsy for symptomatic men with low T was supported, not because of any risk about stimulating occult cancer with subsequent T treatment, but because 1 in 7 of these relatively young men will prove to have cancer.1 Given the increased risk of poor outcomes when PCa is identified in men with low T, identifying such patients as early in the clinical course as possible seems to offer the best opportunity for cure.

Dehydroepiandrosterone (DHEA) is the primary steroid precursor of both androgens and estrogens, and represents an abundant circulating steroid hormone. The progressive decrease of this hormone with age has been related to multiple pathologies, such as cancer, diabetes, atherosclerosis, obesity and Alzheimer's disease. PCa progression is slow and can be extended over the course of a decade. One hypothesis is that low levels of T induce changes in the molecular balance of epithelial prostate cells. Accumulation of changes over years in cells may induce deregulations that lead to tumorigenesis.27 Algarte-Genin et al. reviewed recent studies on rats and demonstrated a protective effect of DHEA for PCa.105 DHEA has been shown to inhibit the development of PCa in rats106 and to inhibit the proliferation of tumorigenic cells.107,108

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Biosynthesis and metabolism of testosterone
  5. Epidemiological evidence
  6. Tissue-based studies
  7. Testosterone and prostate cancer risk
  8. Testosterone and prognosis for prostate cancer
  9. Testosterone replacement therapy and prostate cancer
  10. Conclusions
  11. References

In summary, the hormonal hypothesis remains one of the most important hypotheses in PCa etiology. For two-thirds of a century, we have been rigidly single-minded in our concern that higher T levels represent a risk for PCa despite all evidence to the contrary. Although epidemiological data regarding the role of hormones are still inconclusive, many intriguing leads have been unearthed. The traditional view that higher T represents a risk factor for PCa appears to have little evidentiary support. We obviously have much more to learn about the relationship between T and PCa, but at this point the storyline seems likely to differ from the traditional concept that higher T poses an increased risk of PCa. Further studies with large clinical trials are needed to construct predictive models involving pretreatment T levels and other factors.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Biosynthesis and metabolism of testosterone
  5. Epidemiological evidence
  6. Tissue-based studies
  7. Testosterone and prostate cancer risk
  8. Testosterone and prognosis for prostate cancer
  9. Testosterone replacement therapy and prostate cancer
  10. Conclusions
  11. References