Critical Interpretation of the Studies

The results of the studies summarized above do not provide unequivocal or strong evidence for any particular association between prostate cancer risk and hormone exposure (circulating levels of hormones) or polymorphisms in genes that encode for proteins involved in steroid hormone action or metabolism. The only associations with prostate cancer risk that have been observed consistently in at least three studies are slightly higher circulating testosterone and estrogen levels in high risk African American men as compared with lower risk European American men and a functional polymorphism in the androgen receptor gene; however, these associations are weak at best and mostly not statistically significant. There are no epidemiologic data about prostate cancer risk and exposure to exogenous hormones, including environmental agents with hormonal activity.

Several important points should be taken into consideration in interpreting the above-mentioned observations. First, there are many potential problems with studies that measure circulating hormone levels such as the usually large inter- and intra-assay variability in the immunoassays used [121,173], the fact that typically only single blood samples are studied, and the problem of within-subject variations over time and circadian rhythms. Another difficulty relates to the interrelationships between various hormones [143, 163] which are taken into account in very few studies during data analysis [164]. Second, young Asian men are probably at least partially Westernized in their life-style, and they cannot simply be compared with older Asians. In addition, young men studied today with respect to their hormonal status probably have a prostate cancer risk that is different from the risk currently recorded in older men of the same population, as suggested by the rising prostate cancer rates in Japan. Third, as indicated earlier, the factors that cause the differences in prostate cancer risk between black, white, and Asian men in the US may be different from those that determine differences in prostate cancer risk between Asian or African populations and populations in the US or West European countries. Fourth, circulating hormone levels provide very little information about concentrations at the molecular targets of these hormones in the prostate gland or about steroid hormone metabolic processes within the prostate. For example, less than 10% of circulating DHT is produced by the prostate and a substantial amount of serum 3a,17^-androstanediol glucuronide is derived from non-prostatic sources. Therefore, these two steroids are not very good indicators of prostatic 5a-re-ductase activity [156-158]. Also, aromatase activity has been reported to occur in the human prostate and the LNCaP prostate cancer cell line [180, 181], although there are contradictory findings [182,183]. In addition, estrogen levels in the human prostate exceed those found in the circulation [184], suggesting that local formation of estrogens may occur in the prostate and may contribute to disregulation of prostate growth. Finally, although there are reports of functional polymorphisms in genes encoding for proteins involved in steroid hormone action or metabolism, their influence on steroid hormone metabolizing enzyme activity or steroid hormone receptor activity within the prostate is not known. It is likely that these polymorphisms have only limited and probably cell type-specific influences on these regulatory processes, given the highly complex and often tissue-specific mechanisms of regulation of gene expression.

On the basis of the above-summarized studies, one may hypothesize that prostate cancer risk is positively associated with one or more of the following hormonal factors:

1. Serum levels of (bioavailable) testosterone as indicated by studies comparing healthy low and high risk men [133,134,139,143,146]

2. Serum levels of androgen precursors (DHEA) as indicated by a prospective study [160] and a study comparing healthy Chinese and US Caucasian men (androstenedione) [142]

3. Peripheral and possibly prostatic activity of 5a-reductase [134,142,151,164]

4. Serum levels of estrogens as indicated by studies comparing healthy low and high risk men [62-64,133,134,143]

5. Increased androgen receptor transactivation activity [155,169,170].

However, for each of these hypotheses there are, as indicated earlier, contradictory data, and the observed associations were at best weak.

Two of the four hypotheses implicate higher bioavailable circulating androgen levels in high risk men in comparison with low risk populations [173], suggesting increased androgen production [135]. However, this seems not to be true for all high risk groups. Meikle and co-workers [185, 186] reported that serum levels of testosterone and DHT were significantly lower, not higher, in blood relatives of prostate cancer patients (brothers and sons of prostate cancer patients who have a three- to fourfold excess risk) than in unrelated control subjects. Zumoff et al. [187] observed that circulating levels of testosterone, but not DHT, in prostate cancer patients were markedly lower in those younger than 65 years than those of 65 years and older, whereas control subjects had testosterone levels that were similar to those of prostate cancer patients of 65 years and older. In several of the earlier summarized epidemiologic studies, some hormonal findings were markedly different when comparing younger (18 to 25 -40 years) and older healthy men (over 40 years of age), or comparing younger (less than 62 to 70 years) and older (older than 65 to 70 years) prostate cancer patients with their age-matched controls. Circulating testosterone levels paradoxically decrease with aging, while prostate cancer risk increases [143-145, 188]. At the same time, SHBG levels increase with age and estrogen levels remain constant or increase [143,145,188]. Thus,bioavailable estrogens and particularly testosterone decrease with increasing age and increasing risk for prostate cancer. This may explain the lower prostatic concentrations of DHT with aging reported by Krieg et al. [184], but is in contrast to increasing pros-tatic estrogen levels with aging observed by this group.

These studies suggest that the role of androgens and estrogens in prostatic carcinogenesis may differ in younger men (or perhaps men with early onset prostate cancer) and older men (or men with late onset cancer), and may be different in men that are at high risk because of familial predisposition and those at high risk associated with their ethnic background or living environment. It is also possible that risk-increasing effects of elevated circulating levels of andro-gens and possibly estrogens may be effectuated early in life [133,134,140,142] or even before birth [141], rather than in one or two decades preceding the diagnosis of prostate cancer.

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