Zumoff et al. However, control subjects had testosterone levels that were similar to those of prostate cancer patients of 65 years and older. Circulating testosterone levels are also known to paradoxically decrease with aging, whereas prostate cancer risk increases — , At the same time, SHBG levels increase with age and estrogen levels remain constant or increase , , Thus, bioavailable estrogens and particularly testosterone decrease with increasing age and increasing risk for prostate cancer. This situation may explain the lower prostatic concentrations of DHT with aging reported by Krieg et al.
These observations suggest that the role of androgens and estrogens in prostate carcinogenesis may differ in younger men early onset prostate cancer and in older men 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 androgens and estrogens may be effectuated early in life , , , or even before birth , , rather than in the one or two decades preceding the diagnosis of prostate cancer.
Another risk factor may be increased androgen receptor activity related to genetic polymorphisms in the androgen receptor gene. Although body mass index or obesity does not appear to be a risk factor, there are some indications that muscle mass is positively correlated with risk, perhaps reflecting exposure to endogenous androgens or anabolic steroids. Heavy alcohol use accompanied with liver disease may increase risk and be related with decreased clearance of estrogens and elevated circulating estrogen levels.
Estrogen levels were also elevated in healthy black men living in the United States compared with European-American men, and this is perhaps associated with the very high risk for prostate cancer of black men living in the United States. However, no association between risk and circulating estrogen levels was found in nested case—control studies in predominantly European-American cohorts. Thus, the epidemiologic evidence for involvement of androgenic and estrogenic steroid hormones in human prostate carcinogenesis remains inconclusive The strongest single risk factor for prostate cancer appears to be a western lifestyle, particularly western dietary habits, including a high-fat intake.
It is conceivable that dietary risk factors, such as fat, exert their enhancing effects mediated by a hormonal mechanism that involves androgens 11 , 15 , For example, heavy alcohol use accompanied with liver disease may increase risk and be related with decreased clearance of estrogens and elevated circulating estrogen levels. However, it is unlikely that lifestyle is the sole factor that explains the differences in prostate cancer risk between Asian and American populations 10 , 11 , The single most important combination of risk factors is to be of sub-Saharan African descent and to reside in the United States—African-Americans, as a group, have twice the risk of European-Americans.
The reasons for the black—white disparity in prostate cancer rates in the United States are not understood. Environmental exposures in the broadest sense of the term are probably responsible for a large fraction of this disparity 10 , 11 , 15 , A relation with similar racial disparities in exposure to potential carcinogens and high-risk dietary habits has been proposed 11 , 22 , However, environmentally influenced hormonal mechanisms may be involved as well, possibly acting in utero For example, young, African-American men and pregnant, African-American women have been reported to have higher circulating levels of androgens and estrogens than European-Americans Estrogen levels were also elevated in healthy black men living in the United States compared with European-American men, and this finding is perhaps associated with the very high risk for prostate cancer of black men living in the United States.
The epidemiologic evidence for involvement of androgenic and estrogenic steroid hormones in human prostate carcinogenesis remains inconclusive The most promising hormonal risk factor candidates are elevated circulating testosterone and estrogen levels and polymorphisms in the androgen receptor gene associated with increased receptor transactivation activity. Spontaneously occurring prostate tumors are rare in most species 5 — 7 , , with exception of the dog and, particularly, humans.
It is not understood why prostate cancer is so common in men, whereas it is very rare in almost all other species. There are compelling reasons to implicate hormones, particularly androgenic and estrogenic steroids, in human prostate carcinogenesis, as indicated earlier. The same steroid hormones are also very powerful factors in the induction of prostate cancer in rodent species in which spontaneous prostate neoplasms are rare 15 , 56 , , Pertinent studies concerning the role of androgens and estrogens in experimental prostate carcinogenesis are summarized in the following sections.
It is important to first point out that the various lobes of the rat prostate differ in their propensity to develop prostate carcinomas, either spontaneously or induced by carcinogens or hormones 15 , , The rodent prostate, unlike the human or canine prostate, consists of distinct paired lobes: the ventral, dorsal, lateral, and anterior lobes; the dorsal and lateral lobes are frequently referred to as the dorsolateral prostate, and the anterior lobe is more commonly termed the coagulating gland.
In the human and canine prostate, these lobes have merged into one gland, in which different zones have been defined A homologue of the rodent ventral lobe is not present in the human gland The induced tumors were adenocarcinomas in all studies but one, in which some squamous cell carcinomas were also observed Only the studies reported by Pollard et al. In the only other studies with the Lobund—Wistar strain, a low incidence of prostate cancer was found but a high incidence of seminal vesicle tumors was found , The actual dose of testosterone considerably fluctuated over time in many of these studies from five to 10 times control values down to control values , , but, even when the level of circulating testosterone was kept steadily elevated by twofold to threefold, prostate carcinomas were induced These data indicate that testosterone acts as a complete carcinogen for the rat prostate.
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Noble was the first to demonstrate that testosterone is carcinogenic for the rat prostate. He also established that sequential treatment with testosterone and estrogens was even more effective than testosterone per se in the Noble or NBL rat strain that he developed. Carcinomas developing from the acinar dysplasia in the periphery of the prostate gland have not been observed, but the absence of malignant progression of these lesions, which are morphologically similar to human prostatic intraepithelial neoplasia, has not been established with certainty , When diethylstilbestrol DES was combined with testosterone, the treatment resulted in widespread dysplasia in the ventral prostate, but less or no dysplasia in the dorsolateral prostate Long-term treatment of NBL rats with DES and testosterone induced a low carcinoma incidence in the dorsolateral prostate and some early-stage carcinomas carcinoma in situ in the ventral lobe When the combined testosterone and estradiol treatment was given to Sprague—Dawley rats, dysplasia developed in the same high frequency as in NBL rats, but the incidence of carcinomas was considerably lower , Carcinogenic effects of perinatal exposure to DES on the accessory sex glands in male experimental animals have been described in mice, rats, and hamsters 15 , — In one animal, a lesion was found in the area of the coagulating gland and colliculus seminalis that resembled early neoplasia Of eight prenatally DES-exposed male mice that survived for 20—26 months, one had an adenocarcinoma of the coagulating gland, three had hyperplasia of the coagulating gland, two had hyperplasia of the ventral prostate, one had a carcinoma of the seminal vesicle, and two had squamous metaplasia of the seminal vesicle , No such lesions occurred in control animals.
Prenatal DES exposure of mice also induces testicular tumors particularly of the rete testis and non-neoplastic lesions in the testes and epididymis Subsequent treatment with DHT and estradiol from 9—12 months of age increased the severity of the dysplasia when the prostates were examined at 12 months, suggesting permanent estrogen hypersensitivity of these tissues. Arai et al. One group was neonatally castrated and the second group remained intact.
Two of 11 castrated, DES-exposed rats developed squamous cell carcinomas in the area of the dorsolateral prostate, coagulating gland, and ejaculatory ducts, and all these animals had papillary hyperplasia and squamous metaplasia of the coagulating gland and ejaculatory duct. Squamous metaplasia was also found in some of eight noncastrated DES-exposed rats, but no hyperplasia or neoplasia developed. Vorherr et al.
The results of these studies demonstrate that prenatal and neonatal estrogen exposure of rodents can be carcinogenic for the prostate. Data also suggest that these treatments may imprint permanent alterations in the hormonal sensitivity of the prostate that may play a role in the carcinogenic effect of perinatal estrogen exposure.
Very few reports are available of induction of prostate tumors by chemical carcinogens administered systemically or via the oral or inhalation routes. Direct application of chemical carcinogens to prostate tissue in experimental animals produces sarcomas or squamous cell carcinomas 7 , Short-term hormonal stimulation of cell proliferation in the prostate at the time of carcinogen administration has been demonstrated to increase the sensitivity of the target cells for tumor induction.
However, in some studies, only a very small or no enhancing effect was found of stimulation of prostatic cell proliferation on prostate carcinoma induction by carcinogens , , , Nevertheless, stimulation of cell proliferation appears to be co-carcinogenic for prostate cancer induction by many chemical carcinogens.
This enhancement may not occur if certain requirements are not adequately met , , For example, after a single injection of BOP or MNU given to F rats without concurrent stimulation of prostatic cell proliferation, long-term testosterone treatment did not enhance prostatic carcinogenesis The enhancing effect of testosterone on prostate carcinogenesis is remarkably confined to the dorsolateral and anterior prostate, and no tumors occur in the ventral prostate.
In fact, long-term testosterone treatment produces a shift of the site of DMAB- and BOP-induced carcinoma occurrence from exclusively the ventral lobe to predominantly the dorsolateral and anterior lobes , , The dose—response relationship between testosterone dose and prostate carcinoma yield is very steep. A slight less than 1. These concentrations are within the normal range of circulating testosterone levels in the rat Thus, testosterone is a powerful tumor promoter for the rat prostate.
Cadmium can be carcinogenic for the rat ventral prostate as demonstrated by Waalkes et al. The selective sensitivity of the ventral prostate lobe for the carcinogenic action of cadmium is most likely due to its lack of cadmium-binding proteins These observations indicate that cadmium induces proliferative lesions in the rat ventral prostate only when testicular function, conceivably testosterone production, is intact.
In addition, these data suggest that androgens also act as tumor promoters in this system, but this hypothesis has not been tested. Other mechanisms may also be involved, because, for example, testosterone considerably increases cadmium disposition and retention in the rat ventral prostate These observations suggest that testosterone treatment was required for tumor development, perhaps as tumor promoter Stimulation of prostatic epithelial cell proliferation by androgens during exposure to chemical carcinogens increases the susceptibility of the rat prostate to cancer induction in a co-carcinogenic fashion.
Testosterone appears to be a weak complete carcinogen, but it is a very strong tumor promoter for the rat prostate at near-physiologic plasma concentrations The very powerful tumor-promoting activity of androgens perhaps explains their weak complete carcinogenic activity on the rat prostate.
A slight elevation of circulating testosterone can lead to a marked increase in prostate cancer in rat models. This observation is highly relevant in view of the aforementioned possible weak association between human prostate cancer risk and slightly elevated circulating androgen levels found in some epidemiologic studies Thus, the experimental data provide strong support for the concept that minimal increases in circulating androgens may have substantial enhancing effects on prostate cancer risk.
The addition of estradiol to chronic treatment with testosterone strongly enhances the carcinogenic activity of the androgen for the rat dorsolateral prostate. The sensitivity for the carcinogenic effects of this hormone combination appears to be confined to the periurethral, proximal ducts of the dorsolateral and anterior prostate. The estradiol plus testosterone treatment also induces acinar lesions that are similar to human prostatic intraepithelial neoplasia. These observations strongly suggest a critical role for estrogens in prostate carcinogenesis.
Perinatal estrogen exposure is also carcinogenic for the male rodent accessory sex glands. The periurethral, proximal ducts of the dorsolateral and anterior prostate and seminal vesicle and the intraprostatic urethral epithelium appear to be the most sensitive rodent male genital tract tissue to the carcinogenic effects of perinatal estrogen exposure.
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Such squamous metaplastic changes have also been reported to occur in human fetal prostatic tissue transplanted into nude mice that were subsequently treated with DES These human observations suggest that the DES findings in rodents may have human relevance. As stipulated before, there are compelling reasons to assume that androgens play a critical role in prostate carcinogenesis, and there is experimental evidence to suggest that estrogens are involved as well Because of the hormonal nature of these steroids, receptor mediation has been proposed as the major mechanism by which androgens and estrogens act in the causation of prostate cancer For androgens, mechanisms other than those mediated by androgen receptors seem unlikely, except for the generation of estrogens via aromatization.
For estrogens, however, nonreceptor-mediated genotoxic effects are conceivable, in addition to receptor-mediated processes These various potential mechanisms are discussed in the following sections. First, it is important to emphasize that considerable evidence indicates interactions between epithelial and stromal cells in the normal prostate.
Such interactions are undoubtedly critical and may be essential in prostate carcinogenesis as well, because prostatic mesenchyme is known to be a mediator of androgen action in the developing and adult rodent prostate and possibly the human prostate , No studies, however, have directly addressed the role of stromal—epithelial interaction in human or rodent prostate carcinogenesis. Krieg et al.
DHT concentrations in the epithelium decreased considerably with aging, but they remained stable in stromal cells, whereas testosterone concentrations appeared unaffected by age in either compartment. However, concentrations of estradiol and estrone in the stroma, but not the epithelium, increased markedly with aging. These observations suggest that the prostatic stroma is an important site for both androgen and estrogen action and metabolism, such as aromatase activity, which seems to increase with aging because estrogens accumulate with aging and androgen levels remain stable.
This is unlike the concentrations of estrogens and androgens in the circulation or in epithelial cells, where both decrease. Thus, it is conceivable that with aging and increasing risk for prostate cancer the prostatic stroma continues to be an important androgen signal mediator to the epithelium and is an increasingly important local producer of estrogens. The results of the earlier summarized rodent experiments clearly indicate carcinogenic and strong tumor-promoting properties of androgens, and the results of a limited number of epidemiologic studies provide some support for the notion that androgens may have such effects in humans.
However, the mechanisms of the carcinogenic and tumor-promoting effects of androgens on the rodent prostate are not known with certainty. The very steep relationship between testosterone dose and prostate carcinoma response in rat models is suggestive of involvement of an androgen receptor-mediated mechanism Other mechanisms may nevertheless be involved as well. For example, Ripple et al.
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The postulated role of androgens in human prostate carcinogenesis has been ascribed to their androgen receptor-mediated stimulating effects on prostatic cell proliferation , No direct evidence, however, is available that elevation of circulating testosterone leads to increased cell proliferation in the human prostate. It has been well established that androgen administration to castrated rodents causes elevation of prostatic cell proliferation similar to that observed in cell cycle synchronization experiments with cells in vitro.
However, the increase in prostatic cell proliferation caused by testosterone or DHT administration in castrated rodents is only transient, and after a few days cell turnover returns to its normal very low levels Thus, continued androgen treatment of rodents does not result in permanently elevated cell proliferation rates in the male accessory sex glands, but rather appears to support differentiation. Furthermore, DHT may even suppress prostatic cell proliferation in intact rats Thus, a mere continuous stimulation of cell proliferation is unlikely to be the major mechanism of the enhancing effects of testosterone on prostatic cancer induction in rodents and possibly humans.
Conceivably other, nonhormonal factors affect prostatic cell proliferation. For example, over the lifetime of a man, the prostate undergoes repeated inflammatory insults prostatitis with reactive cell proliferation and generation of reactive oxygen species as possible consequences , , and sexual activity conceivably also affects prostatic cell turnover. Support for a cell proliferation hypothesis is provided by rodent experiments that indicate that increased prostatic cell proliferation at the time of exposure to carcinogens can enhance the sensitivity of the tissue to the carcinogenic effects of these agents , — Stimulation of cell proliferation during carcinogen exposure increases the likelihood that promutagenic DNA damage, such as carcinogen—DNA adducts, will be fixed as permanent mutations.
In humans, increased cell proliferation may thus enhance the carcinogenic effects of low-level exposure to environmental and endogenous carcinogens. The rate of cell proliferation at the time of carcinogen exposure may be only one of several androgen-related factors that determine sensitivity of the prostate to cancer induction by carcinogens through androgen-receptor mediated mechanisms. For example, Sukumar et al. However, this hypothesis has not been critically tested.
These cells could thus have a selective growth advantage over normal cells, which do not respond to chronic testosterone treatment with sustained proliferation It is also possible that androgens, in addition to other factors, influence the effectiveness of indirect-acting carcinogens that are metabolically activated and otherwise metabolized in the prostate itself. Pertinent to any hypothesis implicating androgens in prostate carcinogenesis are considerations related to androgen receptor function and androgen metabolism, from steroid biosynthesis, to conversion of testosterone to DHT and to DHT catabolism.
Functional polymorphisms in the genes that encode for these enzymes and the androgen receptor have been hypothesized to underlie this notion 18 , The evidence for these polymorphisms being important in human prostate carcinogenesis has been summarized in detail and evaluated together with the results of endocrinologic studies in earlier sections.
However, there is stronger evidence to suggest that risk is associated with a functional polymorphism in the androgen receptor gene, short lengths of CAG repeats in the transactivation domain of the protein that are linked with increased transactivation activity in vitro — , , , — However, this association is weak at best.
Several other polymorphisms identified in genes encoding for the androgen receptor and other androgen metabolizing enzymes studied have been unevenly distributed among populations that differ in prostate cancer risk — , , or to be associated with risk in case—control studies — , , , The study of these types of polymorphisms is a rapidly evolving field of investigation and will no doubt lead to significant and relevant new findings in the near future The observation of slightly, but mostly not significantly, higher circulating testosterone levels in high-risk African-American men compared with lower-risk European men suggests that their rates of androgen biosynthesis may be higher.
Although lower as well as higher testosterone concentrations have been found in lower-risk Asian or African men compared with European- or African-Americans, testosterone levels were lower in Asians living in Asia than in American populations regardless of their ethnicity in the only two studies that included Asian populations.
In addition, directly measured testosterone production rates were lower in Chinese in China than in both Chinese-Americans and European-Americans These observations are consistent with the hypothesis that environmental factors, such as diet, determine prostate cancer risk at the population level by influencing androgen production such that they are lower in low-risk than in high-risk circumstances Assessing the role of androgen in prostate carcinogenesis is complicated by the fact that the prostatic stroma is an important site for androgen action and metabolism in the prostate in addition to the epithelium.
For example, epithelial DHT concentrations decline dramatically with aging, but they remain stable in the stroma even though the source for intraprostatic DHT, circulating testosterone, also diminishes with aging.
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These observations illustrate the difficulties in interpreting the results of studies of circulating androgenic or other hormone levels of genomic polymorphisms in relevant genes, because they do not necessarily provide relevant information about what is going on at the level of the prostatic epithelial cell and its important immediate environment, the prostatic stroma. The results of the earlier summarized epidemiologic studies provide limited evidence for an association between prostate cancer risk and circulating levels of estrogens, which appear to be higher in men of African descent younger than 50 years of age than in European-American men.
This observation suggests that estrogens may be involved in prostate carcinogenesis, because men of African descent living in an American environment have the highest risk for prostate cancer of any population. Most of the direct evidence in support for a role of estrogens in prostate carcinogenesis comes from studies with treatment of NBL rats with testosterone and estradiol , It appears that the estrogen-related mechanisms underlying this effect are a mixture of estrogen receptor-mediated and nonreceptor processes, which are discussed in the following paragraphs.
In addition, there is evidence to suggest that the mechanisms involved in hormonal induction of rat prostate cancer, originating from periurethral prostatic ducts, are different from those involved in the induction by testosterone and estradiol of dysplastic lesions developing in the dorsolateral prostate acini. As alluded to earlier, there is evidence for the presence of the CYP19 enzyme aromatase in the human prostate, which could provide a local source of estrogens from conversion of testosterone — , but there are contradictory reports , The local production of estrogens in the human prostate is possibly a stromal process, and stromal aromatase activity may increase with aging Data on the presence of aromatase in the rodent prostate are also somewhat contradictory, because aromatase activity has been reported in the rat ventral prostate and a transplantable rat prostate carcinoma , but it was not detectable in mouse prostate These discrepancies, which may be due to interspecies or methodologic differences, point to the need for further research.
Estrogen receptors are found in the prostate, and Lau et al. Thus, direct receptor-mediated effects of estrogens on the prostate are plausible. However, rodent studies that used antiestrogen treatments tamoxifen and ICI, have yielded contradictory results about the involvement of estrogen receptor mechanisms in prostate carcinogenesis. The prostate tumor-promoting effects of testosterone may involve estrogen generated by aromatization.