Hormones

Endogenous hormones, especially androgens are required for the growth, maintenance, and function of the prostate, affecting both the proliferation and the differentiation status of the luminal epithelium (Kellokumpu-Lehtinen 1985, Naslund, Coffey 1986). The effect of steroid hormones is mediated through nuclear receptors that bind to DNA sequences named hormone response elements in a ligand-dependent manner. Nuclear receptors repress or stimulate transcription by recruiting corepressor or coactivator proteins in addition to directly contacting the basal transcription machinery (Lee et al. 2001).

Studies of androgens and prostate cancer go back over 60 years, for which Charles Huggins won the Nobel prize for his discoveries concerning the hormonal treatment of prostate cancer in 1966 (Huggins, Hodges 1941).

Castration results in the involution of the prostate gland as a result of diffuse atrophy of the luminal epithelial cells, but not the stromal cells (English, Santen

& Isaacs 1987). The replacement of androgen results in the proliferation of the epithelial cells, but once normal volume is attained additional androgenic stimulation does not further increase the size of the gland as a result of balance between proliferation and apoptosis (Bruchovsky et al. 1975, Arnold, Isaacs 2002). Withdrawal of testosterone by surgical or medical castration is a well

known treatment for extracapsular prostate cancer in humans (Tammela 2004).

This treatment is often successful in reducing the size of metastases and bone pain until androgen independent growth is acquired. Furthermore, there are case reports of prostate cancer in men who used androgenic steroids as anabolic agents or therapy for pituitary dysfunction, suggestive of causal relationship between androgens and prostate cancer (Roberts, Essenhigh 1986, Ebling et al.

1997).

Epidemiologic studies of androgen levels and prostate cancer risk have been inconsistent (Meikle, Smith & West 1985, Nomura et al. 1996). Eaton et al.

(1999) performed a meta-analysis from the data of eight prospective studies published during 1966-1998 in order to compare mean serum concentrations of sex hormones in men who subsequently developed prostate cancer with those men who remained cancer-free. There was no evidence that the serum concentrations of testosterone or DHT were different between cases and controls.

However, all five studies (Gann et al. 1996, Nomura et al. 1996, Guess et al.

1997, Vatten et al. 1997, Dorgan et al. 1998) that measured the DHT metabolite androstanediol glucuronide reported a higher concentration among cases relative to controls with a pooled ratio of 1.05 (95% CI 1.00-1.11). This may reflect an increased conversion of testosterone to DHT within prostatic tissue, resulting in increased cell growth and progression from subclinical tumor foci into a clinically manifest form. More recent studies did not detect an association between serum testosterone, sex hormone binding globulin (SHBG), or androstenedione concentrations and the occurrence of subsequent cancer (Heikkilä et al. 1999, Chen et al. 2003). Chen et al. (2003) also measured the levels of 3α-androstanediol glucuronide, but the concentration did not differ significantly between cases and controls (15.08 nmol/l vs. 13.80 nmol/l; P=0.06).

Meta-analysis of prospective epidemiologic studies tentatively suggest that men who would be predicted to have higher intraprostatic levels of DHT based on higher serum levels of androstanediol glucuronide appear to have a higher risk of prostate cancer (Eaton et al. 1999). This hint of a link is now supported by recent findings from the Prostate Cancer Prevention Trial (Thompson et al.

2003). In that trial, 18,882 healthy men with median age of 63 years were randomised to take finasteride, an inhibitor of 5 -reductase type 2, or placebo for seven years. At the time when the trial was stopped, the period prevalence of prostate cancer was 24% lower in the finasteride group than in the placebo group (Thompson et al. 2003). Because the trial period was so short (slightly less than seven years on average), it is likely that many of the men diagnosed with prostate cancer already had one or more foci at the start of the trial. Thus, the trial indirectly suggests that DHT is at least important in the promotion of the growth of existing small prostate tumors. Interestingly, the period prevalence of high-grade cases (Gleason score 7-10) was greater in the finasteride group than in the placebo group, indicating that low intraprostatic DHT due to finasteride treatment may lead to the loss of differentiation of the prostatic tissue (Thompson et al. 2003). However, it is also possible that finasteride merely altered the visual appearance of the epithelium such that pathologists perceived worse histological patterns (Scardino 2003).

Although the development of prostate cancer is dependent upon androgens, animal studies have suggested that androgens alone are insufficient to induce tumorigenesis. Aromatase knockout mouse, deficient in estrogens and elevated in androgens due to a non-functional aromatase enzyme, developed prostatic hyperplasia, but no malignant changes were detected (McPherson et al. 2001).

Excessive exposure to estrogens during critical stages of development or long-term treatment of adult animals with estrogens and androgens leads to prostatic neoplasia (Leav et al. 1988, Bosland, Ford & Horton 1995, Bosland 2000).

Estrogens regulate the development and function of prostate by indirect and direct mechanisms (Härkönen, Mäkelä 2004). The direct effect of estrogen treatment on adult prostate has been best described in rodents. A specific direct response to estrogens is the induction of epithelial squamous metaplasia and it requires estrogen receptor ERα in the prostate (Cunha et al. 2001). Squamous epithelial metaplasia has also been observed in human prostate, detected often after hormonal therapy for prostatic adenocarcinoma (Das et al. 1991, Parwani et al. 2004). Risbridger et al. (2001) showed that transformation of the epithelium involved proliferation of cells with a basal cell phenotype. Aside from direct signaling by estrogen through its steroid receptor, estrogen may influence prostate cancer risk via its mutagenic metabolites. Certain catechol metabolites of estrogen, including 2-hydroxyestradiol and 4-hydroxyestradiol, may be converted in situ into DNA damaging agents (Yager 2000). Estrogens are also believed to have beneficial effects in the prostate. Phytoestrogens, and isoflavones in particular show structural similarities to estradiol and demonstrate a number of anti-carcinogenic properties, including the inhibition of angiogenesis (Fotsis et al. 1993), and tumor cell growth (Geller et al. 1998) although the mechanisms behind these actions are still poorly understood.

Furthermore, oral estrogen treatment with diethylstilbestrol used to be the most common hormonal treatment for prostate cancer. However, it was largely abandoned in the 1970s due to its significant thromboembolic and cardiovascular toxicity (Cox, Crawford 1995). The therapeutic effect of estrogen in preventing prostate cancer was mainly obtained indirectly by feedback inhibition of the hypothalamic release of luteinizing hormone (LH)/follicle stimulating hormone (FSH)-releasing hormone (LRH) leading to lowered serum androgen levels (Härkönen, Mäkelä 2004).

The incidence of prostate cancer rises exponentially in elderly men, in whom the ratio of estrogen to androgen increase due to a decline in testicular function and increase in aromatization of adrenal androgens by peripheral adipose tissue during aging (Gray et al. 1991, Griffiths 2000). However, there is no conclusive clinical evidence of a strong correlation between estrogen/androgen ratio and increase in prostate cancer incidence (Gann et al. 1996, Eaton et al. 1999). Eaton et al. (1999) compared the levels of estrogens, luteinizing hormone and prolactin among human prostate cancer cases and healthy controls in their meta-analysis of eight prospective epidemiological studies. No statistically significant differences were seen.

Differences in endogenous sex hormone levels have been hypothesized to explain ethnic differences in prostate cancer risk. According to de Jong et al.

(1991), plasma levels of testosterone and estradiol were significantly lower in 258 Japanese men, when compared to 368 Dutch men. Probably as a result of this difference in testosterone levels, the testosterone:SHBG ratio was lower among Japanese men, while DHT:testosterone ratio was higher. In contrast, Wu et al. (1995) showed that the DHT:testosterone ratio was highest in African-Americans, intermediate in whites, and lowest in Asian-African-Americans, corresponding to the respective incidence rates in these groups. Platz et al.

(2000) measured the concentrations of testosterone, DHT, androstanediol glucuronide, estradiol and SHBG in a sample of 43 African-American, 52 Asian and 55 white US male health professionals. In their study steroid hormone levels did not vary appreciably by race. Similarly, Cheng et al. (2005) did not detect any correlation between ethnic background and androgen levels when they examined testosterone and 3α-androstanediol glucuronide levels among Singapore Chinese, African-American, US white, US Latino and Japanese-American men.