3. Benign prostate hyperplasia (BPH)

karyotype female) [21], and it is deeply associated with the origin of prostate tumors and,

The most striking androgen dependence of the prostate gland is observed by hormonal or surgical castration. In a rat model, removal of the testes results in prostate involution to approximately 10% of its original size after 21 days. Epithelial cells death and stroma reorganization are responsible by such event [25]. Similar to AR, estrogen receptors (ERs) belong to the family of nuclear receptors. The two subtypes, ERα and ERβ, have different physiological roles. They share homology with each other, but are the products of different genes [26]. Both ERα and ERβ are expressed in the prostate. In adults, ERα and ERβ are preferentially found in the stroma and in the epithelium, respectively [27]. Similarly to the AR, ER expression might be suppressed by methylation of its promoters, and this epigenetic alteration was suggested to be involved in both benign prostatic hyperplasia and prostate cancer development [28, 33].

The action of estrogens on prostatic ductal morphogenesis and cell differentiation is complex [14]. However, a brief exposure of rodents to estrogens during neonatal development causes irreversible and dose-dependent effects on morphology, cellular organization and function of the gland [29, 30]. Reduced prostate size at adulthood was associated with decreased responsiveness at puberty due to reduced AR content [31]. The reduced AR levels were justified by

Estrogen exposure to occasional doses during the gestation period causes increased concentrations of androgen receptor in mice, ductal budding and prostate weight later in the adulthood [34]; whereas the neonatal exposure to high doses compromises the growth epithelial differentiation, and accounts for changes in the secretory function, as well as for incidence of prostatic intraepithelial neoplasia (PIN) and prostatitis [14, 29]. The effect of high doses of estrogens on the neonatal prostate is due not only to the changes in the androgen concentrations, via permanent actions on the hypothalamic-gonadal pituitary gland, but also due to direct effects on the prostate gland, since the administration of testosterone is not able to reverse those

High doses of estrogen administered in adult animals function as castration, resulting in the inhibition of the hypothalamic-pituitary-gonadal axis, by suppression of the gonadotrophin releasing hormone, and consequent blockage of the hormone testosterone by the testes [36, 37]. Nonetheless, such effects can be reversed (contrary to those observed in neonates), by

It is well established that some of the circulating androgens are converted into estrogens in various peripheral tissues by the enzyme aromatase [38]. The aromatase was also identified in the human prostate, suggesting that this gland is able to perform the aromatization reaction and it is a feasible local source of estrogen production [39]. Estrogens acts in target cells all over the body and in addition to sexual organs they influence growth, health and cell activity. Despite early work of estrogens used as therapy for androgen-resistant prostate cancer, it can

Estrogens also participate in several pathological changes in the prostate; among the very well described pathologies is the induction of chronic inflammation [40, 41], squamous metaplasia

reported in several species of mammals [42–44], and human prostate cancer [45].

particularly, with the recurrence of androgen independent cancer [22–24].

186 Pathophysiology - Altered Physiological States

increased proteasomal degradation of AR protein at postnatal day 10 [32].

effects [35]; this phenomena is known as estrogenic imprinting.

replacing testosterone or dihydrotestosterone hormones.

be critical in predisposing prostate cancer.

Benign prostate hyperplasia (BPH) is a common urological issue that causes prostate enlargement in men after 40-years-old. It is a noncancerous augmentation of the prostate gland size, with stromal and glandular epithelial hyperplasia in the transition zone. It is estimated that 50% of 50 year old, and 75% of 80 year old men could have some lower urinary tract symptom (LUTS). In such condition the urethra can be partially or totally blocked, resulting in urinary retention, weak urination stream, incomplete bladder emptying and hesitancy; and so carrying secondary problems as urinary tract infections, bladder stones and chronic kidney disease, culminating in kidney failure. The LUTS is reflection of the hormonal changes rising with age, and resulting in abnormal stromal and epithelial cell proliferation (hyperplasia) in the transition zone of the prostate. The molecular etiology of these events remains unclear, but few studies attempt to correlate it to sex steroids hormones [46], also known as gonadocorticoids and gonadal steroids, that interact with vertebrate androgen and estrogen receptors. It is important to mention that the BPH is generally not a precursor lesion to a prostate cancer (PCa) condition.

Some animal models studies, including dogs and chimpanzees, have been performed in order to understand the prostate conditions. Chimpanzees sporadically suffer from age-associated BPH, and are the closest match to human prostate gland. Throughout the time, dogs are like human counterpart because they develop BPH containing distinct nodules of hyperplasia with diffuse areas of compression of the rectum producing constipation, a symptom opposed to the urinary retention in men [47, 48]. In order to supply these deficiencies, some transgenic animal models using other normal mammal species were developed. Prostate-specific 15-LOX-2 transgenic mouse and PPAR∂ knockdown mice naturally develop increased prostate size with age, in addition to epithelial-hyperplasia, and prostatic intraepithelial neoplasia progression [49, 50].

#### 4. Prostate cancer

Nearly 14 million new cases of cancer occurred worldwide during 2012 [51], generating around 8.2 million deaths. More than a half of cancer deaths arose in countries of medium or low human development index (HDI). The four most common types, in this order were lung, female breast, bowel and PCa. Among malignant neoplasms that affect men, PCa is the most common, after non-melanoma skin tumors, especially in the male population from the sixth decade of life. This is a recognized public health problem, since according to data from the Mortality Information System (MIS), 13,773 deaths were caused by PCa in Brazil in 2013 [52].

Considering the statistics worldwide, PCa prevalence is only beaten by lung cancer in men. Unlike some types of tumors, the incidence of PCa has increased over the years. There are two main factors for this association: the improvement of diagnostic methods and the extended life expectancy of men over the years; since PCa has slow growth and its incidence is ageassociated, it is very comprehensible the increased detection of this malignant neoplasia lately in the years. The origin of PCa and the several processes giving direction to PCa carcinogenesis are still unclear, but often are assumed that several components may influence it, among which stands out: diet, genetic, hormonal, and environmental factors; all currently being widely investigated in the literature.

[58], benign prostatic hyperplasia [59], prostatic biopsies [60] and trauma, due to prostatic cell

An Overview on Prostate Pathophysiology: New Insights into Prostate Cancer Clinical Diagnosis

http://dx.doi.org/10.5772/intechopen.74269

189

Despite results enhancing detection at earlier stage and decreasing the number of metastatic patients, the use of prostate-specific antigen (PSA) to detect PCa has low specificity, unnecessary biopsies and frequently mistaken diagnoses. Also, PCa has various features so prognosis following diagnosis is greatly variable. Hence, there is a requirement for new prognostic biomarkers, particularly to differentiate between inactive and aggressive forms of the disease, to improve clinical management of PCa patients. Research continues into finding additional

In order to improve the specificity of PSA as a tumor biomarker, tests called PHI (Prostatic Health Index), that predicts the risk of having PCa and 4 K score™ (predicts the risk of having high-risk of PCa) were launched on the American and European markets [62]. 4 K score™ blood test combines 4 prostatic biomarkers (total PSA, fPSA, intact PSA, and human kallekrein 2(hK2)) with the age of the patient, the digital rectal exam (DRE) findings (presence of a nodule or not), and the result of previous biopsies [63]. The higher the score, the greater the probability of finding tumor cells in a biopsy (Gleason ≥ 7). This test combination is interesting because it does not allow unnecessary biopsies to be performed, whereas post-operative, as well as any surgery,

has risks and can lead to future complications for the patient, affecting his quality of life.

Another non-invasive test available is the ExoDxTM Prostate (IntelliScore) Test18, which, through urinalysis, assesses the risk of developing invasive PCa, and thereby target the best treatment by molecular analysis of three specific genes in exosome and microvesic RNAs released by tumor cells, called extracellular vesicles (further discussed in this chapter) [64]. These related genes (ERG, PCA3 and SPDEF) are most commonly related to tumor progression

It is important to note that these tests are not accessible to the entire population, either because of the high cost of the technology, or because some countries have still not approved it. Thus, the main diagnostic method used nowadays for the screening and detection of the PCa remains PSA testing and rectal examination (DRE). If the results of these exams are altered, a biopsy is necessary to confirm the diagnosis, and determine the aggressiveness and prognosis of the cancer. This is done by histological analysis of the biopsied tissue, following classification according to the Gleason Scale. This system consists of the sum of 2 values that represent the degree of the tumor, and that determine the dominant cellular pattern and the most frequent cellular pattern, respectively. Tumor grades range from 1 to 5, the former representing more differentiated and prostate restricted tumors, while the latter represents totally undifferentiated tumors that have normally infiltrated the glandular stoma. The score, therefore, ranges from 2 (1 + 1) to 10 (5 + 5), and values below 4 on the Gleason Scale represent a well differentiated PCa; between 5 and 7, an intermediate PCa; and between 8 and 10, advanced PCa [66]. The determination of the degree and stage of cancer allows classification into high,

The clinical picture of castrated-resistant prostate cancer (CRPC) is quite heterogeneous, ranging from the asymptomatic increase in the PSA indices to the distant metastasis (commonly bone metastasis), with an important impairment of the patient's quality of life [66]. This is a

lysis releasing PSA into the bloodstream [61].

markers that may allow this goal to be attained.

and, consequently, its aggressiveness and invasion [65].

intermediate and low risk categories.

The treatment of PCa can be very controversial because there are many variables, such as the patient's age, prostatic specific antigen (PSA) concentrations and the stage of the tumor. Patients in inoperable conditions, due to age, are treated with hormone therapy or radiation. The most common hormone therapy for PCa is the androgen deprivation, since the prostate gland is a highly androgen dependent gland, and because the majority of prostate tumors originate from androgen-dependent glandular epithelial cells of the prostate [53]. The therapies in use for PCa will be best addressed later in this chapter.
