2. Prostate gland hormonal regulation

the seminal fluid, confers a characteristic odor of this flowing, and participates in the activation of spermatozoa [8]. The ducts of the prostatic glands open into a sulcus located on each side of the urethral ridge, called the prostatic sinus. The prostate is traversed throughout the prostatic portion of the urethra, from the base to the apex, with a slightly curved course in the anterior-

The prostate is anatomically described as an inverted pyramid whose apex is the lowest portion, and which is located about 1.5 cm behind the lower border of the pubic symphysis and is directly related to the upper face of the urogenital diaphragm. The base of the prostate gland is in a horizontal plane that passes through the middle part of the pubic symphysis, and it is directly related to the cervix of the bladder and the inner ostium of the urethra. Inferiorlateral surfaces are convex and are separated from the superior fascia of the pelvic diaphragm by a venous plexus, and are related to the pubococcygeal muscles [6–9]. The posterior surface is flattened and triangular, and it is related to the bladder of the rectum. The anterior surface is narrow and separated from the pubic symphysis by retropubic fat tissue. The upper part is related to the seminal glands and to the lower extremities of the vas deferens, and near its base

Despite not being clearly distinguished anatomically, the following prostate lobes are traditionally defined: right, left and a middle lobe [5–8]. In pathology, the prostate is described in different zones (peripheral zone, central zone, transition zone and anterior fibro-muscular zone) [9]. The right and left lobes are not isolated from each other, being connected, prior to the urethra, by the isthmus of the prostate, constituted by fibromuscular tissue. Their muscular fibers represent the superior continuation of the external sphincter muscle of the urethra to the cervix of the bladder, and it is devoid of glandular tissue. The middle lobe, of variable size, is the part of the prostate that protrudes internally from the upper part of the posterior face of the organ, between the ejaculatory duct and the urethra [5–8]. However, structurally, the middle lobe is indeed inseparable from the right and left lobes. In each prostate lobe we can identify four lobules: (I) Posterior-Inferior, located posterior to the urethra, and inferior to the ejaculatory ducts. It constitutes the face of the prostate, palpable to digital rectal examination; (II) Lateral-Inferior, directly lateral to the urethra, forming the major part of the right or left lobe; (III) Superomedial, deeply to the inferoposterior lobe, surrounding the ipsilateral ejaculatory duct; (IV) Anteromedial, deeply to the inferolateral lobe, directly lateral to the proximal

The superior fascia of the pelvic diaphragm reflects in the superior direction from the visceral fascia of the pelvis to envelop the prostate, and then continues superiorly over the bladder. The portion covering the prostate is dense and fibrous, being called the fascia of the prostate. It is located externally to the prostate capsule and is separated from it, laterally and anteriorly, by the loose connective tissue harboring the prostatic venous plexus. The fascia of the prostate fuses anteriorly with the tendinous arch of the pelvic fascia, which at the level of the pube is called the medial puboprostatic ligament [5–7]. Smooth muscle fibers fulfill this ligament, and it is called the puboprostatic muscle. The lateral puboprostatic ligament extends from the fascia of the prostate to the tendon arch of the pelvic fascia. Inferior to the puboprostatic ligaments, the prostate associates with the medial borders of the pubococcygeus muscle, and

posterior direction, and closer to its anterior face [5–8].

184 Pathophysiology - Altered Physiological States

portion of the prostatic urethra.

presents small depressions for the entrance of the ejaculatory ducts [6].

There are considerable variations related to the prostate anatomy, biochemistry and pathology of several mammal species. In humans, the sexual accessory tissues (or glands) produce high concentration of several biologically active substances, such as fructose, citric acid, spermine, prostaglandins, zinc, proteins including immunoglobulins, and specific enzymes (i.e. esterases and phosphatases) [11].

The growth, differentiation and maintenance of the activity of the prostate gland [12] are mainly controlled by androgens, which is the basis of the anti-androgenic therapies for the treatment of primary prostate cancer. The development and physiology of the prostate is also directly modulated by somatothrophic hormones (such as insulin, prolactin and growth hormone), retinoic acid and estrogen [13, 14], as well as a biomolecular scenario of complex interactions between the epithelium and stroma [15], which sum up to a complicated and poorly understood regulatory mechanism.

Receptors type androgen receptor (AR) and estrogen receptor (ER) are responsible for mediating the physiological effects of androgens and estrogens, respectively [16, 17]. Briefly, the receptor located in the cytoplasm binds to testosterone or dihydrotestosterone, dissociates a heat shock protein (HSP), dimerizes, and it is translocated to the nucleus, where, together with a variety of co-activators and co-repressors, activates or inactivates different sets of genes [18]. The classic AR has 110 kDa and several features in common with members of the nuclear receptor family, such as estrogen receptors, progesterone, thyroid hormones, and peroxisome proliferator-activated receptors (PPARs) [19].

Testosterone and dihydrotestosterone (DHT) act through AR. The AR primarily functions as a transcription factor. It is an extremely important molecule, responsible for the primary male sex differentiation (formation of gonads and external genitalia), and for the pubertal acquisition of the male secondary characteristics (events associated with puberty and adolescence) [20]. It is also liable for most cases of complete androgen insensitivity (resulting in infertile XY karyotype female) [21], and it is deeply associated with the origin of prostate tumors and, particularly, with the recurrence of androgen independent cancer [22–24].

There are several pathological complications, including benign and malign proliferative alterations, often aging escalate-associated, that affect prostate gland. So, studies focusing on the growth regulation and physiology of the prostate are very precious to understand the origin

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

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

187

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].

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

and progression of these pathologies.

4. Prostate cancer

3. Benign prostate hyperplasia (BPH)

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

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

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 replacing testosterone or dihydrotestosterone hormones.

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 be critical in predisposing prostate cancer.

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].

There are several pathological complications, including benign and malign proliferative alterations, often aging escalate-associated, that affect prostate gland. So, studies focusing on the growth regulation and physiology of the prostate are very precious to understand the origin and progression of these pathologies.
