CHAPTER ONE

INTRODUCTION

Benign prostatic hyperplasia (BPH) is the nonmalignant enlargement of the prostate gland. It refers to stromal and glandular epithelial hyperplasia that occurs in the periurethral transition zone of the prostate that surrounds the urethra. BPH clinically manifest as lower urinary tract symptoms (LUTS) consisting of irritative (urgency, frequency, nocturia) and obstructive symptoms (hesitancy, a weak and interrupted urinary stream, straining to initiate urination, a sensation of incomplete bladder emptying) (Miller and Tarter, 2009). Prolonged obstructions may eventually lead to acute urinary retention (AUR), recurrent urinary tract infection (UTI), hematuria, bladder calculi, and renal insufficiency (Curtis, 2006). The prevalence of LUTS due to BPH increases with increasing age. Moderate to severe symptoms occur in 40 and 80% of men after the age 60 and by 80 years, respectively. Nearly all men develop microscopic BPH by the age of 90 years (Ogunbiyi and Shittu, 1999). It is also described as quality of life disorder, affecting manÕs ability to initiate or terminate urine flow stream (the symptoms interfere with the normal activities), and reduces the feeling of well being. The causes of BPH are not fully known, but the overgrowth of smooth muscle tissue and glandular epithelial tissue is attributed to a number of different causes such as aging, late activation of cell growth, genetic factors, and hormonal changes (Wang and Jicun, 2015).

1.1 Epidemiology

Benign prostatic hyperplasia (BPH) is a histological diagnosis associated with unregulated proliferation of connective tissue, smooth muscle and glandular epithelium within the prostatic transition zone (Auffenberg et al., 2009). Prostate tissue is composed of two basic elements: A glandular element composed of secretory ducts and acini; and a stromal element composed primarily of collagen and smooth muscle. In BPH, cellular proliferation leads to increased prostate volume and increased stromal smooth muscle tone. McNeal, (1984) describes two phases of BPH progression. The first phase consists of an increase in BPH nodules in the periurethral zone and the second a significant increase in size of glandular nodules (McNeal,

1984).

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BPH may cause physical compression of the urethra and result in anatomic bladder outlet obstruction (BOO) through two distinct mechanisms: First, an increase in prostate volume, termed the static component; second, an increase in stromal smooth muscle tone, termed the dynamic component (McVary, 2006). BOO, in turn, may present clinically as lower urinary tract symptoms (LUTS), urinary tract infections, acute urinary retention (AUR), renal failure hematuria, and bladder calculi (Stroup et al., 2012).

Notably, two factors complicate the natural history and clinical presentation of BPH, BOO and LUTS; first, prostate volume does not linearly correlate with the severity of BOO or LUTS; and second, progressive BPH and BOO can lead to primary bladder dysfunction, which in turn can exacerbate the severity of LUTS independently of BOO(McVary, 2006). Collectively, BPH, BOO and LUTS are associated with increased risks of mortality, depression, falls and diminished health-related quality-of-life as well as with billions of US dollars in annual health expenditures (Tailor et al., 2006).

In the last decade, epidemiological models of BPH and BOO have evolved substantially. Although age and genetics play important roles in the etiology of BPH and BOO, recent data have revealed novel, modifiable risk factors that present new opportunities for treatment and prevention. These risk factors appear to potentially influence the natural history of BPH and BOO throughout the different stages of clinical progression (Tailor et al., 2006).

1.2 Prostate Anatomy and Histology

The human prostate is a compact walnut-sized musculoÐglandular organ in contact with the inferior surface of the bladder, weighs about 20 gm in adult males and forms part of the malesÕ reproductive system. The gland is made up of two lobes or region, enclosed by an outer layer of tissue and is located in front of the rectum and just below the bladder. It also surrounds the urethra (Leissner and Tisell, 1979).

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Fig. 1: The prostate and nearby organs (Leissner and Tissel, 1979)

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ÒThe prostate gland is dependent on the hormonal se cretion of the testes for growth and development (Ball and Risbridger, 2003). The prostate growth accelerates at sexual maturity due to androgen action on both stromal and epithelia cells (Verhamme et al., 2002). Between the ages of 31 and 50 years the prostate doubles in size every 4-5 years. Between 51 and 70 years doubling time increased to 10 years and over 70 it reaches 100 years. In other words, after the age of 70 years the prostate may have almost attained its possible maximum size (Verhamme et al., 2002).

The human prostate is divided into three anatomically distinct-zones: peripheral, transitional and central zones which are surrounded by a dense and continue fibro-muscular stroma (McNeal, 1984). BPH, a non malignant overgrowth found in older men mainly develop in the transitional zone while prostate cancer (PCA) arises primarily in the peripheral zone (Abate and Shen, 2000). At histological level human prostate contains mainly two types of cell that are called epithelial and stroma cells and in ratio of 2:1 in human (Mayers and Robert, 2000). The epithelial cell layer is composed of four differential cell types known as basal, secretary, luminal neuroendocrine (NE) and transitional amplifying cells that are identified by their morphology, location and distinct marker expression. The basal cells form a layer of flattened to cuboidal shaped cells above the basement membrane and express p63, a homology of tumor suppressor genes (p53), an antiapoptic factor, cluster designation (CD44), hepatocytes growth factor (HGF) and higher molecular weight cytokeratins (CK5and14) (Mayers and Robert, 2000). The expression of androgen receptor (AR) is lower or undetectable in the basal cells which makes the basal cell independent of androgens for their survival (Mayers and Robert, 2000). The Lumina cells are the major cell types of prostate that form a layer of columnar Ð shaped cells above the basal layer and constitute the exocrine compartment of the prostate, secreting prostate- specific antigen (PSA) and prostatic acid phosphatase (pap) into the lumen. They are terminally differentiated and is not androgen dependant and non proliferating cells expressing low molecular weight CK8 and 18, CD 57 and P27kipl (a cell cycling inhibitor). Neuroendocrine cells are rare cells scattered in the basal and Lumina layer of the prostate and terminally differentiated and is not androgen insensitive cells, expressing chromogranin A, synaptophysin and Neuro-specific enolase (NSE). Additionally, there is small group of intermediate cells referred to as transitional amplifying cells (TA) that express both basal as well as luminal cell markers and PSA (Ball and Risbridger,2003). The epithelial layer is surrounded by a stromal layer, which forms a peripheral

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boundary of the prostate gland. The stromal cell layer consist of several types of cell that include smooth muscle cells, (the most abundant cell type in stromal) fibroblasts and myofibroblasts. The stromal cells express mesenchymal markers such as CD34, CD44, CD117 and CD90 (McNeal, 1984). Prostate epithelium is structurally and functionally, a highly complex tissue composed of multiple differentiated cell types, including basal, luminal and neuroendocrine cells with small population of relatively undifferentiated cells generally known stem cells that are endowed with self renewal and differentiation (Pece et al., 2010).

1.2.1 Functions of the Prostate

The prostate makes some of the fluid for semen, may keep urine out of the semen probably because of presence of the internal urethral sphincter complex within the prostate gland (Rosenthia, 2012). The prostate gland secretion contain, milky fluid that contains calcium citrate, phosphate ion, a clothing enzyme and profibrinolysin. During emission, the capsule of the prostate gland contract simultaneously with the contraction of the vas deference so that the thin milky fluid of the prostate add further to the bulk of the semen which may be slightly alkaline. The alkaline nature of this semen is quite important for successful fertilization of the ovum (De Jong et al., 2014). The fluid of the vas deference is relatively acidic owing to the presence of citric acid and metabolic end product of the sperms and consequently, help to inhibit sperm fertility and probably the slightly alkaline prostatic fluids help to neutralize the acidity of the seminal fluids during ejaculation and thus enhance the motility and fertility of the sperm. The prostatic fluid also contains prostatic specific antigen (PSA) which liquefies semen in seminal coagulum and allows sperm to swim freely (Morgan et al., 2011). The fluid also contains some metals such as magnesium, zinc, calcium, selenium which are needed for prostate function (Morgan et al., 2012).

1.2.2 Causes of Prostate Enlargement

The cause of prostate enlargement is unknown, but most agree that it is linked to changes in hormonal levels in a manÕs body due to ageing (Quinn and Babb, 2002). In some men, the symptoms are mild and do not require treatment. In others, symptom can be very bothersome and have a major impact on menÕs quality of life (Aghaji and Odoemene, 2008). As men age, the prostate cells growth become less well controlled by cell signaling activity. Also, cells in prostate

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become less responsive to the signals that reduce apoptosis or programmed cell death. This result in an over abundance of cells in the prostate (Berry et al., 2008). This break down in cellular

regulation that occurs with age allows prostate cells to proliferate and promote the formation of
additional tissue which is a smooth muscle and tend to increase in the overall muscle tone of
the prostate and can contribute to` blockage of the urinary tract (Roehrbornet al., 2011).

Derivative of testosterone called dihydrotestosterone (DHT) stimulate growth of the prostate (Obidoa, 2007). DHT is derived from testosterone via conversion by enzyme 5? -reductase which is an important pharmacologic target for BPH therapies (Seftel et al., 2008). Globally, the numbers of BPH patients are increasing with its attendant consequences. The increase may be as a result of increased dependency on synthetic food product that are deficient in vital element that correlate with prostate growth, or the increase may be because of lack of early diagnosis, increase rate of obesity among men, increased sedentary life style of men, increase rate of smoking and lack of early management and prevention due to insufficient knowledge of etiological causes. The growth of prostate may probably be due to physiological response to stimulation of the gland by the relative increase of male hormone testosterone over the depreciating female hormone ÒestrogenÓ concentratio n as men age (Akang et al., 2006).

The response of prostate to the imbalance in testosterone level may be that, at early stage of manÕs life, the 5-alpha-reductase enzyme that reside in the prostate exists mostly in inactive form due to increase in the level of blood testosterone following increased synthesis by the testes.

But as one continues to age, the activity of the 5Ð alpha-reductase enzyme may increase following decreased in testosterone synthesis, by the testes. The decrease in testosterone synthesis by the testes may result from decrease absorption and utilization of zinc by the cells of seminiferous tubules which may become less responsive to zinc utilization. The decrease in testosterone level may also result from the activity of the 5 Ð alpha-reductase enzymes that convert free testosterone to dihydrotestosterone. Dihydro-testosterone has more affinity for binding on the androgen receptor (AR) site on the surface of the prostate gland than does testosterone. The binding of the dihydrotestosterone to androgen receptor may result in conformational changes in the receptor leading to alteration of cell regulation (Akang et al., 2006).

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1.2.3 Conversion of Testosterone to Dihyrotestosterone in the Prostate

Stimulation of the prostate causes testosterone to enter the cell and, if 5-alpha reductase is present, it is converted into dihydrotestosterone, which binding to the androgen receptor(AR), causes a conformational change in the receptor, this in turn cause dissociation of heat shock protein transport from the cytosol into the cell nucleus, and causes dimerization to occur. The androgen receptor dimer binds to a specific sequence of DNA known as a hormone response element (HRE)which result in interaction with other protein in nucleus resulting to up or down regulation of specific gene transcription (Paracchiniet al., 2003). The up regulation or activation of transcription result in increase synthesis of messenger RNA which, in turn is translated by ribosomes to produce specific protein (Paracchiniet al., 2003). One of the known target genes of androgen receptor activation is insulin, like growth factor 1(IGF-1) (Routh and Lerbovich, 2005). These changes in the level of protein in cells, may be one way that androgen receptor control cell behaviour (Vlahopoulis et al., 2005). One function of androgen receptor that is independent of direct binding to its target DNA sequence is facilitated by recruitment via other DNA binding protein that activate several genes that cause muscle growth (Fu et al., 2009).Androgen receptors are modified by acetylation, which directly promotes contact, independent growth of prostate cancer cells (Davison and Bell, 2008). Other risk factors for developing BPH include obesity, lack of physical activity, erectile dysfunction (Sadleret al, 2010).