Biochemical Changes Associated With Benign Prostatic Hyperplasia (Bph) In Ageing Men Attending Clinic At University Of Nigeria Teaching Hospital
This study was aimed at investigating biochemical changes associated with benign prostatic hyperplasia in ageing men attending clinic at the university of Nigeria Teaching Hospital, Ituku-Ozalla, Enugu State, Nigeria. The assessment included 50 men with BPH attending clinic in addition to 50 healthy men (control). All samples were divided into 5 groups and with varying age ranges (Group 1: Normal control, Group 2: BPH patients ≤ 60 years, on treatment, Group 3: BPH patients ≤ 60 years, not on treatment, Group 4: BPH patients ≥ 60 years, taking treatment, Group 5: BPH patients ≥ 60 years, not on treatment).PSA levels of BPH positive subjects under treatment increased significantly (p < 0.05) compared with the control. There was a significantly (p < 0.05) high level of calcium in subjects who were ≤60 years of age that are on treatment compared with group 1 (control). Also, the level of blood urea nitrogen (BUN) recorded a high significance (p < 0.05) in comparison to the normal control. In the same study, zinc level decreased non-significantly (p > 0.05) in the groups under investigation and the level of sodium in the blood of positive treated and untreated BPH patients was non-significantly (p > 0.05) high when compared to the healthy subjects. Iron level showed a non-significant (p > 0.05) elevation in subjects ≤ 60 years of age who were on treatment and a significantly level (p < 0.05) in the other groups under investigation. Furthermore, there was a significant (p<0.05) elevation in the level of potassium ion concentration of BPH patients of group 2 and 5 as was also observed in the levels of magnesium group 2 and 4; though, the level of magnesium dropped significantly in BPH untreated group (group 3 and 5). The result of this study also showed a non-significantly (p > 0.05) higher level of selenium in BPH positive patients of all the groups under investigation compared with group 1 (normal control) while creatinine levels showed a significant (p< 0.05) elevation in all the groups being investigated when compared with group 1.
TABLE OF CONTENTS
Table of contents
List of figures
List of Abbreviations
CHAPTER ONE: INTRODUCTION
1.2 Prostate Anatomy
1.2.1 Functions of the prostate
1.2.2 Causes of prostate enlargement
1.2.3 Conversion of testosterone to dihydrotestosterone in the prostate
1.3 Complications of prostate enlargement
1.3.1 Effect of enlarged prostate on the bladder
1.3.2 Effect of enlarged prostate on sexual performance
1.4 Symptoms prostate enlargement
1.5 Diagnoses of BPH
1.5.2 A urine culture
1.5.3 A prostate specific antigen (PSA) test
1.5.5 Pressure-flow urodynamic studies
1.5.7 Filling cystometry
1.6 Chemotherapeutic agents used in the treatment of BPH
1.6.1 Alpha-1-adrenergic receptor blockers
1.6.2 5-alpha-reductase inhibitors
1.7 Surgical treatment of BPH
1.7.1 Dietary and lifestyle consideration
220.127.116.11 Eating vegetables
18.104.22.168 Weight loss
1.7.2 Targeted nutritional interventions
1.7.3 Pygeum africanum
1.8 Biochemical markers associated with BPH
1.9 Biomarkers of prostate enlargement
1.9.1 Prostate specific antigen
1.9.2 Metallic prostatic antioxidants (Zinc and selenium)
1.9.3 Renal function test (creatinine and blood urea nitrogen)
1.9.4 Minerals (Potassium, Iron, Magnesium, Calcium, Sodium)
1.10 Aim and Objectives of the Study
1.10.1 Specific Objectives of the Study
CHAPTER TWO: MATERIALS AND METHODS
2.1.1 Sample collection
2.1.2 Chemicals and reagents
2.2.1 Sample collection
2.2.2 Experimental design
2.2.3 Determination of Prostate Specific Antigen (PSA) Level
2.2.4 Determination of calcium concentration
2.2.5 Determination of magnesium concentration
2.2.6 Determination of sodium concentration
2.2.7 Determination of potassium concentration
2.2.8 Determination of Iron concentration
2.2.9 Determination of selenium concentration
2.2.10 Determination of creatinine concentration
2.2.11 Determination of Blood Urea Nitrogen
2.2.12 Determination of zinc concentration
2.3 Statistical analysis
CHAPTER THREE: RESULTS
3.1 Prostate specific antigen (PSA) level of Normal and Benign Prostatic Hyperplasia subjects attending clinic
3.2 Calcium concentration of Normal and Benign Prostatic Hyperplasia subjects attending clinic
3.3 Blood urea nitrogen of Normal and Benign Prostatic Hyperplasia subjects attending clinic
3.4 Zinc concentration of Normal and Benign Prostatic Hyperplasia subjects attending clinic
3.5 Sodium concentration of Normal and Benign Prostatic Hyperplasia subjects attending clinic
3.6 Iron concentration of Normal and Benign Prostatic Hyperplasia subjects attending clinic
3.7 Potassium concentration of Normal and Benign Prostatic Hyperplasia subjects attending clinic
3.8 Magnesium concentration of Normal and Benign Prostatic Hyperplasia subjects attending clinic
3.9 Selenium concentration of Normal and Benign Prostatic Hyperplasia subjects attending clinic
3.10 Creatinine concentration of Normal and Benign Prostatic Hyperplasia subjects attending clinic
CHAPTER FOUR: DISCUSSION
4.3 Suggestions for further studies
LIST OF ABBREVIATIONS
AUR-Acute Urinary Retention
BOO-Bladder Outlet Obstruction
BPH-Benign Prostatic Hyperplasia
BMI-Body Mass Index
BUN-Blood Urea Nitrogen
CARET-Carotene and Retinol Efficacy Trial
DRE-Digital Rectal Examination
HGF-Hepatocyte Growth Factor
HRE-Hormone Response Element
LUTOS-Lower Urinary Tract Obstruction Symptom
LUTS-Lower Urinary Tract Symptoms
PAP-Prostatic Acid Phosphatase
PSA-Prostate Specific Antigen
UNTH-University of Nigeria Teaching Hospital
UTI-Urinary Tract Symptoms
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 man’s 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).
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).
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 musculo-glandular organ in contact with the inferior surface of the bladder, weighs about 20 gm in adult males and forms part of the males’ 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).
“The prostate gland is dependent on the hormonal secretion 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 epithelial 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 stromal 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, secretory, 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 antiapoptotic 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-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 P27 Kipl (a cell cycling inhibitor). Neuroendocrine cells are rare cells scattered in the basal and Luminal layer of the prostate and terminally differentiated and is not androgen insensitive cells, expressing chromogranin A, synaptophysin and Neuron-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 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 (Rosenthal, 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 man’s 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 men’s 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 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 breakdown 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 (Roehrborn et al., 2011).
Derivative of testosterone called dihydrotestosterone (DHT) stimulate growth of the prostate (Obidoa, 2007). DHT is derived from testosterone via conversion by enzyme 5α-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 “estrogen” concentration as men age (Akang et al., 2006).
The response of prostate to the imbalance in testosterone level may be that, at early stage of man’s 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 5-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-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).
1.2.3 Conversion of Testosterone to Dihydrotestosterone 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 (Paracchini et al., 2003). The upregulation or activation of transcription result in increase synthesis of messenger RNA which, in turn is translated by ribosomes to produce specific protein (Paracchini et al., 2003). One of the known target genes of androgen receptor activation is insulin, like growth factor 1(IGF-1) (Routh and Leibovich, 2005). These changes in the level of protein in cells, may be one way that androgen receptor control cell behaviour (Vlahopoulos 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 (Sadler et al, 2010).
1.3 Complications of Prostate Enlargement
As the size of the prostate increases some degree of morphological changes follow, bring about narrowing of the urethra (Roehrborn et al., 2011). Such changes may result to distortion of the course of the urethra, elongation of the urethra, narrowing of the bladder neck, increase in micturition time, retention of urine, (either acute or chronic), Changes in the urinary bladder and other component of the upper urinary tract, including trabeculation; sacculation and diverticulation; changes in the upper urinary tracts such as ureteral elongation and hydronephrosis, pelvic calycosus and eventually renal failure. This in turn may lead to recurrent infection stone formation and further obstruction(Roehrborn et al., 2011).
1.3.1 Effect of Enlarged Prostate on the Bladder
Effect of an enlarged prostate on the urinary bladder is divided into three phases.
Phase I: Early (period of compensation). In early BPH development, bladder is able to empty completely. It is capable of mobilizing its reserves and its dartos muscle are able to empty completely, in which case there may not be any urine retention at the stage, as the reserves are capable of overcoming the resistance to outflow due to the narrowing effect of the enlarged lobes. There is obvious increase in the micturition time (Wastney et al., 1986). The caliber and force of the urine stream are seriously affected with time and the patient becomes impatient to wait for such time to completely empty his bladder. He therefore voluntarily withhold the leftover after energies for reasonable time has been spent trying to empty his bladder. This is usually the onset of chronic urine retention. If no intervention is forthcoming, the bladder will go into the second phase (Wilt and Dow, 2008).
Phase II: Delayed (period of compromise). At this stage, the bladder has mobilized completely all its reserve and ability to empty has been compromise (Wilt and Dow, 2008). Bladder fails to empty completely, some residual urine is left after micturation which gradually and progressively increase and so builds up a significant residue volume. As the volume of the residual urine build up, the bladder capacity will be exceeded and so can no longer hold back any extra volume added to it, so the bladder empties uncontrollable by any mild stress or increase in ultra abdominal pressure leading to stress incontinence. Action like hilarious laughter, lifting a heavy load may lead to wetting of one’ under wears (Oyogu and Benjamin, 2012). The rate of day-time frequency and nocturia become enormous and unbearable. The patient may not worry about the day time frequency especially in developing world where one can urinate along the roadside while taking a walk or even hold a heart to heart discussion with a nearby friend (Gevaert et al., 2014). He is more worried about the nocturia which many a time is what brings him to physician (Oyogu and Benjamin, 2012). It is actually the disturbance of sleep associated with the nocturia that constitute the patients’ major worry. Following the complaint, the physician may after some reasonable help including catheterization conduct further investigation.
Phase III: Late (period of decompensation). This is dangerous stage that requires experience and meticulous handling. The obstructed urinary bladder is in an overwhelmed state (Oyogu and Benjamin, 2012). Urine flow from kidney to bladder is impaired. This gives rise to obstruction of upper tract. Vesico ureteric reflux occurs, with consequent hydroureters and hydronephrosis. Obstructive uropathy ensues and finally chronic renal failure. At this stage if nothing is done to remedy it, there will be serious impairment of renal function with attendant obstructive uropathy, and the patient may die of renal failure (Gevaert et al., 2014).
1.3.2. Effect of enlarged prostate on sexual performance
Scientists are still uncertain why BPH and its lower urinary tract symptoms are associated with erectile dysfunction. One idea concerns the sympathetic nervous system, which studies show is hyperactive in animals and men with BPH-associated urinary tract symptoms. Nerve fibers in the sympathetic nervous system transmit signals that have an impact on stress and stress-related symptoms. An increase in these signals may lead to over-activity in the sympathetic nervous system, which is associated with erectile problems.
There may be change in libido and erectile dysfunction may result. The onset maybe associated with increase in libido and strong erection due to impediment of prostatic venous blood flow by enlarging prostate. Some time there may be decrease in sexual desire. The BPH subjects some time experience abnormal ejaculation which may be in form of retrograde ejaculation (Rhodes et al., 1999).
1.4 Symptoms of Prostate Enlargement
A very large prostate may be symptom -free or relat ively less symptomatic than a mildly enlarged one. The symptoms and signs are not indications of the size of the gland.The enlargement of prostate will present some common symptom referred to as lower urinary tract obstruction symptom (LUTOS) (Habermacher et al., 2006). In addition to mechanical obstruction by the enlarging prostate, there are some other factors which aggravate the symptoms. Such as: superadded infection, oedema/congestion and stone formation. Some of the commonest symptoms are.
1.5 Diagnosis of Benign Prostatic Hyperplasia
1.6.1 Alpha-1-adrenergic Receptor Blockers: This reduces smooth muscle tone in the prostate and results in rapid improvements in urinary symptoms and flow (Montorsi et al., 2006). Treatment with alpha-1 adrenergic receptor blockers is generally considered as a first line therapy for symptomatic BPH (Crane et al., 2013). The four most prescribed are: alfuzosin (uroxatral) ®, terazosin (Hytrin) ®, Tamsulosin (zeisel) ®, doxazosin (cardura) ®. All are effective in increasing urinary flow rate thereby relieving BPH symptoms. These medications also have side effects, such as low blood pressure and dizziness although tamsulosin may have reduced risk of these side effects). These medications are usually effective up to four years and therefore do not prevent BPH progression (Craneet al., 2013).
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