BIOCHEMICAL CHANGES ASSOCIATED WITH BENIGN PROSTATIC HYPERPLASIA (BPH) IN AGEING MEN ATTENDING CLINIC AT UNIVERSITY OF NIGERIA TEACHING HOSPITAL (UNTH), ITUKU-OZALLA, ENUGU STATE OF NIGERIA


Content

 

ABSTRACT

 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

 Title page

Certification

Dedication

Acknowledgement

Abstract

Table of contents

List of figures

List of Abbreviations

 

CHAPTER ONE: INTRODUCTION

1.1       Epidemiology

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

1.5.1    Urinalysis

1.5.2    A urine culture

1.5.3    A prostate specific antigen (PSA) test

1.5.4    Uroflorometry

1.5.5    Pressure-flow urodynamic studies

1.5.6    Ultrasonography

1.5.7    Filling cystometry

1.5.8    Cystoscopy

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

1.6.3    Antimuscarinics

1.6.4    Phosphodiesterase-5-inhibitors

1.7       Surgical treatment of BPH

1.7.1    Dietary and lifestyle consideration

1.7.1.1 Eating vegetables

1.7.1.2 Weight loss

1.7.1.3 Exercise

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       Materials

2.1.1    Sample collection

2.1.2    Chemicals and reagents

2.1.3    Equipment

2.2       Methods

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

4.1       Discussion

4.2       Conclusion

4.3       Suggestions for further studies

References

Appendices


 

LIST OF FIGURES

 

 

 

 

 

Figure 1: The prostate and nearby organs

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Figure 2: Androgen signaling pathway pathway leading to cell proliferation

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Figure 3: Testosterone pathway inhibited by finasteride in alopecia -

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Figure 4: Bladder effects of antimuscarinics -

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Figure 5: Prostate specific antigen level of subjects with varying age differences attending Clinic


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Figure 6: Calcium level in subjects of different age group attending clinic

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Figure 7: Blood urea nitrogen level in men of different age group attending clinic

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Figure 8: Zinc concentration in men of different age group attending clinic -

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Figure 9: Sodium level in men of different age group attending clinic

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Figure 10: Iron concentration in men of different age group attending clinic

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Figure 11: Potassium concentration in men of different age group attending clinic -

 

Figure 12: Magnesium level in men of different age group attending clinic -

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Figure 13: Selenium level in men of different age group attending clinic

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Figure 14: Creatinine level in men if different age group attending clinic

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LIST OF ABBREVIATIONS

AR

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Androgen Receptor

AUR

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Acute Urinary Retention

BOO

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Bladder Outlet Obstruction

BPH

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Benign Prostatic Hyperplasia

BMI

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Body Mass Index

BUN

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Blood Urea Nitrogen

CARET-

Carotene and Retinol Efficacy Trial

CRP

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C-Reactive Protein

DHT

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Dihydrotestosterone

DNA

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Deoxyribonucleic Acid

DRE

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Digital Rectal Examination

HGF

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Hepatocyte Growth Factor

HRE

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Hormone Response Element

LUTOS-

Lower Urinary Tract Obstruction Symptom

LUTS

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Lower Urinary Tract Symptoms

NE

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Neuroendocrine

NSE

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Neuro-specific Enolase

PAP

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Prostatic Acid Phosphatase

PCA

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Prostate Cancer

PSA

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Prostate Specific Antigen

TURP -               Transurethral Prostatectomy

 

UNTH -              University of Nigeria Teaching Hospital

 

UTI       -              Urinary Tract Symptoms


15

 

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 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).

 

 

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).


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).

 


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

“The 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 (CK5 and 14) (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 Ck 8 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 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 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 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 5a -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” 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 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).


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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).


 


Fig 2: Androgen signaling pathway leading to cell proliferation (Fu et al., 2009)

 

 

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 (Reohrborn 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 ureteric enlongation and hydronephrosis, pelvic calycosis and eventually renal failure. This in turn may lead to recurrent infection stone formation and further obstruction(Reohrborn 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 micturation 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 (Oyiogu 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 road-side 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 (Oyiogu and Benjamin, 2012). It is actually the disturbance of sleep associated with the nocturia that constitute the patients’ major worry. Following the complain, the physician may after some reasonable help including catheterization conduct further investigation.

 

Phase III: Late (period of de-compensation). This is dangerous stage that requires experience and meticulous handling. The obstructed urinary bladder is in an overwhelmed state (Oyiogu 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.

 

 

I.            Incontinence

 

Urinary (or bladder) incontinence happens when an individual is not able to keep urine from leaking out of the urethra, the tube that carries urine out of the body from the bladder. Urine may leak urine from time to time or one may not be able to hold any urine (McVary et al., 2011).

II.            Frequency

 

Normally, the amount of urine the body produces decreases at night. This allows most people to sleep 6 to 8 hours without having to urinate. Some people wake up from sleep more often to urinate during the night. This can disrupt sleep cycles (McVary et al., 2011).


III.             Dysuria

 

The patient notices that he needs extra push to be able to pass urine, with time the patient may discover that he needs to assist his bladder by voluntarily increasing his abdominal muscle pressure to be able to completely empty his urinary bladder (McVary et al., 2011).

 

IV.       Weak urine stream

 

It might take a very long time to empty the bladder when a patient is diagnosed of BPH because of a weak urinary stream. The patient may spend a very long time standing in front of the urinal. If the urethra is partially blocked due to pressure from the prostate, only a small flow of urine can escape the bladder, resulting in weak urine flow and a long wait to empty (McVary et al., 2011).

 

 

V.            Hesitancy

 

In hesitancy the patient has the urge to urinate in the urinal but instead of voiding immediately, he has to wait for sometime before micturation could commence, resulting from the enlarged prostate lobe getting closer to another with the tug of dartus muscle of posterior urethra. With time patient learns to wait and relax his sphincter before he is able to initiate micturation, hence the symptom of hesitancy (McVary et al., 2011).

 

 

VI.       Pain

 

This pain may be inform of painful micturation, suprapublic pain, renal pain, usually as a result of complication of the obstruction. There may be pain in urethra during micturation through suprapubic to renal angle pain as a result of enlargement of the kidneys or stone formation or super added infections (McVary et al., 2011).

VII.       Haematuria (blood in urine)

 

The sub mucosa may become eroded by stones if formed. The mucosa vein could also spontaneously rupture due to over distention by the accumulated urine. Infection can also lead to haematuria(McVary et al., 2011).

 

 

VIII.        Feeling of incomplete emptying of the bladder

 

At the onset of the obstructive effects of the enlarged prostate, the bladder will undergo a period of compensation during which it mobilizes all its reserve to enable it empty completely if the enlargement is allowed to go unabated. A time is reached in which the total reserve is exhausted. Residual urine starts accumulating. The urge is there but the patient cannot completely empty the bladder due to bladder weakness. At this stage, the bladder now reaches a compensation period when more than its normal capacity is exceeded and more urine accumulates. This may manifest with symptoms of renal insufficiency (McVary et al., 2011).

 

 

1.5   Diagnosis of Benign Prostatic Hyperplasia

 

1.5.1        Urinalysis- examination of a urine sample under a microscope— is performed in all patients who have lower urinary tract symptoms. Urinalysis is often the only laboratory test needed when symptoms are mild (International Prostate Symptom Score of 1 to 7) and the medical history and physical examination suggest no other abnormalities (McVary et al., 2011).

 

1.5.2        Urine culture (an attempt to grow and identify bacteria in a laboratory dish) is performed when a urinary tract infection is suspected. In the presence of severe or chronic symptoms of BPH, blood tests to detect abnormalities in creatinine, blood urea nitrogen, and hemoglobin are used to rule out the presence of kidney damage or anemia (McVary et al., 2011).

 

1.5.3        Prostate-Specific Antigen (PSA) Test is generally recommended. PSA values alone are not helpful in determining whether symptoms are due to BPH or prostate cancer because both conditions can cause elevated levels. However, knowing a man's PSA level may help predict how rapidly his prostate will increase in size over time and whether problems such as urinary retention are likely to occur (McVary et al., 2011).

 

1.5.4        Uroflowmetry: In this noninvasive test, a man urinates into an electronic device that measures the speed of his urine flow. A slow flow rate suggests an obstruction of the urethra. If the flow rate is high, urethral obstruction is unlikely, and therapy for BPH will not be effective in most instances. A normal urine flow rate is 15 mL per second or higher(McVary et al., 2011).

 

1.5.5        Pressure-Flow Urodynamic Studies: These studies measure bladder pressure during urination by placing a recording device into the bladder and often into the rectum. The difference in pressure between the bladder and the rectum indicates the pressure generated when the bladder muscle contracts.A high pressure accompanied by a low urine flow rate indicates urethral obstruction. A low pressure with a low urine flow rate signals an abnormality in the bladder itself, such as one related to a neurological disorder(McVary et al., 2011).

 

1.5.6        Ultrasonography: is the imaging study used most often in men with lower urinary tract symptoms. The test involves pressing a microphone-sized device (transducer) onto the skin of the lower abdomen. As the device is passed over the area, it emits sound waves that reflect off the internal organs. The pattern of the reflected sound waves is used to create an image of each organ.Ultrasonography can be used to detect structural abnormalities in the kidneys or bladder, determine the amount of residual urine in the bladder, detect the presence of bladder stones, and estimate the size of the prostate.Less frequently, an imaging study called intravenous pyelography may be performed. This procedure involves injecting a dye into a vein and taking x-rays of the urinary tract. The dye makes urine visible on the x-rays and shows any urinary tract obstructions or stones (McVary et al., 2011).

 

1.5.7        Filling Cystometry:This test involves filling the bladder with fluid and measuring how much pressure builds up and how full the bladder is when the urge to urinate occurs. It is recommended for evaluating bladder function only in men who have a prior history of urological disease or neurological problems that could be affecting bladder function(McVary et al., 2011).

1.5.8        Cystoscopy:In this procedure, a cystoscope (a small lighted viewing device) is passed through the urethra into the bladder to directly view the two structures. Cystoscopy is usually performed just before prostate surgery to guide the surgeon in performing the procedure or to look for abnormalities of the urethra or bladder(McVary et al., 2011).

 

 

1.6              Chemotherapeutic Agents used in the Treatment of BPH

 

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 (urocatral) ®, terazosine (Hytrin) ®, Transulosin (zyasel) ®, doxazosine (cadura) ®. 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 transulosin 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).

 

 

1.6.2          5-alpha-reductase Inhibitors

 

The medications in the 5-alpha-reductase inhibitor class block the conversion of testosterone to dihydrotestosterone and help shrink the prostate and prevent further growth (Marberger, 2010).Food and Drug Administration (FDA) approved 5-alpha-reductase inhibitors such as finasteride (e.g. proscar ®, propecia ® and dutaste ride (avodor) for BPH management. Both medications are capable of reducing prostate size as much as 25% and can reduce AUASI score by 4.5% points in men with enlarged prostate (Mc Vary, 2006).

 

a -adrenergic receptor blocker may be combined with 5-alpha-reductase inhibitor and this increase benefit for men with BPH (Carballidoet al., 2011). Medication in the 5-alpha-reductase inhibitor class are associated significantly with sexual side effect such as decreased libido, impotency, reduced ejaculation (Andriole et al., 2011). Sometimes men experience breast enlargement and tenderness. Important consideration should be taken into account when choosing between finasteride and dutasteride in BPH management. One has to understand that there are two varieties (i.e isoforms) of 5-alpha –reductase enzyme type 1 and type 2 which are present in prostate tissue. Evidence suggests that the “type 1” isoform may be more active in alignant prostate tissue. This is significant because dutasteride inhibit both I and 2 isoform, whereas finasteride inhibits only type I which shows that dutasteride may effectively control growth of cancerous tissue than finasteride. Several studies suggest that the two drugs confer similar benefits and risk in BPH. Dutasteride appears to be a better choice as it might also provide some cancer protection (Emberton et al., 2008).



Figure 3: Testosterone Pathway Inhibition by Finasteride in Alopecia (Carballido et al., 2011).


1.6.3 Antimuscarinics: Many men with BPH also have an overactive bladder, which causes symptoms, such as urinary urgency and incontinence (Kirby and Lepor, 2007). Antimuscarinic drugs block muscarinic receptors in the detrusor muscle. This muscle contracts and squeezes the bladder to facilitate urination, and remains relaxed otherwise, allowing the bladder to stretch and fill. Pharmacologic block of these receptor decreases the incident of overactive bladder symptoms of BPH (McVary et al., 2006). Antimuscarinic drug approved to treat symptom of overactive bladder includes: darifenacine (Enablex ®), tolterodine (Detrol ®), Fesoterodine (Toviaz ®), trospiumchloride (Sanctura), Oxybutynin (Ditropan ®) and solifenacine (vesicare ®) (Sadler et al.,2010). Combination of antimuscarinic medication with alpha-adrenergic blocker can improve BPH symptom, particularly the number of times patients need to urinate during the day and night as well as urinary urgency (Bell et al., 2009). There is insufficient evidence that these medications are effective when used as a single therapy for individuals with predominantly storage problem (Bell et al., 2009). Common side effect associated with this medication includes dry mouth, dry eyes and constipation (Sadler et al., 2010).



 

Figure 4: Bladder Effects of Antimuscarinics (Sadler et al., 2010).


1.6.4 Phospodiesterase-5-inhibitors: Phosphodiesterase inhibitors are used to treat erectile dysfunction, but may also relieve lower urinary tract symptoms in men with BPH (Roehrborn and McConnell et al., 2007). This medication may work via several mechanism. One postulated mechanism is that phosphodiesterase-5-inhibitors block a signaling pathway. They may also increase level of nitricoxide, a compound that relaxes smooth muscles in the lower urinary tract to decrease hyperactivity of the autonomic nervous system affecting the bladder, prostate and penis (Roehrborn and Mc Connell, 2007).

 

A comprehensive review found that phophsodiesterase-5-inhibitors and alpha-blockers lead to a small improvement in flow rates in men with BPH (Theoret et al., 2011). Tadalafil (Galis ®) is the only medication of this class that has been approved by the Food and Drug Administration (FDA) for treatment of urinary symptom. It can cause headaches, flushing, indigestion, back pain and nasal congestion and lead to low blood pressure when combined with a -1 adrencrgic blockers or organic nitrates (nitroglycerin) (Marberger, 2010).

 

 

1.7 Surgical Treatment of Benign Prostatic Hyperplasia

 

BPH can also be treated surgically. This involves removal or reduction of the size of the prostate thereby relieving the lower urinary tract symptom (Okoli et al., 2012). This is done through:

 

(a)                Transurethral needle ablation of the prostate

 

(b)                 Transurethral microwave thermotherapy.

 

Other invasive procedures can be used for patients who have not responded to pharmacological therapies (Tacklind et al., 2010). In transurethral prostatectomy (TURP) the prostate is endoscopically removed, and this serves as benchmark surgical therapy for BPH (Lowe, 2008). In endoscopic procedures, a fine surgical and viewing device are inserted into the patients’ body through small incisions, this type of surgery is less invasive than traditionally “open” surgery. Approximately 4% of men who undergo TURP will become impotent (Roehrborn, 2007). The procedure can also cause transurethral complications in which fluid used to irrigate the surgical area enters the intravascular space and result in cardiopulmonary (heart and lung) complications example high or low blood pressure, slow heart rate, irregular heartbeat, respiratory disease and shock. Men with very large prostate benefit from an open prostate surgery in which the entire prostate is removed, which can result in significant blood loss, incontinency, impotency, pain and longer hospital stays (Habermacher et al., 2006).


(c)                Transurethral laser therapy

 

This is another surgical option that is gaining momentum. The treatment may reduce the length of stay in the hospital, although more information regarding the safety of this therapy is needed. The adoption of laser-based operation for BPH has lead to more cases of BPH being treated surgically (Davidson and Chutka, 2008).

 

In this case, instead of cutting tissue out, the newer technique create channel by vaporizing the tissue using laser energy. Thermotherapy delivers micro waves energy through catheter inserted into the bladder to shrink the inside of the prostate. Here, office based outpatient procedure takes an hour or less and requires only mild sedation. Its shortcoming is that it takes 6-8 weeks for the impact of the treatment to be realized (Davidson and Chutka, 2008).

 

 

Intraprostatic Botulinium Toxin Injection: Is an emerging BPH therapy. Botulinium toxin is a derived bacterial neurotoxin that relaxes muscles, by preventing certain neurotransmitter (acetylcholine) signal. Lower urinary tract symptoms are in part due to excessive smooth muscle contraction around the bladder and prostate in men. Scientists have hypothesized that injection of botulin toxin directly into the prostate may relax those muscle and relieve some urinary symptom (Dineen et al., 2003). Intraprostatic (purified botulinium neurotoxin) injection induces prostate shrinkage (Chappleet al, 2004). A study (34 men with BPH who failed medical treatment) published in September 2012 reported similar findings (Murray and Pizzorno, 2006).

 

 

1.7.1        Dietary and Life Style Consideration

 

A 2008 study found that men who received more than 38% of their calories from fat are nearly one third more likely to develop BPH than men who received less than 26% of their calories from fat (Soliman et al., 1997). This suggests that lowering one’s overall fat intake may help reduce the risk of developing BPH.

 

 

1.7.1.1 Eating vegetables: Studies have shown that men who eat more vegetables are less likely to develop BPH (Dibsdall et al, 2003). In particular, vegetables rich in beta-carotene, lutein and vitamin “C” are associated with a decrease risk of BPH (Helfand, 2007).

1.7.1.2     Weight loss and blood glucose control: Obese men are more likely to develop symptoms of BPH, greater weight, BMI and waist circumferences which are all associated with higher incident of BPH. A study showed that obese men are 3.5 times as likely to develop BPH as normal weight men. Men with diabetes are likely to have increase prostate volume, and have a 2-fold higher risk of BPH compared with normal sugar control.

 

 

1.7.1.3  Exercise

 

Regular physical exercise decreases the risk of developingBPH. Men who walk 2-3 hours per week have a 2-5% lower risk of developing BPH (Helfand, 2007).

 

 

1.7.2        Targeted Nutritional Interventions

 

Plant derived compounds can be used to treat BPH and natural therapies comprise approximately 50% of the treatment for BPH in italy (Madersbacheret al., 2004).

 

Saw palmetto is the most widely used phytotherapeutic treatment for BPH (McConnell et al., 2007). It has been documented as a treatment for swollen prostate glands since the 1800s (Madersbacher et al., 2004). Evidence suggest that saw palmetto has similar efficacy to finasteride and transulosin, the two medications used to treat BPH (Thompson et al.,2003). A pilot study examining the effects of 320mg of saw palmetto extract found that this herbal treatment reduced BPH symptom by over 50% after 8 weeks of treatment (Thompson et al.,2003). Another study found, a combination of saw palmetto and stinging nettle root extract to be as effective as finasteride at treating BPH. Saw palmetto has not been reported to cause any significant side effect (Kuntz and Lehrich, 2002). The presence of phytosterols and beta-sitosterol may contribute to its therapeutic effect (Kuntz and Lehrich, 2002).

 

 

1.7.3        Pygeum Africanum

 

Africanum also known as Afrian plum is used as a treatment for BPH in Europe. P. Africanum may prevent the proliferation of cell within the prostate (Mulhall and Muller 2006).

 

 

1.8              Biochemical markers associated with Benign Prostatic Hyperplasia


 

A biochemical marker is anything that can be used as an indicator of a particular disease state or some other physiological states of an organism (Delrio et al., 2010). It can be substance introduced into an organism as a means to examine organ functions or other aspect of an organism or a substance whose detection indicates a particular disease states. For example, the presence of antibody may indicate an infection. Biochemical markers can be specific cells, molecules or genes, gene products, enzymes, or hormones. Biomarkers have been used in pre-clinical diagnosis for a considerable time. For example body temperature for fever, glucokinase in the blood is a marker for liver disorders blood pressure is used to determine the risk of stroke, cholesterol values are a biomarker and risk indicator for coronary and vascular disease, and C - reactive protein (CRP) is a marker for inflammation. These markers may indicate either normal or diseased processes in the body (Xueet al., 2013). It may be a parameter that can be used to measure the progress of disease or effect on treatment. The parameter can be chemical, physical or biological. Biochemical markers help in early diagnosis, disease, prevention, drug target identification and drug response. Gene based biomarkers are found to be effective and acceptable markers in present scientific world. Categories of biomarkers include:

 

(a)  Disease related biomarkers.

 

(b)   drug related biomarker.

 

(a)   Disease related biomarkers give an indication of the probable effect on treatment of patient (risk indicator or productive biomarker), of a disease that already exists (diagnostic biomarker) or how such a disease may be developed in an individual case regardless of the type of treatment, while prognostic markers show the progression of disease with or without treatment.

 

(b)    In contrast, drug related biomarkers indicate whether a drug will be effective in a specific patient and how the patient’s body will process it. In addition to long-known parameters such as those included and objectively measured in a blood count, there are numerous novel biomarkers used in the various medical specialties. These “new ” biomarkers have become the basis for preventive medicine, meaning medicine that recognizes diseases or the risk of disease early and takes specific counter measures to prevent the development of the disease. Biomarkers are also seen as the key to personalized medicine. Production of response to treatment will become the most important aim of biomarker research in medicine. With the growing number of new biological agents, there is increasing pressure to identify molecular parameters that will not only guide the therapeutic decision but also help to defined the most important targets for which new biological agents, should be tested in clinical studies (Benson, 2010). More recently, biomarker is becoming a synonym for molecular biomarker such as elevated prostate specific antigen as a biomarker for prostate cancer or using enzyme assay as liver function test (Holtzman, 2009).


 

1.9                Biomarkers in Prostate Enlargement

 

1.9.1 Prostate Specific Antigen: Prostatic specific antigen (PSA), also known as gamma-seminoprotein or Kallikrein-3 (KLK3), is a glycoprotein enzyme encoded in human by the KLK3 gene. PSA is a member of the kallikrein related peptidase family and is secreted by the epithelial cells of the prostate gland (Hara and Kimura, 1989). PSA is produced for ejaculation, while it liquefies semen in the seminal coagulum and allows sperm to swim freely. It is also believed to be instrument in dissolving cervical mucus, allowing the entry of sperm into the uterus. PSA is present in small quantities in the serum of men with healthy prostates, but is often elevated in the presence of prostate cancer or other prostate disorders and can be demonstrated in biopsy samples or other histological specimens using immuno-histochemistry. Disruption of this epithelium, for example in inflammation or benign prostatic hyperplasis may lead to some diffusion of the antigen into the tissue around the epithelium and is the cause of elevated blood level of PSA in these condition. The PSA is a serine protease (EC 3.421.77) enzyme, the gene of which is located on the nineteenth chromosome in human. The reference range is less than 4ng/ml for the first commercial PSA test; the hybritech tandem PSA test released in February 1986 was based on study that found 99% of 472 approximately healthy men had a total PSA level below 4ng/ml. However, prostate cancer can also be present in the complete absence of an elevated PSA level, in which case the test result would be a false negative. PSA level can also be increased by prostatic irritation, BPH and recent ejaculation produce a false positive result. Digital rectal examination has been shown in several studies to produce an increase in PSA. The effect is clinically insignificant since DRE causes the most substantially increase in patients with PSA levels already elevated over 40ng/ml (Sakr, 2004).

 

 

1.9.2        Metallic Prostatic Antioxidants (Zinc and Selenium)

 

In the prostate, zinc ion concentrations are ten times higher, than in other body fluid. Zinc ion has a strong inhibitory effect on the activities of PSA and on that of KLK2, so that PSA is totally inactive.


Zinc:Zinc is an integral part of the male hormone system and studies reveal zinc deficiency can cause prostate enlargement. Zinc is required by men to produce testosterone, as men age into their 50s and older, there is a natural decline in zinc (Mayer and Robert, 2000). Therefore zinc deficiency can lead to less testosterone production in men and hence show up with symptom associated with low testosterone. This may be why the prostate after being deprived of adequate zinc may become chronically inflamed and be the genesis of an enlarged prostate and PCa. This is because the prostate tissues are highly dependent on zinc to maintain its health and integrity. High zinc level also mean lower levels of estrogen and prolactin thereby reducing the risk of prostate disease and impotency (Mayers and Robert, 2000). Sources of zinc include: milk, yoghurt and cheese and yeast, peanut, beans etc.

 

Selenium: Selenium is known as a trace mineral, meaning that body the needs tiny amount of it to be healthy. Selenium’s primary role in the body is to help the body produce selenoprotein, compounds that protect the body from damage caused by oxidation. Selenium cannot be synthesized in the body but rather obtained from food sources or supplement. The current recommended dietary intake for selenium is 55 micro grams per day for adults according to office of dietary supplements. A research team from the German St. Josef’s Hospital investigated the connection between blood selenium and benign prostatic hyperplasia in a group of 21 men issue of “Acta oncologica” they discovered that adu lt men with low levels of selenium in the blood were more likely to suffer from an enlarged prostate than men with high blood selenium. A review paper published in July 2011 issue of Urologia notes that selenium help reduce oxidation in the prostate. Excess oxidation can increase inflammation of the prostate, however, the “acta oncologica” paper did not explain why sel enium protect against BPH. Common dietary sources of selenium include nuts, fatty fish, egg and dairy products (Sakr, 2004).

 

 

1.9.3 Renal Function Test (Creatinine and Blood Urea Nitrogen): Serum creatinine and blood urea nitrogen (BUN) provide an estimate of overall renal function. In normal adult, serum creatinine ranges from 0.7 to 1.5mg per 100ml. Creatinine is a metabolic product of creatine, which is derived primarily from the muscle. Therefore the muscle mass of the patient is an important determinant of the absolute serum creatinine level. BUN represents one of the end products of the protein metabolism and it varies from 5-25mg per 100ml. BUN is dependent on several factors including state of hydration, protein intake and catabolic state (Michel, 2010).


1.9.4 Minerals (Potassium, Iron, Magnesium, Calcium, Sodium)

 

Potassium is a mineral that is involved in regulating pH balance and blood pressure, converting blood sugar into energy, maintaining heart function, and contracting muscles. Some argue that a potassium deficiency sets the stage for cancer by altering the pH balance in favor of cancer growth. So far, there is limited scientific evidence linking potassium health benefits and prostate health besides maintaining overall function (Edorh, 2003).

 

Iron is a cofactor in the production of some neurotransmitters, it works with enzymes, and it helps boost the immune system. Too much iron, however, is not healthy (Edorh, 2003). According to a study presented at the 2007 centennial meeting of the American Association for Cancer Research, the combination of high iron intake and low dietary antioxidant consumption may increase the risk of aggressive prostate cancer (Choi, 2008). The study’s authors evaluated men who had participated in the Carotene and Retinol Efficacy Trial (CARET), which consisted of 661 men who subsequently developed prostate cancer. Rich food sources of iron include liver (beef, chicken), beef, kidney beans, lima beans, baked beans, and spinach (Choi, 2008).

Magnesium health benefits include a possible role in prostatitis and in the development of cancer. It’s been suggested that a magnesium deficiency is carcinogenic, and in people who have solid tumors, a high level of supplemental magnesium inhibits carcinogenesis (Sircus, 2008) Studies show that low magnesium levels are associated with cancer and also at least one study has shown that magnesium concentrations in seminal plasma are significantly decreased in men who have chronic prostatitis (Edorh, 2003).

 

Based on the results of several studies of different populations and calcium supplementation, the World Cancer Research Fund classified calcium as a probable cause of prostate cancer. Both calcium from supplements and calcium from dairy put men at higher risk, although additional studies have also found that nondairy sources of calcium also can increase the of risk BPH. The higher the intake of calcium, the higher the risk of BPH (Allen, 2008).

 

 

1.10Aim and Objectives of the Study

 

This study was aimed at investigating biochemical changes associated with benign prostatic hyperplasia in aging men of ages less than 60 and above attending clinic at the University if Nigeria Teaching Hospital, Ituku-Ozalla, Enugu State, Nigeria.



1.10.1 Specific Objectives of the Study

 

The study was designed to achieve the following specific objectives:

 

·         To determine PSA level of BPH patients of ages less than 60 and above with some placed on treatment and some not on treatment.

 

·         To determine serum creatinine level in BPH patients of ages less than 60 and above with some placed on treatment and some not on treatment.

 

·         To determine serumselenium level in BPH patients of ages less than 60 and above with some placed on treatment and some not on treatment.

 

·         To determine the levels of serum electrolytes such as zinc, magnesium, sodium, potassium, calcium and iron levels in BPH patients of ages less than 60 and above with some placed on treatment and some not on treatment.


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