The Role of Dutasteride in the Treatment of Gross Haematuria Due to Benign Prostatic Hyperplasia and Adenocarcinoma of the Prostate

THE ROLE OF DUTASTERIDE IN THE TREATMENT OF GROSS HAEMATURIA DUE TO BENIGN PROSTATIC HYPERPLASIA AND ADENOCARCINOMA OF THE PROSTATE

DR OFURU, VITALIS OBISIKE

NOVEMBER 2014

DECLARATION

I hereby declare that all parts of this work were carried out by me under the quidance of my supervisors except where otherwise declared. It has neither been presented to any other college for a Fellowship nor submitted elsewhere for publication.

…………………………………………….

DR OFURU VITALIS OBISIKE

DEDICATION 3

This work is dedicated to my two little kids Udochi and Chika who have not had much of my care and companionship in these past years.

ACKNOWLEDGEMENT 4

I thank the Almighty God who sustained me through the rigors of training and helped me to put together this piece of work.

My inestimable thanks go to Emeritus Professor O.O Mbonu for his advice and support during the time of writing the proposal.

I cannot thank enough Professor Ndu Eke and Professor A.M.E Nwofor who took pains to supervise this work, and went through it each time I made it available to them. They carefully made corrections and contributions that made the work feasible. Professor Okpani also guided me at the beginning. To him I remain grateful.

I wish to thank Dr. O.N. Ekeke and Dr M.K. Sapira who also supervised me in this work. Dr Sapira suggested this topic to me and critiqued the work such that I almost got discouraged. To say the least, the work couldn’t have been successful without his contributions.

I remain grateful to Drs Timothy Mbaeri, Ezisi Chinyelu, John Ojule, Joseph

Abiahu, Emmanuel Amusan, Chinedu Anyadike and Victor Abhulimen and all others whose names are not mentioned here, who either helped me to collect data in course of this work, or encouraged me in one way or the other.

Lastly, I appreciate my loving mother Mrs Edna Ofuru, for her sacrifice, prayers and encouragement throughout the period of my training. 5

CERTIFICATION

This is to certify that the study titled ‘The role of dutasteride in the treatment of gross haematuria due to benign prostatic hyperplasia and adenocarcinoma of the prostate’ reported in this dissertation and the writing thereof were done by the candidate under our supervision.

Prof. N. Eke FRCS Ed, FRCS (Engl), FWACS, FICS ……………………………………………

Consultant Urologist

University of Port Harcourt Teaching Hospital, Port Harcourt.

Prof. A.M.E. Nwofor BM: BCh, FMCS, FWACS,FACS, FICS, FISS……………………

Consultant Urologist

Nnamdi Azikiwe University Teaching Hospital, Nnewi

Dr. O. N. Ekeke FWACS, FICS ……………………………………......

Consultant Urologist

University of Port Harcourt Teaching Hospital, Port Harcourt.

Dr. M.K. Sapira FWACS, FMCS, FICS ……………………………………………………………

Consultant Urologist

University of Port Harcourt Teaching Hospital, Port Harcourt.

TABLE OF CONTENTS

Contents Page

Title page ……………………………………………………………………………………………………… i

Declaration ………………………………………………………………………………………………….. ii

Dedication …………………………………………………………………………………………………….iii

Acknowledgement…………………………………………………………………………………………i v

Certification ……………………………………………………………………………………………………v

Table of contents …………………………………………………………………………………………..vi

List of figures …………………………………………………………………………………………………vii

List of tables ………………………………………………………………………………………………...viii

List of abbreviations ……………………………………………………………………………………….ix

Summary……………………………………………………………………………………………………….. .xi

CHAPTER 7

1. Introduction ………………………………………………………………………………………….1 2. Literature Review ………………………………………………………………………………… 5 3. Aims and Objectives …………………………………………………………………………….29 4. Materials and Method ………………………………………………………………………….30 5. Results ………………………………………………………………………………………………….39 6. Discussion …………………………………………………………………………………………….63

References ……………………………………………….……………………………………………………76

Appendix I – Proforma…………………………………………………………………………………86

Appendix II – Ethical committee approval ……………………………………………………..93

LIST OF FIGURES

Figure 1: Frequency distribution of patients by age …………………………39

Figure 2: Frequency distribution of duration of haematuria before

presentation……………………………………………………………………………………..40

Figure 3: Kaplan-Meier analysis for duration of haematuria………………50

LIST OF TABLES

Table 1: Puchner and Miller classification of severity of Prostatic haematuria…13

Table 2: Mean prostate size by diagnosis ( T- test analysis)…………….……………….42

Table 3: Mean prostate size by treatment ( T- test analysis)……………………………43

Table 4: Correlation analysis of prostate size by duration of haematuria………..44

Table 5: Mann-Whitney test for Serum PSA of respondents……………………….….45 9

Table 6: Diagnosis and type of treatment………………………………………………………47

Table 7: The minimum and maximum duration of haematuria (in days) and mean duration of haematuria (in days) for each diagnosis and for each treatment type……………………………..……………………………………………………………….49

Table 8: Means and Median for Survival time………………………………………………..52

Table 9: Percentile table for Survival Curve……………………………………………………53

Table 10: Overall comparison of probability of resolution of haematuria using

Log Rank, Wilcoxon and Tarone-Ware tests……………………………………………………54

Table 11: Cross-tabulation of diagnosis and treatment showing mean volume of irrigant fluid used before haematuria stopped and 2 sample student t – test and p-value …………………………………………………………………………………………………………56

Table 12: Fisher’s Exact test for need for surgery when dutasteride is included……………………………………………………………………………………………………….. 58

Table 13: Requirement for blood transfusion…………………………………………….….59

Table 14: Recurrent haematuria after initial resolution…………………………..…….60

LIST OF ABBREVIATIONS

Chapter 1 : BPH- Benign Prostatic Hyperplasia

UTI- Urinary Tract Infection

Chapter 2: MVD- Microvascular Density

VEGF- Vascular Endothelial Growth factor

HIF – Hypoxia Inducible Factor

NADP- Nicotinamide Adenine Dinucleotide Phosphate

DHT- Dihydrotestosterone

T- Testosterone

α- Alpha

CaP- Carcinoma of the Prostate

LUTS- Lower Urinary Tract Symptoms

TURP- Trans Urethral Resection of the Prostate

EACA – Epsilon Aminocaproic Acid

Chapter 4 UPTH- University of Port Harcourt Teaching Hospital

PSA- Prostate Specific Antigen

IVU- Intravenous Urogram

SPSS- Statistical Package for Social Sciences

Appendix PCV- Packed Cell volume

Hb- Haemoglobin

WBC-White Blood Count

DRE- Digital Rectal Examination 11

BCG- Bacille Calmette – Gue ’rin

E/U/Cr- Electrolyte, Urea and Creatinine

SUMMARY

OBJECTIVE: To evaluate the clinical effectiveness of dutasteride in the treatment 12 of gross haematuria due to benign prostatic hyperplasia and adenocarcinoma of the prostate by determining the time it took haematuria to stop and the amount of irrigation fluid used while using dutasteride as the primary mode of treatment.

BACKGROUND: Dutasteride, a dual 5-alpha reductase inhibitor has been found to reduce bleeding from the prostate in a long term by inhibition of angiogenesis, and by apoptosis and has been used preoperatively to reduce bleeding that occurs during prostatectomy. Would the drug be effective in the control of acute haematuria of prostatic origin and so be used as a preliminary mode of treatment?

MATERIALS AND METHOD: Consecutive patients with gross haematuria were evaluated for the causes of haematuria. Seventy five of them identified to be of prostatic origin were further stratified as benign prostatic hyperplasia (BPH), or cancer of the prostate (CaP) based on clinical, biochemical and histologic evidence and randomized to 0.5mg dutasteride and normal saline irrigation on one arm and normal saline irrigation only as control, on the other arm. The time 13 taken for haematuria to stop, the volume of irrigation fluid used, the number of patients that had recurrence, the number of patients transfused, the units of blood transfused and the number of patients that required surgery before haematuria stopped were recorded on both arms. Statistical analysis was done using SPSS version 20.0.

RESULTS: Of the 75 cases, 49 (65.3%) had BPH while 26 (34.7%) had CaP.

Twenty five (51%) of the 49 patients with BPH had normal saline irrigation only while 24 (49%) had dutasteride in addition to normal saline irrigation. Fourteen (53.3%) of 26 patients with CaP had normal saline irrigation while 12 (46.2%) had dutasteride in addition to normal saline irrigation.

Haematuria took a significantly shorter time to stop in those that had

0.5mg dutasteride (4.9 days) than those who had only normal saline irrigation(8.0 days)(p=0.001). Volume of irrigation fluid used was also significantly less in those that had dutasteride than in those who had only normal saline irrigation (10 litres and 21 litres respectively) for BPH patients ( p=0.008) and 8 litres and 17 litres respectively for CaP patients ( p= 0.000).

Inclusion of dutasteride did not however significantly reduce the need for surgery.

CONCLUSION: The result of this study shows that addition of oral dutasteride 14

0.5mg to normal saline irrigation is effective as a preliminary mode of treatment for cases of gross heamaturia caused by BPH and CaP.

KEYWORDS: Haematuria, prostate, benign prostatic hyperplasia, adenocarcinoma of prostate, normal saline irrigation, dutasteride.

CHAPTER ONE

INTRODUCTION

Haematuria is the passage of blood in the urine. It has been described as a danger signal that should not be ignored.1 It may be gross or microscopic.

Microscopic haematuria is the presence of more than five red blood cells per high power field. Gross (macroscopic) haematuria is overt and is often a cause of panic to the patient and the attending medical staff. Haematuria may also be described as initial, total or terminal in relation to the flow of urine. Often, haematuria occurs in episodes, with each episode lasting few minutes to several days. Puchner et al2 defined a haematuric episode as either the passage of grossly bloody urine or blood clots in the urine. An episode of severe uncontrolled haematuria may cause hypovolaemic shock or even death. 15

Haematuria may occur as a feature of many systemic or urological diseases. It contributes substantially to the workload in urology clinics. For instance, haematuria was responsible for 17.7% and 4.3% respectively of the urological and surgical consultations at Ahmadu Bello University Teaching

Hospital, Zaria from 1985 to 1991.3

Benign prostatic hyperplasia (BPH) and adenocarcinoma of the prostate (CaP) have been recognized as common causes of haematuria. In an analysis of 100 consecutive cases of gross haematuria by Mbonu et al4 at

Enugu, Nigeria, BPH was found to be the commonest cause of haematuria, accounting for 27% of cases while CaP accounted for 8%. Similar findings have been noted by other workers in other parts of Nigeria5 and Europe6.

1.1 RESEARCH PROBLEM

Haematuria of prostatic origin is usually difficult to control. When left untreated, more than 60% of patients will have recurrence within a year and more importantly, almost 30% will require surgical intervention7. A number of conservative modalities of treatment are currently used to control haematuria and prevent clot retention. These methods include normal saline irrigation of the urinary bladder, and use of some chemical agents such as alum, povidone iodine or silver nitrate8. However, these approaches are non 16 specific, often not effective, and some may cause bladder irritation and necrosis8

Because of the non specific nature of its current treatment, prostatic haematuria recurs very often, necessitating regular admissions, re- investigations, and blood transfusion. These impose a huge economic burden7. As a result, patients with prostatic haematuria who continue to bleed undergo transurethral resection of the prostate as a last resort9, but this procedure is expensive and is still unavailable in many centres in Nigeria.

Most patients with gross haematuria who require surgery in our environment therefore undergo emergency open prostatectomy.

1.2 RELEVANCE OF THE STUDY

Effective use of a specific drug such as dutasteride, a 5-alpha reductase inhibitor to treat patients with gross haematuria of prostatic origin will reduce the toxicities associated with the intravesical use of chemical agents, regular use of antibiotics to treat associated urinary tract infections (UTIs), and the complications associated with regular blood transfusions may also be minimized. Furthermore, the use of emergency open or transurethral prostatectomy for control of gross haeamaturia will be minimized as dutasteride is cheap, effective and readily available in our centre.

Since finasteride, a type 2 5α –reductase inhibitor has been found to be 17 very effective in the treatment of gross haematuria due to BPH2,10, dutasteride which is a 5α-reductase type 1 and 2 inhibitor may likely have a higher potency in this regard. At present, dutasteride is primarily indicated in the combination therapy of BPH with moderate to severe symptoms. It has been used in the urological practice in University of Port Harcourt Teaching

Hospital for this purpose.

Buccon- Gibod et al11, noted that dutasteride reduced intra operative bleeding related to transurethral resection of the prostate after two weeks preoperative use. In the course of its use in symptomatic BPH patients in our centre, we also observed that the drug decreased bleeding in patients with bleeding BPH. A pilot study was therefore initiated in my centre to test its efficacy in this regard and the findings showed that prostatic bleeding stopped within 3 to 14 days of use of dutasteride (depending on the severity of haematuria).

This study was therefore initiated to test if dutasteride will be effective in the treatment of acute gross haematuria originating from BPH and adenocarcinoma of the prostate.

CHAPTER TWO

LITERATURE REVIEW

2.1 GROSS ANATOMY OF THE PROSTATE GLAND

The prostate gland is a compound tubuloalveolar gland with a fibromuscular stroma that lies just inferior to the urinary bladder12. Although the gland is ovoid in shape, it has been described as having anterior, posterior, and lateral surfaces, with a narrow apex inferiorly and a broad base superiorly, which is contiguous with the base of the bladder13. The normal prostate weighs 18-20g and measures 3cm in length, 4cm in width, and 2cm in depth.

It transmits the posterior urethra which is about 2.5cm long 12,13.

Towards the apex, the prostate is tethered to the pubic bone by the puboprostatic ligaments. Laterally, it is in direct contact with the 19 pubococcygeal portion of the levator ani and is related to its overlying endopelvic fascia. Posteriorly, the prostate is separated from the rectum by the two layers of rectoprostatic fascia of Denonvilliers12,13 . The prostate is perforated posteriorly by the ejaculatory ducts, which pass obliquely to empty near the verumontanum on the floor of the prostatic urethra just proximal to the striated external urethral sphincter13.

2.1.1 Lobes and zones of the prostate

The prostate was initially described by Lowsley as consisting of 5 lobes – anterior, posterior, median, right lateral and left lateral 13. However, the concept of zonal anatomy was popularized by McNeal14 . In the latter’s model the prostate was divided into a peripheral zone, a central zone, a transition zone and an anterior fibromuscular segment .

This zonal model makes possible the identification of the ducts in the urethra, and of the various pathological lesions afflicting the different parts of the prostate13 . The transition zone surrounds the urethra proximal to the ejaculatory ducts and projects under the bladder base 14 . It gives rise to majority of cases of BPH15 . The peripheral zone constitutes the bulk of the 20 apical, posterior, and lateral aspects of the prostate and gives rise to about

70% of cases of cancer of the prostate13,14.

2.1.2 Relations of the prostate.

The prostate gland lies behind the pubic symphisis. The vasa deferentia and seminal vesicles are related to the posterosuperior surface. The rectum lies posterior to the prostate, separated from it by two layers of the recto prostatic (Denonvilliers) fascia12,13.

2.1.3 BLOOD SUPPLY

The arterial supply is derived from the inferior vesical, internal pudendal and middle rectal arteries which arise from the internal iliac artery. The inferior vesical artery gives off branches to the bladder base and seminal vesicles and divides into two large groups of prostatic vessels – urethral and capsular16.

The urethral vessels enter the prostate at the posterolateral part of the vesicoprostatic junction and supply the bladder neck and periurethral portion of the gland through a suburethelial plexus. In BPH, under the influence of vascular endothelial growth factor (VEGF), angiogenesis occurs in the suburethral plexus, causing increase in the suburethral microvascular density

(MVD) and a resultant increase tendency to bleed10,17 . 21

The capsular branches run along the pelvic side wall in the lateral pelvic fascia posterolateral to the prostate, providing branches that course ventrally and dorsally to supply the outer portion of the prostate16. The veins of the prostate drain into the Santorini plexus of veins. As the deep dorsal vein penetrates the urogenital diaphragm it divides into 3 main tributaries: the superficial and the right and left lateral venous tributaries. The superficial tributary passes between the puboprostatic ligaments and overlies the bladder neck and prostate. The right and left lateral venous branches arborize over the prostate, receiving branches from the substance of the prostate and the sub urethral plexus. The right and left lateral venous tributaries communicate freely with the main trunk and the pudendal, obturator and vesical plexuses to form the inferior vesical vein. The inferior vesical vein empties into the internal iliac and from there into the inferior vena cava.

2.1.4 Lymphatic Drainage

The lymphatic drainage of the prostate is primarily to the obturator and internal iliac nodes. Some drainage may initially pass through the pre sacral and external iliac nodes13.

2.1.5 Nerve Supply

Sympathetic and parasympathetic nerves from the pelvic plexus reach the prostate through the cavernous nerves13. Parasympathetic nerves end at the acini and promote secretion. Sympathetic fibres cause contraction of the smooth muscles of the capsule and stroma, and hence α1 adrenergic blockade diminishes prostate stromal and preprostatic sphincter tone, leading to improved urinary flow in men with BPH. Afferent neurons from the prostate pass through the pelvic plexus to pelvic and thoracolumbar spinal centres. A prostatic block may be achieved by instilling local anaesthetics into the pelvic plexus.

2.1.6 Histology

The prostate consists of a thin fibrous capsule under which are circularly oriented smooth muscle fibres and collagenous tissues that surround the urethra. The prostatic stroma which contains the epithielial glands lies deep to this layer. The glands drain into the major excretory ducts which are about

25 in number, and the major ducts open on the floor of the urethra between the veromantanum and the vesical neck12,13. The periurethral glands lie beneath the transitional epithelium of the prostatic urethra.

2.2 PATHOGENESIS OF PROSTATIC HAEMATURIA 23

2.2.1 Rupture of dilated surface vessels

The cause of haematuria in BPH has been attributed to dilated veins which develop at the bladder neck secondary to enlargement of the prostate. These veins are said to rupture when the patient strains to urinate, resulting in gross or microscopic haematuria1. This view was shared by Mbonu et al4 who additionally noted that in BPH, the bleeding points when located, were usually from the surface vessels over the enlarged median lobe of the prostate. This finding was corroborated by Nwofor18 while determining the diagnostic accuracy of available investigations in evaluation of haematuria.

He found that urethrocystoscopy had the advantage of visualizing the surface bleeding points and could be useful therapeutically in arresting them. All these findings suggest that enlargement of the prostate leads to dilatation of surface vessels which may rupture when the patient strains to urinate, resulting in gross haematuria.

2.2.2 Neovascularization and the role of angiogenetic factors

Another mechanism of bleeding from BPH or CaP is rupture of new vessels that were formed during the process of angiogenesis. The high cellular density created by cell proliferation and hypertrophy soon outgrows the 24 blood supply creating a state of ischaemia and anoxia which serve as stimulus for elaboration of vascular endothelial growth factor. Moon et al19 have demonstrated increased microvascular density in BPH and CaP and correlated this with increased VEGF expression. This was said to be as a result of increased intraprostatic level of DHT. Dinlene et al8 corroborated this finding and further stated that the suburethral tissue of the prostate particularly had evidence of increased angiogenesis and microvascular density and attributed this to be the possible cause of bleeding in BPH.

Furthermore, Talks et al20 identified HIF-1α in these tissues and suggested that it may also play an important role in BPH angiogenesis, since hyperplastic tissues had been found to develop more hypoxia than normal tissues. Du Z et al21 corroborated this finding. They additionally demonstrated in immunoassay studies that normal prostate tissues lacked

HIF-1α in contrast to BPH. Accordingly, Parks and his colleagues22 have identified more than 40 hypoxia inducible genes, said to be important in the transcription of proteins such as VEGF and other proteins that play important role in oxygen transport.

Roehrborn et al23 attributed the elaboration of these angiogenetic factors to DHT. Dihydrotestosterone is said to be increased in pathological conditions of the prostate such as BPH and CaP and has been implicated in 25 angiogenesis leading to increased vascularity, and these newly formed vessels may be easily disrupted, providing the basis for recurrent bleeding.

2.2.3 Vasoactive activity of VEGF

Vascular endothelial growth factor which was formerly called vascular permeability factor is highly expressed in hyperplastic prostatic tissue and has been found to be about 50,000 times more potent than histamine in its ability to enhance vascular permeability9. This causes increase intravascular pressure and fragility, resulting in haematuria7.

2.2.4 Effect of rapid bladder decompression

Rapid bladder decompression has also been identified as a cause of prostatic bleeding24. This type of haematuria (ex-vacuo) is caused by rapid expansion of previously collapsed veins. As a result of this, many clinicians advocate slow decompression of the bladder using a clamping technique24.

2.2.5 Bladder wall damage

In chronic bladder outlet obstruction, there are ischaemic and fibrotic changes in the bladder wall which precipitate haematuria in 2 to 16% of patients following complete relief of obstruction25. This is thought to be the 26 cause of bleeding following relief of obstruction (as the bladder wall looses its contractility) and not rapid bladder decompression which was earlier thought. Accordingly Nyman and others24 do not think that rapid decompression has any role in causation of post obstructive haematuria and so recommended quick complete emptying of the bladder provided a prudent supportive care was instituted. This has been corroborated by other workers26.

2.3 CLASSIFICATION OF SEVERITY OF PROSTATIC HAEMATURIA

Puchner et al2 devised a classification system for severity of prostatic haematuria which was based on the previous episodes of haematuria or passage of clots, and necessity of urethral catheterization or cystoscopy.

Table 1. Puchner and Miller classification of severity of Prostatic haematuria2

Mild An episode of bleeding or passage of clots

Moderate Bleeding or clots are present in multiple voids but resolves

within 24 hours

Severe There is clot retention or necessity for urethral catheterization

or cystoscopy, requiring hospital admission 27

2.4 MANAGEMENT OF PROSTATIC HAEMATURIA

2.4.1 Diagnosis

Prostatic haematuria can be a challenging clinical problem with a spectrum of clinical presentations ranging from minor episodes that resolve spontaneously to recurrent severe episodes that may require invasive procedures27. Since haematuria can be caused by a number of clinical conditions3,4, it is important to rule out non prostatic causes before making a diagnosis of prostatic bleeding.

Accordingly, clotting profile, intravenous urography, ultrasound scan of the upper tract, cystoscopy and CT urography are important in the diagnostic armamentarium18. 28

2.4.2 Conservative management28

The first step in the treatment of prostatic haematuria is to pass a wide bore

3-way urethral catheter for vigorous flushing of the blabber followed by continuous blabber irrigation. The catheter is also important for monitoring of blood loss, subsequent care and prevention of complications. Subsequent management will depend on the severity of blood loss and may include, (a) observation only in cases of mild grade haematuria where spontaneous cessation is a possible outcome, (b) normal saline irrigation is usually done to prevent clot retention, and could be sufficient to control bleeding in mild to moderate grade haematuria. (c) Blood transfusion may be given to patients with severe haematuria or recurrent haematuria who become anaemic because of chronic blood loss. (d) Broad spectrum antibiotics are given as adjuncts based on strong clinical suspicion or on confirmation of UTI. In some cases, these measures alone are sufficient to control bleeding, while in others, further interventions may be necessary.

2.4.3 5- Alpha reductase inhibitors

Functional therapy using 5 alpha reductase inhibitors such as finasteride has been shown to be successful in the treatment of recurrent prostatic 29 haematuria due to BPH by causing prostatic involution7. Though an emerging new concept, this method of treatment is gaining acceptability and has been shown to be effective in rapid control of haematuria due to BPH probably by reducing angiogenesis through inhibition of the production of VEGF by

DHT2,10. However, this does not also seem to explain the very rapid onset of its action in prostatic haematuria. Further studies would be necessary for better understanding of this activity.

2.4.4 Chemical agents

A number of chemical agents have been used, either as intravenous infusions, oral medications or as intravesical instillation for the treatment of haematuria. Such agents include epsilon aminocaproic acid (EACA), alum, etamsylate (dicynone ), silver nitrate and formalin. Though these agents are not specific for prostatic haematuria, they are used as second line therapies and are said to have limited successes27.

EACA is a potent inhibitor of urokinase, an enzyme that causes fibrinolysis in the urinary tract. It prevents dissolution of clots in the urinary tract and thus promotes haemostasis8. It’s use is however limited in 30 disseminated intravascular coagulation (DIC) and the drug causes clot retention. Etamsylate is an oral haemostatic agent. It activates thromboplastin formation on damaged sites of small blood vessels, decreases prostaglandin I2 (prostacyclin) synthesis and also facilitates platelet aggregation, thereby decreasing or stopping bleeding28. Silver nitrate and formalin control bleeding by causing thrombosis in bleeding vessels, however, both of them cause necrosis and fibrosis of tissues. Aluminium salts (1% alum) cause precipitation of proteins without systemic effect8.

2.4.5 Surgical treatment

A number of surgical options exist for prostatic haematuria:

2.4.5.1 Emergency transurethral resection of the prostate.

Though this method is expensive, has reduced availability, and is associated with some immediate and post operative complications such as transurethral resection syndrome, yet the method has been found to be successful in severe bleeding from moderately enlarged benign prostate and has been recognized as the surgical option of choice in cases of severe haematuria10.

2.4.5.2 Emergency open prostatectomy 31

This is an option in the setting of limited resources and bleeding from markedly enlarged benign prostate. It is also indicated in refractory cases, and for severe gross haematuria with cardiovascular instability but otherwise stable patients29. Although the procedure has been said to have associated high morbidity and or mortality (and therefore less preferred to TURP)10,

Orakwe et al30 found no notable difference in morbidity or mortality when emergency open prostatectomy was rightly indicated.

2.4.5.3 Hypogastric artery embolization

Minimally invasive procedures have found utility in the treatment of patient with prostatic haematuria with severe lower urinary tract pathology in whom curative surgical options are not applicable due to poor general status, low life expectancy, and high grade tumor status31. Using right femoral (or bilateral femoral accesses occasionally), embolization is achieved with coils and particles under local anaesthesia. Rodriquez et al31 used hypogastric artery embolization as a palliative treatment for bleeding secondary to severe vesicoprostatic pathologies and achieved control between 1-31 months in 78% of cases. The method is however not readily available and takes a longer time to achieve control and so may not be effective in settings of severe or acute haematuria31. 32

2.4.5.4 Selective prostatic arterial embolization

Rastinehad et al27 also aplied the interventional radiologic technique in primary prostatic haematuria. In his method, the prostatic arterial tree was selectively catheterized and subsequently embolized, achieving control in majority of cases. This method is also not readily available and its use is still experimental.

In every case of prostatic haematuria, patient stabilization is the initial aim of treatment. The definitive treatment in each patient is based on the primary pathology.

2.5 5- ALPHA REDUCTASE ENZYME

5α- reductase enzyme is also known as 3-oxo-5 alpha steroid 4- dehydrogenase32.

It is an NADPH-dependent enzyme which converts testosterone to dihydrotestorone (DHT)33. There are two isozymes of 5α- reductase enzyme- type 1 and type 2. The type 1 isozyme is primarily expressed in the liver and skin, whereas the type 2 isozyme is predominantly expressed in the 33 prostate33,34,35. Enzymatic activity for 5α reductase has also been demonstrated in other genitourinary tissues such as epididymis, testes, gubernaculums, and corporal cavernosal tissue36. Preputial skin predominantly expresses the type-1 5α reductase like the epithelial cells in the epididymis, whereas stromal cells in seminal vesicle and around the epididymis express the type 2 isozyme like the prostate34.

All patients who have been identified to have 5α reductase enzyme deficiency have been found to have deficiency of the type 2 enzyme only.

2.6 PHYSIOLOGICAL ROLES OF 5- REDUCTASE ENZYME

An important landmark in the understanding of prostate biophysiology was the observation that the active androgen in the prostate was not testosterone (T), but its metabolite dihydrotestosterone (DHT). Testosterone is converted to DHT by the enzyme 5α reductase and this biochemical change is said to be unique in the prostate37.

2.6.1 Pathogenesis of BPH and prostate cancer

It is thought that 5 alpha reductase enzymes by mediating the conversion of testosterone to DHT play a major role in the development of BPH and prostate cancer ( CaP ) since neither BPH nor CaP develop in men castrated before puberty38. DHT is said to play a beneficial role in the developing 34 prostate but detrimental in the adult prostate in that it causes pathologic prostate growth39. Inhibition of the enzyme is therefore important in the control of pathologic processes in the prostate.

2.6.2 Normal fetal development of male organs

Dihydrotestosterone is important in the differentiation of the urogenital sinus to form the external male genitalia. Imperato-McGinley et al40 in the

1970s observed that males that lacked 5-alpha reductase enzyme could not convert testosterone to DHT and had a form of male pseudohermaphrodism.

2.7 ROLE OF DHT IN THE PATHOGENESIS OF BPH

Benign prostatic hyperplasia is a pathologic process that causes lower urinary tract symptoms (LUTS) in aging men. Histologically, BPH is characterized by an increased number of epithelial and stromal cells in the peri urethral area of the prostate19. The cause of the observed increase in cells has been attributed to epithelial and stromal proliferation or impaired programmed cell death (apoptosis) leading to cellular accumulation. 35

Androgens, estrogens, stromal epithelial interactions, growth factors, and neurotransmitters have all been said to play roles, either singly or in combination in the aetiology of the hyperplastic process19. However, Pelletier and colleagues35 suggested that DHT is primarily responsible for the pathogenesis of BPH since prostatic level of DHT remains high with aging despite progressive decrease in levels of testosterone.

This view however is not supported by some workers. For instance, Mc

Connell et al41 and Marcelli et al42 postulated that androgens do not cause

BPH but that the condition develops in prostates primed with testicular androgen during development, puberty and aging. Similarly, Roberts et al43 and Tans et al44 found no clear relationship between the concentration of circulating androgen and prostate size in aging men. Infact, McKeeh45 et al asserted that there is no evidence that either testosterone or DHT serves as a direct mitogen for growth of the prostate in older men. Neither of them, according to their assertions is mitogenic to cultured prostatic epithelial cells.

The views that appear to be widely held are that androgen withdrawal leads to inactivation of key androgen dependent genes like PSA and activation of specific genes involved in programmed cell death46,47.

2.8 ANDROGEN RECEPTOR ACTIVITY. 36

The androgen receptor (AR), also known as nuclear receptor subfamily 3, group C, member 4 (NR3C4) is a type of nuclear receptor48 which is activated by binding of either of the androgenic hormones testosterone or DHT in the cytoplasm49. Androgen receptors and progesterone receptors are closely related, so at higher doses progestins block androgen receptors50. Both testosterone and DHT bind to androgen receptors. However, DHT binds with a greater affinity51 and this explains the differences in the physiological roles of these hormones such as DNA activation, and subsequent messenger RNA production51. There are clear differences in the signal transduction pathways depending on which hormone is bound to the androgen receptor52 resulting in differences in the up regulation and down regulation of expression of various genes in the androgen metabolic pathway52.

As testosterone enters the cell, it is converted to DHT if 5 alpha reductase enzyme is present. The androgen receptor, when it is bound by steroid, undergoes a conformational change and releases heat shock protein

(HSP)53. Phosphorylation may occur either before or after the steroid binds and the androgen receptor- steroid complex then translocates to the nucleus where dimerization, DNA binding and recruitment of co activators occur54.

Target genes are then transcribed by mRNA and translated into proteins55, 37 which in this case includes vascular endothelial growth factor, that is important for angiogenesis.

2.9 5- ALPHA REDUCTASE INHIBITORS

5α reductase inhibitors are substances that inhibit 5α reductase enzymes, reducing DHT levels and thereby prostate growth56. A number of drugs inhibit these enzymes such as finasteride, dutasteride, turosteride, bexlosteride, and izonsteride57. At present, only finasteride and dutasteride are in clinical use.

While finasteride inhibits only the type II 5α- reductase isoenzyme, at therapeutic doses, the dual 5α- reductase inhibitor, dutasteride, inhibits both type I and type II isoenzymes58.

2.10 DUTASTERIDE

Dutasteride belongs to a class of drugs known as 17β-substituted 4-aza- steriods with the chemical name (5α, 17β)-N { 2,5, bis (trifluoromethyl) pheny1} -3-oxo-4-azaandrost-1-ene-17-carboxamide59.

2.10.1 Pharmacokinetics 38

Dutasteride is a competitive inhibitor of type I and type II 5α reductase isoenzymes60. The drug binds to 5α reductase enzymes forming a stable complex with a slow rate of dissociation and prevents the enzymes from binding to testosterone61. The bioavailability of dutasteride is approximately

60%, 99.5% of the circulating drug is bound to plasma proteins, it has a half- life of up to 5 weeks, and levels higher than 0.1ng/ml is detectable in the serum 4 to 6 months after discontinuation of treatment61.

2.10.2 Clinical effects of dutasteride

Following 2 years of use of dutasteride in a patient with prostate volume larger than 40cm3, the drug relieved lower urinary tract symptoms (improved

International Prostate Symptoms Score {IPSS} by 3.8)62, caused prostate volume reduction greater than 25%62 and suppressed DHT level by over

90%64. The drug also increased urine flow by 1.9ml/s and reduced risk of acute urinary retention by 57%63.

2.10.3 Side effects of dutasteride

Roehrborn CG et al63 noted that the incidence of impotence in men treated with dutasteride was 17.3%, and that the drug reduced libido by 2.1% to

4.2%, caused gynaecomastia in 0.7% to 2.3% and ejaculatory dysfunction in

0.8% to 2.2%56. 39

2.11 SAFETY PROFILE OF 5- ALPHA REDUCTASE INHIBITORS

It is important to mention the safety record of 5ARIS since their use could last for a long time sometimes. Besides a relatively low incidence of sexual dysfunction which may be difficult to differentiate from the usual effects of the aging process, the 5ARIS are relatively safe for treatment for a long period of time63. Thus, finasteride and dutasteride deprive the prostate of androgenic stimulation without causing major sexual dysfunction, osteoporosis, anaemia, muscular atrophy, or hot flushes which are expected consequences of conventional androgen deprivation (medical or surgical castration)65.

This advantage is conferred on the 5ARIS because inhibition of the enzyme results only in lowering the prostatic concentration of DHT, the principal androgenic stimulus within the gland, while leaving serum testosterone levels normal or even slightly elevated by about 10% to 20% as a result of the enzyme block66. Hence intervention with a 5ARI is a method that safely deprives the prostate of one of its primary growth stimuli, shrinks the gland, relieves symptoms, and lowers the risk of disease progression and complications63,65.

2.12 5- ALPHA REDUCTASE INHIBITORS AND THE BLEEDING PROSTATE

Finasteride was the first 5α reductase inhibitor reported to be effective against bleeding BPH67. This was in 1997 when 12 men at the Cleveland clinic had their recurrent BPH bleeding treated with the drug67. In all these patients, bleeding subsided within two weeks and the patients were followed up for a minimum of six months. Finasteride was well tolerated.

That study subsequently recommended that treatment of BPH haematuria with finasteride should be considered an alternative to transurethral resection of prostrate (TURP) or hormonal ablation in those with no significant obstructive uropathy nor adenocarcinoma of the prostate. Other workers have noted the same finding68.

Because of its efficacy in bleeding BPH, finasteride has been preoperatively used in those being prepared for transurethral prostatectomy to reduce intraoperative blood loss66. McConnel et al69 showed that finasteride reduced prostate levels of dihydrotestosterone by 85% after only

1 week of treatment.

Donohue et al70 also showed that 5mg finasteride given daily for 2 weeks before TURP significantly reduced intraoperative blood loss as well as prostatic MVD and VEGF expression and because of these, many researchers were curious about the possible mechanism of action of 5α reductase 41 inhibitors in reducing prostatic bleeding. Lekas et al17postulated that finasteride reduces the prostatic blood flow or vascular density and that this causes gland shrinkage. However, Puchner et al2 attributes the mechanism of action of finasteride to inhibition of anigiogenesis. This was also corroborated by other studies17,68. Putting together the facts that haematuria stops almost immediately after finasteride administration and that angiogenesis is known to be a rapid process, a putative mechanism put up by

Puchner et al2 that explains the effect of finasteride on prostate angiogenesis is that finasteride blocks the conversion of testosterone to dihydrotestosterone and results in decreasing activity of the androgen controlled growth factors.

It is expected that since dutasteride offers more symptomatic relief in

BPH patients62, causes more prostate shrinkage63, and lowers serum level of

DHT more than finasteride64, it will also reduce bleeding in BPH patients.

Although the literature on this is scanty, few studies have however, established that though dutasteride also has effect on VEGF and intraprostatic microvascular density (MVD), a longer duration of treatment was needed to achieve a reasonable response. Andriole et al71 suggested that a minimum of 6 weeks of dutasteride treatment is necessary to have an effect on MVD in prostatic tissue. This view was corroborated by Boccon- 42

Gibod et al11 who suggested that “only longer than 4 weeks of dutasteride treatment would reduce intra operative and postoperative bleeding in trans urethral resection of the prostate (TURP)”.

Another dimension in exploiting the wide potentials of 5α reductase inhibitors is to assay their efficacy in the treatment of haematuria from other prostatic disease and Sieber et al72 have attested to this potentiality.

CHAPTER THREE

AIMS AND OBJECTIVES

3.1 GENERAL

1. To evaluate the clinical effectiveness of dutasteride in the treatment of gross haematuria due to benign prostatic hyperplasia and adenocarcinoma of the prostate. 43

3.2 SPECIFIC

1. To determine the time it took for gross haematuria to stop while using dutasteride as the primary mode of treatment for gross haematuria from benign prostatic hyperplasia and adenocarcinoma of prostate

2. To determine the amount of irrigation fluid used before bleeding stopped while using dutasteride.

3. To determine the number of patients with bleeding prostate who required surgery to stop bleeding while receiving dutasteride

4. To compare these outcomes with those obtained when dutasteride was not used.

CHAPTER FOUR

MATERIALS AND METHOD

This was a one year hospital based prospective study of the role of the dual

5α reductase inhibitor, dutasteride in the management of gross haematuria due to benign prostatic hyperplasia and carcinoma of the prostate in 44

University of Port Harcourt Teaching Hospital (UPTH), Port Harcourt from

January 2012 to December 2012.

4.1 Study Centre

The study centre was University of Port Harcourt Teaching Hospital, a tertiary health institution located in Port Harcourt, Rivers State. The hospital serves as a major referral centre for patients from Rivers and Bayelsa States, and partly from neighbouring Abia, Cross River and Akwa Ibom States. The centre has 2 Urology units.

4.2 Ethical Consideration

Approval for this study was obtained from the Ethical Committee of the

University of Port Harcourt Teaching Hospital. Informed consent was obtained from the patients after explaining benefits of the treatment or any adverse event that may be associated with it. Patients were made to understand that their consent was voluntary and that they would still have access to treatment even if they chose not to join the study. Only those who gave consent were included in the study and all the information given were treated with strict confidentiality.

4.3 Study Population/ Scope of the study

Consecutive patients with gross haematuria of prostatic origin who presented to the Urology unit of University of Port Harcourt Teaching

Hospital, Port Harcourt, between January 2012 and December 2012, and who met the selection criteria were enrolled into the study. Digital rectal examination, laboratory investigations and prostate biopsy when indicated were done by the researcher as part of patient selection. Histopathology examinations for suspected patients with CaP were done by a dedicated

Senior Registrar in Anatomical Pathology and the reports were ratified by a

Consultant Pathologist. Abdominal/ Prostate Ultrasound scans for all the patients were also done by a Senior Registrar in radiology and ratified by a

Consultant Radiologist. Cystoscopies were done as part of the Urology unit routines with the researcher as lead surgeon or assistant. Other aspects of data collection were done with assistance of colleagues. Statistical analysis was done by a Statistician while discussion of results was done by the researcher.

4.4 Sample Size

The sample size was estimated using the following formula73

n 풏풇 = 1 + (n) 46

(N)

Where nf = desired sample size (where population is less than 10,000) n=sample size for population greater than 10,000 =Z2pq/d2

N=estimate of population size = number of patients with gross prostatic haematuria seen in UPTH = 67 (2010 = 44, 2009 = 81, 2008 = 76; average = 67)

Z = the standard normal deviation, set at 1.96, which correspond to the 95% confidence level.

P = proportion of BPH/CAP in Nigeria (target population). I have decided to use 10% here because this is the prevalence of men 40 years and above with prostate specific antigen (PSA) ≥ 4ng/ml as reported by Ukoli et al74. Hence p= 0.1; q= 1-p=(1-0.1) = 0.9 d= degree of accuracy desired, 0.05

Thus n=Z2 pq/d2 = (1.96)2 (0.1) (0.9)/ (0.05)2 =138.30

Since nf = n/ 1+n/N nf = 138.30/ 1+138.30/67

= 45.1

= 45

4.5 Inclusion criteria

Men with gross haematuria with digital rectal examination findings and serum prostate antigen level suggestive of either carcinoma of the prostate 47 or benign prostatic hyperplasia with no other disease condition that could cause haematuria or comobidities that can increase bleeding tendency, were included in the study.

4.6 Exclusion Criteria

1. All cases of gross haematuria with evidence of upper urinary tract pathology e.g. stones or neoplasm.

2. Cases of gross haematuria with evidence of bleeding diasthesis

3. Patients who were on drugs such as aspirin, heparin or warfarin.

4. Patients who have had radical prostatectomy,

5. Patients who have had bilateral orchidectomy or other forms of androgen deprivation therapy, or 5 alpha reductase inhibitors in the past.

6. Those who during treatment and evaluation were found to have bladder tumor (alone or in addition to prostate cancer or BPH) were excluded from the study.

4.7 Method

A comprehensive medical examination including full history, clinical examination and relevant investigations was carried out for all patients by 48 the researcher as provided in the study proforma (appendix i). Consecutive patients with history of gross haematuria were evaluated for causes of haematuria such as BPH, CaP, pathologies of the upper tract such as tumors, stone, cysts, or bleeding disorders, etc as provided in the study proforma.

Digital rectal examination was done for all patients by the researcher to identify those with pathology of the prostate. Serum PSA was done for all patients by a dedicated senior laboratory scientist in the hospital laboratory using immunohistochemistry assay. Those with digital rectal examination finding of hard or nodular prostate and serum PSA of ≥ 10ng/ml had prostate biopsy in order to stratify them as BPH or CAP.

Trans abdominal prostate scan was done for all patients to determine prostate size. Abdominal ultrasound scan was also done for all patients to exclude pathologies of the upper tract such as tumor, cysts, stones etc. This became necessary because cystoscopy was difficult in the setting of acute gross haematuria. By the time patients were stable on the ward, it became reasonably difficult to secure theatre spaces for them since the study depended on the only one endoscopy unit of the hospital. However the researcher ensured that either cystoscopy or intravenous urography (IVU) was done for those who continued to bleed after seven days of onset of 49 treatment. Prothrombin time (PT), partial thromboplastin time (PTT), clotting time (CT) and platelet count were done to rule out clotting abnormalities.

Patients who qualified for the study were allocated into two groups in succession. One group had normal saline irrigation only while the other group had oral dutasteride 0.5mg daily in addition to normal saline irrigation. All patients had size 22 or 24FG 3- way Foley catheter passed under aseptic conditions. The bladder was then vigorously flushed with normal saline using catheter-tip bladder syringe ( bladder washout ) until the effluent was free of blood clots. A drainage bag was then attached to the urine port of the catheter while the irrigation port was attached through a giving set to Normal Saline irrigation fluid hung on a drip stand. The bladder was continuously irrigated with normal saline at a rate which depended on the severity of haematuria. All patients also received intravenous ceftriazone

1g daily, and intravenous gentamycin 80 mg 8-hourly for 3 days and then oral levofloxacin 500mg daily until bleeding stopped. This was done to treat or prevent infection. Blood transfusion was given to any patient who developed cardiovascular instability or had haemoglobin level less than 8g/dl while on treatment.

Haematuria was graded before onset of treatment using a haematuria grading system as devised by Puchner et al2 . A minor grade was one episode 50 of bleeding or passage of clots. A moderate grade was bleeding or clots in multiple voids that resolved within 24 hours. A severe grade resulted in clot retention or required urethral catheterization or cystoscopy, indicating hospital admission.

The time taken for haematuria to stop, the amount of irrigation fluid used, the number of patients who had recurrent haematuria after initial control, the units of blood transfused after initial stabilization at haemoglobin level of ≥ 10g/dl and the number of patients who required surgery on both arms of treatment and for both diagnoses were noted. A patient required surgery if he developed cardiovascular instability as a result of continuous blood loss while on treatment, or if he required more than 3 units of whole blood within one week, depending on the diagnosis. Patients were told to continue dutasteride for at least 6 months after haematuria had stopped and to report any episode of bleeding either by phone call or by coming to the hospital.

Follow up was done through monthly hospital visits for 6 months.

Haemoglobin level was done at follow up to determine blood level.

All the results were prospectively recorded in the study proforma.

4.8 Data Analysis

Data analysis was done using a computer software: Statistical Package for

Social Sciences (SPSS) version 20.0 and results were presented in tables and bar charts. Pearson Chi- Square test was used to test for significance for non continuous variables, and student t- test for continuous variables. Kaplan-

Meier Survival analysis was used for variables measured over time, Mann-

Whitney test for non parametric dependent variables and Fisher’s exact test when samples were too small to use Chi square. Statistical significance was determined at P value less than 0.05 (P < 0.05).

4.9 Limitation

Cystoscopy which is an investigation of choice for evaluation of haematuria was not done for all patients because the study was on acute gross haematuria. Cystoscopy was difficult in this setting. The hospital endoscopic unit, which the study depended on, was not also readily available or functional.

Majority of the patients did not do IVU because the study depended on the hospital facilities. Patients were given long appointments at the

Radiological department and the bleeding had stopped and patient discharged, in most cases before the appointment time. Accordingly, 52 abdominal ultrasound scan was used to rule out pathologies of the upper tract such as tumor, cyst, stone.

There was no standardized method of determining the flow rate of the irrigation fluid. The height of the drip stand was not also constant for every patient. These may have influenced the total volume of irrigation fluid recorded in each case.

CHAPTER FIVE

RESULTS

A total of 87 patients were initially included in the study but 12 were later excluded for various reasons: electrolyte and urea abnormalities (5), clotting 53 abnormalities (3), bladder tumor (3), and bladder stones (1). Seventy five patients met the inclusion criteria. Out of the 75 patients, 49 (65.3%) had benign prostatic hyperplasia, while 26 (34.7%) had carcinoma of the prostate.

Figure 1 shows the Age distribution of the patients. The mean age was

68.8 ± 9.5 years with a range of 49-88 years. The mean age for patients with

BPH was 67.0 ± 9.6 years while the mean age of those with CaP was 71.4 ±

9.0 years.

Sixty seven (89.3%) were married, 7(9.3%) were widowers while 1(1.3%) was divorced. Twenty (26.7%) had primary education, 25 (33.3%) had secondary education , 21 (28%) had tertiary education and 9 (12%) had no formal education. Sixteen (21.3%) were civil servants, 15(20.0%) were farmers, 13(17.3%) were traders, 9(12.0%) were artisans, while 17(22.7%) were retired from public service. Other occupations constituted 5(6.7%).

Figure 1 : Age distribution of patients

The predominant tribes were Ikwerre 25(33.3%), Ibo 11(14.7%), Ijaw

5(6.7%), Ogoni 5(6.7%), Kalabari 4(5.3%), while other tribes constituted

21(28%). Marital Status, level of education, occupation and ethnicity did not significantly influence the outcome of the study. All the patients were

Christians.

Duration of haematuria before presentation ranged from less than 24 hours to more than 7days with a mean of 3.41 days. Nineteen patients

(25.3%) presented less than 24hours of onset of haematuria, 27 (36.0%) 55 presented between 24 hours and 72 hours, 20 (26.7%) presented between 72 hours and 7days while 9 (12.0%) presented after 1 week.

Figure 2: Duration of haematuria before presentation

Fifty seven (76%) of the patients presented with total haematuria, while

18 (24%) developed haematuria following urethral catheterization for the relief of urinary retention. Thirty one (41.3%) patients had seen blood clots in their urine while 44(58.7%) saw no blood clots. However, only 6(8%) had clot retention while 69(92%) had no clot retention. Twenty (26.7%) have had 56 haematuria in the past one year. Six (8.0%) had it only once, 7(9.3%) had it twice, 4(5.3%) had it three times, and 3(4.0%) four times. Mean number of previous episodes of haematuria in the past one year was 2.2 times. All the patients included in this study required urethral catheterization and hospital admission and were therefore classified as severe gross haematuria.

All the patients had enlarged prostates on digital rectal examination, however, eight (10.6%) patients had nodular prostates, 11 (14.7%) patients had hard prostates while 56 (74.7%) had firm smooth prostates.

Trans abdominal ultrasound prostate size estimation showed a range of

49.0g to 296.3g with mean prostate size of 133.3 ± 51.6g. The mean prostate size for patients with BPH was 133.9 ± 6.9 while the mean prostate size for patients with CaP was 131.5 ± 11.4g ( Table 2 ). There was no significant difference in the mean prostate size between patients with BPH and CaP having haematuria (p=861) (Table 2).

The mean prostate size for patients who had dutasteride was 134.8 ±

47.6g while the mean prostate size for patients who had normal saline irrigation only was 131.5 ± 55.6g. The difference of the mean was not statistically significant (p= 0.784) (Table 3).

Table 2: Mean Prostate Size by Diagnosis

Standard Diagnosis N Mean Median Error of Minimum Maximum Mean Benign Prostatic 49 133.9 130.0 6.9 49.0 250.1 Hyperplasia Cancer of Prostate 26 131.5 119.5 11.4 56.0 296.3

Total 75 133.1 124.0 6.0 49.0 296.3 T=0.175 p-value=0.861

Pearson correlation analysis was done to test if there was any relationship

between prostate size and duration of haematuria and it showed a positive

correlation which was statistically significant ( R=0.3, P= 0.012) ( Table 4)

Table 3: Mean Prostate Size by Treatment

(Student T-Test Analysis)

Std.

Std. Error

Treatment N Mean Deviation Mean

Prostate Normal Saline and 36 134.8 47.6 7.9

Size Dutasteride

Normal Saline 39 131.5 55.6 8.9

Irrigation only

T= 0.275 P-value 0.784

Table 4: Correlation Analysis of Prostate Size and Duration of

Haematuria

Duration of

Haematuria Prostate Size

Duration of Pearson 1 .290*

Haematuria Correlation

Sig. (2-tailed) .012

N 75 75

R= 0.290 P-value 0.012

Five (6.7%) had cystoscopy and another five (6.7%) had IVU to exclude upper tract pathologies because these patients continued to bleed 7 days after onset of treatment. All patients included in the study had normal renal function and coagulation assessment.

The serum PSA ranged from 3ng/ml to 68ng/ml with a mean PSA of 14.8

± 9.1ng/ml and modal PSA of 4.0ng/ml for patients with BPH and 3.0ng/ml to

134.0ng/ml with a mean PSA of 47.9 ± 42.1ng/ml and modal PSA of

120.0ng/ml for those with CaP. Mann- Whitney test for non parametric variables was done to test if the mean PSA of patients that had BPH differed from the mean PSA of those with CaP and it was statistically significant

(Table 5)

Table 5: Mann-Whitney Test for Serum PSA of Respondents

Mann- Mean Mean Sum of Wilcoxon p- Diagnosis N SD Mode Whitney Z PSA Rank Ranks W value U Benign Prostatic 49 14.8 13.9 4 30.83 1510.50 Hyperplasia 285.500 1510.500 -3.914 0.000 Cancer of 26 47.9 42.1 120.0 51.52 1339.50 Prostate Mann-Whitney test was used to test mean difference where the dependent variable is non- parametric (not normal distribution)

The mean PSA for patients treated with 0.5mg dutasteride was 22.9ng/ml while the mean PSA for those who had normal saline irrigation only was

29.3ng/ml and this was not statistically different (t- test = -0.903, p=0.370).

Pearson correlation was done to test the relationship between level of PSA and duration of haematuria while using dutasteride. The result showed a negative correlation which was not statistically significant (N=36, r

= -0.060, p- value = 0.730).

All 19 patients with hard or nodular prostates and 45 patients with serum PSA of 10ng/ml to 134ng/ml had prostate biopsy and of these 26

(60.5%) had adenocarcinoma of the prostate.

A cross tabulation of the diagnosis and treatment received shows that 25

(51%) of 49 patients with haematuria of BPH origin were treated conservatively with normal saline irrigation (control group), while 24(49%) were treated with oral 0.5mg dutasteride daily in addition to normal saline irrigation (dutasteride group) (Table 6). Also, of the 26 patients with CaP, 14

(53.8%) were in the normal saline group, while 12(46.2%) were in the dutasteride group.

Table 6: Diagnosis and type of treatment

Treatment

Diagnosis Normal Saline and Normal Saline Total

Dutasteride Irrigation only

BPH 24 (49.0) 25 (51.0) 49

CaP 12 (46.2) 14 (53.8) 26

Total 36 (48.0) 39 (52.0) 75

Heamaturia stopped in all 24(100%) patients with BPH on the dustateride group and in 24 (96%) of the 25 patients on the normal saline control group.

The remaining 1(4%) patient had open prostatectomy and haematuria subsequently stopped. Also, haematuria stopped in all of the 12 (100%) patients with CaP who were on the dutasteride arm but on 12 (85.7%) of the

14 patients on the normal saline control arm. The 2 (14.3%) CaP patients 63 whose haematuria did not resolve had bilateral subcapsular orchidectomy and haematuria resolved subsequently.

In all, haematuria resolved in 36 patients who had dutasteride but in

36(92.3%) of the 39 patients on the normal saline control arm. Three (7.7%) of 39 patients on the normal saline control arm needed surgery

(orchidectomy or prostatectomy depending on the diagnosis) to stop haematuria.

In patients with BPH on the control arm, haematuria lasted between 3 days and 38 days with a mean duration of 8.0 ± 6.8 days and between 2 days and 15 days with a mean duration of 4.9 ± 2.9 days in those treated with dutasteride (table 7). Kaplan Meier Survival Analysis procedure was used to examine the distribution of time it took haematuria to stop for the two different types of treatment. The comparison tests show that there was a statistically significant difference between them (fig. 3 ).

Table 7: The minimum and maximum duration (in days) of haematuria and mean duration (in days) of haematuria for each diagnosis and for each treatment type.

Diagnosis N Means±SD Minimum Maximum

Normal Saline and 24 4.9 ± 2.9 2 15 Dutasteride Benign Prostatic Normal Saline Hyperplasia Irrigation only 25 8.0 ± 6.8 3 38

Normal Saline and Dutasteride 12 4.7 ± 1.9 1 8 Cancer of Prostate Normal Saline Irrigation only 14 6.9 ± 2.3 3 10

Figure 3: Kaplan Meier analysis for duration of haematuria for the two arms of treatment.

The horizontal axis shows the time to effect (time of resolution of haematuria). The vertical axis shows the probability of survival (probability of resolution of haematuria). Thus, any point on the survival curve shows the probability that a patient on a given treatment will have experienced relief at that time.

The plot for Normal Saline and dutasteride was below that of Normal

Saline irrigation only (shorter time) throughout most of the trial, which suggests that normal saline and dutasteride may give a faster relief than normal saline irrigation only.

To determine whether the differences were due to chance, the means and medians for the survival time/ time to resolution of haematuria were compared for the two treatment arms and this showed significant difference in the average time in favour of the dutasteride group(p= 0.009)( table 8 and table 10)

Table 8: Means and Medians for Survival Time Treatment Mean Median Estimate Std. Error 95% Confidence Estimate Std. 95% Confidence Interval Error Interval Lower Upper Lower Upper Bound Bound Bound Bound

Normal Saline and 6.492 0.819 4.885 8.098 5.000 0.458 4.102 5.898 Dutasteride

Normal Saline Irrigation only 11.039 2.512 6.116 15.962 8.000 0.596 6.832 9.168

Overall 8.779 1.390 6.055 11.503 7.000 0.628 5.770 8.230

Table 9: Percentiles Table for the Survival Curve ( Probability of Resolution of Haematuria )

25.0% 50.0% 75.0% Treatment Estimate Std. Error Estimate Std. Error Estimate Std. Error

Normal Saline and Dutasteride 9.000 2.043 5.000 0.458 4.000 0.313

Normal Saline Irrigation only 11.000 2.521 8.000 0.596 6.000 0.770

Overall 11.000 1.044 7.000 0.628 4.000 0.398 69

The percentile table for the survival curve for the two arms of treatment was also compared and it showed significant difference in favour of the group treated with dutasteride. For instance, the 75th percentile is the time at which 75% of the patients are yet to have their haematuria resolved. For the group treated with dutasteride, this was at 4 days. At 50th percentile, 50% of patients still have symptoms and this corresponded to 5 Days. Similarly, 25% of patients had symptoms at 25 percentile, corresponding to 9 days. The values for those treated with normal saline irrigation only were 6days, 8 days, and 11 days corresponding to 75, 50, and 25 percentiles respectively (

Table 9 ).

Table 10: Overall Comparisons of Log Rank, Wilcoxon, and Tarone Wares tests in relation to time to resolution of haematuria.

X2 df p-value Log Rank 6.779 1 0.009 Breslow ( Generalized 10.207 1 0.001 Wilcoxon) Tarone-Ware 8.944 1 0.003

Table 10 provides overall tests of the equality of survival times (probability of resolution of haematuria) across groups. Since the significant values of the tests are all less than 0.05, it means there is a significant difference in the survival curves.

BPH patients on the normal saline control arm required between 6 litres 70 and 55 litres of irrigation fluid with a mean volume of 21.0 ± 11.9 litres to stop haematuria while those that had 0.5mg dutasteride in addition required between 4 litres and 20 litres with a mean volume of 10.4 ± 5.2 litres before haematuria stopped. A two sample student t-test was used to test whether the volume of irrigant fluid used for the two groups were different. This was statistically significant in favour of those who received dutasteride (t= -2.885, p=0.008) (table 11).

The CaP patients on the control arm required between 4 litres and 48 litres of irrigation fluid with a mean volume of 17.4 ± 9.7 litres before haematuria stopped while those on the dutasteride arm required between 3 litres and 20 litres with a mean volume of 8.3 ± 4.6 litres. A two sample student t- test was used to test if the mean volume of irrigation fluid for the two groups were different. It was statistically significant in favour of those who used dutasteride ( t= -4.115, p= 0.000) (table 11).

Table 11: Cross tabulation of diagnosis and treatment showing mean volume of irrigation fluid used before haematuria stopped and two sample student t- test and p value.

Normal Saline Normal Saline

Diagnosis and Dutasteride Irrigation only t-test P-value

Mean±SD Mean±SD

BPH 10.3±5.2 21.0±119 -2.885 0.008

CaP 8.3±4.6 17.4±9.7 -4.155 0.000

One (4%) of 25 BPH patients on normal saline control arm required emergency prostatectomy to stop bleeding while none of the 24 BPH patients on the dutasteride arm had prostatectomy. Fisher’s Exact was used to test if inclusion of dutasteride reduced need for prostatectomy and it was not significant (Fisher’s Exact; p=0.140) (table 12).

Similarly, 2(14.2%) of the CaP patients on the normal saline arm needed orchidectomy to stop bleeding while none of the 12 patients on the dutasteride arm had orchidectomy. Fisher’s Exact was used to test if inclusion of dutasteride reduced need for orchidectomy to stop haematuria and it was not significant (Fisher’s Exact:p=0.280). In all, 3(7.7%) of 39 patients on the control arm had surgery (either prostatectomy or bilateral orchidectomy, 72 depending on the diagnosis) to stop haematuria while none of the 36 patients that took dutasteride had surgery. (Fisher’s exact test: p=0.420)

(Table 12).

Table 12: Fisher’s Exact Test for need for surgery when dutasteride is included

Treatment

Diagnosis Normal Saline and Normal Saline P-Value

Dutasteride Irrigation only

Surgery Surgery

Yes No Yes No

BPH 0 24(100) 1(4.0) 24(96.0) 0.140

CaP 0 12(100.0) 2(14.3) 12(85.7) 0.280

TOTAL 0 26(100) 3(7.7) 36(92.3) 0.420

Fisher’s Exact Test was used for the statistics

A total of 7(9.3%) of the patients were transfused after initial stabilization at haemoglobin 10g/dl. Three of the patients had BPH. One (33.3%) of them received 0.5mg dutasteride while 2 (66.7%) were on the control arm. Fisher’s exact test was performed to test if there was a significant influence of 73 inclusion of dutasteride to reduce need for blood transfusion. The result showed that there was no significant influence (Fisher’s exact test = 0.516)

(table 13). The remaining 4 patients had CaP. Two (50%) were on each side of the treatment. Fisher’s exact test was performed to test if there was a significant influence of the inclusion of dutasteride to reduce need for blood transfusion. The result showed that there was no significant influence

(Fisher’s exact test =0.641) (table 13).

Table 13: Requirement for blood transfusion

BLOOD TRANSFUSION Fishers Normal Saline Normal Saline Diagnosis Exact and Dutasteride Irrigation only Test No Yes No Yes BPH 23 (95.8) 1 (4.2) 23 (92.0) 2 (8.0) 0.516

CaP 10 (83.3) 2 (16.7) 12 (85. 7) 2 (14.3) 0.641

Total 33 3 35 4 Fisher's Exact Test was used for test of significance where the samples are too small to use X2

Fifteen (60%) of 25 BPH patients on the control arm had recurrent haematuria after initial resolution while 4(16.7%) of 24 BPH patients on the dutasteride arm had recurrent haematuria. A chi-square test was used to test if inclusion of dutasteride reduced incidence of recurrent haematuria and it was found statistically significant (X2 = 9.685, p=0.003). Similarly, 7 (50.0%) of

14 CaP patients on the control arm had recurrent haematuria while 1 (8.3%) of 12 CaP patients who received dutasteride had recurrent haematuria. A chi- square test was used to test if inclusion of dutasteride reduced incidence of recurrent haematuria and it was found statistically significant (X2=5.266, p=0.036) (Table 14).

Table 14: Recurrent haematuria after treatment

Treatment

Diagnosis Normal Saline and Normal Saline X2 P-value

Dutasteride Irrigation only

Yes No Yes No

BPH 4(16.7) 20(83.3) 15(60.0) 10(40.0) 9.685 0.003

CaP 1(8.3) 11(91.7) 7(50.0) 7(50.0) 5.266 0.036

Total 5 31 22 17 14.691 0.000

CHAPTER 6

DISCUSSION

DEMOGRAHY

The mean age of patients with BPH in this study was 67.0 ± 9.6 years

It differs from the mean age of 76 in the study by Foley et al7. They evaluated the effect of finasteride on chronic haematuria associated with BPH among

57 patients. The difference may be with the different populations studied.

Foley et al studied Caucasians, but this study was on Nigerians. It may be that they had more elderly people in their study that raised the mean age, but this cannot be proven since no standard deviation was provided in their study. It was however similar to the mean age of 67 reported by

Shamugasundaram et al75. They studied 197 patients who had pre operative dutasteride to reduce intraoperative bleeding.

A subgroup of patients in this study had prostate cancer and their mean age was 71.4 ± 9.0. This compared to the mean age of 71.4 years noted by Ogunbiyi et al76 in Ibadan, 71.6 reported by Eke et al77 in Port

Harcourt, and 71.0 by Nwofor et al78 at Nnewi. Since this subgroup of patients in this study had prostate cancer and are Nigerians, a mean age of

71.4 was not unexpected. 78

However, this age was slightly higher than the overall mean age (68.8 ± 9.5) of patients with haematuria in this study. This was because the greater percentage of the patients were cases of haematuria from BPH.

DURATION OF HAEMATURIA WITH DUTASTERIDE AS PRIMARY MODE OF

TREATMENT

Haematuria stopped in about 5 days in BPH patients who were treated with dutasteride in addition to normal saline irrigation in this study. This finding is not unexpected because dutasteride inhibits the two isoenzymes of 5α reductase enzyme. These two isoenzymes are usually increased in BPH8. By causing total inhibition of 5 alpha reductase enzyme, dutasteride reduces intraprostatic concentration of dihydrotestosterone (DHT)63 thereby reducing the concentration of vascular endothelial growth factors and other androgen controlled growth factors72.

The mechanism of apoptosis and prostate shrinkage which was considered as the mechanism of action of 5ARIs as postulated by Lekas et al17 may not certainly explain this rapid resolution of prostatic haematuria in less than 5 days. This is because prostate shrinkage occurs only after about 6 months of treatment with 5ARIs79. 79

Inhibition of angiogenesis, postulated by Puchner et al2 may also not explain this rapid response. Although angiogenesis is a rapid process, it is thought to occur between 5 days to 7 days2. The rapidity with which acute haematuria clears when dutasteride is used suggests that it may influence an associated pathological condition that resolves in a short time. This condition has been suggested to be inflammation7. Accordingly, dutasteride has been thought to stop acute haematuria through an anti-inflammatory effect while its mechanism of action on recurrent haematuria may be attributable to inhibition of angiogenesis and apoptosis in vascular prostates. The editorial view on the work of Foley et al7 attributed the rapid response to reduction of extravascular edema brought about by reduction in the production of VEGF.

VEGF is said to be a vasodilator found to be about 50,000 times more potent than histamine7.

Reduction of extravascular edema reduces intravascular pressure and prevents the destruction of the fragile new vessels, thereby reducing haematuria.

The finding of 4.9 ± 2.9 days as the mean duration of haematuria from

BPH while using dutasteride in this study was much less than the mean duration of 2 weeks noted by Dahala et al67 when they did a long time follow up in patients with recurrent haematuria associated with benign prostatic 80 hyperplasia who were treated with finasteride. Their study was however on outpatients who had no form of supportive treatment. All patients in this study had supportive treatment like bladder irrigation and antibiotics which may have contributed to the earlier resolution of haematuria.

Besides, the work of Dahala et al was on 12 BPH patients with recurrent haematuria who were treated with finasteride whereas in this study, 24 BPH patients were treated with dutasteride. The sample size may therefore be contributory to the disparity. Furthermore, dutasteride, being a type I and II

5ARI has a greater effect on vascular prostate than finasteride which is a type

II only inhibitor79.

In this study dutasteride was also effective in the control of gross prostatic haematuria in patients with CaP who had not had androgen deprivation therapy before they developed haematuria. Haematuria stopped in less than 5 days (4.7± 1.9) in CaP patients on dutasteride while it stopped in about 7 days in those on the control arm. Though 5ARIs especially finasteride has been noted to have effect on prostatic bleeding caused by

BPH, this has not been noted on those caused by CaP. In the work of Dahala et al67, it was recommended that finasteride should not be used for treatment of prostatic haematuria caused by CaP. The finding of this study, however suggests that dutasteride is also effective in the control of 81 haematuria from CaP and should be used for cases of prostatic haematuria of

CaP origin while awaiting androgen ablation.

The mean duration of haematuria of 4.7 ± 1.9 for CaP patients treated with dustasteride is similar, infact less than the mean duration of 4.9 ± 2.9 days for BPH patients with haematuria treated with dutasteride, but the difference was not statistically significant. However, one expects that the mean duration of haematuria should have been significantly higher in BPH since the microvascular densities and neovascularization are located in the suburothelium in BPH2,8,18.

The difference in the sample sizes (12 for CaP and 24 for BPH) may be responsible for this finding.

VOLUME OF IRRIGATION FLUID AND DUTASTERIDE AS PRIMARY MODE OF

TREATMENT

It required a significantly less amount of irrigation fluid to stop haematuria in patients who took dutasteride ( 10.4 ± 5.2 litres for BPH and 8.3 ± 4.6 litres for CaP ) than in those who did not use dutasteride ( 21.0 ± 11.9 litres for BPH and 17.4 ± 9.7 for CaP). The mechanisms through which dutasteride stops acute haematuria as discussed in the preceeding section include inhibition of both isoenzymes of 5 alpha reductase enzymes8, reduction of intraprostatic 82 levels of DHT, and reduction of synthesis of VEGF and androgen regulated growth factors63.

It is important to mention that normal saline irrigation is used here as a supportive form of treatment, not as a type of treatment itself since its role is mainly prevention of clot retention. Some scholars have however argued that bladder irrigation on its own may decrease the duration of haematuria80.

This argument is based on the fact that irrigation washes off the enzyme urokinase, a serine protease that prevents blood clot formation in the bladder by activation of plasmin80. Again, clot formation is known to cause retention81 and possibly, infection82 which may paradoxically increase bleeding.

In this study, however, patients were continuously irrigated on both arms of the study until haematuria resolved; so whatever influence irrigation had on bleeding is assumed to have been neutralized. Accordingly, the detected difference in volume of irrigant used on both arms of the study, is supposedly a measure of the influence of dutasteride.

REQUIREMENT FOR SURGICAL INTERVENTION

Three (7.7%) of 39 patients on the normal saline arm required surgery 83

(one had prostatectomy, 2 had bilateral orchidectomy, depending on the diagnosis) to stop haematuria while none of the 36 patients on the dutasteride arm required surgery. This was not statistically significant

(p>0.05). The finding in this study was similar to the observation made by

Foley et al7. In their study, none of the 28 patients on the finasteride arm had surgery. However, 26% of those on the control arm had surgery. But, in this study only 7.7% had surgery. The difference may have arisen from the fact that the control in their study were out patients who had no form of supportive treatment. The addition of normal saline irrigation and antibiotics to the control arm in this study may have reduced the need for surgery. Also, the difference in the sample size may have contributed. The control arm in their study had 29 patients while in this study it was 39 patients.

A notable finding in this study was the rapidity of the resolution of haematuria following bilateral orchidectomy. The two CaP patients on the control arm who continued to bleed after 30 days of irrigation had bilateral total orchidectomy, and haematuria was noticed to stop within 24hours of orchidectomy in both patients. This supports the fact that androgens play key roles in the pathogenesis of prostatic bleeding.2,7,17,70 . Serum levels of testosterone and DHT drop by greater than 90% after orchidectomy83. So, 84 orchidectomy removed the influence of DHT and its associated inflammatory effects mediated through VEGF.

SERUM PSA AND RESPONSE OF PROSTATIC HAEMATURIA TO TREATMENT

In this study, the relationship between the serum PSA of patients with prostatic haematuria and the duration of haematuria while using dutasteride was notable. The mean PSA of BPH patients was 14.8 ± 9.1ng/ml with modal

PSA of 4ng/ml and the duration of haematuria while using dutasteride was

4.9 ± 2.9 days. The mean PSA of CaP patients was 47.9 ± 42.1ng/ml and the modal PSA was 120mg/ml while the duration of haematuria while using dutasteride was 4.7 ± 1.9 days. The response of prostatic haematuria to dutasteride increased as the PSA value increased. This explains the negative correlation between the PSA value and the duration of haematuria during treatment (r=0.060, p=0.730). As the PSA value increased, the duration of haematuria decreased which means that response to treatment increased.

The relationship was however not statistically significant. This may be as a result of the extreme values which is shown here by the high standard deviations.

The response of haematuria to treatment in patients that had normal 85 saline irrigation only in this study also increased as the PSA value increased.

This means that the predictor of the response is not the type of treatment, but the PSA value. Since the mean PSA of bleeding BPH patients in this study was 14.8ng/ml it may be said that high PSA is a factor for prostatic haematuria. However, above a critical level of PSA, the tendency to bleed reduces as seen in the patients with CaP haematuria in this study.

HAEMATURIA AND PROSTATE SIZE

The mean prostate size of BPH patients with haematuria was 133.9 ± 6.9g while the mean prostate size of those with CaP was 131.5 ± 11.6g. The difference in the means was not statistically significant (t = 0.176, p = 0. 861).

This means that the prostatic pathology per se is not the major risk factor for bleeding provided the prostate is enlarged. The mean prostate size of patients who received dutasteride was 134.8 ± 47.6g while the mean prostate size of those who had normal saline irrigation only was 131.5 ±

11.4g. The difference in the means was not significant ( t = 0.276, p = 0.784 ).

The common risk factor among these two groups of patients with prostatic haematuria is the fact that both of them had enlarged prostates. Indeed, there was a statistically significant positive correlation between prostate size and duration of haematuria while receiving treatment (r = 0.3. p = 0.012 ). 86

This shows that bigger prostates bleed longer than smaller prostates of the same pathology while receiving same treatment type.

RECURRENT HAEMATURIA AFTER INITIAL RESOLUTION

In this study, 60% of BPH patients on the normal saline control arm had recurrent haematuria within 6 months after initial resolution while only

16.7% of those treated with dutasteride had recurrence within the same period and this was found to be statistically significant (X2=9.685, P=0.003).

This was similar to the finding of 63% of recurrence in the control group and

14% in the finasteride group in the population studied by Foley et al7.

However, in their study, patients received finasteride for 12 months and recurrence was noticed within 6 weeks of discontinuation of treatment. In this study most of the patients discontinued treatment as soon as their haematuria resolved because they could not afford the drug for longer period of time. It is therefore expected that patients who take dutasteride for up to

12 months will have even fewer recurrence rate since dutasteride has a longer half life (5 weeks) and greater than 0.1ng/ml is said to be detected in the serum, after 6 months of discontinuation61.

It was found in this study also that 50% of CaP patients on normal saline arm had recurrent haematuria against only 8.3% of patients who were 87 treated with dutasteride (p<0.05). While this strengthens the argument on the efficacy of dutasteride against control, it goes further to show that BPH has more tendency to bleed than CaP.

CONCLUSION

This study has demonstrated that the addition of dutasteride 0.5mg daily to normal saline irrigation in the control of gross haematuria from prostatic origin is more effective than normal saline irrigation only as shown below:

1. Gross haematuria caused by BPH resolved in about 4.9 days when

0.5mg dutasteride was used while it resolved in about 8 days when

normal saline irrigation only was used.

2. Gross haematuria in CaP patients resolved in about 4.7 days when

0.5mg dutasteride was used while it resolved in about 7 days when

normal saline irrigation only was used.

3. The amount of irrigant required for BPH patients with gross

haematuria when dutasteride was added was 10 litres while the

amount used when it was not added was 21 litres.

4. The amount of irrigant required for prostate cancer patients with gross

haematuria when dutasteride was added was 8 litres while the amount

used when it was not added was 17 litres.

However, those who received dutasteride did not require significantly less surgical intervention than those who did not receive it.

RECOMMENDATIONS

From the results obtained from this study, it is recommended that dutasteride, 0.5mg daily should be added to normal saline irrigation as the primary mode of treatment in cases of acute gross haematuria arising from enlarged prostates.

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100

APPENDIX 1

PROFORMA

This is a case controlled study of the role of dutasteride, a 5α reductase inhibitor in the treatment of haematuria due to benign prostatic hyperplasia and adenocarcinoma of the prostate. The information contained in this study proforma is for the purpose of research only. Your cooperation is highly solicited as we assure you of strict confdentiallity.

1. BIODATA: a. Folder no …………………………………………………

b. Age ……………………………………………………………

c. Ethnic group………………………………………………..

d. Occupation ...…………………………………………………

e. Address …………………………………………………………

f. Religion …………………………………………………………..

g. Marital status………………………………………………….. 101

h. Educationl status ……………………………………………

2. HISTORY OF PRESENT COMPLAINT

(1) a. When did you notice blood in your urine?......

b. Type

-initial……………………………….

- Terminal………………………….

- Total…………………………………

c. Did you notice blood clots in your urine?......

d. Have you had retention since this bleeding started? ………………….

e. Have you had blood in your urine in the past one year? Yes…….. No……….

f. If yes, how many times……………………………………………….

g. How long did the bleeding last? (i) Less than 24hrs (ii) More than 24hrs

h. Were you admitted in the hospital during any of those episodes?

(ii) grade of haematuria

Mild………………………………. Moderate………………………… severe……………………

2 . MEDICATION HISTORY

Yes No Drug 102

a. Hypertension ………………… …………. ………

b. Chronic liver disease ……………… ………….. …………

c. Known BPH on drugs ……………….. ……… …..

d. Coronary arterial disease on anticoagulant

4. SURGICAL HISTORY Yes No Date

a. Open prostatectomy ………… ………….. …………

b. TURP ………… …………… ………….

c. Orchidectomy …………… …………… ………….

d. Others ………….. …………. …………..

5. DRUG HISTORY:

a. Aspirin

b. Heparin

c. Warfarin

d. Cyclophosphamide

e. Phenolphthalein

f. Rifampicin

g. BCG 103

6. SIGNS

 General

Yes No

 Pallor …………………………….. ……………………………

 Jaundice ……………………………… ……………………………

 Fever ……………………………… ……………………………

 Pedal oedema ……………………………… …………………………...

b. VITAL SIGNS pulse…. Temp……. respiratory rate….. BP…….

c. Abdomen: Palpable Not palpable

 Liver …………………………… ……………………………

 Kidney ……………………………. ……………………………

 Bladder ……………….…………… ..…………………………

104

e. DRE  Prostate size:

Mild …………………………. Moderate…………………… marked ……………..

 Consistency

Soft …………………………… firm………………………………. Hard…………………..

- Surface

Smooth………………………………. Nodular …………………………………..

- median groove

Present …………………………………… Obliterated ………………………………….

7. LABORATORY INVESTIGATIONS a. Urinalysis:

 PH …………………………………………………

 Specific gravity ……………………………..

 Protein ………………………………………….

 Glucose………………………………………….

 Blood……………………………………………..

105 b. Urine culture……………………………………….

Sensitivity …………………………………………..

Cytology…………………………………………….. c. Full blood count

 PCV………………………………………………. %

Hb…………………………………………………mg%

Hb Genotype………………………………….

 WBC total………………………………………………………………………………………./mm3

Differential: Neutrohils…………………………………………………………

Eosinophils………………………………………………………..

Basophils …………………………………………………………..

Monocytes …………………………………………………………

Lymphocytes……………………………………………………….

 Platelets count………………………………………………………………………………

d. Serum E/U/Cr e. Clotting Profile: f. Serum PSA: g. Abdominal / Prostate Scan report:

.Abdomen- 106

.Pelvis- Bladder…………………. Prostate…………………….

h. Prostate biopsy report: i. IVU Report: j. Cystoscopy and biopsy report

7. Treatment given a. 3 way catheter. Size ……….

b. Normal saline irrigation ………………………………………

i. Date of commencement………………………………………………..

ii. Haematuria resolves Yes……………………… No ………………...

iii. When did haematuria resolve?……………………………………………

b. 0.5mg dutasteride + normal saline irrigation

i. Date of commencement ………………………………………………

ii. Haematuria resolves ……………. Yes …………………… No ……………….

iii. When did haematuria resolve? ………………………………………….

8. Volume of irrigant fluid used…………………………………………………………

11. Units of blood transfused…………………………………………………......

12. Indication for prostatectomy …………………………………………………………..

13. a. Recurrent haematuria after initial resolution………Yes….. No………

b. How long after resolution did haematuria recur …………………………….

14. Follow up: 107

Duration-

Hb/ PCV-

Urinalysis-

Care-