Project Description

 

CHAPTER ONE

                                                     INTRODUCTION

1.1       Prostate

The prostate is a gland found only in males. It is located in front of the rectum and below the urinary bladder and vas deferens. The prostate secretes an alkaline fluid that forms part of the semen. The size of the prostate varies with age. In younger men, it is about the size of a walnut, but it can be much larger in older men.

The prostate makes some of the fluid that protects and nourishes sperm cells in semen, making the semen more liquid. Just behind the prostate are glands called seminal vesicles that make most of the fluid for semen. The urethra, the tube that carries urine and semen out of the body through the penis, goes through the center of the prostate.

The prostate starts to develop before birth. It grows rapidly during puberty, fueled by male hormones (called androgens) in the body. The main androgen, testosterone, is made in the testicles. The enzyme 5-alpha reductase converts testosterone into dihydrotestosterone (DHT). DHT is the main hormone that signals the prostate to grow (Lu-Yao, 2008).The prostate usually stays at about the same size or grows slowly in adults, as long as male hormones are present.

1.1.1    Prostate pathologies

 

The prostate is usually affected with three major disorders namely; benign prostate hyperplasia, prostatitis and prostate cancer. These are disorders associated with males over the age of 40 years and impact on their health in general (McNaughton et al., 2001).

1.1.1.1 Benign Prostate Hyperplasia (BPH)

Benign prostate hyperplasia (BPH) is an age-related non cancerous enlargement of the prostate   that results from a neoplastic unregulated growth of the prostate gland (Paglone, 2010). It is a disorder associated with males over the age of 40 years and impacts on their health in general (McNaughton et al., 2001).

Most common symptoms of BPH include; increased frequency of urination during the day, nocturia, straining to force urine out, urgency to urinate, decrease in strength of the urinary stream’s diameter. Severe cases of BPH may lead to sepsis, irreversible bladder damage, renal failure or even death (Roehrborn and McConnell, 2002). Perhaps one fourth of men have some degree of hyperplasia by the fifth decade of life. By the eight decade, over 90% of males would have prostatic hyperplasia. However, in only a minority of cases (about 10%) will hyperplasia be symptomatic and severe enough to require surgical or medical therapy (Bushman, 2009). BPH occurs significantly only in men and dogs during aging, though there are significant differences in BPH between the two species. In humans, BPH originates as nodules in the glands and stroma of the transition zone. Massive enlargement and glandular proliferation occur within the noodles in men older than 70 years (Jeyaraj et al., 2000).

In dogs, BPH consists largely of glandular acini, with minimal contribution from the fibro muscular stroma (Walsh and Wilson, 1976). Lower urinary tract symptoms (LUTS) and bladder outlet obstruction (BOO) are the clinical presentations of BPH in men, while constipation is the symptom associated with BPH in dogs (Isaacs, 1984; Jeyaraj et al., 2000).

Clinical manifestation of BPH occur only after prostatic growth has taken place to such an extent (usually within the transition zone of the prostate) that impairs bladder emptying, resulting in lower urinary tract symptoms (LUTS) and bladder outlet obstruction (BOO) (McNeal, 1984; Walsh, 1984). The natural history of BPH therefore involves the pathological and the clinical phases.

The pathological phase is asymptomatic and involves the progression from microscopic to macroscopic BPH. It involves the development of hyperplastic change in the transition zone of the prostate (McNeal, 1978). Microscopic BPH develops in all men who live long enough but only half of them progress to macroscopic BPH (Ziada et al., 1999; Wei et al., 2005).

The clinical phase of BPH involves the progression from pathological to clinical BPH. In clinical BPH, the ratio of stroma to epithelium is 5:1, whereas in pathological BPH, the ratio is 2.7:1. The stroma therefore contributes significantly to the intravescical obstruction seen in clinical BPH (Akduman and Crawford, 2001).

The clinical symptoms of BPH are classified as obstructive (hesitancy, straining, decreased rate of urine flow), urinary retention and post-void dribbling and irritative symptoms (urinary urgency, urinary frequency and nocturia). But the later have a greater impact on quality of life, while symptom severity correlates well with overall health status (Barry, 2001; Scarpa, 2001; Eaton, 2003). Symptomatic BPH consists of two components; a static component related to prostatic tissue mass, and a dynamic component related to prostatic smooth muscle tone (Ejike and Ezeanyika, 2007).

 

1.1.2 Etiology of BPH

The etiology of BPH is still poorly understood. However, it seems that the patho-etiology mechanism is endocrine controlled and involves alterations in the metabolism of androgen and estrogens (Suzuki et al., 1995), and androgen/estrogen imbalance (Obidoa, 2007), also, growth and cyto-differentiation of the prostate (including aberrant growth), under hormonal control (Ball and Risbridger, 2003). Increased intakes of energy, proteins and certain polyunsaturated fats in the diet may be associated with modest increases in the risk of BPH, including pre-neoplastic lesion in the prostate gland due to increased proliferation and associated inflammation (Heber, 2002).

The adult prostate gland is derived from the urogenital sinus and is a relatively growth-quiescent organ (in the absence of disease) in which there is a balance between the levels of cell proliferation and death (Bianco et al., 2002). The growth of the prostate rise from 1 gram at birth to about 4 grams before puberty, and then to an average of 20 grams after virilization (say by age 20 years) (Berry et al., 1984; Isaacs, 1984; Meikle et al., 1997). This period is regarded as the adolescent growth spurt, and it coincides with an increase in testosterone secretion (though BPH never occur then). There is however a later period of growth, starting probably in the fifth decade when androgen levels begin to drop and BPH paradoxically develops (Horton, 1992).There is also evidence that metabolic disturbances may promote BPH pathogenesis. Metabolic disturbances typified by the metabolic syndrome are known to increase insulin and insulin-like growth factor levels and high serum concentrations of insulin and IGF-1 are associated with clinical benign prostate hyperplasia (Chokkalingam et al., 2002; Dahle et al., 2002; Parsons et al., 2006; Ejike and Ezeanyika, 2008).

1.1.3 Prostatitis

Prostatitis refers, in its strictest sense, to the histological (microscopic) inflammation of the tissue of the prostate gland. Prostatitis can be associated with an appropriate response of the body to an infection, but it also occurs in the absence of infection (Curtis, 1999; Krieger et al., 1999).

Prostatitis is classified into the following;

Acute prostatitis: this is a bacterial infection of the prostate gland that requires urgent medical treatments. It is characterized with pains and presence of white blood cells (WBCs) in the urine.

Chronic bacterial prostatitis: This is a relatively rare condition that usually presents as intermittent urinary tract infections. It is usually accompanied with or without pain with white blood cells in the blood.

Chronic prostatitis/ chronic pelvic pain syndrome: This is the most common but least understood form of prostatitis which may be found in men of any age. It may be inflammatory or non-inflammatory and always accompanied by pains and non-bacterial (Habermacher et al., 2006).

Asymptomatic inflammatory prostatitis: this does not have any history of genitourinary pain but there is a presence of leucocytes, usually during evaluation for other conditions. Between 6-19% of men have pus cells in the semen but no symptoms (Korrovits et al., 2008).

1.1.4 Prostate cancer

Prostate cancer is the most common malignancy and the second most common cause of cancer deaths in males. It has long been taught that men die with prostate cancer rather than from it. However, 25% of men who have prostate cancer die from the disease, whilst many more experience substantial morbidity (Zelefsky et al., 2008). The incidence has risen over the past decade, although this increase may be partly due to more frequent diagnosis, following heightened community awareness and the introduction of tests such as the measurement of serum prostate specific antigen (PSA) (Michael, 2013). Several types of cells are found in the prostate, but almost all prostate cancers develop from the gland cells. Gland cells make the prostate fluid that is added to the semen. The medical term for a cancer that starts in gland cells is adenocarcinoma. Other types of cancer can also start in the prostate gland, including sarcomas, small cell carcinomas, and transitional cell carcinomas. But these types of prostate cancer are so rare that if you have prostate cancer, it is almost certain to be an adenocarcinoma. Some prostate cancers can grow and spread quickly, but most grow slowly. In fact, autopsy studies show that many older men (and even some younger men) who died of other diseases also had prostate cancer that never affected them during their lives. In many cases neither they nor their doctors even knew they had it (Dearnaley, 1994).

1.1.5 Androgens

Androgens, also called ‘androgenic hormone’ or testoid, is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. The primary well known androgen is testosterone, produced largely (95%) by the leydig cells of the testis, it is the major circulating androgen, but must first be reduced to dihydrotestosterone (DHT) by the enzyme, 5α-reductase (NADP⁺ -ene-oxidoreductase; E.C: 1.3.1.22) for maximal androgenic activity in the prostate (Pasupuleti and Horton, 1990; Wright et al., 1999; Bartsch et al., 2002).

1.2       Functions of androgens

During puberty, androgen, luteinizing hormone (LH) and follicle stimulating hormone (FSH) production increase, and the sex cord hollow out, forming the seminiferous tubules, and the germ cells start to differentiate into sperm. Throughout adulthood, androgens and FSH cooperatively act on sertoli cells in the testis to support sperm production (Stephen and Saffron, 2001).

Inhibition of fat deposition by blocking a signal transduction pathway that normally supports adiposity function. This probably is the reason why males typically have less body fat than females. Androgens also increase beta-adrenergic receptors while decreasing alpha adrenergic receptors-which result in increased levels of epinephrine/ nor-epinephrine due to lack of alpha-2-receptor negative feedback and decreased fat accumulation due to epinephrine/nor epinephrine acting on lipolysis-inducing beta receptors (Singh et al., 2006).

Androgens promote the enlargement of skeletal muscle cells and probably act in a coordinated manner to function by acting on several cell types in skeletal muscle tissue which makes males to have more skeletal muscle mass than females, increased expression of androgen receptor due to higher androgen levels (Vlahopoulos et al., 2005).

Circulating levels of androgens can influence human behavior because some neurons are sensitive to steroid hormones. Androgen levels have been implicated in the regulation of human aggression and libido (Singh et al., 2006).  Indeed, androgens are capable of altering the structure of the brain in several species, including mice, rats, and primates, producing sex differences (Zuloaga et al., 2008).

1.2.1 Androgens and prostate disorders

Physiologic functions and pathologic conditions of the prostate, like all other endocrine glands, are regulated by numerous endogenous hormones and growth factors. Testosterone is the predominant circulating androgen in males. It is a steroid hormone, synthesized from cholesterol in leydig cells within the interstitial of the testis. Its production is stimulated by luteinizing hormone (LH), secreted by the anterior pituitary gland in response to the cyclic release of luteinizing hormone releasing hormone (LHRH) by the hypothalamus. LHRH release, in a negative feedback fashion, is inhibited by testosterone. Greater than 95% of endogenous androgen is produced by testis, with the remainder produced as androstendione by adrenal cortex. This small amount of non testicular androgens has a minimal impact on prostate function in physiologically normal males (Partin and Rodriguez, 2002). Testosterone, once taken up form the systemic circulation by the prostatic glandular and stromal cells and within the prostate, testosterone is rapidly and irreversibly converted to dihydrotestosterone (DHT) by the enzyme 5α-reductase (5AR). This leads to a five fold higher concentration of DHT versus testosterone within the intracellular prostate, versus an eleven-fold higher concentration of testosterone within the circulation. DHT binds to the androgenic receptor within the cytosol, is actively transported into the nucleus, and serves as a transcription factor for prostatic gene expression and thus cellular function. The higher concentration of intracellular DHT, in addition to its higher affinity for the androgen, supports the importance of 5AR in normal and pathological prostate physiology (Partin and Rodriguez, 2002).

As men age, serum levels of testosterone drop while those of estradiol and prolactin increase. The prostate is particularly sensitive to this alteration in the balance of these hormones. Prolactin is a pro-lactation hormone that is also induced under stress conditions as the case in career and family stress that come with the middle-ages. The binding of prolactin to the prostatic cells increase the activity of 5AR and the androgen receptor thereby increasing androgen binding and uptake (McPherson et al., 2001). With age, the level of sex hormone binding globulin, otherwise called testosterone binding globulin (to reflect its higher affinity for testosterone), increases. Sex hormone binding globulin (SHBG) bind about 44% of testosterone while albumin binds about 54%, leaving only 2% circulating unbound or free. Only this free testosterone and the fraction bound to albumin are available to interact with testosterone sensitive tissues. This is because the circulating dimeric form of SHBG has a molecular mass of approximately 90kDa (thus preventing it from traversing the capillary barrier) (Hammond, 2002). Increase in SHBG therefore reduces available testosterone, thereby causing the relaxation of the negative feedback inhibition that regulates testosterone action, and more testosterone is produced (Ejike and Ezeanyika, 2009).

Estrogens in its natural form are steroid hormones, while some synthetic ones are non-steroidal. Estrogens are compounds named for their importance in both menstrual and estrous reproductive cycles. They are primary female sex hormones.

Like all steroid hormones, estrogens readily diffuse across the cell membrane. Once inside the cell, they bind to and activate estrogen receptors which in turn modulate the expression of many genes (Whitehead and Nussey, 2001), as well activate G- protein- coupled receptor, GPR30 (Prossnitz et al., 2007), the estrogen: estrogen receptor (ER) complex binds to specific DNA sequence called a hormone response element to activate the transcription of target genes (Lin, 2004). Estrogens are present in both men and women but significantly higher level in women of reproductive age where they promote the development of female secondary sexual characteristics, such as breast, and are also involved in the thickening of the endometrium, and regulation of menstrual cycle. In males, estrogen regulates certain functions of the reproductive system important for the maturation of sperm (Hess et al., 1997; and necessary for a healthy libido (Hill et al., 2004).

 

1.2.3 Functions of estrogens

Estrogens perform some structural functions which include;

Promotion of formation of female secondary sex characteristics, acceleration of metabolism, increase of fat stores, endometrial growth stimulation, increase uterine growth, vaginal lubrication increase as well as thickening of its wall, reduce bone resorption, and increase bone formation, maintenance of vessel and skin.

Protein synthesis by increased hepatic production of binding proteins.

In blood coagulation by increasing circulating levels of factors 2, 7,9,10, plasminogen, decrease in anti-thrombin III, and increasing platelet adhesiveness.

In lipid metabolism by increasing high density lipoprotein (HDL), triacylglycerol and decreased LDL, fat deposition.

In fluid balance (salt and water retention)

In gastrointestinal tract by reducing bowel motility and increasing cholesterol in bile.

In melanin by increasing pheomelanin, reduce eumelanin and in lung function by supporting alveoli (Massaro and Massaro, 2004).

Estrogen together with progesterone promotes and maintains the uterus lining in preparation for implantation of fertilized egg and maintenance of uterus function during gestation period, as well as up-regulating oxytocin receptor in myometrium.

During ovulation, surge in estrogen levels induces the release of luteinizing hormone, which then triggers ovulation by releasing the egg from the grafian follicle in the ovary.

Estrogen also promotes sexual receptivity (Christensen et al., 2011), and induce lordosis behavior (Handa et al., 2012). It also promotes sexual desire (Warnock et al., 2005).

• Metabolic factors associated with prostate pathologies

The metabolic syndrome describes a clinical constellation of metabolic abnormalities such as insulin resistance, increased level of central (visceral) adiposity/obesity, low levels of high density lipoprotein and elevated triacylglycerols, impaired fasting glucose and hypertension (Grundy et al., 2004). It has been suggested that some prostate pathologies, like BPH represents a prostate growth path, promoted by oxidative stress, inflammatory mediators and insulin-like growth factor (IGF) systems (Khandawala et al., 2000; Wang et al., 2004). There are evidences that metabolic syndrome is linked to, and may lead to prostate pathologies (Kasturi et al., 2006; Ozden et al., 2007). Hyperinsulinemia and insulin resistance, both of which accompany obesity, and are known features of adiposity, result in the deregulation and/or over-expression of the IGF system. These have been shown to be involved in both benign and malignant proliferative disorders of the prostate (Khosravi et al., 2001; Hammersten and Hogstedt, 2001). In 2006, Nandusha and Co correlated insulin profile parameters with prostate size and found that fasting serum insulin and insulin resistance levels were significantly higher in non-diabetic BPH cases when compared to the control values. Hyperinsulinemia ensures that fats are not mobilized from fat stores, resulting in obesity, while insulin resistance could lead to diabetes (Nandusha et al., 2006).

Obesity (BMI≥30kg/m²) is the result of imbalances in energy intake and expenditure. Abdominal obesity increases the estrogen to androgen ratio and may increase sympathetic nervous activity, both hypothesized to influence the development of prostate pathologies and severity of urinary obstructive symptoms (Mongui and McVary, 2009). Average prostate weight has been shown to increase with increasing body weight, and that prostate volume is greater in obese and central obesity group than in normal subjects (Lee et al., 2006; Parsons et al., 2006).

Diabetes mellitus is characterized by impaired glucose metabolism. Type 2 diabetes mellitus has been shown to play a role in the etiology of prostate disorders (Stamatiou et al., 2009). The association between prostate pathologies, especially BPH and diabetes may be that, both disorders share a common patho-etiology mechanism mediated by androgen-responsive growth factors (Stamatiou et al., 2009). Type 2 diabetes results in excessive presence of cholesterol in the blood-hypercholesterolemia. Cholesterol is the backbone for steroid hormone biosynthesis. It has been shown that serum total cholesterol levels are correlated with symptoms of BPH (Ezeanyika et al., 2006a). Studies with rats have shown that hypercholesterolemia caused changes in plasma profile of sex steroids. It may therefore alter prostate morphology by affecting the sex steroid axis and thus contribute to BPH (Mitropoulous et al., 2004; Parsons et al., 2008).

Studies have shown that metabolic syndrome usually result from improper nutrition and sedentary lifestyle. High intake of dietary fats, and energy, low intake of dietary fibre and complex carbohydrates have been linked to prostatic disorders (Dagnelie et al., 2004). Dietary fat may alter androgen and IGF levels and promote cell proliferation in the prostate (Bosland, 2000). Ejike and Ezeanyika (2009) have shown that low dietary fibre and high animal fat may affect the prostate at all levels of human development-in uterus, childhood and adulthood, and lead to BPH.

1.3       Prevalence of prostate pathologies

Autopsy result show that BPH is present in 40% and 90% of men aged 50-60 years and 80-90 years respectively (Berry, 1984). The global prevalence among those aged 60 years and above exceeds 50% (Marberger et al., 2004). In the United States alone, BPH generated 1.1 billion dollars in health care expenditures and accounted for over 4.4 million office visits, 117,000 emergency room visits and 105,000 hospitalization in the year 2000 (Wei et al., 2005). More than 200,000 transurethral resection of the prostate for BPH are performed annually in the United States (Graves and Gillum, 1997). Neslund et al. (2007) reported a prevalence of 42% and Fernandez et al. (2009) reported 16.6% prevalence for LUTS in Spain. In Tunisia, Horchani et al. (2007), reported prevalence of 26.4% for BPH symptoms and 16.1% for LUTS in the same male population. In Nsukka, Nigeria, a prevalence of 25.35% was reported for BPH symptoms (Ezeanyika et al., 2006b).

Prostate cancer is more prevalent in the developed countries probably because of feeding habit and it is well documented there than in the developing countries (Ezeanyika et al., 2006a). It is the most common cancer world-wide for males and the fifth most common cancer overall with an estimated 900,000 new cases diagnosed in 2008. According to American Cancer Society’s estimates in 2013, about 238,590 new cases may be diagnosed, with about 29,720 to die of prostate cancer in 2013.

 

1.3.1 Treatment/ Management option of Prostate pathologies

Treatment for prostate disorders may involve active surveillance, surgery, radiation therapy including, brachytherapy (prostate brachytherapy) and external beam radiation therapy, High-intensity focused ultrasound (HIFU), chemotherapy, cryosurgery, hormonal therapy, or some combination. The selection of treatment options may be a complex decision involving many factors. For example, radical prostatectomy after primary radiation failure is a very technically challenging surgery and may not be an option (Mouraviev et al., 2006). This may enter into the treatment decision.

 

Active surveillance

Active surveillance refers to observation and regular monitoring without invasive treatment. In the context of prostate disease this usually comprises regular PSA blood test and prostate biopsies. Active surveillance is often used when an early stage, slow-growing prostate disorders are suspected. However, watchful waiting may also be suggested when the risks of surgery, radiation therapy, or hormonal therapy outweigh the possible benefits. Approximately one-third of men that choose active surveillance for early stage tumors eventually have signs of tumor progression, and they may need to begin treatment within three years (Wu et al., 2004).

 

Hormonal therapy

Hormonal therapy uses medications or surgery to block prostate diseased cells from getting dihydrotestosterone (DHT), a hormone produced in the prostate and required for the growth and spread of most prostate cancer cells. Blocking DHT often causes prostate disorders like BPH, cancer, to stop growing and even shrink. However, hormonal therapy rarely cures prostate cancer because cancers that initially respond to hormonal therapy typically become resistant after one to two years. Hormonal therapy is, therefore, usually used when the disease has spread from the prostate. It may also be given to certain men undergoing radiation therapy or surgery to help prevent return of the disease (Robson and Dawson, 1996).

 

Radical prostatectomy

Radical prostatectomy is effective for tumors that have not spread beyond the prostate ( Bill-Axelson et al., 2005) cure rates depend on risk factors such as PSA level. However, it may cause nerve damage that may significantly alter the quality of life of the prostate diseased survivor.

 

 

 

Transurethral resection of the prostate

Transurethral resection of the prostate, commonly called a “TURP,” is a surgical procedure performed when the tube from the bladder to the penis (urethra) is blocked by prostate enlargement. In general, TURP is for benign disease and is not meant as definitive treatment for prostate cancer. During a TURP, a small instrument (cystoscope) is placed into the penis and the blocking prostate is cut away.

 

High intensity focused ultrasound (HIFU)

HIFU was first used in the 1940s and 1950s in efforts to destroy tumors in the central nervous system. Since then, HIFU has been shown to be effective at destroying malignant tissue in the brain, prostate, spleen, liver, kidney, breast, and bone (Gardner and Koch, 2005).

HIFU for prostate cancer utilizes high intensity focused ultrasound to ablate/destroy the tissue of the prostate. During the HIFU procedure, sound waves are used to heat the prostate tissue, thus destroying the cancerous cells. In essence, ultrasonic waves are precisely focused on specific areas of the prostate to eliminate the prostate cancer, with minimal risks of affecting other tissue or organs. Temperatures at the focal point of the sound waves can exceed 100°C (212 °F) (Gardner and Koch, 2005). The ability to focus the ultrasonic waves leads to a relatively low occurrence of both incontinence and impotence. (0.6% and 0-20%, respectively) (Uchida et al., 2006).

 

Palliative care

Palliative care for advanced stage prostate cancer focuses on extending life and relieving the symptoms of metastatic disease. Abiraterone acetate is showing some promise in treating advance-stage prostate cancer. It causes a dramatic reduction in PSA levels and Tumor sizes in aggressive advanced-stage prostate cancer for 70% of patients. Chemotherapy may be offered to slow disease progression and postpone symptoms. The most commonly used regimen combines the chemotherapeutic drug docetaxel with a corticosteroid such as prednisone. One study showed that treatment with docetaxel and prednisone prolonged life from 16.5 months for those taking mitoxantrone and prednisone to 18.9 months for those taking docetaxel + prednisone (Tannock et al., 2004). Bisphosphonates such as zoredronic acid have been shown to delay skeletal complications such as fractures or the need for radiation therapy in patients with hormone-refractory metastatic prostate cancer (Saad et al., 2002).

Many other single agents have been shown to reduce PSA, slow PSA doubling times, or have similar effects on secondary markers in men with localized cancer in short term trials, such as pomegranate juice or genistein, an isoflavone found in various legumes (Pantuck et al., 2006).

1.3.2 Agents that relax smooth muscles

Prostatic smooth muscle tone is under the influence of the autonomic nervous system. It contracts under the influence of noradrenergic sympathetic nerves, thereby constricting the urethra (Oesterling, 1995). Prostatic tissue contains high levels of both alpha-1 and alpha-2 adrenoreceptors. A total of 98% of the alpha-1 adrenoreceptors are associated with stromal elements of the prostate (Kobayashi et al., 1993). Alpha-1 receptor blockers by induction, result in the relaxation of smooth muscles and the relief of bladder outlet obstruction enhancing urine flow. Alpha blockers used in the treatment of BPH are divided into selective and non selective alpha blockers. Some examples of selective alpha blockers are prazosin, alfuzosin, tamsulosin, terazosin and doxazosin, while phenoxybenzamine, nicergoline and thymoxamine are examples of non selective alpha blockers.

 

1.3.3 Agents that reduce prostate volume

Hormonal treatments find application in treatment targeted at reduction in prostate volume. Hormonal therapy involves the use of drugs that mimic hormones, to interfere with the cycle of testosterone production and action. Some of the methods used are;

 

Luteinizing Hormone Relaxing Hormone (LHRH) analogues. LHRH is released by the hypothalamus and it interferes with the feedback mechanism that stimulates and controls testosterone production in the testis. LHRH analogues are chemically similar to LHRH. Some LHRH analogues used are leuprolide, gosereline and buserelin (Garnick and Glode, 1986, Peeling, 1989). They however cause an internal flare in testosterone concentration. Aberelix is a gonadotrophin-releasing hormone antagonist and does not cause the flare phenomenon (McLeod et al., 2001).

Anti-androgens

Anti-androgens inhibit the function of androgens at the cellular levels. When combined with castration, maximal androgen blockade (MAB) or complete androgen blockade (CAB) is achieved. They are classified according to their chemical structures as steroidal and non-steroidal anti-androgens. Non-steroidal anti-androgens do not lower serum testosterone but tend to increase it, whereas steroidal anti-androgens significantly reduce both serum testosterone and luteinizing hormone (LH) (Aus et al., 2005). The non steroidal anti-androgens currently available are nilutamide, flutamide and bicalutamide (Lundgren, 1987; Decensi et al., 1991). Cyproterone acetate or medroxy progesterone acetate are the steroidal anti-androgens used in hormonal therapy (Aus et al., 2005).

 

1.3.4 Medications that inhibit 5, alpha-reductase

Finasteride, this acts predominantly on the type-2 isoenzyme of 5α-reductase inhibiting it. Finasteride reduces serum dihydrotestosterone levels by 85-90% (Roehrborn, 1998).

Dutasteride, this blocks both iso-enzymes of 5α-reductase (Foley and Kirby, 2003). It shows a 60-fold greater inhibition of type-1 isoenzymes than finasteride and is also active against the type-2 isoenzyme (Bartsch et al., 2002). The major side effects of hormonal therapy are loss of libido and impotence. Other physiological changes include hot flashes, altered and diminished body hair, gynaecomatsia, osteoporosis, muscle atrophy, anemia, depression, shortness of breath, gastrointestinal upset, hepatotoxicity and wound infection (Aus et al., 2005)

 

1.3.5 Diet and prostate pathologies

Asians have the lowest incidence and prevalence rates of prostatic disease. However, when these Asians relocate to high prevalence regions like USA, within their generation, the diseases become common and often resemble that of the local community (Tsugane et al., 1990; Shimizu et al., 1991). This shows the place of diet in prostatic diseases.

Traditional Asian diets are rich in soy beans. Soy is known to be rich in isoflavonoids. Genistein is the major isoflavone in soy and may help reduce the risk of prostate disorders by its estrogenic properties or by the inhibition of 5α-reductase (Shirai et al., 2002). Other isoflavones are formonetin, biochanin and diadzein. Genistein and diadzein are also said to be capable of lowering androgen levels and increasing sex hormone binding globulin (SHBG) levels (Shirai et al., 2002). Isoflavones also stimulate UDP-glucuronosyl transferase (which catalyzes the conjugation of steroid hormones to UDP-glucuronic acid) activity, thereby reducing the level of steroid hormones in the system by facilitating their excretion (Sun et al., 1998). They inhibit the activities of the enzyme 17β-hydroxysteroid dehydrogenase and aromatatse (the former is the last of the two enzymes required for the formation of testosterone from dehydroepiandrosterone) (Campbell and Kurzer, 1993; Keung, 1995). Food substances containing these bioactive isoflavones are therefore useful in protecting against and managing prostate disorders. Furthermore, animal and in vitro studies show that retinoid and carotenes found in colored fruits and vegetables and lycopenes found largely in tomatoes and tomato-based foods also have a protective role with respect to BPH pathogenesis (Edinger and Koff, 2006; Rohrmann et al., 2007).

Zinc intake and absorption is critical for the prostate especially during prostate disorders. Zinc is involved in various aspects of androgen metabolism and has been shown to reduce the size of the prostate and the symptoms in patients with prostate disorders. Zinc inhibits the activity of 5α-reductase and reduces prolactin binding to prostate receptors (Leake et al., 1984a and b). However, zinc is known to reduce the absorption of copper, so zinc supplementation should rationally go with copper supplementation.

 

1.4. Botanical/ Phytotherapy     

The use of plant extracts in the treatment of prostate disorders is becoming widespread (Gerber, 2002). It is estimated that therapeutic agents constitute approximately 50% of all medicines prescribed for BPH in Italy and almost 90% in Germany and Australia. The most popular phytotherapeutic agents are extracted from the seed barks and fruits of plants (Lowe and Fagelman, 1999) and are preferred because they are seen as natural and do not cause adverse side effects that chemical agents are known to cause. Concerns about organ damage as often occurs with chemotherapy are also limited when botanicals are used. Some of the botanicals used in the treatment of prostate disorders that have received some scientific attentions are;

Saw palmetto

Saw palmetto or American dwarf palm (Serenoa repens or Sabal serulata) is one of the many plant materials available for the treatment of BPH (Tacklind et al., 2009). The liposterolic extract of saw palmetto berries contain capric, caprylic, caproic, lauric, palmitic and oleic (fatty) acids and β-sitosterol and stigmasterol as the major phytosterols. It has three major activities that improve BPH symptomatology and inhibition of 5α-reductase (Deios et al., 1994; Weisser et al., 1996); inhibition of DHT binding to prostatic cells (El-Sheikh et al., 1988); and inhibiting both lipoxygenase and cycloxygenase (arachidonic acid cascades) (Breu et al., 1992).

Nettles root

Extracts of stinging nettle (Urtica dioica) roots have been used extensively in the management of prostate pathologies (Krzeski et al., 1993). The mechanism of its action is still unclear, but it has been shown to inhibit prostate Na⁺/K⁺ ATPase thereby inhibiting binding of SHBG to its receptor (Hirano et al., 1994; Hryb et al., 1995; Gansser and Spiteller, 1995).

African Palm tree

Extracts of African plum (Pygeum africanum) tree bark inhibit the proliferative effects of growth factors such as epidermal growth factor (EGF), basic fibroblast growth factor (bFGF) and insulin growth factor-1 (IGF-1) (Yablonsky et al., 1997) and antagonize the production of metabolites in the 5-lipoxygenase pathway (Gerber, 2002). Through these methods, the extracts are thought to reduce BPH (Wilt et al., 2002).

 

Rye pollen

Extracts of Rye grass (Secale cereale) pollen are thought to improve detrusor activity, reduce prostatic urethral resistance and inhibit 5α-reductase activity and androgen metabolism in the prostate. By these methods, modest alleviation of BPH symptoms is achieved (Lowe and Fagelman, 1999).

Pumpkin seed

Dried or fresh seeds of pumpkin (Curcubita pepo) contain phytosterols that act through yet unclear mechanism to relieve BPH symptoms (Carbin et al., 1990; Schulz et al., 1998). Pumpkin seed oil has also been shown to inhibit testosterone induced hyperplasia of the prostate (Gossell-Williams et al., 2006). Other plants such as South African star grass (Hypoxis rooperi), Cactus flower (Opuntia) and pine flower (Pinus) (Gerber, 2002), purple coneflower (Skaudickas et al., 2009), flax seed lignin (Zhang et al., 2008), Piper cubeba (Yam et al., 2008), Bixa orellana (Zegarra et al., 2007), coconut oil (Arruzazabala et al., 2007) and Cuban royal palm (Noa et al., 2005) show some promise but have been studied in less details.

1.4.1 Moringa oleifera

Moringa oleifera belongs to the order/family, Moringaceae. It is the most widely cultivated species of a monogeneric family, the moringaceae that is native to the sub-Himalayan tracts of India, Pakistan, Bangladesh and Afghanistan. This rapidly-growing tree is also well known as; Horseradish tree, Drumstick tree, Benzolive tree, Kelor, Marango, Mlonge, Moonga, Mulangay, Ben oil tree. It is popularly known in Nigeria by the Igala-Hausa as ‘Geligedi’, Ibo as ‘Ikwe oyibo’ and ‘Oku ghare ite’ Yoruba as ‘Ewe ile’ and ‘Ewe igbale’.The tree is widely cultivated in many locations in tropics, it is a perennial plant. It is already an important crop in India, Ethiopia, the Philippines, and the Sudan. It is being grown in the West, East and South Africa, tropical Asia, Latin America, the Caribbean, Florida and the Pacific Islands. All parts of the moringa tree are edible and have long been consumed by humans. Many uses of moringa includes; biomass production, animal forage, biogas (from leaves), domestic cleaning (crushed leaves), blue dye (wood), fencing (living trees), fertilizer (seed-cake), foliar nutrient (juice from the leaves), gum (from tree trunks), honey (flower necter), honey and sugar cane juice-clarifier (powdered seeds), medicine (all plant parts), tannin for tanning hides (bark and gum), water purification (powdered seeds) (Fuglie, 1999). Moringa seed oil (yield 30-40% by weight), also known as Ben-oil, is a sweet non-sticking, non drying oil that resist rancidity. The oil has been used in salads, for fine machine lubrication, and in the manufacturing of perfume and hair care products (Tsaknis et al., 1999). In the west, the powdered seed is used to flocculate contaminants and purify drinking water (Olsen, 1987; Gassenschmidt et al., 1995), the seeds are eaten green, roasted, powdered and steeped for tea or used in curries (Gassenschmidt et al., 1995).

 

 

 

1.4.1.1 Nutrition

Moringa trees have been used to combat malnutrition, especially among infants and nursing mothers. It is a natural nutrition for the tropics. Leaves can be eaten fresh, cooked or stored as dried powder for many months without refrigeration, and with less nutritional value. Moringa leaves contain more vitamin A than carrots, more calcium than milk, more iron than spinach, more vitamins than oranges and more potassium than bananas. The protein quality of moringa leaves rivals that of milk and eggs (Fuglie, 2000).

 

1.4.1.2 Phytochemistry

Phytochemical refers to only those chemicals which may have an impact on health, or on flavor, texture, smell, or color of the plants, but are not required by humans as essential nutrients. Phytochemicals of moringa species reveal that the plant family is rich in compounds containing the simple sugar, rhamnose, and it is rich in a fairly unique group of compounds called glucosinolates and isothiocyanates (Fahey et al., 2001). For example, specific components of moringa preparations that have been reported to have hypotensive, anticancer, and antibacterial activity includes; 4-(4^´-O-acetyl-α-L-rhamnopyranosyloxy) benzylisothiocyanate, 4-(α-L-rhamnopyranosyloxy)benzylisothiocyanate, niazimicin, Pterygospermin, benzylisothiocyanate, and 4-( α-L-rhamnopyranosyloxy)benzylglucosinate. It is also rich in vitamins and minerals, as well as other more commonly recognized phytochemicals such as carotenoids (including-6-carotene or pro-vitamin A) (Fuglie, 1999).

 

1.4.1.3 Disease treatment and prevention

The benefits for the treatment and prevention of disease or infection that may accrue from either dietary or topical administration of moringa preparations (e.g. extracts, decoctions, poultices, cream, oils, emollients, salves, powders, porridges) are not quite so well known (Palada, 1996). Even at that, moringa preparation have been cited in the scientific literature as having antibiotic , antitrypanosomal, hypotensive, antispasmodic, antiulcer, anti-inflammatory, hypocholesterolemic, and hypoglycermic activities, as well as having considerable efficacy in water purification by flocculation, sedimentation, antibiosis and even reduction of schistosome cercariae titer, evaluation of a variety of detoxification and antioxidant enzymes and biomarkers as a result of treatment with moringa or with phytochemicals isolated from moringa (Kumar and Pari, 2003).

 

1.4.1.4 Antibiotic activity

This is clearly the area in which the preponderance of evidence-both classical scientific and extensive anecdotal evidence is overwhelming. The identification of a compound called pterygospermin, is a compound which was reported, readily dissociated into two molecules of benzyl isothiocyanate (Narasimha-Rao and Kurup, 1953), the compound has antibiotic activity against H. pylori at concentration up to1000-fold lower than other plants which had been used in earlier studies against a wide range of bacteria and fungi (Galan et al., 2004)

 

1.4.1.5 Cancer prevention

Moringa species have long been recognized by folk medicine practitioners as having value in tumor therapy (Hartwell, 1971). Compounds of these plants; 4-(4^´-O-acetyl-α-L-rhamnopyranosyloxy) benzylisothiocyanate, and 4-(α-L-rhamnopyranosyloxy) benzylisothiocyanate showed cancer preventive potential (Fahey et al., 2004). 4-(4^´-O-acetyl-α-L-rhamnopyranosyloxy) benzylisothiocyanate, and   niazimicin, a phytochemical of Moringa oleifera were shown to be potent inhibitors of phorbol ester (TPA)-induced Epstein-Barr virus early antigen activation in lymphoblastoid (Burkitt’s lymphoma) cells (Murakami et al.,1988). Studies also showed that niazimicin also inhibited tumor promotion in a mouse two-stage DMBA-TPA tumor model (Murakami et al., 1998). Bharali and colleagues have examined skin cancer tumor prevention following ingestion of drumstick (moringa seed pod) extract.

 

1.4.2 Vernonia amydalina

Vernonia amygdalina is a member of the Asteraceae family. It is a small shrub that grows in the tropical Africa. Typically it grows to a height of 2-5cm. the leaves are elliptical and up to 20cm long with a rough bark (Ijeh and Ejike, 2011). Vernonia amygdalina is popularly known as bitter leaf in English because of its bitter taste. African common names includes; onugbu or olubu (Igbo), ewuro (Yoruba), Ilo (Igala), ityuna (Tiv), grawa (Amharic), etidot (Ibibio), muluuza (Luganda), labwori (Acholi), olusia (Luo), and ndole (Cameroon) (Egedigwe, 2010; Kokwaro, 2009).

The leaves are dark-green colored with a characteristic odor and a bitter taste. The specie is indigenous to tropical Africa and is found wild or cultivated all over sub-Saharan Africa (Bosch et al., 2005). The leaves are eaten after crushing and washing thoroughly to remove the bitterness (Mayhew and Penny, 1998). All parts of the plant are pharmacologically useful. Both the roots and leaves are used in phyto-medicine to treat fever, hiccups, kidney disease and stomach discomfort, among others (Gill, 1992; Hamowia and Saffaf, 1994). It also showed antihelmintic and anti-tumoriagenic properties (Abosi and Raseroka, 2003) as well as anti-tumorigenic properties (Izevbigie et al., 2004). Research also confirmed that the leaf extract demonstrated hypoglycemic and hypolipidemic effects in experimental animals (Nwanjo, 2005).

Consequently, Vernonia amygdalina extracts and isolated chemical constituents have been studied for their potential pharmacological effects, including, induction of apoptosis as determined in cell culture and animal studies (Sweeney et al., 2005; Song et al., 2005), enhanced chemotherapy sensitivity as with cancerous cells (Sweeney et al., 2005), inhibition of growth of growth signals of cancerous cells (Izevbigie et al., 2004; Opata and Izevbigie, 2006), suppression of metastasis of cancerous cells in the body by the inhibition of NFKB, an anti-apoptic transcription factors as demonstrated in animal studies (Song et al., 2005), reduction of estrogen level in the body by the suppression of aromatase activity, provision of antioxidant benefits (Erasto et al., 2007), enhancement of the immune system (Sweeney et al., 2005), decreased blood glucose by 50% compared to untreated diabetic animals in a study conducted using streptozotocin-induced diabetic laboratory animals (Nwanjo, 2005) and in vitro antihelmintic and antiparasitic properties (Ademola, 2011).

 

1.5 Study Rationale/Justification

The rate of prostate disorders is on the increase and asymptomatic in most cases. Hence, the need to investigate the use of natural products in its management or treatment. Medicinal plants have been of great help right from creation and have limited cases of threat like the synthetic drugs. Moringa oleifera which is popularly called ‘miracle tree’ and Vernonia amygdalina, have been used in the treatments and management of various ailments. However, no scientific report is available regarding the traditional use of, especially Moringa oleifera in the treatment and management of prostate disorders. In view of this, there is a need to investigate the use of these plants in the treatment or management of prostate disorders.

 

1.6 Aim and objectives of the study

1.6.1 Aim of the study

This study is aimed at investigating the effects of Moringa oleifera and Vernonia amygdalina leaves on prostate pathologies (Benign Prostate hyperplasia, Prostatitis and Prostate cancer) in experimental rats.

1. To determine the effects of aqueous leaf extract of Moringa oleifera on some biochemical indices in albino rats.
2. To determine the effects of aqueous leaf extract of Vernonia Amygdalina on some biochemical indices in albino rats.
3. To determine the effects of the two extracts on lipid profile of rats.
4. To compare the effectiveness or potency of the two aqueous leaf extracts on some biochemical indices in albino rats.
5. To determine the effectiveness of Moringa oleifera and Vernonia amygdalina extract on some biochemical indices in albino rats.

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