Clinical Director, The Brody School of Medicine at East Carolina University
It is unknown whether early adjuvant radiation is better than delayed salvage therapy in patients with adverse pathology findings after radical prostatectomy anxiety symptoms before sleep buy 25 mg phenergan with mastercard. However anxiety upon waking buy phenergan 25 mg visa, it is far less frequently used today because studies suggested increased risks of diabetes mellitus anxiety symptoms in spanish cheap phenergan on line, cardiovascular disease anxiety symptoms in adults purchase phenergan 25mg amex, and osteopenia leading to fractures (Krupski et al, 2004; Saigal et al, 2007; Tsai et al, 2007; Keating et al, 2012). Cardiovascular evaluation is prudent before treatment of men at risk for cardiovascular complications. Antiandrogens produce less sexual dysfunction and osteoporosis but have a greater risk for adverse cardiovascular complications. Cryoablation has been used as primary whole-gland therapy, as a salvage treatment option after radical prostatectomy or radiotherapy (Babaian et al, 2008), and as focal therapy for low-risk prostate cancer (see section on focal therapy). In general, patients with clinical stage T1c to T2 disease who have a life expectancy greater than 10 years, who have no evidence of metastatic disease, and who are not concerned with potency are considered candidates for whole-gland primary cryoablation. The role of cryoablation remains undetermined for patients with clinical stage T3 disease (Babaian et al, 2008). Third-generation cryoablation is a procedure in which 12 cryoablation needles are stereotactically inserted through the perineum into the prostate with transrectal ultrasound guidance under general or spinal anesthesia. An ice ball forms in the tissue, and its expansion is monitored by transrectal ultrasonography. Simultaneously, a warming Foley catheter is inserted to protect the urethra and helium gas is used to warm and preserve the prostatic urethra. The rectum can be protected by injection of a saline solution in the space between the prostate and the rectum. A double freeze-thaw cycle results in more extensive tissue damage and cell death than a single cycle. The proposed advantages of cryoablation are that it is minimally invasive, it does not involve radiation exposure or surgical risk, repeated treatments are possible, and preservation of potency is possible in some patients (Asterling and Greene, 2009). Cryoablation can target the whole prostate gland or can be performed as a focal treatment, usually freezing half of the prostate (Finley et al, 2010). Some reports have claimed oncologic effectiveness equivalent to other conventional treatments for clinically localized prostate cancer (Bahn et al, 2002; Donnelly et al, 2002; Elkjaer and Borre, 2014); however, other studies have reported that the outcomes are not as good as with radiotherapy or surgery (Roach, 2010b). Whole-Gland Primary Cryoablation Cryoablation has been reported to be a safe, effective alternative as primary treatment for localized prostate cancer (Lian et al, 2011) and has been advocated in elderly men who may have underlying comorbidity that precludes radical prostatectomy (Loeb et al, 2007; Chin et al, 2012). The Phoenix definition is claimed to be the best predictor of tumor recurrence (Pitman et al, 2012). Biochemical recurrence-free rates of 60% to 90% at 5 to 10 years of follow-up after cryoablation have been reported (Long et al, 2001; Bahn et al, 2002; Donnelly et al, 2002; Prepelica et al, 2005; Cohen et al, 2008; Jones et al, 2008; Sverrisson et al, 2014). In many cryoablation programs, part of the follow-up protocol is biopsy at 3 to 6 months and again in 2 to 5 years after the treatment. Post-treatment positive biopsy rates of up to 47% have been reported (El Hayek et al, 2008; Donnelly et al, 2010; Ko et al, 2010; Lian et al, 2011; Chin et al, 2012), with most being in the range of 20% (Sverrisson et al, 2014). It is noteworthy that in some cases, positive biopsy rates have been calculated by dividing the number of positive biopsies by the number of patients in the entire treated cohort, including in the denominator those who did not undergo biopsy, thus diluting the positive biopsy rate. Conflicting results have been reported on comparisons of cryoablation with other primary treatments for localized prostate cancer (Chin et al, 2008; Donnelly et al, 2010). In contrast, a single-institution study comparing the outcomes from radical prostatectomy and cryoablation performed during the same period found that cryoablation had less favorable disease-free survival, regardless of the risk subgroup (Caso et al, 2012). A reason for the higher recurrence rate with cryoablation could be that in leaving the urethra in situ, some cancer cells may remain, and some benign periurethral prostatic epithelial cells might subsequently transform into cancer. The other more likely cause of the high recurrence rate is a high rate of insufficient treatment margins, especially peripheral margins. Complications of cryotherapy have included urinary incontinence, urethral sloughing, osteitis pubis, transient penile paresthesia, perineal and rectal pain, rectal fistula, the need for a transurethral resection of the prostate for urinary obstruction, and erectile dysfunction (Pisters et al, 2008). Studies have reported conflicting evidence regarding comparisons of urinary and sexual bother with cryoablation compared with radical prostatectomy or radiotherapy (Donnelly et al, 2010; Malcolm et al, 2010; Caso et al, 2012); however, a preponderance of evidence indicates that cryoablation is associated with more erectile dysfunction (Asterling and Greene, 2009; Roach, 2010a). Approximately one third of previously potent men treated with whole-gland cryoablation might be expected to be potent after cryoablation. The morbidity profile is improved with current argon-based technology; however, a sudden death from argon gas emboli during prostate cryoablation has been reported (Sandomirsky et al, 2012). Complications associated with salvage cryoablation are more frequent than for primary treatment (Bales et al, 1995; Perrotte et al, 1999; Pisters et al, 1999). Whole-Gland Salvage Cryoablation Cryoablation has been used for salvage therapy in patients in whom radiotherapy, radical prostatectomy, or initial treatment with cryoablation has failed (Wenske et al, 2013) and who have a negative metastatic workup (Ismail et al, 2007; Pisters et al, 2009). However, because of the necessary preservation of a thin rim of periurethral tissue for whole-gland ablation or from a more substantial spared portion of the gland with subtotal treatment, the likelihood of cure is limited. The most common complications were stress incontinence, infection, stricture, and erectile dysfunction (Rebillard et al, 2008). For instance, in a small series of patients treated with one commercially available device and no adjuvant hormone therapy (Koch et al, 2007), 10% of patients developed urinary retention after treatment, 20% were incontinent, and 5% had a rectal injury. The published reports from Europe are confounded by deficiencies in study design, inhomogeneous patient populations, undersampling of the prostate on biopsies, and frequent use of transurethral resection of the prostate and androgen ablation therapy. There was a 48% failure rate and one prostate cancer death; three severe strictures; two fistulae in salvage cases; and three cases that could not be performed because of rectal wall thickness. Some studies have reported excellent survival outcomes and minimal associated morbidity. Others have reported that the main potential advantage of salvage cryoablation may be that it could delay the need for hormone therapy (Ng et al, 2007).
Serum prostate specific antigen complexed to alpha 1-antichymotrypsin as an indicator of prostate cancer anxiety symptoms home remedies purchase phenergan 25mg. Noggin is required for normal lobe patterning and ductal budding in the mouse prostate anxiety symptoms heart pain phenergan 25mg without prescription. Prostate epithelial cells utilize glucose and aspartate as the carbon sources for net citrate production anxiety xiphoid process buy on line phenergan. Molecular mechanism of estrogen action in the male: insights from the estrogen receptor null mice anxiety in teens discount phenergan 25mg online. Role of mesenchymal-epithelial interactions in normal and abnormal development of the mammary gland and prostate. Normal and abnormal development of the male urogenital tract: role of androgens, mesenchymal-epithelial interactions, and growth factors. The possible influence of temporal factors in androgenic responsiveness of urogenital tissue recombinants from wild-type and androgen-insensitive (Tfm) mice. Transcriptional activation modulated by homopolymeric glutamine and proline stretches. Spermine and citrate as metabolic biomarkers for assessing prostate cancer aggressiveness. Trop2 identifies a subpopulation of murine and human prostate basal cells with stem cell characteristics. Phosphorylation status of the nuclear cytosolic androgen receptors in the rat ventral prostate. Specific region in hormone binding domain is essential for hormone binding and trans-activation by human androgen receptor. Lactate dehydrogenase isoenzymes in human prostatic fluid: an aid in recognition of malignancy Analysis of specific proteins in prostatic fluid for detecting prostatic malignancy. The relative importance of androgen and estrogen in the selective uptake of Zn65 by the dorsolateral prostate of the rat. The effect of growth hormone and prolactin preparations on the control by interstitial cell-stimulating hormone of uptake of 65-Zn by the rat dorsolateral prostate. An acid phosphatase occurring in serum of patients with metastasizing carcinoma of the prostate gland. Differential effect of finasteride on the tissue androgen concentrations in benign prostatic hyperplasia. Androgens are necessary for the establishment of secretory protein expression in the guinea pig seminal vesicle epithelium. Endogenous steroid levels in the human prostate from birth to old age: a comparison of normal and diseased tissues. Prostate stem cell antigen expression is associated with Gleason score, seminal vesicle invasion and capsular invasion in prostate cancer. Lactate dehydrogenase isoenzymes in hyperplasia and carcinoma of the prostate: a clinical study. Mammalian transglutaminases: identification of substrates as a key to physiological function and physiopathological relevance. Prolongation and improvement of prostasome promotive effect on sperm forward motility. Development of monoclonal antibodies specific for human glandular kallikrein (hK2): development of a dual antibody immunoassay for hK2 with negligible prostate-specific antigen crossreactivity. Percentage binding of testosterone, androstenedione and dehydroisoandrosterone in human plasma. Changes in dihydrotestosterone metabolism associated with the development of canine benign prostatic hyperplasia. Immunological alterations in the ejaculate of chronic prostatitis patients: clues for autoimmunity. Testosterone-induced coronary vasodilatation occurs via a non-genomic mechanism: evidence of a direct calcium antagonism action. Ab initio structure of human seminal plasma prostatic inhibin gives significant insight into its biological functions. Isocitric and citric acid in human prostatic and seminal fluid: implications for prostatic metabolism and secretion. Extracellular organelles (prostasomes) are immunosuppressive components of human semen. The hypophyseal-testicular axis and sex accessory glands following chemical sympathectomy with guanethidine of pre-pubertal to mature rats. Androgen receptor phosphorylation, turnover, nuclear transport, and transcriptional activation: specificity for steroids and antihormones. Quantitation of prostatic specific antigen serum by a sensitive enzyme immunoassay. Control of gene expression and assembly of chromosomal subdomains by chromatin regulators with antagonistic functions. Prepubertal development of rat prostate and seminal vesicle following chemical sympathectomy with guanethidine. Sonic hedgehog activates mesenchymal Gli1 expression during prostate ductal bud formation. Some physico-chemical characteristics of "-seminoprotein," an antigenic component specific for human seminal plasma. Reverse transcription-polymerase chain reaction detection of prostate-specific antigen, prostate-specific membrane antigen, and prostate stem cell antigen in one milliliter of peripheral blood: value for the staging of prostate cancer. Purification and characterization of zinc alpha2glycoprotein-prolactin inducible protein complex from human seminal plasma. Facile synthesis of site-specifically acetylated and methylated histone proteins: reagents for evaluation of the histone code hypothesis.
This is carried in a cephalad direction to the level of the vas deferens in men and the round ligament in women anxiety symptoms change purchase generic phenergan pills. At this point a peritoneotomy is made lateral to either medial umbilical ligament and the urachus is controlled and divided anxiety heart rate order phenergan 25mg amex. The peritoneum is incised lateral to the medial umbilical ligaments bilaterally to the level of the internal inguinal rings at which point the vas deferentia in men and the round ligaments in women will be identified and are divided anxiety symptoms pain discount phenergan 25 mg online. Attention is then turned to the bowel mobilization to achieve adequate exposure of the great vessels and the ureters anxiety from weed purchase phenergan 25mg. On the right side the white line of Toldt is incised and carried around the cecum where then the posterior peritoneum is incised to allow mobilization of the root of the small bowel mesentery. On the left side the white line of Toldt is likewise incised, and a window is created below the sigmoid colon mesentery to communicate with the rightsided posterior peritoneotomy. This space will later be used to transpose the left ureter to the right lower quadrant for urinary diversion. With the aid of a self-retaining retractor such as a Bookwalter, exposure is maximized and the bowel retracted cephalad. Communication with the anesthesiologist at this point is vital to ensure that inadvertent compression of the vena cava has not resulted. A moistened laparotomy pad or pads should be placed behind retractor blades to protect the abdominal contents. After adequate exposure is achieved, the bilateral ureters are dissected free from their attachments beginning a few centimeters above where they cross the iliac arteries to the level of the detrusor hiatus. The superior vesical artery should be ligated and divided before completing the ureteral dissection as this aids in maximizing ureteral length. The ureter is then controlled with either suture ties or suture ligature and is divided. Although controversial, the distal ureteral margin can be sent for frozen section analysis to evaluate for the presence of urothelial carcinoma. Although studies have shown a correlation between findings of carcinoma in the ureteral margin and subsequent upper tract recurrence (Schumacher et al, 2006), an impact on survival has not been well established (Raj et al, 2006). Additionally the study by Raj and colleagues indicated that despite sequential resection to achieve a negative margin in 48 instances of an initial positive ureteral margin, upper tract recurrence was not eliminated (Raj et al, 2006). According to surgeon preference, temporary ureteral catheters directed off the surgical field can be used to maintain urinary flow during the remainder of the procedure, or the ureters can be temporarily ligated to avoid spillage of urine into the operative field. The anatomic boundaries of a standard template dissection consist of the genitofemoral nerves laterally, the internal iliac artery medially, Cooper ligament inferiorly, and the point at which the ureter crosses the common iliac artery superiorly. In cases of advanced disease, an extended dissection inclusive of the entire common iliac lymph node packet and the presacral lymph node packet can be obtained. Although further extension cephalad to include the para-aortic packet to the level of the inferior mesenteric artery has been studied in bladder cancer, none have demonstrated any additional staging information beyond a dissection from the common iliac arteries distally (Bochner et al, 2004, Bruins et al, 2014). Care should be taken during lymphadenectomy to avoid injury to the obturator nerve and to ensure control of lymphatics at the caudal and cephalad extremes. Surgical quality as measured by nodal yield has demonstrated a survival benefit in bladder cancer. Herr (2004) and colleagues found that in patients in whom at least 10 lymph nodes were removed, 5-year survival improved from 44% to 61%. Later an examination of 1260 patients Psoas muscle covered by fascia Dissection of external iliac artery from pelvic sidewall Chapter95 TransurethralandOpenSurgeryforBladderCancer 2247 Circumflex vein and artery Testicular vein and artery Genitofemoral nerve Psoas muscle Vas deferens External iliac nodes Obturator nerve Obturator vein and artery Paracaval Para-aortic Right Common Left Common Iliac Iliac Presacral Right Left Ext. Iliac Iliac Right Obturator & Hypogastric Left Obturator & Hypogastric Internal iliac artery Vas deferens Ureter A Peritoneum B C D Figure 95-7. B, Distributions of the eight node packets from an extended pelvic and retroperitoneal lymph node dissection. Completion of the pelvic lymphadenectomy aids in the exposure and identification of the vascular pedicles to the bladder. Control of the main branches to the bladder, including the superior, middle, and inferior vesical arteries, can be achieved with the aid of a vascular stapler. The rectal cul-de-sac is identified and the peritoneum is incised where it overlies the seminal vesicles. If there is a large tumor at the base of the bladder, care must be observed to ensure an adequate margin of resection at this point. The rectum is dissected free with either blunt dissection or sharp dissection in the midline and is carried to the level of the prostate, at which point Denonvilliers fascia is encountered and incised. In cases of advanced disease, previous pelvic radiation, or reactive fibrosis from previous resection or intravesical chemotherapy, difficulty in developing this plane may be encountered. In such instances blunt dissection should not be performed, as this may cause inadvertent injury to the rectum. Instead, under direct visualization, sharp dissection should be performed with care taken to maintain rectal integrity. If a rectal injury is encountered, primary repair with or without flap coverage and/or bowel diversion should be performed (Kozminski et al, 1989). After release of the rectum in the midline, dissection is carried laterally and the posterior vesical pedicles are identified. Similar to the lateral pedicles, they can be controlled with surgical clips, ties, vascular staplers, or sealing instruments. A, the posterior plane beyond the cul-de-sac, which separates the bladder and prostate from the rectum. With a gloved finger surgeons should shield the rectum from the tips of such instruments while in use. After completion of the posterior dissection, the urethra should be palpable and at this point attention can be turned to the anterior dissection in a fashion similar to a radical prostatectomy. The endopelvic fascia overlying the levator muscles is incised sharply, allowing for identification of the confluence between the urethra and the dorsal venous complex.
Mesenchymal condensation occurs in both males and females anxiety while driving cheap phenergan uk, so it is not sufficient to drive prostate development but may be necessary anxiety symptoms in women buy cheap phenergan 25mg on-line. For example anxiety symptoms explained buy 25 mg phenergan fast delivery, mice with engineered mutations of the mesenchyme-specific growth factor Fgf10 gene generate small abortive epithelial buds and fail to grow prostates (Donjacour et al anxiety symptoms 2 25mg phenergan with mastercard, 2003). This transcription factor influences the degree of branching in the mature mouse prostate, where it can also act as a tumor suppressor (Bieberich et al, 1996; Bhatia-Gaur et al, 1999; Abate-Shen et al, 2008). Thus the action of androgens appears to be indirect, leading to the hypothesis that mesenchymal cells secrete inductive factors in response to androgens called andromedins (Yan et al, 1992). Noggin mutations selectively impair budding of the ventral lobes of the prostate, leaving anterior and dorsolateral budding unimpaired (Cook et al, 2007). Overall, however, the process appears to be a very robust one, with evidence of prostate epithelial bud formation persisting in the presence of a variety of genetic mutations that affect future steps in prostate ductal morphogenesis, particularly branching morphogenesis. Epithelial branching morphogenesis occurs through signaling cascades that inhibit further outgrowth along the long axis of an extending epithelial bud while stimulating lateral growth at its tip (Hogan, 1999). Through engineered deletion of genes in transgenic mice, several individual genes and components of classic morphogenetic pathways have been shown to be required for branching morphogenesis. Indeed, morphologic aberrations seen on interruption of a cellular pathway may be the most sensitive measure of a role for that pathway in regulation of prostate growth. Accordingly, a wide variety of genes and pathways have been strongly implicated in prostate branching morphogenesis, only a few of which are covered here. For a more comprehensive perspective, including additional pathways such as those centered around Notch and Forkhead proteins, the reader is referred to recent reviews (Leong and Gao, 2008; Matusik et al, 2008). This relatively subtle phenotypic change may be important, however, as indicated by a dramatic decrease in the ability of Nkx3. In addition to its role in the initiation of prostate development, Sox9 appears required for bud growth and branching as well as ductal outgrowth (Thomsen et al, 2008). Epithelial branching morphogenesis, be it in the lung, salivary gland, mammary gland, or prostate, requires such signals to proceed. Both of these ligands preferentially bind to Fgfr-2 over the three other family members (Fgfr 1, 3, and 4) (reviewed in Thomson, 2001, 2008). This arrangement, along with androgenindependent growth of prostate organ cultures exposed to these ligands, has led to the proposal that they act as andromedins (Yan et al, 1992; Lu et al, 1999). Across a variety of organs, elaboration of secreted hedgehog (Hh) ligands (Sonic hedgehog, Indian hedgehog, and Desert hedgehog) by epithelial cells and reception in adjacent mesenchyme coordinate the activities of the Gli family proteins in regulating hedgehog pathway target genes. The roles of these particular genes in prostate development have yet to be ascertained, but, as a whole, Hh pathway target genes have been implicated in placement of prostate epithelial buds and in subsequent ductal branching and outgrowth. In particular, buds form in the absence of the dominant Hh ligand in the prostate (Berman et al, 2004) but are mislocalized in prostates of mice bearing mutations of downstream effectors of the pathway, Gli proteins (Doles et al, 2006). Later in development, Hh ligands enhance epithelial outgrowth and branching (Freestone et al, 2003), which proceed abnormally in prostate organ cultures treated with Hh pathway antagonists (Lamm et al, 2002; Freestone et al, 2003; Berman et al, 2004). In adult animals the pathway may play a role in homeostasis, as indicated in a failure of prostates to regenerate after castration of animals treated with antibodies or small molecules that block Hh signaling (Berman et al, 2004). Taken together, these data indicate a growth-promoting role for the pathway in prostate epithelium, one that may have clinical relevance in pathologic prostate growth (reviewed in Shaw and Bushman, 2007). In organogenesis this superfamily is best known as a mesenchymal mediator of epithelial growth suppression, but (less frequently) they can also stimulate growth and/or be produced by epithelial cells. The rodent prostate is divided into paired anterior, dorsolateral, and ventral lobes. Each empties into the urethra separately at its proximal extreme, with the distal end floating freely in the pelvic cavity. In contrast, the human prostate, like that of most primates and canine species, grows as a single organ encircling the urethra. The individual prostate zones, however, have distinct architectural and molecular features and have a propensity to develop distinct pathologies (Table 102-1). In rodents, the anterior, ventral, and dorsolateral lobes are named for the distinct locations of the urethra from which they originate. Each lobe also has a different branching pattern with a distinctive histologic appearance. These differences, reviewed by Timms (2008), have been likened to different zones of the human prostate histologically (Price, 1963), molecularly (Berquin et al, 2005; Thielen et al, 2007), and in terms of propensity to be affected by disease (the dorsolateral prostate, for instance, is most similar to the human peripheral zone). Stem cells within the basal cell compartment(dark blue) express basal cell proteins, as well asTacstd2andc-kit. Basalstemcellspopulatethebasalcellcompartment(medium blue)and eventually intermediate cells (light blue). Intermediate cells proliferate and differentiate into quiescentluminalcells(orange). Formallineagetracinghasnotbeenperformedinallofthesecelltypes; thus the true differentiation pathway remains to be determined. That is, the development, growth, and function of the male and female urogenital tract require stromalepithelial interaction and action of steroid sex hormones. Androgen acts on the mesenchyme to indirectly induce prostate epithelial outgrowth during development and homeostasis in adulthood. Luminal Epithelial Cells the luminal epithelial cell is the "workhorse" of the prostate gland, responsible for epithelial barrier integrity and production of prostatic secretion. They are also rich in keratin filaments (subtypes 8 and 18) (van Leenders and Schalken, 2003).
Evidence also indicates that estrogen action mediated through the separate receptors may contribute to the etiology and progression of multiple prostate disease states (Table 103-2) anxiety symptoms or ms purchase phenergan 25mg without prescription. Serum estrogen levels increase in men with age anxiety 2016 cheap 25mg phenergan amex, absolutely or relative to testosterone levels anxiety wrap for dogs 25 mg phenergan with mastercard. The 89L allele has been associated with lower enzyme activity anxiety 38 weeks pregnant cheap phenergan 25mg without prescription, whereas the 49T allele has been associated with higher activity. Androgen withdrawal may partially exert its effect on the prostate through vascular effects (Buttyan et al, 2000). Castration induces acute and drastic vasoconstriction of blood vessels in the rat prostate (Hayek et al, 1999). There is indirect evidence to suggest that abnormalities in the prostatic vascular system produced by other disease states. In the Olmsted County Study cohort, in men with above-median levels of bioavailable testosterone, the serum estradiol level correlated positively with prostate volume, even after adjusting for age (Roberts et al, 2004). Data on obesity, serum testosterone, estradiol, and prostate volume are conflicting (Zucchetto et al, 2005). From experimental studies with aromatase inhibitors, it appears that decreases in intraprostatic estrogen in animal models may lead to reduction in drug-induced stromal hyperplasia (Farnsworth, 1996, 1999). There are high levels of progesterone receptor in the normal and hyperplastic prostate. RegulationofProgrammedCellDeath Programmed cell death (apoptosis) is a physiologic mechanism crucial to the maintenance of normal glandular homeostasis (Kerr and Searle, 1973). Cellular condensation and fragmentation precede phagocytosis and degradation, during which the apoptotic cell is phagocytosed by neighboring cells and degraded by lysosomal enzymes. In the rat prostate, active cell death occurs naturally in the proximal segment of the prostatic ductal system in the presence of normal concentrations of plasma testosterone (Lee et al, 1990). Following castration, active cell death is increased in the luminal epithelial population as well as in the distal region of each duct. Tenniswood (1986) suggested that there is regional control over androgen action and epithelial response, with androgens providing a modulating influence over the local production of growth regulatory factors that varies in different parts of the gland. In the rat prostate, at least 25 different genes are induced following castration (Montpetit et al, 1986). Normal glandular homeostasis requires a balance between growth inhibitors and mitogens, which respectively restrain or induce cell proliferation but also prevent or modulate cell death. Further evidence of the importance of stromal-epithelial interactions in the prostate comes from the elegant developmental studies of Cunha and colleagues, which demonstrate the importance of embryonic prostatic mesenchyme in dictating differentiation of the urogenital sinus epithelium (Cunha et al, 1980, 1983, 2003; Cunha and Donjacour, 1987; Cunha, 1994, 1996). The process of new gland formation in the hyperplastic prostate suggests a "reawakening" of embryonic processes in which the underlying prostatic stroma induces epithelial cell development (McNeal, 1990). GrowthFactors Growth factors are small peptide molecules that stimulate, or in some cases inhibit, cell division and differentiation processes (Steiner, 1995; Lee and Peehl, 2004). Cells that respond to growth factors have on their surface receptors specific for that growth factor that in turn are linked to a variety of transmembrane and intracellular signaling mechanisms. The growth of canine prostate epithelium can be regulated by cellular interaction with the basement membrane and stromal cells. Isaacs and Coffey (1989), using a marker of canine prostatic epithelial cell function, demonstrated that epithelial cells grown on plastic quickly change their behavior. In contrast, if the cells are grown on prostatic collagen, they maintain their normal secretory capacity and cytoskeletal staining pattern and do not grow rapidly. Growth factors may also be important in modulating the phenotype of the prostate smooth muscle cell (Peehl and Sellers, 1998). There is mounting evidence of interdependence between growth factors, growth factor receptors, and the steroid hormone milieu of the prostate (Rennie et al, 1988; Lee and Peehl, 2004). However, further research is necessary to establish the role of growth factors in a disease process in which cellular proliferation is not obvious. Indirect evidence to support this view comes from studies of reconstituted mouse prostate (Yang et al, 1997). In addition, there is increasing evidence that sympathetic pathways may be important in the pathogenesis of the hyperplastic growth process (McVary et al, 1994, 2005). Thus T cells present in the local prostate environment were thought to be capable of secreting potent epithelial and stromal mitogens that promote stromal and glandular hyperplasia. To date, however, no firm cause-and-effect relationships have been established between prostatic inflammation and related cytokine pathways and stromal-epithelial hyperplasia. B, Role of smooth muscle cells (indicated in red) in maintenance and propagationofimmuneinfiltrationintheagingprostate. The results did not appear to be due to differences in health-seeking behavior between the two groups. A segregation analysis showed that the results were most consistent with an autosomal dominant inheritance pattern. A more recent familial aggregation study in the finasteride database confirmed that a strong family history of early onset and large prostate volume is more likely to be associated with inheritance of risk than symptom severity or other factors (Pearson et al, 2003). Interestingly, another glandular organ that remains androgen responsive throughout life, the seminal vesicle, does not develop hyperplasia. Obviously, other mechanisms or cofactors must be present in these two unique species making them susceptible to the disease. Nonandrogenic substances from the testis, perhaps transmitted through the vas deferens or deferential blood vessels, for example, may play some role (Dalton et al, 1990). Rats with intact testes treated with exogenous androgen demonstrate a greater degree of prostatic growth than castrated rats treated with androgen. Sutkowski and coworkers (1993) have demonstrated that human spermatocele fluid is mitogenic to both human prostatic epithelial and stromal cells in culture.
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