General Physiology

240

Practical Urology: EssEntial PrinciPlEs and PracticE

Table 18.1. components of prostatic secretions

exerts its effects on a wide range of cellular func-

Component

Possible role

tions. After DHT binds to androgen receptors in

the cytoplasm the complex is dimerized, then

citric acid

Binds metal ions

transported to the nucleus where it directs tran-

Polyamines (spermine,

Most positively charge

scription. In the nucleus DHT binds the andro-

putrescene)

organic molecules in

gen receptor with much greater potency than

nature, involved in cell

T. Dimerized DHT-androgen receptor complex

growth, gate substances

along with coactivators bind to androgen

through channels

response elements (DNA sequences) on DNA to

Phosphorylcholine

reduced in cancer,

influence transcription factors and mRNA pro-

duction (Fig.18.2).The TATA box DNA sequence

Prostaglandins (15 types)

regulates Psa binding

to semenogelins i and ii,

determines the RNA polymerase binding start

antibacterial

location and the androgen response element

cholesterol/lipids

dictates how frequently the mRNA is tran-

scribed. These synthetic processes occur over

Zinc

hours to days. However, DHT can also trigger

Psa

inhibits Psa activity,

rapid changes in cellular function through sepa-

rate mechanisms.

Kallikrein 2

causes semen to clot

Besides DHT, estrogens and adrenal steroids

semenogelins i and ii

influence prostate function and growth. T can

be converted to estradiol and estrone by aro-

Prostase KlK-l1 and 11

activates alternate

matase in adipose tissues. Another hormone,

Prostatic acid phosphatase

pathway

prolactin, regulates zinc metabolism, citrate and

Prostate-specific protein

fructose production, as well as androgen uptake

and metabolism. Estrogens combined with

Prostate-specific

androgens and possibly prolactin are thought to

membrane antigen

play a role in the development of BPH.2

Prostate stem cell antigen

It is not well understood how signals from

neuroendocrine cells in the prostate such as

immunoglobulins-igg

serotonin, paracrine factors (such as basic

transferrin

Binds iron

fibroblast growth factor bFGF), and extracellu-

lar matrix regulate the growth and function of

the prostate (Fig. 18.1). To a lesser extent DHT

Androgens affect neural morphology, number,

also regulates stromal growth factors termed

and autonomic receptor function.3-7 Castration

andromedins.

reduces prostate size, the volume of prostatic

Circulating catecholamines elicit contraction

secretion, muscarinic receptor expression, and

of the prostatic capsule and stroma (norepi-

noradrenergic innervation of the prostate. The

nephrine, oxytocin).9,10 Although experiments

major androgen-regulating prostate physiology

show that adrenergic mechanisms trigger apop-

and growth is dihydrotestosterone (DHT).8 The

tosis in vitro,11,12 their long-term administration

prostate contains five times more DHT than T.

does not reduce prostate volume, prostate-

DHT is synthesized from testosterone (T) by the

specific antigen (PSA), or cause histological

action of 5 reductase (5AR) (Fig. 18.2). It exists

changes.

as two isoforms, Type I and type II. The prostate

Afferent nerves transmit the discomfort of

contains mostly type II. Type I 5AR is found in

prostatitis and are involved in pathogenesis of

skin and liver. Expression of 5AR is regulated by

male pelvic pain syndrome.12 Prostate afferents

androgens. During development, both epithelial

contain neuropeptides that can trigger inflam-

and mesenchymal cells contain DHT, which reg-

matory and immune responses. Secretory prod-

ulates growth. In the adult 5AR is expressed by

ucts,cytokines,and growth factors such as nerve

stromal tissues and basal epithelial cells. DHT is

growth factor (NGF), epidermal growth factor

absent in secretory epithelium.

(EGF), transforming growth factor beta(TGFb),

Free T enters cells by diffusion whereupon it

insulin growth factor, and basic fibroblast

is converted to DHT. DHT in epithelial cells

growth factor (bFGF) that are produced in the

Testosterone

Extracellular

bFGF

matrix

Integrins

TGFb

5aR

E-cadherin

Epithelial

cell

prostate direct nerve growth and neurotrans-

are millimeters from the neurovascular bundle

mitter expression in addition to prostate growth

supplying the penis and dissection of these

and development.13-16

structures must avoid thermal injury. During

robotic prostatectomy some nerve fibers within

this capsule and fascia can be visualized.Prostatic

Prostate Innervation

nerves course within the posterior leaf of

Denonvilliers fascia. Often these nerves are mis-

Understanding the neurophysiology and auto-

taken as branches of the cavernous nerves since

those are also NAPHase positive and manufac-

nomic pharmacology of the bladder outlet and

ture nitric oxide (NO). Lastly, some branches

prostate is of paramount importance for eluci-

enter the prostate from the neurovascular bun-

dating the etiology and designing treatments for

dle near the apex. It is tempting to speculate that

lower urinary tract symptoms (LUTS) associated

this abundant innervation implies significant

with benign prostatic hyperplasia (BPH). The

functional importance.

prostate receives input from parasympathetic

Sympathetic nerves provide most of the effer-

and sympathetic nerves.17-27 Noradrenergic, cho-

ent neural input to the prostate. Nearly 80% of

linergic, peptidergic, and nitrergic nerves have

the prostate’s innervation is derived from sympa-

been demonstrated in the prostate.19-21,28-34 Cell

thetic outflow whereas 21–33% originates from

bodies for these neurons reside in the capsule

parasympathetic pathways.25 Nearly two-third of

and near the base of the seminal vesicle.19,27 It is

the neurons in the pelvic plexus supplying the

crucial for surgeons to realize that nerves near

prostate are noradrenergic.35 Noradrenergic

the lateral aspect of the seminal vesicle

nerve fibers are prominent around the prostatic

network,which interacts with pathways involved

relieves storage and voiding components of

in micturition and sexual function.26 In addi-

LUTS in BPH patients.54-57 The a -adrenoceptor

tion to the expected labeling in autonomic

1A

is the dominant subtype representing about

centers, prostate-labeled neurons reside in Bar-

60–85% of the a1-adrenoceptor population. The

rington’s nucleus (micturition center), raphe

a1A-adrenoceptor mediates the contractile

magnus, reticular formation, A5, A7, periaque-

response of the human prostate in vitro.58,59

ductal gray, red nucleus, and subcoeruleus. The

However, there is some variability in expression

physiological significance of these associations

among men as indicated by differential responses

is unclear but they raise the possibility that the

to alpha-subtype drugs that correlate with the

function of the prostate or prostatic urethra is

a and a

1b

ratio in the specimens.60

somehow linked to that of the bladder/urethra

1A

Noradrenergic nerves are also considered

and penis.

responsible for maintaining prostatic smooth

CGRP-immunoreactive nerves, considered to

muscle tone,61 and approximately 50% of the

represent sensory nerves, are few compared to

total urethral pressure in BPH patients may

the other phenotypes characterized. NOSand

be due to a-adrenoceptor-mediated muscle

CGRP-immunoreactive terminals have similar

tone.62,63 Conceivably a global increase in

profiles, but the immunoreactivities are not co-

sympathetic tone leads to increased urethral

localized.29 Pituitary adenylate cyclase activat-

resistance and prostatic tone. Thus a blockers

ing peptide (PACAP), presumably in pelvic

have shown clinical utility for voiding symp-

afferents, is expressed by nerves supplying the

toms or painful ejaculation in young anxious

prostate.29 The proximal central prostate con-

men.64

tains more peptidergic fibers (vasoactive intes-

In addition to causing contraction of the out-

tinal polypeptide [VIP] and opiate-related

let, hypogastric nerve stimulation (sympathetic)

peptides metand Leuenkephalins [ENK],32,44

increases secretion.8,65-68 Yet this secretion is

neuropeptide Y [NPY], peptide histidine leucine

blocked by the muscarinic agonist atropine,66-68

[PHI], somatostatin [SOM], galanin [GAL],

implying that sympathetic cholinergic nerves

bombesin [BOM], substance P [SP], calcitonin

control exocrine function (see reviews by

gene-related peptide [CGRP], and pituitary ade-

Elbadawi and Goodman,17 Dail,21, and Smith69).

nylate cyclase peptide [PCAP]) than the anterior

Likewise, muscarinic agonists including pilo-

capsule, which exceeds the distal central zones,

carpine and urecholine induce prostatic secre-

which in turn is greater than the peripheral

tion.8,17,65,66,70 This secretion is mediated by

zone.

muscarinic receptors expressed by epithelial

cells.46,71,72 Cholinomimetic drugs barely con-

Neurophysiology

tract prostate capsule accounting for only

10–15% of that of a agonists. Anti-muscarinics

and Neuropharmacology

such as atropine completely block secretory

responses to these agonists as well as hypogas-

tric nerve-evoked secretion. Despite this obser-

Stimulation of the pelvic nerve produces a slight

vation, a decrease in ejaculate volume is rarely a

contraction of the prostate, whereas hypogastric

complaint of men on anticholinergics. Of the

nerve stimulation evokes a profound contrac-

five molecular muscarinic receptor subtypes the

tion and secretion.45 Contraction of the prostatic

M1 receptor is expressed by prostatic epithelium,

capsule, due to firing of the hypogastric nerve,

whereas the stroma expresses the M2 receptor

increases bladder outlet resistance. Contractile

protein.

responses are mediated by noradrenergic rather

Many prostatic nerves stain for nitric oxide

than cholinergic mechanisms. Noradrenaline

synthase (NOS) or heme-oxygenase (HO), sug-

stimulates contraction-mediating a-adrenocep-

gesting that they manufacture nitric oxide and

tors localized to predominately prostatic stroma.

carbon monoxide.29,33,73-77 NOS is expressed by

Although both a1 and a2 receptors can be iden-

both sensory and motoneurons. In men with

tified in the human prostate,46,47 the contractile

BPH, this finding may explain the efficacy of

properties are mediated primarily by a1-adre-

PDE5 inhibitors to reduce LUTS (Fig. 18.2).

noceptors.46,48-53 Many clinical investigations

NO inhibits secretion and reduces contractile

have confirmed that a1-adrenoceptor blockade

action. NO alone has no consistent effect in the

244

Practical Urology: EssEntial PrinciPlEs and PracticE

prostate yet relaxes the urethra.78 Relaxation of

size (static component) may be too simplistic a

NE-contracted prostatic tissue can be prevented

concept and fails to reconcile data that men

by NOS inhibition.29,42 Similar to its effect on the

without urodynamic evidence of reduced

urethra, exogenous NO relaxes prostatic tissues.

obstruction and no change in voiding flow rates

NO may play a role in controlling smooth mus-

can benefit from these drugs (Fig. 18.2). Because

cle tone in the prostate. Indeed, phosphodi-

LUTS attributed to BPH is multifactorial

esterase type 5 (PDE5) inhibitors which raise

(increased resistance, changes in the detrusor,

cGMP may increase urine flow rates and lower

urothelium, interstitial cells, or nerves), drugs

LUTS in men with BPH.79-81 Yet, a reduction in

probably target multiple sites. Indeed, the asso-

symptoms without a corresponding increase in

ciation of LUTS with metabolic syndrome and

urinary flow suggests actions at other sites than

erectile dysfunction implies a complex interac-

the outlet for PDE5 inhibitors.

tion of pathophysiological processes. Moreover,

Transmitters released from prostatic nerves

the prevalence of overactive bladder (OAB)

may alter the composition of prostatic secre-

increases with age, especially in men. Thus, the

tions.68,70,82,83 The concentration of sodium in

multiple sequelae of obstruction combined with

prostatic secretions is essentially the same as

underlying OAB suggest that a wide range of

that in plasma. In contrast, sodium and potas-

therapies may be effective. In fact if one scans

sium concentrations in neurally evoked pros-

the literature for prospective randomized trials

tatic secretions exceed those in plasma.

for BPH and calculates the potential combina-

In carbachol-stimulated secretions the pro-

tions of

approved

5AR

inhibitors (n = 2)

tein concentration and prostatic acid phos-

a-adrenergic antagonists (n = 7), PDE 5 inhibi-

phatase activity were reduced compared to

tors (n = 4), and antimuscarinics (n = 6) used

noradrenalineor phenylephrine-stimulated

singly, doubly, or in triple drug combinations,

secretion.70

greater than 72 regimens can be identified! And

Nerves maintain the functional integrity of

this fails to include vasopressin analogs or botu-

glandular tissue. Several studies have shown

linum toxin.

that surgical denervation reduces prostatic

In general, the rapid onset and relief of most

weight and causes atrophy of acini.84-86 Similarly,

bothersome storage symptoms of urgency, fre-

chemical sympathectomy decreases the weight

quency, and nocturia by a-adrenergic antago-

of the prostate and glands appear dilated.87,88

nist has led to their use as drugs of first choice.

Botulinum toxin, which prevents neurotrans-

The evolution from non-a1

selective multidose

mitter release, causes long-term shrinkage of

regimens

(prazosin,

phenoxybenzamine) to

prostate with a reduction in PSA.43 Interestingly,

once-daily preparations (doxazosin, terazosin,

men with longstanding spinal cord injury

alfuzosin) and then to agents with fewer effects

exhibit reduced prostate size, decreased mRNA

on the vasculature due to a1A selectivity (tamsu-

for the androgen receptor, and lower levels

losin, silodosin) has occurred. Some agents such

PSA.89 Whether this is due to changes in neural

as doxazosin GITS with slow release allow initia-

activity or chronic infections is unclear.

tion at higher doses for non-subtype-selective

blockers, thereby avoiding slow dose titration.

Treatment of LUTS Attributed

In a meta-analysis comparing efficacy as indi-

cated by symptom scores and maximal flow

to BPH

rates, all agents are similar.90 The only exception

to this is suggested by a comparative trial

between doxazosin and alfuzosin.91 Although

The treatment of LUTS due to BPH has been

increases in urinary flow rates were similar,

complicated by the proliferation of clinical trials

symptom improvement was greater for dox-

demonstrating efficacy of agents spanning sev-

azosin. Given similar a-adrenergic antagonist

eraldrugclassesrelativetoplacebo.Traditionally,

properties, and the major difference being lack

one is left to believe that LUTS due to BPH

of CNS penetration for alfuzosin, implies that

results from merely bladder outlet obstruction.

central action on a blockers participates in

Reduction in outlet resistance by relaxation of

symptom relief especially for storage symptoms.

the urethra and prostatic smooth muscle

Because the a1A receptor regulates contraction

(dynamic component) or a reduction in prostate

of the seminal vesicles and vas deferens, agents