What is Prostate?

The Prostate Gland and BPH. Basic Science



Function

Secretory
Produces 30% of the volume of seminal fluid
Provides nutrients for sperm
Proteases such as PSA (chymotrypsin) maintain semen fluidity by acting as an anticoagulant
Neutralises acidity of vagina
Antibiotic function of some secretions from the central zone.

Muscular pump
Smooth muscle surrounding the glands forces ejection of prostatic fluid to mix into seminal fluid during ejaculation


Development

Wk 7 male and female identical.
Mullerian ducts degenerate in male
Wolffian ducts differentiate - ejaculatory ducts, SV, vas and central zone of prostate
Wk 10-15 prostate derived from urogenital sinus (UGS) (peripheral zone)
Prostatic utricle is remnant of Mullerian or paramesonephric duct
3rd trimester gland quiescent till puberty


Structure

70% glandular / 30% fibromuscular


Zonal anatomy (McNeal 1968)

TZ - 5-10% glandular tissue

CZ - 25% glandular tissue structurally / immunohistochemically distinct from other zones.

Possibly originated from Wolffian duct

PZ - 70% glandular tissue

Derived from urogenital sinus


Transition zone BPH, 20% cancers
Central zone, 1-5% cancers
Peripheral Zone, 70% cancers


Blood supply: Inferior vesical and middle rectal arteries - branches of internal iliac artery
Venous drainage:
Prostatic venous plexus - sides & base of prostate
Located between capsule + fascial sheath
Drain to internal iliac veins
Communicate with vesical venous plexus, vertebral venous plexus

Innervation

Via cavernosal nerves which follow arterial supply
Parasympathetic fibres arise from pelvic splanchnic nerves S2, S3, & S4, promote secretions
Sympathetic fibres derived from inferior hypogastric plexuses, contraction of SM of capsule & stroma

Sphincters:

Rhabdosphincter (distal sphincter/urethral sphincter mechanism)
Three components: smooth muscle, then striated muscle, then periurethral component of levator ani (pubourethral sling)
Under conscious control
Signet ring shaped, deficient posteriorly

Bladder Neck
Both sexes, at bladder neck, cholinergic innervation, continence mechanism

Preprostatic sphincter
Males, supraverumontanal, adrenergic innervation, genital sphincter
Separate from rhabodosphincter
Smooth mucle, not under conscious control



Lymphatic drainage:
Lymph vessels terminate mainly in internal iliac and obturator lymph nodes
Some travel to external iliac lymph nodes & presacral nodes


Seminal vesicle
Pear shaped structure, 5cm long
Lies between fundus of bladder and rectum / (ureter enters bladder medial to tip of SV)
Provide majority of volume of seminal fluid, does not store sperm
Join vas deferens to form ejaculatory duct, opens posterior wall of prostatic urethra
Blood supply - sup / inf vesical arteries



Ejaculation
Emission of semen into urethra: peristalsis of vas / seminal vesicles, contraction of smooth muscle in prostate - sympathetic
Ejaculation clonic spasm bulbospongiosus muscles – parasympathetic
Sequence:
Bladder neck tightens
Emission of vasal ampullary sperm
Contraction of bulbospongiosus
Contraction of prostatic smooth muscle
Urethral sphincter mechanism overcome
Further contraction of prostate and seminal vesicle contraction




Seminal plasma

2ml seminal vesicle secretion, 0.5ml prostatic secretion, 0.1ml Cowper’s glands and glands of Littré

Role of seminal plasma
Optimise fertilisation
(ejaculated sperm v aspirated sperm)
protective effect
enhance motility and survival directly
Protective effect on urinary tract
biological esp. Zn, spermine, Ig
mechanical washing
Lubrication


Prostatic secretions

o Proteins: Acid phosphatase, PSA, Leucine aminopeptidase, Diamine oxidase, Β Glucuronidase, Plasminogen activator, Complement C3 and C4, transferrin, transferritin, Growth factors, annexin 1

o Non-proteins: Citrate (240-1300x conc elsewhere), Spermine, Spermidine, Putrescine, Zinc (high concentrations), Myoinositol, Cholesterol

o Functions: zinc for the structure of sperm chromatin and antibacterial. PSA for semen liquefaction. Cholesterol may stabilize sperm against temperature and environmental shock Citrate is important for electrochemical neutrality in combination with zinc and polyamines


Fructose

§ From seminal vesicles
§ Patients with congenital absence of seminal vesicles don’t have fructose in ejaculate [Barak 1994]
§ Concentration has some androgenic regulation but also depends on nutritional status and frequency of ejaculation
§ Provides anaerobic and aerobic energy source for sperm
§ Indirectly linked to forward sperm motility through prostasome function [Fabiani et al 1995]

Prostaglandins

§ Seminal vesicles are richest source in body (originally thought to be from prostate – hence the name) many types
§ Very potent pharmacological actions
§ Erection, ejaculation, sperm motility and transport
§ Effects on cervical mucus and vaginal secretions

Cell biology

Cellular organization is of a complex ductal system of epithelial cells embedded in a
stromal matrix

Epithelial: Exocrine and neuroendocrine cells
3 types: basal, luminal and neuroendocrine
Have different functions but are believed to originate from a common progenitor stem cell
Separated from stromal cells by the basement membrane
DHT formed mainly in these cells, and DHT then diffuses to stroma (where there are most of the androgen receptors)
Stromal nuclei produce growth factors, which then drive epithelial cells

Stroma: smooth muscle cells and fibroblasts
Has most of the androgen receptors
DHT diffuses from stromal cells, which produce growth factors, and these factors then work in an autocrine and paracrine fashion, stimulating epithelial cells

Cell type Function
Basal cells Proliferation
Luminal cells Secretion of prostatic fluid
Neuroendocrine Unknown - control growth and secretion?

Fibroblast Secrete growth factors (androgen dep)
Smooth muscle Contraction to eject prostatic fluid


Cellular organisation in the glandular prostate

Epithelial Cells

Neuroendocrine
Morphologically found in two forms
Open ended flask shaped cells with long extension towards the glandular lumen.
Closed cells without dendrite luminal extensions but with occasional horizontal processes.
Prostate has largest number of NE cells of any urogenital organ.
Function: Unknown but may play a role in the regulation of the normal growth and gland development (paracrine and autocrine) and may be important in the development of disease.

Basal cells
Spindle shaped, lying parallel to the basement membrane
Cigar shaped nuclei and high nucleus to cytoplasm ratio
81% of all proliferation occurs in the basal layer
Ratio of basal cells to luminal is 1:3 in normal and BPH tissue and 1:6 in hyperplastic situations
Major function: Proliferation
Includes stem cells

Luminal cells
Tall, columnar cells high in cytoplasm
Secretory cells contributing to the seminal fluid
PSA - Prostate specific antigen
PAP - Prostatic acid phosphatase
Only 1/10 the proliferative index of basal cells
Function - secretory - androgen dependent, as is survival
These cells most abundantly express the adrenoreceptor in BPH, cf basal cells

Cytokeratins:
Prostate: K5/14 basal cells and K8/18 in luminal cells

Stromal cells

Smooth muscle cells and fibroblasts
Little information about stromal cell types
Fibroblasts appear to initiate glandular growth and then differentiate into smooth muscle cells.
In cancer loss of muscle and gain of fibroblasts is associated with increased epithelial cell division
In culture a cell type called myofibroblasts appears and this may be an intermediate cell type
Both cell types express andrenoreceptors in BPH
98% of all α-adrenoreceptors in the prostate (90% α1 (60% α1a), 10% α2)



Stromal epithelial interaction theory

Interation between the stroma and the epithelium is important in growth and maintenance of the prostate
Reischauer suggested this first in 1925, and the theory was adopted by Cunha (1973)
Cunha showed that murine embryonic prostatic stroma could induce adult bladder epithelial cells to replicate and form prostate like glandular structures from the bladder cells. This effect does not occur in castrated animals, thus indicating the importance of androgens.
This interaction is thought to be the driving factor in the development of BPH, with androgens stimulating the local production of growth factors. These factors are responsible for the abnormal proliferation of the prostatic stroma and the appearance of micronodules and macronodules

Other Theories for BPH development

Embryonic reawakening: McNeal suggests that the initial abnormality in nodule genesis is a spontaneous reversion of a clone of stromal cells to the embryonic state

Oestrogen hypothesis: oestradiol modulates the action of androgens by altering the sensitivity of the prostate to androgens. A small increase in oestradiol concs results in an increased number of androgen receptors and prostate size. A large increase in oestradiol has the opposite effect. With aging, the oestrogen to androgen ratio increases, and these changes mimic those seen in BPH. Glandular BPH has been induced in castrated dogs by oestrogen and androgen administration (Walsh and Wilson, 1976)

Stem cell hypothesis: Isaacs and Coffey 1989. Number of stem cells, which is the rate limiting factor in prostate growth, slowly increases over time.


Growth Factors


FGF
IGF
TGFα all stimulatory (TGFα accounts for 20% of stimulatory factors)
EGF

TGFβ inhibitory

They all regulate the epithelial and mesenchymal interactions responsible for prostate development.
TGFβ inhibits prostate epithelial growth, but stimulates prostatic mesenchymal cells.

Following androgen withdrawal, there is decreased production of EGF, IGF and FGF, and an increase in expression of TGFβ1 and 2 receptors. This leads to prostatic involution.

Growth Factors in BPH:

bFGF stromal/epithelial autocrine/paracrine stimulatory
KGF stromal paracrine stimulatory
TGFβ1 stromal autocrine/paracrine inhibitory
TGFβ2 epithelial autocrine/paracrine inhibitory
IGF stromal paracrine stimulatory

In BPH there is no change in EGF, a large increase in FGF2, and keratinocyte growth factor and IGF appear.


Apoptosis and programmed cell death

Apoptosis is important in the development of BPH.
Activation of endonucleases occurs relatively early in the apoptotic pathway. This results from the hydrolysis of DNA, and the endonucleases are Ca2+/Mg2+ dependent.
Prostate stroma expresses α1a receptors, and pts treated with terazosin and doxasosin show induction of apoptosis, without affecting proliferation. Apoptitic index is higher in pts treated with an α blocker and proscar. Expression of TGFβ1 is increased with all therapies. However, α blocker treatment is not associated with a decrease in size of the prostate clinically.




BPH
LUTS
Urodynamic obstruction
BPE


LUTS, anatomical hyperplasia and urodynamic obstruction are interrelated.
Some pts have all three.
However, a large number have anatomical hyperplasia and urodynamic obstruction without LUTS.
Other have LUTS and urodynamic obstruction without anatomical hyperplasia, such as with bladder neck obstruction or a urethral stricture.
The last group have anatomical hyperplasia and symptoms of LUTS without urodynamic obstruction, and such pts may have a slow stream when voiding, but this is due to detrusor failure.

Anatomical hyperplasia
BPH consists of a mixture of glandular tissue and stromal components developing in a nodular fashion.
Glandular tissue that participates in BPH nodule formation is derived exclusively from branches of the few small ducts that join the urethra at or near its point of angulation at the base of the veru.
Nodules develop either in TZ or in periurethral stroma
Very different histologically: periurethral nodules are purely stromal in character or show only a few small glands. (TZ nodules are a proliferation of glandular (epithelial) tissue with a reduction in the relative amount of stroma ? correct)
In BPH stromal to glandular (epithelial) tissue is 5:1, while normally it is 2:1 in normal prostates
BPH has been described as primarily a stromal process
Causes obstruction in 2 ways
Static obstruction from increased tissue mass
Dynamic obstruction from contraction of the bladder neck, prostatic fibromuscular stroma and capsule
This sympathetic mediated obstruction may be responsible for upto 40% of bladder outflow obstruction




Natural History and Epidemiology

Initial development of BPH starts age 25-30 yrs, with a prevalence of 10% in that age range (data from autopsies involving 1075 prostates, Berry et al, J Urol 1984)
6th decade prevalence is >50%
by age 85, 90% affected
Data from Berry showed normal prostates weigh 20 +/- 6g in men 20-30 yrs, and remains constant throughout life
In pts with LUTS aged 60-80 yrs average weight is 40-50g


Risk factors and androgens

Age
Functioning testes leading to production of testosterone
BPH develops when test levels are on the decline
Role of androgens likely to be facilitative rather than causative

Intracellular androgens:
Testosterone metabolized to DHT, by 5 alpha reductase
Types 1 5a red (skin and liver) and type 2 (intraprostatic)
DHT: testosterone in prostate is 5:1
Both DHT and test bind to androgen receptors, DHT > testosterone, leading to greater subsequent intracellular changes of DNA activation and mRNA production
Males with 5a reductase def have no prostates

Androgen control:

Gene encoding 5a red enzyme type 1 found on Chr 5: expressed in nongenital skin and liver (inhibited by dutasteride)
Gene encoding 5a red enzyme type 2 found on Chr 2: expressed in prostate (stroma and basal epithelial cells) and genital skin (inhibited by finasteride and dutasteride)