Benign Prostate Hyperplasia

|Etiology

Benign Prostate Hyperplasia

EtiologyThe precise molecular etiology uncertainnew epithelial gland formation only in

fetal development proliferation or impaired programmed cell

deathAndrogens, estrogens, stromal-epithelial

interactions, growth factors, and neurotransmitters may play a role

Benign Prostate Hyperplasia

Apoptosis

Stromal-epithelial

Estrogen

•Androgens do not cause BPH butrequire factor•Castrated patient don’t develop BPH•Bioavailable testosteron ~ decline with increasing age• Estradiol/testosteron ratio ~ Prostate volume absence of relationship in larger study

Androgen

Benign Prostate Hyperplasia

Growth Factor

Apoptosis

Stromal-epithelial

Estrogen

Androgen

Benign Prostate Hyperplasia

Growth Factor

Apoptosis

Stromal-epithelial

Estrogen

Benign Prostate Hyperplasia

Androgen

Growth Factor

Apoptosis

Stromal-epithelial

Estrogen

Benign Prostate Hyperplasia

Androgen

• Androgen withdrawal Down Regulation androgen-dependent genes

(e.g., PSA)activation genes in programmed cell death• No evidence Androgens (testosterone or DHT) Have direct mitogen effect on prostate

• Growth factors and their receptors are regulated by androgens

• T & DHT mitogenic effects mediated indirectly by autocrine and paracrine pathways.

Growth Factor

Apoptosis

Stromal-epithelial

Estrogen

Benign Prostate Hyperplasia

Androgen

• The prostate, unlike other androgen-dependent organs, maintains its ability to respond to androgens throughout life.

• Estrogen increase AR expresion

• Despite peripheral levels of testosterone are decreasing (estrogen/bioav testosteron >>) prostate sensitive to the androgen (Testosteron/DHT)

Androgen Receptor

Growth Factor

AR mutations

CAG repeats ~ prostate size

Netherlands no relationship

CAG repeats ~ prostate volume

CAG repeats were uncommon

in N men

Apoptosis

Stromal-epithelial

Estrogen

Benign Prostate Hyperplasia

Androgen

Testosterone convert to DHT by 5 alpha reductase

Intraprostatic DHT concentrations are maintained but not elevated in BPH

Initial study bias

Dihydrotestosterone

Growth Factor

Steroid 5α-Reductase

Type 1

Extraprostatic (skin , liver)

Inhibited by dutasteride(Avodart) but not

by finasteride(Proscar).

Type 2

intraprostatic

sensitive to

inhibition by finasterideand dutasteride

5α-Reductase Location

• Type 2 5α-Reductase show primarily in stromal cellStromal

• Type 1 5α-Reductasepositive staining in only 7% of BPH

• 2 of 29 BPH specimens

Epithelial

Apoptosis

Stromal-epithelial

Estrogen

Benign Prostate Hyperplasia

Androgen

Stromal cell plays a central role in

androgen-dependent prostatic growth and that

type 2 5 Alpha -reductase within the

stromal cell is the key androgenic amplification step

Growth Factor

Apoptosis

Stromal-epithelial

Estrogen

Benign Prostate Hyperplasia

Androgen

Growth Factor

Apoptosis

Stromal-epithelial

Androgen

Estrogens

Benign Prostate Hyperplasia

•Animal model estrogens play a role in the pathogenesis of BPH

1. “sensitize” the aging dog prostate to the effects of androgen

2. In-vitro studies, upregulation of ER-alpha upregulation of fibroblast growth factor (FGF)-2, FGF-7

3. Knockout mice constraining influence on the prostate

•In human BPH less clear.

Growth Factor

Apoptosis

Stromal -epithelial

Androgen

Benign Prostate Hyperplasia

Estrogens

Growth Factor

Estrogen

Androgen

Benign Prostate Hyperplasia

oProgrammed cell death (apoptosis) is a physiologic mechanism crucial to the maintenance of normal glandular homeostasis oCellular condensation, fragmentation,

phagocytosis and degradation, lysosomalenzymesoAfter castration, active cell death is

increased ( in the luminal epithelial population as well as in the distal region of each duct)

Stromal-Epithelial

Apoptosis

Growth Factor

Estrogen

Androgen

Benign Prostate Hyperplasia

oAndrogen/growth factor stimulate cell proliferation in experimental model human : no clear evidenceoIncrease expression BCL2 antiapoptotic

geneoCombination androgen-estrogen >gland

size, <DNA synthesis rate inhibit the rate of cell death

Stromal-Epithelial

Apoptosis

Growth Factor

Estrogen

Apoptosis

Androgen

Growth Factor

Stromal-Ephitelial

Benign Prostate Hyperplasia

oOne class of stromal cell excretory protein (i.e., extracellular matrix) partially regulates epithelial cell differentiation.

odefect in a stromal component loss of a normal “braking” mechanism for proliferation

Estrogen

Apoptosis

Androgen

Stromal-epithelial

Benign Prostate Hyperplasia

Growth Factors

Estrogen

Apoptosis

Androgen

Stromal-epithelial

Proliferation

• FGF families (FGF-1, FGF-2, FGF-7, FGF-10 and FGF-17)

• 2. VEGF

• 3. IGF

Inhibition

•TGF-β• lost or downregulatedin BPH•~ Prostate Ca•Autocrine : stromal proliferation mediated by FGF-2

Augmenting

• DHT

Inflammatory Pathways and Cytokines

Growth Factors

Autocrine & Paracrine (2nd evidence)

FGF-2• 2-3x elevetion on BPH

• Produced by Stromal Stromal

FGF-7

• Produced by Stromal R exclusively in ephitelial

• Ephitelial IL-1α Stromal

Estrogen

Apoptosis

Androgen

Benign Prostate Hyperplasia

Other Signaling Pathways

Stromal-epithelial

Sympathetic signaling pathways hyperplastic growth process & alpha-

Adrenergic blockade induce Either with or without sympathetic

modulation local RAS pathways proliferation and smooth muscle contraction.

Inflamatory-Cytokine

An additional source of growth inflammation (activated T cells)express VEGF: HB-EGF and bFGF/FGF-2 potent epithelial and stromal mitogens• IL-2, IL-4, IL-7, IL-17, interferon-gamma• IL-2, IL-7, and IFN-

gammaproliferation stromal cells in vitro

Estrogen

Apoptosis

Androgen

Benign Prostate Hyperplasia

Other Signaling Pathways

Stromal-epithelial

Sympathetic signaling pathways hyperplastic growth process & alpha-

Adrenergic blockade induce Either with or without sympathetic

modulation local RAS pathways proliferation and smooth muscle contraction.

Inflamatory-Cytokine

• epithelial cell senescence IL-8promote proliferation of nonsenescent epithelial and stromal cells

• Macrophage inhibitory cytokine-1downregulated in BPH

• COX-2 upregulated

Estrogen

Apoptosis

Androgen

Benign Prostate Hyperplasia

Other Signaling Pathways

Stromal-epithelial

Sympathetic signaling pathways hyperplastic growth process & alpha-

Adrenergic blockade induce Either with or without sympathetic

modulation local RAS pathways proliferation and smooth muscle contraction.

Inflamatory-Cytokine

Estrogen

Apoptosis

Androgen

Inflamatory-Cytokine

Benign Prostate Hyperplasia

Other Signaling Pathways

Stromal-epithelial

Sympathetic signaling pathways hyperplastic growth process & alpha-

Adrenergic blockade induce Either with or without sympathetic

modulation local RAS pathways proliferation and smooth muscle contraction.

Other Signaling Pathways

o Sympathetic signaling pathways hyperplastic growth process & alpha-Adrenergic blockade induce apoptosis

o Either with or without sympathetic modulation local RAS pathways proliferation and smooth muscle contraction.

Estrogen

Apoptosis

Androgen

Inflamatory-Cytokine

Benign Prostate Hyperplasia

Other Signaling Pathways

Stromal-epithelial

Sympathetic signaling pathways hyperplastic growth process & alpha-

Adrenergic blockade induce Either with or without sympathetic

modulation local RAS pathways proliferation and smooth muscle contraction.

Genetic and Familial Factors

oFamilial Hystory + 50% of men

undergoing prostatectomy, < 60 yo

oFamilial Hystory - 9%, > 60 yo

oMonozygotic > Dixygotic

oCohort Study, 2000 participans

Familial risk + elevated moderate to

severe urologic symptoms

Mean PV 82,7 mL Vs 55,5 mL

Benign Prostate Hyperplasia

Other Signaling Pathways

Sympathetic signaling pathways hyperplastic growth process & alpha-

Adrenergic blockade induce Either with or without sympathetic

modulation local RAS pathways proliferation and smooth muscle contraction.

Estrogen

Apoptosis

Androgen

Inflamatory-Cytokine

Benign Prostate Hyperplasia

Other Signaling Pathways

Stromal-epithelial

Sympathetic signaling pathways hyperplastic growth process & alpha-

Adrenergic blockade induce Either with or without sympathetic

modulation local RAS pathways proliferation and smooth muscle contraction.

Other Etiologic Factors

•Human Spermatocelefluid

• Prolactin Transgenic mice overexpressing