Download - Etiology of BPH
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