BPH- pathophysiology

1. PATHOGENESIS OF BPH
Dept of Urology
Govt Royapettah Hospital and Kilpauk Medical College
Chennai
1

2. Moderators:
Professors:
 Prof. Dr. G. Sivasankar, M.S., M.Ch.,
 Prof. Dr. A. Senthilvel, M.S., M.Ch.,
Asst Professors:
 Dr. J. Sivabalan, M.S., M.Ch.,
 Dr. R. Bhargavi, M.S., M.Ch.,
 Dr. S. Raju, M.S., M.Ch.,
 Dr. K. Muthurathinam, M.S., M.Ch.,
 Dr. D.Tamilselvan, M.S., M.Ch.,
 Dr. K. Senthilkumar, M.S., M.Ch.
Dept of Urology, GRH and KMC, Chennai. 2

3.  Histologic BPH - microscopic evidence of prostatic
stromal and epithelial hyperplasia. ( transition zone
and periurethral glands.)
 Macroscopic BPH- enlargement of the prostate
arising from the stromal and epithelial proliferation.
( no consensus establishing the degree of prostate
enlargement required to support the diagnosis of
macroscopic BPH).
 Clinical BPH - clinical manifestations attributed to
the enlarged prostate. (lower urinary tract
symptoms (LUTS), bladder outlet obstruction,
incomplete bladder emptying, acute and chronic
urinary retention, urinary tract infection (UTI),
urosepsis, bladder stones, and hematuria)
3
Dept of Urology, GRH and KMC, Chennai.

4. clinical BPH ,diagnosis of exclusion
prostate cancer prostatitis,
bladder cancer bladder stones
overactive bladder interstitial cystitis,
radiation cystitis UTI, urethritis
primary bladder neck hypertrophy
diabetes,
Parkinson’s disease
lumbosacral disc disease
multiple sclerosis.
4
Dept of Urology, GRH and KMC, Chennai.

5. • Benign prostatic hyperplasia (BPH) is a
pathologic process that contributes to LUTS,
NOT THE SOLE CAUSE OF LUTS
• mass-related increase in urethral
resistance.
• age-related detrusor dysfunction.
• MAY OR MAY NOT produce clinically
significant LUTS / Urodynamically proven 5
Dept of Urology, GRH and KMC, Chennai.

6. Etiology of Benign Prostatic Hyperplasia
• BPH is characterized by an increased
number of epithelial and stromal cells in the
periurethral area of the prostate.
• increase in cell number –
1.epithelial and stromal proliferation
2.impaired programmed cell death
6
Dept of Urology, GRH and KMC, Chennai.

7. • No clear evidence proliferative process.
• early phases of BPH , associated with a rapid
proliferation of cells,
• established disease , maintained in the
presence of an equal or reduced rate of cell
replication.
• Increased expression of antiapoptotic pathway
genes (e.g., bcl-2)
• Androgens-actively inhibit the cell death
7
Dept of Urology, GRH and KMC, Chennai.

8. theories
 Hormonal -Androgens, estrogens,
 Stem cell theory
 Stromal epithelial interaction,growth factor
 Genetic,familial factors
8
Dept of Urology, GRH and KMC, Chennai.

9. • viewed as a stem cell disease .
• Dormant stem cells in the normal prostate
rarely divide, but when they do, they give rise to
a second type of transiently proliferating cell
capable of undergoing DNA synthesis and
proliferation - Maintains the number of cells in
the prostate.
9
Dept of Urology, GRH and KMC, Chennai.

10. The aging process
↓
block maturation
process
↓
↓ progression to
terminally
differentiated cells
↓
↓ rate of cell death.
proliferating cells
↓
mature
↓
process of terminal
differentiation
↓
finite life span –
↓
programmed cell death
10
Dept of Urology, GRH and KMC, Chennai.

11. • Hormones may exert their influence over the
stem cell population advancing age ,during
embryonic and neonatal development .
• The size of the prostate may be defined by the
absolute number of potential stem cells present in
the gland - Dictated at the time of embryonic
development.
• Early imprinting of prostatic tissue by
postnatal androgen surges is critical to
subsequent hormonally induced prostatic 11
Dept of Urology, GRH and KMC, Chennai.

12. The Role of Androgens
• Androgens do not cause BPH, the development
of BPH requires the presence of testicular
androgens during prostate development, puberty,
and aging
• castrated prior to puberty do not develop BPH.
• genetic diseases impair
androgen action or production
prostatic levels of DHT & AR remain high with aging
. (peripheral levels of testosterone are decreasing.)
• Androgen withdrawal - partial involution of
established BPH . 12
Dept of Urology, GRH and KMC, Chennai.

13. 13
Dept of Urology, GRH and KMC, Chennai.

14. The Role ofAndrogens
• In the prostate, 5α-reductase converts the hormone
testosterone into DHT, the principal androgen .
• 90% of total prostatic androgen is in the form of DHT,
principally derived from testicular androgens.
• Adrenal androgens - 10% of total prostatic androgen,
• Both testosterone and DHT bind to the same high-affinity
androgen receptor protein.
• DHT is a more potent , higher affinity for the AR.
14
Dept of Urology, GRH and KMC, Chennai.

15. The Role ofAndrogens
• Despite the importance of androgens in
normal prostatic development and secretory
physiology, no evidence that either
testosterone or DHT serves as the direct
mitogen for growth of the prostate in older
men.
• Neither hormone is mitogenic to cultured
prostatic epithelial cells . 15
Dept of Urology, GRH and KMC, Chennai.

16. Androgen Receptors
• The prostate, maintains its ability to
respond to androgens throughout life.
• AR levels in the prostate remain high
throughout aging .
• Nuclear AR levels may be higher in
hyperplastic tissue than in normal controls .
• Age-related increases in estrogen,
increase AR expression
16
Dept of Urology, GRH and KMC, Chennai.

17. DHT and 5α-Reductase
• Intraprostatic DHT concentrations are
maintained same / elevated in BPH.
• the aging prostate - high level of DHT ,
high level of AR; the mechanism for
androgen-dependent cell growth is
maintained.
17
Dept of Urology, GRH and KMC, Chennai.

18. DHT and 5α-Reductase
• Two steroid 5α-reductase enzymes have
been discovered.
• Type 1 5α-reductase - extraprostatic tissues
,skin and liver
• Type 2 5α-reductase - predominant prostatic
enzyme.
• Type 2 enzyme is critical to normal 18
Dept of Urology, GRH and KMC, Chennai.

19. DHT and 5α-Reductase
• Type 2 5α-reductase - stromal cell
• Epithelial cells uniformly lack type 2 protein.
• Stromal cell plays a central role
• type 2 5α-reductase enzyme within the
stromal cell is the key androgenic
amplification step.
• circulating DHT produced in the skin and
19
Dept of Urology, GRH and KMC, Chennai.

20. DHT and 5α-Reductase
• androgen withdrawal – prostrate involution through vascular
effects.
• Castration - acute and drastic vasoconstriction of blood
vessels
20
Dept of Urology, GRH and KMC, Chennai.

21. The Role of Estrogens
• Serum estrogen levels increased in
aging men
• Intraprostatic levels of estrogen
• Larger volumes of BPH - higher levels of
estradiol
• induction of the AR .
• “sensitize” the aging prostate to the effects
of androgen.
21
Dept of Urology, GRH and KMC, Chennai.

22. The Role of progesterone
• high levels of progesterone receptor - normal and
hyperplastic prostate.
• the role of the progesterone , in BPH remains to be
defined.
22
Dept of Urology, GRH and KMC, Chennai.

23. Regulation of Programmed Cell Death
• Programmed cell death (apoptosis) is a
physiologic mechanism crucial to the
maintenance of normal glandular
homeostasis .
• Androgens - suppress programmed cell death
• Following castration, active cell death is
increased in the luminal epithelial population
as well as in the distal region of each duct. 23
Dept of Urology, GRH and KMC, Chennai.

24. Regulation of Programmed Cell Death
local growth factor or growth factor receptor
abnormalities
↓
increased proliferation or decreased levels of
programmed cell death.
24
Dept of Urology, GRH and KMC, Chennai.

25. Stromal-Epithelial Interaction
• Prostatic stromal and epithelial cells
maintain a sophisticated paracrine type of
communication.
• Stromal cell excretory protein (
extracellular matrix) partially regulates
epithelial cell differentiation.
• BPH , a defect in a stromal component
that normally inhibits cell proliferation,
25
Dept of Urology, GRH and KMC, Chennai.

26. Growth Factors
 Growth factors are small peptide molecules
that stimulate, or inhibit cell division and
differentiation processes .
Variety of growth factors have been
characterized in normal, hyperplastic, and
neoplastic prostatic tissue.
 bFGF (FGF-2),
 acidic FGF (FGF-1),
 Int-2 (FGF-3),
 keratinocyte growth factor (KGF, FGF-7),
 transforming growth factors (TGF-β), and
 epidermal growth factor (EGF)
26
Dept of Urology, GRH and KMC, Chennai.

27. 27
Dept of Urology, GRH and KMC, Chennai.

28. Growth Factors
• interdependence between growth
factors, growth factor receptors, and
the steroid hormone milieu of the
prostate
• DHT augmenting or modulating the
growth factor effects.
• TGF-β, inhibit epithelial cell
proliferation, may normally exert a
restraining influence over epithelial
28
Dept of Urology, GRH and KMC, Chennai.

29. Role of Inflammatory Pathways and Cytokines in BPH
 additional source of growth factors in human BPH
tissue - inflammatory cell infiltrates
Infilteration by activated T – cells
↓
Secrete,produce – VEGF,bFGF,EGF
↓
Stromal & glandular hyperplasia.
29
Dept of Urology, GRH and KMC, Chennai.

30. Genetic and Familial Factors
• BPH - inheritable genetic component.
• Autosomal dominant inheritance pattern.
• Approximately 50% of men undergoing
prostatectomy for BPH at less than 60 years of
age could be attributable to inheritable form of
disease.
• In contrast, only about 9% of men undergoing
prostatectomy for BPH at more than 60 years of
age would be predicted to have a familial risk.
• monozygotic twins demonstrate a higher
concordance rate of BPH than dizygotic twins
30
Dept of Urology, GRH and KMC, Chennai.

31. Genetic and Familial Factors
• Familial BPH - large prostate size,
with hereditary BPH , mean prostate volume of
82.7 mL
with sporadic BPH , 55.5 mL
31
Dept of Urology, GRH and KMC, Chennai.

32. pathogenesis
Anatomic Features -
• McNeal (1978) - BPH first develops in
the periurethral transition zone of the
prostate.
• the transition zone – itself enlarges
with age (unrelated to the development of
nodules ).
32
Dept of Urology, GRH and KMC, Chennai.

33. • presence of the prostatic capsule -
development of LUTS .
• transmits the “pressure” of tissue
expansion to the urethra - increase in
urethral resistance.
• incision of the prostatic capsule -
significant improvement in outflow
obstruction, DESPITE THE VOLUME OF
THE PROSTATE REMAINS THE SAME. 33
Dept of Urology, GRH and KMC, Chennai.

34. Histologic Features.
• BPH - true hyperplastic process.- an
increase in the cell number .
• early periurethral nodules - stromal in
character
• . the earliest transition zone nodules -
proliferation of glandular tissue
34
Dept of Urology, GRH and KMC, Chennai.

35. Histologic Features.
glandular nodules - newly formed small
duct branches that bud off from existing ducts,
a totally new ductal system within the nodule.
• increase in transition zone volume with age
=increased number of nodules + an increase in
the overall size of the zone.
• During the first 20 years of BPH
development-
↑number of nodules, and growth of
each new nodule is generally slow.
35
Dept of Urology, GRH and KMC, Chennai.

36. Importance of Prostatic Smooth Muscle
• prostatic smooth muscle represents a
significant volume of the gland.
• both passive and active forces in
prostatic tissue play a major role in the
pathophysiology of BPH .
36
Dept of Urology, GRH and KMC, Chennai.

37. Passive component Active component
The elastic elements in the stromal
and epithelial cells and the ECM
contributes
prostatic smooth muscle -
regulated by the adrenergic
nervous system
α1A- most abundant
adrenoreceptor subtype
Resonds to androgen ablation- primarily
- epithelial cell population
Responds to α blockade.
37
Dept of Urology, GRH and KMC, Chennai.

38. The Bladder's Response to Obstruction
• the bladder's response to obstruction - an adaptive
one.
• lower tract symptoms - due to obstruction-induced
changes in bladder function, NOT ONLY DUE to
outflow obstruction .
• One third of men continue to have significant voiding
dysfunction after surgical relief of obstruction .
38
Dept of Urology, GRH and KMC, Chennai.

39. 39
Dept of Urology, GRH and KMC, Chennai.

40. The Bladder's Response to Obstruction
Obstruction-induced changes in the bladder - two
basic types.
• detrusor instability or decreased compliance
symptoms of frequency and
urgency
• decreased detrusor contractility
deterioration in the force of the
urinary stream, hesitancy, intermittency, increased 40
Dept of Urology, GRH and KMC, Chennai.

41. The Bladder's Response to Obstruction
• initial response of the detrusor to obstruction -
development of smooth muscle hypertrophy.
• Increase in muscle mass,associated with significant
intra- and extracellular changes in the smooth muscle ,
↓
• detrusor instability and in some cases impaired
contractility.
41
Dept of Urology, GRH and KMC, Chennai.

42. The Bladder's Response to
Obstruction
• changes in smooth muscle cell contractile protein
expression,
• impaired energy production (mitochondrial
dysfunction)
• calcium signaling abnormalities,
• impaired cell-to-cell communication
42
Dept of Urology, GRH and KMC, Chennai.

43. The Bladder's Response to
Obstruction
• smooth muscle cells revert to a
secretory phenotype.
↓
• phenotypic switch - increased ECM
production
significant increase in detrusor ECM
43
Dept of Urology, GRH and KMC, Chennai.

44. • The major endoscopic detrusor change,
trabeculation, is due to an increase in
detrusor collagen . ↓
• significant residual urine , incomplete
emptying may be due to increased
collagen rather than impaired muscle
function.
• Severe trabeculation, however, is seen in 44
Dept of Urology, GRH and KMC, Chennai.

45. The Bladder's Response to Obstruction
• obstruction - modulate normal neural-detrusor
responses ↓
• Altered neural control of micturition
↓
• bladder contractility,
• impaired central processing,
• altered sensation .
45
Dept of Urology, GRH and KMC, Chennai.

46. Independent of obstruction, AGING
↓
Atherosclerosis , chronic bladder ischemia or
hypoxia
↓
changes in bladder function, histology, and
cellular function .
46
Dept of Urology, GRH and KMC, Chennai.

47. Summary
 The exact etiology of BPH is yet to be
elucidated
 Androgens do not cause BPH but the
presence of androgens during developmental
,puberty and aging is required for BPH
 Androgens regulate the effects of growth
hormones
47
Dept of Urology, GRH and KMC, Chennai.

48. Thank you
48
Dept of Urology, GRH and KMC, Chennai.