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MODUL TUTOR

SKENARIO-2

Tim Kurikulum Pendidikan Preklinik


Program Pendidikan Dokter
Universitas Islam Malang
2010
JADWAL TUTORIAL SKENARIO 2
SENIN SELASA RABU KAMIS JUM`AT SABTU
WAKTU
15/11/09 16/11/09 17/11/09 18/11/09 19/11/09 20/11/09
07.30 – 09.10 SDL Libur Tutorial 1 Tutorial 3 SDL
skenario 2 skenario 2
09.20 – 11.00 SDL Libur SDL SDL Kuliah
Hemodialysa
Pakar
11.00 – 12.00
12.00 – 13.40 SDL Libur Tutorial 2 Kuliah PK SDL
skenario 2 Pemeriksaan
khusus PMS
RHM
13.50 – 15.30 SDL SDL SDL SDL SDL

Kok macet…
Skenario 2. Tn. P 60 tahun datang ke rumah sakit dengan keluhan tidak bisa buang air kecil.
Buang air kecil dirasakan agak sulit sehingga harus diawali dengan mengejan sejak 6 bulan yang
lalu. Mengejan awalnya hanya ringan, namun semakin lama semakin kuat hingga tidak bisa
keluar sama sekali.
Data tambahan : identitas
Nama : Tn. P
Usia : 60 tahun
Jenis Kelamin : laki-laki
Status : Menikah
Agama : Islam
Alamat : Lowok waru Malang
Keluhan utama : tidak bisa buang air kecil
Riwayat penyakit sekarang :
Keluhan prostatism, gejala hesistansi maupun iritatif mulai dari air kencing netes terus, tidak bisa
kencing, keluhan sebelumnya, sejak 6 bulan yang lalu bila akan kencing harus menunggu pada
saat permulaan miksi, pancaran lemah, terputus, menetes (dribbling) dan merasa tidak tuntas.
Urgensi (+), frekuensi (+) BAK > 8 x, Nocturia (+) BAK > 2x
Riwayat penyakit sebelumnya :
belum pernah menderita seperti ini, mempunyai riwayat penyakit hipertensi dan DM terkontrol.
Riwayat penyakit keluarga :
tidak ada anggota keluarga yang mengalami sakit seperti pasien
Riwayat pengobatan :
captopril 1 x 25 mg dan glibenclamide 1 x 5 mg dari Puskesmas
Riwayat kebiasaan :
perokok dan peminum kopi
Pemeriksaan fisik
Keadaan umum : kesakitan, Kesadaran : CM GCS 4 5 6, TD : 140/90 mmHg, N: 100
X/menit, t: 37°C, RR: 20x/menit, TB: 165 cm, BB: 76 Kg,.
Kepala : Normo cephalic, simetris, nyeri kepala, benjolan tidak ada.
Leher : JVP normal, kaku kuduk tidak ada, pembesaran kelenjar -
Thoraks :
1. Paru : Gerakan simitris, retraksi supra sternal (-), retraksi intercoste (-), perkusi resonan,
rhonchi -/- pada basal paru, wheezing -/-.
2. Jantung : Batas jantung kiri ics 2 sternal kiri dan ics 4 sternal kiri, batas kanan ics 2
sternal kanan dan ics 5 mid axilla kanan.perkusi dullness. Bunyi s1 dan s2 tunggal, gallop
(-), mumur (-). capillary refill 2 – 3 detik .
Abdomen : Bising usus +, tidak ada benjolan, nyeri tekan pada suprapubic, perabaan massa tidak
ada, hepar tidak teraba, asites ( - ),distensi suprapubic.
Ekstrimitas : tidak ada kelainan
Status lokalis urologi :
Suprapubic : nyeri tekan + mobil
Mass cystic + setinggi pusat
Genital : OUE normal
Penis normal
Scrotum normal
Colok dubur/DRE :
Inspeksi : Haemorrhoid –
Palpasi : Tonus ani +
Mukosa intak
Prostat teraba membesar, ukuran : pole atas teraba, konsistensi kenyal,
permukaan rata, lobus kanan dan kiri simetris, tidak didapatkan nodul,
fisura mediana menghilang, sensitivitas tidak nyeri, mobile, BCR + (bulbo
cavernot reflek)
Flank Nyeri -/-, nyeri ketok Costo Vertebral Angel -/-, mass -
WDx : Retensio urine susp BPH
DDx :
1. Urolithiasis,
2. Neurogenic bladder,
3. Ca prostat,

Pemeriksaan Penunjang
Laboratorium :
Hb : 14,9, Leukosit : 5200/cmm, Trombosit : 204.000/cmm, SGOT : 38, SGPT : 24, GD :
102/189, ureum : 31, creatinin : 1.43, BT/CT : 2.10/11.30, Albumin : 4.3, PSA : 0.73, Taus P :
Volume prostat 40,25
Foto BOF : kesimpulan normal
Dx: BPH
1`st jump : Key words
2`nd jump : Problem list
1. Mengapa Tn. P tidak bisa buang air kecil ?
2. Apa saja penyebab kelainan diatas ?
3`rd jump : Brainstorming
Mahasiswa melakukan curah pendapat untuk menganalisa problem list yang sudah ditentukan.
Setiap mahasiswa harus melakukan curah pendapat.
4`th jump : Mapping Conssept
5`th jump : Learning Obyectives
1. Mengetahui anatomi, histologi, dan fisiologi saluran kemih bagian bawah
2. Mengetahui macam-macam keganasan pada saluran kemih bagian bawah (Jinak/Ganas)
3. Menjelaskan faktor predisposisi terjadinya BPH
4. Menjelaskan cara penegakan diagnosa BPH
5. Menjelaskan algoritma pengelolaan keganasan saluran kemih dan mekanisme referal
6. Menjelaskan penatalaksanaan dan KIE penderita BPH
7. Menjelaskan komplikasi BPH
6`th jump : Self Directed Learning.
Mahasiswa belajar sendiri dengan cara: kuliah, konsultasi pakar, jurnal dari internet,
pustaka, praktikum, skill lab, penugasan, diskusi bebas
7`th jump : Reporting.
Mahasiswa mengkaji ulang langkah 4 dan 5 dan mencoba menjelaskan LO sesuai dengan
hasil langkah 6 yang telah didapat. Pada langkah ke 7 ini, mahasiswa harus menunjukkan
referensi, tetapi tidak boleh dibaca saat diskusi terakhir. Pada langkah ke 7, setelah
diskusi selesai, tutor memberikan feedback tentang LO dan mengoreksi hasil diskusi
menjadi benar, sehingga saat diskusi berakhir semua mahasiswa mempunyai pemahaman
yang benar dan sama untuk semua skenario.

Pemeriksaan Awal
Maping konsep. •Algoritma pengelolaan keganasan saluran kemih dan mekanisme referal
Anamnesis
• Pemeriksaan fisik, colok dubur
• Urinalisis
• Test Faal Ginjal
• PSA
• Catatan Harian miksi
IPSS dan QoL
Jika pada pemeriksaan awal
didapatkan:
• DRE curiga ganas
• PSA Abnormal
• Hematuri
Ringan (IPSS < 7) Sedang sampai Berat
• Nyeri
• Gejala tdk IPSS 8-9 dan 20-35
• Kelainan neurologis
mengganggu
• Teraba buli2
• Tidak ingin terapi
• Faal ginjal Abnormal
Pemeriksaan Tambahan:
• Riwayat pernah
• Uroflometri tindakan operasi urologi
• PVR • Menderita
• USG urolithiasis, keganasan
UG
Diskusi dengan pasien
tentang pemilihan terapi
Rujuk
Memilih terapi Memilih terapi
non invasif invasif

Watchfull waiting

Gagal Medikamentosa Gagal


Mapping Konsep. Pathofisiologi BPH

BENIGNA PROSTAT HYPERPLASIA

Etiology : 2 komponen mempengaruhi Gejala


1. Teori Hormonal LUTS/Prostatism
komponen mekanik: pembesaran kelenjar
2. Teori Growth Factor (Faktor periuretra mendesak uretra pars prostatika
Pertumbuhan) -gangguan aliran urine (obstruksi infra vesikal)
komponen dinamik: tonus otot polos prostat dan
3. Teori peningkatan lama hidup sel-sel kapsulnya, merupakan alpha adrenergik reseptor-
prostat Stimulasimenghasilkan kontraksi otot polos
prostat ataupun kenaikan tonus.

Pathofisiology:
Compensasi phase:
penyempitan lumen uretra pars prostatika- hambatan aliran
urine -peningkatan tekanan intravesikal- buli-buli harus
berkontraksi lebih kuat- hipertrofi otot detrusor, trabekulasi,
terbentuknya selula, sakula, dan divertikel buli-buli
Decompensasi phase:
Retensio urine
Refluks vesiko-ureter
Hydroureter
Hydronephrosis
Gagal ginjal

MANIFESTASI KLINIK:
1. OBSTRUKTIF :
a. Harus menunggu pada permulaan miksi (Hesistancy)
b. Pancaran miksi yang lemah (weak stream)
c. Miksi terputus (Intermittency)
d. Menetes pada akhir miksi (Terminal dribbling)
e. Rasa belum puas sehabis miksi (Sensation of incomplete bladder emptying).
2. IRITATIF :
a. Bertambahnya frekuensi miksi (Frequency)
b. Nokturia
c. Miksi sulit ditahan (Urgency)

PENATALAKSANAAN :
1. WATCHFULL WAITING: follow up/ evaluasi rutin IPSS, Flowmetri, PSA 3-6 bln
2. MEDIKAMENTOSA:
a. mengurangi resistensi leher buli-buli dengan obat-obatan golongan α blocker (penghambat
alfa adrenergik)
b. menurunkan volume prostat dengan cara menurunkan kadar hormone
testosteron/dehidrotestosteron (DHT)
Obat Penghambat adrenergik α , Obat Penghambat Enzim 5 Alpha Reduktase, Fitoterapi
3. PEMBEDAHAN: TUR-P, Open prostatektomi, dll
Maping konsep. Penatalaksanaan BPH

IPPS Sedang hingga Berat RUJUKAN Karena adanya abnormalitas

PEMERIKSAAN TAMBAHAN: PEMERIKSAAN TAMBAHAN:


• Urodinamika Pencitraan (IVP, USG, Uretrografi
• Uretrosistoscopi retrograde)
Uretrosistoscopy
Sitology urine

Non BPH dengan Komplikasi


Obstruksi Bukan BPH
Obstruksi Retensi urine berulang
Karsinoma prostat
Hematuria
Karcinoma buli buli
Batu buli-buli
Striktura uretra
Bukan BPO ISK berulang
BPO Buli buli neurogenik
Insufisiensi ginjal

Terapi sesuai Terapi intervensi Terapi sesuai Diagnosis


diagnosis

Terapi Invasif minimal Pembedahan


Gambar : Histologi adeno Ca prostat Gambar : Histologi BPH
Tinjauan Pustaka

BPH
ETIOLOGY AND PATHOPHYSIOLOGY
Benign prostatic hyperplasia (BPH) is a pathologic process that contributes to, but is not the sole cause of, lower urinary
tract symptoms (LUTS) in aging men. Despite intense research efforts in the past five decades to elucidate the
underlying etiology of prostatic growth in older men, cause-and-effect relationships have not been established. For
example, androgens are a necessary but not a clearly causative aspect of BPH. Previously held notions that the
clinical symptoms of BPH (prostatism) are due simply to a mass-related increase in urethral resistance are too
simplistic. It is now clear that a significant portion of LUTS is due to age-related detrusor dysfunction. Bladder
outlet obstruction itself may induce a variety of neural alterations in the bladder, which contribute to symptomatology.
Moreover, bothersome LUTS may be seen in men with polyuria, sleep disorders, and a variety of systemic medical
conditions unrelated to the prostate-bladder unit. Undoubtedly, the constellation of cellular pathologies that give rise to
the symptoms of LUTS is far more complex than we currently realize. Only by unraveling these complexities, however,
will we be able to design alternative strategies to treat successfully and possibly prevent the adverse impact of BPH on
lower urinary tract function.
The nomenclature of voiding dysfunction in aging men is confusing and often inaccurate ( Thomas and Abrams, 2000 ).
The term BPH should be used with reference to the histologic process of hyperplasia, which can be demonstrated
microscopically. Men with benign prostatic enlargement (BPE) presumably have an increase in total prostate volume
because of BPH. BPE may or may not produce clinically significant LUTS and may or may not produce
urodynamically proven bladder outlet obstruction. In the ensuing discussion of BPH etiology, we refer to the pathologic
process of benign prostatic growth and enlargement.

Etiology of Benign Prostatic Hyperplasia


BPH is but one cause of the LUTS in aging men commonly, and probably incorrectly, referred to as prostatism.
Histopathologically, BPH is characterized by an increased number of epithelial and stromal cells in the periurethral area
of the prostate. The observation of new epithelial gland formation is normally seen only in fetal development and gives
rise to the concept of embryonic reawakening of the stroma cell's inductive potential ( Cunha, 1983 ). The precise
molecular etiology of this hyperplastic process is uncertain. The observed increase in cell number may be due to
epithelial and stromal proliferation or to impaired programmed cell death leading to cellular accumulation.
Androgens, estrogens, stromal-epithelial interactions, growth factors, and neurotransmitters may play a role, either
singly or in combination, in the etiology of the hyperplastic process.

Hyperplasia
In a given organ, the number of cells, and thus the volume of the organ, is dependent upon the equilibrium between cell
proliferation and cell death ( Isaacs and Coffey, 1987 ). An organ can enlarge not only by an increase in cell
proliferation but also by a decrease in cell death. Although androgens and growth factors stimulate cell
proliferation in experimental models, the relative role of cell proliferation in human BPH is questioned because
there is no clear evidence of an active proliferative process. Although it is possible that the early phases of BPH are
associated with a rapid proliferation of cells, the established disease appears to be maintained in the presence of an
equal or reduced rate of cell replication. Increased expression of antiapoptotic pathway genes (e.g., bcl-2) supports this
hypothesis ( Kyprianou et al, 1996 ; Colombel et al, 1998 ). Androgens not only are required for normal cell
proliferation and differentiation in the prostate but also actively inhibit cell death ( Isaacs, 1984 ). In the dog,
experimental BPH can be produced by androgens combined with estradiol ( Walsh and Wilson, 1976 ; DeKlerk et al,
1979 ; Berry et al, 1986a ; Juniewicz et al, 1994 ). Despite a significant increase in gland size, there is actually a
reduction in the rate of DNA synthesis compared with untreated controls ( Barrack and Berry, 1987 ), indicating that
androgens and estrogens both inhibit the rate of cell death. Neural signaling pathways, especially α-adrenergic
pathways, may also play a role in balancing cell death and cell proliferation ( Anglin et al, 2002 ; Partin et al, 2003 ).
The hyperplasia results in a remodeling of the normal prostatic architecture ( Untergasser et al, 2005 ). Epithelial
budding from preexisting ducts and the appearance of mesenchymal nodules characterize the early stages of the
process, but the tissue phenotype of patients with established disease is highly variable.
BPH may be viewed as a stem cell disease ( Barrack and Berry, 1987 ). Presumably, 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, thus maintaining the number of cells in the prostate. When the
proliferating cells mature through a process of terminal differentiation, they have a finite life span before undergoing
programmed cell death. In this paradigm, the aging process induces a block in this maturation process so that the
progression to terminally differentiated cells is reduced, reducing the overall rate of cell death. Indirect evidence
for this hypothesis comes from the observation that secretion, one parameter of epithelial cell differentiation, decreases
with age, suggesting that the number of differentiated cells capable of secretory activity may be decreasing ( Isaacs and
Coffey, 1987 ). A survey of human BPH specimens for a marker of cellular senescence (senescence-associated β-
galactosidase [SA-beta-gal]) demonstrated a higher portion of senescent epithelial cells in men with large prostates,
suggesting that an accumulation of those cells may play a role in the development of prostate enlargement ( Choi et al,
2000 ). More recent studies support the hypothesis that impaired cell senescence may play a significant role in the
etiology of BPH ( Castro et al, 2003 ).
Hormones may exert their influence over the stem cell population not only with advancing age but also during
embryonic and neonatal development ( Naslund and Coffey, 1986 ). The size of the prostate may be defined by the
absolute number of potential stem cells present in the gland, which in turn may be dictated at the time of embryonic
development. Studies in animal models have suggested that early imprinting of prostatic tissue by postnatal
androgen surges is critical to subsequent hormonally induced prostatic growth ( Naslund and Coffey, 1986 ;
Juniewicz et al, 1994 ). As with the hormonal regulation of adult prostatic tissues, sex steroid hormones may exert their
imprinting effect directly or indirectly through a complex series of signaling pathways ( Lee and Peehl, 2004 ).

The Role of Androgens


Although androgens do not cause BPH, the development of BPH requires the presence of testicular androgens
during prostate development, puberty, and aging ( McConnell, 1995 ; Marcelli and Cunningham, 1999 ). Patients
castrated prior to puberty or who are affected by a variety of genetic diseases that impair androgen action or production
do not develop BPH. It is also known that prostatic levels of dihydrotestosterone (DHT) as well as the androgen
receptor (AR) remain high with aging despite the fact that peripheral levels of testosterone are decreasing. Moreover,
androgen withdrawal leads to partial involution of established BPH ( Peters and Walsh, 1987 ; McConnell et al, 1994 ).
Assuming normal ranges, there is no clear relationship between the concentration of circulating androgens and prostate
size in aging men. In the Olmsted County cohort (median age 60.9) serum bioavailable testosterone levels were found
to decline with increasing age, while the estradiol/bioavailable testosterone ratio increased ( Roberts et al, 2004 ).
Bioavailable testosterone correlated negatively and estradiol/bioavailable testosterone ratio positively with prostate
volume, but this associated was much less apparent after age adjustment. A much smaller study from Turkey also failed
to show a clear relationship between serum androgen levels and prostate size ( Tan et al, 2003 ).
In the brain, skeletal muscle, and seminiferous epithelium, testosterone directly stimulates androgen-dependent
processes. In the prostate, however, the nuclear membrane bound enzyme steroid 5α-reductase converts the
hormone testosterone into DHT, the principal androgen in this tissue ( Fig. 86-1 ) ( McConnell, 1995 ). Ninety
percent of total prostatic androgen is in the form of DHT, principally derived from testicular androgens. Adrenal
androgens may constitute 10% of total prostatic androgen, although the importance of this stored hormone source in the
etiology of BPH is negligible. Inside the cell, both testosterone and DHT bind to the same high-affinity androgen
receptor protein ( Chatterjee, 2003 ). DHT is a more potent androgen than testosterone because of its higher affinity for
the AR. Moreover, the DHT-receptor complex may be more stable than the testosterone-receptor complex. The
hormone receptor then binds to specific DNA binding sites in the nucleus, which results in increased transcription of
androgen-dependent genes and ultimately stimulation of protein synthesis. Conversely, androgen withdrawal from
androgen-sensitive tissue results in a decrease in protein synthesis and tissue involution. Besides inactivation of key
androgen-dependent genes (e.g., prostate-specific antigen), androgen withdrawal leads to the activation of
specific genes involved in programmed cell death ( Kyprianou and Issacs, 1989 ; Martikainen et al, 1990 ). Despite
the importance of androgens in normal prostatic development and secretory physiology, there is no evidence that either
testosterone or DHT serves as the direct mitogen for growth of the prostate in older men. Indeed, neither hormone is
mitogenic to cultured prostatic epithelial cells ( McKeehan et al, 1984 ). In the rat ventral prostate, differential gene
expression experiments failed to demonstrate direct activation of mitogenic pathways ( Wang et al, 1997 ). However,
many growth factors and their receptors are regulated by androgens (see later). Thus, the action of testosterone and
DHT in the prostate is mediated indirectly through autocrine and paracrine pathways.

Figure 86-1 Testosterone (T) diffuses into the prostate epithelial and stromal cell. T can interact directly with the
androgen (steroid) receptors bound to the promoter region of androgen-regulated genes. In the stromal cell a
majority of T is converted into dihydrotestosterone (DHT)—a much more potent androgen—which can act in an
autocrine fashion in the stromal cell or in a paracrine fashion by diffusing into epithelial cells in close proximity.
DHT produced peripherally, primarily in the skin and liver, can diffuse into the prostate from the circulation and act
in a true endocrine fashion. In some cases, the basal cell in the prostate may serve as a DHT production site, similar
to the stromal cell. Autocrine and paracrine growth factors may also be involved in androgen-dependent processes
within the prostate.

Androgen Receptors.
The prostate, unlike other androgen-dependent organs, maintains its ability to respond to androgens throughout
life. In the penis, AR expression decreases to negligible rates at the completion of puberty ( Roehrborn et al, 1987 ;
Takane et al, 1991 ). Thus, despite high circulating levels of androgen, the adult penis loses its ability for androgen-
dependent growth. If the penis maintained high levels of AR throughout life, presumably the organ would grow until
the time of death. In contrast, AR levels in the prostate remain high throughout aging ( Barrack et al, 1983 ; Rennie et
al, 1988 ). In fact, there is evidence to suggest that nuclear AR levels may be higher in hyperplastic tissue than in
normal controls ( Barrack et al, 1983 ). Age-related increases in estrogen, as well as other factors, may increase AR
expression in the aging prostate, leading to further growth (or to a decrease in cell death), despite decreasing levels of
androgen in the peripheral circulation and “normal” levels of DHT in the prostate.
The potential role of AR mutations, polymorphisms, or other alterations in the pathogenesis of BPH is unclear
( Chatterjee, 2003 ). A polymorphism in the number of CAG repeats (short versus control) in the AR gene has been
associated with larger prostate size ( Giovannucci et al, 1999a ) and an increased risk of surgery ( Giovannucci et al,
1999b ). However, another study from the Netherlands showed no relationship between the number of CAG repeats and
BPH ( Bousema et al, 2000 ). The later study also found no relationship between BPH and vitamin D receptor
polymorphisms, although one Japanese study suggested an association ( Habuchi et al, 2000b ). A more recent study of
U.S. men showed a positive correlation between short CAG repeats and prostate volume ( Roberts et al, 2004a ), but a
study of Finnish men found that short CAG repeats were significantly less common in men with BPH compared with
control subjects ( Mononen et al, 2002 ). Given the significant variation in reported findings, if short CAG repeats play
a role in BPH pathogenesis, it is likely to be minor.

Dihydrotestosterone and Steroid 5α-Reductase.


Intraprostatic DHT concentrations are maintained but not elevated in BPH. Initial studies of resected prostatic
tissue suggested that prostatic DHT levels were higher in the hyperplastic gland than in normal control tissues.
However, the controls used for these early studies were largely accident victims. Ongoing metabolism of DHT after
death lowers the level of this androgen in cadaveric tissues. This was clearly shown in a study by Walsh and colleagues
(1983) in which prostatic surgical specimens from men without BPH were used as the control. These investigators
demonstrated that DHT levels are the same in hyperplastic glands as in normal glands. However, the aging prostate
maintains a high level of DHT as well as a high level of AR; thus, the mechanism for androgen-dependent cell growth
is maintained. There is little question that androgens have at least a permissive role in the development of the disease
process.
Two steroid 5α-reductase enzymes have been discovered, each encoded by a separate gene( Russell and Wilson,
1994 ). Type 1 5α-reductase, the predominant enzyme in extraprostatic tissues, such as skin and liver, is normally
expressed in the 5α-reductase deficiency syndrome and is inhibited by dutasteride but not substantially by finasteride.
Type 2 5α-reductase is the predominant prostatic 5α-reductase, although it is also expressed in extraprostatic tissues.
Mutations in the type 2 enzyme are responsible for the clinical phenotype observed in the 5α-reductase deficiency
syndrome. It is exquisitely sensitive to inhibition by finasteride and dutasteride ( Carson and Rittmaster, 2003 ). Clearly,
the type 2 enzyme is critical to normal development of the prostate and hyperplastic growth later in life. The role
of type 1 5α-reductase in normal and abnormal prostate growth remains to be defined. Given that finasteride produces
prostate size reduction identical to that with dual type1/type 2 inhibitors and roughly equivalent to that with castration,
it is unlikely that type 1–derived DHT is critical to hyperplastic growth.
Immunohistochemical studies with type 2 5α-reductase specific antibodies show primarily stromal cell
localization of the enzyme ( Silver et al, 1994b ). Epithelial cells uniformly lack type 2 protein, and some basal
epithelial cells stain positively. Type 1 5α-reductase protein could not be detected in BPH or prostate cancer using
initially available antibodies ( Silver et al, 1994a ), although trace levels of type 1 messenger RNA (mRNA) have been
seen in normal prostates, BPH, and cancer ( Shirakawa et al, 2004 ). A study with a selective type 1 antibody
demonstrated positive staining in only 7% of BPH cases ( Thomas et al, 2003 ). In the same study, type 1 enzymatic
activity was found in only 2 of 29 BPH specimens.
These data demonstrate that the stromal cell plays a central role in androgen-dependent prostatic growth and that
the type 2 5α-reductase enzyme within the stromal cell is the key androgenic amplification step. Thus, a paracrine
model for androgen action in the gland (see Fig. 86-1 ) is evident. In addition, it is possible that circulating DHT
produced in the skin and liver may act on prostate epithelial cells in a true endocrine fashion ( McConnell, 1995 ).
If dual type 1/type 2 5α-reductase inhibition has clinical utility over selective type 2 inhibitors, it is likely to be due to
inhibition of peripherally produced DHT.
Polymorphisms in the type 2 5α-reductase enzyme (SRD5A2) have been reported, but their linkage to BPH is uncertain.
The SRD5A2 gene on chromosome 2p23 frequently encompasses A49T and V89L substitutions and a TA dinucleotide
repeat polymorphism. The 89L allele has been associated with lower enzyme activity, whereas the 49T allele has been
associated with higher activity. Longer TA repeats are associated with mRNA instability and thus decreased enzyme
activity. The number of L alleles, but not testosterone alleles or TA repeats, in one study correlated significantly with
the presence of BPH ( Salam et al, 2005 ). In the Olmsted County population, consistent associations between SRD5A2
genotypes and BPH were not demonstrated, although there was a weak correlation between V89L polymorphisms and
prostate volume ( Roberts et al, 2005 ).
Androgen withdrawal may partially exert its effect on the prostate through vascular effects ( Buttyan et al, 2000 ;
Ghafar et al, 2002b ). Castration induces acute and drastic vasoconstriction of blood vessels in the rat prostate ( Hayek
et al, 1999 ; Shabisgh et al, 1999 ). This effect does not appear to be mediated through vascular endothelial growth
factor ( Burchardt et al, 2000 ). There is indirect evidence to suggest that abnormalities in the prostatic vascular system
produced by other disease states (e.g., diabetes) may be a risk factor of BPH ( Berger et al, 2005 ).
The Role of Estrogens
There is animal model evidence to suggest that estrogens play a role in the pathogenesis of BPH; the role of
estrogens in the development of human BPH, however, is less clear. In the dog, where estrogens act synergistically
with androgens to produce experimental BPH, estrogen appears to be involved in induction of the AR ( Moore et al,
1979 ). Estrogen may, in fact, “sensitize” the aging dog prostate to the effects of androgen ( Barrack and Berry, 1987 ).
The canine prostate contains an abundance of high-affinity estrogen receptor. In the dog, estrogen treatment stimulates
the stroma, causing an increase in the total amount of collagen (Berry et al, 1986a, 1986b 16] [17]). There are at least
two forms of the estrogen receptor. Estrogen receptor α is expressed by prostate stromal cells, and estrogen receptor β is
expressed by prostate epithelial cells ( Prins et al, 1998 ). The estrogenic response of the prostate is determined by the
type of estrogen receptor present within the prostatic cells. Experiments in knock-out mice suggest a “constraining
influence” of estrogens on the prostate ( Krege et al, 1998 ). In vitro studies suggest that upregulation of estrogen
receptor α in cultured prostate stromal cells is also associate with upregulation of fibroblast growth factor 2 (FGF-2),
FGF-7, and other growth factors; the addition of androgens downregulated the estrogen receptor and various stroma-
derived growth factors (Smith et al, 2000, 2002, 2004 [159] [160] [161]).
Serum estrogen levels increase in men with age, absolutely or relative to testosterone levels. There is also suggestive
evidence that intraprostatic levels of estrogen are increased in men with BPH. Patients with larger volumes of BPH tend
to have higher levels of estradiol in the peripheral circulation ( Partin et al, 1991 ). In the Olmsted County cohort, in
men with above median levels of bioavailable testosterone, the serum estradiol level correlated positively with prostate
volume, even after adjusting for age ( Roberts et al, 2004b ). Data on obesity, serum testosterone, estradiol, and prostate
volume are conflicting ( Zucchetto et al, 2005 ) Although there are relatively low concentrations of classical high-
affinity estrogen receptors in human BPH ( Farnsworth, 1999 ; Sciarra and Toscano, 2000 ), there may be a sufficient
amount for biologic activity.
From experimental studies with aromatase inhibitors it appears that decreases in intraprostatic estrogen in animal
models may lead to reduction in drug-induced stromal hyperplasia ( Farnsworth, 1999 ). At present, however, the role
of estrogens in human BPH is not as firmly established as the role of androgens. Species variation and cause-effect
relationships are problematic.
There are high levels of progesterone receptor in the normal and hyperplastic prostate. However, the role of the
progesterone receptor in normal prostatic physiology as well as in BPH remains to be defined.

Regulation of Programmed Cell Death


Programmed cell death (apoptosis) is a physiologic mechanism crucial to the maintenance of normal glandular
homeostasis ( Kerr and Searle, 1973 ). Cellular condensation and fragmentation precede phagocytosis and degradation,
during which the apoptotic cell is phagocytosed by neighboring cells and degraded by lysosomal enzymes. Apoptosis
occurs without activation of the immune system but requires both RNA and protein synthesis (Lee, 1981). In the rat
prostate, active cell death occurs naturally in the proximal segment of the prostatic ductal system in the presence of
normal concentrations of plasma testosterone ( Lee et al, 1990 ). Androgens (presumably testosterone and DHT) appear
to suppress programmed cell death elsewhere in the gland. Following castration, active cell death is increased in the
luminal epithelial population as well as in the distal region of each duct. Tenniswood (1992) suggested that there is
regional control over androgen action and epithelial response, with androgens providing a modulating influence over
the local production of growth regulatory factors that varies in different parts of the gland. Members of the transforming
growth factor β (TGF-β) family are likely candidates for this regulatory step ( Martikainen et al, 1990 ).
In the rat prostate, at least 25 different genes are induced following castration ( Montpetit et al, 1986 ). Normal
glandular homeostasis requires a balance between growth inhibitors and mitogens, which respectively restrain or induce
cell proliferation but also prevent or modulate cell death. Abnormal hyperplastic growth patterns, such as BPH, might
be induced by local growth factor or growth factor receptor abnormalities, leading to increased proliferation or
decreased levels of programmed cell death.

Stromal-Epithelial Interaction
There is abundant experimental evidence to demonstrate that prostatic stromal and epithelial cells maintain a
sophisticated paracrine type of communication. The growth of canine prostate epithelium can be regulated by
cellular interaction with the basement membrane and stromal cells. Isaacs, using a marker of canine prostatic epithelial
cell function, demonstrated that epithelial cells grown on plastic quickly lose their ability to secrete this protein ( Isaacs
and Coffey, 1987 ). In addition, the cells begin to grow rapidly and change their cytoskeletal staining pattern. In
contrast, if the cells are grown on prostatic collagen, they maintain their normal secretory capacity and cytoskeletal
staining pattern and do not grow rapidly. This is strong evidence that one class of stromal cell excretory protein (i.e.,
extracellular matrix) partially regulates epithelial cell differentiation. Thus, BPH may be due to a defect in a
stromal component that normally inhibits cell proliferation, resulting in loss of a normal “braking” mechanism
for proliferation. This abnormality could act in an autocrine fashion to lead to proliferation of stromal cells as well.
Further evidence of the importance of stromal-epithelial interactions in the prostate comes from the elegant
developmental studies of Cunha, which demonstrate the importance of embryonic prostatic mesenchyme in dictating
differentiation of the urogenital sinus epithelium ( Cunha et al, 1983 ). The process of new gland formation in the
hyperplastic prostate suggests a “reawakening” of embryonic processes in which the underlying prostatic stroma
induces epithelial cell development ( Cunha et al, 1983 ; McNeal, 1990 ). Many of the prostatic stromal-epithelial
interactions observed during normal development and in BPH may be mediated by soluble growth factors or by the
extracellular matrix (ECM), which itself has growth factor–like properties. This model is even more intriguing, given
the cellular localization of 5αreductase (and thus DHT production) in the prostate stromal cell ( Silver et al, 1994b ).
The complexity of the stromal-ECM-epithelial relationship is revealed in studies of the ECM signaling protein CYR61.
CRY61 (an early immediate response gene) is an ECMassociated protein that promotes adhesion, migration, and
proliferation of epithelial and stromal cells. A variety of growth factors increase the expression of CYR61 in both cell
types, and the suppression of CYR61 expression by an antisense oligonucleotide significantly affects normal cell
morphology ( Sakamoto et al, 2004 ). CRY61 expression is significantly increased in human BPH tissues and is
induced by lysophosphatidic acid (an endogenous lipid growth factor) (Sakamoto et al, 2003, 2004 [144] [143]).
As our understanding of stromal-epithelial cell relationships in the prostate increases, it is possible that therapies may
be designed to induce regression of established BPH by modulating these autocrine/paracrine mechanisms.

Growth Factors
Growth factors are small peptide molecules that stimulate, or in some cases inhibit, cell division and differentiation
processes ( Steiner, 1995 ; Lee and Peehl, 2004 ). Cells that respond to growth factors have on their surface receptors
specific for that growth factor that in turn are linked to a variety of transmembrane and intracellular signaling
mechanisms. Interactions between growth factors and steroid hormones may alter the balance of cell
proliferation versus cell death to produce BPH ( Fig. 86-2 ). Lawson's group was the first to demonstrate that
extracts of BPH stimulate cellular growth. This putative prostatic growth factor was subsequently found on sequence
analysis to be basic fibroblastic growth factor (bFGF) ( Story et al, 1989 ). Subsequently, a variety of growth factors
have been characterized in normal, hyperplastic, and neoplastic prostatic tissue. In addition to 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) have been implicated in prostate growth. TGF-β is a potent inhibitor of proliferation in
normal epithelial cells in a variety of tissues. In models of prostatic cancer, there is evidence that malignant cells have
escaped the growth inhibitory effect of TGF-β ( McKeehan and Adams, 1988 ). Similar mechanisms may be operational
in BPH ( Salm et al, 2000 ), leading to the accumulation of epithelial cells ( Kundu et al, 2000 ). Growth factors may
also be important in modulating the phenotype of the prostate smooth muscle cell ( Peehl and Sellers, 1998 ).

Figure 86-2 Prostate hyperplasia is probably due to an imbalance between cell proliferation and cell death. Androgens
play a necessary—but probably permissive—role. Growth factors are more likely to be sites of primary defects. DHT,
dihydrotestosterone; EGF, epidermal growth factor; IGF, insulin-like growth factor; KGF, keratinocyte growth factor;
TGF, transforming growth factor

There is mounting evidence of interdependence between growth factors, growth factor receptors, and the steroid
hormone milieu of the prostate ( Rennie et al, 1988 ; Lee and Peehl, 2004 ). Although data on the absolute level of
growth factor and growth factor receptors in hyperplastic as opposed to normal tissue are conflicting, it is likely that
growth factors play some role in the pathogenesis of BPH. However, further research is necessary to establish the role
of growth factors in a disease process in which cellular proliferation is not obvious.
If cellular proliferation is a component of the BPH process, it appears that growth stimulatory factors such as
the FGF-1, -2, -7, and -17 families; vascular endothelial growth factor (VEGF); and insulin-like growth factor
(IGF) may play a role, with DHT augmenting or modulating the growth factor effects. In contrast, TGF-β, which
is known to inhibit epithelial cell proliferation, may normally exert a restraining influence over epithelial
proliferation that is lost or downregulated in BPH ( Wilding et al, 1989 ; Sporn and Roberts, 1990, 1991 [163]
[162]; Peehl et al, 1995 ; Cohen et al, 2000 ; Walsh et al, 2002 ; Lee and Peehl, 2004 ). TGF-β1 is a potent mitogen for
fibroblasts and other mesenchymal cells but is also an important inhibitor of epithelial cell proliferation ( Roberts and
Sporn, 1993 ). TGF-β1 also regulates ECM synthesis and degradation and can induce cells to undergo apoptosis. In
addition, TGF-β upregulates the production of basic fibroblast growth factor (bFGF-2), which is known to be an
autocrine growth factor for prostate stromal cells ( Story et al, 1993 ), and at least on one prostate smooth muscle cell
line (PSMC1), TGF functions as an autocrine mitogen ( Salm et al, 2000 ). Thus, upregulation of TGF-β1 (which is
expressed in prostate stromal cells) during BPH would favor expansion of the stromal compartment.
Indirect evidence to support this view comes from studies of reconstituted mouse prostate ( Yang et al, 1997 ).
Interestingly, the observation that TGF-β1 may regulate smooth muscle contractile protein expression suggests that
TGF-β isoforms may be physiologic regulators of prostatic smooth muscle function ( Orlandi et al, 1994 ). Cohen and
colleagues (2000) found that stromal cells isolated from BPH specimens exhibited a blunted TGF-β growth inhibition
relative to normal stromal cells and that the blunted response appeared to be due to a reduction in TGF-mediated
increase in IGF binding protein 3 (IGFBP-3) expression. TGF-β may stimulate the overexpression of versican
(chondroitin sulfate proteoglycan 2) in the ECM through inhibition of key metalloproteases (ADAMTS lineage) that
normally degrade versican, leading to accumulation in the ECM ( Cross et al, 2005 ). An increased risk for BPH was
described in patients with a codon 10 polymorphism in TGF-β( Li et al, 2004 ).
The first evidence of increased FGF-2 levels in BPH came from the studies of Begun and coworkers (1995) , who
demonstrated a two- to threefold elevation of FGF-2 in BPH compared with histologically normal glands. Further
studies have demonstrated that both FGF-2 and FGF-7 are overexpressed in BPH tissues ( Ropiquet et al, 1999 ). The
major target of FGF-2 is thought to be the stroma itself (autocrine), although transgenic mice overexpressing FGF-2
develop glandular epithelial hyperplasia ( Konno-Takahashi et al, 2004 ). KGF, a member of the FGF family (FGF-7),
is produced in prostatic stromal cells ( Yan et al, 1992 ). However, cell surface receptors for stroma-derived KGF are
expressed exclusively in epithelial cells. As a result, FGF-7 (or a homolog) is the leading candidate for the factor
mediating the stromal cell–based hormonal regulation of the prostatic epithelium. There is direct evidence that
FGF-7 plays this role in the androgen-dependent mesenchymal-epithelial interactions involved in development of the
seminal vesicle ( Alarid et al, 1994 ). Abnormalities in stromal FGF-7 production or epithelial FGF-7 receptor could
promote epithelial cell proliferation. Indirect evidence supporting this hypothesis comes from a study of transgenic
mice overexpressing FGF-7 that develop atypical prostatic hyperplasia ( Kitsberg and Leder, 1996 ). McKeehan's
laboratory demonstrated that FGF-10, a homolog of FGF-7, is expressed at high levels in the rat prostate, specifically in
stromal cells of smooth muscle origin ( Lu et al, 1999 ; Nakano et al, 1999 ). FGF-10 expression is increased by
androgens and may have a mitogenic effect on prostate epithelium. Others studies suggest that cells expressing FGF-7
are localized in the stroma immediately adjacent to the epithelium, suggesting that the epithelial cells may induce FGF-
7 expression ( Giri and Ittmann, 2000 ). The paracrine factor most likely responsible for this effect is cytokine
interleukin (IL)-1a ( Giri and Ittmann, 2000 ; Lee and Peehl, 2004 ).
Some investigators have speculated that local hypoxia in the prostate (perhaps from atherosclerosis or other vascular
events) is the initial event that induces FGF production ( Lee and Peehl, 2004 ). Further growth of BPH nodules could
impede blood flow, leading to further hypoxia ( Berger et al, 2003 ). Hypoxia leads to upregulation of hypoxia
inducible factor 1, which in turn increases the secretion of FGF-2 and FGF-7 from stromal cells.
Other growth factors implicated in BPH include FGF-17 ( Polnaszek et al, 2004 ), FGF-10, and VEGF ( Walsh et al,
2002 ). It remains difficult to ascertain which of the growth factors and growth factor receptors are key mediators of the
BPH disease process and which are bystanders.
A unique animal model provides additional evidence that FGF-like factors may be involved in the etiology of BPH. A
transgenic mouse line expressing the Int-2/FGF-3 growth factor demonstrated androgen-sensitive epithelial
hyperplasia in the male mouse prostate histologically similar to human and canine BPH ( Tutrone et al, 1993 ).
Insulin-like growth factors, binding proteins, and receptors also appear to be important modulators of prostatic growth,
at least as it relates to cell growth in culture ( Peehl et al, 1995 ; Lee and Peehl, 2004 ). A transgenic mouse model with
overexpression of IGF-1 demonstrated prostate gland enlargement ( Konno-Takahashi et al, 2003 ). Studies of BPH
tissue demonstrate a higher concentration of IGF-2 in the periurethral area than in the peripheral zone ( Monti et al,
2001 ). A study of Chinese men demonstrated a significant correlation between circulating IGF-1 and IGFBP-3 level
and BPH ( Chokkalingam et al, 2002 ), but a study of the Olmsted County cohort failed to demonstrate any relationship
between serum IGF-1 and prostate volume ( Roberts et al, 2003 ).

Other Signaling Pathways


Sympathetic signaling pathways are important in the pathophysiology of LUTS, as reviewed subsequently. In addition,
there is increasing evidence that sympathetic pathways may be important in the pathogenesis of the hyperplastic growth
process. Alpha blockade, in some model systems, can induce apoptosis ( Anglin et al, 2002 ; Partin et al, 2003 ). α-
Adrenergic pathways can also modulate the smooth muscle cell phenotype in the prostate ( Lin et al, 2001 ). All the
components of the renin-angiotensin system (RAS) are present in prostatic tissue and may be activated in BPH (Dinh et
al, 2001a, 2001b, 2002 [41] [43] [42]; Fabiani et al, 2001, 2003 [46] [45]; Nassis et al, 2001 ). Either with or without
sympathetic modulation, local RAS pathways may contribute to cell proliferation and smooth muscle contraction.
The early growth response gene 1 (EGR-1) transcription regulation pathway was found to active in a BPH cell line
( Mora et al, 2005 ). Also of interest is the finding that α2-macroglobulin, a large protein that binds prostate-specific
antigen (PSA) and many growth factors, is very highly expressed in human prostate and is upregulated in BPH ( Lin et
al, 2005 ). Trapping and inactivation of inhibitory molecules could promote growth pathways.
The Potential Role of Inflammatory Pathways and Cytokines in Benign Prostatic Hyperplasia
An additional source of growth factors in human BPH tissue may be the inflammatory cell infiltrates seen in
many men with BPH. In the 1990s, descriptive studies suggested a link between inflammation and BPH-related
growth. Theyer and associates (1992) reported extensive infiltration of human BPH tissues by activated T cells.
Peripheral blood and tumor infiltrating T cells are known to express VEGF, a potent epithelial mitogen ( Blotnik et al,
1994 ; Freeman et al, 1995 ). T cells are known to produce and secrete a variety of other growth factors, including HB-
EGF and bFGF/FGF-2 ( Blotnik et al, 1994 ). Thus, T cells present in the local prostate environment were thought to be
capable of secreting potent epithelial and stromal mitogens that promote stromal and glandular hyperplasia.
In the last 5 years, specific inflammatory mediator pathways have been studied in detail to elucidate the potential role of
these pathways in BPH pathogenesis. A large number of cytokines and their receptors are seen in BPH tissue ( Konig et
al, 2004 ). Specifically, significant levels of IL-2, IL-4, IL-7, IL-17, interferon γ (IFN-γ), and their relevant receptors
are found in BPH tissue ( Kramer et al, 2002 ; Steiner et al, 2003a, 2003b [167] [168]). IL-2, IL-7, and IFN-γ stimulate
the proliferation of prostatic stromal cells in vitro ( Kramer et al, 2002 ). Prostatic epithelial cell senescence results in
increased expression of IL-8, which can promote proliferation of nonsenescent epithelial and stromal cells ( Castro et al,
2004 ). Macrophage inhibitory cytokine 1 is expressed in normal prostate tissue but significantly downregulated in BPH
( Kakehi et al, 2004 ; Taoka et al, 2004 ). Chronic inflammation in BPH is also associated with focal upregulation of
cyclooxygenase 2 (COX-2) in the glandular epithelium ( Wang et al, 2004 ). To date, however, no firm cause-and-effect
relationships have been established between prostatic inflammation and related cytokine pathways and stromal-
epithelial hyperplasia.

Genetic and Familial Factors


There is substantial evidence that BPH has an inheritable genetic component. Sanda and colleagues (1994)
conducted a retrospective case-control analysis of surgically treated BPH patients and control subjects at Johns
Hopkins. The BPH patients were men whose resected prostate weights were in the highest quartile (greater than 37 g)
and whose age at prostatectomy was in the lowest quartile. The hazard-function ratio for surgically treated BPH
among first-degree male relatives of the BPH cases compared with the first-degree male relatives of the controls
was 4.2 (95% confidence interval [CI], 1.7 to 10.2), demonstrating a very strong relationship ( Table 86-1 ). The
results did not appear to be due to differences in health-seeking behavior between the two groups. A segregation
analysis showed that the results were most consistent with an autosomal dominant inheritance pattern. Utilizing this
model, 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. In addition, monozygotic twins demonstrate
a higher concordance rate of BPH than dizygotic twins ( Partin et al, 1994 ).

Table 86-1 Family History of Early-Onset Benign Prostatic Hyperplasia (BPH) Increases Risk of Clinical
Significant BPH
Frequency of Clinical Age-Adjusted Significance ‡
Case Control Odds Ratio Relative Risk of Chi-
BPH (%)[*] Relatives Relatives Relatives (unadjusted)[†] Clinical BPH[‡] Square P Value
All first-degree male 28.3 8.6 4.2 (1.7-10.2) 4.4 (1.9-9.9) 13.36 0.0003
relatives
Fathers of proband 33.3 13.2 3.3 (1.1-10.2) 3.5 (1.3-9.5) 5.94 0.0148
Brothers of proband 24.2 3.9 8.0 (1.6-40.5) 6.1 (1.3-29.7) 6.85 0.0089

From Sanda MG, Beaty TH, Stutzman RE, et al: Genetic susceptibility of benign prostatic hyperplasia. J Urol
1994;152:115-119.
*
Percent of informative male relatives with history of prostatectomy (open or transurethral) for BPH (60 case relatives
and 105 control relatives).

Chi-square analysis of proportions; Taylor 95% confidence intervals in parentheses.

Cox proportional hazards survival model. Censored outcome—prostatectomy. Time variable—age at death or current
age. Values in parentheses indicate 95% confidence intervals.

In a community-based cohort study of more than 2000 men, Roberts and colleagues (1997) found an elevated risk of
moderate to severe urologic symptoms in men with a family history of an enlarged prostate and a family history of BPH
compared with those with no history. Analysis of the subjects who participated in the U.S. finasteride clinical trial
identified 69 men who had three or more family members with BPH, including the proband (Sanda et al, 1996).
Regression analysis demonstrated that familial BPH was characterized by large prostate size, with a mean prostate
volume of 82.7 mL in men with hereditary BPH compared with 55.5 mL in men with sporadic BPH. Serum
androgen levels and the response to 5α-reductase inhibition were similar in familial and sporadic BPH. A more recent
familial aggregation study in the finasteride database confirmed that a strong family history of early onset and large
prostate volume is more likely to be associated with inheritance of risk than symptom severity or other factors ( Pearson
et al, 2003 ).
These studies clearly demonstrate the presence of a familial form of BPH and suggest the presence of a gene
contributing to the pathogenesis of the disease. The studies of Miekle and coworkers (1997, 1999) also support a
genetic basis for BPH. Preliminary studies demonstrate evidence of DNA mutations ( White et al, 1990 ), DNA
hypomethylation ( Bedford and van Helded, 1987 ), and abnormalities of nuclear matrix protein expression ( Partin et
al, 1993 ), miscellaneous genetic polymorphisms ( Werely et al, 1996 ; Konishi et al, 1997 ; Habuchi et al, 2000a ), and
abnormal expression of the Wilms' tumor gene (WT-1) ( Dong et al, 1997 ) in human BPH. However, the specific gene
or genes involved in familial BPH or that contribute to the risk of significant prostatic enlargement in sporadic disease
remain to be elucidated.

Other Etiologic Factors


Androgens and soluble growth factors are clearly not the only important factors for the development of BPH. All
mammalian prostates studied have testosterone, DHT, and AR as well as most of the known growth factor signaling
pathways; however, only dog and man develop BPH. Interestingly, another glandular organ that remains androgen
responsive throughout life, the seminal vesicle, does not develop hyperplasia. Obviously, other mechanisms or
cofactors must be present in these two unique species making them susceptible to the disease. Nonandrogenic
substances from the testis, perhaps transmitted through the vas deferens or deferential blood vessels, for example, may
play some role (Darras et al, 1979; Dalton et al, 1990 ). Rats with intact testes treated with exogenous androgen
demonstrate a greater degree of prostatic growth than castrated rats treated with androgen. Sutkowski and coauthors
(1993) have demonstrated that human spermatocele fluid is mitogenic to both human prostatic epithelial and stromal
cells in culture. Similar results have been seen in castrated versus testes-intact dogs treated with exogenous androgen
and exogenous testosterone and estradiol combination ( Juniewicz et al, 1994 ). In addition to increases in prostate
weight, the incidence of histologic BPH was significantly higher in the dogs with intact testes. Grayhack and colleagues
(1998) have identified a putative substance that may be a candidate for such a factor.
Prolactin has long been speculated to play a role in BPH because of the known effects of this hormone on prostate cells
in vitro. Transgenic mice overexpressing the prolactin gene develop significant enlargement of the prostate ( Wennbo et
al, 1997 ). However, despite the documented presence of prolactin receptors in the human prostate and low circulating
levels of the hormone, the role of prolactin in human prostate disease is unclear.
Molecular profiling, fingerprinting, microarrays, and high-throughput screening tools have uncovered new genes, as
well as known genes not previously associated with BPH. Preliminary findings from the Getzenberg laboratory
( Prakash et al, 2002 ; Shah and Getzenberg, 2004 ) and other groups ( Fromont et al, 2004 ; Dhanasekaran et al, 2005 )
suggest that new markers for BPH and new therapeutic targets will be forthcoming in the next few years.

Pathophysiology
The pathophysiology of BPH is complex ( Fig. 86-3 ). Prostatic hyperplasia increases urethral resistance, resulting
in compensatory changes in bladder function. However, the elevated detrusor pressure required to maintain urinary
flow in the presence of increased outflow resistance occurs at the expense of normal bladder storage function.
Obstruction-induced changes in detrusor function, compounded by age-related changes in both bladder and
nervous system function, lead to urinary frequency, urgency, and nocturia, the most bothersome BPH-related
complaints. Thus, an understanding of BPH pathophysiology requires detailed insight into obstruction-induced bladder
dysfunction.

Figure 86-3 The pathophysiology of benign prostatic hyperplasia (BPH) involves complex interactions between
urethral obstruction, detrusor function, and urine production.

Pathology
Anatomic Features.
McNeal (1978) demonstrated that BPH first develops in the periurethral transition zone of the prostate. The
transition zone consists of two separate glands immediately external to the preprostatic sphincter. The main ducts of the
transition zone arise on the lateral aspects of the urethral wall at the point of urethral angulation near the
verumontanum. Proximal to the origin of the transition zone ducts are the glands of the periurethral zone that are
confined within the preprostatic sphincter and course parallel to the axis of the urethra. All BPH nodules develop either
in the transition zone or in the periurethral region (McNeal, 1978, 1990 [106] [105]). Although early transition zone
nodules appear to occur either within or immediately adjacent to the preprostatic sphincter, as the disease progresses
and the number of small nodules increases, they can be found in almost any portion of the transition or periurethral
zone. However, the transition zone also enlarges with age, unrelated to the development of nodules ( McNeal,
1990 ).
One of the unique features of the human prostate is the presence of the prostatic capsule, which plays an important
role in the development of LUTS ( Caine and Schuger, 1987 ). In the dog, the only other species known to develop
naturally occurring BPH, symptoms of bladder outlet obstruction and urinary symptoms rarely develop because the
canine prostate lacks a capsule. Presumably the capsule transmits the “pressure” of tissue expansion to the urethra and
leads to an increase in urethral resistance. Thus, the clinical symptoms of BPH in man may be due not only to age-
related increases in prostatic size but also to the unique anatomic structure of the human gland. Clinical evidence of the
importance of the capsule can be found in series that clearly document that incision of the prostatic capsule
(transurethral incision of the prostate) results in a significant improvement in outflow obstruction, despite the
fact that the volume of the prostate remains the same.
The size of the prostate does not correlate with the degree of obstruction. Thus, other factors such as dynamic
urethral resistance, the prostatic capsule, and anatomic pleomorphism are more important in the production of clinical
symptoms than the absolute size of the gland. In some cases, predominant growth of periurethral nodules at the bladder
neck gives rise to the “middle lobe” ( Fig. 86-4 ). The middle lobe must be of periurethral origin because there is no
transition zone tissue in this area. It is not clear whether middle lobe growth occurs at random in men with BPH or
whether there is an underlying genetic susceptibility to this pattern of enlargement.

Figure 86-4 Gross appearance of hyperplastic prostatic tissue obstructing the prostatic urethra forming
“lobes.” A, Isolated middle lobe enlargement. B, Isolated lateral lobe enlargement. C, Lateral and middle
lobe enlargement. D, Posterior commissural hyperplasia (median bar). (From Randall A: Surgical
Pathology of Prostatic Obstruction. Baltimore, Williams & Wilkins, 1931.)

Histologic Features.
BPH is a true hyperplastic process. Histologic studies document an increase in the cell number ( McNeal, 1990 ). In
addition, thymidine uptake studies in the dog clearly indicate an increase in DNA synthesis in experimentally induced
BPH ( Barrack and Berry, 1987 ). The term benign prostatic hypertrophy is pathologically incorrect.
McNeal's studies demonstrate that the majority of early periurethral nodules are purely stromal in character
( McNeal, 1990 ). These small stromal nodules resemble embryonic mesenchyme with an abundance of pale ground
substance and minimal collagen. It is unclear whether these early stromal nodules contain mainly fibroblast-like cells or
whether differentiation toward a smooth muscle cell type is occurring. In contrast, the earliest transition zone nodules
represent proliferation of glandular tissue that may be associated with an actual reduction in the relative amount of
stroma ( Fig. 86-5 ). The minimal stroma seen initially consists primarily of mature smooth muscle, not unlike that of
the uninvolved transition zone tissue. These glandular nodules are apparently derived from newly formed small
duct branches that bud off from existing ducts, leading to a totally new ductal system within the nodule. This type of
new gland formation is quite rare outside embryonic development. This proliferative process leads to a tight packing
of glands within a given area as well as an increase in the height of the lining epithelium. There appears to be
hypertrophy of individual epithelial cells as well. Again, the observed increase in transition zone volume with age
appears to be related not only to an increased number of nodules but also to an increase in the overall size of the zone.

Figure 86-5 Larger glandular nodule (upper left) with focus of stromal hyperplasia. Tangent ducts bordering nodule
show epithelial hypertrophy and formation of new gland branches, which are seen exclusively on wall of duct that
faces nodule. Hematoxylin and eosin, ×70. (From Bostwick DG: Pathology of the Prostate. New York, Churchill
Livingstone, 1990.)

During the first 20 years of BPH development, the disease may be predominantly characterized by an increased number
of nodules, and the subsequent growth of each new nodule is generally slow ( McNeal, 1990 ). Then a second phase of
evolution occurs in which there is a significant increase in large nodules. In the first phase, the glandular nodules tend
to be larger than the stromal nodules. In the second phase, when the size of individual nodules is increasing, the size of
glandular nodules clearly predominates.
There is significant pleomorphism in stromal-epithelial ratios in resected tissue specimens. Studies from primarily
small resected glands demonstrate a predominance of fibromuscular stroma ( Shapiro et al, 1992b ). Larger
glands, predominantly those removed by enucleation, demonstrate primarily epithelial nodules ( Franks, 1976 ).
However, an increase in stromal-epithelial ratios does not necessarily indicate that this is a “stromal disease”; stromal
proliferation may well be due to “epithelial disease.”

Importance of Prostatic Smooth Muscle


Regardless of the exact proportion of epithelial to stromal cells in the hyperplastic prostate, there is no question that
prostatic smooth muscle represents a significant volume of the gland ( Shapiro et al, 1992a ) ( Fig. 86-6 ). Although
the smooth muscle cells in the prostate have not been extensively characterized, presumably their contractile properties
are similar to those seen in other smooth muscle organs. The spatial arrangement of smooth muscle cells in the prostate
is not optimal for force generation; however, there is no question that both passive and active forces in prostatic
tissue play a major role in the pathophysiology of BPH ( Shapiro et al, 1992a ). The factors that determine passive
tone in the prostate remain to be elucidated. The series elastic elements in the stromal and epithelial cells and (most
important) the ECM contribute to passive tissue force, independent of active smooth muscle contraction. However,
stimulation of the adrenergic nervous system clearly results in a dynamic increase in prostatic urethral
resistance. Blockade of this stimulation by α-receptor blockers clearly diminishes this response. However, α-
blockade does not decrease passive tension in the prostate, which may be an equal determinant of urethral resistance.

Figure 86-6 Prostate sections obtained from men with symptomatic benign prostatic hyperplasia were analyzed by
double immunoenzymatic staining and quantitative image analysis. The percent area density of smooth muscle and
connective tissue is significantly greater than glandular epithelium and glandular lumen area density (mean ± SEM).
(From Shapiro E, Hartanto V, Lepor H: Anti-desmin vs. anti-actin for quantifying the area density of prostate
smooth muscle. Prostate 1992;20:259.)

Several additional observations on the prostatic stromal/smooth muscle cell are important. It is generally assumed that
the stromal cells are resistant to the effects of androgen withdrawal. In short-term studies, androgen ablation appears to
affect primarily the epithelial cell population. In general, however, stromal cells have much slower turnover rates than
epithelial cells. If the effect of androgen ablation is primarily to increase cell death rates, a decrease in stromal cell
numbers may not be appreciated until a year or more of therapy. Thus, further study is required to determine whether
the stromal cell is really resistant to androgen withdrawal. Likewise, it cannot be assumed that hormonal therapy has no
effect on the stroma even if stromal cell volumes are not decreased. In a variety of smooth muscle cell systems (e.g.,
vascular and myometrial), contractile proteins, neuroreceptors, and ECM proteins are regulated by a variety of
hormones and growth factors. In vitro, androgens have been shown to modulate the effects of α agonists on prostate
smooth muscle cells ( Smith et al, 2000 ). Thus, a given therapy may affect stromal cell function without decreasing the
absolute number or volume of cells.
Studies of human tissue samples by Lin and colleagues (2000) have clearly shown that the smooth muscle cells from
men with BPH have a significant downregulation of smooth muscle myosin heavy chain and a significant upregulation
of nonmuscle myosin heavy chain. This myosin expression pattern is typical of dedifferentiated smooth muscle and
indicates either proliferation or loss of normal modulation pathways.
Active smooth muscle tone in the human prostate is regulated by the adrenergic nervous system ( Schwinn,
1994 ; Roehrborn and Schwinn, 2004 ). The α1-adrenoreceptor nomenclature has been standardized ( Hieble et al,
1995 ) to reconcile differences in nomenclature based on pharmacologic and molecular studies. Receptor binding
studies clearly demonstrate that the α1A is the most abundant adrenoreceptor subtype present in the human
prostate (Lepor et al, 1993a, 1993b [86] [87]; Price et al, 1993 ; Roehrborn and Schwinn, 2004 ). Moreover, the α1A
receptor clearly mediates active tension in human prostatic smooth muscle ( Lepor et al, 1993a ). It is still unclear
whether other factors may regulate smooth muscle contraction. Endothelin and endothelin receptors (Kobayashi et al,
1994a, 1994b [73] [74]; Imajo et al, 1997 ; Walden et al, 1998 ) have been reported in human prostate. However, the
physiologic role of this potent contractile agent in prostate smooth muscle function remains to be defined. Various
components of the kallikrein-kinin system (e.g., bradykinin) may play a role in the regulation of both smooth muscle
proliferation and contraction in the prostate ( Walden et al, 1999 ; Srinivasan et al, 2004 ). The presence of type 4 and
type 5 phosphodiesterase isoenzymes in the prostate implies that phosphodiesterase inhibitors may be appropriate
candidate therapies for BPH-related LUTS ( Uckert et al, 2001 ).
The role of adrenergic stimulation in the prostate may exceed simple smooth muscle contraction. Adrenergic
neurotransmitters are known to regulate expression of contractile protein genes in cardiac myocytes ( Kariya et al,
1993 ) and to be involved in the development of cardiac hypertrophy ( Matsui et al, 1994 ). Interestingly, evidence
suggests that testosterone may regulate the expression of adrenergic receptors, at least in the kidney ( Gong et al,
1995 ). It is possible that adrenergic neurotransmitters may play a role in prostatic smooth muscle cell regulation as
well as contraction ( Smith et al, 2000 ). α-Adrenergic blockade in patients with documented BPH leads to a significant
downregulation of normal contractile protein gene expression, specifically smooth muscle myosin heavy chain ( Lin et
al, 2001 ).
Autonomic nervous system overactivity may contribute to LUTS in men with BPH. McVary and coworkers (2005)
demonstrated that autonomic nervous system activity, as measured by a standard set of physiologic tests, plasma, and
urinary catecholamines, correlates positively with symptom score and other BPH measures. Serum norepinephrine
increase after tilt predicted prostate size (transition zone).

The Bladder's Response to Obstruction


Current evidence suggests that the bladder's response to obstruction is largely an adaptive one. However, it is also clear
that many lower tract symptoms in men with BPH or prostate enlargement are related to obstruction-induced changes in
bladder function rather than to outflow obstruction directly. Approximately one third of men continue to have
significant voiding dysfunction after surgical relief of obstruction ( Abrams et al, 1979 ). Obstruction-induced changes
in the bladder are of two basic types. First, the changes that lead to detrusor instability or decreased compliance are
clinically associated with symptoms of frequency and urgency ( Andersson, 2003 ). Second, the changes associated
with decreased detrusor contractility are associated with further deterioration in the force of the urinary stream,
hesitancy, intermittency, increased residual urine, and (in a minority of cases) detrusor failure. Acute urinary
retention should not be viewed as inevitable result of this process. Many patients presenting with acute urinary retention
have more than adequate detrusor function, with evidence of a precipitating event leading to the obstruction.
Much of our knowledge of the detrusor's response to obstruction is based upon experimental animal studies. Limited
information is available on the natural history of the human bladder's response to obstruction. Gosling has demonstrated
that the major endoscopic detrusor change, trabeculation, is due to an increase in detrusor collagen ( Gosling and
Dixon, 1980 ; Gosling et al, 1986 ). Severe trabeculation is associated with significant residual urine ( Barry et al,
1993 ), suggesting that incomplete emptying may be due to increased collagen rather than impaired muscle function.
Severe trabeculation, however, is seen in fairly advanced disease. In experimental animal models, the initial response
of the detrusor to obstruction is the development of smooth muscle hypertrophy (Levin et al, 1995, 2000 [89]
[90]). It is likely that this increase in muscle mass, although an adaptive response to increased intravesical
pressure and maintained flow, is associated with significant intra- and extracellular changes in the smooth
muscle cell that lead to detrusor instability and in some cases impaired contractility. Obstruction also induces
changes in smooth muscle cell contractile protein expression, impaired energy production (mitochondrial dysfunction),
calcium signaling abnormalities, and impaired cell-to-cell communication (Levin et al, 1995, 2000 [89] [90]).
There is considerable evidence that the response of the detrusor smooth muscle cell to stress (increased load related to
outlet obstruction) is not as adaptive as the response of skeletal muscle to stress. In the latter case, a relatively normal
repertoire of contractile protein genes are upregulated and an increased number of normally organized contractile units
assemble in the muscle cell. In the detrusor smooth muscle cell, load-induced hypertrophy leads to a change in myosin
heavy chain isoform expression ( Lin and McConnell, 1994 ; Cher et al, 1996 ) and to a significant alteration in the
expression of a variety of thin filament–associated proteins (Mannikarottu et al, 2005). Taken together, these
observations strongly suggest that smooth muscle cells revert to a secretory phenotype in response to obstruction-
induced hypertrophy. One consequence of this phenotypic switch is increased ECM production. The detrusor smooth
muscle cell is a key contributor to the complex of symptoms associated with prostatic obstruction. Additional research
in this area is required ( Christ and Liebert, 2005 ).
In experimental animal models, unrelieved obstruction is associated with the development of significant increases in
detrusor ECM (collagen) (Levin et al, 1995, 2000 [89] [90]). This also appears to be the case in the human, although
cause-and-effect relationships have not been established ( Gosling and Dixon, 1980 ; Levin et al, 2000 ). In addition to
obstruction-induced changes in the smooth muscle cell and ECM of the bladder, there is increasing evidence that
obstruction may modulate neural-detrusor responses as well (Steers et al, 1990, 1999 [165] [166]; Clemow et al,
1999, 2000 [32] [33]). Altered neural control of micturition has been noted in aging rats, including reduced bladder
contractility, impaired central processing, and altered sensation ( Chai et al, 2000 ).
Independent of obstruction, aging produces some of the same changes in bladder function, histology, and cellular
function ( Nordling, 2002 ). There is suggestive evidence from animal models that atherosclerosis and the resultant
chronic bladder ischemia or hypoxia induced by other mechanisms (e.g., increased bladder wall tension) may contribute
to bladder pathology (Tarcan et al, 1998, 2000 [176] [177]; Azadzoi et al, 1999a, 1999b, 2003, 2004 [7] [8] [6] [5];
Ghafar et al, 2002a, 2002c [51] [53]; Levin et al, 2004 ).
Email to Colleague Print Version

DAFTAR PUSTAKA

1. Beers, Mark H., MD, and Robert Berkow, MD., editors. "Urinary Incontinence." Section
17, Chapter 215 In The Merck Manual of Diagnosis and Therapy. Whitehouse Station, NJ:
Merck Research Laboratories, 2004.
2. Noel A. Armenakas, MD. The Merck Manual of Diagnosis and Theraphy. February 2007
3. Muhammad Waseem, MD, Associate Professor of Emergency Medicine in Clinical
Pediatrics, Weill Medical College of Cornell University; Consulting Staff, Department of
Pediatrics, Bronx Lebanon Hospital; Consulting Staff, Department of Emergency Medicine,
Lincoln Medical and Mental Health Center
4. Bladder Health Council, American Foundation for Urologic Disease. 300 West Pratt St.,
Suite 401, Baltimore, MD 21201. (800) 242-2383 or (410) 727-2908.
5. Reynard, John at al, Oxford Handbook of Urology, 1st Edition 2006 Oxford University