Pasadena City College What Is Benign Prostatic Hyperplasia Discussion Hello I attached the art Summary of Article as 1. Introduction 2. Results 3. Conclu

Pasadena City College What Is Benign Prostatic Hyperplasia Discussion Hello

I attached the art

Summary of Article as
1. Introduction
2. Results
3. Conclusion
4. Summary if one is provided

As long as you want as long as you cover the main points of the paper can be short ANDROLOGY
ISSN: 2047-2919
REVIEW ARTICLE
Correspondence:
Sandro La Vignera, Policlinico “G. Rodolico”,
Via Santa Sofia 78, 95123 Catania, Italy.
E-mail: sandrolavignera@unict.it
Keywords:
benign prostatic hyperplasia, prostate, radical
prostatectomy, testosterone
Received: 13-Dec-2015
Revised: 20-Jan-2016
Accepted: 22-Feb-2016
Endocrine control of benign
prostatic hyperplasia
1
1
S. La Vignera, 1R. A. Condorelli, 2G. I. Russo, 2G. Morgia and
A. E. Calogero
1
Department of Clinical and Experimental Medicine, University of Catania, and 2Department of
Urology, University of Catania, Catania, Italy
doi: 10.1111/andr.12186
SUMMARY
Benign prostatic hyperplasia (BPH) is the most common benign proliferative disease among aging men. Androgens play a key role in
the development and growth of the male genital tract favoring differentiation and proliferation of stromal and epithelial cells of the prostate gland. It is known that growth factors play a crucial role in the cross-talk between stromal cells and epithelial cells. These factors,
mainly secreted by stromal cells, act in an autocrine/paracrine manner to maintain prostate cellular homeostasis. A number of experimental studies support the interdependence between growth factors (IGF, FGF, TGF) and the steroid hormone milieu of the prostate.
Alterations of these interactions may alter the balance between proliferation and cell death leading to the development of BPH. The onset
of BPH is closely related to an inflammatory microenvironment. Chronic inflammation, which generally follows the acute inflammation
because of infectious agents, is favored by hormonal or metabolic abnormalities. However, a close correlation between these mechanisms and metabolic or sexual hormones (androgen/estrogen ratio) alteration has been shown suggesting a key role of hypogonadism in
the development of prostate inflammation. This review clear shows that the BPH pathogenesis and the subsequent onset of the lower
urinary tract symptoms (LUTS) depends from different etio-pathogenetic factors whose mechanism of action remains to be evaluated.
INTRODUCTION
The most common benign proliferative disease among men
during aging is benign prostatic hyperplasia (BPH). Its incidence
increases by 42% in men between 40 and 50 years up to 90% in
those over 80 years (McVary, 2006). BPH is a hyperplastic process of the prostate that develops in the transition zone (TZ),
particularly in the periurethral area, and is characterized by
hyperplasia of the stromal component, and to a lesser extent, of
the epithelial cells (McNeal, 1990).
Benign prostatic hyperplasia is clinically characterized by an
increase prostate volume (benign enlargement of the prostate,
BEP), detectable by ultrasound or digital rectal examination
which causes cervical-urethral obstruction because of the
mechanical compression exerted on the urethra (benign prostatic obstruction, BPO).
Benign prostatic hyperplasia is therefore a disease that occurs
during aging characterized by the development of a broad spectrum of symptoms associated with the functions of the lower urinary tract (low urinary tract symptoms, LUTS) (Roehrborn, 2008;
Nicholson & Ricke, 2011; Vignozzi et al., 2014). These symptoms
depend on two components: the static one which is caused by
the mass of the gland, and the dynamic one, because of the tone
404
Andrology, 2016, 4, 404–411
of the smooth muscle of the bladder neck, prostate and its capsule. a1-adrenergic receptors play a crucial role in these
mechanisms.
Low urinary tract symptoms may be categorized into two
types: filling or irritative symptoms (increased frequency of urination, nocturia, urinary urgency, burning during urination) and
voiding or obstructive symptoms (reduced urinary flow and
incomplete emptying of the bladder) (Abrams et al., 2009). The
changes caused by BPO into the bladder can also be divided into
two phases: an initial one characterized by an obstruction compensated by an increased detrusor muscle activity (detrusor
instability) subsequently to the incomplete emptying of the
bladder; and a second phase characterized by a reduced activity
of the detrusor contractility. It is noteworthy that LUTS are also
associated with other abnormalities such as inflammation and
a-adrenergic receptor (a1) hyperactivity on the prostate gland
and the muscle components of the bladder (Donnell, 2011; Vignozzi et al., 2012).
Androgens play a crucial role in the differentiation and into
prostate growth during the fetal period and puberty, whereas
they play a permissive role during adulthood (Ho & Habib,
2011). The role of androgens in the development of BPH is still
© 2016 American Society of Andrology and European Academy of Andrology
ENDOCRINE CONTROL AND BPH
controversial. Although the a-blockers are frequently prescribed
for BPH treatment, they are not able to reduce the volume of the
gland and are often insufficient to eliminate the symptoms of
the prostatic disease. Conversely, 5a-reductase inhibitors (5ARI), which suppress the conversion of testosterone (T) into its
active metabolite dihydrotestosterone (DHT), are particularly
effective in reducing the volume of BPH (Barkin, 2011). Clinical
data indicate that the association between 5-ARI and a-blockers
produces a better clinical improvement compared with each
molecule administered alone. This suggests that the interaction
between androgen/androgen receptor (AR) plays a crucial role
in the development of BPH (reawakening theory); hence changing the activity of this pathway can represent the best therapeutic approach. On the other hand, the incidence of BPH increases
with aging and with the related reduction in testicular T production (Harman et al., 2001). Therefore, it may be hypothesized
that other factors such as growth factors, estrogen, inflammation, may play a key role in BPH etiology.
BENIGN PROSTATE HYPERPLASIA: ROLE OF THE
ANDROGEN PATHWAY
Signaling pathway androgen/androgen receptor
Androgens play a key role in the development and growth of
the male genital tract favoring differentiation and proliferation
of stromal and epithelial cells of the prostate gland. In the prostate, the enzyme 5a-reductase type 2, more expressed in stromal
cells, converts T into DHT, the main androgen in this tissue
(Fig. 1).
5a-reductase is an enzyme responsible for the conversion of T
to DHT. The latter is the more potent androgen and its activity is
4–5 times higher than that of T, 5a-reductase makes simple the
double bond existing between carbon 4 and carbon 5. This modification greatly increases the affinity of DHT to androgen receptors, enhancing, consequently, the activity. 5a-reductase is
expressed especially in the prostate, testes, hair follicles, and
adrenal glands. Its action is important already during the uterine
life, when DHT determines the development of the male external
Figure 1 In the stromal cell a majority of testosterone (T) is converted to
dihydrotestosterone (DHT) by enzyme 5a-reductase type 2. DHT acts stimulating the proliferation of stromal and epithelial cells with autocrine and
paracrine signaling. Such action may be direct or mediated by the production/activity of several growth factors.
© 2016 American Society of Andrology and European Academy of Andrology
ANDROLOGY
genitalia. In the cases of recessive genetic defect isoform 5areductase type II is insufficient, there is an abnormal development of the external genitalia in the fetus, which results in
disorders of sexual and infertility in adulthood. From puberty
onwards, DHT supports the development of the secondary sexual characteristics, such as the lowering of the voice, growth of
facial hair and body, the receding hairline, and sebum secretion.
DHT is also important for the development of muscle mass and,
psychologically, for the appearance of the sexual behavior. An
excess is involved in the development of BPH, acne, seborrhea,
androgenetic alopecia, and hirsutism. A deficit of DHT is implicated in the occurrence of gynecomastia (Bartsch et al., 2000;
Azzouni & Mohler, 2012). In the human body there are two isoforms of the 5a-reductase, encoded by two different chromosomes and with different sensitivity to regulatory factors,
respectively, called 5a-reductase type I and 5a-reductase type II.
The isoform of type I is mainly concentrated in the skin, sebaceous glands, central nervous system, and liver. The type II isoform is expressed primarily in the prostate and at the level of the
hair follicles. To inhibit the activity of these enzymes they have
been developed two drugs. The first, called Finasteride, is a
selective inhibitor of type II isoform. The second, called Dutasteride inhibits both isoforms (Bartsch et al., 2000; Azzouni &
Mohler, 2012).
Approximately 90% of prostatic androgens are in the form of
DHT, derived mainly from testicular androgens (only 10% comes
from androgens of adrenal origin). DHT acts in an autocrine
manner into the stromal cell or in a paracrine manner on the
nearby epithelial cells. In prostatic cells, DHT binds with high
affinity to the androgen receptor (AR) (Roehrborn, 2008; Nicholson & Ricke, 2011; Vignozzi et al., 2014)., which translocates into
the nucleus to bind to specific androgen responsive elements in
the promoter region of target genes stimulating the transcription
and ultimately protein synthesis. The inactivation of key androgen-dependent genes (e.g., prostate-specific antigen) and androgen deprivation leads to the activation of specific genes involved
in programmed cell death. In addition to these direct effects,
DHT acts also by regulating the expression/activity of several
growth factors and their receptors, such as epidermal growth
factor (EGF), insulin-like growth factor 1 (IGF-I), and fibroblast
growth factor (FGF)-related proteins such as keratinocyte growth
factor (KGF) (Carson & Rittmaster, 2003) (Fig. 1).
In humans, prostate development and growth occur in three
distinct phases. The first phase occurs during the fetal period
and ends at birth; the second one begins at puberty, with a process of cell development and differentiation leading to the adult
prostate; and the third one of selectively volumetric growth
develops in adulthood and during aging and involves only one of
the three different anatomical areas of the prostate, the periurethral zone or TZ, leading to the development of BPH.
Although the development of the prostate during the first two
phases is clearly an androgen-dependent process (Corona et al.,
2011), the role of androgens on the development of BPH is still
debated. The incidence of BPH increases continuously during
aging concomitantly with a decreased testicular function and,
therefore, in presence of lower serum T levels (Harman et al.,
2001; Lenzi et al., 2009). Moreover, no correlation between
serum T levels and prostate size has been found clinically
(Roehrborn, 2008; Nicholson & Ricke, 2011; Vignozzi et al.,
2014). Finally, treatment with androgens in hypogonadal
Andrology, 2016, 4, 404–411
405
S. La Vignera et al.
patients does not appear to increase the risk of development of
BPH/LUTS and, in some cases, androgen replacement therapy
appears to be correlated with an improvement of LUTS (Shigehara et al., 2011; Corona et al., 2014; Vignozzi et al., 2014). These
observations seem to support, therefore, the hypothesis that
androgens are not directly related to the development of this
disease.
On the other hand, several experimental and clinical studies
have shown different results. Indeed, T replacement therapy in
young castrate dogs causes BPH development. Clinical studies
showed that BPH never develops in men undergoing surgical
castration before puberty, as well as in patients with primary or
central hypogonadism (Nicholson & Ricke, 2011). Men with a
reduced expression of the enzyme 5a-reductase type 2 have a
small prostate (Imperato-McGinley & Zhu, 2002); furthermore,
in men with congenital deficiency of 5a-reductase type 2 do not
have palpable prostate and the presence of a normal prostate
epithelium is rare (Imperato-McGinley & Zhu, 2002).
More recently, the role of the AR as a promoter of the development of prostate tissue has been shown by the suppression of AR
in transgenic mice that spontaneously develop BPH as a result of
prolactin (PRL) overexpression. These studies demonstrate that
the signaling pathway of PRL is important for stromal cell proliferation and that the AR receptor is able to modulate the epitheliumstromal cell interaction (Lai et al., 2013). Finally, it noteworthy
that 5-ARI (dutasteride, finasteride) administration is able to significantly decrease the size of the gland and, for this reason, 5-ARI
is the treatment of choice in patients with BPH (Barkin, 2011).
To explain these conflicting observations, it has been hypothesized that DHT intraprostatic concentrations, rather than circulating T levels, are implicated in the development of prostatic
hyperplasia (Vignozzi et al., 2014). Indeed, both AR and intraprostate DHT concentrations remain stable during aging. Moreover, as proposed by Morgentaler and Traish, the saturation
model theory (Morgentaler & Traish, 2009) hypothesize that the
prostate is relatively insensitive to serum T level variations in
men with normal or mild hypogonadism because the AR receptor in prostate cells is normally saturated by relatively low androgens intratissue concentration. In these conditions, therefore,
the AR can be fully activated in spite of the possible decrease in
circulating T levels. Moreover, the saturation theory was demonstrated in humans in another recent study conducted by Maggi
and coll. that showed that PSA it may represent a new tool in
confirming hypogonadism. In particular in this study after
adjusting for age, low PSA was associated with hypogonadismrelated features (i.e., delayed puberty, lower testis volume) and
associated conditions, such as metabolic syndrome, type 2 diabetes, cardiovascular diseases (Rastrelli et al., 2013).
Androgen/androgen receptor and growth factors
Growth factors play a crucial role in the cross-talk between
stromal and epithelial cells. These factors, mainly secreted by
stromal cells, act in an autocrine/paracrine manner to maintain
prostate cellular homeostasis. In addition, numerous experimental studies support the interdependence between growth
factors [insulin-like growth factor (IGF), fibroblast growth factor
(FGF), transforming growth factor (TGF)] and the intra-prostatic
steroid hormone milieu. Alterations of these interactions can
modify the balance between cell proliferation and death leading
to the development of BPH.
406
Andrology, 2016, 4, 404–411
ANDROLOGY
Insulin like growth factor pathway
An important family of growth factors implicated in the development of BPH is insulin-like growth factors (IGF), their receptors and IGF binding-proteins (IGFBP) that regulate the
availability of the same factors. IGF-II and IGF receptor type I
are expressed at higher levels in stromal cells of BPH compared
with normal cells; these changes are followed by a decrease in
the levels of IGFBP-2 and by an increased in the levels of IGFBP5. Other studies have reported that DHT concentrations and
IGF-II activity are higher in the stromal cells of the periurethral
tissue in BPH patients compared with normal stromal cells
(Monti et al., 2001).
In an experimental model of rat in which the AR was suppressed specifically in stromal cells, Yu et al. (2011) found a
lower prostate epithelial cell proliferation, a decreased AR
expression and a decreased IGF-I concentration in stromal cells,
suggesting that the AR expressed in these cells may contribute to
the development of BPH by regulating the signaling of IGF (Lai
et al., 2012).
Fibroblast growth factor pathway
The mitogenic activity of FGF-1, 2, and 7 on prostate epithelial
and stromal cells has been shown to correlate with the development of BPH. Both FGF-2 and FGF-7 (also called KGF) are overexpressed in BPH. Moreover, a correlation between epithelial
cell proliferation index and FGF-7 levels has been reported in
the hyperplastic prostate tissue. Interleukin-1a, produced by
prostate epithelial cells, has been hypothesized to be the paracrine factor responsible for the induction of FGF-7 (Giri & Ittmann, 2000).
Transforming growth factor ß1
The transforming growth factor-b (TGFb1), both in vitro and
in vivo, is implicated in the development of BPH by inducing the
differentiation of fibroblasts into myofibroblasts and remodeling
the stromal cells. It is regarded as a key inducer in the reorganization of pathogenic prostatic stromal cells (Sampson et al.,
2013). Its effects are mediated by an alteration of the different
components of the IGF-I axis, in particular by the induction of
the protein IGFBP-3, whose levels are particularly high in the
stromal cells of BPH. In addition, TGFb1 is mainly located in the
epithelial cells of BPH and its expression is higher in BPH tissue
compared with normal tissue (Sampson et al., 2013). Thus, the
secretion of TGFb1 regulates epithelial cell response to IGF-I
stromal cell–cell interaction and this again reflects the complexity of the interactions stroma-epithelium underlying the development of prostate disease.
BENIGN PROSTATE HYPERPLASIA: ROLE OF THE
ESTROGEN PATHWAY
Estrogens regulate their effects at the level of the target cells
through interaction with estrogen receptors (ER). Both ER-a and
ER-b, similarly to the AR, are transcription factors24. ER-b is similar to ER-a in DNA-binding and ligand domains, but differs for
the N-terminal transactivation domain. The role of estrogen in
the pathogenesis of BPH is based on the observation that treatment of dogs with estrogen (in addition to androgens) leads to
the development of BPH and LUTS BPH-related (Coffey &
Walsh, 1990).
© 2016 American Society of Andrology and European Academy of Andrology
ENDOCRINE CONTROL AND BPH
In men, while serum androgen levels decrease during aging,
the levels of 17ß-estradiol (E2) remain constant increasing the
ratio E2/T. This altered relationship is clearly associated with the
development of the disease BPH/LUTS (Roberts et al., 2004).
Some authors have shown a correlation between serum estrogen
levels and the prostate volume (Hammarsten et al., 2009).
Finally, E2 levels in the stromal cells of BPH patients increase
during aging, and this seems to be associated with a high expression of aromatase, the enzyme that converts androgens into
estrogens (Ho et al., 2008). However, previously, other authors
had not shown the same results (Negri-Cesi et al., 1998).
The role of ER-a and ER-b in the pathogenesis of BPH is not
yet fully understood. It is thought that the two receptor subtypes
may perform different functions depending on the interaction
with different ligands, changes in the balance between classical
and non-classical signaling, and interactions with different corepressors and co-activators. In general, activation of ER-a in the
prostate is associated with hyperplasia and inflammation
(Nicholson & Ricke, 2011). In addition, the epithelial-tomesenchymal transition is an important mechanism in the etiology of BPH and ER-a plays a crucial role in this mechanism
(Shao et al., 2014); while ER-b are located in the epithelial cells
(Macoska, 2011), ER-a are primarily found in stromal cells. ER-b
is associated with antiproliferative activity, indeed, ER-b knockout mice develop hyperplasia of the stromal cells during aging.
Moreover, in rats, neonatal exposure to diethylstilbestrol cause
prostatic hyperplasia and dysplasia, which probably results from
an up-regulation of ER-a and down-regulation of ER-b. Finally, it
has been reported that the activation of ER-b causes apoptosis in
BPH with an androgen-independent mechanism (McPherson
et al., 2010). The epithelium-stroma interactions mediated by
growth factors are well-known, while the role of estrogen in
these interactions is not yet clear. However, it is known tha…
Purchase answer to see full
attachment