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R e v i e w o f P ro s t a t e

Anatomy and Em b r yolog y


and the Etiology of Benign
P ro s t a t i c H y p e r p l a s i a
LaTayia Aaron, BSa,b, Omar E. Franco, MD, PhDb,
Simon W. Hayward, PhDa,b,*

KEYWORDS
 Prostate embryology  Prostate anatomy  BPH  LUTS

KEY POINTS
 Development of the prostate in humans and laboratory animals follows similar principles but the de-
tails vary.
 The anatomy of the human prostate is significantly different from that seen in laboratory animals.
 The disease profile of the human and rodent prostate is very different.
 Animal models describe certain aspects of human BPH but not the whole disease profile.
 Care should be taken in extrapolating observations made in rodents and applying them to humans.

INTRODUCTION seminales” said “the prostate and Cowper’s


glands and those of the urethra which in the per-
The human prostate is a walnut-sized organ at the fect male are soft and bulky with a secretion salty
base of the urinary bladder. It is the seat of three to the taste, in the castrated animal are small,
major causes of morbidity: (1) benign prostatic flabby, tough and ligermentous and have little
hyperplasia (BPH), (2) prostate cancer, and (3) secretion.”2
prostatitis. As such it commands more attention The adult prostate is a compound tubular-
than might be expected from an organ of this alveolar gland found in most mammals.3 The gross
size. Anatomic illustrations of the prostate have structure differs considerably between species.
been published dating at least as far back as the Much of the descriptive work on the development
mid-sixteenth century when Andreas Vesalius, in of the prostate from its origins in the hindgut to
1543, published his observations of the male descriptions of the adult organ was performed by
accessory glands.1 The links between testicular anatomists and pathologists working in the early
and prostatic function have also been known for to mid-twentieth century. Subsequent work has
hundreds of years. John Hunter, writing in 1786 outlined the molecular basis for these descriptions.
in “Observations on the glands situated between Interest in prostate biology is centered around the
the rectum and the bladder, called vesiculae human organ and that of the species, notably rats

Disclosure Statement: The authors have nothing to disclose.


urologic.theclinics.com

This work was supported in part by National Institutes of Health grants 1R01 DK103483 and 2 R25 GM059994-13.
a
Department of Biochemistry and Cancer Biology, Meharry Medical College, 1005 DR DB Todd JR Blvd, Nashville,
TN 37208, USA; b Department of Surgery, NorthShore University HealthSystem Research Institute, 1001 University
Place, Evanston, IL 60201, USA
* Corresponding author. Cancer Biology, NorthShore University HealthSystem Research Institute, 1001 Univer-
sity Place, Evanston, IL 60201.
E-mail address: shayward@northshore.org

Urol Clin N Am 43 (2016) 279–288


http://dx.doi.org/10.1016/j.ucl.2016.04.012
0094-0143/16/$ – see front matter Ó 2016 Elsevier Inc. All rights reserved.
280 Aaron et al

and mice, used to model human diseases. A clear produced by the fetal testis. In the absence of
understanding of the differences in the structure of either these hormones or appropriate receptors,
human and rodent prostates is important in because of either an absent testis, lack of testic-
assessing the results of animal studies. ular function, or a mutation in the androgen
receptor gene, the fetus develops a female pheno-
HUMAN AND RODENT PROSTATE type. In the male, sexual differentiation is an asym-
EMBRYOLOGY AND POSTNATAL metric process consisting of the regression of the
DEVELOPMENT müllerian duct system, under the influence of Anti-
Müllerian hormone expressed in the testicular
The early mammalian embryo has the potential to Sertoli cells and stabilization, by androgens, of
develop toward a male or female phenotype. In the wolffian ducts.
genetically normal individuals this course is deter- The second part of male sexual differentiation
mined at conception and is reflected at the occurs under the influence of testosterone
embryonic stage by the interactions of four critical produced by the Leydig cells of the fetal testis.
units: (1) the wolffian duct, (2) the müllerian duct, This involves changes in the tubules connecting
(3) the urogenital sinus (UGS), and (4) the fetal the testis with the mesonephros to form the vasa
gonad. efferentia, the formation of the convoluted epidid-
In humans the wolffian ducts start to develop ymal duct and the vas deferens. The androgenic
approximately 25 to 30 days after conception in stimulus also acts to masculinize the UGS and
2- to 3-mm-long embryos. These ducts initially the external genitalia. This process involves the
act as excretory canals for the mesonephros, formation of the prostate and the prostatic utricle,
which performs the renal function in the early the closure of the labial-scrotal lobes, and the
embryo. The ducts do not become incorporated formation of the penis.
into the genital system until the excretory function The rudimentary prostate starts to appear in
has been taken over by the definitive kidney. The 50-mm human embryos as epithelial buds growing
ureters are a diverticulm of the wolffian duct, which laterally from the walls of the UGS at the site of the
becomes separated from the genital tract struc- müllerian tubercle. Under local mesenchymal con-
tures during development and which is the only trol, the buds form solid branching cords that start
part of the wolffian duct–derived structures that to develop a lumen giving rise, by birth, to a
is preserved in the adult female. In such species network of tubules and alveoli. As the lumen forms,
as birds and reptiles, where the mesonephros some of the apical cells become structurally polar-
has a prolonged excretory function, the wolffian ized and seem to start some secretory activity. The
ducts are preserved in an ambisexual state, in organ develops a stroma containing a large pro-
some cases until birth. In the human, by the time portion of smooth muscle, whereas the ducts
the embryo has reached 4 to 5 mm the ducts and acini are lined with a layer of flat basal epithe-
have elongated and lumenized to link the hindgut lium and a luminal layer of tall columnar secretory
(which caudally becomes the cloaca) with the epithelium.4 The basal and luminal epithelial cells
mesonephros and gonad. are distinguishable on the basis not only of
The müllerian ducts develop later than the wolff- morphology but also functionally and by their
ian ducts, at about 6 weeks of gestation. A cleft expression of different cytokeratin classes (kera-
lined with epithelial cells is formed between the tins 5 and 14 in basal cells, 8 and 18 in luminal).5
gonadal and mesonephric parts of the urogenital Details of prostatic development, in particular
ridge. This closes to form a tube that then extends molecular details, have been largely established
through the surrounding mesenchyme parallel using animal models, in particular the rat and
to the wolffian ducts. By the eighth week of gesta- mouse. The availability of tissues from these
tion the müllerian ducts, which by this time are animals and, more recently, the development of
between the wolffian ducts, reach (but do not break transgenic and gene knock-out models makes
into) the UGS forming the müllerian tubercule. them amenable to such studies. Historically,
The UGS is produced in the 7- to 9-mm embryo several workers in the field, notably including
by the formation of the urorectal septum, which Dorothy Price, established the basic develop-
divides the cloaca into the rectum and the UGS. mental profile of the rodent prostate.3,6,7 Rodent
The upper part of the UGS forms the urethra, prostatic embryogenesis mirrors the processes
whereas the part below the müllerian tubercule seen in humans, although the timing reflects the
forms part of the vagina in the female and the much faster development of these species; for
penile urethra in the male. example, an UGS is present in the mouse by
The process of male sexual differentiation is embryonic day 16 and in the rat at embryonic
determined under the influence of androgens day 18 with early prostatic buds being seen a day
Prostate Anatomy and Embryology and BPH 281

or so later. Richly illustrated descriptions of the ANATOMY OF THE HUMAN AND RODENT
gross8 and molecular9 phenotypes of the devel- PROSTATE
oping rodent urogenital tract have been published
recently that vastly expand the details available in In 1912, Lowsley14 used serial sections as
the historic documents. The GenitoUrinary Devel- anatomic models to describe the lobes of the fetal
opment Molecular Anatomy Project consortium human prostate to clarify the origin of the middle
maintains an updated database of gene expres- and posterior lobes as described by earlier inves-
sion at its Web site: http://www.gudmap.org. tigators.24 Using tissue from a 3-month gestation
Growth and development of the prostate begins fetus, Lowsley identified five separate groups of
with formation of prostatic buds from the fetal UGS prostatic ducts originating from the UGS and
and are complete at sexual maturity.10 In the used the term “lobes” to describe them. These
mouse this begins at 17 days gestation,11,12 at were designated the middle lobe, two lateral,
19 days in the rat,6 and approximately at 10 weeks posterior, and ventral lobes. Lowsley described
in the human fetus.13,14 The initial event in morpho- the ventral lobe as being formed by the glands
genesis of the prostate is the outgrowth of solid arising from the anterior or ventral wall of the pros-
epithelial buds from the UGS epithelium into the tatic urethra and consisting of four pairs of epithe-
surrounding UGS mesenchyme.10 The prostatic lial buds. The middle lobe was formed by roughly
buds proliferate under the influence of testicular 12 tubules associated with the posterior urethra
androgens to form solid cords of epithelial cells and was situated between the bladder and the
that grow into the UGS mesenchyme in a particular ejaculatory ducts under the floor of the urethra.
spatial arrangement to establish the lobar divisions The paired left and right lateral tubules, the largest
of the prostate.11,12,14,15 At birth in rodents the group of tubules, originated from the sides of the
prostate is small with a limited number of undevel- urethra and followed the prostatic furrows. The
oped buds; postnatally these cells proliferate, pre- tubules grew laterally and posteriorly, were distal
dominantly at the tips,16 and undergo a process of to the ejaculatory ducts, and located on the caudal
canalization in a proximal to distal direction (from portion of the urethra, giving rise to the posterior
the urethra toward the tips). Concurrent with this, lobe. Although their direction of growth was pre-
the epithelial cells differentiate to luminal and basal dominantly toward the bladder, a small number
phenotypes.17 The prostatic basal cells, at least in of ducts followed the anterior course of growth
rodents, are complex structures with processes as seen in the lateral lobe.
that wrap around the ducts; this phenotype is not Lowsley’s work started a debate over the
obvious from traditional histologic sections.18,19 nomenclature used to describe the prostate anat-
Concurrent with epithelial differentiation, the UGS omy that continued for 70 years or so. In the adult
mesenchyme proliferates and differentiates into human the lobes that he described are fused and
interfasicular fibroblasts and prostatic smooth cannot be separated or defined by dissection,
muscle.20 Postnatally, under the influence of giving rise to several different views on the
androgens, the epithelial cells undergo differentia- anatomic division of the human prostate.25–28
tion, including the expression of androgen The situation is further confused by the fact that,
receptors, and begin to synthesize a variety of in most other animals, including some other pri-
lobe- and species-specific secretory products.21 mates, the various prostatic lobes are separable
In the mouse most prostatic branch points in varying degrees on an anatomic, histologic,
develop before 15 days of age22 and most of the and physiologic basis.
growth and development of the prostate is The nomenclature that is now most commonly
complete by 60 days of age.23 In contrast, the hu- used to describe the structure of the human pros-
man prostate does not grow significantly between tate is that of McNeal.25 McNeal divided the pros-
birth and puberty, when growth commences in tate into three major areas that are histologically
response to rising androgen levels. The prostate distinct and anatomically separate (Fig. 1). These
then slowly increases in size over several years. areas are the nonglandular fibromuscular stroma
It should be noted that, while androgens drive that surrounds the organ and the two glandular re-
the development and growth of the prostate, gions termed peripheral and central zones, which
they also play a key role in maintaining a growth- contain a complex yet histologically distinct ductal
quiescent adult organ. It is noteworthy that young system. The central zone was described as a
adult males, in whom androgen levels are at their wedge of glandular tissue that constitutes most
lifetime peak, do not suffer from prostatic enlarge- of the base of the prostate and surrounds the ejac-
ment or cancer; rather, these are diseases associ- ulatory ducts. The peripheral zone made up the
ated with aging and a decrease in serum androgen remainder of the gland. It surrounded most of the
titers. central zone and extended caudally to partially
282 Aaron et al

Fig. 1. Structure of human and mouse prostate. (Left) Diagram of an adult human prostate showing the urethra
and bladder in relation to the three major glandular regions of the prostate as described by McNeal: central zone,
peripheral zone, and transitional zone. (Right) Diagram depicting the four major prostatic lobes of the mouse
prostate, the rat has a similar organization: lateral prostate, dorsal prostate, ventral prostate, and anterior
prostate. (Adapted from Sugimura Y, Cunha GR, Donjacour AA. Morphogenesis of ductal networks in the mouse
prostate. Biol Reprod 1986;34:963; and [left] McNeal JE. Anatomy of the prostateand morphogenesis of BPH. Prog
Clin Biol Res 1984;145:27–53.)

surround the distal portion of the urethra. These ducts and acini are much larger and of irreg-
McNeal’s classification of the central zone ular contour. The acini are polyhedral in cross-
included the middle lobe and part of the posterior section. The muscular stroma is much more
lobe described in Lowsley’s earlier studies, compact than in the peripheral zone. The central
whereas the peripheral zone included Lowsley’s zone has a low incidence of disease.
lateral lobes and a portion of the posterior lobe. The transitional zone surrounds the urethra
McNeal also identified an additional, smaller, glan- between the bladder and the verumontanum.
dular region that surrounded the prostatic urethra, This is a small volume of the prostate, perhaps
referred to as the transition zone. 5% in the normal organ, but is the principal site
The peripheral zone ducts exit directly laterally of BPH pathogenesis. Nodular expansion of this
from the posterolateral recesses of the urethral region of the prostate results in compression of
wall. The system consists of small, simple round the urethra and the partial bladder outlet obstruc-
to oval acinar structures emptying into long narrow tion associated with BPH.
ducts surrounded by a stroma of loosely arranged Unlike the human, the rodent prostate is not
and randomly interwoven muscle bundles. Ducts merged into one compact anatomic structure.
and acini are lined with simple columnar epithelium. The rodent prostate is composed of four distinct
This area is the principal site of prostatitis and car- lobular structures (see Fig. 1): (1) anterior lobe
cinoma of the prostate, although not of BPH. The (also known as the coagulating gland), (2) dorsal
peripheral zone includes the proximal urethral lobe, (3) ventral lobe, and (4) lateral lobe.16 These
segment of the prostate. This comprises the region lobes exist as pairs on the left and right sides.
of the prostate between the base of the urinary Because of differences in lobe-specific branching
bladder and the verumontanum (the area where morphogenesis, the final shape of each lobe is
the ejactulatory ducts feed into the urethra). The distinct.10
principal feature of this region, which comprises In rats and mice, the ventral lobes are located
about 5% of the total prostate mass, is the prepro- immediately below the urinary bladder on the
static sphincter. The sphincter is a cylindrical sleeve ventral aspect of the urethra. The lateral lobes lie
of smooth muscle that stretches from the base of just below the coagulating glands and seminal
the bladder to the verumontanum. vesicles, partially overlapping the ventral lobes
The central zone ducts run predominantly and dorsally blend with the dorsal lobe.29,30 The
proximally, closely following the ejaculatory ducts. dorsal lobes are found inferior and posterior to
Prostate Anatomy and Embryology and BPH 283

the urinary bladder, behind and below the coagu- resulting in focalized formation of new ductal archi-
lating glands and seminal vesicles. The anterior tecture in the transition zone of the prostate (see
lobes, or coagulating glands, are directly adjacent Fig. 2). He described pure stromal nodules and,
to the seminal vesicles. more commonly, nodules that had been invaded
Lobe/zone homology between the rodent by epithelium to form new glandular architecture.
and human prostates has been suggested by McNeal also made the point that the glands them-
various authors. However, the 2001 Bar Harbor selves appear normal (Fig. 3); it is the overall focal
Consensus meeting concluded that “there is no organization that is definitive of BPH (see Fig. 2).
existing supporting evidence for a direct relation- This is in contrast to the epithelial or stromal hyper-
ship between the specific mouse prostate lobes plasia seen in many rodent models. These focal
and the specific zones in the human prostate.”31 nodules adjacent to the urethra give rise to urethral
compression and obstruction. One of the central
ETIOLOGY OF BENIGN PROSTATIC tenets of McNeal’s hypothesis was that adult pros-
HYPERPLASIA tatic epithelium should retain an ability to respond
to inductive signaling with proliferation and new
There are three well-studied conditions that affect ductal branching morphogenesis. We, and others,
the prostate: (1) BPH, (2) prostate cancer, and (3) verified this concept for adult rat, mouse, and
prostatitis. BPH is a nonmalignant enlargement human prostatic epithelium.38–40
of the prostate gland and refers to the stromal Work on canine BPH showed that the condition
and glandular epithelial hyperplasia that occurs can be induced with androstanediol and with com-
in the transition zone of the prostate (Fig. 2).32 binations of androstanediol and estradiol. A com-
Clinically, the condition manifests with lower bined dose of dihydrotestosterone and estradiol
urinary tract symptoms (LUTS) consisting of was also found to induce the disease.41,42 In
obstructive (weak urination stream, incomplete men, levels of serum testosterone decrease by
bladder emptying, hesitancy) and irritative symp- about 35% between the ages of 21 and 85 against
toms (frequency, urgency, nocturia).33 LUTS can a constant level of estradiol. Thus, there is a
result from a variety of conditions including prob- change in the androgen/estrogen ratio, which
lems relating to bladder innervation and aging, has been suggested to be sufficient to promote
and the outflow obstruction caused by BPH. the growth of BPH. However, because these
LUTS caused by BPH increases with age, and changes are not significant until after the first initi-
nearly all men develop histologic BPH by 90 years ation of the disease, their relationship to its induc-
of age.34 BPH is not generally considered to be a tion can be questioned.43
precursor lesion to prostate cancer. McNeal’s hypothesis does not address the
BPH is a common condition linked to aging and underlying issue of why “mesenchymal reawaken-
the presence of functional testes. McNeal35–37 pro- ing” may occur or whether there are other etiologic
posed the idea that BPH results from a “reawaken- factors in play. Common comorbidities suggest a
ing” of inductive potential in adult prostatic stroma role for inflammation and possibly metabolic

Fig. 2. Appearance of BPH in human prostate. (Left) Gross anatomy of a human prostate affected by BPH in the
transitional zone. Hyperplastic nodules (arrowheads) are clearly visible in the transitional zone (TZ) but not the
peripheral zone (PZ) of the gross sample. (Right) (H&E) stained wholemount cross-section of a human prostate
affected by BPH in the transitional zone. The architectural organization of the glandular structures within
the nodules (arrowheads) is evident in this low-magnification figure. (Courtesy of Scott B. Shappell, MD, PhD,
Dallas, TX.)
284 Aaron et al

increased T and B lymphocytes.52 Elevated levels


of inflammatory cells have also been detected in
the interstitium and surrounding epithelial glands
of human BPH.53 Infiltration of inflammatory cells
in BPH is accompanied by increases in proinflam-
matory cytokines. Elevated levels of interleukin-2,
-8, -17, and interferon-g have been shown in
BPH samples.54–56 Cytokine expression is seen
in early development where the cytokines have
direct mitogenic effects on the prostate.57,58
The mechanistic basis for the initiation and
progression of BPH from asymptomatic to symp-
tomatic remains unclear. Several potential causes
have been attributed to the overgrowth of smooth
muscle tissue and glandular epithelial tissue in the
prostate. These include aging, genetic factors,
hormonal changes, and lifestyle.33,59,60 Although
there is still much work to be done to fully
Fig. 3. Structure of individual glands within a focus of
BPH. Prostatic glands are composed of columnar understand the basis of BPH progression, such re-
luminal epithelial cells and more flattened basal cells sources as animal models to study BPH are limited
surrounded by well-differentiated smooth muscle. and there is a pressing need for new approaches.
Occasional capillaries are seen spaced around the BPH was primarily treated surgically for many
ducts adjacent to the basal epithelium (Hematoxylin years. However, in the 1990s this was superseded
and Eosin stain original magnification 200). by the medical approaches that are now front-line
therapy. 5a-Reductase inhibitors, such as finaste-
ride and dutasteride, and a-adrenergic blockers,
anomalies in the pathogenesis of BPH. Obesity is such as doxazosin and tamsulosin, are used to
an epidemic in many developed countries. Low shrink and relax the organ, respectively. The
levels of physical activity compound this situation, MTOPS study demonstrated that a combination
giving rise to many diseases and patterns of of the a-blocker doxazosin and the 5a-reductase
comorbidity including cardiovascular disease, inhibitor finasteride is more effective at reducing
increased insulin resistance, and type II diabetes. LUTS progression than either drug given alone.48
Insulin resistance may well be an underlying factor Although these approaches are effective in many
resulting in metabolic syndrome, a condition patients, a significant proportion, in the range of
affecting around 50 million Americans. Metabolic 35%, showed progressive disease even in the
syndrome includes impaired glucose metabolism, face of the two-drug combination.48,49 A detailed
elevated weight, altered fat distribution, and understanding of the pathways that lead to the
hypertension, along with elevated C-reactive pro- genesis of BPH nodules would assist in the design
tein (which is associated with chronic intrapro- of better or complementary therapies.
static inflammation in BPH).44,45 Although causal
links to BPH remain unproven, there seems to be ANIMAL MODELS IN THE STUDY OF BENIGN
a link between metabolic syndrome and LUTS.46 PROSTATIC HYPERPLASIA
Diabetes and increased LUTS severity are signifi-
cantly correlated, even when other covariables, Animal models are necessary for systematic and
such as age, are factored out.47 mechanistic studies of human prostate diseases.
Obesity is a well-recognized proinflammatory The dog and the chimpanzee are the only animals
condition, and increased inflammation is closely other than humans known to suffer from BPH. As
associated BPH severity, progression, and might be expected in a closely related species,
increased urinary retention.48,49 In a mouse model the anatomy of the chimpanzee prostate is a close
of chronic prostatitis, regions of epithelial hyper- match for the human organ. However, chimpan-
plasia and dysplasia were found adjacent to areas zees are not a useful experimental model, and
of inflammation.50 In addition inflammation, activa- reports of BPH in this species demonstrate that,
tion of nuclear factor-kB signaling, and subse- as in humans, the disease is sporadic and associ-
quent and expression of constitutively active ated with aging.61 Historically several studies were
androgen receptor variant 7 have been shown performed on spontaneously arising BPH in the
to correlate with BPH progression and prostate canine prostate. Canine BPH, like its human coun-
volume.51 Stromal nodules of BPH contain terpart, arises with increasing frequency with age
Prostate Anatomy and Embryology and BPH 285

and requires functional testes. The diseases differ, using the ARR2PB promoter allowing for targeted
in that human BPH is strongly focal with distinct expression of 15-LOX-2 or 15-LOX-2sv-b, a splice
nodules of hyperplasia within the gland, whereas variant lacking arachidonic acid-metabolizing
the canine disease is diffuse, occurring throughout activity. These manipulations resulted in age-
the gland.42,62 In the dog, there is therefore a dependent increases in prostatic wet weight with
general expansion of the gland, which is less predominantly epithelial hyperplasia.66 A condi-
anatomically fixed than in humans, resulting in tional knockout of PPARg in the mouse prostate
compression of the rectum, producing constipa- also resulted in increases in prostate size with
tion as a symptom as opposed to the urinary epithelial hyperplasia that progressed to prostatic
retention found in humans. Practical consider- intraepithelial neoplasia and occasional cancer.67
ations, notably that the disease occurs in older This observation makes the point that epithelial
animals (generally >8 years) and the costs associ- hyperplasia in the mouse might be an early prema-
ated with maintaining colonies of large mammals, lignant change, clearly differentiating it from
have severely limited work in this model. human BPH.
BPH in humans has several common compo- Nonobese diabetic mice represent a model of
nents; the essential element is the focal nodular immune dysregulation and type I diabetes. First
growth that usually occurs close to the urethra. reported in 1980, these mice exhibit spontaneous
There is also commonly inflammation and the development of autoimmune insulin-dependent
activation of associated transcription factors, diabetes mellitus.68 These mice are important
such as nuclear factor-kB, and upregulation of because the autoimmune response is not fully
the androgen receptor and constitutively active penetrant; as a result, subgroups of mice exhibit
variants. This process is associated with compres- diabetes, with or without prostatic inflammation.
sion of the urethra and LUTS caused by partial This allows for independent assessment of the
bladder outlet obstruction. The anatomy of the effects of these two human BPH-relevant vari-
rodent prostate largely precludes the recapitula- ables. Histochemical analysis reveals a reduction
tion of all of these characteristics in a single model. of the epithelium and increased stroma. As a
For this reason it is important to assess which result, muscular and collagen hypertrophy in the
particular aspects of the human disease are pre- prostatic gland when inflammation occurs.69 In
sent in any given model. Most of the models that noninflamed but nonobese diabetic/severe com-
are available develop some form of hyperplasia, bined immune deficiency mice, a strong epithelial
either of the epithelium, stroma, or both; however, hyperplastic phenotype in the anterior and ventral
the glandular structures are generally histologically prostate has been noted.70
abnormal, and appropriate caution must be exer-
cised in interpreting the data. Focalized glandular SUMMARY
expansion with normal-appearing new glands, as
seen in human BPH nodules, is not evident in Many researchers have studied the embryology,
most animal models. For these reasons, most of development, and anatomy of the human prostate.
these should not be considered models of BPH, Debates over the nomenclature to describe the
but, rather, of whichever processes of the disease gland have been settled and standardized nomen-
they most accurately reflect. clature exists. BPH is a complex disease that
Manipulating the hormonal environment has probably has multiple causes often occurring in
been used in rats to induce prostate cancer.63 patients with complex comorbidities, prominently
Similar manipulations can also be applied to including obesity and diabetes.
induce bladder outflow obstruction and inflamma- Animal models have proven to be useful in
tion.64 Applying such a regimen to mice to mimic understanding the underlying mechanisms of
the changes in the testosterone/estrogen ratio many human diseases. However, the structure of
seen in the aging human male results in bladder the human and rodent prostates is very different.
outflow obstruction and urination patterns that in Extrapolation of data between species requires
some ways mirror human LUTS.65 In this model an understanding of these differences and of the
there are increases in glandular ducts surrounding limitations of specific models.
the proximal urethra with the potential to
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