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Prostate development: a historical perspective
r 2008, Copyright the Author Differentiation (2008) 76:565–577 DOI: 10.1111/j.1432-0436.2008.00278.x Journal compilation r 2008, International Society of Differentiation
R E V IE W A RT I C L E
Barry G. Timms
Prostate development: a historical perspective
Received February 14, 2008; accepted in revised form February 19, 2008
Abstract The regional anatomy of the human prostate has been debated periodically over the last century with various levels of controversy and agreement, beginning with the concept of lobes and replaced by the current model of zones. During this period a variety of classifications have been proposed, based upon the studies of glandular morphogenesis, responses to hormones or histopathology. The current paradigm suggests that the regional differences seen in the prostate of both animal models and the human are a consequence of specific epithelial–mesenchymal interactions along the cranial–caudal axis of the urogenital sinus. The distinctive regional patterns seen in the rodent prostate and the histological heterogeneity of the human adult gland all point to the modification of the distal portion of the ducts, while the proximal segments retain their spatial relationship to the urethra that was formed during fetal development. This suggests that the early epithelial budding that occurs in utero represents a common, fairly symmetrical pattern of growth in many species, while the regional differences in branching morphogenesis and cytodifferentiation are controlled by the instructional influences of mesenchyme and temporal expression of growth factors. Perturbation of the normal processes involved during critical periods of fetal development during reproductive organ development may also play a role in the susceptibility of the prostate to disease in adulthood. Past descriptions of detailed anatomical studies, which span over a century, have provided much insight into the architecture and processes that form a complex tubulo-alveolar gland. New insights into the ductal detail and the advent of sophisticated . ) Barry G. Timms (* Division of Basic Biomedical Sciences Sanford School of Medicine University of South Dakota 414 E. Clark St. Vermillion SD 57069, USA Tel/Fax: 1 605 677 5144 E-mail: [email protected]
analyses of cell–cell interactions and molecular mechanisms controlling pathways of cellular growth, differentiation, and apoptosis will likely lead to new approaches for prevention and therapy of prostatic diseases. Key words prostate development anatomy 3-D reconstruction
Introduction When Andreas Vesalius published his anatomical illustrations in 1543, his observations of the male accessory sex glands formed part of the wider objective to clarify earlier misunderstandings about human organ function (Saunders and O’Malley, 1950). From those historical beginnings to the modern day concepts of cellular mechanisms, our understanding of the structure and function of the prostate has made enormous progress. Nonetheless, some details, including normal development and processes that lead to disease, remain enigmatic. Although the clinical manifestations of prostate disorders are not typically observed until later in life, there is some evidence to suggest that the pathology may have fetal origins (Bateson et al., 2004). It is now widely known that except for skin cancer, prostate cancer is the most common cancer among men, and accounts for almost one in every three cancers diagnosed in US males (American Cancer Society, 2007). Despite major advances in basic science and clinical medicine, prostate disease is still a major health concern. Also, the detailed understanding of adult prostatic anatomy in the human male has not progressed as well as for other glandular structures because of a confusing history of structural terminology. The adult prostate is a complex tubulo-alveolar gland that still presents some challenges in understanding its three-dimensional (3-D) architecture. For this reason, there is reliance upon suitable animal models, and much has been learned during the past three decades that has proven invaluable in pos-
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tulating explanations for the human process of both normal growth and development and the etiology of disease.
A history of prostate anatomy Classical anatomical descriptions of the prostate began in the late 1800s. Aside from the work of Vesalius, an early description of the mammalian accessory sex glands was reported by Gerard Blasius in his treatise on comparative anatomy, which was published in 1674 and described simply as ‘‘glandulae’’ surrounding the neck of the bladder (Cole, 1949). At about the same period the importance of the clinical perspective was being developed through the observation by Samuel Collins that prostate enlargement caused bladder neck obstruction (Zuckerman, 1936). This was further established in the 18th century by Giambattista Morgagni, the founder of modern pathology (Franks, 1954). In his review of benign prostatic hyperplasia (BPH), Franks notes that Morgagni was able to identify the site of origin for prostate hyperplasia and the association of the pathology with elderly men. As far as the functional capacity of the gland, John Hunter made several important observations from cadaveric dissections. In 1786 he wrote that ‘‘The prostate and Cowper’s glands, and those of the urethra, which in the perfect male are soft and bulky, with a secretion salt to the taste, in the castrated animal are small, flabby, tough and ligamentous, and have little secretion.’’ Zuckerman (1936) points out the notable fact that even though the inference of the observation would suggest that castration might be considered a treatment for the relief of prostate enlargement, the therapeutic value was not considered until almost a century later. The current understanding of prostate development and anatomy progressed through the publication of new findings each decade over the past century (Pallin, 1901; Lowsley, 1912; Johnson, 1920; Price, 1936; LeDuc, 1939; Huggins and Webster, 1948; Gil Vernet, 1953; McNeal, 1968, 1978, 1983; Timms et al., 1994). McNeal (1980) suggested that the advancement of this understanding was partly hampered by compliance to older anatomical descriptions that were accepted, rather than challenged, until later studies (Franks, 1954; McNeal, 1968; Tisell and Salander, 1975). In the late 19th century an extensive literature was published in Germany that focused on the anatomical details of embryological development, including the accessory sex glands and urogenital structures. Aumu¨ller (1979) reviewed these studies, in which the classic works of Pallin (1901), Lowsley (1912), and Johnson (1920) were discussed and compared. These anatomical studies were facilitated by the use of a novel procedure of tissue section reconstruction, called ‘‘plattenmodellirmethode’’ described by Born (1883). This technique of us-
ing wax modeling to provide a basis for illustrating prostate development was used in several papers (Evatt, 1908; Johnson, 1922; Dauge et al., 1986). However, Lowsley’s diagram of a newborn male prostate was probably one of the most influential, and later controversial, anatomical descriptions of prostate anatomy (Fig. 1). There was no doubt that this model was an accurate reconstruction of serial histological sections, the questions that were raised over the ensuing years were more to do with the accuracy of anatomical interpretation. This model influenced many investigators and was used as a standard for describing prostate anatomy in several contemporary medical textbooks. From this model, Lowsley defined the concept of prostate lobes and the regional focus of disease. A history of the divergent views surrounding this concept was discussed by McNeal (1980). Several alternative models of prostate anatomy emerged over a period of 50 years (Fig. 2) and the currently accepted concept of prostate zones was eventually established in the early 1980s (McNeal, 1983). A recapitulation of earlier work by Price (1963) prompted additional examination of the embryonic development of the prostate with the conclusion that the organization of the ductal outgrowths from the urogenital sinus (UGS) provides a related but optional model for the concept of prostate regions or zones (Timms et al., 1994).
Embryology of the human prostate The anlage of the human prostate begins about the 10th week of gestation and is a consequence of sequential prior events, including production of testosterone by the fetal testis around 8 weeks. The initial outgrowths of the prostatic buds from the UGS occur in response to the binding of 5a-dihydrotesterone to androgen receptors localized in the surrounding mesenchymal tissue (Shannon and Cunha, 1983; Takeda et al., 1985; Takeda and Chang, 1991). These outgrowths begin as solid cords of epithelial cells that elongate and undergo extensive branching morphogenesis during the latter stages of fetal growth. During the postnatal period, under the influence of androgens, the ducts form a patent lumen, and the epithelium lining the acini differentiate and synthesize a variety of secretory products. The fully developed adult human prostate lies at the neck of the bladder and surrounds the urethra (Fig. 3A). The anterior or ventral aspect of the gland is almost entirely fibromuscular, while the glandular region occupies the posterior part of the tissue and surrounds the ejaculatory ducts as they enter the urethra on each side of the verumontanum. Compared with the compact human gland, the adult prostate of many other mammals has distinct
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Fig. 1 An illustration derived from a wax model reconstruction of a newborn male prostate. This sagittal view through the prostatic urethra shows the lobes described by Lowsley (1912). Anterior branches of lateral lobes (Lat.), posterior lobe (P.L.) and middle lobe (M.L.).
Fig. 2 (A) Sagittal diagram of the human prostate showing regional classification of the gland described by Gil Vernet (1953). Intrasphincteric submucosal glands (1); middle portion of cranial gland (2); anterior lobe of the cranial (3); superior duct (4), middle duct (4 0 ) and inferior duct (400 ) of the caudal gland; glands of Littre´ (5); ejaculatory duct (6). (B) Sagittal diagram of adult human prostate showing distal urethra (UD), proximal urethra (UP) and ejaculatory duct (E). These structures are shown in relation to three
major glandular regions of the prostate described by McNeal (1983). Central zone (CZ), peripheral zone (PZ) and transitional zone (TZ). (C) Graphical three-dimensional representation of McNeal’s three glandular zones of the prostate (Lee et al., 1989). Peripheral zone (yellow), central zone (red), transition zone (blue), anterior fibromuscular stroma (green). (Reproduced from Naz, RJ, Prostate: Basic and Clinical Aspects. CRC Press, Boca Raton, 1997. With permission.)
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Fig. 3 (A) Diagrams of frontal and sagittal sections of the male urogenital complex illustrationg the anatomical position of the adult prostate and associated structures. The prostatic zones described by McNeal (1983) are indicated: central zone (CZ), peripheral zone (PZ), anterior fibromuscular stroma (AFS), and transition zone (TZ). (B) Male accessory sex organs of the adult
male rat. A, anterior view; B, lateral view; C, anterior view with the bladder deflected caudally. Ampullary gland of the vas deferens (AG); bladder (B); coagulating gland (CG); dorsal prostate (DP); lateral prostate (LP); seminal vesicle (SV); ventral prostate (VP); vas deferens (VD); deferential vein (DV).
regional lobes (Fig. 3B). The location of disease in the human suggested a similar, though less obvious lobular arrangement, based upon early embryological studies (Price, 1963). Lobe homology has been proposed to exist between animal models and the human and is the basis for studying these models to better facilitate an understanding of normal and abnormal pros-
tate growth mechanisms (Dunning, 1963; McNeal, 1983). Consistent among all the anatomical research on the prostate is the finding that origins of the fetal prostatic ducts emerge in a ventral, lateral, and dorsal pattern from the UGS. Whether these ducts form distinct lobes or regions in the human has been a perennial question,
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partly addressed through distinctions in histology, biochemistry, or pathology. In this regard, McNeal’s description of zonal anatomy is now accepted as the standard reference for understanding the normal and abnormal structure of the human prostate (Lee et al., 1989).
Prostate development and anatomy Through the use of anatomical models from serial sections, Lowsley (1912) described the lobes of the fetal human prostate and attempted to clarify some of the controversy regarding the origin of the middle and posterior lobes described by earlier investigators using similar anatomical techniques (Pallin, 1901; Evatt, 1908). Using tissue from a 13-week human fetus, Lowsley identified five separate groups of prostatic ducts emanating from the UGS and called them lobes (Fig. 1). The ventral lobe consisted of four pairs of epithelial buds and the median lobe was formed by about a dozen tubules associated with the posterior urethra, and growing cranially between the neck of the bladder and the openings of the ejaculatory ducts. The largest group of tubules was the paired left and right lateral tubules, which originated from the sides of the urethra and followed the prostatic sulci, or furrows. These epithelial outgrowths grew posteriorly and laterally. Distal to the ejaculatory ducts, the tubules were located on the caudal portion of the urethra and formed the posterior lobe. Their direction of growth was primarily toward the bladder. However, a small number of ducts followed the anterior course of growth seen in the lateral lobe. Through examination of samples from later stages of fetal growth (30 weeks) and a newborn male, Lowsley was able to determine the average number of tubules that were associated with each lobe. The largest number of ducts was found in the lateral region, followed by those of the middle and posterior lobes. Although the 3D wax model presented a novel perspective of the newborn prostate anatomy, the spatial relationship of the ductal origins from the urethra was obscured by the developing complexity of ductal branching, especially at the point where the posterior and middle lobes merged. Using a similar wax model reconstruction approach, Johnson (1920) prepared anatomical drawings at 10 and 14 weeks of fetal growth. He could not confirm the definitions of lobes except for the middle lobe ducts. He grouped the anterior, dorsal, and lateral ducts as gland buds. He did note that some ducts emanated from the urethra above and below the entrance of the ejaculatory ducts. The models clearly show a bilateral symmetry of prostatic ductal outgrowth and a pattern of bud formation around the ejaculatory ducts that would be described in much later studies (Timms et al., 1994), but not mentioned in his paper. The relationship of ductal
outgrowths from the UGS that is observed in the fetus remains unchanged in the adult gland and suggests an intimate link between the two ends of the growth spectrum (Price, 1963). What differs between these two stages of growth is the complex branching morphogenesis that occurs postnatally and following puberty, forming the actively functioning secretory gland. The lobe concept was disputed by Franks (1954). Instead, he described three concentric regions, the short inner mucosal glands around the urethra, a central group of long, branched ducts and long external glands, which he termed the ‘‘prostate gland proper.’’ This new terminology was derived mainly from observations on diseased glands, noting that the focal location of BPH was within the inner glands, and carcinoma was predominantly found in the external ducts. This new nomenclature found its way into anatomical texts. A semantic shift in nomenclature prompted McNeal to further propose a new concept of zonal anatomy (McNeal, 1968, 1978). Again, using serial sections in different planes, McNeal examined many human prostate samples, and using the verumontanum as a reference point, described a schematic 3-D model. As the urethra passes through the prostate, the proximal segment extends from the bladder neck to the verumontanum, where it angles at 351–401 to form the distal segment to the external urethral sphincter. The central zone was described as a wedge of glandular tissue forming most of the base of the prostate and surrounding the ejaculatory ducts (Fig. 2B). The peripheral zone made up the remainder of the gland, surrounded most of the central zone, and extended caudally to partly surround the distal portion of the urethra. This newer classification of the central zone included the middle lobe and part of the posterior lobe described in earlier studies, and the peripheral zone therefore included Lowsley’s lateral lobes and a portion of the posterior lobe. The zonal classification was further confirmed from histological examination, which showed a definite epithelial and acinar heterogeneity between zones. These histological differences had been previously noted by Tisell and Salander (1975), but the regional anatomy nomenclature of middle, posterior, and lateral lobes was still used. Because of the histological similarities reported in both studies, McNeal suggested that the middle lobe was equivalent to his description of the central zone and the lateral and posterior lobes could be combined as an analogous peripheral zone (McNeal, 1980). A further observation by McNeal was the identification of urethral glands, surrounded by the urethral sphincter, as the exclusive site of BPH. This region was subsequently termed the transition zone. Ducts from this zone were found to exit laterally from the urethra close to the origin of the most cranial ducts of the posterior zone. A clear illustration of the zonal anatomy concept was illustrated in a 3-D schematic model by Lee et al. (1989; Fig. 2C).
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Fig. 4 Serial section reconstructions of the rat urogenital complex on GD 18, 19, 20, 21, and postnatal day 2 (D2), illustrating the stages of early prostate development. Prostate morphogenesis begins at GD 18 with small ventral prostate buds and by GD 19 the dorsal, ventral, lateral, and coagulating gland buds have developed. On GD 21 (the day before birth), ductal budding from the urogenital sinus is essentially complete. U, urethra; DP, dorsal prostate; LP, lateral prostate; VP, ventral prostate; CG, coagulating gland; SV, seminal vesicle; VD, vas deferens. Secondary and tertiary distal tip branching is observed in the ventral prostate after birth (D2). Branching has also been initiated in the seminal vesicles and coagulating glands. By comparison, minimal to no branching is evident in the dorsal and lateral prostate ducts. (Redrawn from Timms et al., Toxicol Sci 67:264, 2002. With permission.)
Along with the concept of zonal anatomy, McNeal introduced the hypothesis of a ‘‘reawakening of embryonic inductive interactions’’ in which he describes inappropriate new ductal budding that occurs during the pathogenesis of BPH. This was thought to be induced by adjacent areas of stromal proliferation and confirmed a similar hypothesis proposed by Reischauer (1925), and discussed by LeDuc (1939). The significance of this stromal–epithelial interaction in both normal and abnormal growth of the prostate has become the subject of numerous studies and reviews (Cunha, 1972; Cunha et al., 1980, 1987, 1995; Tenniswood, 1986; Aumu¨ller, 1989; Shapiro, 1990). In a review of the different models of prostate anatomy (Villers et al., 1991; Villers, 1994), there is reference to a less widely known publication Gil Vernet (1953) in which an extensive histological analysis of the prostate during many stages of growth from the embryo to adulthood, plus pathology is presented. Interestingly, the author subdivided the two main glandular regions according to their position along the proximal–distal urethral axis (Fig. 2A).
Animal models of prostate development Restrictions on the use of normal human fetal tissue for scientific studies have led to a continued necessity for
suitable animal models, on the principle that satisfactory homologies exist to extrapolate findings to humans. With regards to anatomy, there have been many parallel animal studies. Extensive light and electron microscopical analysis of the rat prostate has been performed during embryonic, postnatal, and adult stages of growth (Price, 1936; Price and Williams-Ashman, 1961; Brandes, 1966; Jesik et al., 1982). Because of the 3-D complexity of the developing prostatic ductal system, these studies only provided a descriptive summary of morphogenesis and architecture. Using the alternative technique of whole-mount micro-dissection of mouse and rat prostate, a precise delineation of all the ductal networks in early postnatal and adult growth has been determined (Sugimura et al., 1986; Hayashi et al., 1991). However, the spatial relationships of the individual lobes and their ductal origins from the urethra cannot be determined using this methodology. A significant observation, previously reported by Price (1936) is that the relationship of the ductal openings into the prostatic urethra remains the same throughout the entire development period and into adulthood. This suggests that the determination of regional ductal budding patterns during prostate development could be indicative of adult glandular architecture. In addition, a comparison of these patterns between species would permit confirmation of homologies. The application of a novel 3-D, computer-
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Fig. 5 (A) Schematic illustration of the fetal rodent urogenital sinus (UGS) showing the ductal budding pattern. The cranial ducts of the ventral line of budding are associated with a ventral mesenchymal pad. Following contact and growth into this pad, the distal tips of the ventral prostatic buds will undergo branching morphogenesis (light blue/dark blue). Adjacent buds along this line usually form part of the lateral lobe (gray). Mesenchyme surrounding dorsal outgrowths is contiguous with that of the Wolffian duct but not depicted in the diagram. Condensations of mesenchyme are also found at the tips of the lateral buds (not illustrated). The most cranial outgrowths on the dorsal aspect of the UGS form the coagulating gland. All buds grow into a periurethral
mesenchyme that is surrounded by sleeve of smooth muscle at the caudal portion of the UGS. As the buds elongate this smooth muscle encapsulates the proximal regions of the ducts. The dorsal line of buds is associated with ridges on either side of the UGS and surrounds the paired orifices of the ejaculatory ducts and the prostatic utricle. (B) Three-dimensional reconstruction the mouse UGS from a ventral–caudal perspective, showing the paired lateral (LP), and ventral (VP) ducts. The distal tips of the ventral ducts (arrow) are embedded in the ventral mesenchymal pad (VMP) where branching morphogenesis has been initiated. Similar, but smaller condensations of mesenchyme are found at the tips of the lateral ducts (arrowhead).
assisted reconstruction technique has led to a better understanding of these ductal budding patterns and an opportunity to provide visual confirmation of the homologies that exist between the mouse, rat, and human
prostate (Timms et al., 1994). This 3-D method is essentially a modern version of the older wax model reconstruction that requires contour tracing of anatomical structures within each histological section
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Fig. 6 Comparisons of the early wax model reconstructions of a rodent (Born, 1883) and human fetal prostate (Johnson, 1920; A and C) with surface-rendered computer reconstructions of a normal newborn rat prostate (B) and 13-week human male. Similar developmental features of prostate duct development are observed. Urethra (red); lateral prostate (yellow); dorsal prostate (green—caudal ducts; gray—cranial ducts); coagulating gland (dark blue); ventral prostate (light blue); seminal vesicles (purple); vas deferens (light purple); utricle (white).
of a serially sectioned organ such as the developing prostate. Advances in software have led to the ability to prepare detailed surface-rendered models of tissues as small as a cubic millimeter and provide volumetric data (vom Saal et al., 1997; Timms et al., 2005). Such reconstructions are useful for rotational viewing and stereo-pair images and provide a unique opportunity to view spatial relationships of entire or selected regions of the prostate. Using 3-D reconstruction, prostate development in the rat from the earliest evidence of epithelial budding at gestation day 18, through postnatal day 2, clearly illustrates the temporal and spatial relationships of the ductal budding patterns (Fig. 4). Ventral and dorsal budding occur at about the same time. However, at later stages of development (GD 21), just before birth, initial stages of branching morphogenesis begins at the distal tips of the ventral ducts. Both primary and secondary branch points have occurred by day 2 after birth. A schematic of the typical epithelial budding pattern that occurs during late gestation in the developing rat and mouse prostate is illustrated in Figure 5A. Several lines of ductal outgrowths, or buds, follow a fairly symmetrical arrangement and are defined by their
origins on both the caudal–cranial and ventral–dorsal axes of the urethra (Timms et al., 1994). This study suggested that even though some epithelial buds develop as contiguous outgrowths, their subsequent fate will be dictated by juxtaposition to inductive mesenchyme. Further significant findings from these studies identified specific regions of mesenchymal tissue that were associated with specific patterns of distal tip branching morphogenesis. This was most clearly observed in the ventral region and was classified as the ‘‘ventral mesenchymal pad’’ (Fig. 5B). Later studies reported that this pad occured in both male and female animals (Timms et al., 1995) and is associated with the production of fibroblast growth factor 10 (Thomson and Cunha, 1999). Other condensations of mesenchyme on the lateral aspect of the urethra are also evident but not as clearly defined. It became apparent from such studies that the mesenchyme immediately surrounding the urethra (peri-urethral mesenchyme) likely differs in both composition and instructive growth factors. The former is associated with the initial outgrowth of the basal epithelial layer of the urothelium forming the solid cord of epithelial cells (prostate buds), while subsequent branching morphogenesis at the distal tips is initiated
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Fig. 7 Three-dimensional anaglyph views of the serial section reconstruction of a mouse urogenital sinus (UGS), shown from the normal anatomical aspect (gestation day 19). Urethra (red); dorsal buds (green); coagulating gland (dark blue); seminal vesicles (purple). Sequential views surrounding the central image, rotated at 301 increments, show a full 3601 view.
through contact with the specific adjacent mesenchyme. Unique regional branching patterns with different temporal relationships were observed in earlier studies (Sugimura et al., 1986; Hayashi et al., 1991) and confirmed by the 3-D methods. Just recently, a novel morphological approach using scanning electron microscopy (SEM) has also confirmed the budding patterns of the developing mouse prostate (Lin et al., 2003). In addition, a combination of whole-mount micro-dissection, immunofluorescence, confocal microscopy, and computer analysis has been used to study the complex anatomy of branching morphogenesis in wild-type and mutant mice by developing a ‘‘skeletonized’’ model of the ventral and anterior ducts (Almahbobi et al., 2005). Each approach has its own merits and drawbacks. Computer reconstruction provides real-time rotational viewing of the whole microanatomy of the developing prostate, but is a laborintensive process. The SEM approach is more rapid but only permits visualization and counting of the number and location of the prostate buds. The skeletonized model has proved a useful technology for studying detailed patterns of branching morphogenesis, but still relies upon micro-dissection and the inherent disruption of spatial relationships with neighboring ductal regions. Intriguing, but not unexpected similarities between the older wax-model reconstructions and recent computer
Fig. 8 Computer-assisted serial section reconstructions from a fetal mouse (gestation day 18; left) and human prostate (70 mm crownrump length/11 weeks; right). The seminal vesicle (SV) on the right side of each reconstruction have been omitted to facilitate viewing of the prostatic budding patterns. In the mouse, dorsal prostatic bud outgrowths (DP) are associated with the prostatic furrows of the urogenital sinus along the caudal–cranial axis. The coagulating gland (CG) exhibits three pairs of outgrowths and is associated with the dorso-cranial aspect of the urogenital sinus (UGS). The human fetal prostate shows dorsal outgrowths (green) that form a ‘‘horse-shoe’’ shaped pattern around the ejaculatory ducts (Ed) and prostatic ut-
ricle (Ut). A parallel line of buds grows from the lateral wall of the urogenital sinus (L). The most caudal of these buds exhibit an anterior direction of growth (). Several small periurethral outgrowths are evident in the proximal portion of the dorso-cranial urethra (arrow). The seminal vesicle (SV1) appears as a dorsal swelling on the vas deferens (VD1). Both views are from a superior right dorso-lateral perspective. At these stages of fetal growth the mouse and the human prostate budding patterns demonstrate striking similarities. The reconstruction of the human fetal prostate also shows the potential relationship to the future adult regions of the central (CZ), peripheral (PZ), and transitional (TZ) zones.
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Fig. 9 Three-dimensional reconstruction of the accessory sex glands (ASG) from a normal 6-day-old mouse. At this stage of postnatal development extensive ductal branching and organ development has occurred. Because of the complexity of tissue organization, individual components of the ASG have been removed to better illustrate spatial relationships. (A) Branching of the seminal vesicles (SV) is essentially completed at this stage of growth. The ampullary glands (AG) associated with the proximal region of the vas deferens (VD) are also formed. Elongation of the proximal urethra (U) occurs after birth, while the urogenital sinus region (UGS) remains similar in shape to that of the newborn. (B) The coagulating glands (CG) are typically formed by growth of a pair of major ducts on the left and right cranial aspects of the UGS. The coagulating gland ducts branch and become attached to the anterior curved surface of the seminal vesicles. (C) The distal tips of the lateral (LP1; LP2) and dorsal (DP) prostate have undergone some
primary bifurcation and swelling and make a right-angle turn at the boundary of the smooth muscle layer surrounding the UGS (not shown: see Fig. 5). Some distal lateral ducts grow in a ventral direction (LP1) while the more caudal and cranial distal ducts grow in a dorsal direction (LP2). (D) Two to three pairs of major ventral ducts (VPd) elongate with the urethra. The distal region of these ducts has developed extensive branching morphogenesis (VP) and formed into the distinctive lobe that is defined by the ventral mesenchymal pad of fetal stroma (not shown: see Fig. 5). The proximal ducts are also en-sheathed by a layer of periurethral smooth muscle (not shown). (E) and (F) Stereo pair images of the AGS structures (convergent viewing) illustrating the spatial relationships of the structures depicted in (A–D). Note the caudal curvature of the distal dorsal ducts and the two opposing directions of distal growth in the lateral prostate regions.
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Fig. 10 Three-dimensional serial section reconstruction of the urogenital sinus (UGS, red) from gestation day 19 mice exposed to low doses of estrogenic chemicals: diethylstilbestrol and bisphenol A during fetal development. All images are viewed from a left-lateral perspective. The images illustrate the differences in patterns of prostate ductal development following fetal exposure
to these chemicals compared with oil-treated controls. There is a significant increase in the total number of ducts in estrogen treated animals and a corresponding increase in overall prostate volume. Ventral prostate (VP, light blue); dorsal prostate (DP, green); lateral prostate (LP, yellow). Redrawn from Timms et al. (2005).
models are apparent (Fig. 6), but the more interesting similarities are those of the budding patterns between the developing rodent and human prostate (Figs. 6B,6D). The advantage of the 3-D models is the ability to rotate the images at the time of reconstruction or view in 3-D using anaglyph images (Fig. 7). The opportunity to accurately describe potential homologies follows naturally from such observations of similarities between species. For example, in the rat and mouse, the cranial buds of the dorsal prostate surrounding the ejaculatory ducts and associated with the Wolffian duct mesenchyme, compare to the central zone of the human (Figs. 6B,8). The most caudal lateral and dorsal ducts (Figs. 5A,6B,8) match the human peripheral zone, while the cranial ducts in the proximal region of the dorsal urethra (coagulating gland region), compare to the location of the transition zone (Fig. 8). Thus, examination of these regions in animal models with regard to understanding the mechanisms of growth control, epithelial–mesenchymal interactions and cellular differentiation is pertinent to understanding normal and pathological processes in the human prostate. Given the extensive branching morphogenesis that occurs in the first week after birth in the rat and mouse prostate, it has been a challenge to reconstruct the developing gland beyond the fetal period, or day of birth. However, as part of related studies to examine the effects of endocrine disruptors on prostate development (Hofkamp et al., 2008), the anatomy of the mouse prostate 6 days after birth was recently reconstructed. This technique clearly illustrates the complex postnatal architecture of the developing gland at this time (Fig. 9). The benefit of these models becomes apparent when specific anatomical regions are selectively removed to reveal adjacent structures. The in situ relationships are also preserved and the magnitude of branching devel-
opment in the ventral prostate, coagulating gland, and seminal vesicles is a prominent feature. The development of the ampullary glands surrounding the proximal part of the vas deferens is also revealed at this stage of postnatal growth. Because of the marked differences in ductal branching patterns that occur within the prostate, variations in temporal influences and spatial organization of the adjacent mesenchyme are important modulators of prostate morphogenesis (Sugimura et al., 1985; Mizuno and Yasugi, 1990; Timms et al., 1995; Cunha et al., 2004). These effects are likely imprinted during fetal development, including in utero hormone actions and have recently been discussed as the concept of developmental origins of health and disease (Silveira et al., 2007). This is important in the light or recent concerns about environmental influences and the sensitivity of the prostate to circulating levels of endogenous or exogenous hormones during critical periods of development (Risbridger et al., 2005; Edwards and Myers, 2007). Many studies now demonstrate that environmental chemicals have the capacity to disrupt normal functioning of the endocrine system through a variety of mechanisms (Naz, 2005). In this regard, examination of the prostate ductal budding patterns has proved to be a useful biological marker (vom Saal et al., 1997; Timms et al., 1999, 2002). From these investigations it became clear that the dorso-lateral region of the rodent prostate exhibits a unique growth response sensitivity following exposure to endocrine disruptors during fetal development (Fig. 10; Timms et al., 2005). This effect was a consequence of an increased number of prostatic buds developing from the UGS and a concomitant increase in the volume of the ducts. A recent study of the rat prostate exposed to environmental chemicals during development suggests that the process of ductal
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outgrowth and branching morphogenesis may be disrupted by independent mechanisms (Hofkamp et al., 2008). As discussed above, mesenchymal–epithelial interactions are important for regulating control of both development and subsequent growth of the prostate. Exposure to exogenous estrogens causes disruption of the level of expression of androgen and estrogen receptors in mesenchymal tissue (Richter et al., 2007). This supports the hypothesis that fetal estrogen exposure, within a physiological range, stimulates prostate growth by increasing expression of the androgen receptor gene in the mesenchyme. In animal models, a consequence of this disruption can lead to permanent increases in prostate size into adulthood (Gupta, 2000) and the potential for development of neoplastic transformations (Ho et al., 2006; Prins et al., 2008). Advances in our knowledge of the molecular mechanisms that control the growth and intricate micro-architecture of a complex gland have provided a foundation to determine the pathways and patterns for aberrant growth and disease. Acknowledgments The author wishes to thank Sandy Bradley and Luke Hofkamp for expert technical assistance with the 3-D reconstructions. In particular, Ms. Bradley devoted a considerable amount of time and effort in the preparation of the postnatal mouse reconstruction (Fig. 9). The continued support of Dr. Eric Neufeld, Department of Computer Science, University of Saskatchewan and Dr. Scott Lozanoff (University of Hawaii), in providing timely upgrades to WinSURFr is greatly appreciated.
References Almahbobi, G., Hedwards, S., Fricout, G., Jeulin, D., Bertram, J.F. and Risbridger, G.P. (2005) Computer-based detection of neonatal changes to branching morphogenesis reveals different mechanisms of and predicts prostate enlargement in mice haploinsufficient for bone morphogenetic protein 4. J Pathol 206: 52–61. American Cancer Society (2007) Cancer Facts & Figures Available at: http://www.cancer.org/docroot/stt/stt_0.asp Accessed February 2008. Aumu¨ller, G. (1979). In: Oksche, A. and Vollrath, L. eds. Prostate Gland and Seminal Vesicles, Handbuch der mikroskopischen Anatomie des Menschen. Chapter 1: Histogenesis and Organogenesis, pp. 3–52. Chapter 2: Prostate Gland, pp. 53–182. Vol. VII/6, Springer-Verlag, Berlin. Aumu¨ller, G. (1989) Morphologic and regulatory aspects of prostatic function. Anat Embryol 179:519–531. Bateson, P., Barker, D., Clutton-Brock, T., Deb, D., D’Udine, B., Foley, R.A., Gluckman, P., Godfrey, K., Kirkwood, T., Lahr, M.M., McNamara, J., Metcalfe, N.B., Monaghan, P., Spencer, H.G. and Sultan, S.E. (2004) Developmental plasticity and human health. Nature 430:419–421. Born, G. (1883) Die Plattenmodellirmethode. Arch Mikrosk Anat 22:584–599. Brandes, D. (1966) The fine structure and histochemistry of prostatic glands in relation to sex hormones. Int Rev Cytol 20:207– 276. Cole, F.J. (1949) A history of comparative anatomy. The Macmillan Press, London. Cunha, G.R. (1972) Epithelio-mesenchymal interactions in primordial gland structures which become responsive to androgenic stimulation. Anat Rec 172:179–195.
Cunha, G.R., Chung, L.W., Shannon, J.M. and Reese, B.A. (1980) Stromal–epithelial interactions in sex differentiation. Biol Reprod 22:19–42. Cunha, G.R., Donjacour, A.A., Cooke, P.S., Mee, S., Bigsby, R.M., Higgins, S.J. and Sugimura, Y. (1987) The endocrinology and developmental biology of the prostate. Endocr Rev 8:338– 362. Cunha, G.R., Foster, B., Thomson, A., Sugimura, Y., Tanji, N., Tsuji, M., Terada, N., Finch, P.W. and Donjacour, A.A. (1995) Growth factors as mediators of androgen action during the development of the male urogenital tract. World J Urol 13:264–276. Cunha, G.R., Ricke, W., Thomson, A., Marker, P.C., Risbridger, G., Hayward, S.W., Wang, Y.Z., Donjacour, A.A. and Kurita, T. (2004) Hormonal, cellular, and molecular regulation of normal and neoplastic prostatic development. J Steroid Biochem Mol Biol 92:221–236. Dauge, M.C., Delmas, V. and Mandarim De Lacerda, C.A. (1986) Contribution a L’etude du Developpement fe la Prostate Humaine aux Premiers Stades de la Periode Foetale. Etude Morphometrique. Bull Assoc Anat 70:5–11. Dunning, W.F. (1963) Prostate cancer in the rat. Nat Cancer Inst Monogr 12:351–369. Edwards, T.M. and Myers, J.P. (2007) Environmental exposures and gene regulation in disease etiology. Environ Health Perspect 115:1264–1270. Evatt, E.J. (1908) A contribution to the development of the prostate in the man. J Anat Physiol 43:314–321. Franks, L.M. (1954) Benign nodular hyperplasia of the prostate: a review. Ann R Col Surg Eng 14:92–106. Gil Vernet, S. (1953) Pathologia urogenital: Biologia y pathologia de la prostata, book 2. Vol. 1, Paz Montalvo, Madrid. Gupta, C. (2000) Reproductive malformation of the male offspring following maternal exposure to estrogenic chemicals. Proc Soc Exp Biol Med 224:61–68. Hayashi, N., Sugimura, Y., Kawamura, J., Donjacour, A.A. and Cunha, G.R. (1991) Morphological and functional heterogeneity in the rat prostatic gland. Biol Reprod 45:308–321. Ho, S.M., Tang, W.Y., Belmonte de Frausto, J. and Prins, G.S. (2006) Developmental exposure to estradiol and bisphenol A increases susceptibility to prostate carcinogenesis and epigenetically regulates phosphodiesterase type 4 variant 4. Cancer Res 66:5624–5632. Hofkamp, L., Bradley, S., Tresguerres, J., Lichtensteiger, W., Schlumpf, M. and Timms, B. (2008) Region-specific growth effects in the developing rat prostate following fetal exposure to estrogenic UV filters, in press. Huggins, C. and Webster, W.O. (1948) Duality of human prostate in response to estrogen. J Urol 59:258–266. Jesik, C.J., Holland, J.M. and Lee, C. (1982) An anatomic and histologic study of the rat prostate. Prostate 3:81–97. Johnson, F.P. (1920) The later development of the urethra in the male. J Urol 4:447–501. Johnson, F.P. (1922) The homologue of the prostate in the female. J Urol 8:13–33. LeDuc, I.E. (1939) The anatomy of the prostate and the pathology of early benign hypertrophy. J Urol 42:1217–1241. Lee, F., Torp-Pedersen, S.T., Carroll, J.T., Siders, D.B., Christensen-Day, C. and Mitchell, A.E. (1989) Use of transrectal ultrasound and prostate-specific antigen in diagnosis of prostatic intraepithelial neoplasia. Urology 34:4–8. Lin, T.M., Rasmussen, N.T., Moore, R.W., Albrecht, R.M. and Peterson, R.E. (2003) Region-specific inhibition of prostatic epithelial bud formation in the urogenital sinus of C57BL/6 mice exposed in utero to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Sci 76:171–181. Lowsley, O.S. (1912) The development of the human prostate gland with reference to the development of other structures at the neck of the urinary bladder. Am J Anat 13:299–349. McNeal, J.E. (1968) Regional morphology and pathology of the prostate. Am J Clin Pathol 49:347–357.
577 McNeal, J.E. (1978) Origin and evolution of benign prostatic enlargement. Invest Urol 15:340–345. McNeal, J.E. (1980) Anatomy of the prostate: an historical survey of divergent views. Prostate 1:3–13. McNeal, J.E. (1983) The prostate gland: morphology and pathobiology. Monogr Urol 4:3–33. Mizuno, T. and Yasugi, S. (1990) Susceptibilty of epithelia to directive influences of mesenchymes during organogenesis: uncoupling of morphogenesis and cytodifferentiation. Cell Differ Dev 31:151–159. Naz, R.K. (2005) Endocrine disruptors: effects on male and female reproductive systems. CRC Press, Boca Raton, FL. Pallin, G. (1901) Beitrag zur anatomie und embryologie der prostata und der samenblasen. Arch Anat Physiol 1:135–176. Price, D. (1936) Normal development of the prostate and seminal vesilcles of the rat with a study of experimental postnatal modifications. Am J Anat 60:79–127. Price, D. (1963) Comparative aspects of development and structure in the prostate. Nat Cancer Inst Monogr 12:1–27. Price, D. and Williams-Ashman, H.G. (1961) The accessory reproductive glands in the mammals. In: Young, W.C. ed. Sex and internal secretions. Bailliere, Tindall and Cox, London, pp. 366–448. Prins, G.S., Tang, W.Y., Belmonte, J. and Ho, S.M. (2008) Perinatal exposure to oestradiol and bisphenol A alters the prostate epigenome and increases susceptibility to carcinogenesis. Basic Clin Pharmacol Toxicol 102:134–138. Reischauer, F. (1925) Die entstehung der sogenannten prostatahypertrophie. Virch Arch Pathol Anat Physiol 256:357–389. Richter, C.A., Taylor, J.A., Ruhlen, R.L., Welshons, W.V. and vom Saal, F.S. (2007) Estradiol and bisphenol a stimulate androgen receptor and estrogen receptor gene expression in fetal mouse prostate mesenchyme cells. Environ Health Perspect 115:902–908. Risbridger, G.P., Almahbobi, G.A. and Taylor, R.A. (2005) Early prostate development and its association with late-life prostate disease. Cell Tissue Res 322:173–181. Saunders, J.B., de C.M. and O’Malley, C.D. (1950) The illustrations from the works of Andreas Vesalius of Brussels. Dover Publications Inc, New York. Shannon, J.M. and Cunha, G.R. (1983) Autoradiographic localization of androgen binding in the developing mouse prostate. Prostate 4:367–373. Shapiro, E. (1990) Embryologic development of the prostate. Urol Clin North Am 17:487–491. Silveira, P.P., Portella, A.K., Goldani, M.Z. and Barbieri, M.A. (2007) Developmental origins of health and disease (DOHaD). J Pediatr (Rio J) 83:494–504. Sugimura, Y., Cunha, G.R. and Donjacour, A.A. (1986) Morphogenesis of ductal networks in the mouse prostate. Biol Reprod 34:961–971. Sugimura, Y., Norman, J.T., Cunha, G.R. and Shannon, J.M. (1985) Regional differences in the inductive activity of the me-
senchyme of the embryonic mouse urogenital sinus. Prostate 7:253–260. Takeda, H. and Chang, C. (1991) Immunohistochemical and in-situ hybridization analysis of androgen receptor expression during the development of the mouse prostate gland. J Endocrinol 129:83–89. Takeda, H., Mizuno, T. and Lasnitzki, I. (1985) Autoradiographic studies of androgen-binding sites in the rat urogenital sinus and postnatal prostate. J Endocrinol 104: 87–92. Tenniswood, M. (1986) Role of epithelial–stromal interactions in the control of gene expression in the prostate: an hypothesis. Prostate 9:375–385. Thomson, A.A. and Cunha, G.R. (1999) Prostatic growth and development are regulated by FGF10. Development 126:3693– 3701. Timms, B.G., Howdeshell, K.L., Barton, L., Bradley, S., Richter, C.A. and vom Saal, F.S. (2005) Estrogenic chemicals in plastic and oral contraceptives disrupt development of the fetal mouse prostate and urethra. Proc Natl Acad Sci USA 102:7014–7019. Timms, B.G., Lee, C.W., Aumuller, G. and Seitz, J. (1995) Instructive induction of prostate growth and differentiation by a defined urogenital sinus mesenchyme. Microsc Res Tech 30:319– 332. Timms, B.G., Mohs, T.J. and DiDio, L.J.A. (1994) Ductal budding and branching patterns in the developing prostate. J Urol 151:1427–1432. Timms, B.G., Petersen, S.L. and vom Saal, F.S. (1999) Prostate gland growth during development is stimulated in both male and female rat fetuses by intrauterine proximity to female fetuses. J Urol 161:1694–1701. Timms, B.G., Peterson, R.E. and vom Saal, F.S. (2002) 2,3,7,8Tetrachlorodibenzo-p-dioxin interacts with endogenous estradiol to disrupt prostate gland morphogenesis in male rat fetuses. Toxicol Sci 67:264–274. Tisell, L.E. and Salander, H. (1975) The lobes of the human prostate. Scand J Urol Nephrol 9:185–191. Villers, A. (1994) Anatomy of the prostate: insight into benign prostatic hyperplasia anatomy and pathogenesis. Prog Clin Biol Res 386:21–30. Villers, A., Steg, A. and Boccon-Gibod, L. (1991) Anatomy of the prostate: reviews of the different models. Eur Urol 20:261–268. Vom Saal, F.S., Timms, B.G., Montano, M.M., Palanza, P., Thayer, K.A., Nagel, S.C., Dhar, M.D., Ganjam, V.K., Parmigiani, S. and Welshons, W.V. (1997) Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses. Proc Natl Acad Sci USA 94:2056–2061. Zuckerman, S. (1936) The endocrine control of the prostate. Proc Royal Soc Med 29:1557–1567.
R E V IE W A RT I C L E
Barry G. Timms
Prostate development: a historical perspective
Received February 14, 2008; accepted in revised form February 19, 2008
Abstract The regional anatomy of the human prostate has been debated periodically over the last century with various levels of controversy and agreement, beginning with the concept of lobes and replaced by the current model of zones. During this period a variety of classifications have been proposed, based upon the studies of glandular morphogenesis, responses to hormones or histopathology. The current paradigm suggests that the regional differences seen in the prostate of both animal models and the human are a consequence of specific epithelial–mesenchymal interactions along the cranial–caudal axis of the urogenital sinus. The distinctive regional patterns seen in the rodent prostate and the histological heterogeneity of the human adult gland all point to the modification of the distal portion of the ducts, while the proximal segments retain their spatial relationship to the urethra that was formed during fetal development. This suggests that the early epithelial budding that occurs in utero represents a common, fairly symmetrical pattern of growth in many species, while the regional differences in branching morphogenesis and cytodifferentiation are controlled by the instructional influences of mesenchyme and temporal expression of growth factors. Perturbation of the normal processes involved during critical periods of fetal development during reproductive organ development may also play a role in the susceptibility of the prostate to disease in adulthood. Past descriptions of detailed anatomical studies, which span over a century, have provided much insight into the architecture and processes that form a complex tubulo-alveolar gland. New insights into the ductal detail and the advent of sophisticated . ) Barry G. Timms (* Division of Basic Biomedical Sciences Sanford School of Medicine University of South Dakota 414 E. Clark St. Vermillion SD 57069, USA Tel/Fax: 1 605 677 5144 E-mail: [email protected]
analyses of cell–cell interactions and molecular mechanisms controlling pathways of cellular growth, differentiation, and apoptosis will likely lead to new approaches for prevention and therapy of prostatic diseases. Key words prostate development anatomy 3-D reconstruction
Introduction When Andreas Vesalius published his anatomical illustrations in 1543, his observations of the male accessory sex glands formed part of the wider objective to clarify earlier misunderstandings about human organ function (Saunders and O’Malley, 1950). From those historical beginnings to the modern day concepts of cellular mechanisms, our understanding of the structure and function of the prostate has made enormous progress. Nonetheless, some details, including normal development and processes that lead to disease, remain enigmatic. Although the clinical manifestations of prostate disorders are not typically observed until later in life, there is some evidence to suggest that the pathology may have fetal origins (Bateson et al., 2004). It is now widely known that except for skin cancer, prostate cancer is the most common cancer among men, and accounts for almost one in every three cancers diagnosed in US males (American Cancer Society, 2007). Despite major advances in basic science and clinical medicine, prostate disease is still a major health concern. Also, the detailed understanding of adult prostatic anatomy in the human male has not progressed as well as for other glandular structures because of a confusing history of structural terminology. The adult prostate is a complex tubulo-alveolar gland that still presents some challenges in understanding its three-dimensional (3-D) architecture. For this reason, there is reliance upon suitable animal models, and much has been learned during the past three decades that has proven invaluable in pos-
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tulating explanations for the human process of both normal growth and development and the etiology of disease.
A history of prostate anatomy Classical anatomical descriptions of the prostate began in the late 1800s. Aside from the work of Vesalius, an early description of the mammalian accessory sex glands was reported by Gerard Blasius in his treatise on comparative anatomy, which was published in 1674 and described simply as ‘‘glandulae’’ surrounding the neck of the bladder (Cole, 1949). At about the same period the importance of the clinical perspective was being developed through the observation by Samuel Collins that prostate enlargement caused bladder neck obstruction (Zuckerman, 1936). This was further established in the 18th century by Giambattista Morgagni, the founder of modern pathology (Franks, 1954). In his review of benign prostatic hyperplasia (BPH), Franks notes that Morgagni was able to identify the site of origin for prostate hyperplasia and the association of the pathology with elderly men. As far as the functional capacity of the gland, John Hunter made several important observations from cadaveric dissections. In 1786 he wrote that ‘‘The prostate and Cowper’s glands, and those of the urethra, which in the perfect male are soft and bulky, with a secretion salt to the taste, in the castrated animal are small, flabby, tough and ligamentous, and have little secretion.’’ Zuckerman (1936) points out the notable fact that even though the inference of the observation would suggest that castration might be considered a treatment for the relief of prostate enlargement, the therapeutic value was not considered until almost a century later. The current understanding of prostate development and anatomy progressed through the publication of new findings each decade over the past century (Pallin, 1901; Lowsley, 1912; Johnson, 1920; Price, 1936; LeDuc, 1939; Huggins and Webster, 1948; Gil Vernet, 1953; McNeal, 1968, 1978, 1983; Timms et al., 1994). McNeal (1980) suggested that the advancement of this understanding was partly hampered by compliance to older anatomical descriptions that were accepted, rather than challenged, until later studies (Franks, 1954; McNeal, 1968; Tisell and Salander, 1975). In the late 19th century an extensive literature was published in Germany that focused on the anatomical details of embryological development, including the accessory sex glands and urogenital structures. Aumu¨ller (1979) reviewed these studies, in which the classic works of Pallin (1901), Lowsley (1912), and Johnson (1920) were discussed and compared. These anatomical studies were facilitated by the use of a novel procedure of tissue section reconstruction, called ‘‘plattenmodellirmethode’’ described by Born (1883). This technique of us-
ing wax modeling to provide a basis for illustrating prostate development was used in several papers (Evatt, 1908; Johnson, 1922; Dauge et al., 1986). However, Lowsley’s diagram of a newborn male prostate was probably one of the most influential, and later controversial, anatomical descriptions of prostate anatomy (Fig. 1). There was no doubt that this model was an accurate reconstruction of serial histological sections, the questions that were raised over the ensuing years were more to do with the accuracy of anatomical interpretation. This model influenced many investigators and was used as a standard for describing prostate anatomy in several contemporary medical textbooks. From this model, Lowsley defined the concept of prostate lobes and the regional focus of disease. A history of the divergent views surrounding this concept was discussed by McNeal (1980). Several alternative models of prostate anatomy emerged over a period of 50 years (Fig. 2) and the currently accepted concept of prostate zones was eventually established in the early 1980s (McNeal, 1983). A recapitulation of earlier work by Price (1963) prompted additional examination of the embryonic development of the prostate with the conclusion that the organization of the ductal outgrowths from the urogenital sinus (UGS) provides a related but optional model for the concept of prostate regions or zones (Timms et al., 1994).
Embryology of the human prostate The anlage of the human prostate begins about the 10th week of gestation and is a consequence of sequential prior events, including production of testosterone by the fetal testis around 8 weeks. The initial outgrowths of the prostatic buds from the UGS occur in response to the binding of 5a-dihydrotesterone to androgen receptors localized in the surrounding mesenchymal tissue (Shannon and Cunha, 1983; Takeda et al., 1985; Takeda and Chang, 1991). These outgrowths begin as solid cords of epithelial cells that elongate and undergo extensive branching morphogenesis during the latter stages of fetal growth. During the postnatal period, under the influence of androgens, the ducts form a patent lumen, and the epithelium lining the acini differentiate and synthesize a variety of secretory products. The fully developed adult human prostate lies at the neck of the bladder and surrounds the urethra (Fig. 3A). The anterior or ventral aspect of the gland is almost entirely fibromuscular, while the glandular region occupies the posterior part of the tissue and surrounds the ejaculatory ducts as they enter the urethra on each side of the verumontanum. Compared with the compact human gland, the adult prostate of many other mammals has distinct
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Fig. 1 An illustration derived from a wax model reconstruction of a newborn male prostate. This sagittal view through the prostatic urethra shows the lobes described by Lowsley (1912). Anterior branches of lateral lobes (Lat.), posterior lobe (P.L.) and middle lobe (M.L.).
Fig. 2 (A) Sagittal diagram of the human prostate showing regional classification of the gland described by Gil Vernet (1953). Intrasphincteric submucosal glands (1); middle portion of cranial gland (2); anterior lobe of the cranial (3); superior duct (4), middle duct (4 0 ) and inferior duct (400 ) of the caudal gland; glands of Littre´ (5); ejaculatory duct (6). (B) Sagittal diagram of adult human prostate showing distal urethra (UD), proximal urethra (UP) and ejaculatory duct (E). These structures are shown in relation to three
major glandular regions of the prostate described by McNeal (1983). Central zone (CZ), peripheral zone (PZ) and transitional zone (TZ). (C) Graphical three-dimensional representation of McNeal’s three glandular zones of the prostate (Lee et al., 1989). Peripheral zone (yellow), central zone (red), transition zone (blue), anterior fibromuscular stroma (green). (Reproduced from Naz, RJ, Prostate: Basic and Clinical Aspects. CRC Press, Boca Raton, 1997. With permission.)
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Fig. 3 (A) Diagrams of frontal and sagittal sections of the male urogenital complex illustrationg the anatomical position of the adult prostate and associated structures. The prostatic zones described by McNeal (1983) are indicated: central zone (CZ), peripheral zone (PZ), anterior fibromuscular stroma (AFS), and transition zone (TZ). (B) Male accessory sex organs of the adult
male rat. A, anterior view; B, lateral view; C, anterior view with the bladder deflected caudally. Ampullary gland of the vas deferens (AG); bladder (B); coagulating gland (CG); dorsal prostate (DP); lateral prostate (LP); seminal vesicle (SV); ventral prostate (VP); vas deferens (VD); deferential vein (DV).
regional lobes (Fig. 3B). The location of disease in the human suggested a similar, though less obvious lobular arrangement, based upon early embryological studies (Price, 1963). Lobe homology has been proposed to exist between animal models and the human and is the basis for studying these models to better facilitate an understanding of normal and abnormal pros-
tate growth mechanisms (Dunning, 1963; McNeal, 1983). Consistent among all the anatomical research on the prostate is the finding that origins of the fetal prostatic ducts emerge in a ventral, lateral, and dorsal pattern from the UGS. Whether these ducts form distinct lobes or regions in the human has been a perennial question,
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partly addressed through distinctions in histology, biochemistry, or pathology. In this regard, McNeal’s description of zonal anatomy is now accepted as the standard reference for understanding the normal and abnormal structure of the human prostate (Lee et al., 1989).
Prostate development and anatomy Through the use of anatomical models from serial sections, Lowsley (1912) described the lobes of the fetal human prostate and attempted to clarify some of the controversy regarding the origin of the middle and posterior lobes described by earlier investigators using similar anatomical techniques (Pallin, 1901; Evatt, 1908). Using tissue from a 13-week human fetus, Lowsley identified five separate groups of prostatic ducts emanating from the UGS and called them lobes (Fig. 1). The ventral lobe consisted of four pairs of epithelial buds and the median lobe was formed by about a dozen tubules associated with the posterior urethra, and growing cranially between the neck of the bladder and the openings of the ejaculatory ducts. The largest group of tubules was the paired left and right lateral tubules, which originated from the sides of the urethra and followed the prostatic sulci, or furrows. These epithelial outgrowths grew posteriorly and laterally. Distal to the ejaculatory ducts, the tubules were located on the caudal portion of the urethra and formed the posterior lobe. Their direction of growth was primarily toward the bladder. However, a small number of ducts followed the anterior course of growth seen in the lateral lobe. Through examination of samples from later stages of fetal growth (30 weeks) and a newborn male, Lowsley was able to determine the average number of tubules that were associated with each lobe. The largest number of ducts was found in the lateral region, followed by those of the middle and posterior lobes. Although the 3D wax model presented a novel perspective of the newborn prostate anatomy, the spatial relationship of the ductal origins from the urethra was obscured by the developing complexity of ductal branching, especially at the point where the posterior and middle lobes merged. Using a similar wax model reconstruction approach, Johnson (1920) prepared anatomical drawings at 10 and 14 weeks of fetal growth. He could not confirm the definitions of lobes except for the middle lobe ducts. He grouped the anterior, dorsal, and lateral ducts as gland buds. He did note that some ducts emanated from the urethra above and below the entrance of the ejaculatory ducts. The models clearly show a bilateral symmetry of prostatic ductal outgrowth and a pattern of bud formation around the ejaculatory ducts that would be described in much later studies (Timms et al., 1994), but not mentioned in his paper. The relationship of ductal
outgrowths from the UGS that is observed in the fetus remains unchanged in the adult gland and suggests an intimate link between the two ends of the growth spectrum (Price, 1963). What differs between these two stages of growth is the complex branching morphogenesis that occurs postnatally and following puberty, forming the actively functioning secretory gland. The lobe concept was disputed by Franks (1954). Instead, he described three concentric regions, the short inner mucosal glands around the urethra, a central group of long, branched ducts and long external glands, which he termed the ‘‘prostate gland proper.’’ This new terminology was derived mainly from observations on diseased glands, noting that the focal location of BPH was within the inner glands, and carcinoma was predominantly found in the external ducts. This new nomenclature found its way into anatomical texts. A semantic shift in nomenclature prompted McNeal to further propose a new concept of zonal anatomy (McNeal, 1968, 1978). Again, using serial sections in different planes, McNeal examined many human prostate samples, and using the verumontanum as a reference point, described a schematic 3-D model. As the urethra passes through the prostate, the proximal segment extends from the bladder neck to the verumontanum, where it angles at 351–401 to form the distal segment to the external urethral sphincter. The central zone was described as a wedge of glandular tissue forming most of the base of the prostate and surrounding the ejaculatory ducts (Fig. 2B). The peripheral zone made up the remainder of the gland, surrounded most of the central zone, and extended caudally to partly surround the distal portion of the urethra. This newer classification of the central zone included the middle lobe and part of the posterior lobe described in earlier studies, and the peripheral zone therefore included Lowsley’s lateral lobes and a portion of the posterior lobe. The zonal classification was further confirmed from histological examination, which showed a definite epithelial and acinar heterogeneity between zones. These histological differences had been previously noted by Tisell and Salander (1975), but the regional anatomy nomenclature of middle, posterior, and lateral lobes was still used. Because of the histological similarities reported in both studies, McNeal suggested that the middle lobe was equivalent to his description of the central zone and the lateral and posterior lobes could be combined as an analogous peripheral zone (McNeal, 1980). A further observation by McNeal was the identification of urethral glands, surrounded by the urethral sphincter, as the exclusive site of BPH. This region was subsequently termed the transition zone. Ducts from this zone were found to exit laterally from the urethra close to the origin of the most cranial ducts of the posterior zone. A clear illustration of the zonal anatomy concept was illustrated in a 3-D schematic model by Lee et al. (1989; Fig. 2C).
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Fig. 4 Serial section reconstructions of the rat urogenital complex on GD 18, 19, 20, 21, and postnatal day 2 (D2), illustrating the stages of early prostate development. Prostate morphogenesis begins at GD 18 with small ventral prostate buds and by GD 19 the dorsal, ventral, lateral, and coagulating gland buds have developed. On GD 21 (the day before birth), ductal budding from the urogenital sinus is essentially complete. U, urethra; DP, dorsal prostate; LP, lateral prostate; VP, ventral prostate; CG, coagulating gland; SV, seminal vesicle; VD, vas deferens. Secondary and tertiary distal tip branching is observed in the ventral prostate after birth (D2). Branching has also been initiated in the seminal vesicles and coagulating glands. By comparison, minimal to no branching is evident in the dorsal and lateral prostate ducts. (Redrawn from Timms et al., Toxicol Sci 67:264, 2002. With permission.)
Along with the concept of zonal anatomy, McNeal introduced the hypothesis of a ‘‘reawakening of embryonic inductive interactions’’ in which he describes inappropriate new ductal budding that occurs during the pathogenesis of BPH. This was thought to be induced by adjacent areas of stromal proliferation and confirmed a similar hypothesis proposed by Reischauer (1925), and discussed by LeDuc (1939). The significance of this stromal–epithelial interaction in both normal and abnormal growth of the prostate has become the subject of numerous studies and reviews (Cunha, 1972; Cunha et al., 1980, 1987, 1995; Tenniswood, 1986; Aumu¨ller, 1989; Shapiro, 1990). In a review of the different models of prostate anatomy (Villers et al., 1991; Villers, 1994), there is reference to a less widely known publication Gil Vernet (1953) in which an extensive histological analysis of the prostate during many stages of growth from the embryo to adulthood, plus pathology is presented. Interestingly, the author subdivided the two main glandular regions according to their position along the proximal–distal urethral axis (Fig. 2A).
Animal models of prostate development Restrictions on the use of normal human fetal tissue for scientific studies have led to a continued necessity for
suitable animal models, on the principle that satisfactory homologies exist to extrapolate findings to humans. With regards to anatomy, there have been many parallel animal studies. Extensive light and electron microscopical analysis of the rat prostate has been performed during embryonic, postnatal, and adult stages of growth (Price, 1936; Price and Williams-Ashman, 1961; Brandes, 1966; Jesik et al., 1982). Because of the 3-D complexity of the developing prostatic ductal system, these studies only provided a descriptive summary of morphogenesis and architecture. Using the alternative technique of whole-mount micro-dissection of mouse and rat prostate, a precise delineation of all the ductal networks in early postnatal and adult growth has been determined (Sugimura et al., 1986; Hayashi et al., 1991). However, the spatial relationships of the individual lobes and their ductal origins from the urethra cannot be determined using this methodology. A significant observation, previously reported by Price (1936) is that the relationship of the ductal openings into the prostatic urethra remains the same throughout the entire development period and into adulthood. This suggests that the determination of regional ductal budding patterns during prostate development could be indicative of adult glandular architecture. In addition, a comparison of these patterns between species would permit confirmation of homologies. The application of a novel 3-D, computer-
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Fig. 5 (A) Schematic illustration of the fetal rodent urogenital sinus (UGS) showing the ductal budding pattern. The cranial ducts of the ventral line of budding are associated with a ventral mesenchymal pad. Following contact and growth into this pad, the distal tips of the ventral prostatic buds will undergo branching morphogenesis (light blue/dark blue). Adjacent buds along this line usually form part of the lateral lobe (gray). Mesenchyme surrounding dorsal outgrowths is contiguous with that of the Wolffian duct but not depicted in the diagram. Condensations of mesenchyme are also found at the tips of the lateral buds (not illustrated). The most cranial outgrowths on the dorsal aspect of the UGS form the coagulating gland. All buds grow into a periurethral
mesenchyme that is surrounded by sleeve of smooth muscle at the caudal portion of the UGS. As the buds elongate this smooth muscle encapsulates the proximal regions of the ducts. The dorsal line of buds is associated with ridges on either side of the UGS and surrounds the paired orifices of the ejaculatory ducts and the prostatic utricle. (B) Three-dimensional reconstruction the mouse UGS from a ventral–caudal perspective, showing the paired lateral (LP), and ventral (VP) ducts. The distal tips of the ventral ducts (arrow) are embedded in the ventral mesenchymal pad (VMP) where branching morphogenesis has been initiated. Similar, but smaller condensations of mesenchyme are found at the tips of the lateral ducts (arrowhead).
assisted reconstruction technique has led to a better understanding of these ductal budding patterns and an opportunity to provide visual confirmation of the homologies that exist between the mouse, rat, and human
prostate (Timms et al., 1994). This 3-D method is essentially a modern version of the older wax model reconstruction that requires contour tracing of anatomical structures within each histological section
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Fig. 6 Comparisons of the early wax model reconstructions of a rodent (Born, 1883) and human fetal prostate (Johnson, 1920; A and C) with surface-rendered computer reconstructions of a normal newborn rat prostate (B) and 13-week human male. Similar developmental features of prostate duct development are observed. Urethra (red); lateral prostate (yellow); dorsal prostate (green—caudal ducts; gray—cranial ducts); coagulating gland (dark blue); ventral prostate (light blue); seminal vesicles (purple); vas deferens (light purple); utricle (white).
of a serially sectioned organ such as the developing prostate. Advances in software have led to the ability to prepare detailed surface-rendered models of tissues as small as a cubic millimeter and provide volumetric data (vom Saal et al., 1997; Timms et al., 2005). Such reconstructions are useful for rotational viewing and stereo-pair images and provide a unique opportunity to view spatial relationships of entire or selected regions of the prostate. Using 3-D reconstruction, prostate development in the rat from the earliest evidence of epithelial budding at gestation day 18, through postnatal day 2, clearly illustrates the temporal and spatial relationships of the ductal budding patterns (Fig. 4). Ventral and dorsal budding occur at about the same time. However, at later stages of development (GD 21), just before birth, initial stages of branching morphogenesis begins at the distal tips of the ventral ducts. Both primary and secondary branch points have occurred by day 2 after birth. A schematic of the typical epithelial budding pattern that occurs during late gestation in the developing rat and mouse prostate is illustrated in Figure 5A. Several lines of ductal outgrowths, or buds, follow a fairly symmetrical arrangement and are defined by their
origins on both the caudal–cranial and ventral–dorsal axes of the urethra (Timms et al., 1994). This study suggested that even though some epithelial buds develop as contiguous outgrowths, their subsequent fate will be dictated by juxtaposition to inductive mesenchyme. Further significant findings from these studies identified specific regions of mesenchymal tissue that were associated with specific patterns of distal tip branching morphogenesis. This was most clearly observed in the ventral region and was classified as the ‘‘ventral mesenchymal pad’’ (Fig. 5B). Later studies reported that this pad occured in both male and female animals (Timms et al., 1995) and is associated with the production of fibroblast growth factor 10 (Thomson and Cunha, 1999). Other condensations of mesenchyme on the lateral aspect of the urethra are also evident but not as clearly defined. It became apparent from such studies that the mesenchyme immediately surrounding the urethra (peri-urethral mesenchyme) likely differs in both composition and instructive growth factors. The former is associated with the initial outgrowth of the basal epithelial layer of the urothelium forming the solid cord of epithelial cells (prostate buds), while subsequent branching morphogenesis at the distal tips is initiated
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Fig. 7 Three-dimensional anaglyph views of the serial section reconstruction of a mouse urogenital sinus (UGS), shown from the normal anatomical aspect (gestation day 19). Urethra (red); dorsal buds (green); coagulating gland (dark blue); seminal vesicles (purple). Sequential views surrounding the central image, rotated at 301 increments, show a full 3601 view.
through contact with the specific adjacent mesenchyme. Unique regional branching patterns with different temporal relationships were observed in earlier studies (Sugimura et al., 1986; Hayashi et al., 1991) and confirmed by the 3-D methods. Just recently, a novel morphological approach using scanning electron microscopy (SEM) has also confirmed the budding patterns of the developing mouse prostate (Lin et al., 2003). In addition, a combination of whole-mount micro-dissection, immunofluorescence, confocal microscopy, and computer analysis has been used to study the complex anatomy of branching morphogenesis in wild-type and mutant mice by developing a ‘‘skeletonized’’ model of the ventral and anterior ducts (Almahbobi et al., 2005). Each approach has its own merits and drawbacks. Computer reconstruction provides real-time rotational viewing of the whole microanatomy of the developing prostate, but is a laborintensive process. The SEM approach is more rapid but only permits visualization and counting of the number and location of the prostate buds. The skeletonized model has proved a useful technology for studying detailed patterns of branching morphogenesis, but still relies upon micro-dissection and the inherent disruption of spatial relationships with neighboring ductal regions. Intriguing, but not unexpected similarities between the older wax-model reconstructions and recent computer
Fig. 8 Computer-assisted serial section reconstructions from a fetal mouse (gestation day 18; left) and human prostate (70 mm crownrump length/11 weeks; right). The seminal vesicle (SV) on the right side of each reconstruction have been omitted to facilitate viewing of the prostatic budding patterns. In the mouse, dorsal prostatic bud outgrowths (DP) are associated with the prostatic furrows of the urogenital sinus along the caudal–cranial axis. The coagulating gland (CG) exhibits three pairs of outgrowths and is associated with the dorso-cranial aspect of the urogenital sinus (UGS). The human fetal prostate shows dorsal outgrowths (green) that form a ‘‘horse-shoe’’ shaped pattern around the ejaculatory ducts (Ed) and prostatic ut-
ricle (Ut). A parallel line of buds grows from the lateral wall of the urogenital sinus (L). The most caudal of these buds exhibit an anterior direction of growth (). Several small periurethral outgrowths are evident in the proximal portion of the dorso-cranial urethra (arrow). The seminal vesicle (SV1) appears as a dorsal swelling on the vas deferens (VD1). Both views are from a superior right dorso-lateral perspective. At these stages of fetal growth the mouse and the human prostate budding patterns demonstrate striking similarities. The reconstruction of the human fetal prostate also shows the potential relationship to the future adult regions of the central (CZ), peripheral (PZ), and transitional (TZ) zones.
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Fig. 9 Three-dimensional reconstruction of the accessory sex glands (ASG) from a normal 6-day-old mouse. At this stage of postnatal development extensive ductal branching and organ development has occurred. Because of the complexity of tissue organization, individual components of the ASG have been removed to better illustrate spatial relationships. (A) Branching of the seminal vesicles (SV) is essentially completed at this stage of growth. The ampullary glands (AG) associated with the proximal region of the vas deferens (VD) are also formed. Elongation of the proximal urethra (U) occurs after birth, while the urogenital sinus region (UGS) remains similar in shape to that of the newborn. (B) The coagulating glands (CG) are typically formed by growth of a pair of major ducts on the left and right cranial aspects of the UGS. The coagulating gland ducts branch and become attached to the anterior curved surface of the seminal vesicles. (C) The distal tips of the lateral (LP1; LP2) and dorsal (DP) prostate have undergone some
primary bifurcation and swelling and make a right-angle turn at the boundary of the smooth muscle layer surrounding the UGS (not shown: see Fig. 5). Some distal lateral ducts grow in a ventral direction (LP1) while the more caudal and cranial distal ducts grow in a dorsal direction (LP2). (D) Two to three pairs of major ventral ducts (VPd) elongate with the urethra. The distal region of these ducts has developed extensive branching morphogenesis (VP) and formed into the distinctive lobe that is defined by the ventral mesenchymal pad of fetal stroma (not shown: see Fig. 5). The proximal ducts are also en-sheathed by a layer of periurethral smooth muscle (not shown). (E) and (F) Stereo pair images of the AGS structures (convergent viewing) illustrating the spatial relationships of the structures depicted in (A–D). Note the caudal curvature of the distal dorsal ducts and the two opposing directions of distal growth in the lateral prostate regions.
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Fig. 10 Three-dimensional serial section reconstruction of the urogenital sinus (UGS, red) from gestation day 19 mice exposed to low doses of estrogenic chemicals: diethylstilbestrol and bisphenol A during fetal development. All images are viewed from a left-lateral perspective. The images illustrate the differences in patterns of prostate ductal development following fetal exposure
to these chemicals compared with oil-treated controls. There is a significant increase in the total number of ducts in estrogen treated animals and a corresponding increase in overall prostate volume. Ventral prostate (VP, light blue); dorsal prostate (DP, green); lateral prostate (LP, yellow). Redrawn from Timms et al. (2005).
models are apparent (Fig. 6), but the more interesting similarities are those of the budding patterns between the developing rodent and human prostate (Figs. 6B,6D). The advantage of the 3-D models is the ability to rotate the images at the time of reconstruction or view in 3-D using anaglyph images (Fig. 7). The opportunity to accurately describe potential homologies follows naturally from such observations of similarities between species. For example, in the rat and mouse, the cranial buds of the dorsal prostate surrounding the ejaculatory ducts and associated with the Wolffian duct mesenchyme, compare to the central zone of the human (Figs. 6B,8). The most caudal lateral and dorsal ducts (Figs. 5A,6B,8) match the human peripheral zone, while the cranial ducts in the proximal region of the dorsal urethra (coagulating gland region), compare to the location of the transition zone (Fig. 8). Thus, examination of these regions in animal models with regard to understanding the mechanisms of growth control, epithelial–mesenchymal interactions and cellular differentiation is pertinent to understanding normal and pathological processes in the human prostate. Given the extensive branching morphogenesis that occurs in the first week after birth in the rat and mouse prostate, it has been a challenge to reconstruct the developing gland beyond the fetal period, or day of birth. However, as part of related studies to examine the effects of endocrine disruptors on prostate development (Hofkamp et al., 2008), the anatomy of the mouse prostate 6 days after birth was recently reconstructed. This technique clearly illustrates the complex postnatal architecture of the developing gland at this time (Fig. 9). The benefit of these models becomes apparent when specific anatomical regions are selectively removed to reveal adjacent structures. The in situ relationships are also preserved and the magnitude of branching devel-
opment in the ventral prostate, coagulating gland, and seminal vesicles is a prominent feature. The development of the ampullary glands surrounding the proximal part of the vas deferens is also revealed at this stage of postnatal growth. Because of the marked differences in ductal branching patterns that occur within the prostate, variations in temporal influences and spatial organization of the adjacent mesenchyme are important modulators of prostate morphogenesis (Sugimura et al., 1985; Mizuno and Yasugi, 1990; Timms et al., 1995; Cunha et al., 2004). These effects are likely imprinted during fetal development, including in utero hormone actions and have recently been discussed as the concept of developmental origins of health and disease (Silveira et al., 2007). This is important in the light or recent concerns about environmental influences and the sensitivity of the prostate to circulating levels of endogenous or exogenous hormones during critical periods of development (Risbridger et al., 2005; Edwards and Myers, 2007). Many studies now demonstrate that environmental chemicals have the capacity to disrupt normal functioning of the endocrine system through a variety of mechanisms (Naz, 2005). In this regard, examination of the prostate ductal budding patterns has proved to be a useful biological marker (vom Saal et al., 1997; Timms et al., 1999, 2002). From these investigations it became clear that the dorso-lateral region of the rodent prostate exhibits a unique growth response sensitivity following exposure to endocrine disruptors during fetal development (Fig. 10; Timms et al., 2005). This effect was a consequence of an increased number of prostatic buds developing from the UGS and a concomitant increase in the volume of the ducts. A recent study of the rat prostate exposed to environmental chemicals during development suggests that the process of ductal
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outgrowth and branching morphogenesis may be disrupted by independent mechanisms (Hofkamp et al., 2008). As discussed above, mesenchymal–epithelial interactions are important for regulating control of both development and subsequent growth of the prostate. Exposure to exogenous estrogens causes disruption of the level of expression of androgen and estrogen receptors in mesenchymal tissue (Richter et al., 2007). This supports the hypothesis that fetal estrogen exposure, within a physiological range, stimulates prostate growth by increasing expression of the androgen receptor gene in the mesenchyme. In animal models, a consequence of this disruption can lead to permanent increases in prostate size into adulthood (Gupta, 2000) and the potential for development of neoplastic transformations (Ho et al., 2006; Prins et al., 2008). Advances in our knowledge of the molecular mechanisms that control the growth and intricate micro-architecture of a complex gland have provided a foundation to determine the pathways and patterns for aberrant growth and disease. Acknowledgments The author wishes to thank Sandy Bradley and Luke Hofkamp for expert technical assistance with the 3-D reconstructions. In particular, Ms. Bradley devoted a considerable amount of time and effort in the preparation of the postnatal mouse reconstruction (Fig. 9). The continued support of Dr. Eric Neufeld, Department of Computer Science, University of Saskatchewan and Dr. Scott Lozanoff (University of Hawaii), in providing timely upgrades to WinSURFr is greatly appreciated.
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