Key points

Introduction

The human prostate is a walnut-sized organ at the base of the urinary bladder. It is the seat of three major causes of morbidity: (1) benign prostatic hyperplasia (BPH), (2) prostate cancer, and (3) prostatitis. As such it commands more attention than might be expected from an organ of this size. Anatomic illustrations of the prostate have been published dating at least as far back as the mid-sixteenth century when Andreas Vesalius, in 1543, published his observations of the male accessory glands. The links between testicular and prostatic function have also been known for hundreds of years. John Hunter, writing in 1786 in “Observations on the glands situated between the rectum and the bladder, called vesiculae seminales” said “the prostate and Cowper’s glands and those of the urethra which in the perfect male are soft and bulky with a secretion salty to the taste, in the castrated animal are small, flabby, tough and ligermentous and have little secretion.”

The adult prostate is a compound tubular-alveolar gland found in most mammals. The gross structure differs considerably between species. Much of the descriptive work on the development of the prostate from its origins in the hindgut to descriptions of the adult organ was performed by anatomists and pathologists working in the early to mid-twentieth century. Subsequent work has outlined the molecular basis for these descriptions. Interest in prostate biology is centered around the human organ and that of the species, notably rats and mice, used to model human diseases. A clear understanding of the differences in the structure of human and rodent prostates is important in assessing the results of animal studies.

Introduction

The human prostate is a walnut-sized organ at the base of the urinary bladder. It is the seat of three major causes of morbidity: (1) benign prostatic hyperplasia (BPH), (2) prostate cancer, and (3) prostatitis. As such it commands more attention than might be expected from an organ of this size. Anatomic illustrations of the prostate have been published dating at least as far back as the mid-sixteenth century when Andreas Vesalius, in 1543, published his observations of the male accessory glands. The links between testicular and prostatic function have also been known for hundreds of years. John Hunter, writing in 1786 in “Observations on the glands situated between the rectum and the bladder, called vesiculae seminales” said “the prostate and Cowper’s glands and those of the urethra which in the perfect male are soft and bulky with a secretion salty to the taste, in the castrated animal are small, flabby, tough and ligermentous and have little secretion.”

The adult prostate is a compound tubular-alveolar gland found in most mammals. The gross structure differs considerably between species. Much of the descriptive work on the development of the prostate from its origins in the hindgut to descriptions of the adult organ was performed by anatomists and pathologists working in the early to mid-twentieth century. Subsequent work has outlined the molecular basis for these descriptions. Interest in prostate biology is centered around the human organ and that of the species, notably rats and mice, used to model human diseases. A clear understanding of the differences in the structure of human and rodent prostates is important in assessing the results of animal studies.

Human and rodent prostate embryology and postnatal development

The early mammalian embryo has the potential to develop toward a male or female phenotype. In genetically normal individuals this course is determined at conception and is reflected at the embryonic stage by the interactions of four critical units: (1) the wolffian duct, (2) the müllerian duct, (3) the urogenital sinus (UGS), and (4) the fetal gonad.

In humans the wolffian ducts start to develop approximately 25 to 30 days after conception in 2- to 3-mm-long embryos. These ducts initially act as excretory canals for the mesonephros, which performs the renal function in the early embryo. The ducts do not become incorporated into the genital system until the excretory function has been taken over by the definitive kidney. The ureters are a diverticulm of the wolffian duct, which becomes separated from the genital tract structures during development and which is the only part of the wolffian duct–derived structures that is preserved in the adult female. In such species as birds and reptiles, where the mesonephros has a prolonged excretory function, the wolffian ducts are preserved in an ambisexual state, in some cases until birth. In the human, by the time the embryo has reached 4 to 5 mm the ducts have elongated and lumenized to link the hindgut (which caudally becomes the cloaca) with the mesonephros and gonad.

The müllerian ducts develop later than the wolffian ducts, at about 6 weeks of gestation. A cleft lined with epithelial cells is formed between the gonadal and mesonephric parts of the urogenital ridge. This closes to form a tube that then extends through the surrounding mesenchyme parallel to the wolffian ducts. By the eighth week of gestation the müllerian ducts, which by this time are between the wolffian ducts, reach (but do not break into) the UGS forming the müllerian tubercule.

The UGS is produced in the 7- to 9-mm embryo by the formation of the urorectal septum, which divides the cloaca into the rectum and the UGS. The upper part of the UGS forms the urethra, whereas the part below the müllerian tubercule forms part of the vagina in the female and the penile urethra in the male.

The process of male sexual differentiation is determined under the influence of androgens produced by the fetal testis. In the absence of either these hormones or appropriate receptors, because of either an absent testis, lack of testicular function, or a mutation in the androgen receptor gene, the fetus develops a female phenotype. In the male, sexual differentiation is an asymmetric process consisting of the regression of the müllerian duct system, under the influence of Anti-Müllerian hormone expressed in the testicular Sertoli cells and stabilization, by androgens, of the wolffian ducts.

The second part of male sexual differentiation occurs under the influence of testosterone produced by the Leydig cells of the fetal testis. This involves changes in the tubules connecting the testis with the mesonephros to form the vasa efferentia, the formation of the convoluted epididymal duct and the vas deferens. The androgenic stimulus also acts to masculinize the UGS and the external genitalia. This process involves the formation of the prostate and the prostatic utricle, the closure of the labial-scrotal lobes, and the formation of the penis.

The rudimentary prostate starts to appear in 50-mm human embryos as epithelial buds growing laterally from the walls of the UGS at the site of the müllerian tubercle. Under local mesenchymal control, the buds form solid branching cords that start to develop a lumen giving rise, by birth, to a network of tubules and alveoli. As the lumen forms, some of the apical cells become structurally polarized and seem to start some secretory activity. The organ develops a stroma containing a large proportion of smooth muscle, whereas the ducts and acini are lined with a layer of flat basal epithelium and a luminal layer of tall columnar secretory epithelium. The basal and luminal epithelial cells are distinguishable on the basis not only of morphology but also functionally and by their expression of different cytokeratin classes (keratins 5 and 14 in basal cells, 8 and 18 in luminal).

Details of prostatic development, in particular molecular details, have been largely established using animal models, in particular the rat and mouse. The availability of tissues from these animals and, more recently, the development of transgenic and gene knock-out models makes them amenable to such studies. Historically, several workers in the field, notably including Dorothy Price, established the basic developmental profile of the rodent prostate. Rodent prostatic embryogenesis mirrors the processes seen in humans, although the timing reflects the much faster development of these species; for example, an UGS is present in the mouse by embryonic day 16 and in the rat at embryonic day 18 with early prostatic buds being seen a day or so later. Richly illustrated descriptions of the gross and molecular phenotypes of the developing rodent urogenital tract have been published recently that vastly expand the details available in the historic documents. The GenitoUrinary Development Molecular Anatomy Project consortium maintains an updated database of gene expression at its Web site: http://www.gudmap.org .

Growth and development of the prostate begins with formation of prostatic buds from the fetal UGS and are complete at sexual maturity. In the mouse this begins at 17 days gestation, at 19 days in the rat, and approximately at 10 weeks in the human fetus. The initial event in morphogenesis of the prostate is the outgrowth of solid epithelial buds from the UGS epithelium into the surrounding UGS mesenchyme. The prostatic buds proliferate under the influence of testicular androgens to form solid cords of epithelial cells that grow into the UGS mesenchyme in a particular spatial arrangement to establish the lobar divisions of the prostate. At birth in rodents the prostate is small with a limited number of undeveloped buds; postnatally these cells proliferate, predominantly at the tips, and undergo a process of canalization in a proximal to distal direction (from the urethra toward the tips). Concurrent with this, the epithelial cells differentiate to luminal and basal phenotypes. The prostatic basal cells, at least in rodents, are complex structures with processes that wrap around the ducts; this phenotype is not obvious from traditional histologic sections. Concurrent with epithelial differentiation, the UGS mesenchyme proliferates and differentiates into interfasicular fibroblasts and prostatic smooth muscle. Postnatally, under the influence of androgens, the epithelial cells undergo differentiation, including the expression of androgen receptors, and begin to synthesize a variety of lobe- and species-specific secretory products.

In the mouse most prostatic branch points develop before 15 days of age and most of the growth and development of the prostate is complete by 60 days of age. In contrast, the human prostate does not grow significantly between birth and puberty, when growth commences in response to rising androgen levels. The prostate then slowly increases in size over several years. It should be noted that, while androgens drive the development and growth of the prostate, they also play a key role in maintaining a growth-quiescent adult organ. It is noteworthy that young adult males, in whom androgen levels are at their lifetime peak, do not suffer from prostatic enlargement or cancer; rather, these are diseases associated with aging and a decrease in serum androgen titers.

Anatomy of the human and rodent prostate

In 1912, Lowsley used serial sections as anatomic models to describe the lobes of the fetal human prostate to clarify the origin of the middle and posterior lobes as described by earlier investigators. Using tissue from a 3-month gestation fetus, Lowsley identified five separate groups of prostatic ducts originating from the UGS and used the term “lobes” to describe them. These were designated the middle lobe, two lateral, posterior, and ventral lobes. Lowsley described the ventral lobe as being formed by the glands arising from the anterior or ventral wall of the prostatic urethra and consisting of four pairs of epithelial buds. The middle lobe was formed by roughly 12 tubules associated with the posterior urethra and was situated between the bladder and the ejaculatory ducts under the floor of the urethra. The paired left and right lateral tubules, the largest group of tubules, originated from the sides of the urethra and followed the prostatic furrows. The tubules grew laterally and posteriorly, were distal to the ejaculatory ducts, and located on the caudal portion of the urethra, giving rise to the posterior lobe. Although their direction of growth was predominantly toward the bladder, a small number of ducts followed the anterior course of growth as seen in the lateral lobe.

Lowsley’s work started a debate over the nomenclature used to describe the prostate anatomy that continued for 70 years or so. In the adult human the lobes that he described are fused and cannot be separated or defined by dissection, giving rise to several different views on the anatomic division of the human prostate. The situation is further confused by the fact that, in most other animals, including some other primates, the various prostatic lobes are separable in varying degrees on an anatomic, histologic, and physiologic basis.

The nomenclature that is now most commonly used to describe the structure of the human prostate is that of McNeal. McNeal divided the prostate into three major areas that are histologically distinct and anatomically separate ( Fig. 1 ). These areas are the nonglandular fibromuscular stroma that surrounds the organ and the two glandular regions termed peripheral and central zones, which contain a complex yet histologically distinct ductal system. The central zone was described as a wedge of glandular tissue that constitutes most of the base of the prostate and surrounds the ejaculatory ducts. The peripheral zone made up the remainder of the gland. It surrounded most of the central zone and extended caudally to partially surround the distal portion of the urethra. McNeal’s classification of the central zone included the middle lobe and part of the posterior lobe described in Lowsley’s earlier studies, whereas the peripheral zone included Lowsley’s lateral lobes and a portion of the posterior lobe. McNeal also identified an additional, smaller, glandular region that surrounded the prostatic urethra, referred to as the transition zone.

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.)

The peripheral zone ducts exit directly laterally from the posterolateral recesses of the urethral wall. The system consists of small, simple round to oval acinar structures emptying into long narrow ducts surrounded by a stroma of loosely arranged and randomly interwoven muscle bundles. Ducts and acini are lined with simple columnar epithelium. This area is the principal site of prostatitis and carcinoma of the prostate, although not of BPH. The peripheral zone includes the proximal urethral segment of the prostate. This comprises the region of the prostate between the base of the urinary bladder and the verumontanum (the area where the ejactulatory ducts feed into the urethra). The principal feature of this region, which comprises about 5% of the total prostate mass, is the preprostatic sphincter. The sphincter is a cylindrical sleeve of smooth muscle that stretches from the base of the bladder to the verumontanum.

The central zone ducts run predominantly proximally, closely following the ejaculatory ducts. These ducts and acini are much larger and of irregular contour. The acini are polyhedral in cross-section. The muscular stroma is much more compact than in the peripheral zone. The central zone has a low incidence of disease.

The transitional zone surrounds the urethra between the bladder and the verumontanum. This is a small volume of the prostate, perhaps 5% in the normal organ, but is the principal site of BPH pathogenesis. Nodular expansion of this region of the prostate results in compression of the urethra and the partial bladder outlet obstruction associated with BPH.

Unlike the human, the rodent prostate is not merged into one compact anatomic structure. The rodent prostate is composed of four distinct lobular structures (see Fig. 1 ): (1) anterior lobe (also known as the coagulating gland), (2) dorsal lobe, (3) ventral lobe, and (4) lateral lobe. These lobes exist as pairs on the left and right sides. Because of differences in lobe-specific branching morphogenesis, the final shape of each lobe is distinct.

In rats and mice, the ventral lobes are located immediately below the urinary bladder on the ventral aspect of the urethra. The lateral lobes lie just below the coagulating glands and seminal vesicles, partially overlapping the ventral lobes and dorsally blend with the dorsal lobe. The dorsal lobes are found inferior and posterior to the urinary bladder, behind and below the coagulating glands and seminal vesicles. The anterior lobes, or coagulating glands, are directly adjacent to the seminal vesicles.

Lobe/zone homology between the rodent and human prostates has been suggested by various authors. However, the 2001 Bar Harbor Consensus meeting concluded that “there is no existing supporting evidence for a direct relationship between the specific mouse prostate lobes and the specific zones in the human prostate.”