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=Post-natal Growth Changes in the Human Prostate=

By G. I. M. Swyer

From the Department of Anatomy, University of Oxford


==I. Introduction==

In spite of the very extensive researches which have been carried out upon the subject of benign enlargement of the {{prostate}}, it remains a condition which is very prevalent among old men, causing them great discomfort and inconvenience, for the relief of which recourse has still to be made to surgery in the majority of cases. It is true that such treatment can lay claim to many successes, but it is, nevertheless, by no means devoid of dangers, and from the standpoint of rational medicine, it must be considered as a measure which is adopted because no more scientific method of treating this malady is known.


The literature contains relatively few accounts of the normal growth of the prostate, and since a sound knowledge of normal growth is an indispensable basis for the elucidation of pathological growth, it was considered that an investigation of normal growth would be a not unprofitable prelude to the study of benign prostatic enlargement, the results of which are to be published elsewhere. In the account which follows, there are included histological observations on all the principal systems of the prostate—glands, collecting ducts, uterus masculinus, ejaculatory ducts and urethral mucosal glands—at the various stages of its post-natal development. These comprise the condition at birth, before puberty, at puberty, and in the adult.

Growth curves, relating the variation of prostatic volume with age, have also been constructed.

Material and methods. For the greater part of the work, material has consisted of prostates obtained at routine autopsy from the London Hospital, the Radcliffe Infirmary, Oxford, ‘and Birmingham. These prostates were fixed in formalin or alcoholic Bouin’s fluid, some of them having previously been bisected transversely or slit along the anterior commissure. À number of operative specimens of enlarged prostates were also available. The volumes of most of the prostates were measured by the method of water displacement; before measurement, which was always carried out with the fixed specimen, all the surrounding connective tissue, bladder, seminal vesicles, etc., were trimmed away so as to give an accurate measure of the size of the prostate itself.

A total of 113 prostates were prepared for histological examination; most of these were cut into about five transverse slices and a few sections taken from each ; some were sectioned serially throughout. The sections were variously stained in haematoxylin and eosin, Masson’s trichrome stain, orcein and Van Gieson, and Weigert’s elastin stain.

For the construction of the growth curves, 192 prostates of all ages were used. Details of the prostate material used are shown in Table 1.

Table 1. Details of human prostate

material used Al Prepared for Volume Age group specimens histology known At birth 8 8 5 Up to 5 7 3 5 6-10 6 4 6 10-15 4 3 4 16-20 9 4 9 21-25 10 3 10 26-30 Il 5 il 31-35 16 3 16 36-40 15 7 15 41-45 12 5 12 46-50 16 7 16 51-55 18 10 15 56-60 18 8 18 61-65 26 11 24 66-70 10 5 9 71-75 il 4 11 76-80 5 1 5 Over 80 1 — 1 Age unknown 35 22 — Totals 238 113 192 Post-natal growth changes in the human prostate

==II. The Prepubertal Prostate==

===Embryology===

As this work is concerned with the growth changes occurring in the prostate after birth, it will not be expedient to enter into any detailed discussion of the embryology of the organ. The most complete account of this has been given by Lowsley (1912), to whose paper the reader is referred for further details; it will suffice here to mention that Lowsley described the prostate gland as originating from five independent groups of tubules which begin to develop in the wall of the proximal part of the urethra at about the twelfth week of intra-uterine life. These groups form the median or prespermatic lobe, a pair of lateral lobes, an anterior lobe and a posterior lobe.

===The prostate at birth===

At birth, the prostate is composed chiefly of connective tissue with a relatively small proportion of intermixed smooth muscle. Embedded within the stroma so formed is the duct system radiating outwards from its origin in the urethra. At this stage, as in all succeeding ones up to puberty, the ducts end blindly near the periphery and the alveoli of the adult prostate are represented only by end-buds. The form of the urethra is the same as in the adult prostate and from it, in addition to the ducts already mentioned, there leads the uterus masculinus, the opening of which is situated in the median plane on the verumontanum, usually immediately cranial to the openings of the ejaculatory ducts, although it is not aliogether uncommon to find the order reversed.

Prostatic ducts. The prostatic ducts open into the urethra chiefly in the distal half to two-thirds of its prostatic part, but excluding its distal tenth or so. The openings are grouped around the prostatic sinuses, a variable proportion opening into the floor of the sinuses, with the remainder opening on the lateral parts of the verumontanum or on the lateral walls of the urethra. Ducts of the anterior lobe may be present, when they usually lead straight back into the ventral wall of the urethra; they exist only in the caudal third of the organ.

Typically, the ducts are composed of cubical or low columnar cells with large, centrally placed nuclei. Two layers of cells may be regarded as the basic arrangement but in many parts of the prostate this number is exceeded to a varying extent. In places the ducts may appear as solid cords of cells; whether these are the primary cords which have not yet become canalized, or whether they are ducts whose lumina have secondarily become obliterated is a matter for conjecture. The fact that ih the prostate at birth many of the ducts are patent in their peripheral parts, while the solid cords are found nearer the centre, is evidence in favour of the view that the solid cords are formed secondarily rather than that they àre persistent uncanalized ducts. Here and there in these cords can be found the appearance of pseudo-acinar formation (PI. 1, figs. 1, 2). The same appearance is seen in the thickened hyperplastic walls of patent ducts, and is similar to that found in certain tumours, such as prostatic adenocarcinoma and ovarian papillary cystadenoma, and also in chronic cystic mastitis. It is also strictly comparable with that found by Zuckerman & Sandys (1939) in the Hanuman langur (Presbytis entellus) subjected to oestrogenic stimulation, and, as those authors suggest, may well be part of a process of budding off of new ducts. In a rather small proportion of cases, these pseudoacini contain eosinophilic colloidal material which may represent products of cell breakdown.

In addition to the hyperplasia of the epithelium of the ducts mentioned above, squamous metaplasia is frequently found. It most commonly affects ducts in the region of the prespermatic lobe and may lead to their complete blockage (PI. 1, fig. 4). Here again, pseudo-acinar formation may occur. Metaplasia of the duct epithelium is not found in the periphery of the prostate.

End-buds. In general, the epithelium of the endbuds resembles that of the ducts; many of the endbuds possess no lumen, though this is not true for all (PI. 1, fig. 5). Occasionally, end-buds are found with a secretory epithelium of tall columnar cells with basal nuclei, the type, in fact, being that of the active adult prostatic alveoli (PI 1, fig. 6). Moore (1936 a) has drawn attention to this phenomenon and stresses its essentially focal nature, which he regards as expression of subtotal stimulation; the probable nature of the stimulus will be discussed later (p. 132).

Urethra. The epithelium lining the urethra is fundamentally of the transitional type, there being a varying number of somewhat irregularly disposed layers of cells (the number may reach 10), of which those next the lumen are cuboiïdal in shape, being slightly flattened tangentially, while the more deeply lying cells are cubical or of very short columnar type. In general, the above description is true for both the anterior and the posterior walls of the urethra, but very commonly, the epithelium overlying the verumontanum* shows areas of hyperplasia, the number of layers being considerably increased, while the luminal layers show squamous metaplasia, the cells being pale staining and undergoing keratinization (PI. 2, fig. 8). The extent of this metaplasia is variable; occasionally it is not found at all, or it may occur only in a few isolated pockets. On the other hand, it may extend throughout the crista urethralis and reach onto the anterior walls of the urethra, these extensions usually being more or less focal.


The posterior wall of the urethra bulges forwards as
the crista urethralis; this bulge is most prominent in the region of the openings of the ejaculatory ducts and uterus masculinus (verumontanum or colliculus seminalis). The portions of the crista above and below the verumontanum are sometimes referred to as the superior and inferior cristae respectively.



Small crypt-like infoldings of the epithelium are generally found, being most frequent in the region of the prostatic sinuses; they probably represent the forerunners of the mucosal glands.

Uterus masculinus. The uterus masculinus is à conspicuous feature of the new-born prostate, often being very large and distended (PI. 1, fig. 7; PI. 2, fig. 10). Frequently it extends cranially almost to the entrance of the ejaculatory ducts into the posterior surface of the prostate. It lies, together with the ejaculatory ducts, in a stroma which is somewhat less dense (possibly because it is slightly oedematous) than that of the remainder of the prostate and which is practically devoid of smooth muscle fibres. This stroma is usually clearly demarcated from the remainder of the prôstate by a concentric , condensation of smooth muscle and connective tissue forming a capsule.

The form of the uterus masculinus is variable, and, in this connexion, Vintemberger (1926) described two main types: the diverticular and the glandular type, with intermediate forms. He found that the differentiation could be traced back even to the foetal stage, although in its early development the uterus masculinus consists merely of solid cords of cells. As seen in the new-born, the uterus masculinus is most commonly represented by a distended sac, from which a few duct-like diverticula may extend a short distance into the stroma; they have not been observed to penetrate the capsule. This is the diverticular type of Vintemberger. The glandular type of utricle, less commonly seen, consists at birth of an irregular series of cords of cells passing in all directions from a main lumen, which may be very small, and which has sometimes been observed to open into the urethra by two mouths. Occasionally, the utricle is T-shaped in cross section, its main lumen not being distended ; this form is reminiscent of that found in many species of monkey.

Fundamentally, its epithelium consists of small cuboidal cells, but it is usual to find extensive hyperplasia with squamous metaplasia of the same type as previously described for the prostatic ducts and verumontanum. Hyperplasia and metaplasia

are found in the diverticula also. The lumen of the:

uterus masculinus is frequently occupied by a mass of desquamated débris.

Ejaculatory ducts. The ejaculatory ducts are lined by an epithelium consisting of two layers of cells, those next the lumen being short columnar while those of the basal layer are cubical in shape.

Wagenen,

The nuclei are large and occupy the greater part of the cells. Occasionally, the epithelium is hyperplastic near the urethra.

The foregoing account shows that hyperplasia and squamous metaplasia of the epithelium of the ducts, verumontanum and uterus masculinus is a conspicuous feature of the new-born prostate and it may be mentioned that it was first reported by Aschoîf (1894) and confirmed by Schlacta (1904). It is of precisely the same nature as that observed in the prostate of the rhesus monkey (Macaca mulatta) subjected to oestrogenic stimulation (van 1935; Parkes & Zuckerman, 1985; Zuckerman, 1938) and there seems little doubt that it results from the action of maternal oestrogens circulating in the foetal blood. This view was taken by Halban (1904, 1905) on purely theoretical grounds, and has recently been confirmed by Sharpey-Schafer & Zuckerman (1941) who studied the effects of oestrogens on the prostates of babies. Unlike the rhesus prostate subjected to prolonged oestrogenic stimulation, the ejaculatory ducts of the new-born prostate do not, as a rule, show any hyperplasia at their terminations and, following Zuckerman’s suggestion (1936 a, b), it is therefore to be presumed that no invasion and replacement of Wolffian epithelium by urogenital sinus epithelium normally occurs in man.

The occasional occurrence of apparently actively secreting prostatic glandular epithelium would appear to require for its explanation a stimulation by male hormone and this is the view to which Moore (1936 a) subscribes, its essentially focal distribution being interpreted as the result of subtotal stimulation. The présence of small amounts of male hormone can be ascribed to the action of maternal anterior pituitary gonadotropic hormone stimulating the foetal testis with a consequent elaboration of the androgen.

Urinary retention and hydronephrosis in newborn babies have been ascribed to prostatic obstruction resulting from oestrogenic stimulation ; it seems
doubtful, however, whether this explanation is correct. Although showing unmistakable signs of oestrogenie stimulation, the new-born prostate is seldom enlarged to anÿ extent. In one personally investigated case of retention with hydronephrosis the prostate was definitely of normal size (volume 1-25 c.c.). There was no difficulty in passing a catheter, and the verumontanum, though prominent, was in no way pathological; hyperplasia and squamous metaplasia were not excessive, nor could enlargement of the uterus masculinus be considered as sufficient to have caused obstruction. On the other hand, there existed at the internal urethral meatus a pair of thin, valvular mucosal folds on either side, so shaped and disposed as to Post-natal growth changes in the-human prostate

prevent the passage of urine, while offering little obstruction to the passage of a catheter (PL 2, fig. 9). In this case, doubtless, the obstruction was due to these mucosal valves, an account of whose congenital occurrence has been given by Young & McKay (1929), and it is probable that a similar state of affairs existed in the other cases of urinary obstruction in the new-born which have been reported.

The post-natal prepubertal prostate

Within 6 or 7 weeks of birth, the specific indications of oestrogenic stimulation disappear from the prostate: the metaplasia of the epithelium of the verumontanum, terminal parts of the prostatic ducts and uterus masculinus is no longer evident, while the distension of the last subsides so that it assumes the shape of a sagittal slit, not infrequently.

with a T-shaped extension anteriorly. In this condition the prostate continues up to about the ninth year with very little increase in size or differentiation.

Prostatic ducts. The most conspicuous feature of the prepubertal prostate is the extensive hyperplasia of the duct epithelium. This frequently proceeds to complete blockage of the lumen. Subsequently, pseudo-acinar formation occurs, often associated with lateral proliferations from the ducts which represent a process of development of side branches whereby the duct system undergoes elaboration. Colloid may be found in these new lumina, and might be derived from the products of disintegrated cells, although secretion cannot be excluded, and, in fact, would seem to be the most likely explanation of the large amounts of colloid seen in some of the older prepubertal prostates (see p. 133). The process of hyperplasia and pseudoacinar formation is found chiefiy in the central parts of the prostate; near the periphery, hyperplasia of the epithelium, though found, is not extensive,

End-buds. The end-buds of the prostatic ducts tend to become more patent with advance in age, though they remain small in size and their epithelium is not of the true secretory type. This epithelium consists of a single layer of cells, except in the poorly differentiated end-buds where there maybe two or three layers; the cells are very short columnar with fairly large nuclei which can already be seen assuming a basal position similar to tliat found in the fully differentiated alveolar epithelium.

Urethra. The general character of the urethral mucosa remains similar to that already described, except, of course, that metaplasia is no longer found. As a rule, some degree of hyperplasia is present and the crypt-like infoldings tend to increase in number. Often, in the walls of these, and in the unfolded mucosa besides, foci of pseudoacinar formation are to be found, leading, it would seem, to the development of the urethral mucosal glands (PI. 2, fig. 11). This occurrence in the hyperplastic urethral mucosa may be regarded as additional evidence for the correctness of the same interpretation of the comparable appearance in the hyperplastic duct epithelium, where, as was mentioned, some doubt could exist concerning the possibility that the foci were really the remains of a persistent lumen rather than a newlyÿ formed one. Where the foci of pseudo-acinar formation are found in the urethral mucosa there is little likelihood of confusing them with persistent duct lumina.

Uterus masculinus. The uterus masculinus is lired by an epithelium consisting of two or three layers of cuboidal cells with fairly large nuclei. In most cases, numerous duct-like diverticula are present and these show extensive hyperplasia, with foci of pseudo-acinar formation, eosinophilic colloid being found in some of the lumina. A characteristically complex glandular type of uterus masculinus in a five-year-old prostate is shown in PI 2, fig. 12. The stroma is still somewhat less dense than that of the remainder of the prostate, but now some smooth muscle fibres are to be found. The surrounding capsule is usually distinct and contains smooth muscle fibres.

Ejaculatory ducts. The ejaculatory ducts call for no comment, answering to the description already given.

Anterior lobe. Occasionally, ducts of the anterior lobe, distinguishable from anterior extensions of the lateral lobes, are found. They drain backwards into the ventral urethral wall and show features similar to those of the lateral lobes.

Between ages of about 9 years and puberty, cyst-like dilatations of the prostatic ducts are very commonty found, the lumina being filled with eosinophilic colloid (PI. 8, fig. 14). Although hyperplasia is frequently intense, it seems unlikelÿ that cell breakdown could account for the quantities of colloid found and it may therefore be presumed that the epithelial cells possess some secretory ability, although even at this stage, the occurrence of epithelium of the true secretory type is rare.

==III. Changes at Puberty==

The transformation of the prepubertal prostate into the adult type of organ takes place during a relatively very short period of time, probably a matter of 6 months to 1 year, and because of this, it is naturally a difficult matter to obtain prostates in the intermediate stages. Thus, whereas a specimen 13 years of age may show only slight signs of pubertal changes, another of 14 years may be in the full adult state (see examples, p. 134 et seq.). The increase in size of the prostate at pubertÿ is 134

very rapid, especially when ‘contrasted with its rate of growth before puberty. From birth to 13 years the average volume increases from about 1 to 4 c.c., while between the thirteenth and fourteenth years the volume rises to about 10 t.c. (see Textfigs. 1, 2). This enlargement is due almost entirely . to the development of the alveolar system.

The earliest changes seen consist of enlargement of the lumina of the end-budbs of the prostatic ducts and of the thinning out of their epithelium to a single cell layer. The cells become elongated radially and their nuclei assume a basal disposition. In most cases the cells remain small, though here and there they attain proportions nearer to those of the adult alveoli. Colloidal material may be found, but it is more common in the distended ducts already mentioned. Many of the ducts remain hyperplastic, with foci of pseudo-acinar formation. The epithelium of the urethra also is hyperplastic and, especially over the verumontanum, tends to be folded in complex fashion, with numerous areas of pseudo-acinar formation.

Alveoli. The further development of the alveolar system consists in the extension to all the end-buds of the changes already described, and their subsequent elaboration to attain the typically adult condition. In many cases this process does not reach completion for some years, so that it is not uncommon to find groups of juvenile end-buds in otherwise fully differentiated prostates up to the age of 20 years or more (PI. 2, fig. 18). The alveoli are somewhat distended and the epithelium shows numerous peninsular extensions into the lumina. The larger of these extensions are supported on delicate stromal processes but in the smaller extensions the epithelium appears simply to be bulged into the lumen with only the basement membrane intervening between the two layers of epithelial cells. Typically, the cells are tall columnar with lightly staining basophilic cytoplasm and fairly large basally disposed nuclei. Owing to the elaborate nature of the epithelium, any given section will pass through the cells in various planes and so may give rise to the appearance in some places of several layers of cells of varying shape, but careful examination is usually sufficient to indicate the cause of this. The luminal borders of the cells are often indefinite as a result of the adherence to them of what are presumably secretory products. The stroma is condensed around each alveolus and in most cases contains a fairly high proportion of smooth muscle fibres.

Prostatic ducts. Characteristic changes are undergone by the prostatic ducts, in which hyperplasia of the epithelium is still to be found but now the foci of pseudo-acinar formation coincide with the site of alveolus development, the cells surrounding the new lumina elongating and assuming the same characteristics as those of the prostatic alveoli themselves (PI. 8, fig. 16). In this way the ducts themselves come to be part of the alveolar system and the secretory epithelium may extend right up to their openings into the urethra (PI. 4, fig. 20). A variable number of ducts, however, generally retain a non-secreting type of epithelium consisting of the usual cuboidal cells.

Uterus masculinus. Changes occur in the uterus masculinus also, the diverticular epithelium tending to become of secretory type and hyperplasia becoming reduced in intensity. As a rule, however, it is not until two or three years later that definitely secretory alveoli are to be found in the uterus masculinus. ‘

The changes in the prostate at puberty can more adequately be illustrated by reference to brief descriptions of some typical prostates taken just before and during puberty. Three such examples are given below:

H.P. 22—age 10 years. Glandular system. This is undifferentiated and consists of a proliferating series of ducts radiating posteriorly and laterally with some anterior extension of the most laterally disposed ducts. Most of the ducts are canalized. The epithelium, while consisting typically of about two layers, is in many places hyperplastic, especially near the urethra. The anterior extensions of the lateral lobes consist almost entirely of solid cords of cells. There is a well-developed anterior lobe, the duct epithelium showing extensive hyperplasia. These ducts open into the anterior wall of the urethra.

Urethra. Numerous mucosal glands are present in the anterior wall, their epithelium closely resembling that of the urethra itself. This last consists mostly of from four to six layers of tightly packed cells with intensely basophilic nuclei.

Uterus masculinus. Cranially, this consists of a horseshoeshaped main lumen, the central part of which is canalized while the postero-lateral limbs are solid cords of cells. There are numerous diverticula, mostly composed of solid cellular cords.

More caudally, there is a central T-shaped lumen from which solid cords extend anteriorly and, to a less extent, laterally along the crista lateral to the ejaculatory ducts; others extend posterior to the ejaculatory ducts. Circularly disposed muscle fibres demarcate the entire utricular system fairly clearly but do not enclose it completely.

H.P. 97—age 37 years. Glartdular system. This is mainly similar to that described above. There is an anterior lobe in the caudal third of the prostate. Though the ducts themselves are mostly canalized, end- and side-knobs are generally solid. Only a few of the ducts near the periphery are distended but those nearer the urethra, i.e. in the utricular bed, are very distended and filled with eosinophilic colloid (PL 3, figs. 14, 15).

Epithelial hyperplasia is practically restricted to ducts in the utricular bed and the anterior lobe.

Urethra. The epithelium consists of many layers of cells Post-natal growth changes in the human prostate resembling the epithelial cells of the rest of the prostate. Mucosal glands are richly developed.

Uterus masculinus. The main lumen is a distended irregular cyst lying anterior to and between the ejaculatory ducts; it is lined with from four to ten layers of tightly packed cells with somewhat irregular, relatively large nuclei. Densely solid cords of cells radiate anteriorly and posteriorly. Differentiation of definitely utricular extensions from epithelial elements derived from the prostatic duct system proper is very difficult (PI. 3, fig. 15).

H.P. 49—age 15 years. For the most part the prostatic ducts and acini are fully differentiated, the latter being lined by a single layer of columnar secretory cells with small basal nuclei. In most alveoli the epithelium is folded and projects as fringe-like processes into the main lumen. In many cases these processes are supported on a central stromal projection. Many of the acini and ducts are distended with secretion. Within the posterior and lateral parts of the gland none of the acini appear to be undifferentiated ; in the anterior extensions of the lateral lobes, however, the ducts and alveoli are not differentiated and have the characteristics typical of immature prostates. Hyperplasia of the epithelium is also found in the ducts of the prespermatic region.

Urethra. Anteriorly the urethral epithelium is composed of spindle cells showing slight hyperplasia; there are a few shallow crypts. Posteriorly it consists chiefly of columnar cells, with moderately deep crypts in the more cranial levels. There are numerous mucosal glands on the crista, where the epithelium consists of from four to ten layers of cells.

Uterus masculinus. This consists of a short sagittal diverticulum of the crista directed backwards and slightly to one side. À few crypt-like out-pouchings extend a short distance from the main lumen. Hyperplasia of the epithelium is widespread, being particularly conspicuous in the crypts. Mucinous degeneration is found here and there posteriorly.

The opening of the uterus masculinus extends further caudally than do those of the ejaculatory ducts. The stroma surrounding the organ is slightly, but not at all clearly, differentiated from the remainder of the prostate.

With regard to the factors underlying the changes at puberty, there can be no doubt that they are due to the action of the male hormone, whose secretion by the testis in effective amounts commences at this time. The fact that castration before puberty leads to failure of development of the prostate, along with the other accessory sexual organs, has long been known. John Hunter (1786) pointed out that ‘the prostate and Cowper’s glands, and those of the uretha, 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’. Berthold (1849) gave the first scientific proof of the implication of the testis in the effects of castration, when he showed that these effects in cocks could be prevented by testicular grafts; this was the first demonstration of a specific hormonal mechanism. The most direct proof of the prostatic changes at puberty being the result of the action of the male hormone has been given by studies of the results of its administration to monkeys (Zuckerman & Parkes, 1936b, 1938).

There still remains the question of the causation of the hyperplasia observed in the ducts of the prepubertal prostate and for the moment it seems that stimulation by very small quantities of male hormone provides the most likely explanation, on the basis that weak androgenic stimulation may cause more or less undifferentiated growth of sensitive epithelium, while stronger stimulation results in the differentiation of secretory cells such as is known to occur. In support of this suggestion it may be noted that the prostate of the rhesus monkey subjected to weak androgenic stimulation shows some hyperplasia of the, ducts resembling that found in the prepubertal human prostate. It is necessary, however, to bear in mind that oestrogens also cause hyperplasia of at least the terminal parts of the ducts, a fact which has been shown experimentally in the Hanuman langur by Zuckerman & Sandys (1939) and has been reported as occurring in the human prostate by Moore & McLellan (1938). It is also well known that oestrogens are excreted by adult males, though regarding their excretion before puberty knowledge is less certain. Nathanson, Towne & Aub (1941), however, have recently reported on the excretion of sex hormones in childhood. They find that from 8 to 7 years of age, both boys and girls excrete a small amount of oestrogens and 17-ketosteroids (androgens) in the urine, there being very little sex difference. From 8 to 11 years there is an increased excretion of these hormones, that of 17-ketosteroids increasing more rapidly in boys, that of oestrogens in girls. On the whole, therefore, the first explanation seems to be the more acceptable, though a synergic action between very small amounts of both hormones cannot be excluded.

==IV. The Adult Prostate==

In this section are discussed those changes which occur in the prostate after puberty. The stroma of the prepubertal prostate constitutes a fraction of the whole which greatly exceeds that contributed by the epithelial elements, but at pubertyÿ the position becomes reversed. So it remains throughout the greater part of adult life except that when senile involutional changes set in, there is a corresponding diminution in the proportion of the epithelial elements. During the second and third decades growth in the size of the whole prostate is rapid and, in general, is due chiefly to an increase in the number of glandular alveoli. Thereafter, the average size of the prostate remains fairly constant 136

up to the age of fifty, as will be seen in a later section. In the sixth and later decades, the size of the prostate varies in a complex fashion related to the frequent occurrence of pathological processes. These, however, will not be discussed here, for we are concerned only with what may be considered as normal growth changes, and these are most probably involutional during this latter period of life. Lobes of the prostate. It is necessary, in the first place, to reconsider the arrangement of the glands of the prostate since differences exist in this respect between the prepubertal and the adult prostate. It will be recalled that Lowsley considered the foetal prostate to contain, at least during a certain period, five lobes, comprising two lateral lobes, an anterior, a median and a posterior lobe. Of these, the anterior lobe is generally recognized as undergoing atrophy in the majority of instances and as being represented in only a small proportion of adult prostates. The median lobe is present in most cases in the adult, although its degree of development varies very considerably in different individuals.

In a few cases no glandular tissue can be dis tinguished in the region of the prespermatic or _median lobe, while, in yet others, such glandular tissue as may be present in this region is derived by the medial encroachment of the lateral lobes forming a prespermatic commissure. It is difficult to be certain of the exact origin of the prespermatic glandular tissue in many cases, but it seems probable that this is more often commissural than has generally been supposed. In this connexion it may be pointed out that in the prostates of several species of monkey the lateral lobes form, in the cranial parts, unmistakable pre- and retrospermatic commissures, and there seems to be good reason to suppose that a similar state of affairs exists in man.

Concerning the posterior lobe as described by -Lowsley, there is considerable doubt as to whether it finds any representation in the majority of adult prostates. Certain it is that no definite fibrous lamella can be found separating the lateral lobes from glandular tissue occupying the position described by Lowsley for the posterior lobe. Strongly suggestive evidence for the non-existence of a posterior lobe in the majority of cases has been obtained by LeDuc (1939) using a technique involving the injection of prostatic ducts with Indian ink. Special efforts to inject ducts whose orifices lay in the posterior urethral wall caudal and lateral to those of the ejaculatory ducts, that is, in the area described by Lowsley as containing the orifices of the ducts of the posterior lobe, showed that of fifty ducts injected (thirty-six on the inferior crista, fourteen in the distal urethra) only four led directly posteriorly and that of these, only two corresponded in any way with Lowsley’s description. These two ducts led directly up to the mid-line, posterior to the urethra and ejaculatory ducts but did not drain any tissue of the lateral lobes. The other two were such short and rudimentary ducts that no importance could be attached to them. In several specimens, however, lateral lobe ducts could be seen to form a retrospermatic commissure and this LeDuc regards as being the most usual arrangement.

Central glands. A further group of glands, of which only small mention has so far been made, is that to which the names inner, central, periurethral, accessory and submucosal have variously been given. They were first described in 1894 by Jores who located them in groups on the trigone and vesical neck, and in the urethral walls below the neck of the bladder. Subsequently, these glands were found to be sparse in early life, but to increase in number in succeeding age groups, although in some instances they are absent altogether. Several ôther authors have described these glands, including Albarran & Motz (1902), Loeschke (1920), Adrion (1922), Jacoby (1923), Young & Davis (1926) and Stieve (1930). Jacoby drew attention to their wide variation in size and distribution and showed that some of them might drain into ducts of other prostatic glands. Stieve was unable to discover any difference in cellular structure between the central and the outer prostatic glands.

Attention was first drawn to the central glands as a result of the paper of Motz & Perearneau (1905) wherein these authors sought to show that all hyperplasia of the prostate has its origin in these glands. Subsequently evidence has accumulated which throws doubt upon this hypothesis, and the importance of the central glands has diminished accordingly. In viéw of the findings of Jacoby and of Stieve mentioned above, it may be questioned whether or no any useful purpose is to be served by the continuation of the practice of describing central and outer prostatic glands.

Alveolar epithelium. The alveolar epithelium of the adult prostate shows considerable variation in different prostates and in different parts of the same prostate. As Macklin (1928) points out, there is a striking lack of harmony in the descriptions of the numerous writers regarding almost every point of discussion. In the first place, there is disagreement as to the number of layers of cells, a single layer being described by Walker (1910) for the adult rat and by Weski (1903) for the human subject. The latter author occasionally finds a second layer of flattened elements crowded between the bases of the columnar cells, and here the structure is such that the nuclei of the latter are above the level of the free border of the former, thus giving rise to the false impression of a double layered condition. A number of workers consider two layers as normal, describing a stratum of flattened or cuboidal cells underlying the lining of cylindrical cells (Langerhans, 1874; Rüdinger, 1883; Disselhorst, 1904, for the human as quoted by Petersen, 1909 ; Prenant & Post-natal growth changes in the human prostate

Bouin, 1910). Personal observation leads the present writer to favour the opinion that a single layer is the normal arrangement.

Petersen (1909) described a secretory cycle for the epithelial cells and the later description of Moore (1936b) agrees with it in most respects. The resting cell is cuboidal, non-granular and coarsely reticular with a large, oval, centrally placed nucleus. In the early stages of activity, the cytoplasm is occupied by rounded, basophilic granules of various sizes. These, in developing, change their staining reaction to acidophilic, in the intermediate stages some of the granules being partly basophilic and partly acidophilic. As development proceeds, the now elongated cell is crowded with small eosinophilic granules whose staining reaction is similar to that of the material in the lumen, and the nucleus is usually pushed towards the base. The mature eosinophilic granules are discharged into the lumen and concomitantly the basal protoplasm clears, assuming a fibrillar or net-like structure. The peripheral region, however, remains at first densely staining and is sometimes prolonged into the lumen. Petersen was able to demonstrate granules in the fresh condition which corresponded to those in the fixed cells. Dominici (1913) found that the number of mitochrondria varied with cellular activity and regarded them as taking an indirect part in secretion formation, though not becoming directly transformed into it. Cowdry (1918) described the mitochondria as being very minute and of granular form.

During the third decade there is a gradual, though somewhat irregular increase in the complication of folding of the alveolar epithelium; thereafter, a process of simplification sets in, there being a disappearance of the peninsular extensions of the epithelium so that in the fifth and later decades their numbers are few or they may be altogether non-existent. Because of this, the outline of the alveoli becomes less irregular and there is a concomitant tendency to cystic dilatation. Involutional processes, which seem to commence as early as the fourth decade, are particularly evident in the more peripherally situated alveoli, especially after the age of about 40 years, the epithelium being reduced to a thin, flattened layer of small cuboidal cells, slightly elongated in a tangential direction. These alveoli are frequently dilated (PI. 4, fig. 21). Actively secreting alveoli seldom disappear entirely from the prostate but, in general, their proportion diminishes with increasing age.

Shedding of the alveolar epithelium is frequently seen in parts of the adult prostate. It occurs probably in two forms: in the first, associated particularly with acute febrile conditions, the whole epithelium may strip off, when histologically, the more or less unchanged columnar cells can be seen in clumps in the lumen. When shedding occurs in the young adult prostate, this is the form in which it is found and it must be considered as resulting, not from a change in the endocrine environment of the epithelial cells, but from the action of toxins. The second form of shedding is associated with hyperplasia of the alveolar epithelium and has not been observed below the age of 35 years. Here, because of a departure in form of the epithelium from that of the normal, androgenically stimulated structure, the whole process must be considered as pathological.

Corpora amylacea. After the age of about 20 years, corpora amylacea are common findings in the prostatic alveoli and have been made the subject of close study by Moore (1936b). He regards them as characteristic of involuting and involuted glands. Between the ages of 20 and 40 years, small corpora amylacea are found in about 25 % of prostates; thereafter, they occur with greater frequency. When found in the younger prostates, they are usually associated with some atrophy of the epithelium and are generally from cases of tuberculosis or some other chronic infection. They always differ from those of senile prostates; there are few concentric rings, facets are rare, central pigmentation is unusual and there is no calcification. Central softening is more frequent than in those from senile prostates. The concentric lines typical of corpora amylacea from senile prostates are due to successive deposits and indicate that they take months or years to grow. When concentric lines are found in corpora amylacea from younger prostates they are less distinct, further apart and frequently wavy, while the layers are less compact, all features indicative of softer consistence and less secondary organization and dehydration, reflecting their more recent origin.

Prostatic ducts. The character of the collecting ducts shows considerable variation in adult prostates, and it is by no means easy to draw conclusions as to the association of any particular changes with increase in age. Ducts with a secretory epithelium and others with ordinary cuboidal cells are found, apparently indiscriminately, throughout adult life, although there is no doubt that in old age secretory ducts are the exception rather than the rule. In many cases secretory alveoli are developed in the walls of collecting ducts right up to their openings into the urethra, but occasionally it is difficult to differentiate them from mucosal glands when the latter are particularly richly represented (PI. 4, fig. 19). Small concretions may be found in the alveoli in the walls of secretory ducts.

Hyperplasia of the duct epithelium seldom dis appears entirely from the prostate and, in fact, tends to show an increase in frequency in the fifth and later decades. PI. 4, fig. 25 shows the hyper138

plastic epithelium of a duct in a 52-year-old prostate; foci of pseudo-acinar formation resembling those of juvenile prostates can be seen in the thickened wall. À gradual falling off in the intensity of androgenic stimulation might be responsible for this, as well as for the less common occurrence of secretory ducts in old age. During the third and first half of the fourth decade, it is almost the rule to find hyperplasia of the ducts in the most antero-lateral extremities of the lateral lobes in the lower half of the prostate. The appearance leads to the conclusion that active proliferation of the glandular system persists longer in this region than elsewhere, with the resultant development of glandular tissue bridging the anterior commissure. In these zones, all the characteristics of proliferation found typically in juvenile prostates are to be seen. Similar hyperplasia and evidence of proliferation is often found in the prespermatic region also. The possible significance of these observations in relation to the development of benign hypertrophy is to be discussed in another publication.

Many of the foregoing points can best be illustrated by reference to the following descriptions of the glandular systems of several prostates of various ages:

H.P. 116—age 23 years. In the lower part of the prostate anterior extensions of the lateral lobes form a practically complete band of glandular tissue throughout the anterior commissure. Most of the alveoli are completely differentiated. There are no abnormal epithelial changes. Juvenile hyperplasia is well marked in the collecting ducts, especially those of the most anterior of the lateral lobules.

H.P. 47—age 30 years. Proliferation of the most anterior of the lateral glands forwards into the anterior commissure is seen; the latter is completely bridged only in the most caudal part of the prostate. These are the only glands which are not fully differentiated. No glands drain into the anterior wall of the urethra. No stratification of the ducts in the prespermatic region is seen; these ducts are secretory right up to their urethral openings.

H.P. 55—age 31 years. There seems to be a reduction in the proportion of glandular to stromal tissue suggestive of involution. There is some antero-lateral extension, but this does not reach the midline.

In the cranial part most of the alveoli have a normal outline though there is a suggestion of general anteroposterior compression. The epithelium is low and not very active; stratification, up to four layers of cells, is présent in parts. There is a little secretion and a few small concretions are present. In the more caudal levels most of the alveoli appear collapsed, being much smaller than normal. Peninsular extensions are small or absent.

Several of the collecting ducts, which open in all the usual situations, are secretory right up to their urethral openings.

H.P. 109—age 35 years. Most of the alveoli in the cranial part of the prostate present a normal appearance and have a secretory epithelium, though this has fewer peninsular extensions than in a vounger adult prostate. There is epithelial shedding in some alveoli. In the remainder of the prostate these changes are more marked and the general appearance suggests that the prostate has experienced a cessation of androgenic stimulation, which has caused some collapse of the alveoli, together with some acute interference which has resulted in extensive ante-mortem shedding of the epithelium which has plugged most of the ducts with masses of cells. In addition, the epithelium of the ducts has been stripped in many places, leaving only a very thin layer of flattened cells with almost invisible nuclei. It is from this basal layer that subsequent regeneration could have taken place.

H.P. 70—age 37 years. In the cranial levels the glands do not extend anterior to the urethra, but lower down they reach the anterior commissure. In addition, there is a true anterior lobe with ducts draining straight back to the urethra in the caudal half of the prostate.

The cranial alveoli are mostly normal in appearance, though heaping and shedding of the epithelium is seen here and there. At lower levels the peninsular extensions become fewer in number. Secretory epithelium is still the rule but near the periphery there are several alveoli which are elongated tangentially and which have a flattened epi- . thelium. In the most caudal parts, distended cystic alveoli are typical.

In the subcervical region, peri-urethral glands are clearly visible. In general, they are lined by two layers of cells of which the inner layer is of columnar secretory type. Hyperplasia is present here and there.

The epithelium of the ducts is hyperplastic in many places. In some parts the luminal cells are columnar secretory; in others they are more or less flattened cuboidal. Many of the deeper cells are polygonal and must therefore be regarded as metaplastic. Pseudo-acinar formation is to” be seen in a few places. The openings of the ducts are situated in the usual locations. In the prespermatic region ducts appear to open right on the summit of the crista.

H.P. 118—age 45 years. The glandular system has a normal distribution. The anterior commissure is bridged only in the lower part of the prostate. Extensive evidence of involution of the epithelium is seen in all parts. Many of the more peripheral alveoli are dilated and lined by very low epithelium the cells of which have very little cytoplasm (PL 4, fig. 21). Many are also filled with concretions.

Hyperplasia of juvenile type is found in many of the ducts in the prespermatic region, as well as in the anterolateral extensions. In the lower section of the prostate almost all the ducts anterior to the urethra are hyperplastic and show secondary duct formation in their walls.

H.P. 72—age 48 years. The glandular system has a normal distribution, with a normal proportion of glandular to stromal tissue. Most of the alveoli have a healthy adult appearance, though the epithelium is somewhat irregular and shows shedding in places. They contain secretion and also numerous small corpora amylacea. Some of the peripheral alveoli are dilated, with a flattened epithelium. In the antero-lateral extensions the alveoli have a particularly active appearance. Collecting ducts are secretory right up to their openings into the urethra. Post-natal growth changes in the human prostate

Uterus masculinus. It has already been pointed out in discussing the uterus masculinus of the newborn prostate that this structure assumes a form traceable to one or other of two main types, diverticular or glandular, or to a type intermediate between them. This statement remains true for the adult prostate.

The degree of variation of the uterus masculinus in the adult prostate must be emphasized. Apart from variation of form, there is great variation in extent, in some cases the prespermatic region being almost completely occupied by the utriculus, while in others serial sections are necessary to demonstrate it, so limited is its representation. Nor is there any relationship between the size of the prostate and the extent of the utriculus masculinus; PI. 4, figs. 24 and 22 show the extensive utriculi of a 22- and a 23-year-old prostate respectively (volumes 20 and 83 c.c.), while PI. 4, fig. 28 shows the very small utriculus from a 62-year-old prostate which had undergone benign hypertrophy (volume 40 c.c.). (Note that the magnification of figs. 24 and 22 is x 11 while that of fig. 23 is x 82.)

The uterus masculinus opens on the summit of the crista urethralis, usually, but not always, in the median plane and most commonly just proximal to the orifices of the ejaculatory ducts. Occasionally, it opens into one or other of the ejaculatory ducts, and Vintemberger (1926) states that such an arrangement occurs in about 8 % of cases. Sometimes there are multiple openings of the uterus masculinus, while another modification consists in there being a main opening, with some of the diverticula opening independently. In both these latter arrangements it must be assumed that there has been some absorption of Müller’s tubercle into the main lumen of the utriculus.

In a few cases, the uterus masculinus may possess two main lumina, which may unite anteriorly to open on to the crista by a common orifice, or may open by two separate mouths. Such arrangements might be regarded as an indication of the bilateral origin of the utriculus from the Müllerian ducts.

The capsule surrounding the utriculus in the adult prostate is generally much less readily made out than in younger prostates. In many cases it is clearly incomplete and the question arises as to whether or no there exist connexions between the utricular glands and the adjacent prostatic collecting ducts. This question becomes important in view of the hypothesis put forward by Cunéo (1936) that the glandular elements in prostatic hypertrophy are derived by the lateral extension of the utricular glands. This matter is discussed in detail in another publication but for the moment it will suffice to state that there can be no doubt that in some prostates connexions do exist between utricular diverticula and adjacent prostatic collecting ducts. In many specimens it is not possible to define the limits of the utricular system by simple histological examination, while it is often impossible to differentiate between glands of utricular origin and those of urogenital sinus origin in the prespermatic region. However, by means of serial sections and projectoscopic tracings from these, it was possible in some cases actually to demonstrate the continuity of glands both with the main lumen of the utriculus and with prostatic collecting ducts. It is important to note that such connexions were demonstrable in prostates of ages well below those in which benign hypertrophy is found, and which showed no evidence of that pathological process (see PL 4, fig. 22 and PL. 8, fig. 17).

Before the age of twenty years, although growth and differentiation of the glands of the uterus masculinus occurs, they seldom show evidence of active secretion. Hyperplasia of the epithelium and foci of pseudo-acinar formation are still common. In the third decade, however, the glands have frequently reached a high degree of complexity and closely resemble the true prostatic glands, having a similar epithelium with numerous peninsular extensions (PI. 3, fig. 18). Such a condition is usual up to the age of about 45 years, after which, although often present, the glands appear to undergo dedifferentiation and it is relatively seldom that they bear much resemblance to the true prostatic glands. The epithelium in the older specimens is generally composed of small cuboidal cells and some degree of hyperplasia is commonly found. Small corpora amylacea are frequent in the utricular glands. The epithelium of the main lumen generally consists of about two layers of cuboidal cells which, at least in the younger adults, often presents a secretory appearance although in older age it, like the epithelium of the utricular glands, tends to become inactive.

The following descriptions of the utricular systems of several adult prostates of different ages should serve to illustrate and in places extend some of the points made above:

H.P. 44—age 22 years (PI. 4, fig. 24). The uterus masculinus consists cranially of a central lumen lying in the anterior part of the crista. More caudally there is a dorsal extension of the utriculus consisting of a main lumen with associated glands and lying between the ejaculatory ducts. Still more caudally the dorsal and ventral components unite to form a single system. Thus, the uterus masculinus is composed of a central lumen which bifurcates above into a ventral and a much shorter dorsal lumen, both extensions, like the main body, being associated with numerous tubular glands. The mouth of the uterus masculinus does not appear in any of the sections; the ejaculatory ducts, however, appear to open into the utricular system. Furthermore, throughout the serial sections of the utriculus it is possible to distinguish between utricular and prostatic glands at all levels, and the evidence does not suggest the extension of utricular glands into the general body of the prostate in this specimen.

H.P. 38—age 23 years. At a level below the opening of the uterus masculinus there is à sagitally disposed fibromuscular bar. At a higher level the uterus masculinus consists of à radiating tree of ducts apparently separated from the prostatic glandular tissue within the crista by a circular band of mxscle. At this level there are numerous separate openings of the utricular glands on the crista; it is to be presumed that the main mouth is situated slightly lower down. The main ducts are tubular and are actively proliferating, the epithelium consisting of one or two layers of small cells with oval nuclei. In a few places these'cells have differentiated into secretory epithelium. Although, as was mentioned above, the utricular glands appear to be separated from neighbouring glands in the crista by a band of muscle fibres, these other glands s0 closely resemble the utricular glands that it is impossible definitely to state that they too are not of utricular origin.

At more cranial levels there is a mass of prespermatic glandular tissue unlike properly differentiated prostatic glands, but very similar to the utricular glands. This prespermatic tissue is undoubtedly connected with the outlying prostatic glands, and the fact that the prespermatic tissue at still higher levels consists of fully differentiated prostatic glands very strongly suggests an extensive ramification of Müllerian elements among the true prostatic glands in this prostate.

H.P. 116—age 23 years. The utricular system consists of à somewhat indefinite T-shaped main lumen with masses of glandular acini on either side, the whole system filling the crista and extending far back between the ejaculatory ducts (PL 4, fig. 22). It is impossible, even with the aid of serial sections, to differentiate the limits of the utricular glands and those of the laterally disposed ducts. There is a strong suggestion of extensive lateral proliferation of utricular glands into the anterior parts of the lateral lobes of the prostate. At more cranial levels there are some prespermatic glands and-ducts having direct connexions with the utricular glands lower down.

As in some other specimens, the uterus masculinus appears to open not by a single mouth but by means of numerous small ducts; it is to be presumed that part of the main lumen has been absorbed during development into the crista and urogenital sinus. The sections, unfortunately, are not suffciently clear to enable one to make a definite statement on this point,

H.P. 55—age 31 years. The uterus masoulinus appears to consist of a mass of glandular acini situated in small part between, but mostly in front and on either side of the ejaculatory ducts. The exact limits of the system cannot be defined; it appears to merge with prostatic collecting ducts on either side. The epithelium resembles that of the prostatic alveoli, being folded, with peninsular extensions, and of secretory type. For the most part, however, there seems to be more than one layer of cells.

H.P. 109—age 35 years. That portion of the utriculus visible in the sections consists of an irregular main body, most of the lumen of which has been occluded, situated moderately far back, together with a series of secretory glands running forward between the ejaculatory ducts, and spreading somewhat laterally in front of them. Some of these appear to open independently on the crista. Although the prostatic collecting ducts appear to be situated a moderate distance laterally from the utricular glands, it is very difficult to be certain of the precise limits of the latter and of their possible connexion with prostatic ducts.

The epithelium of the utricular glands has undergone similar changes to those in the prostatic glands and ducts (see p. 138 where the glandular system is described). .

The epithelium of the main body appears to be actively proliferating. It consists of some two layers of small, darkly staining basal cells, and a differentiated luminal layer of tall columnar secretory cells which are so swollen as to have obliterated the lumen in most places. Here and there are to be seen some intraglandular stromal nodules, similar to those seen in the utriculus of the langur (Presbytis entellus) subjected to oestrogenic stimulation (Zuckerman & Parkes, 1936a). These have a whorl-like appearance, not unlike the nodules found in the urethral stroma in later life, and seem to be surrounded by a definite wall of epithelial cells. - :

H.P. 10—age 317 years. The part of the uterus masculinus visible in the sections consists of an irregular main lumen lying between the ejaculatory ducts and giving off a complex series of glandular diverticula anteriorly. Some of these latter pass close to and may in fact be connected with certain of the prespermatic lobules. A few much smaller diverticula also pass a short distance posteriorly.

The epithelium of the main lumen consists basically of some three layers of cuboidal cells with relatively large nuclei. In parts there is hyperplasia and probable metaplasia, the lumen containing a fairly large mass of shed cells. The epithelium of the diverticula is similar to that of the main lumen and again hyperplasia and metaplasia are to be seen in places. Peninsular extensions are present in several of the lumina, but typical columnar secretory cells are to be seen in one or two places only.

H.P.14—age 39 years. The uterus masculinus has a coronal main lumen from which a few small diverticula arise anteriorly, while posteriorly a series of glandular alveoli penetrate between the ejaculatory ducts. Anteriorly and laterally there is a well-marked surrounding stromal condensation containing some muscle fibres but posteriorly it becomes indefinite. The epithelium resembles that of the prostatic alveoli except that in the coronal lumen it is composed chiefly of one or two layers of small cuboidal cells; hyperplasia is seen in a few places. Some small corpora amylacea are present. L

At à more caudal level the main arrangement is similar to that described above, but here the diverticula extend anterior and lateral to the ejaculatory ducts, although there is no suggestion of involvement with the prostatic ducts. The surrounding capsule is less clearly marked than in more cranial levels. Post-natal growth changes in the human prostate

H.P. 53—age 44 years. There is a small main lumen, sagittal in disposition, with glandular diverticula extending posteriorly, anteriorly and a short distance laterally in front of the ejaculatory ducts. There is no definite capsule surrounding the organ, but in no place do utricular glands appear to Be extending into the region of the prostatic collecting ducts. The utriculus extends cranially between the ejaculatory ducts and is seen as a somewhat angled sagittal slit accompanied by several small diverticula. The epithelium consists of two or three layers of cuboidal cells, with secretory differentiation in parts, especially in the diverticula. There is some shedding of these secretory cells.

H.P. 72—age 48 years. The utriculus consists of a fairly long sagittal slit from which a few small glandular diverticuls spring, chiefly anteriorly. The epithelium is of secretory type, resembling that of the prostatic glands, though there seem to be two or three layers of basal cuboidal cells in most parts. There is a clearly defined stromal condensation surrounding the uterus masculinus and ejaculatory ducts, and containing some muscle fibres, running chiefly in a craniocaudal direction.

- At a level just caudal to the utriculus a median sagittal bar consisting of collagenous and muscular tissue can be seen.

H.P. 23—age 49 years. The main lumen of the uterus masculinus is an obliquely disposed slit from which there extend several glandular diverticula. On one side these pass in front of the ejaculatory ducts; on the other, the main lumen reaches a comparable position. The glands do not extend very much lateral to the ejaculatory ducts and they do not appear to be associated with the prostatic collecting ducts passing forwards to the crista. Stromal differentiation of the utriculus from the remainder of the prostate is indefinite.

The epithelium of the main lumen is poorly preserved and appears to consist of two or three layers of small cuboidal cells. In several of the diverticula the epithelium consists of columnar secretory cells and is folded, with peninsular extensions.

Ejjaculatory ducts. The epithelium of the ejaculatory ducts is probably the least subject to variation in the whole prostate; throughout life it preserves the same characteristics as are found at birth and which have already been described. There is, however, some tendency to irregularity in later life and in some cases it undergoes complex folding with the formation of numerous tongue-like projections, particularly near the terminal parts of the ducts. Throughout their course through the prostate the ejaculatory ducts are enclosed within a fibromuscular capsule which contains some elastic tissue. At cranial levels this capsule is usually clearly demarcated, and it may continue so distally, when it comes to surround the uterus masculinus lying between the two ejaculatory ducts. In many cases, however, it becomes indefinite in this distal region. The capsule and the stromal tissue enclosed within it are the remains of the mesoderm of the genital cord of the embryo.

==V. The Growth Curve of the Human Prostate==

The general tendencies in the growth of the prostate can best be illustrated by means of a scatter diagram correlating age with mass or volume. In the present work, the age-volume relationship has been studied, the method of determining the volume having already been described in the Introduction (p. 130). The practice of fixing the prostates before determining their volumes was adopted from considerations of convenience; it has the objection, however, that it causes shrinkage of the tissue. This is not of very great extent (nor is it . very different for the two fixatives used), and since it is greater in the case of glandular than in fibrous prostates (such as are found in old age), it would tend to diminish rather than enhance the growth tendencies shown in the curve. Of the prostates available, there were 192 of which both the age and the volume were known. They have been differentiated into those which show evidence of the pathological changes of benign hypertrophy (even when these were only microscopie) and those which do not (designated ‘normal').

Text-fig. 1 is a scatter diagram showing the agevolume relationships of the 192 prostates. Prostates showing hyperplasia are indicated by black circles. Smooth curves have been drawn through the diagram, indicating the mean tendencies of growth in the normal and the hyperplastic prostates.

A further analysis of the growth of the prostate has been made by plotting the mean volumes of successive 5-year age groups. In the age groups 46-50 and on, the mean volumes of those prostates showing hyperplasia and of those that do not have also been plotted separately. The data are to be found in Table 2. Text-fig. 2 shows these data plotted out; hollow circles represent the mean volumes of all prostates in the age group, shaded circles the mean volumes of the normal prostates and black circles those of hyperplastic prostates. The figures refer to the number of specimens in the age group.

It will be seen that the volume of the prostate shows only a very slow increase from the time of birth until puberty is reached. At that time, a rapid increase in size occurs, and is maintained until the third decade is reached, during the latter half of which it levels off and the volume maintains a plateau until the age of about 45 ; zars. Up to this point, the curve is in agreement with that shown by Walker (1922), but in later age groups, two tendencies are manifested, which do not appear in the growth curve of that author. The prostate may either undergo benign hypertrophy, in which case its volume commences to increase at a rapid pace and continues to do so until death, or it may not show this pathological change, in which case it commences to atrophy, its volume progressively decreasing. As has been mentioned already, the atrophy affects chiefly the glandular zones, so that these prostates become relativelÿ more and more

fibrous. These alternative growth tendencies in the latter half of life correspond with those found in the prostates of dogs by Zuckerman & McKeown (1938).



100 F volume, 0.c.



Ï Ï 1 166] °130 6



Age, years

Text-fig. 1. Age-volume relationship of the prostate. Post-natal growth changes in the human prostate 143

Table 2. Mean volumes of prostates by age groups



No. of No. of No. of prostates Mean vol. prostates Mean vol. prostates Mean vol. Age group total c.c. normal c.c. enlarged c.c. 0- 2 9 l'4 ’ 9 l'4 — — 5-10 7 2-4 7 2-4 — — 11-15 4 4-25 4 4:25 — — 17-20 9 13-4 9 134 — — 21-25 10 20-0 10 20-0 — — 26-30 11 22.5 11 22-5 — — 31-35 16 20-1 16 - 20:1 _ _— 36-40 15 21-6 15 21:6 — — 41-45 12 20-5 12 20-5 — — 46-50 16 22-3 14 21-1 (2 — ) 51-55 15 20-5 12 19-1 3 26-3 56-60 18 24.5 10 ° 184 8 30-8 61-65 24 255 9 17-8 15 30-1 66-70 9 44-9 (1 18 ) 8 457 71-75 11 54.8 (1 21 ) 10 58-0 60 I I I T T L 0® L @)i 50 + / — 8 9 l 40 — . — | ! l o $ 8 5/ g 30 6 — % 3/ e 24 11 16,/ 18 16 15 12 20+ 10 14 = 15 = 2 @.# 10 9 9 10 = 7 4 9 0 | I ] | ] | 0 10 20 30 40 50 60 70 80 Age, years

Text-fig. 2. Mean volumes of prostates by age groups. 10-2 144

==VI. Summary==

1. The embryology of the prostate is briefly . reviewed.

2. The prepubertal prostate consists of a radiating series of ducts ending blindly near the periphery and embedded in a fibro-muscular stroma. At birth, hyperplasia and squamous metaplasia are characteristically found in the central parts of the collecting ducts, in the uterus masculinus, and on the crista urethralis. The uterus masculinus is frequently in the form of a distended sac. These features are all the result of stimulation by maternal oestrogens. Evidence of subtotal stimulation by androgens secreted by the foetal testis under the influence of maternal gonadotropic hormone is given by the occasional occurrence of groups of fully differentiated actively secreting alveoli in the prostate at birth.

8. The specific indications of oestrogenic stimulation disappear from the prostate within 6 or 7 weeks of birth. Very little increase in size or differentiation occurs thereafter until about the ninth year. Hyperplasia of the epithelium of the ducts in the central part of the prostate, with pseudo-acinar formation and duct proliferation are characteristic at this stage. By a similar process, the urethral mucosal glands commence development at about this time.

4. At puberty, under the influence of the male hormone whose secretion in effective amounts by the testis now commences, the prostate commences rapid growth and, within 6 months to one year, becomes transformed into the adult type of organ.

5. The arrangement of the glandular tissue in the adult prostate is discussed and contrasted with that found in the foetal prostate. Emphasis is laid on the variability of the alveolar epithelium in adult prostates; part of this is due to the occurrence of a secretory cycle, and part to the occurrence of evolutional and involutional changes. Alveolar epithelial shedding is described as occurring in two forms, related to two main causative factors: toxins and alteration in the endocrine environment.

Hyperplasia of the duct epithelium, so characteristic of the juvenile prostate, is commonly found in the adult organ, and especially in the anterolateral extensions of the lateral lobes; the possible significance of this finding in respect to the development of benign senile enlargerment is discussed.

Variability of the uterus masculinus is described, as also is the occurrence of direct communications between’utricular and true prostatic glands, from which it may be concluded that some of these latter may be of Müllerian origin in certain prostates.

6. The growth curve of the human prostate is of complex form. Very little increase in size occurs until puberty when there is a rapid enlargement, a high rate of growth being maintained until about the middle of the third decade, after which a plateau is followed until the age of about 45 years. Thereafter, those prostates which do not undergo benign enlargement decrease progressively in size, while those which-do recommence a rapid enlargement which persists until death.

I wish to express my indebtedness to Dr A. H.T. Robb-Smith, W. W. Woods and C. F. V. Smout for their kindness in providing the prostates, and to Dr S. Zuckerman for his invaluable guidance during the course of this work. The photomicrographs are the work of Mr W. Chesterman, to whom my sincere thanks are due.

==References==

Aperow, W. (1922). Beitr. path. Anat. 70, 179.

ALBARRAN, J. & Morz, B. (1902). Ann. Mal. Org. gén.-urin. 20, 768. ‘

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==Explanation of Plates==

PLATE 1

Fig. 1. Pseudo-acinar formation in hyperplastic prostatic ducts at birth; colloid can be seen in one of the lumina. x370. ‘

Fig. 2. Pseudo-acinar formation in hyperplastic prostatic ducts at birth. x 370. ‘

Fig. 3. Pseudo-acinar formation in hyperplastic prostatic ducts, age 10 years. x 300.

Fig. 4 Hyperplasia and squamous metaplasia in collecting ducts at birth. The ducts are completely or partly blocked. x 300.

Fig. 6. End-buds of the prostatic ducts at birth; some possess a lumen, other do not. x 53.

Fig. 6. End-buds with secretory epithelium at birth; the epithelium -consists of tall columnar cells with palestaining cytoplasm and basal nuclei. Secretory material can be seen adhering to the cells in a few places. x 370.

Fig. 7. The urethra, uterus masculinus and ejaculatory ducts of a new-born prostate seen in transverse section. The utricle is a distended sac with a very thin epithelium. The concentric condensation of connective tissue forming a ‘capsule’ can be seen. x 22.

PLATE 2

Fig. 8. Transverse section through the verumontanum at irth. The epithelium is hyperplastic and metaplastic, the luminal cells being large and clear, and undergoing keratinization. The anterior wall has not been affected.

x 53.

Fig. 9. Prostate from a case of congenital hydronephrosis.

he gross specimen has been slit along the anterior com missure and shows the crista urethralis with mucosal valves at the internal meatus.

Fig. 10. Transverse section through a new-born prostate showing a distended uterus masculinus lined by a hyperplastic desquamating epithelium, and containing a large amount of débris in its lumen. The ‘ capsule” enclosing the uterus masculinus and the ejaculatory ducts can easily be made out.

Fig. 11. Portion of an infolding of the urethral mucosa of a 7-year-old prostate. Four loci of pseudo-acinar formation can be seen. x 370.

Fig. 12. Complex glandular type of uterus masculinus in a 5-year-old prostate. It consists of a T-shaped main lumen with numerous radiating duct-like diverticula, all

showing evidence of extensive hyperplasia. There are .

numerous foci of pseudo-acinar formation. x 35.

Fig. 13. Juvenile end-buds in a 19-year-0ld prostate; most of the alveoli in this prostate are of normal adult type. x 42. ‘

PLATE 3

Fig. 14. Dilated ducts with hyperplastic epithelium and eosinophilic colloid inclusions in the prespermatic region of a 13-year-old prostate. x 77.

Fig. 15. The prespermatic region of the prostate shown in fig. 14. The uterus masculinus can be seen but is practically indistinguishable from the surrounding ducts, some, at least, of which may in fact be of utricular origin.

x 16.

Fig. 16. Hyperplastic epithelium of a prostatic duct in a 15-year-old prostate, showing development of secretory alveoli. x 370.

Fig. 17. The prespermatic region of a 23-year-old prostate.

he ejaculatory ducts can be seen posteriorly, and anterior to them is a mass of glandular tissue, partly of utricular and partly of non-utricular origin. By means of serial sections and projectoscopic tracings, interconnexions between these two sets of glands could be traced. x11.

Fig. 18. Utricular glands in a 41-year-old prostate. Their close resemblance to true prostatic glands is apparent.

x 53. ‘ PLATE 4 Fig. 19. A collecting duct with secretory epithelium extending up to the opening into the urethra (which is situated on the left). 49 years old. The urethral mucosal

ds are very complex and are practically indistinguishable from the adjacent alveoli of the collecting duct. x 35.

Fig. 20. A collecting duct with secretory epithelium extending up to the opening into the urethra. 15 years old. x 35.

Fig. 21. Dilated peripheral alveoli in a 45-year-old prostate. The epithelium has involuted and several corpora amylacea can be seen, some of them showing concentric rings. x 35.

Fig. 22. The uterus masculinus of a 23-year-old prostate. There is a T-shaped main lumen which is difficult to differentiate from the surrounding, extensively developed, glandular system. It is quite clear that the lateral limits of this latter cannot be defined, and differentiation from the adjacent prostatic collecting ducts is impossible. The ejaculatory ducts can be seen posteriorly. x 11.

Fig. 23. The very small uterus masculinus of à 62-year-old prostate which had undergone benign hypertrophy. Posterior to it are seen the ejaculatory ducts. The manner of opening of the utriculus into the urethra is suggestive of its double origin. x 32.

Fig. 24. The uterus masculinus of a 22-year-old prostate. Ît can be seen to consist of a main Tamen anteriorly, with very extensive glandular diverticula radiating in all directions, but particularly posteriorly. On either side can be seen the ejaculatory ducts. x11.

Fig. 25. The hyperplastic epithelium of a collecting duct rom à 52-year-old prostate. Foci of pseudo-acinar formation can be seen. x 300.

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