Download PATHOLOGICAL CONDITIONS INDUCED BY

PATHOLOGICAL CONDITIONS INDUCED BY OESTROGENIC
COMPOUNDS IN T H E COAGULATING GLAND AND
PROiSTATE O F T H E MOUSE
HAROLD BURROWS, C.B.E.
(From The Research Institute, The Cancer Hospital ( F r e e ) , London)
Lacassagne, de Jongh, and Burrows and Kennaway have recorded
the appearance of stratified, squamous, keratinixing epithelium in the
prostates of mice which have undergone prolonged treatment with
oestrin. Subsequent work by the author has shown that the organ
characteristically affected in this way is the coagulating gland.' This
Kctohydvoxyocrtrin.
Ketomothoxyoestvin.
III
IV
OH
Tri hydvoxy-
Equilrnin.
oestvin.
CHART I
organ was commonly regarded as a part of the prostate until Walker
in 1910 first discovered its separate nature and function. Further observations have now been made upon the effects produced by oestrin
on the coagulating gland and prostate, and they appear worth consideration in connection with human pathology. Lesions have been
brought about in the coagulating gland and prostate of the mouse by
four closely allied oestrogenic substances, namely ketohydroxyoestrin,
ketomethoxyoestrin, trihydroxyoestrin and equilin (Chart I). A fifth
compound, equilenin, which is of somewhat similar structure, has
1 Acknowledgments are due to Professor Tom Hare, who first drew the author's attention
to the coagulating gland.
2 The constitutional formula of equilin is not yet established.
490
PATHOLOGICAL
CONDITIONS INDUCED BY OESTROGENIC COMPOUNDS
491
shown effects which suggest that it may be a link between the highly
potent substances just named, and others which are inert. The completed experiments with this compound are too few to establish any
final opinion as to its action. Only three post-mortem results are
available, and in two of these cases, after 191 and 230 days of treatment
respectively, no detectable changes in the prostate or coagulating gland
are seen. I n the third mouse, which was killed on the 239th day of the
experiment, there were a pronounced keratinization of a structure
which the author regards as an uterus masculinus (p. 503) ; and possibly a slight stratification in the ducts of the coagulating gland, though
this latter point is somewhat doubtful.
The number of mice studied with each of the oestrogenic compounds
is shown in Table I.
TABLE
I: Experimental Maleria2
Compound wed
Ketohydroxyoestrin
Ketomethoxyoestrin
Equilin
Trihydrox yoest,rin
Equilenin
TOTAL
Number of mice
187
40
10
Number examined histologically a t date of writing
(Sept. 21, 1934)
67
11
n
a
5
1
10
4
252
86
All of the substances used have been chemically pure. I n the great
majority of the experiments the compound to be tested, dissolved (0.1
or 0.01 per cent) in benzene o r alcohol, has been applied twice a week
by means of a small paint brush to the non-epilated skin of the interscapular region. I n a few experiments oily solutions have been injected subcutaneously. Throughout the following account the term
oestrin will indicate ketohydroxyoestrin, with which most of the experiments were done.
The results hitherto obtained suggest that the compounds used a r e
not all equally potent in producing lesions of the accessory genital organs. Several factors, however, have to be considered before a judgment on this point can be made with safety: differences of solubility
of the materials in the media employed is one, and there are others.
For this reason no attempt will be made in these notes to assess the
comparative potencies of the various compounds employed.
ANATOMY
The prostate of the mouse has been described by Deanesly and
Parkes as consisting of paired anterior, ventral and dorsal lobes with
a single small median
The structures included in this descrip3 Disselhorst specifies these “anterior” and “dorsal” lobes as the upper and lower portioiis
of the posterior lobes, regarding the mouse for anatomical purposes as erect, while Deanesly
and Parkes base their description on the animal in the prone position.
492
HAROLD BURROWS
tion comprise two distinct organs which differ from each other in function and histological appearance. The lobe termed anterior by
Deanesly and Parkes, which is closely attached to the seminal vesicle,
is the coagulating gland (Figs. 1, 2 ) . I t s duct opens into the prostatic
urethra close to the common ejaculatory ducts on the cranial side. The
APPARATUS0% YOUNG ADULT MALE MOUSE
FIG.1. VENTRAL ASPECT OF GENITO-URINARY
Cg = Coagulating gland. C = Cowper ’8 gland. Pgl = Preputial gland. GO = Genital
omenturn. VS = Seminal vesicle. B1= Bladder. P r = Prostate.
I
FIG.2. SECTION
THROUQH ACCESSORY
GENITALIAOF NORMALMALE MOUSE
Cg = Coagulating gland. VS = Seminal vesicle. P r = Prostate. N B = Neck of bladder. The section is slightly oblique 80 that the seminal vesicle and coagulating gland are not
completely shown 011 the right side. X 4.
secretion of this gland causes coagulation of the contents of the seminal vesicle immediately after ejaculation, and thus produces the “copulation plug. ” Walker found that the secretion of the coagulating
gland was not specific for each species: that of the guinea-pig, for example, being capable in extremely small amounts of causing coagula-
PATHOLOGICAL CONDITIONS INDUCED BY OESTROGENIC COMPOUNDS
493
tion of the fluid secreted by the seminal vesicles of the rat. The contents of the prostate showed no such capacity.
I n the following account the ventral, dorsal, and median lobes, in
the terminology of Deaiiesly and Parkes, will be regarded a s the prostate as distinct from the coagulating gland.
FIG. 3.
SECTION THROUGH AN
ALVEOLUSOF
THE
COAGULATING
GLANDO F
-4 NORMAL MOUSE.
X 360
THROUGH ACCESSORY
GENITALORGANSOF MOUSETREATED
BY OESTRIN
FIG.4. SECTION
The coagulating glands on both sides have been converted into sacs (Cg) lined with keratinizing stratified epithelium. VS = Atrophic seminal vesicle. B1= Bladder. P r = Prostate.
VD = Vas deferens. Mouse 835, 102d day. X 5.
EFFECTS
OF OESTRINO N
THE
COAGULATING
GLANDS
Under the continued administration to mice of sufficiently large
doses of oestrin, the coagulating glands, the alveoli of which normally
are lined by a single layer of cuboidal o r columnar epithelium (Fig. 3 ) ,
become converted into sacs lined by a squamous, stratified epithelium,
the superficial layers of which, with time, undergo keratinization. I n
some instances these sacs become filled with keratinized material alone,
in others with masses of keratinized material together with desquamated nucleated and noii-nucleated epithelial cells, and polymorphonu-
FIG.
5.
SECTION THROUGH T HE W A L L OF A COAGULATING
BY OESTRIN
GLANDTO
SHOW
METAPLASIAINDUCED
The sac is filled eiitirely with layers of keratinized material amongst which no iiucleated
cells can be seen. The iiiiier surface of the wall of the sac faces t o the left. Mouse 800,
164th day. X 240.
FIG.
6. SECTION THROUGH T H E W A L L OF A COAGULATING GLAND TO ILLUSTRATE POLYMORPHONUCLEAR INVASION
AND SHEDDING
OF THE SURFACE
LAYERS
OF STRATIFIED
EPITHELIUM
The contents o f the sac a r e masses of keratinized material, nucleated and iioii-nucleated
epithelial cells, aiid leucocytes. Mouse 788, 155th day. X 240.
494
PATHOLOGICAL CONDITIONS I N D U C E D BY OESTROGENIC COMPOUNDS
495
clear leucocytes (Figs. 4, 5 , 6). The pouches so formed resemble in
their microscopic structure of the vagina of the mouse, and they undergo changes which recall the cyclical phenomena of oestrus occurring
in that organ. Thus the formation of a many-layered, stratified epithelium undergoing copious keratinization (Fig. 5 ) may be followed
by a polymorphonuclear invasion of the epithelium the superficial layers of which are shed, leaving a lining of squamous epithelium denuded
of horny cells and only three or four cells in thickness (Fig. 6).
The metaplasia described above appears to be constant in its appearance. Though there may be, and almost certainly are, individual
FIG.7.
SECTION
THROUGH PROSTATE
OF NORMAL
ADULTMOUSE. X 170
variations of susceptibility, every mouse hitherto examined after continued treatment with repeated doses of oestrin for three months o r
longer has shown the characteristic metaplasia of the coagulating
glands.
EFFECTS
OF OESTRINON THE PROSTATE,
PROSTATIC
URETHRA,
AND
PERIURETHRAL
GLANDS
The alveoli of the prostate in the normal mouse are lined by a single
layer of cells arranged in an orderly manner and containing sufficient
cytoplasm to make each nucleus appear isolated and distinct when examined in thin sections (Fig. 7). When stained with eosin and haemotoxylin, the cytoplasm takes a pale pinkish tinge, while the nuclei
are purple and usually do not stain very deeply (Fig. 7). Under the
continued administration of oestrin three alterations are induced. ( a )
In the early stages the orderly disposition gradually disappears so that
the alveoli become lined by disarranged cells, which are no longer in a
496
HAROLD BURROWS
single row. There appears t o have been proliferation of the cells,
which in places lie in superimposed layers; and their nuclei-as the
condition advances-are stained a deeper purple or blue and become
crowded together owing to a diminished proportion of cytoplasm
(Fig. 8). ( b ) Accompanying these epithelial changes is a gradual increase of the connective-tissue stroma of the gland (Fig. @). At this
stage the condition resembles benign hyperplasia of the human prostate (Fig. 23). (c) Eventually a high grade of metaplasia occurs, the
disordered epithelium of the ducts and alveoli being replaced by a
stratified epithelium consisting of cells which are larger and more regular in shape and dimensions than those they have replaced. These
stratified cells have relatively definite outlines ; their cytoplasm stains
PIG. 8.
SECTION THROUQH PROSTATE SHOWIKQ IIYPERPLASIA 03’ EPITHELIUM AND CONNECTIVE
TISSUEINDUCED
BY OESTRIN
Mouse 856, 97th day.
X 115.
rather faintly, and their round or oval nuclei are vesicular and do not
clearly show any structure (Fig. 9). This stratified epithelium in the
prostate, unlike that which appears in the coagulating gland, has not
been observed t o undergo keratinization. This difference may be one
of degree only, f o r the metaplasia in the coagulating gland in its earlier
phases passes through a non-keratinous stage resembling that just described as occurring as a late event in the prostate.
A noteworthy feature of these transformations in the epithelium
of the prostate is the sequence in which they develop in the different
regions of the gland. The earliest changes are seen in the ducts and
gradually spread from these foci toward the periphery, so that in some
cases, while an advanced pathological condition may be observed in the
ducts and proximal alveoli of the prostate, the peripheral regions may
FIG.9.
SECTION THROUGH PROSTATE SHOWING CONVERSION O F CELLS
STRATIFIED EPITHELIUM
LININGALVEOLI
INT'0A
Tlic:re is an increase of coniiective tissue also. Mouse 846, 312th day. X 170. Cf. Fig. 23.
FIG.10.
SECTION THROUGH PROSTATE SHOWING ADVANCED METAPLASIA( S T )
AND ALVEOLI
OF A VENTRAL (ANTERIOR)
LOBULE
Ur = Prostatic urethra. Mouse 846, 312th day.
497
X 62.
OF THE DU'
CTS
498
HAROLD BURROWS
appear to be little affected. Thus a stratified epithelium may be present i n the ducts and proximal alveoli and a pronounced hyperplasia in
an intermediate zone, while the peripheral regions of the gland may
appear almost normal.
Although in the mouse, as in man, the greater part of the prostate
arises by outgrowths from the dorsal wall of the urethra, so that the
main ducts of the fully formed gland open in or near to the prostatic
grooves on each side of the verumontanum, there are in addition two
or more lobules which discharge through the ventral wall of the prostatic urethra. These ventral lobules, like those which constitute the
FIG.11. LONGITUDIKAL
~ E C T I O N THROUGH TEE URETHRA
DISTALTO
THE COLLICULUSSDMINALIS,
METAPLASIAOF THE EPITHELIUM
OF THE DUCT O F A PERIURETHRAL GLAND
The urethral epitlielium has a h undergone a change towards stratification. Mouse 860,
372d day. X 115.
SHOWING
main body of the gland, may exhibit metaplasia in response to the administration of oestrin (Fig. 10).
Such changes caused by oestrin are not confined to the coagulating
gIand and prostate. The periurethral glands of the prostatic urethra
and their ducts may be similarly affected (Fig. ll),and the transitional
epithelium of the prostatic urethra may become much thickened o r
even converted into a stratified layer many cells in depth (Fig, 12).
Eventually the columnar epithelium which lines the lower ends of the
common ejaculatory ducts may be partially replaced by stratified epithelium. When it occurs, this replacement, as in the preceding instances, spreads in a well defined manner, the stratified epithelium first
appearing at or near the mouths of the ducts, and extending gradually
along their cranial walls; so that sections often will show the caudal
FIG. 12. TRANSVERSE
SECTION
OF PROSTATIC
URETHRA
(Ur) SHOWING
REPLACEMENT
OF
TRANSITIONAL
EPITHELIUM
BY A STRATIFIED
EPITHELIUMMANY CELLS IN THICKNESS
Mouse 869, 70th day of treatment by equiliii. X 60.
FIG. 13.
SQUAMOUS STRATIFIED EPITHELIUM(ON RIGHT) REPLACING
THE NORMAL
COLUMNAR
CELLS(ON LEFT)WHICHLINE THE COMMON
EJACULATORY
DUCT
Mouse 858, 104th day of treatment with oestrin. X 115.
499
500
HAROLD BURROWS
part of the circumference of each duct with a normal lining of columnar
cells, while the cranial part consists of a thick stratified layer (Fig. 13).
EEVERSIBILITY
OF THE EFFECTS
OF OESTRIN
A point of particular interest is that the alterations produced by
oestrin in the prostatic urethra and the glandular structures connected
therewith, including the coagulating gland, are reversible. If the ap-
ORGANSOF TWO MICE, ILLUSTRATINQ
REVERSIBILITY
OF
FIQ.14. GENITO-URINARY
OESTRIN
EFFECTS OF
Both mice were treated alike with bi-weekly applications of oestrin for 168 days. For the
next 42 days oestrin was applied to A as before, while B was untreated. I n the latter the
return to their normal size of the seminal vesicles, Cowper '8 g l a d , testes, and genital omeiitum
are shown. In B the coagulating gland has become translucent, while it is opaque in A.
Mice 955 and 956.
plications of oestrin be stopped, the d6bris of keratin and desquamated
cells filling the distended alveoli of the coagulating gland disappears,
and the alveoli become lined again with a single layer of cuboidal or
columnar cells which now resume their normal aspect and function.
Coincidentally with these restorative changes the gland ceases to retain
the obvious form of a sac, its walls becoming again much plicated. Following the cessation of treatment with oestrin, the stratified epithelium
disappears entirely from the prostate, also, the secretory cells of which
are restored likewise to their proper appearance and activity (Figs.
14-16). I n every situation where a stratification of epithelium or a
desquamative hyperplasia has appeared in response t o applications
of oestrin it will give place, it seems, to the epithelium appropriate t o
the normal tissue if the administration of oestrin be stopped. (A reversibility of effect is seen in an equally striking degree in the seminal
vesicle, though the alterations produced by oestrin in this organ are
of a different form from those seen in the coagulating gland and prostate and will not be included in the present discussion.)
PATHOLOGICAL CONDITIONS INDUCED BY OESTROGENIC COMPOUNDS
501
This reversion to the normal state comes about in a definite succession, the more peripherally situated alveoli, which were the last to be
affected, being the first to recover. Such a sequence is seen most
clearly in the prostate, which returns t o its normal condition more rapidly than the coagulating gland. Although the gross epithelial transformations appear earlier in the coagulating gland, and involve the
entire organ much more rapidly than the changes in the prostate, yet
the peripheral alveoli of the coagulating gland are not affected quite
so soon as the ducts and proximal alveoli. And again, during the re-
FIG.
15.
SECTION THROUGH THE PROSTATE OF
TION GLANDS (Cg) AS
MOUSEA (956) IN FIG.14,
KERATINIZED
SACS. x 4
SHOWING COAGULA-
FIG.16. SECTION
THROUGH THE PROSTATE
OF MOUSE B (955) OP FIG. 14
The coagulation glands ( C g ) are lined with a single layer of columnar epithelium and
contain secretion of normal appearance. The semiual vesicles (VS) also are distended with
secretion. X 4.
version to normal after the cessation of treatment with oestrin, a difference may be noticed between the recovery in the distal parts of the
gland as compared with the proximal portions. Thus, during the
process of recovery, a normal secreting epithelium may be visible at
the peripheral end of a sac the proximal end of which is still lined by
a stratified epithelium (Fig. li).*
4 Espinasse (Nature 134: 738, 1934) has called attention t o a similar gradient of reactivity to oestrin in the surviving remnants of the niiillerian ducts in the female, namely, the vagina, uterus, and oviducts. The effects of oestrin are most pronounced in the vagina and
diminish in intensity along the uterus and toward the oviducts.
502
HAROLD BURROWS
No easy explanation is forthcoming to account for this variation
of the effect of oestrin on the different parts of the glands, inasmuch
as the active substance is conveyed by the blood stream and therefore,
it would seem, must reach in an equal concentration all the tissues concerned. Possibly the differences of susceptibility may be connected
with the embryological origins of the tissues concerned. Lacassagne
has suggested that the selective action of oestrin on the prostate of the
mouse-using this term to include the coagulating gland-may indicate
FIG.17. SECTION
SHOWING
SEQUENCE
OF CHANGESDURING RECOVERY
FROM
THE
EFFECTS
OF
GLAND
then stopped. The mouse was killed
the large sac of the coagulating glaiid
a large keratinous mass ( K ) remains.
which appear normal and this p a r t of
O E S T R I N I N T H E COAGULATING
Oestrin treatment was continued f o r 220 days and
twenty-five days later. I n the proximal (lower) p a r t of
which is shown, stratified epithelium ( S t ) is present and
The distal portion ( A ) is lined by a single layer of cells
the cavity is filled with secretion. Mouse 941. X 60.
that this structure arises from Muller’s ducts. Wesson and also Arey
have stated that a portion of the dorsal wall of the urethra adjacent
to the ejaculatory ducts is derived from the wolffian ducts. It seems
possible that the mullerian ducts might in a similar manner contribute
to the formation, not only of the utriculus itself, but to a portion also
of the contiguous part of the urethral wall from which the coagulating
glands, and perhaps portions of the prostate also, are developed. It
might be, perhaps, that in the male an actual remnant of the lower end
of the mullerian duct would respond the most readily to oestrin inasmuch as the uterus and vagina, which react specifically to this hormone
in the female. are derived directly from Miiller’s ducts. A further pos-
PATHOLOGICAL
CONDITIONS
INDUCED BY OESTROGENIC COMPOUNDS
503
sibility might be that an organ developed as a secondary outgrowth
from the mullerian duct would be somewhat slower in its response, and
that the degree of response would gradually diminish in intensity with
the remoteness of the tissue concerned from the point of its embryological origin. Whatever the explanation is, the fact may be one of
importance in human pathology, for a similarly graduated distribution
of hyperplasia seems to the author t o occur in benign enlargements of
the prostate in man.
FIG. 18.
SECTION THROUGH T H E PROSTATIC U R E T H R A AND SURROUNDING STRUCTURES OF A
MOUSEWHICH HADBEENTREATEDWITH OESTRIN FOR 153 DAYS
Immediately above the two common ejaculatory ducts is a large sac (X) filled with keratinous material and shed cells. Cg = Coagulating gland. Ur z Prostatic urethra. The suggestion is made that this sac is a uterus masculiiius. Mouse 880. X 4.
FIG.19. NAKED-EYE
VIEW
OF A S U ~ O S E
UTERUS
D
MASCULINUS(X)
JUST BEHIND
THE URINARY
BLADDER
(Bl)
WHICH IS SITUATED
Mouse 886, 157th day.
I n connection with the possibility that oestrin may act specifically
on structures derived from the mullerian apparatus, the following
two observations may be of interest:
(1) I n several of the mice which have been treated with oestrin,
though not in all, a median sac has been found on the dorsal aspect of
the prostatic urethra between the distal ends of the vasa deferentia
and projecting toward the peritoneal cavity immediately behind the
urinary bladder (Figs. 18-20). The lower ends of the vasa deferentia
are displaced by these sacs (Fig. 20) and the coagulating glands are
closely associated with their lateral walls (Fig. 18). Such sacs, the
largest hitherto observed being 13 x 13 x 10 mm., are lined by stratified
keratinizing epithelium, and in some instances, like the uterus in the
female after similar treatment with oestrin, are distended by clear
fluid (Fig. 20). It seems probable that these structures represent the
utriculus masculinus-an acknowledged relic of the miillerian apparatus-persistent in some individual mice only and rendered manifest
504
H A R O U ) BURROWS
by the action of oestrin. Rauther, while admitting the existence of a
utriculus masculinus in the new-born mouse, states that neither this
nor any other remnant of the mullerian ducts is to be found in the fully
grown mouse. This is contrary to Leuckart ’s observations ; and it is
to be remembered that some inconstancy in their persistence and postnatal development is a recognised feature of many vestigial structures,
and no generalisation as to their absence or survival in the adult can
be made without the examination of a large number of individuals,
F I G . 20. NAKED-EYE
VIEW OF ANOTHERSUPPOSED
UTERUSMASCULINUS( X )
The lower ends of the vasa defereiitia (VD) have been carried upward on each side of
the sac. B1= Bladder. Mouse 976, 173d day of treatment with trihydroxyoestrin.
( 2 ) Becently, in a mouse which had been treated by oestrin for
sixty-two days, an organ consisting of a number of tubules lined with
squamous, stratified epithelium and completely filled with keratinous
material, has been found connected with the epididymis, where vestiges
of the cranial end of Miiller’s duct might be expected (cf. the sessile
hydatid of Morgagni in man). A s measured in a microscope section
the plane dimensions of this organ are 2 x 3 mm (Fig. 21).
DISCUSSION
When the foregoing observations are considered in connection with
the pathology of prostatic lesions in man, certain questions arise.
(1) Does a n y representative of the coagulating gland ezist i.n
man8 This question may seem perhaps academic rather than clinical
and practical. At present it remains unanswered. Walker, in the
paper already quoted, states that he was unable t o find in man any
representative of the coagulating gland, though he thought the coagulated particles found in human semen suggested the presence of such
a gland.
( 2 ) C a n the benigm prostatic enlargements commonly found in elderly m e n be compared w i t h those which have been induced in mice by
the administration of o e s t r i d
( a ) Anatomical distribution of the changes: Unfortunately the exact situation of lesions in the human prostate cannot be described ac5 Speaking of the water vole (Hypudaeus), Leuckart mentions a ‘ ‘maiiiiliche Scheide’ ’
consisting of a “blindsackformiger Recessus” and goes on to say that the structure in Mus
musculus is quite similar (loc. cit. p. 259).
PATHOLOGICAL
CONDITIONS INDUCED BY OESTROGENIC COMPOUNDS
505
curately in the current anatomical phraseology. It is customary to
refer to the various “ lobes ” of the prostate. But this gland is compact, and though developed by several groups of outgrowths from the
prostatic urethra, the primitive lobules so formed soon become amalgamated, and are then for the most part no longer distinguishable to
the naked eye and certainly have not the form of lobes. To this circumstance must be attributed the discrepancies which appear in the
literature when pathological conditions are described as having arisen
FIG.21.
KERATINIZED
STRTJCTURE
( Z ) ATTACHED
TO THE EPIDIDYMIS
(Ep) OF A MOUSEWHICH
HAD BEEN TREATEDWITH OESTRINFOR 62 DAYS
Testis ( T ) sliows absence of spermatozoa and spermocytes. VD z Vas deferens. Twelve
days before any oestriii was applied the mouse had been rendered cryptorchid by dividing the
gubernacula and displaciiig the testes into the abdomiiial cavity. Mouse 953. X 24.
in this or that particular “lobe. ” Nevertheless, pathologists are likely
to agree that hyperplasiat of the prostate shows little tendency to affect
the posterior lobe, the embryological origin of which is situated distally to the utriculus. From general observation, unchecked by exact
inquiry, it seems that the parts of the prostate which are subject t o the
most pronounced degrees of hyperplasia in elderly men are the middle
lobe and the cranial portions of the lateral lobes. It further appears
that the hyperplasia in its most advancedform is seen especially in those
506
HAROLD BURROWS
regions which lie nearest to the proximal part of the prostatic urethra
itself. Thirty years ago Wallace expressed an opinion of this kind
when pointing out that after so-called enucleation of an enlarged adenomatous prostate there is always left behind a definite laminated
envelope containing glandular tissue derived from the expanded outer
portion of the organ. Such a distribution is in conformity with that
of the metaplasia noticed by Schlacta in the prostates of newborn
babies (p. 510) and by the author in the coagulating glands and prostates of mice which have been subjected to prolonged treatment with
oestrin. Riches and Muir examined 59 prostates removed at autopsy
FIG.
22.
NEWBORN
CHILD
STRATIFIED
EPITHELIUM.
X 170
Cf. Figs. 9 and 10.
SECTION THROUGH THE PROSTATE OF A
AT F U L L TERM, SHOWINa
and showing benign hypertrophy. The regions which they found involved are as follows:
Regiom Involved in 50 Cases of Benigla Hypertrophy of the Prostate (Riches and Nuir)
Lateral lobes .......................................................
90 per cent
Middle lobe associated with lateral lobes ...............................
34
Middle lobe alone (all being early cases) .............................
6
Anterior lobe ......................................................
1
Posterior lobe, associated in every instance with changes in the lateral lobes., 6
( b ) Resemblance between the histologic changes produced experiinentally in mice b y oestriul. a d those appearing in the human prostate:
Two successive changes have been described above as occurring in the
prostate of the mouse under the influence of oestrin, namely (1) a hyperplasia of the secreting epithelium together with an increase of the
connective-tissue stroma, and ( 2 ) replacement of the cells lining the
alveoli of the gland by a stratified epithelium. As remarked already,
0
hlbarran’s glaiids are included with the middle lobe here,
PATHOLOGICAL
CONDITIONS INDUCED BY OESTROOENIC COMPOUNDS
507
it may perhaps be correct to refer to these as different stages of a
single process, the borderline between hyperplasia and metaplasia
being difficult to define. However this may be, both changes are to be
seen in the prostates of elderly men, though the appearance of stratified
epithelium in these is relatively uncommon. The earlier o r hyperplastic changes which are commonly characteristic of benign enlargements of the human prostate (Fig. 23) closely resemble in essential
details those seen in the prostate of the mouse which has been treated
with oestrin. The less frequent condition in which stratified epithelium appears was first recorded in 1865 by Thiersch, whose observa-
FIG.23.
SECTIONTAKENFROM PROSTATIC
TISSUEREMOVED
FOR THE RELIEFOF A SUPPOSEDLY
BENIGNE N L a R G E M E N T
Stratification of the epithelium of the alveoli and ducts was fouiid in one place, the bulk
of the material showiiig typical beiiigii hyperplasia. X 170. Cf. Figs. 9 aiid 10.
tions were based on material removed from a patient with cancer.
Since that time numerous pathologists have described the occurrence
in the human prostate of stratified epithelium. Thus it will be seen
that, so far as histological changes are comparable between mouse and
man, there appears to be no essential difference between the enlarged
prostates of elderly men and the prostates of mice which have been
submitted to long continued dosage with oestrin. The similarity extends further, for the morbid consequences are almost identical; the
majority of the affected mice, if the administration of oestrin be continued, eventually succumb t o urinary obstruction with distension and
occasionally sacculation of the bladder, constant dribbling of urine
from overflow, dilatation of the ureters, and hydronephrosis. Some
of the mice die from abscesses arising in the coagulating gland.
Here it may be mentioned that a common sequel to keratinisation
508
HAROLD BURROWS
of the coagulating gland is a polymorphonuclear invasion of the epithelium (Fig. 6). This invasion takes place simultaneously over a
wide area and can hardly be attributed t o infection. A similar phenomenon is recognized as a regular feature of the oestrus cycle in
the vagina of the mouse, and the appearance of leucocytes in a vaginal
smear from this animal is accepted as a proof that the period of oestrus
has terminated. The matter is one of physiological interest, and may
be considered in yet another condition, namely vitamin A deficiency.
I n this condition, as shown by Wolbach and Howe, a wide-spread keratinization of epithelium occurs in various organs. This process is
often accompanied by suppuration which has been attributed hypothetically to an increased susceptibility t o infection, or t o an absence
of ciliated epithelium. It is possible that masses of desquamated,
keratinized cells may offer a suitable nidus f o r some bacteria, and
these may be present by chance in the blood and may be extravasated
like the leucocytes and so cause an abscess as a secondary event. But
the leucocytic invasion, as induced in the keratinized coagulating gland
and vagina by oestrin, is almost certainly not the direct outcome of
any bacterial action.
(3) Do oestrogenic hormones play aizy part in the causation of
beiiiyz edargenzeuzts of the prostate in man?
( a ) T h e presmce of oestrogewic hormones ijn males: Oestrogenic
substances have been found in the blood, testes, and urine of men by
6sterreicher and by other enquirers. Although the amounts found by
them are small, the quantities produced in the system might be sufficient, if continuously produced over many years, to bring about effects
which would require much greater dosages if these were supplied only
at intervals, as in the experiments on mice described above. But the
whole subject of the detection and estimation of small amounts of
oestrin in urinc requires further investigation. Zondek has shown that
very large amounts of oestrin injected into young rats are rapidly inactivated or destroyed, and Frank and Goldberger have observed the
same phenomenon in rabbits. It is known that a given dose of oestrin
injected into an animal shows a more pronounced result if given in
separate fractions with intervals of time between administrations, than
if administered all at once.
The changes induced by oestrin in the prostates of mice have not
required enormous dosage. Each bi-weekly application (p. 491) of a
solution of 0.01 per cent of oestrin contains about 3 micrograms of
oestrin or 30 international units, so that 60 units were given in the
course of a week. No calculation can be made of the proportion of
this dosage which became absorbed. The quantities mentioned represent the maxima theoretically available. Such amounts constantly
produced advanced changes in the mouse’s prostate. It seems reasonable t o suspect that a very much smaller quantity, if supplied
continuously, would be enough to cause pathological changes in some
of the individuals so treated. From these considerations there appears to be no valid objection, based on known facts, to the hypothesis
PATHOLOGICAL CONDITIONS INDUCED BY OESTROGENIC COMPOUNDS
509
that prostatic enlargements in elderly men are brought about by the
action of oestrogenic hormones.
( b ) D i w c t e v i d m c e that prostatic citlargemewt may be brought
about in the human species by the action of ocstrifi: The information
most desired on this problem, so f a r as it coiicerns men of advanced
years, is not yet available, for the accumulation of data in present circumstances is slow. The need is t o ascertain whether the subjects of
prostatic enlargement are or have been under the influence of exceptionally large quantities of the hormone concerned. It may be that in
these individuals oestrin or a related substance is produced in excessive
quantities or that its inactivation is retarded. But the hormone is
effective in very small amounts and biological assay is in practice the
only test available. Isolated aiid occasional estimations of the output
in the urine of individual patients in these circumstances are laborious
and not entirely satisfactory. A great number of observations will
be necessary to establish a reliable conclusion.
Nevertheless, there is evidence already at hand that the human
prostate reacts t o oestrogenic hormones in the same manner as that
of the mouse. The prostate of the human male child is, like the mamma,
considerably enlarged at birth, diminishing in size during the first few
weeks of extrauteririe life. I n women oestrin is produced in large
quantity during pregnancy, and enters the foetal circulation. Philipp
examined the urine of 24 newborn babies and constantly found oestrin
present during the first three days after birth. By the sixth postnatal day oestrin had disappeared from the urine. Siegert and
Schmidt-Neumann took blood from the umbilical veins of 26 newborn
babies, and the sera from these samples yielded positive tests f o r
oestrin in 19 instances.
As early as 1894 Aschoff had demonstrated the presence of stratified
epithelium in the utriculus masculinus, prostate, and periurethral
glands of the newborn child. Teii years later IIalban, as the result
of clinical and pathological observations, s u g p t e d that the peculiar
conditioiis present in the mamma arid urogenital organs of newborn
children were attributahle t o hormones derived from the mother.
Schlacta, a t about the same time, studied the prostatic conditions present not only in the newborn, but in the foetus, and in infants up t o
six months old. The results of his inquiry, published with illustrations iii 1904, are of great interest, which is not lessened by the fact
that, like lialban’s deductions, they were made at a date prior to the
identification of any of the sex hormones. Schlacta found epithelial
changes in the prostate, utriculus masculinus, and urethra, beginning
in the utriculus. Early in the eighth month of gestation, the normal
epithelium of the prostatic ducts was becoming replaced by a stratified
epithelium undergoing desquamation. I n the prostate itself only the
“upper lobe” and the upper portions of the anterior part of the gland
were affected. The change was symmetrical, and where the metaplasia was most marked there was a retardation of development of
510
HAROLD BURROWS
the growing glandular buds. The stratified epithelium contained a
considerable amount of glycogen. I n further investigations Schlacta
found no trace of stratified epithelium in the prostates of foetuses at
the beginning of the seventh month, though this was present in the
utriculus masculinus at this time. I n the eighth month the prostate
showed abundant stratified epithelium, and five newborn babies all
showed the condition in a pronounced form. Prostatic metaplasia was‘
still to be seen in a baby of two months, but was absent from infants
of four months and eleven months. These observations of Schlacta
on the appearance and disappearance of prostatic metaplasia in the
newborn are in perfect accord with those which have been made recently in the laboratory following the administration of oestrin to
mice, and both sets of changes might be attributed to a similar agency.
The characteristic condition found in the prostate of a newborn child
is shown in Fig. 22.
Occasionally in newborn male babies there is difficulty in urination
owing to distension of the utriculus. Possibly this transient condition may be explained as the consequence of a response of the utriculus
to the copious dosage with oestrin to which the foetus is submitted in
the later stages of its sojourn in the uterus, and may be compared with
that which has been described already as occurring in certain mice
which had been treated with oestrin (Figs. 18-20).
(4) Does oestrivt play a part in the causation of prostatic cancer?
Experimentally there is no direct evidence in favour of an affirmative
answer to this question. Carcinoma of the prostate has not been induced in mice by oestrin. Nevertheless, there are facts which demand
reflection before such a query can be finally dismissed. I n human
pathology Cheatle and Wale have called attention to the resemblance
under the microscope between sections of prostates removed for nonmalignant enlargement in man, and sections of mammae affected with
cystic desquamative hyperplasia or Schimmelbusch’s disease-or, in
the old terminology, chronic cystic mastitis. And it is an interesting
fact that oestrin brings about in mice a similar condition of desquamative hyperplasia not only in the prostate but in the mamma also. I n
the latter situation this condition induced by oestrin is sometimes
followed by cancer, even in males (Goormaghtigh, Lacassagne (1)).
At the Royal College of Surgeons of England, in July, the author
showed an example of mammary cancer with metastases in the lungs
and elsewhere, which had developed in a castrated male mouse after
the prolonged administration of oestrin.
I n view of the fact that oestrin may cause desquamative hyperplasia in both the mamma and the prostate, and that the condition in
the mamma is apt to be associated with cancer both in the human
species and in mice, it is difficult to avoid the suspicion that oestrin or
an allied substance may be one of the factors in the induction of
cancer of the prostate.
PATHOLOGICAL
CONDITIONS INDUCED BY OESTROGENIC COMPOUNDS
511
CONCLUSIONS
The prolonged administration of oestrin to mice causes hyperplasia
and metaplasia in the prostate gland.
The prostates of children before birth undergo similar changes,
presumably under the influence of oestrin derived from the placenta.
‘
Both in mice and newborn children, the prostatic changes thus
induced are completely reversible ; restitution to the normal state
following a cessation of the supply of oestrin.
The changes found in benign enlargement of the human prostate in
advanced life resemble in character and situation those observed in
mice under the influence of oestrin and in newborn babies.
The question is discussed whether the benign enlargement of the
prostate in elderly men may be due to the action of oestrogenic hormones and may be a reversible condition.
NOTE: The author is much indebted to Sir G. Lenthal Cheatle, who placed a t his
disposal a large collection of complete sections of human prostates showing pathological
changes. For the supplies of oestrin, equilin and equilenin used in these experiments
he is entirely indebted to the kindness and generosity of Dr. Girard. The ketomethoxyoestrin was prepared in this Institute by Dr. Cook, and to him also grateful acknowledgment is expressed.
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