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The effects of oestrin on the urogenital tract of the male monkey.

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THE EFFECTS OF' OKSTRZN ON THE UROGEKITAL
TRACT O F THE hlSLE MONKEY
THREE TEXT FIGURES A K D THREE PLdTES (TWEZTTY FIGUKES)
1P;TROl)UCTION
The newborn male moiikey S ~ O W Scertain external changes
such as pink erect nipples and descended
(Wislocki, 'S),
testicles vTith s\veIling and reddening of the scrota1 skin, which
have been ascribed to the influence of the hormones so
abuiidniit iii tlie maternal circnlation. Although the modifications subside within a few days after hirtli, the older male is
also seiisitix7.e lo the injection of similar hormones (Eiigle,
' 3 2 ) . These sexnal skin reactions iii tlie male parallel those iii
the female moiikrp first shox7n by Blleii ('27, '28). Oiily recently has any reaction i n the male moiikey other thaii tliesc
superficial clianges been noted in relation to injected hormones
(Geschickter, Lewis and Hartman, '34 ; Yarkes and Zuckerman, '35 ; Conrrier and Gros, '35 h ; van Wagenen, ' 3 5 ) .
This paper is purticnlarly coiiecrned with tlic response of the
fibromuscular stroma and the inucosa of certain parts of thc
urogenital tract of thc sub-adult mollkey to the injection of
the follicular hormone.
3lATEKIAL
Fi17e male macaque moilkeys w r e used in this stud^, two
controls, 11.m. 87 and il1.m. 99 weighiiig 1620 gm. and 3000
gm. respectively, and lhrec experimental animals weighing
between 2000 gm. am1 2450 gm. Of the latter K m . 35 received 1 ce. of theclin a clay f o r 10 days; X m . 86 received a
387
THE ANATOMICAT> RECORD, VOL. 63, KO. 4
388
G.
17.4~ WAGENEN
total of 60 cc. over a period of 34 days; aiid 1I.m. 36 received a
total of 120 cc. over 42 days. Oiie cc. of theelin (ketoliydroxyoclstriii) assaycd a t 50 R.U. The aiiimal receiving the
smallest dose eshibited only slight signs of theelinization.
Tlicre w i s a n enlargement of the nipples and the scrotal sac
der-eloped a s a loose transverse fold of skin. The animal receiving 60 cc. of tlicclin showed a greatly eiilarged, thick a d
turgid scrotal sac of a size iiot exceeded by that of the animal
receiving txice tliat amourit of theelin. The animals iiijected
with the two larger amoniits, h2.m. 86 and K m . 36, showed
great apprehensioii wlieii the cage was approached. In these
two animals there was a dribbling of urine after the t w ~ n l i c t l i
clay of injection. Tii h1.m. 86 there ivas a paradosial incontinence and a distended blaclder wat; fourid a t autopsy, but the
bladder was fouiid empty in thc case of tlie animal receiving
thc greatest dose.
The illustrations f o r this stndy of the effects of theelin
in the male moiikey a r e largely of 3l.m. 86, the cxpcrimental
animal recipient of 3000 R.U., and its coiitrol 31.m. 87. The
description of reactions along the urogenital tract will be
given in some detail in the case of K m . 86 for this experimental animal showed tlie maximum of most of the iirogeiiital
m d external changes. Only oiic izew reaction, a leucocytic infiltration along the urethra in the animal receiving 120 cc. of
thechi, appeared to be a result of tlie greater dose and the
longer treatment.
DESCRTPTION O F MAXIMUM CHANGES
Results of 60 ce. of tlieelin. Xonkey Kin. 86 weighed 1835
gm. at the bcgiiiniiig of the iriject,ioiis and 2450 gm. 34 days
later at autopsy. Its control, 31.m. 87, weighed 3000 gm. at
autopsy. The exteriial appearance of the gcnital region of
these two animals is shown in figures 1 and 2. The experimental animal had received 100 R.U. of tlic horinoiie daily in
amounts of 1cc. thceliii (50 R.U.) in tlie morning and 1 cc. in
the afternoon. The first change noted was a flushing of the
nipples and scrotal skin. 0 1 1 the tenth clay there mas a definite
THEELIN EFFECTS O N THE UROGENITAL TRACT
389
increase in the scrota1 aiid peiiile skin folds which was followed by a gradual, edematous filling out to the proportions
seen in figure 2. This heavy, transluscent scrota1 mass on
section gave out fluid in little spurts as tissue spaces were
opened. Bachman, Collip and S e l p ( '35) have found that the
skin covering this area is much tlGclrened.
Gross anatoniy of the trrogewital tract. Figure 3 shows the
increase in the size of the prostatc and seminal vcsicles of the
injected animal over that of the control. Most striking is the
Pig. 1 Genital region of control monkey M.III,87.
Fig. 3 Thc reaction of the gciiital region to theelin in experimental aiiiinal
M.m. S G .
enlargement of tlie seminal vesicles which weighed five and
one-half times a s much its the seminal vesicles of ilie control
animal. Becansc of the necessity of preserving its relation to
the urethral mucosa the prostate was not weighed. It was
measured, however, aiicl x a s estimated conservatively as over
30 p c cciit
~
larger than that of the control. The greatest increase was in tlic depth of tlic glaiid measured a t right angles
to the leiigtli of the urethra. The increase in this dimension
was accompanied by a flai.teiiiiig of tlie lateral walls of the
390
G.
VAN
WBGENEN
caudal lobe giving the mass of the prostate a more dorsal
position witli respect t o the nrelhra. This change in rclatire
position can be seen in figures 4 and 5. The testes of both
animals were similar in size and lay well above the scrotum.
In the experimental aiiiiiial the upper pole of the right testis
la7 3+ em. a w q from the exteriial inguinal ring mid tlie left
testis 2; em. Ti1 the control animal tlie right and left testes
mere s o m e d i a t nearer, 2 and l i cm., rcspectively.
Fig. 3 J)issrc.tions t o show the increaw in size of the seminal vesicles and
prostate. A , M.111. 8 7 the roiitrol animal wrighing 3000 gm. Natural size. P.,
h1.m. 86, had received 60 r r . of tlieelin and weighed 2450 gm. Natural size.
the urogeuital tyact. The great
smooth miiscle response within the walls of the seminal
1 figure 16. When this photograph is comvesicles is s h 0 ~ 1 iii
pared with figure 17, from the control animal, it is see11 at once
that the circular layer of smooth mnscle of a siiiglc tubule is
five o r more times wider in the experimental animal. This increase in width holds f o r the longitudinal muscle layers as
well, and corresponds roughly to tlie difference in weight of
the glands. Numerous mitoses were found in the large smooth
musclc cells of the hypertrophied glands. The lining epithelium of the seminal vesicles in this animal as well as in the
control is inactive. In the experimental animal it appears
X i c ~ o s oyic
c
awatorily
of
THEELIN EFFECTS O N THE UROGENITAL TEACT
391
to have decreased in surface value since the numerous outpocketings and tissue bridges seen in cross sections of normal
tissue are fewer in number. These microphotographs showing
the increase in the smooth muscle tissue of the wall of the
seminal vesicles are similar t o those of Freud ('33) who effected by oestrin injections, the same chariges in the castrate
rat.
In the prostate of M.m. 86 there was a definite relative increase of fibromuscular to glandular tissue (figs. 4 and 5), the
reaction being more proriounced in the cranial than in the
caudal lobe of this gland. The prostatic glands in bot2h experimental and control animals were lined with epithelium
composed of a single layer of cuboidal cells.
The utriculus masculinus (fig. ij), which appears in the
normal tissue as a narrow triangular or transverse slit between the ejaculatory ducts and the prostatic urethra, lined
witli cuboidal epithelium, has undergone a surprising proliferation (figs. 6 and 7). This blind tube extending up
through the posterior wall of the prostatic urethra and into
the fibromuscnlar tissue which surrounds the ejaculatory ducts
offers an opportunity to observe the full effect of the hormone
upon the epithelium. While the keratinized superficial layers
of epithelium of the vagina and skin are shed, it is unlikely in
this protected position that many of the superficial cells of the
utricle escape. The utriclc, throughout the greater part of its
length, is a solid core of coilcentrically arranged epithelial
layers, in the basalis of whiclr there are numerous mitotic cells
lying, of course, at the periphery.
The colliculus seminalis and the longitudinal ridge extending cephalically and caudally from it are also covered by
keratinized epithelium. This proliferation gradually extends
laterally to cover the entire floor of the canal in the lower
levels of the prostatic urethra (figs. 8 and 9).
I n the membranous urethra the condition remains unchanged and figure 10 shows the superficial layers of keratinized epithelium streaming out into the lumen. The complete
section shown in this figure passed through the bulbo-urethral
T H E ALATOMICAL RECORD, VOL.
63, N O . 4
392
G. VAN WAGENEN
gland. Still lower, in the region of the opening of the ducts of
the bulbo-urethral gland, the hyperplastic epithelium expands
to line the entire urethral canal.
The greater length of tlie urethra, consisting of most of the
bulbous portion and all of the cavernous portion, is lined,
therefore, with a metaplastic epithelium (fig.12). The normal
appearance of the urethra of the pars memhranosa and cavernosa is shown in figures 11 and 13. The influence of theelin
changes the epithelium of tlie normal urethral mucosa from a
structure only four or five cells in width to an epithelium resembling that of the vagina. Indeed the urethral epithelium of
the experimental animal in question presents all the zones described in the human and macaque vaginal mucosa (Dierks,
'29 ; Smith, '29 ; Davis and Hartman, ' 3 5 ) .
EFFECTS O F GREATER AND LESSER DOSES
0.ile-hzt.lzdred an,d twcnty cubic centimeters of theelipa. A
young male monkey weighing 2000 gm,, R1.m. 36, was given
double the amount of theelin used in the previous experiment.
This animal received in all 120 cc., 6000 R.U., in twice daily injections over a period of 42 days.
12 control animal, B1.m. 199 weighing 1620 gm., was added,
mainly to check any normal variations in the urethral mucosa.
I n the experimental animal, Wm. 36, the scrota1 enlargement reached a size similar to that in 3f.m. 86 but remained at
that height. The seminal vesicles, prostate, prostatic utricle
and mucosa (fig. 18) showed the same metaplastic changes but
there was a lcucocytic infiltration of the mucosa and suhmucosa throughout the urethra in the affected regions. These
leucocytes were fewer in the submucosa of the prostatic
urethra but were present in tremendous numbers throughout
the length of the penile urethra. At many places they invaded
the basalis of the mueous membrane in such numbers that the
usual orderly arrangement of cells was lost (fig. 19).
Ten cubic centimeters of the&$. A third experimental mimal, M.m. 33 weighing 2260 gm. was given a much smaller
quantity of theelin in an attempt to find a threshold. A total
THEELIN EFFECTS ON THE UBOGEXITAL TRACT
393
of 500 R.U.. of theelin given at 1 cc. a day produced a slight
effect upon the seminal vesicles, but no appreciable effect upon
the prostate or the prostatic utriclc. Only the floor (dorsal
wall) of the pars cavernosa urethrae showed epithelial proliferation (fig. 20). There was no definite cornification although some of the dist a1 cell layers showed vacuolation.
EFFECT ON MAMNARY GLANDS
Those of the control animal K m . 87 are shown in figure 21.
and those of the second control were similar. An orderly increase in the growth of the gland according to the quantity of
theelin received was evidenced by the injected animals.
Figures 22 and 23 illustrate this for h1.m. 86 and K m . 36, the
terminal knobs showing that the gland ducts were actively
growing. The spread of the mammary glands of 1I.m. 36
(6000 R.U.) covered about the same area as did those from
our normal serjes taken from a young female monkey weighing
2070 gm. In tlie normal female gland there were more tubules
centrally located and the terminal knobs were not so large.
DISCTJSSIOX
Lacassape ( '33) demonstrated that oestrin will produce a
definite growth in the dorsal prostatic lobes of the mouse.
This was confirmed and expanded by Burrows and Kennaway
( '34). Increased weight of the seminal vesicles in the castrate
rat after oestrin injections has been reported (Freud, '33;
David, Freud and de Jongh, '34 ; Korenchevsky and Dennison,
'34; Overholser and Nelson, ' 3 5 ) . Freud found this to be
caused by fibromuscular growth and the results in the monkey
agree with this conclnsion. A study of sections of the urogenital tract in our group of experimental animals has led us
to believe that there is a very definite and quantitatively appreciable increase in the fibromuscular tissue of the seminal
vesicles and prostate in the monkey as a response to theelin.
Courrier and Gros ( '35 a and b) in very recent papers on
the effect o f folliculin in the immature magot (Macacus ecaudatus) describe an intense reaction of the margin of the anus
not fonnd in other. species which have been studied, and have
further found an epithelial hyperplasia such as has been described in this study.
Histologically the nearest picture to the change that takes
place in the urethra of the male monkey which has received
theelin is that which has been described in the cervix of the
female monkey by Overholser and Allen ( ' 3 5 ) . They induced
an atypical growth in the cervix by repeated trauma and the
prolonged injection of oestrin. The new tissue which apparently developed from the columnar cells of the glands was a
squamous epithelium. Engle arid Smith ( '35) have described
similar changes.
SUMhf ARY
3 . Theelin caused an hyperplasia of the fibromuscular
stroma of the seminal vesicles and prostate of the macaque
monkey. The seminal vesicles of an injected animal weighed
five and one-half times that of its control.
2. Theelin also effected an epithelial hyperplasia and metaplasia in specific parts of the urogenital tract. The l or 2 cell
deep cnboidal epithelium of the prostatic utricle and tlie 3 or 4
cell epithelium of tlie colliculus seminalis and the bulbous and
cavernous urethra became stratified squamous in type and 15
t o 25 cells in depth. Keratinization of the superficial layers
gave it the appearance of vaginal epithelium.
3. The foregoing results were brought about by injection
of 3000 R. I?. of theelin into a monkey weighing 2450 gm.
These effects were not intensified by the m e of 6000 R.TJ.
in a 2000 p.
animal. The only additional observation was the
presence of an intense leucocytic infiltration along the urethra.
Five hundred R.U. of theelin in an animal of 2260 gm. produced little external change, no change in the iitriculus prostaticus and only a slight proliferation without keraiiriization of
lhe dorsal wall of the cavernous urethra.
The writer is indebted to Dr. Arthur H. Jlorse f o r many
valuable suggestions and to Miss Ruth Vogel and Mr. Joseph
Negri for technical assistance.
THEELIN EFFECTS O N THE UROGENITAL TRACT
395
The theelin used in the research was provided through the
generosity of Dr. Oliver Kamm of Parke, Davis and Company.
This investigation has been aided by a grant from the Besearch Fund of the Yale University School of Medicine.
LITERATURE CITED
ALLEN, EDGAE1927 The menstrual cycle of the monkey Yaeacus rhesus: Observations on normal animals, t h e effects of removal of the ovaries and
the effects of injections of ovarian and placental extracts into the
spayed animals. Contrib. Emhryol., no. 98, Cariipgie Inst. Wash., vol.
19, pp. 1-44.
1928 Beactions n f immature monkeys (Xacacus rhesus) to injections of ovarian hormone. J. Morph., 1701. 46, pp. 479-519.
1935 The effects O f prolonged
BACHMAN,
CBRL, J. B. COLLIP AND H ~ N SELYE
S
oestriol administration upon the sex skin of Maeaea mulatta. Proc.
ROY.SOC.,
vol. 117, pp. 16-21.
BURROWS,
D., AND N. 31. KENNL4TVAY 1934 &I some effects produced by applying oestrin to the skin of mice. Am. J. Cancer, vol. 20, p. 48.
COURRIER, R., AND GASTONGROS 1935 a Action de la folliculine chcz le Singe
male impubhre. Apparition d ' m e peau sexuelle. Compt. Rend. des
Sc. de la Soe. de Biol., vol. 118, pp. F83-685.
19351) Modification des anncxes. Compt. Rend. des Sc. de Biol.,
vol. 118, pp. 686-689.
DAVID,K., J. FREUD
A N D 8. R. DE JONGH
1934 Conditions of hypertrophy of
seminal vesicles in rats. Hiochem. J . , vol. 28, pp. 1360-1367.
1935 Changes in vaginal epithelium durDAVIS,M. E., AXD GAEL G. HARTMAN
ing prcgnancy in relation to thc vaginal cycle. J. Am. &fed. ASSOC.,
vol. 104, pp. 279-285.
DIERKS,I i L A A S 1029 Experimeiitelle Untersuchungen an mmsrhlirhen VaginalPchleinihaut. Arch. f. Gyn., vol. 138, pp. I 11-1 30.
EN-GT.E,
E. T. 1942 Esperiinentallj- induced descent of the testis i n the lfacacus
monkey by hormones from the anterior pituitary and pregnancy urine.
Endoerin., vol. 16, pp. 613-520.
ENGLE,E. T., AND P. E. S M I ~
1935 Sonie uterine effects obtained in female
monkeys during continued oestrin administration m i t h especial rcference t o the cervix uteri. Anat. Rec., vol. 61, pp. 471-484.
FREUD,
a. 1933 Conditions of hypertrophy of the seminal .resicles in rats.
Biocliem. J., vol. 27, pp. 1438-1450.
GESCHICKTER,
C. F., DEAX LEWISAXD CARL G. HARTMAN1934 Tumors of the
breast related t o the oestrin hormone. Am. J. Cancer, vol. 21, pp.
828-859.
KORENCHEVSKY,
V., AND M. DENXISON 1934 The effects of oestronc on normal
and castrated male rats. Biochem. .J., vol. 28, pp. 14i4-1483.
LAPASSAG~YE,
A. 1933 MBtaplasie Ppiderinoide tie la prostate provoyube, ehcz
la souris, par des injections r6p6t6es de fortes doses de folliruline. C.
R. Soe. Biol., vol. 113, p. 590.
at. D., AKD \I7.0. NELSON 1935 Comparison of the effcc>tsof estrin
and male hormone injected separately and simultnueouslp upon the
seminal vesicle in immature rats. Anat. Rcc. (Suppl.), bol. 61, p. 38.
OVERHOLSER, If.D., AND EDGAR ALLEN 1935 Atypical growth induced in cervical epithelium o f the nioiikey by prolonged injeetions of ovarian
hormone combined with chronic trauma. Burg. Gyii. and Obst., \. 01.
60, pp. 139-136.
PARICES,
A. S.,AND S. ZT~CKERMAN
193.5 Effect of oestroiie on t h e primate
prostate. J. Physiol., vo1. 84, pp. 1-2.
SMITH,BEII.TXAM
G. 1934 The structure of the human oagiiial mueosa in relation t o the menstrual cycle and pregnancy. hu. J. Auat., vol. 54,
pp. 27-85.
VAN WAGENEN,
G . 1935 Effects of theclin on thc nialc genital tract. Science,
vol. 81, p. 366.
WISLOCBI,G . X. 1933 Chap. 11, The reproductive systan., from Anatomy of
the Rhesus monkey, edited by Llartman and S t r a w , The Williams L%
Wilkins Company, Baltimore.
OVERHOLSEB,
PLATES
397
PLhTE 1
EXPLANATTON OF FIGURES
4 From h1.m. 86 which received 3000 R.U. of theelin. A section through the
cranial lobe of the prostate, ejaculatory ducts, utricle and urethra. x 8.
5 Control, N.m. 87. A section through the cranial lobe of the prostate, ejaeulatory ducts, utricle and urethra. x 8.
6 A greater magnification of thc utriculus prostaticus taken from figure 4. To
show the epithelial response to theelin. X 42.
7 A greater magnification of the normal utricle from figure 5. x 42.
8 Theelin injected monkey 3l.m. 86. A section through t h e caudal lobe of the
prostate and the prostatie urethra t o show the epithclial proliferation on the dorsal
wall of the urethra just below the orifice of t h e utricle. X 8.
9 Control monkey M.m. 87. A section at a similar level for coniparison with
figure 8. X 8.
398
399
PLATE 2
EXPLdNATION OF FIGURES
10 M.m. 86 injerted with 3000 R.U. of theelin. A sertion through the distal
portion of the membranous urethra. The complete section induded Cowper’s
gland. Epithelial prehferation i s still roiifincd t o tlie dorsal wall of the uretlira.
X 15.
11 Control monke? K i n . 87. This section froin a similar level is chosen for
comparison with figure 10. z( 15.
12 Theelin injected inonkep M.m. 86. A section through the proximal p a r t
of the carernous urethra. The dorsal epithelial thickening has extended laterally
along the urethral wall t o liiic completely the canal. This section is charaetcristie
of the greater part of the length of the lrulboun and t h p full length of tlic
cavernous urethra. Y 8.
13 Control monkey X.m. 87. The cavernous urethra. X 8.
14 Theelin injeetcd animal 31.m.86. A higher magnification of t h e epithelium
of the cavernous urcthra. I t could he mistaken f o r a section through vaginal
epithelium. Note t h r intra-epithelial zone of comification. X 165.
15 Control monkey I h i . 87. A section through the niucoya of the normal
cavernous urethra for comparison with figure 14. X 165.
400
401
PLBTJ; 3
ESPLANA'MON OF FIGURES
16 Proiii 1f.m. SG which rracived 30U0 ILLr. of tlirrlin. Tlic seminal vesicles
show great dexelopincnt of the smooth niuscle of the walls. X 55.
1 7 Seminal besiclrs from the coiitrol animal 1l.m. 87. X 55.
18 Froni B1.m. 36 which rcccired 120 w. of theelin. h section t o show tlic
cpithelial proliferation of the c+olhculus semiiialis at a short distance above the
opening of the utriclc. X 10.
19 From 31.m. 36. I n this section of the Cawriious urethra the lrucocytic infiltration is seen f o r the most part in t h e submucosa but 011 the left side thc leucocytes hare penrtratcd the basalis quite disrupting the orderly arrangcment of the
deepcst epithelial laprs. X 45.
20 From M.m. 35 which received 10 ce. of theelin. I n this sertion o f tllc
cn~eriiousuiethra 0111- t h r central portion of the posterior ~ r a l lof the urethra
shows proliferation of the epithelium. 'Cherc i s so1110 vacuolation of cells in this
rcgion hut no kcratinization. X 65.
2 1 The iiiammaip glands of the control monkey 11.m.8 7 . Two-thirds natural
&e.
22 1fanimary glands of 3f.m. 86 which rereiFecl 60 cc. of threliii. Two-thirds
natural sizr.
2:+ The inammar> gland of 1I.m. 36 which rewired 120 cc. of tlwcliu. Twothirds natural size.
402
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