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Reduction of the thymus by gonadotropic hormone.

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REDUCTION O F THE THYIIUS BY (IOKXDOTROPTC
HORMONE
HERBERT M. E V A N S AND MIRIAN E. SIMPSON
Instztute of Experimental Eiology, University of California, BerLeley
The meagerness of well-established results from the numerous efforts to determine the function of the thymus is too
well known f o r further comment. ( SCC,for instance, Trendelenburg's reccrit account, '34.) It is not too much to state
that no investigator has as yet been able to secure specific
effects from ablation of the thymus or from efforts to
experimentally imitate increased thymic function. Security
in the conception of the thymus as an organ of interiial
secretion arid light on its role may, however, come from a
study of the effect of other internal secretions on ihc thymus.
The present study aims t o report one such effect-one resulting from injection of a gonadotropic hormone. Chronic
injection of this hormone led to a striking reduction of thymic
substance sometimes resulting in almost complete disappearance of the gland-an effect which, as will be disclosed, is
probably t o be attributed t o the intermediation of malc o r
female sex hormone.
The years of painstaking quantitative studies devoted by
August Hammar to normal arid altered thymic stnzcture
established the striking and sensitive dependence of the thymus upon the maintenance of normal body weight arid
satisfactory general nutrition, demonstrating as it did the
'Aided by grants from the Committee for Research i n Prohlcms of Sex of the
National Research Council, and from the Rockefeller Foundation of New York
City. These funds have been gcnerously augmented by the Board of Research
of the University of California, Bcrkeley. The authors desire to record their
appreciation of tlie invaluablc aid of Donald H. Wonder in the preparation and
standardization of tlie hormones employed in these studies.
423
424
IiEBBERT &
EVANS
I.
B E D MIHIAM E. SIMPSON
rapid recession of the thymus in practically all disturbaiices
of growth o r nutrition. This rclationship is so securely
established that any claims f o r experimental contrivances
wliich electively reduce tlie thymus cannot be accepted if
impairment of body weight or of growth or other adverse
effects are demonstrable. The experimental procedures herein
reported were not associated with loss of body substance;
they were, indeed, associated with slight gains in adults or
with moderate or marked gains of weight in immature animals.
The gonadotropic hormone used in these experiments is the
most potent gonadotropic substance known to us, namely, that
found in the placenta or in tlie blood stream of mares early
in pregnancy (Cole and Hart, '30; Evans, Meyer and X i m p son, '33 ; Catclipole and Lyons, '34). The particular product
used was an extract of mare's placenta and uterus at the
appropriate early period of pregnancy.
CIIRONIC TREATMENT O P NORilIA4L ANIMALS WIT11 EQUINE
GONADOTROPIC HORMONE
A. Immature females
Female rats, 25 days of age, mere injected once daily snbcutaneously with 50 R.U. of gonadotropic hormone for 26 to
65 days. Normal uninjected littermate controls were sacrificed at the end of this injection period along with the injected
aninials. A report has already been made of the striking
hypertrophy of the ovaries and of the anterior liypophysis
which characterized these injected
Only the e-flfect
on the thymus is considered here. As will be seen in table 1
(S25), the thymus of the controls weighed between 202 and
535 rng., averaging 264 mg., while the thymus of their littermates treated chronically with potent gonadotropic hormone
were reduced to weights of only 8 t o 83 mg., average 46 mT.
* The original yurposc f o r which chronic injections of this gonadotropic hormone
was undertaken was t o determine the effect on the ovary. The eEeets on the
ovaries and liypophyses have been reported elsenhere (Ex-ans, Simpson, and
McQuecn-Williaiiis, '34 ; Evans and Simpson, '34).
TABLE 1
Bcsponse of thynaus of ntniure and i n m a l u r e ittale and fentole rats t o chronzc
injection of the gonndofroprc hormone s ~ c u r c dfrotn pregnant m a w s
EQUINE GONADOTROPIC IIOBJIOXE
5 0 x. u. n.411~8
TYfR O F A N I X A L
Fcinales immature
(5%)
bUB
days
days
25
25
25
23
23
2.5
23
65
63
65
65
65
65
65
63
65
63
61
23
26
2 .?
2.5
2J
25
_____
Average
Females mature
(S27)
[ncreese i n
~ o d yweight
Thymus
ncreaee i n
~ o d ywc.ight
Thymus
gm.
lng.
gn1.
mg.
139
126
164
124
96
120
21 4
14G
13-1
110
37
141
133
202
280
260
2 15
127
300
220
231
204
236
53,
130
100
98
112
129
106
118
111
94
98
142
98
111
46
4
_____
177
177
177
176
177
177
177
ti5
6.i
- 42
177
177
196
193
196
65
65
65
50
-42
196
_____
65
65
63
65
B5
- 82
28
3
1
18
~
6"
6
9
0
30
20
Average
7
62
.i
i
35
49
24:3
'
GO
33
44
25
8
33
83
46
03
49
57
11
65
40
32
65
63
63
65
65
20
86
Plateauci
82
10
10
10
30
186
127
b3
63
60
80
.530
122
120
Males rnature
(R26)
ti0
_____
122
130
133
121
120
120
F3
6
65
65
250
301
278
334
350
"24
310
292
27
36
39
42
(1i
65
6.5
117
30
17
3.5
207
:7
i
Average
10(i
132
26
33
10
~
Svcrage
305
264
146
97
129
174
139
17
4;
ti 3
hlales immature
(H24)
CONTROL
Platcauci
191
2 7CI
272
330
265
285
400
290
196
260
347
290
290
400
201
284
This animal also did not show the characteristic hppophyseal hypertrophy
seen in other members of this group. The hypophysis weighed 12.5 rng. Those
nf others in the group 26, 21, 26, 26 mg.
'hTo animal is included in the table which lost ncight during t h e last 1 0 t o
20 days of injection. Animals are also excluded known t o be sick, e.g., Iv-hcezy
rats, rats injured i n fighting, cte.
426
426
ZIEFCBERT M. EV.4NS A N D iLlIIlIAM E. SIMPSON
B. Mature fenznles
Mature females, 6 t o 64 months of age, were treated once
daily subcutaneously with an identical amount of the same
preparation injected into the immature females. The adult
females were also sacrificed after 20 t o 65 daily injections
were given. Here also, associated with the massive hyyertrophy of the ovaries3 and of the pituitary, an astonishing reduction of the thymus was encountered; at times the vestiges
of thymus present were too small to give security in dissection
for weighing (those cases noted in the table where the weight
was 10 mg. o r less). Even the thymi of the females treated
f o r the shorter periods, 20 t o 30 days, showed extreme atrophy
(average 30 compared with a 127 mg. average in the controls).
See table 1,S27.
C. Immature males
Immature males, 25 days of age, were similarly injected for
20 to 65 days. With the single exception of the animal injected only f o r 20 days, all animals showed thymi reduced
f o one-fifth the weight of normal uninjccted animals of the
same sex and age, 60 compared with 290 mg. See table 1,XZ-4.
D. Mature males
A group of adult males, 4 to 4: months old, was also treated
for varying periods, 30 t o 147 days. I n this group the atrophy
of the thymus was extreme, except in one animal, sacrificed
after only 30 days’ injection. The average thymus weight
was 37 mg. compared with 284 mg. average in control males.
See table 1, S26.
It is to he pointed out that at time of sacrifice all animals
included in the tables were in excellent nutritive condition.
All immature animals had gained weight during the injection
These ovaries a s can be seen by consulting the paper dealing with this matter
(Evans, Simpson and McQueen-Williams, ’34) sometimes attained a weight of
2 t o 3 grn. The original object of this experiment was to see if the ovary
beearne rxhaiistrd by long continued injection mith the equine hormone. It was
found, however, that they weighed between 1 and 2 gni. after more than 2 months’
injection.
EEDUCTIOX' O F THYMUS BY EOBMONE
427
p e r i ~ d . ~All adults hail either gained slowly or were in
growth stasis. None were included that had lost any weight
during the last 10 t o 20 days of the injection period. There
is no reason, therefore, for referring the thymic atrophy to
malconfition of the animal. Instances were noted such as a
rat injected 30 days in which the thymus weighed more than
that of any other animal in the group, namely, 207 mg. yet
during the full period of administration no body growth
occurred in the animal, whereas others in the gronp gained
as much as 20 am.yet the thymus was completely atrophic.
INJECTION O F GONADECTO&IIZED RATS WITH THE EQUINE
GONADOTROPIC HOJZMONF;
The following experiments show that, regardless of the sex
employed, gonadectoiiiy prevents this experimental reduction
of the thymus by gonadotropic hormone.
A. Females
Females 38 days of age were castrated and immediately
thereafter injected with 125 R,.U. of pregnant mare gonadotropic hormone daily for 20 days (table 2 ) . At the end of
this period, they were sacrificed. Normal miinjected littermate controls were maintained and sacrificed at the same time.
The thymi of the untreated controls average 393 mg. in weight,
those of the ovariectoniized aiiinials treated with the hormone
averaged 453 mg. The gonadotropic hormone, therefore,
exerted no clear degenerative influence on the thymus in the
~ group of normal females of the
absence of thc o ~ a r i e s . A
same age, many of them littermates t o the above, were injected
with the same hormone during the 20-day period, and their
' Comparison with normal uninjectcil animals shows, however, t h a t a dcfinitc
although not serious interferenre with growth resnlted from administration of
thesc substances t o the males. The administration of gonadotropic hormone from
other sources (anterior hypophyses, urine of pregnancy) will u l t i m a t ~ l ybe neeessary before we can refer t h e sloww growth seen in the male t o the eff'rcts of the
gonadotropic hormone itself.
Gonadectoiny also prevented the hypcrtrophy of the anterior hypophysis which
restilted froin the administration of' the same gonadotropic hormone (Evans and
Simpson, '34).
425
HERBERT 31. EVANS A N D MIRIAM E. SIPIIPSUN
thymi showed significant decrease in weight (I03 nig.) showing that the dose and period of injection were adequate.
TABLE 2
Besponse of the thynws of male and female castrated ruts t o the gonadotropic
hormone from p r e g m n t m u m s
1
TNBlGOIED
~ _ _ _
)URATlOb
‘PREATXENT
I
Castrate
-~
OF
NJFICTIOI
xormal
Normal
Cwtrnte
in hodv
weight
days
Males
equine
hormonc
12.5 R.U
daily
(WE38
20
ym.
mg.
50
72
76
34
40
363
157
187
10
62
80
440
426
507
445
48
44
61
70
12
-.
_
57
Avrra ge
30
-_
10s
90
102
98
102
128
30
gm.
m.
my.
68
390
41 0
41 0
310
440
224
96
~
-
99
52
62
44
-
~
70
___
146
1 46
” ,.
156
510
140
158
490
460
152
101 I
~
MLllCS
ryuine
hormone
2.5 R.V.
d;lily
(W138 I,
I
.ncrease
-~
-___
CONTROL
I-SZ
3 64
3 20
375
550
485
320
353
dvcragc
- -~
E’emales
equine
hormone
12.5 R.lJ
38
d xily
(W1238’
~ _ _
Avcrage
I
’
~
20
I
GO
76
48
62
58
42
401
435
530
300
400
51.5
176
58
393
150
104
73
102
78
56
49.5
720
310
250
545
~~
-
4.53
40
GO
62
48
46
~-
~
47
111
39
170
115
I
- -
B. &tales
A group of six young males (39 t o 45 days of age), were
castrated and injected at once -6th the same unitage of
gonadotropic hormone used iii the preceding experiments.
Injections were continued 20 days. As in the caw of females,
the thymus did not show the characteristic atrophy after
REDUCTION O F THYMUS EY H O R M O X E
429
castration, the average weight being 474 mg. as cornpared to
364 mg. in the normal males of the same agc. The nornial
litterniates of these animals receiving the same dose f o r the
same period of time had ihpmi reduced to a fourth of this
figure (101 mg.).
I n the second group of six castrate males, injections were
also begun immediately after opcration, but continued 30 days,
the dosage being 25 R.C. daily. Similar results were obtained,
i.c., 110 reduction of the thymus ; the thymi averaged 4’73 mg.,
those of their normal uninjected castrate controls, 470 ing.,
those of their normal uninjcctcd controls, 401. mg.
TREATXENT W I T H GOXADOTROPTC HORMONE 01’ M-4LES STERILE
DUE TO CRYPTORCHlDIfilLl OR VlTAbIIK I3 1)EFICIESCY
An attcmpt was next made to determine which tissue of
the testicles, the seminiferous cpithelium or thc Ley& gtissne,
is respoiisible f o r the gonadal secretion stimulated by thc
gonadotropic hormone that causes the thymic atrophy. For
this reason aninials were selected in which sperniatogenic
tissue had been destroyed without loss of Leydig tissue. Such
animals wore obtained in bmo ways, 1) by rendering them
cryptorchid, and, 2) by maintaining them for a long period
on a dict deficient i n vitamin E. These two types of sterile
animals were then treated as above with equine gonadotropic
hormone.
Cryptorchid males
The males were cryptorchidized by anchoring the tcsticles
to the lateral body wall in a snbphenic position with two or
more ligatures which passed through the mliole tuiiica albuginea. A period o€ 21 days was allowed t o elapse between
operation and injection in order to allow extensive dcgeneration of the seminiferous epithelium. S f t c r this interval had
elapsed, one testicle was removed and sectioned f o r information as to its condition. Ripe germ cells were no longer present
in the testes; in fact, few cells other than spermatogonia and
Xertoli cells remained in the tubules. Leydig tissue had suf-
430
HERBERT 1\12. EVARTS A N D MIRIAM E. SIMPSOh-
fered no decrease in amount. As is well known, sex interest
and the seminal vesicles of crj-ptorchidized animals remain
normal-fact s which have been brought into relation with the
persistence of the interstitial tissue of the testes.
The animals were now injected with 50 R.U. daily of the
same pregnant mare gonadotropic hormone used in the preceding studies. Injections were continued for 55 days. A t
autopsy the marked enlargement of the seminal vesicles and
hypertrophy of the intertubular strands of Leydig cells portrayed clear effects of the gonadotropic hornione on this
portion of the testis. The testicular tubular epithelium, however, doubtless because of the coelomic location of the testis,
had not been stimulated. Atrophy was even more complete
than at onset of injection. There was virtually an absence of
germinal tissue.
Coincident with hypertrohpy of the Leydig tissue and the
accessory organs of reproduction, there was a definite reduction of the thymus (table 3 ) . The thymic atrophy was, in
fact, as marked in three of the fiw animals as that secured
in normal males by treatment with gonadotropic hormone.
The results were therefore in marked contrast to those obtained in the injected castrate males, but in agreement with
the behavior of normal males.
T7C'itaw?
in E deficient males
A further check on the striking results secured by the ireatnient of cryptorchid males was obtained by the employment
of males in which the seminiferous epithelium had been
gravely injured o r destroyed by tlic second contrivance, the
elimination of vitamin E from the diet.
Nine males were placed from the date of weaning on a
dietary regimen devoid of vitamin E.s When about 7 months
of age, at a time when, according l o our previous experience,
a Diet contained commercial casein, 27.0; coriistarch (eooked), 35.0 ; lard, 22.0;
brewers' yeast, 10.0; salts (E. V. McCollum a n d N. Simnionds, J. Biol. Chcm.,
vol. 33, p. 63, 1918), 4.0; cod liver oil, 2.0. This diet is niixcci togcther (except
f o r the cod liver oil) and allowed t o stand 2 weeks before feeding. The cod liver
oil is added the day of feeding.
431
REDUCTION O F T H Y N U S BY H O R M O X E
the degeneration of the tubular epithelium sliould be almost
complete, the left testis was removed from each animal, in
order t o establish its condition. The testes proved t o be
TABLE 3
Eflect of the gonudotropic hormone from pregnant inares on the thymus of
male rats sterilized b y dietary or operative means, yet possessing
normal interstitial tissue
EQUIl
GONAD0
OPIO
OIlMONl
CONTROL
~
t
TYPE OF AliIYAL
R.U. da
uratior
of
ijection
Cryptorchid adult males ( 5 2 1 )
-
A01
days
dU?/8
m.
188
176
174
185
173
185
55
1*5
55
55
32
7
34
55
S5
Fhymus
Increase
in body
weight
mu.
gin.
w1g.
10
52
6
34
18
249
195
162
156
167
143
85
73
30.5
80
21 8
6S
-2
44
68
36
3s
Average
Males reared and maintained or
diet deficient in vitamin E
(822)
31
25
25
1.1
-6
25
216
216
216
148
1.19
148
25
26
25
2R
35
3 -5
F
If
Average
Males reared and maintained 01
diet deficient in vitamin E,
suppleniented by wheat
germ oil (523)
Average
128
39
64
52
72
8ri
32
0
-8
- 19
6
- 18
10
26
~
148
216
2116
-6
8
18
- fj
6
.
i
21.5
25
25
25
21\5
315
216
216
25
25
25
26
216
215
10
87
Thp-
xnus
185
180
130
160
100
163
91
129
1.55
60
85
61
-
0
24
24
20
8
26
26
83
27
164
137
83
10
10
-
18
72
0
36
28
26
13
132
-
110
195
141
214
26
16,j
highly degenerate. The tubules were lined hy Sertoli cells
and spermatogoiiia, with a few, frequently enlarged spermatocytes. So-called giant cells were present in the lumen. In
432
HEEtBElLT 31. EVAHS .4h7’D M I R I A X E. SIMPSON
some of the aniiiials an occasional tubule contaiiied spermatids
or even a few spermatozoa. The few sperm found in the
testicular tubules or epididymis w7ere usually dcfornied aiid
non-motile. Interstitial tissue was approximately normal in
amount. As is well known (Evans and Burr, ’ W ) , these
animals resemble cryptorchidized males in possessing, while
sterile, normal accessory organs of reproduction and a noi-ma1
libido sexualis. Though these animals mated occasionally with
estrous females, no litters resulted.
These animals, whose sterility had been proved both by
functional tests and by histological examination of the testis
aiid epididymis, were then injected f o r periods of 25 to 35
days with equine gonadotropic hormone. At autopsy it was
found that the thymus was recluced to about half the weight
of that of the control uriinjected animals on the identical diet
(72 mg. vs. 165 mg.) (table 3).
Another group of males sterilized through lack of vitamin E mas handled exactly as was the above group, except
that coincidentally with the administration of gonadotropic
hormone abundant vitamin E mas fed these animals (12 drops
of wheat germ oil daily). The vitamin E supplemented by
the gonadotropic hormone did not, however, provoke a regrowth of the seminiferous epithelium during the 20 days
of the experiment. At autopsy, the testes of these animals,
just as in thc group receiving the gonadotropic liormone but
not vitamin E, consisted of atrophic tubules and hypertrophied
Leydig tissue. The thymi of these animals just as those i n
the preceding group were reduced to half, or less than half
of their previous weight (72 as compared with 165 mg.). The
injected animals and their controls both increased in hodp
weight slightly during this period, due to the improved condition of the animals on addition of vitamin E to the diet.
This group of males was originally chosen for another use. It was known
t h a t administration of high vitamin E alone ~ o i i l dnot (or rarely a t least)
restore testes of males rendered sterile due t o deficiency of E. IIere it was
hoped t h a t simultaneous presence of vitamin E and a potent gonadotropic liorniorie
would accelerate the regeneration of the seniiniferous epithelium. No aceelrratcd
regeneration was demonstrable in these experiments, but it is possible t h a t 20
day^ was inadequate time f o r repair.
REDUCTTOE O F THYMUS BY H O R M O N E
433
TREATMENT O F GONADECTOMIZED MALE RATS WITH FERIALE
S E X IIORMONES
The experiments heretofore detailed led us naturally to the
conviction that the sex hormones, male or female, were directly
responsible for the reduction of the thymus which followed
administration of gonadotropic hornionc. I n this way a n
explanation was afforded the thymus reduction which occurred
when cryptorchid or vitamin E deficient males were treated
with gonadotropic hormone, but did not occur on similar injection of gonadectomized uilimals.
A direct test of this hypothesis was attempted by treatment
of animals with a n estrogenic hormone, amniotin and with
ovarian implants containing both the estrus promoting substance and lutein hormone. Males, both castrate and iiormal,
were iiijected with thew substances alone, o r coi~icidentallp
received gonadotropic Iiormone. The arnniotin was given in
doses of 37.5 o r 40 R.U. daily snbcntaneously. U a t u r e rat
ovaries wcre used as implants, one and one-half glands heing
given each 4 days. The ovaries were minced sufficiently to
inject into thc muscle through a coarse cannula.
As can be secn in table 4,the female sex hormor,e, amniotin,
administered alone had no effect on the thymus of the castrate
male, but when given simultaneously with the gonadotropic
hormone had a definite thymus reducing action. I t s efiect
was, however, not as extensive as was secured with treatriient
of normal animals with gonadotropic hormone. Similarly,
after ovarian grafts alone, the thynius of the castrates remained normal ; after combination with gonadotropic hormone,
there was a slight recluetion.
It is not unlikely that the administration of gonadotropic
hormones to normal animals produces a greater total supply,
and it would appear certain that it produces a more continuous supply of the male and female sex hormone than can be
imitated by direct administration of these hormones. It woulcl
appear probable that more concentrated, frequent and pros The amniotin used was kindly fiirnished by E. R. Squibb 6- Son througll the
courtesy of Dr. .J. A. Morrell.
TABLE 4
E f e c t of the gonadotropic hormone f r o m pregnant mares on the thymus of
castrate male rats receiving female sex hormones
DIIRATION
OF
NJECTIOE
-
-
[nerease
weight
-
I-
--
,~
daw
Eqnine hormone 12.5 R.U. daily
(W1838)
00
-_
-_ _ _ ~ Average
Equine hormone 25 R.U. daily
(W1381)
- -
30
II
_ _Average
_ ~ ~ Ainniotin 37.3 KIT. daily
(W1383)
20
180
50 I 455
44.5
48
440
73
426
76
34
44
-~
53
__
108
410
90
440
102
470
98
645
102
460
128
-_473
27
.
I
1
80
64
70
12
40
I 163
1I
167
187
10
I
--I
I
--
___
Equine hormone 13.5 Xu. and
ainniotin 40 R.U. dailj
360
270
30
_ _ _Average
E:quine hormone 25 R.U.and
37.5 R.U. daily
___-
___I
GO
I
198
233
-Equine horinonc 23 K.TJ. daily
and ovarian grafts 1.5 ovaries 1
each fourth day
___hvcrage
I
1-
95
94
84-1
130
480
-301-
* F o r wcights on control uninjected castrate and llormal rats, see eoritrols of
30-day injected groups, table 2.
434
BEDCCTION O F TIlYNBIUS BY H O l t N O N E
435
lorigcd injection of either male or female sex hormone monld
be effective in reducing the thymus.
S UMM ART
1. Chronic treatment of male or female rats, whether mature
or immature, with equine gonadotropic hormone rcsults in
atrophy of the thymus.
2. But when the testes o r ovaries are removed, gonadotropic treatment does not cause thymic atrophy.
3. The testicular component iiivolved in this reaction appears to be the interstitial tissue and not the germinal
epithelium a s treatment with thc gonadotropic hormone after
destruction of the germinal tissue by procedures which leave
the interstitial tissue arid its dependent accessory organs
intact (cryptorchidism or vitamin E deficiency) leads t o the
same atrophic changes in the thymus as in normal males.
LITERATURE CITED
CATCHPOLE, H. R., AND W. R. LYONS 1934 The gonad-xtimiilating hormone of
pregnant mares. Am. J. Anat., ~ o l 55,
.
pp. 167-218.
COLE, 11. II., AND G. 13. HART 1030 The potency of blood serum of mitres i n
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