Title

HISTLOGICAL CHANGES OF THE HYPOPHYSIS, OTHERENDOCRINE ORGANS AND BONES OF MICE CAUSEDBY ORAL ADMINISTRATION OF A LARGE QUANTITYOF LEUCIN

Author(s) IMAI, TERUKAZU

Citation 日本外科宝函 (1959), 28(1): 113-136

Issue Date 1959-01-01

URL http://hdl.handle.net/2433/206750

Right

Type Departmental Bulletin Paper

Textversion publisher

Kyoto University

HISTOLOGICAL CHANGES OF THE HYPOPHYSIS, OTHER ENDOCRINE ORGANS AND BONES OF MICE CAUSED BY ORAL ADMINISTRATION OF A LARGE

QUANTITY OF LEUCIN.

by

TERUKAZU IMAI

The F'irst Surgical Division, Kyoto University Medical School (Chief, Prof. Dr. C1mATo ARAKI)

(Received for publication Sept. 2, 1958)

INTRODUCTION

113

Engel and several other authors reported that ACTH and adrenocortical hormone

have an intimate relation with the metabolism of amino acid, while, on the other

hand, there are ve1・~· few reports that some kinds of amino acid have some influence on the secretion of a certain hormone. HARADA and his coworkers found

that the administration of a large amount of histiclin to rats brought about an

increase in body weight, and also an increase in α－cells, hypertrophy of ふcellsand

atrophy of β－cells in the anterior lobe of the pituitary gland. In addition, they

observed that the administration of histidin restored not onl>・ the decrease in body weight but also the decrease in α－cells and the hypertrophy and hyperplasia of _

かcellsof the adenohypophysis occurring in thyroidectomized rats. Also, they reported that in rats having been administered lucin for four weeks, an increase

in body weight together with an increase in the α－cells in the pituitary took place.

In the hope of experimental production of acidophilic adenoma of the hypophysis I administered a large amount of leucin to mice for long periods and examined

the hypoph~·siへ other endocrine organs and bones histologically.

EXPERIMENT I

ANIMALS AND lVmTHOD.

Animals used for this experiment were mice, both male and female, one

month after birth. The~· were put into separate wire-mesh boxes and brought up.

An amount of 150 mg leucin was administered orally each day and their body

weights we1℃ weighed m引‘〉 four da~・日 ea1ヤ in the morning before feeding. After

10 weeks and 20 weeks respectively, theγwere killed, and the hypophyses, th~Toids,

adrenal glands, sexual organs and bones were histologically examined.

The number of experimental animals used were 10 males and 10 females for

both the leucin administered group and the control group respectively. Five of each

group were killed after 10 weeks and the remaining 5 after 20 weeks.

Leucin was dissolved・ in lukewarm water and then hardened with. casein into

114 日本外科宝函第28巻第1号

a solid food in form of a cube of approximate!)・ 0.7 cm1, and administered orally with an addition of a little amount o！目 vitaminB,.

The hypophysis was fixed in Bouin’s solution and imbedded in paraffin and stained b:,-the GoMORI’s aldeh)・de-fuchsin method and the Halmi’s method. The th)TOid, gonad and adrenal corte:-;. were fixed in formalin and stained by hematoxylin-eosin. For the adrenal cortex, the Sudan III stain was also used. The bones, after having been decalc泊eelby 10% trichloroacetic acid, were imbedded in celloidin and stained b>・ hematoxylin-eosin.

RESULT OF EXPERIMENT

I. BODY WEIGHT

From the beginning of the experiment, the body weights of the mice were continuously weighed in e¥・c1下 fourth morning before feeding. No prominent

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di百erencein the body weight was noticed during the period of 10 weeks between

the control and the leucin group. After 10 weekぉ， the average weight of the

control males was 22.4 g and that of the leucin administered males 22.4 g, whereas

that of the control females was 20.3 g and that of the leucin administered females

23.7 g. In other words, a slightly more increase in the body weight was noticed

in the leucin administered group than in the control group. But after a period of

20 weeks, considerable di汀erencesin the body weight were noticed between the

control group and the leucin group, roughly in accord with the morphological

change of adenohypophysis to be mentioned later. Namely, the average body weight

Body Weight in the Leucin Administered and Control Groups.

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of the male mice of the control group wei広hed 24.4 g with the maximum weight

of 28.0 g and the minimum weight of 21.0 g, whereas the average weight of the

leucin administered group was 28.2 g with the maximum weight of 32.0 g and

the minimum weight of 24.0 g. The control female日 showedan average of 23.0 g

with the maximum weight of 26.0 g and the minimum weight of 21.0 g, whereas

the leucin administered females weighed in average 25.2 g, with the maximum

weight of 30.0 g and the minimum weight of 22.0 g. In other words, the males

and females of the leucin administered groups showed a prominent increase over

those of the control groups (Fig. 1, Tables 1 and 2).

ll. H'l POPHYSIS

λ11 hypophyses ＂’ere fixed in Bouin’s solution, irnbedded in paraffin and then

cut into serial sections of approximately 3 microns in the horizontal plane. Sections

near the middle of all section series were stained b~ · the GoMORI’s aldehyde-fuchsin

第 1号第28巻日本外科宝函116

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Co凡 -tro.f

合 SCliro帽 Of'ko6eCe ( (.

＠：平 Acidofh：ん CeU.. A ： 宇 Clinnnψ•Ao6e α(.t .

Percentag・es of -'.'-cidophil忙 an<lChromo向 beCells in A<lenohypophysis of Leucin Administered ;¥J1cc.

o : i Ae«l.op~ ilu c~u

Fig-. 2

117

method and the HALMr's method. Then, by the Rasmussen’s method, the number

of acidophilic cells （α－cells), chromophobe cells （γーcells)and basophilic cells （β－

cells) of the anterior lobe were counted and their percentages were taken.

In all the leucin administered animals, there was an increase in α－cells and a

decrease in ry-cells in both the 10 week administered group and the 20 week

administered group. The changes were more prominent in the 20 week administered

Fig-. 3 Hypohysis in Control Mice. Halmi's

Stain x 1000

group. There was no change in β－

cells.

However, the change in the form

of the anterior lobe cells, namely

hypertrophy, atroph~’ of the cells, or

the appearance of an~’ abnormal cells could not be found (Fig. 2 and Table

3) (Figs. 3, 4 and 5).

Fig-. 4 Hypophysis in Mice Administer巴d

Leucin for 10 Weeks. Halmi’s Stain

x 1000

Fig-. 5 Hypophysis in Mice Administered

Leucin for 20 Weeks. Halmi’s Stain

x 1000

Table 3 Percentages of Three Kinds of Cells in Adenohypophysis of Leucin Administered Mice.

Control

Leucin Administered for 10 Weeks.

Leucin Administered for 20 Weeks.

Control

Leucin Administered for 10 Weeks.

Leucin Administered for 20 Weeks.

jAci

合： 50.2 I 45.4 I 4.4

合！ 58.9 I 37.7 I 3.4

合 I 60.7 i 34.6 I 4.7

♀ I 49.o I 45.5 I 5.5

♀ i 52.2 ! 41.1 I 3.7

♀ I 57.2 I 37.9 I 4.9

118 日本外科宝函第28巻第1号

Fig・. 6 Thyroid Gland in Control Mice. H.

E. Stain x 400

Fig-. 8 Thyroid Gland in Mice Administered Leucin for 20 Weeks. H. E. Stain x 400

IV. ADRENAL CORTEX

Fig-. 7 Thyroid Gland in Mice administered Leucin for 10羽Teeks. H. E. Stain

" 400

fil. THYROID GLAND

Th~Toid glandぉ werefixed in 10%

formalin, imbedded in paraffin and

staind lハ hematm.~·lirトeosin.

In the group to which leucin was

administered for 10 weeks，合veout

of ten, and in that for 20 weeks, four

out of ten were noticed to have tall

epithelial cells with elongated nuclei,

some of which were poor in chromatin.

II川 vcvcr,there was almost no remar-

kable change in the blood vessels and

in the amou11t of colloid (Figs. 6, 7

and 8.).

Adrenal glands were stained I>:> hcmatoxylin-eosin and lηthe Sudan III method.

Generall.¥・, in the case of h.¥・perfunction of the adrenal cortex, there are usually

the increase in the weight of adrenal glands, the h.¥・pertroph.¥・ of the cells in the

fascicular zone and the decrease in the lipoids contained in them, but in the leucin

administered mice there was no prominent increase in the weight of the adrenal

gland (Table4). However, the histological examination of the adrenal glands of

both the 10 week leucin administered mice and the 20 wee！、 leucin administered

mice I℃vca led a r崎emar tble h.¥・pertr命oph.¥・of fa「＇cicular zone cells, and a decrease

in lipoid granules in their l】l-oto11lasms. This is in accm・dwith the morphological

change of ad renal co1・tcxseen句 inthe ca日cwhere ACTII is administered for a long

period. Furthermore, worth.＼’of note ¥l'CI℃ prominent h.¥・pertrophy and hyperplasia

119

'fable 4 Mean Value of Weights of Suprarenals in Both Leucin Administered and Control Groups.

Control

Leucin Administration

Control

Leucin Administration

Mean Value of Body Weig-hts (g J

台I 22.4

~ 22.4

♀I 20.3

¥1 23.7

羽Teight !Ratio to IMean Value (mg l !Body Wei-lof 「ht IB川引（~子） lhts ( g J

6.6 --1 0：~9－「－24.48.5 I o.38 1- 28.2

13.1 I o.65 I 23.o 11.0 I o.46 I 2s.2

20 Weeks

Suprarenals

Wei戸ht 1Ratio to (mg 1 1Body Wei-

'ght

（子）

6.4 23

12.0

14.2

Fig・. 9 Adrenal Gland in Control Mice. H. Fig・. 11 Adrenal Gland:in Male Mice Administered Leucin for 10 Weeks. H. E. Stain x 100

E. Stain x 100

a‘ Fig・. 10 Adrenal Gland in Control Mice. H.

E. Stain x 400

of the X-zone in female mice with

manv vacuoles in the same zone. These

changes were especially marked in the

20 week administered group.

At a glance, this is similar to the

“fatty metaplasia'・ as advocated 旬、

Ohi, seen in the case where progesterone

or testosterone have been administered,

but no lipoid drop could be found in

the vacuoles of the X-zone ¥)y fat stain.

Therefore, this seems to be none other

than a simple vacuole formation (Figs.

120 日本外科宝函第28巻 ；（~ l号

Fig-. 12

活躍’ ~.. ,

Adrenal Gland in Male Mice Administered Leucin for JO

Weeks. H. E. Stain × 400

Fig. 14 .. 「＼JrcnalGlanJ in Female .Jl1cc Administered Leucin for 20 Wee-ks. H. E. Stain× 400

9, 10, 11, 12, 13, 14 and 15).

N- GONAD

Fig. 13 Adrenal Gland in Female Mice Administered Leucin for 20 Wee-ks. H. E. Stain x 100

Fig・. 15 Adrenal Gland in Female Mice Administered Leucin for 20 Wee-

ks. Sudan Ill Stain x JOO

;-;o prominent increase or decrea日ewas noticed in the weight and in the ratio

to boc1y weight of the gonad in both of the groups to which leucin had been

administered for 10 wee!、sand 20 wじじl凶 respectively (Tables 5 and 6).

121

Table 5 Mean Value of Weights of Testes in Both Leucin Administered and Control Groups.

Control

Leucin Administration

10 Weeks

Testes

I~＇＝ Valu•I W•i ht of I (mgr Body Weig」hts (g)

I 22.4 179

I 22.4 250

IRatio to Body Wei-g-ht

（子）

8.00

11.16

1 ：＼~ean Value

iBody Weig-(ts (g)

I 24.4

/ 2s.2

20 Weeks

rr:~rt l邸内eト

I （王子）

201 8.24

202 7.23

Table 6 Mean Value of Weights of Ovaria in Both Leucin Administered and Control Groups.

I 10 Weeks I 20 Weeks

Ovarium Ovarium

!Mean Value Wei~·ht Ratio to -Mean Value[ Weifht Ratio to of 〔mg Body Wei-of (mg Body Wei-Body Weig- ght Body Weig- ght hts (g〕

（子）hts (g)

（？）

Control 20.3 22.4 1.10 23.0 19.0 0.83

Leucin Administration 23.7 25.8 1.09 25.2 14.2 0.59

Microscopical!~－， the testes of both groups showed a certain increase in number

of the interstitial Leydig cells, but there was no noticeable change in spermatoge-

nesis in the seminif erous tubles.

The ovaria of both of the leucin administered groups showed an exceeding

increase in corpora lutea, i. e. in the sections made from the middle part of the

ovarium, 15 to 23 corpora lutea were counted in the leucin administered groups as compared with 7 to 10 corpora 1t府 ain the cor巾叫 groups.It goes without: saying

that the increase in corpora lutea in the leucin administered groups was due to

the acceleration of luteinization. No abnormality was found in the development of

follicles (Figs. 16, 17, 18, 19, 20 and 21).

Fig-. 16 Testis in Control Mice. H. E. Stam メ！OQ

Fig. 17 Testis in Mice Administered Leucm for 10 Weeks. H. E. Stain x 190

122 日本外科宝函第28巻第1号

Fig. 20 0、ariumin ~lice Auministerct.l Leucin for 10 Weeks. H.:E. Stain × 20

Fig・. 19 Ovarium in Control Mice. H. E. StRin x 20

Fig. 21 0、ariumin ;Mic巴 AdministeredLcucin for 20 Weeks. H. E. Stain x 20

ドorthe purpose of observing the effect on bocl~· weight h~· the administration of leucin to mice from the intrauterine life, the following experiment was made.

Leucin administered mice were crossed. Also during the period of pregnancy

and of lactation, leucin was continuoush・ administered. The o仔springsof these mice

were put into separate mesh-boxes one month after birth. Thereafter, 150 mg of

leucin w部 administered oral!~· each day for 10 weeks ancl 20 weeks respectiye]y

as previous！γmentioned, after which the mice were sacrificecl and the endocrine

organs were histological！γ examined.

RESULT OF EXPERDIENT

I-BODY ・wEIGHT

In making a comparison of the bod>・ weights of mice one month after birth,

the litters each of which consisted of the same number of babies, were used.

Nam clγ，3 groups each consisting of 6 babies of the same litter wc1℃ used each

for leucin administered and control grou11s, respectively.

In the groups which had been administered leucin since the intra11terine life

123

an increase in bod:-・ weight was more marked in comparison to the control groups.

Males of the control groups had the maximum bod：－’ weight of 9.0 g and the

minimum weight of 7.0 g, whereas those of the leucin administered groups showed

the maximum bod:-・ weight of 14.0 g and the minimum of 6.0 g. Of the female

groups, the control groups showed the maximum l〕od：－・ weightof 9.0 g and the

minimum of 8.0 g, whereas the leucin administered females showed the maximum

of 14.0 g and the minimum of 7.0 g. Namely, Leucin administered groups, the

body weight of 12.0 g to 14.0 g were seen in 8 out of. 18 mice.

The increase in body weight during the following 10 weeks was practicall：－・

the回 mein grade as in the previous experiment and the animals of both sexes

maintained the di百erencein the bod＞’ weights which had been present from the

Body Weight in the Leucin Administered and Control Groups.

Befo叶 4 1 s I 12 i 16 I 20 ; 24 2s I 32 1 36 1 40 44 I 48 ; 52 I 56 f 60 I 64 i初 j1必

I i·~i -10部両 15~五百 l詑 2川両~；；；制~0: 2山知6:gl10.0 10.0 11.0 14.0, l .i.D 15.5 16.0 18.0 18心20.020心 18.5119.0;19.0 18.叫1s.0120.0110.01 11.0 12.0 12.0 12.0 15.0 16.5 18.0 18.0 21.0 21.5 20.0! 20.0l 19.0 2C.叫20.0121.5'9.5 11.5 12.0 14..0. lS.0 16.0 17.0 18.5 19.0 20.0 22.5 20.0121.0l 21.0l 20.α22.5122.5 9.0 9.0 10.5 14.0 16θ18.0 15.o 20.0 22.0 22.0 23.0 22.oi 23.0122.sl 23.α 24.0l 24.0I 28.0

i 0.0 10.0 11.5 13.5 15.5, 18.0 18.5 18.5' 21.0: 22.0 21.0 22.0 21.0123.0123訓お.0122.01 26.0 ! 8.0 10.0 11.5 11.0 12.0 14.0 16.0 16.0 1/.0 18.0 19.0 20α19.0118心118α19.0I20.01 21.0 9.0 10.0 11.0 12.0 14.0 16.0 18.0 19.0 21.5 20.0 20.0 21α21.0122.0122.α23.01 22.01 24.0

110.0 9.0 10.5 12.5 13.0 15.5 1刊 16.019.0 20.0. 19.0 20.0122.0123.0122.5! 2i.0120.0123.0

13.o 13.o 16.o! 16.o 1s.o 16.0 11.ol 20.oi 20.oi 22。~ 20.ol 22.o 23.o 2rn1 22.0' 23.ol 22.o 10.0 10.0. 12.0, 12.0 13.0 11.0 14.0i 15.0l 16.0l 21.0121.0' 20.0 21.0 23.0120.0 20.0121.0 8.0' 7.0, 10.0112.0 11.0 12.0 14.0l 16.0! 16.0! 18.0l 20.0 19.0; 180 19.0l 18.0' 20.0120.0 11.0 1 o.o 15.0: 11 .o 1 s.o 20.0 rn.ol 20.ol 20.0! 2.1.ol 24.0 25.0 2 1.0 23.ol 24.01 23.0l 24.0 12.0 1 o.o 10.011 o.o 11.0 12.0 12.0l l 6.0l 16.0l 16.0I 18.01 20.0 20.0 22.01 22.01 23.0l 25.0 10.0116.0 18心i20.0 20.0 18.0 21.0l 24.0i 26.0i 24.0l 25.0! 25.0 23.0 25.0l 26.（〕26.0128.0I 30.0 18.0' 20.0 2i.0123.0 22.0 22.0 24.0l 23.0l 24.0l 2i.0122.0123.0 26.0 26.0: 26.0: 21.0126.0128.0 1 50 20.0 22.01 24θ125.0 25.0 26.0l 23.0l 23.0122.0123.0l 26.0 25.0 27ο125.0i 26.0126.0 32.0 12.0; I G.0 19.0' 21.0 22.0 24.0 28.0126θ126οI 25.01 26.0, 25.0 27 .O 24.01 23.0i 25.0124.5! 32.0 12.01 !G.0 16.0' 16.0 18.0 20.0 22.0124.0i 22.5123.0123.0 22.0 23.0 22.0' 2!.0 23.012.J.（〕126.0

Body Weight in the Le氾cinAdministered and Control Groups.

同伽ej 4 8 ' 12 / 16 [ 20 I 24 ! 28 / 32136 [ 40 44 [ 48 j 52 j 56 / 60 [ 64 ／初 j140

← 8.0 I 10.ol 11山 .ol13.5 16.0可 正不可1石附l18.ol 18.0 19.5 20.0 20.5 20.0: 20.s 8.0 I 9.5112.0113.5114.0 16.0 15.0 16.0118.0 16.5 17.5118.0117.5 18.0 18.5 18.5 18.0 18.0 9.o I 10.ol 13.ol 14..ol 16.0i 16.oi 15.ol 18.ol 11.0118.0, 19.o. 19.5120.0. 20心 19.519.5 20ぶ20.0

I 9.5i 12.ol 14.0l 1::i.o 14.0 17.0l 16.s 18.0l 18.0' 18.5120.0120.0 20.5 20.5 20.0 20.0: 20.0 8.0 110.0112.0112.0l !4.0 19.0 19.0, 20.0120.0l18目021.0 23.0l 22.0 21.0 22.0 22.0 21.0 23.0

I I I 13.5111.5 ls.s 15.oi 18.ol 16.ol 18.o, 18.o 18.ol 19.o 20.0

~：~ I ~g ：~I n ：~I 9.0 I川 11山 .51H.O 16.0i 18.刊 O川叫22.0初θ119.0削 山削山21. 23:g

討嗣i：；間fi!il話i：石；：1f~：fii~凶器13.0 14.0l 15.0 17.0l 2（〕.r2c .c 20.01 no 25.0I 25.0I 27 .c 24.0 26.0 26.0 25.0. 27 .Ol 26.0 12.0 16.0. 16.0 16.θ1116 .~ 22「22.024.0 23.0J 23.0j 23.C 22.0 z:rn 22.0 24.0j 22.0l 24θ

'13.0, 18.0, 18.0 18.0J 20.0. 2r . ~ '.' l.0・ 23.0 22.0l 21.0l 23.C 23.0 23.0 22.0 ~.！.（） 23.0l 24.0i 26.0 12.0112.0113.0112.0 14.0 1 7. ~ 16.0 18.020.0l18.0! 2C.8 18.0' '.'O.O 22.0 20心 20.0120.0:24.0 8.0 JO.O 8。10.0112.016.0 1 ri.o・ 1 s.o ~ 11 .o: 19.0I 2c .c 20.0こ0.021.0 ~＇.： .0 23.0l 23.0. '.'LO

16:g 1；：山22:gl20:g: ~~：~ ~0山2ci:g~irn ~6：~ ~~：例 ~~：~ ~~·~I 22 ：~1判部

Table 7

岡、。己

n

－z〉仏国国一三回件。円邑

（UHaC口

同

】

瓜

w

8.0 7.0 8.0 9.0 7.0 8.5 9.0 8.0 8.0 8.0

12.0 s.o 7.0 12.0 14.0 10.0 12.0 9.0 12.0 12.0

¥io. 1 九＼o.2 No. 3 No. 4 No. 5 l'¥o・6No. 7 No. 8 No. 9 No.JO

1'¥o. I No. 2 No・3K口.4 No. 5 No. 6 No. 7 No. 8 No. 9 No.10

Days

。

cロけ円《）目。円

OE同】

0ヤ

Table 8

Days

No. 1 No. 2 No. 3 No. 4 No. 5 No. 6 No. 7 No・8No. 9 No.10

。。ロC10－C円CZ一方

-IO

No. I No. 2 No. 3 No. 4 No. 5 No・6No. 7 No. 8 No・9No.IO

7.0 12.0 14.0 12.0 12.0 12.0 12.0 6.0 12.0 14.0

岡、巾gngkp仏吉田口一凶作巾円巾仏

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判

第 1号第28巻日本外科宝函

Bod.If Weigιt

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Body Weight Increase Curve of Both Leucin Administered and Control Mice. Fig・. 22

Percentages of Three Kinds of Cells in Adenohypophysis of Mice Administered

Leucin since Intrauterine Life.

Table 9

IAcidophili Cell

Co凶rol 合 I 50.2 I 45.4 ~ A Leucin Administered for 10 Weeks since Intrauterine Life

Le<J.cin Admini~tered for 20 Weeks sin巳eIntrauterine Life

Control

Leucin Administer巴dfor 10 Weeks since Intrauterine Life

Leucin Administered for 20 Week，言 sinceIn北rauterineLife

5.5

5.0

6.8

H

5.1

45.5

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34.6

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。：も Aι＜d•tA＜＇ふ’c Cell.

・： 5iも Actolofι－~~•c Ce~~－ .Cl.: i ('!fro却今o/.o6ec.，~.ど・A：♀ C/iro7>fopk6eCelZf.

Fig. 23 Percentages of Acidophilic and Chromophobe Cells in Adenohypophysis of Mice Administered Leucin since Intrauterine Life.

commencement of this experiment (one month after birth). After 20 weeks, as in

the previous experiment, they showed a much greater difference as compared with

the control groups : The average weight of the male control groups was 24.4 g,

the maximum being 28.0 g and the minimum 21.0 g, whereas the males of the leucin administered groups showed an average of 29.6 g with the maximum of

32.0 g and the minimum of 28.0 g. The mean value of the female control groups

was 23.0 g with the maximum of 26.0 g and the minimum of 21.0 g, whereas the

leucin administered female groups showed an average of 25.2 g with the maximum

of 27.0 g and the minimum of 24.0 g (Fig. 22. Tables 7 and 8).

126 日本外科;,;i， ~J、l 第28巻 ;;rD号

Fig-. 24 Hypophysis in Mice Administered Leucin for 20明、ekssince Intrau-terine Life. Halmi's Stain x 1000

f孟’ 植民

Fig・_ 25 Thyroid Gland in Mice Administered Leucin for 20 Weeks since Intrauterine Life. H. E. Stain× 400

IV. 人DR日＂＇.＼＇ ALぐりRTEX

II. HYPOPHYSIS Fixation and staining 羽＇erethe

same as previously mentioned. In the

anterior lobe of the h~·poph~·sis there

waメ aconsiderable increase in α－cells

and a decrease in γーcellsin groups to

which leucin was administered for 10 weeks and 20 ,,-ccl、日 respective!;;.These

changes were more outstanding than

in previous experiments. However,

neither hypertrophy nor atrophy of

the cells and no appearance of any

abnormal cell were noticed (Table 9,

Figs. 23 and 24).

III THYROID GLAND

Even if a large amount of leucin

had been administered to the mice

since the intrauterine life, nothing

more than a slight change appeared

in the thyroid gland. In the mice

administered with leucin for 10 weeks,

3 out of 10, and in the mice admin-

istered with leucin for 20 weeks, 4 out

of 10, showed an increase in height

of their epithelial cells, but no change

was found in the blood vessels or in

the amount of colloid (Fig. 25).

Table IO Mean Valu巴 of羽！eightsof Suprarenals in Both LeL1cin Administered and Control Groups.

10 Weeks 20 Weeks

国

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一

一

一

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巴

一

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9

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6

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一

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6

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Control

Suprarenals 羽Teig・ht [Ratio to (mg) Body Wei・

広ht

（芋）

竺_J_~

127

The weight of the adrenal gland and its ratio to bod~＇ weight showed no

remarkable increase or decrease in each of the experimental leucin groups as compared with the control groups (Table 10).

Fig・. 26 Adrenal Gland in Female Mice Administered Leucin for 10 Wee-ks since Intrauterine Life. H. E.

Stain x 100

Fig. 27 Adrenal Gland in Female :¥1ice Administered Leucin for 20 Wee-ks since Intrauterine Life. H. E. Stain x 100

Microscopically, as in the previous experiment, adrenal glands of both the

males and the females revealed marked hypertrophy of the cells in the fascicular

zone, and the decrease in the lipoid of these cells and hyperplasia and vacuole

formation were found in the X-zone of female mice. These changes were more

remarkable in mice receiving leucin administration since their intrauterine life

(Figs. 26 and 27).

y. GONAD

Fig・. 28 Testis in Mice Administered Leucm for 10 Weeks since Intrauterine Life. H. E. Stain x 100

－

"

Fig. 29 Ovarium in l¥fice Administered Leucm for・20Weeks since Intrauterine Life・ JI. E. Sta.in x 20

128 日本外科宝函第28巻第1号

The weights of the ovarium and the testis and their ratio to body weight in

the experimental leucin groups did not日howan＞’significant di汀erencefrom those

in the control groups (Tables 11 and 12).

Histological examination revealed a tendency to increase in the interstitial

Leydig cells in the testis, but no change in the seminiferous tubles or in the

spermatogenesis. In the ovarium, luteinization was exceedingly prominent. No

outstanding change in the follicles was found (Figs. 28 and 29).

Table 11 Jkan Value of Weights of Testes in Both Lem~in Administered and Control Group.

! IO Weeks j 20 Weeks

!: I Testes j I－吋j；：：て}lean Value We出1t !Ratio to Mean Value! Weigl 。f I (mg) !Body Wei・ of I (mg) IBody wei・

["'"'' Weig I 山一）… ig1 lght ht日（宮 I i i (mg l由 Cg) I I （~ I ¥ g I I ' g

Control j 22.4 j 179 j 8.00 ! 24.4 j 201 j 8.24

Leucin Admin附山n I 22.4 I 209 I 9.33 I 29.6 I 210 7.09

Table 12 Mean Value of Weights of Ovaria in Both Leucin Administered and Control Groups.

Control

Leucin Administration

VI. BONE

10 Weeks 20 Weeks

川町h~l明；i- ~；：~；：，：· i五「「τ丁τIO 23.0

Ovarium Weight 1Ratio to (mg) !Body Wei・

ght

19.0

（？）

0.83

0.95 25.2 23.8

Fig-. 31 Bony Tissue:in Mic巴 AdministeredLeucin for 10 Weeks. H. E. Stain

×？QO

Fig-. 32 Bony Tissue in Mice Administered Leucin for 20 Weeks. H. E. Stain xzoo

Fig-. 33 Bony Tissue in Mice Administered Leucin for 20 Weeks since Intrau-

terine Life. H. E. Stain x 200

129

The proximal end of the tibia was taken and decalcified in 10% trichloroacetic

acid, imbedded in celloidin and stained by hematoxylin-eosin.

In the 10 week leucin administered mice, the tibia showed a wider epiphyseal line as compared with that of the control mice, and also an advanced di百erentia-

tion of the cartilage cell columns in the epiphyseal line with several slightly calcified areas in the cartilage.

In the 20 week leucin group, though there was no great di百erencein the width of the epiphyseal line from that of the 10 week group, the columns of cartilage cells became narrower and the ossifying tissue appeared more abundnatly in the cartilage.

Moreover, in both the 10 week group and the 20 week group of the mice

which had received administration of leucin from the intrauterine life, each column

of cartilage cells of the epiph~＇seal line became sparse and h~·aloicl tissue was found to invade the intercolumnar space. The process of calcification was remark-d】lyadvanced and accompanied b¥・ h~＇peractive ossification. This change was much

more noticeable in the 20 week leucin administered group (Figs. 30, 31, 32 ancl 33).

COMMENT

The long-term administration of a large amount of leucin increases the body

weight considerably, and promotes the bon~γ growth in the epiphyseal line. If

leucin was administered since the intrauterine life, the body weights one month

after birth were exceedingly larger, a fact indicating that leucin brings about the

most remarkable e百ecton the embryonal body growth.

130 日本外科宝函 第28巻第1号

Moreover, an increase in α－cells in the adenohypophysis was recognized to be more prominent when leucin was administer百 1for long periods. This seemed to be roughly parallel in grade with an increase in body weight. In the adrenal cortex, as was seen in the case of ACTH administration for a long time, the hypertrophy of the cells in the fascicular zone and the decrease in lipoid in those cells were noticed, both changes being the de自nite evidences of the hyperactivity of the adrenal cortex. Moreover, an interesting change is that prominent hypertro司

phy and hyperplasia, and vacuole formation of the X-zone in female mice were noticed. Such changes were more prominent in those which had received adminis-tration of leucin for long periods.

In the gonad, an increase in the interstitial cells in the testis and the incre-ased luteinization in the ovarium were noticed. There was nothing particular in the change of the thyroid gland.

EXPERIMENT II

Since Stokstand announced that aureomycin effected the accelerated body growth of young animals (1949), similar e古田tswere reported one after another of many other antibiotics.

In 1955, Ozawa administered aureomycin, achromycin and penicillin to young mice oral!~＇ and/or parenterally and noticed that this accelerated the body growth. He assumed that the e町ectwas due to the hyperfunction of the pituitary-adreno-cortical system.

In this experiment I have orally administered 10 mg of achromycin every day to mice one month after birth, and have weighed them in the early morning before feeding every fourth day, and have killed them after forty days to examine histoiogically the endocrine organs and bones.

RESULTS OF EXPERIMENT

I. BODY羽THIGHT

Table 13 Body Weight in the Achromycin Administered and Control Groups.

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The degree of the increase in body weight during the period of 40 days from

the beginning of this experiment was almost the same as that of OzA w A’s exper-iment. The experimental group to which achromycin had been administered began to show a greater increase in body weight than the control group from the third

week after commencement of the experiment. The increase was almost the same

in degree as that obtained by the leucin administration (Fig. 34 and Table 13).

II. HYPOPHYSIS

Some increase in the eosinophilic cells and decrease in the chromophobe cells

of the adenohypophysis were seen in the achromycin administered groups, though the changes were not so marked. Besides, there was no change in the morphology

of the cells (Table 14).

132 日本外科宝函第28巻第1号

Table 14 Percentages of Three kinds of Cells in Adenohypophysis of Achromycin Administered Mice.

i Aci州 1ilicCell I Chrom仰 beCell I Bお ophili、0此rol 一一一「一一 －5忌←一丁 一一 ~5ユ一一一「一一一つ7一

Achromycin Adrninistra n I 52.1 / 42.7 I 5.2

Fig. 35 Thyroid Gland in Mice Administered Achromycin. H. E. Stain x 400

III. THYROID GLAND

Fig・. 36 Adrenal Gland in Mice Administered

Achromycin. H. E. Stain x 100

In the achromγci11 administered mice, no histological change took place in the thyroid gland (Fig. 35).

IV ADRENAL （りRTKX

The weights of the adrenal gland and their ratio to the boclγweight in the

achromycin administered group日 showed, though slight, a tendency to decrease in

comparison with those of the control group:-:. But histologicallγ，no special change

could be found (Table 15 and Fig. 36).

Table 15 Mean Value of羽Teightsof Suprarenals in Both Achrornyr:in Administ巴redand Cotnrol Groups.

Control

Achr・omycinAdministration

brean Value of 1-wぶ htBody Weiεhts ! (mg) 〔g) i

19.7

22.8 3.3

Suprarenals

I Ratio to Body Weight

（子）

0.14

133

V. GONAD

The testicular weights and their ratio to the body weights of the achromycin administered mice showed some decrease in comparison with the control group. But histologically, no change could be noticed of the interstitial cells, of the semin-iferous tubles and of the spermatogenesis (Table 16 and Fig. 37).

舟．

Table 16 Mean Value of Weights of Testes in Both Achromycin Administered and Control Groups.

Control

Achromycin Administration

Fig・. 37

Testes

weirt Ratio to (mg Body （手Wetht

19.7 170 8.63

22.8 123 5.49

遡艦Fig・. 38 Bony Tissue in Mice Administered

Achromycin H. E. Stain x 200

The proximal end of the tibia was histologically examined, but there was no outstanding di町erencein the width of the epiphyseal line, the di百erentiationgrade of the cartilage cell columns, etc., between the achromycin administered group and the control group and, moreover, no histological change of bony growth could be found in the achrom)・cin group (Fig. 38).

COMMENT

It is certain that the administration of achromycin to mice causes some increase in the borl)・ weight, and in the eosinophilic cells of the hypophysis, with a decrease in the chromophobe cells, but no particular histological change in other endocrine organs. No sign of h)・peractivit)・ of lJon~· growth could be found.

DISCUSSION

The anterior pituitar・y cells have been classified into three kinds of cells, namely the eosinophilic cells （αーcells),the basophilic cells （β－cells) and the chrom-ophobe cells （γ－cells). Recently, HALM! (1950, 1952), and PuRvEs and GRIESBACH (1951) described that the basophilic cells of the hypophysis were to be divided in, to two types of cells from the 11ffinjty of the granule for aldehyde fuchsin or

134 日本外科宝函第28巻 第 1号

light green. The one is aβ－cell in a narrow sense which has the affinity for

aldehyde fuchsin, and the other is a o-cell which can be easily stained with light

green.

However, it has not been decided what kind of pituitary’ hormones originates

from each kind of adenoh:yアpophy日ialcells.

BENDA and FISCHER (1910) , and BAILEY and DA vmoFF ( 1925) , etc. reported,

according to the histological findings of the anterior lobe of the pituitan' gland in

the case of acromegalγ，that the growth hormone is secreted probabl~＇ fromα－cells,

an<l this assumption seems to be definite.

In regard to thyrotrophin, ZEcKwER and coworkers (1935) and Morris (1951)

claim that the thyroidectomy cells (T-cells) originate from the αーcells,and

ScttARF and FoRSTER (1954) claim that the~・ originate from the γ－cells, or PuRvEs

and GRIESBACH (1954) and HALMI (1952) claim that they originate from the

o-cells, and thus in any case, nothing is definitely known at present; recent!~＇， the

theory that thyrotrophin is secreted from o-cells seems to be prevailing.

As regards gonadotrophin, there is a theory which claims that the β－cells secrete gonadotrophin, because the amount of gonadotrophin increases in the urine

after castration and, at the same time，β－cells increase in the hypophysis. On the

other hand, WoLFE (1935) or SHADWICK (1936) reported that the α－cells of hypo-

physis in rats, in the stage of oestrus, were filled with granules which were dyed

with orange G, and that during their stage of clicstrus, the decrease in the number

and in the stainability of these granules was acknowledged, and on the other hand, the β－cells, during their stage of proestrus, carried a large amount of

basophilic granules which extreme!..,・ decreased during the stages of oestrus and

metestrus. Therefore, it has been assumPcl that FSH is secreted from the β-cells

and LH from α－cells.

As regards AC、：TH,there is no definite the0t・：＂at present. FINERTY (1952) in an experiment of stress given by’hot water, reported that there was a slight

increase in basophilic substance and an outstanding increase in granules stainable

with the acid hematein in the protoplasm ofα－cells, but no change whatsoever in

the β－cells. Ever since, a theory that ACTH was secreted fromα・cellsbecame

prominent. 1¥Tυreovcr, HERBAUT (1952) succeeded in separating the granules from

r~－cells using a centrifugal method and acknowledged an i¥仁TH-like function as well as an LH・likefunction in these granules. He also reported that he found a

TH-like a日 wellas an FSH-like function in the granules separated from the β－c巴lls川・ thesame way.

In leucin administered mice, I found an outstanding increase in the number

of α－cells and a dec1℃a~c in that of γ・cellsin the adenoh:-poph,¥・siへbutnoticed no definite change in the number of β－cells. In addition, I found, in the adrenal cortex, a hypcrtroph,¥ of the fascicular zone and a decrease in the lipoicl drop

within the cells. These findings of the adrenal cortex are quite similar to the

change in the adrenal cortex of the animals administered ACTH for long periods.

Also, I found a tendenc.¥・ to increa日Cin the interstitial Leシdigcells in the testis,

135

and that句 increasein corpora lutea in the ovarium. These changes seem to ha¥'c

an intimate relation with the increase in the a-cells of the hypophysis, and to

support the theory that ACTH and LH are secreted from α－cell.

CONCLUSION

I. The oral administration of a large amount of leucin brought about the

increase in body weight to some extent and, at the same time, the promotion

of the bon.v growth in the epiphyseal line. The increase in bod~’ weight was much

more remarkable when leucin was administered since the intrauterine life.

2. The eosinophilic cells of the adenoh:-・pophysis showed a prominent increase

in the leucin administered mice but no morphological change of the cells was

noticed.

3. In the adrenal cortex, the h~·pertro1〕hy of the cells in the fascicula1・zone

and the decrease in lipoid within those cells were observed. These findings were

similar to those gained when ACTH was administered to the animal for long

periods. In addition, in the case when leucin was administered to female mice, a

marked hyperplasia of cells and a vacuole formation in the X-zone were found.

4. In the testis, an increase in the interstitial Leydig cells was noticed, and

in the ova1‘ium corpora lutea were found to increase in number.

5. As regard the thyroid gland, no special change was noticed.

6. In the experiment of achromycin administered mice, some increase in the

bo〔行 weightand some increase in the α－cells of the hypophysis were found but

no marked histological change was noticed in other endocrine organs.

From the above findings, I uphold the theory that ACTH and LH are secreted

from α－cells.

Thanks are expressed to Dr. Naoki Kageyama for his kind suggestions during this study.

Referrences 1）、Anderson,G.羽T., Cunningham, J. D. & Slin-ger, S. J.: Effect of Terramycin and certain ph-enylarsenic acid derivatives on the growth and intestinal flora of turkey pout ts., J. Nutrition, 84, 539, 1952. 2) Chadwick, C. S.: Cyclic morp-hologic variations in the anterior hypophysis of the guinea pig., Am. J. Anat., 60, 129. 1936. 3) Finerty, J. C., Hess, M. & Binhammer, R. :

Pituitary cytological manifetations of heig-htened adrenocorticotrophic actiYity., Anat. Rec.,114, 155, 1952. 4) Fischer, B.: Die Beziehun -gen des Hypophysen Tumors zur Akromegalie und Fettsucht., Frankf. z. Pat.h,. 5, 357, 1910. 5) Halmi, N. S. : Tow types of basophils in the anterior pituitary of the rat and their respective cytophysiological significance., Endocrinol., 47, 289, 1950. 6) Halmi, N. S. : Further observat-ions on two types of basophil cells in the anteト

ior pituitary., Ant. Ree, 109, 300, 1951. 7) Halmi, N. S. : Differentation of two types of

basophils in the adenohypophysis of the rat and the mouse., Stain Technol., 27, 61, 1952. 8) Harada, M., Nakagawa, M., Kitaura, T. &

Matsushima, l¥I. : The influence of a long term administration of Histidine Hydrochloride on the rat’B anterior pituitary glands., Wakayama Med. Rep., 3, 103, 1956. 9) Inouye, T: Histopa-thological Studies on the distribution and chan-ges in epithelial cells of adenohypophysis. Rep-ort Ill A study on the appli~ation of the calcula-ting、methodto mouse and rabbit.. Japan. Arch. of Internal Med., 3, 1048, 1956. 10) Kirkman, H. : A cytological study of the anterior hypop-hysis of the guinea pig and a statistic analysis of its cell types., Am. J. Anat., 61, 233, 1937. 11) Ohi, T. : '.¥foqJhological studies on the ad re-nocortical function of the rat., Japan Endocr-inol. Society., 31, 468, 1956. 12) Ozawa, E.: Studies on growth promotion hy antibiotics., J. Antibiotics., 8, 205, 1955. 13) Ozawa, E. : Stud-ies on gTO＼＼’th promotion by antibiotics., J.

136 日本外科宝函第28巻第1号

Antibiotics., 9, 71, 1956. 14) Purves, H. D. &

< ;riesbach, W. E. : The significance of the Go-

mori staining of the basophils of the rat pituit-a1-y., En<locrinol., 49, 244, 1951. 15) Rasmussen

A. T. : The percentage of the different age of

eells in the male adult human hypophysis., Am.

J. Path., 5, 263, 1929. 16) Romeis, B. : Die Hy-pophyse In V. Mollendorff Han<lbuch der !¥Iii王子

oskopischer Anatomie des Menschens., Julius

Spoinger. Berlin, 6. Part 3. 591, 1940.

17) Sayers, G. : The adrenal cortex and home-

和文抄録

ostasis .. Physiol. Rev., 30, 241, 1950.

18) Tanimoto, K. : The experimental studies

on the effect of Estrogen io bony tissue and

endocrine organs., Wakayama Med. Rep., 6,171,

1955. 19) Stockstand, E. L. R. & Jukes, T. H:

The multiple nature of the animal protein fac-

tor., J. Biol. Chem., 180, 6•17, 1949. 20) Wolfe,

J. :u. The normal le、elof the various cell ty-

pes in the anterior pituitaries of mature and

immature female rats and further observation

011 er<.:licじhanges.,Anat. Rec., 61, 321, 1935.

経口的ロイシン大量投与マウスに於ける

内分泌臓器並ぴに骨の組織学的検索

京都大学外科学第 1講座 （指導：荒木千里教授）

今 井 昭 和

ACTH或は副腎皮質ホルモンがアミノ酸の代謝と密 ける酸好性細胞の増加と密接な関係を有するものと思

援な関係を有する事は F.L.Engel及び若干の人々に われる．

より報告されているが．逆に一定のアミ ノ酸が或種の 更に興味ある変化と して，胎生時よ りロイシンの投

ホルモン分泌に関係を有すると云弓事はp l¥I. Harada 与を行った場合p 生後1岩月目の体重にかなり著明な

et alによるヒスチヂン及びロイシンと下垂体の関係 増加が認められた．

を論じた以外には無い様である． 更に；；＿，ロイ シン投与群の副毒性マウスの副管皮質に

私は生後 1ヵ月のマウスに大量の円〈シンを経口的 於て X-Zoneの著明な地殖肥大，及び空胞形成が認め

に長期間の投与を試みたとこ ん，若干の体重増加を認 られたがp その発生機構については今後研究にまちた

めると共にp 座骨の骨端線部組織像に於て骨生長の促 い．

進像を認めp 同時に脳下垂体前葉に於ては善明な酸好 叉一方，種々の抗生物質が幼弱動物の発育を促進す

性細胞の増加p 嫌色素性細胞の減少を認めた．更に副 る事が知られているがp 私は Achromycinの少量を

腎皮質に於ては＇ f：［状帯細胞の肥大及びリポイドの減少 経口的に投与し， 内分泌臓器及び骨の組織学的検索を

をぷ内 これは AC、'TH長期投与における副腎皮質の 行ったがp Aehrornycin投与に際しては若干の体重

像と一致した． 更に又， 性腺の変化としてp 皐丸の l曽加とp 下垂体に於ける酸好性細胞のj曽加以外には特

Ley dig細胞の増加，卵巣の黄体形成促進像が認めら 別変った変化は認められなかった．

れた．か与 る副腎皮質及び性fj~j：の ＇ft （仁l土脳下垂体に於