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Testicular function and the action of gonadotropic and male hormones in hyperthyroid male rats.

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Relatively few attempts have been made to study testicular
function in hyperthyroiclism. Aloaterosso ( '13) , Guderuatsch
('15) and Belameiietz ('28) found that thyroid fed rats suffered decreased testicular -\.vcight. Conrrier ( '21) discovered
no cliarige in teslicular struetiire of thyroid fed cats, and litter
('28) reported that t h y o i d feeding of rats and dogs caused
precocious puberty. 111 contrast, Da Costa and Carlson ('33)
found thyroid feeding slightly tlclaped pnbei-ty and decreased
the testicular weight in rats. Hoskins ('16) slid IIerring
('17) ivorking with rats, Cameron and Carmichael ('20) with
rats and rabbits, all report sliglitlp heavier testes as a result
of thyroid feeding. Cohcn ( '35) fcecling relatively large
amounts of thyroid found testicular weight inc*reasccl aiid
slight decrease in seminal vesicle arid prostate weight. The
structures werc normal histologically.
Obviously, knomlcdge of the thyroid-testis relation is exceedinglly limited, for ci-eii the conclusion that rclatirely high
doses of tliyroici substance damage the testis is unwarranted
by wideace foiirid in the literatarc. Expcrimmts were
planned to clarify the functional i*elation of the thyroid mid
testis. It WRS proposed first to demonstrate the effect, if any,
of administration of clesiccatcd thyroid and thpro.iin on the
germinal and eiiclocrine activity of the testis; seCorid, to determine the action of gonadotropic a i d male liormone in
Aided bp a grant admixiistried hy 111. P. R. Mniith from t11e Hotkcfcllcr
Fouiirlatioii, S r r r - Yoik City.
973
liypertliyroid animals : and third, to asccrtaiii the effect of
thyroxin injection oii the goiiaclotropic liorrnorie content of
the bloocl.
EXPEE131 E;V’I’AL
The carlier work ~ v a sdone 011 rats weigliiiig from 200 to
300 gm., the later and major powtion on litters of Long-Evans
strain of known agc. The mice ivere of highly inbred Bagg
albino stock. Na-thyroxin, protiact of’ the British Drughouse,
and Thyiwxiiic cr.~-stallinesynthetic, made by H o f f m a n - h
Roche et Cie, iverc used.z
T ~ s t i c u l ~endocrine
r
activity was judged either by tlie
weight of the entire reproductire tract, exclusive of the testis
and cpidiclymis, or ’np the scmiiial vesicle a i d prostate cytology test. This latter test is best adapted to conditions
where very little andyogenic horrnoiic is present, whcrcas
weight of the entire tract is best adapted to show gross variation from the normal 1 ~ in ~the 1amount of testis liorrnorie
available.
Rpcrmatogeiietic activity was deiermiricd by counting tlie
sperm in the tail of the epididymis. Tlsc epiclidpiis WRS
weighed, tlie tail minced, and the fr.;z,mcnts tho~onglilp~ v a s l i ~ c l
with several changes of saline to remove the sperm so tliat UYI
accurate count could hc made 011 an liaemocytometer. It xvas
found most satisfactory t o suspeiid the coiiteiits of one epididpmis in about 400 c ~ of. saline. Ten counts made of each
sample were found adequate, f o r teii additioiial counts did iiot
affect tlie aveiage values ohtaiiiecl.
The great variation in number of spcrm found in normal
animals, even among litter mates, made it necessary a s a control measure to count tlie sperm present in one cpidiclymis
hcfore beginning treatmcnt. Following tlic treatment a count
The pregnancy w i n e extract used was Antnitrin S and the pituitary gonndotropic material was an alkaline extract of dried sheep pituitaries, both furnished
hy Parke Davis and Co. The sheep pituitary powder ~ v a sextrnrtcd f o r 24 hours
i n the cold with dilute NaOH, centrifuged, and thc supernatant fluid neutralized
with dilute HCl and rreentrifngod.
Prof. F. C. Koch and Dr. T. F. Gallaghe1 prcpa~etl the nialr liormoiie fioin
urine and reported that there mere 23 B.V. per cubic centimeter of olive 011.
mas made on the remaining e p i d i d p i i s at autopsy. Normally
the number of sperm iii tlie right arid left epididymis is
appi-oximately the same, but following nnilatcral castration
the number in the rcruaiiiing epidiclyuis is iricreasecl (Smelser,
' 3 3 ) . This iucrcasc was found to bc corisistent aiid tlic values
obtaiiied were statistically significant. The effect of the espcrimental treatment on spermatogenesis is sho~imby its
influeiicc on ilie expected increase in spcrm following unilateral castration.
1. E f f e c t
01 fAy1 oxiu
injcctioiz
Twenty-five acinlt male rats, divided into several groups,
mere unilaterally castrated aiicl sperm counts made, ten uriinjected unilateral castrates scrviiig as coritr01s. F or 30 da3-s
the animals were iiijccted daily with 0.028 to 0.28 mg. Kathyroxin. The higher dosagcs were decitledly toxic (three of
tlie five animals receiving 0.28 mg. died) while tlie lowest
amount caused little or no weight loss.
The testis weight of each animal receivkg the lo\vest dosage
(0.028 mg.) shomcd a slight iiicrcase over the weight of the
control testis, as did the testis weight of the u n i n j e c t d controls. Howerer, testicular weight of all groups suhjectecl to
higher dosages decreased bclow that of tlie coiitrol tesiis.
Histological examination of tliesc testes in no case revealed
a strikirig deviation from iio~rnal,even tlie testes of animals
treated with ilie largest amount of thyroxin containing man:active seminiferous tnhules. None sliowd degenerative
changes i n any wa:- coinparable in animals subjected to x-ray,
or made cryptorchid. Fewcr tuhulcs contained m a t u r t sperm
than in the controls, and in many iristarices tkic tubules were
smaller in diameter. Thesc changes, although difficult to estimate quantitatively, were sufficient to accunut for the d c ( w a s c
in number of sperm discusscd later.
The seminal vesicles and prostates of this series were
markedly affected hy all dosages. Ziijection of the larger
amounts of thyroxin prodiicecl pronoiinced atrophy of the
acccssories. The srmiiial vesicles wcw small, flahly ancl, iu
those animals receiving more tliaii 0.056 mg. Na-thyroxin
daily, coinpletely devoid of secretion. Accessories of tliose
rats receiving less than 0.056 mg. daily iii no case approached
normal, although a small amount of thin, watery fluid was
present in a iinmhcr of instances. 111 several cases tlie awessories, examined after 2 ~veeltstreatment, were found well 011
tlie JT-ap to the atrophic coiiditi on tlcscriheci ahove.
TSALE 1
Tkc action of Bniiiitrin S zn correctiizg tlze disabdities caused by t7iyrortn
adniznislrntion
'HYROXLN I N J E C T E D , 0.01-~.02 X G .
PER 50 GM. BODY WEIOH'I' DAILY
THYROXIN AKD A N T U l T R l N S
( 2 5 R.U. DAILY)
I.ITTfifi
NO.
Sperm
lumber
Body
weight
.w.
1.390
"Ic
-42
:'o
--31
1.772
2.506
-42
-33
-16
- 28
-
restis
veighi
2.263
2.565
2.393
2.793
"105
-7
-34
+24
-3(i
Testis
weight
TJJYLOXIX
DOSE
gin.
nqv.
3.768
3.023
5.097
0.01
0.02
0.02
46
10
-7
4.0:39
47
....
0.01
0.02
18
4.750
2.904
6.237
0.02
0.111
0.01
31
34
-1 6
3..502
2.888
0.02
0.02
-15.6
3.910
~
-10
0
34
34
55
47
31
31
t9.4 I +2xI -15.9
Testis weight and sperni number are eiprrssed in per rent of the vaiuc,s obtained
by uidatrsl castration a t the beginning of the experiment.
In a sccoiicl series of experimeiits, weights of the accessories yielded a more objcctire measure of the effect of
thyroxin injections, weights in the h:-pcrtliyroid animals
averaging 2.2 gm. compared t o about 3.5 gm. in iiormal aiiimals (table 1).
In all but the lowest dosage group the seminal vesicles were
essentially castrate in typc. There w e r ~no 'haloed' secretion
granules such as described by Xoore, Price and Gallagher
( '30) and tlic cclls x-e-ere cuboidal, rather than colLimiiar, thcre
being little o r 110 cytoplasm distal to the nucleus. Sectioiis
TESTICLyLAR F C N C T I O S I N HYk'ERTllYEOIDISM
277
of the seminal vesicles from r a t s receiving the milder trcatmeiit (0.028 mg. Ka-thyroxin daily) revealed a higlier epithelium in three cases, prcse~ltirlgsome, tllough far less that1
the normal amount, of granular cytoplasm.
Sperm counts ~ w r not
e made in the first expcrimcnts since
the necessary methods had not been sufficiently perfected.
Ho1ws7ert epididymal weight i n all cases, coupled ~ l i i l Spcrl11
i
counts i n most cases, clearly demonstrates the marked injurious ef!fect of h~pertliyroidismo n sperm production in all hut
tlie lowest dosage group. Following unikzteral gonadectomy,
epidicl-i.mal weight as well as sperm number innxiably inci'ea sed i n controls. Excluding the lowest dosage group, the
e pidiclymal w-cighis we re clccr eased hy tli P thyroxin in6c3 ct ions.
In the lowest dosage group, epiditlymal weights of three of
the fivc animals mere decreased. In thcse experiments, some
corrclation betweeii epicliclyrnal weights and sperm production
was evident bat weights cannot be taken to indicate qperm
production alone.
Sperm counts in animals receiving miiiimal treatment (0.0%
mg. thyroxin daily) do not indicate great damage to spermatogenetic activity, confirming the data on epidiclymal weights.
In each case the sperm count was considerably higher at the
d o s e of the experiment than at its initiation. Dosages higher
than these, however, decreased spermatogenesis so that, in
some cases, the epididymes were pi-actically tlevoid of spermatozoa. Table 1 shows that the sperm number of the thyrosin injected animals in tlie second series decreased an
average of 22 %.
2. 12e:cocery
The relatirelj- slight effect of thyroxin injectioii on testis
structure suggests that impairment of testicnlar function is
dependent upon contiiiucd tr*eatmeltt. Three normal animals
were treated with Sa-thyroxin f o r 1montli, causing a 15% to
30%) body xeiglit loss. Oiie cpicliclymis mid scminal vesicle
was then r c m o v d and the injections discontinued.
278
GEORGE I<. SMELSER
The seminal vesicle histology approached that of cimtratcs,
there being no secretion granules aiid a ciihoiclal epi thelium,
although the testes were csseritially normal in structure.
Body weight v a s ra1)idly regained, and at autopsy 30 clays
latcr the reproductive tract was quite iiormal. The seminal
vesicles were distended, aiid the columnar epitliclial cells were
filled with typical secretion droplets. Tlie k s t e s and epididymes mere heavier., the testicular tubules active, m c l tlie
iinmbcr of spermatozoa was iiicretised.
tlryroid fecdilzg
To cliecli- the method of administration, and to ohtain a
basis f o r comparisoii with other studies, the effect of feecliiig
desiccated thyroid gland was clcterminecl. Five adult male
rats mere unilaterally castrated to secure reference controls
on testis twiglit and number of sperm. F o r 30 (lays each recviretl daily o w Burroughs and Wellcome ‘Tabloid,’ contaiiiin# the equivalent of 0.324 gin. fresh gland.
Tlic results w x e comparable lo tliose of the thproxin series.
Tcsticular weight was but slightly deci*eased, although hod:weight was reduced f r o m 13Yc to 22%. Sections of the tcsteh
revealed many active tubules and no indication of marlied
damage, though tlie proportioil of active tubules must haw
h e n afl’ccted f o r spermatogenesis was se.verely depressed arid
the epi(lidpmes, reduced in weight, contained fewer sperm i n
all caws. Sperm riumher decreased an average o f 30;L
w h e i w s the average in controls increased 8Oc/,. Tlie acressor-ies were reduced, and tlie seminal vesiclrs were small,
flabby, and d e w i d of secretion. Scctioiis of the semiml vcsicles revealed a cuboiclal secretory epithelium coiitaiiiiiig 110
secrctiori granules.
3. J Y f f f C t of
X e p u i i . with A n t u i t T i i i S
The ahove experiments show that injection and feeding of
thyroid preparations depress the secretor:- activity of the
accessories and tlie productioii of spermatozoa. Tlic abscwce
of any gross t1istin.bance of testicular morphology, niicl prompt
4.
recovery upon discoiitiiiuiiig injections, suggest that an insufficient supply of gonadotropic hormones may be responsible
f o r the condition.
To determilie if tliis was tlie case, nine pairs of litter mute
adult male rats were unilaterally castrated, the testes and
epididymes weighed, and sperm counts made. The animals
mere then iiijected daily with 0.01 to 0.02 gm. thyroxin per
50 gni. l ~ o d yweight €ram 31 to 55 claps. Oiie of each pair
receivcd in addition 25 R.Y. Anluilrin S daily. Rot11 groups
lost. approximately the same weight with the injections.
At autopsy, llie testis, epididymis, arid accessories were
weighed, illid the iiumher of sperm was determined :IS IE~OIT,
and the differences between the values obtaiiied at autops;v
and the preliminary biopsy were compared.
ils in the pwceding experiments, the testiciilar weight of
the rats receiring thyroxin alone did not change materially,
but spermatogenesis was decreased, as clearly demonstrated
b:- tlie sperm counts, for these showed a 22% average decrease
i n sperm numl)er (table 1). The degree of snppression, as
before, seemed roughly proportional to tlie decreased body
weight.
The daily injection of 25 R.V. of Antnitrim S at least partially niairitairied iiormal spermatogenesis, for sperm counts
in this group averaged a 28% gain. T h r e ~of tlie nine ariimals
had a lowcr sperm count than before treatment, but each of
these rated higher than their litter mate receiving tliproxin
but no gonadotropic extract.
The seminal vesicles of the rats treated with thyroxin alone
were small, flabby, and devoid of secretion, again confii~~iiiig
previous observations. Accessory weights (table 1) were
greatly reduccd from R normal average of 3.5 gm. to 2.2 gm.
The simultaneous injection of gonadotropic hormone effectively prevented this reduction in each case, maintaining tlle
average accessory weight at normal. The seminal vesicles of
the rats receiring the eomhined injections %$-erelarge and distended with secretion, demoristratiiig good sccretorv a
280
GEORGE: li. Sh!tELSNl%
Apparently mfficieiit available gonadotropic liormones ma;v
prevent deleterious effects of thyroxin o n both sperm production and tlie condition of the accessories.
Action of w a l c llorrnow o n hyperthyroid castrate .~ncilr.c
Reiss and Pereny ( '28) and Van IIorn ('31, '33) reported
that thyroid-fed castrated females require more estrin t o produce raginal coriiificatioii than do normals. This suggests,
that the castration-like atrophy of the accessories in hyperthyroid male rats might be due to a n increased amount of
male hormone required to maintain them in normal condition.
Thirty-five adult rats (200 to 250 gm.) from eight litters
were used to determine tlie effectiveness of male hormone in
normal and hyperthyroid castrate rats. The animals werc
bilaterally castrated and each litter divided so that eacli member received either thyroxin, male hormone, tliyroxiii plus
male hormoiie, o r was reserved a s a11 uninjecteci control. Rp
this arrangement of litter mate controls, greater significance
may be at tachcd to dif'ferences between groups. The amount
of thyroxin injcctecl (0.1 mg. daily) was known to be sufficient
to affect the accessories o f a normal rat. Male hormone was
administered in amounts within accurate assay range (2.5 to
5.0 ELT.)of the criterion used (Hansen, '32). Since oil was
used a s a vehicle f o r the male hormone, small amounts
to
% cc.) were injected to aid complete absorption. No oil was
found at autopsy. All injectioiis were subcutaneous and daily
for from 8 to 20 days.
The r a t s were autopsied the day following the last injecweighed, and tlie protion, the accessory reprodnctive tr
state fixed in Rouin. Secretory epitlielinm height in ten
different regions in each prostate was measured v i t h a n OCLIl a r micrometer. An attempt was made to choose rcgioiis f o r
measuring which ere representative of the wliole, and those
in Tvhich curvature of the aciiius distorted thc shape of the
epithelial cells were avoided.
Moore, Price and Gallagher ('30) and Hansen ('32) denionstrated that castration for a period o f 4 to 5 days resulted in
5.
(so
disuppcarance of all ‘light areas’ iii tlie prostate cells, though
iiijectioii of small amouiits of male hormone prevented this.
T a~ sensitive aiici
Prostate epitlieliam Iieiglit has been S ~ O as
reliable test for iriale hormoiie. Tt7ithin 10 clays postcastration
epithelial height is marlicdly reclucecl, but injection of sniall
amounts of male hormone prevents this. Tliesc two cytological criteria are particularly adapted to testing for the pl-esence of small amounts of hormone such as those im~olved.
Table 2 sliows that iiijectioii of from 2.5 t o 5.0 I3.U. daily
of testis hormone maintains thc accessory weights of castrates 21?, abm-e that of miinjected castrate litter mate controls. 1,itter mates receiving the same amount plus thyroxin
failed t o S h O \ v this male liormoiie action, the accessory weights
averaging only 2% over the uniiijected controls. The injection of thyroxin, though reducing body weight, liaci no effect
o n accessory weights of castrates.
Cytological examination of tlic prostates failed to reveal
the ‘light areas ’ in secretory cells of the untreated castrates
and those receiving thyroxin. Howerer, they were readily
demonstrable in each castrate treated with male hormone
alone. Of the eleven castrates receiving both male hormone
and thyroxin, ‘light areas’ were found in only two instances,
both questionable, since they were faint a d in but few acini.
The average epithelial height of the castrate rats receiving
male hormone averaged 29% over their uninjected litter mate
controls (table 2 ) , whereas in those receiving the same amount
of male hormone plus thyroxin it was but 10% higher.
On the basis of the three criteria used, accessory weight,
presence of the ‘light areas’ in the secretory cells, and height
of tlie secretory epitlielium, it is clear that male hormone adniinistercd parenterally is markedly less effective in hyperthyrojd rats. This inhibition of male hormone action by
thyi*oxinoffers at least a partial explanation of the atrophic
reproductire organs iii hyl~erthyroicl animals described
explain decreased spormatoearlier. It does not, lio~veve~,
genesis in such aiiiinwls, which strongly suggests a pituitary
gland involvement.
282
GEODGE I<. SMELSER
+ + + + +++++++
I I I I I
I
1
I
I
I
i l i
I
6.
d c tio 1.2 of g oiiado t r o pic 11o I - nt o s
t ii y ro id wial es
i l l iMl?lafl.o'e
I%yjt-'cr.--
Since evidence indicates that the h~-pophysisor its hormories, as well as the male hormone, a r e irivolved in the
deleterious effects of thyroxin administration, experiments
were d e ~ i ~ etod determine tlic effectiveness of gonadotropic
hormones in immature 1i;r.pcrthyroid animals, and t o a v e r tain whether thyroxin, administered iii closes too small t o
depress growth, affects prepubertal devclopineiit of the male
genital system.
At autopsy, the testes and uccessoriw we1.e weighed, and
thc testes sectioned. Outlii1e cliwvings of twenty tiihilcs of
each teCitis were made with the aid of a projection apparatus,
the area of the tubule draxTings lwiiig determined by tracing
the ontlinrs with a plariimetci*. Only true cross s~ctioiismere
chosen for drawing.
Sixty IZi-da;r.-old male r a t s from ten litters of six each we~-e
used. Each litter had one uninjected coilti-01, one rat received
thyroxin, two received gonadotropic extract, and two ponadotropic extract plus thyroxin. Thyroxin in a dosage of 0.02 mp.
per 10 gm. body weight was injected daily, a n amount which
does riot affect body growtli. Two and one-lialf to 5 rat units
of Arituitriri S or an extract of from 25 to 35 mg. of sheep
hypophyses were the daily dosages. All injections began 011
the sixteenth day of life; Antuiti.in S recipients werc carried
from 20 to 26 days, those rec&T;.ing sheep pituitary extract
from 15 t o 20 days. A long test, period was used to allow
sufficient time f o r the thyroxin to act. Animals were autopsied well before gonad clevelopment at puberty could complicate results.
Autopsy data show that injection of 2.5 to 5.0 R.U. dntuitrin
S incrcased testieular weight an average of 9 % over the 1111injected litter mate controls. Sheep pituitary extract, however, prodnccd a 40% increase in testicular weiglit (table 3).
Both gonadotropic prepamtioils seemed iiieffectuai on the
gonads of hyperthyroid animals, f o r the testes not only failed
t o increase in weight, bnt W'CJ-C as small or smaller t l i m those
TABLE 3
E f f e c t of ,gonadotropic hornionm
the male reyroducl iue system of ?corrr~uZund hvperthyrord
OTL
imnwture Tats
A. Sheep pituitary extract
PITUlTARP
PITUITARY
EXTRAOT
RXTRACT AND
THYROXIN
UNINJECTED
COKTROLS
~
LITTEE
NO.
~
>.
n
7%
5;
?+
5 5.; .?'G
ee
z5
;e
.
4
3
-
K
2
e
ii
~
-c
?
.-e '3
c1
H
2
ro
w
m
.D
z3
TIFfROXIN
~
5
2%
i;
mg.
mg.
1
225
267
443
2
244
238
29.3
279
649
462
3
320
266
399
338
611
510
492
516
702
716
778
752
808
335
.
3i9
4
348
352
353
505
420
409
843
709
588
672
601
480
695
846
1026
1037
398
I017
225
303
329
FQZ
573
892
172
3x1
695
504
LO34
712
860
393
628
493
578
821
~
<
~
5
AV.
287
I
~
~
~
~
mg.
1718.
3.52
563
388
386
532
7x9
496
766
~
gw
zg
9
4s
ti
z
<
E~
F
~
w.
mg.
723
...
...
0.01
441
232
490
0.01
6$)0
0.01
0.01
0.01
n.oi
0.01
n.01
...
...
0.01
0.01
399
771
3x3
B. Pregnancy urine extract
ANTUITRIN S
I N D THYROXIN
UNIXJECTED
rONTROLS
ANTUITRIN S
'rHYROX1N
~
LITTER
NO.
*
c1
E
m
,$
.
I
r
0)
,
R
52
u M
yi
W
2
E
t.3
zg
g " !
~
2M
2
d
5%
2
P
?
B
~
-
'a
*.fiP
5
i.
~
~
7 w .
mg.
757
1113
1191
1861
586
812
Ll94
1192
1518
1291
1294
0.01
0.02
493
887
814
1382
671
705
936
779
1531
1320
ti12
0.02
0.02
281
612
600
976
441
71.5
750
1193
1033
697
0.02
400
284
.i39
469
1524
813
1306
630
330
687
1370
908
4'78
786
415
473
74(1
694
mi7.
mg.
Av.
ti'G
I
:
.r
563
mg.
(1.0'2
n.02
0.0.
0.02
X6 7
96ri
I
1220
816
1017
1240
835
1267
814 12'72
0.02
0.02
~
886
644
X69
All injections were daily, the pituitary dose is in terms of dried anterior lobe powder, thP
thyroxin dose is per 10 gm. body weight and was increased as the animals gained. The figures
for tubules aro the average cross section, in square millimeters, of tmentj- tubules incasured
at x 200 magnification.
084
of the rats receiviiig thTrosin alone. Tlic alwence of a response
from tlir sheep pituitary iiijevtions, which caused a 40% increase in testis weight in the normal, demonstrates clearly
the depressing effect of thyroxin 011 the action of gonadotropic hormones.
The administration of the above amounts of gonadotropic
hormoiies was without eff
o n the cross section area of the
testicular tuhules, a fact ~ l i i c l iis pnrticnlarly puzzling because it markedly iricreased testicular weight in the nonthyroxin treated animals. Possibly the weight increase from
this treatment is due t o an increase in the number or length
of the tuhnles. Thyroxin, however, c a i i s d a mar;licd ancl con sistent decrease in the cross section a r c a of the seminiferous
tubules. Tnjcction of sheep pituitary extract in addition to
thyroxin did not modify this effect, but pregiiancy urine extract partially maintained the tubule diameter in such animals.
The series treated with pregnancy urine extract mid thyroxin
mcre autopsicd when many semi~iiferous l a h l e s contained
metamoi-pliosing spermatids, but not mature sperm. This
stage is very definite and adaptable t o thc present piirpose,
for presence of mature sperm would indicate some stimulation, while absence of elonga te spermatids \ ~ o u l dindieate
suppression.
In no animal treated with gonadotropic extracts mere tubules found in a more adranccd stage of spermatogenesis than
in the controls, but about half of those treated with thyroxin
o r thyroxin plus gonadotropic extract shox-ed no metamorphosing spermatids in an>- of the tubules. This fiutlier demonstrates that thyroxin administration suppi*esses or delays
spermat ogmesis.
Injections of hoth types of gonadotropic preparations
g e a t l y increased acccsso1.p weight, tlic pregnancy urine cansing 113F increase, the sheep pituitary extract i9%. Both
failed to produce this increase when administered concurrently with thyroxin. However, accessory w i g h t s of gonadotropic treated hpperthyroids, though n o greater tlian untreated controls, mere heavier tlian in the thy-1.osin injected
animals.
Careful examination of histological preparations w a s made
to cletermine whether the development of interstitial cells differccl between the hyperthyroid and normal gonadotropic
liornione treated animals. Sections of control and esperio
mental tcstcs were studied as n n k n o w x by t ~ iiidisiduals
and differentiated o n the basis of the relatire amount of interstitial cells. The amounts of hormone administered WCI'C too
small, liox evei', to produee marked interstitial cell 2iypcrtrophy, and the differences therefore were not yronoiinced.
Observations were rcpeatecl on different clays and the two
individuals confirmed one another. In txo-thirds of tlie cases
the interstitial cell masses of tlie hTperthproid r a t s w c ~ eless
well derelopecl than in the normuls rccciring gonadotropic
extract. This ~ - o u l dindicate that hyperthyroidism interferes
interstitial cells as well
with tlie pituitary factor tliat aff
as the one which controls the germinal epithelium.
Injection of thyroxin alone clcarly inhibited the development of the reprocluctivc tract. The testes were markedly
rcduced i n weight ( 2 1 9 ) below their controls, wlieii tlic t r r a t merit extenclccl 25 days, aiid spermatogenesis was delayxl in
comparison with litter mates. The decrease in diameter of
tlie seminiferous tubules ( 3 3 % ) is further indication of tlie
effect on the ganietogcnetic function. The accessory w i g h t s
of these animals were 257. under those of normal litter mates,
sho~i13gthat the eff s demoristrated in adults call he obtained in prepubertal animals. Prcpuhwtal testis liormoiie
secretion has been demonstrated, TTiesner ( %), Smelser and
Clark ( '36) and Price ('36).
7. Gowadotropic
actiz%it?yof hypcrtliyroid
wstr
The preceding experiments show that testicula1. depression
in lipperthyroidism is due to suppression of the action of
gonadotropic hormones. Tt seemed possible that this might
be due to either the destruction of the gonadotropic hormones
o r to a more rapid excretion. Since attempts made to demonstrate gonadotropic hormone in the urine of normal, hyperthyroid, and castrate rats failed, thc first postulate was tested.
Emcry ( '32) dcinoiistratccl goimlotropic liormone in tlie
ser'uIn of castlati tc rats, securing positive imctioii in tho in1matI1r-r r a t
iiijccting. I9 cc. (14 to IG w. iriiiiiriinm) H P ~ U
of castrate male rats. This amonnt of serum requires pooling
the 1,lood of f o u r to six animals a n d ~v-as,therefore, imprartical for tlie present espcrimeiit. By dividing 3 to 1 cc. serum
of castmtc male rats into 3 cv. amoinits iiijcctccl twice dailr
iuto inim;itiu.e (22 c l a y old) fernale mice, a positive orar*ian,
ntpviiie, and vaginal i*c+portsewas obtained. This amount is
ohtniiiahlc f r o m ii single adult. T ~ L IilS\\'as possible to d c t ~ mine the amount of gonaclotropic hormone available al a
givc1n time.
Two spries of experiments ~ w r cpcrfoi-mccl to dctermine
the i iiflimwe. of tliy~*oxin
injection on the amount of gonadoti.opic hormonc in the blood of castrate malc rats. In the
first, sc\ren lit tprs compi*ising eighteen animals u-pre used, of
which six w e r ~r c s e n e d as controls. Iiijcctioiis of 0.1 me:.
t l i y o s i n dnily were started at the time of castration aiitl coiitiiiuetl until autopsy, approdmately 1% (hys later. Veigltt
loss of tlie h j pcrtliyroid castrate was marked and comlxirahle
to that of the normal liyper*tliy-oicl animals in the first mperiment. In all but two instaiices, expei5mciital and contr*ol
sera w e ~ cfrom litter. mates, and were tested oil litter niatc
mice (table 3 h ) .
T n the second sericis, thyroxin iiijections of 0.1 mg. daily
v.-cre d a r t e d 60 t o 75 days postcastmtion a i d continlied f o r
20 to :30 clays. At autopsy the rats ~ w r ebled a i d the sci'uin
assayed as bcforc. The effect of these injcctions 011 thc orai*iari and ntcrinc w i g h t and tlic mginal orifice of tlic teit niirc
is given iii t a l h l B .
I t will be noted that injection of normal a i d Iiypc~athyroicl
Cast i*atcmale ser-um invariuhly proclucecl vaginal (*anulizatio?i
i n thr test mice and, witli hut two exceptions, ovarian and
uleriiic response as well. A\TerilqC orariaii responsc. to scq-llrn
i u j e r t i o n ~of tlie first series ~ 1 - 0 ~ 1siiggcst
~1
that tlic h y c r thyroid swum coiitaincd sliglitly more g:.onadotrol)ic 11or.1nonc
tlulri thc normal, hut this is d i to~ high
~ ovnt.ian iv.oig:.hts of
~
one litter, which through death is riot represented ill ihe eoiitrol group. Omitting this, 110 differelwe betwwn the two
groups is indicated. Average oniriiin weight of t h assay
micc in the second scries is markedly greater than in the first,
though the uninjectd controls are sliglitly ligliter. Rctmiiigly, gonadotiwpic activity of the blood of castrs te males
may conlinue to incrcnscl for wrnc time aftpr goriadectomp.
ovarian
LITTER NO.
weight
mn
0v:trian
weight
T-trrine
weight
1Tc.q.
mg.
3.0
7.4
3.4
8.9
12.0
m!?.
mn.
mg.
..
...
..
..
9.4
6.7
76.7
9.3
58.6
68.5
5.0
37.2
5.7
5.0
45.6
44.5
4.2
44.3
3.2
3.9
43.8
41 .6
4.3
3,;2
,i.2
3.6
10.1
3 .(i
4.5
4.6
22.8
3.1
30.i
1.1
13.1
15.2
30.0
5.1
23.8
41.5
3.9
16.3
4.1
61.2
3R.1
3.3
22.6
2X.0
6.0
7.i.5
4.1)
4.9
64.4
.i.4
G.l
45.1
5. k
3H.U
3.0
7.0
13.2
7.8
59.7
37.3
S..;
63.5
19.4
3.6
9.0
4.3
..)
37.3
6.7
38.0
53.4
3.8
16.3
6.1
6.2
43.1
35
10.8
m -
i
Asel age
Uitwinr
weight
6!l.7
4.5
I
0vxri;Ln
weight
--
.)..)
Avernee
T-terini,
weiph 1
8.7
49.9
I
Ovarian rcspoiise to the iiormel castrate male sc~rumis greater
tliaii to the Iippcrthyroid ill this series but this is largely due
t o one animal.
A ppar erit17 liypc r th ;vroidism clo e s 110t g ~ tl
i y
i a ffcct the
amount of gonadotropic hormone i n t h r blood. Therefore
sucli postulate\ as excessive excretion 01-destruction of this
hor-rrionc do not account either for t esticnlay hgpofnnction,
or Iailure of tlie testis to ~ c ~ s p o ntod injection of gonadotropic
hormones in Iryp,erthyroid animals.
DIRC’TRSIOS
Kxperimciits reported liere clearly demonstrate that injections of thyrosiii o r feeding oP thyroid gland has R deleterioiis
effect on both the condition of tlic acccssoi*ies and sperm prodiiction. H-\.pogonadism is apparent not oirly i n those gi’oups
receiving such large amounts of thyrodn as to affect their
geiieral body size, but also i n those receiving such minimal
doses a s to cause 110 weiglit loss. This is of especial significance in relation to the concept that any sldrersc effcct that
tllyroid feeding has on the reproductive sT-stem is secoIrdary
to the deleterious effects on the bodr as a idiole. In these
experiments the effect 011 tlie reproductive system is roughly
proportional to dosage and loss of body \wiglit, but is inclependent of a general body clwline.
The castrate condition oE the accessories does not scem
entirely explained I)? decmascd cfiectiveness of testis hormone since 5 units of male hormone gave, in a few instances,
slight stiinnlatioii in the 2i~pcrthyroidcastrate. 12 reduction
of this degree in the effertiveness of male liormo-ne suggests
that the amount sc~creteclalso is reduced. This explanation
accounts for. the marked depr. ion of the accessories of
hyperthrroid males.
Groups iweiving the lighter thyroid dosages reveal a n int e ~ e s t i i i gdifference in tlie reaction of gametogenesis and
accessories to hyperthyroidism. Sperm production of groups
receiving ligliter thyroid dosage was but slightly affected,
whereas their accessoriw were of castrate type. Since hyperthyroidism decreases effectiveness of both gonadotropic and
TIITI k X 4 ’ 1 U X I C 4 L BtCOHD \ O r
‘ii h O 3 AhY
S T I’PI,FDIFVT T O
2
290
GEOEGE R. SMELSEB
testis hormone, the accessyries must reflect a decrease in
amount as well as potenq- of testis hormone. Sperm production, however, is affected only by the gonadotropic action,
thus explaining tlie greater sensitivity of the accessories to
hyperthyroidism.
It would seem that testicular suppression in Iipperthyroidism is due i n part to reduction i n available gonadotropic hormone. The reports of Evans and Simpsoii ('30), Van Horn
('31) and Cohm ('35) that thyroid feeding caused an increased gonadotropic potency of tlie liypopliysis of male and
female rats, removes the possibility that a deficient pituitarjgland is responsible f o r tlie testis condition. Indeed, Van
Horn suggested that the increase in anterior lohc potency of
the femalc rat was in reality due to decrease iii ovarian hormonci, making the pituitary change a secondary one. A
morphological basis f o r the increased p o t e i i c ~of these hypophp e s has been reported { Severinghaus, Smelser aiid ("lark,
'34). The basophiles were of maximum size, markedly. increased in number, and castration cells numerous. The hyperthyroid r a t basopliiles resemble those of a castratp. The
injection of qoiiaclotropic extracts prevented the castrationlike changes in the accessories and the structnral alterations
i n the hypoplipsis. (Unpublished observation of Scveringliaus
and Smelser ) . -4pparently basophilic pituitary changes in
hyperthyroidism are secondary, che to decreased testicular
actix-ity.
The paradox of a 1~Spofuiictioning.testis i n thc presence of
a11 exccssivcly potent pituitary gland may bc explained hy the
decrease in the effect of gonadotropic liormoiics i n hyperthyroid animals. Schoclmert ( '31) and Leonaid nn(1 Hcuisen
( '26) showed that certain gonadot ropic hormones were more
effective in thj-roidectomized animals, a n d coin~crsel-,tliat
t h e r a r e less effect is-e in hyperthywid female rats, was cleinonstrated by Fluhmaiin ( '34) a i d Tyndale and T,evi~i ( '37).
The present study extends this finding to the male. Small
dosngcs of gonadotropic liormones are witliout el'fwt on the
testis weight of hyperthyroid aiiimals, althongh large amonnts
TXSTICUI,A€I FU NCTIOK I N HYPEEtTHYI;OIDlSM
291
(25 R.U. clailp) of Aiituitrin S maintained the testes of hyperthyroid animals. Since the condition of tlie accessories cann o t be taken as reflecting only interstitial cell activity, because
of tlie decreased effectiveness of testis hormone, decisions
regarding action of pituitary hormones on the interstitial
cells of liyperthy-oid animals must rest on rather an insecure
f omidation. Examination of his tological seetioiis s a g p s t s
that both the tabules and interstitial cells are involved in
hyperthyroidism, The sensitii-ity of the accessories to small
amounts of thyroxin and the action of male hormone in hyperthyroid eastrates likewise support this view.
Rciss and Per6ny ('as),Van Horn ('31, '33) showed that
thyroid feeding increased tlircefold tlie amount of estrin
necessary to produce vaginal cornification in tlic spayed rat.
A comparable, though more extreme, situation exists relative
to the male sex hoymoae, for R daily injection of 5 B.U. had
little or no effect on the liyperthproid castrate, diereas, in
the normal its effect is appreciable both grossly and histologically. Thyroxin is without effect on the accessories of
castrates, indicating that atrophic accessories of hyperthyroid
animals are produced through modification of theiP response
to endocrines, and not through a change in their basic morpholoLq.
The present data do not oltf'er any explanations of the m u s e
of decreased response to male hormone in hyperthyroidism.
The determination of thc presence of gonadotropic material
in the blood of hyperthyroid animals offers ail explanation
of the mechanism by wliicli experimental hyperthyroidism
affects the testis. The data sliox- that, even in the extreme
hyperthyroidism produced in these cases, amounts of goriadotropic material were found in the blood of lipertliyroid animals equal t o that circulating in normal castrate litter mate
controls. Thcse facts dispose of the postulates that tlie gonad
condition is due to such lioumones heing excreted or destroyed
at an cscessive rate. With the eliinination of these lippotheses,
the most reasonable coiiclusioii seems to he that thyroicl administration decreases the ~*eaetirityof the end orga~i,the
testis, or raisecl the tcsticular thrcshold of response to goiladotropic hormone.
Tlic conti~idictoryreports corice.rning the effects of hypertli>-roidism can, in a large measure, he harmonized on the
hasis of these experiments. The e€fect of thyroxin o n testis
weight ranged from a slight gaiii t o a marked loss, depending
upon the dosage used, and suggest that some of the conflicting
reports a r c clue t o differences i n degree of thr hyperthyroidism iiidueed. Xaintenance of the game togenesis xiicl accessories at nearly normal levels in hy-pei*thproid animals by the
injection of gonadotropic material fits in me11 with the report
of Abclin and T i e d m e r ('32) that admiiiistmtioii of goiiadotropic extract produced vaginal c~oniificationdiiriiig the cliestrus induced by liyperth yroidism.
T t is extremely difficult to correlate some of tlie conditioiis
existing in the hyperthyroid male and femulc rat. In the male
the gonad picture is one of decreased secretion of glands and
effectivencss of hormones. Thp+oid feeding lengthens tlie
estrous cycle of the female (Cameron and Amics, '36 : IVnng',
'27; atid Van Horn, '31, ' 3 )but
, this is due to a n iiicr.ease in
l h e function of tlie corpus hitcum (Weicltert, '30). Weicherb
and Boyd ('33) suggested that ark increase iii pituitary secretion might be oric explanation of the active corpora lutcsa.
No such increase is noted in thr gonadotropic content of the
blood of Iiyperthyroid castrate males.
I n conclusion, it may be said tliat experimentally iducecl
hppertliyroidism in male rats adversely affects the r r p ~ o d n c tive system. Hypertliproidism acts in at least tsi-o ways.
First, the testis hormone present is less effective, causing
reduced secretory activity of accessory oi*gms arid castration
changes in the hypophysis. Second, the gonadotropic liormones a r e less effective resulting iii a rccluctioii in number of
sperm and amount o f testis liormonp produced. The latter
is bronght about by clecreased reactivitT of the ~ i c organ.
l
ST'lllblARY
1. Administration of thyroxin or dried tliyroid gland causes
a decrease in testis weight, sperm productioii, and liormone
secretion, which is iiot duc to injury to the body as a whole.
2 . If thyroxin Ireatmcnt is discontinued a rapid and complete recovery ensues.
3. Normal tcsticnlar function may he maintained during the
hyperthyroid period by injection of gonadotropic extracts.
4. There is marked decrease in cffectircness of gonadotropic hormones in hyperthyroicl males. Both hornioncs seem
similarly affected, tliough evidence is more conclusivc relative
to the gametogenetic factor.
5. The amount of testis hormone required to stimulate the
acccssories of the castrate rat is incrcaiecl in hyperthyroid
animals.
6. Hypcrthyroiilism does not affect thc amount of gonadotropic hormonc found in the blood of castrates, tlnis inclicating
a norrrial secretion rate, nncl that exci.etion or dcstmction of
thc hormones is riot exaggerated.
7. Testieular hypofunction in 113perthyroidism may he cxplained by n decrease in the ahility 01the testis to respond
t o pituitary horniorics, o r an iiicreasc in its threshold to
gonadotropic h o rmone s.
I wisIi t o express my appiw$atioii t o Dr. P. l3. Smith €or
his interest a i d enconr-agement.
LI'I'HRATU R E C I T E D
ABELIX, I., AND F:. W m n u r x 1932 ficliilrltlriiso iind Ortiririm. -4rc11. f . E q .
Path. u. Phnrmak., Bd. 166, S. 584-591.
U E IA~ -E K E T Z,
S. 1938 f%er die Wirkung dcr TIiS'"eokriiifiitterungr anf die
Hoden dry wciisen Ratten. h a t . A m . , Bd. 65, 8. 155-161.
CAXE;ROS,G . R., A K I ) h. B. P. Ani~s~s19% Thtt effect of thvroid fceding OIL
t h c oestrous cycle of the giiinw pig and miec. .i\ustralian J . Exp. Iliol.
and Mcd. Scienccs, vol. 3, p. 37.
CAxmon-, A. T., AND .J. CARMICHAEL1920 Contributioiis t o tile biocheiiiistry of
iodine. 111. Tlir coiripar:itivc effects of thyroid and iodidc feeding oil
g r o w t h i n n.liitz rats and i n rabbits. J . Biol. (-'lit=rii., vol. 4.5,111).60-10U.
294
GEOIlGE K. XMELSER
ROSE :$. 1933 Effect of expe~iriientall.; prodnccd 11) pei*th:-roidinm upon
the reploductire and asso&dted organ.; of the male rat. Am. J . Anat.,
vol. 5 6 , pp. 143-139.
COC-KEIER,
R. 1921 -kctinil de l'iiigestion de corl~sth:, roidc sur glandc germinat i r e male. C". R. Soc. de Riol., T. 85, pp. 4X4-486.
1918 Xrtion de l'iiigestion de corps thyroide sur lo thgrnus snr le
testieule et siir la thyroidc. Contributioii A 1'liistophysiologie thproidicnnc. Rev. Franc. d'Endoerin., T. 6, pp. 10-45.
The effect of feeding desiwnted thyroid
]>)A COSTA, R., AND A. J. CAXLSON 1933
upon the sexual maturation of the albino i a t . Am. J. Physiol., rol.
104, pp. 247-252.
Enfmu, F. E. 1932 The anterior pituitwrv sex I~orrnoiiein the blood and urine
of rats. -4111. J. Physiol., vol. 101, pp. 2U-250.
EVANS,
H. &I., A N D M. E. SjrnrPsoN 1930 Some effects on the lippnphysis of
11: per- and 11) p o t ~ ~ ~ ~ o i r I i Anat.
n r r ~ . Rec., vol. 45 (SlqqJl.), p. 215.
>'LUIIMANN, c. F. 1934 The inflnence of the t h j r o i d 0 1 1 the action of gnnadstimulating hormones. Am. J . Physiol., rol. 108, pp. 408-508.
GUDRRNATSCH,J. I?. 1915 Fcediiig experlinents oil rats. Anat. I<r.e., vol. 9,
pp. 78-80.
H~XSEN
I., €3. 1933 R a t semind vesicles a n d prmttate glands as qimntitative
indicators of testicnlni hormone. Endocrinology, rol. 17, pp. 163-17!).
HE~RKING,
P. T. 1!117 The
ion of thyroid upon the gron-th of the body and
the o r g a i ~of the d i i t c rat. Qiiurt J. Exp. PliTsiol., \ol. 11, pp. 131CoTiEN,
253.
H O ~ K I NE.
S , R. 1916 The growth of the body and organs of tlic albino rat a s
affected by fecding various ductless glands (tlrproitl, tliyniiis, hypo,011ysis and pinral). J. Exp- Zool., rol. 31, p p 295-3413.
Iscovr,sco, 11. 1913 Action physiologie en particnlier sur la rroissaiire d'un
lipoid extrait de In thyroidc. C. R. Soc. de Biol., T. 7 5 , pi). 3G1-363.
LEONARD,
8. L , AKD I. B. HAKSEN 1936 Jnfliienee of thyroidectomp nil cffectireness of ~.onad-sti~iiulatiiig
hormones. Anat. Kec.. vol. 61, pp. 203-209.
JfOORE, C. R., 1). PRICE
BND T. F. ~ A ~ U S G H F 1930
X
Hat-proStatC CytOlogy XS a
testis-hormone indicator and the p~eventioiiof castration cliangcs by
testis-extract injections. A J ~J.. a n a t . , 80l. 4.7, 13 71.
XON'PE:KOPSO,
E. 1912 L'azione dcl diginno c dell 'rstratto seern di tiroide sulla
struttura dell 'rpilio del tulm scininifei o del topo. Arch. dc Kiolngie,
1'. 28, pp. 35-62.
PRICE,
DORO~~HY
1936 h-nrinal dere1o~)irientof tlrc pwsta ti, :md seminal vcsiclcs
of the r a t with a study of espeiimeiital post natal niodifieations. &\in.
J. Anat., vol. 60' pp. 79-127.
REIYS,31.. A N D S. PERCPI'Y1928 Thyreoiclealrori~in~i
und Hriinut. Endnkriiiologie,
Bd. 2, R. 181.
SPHOPKAERT,
J. A. 1931 Influciice de la. thyroideetoinie sur la rbpoiise des
testiciiles et du s i & m i e genital secondaire male niix injections de m b stances 1)r-6liypoph~
mires c h r z lc rat. Pomp Ikmd. Roc. d r Biol.,
T. 108, p. 431.
TESTICULAR FUNCTlOX I N HS’FEl1THYBOlDISM
295
SEVERIXGHAUS,
A. E., C:. I<. SYI~!LLSFR
.L\C H. If. CLARK 1934 Anterior pituitary
c*hanges in adult male rats following thyroxin injections or thyroid
feeding. Proc. Soc. Exp. Bicil. 2nd Mcd., xol. 31, pp. 1123-1127.
SX!LLS%,Ci. K. 1933 Compensatory Iiypcr-actinty of tlic testis following uni
lateral castration. Anat. Rw., vol. 57 (Ruppl.), p. 2X.
1937 Testieular fnnctiori i n h ~ p c r t hroidisrn.
?
Anat. Rec., vol. 70
(Yuppl.), p. 63.
RAIPI.SEIL, G . K., d ~ 1 )11. M. CLARK 1936 Age differciicc in onset of gonadal
endocrine activity in male and feinale rats. Annt. Rrc., vol. 64 (SnppI.),
p. 41.
YYXDALE, 13. IT., AUD 1,. L ~ I K1937 Ovarian IGeight response t o menopause
urine injections in noimal and h ~ p o p h ~ s e c t o m i z eand
d
hypophysectomized thyroxin treatcd irninnturc rats. Ani. J. Physiol., vol. 120,
pp. 486-493.
TANHORN.W. &I. 1931 Relation of the thyroid to {lie h)popliysis a n d ovwy.
Anat. Hec., 1701. 51 (Suppl.), p. 38.
1933 Tho rclation of tlir thyroid to the hypophysis a n d o w r j .
Endocrinology, vol. 17, pp. 150-163.
WANG, G. IT. 1927 The cffrct of thyioid feeding on Ihe spontancous activity of
the albino rat and its relation to ncco~npnn.yingphjsiological changrs.
Hull. Johns Wopkins Rosy., vol. 40, pp. 303-317.
m 7 ~ AC. h~’. ~1930
~ ~Effect
~ ~of experimental
~ ,
Iiyperth>roidisni o n reproductive
processes of female albino rats. Phqsiol. Zool., vol. 3, 1). 461.
% r ~ l ~ C.
~ K..
~ ~AND
~ iR.: W. K o Y o
1933 Induction of typical paeudopregnancg
in the albino r a t h? means of cxpciimcntal h3pertligroidism. Anat.
Rec., oot. 68, pp. 57-69.
WIESXER,B. P. Iq34 The post-natal de\elopment o€ the genital organs in the
albino rat. J. Obst. anit Gyi. of the Brit. Empire. vol. 41, 11. 86;.
193.7 The po8t natal t1exeloj)ment of the geuital organs in tlir alhino
rat. J. Obst. and Gpn. of llic Biit. Eiiipiie, rol. 42, p. 8.
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