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Some effects of testosterone and testosterone-propionate in the rat.

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80ME EFFECTS O F TESTOSTER,ONE AND
TESTOSTERONE-PROPION-4~~~
I N THE RAT'
CARL R. XOORE AXD 1)OHOTHY P R l C E
Illull Zoological Laborulory, The rnir:erszt!/ uf Ckicayo
The availability of androgens as piire chcmical compounds
makes it possible not oiily to compare their effects i n the
orgaiiisni with the effects of hormones secreted bg- the testes
hut also to extend oiir knowledge of their action. It is important, therefore, to study closely the coniparatirc responses
of the organism under the influciice of naturally secreted horinoiie and the pure chemical substances, and o u r earlier studies
011 androsterone (Noorc and Price, '37) a r e continued here
with the utilization of testosterone and testosterone-propioiiate.
Appropriate procedures provide at least a rough ineaiis of
determiniiig chanyes in the secretory activity of the normal
testes.
The present brief report of expcrienccs with these two pure
chemical substances is based upon a careful study of more
than 200 albino male r a t s born i n our breeding colony. Since
inevitable variatioii is believet1 to he less among litter males
than amoiig animals clioseii at i-aiidoni our judgment of effects
has been based upon differences eshibitecl withiii the litter by
treated a s compand with untreated animals.
It is a gciiuiiie pleasure to ackiiowledge the courtesies exiendecl (luring this study by Dr. Gregory Strag-nell of Schering
Corporation in supplying the pure synthetically prepared
aiidrogeiiic compounds.
This invrstigstion has h e m airled hy
:I
grant from the Rockefeller Foundation
to The University of Chicago.
59
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60
CARL R, JIOOItE ATSD DOROTIIY P R I C E
A . EFFECT8 I N ChS'I'RA4'l'E M A L E S
The determination of effects of testosterone and the propionatc have been based 011 fresh weights of indiridual parts as
corripared with those recovered from normal litter mate
controls, aiicl upon the histological character of the tissues,
especially the ventral lohe of the prostate gland and the seminal vesicles. J17iththe aid of a binocular dissecting microscope
all tissues have been removed immediately upon sacrifice of
the animal and weighed to fractions of a milli;oram on a
torsion balance, after careful removal of all fat and coiiiiective
tissue.
Tn young males sacrificed on day 15 or earlier, daily injection periods residted in R precocious development of the accessory organs as judged by weight increases, and also by a
precocious secretory cliff erentiation ; seminal vesicles, which
normally show m a k secretion granules only about day 35 or
later, differentiate into a secretory type of seminal vesicle by
day 18 that is indistinguishable microscopically from that of
mature adult males. Daily injections of 0.4 mq. testosterone
into males after castration on day 15 and sacrifice on day 35.
result in seminal vesicles weighing 19002, more than those
of untreated litter mate controls. Testosterone propionate,
as will be showii below, is even more effectire.
The microscopical character of the nownial and castrate
prostate and seminal vesicle of the r a t has hcen descrihed
earlier (Moore, l'rice and Gallagher, '30 ; Rrooi-e, Hughes and
Gallagher, '30). Tt may be mentioned in general that 110th
tesosterone aiitl the propionate in eff ectire doses pither maintain the normal secretory state of these organs in castrated
males of m y age, or restore long-time castrate tissues t o the
normal secretory state. No qiialitative differences have appeared in these ti ssiies conditioned by chemical ancliwgeiis
that would distiiijiuish them from tissues of normal males
wlien proper dosages are employed.
On adult males, clowges of tesosterone and the propionate
required for testicular replacement have heen determined
from daily injections begun immediately after castration and
EFFECTS OF TESTOSTEBOKE IN T H E RAT
61
continued f o r a period of 20 days. ‘l’he two criteria eniplo-yecl
to determine tpsticular replaccmeiit, and Iqrcseiiting different dosage rcquirpnients, have been 1) thc qnantity of substaiice adniinisteretl daily that is necessary t o maintain ilie
hi st ologi cal n 01-inalitp of tli e vent 1-21 pros t at c aiid wminal
vesicles ; 2 ) the daily dosage requirement f o r maintpnance
of the noi-ma1 fresh weight of the st~minalvesicles. llcqniwrneiits for. the second inclicator a r e usually ahout three to four
t inies reqaiiwnen t s for niaiiit emrice of liist ological 110rmalitv.
H isf ological
210
w2aZity
Histological norniali ty of the ventral prostate consists in the
mairileiiarice or production of an active secretory epi theliurn
in aciiii, the cells of 11-liich contain well-defined light areas
marking the position of the Crolgi apparatus miclway between
Ihe nnclcns a i d luminal end of the cell. Such diagnostic light
areas make their appearaiice in ventral lobe cells nbont day 13
(Price, ’36) ; they are promiiicnt from day 30 throughout the
hormone sccreting period, and in adults they disappear ahout
the fourth day after castration. They are clearly renxded in
tissues after Eonin fixation and Harris hematoxyliii stain.
Histological normality of seminal vesicles consists of the
~ ~ r e s e n cofe a lining epithelium of high columnar cells coiitaining definite secretion granules, surrounded hj- clear ‘halo’
areas in stronger preparations, easilv demonstrated by Fouin
fixation and Ehrlich ’s liematoxylin stain. These graniiles
make their first appearance ill normal animals about days 35
to 40 depending upon the state of hormone secretion, or degree of maturity, and in castrates they disappear approximately 48 hours after castration.
More than fifty animals were utilized in the determination
of dosage requirements of testosterone and the propionate t o
maintain a normal histology of the ventral prostate and
seminal vesicles in castrated adults, as wcll as requirements
to maintain uoimal weight of seminal resides. Ventral prostates required from 30 t o 50 gamma daily of testosterone for
62
CARL B. N O O R E A N D DOROTHY PRICE
histological normality and the lowest effective dose of propionate was not determined. Seminal vesicles contained melldefined secretion granules with a daily dose of 200 gamma
testosterone and with somewhat less than 50 gamnia of propionate. Xaintenance of seminal vesicle weight in adults was
obtained with 600 to 700 gamma daily and with 150 gamma
of propionate.
Growth maiiLteiaarirf: of seilziiaal r e s i d e s . It early became
evident that dosages of clicniical androgens required t o maintain the growth of seminal vesicles equal to that of iiormal
litter mates diff'ered with agc of the animals. The observations 011 one litter consistiiig of seven males, the castrates of
which ~vei-etreated ~t7ithtestostcroiie between clays 30 and 50
TABLE 1
E f e c t s of testosterone in c n s t r d e d mts. CartratiaiL day 3D; iiijertions (Tail!/ days
30 t o 4 9 ; sacrifice day 50
T v P i g h t , &!rams
Cast. 0.1 nig.
Cast. 0.2 rng.
Cast. 0.4 mg.
Cast. control
Cast. control
Norm. control
Norm. controI
'rota1
prostate
complex
Seminal
Per cent change
vesicles
from normal
0.1:354
0.3337
0.4416
0.0384
0.0501
0.1166
0.1971
0.0188
0.1606
0.4504
0.0054
0.0066
0.0257
0.0454
S P ~ w
. s.
-
47
+ 352
+1168
Prostate A C
ves. ratio
~ .
7
2
0.9
7
7
4.5
4.5
are presented in tahlc 1 as an example of treatments given
othei. litters of different ages. Ten litters iiieliidiiig more
than fiftr males have been aamined directly for these determinations and many animals of litters used for other
purposes afforded additional data. For each litter the period
of treatment was 20 days with injectioiis of castrates beginning immediatelp after operation, the litters being sacrificed at ages 35 t o 90 days; the rat is essentially mature bp
the eightieth or niiitieth day of life, since it ~ a d i l sires
~ 7 young
and has attained a mature prostate-seminal vcsicle ratio.
Attention t o table 1 reveals the average seminal vesicle
weight of two norrnal males on day 50 to he 35 nig. in comparison with 6 mg. in untreated castrates. Seminal vesicles
EFFISCTS O F TESTOSTERONE IN T l I E RAT
63
of the castrate receiving 0.2 nig. testosterone daily showed
a weight increase 3 5 2 7 . greater than the normal litter mate
average, but in tlie one receiving 0.1 mg. daily the seminal
vesicle weight was 47% below that of the normal controls.
Other litters i*evealed that the growth-replacement dose of
testosterone between the thirtieth and fiftieth day was approximately 0.15 mg. daily. Tn table 2 a summary of observations is given f o r replacement dosages f o r both testosterone
and t-proprionate f o r different 20-clap periods during the age
of most rapid growth of reproductive parts. It can be seen
that whereas 0.1 mg. daily dose of testosterone serves a s an
adequate substitution f o r the testicle in promoting growth of
seminal vesicles from day 15 to dav 35 it requires a daily dose
TABLE 2
Daily d o s a g m for growth ntainteitmre of .wminnl ~estkles,darinq 2;arzoim
dO-dny p e r i i d s
. l u t o p v i N B P . d a ~ s TmtmteronP
3 ri
60
60
70
80
90
-0.1
mg.
0.15 mg.
....
t 0 . 3 0 mg.
+0.60 mg.
....
1' p r o p w n a t e
....
0.05 rng.
0.08 mg.
0.08 mg.
0.15 mg.
0.15 mg.
of slightly 111ore than 0.6 mg. between days 60 and 80 to maintain growth of these organs i n castrates equivalent to littermate controls. A similar trend is shown f o r t-propionate but
dosage requirements a r e much below those of testosterone.
The greater effectiveness of the former lias been pointed out
by most workers nsing these substances.
Pmstate-seiniizal vesicle ratio. The question is pertinent
whether testosterone or tlie propionate has a selective effect
upon one end organ or provides a general stimulation equivalent to that of testis-secreted hormone. This question was
examined by Moore and Price ('37) with respect to the effects
of androsterone, basing judgment upon a n analysis of the
relative weights of the total prostate complex to the seminal
vesicles. I t was determined on normal males of different a p s
64
C d R L B. MOOKE ANU D O l t O T l i Y PlZICE
that the pl.ostate-seaiiiia1 vesicle ratio value prior to the onset
of intensive hormone secretion was high aiid as testes secreted
more hormone tlicre was a gradnal decline from a value of
10, 01- greater, t o a value of 1 at an age of approximately
SO t o 90 days. Xubsequeiit to this period a i d throughout re~~i*oductive
life this value constituted the normal onc, and
whereas tlie ratio value declined with approach to maturity
i t was surprisiiigly coiistant f o r the litter. T i 1 tabIe 1 the cletermination of the prostate-seminal vesicle ratio is included
f o r oiie litter. Iii this litter sacrificed on day 50, each of two
normal males showed a ratio valile of 4.5 whereas the value
for two castrates was 7. Tlie castrate injected with doses of
testosterone inadequal e t o maintain normal growth of seminal
vesicles (0.1 mg.) revealed a ratio value greater than that f o r
normal litter mates but a second castrate receiving a n excessive dosage (0.4 mg.) exhihitecl a ratio value much below
the normal for the age arid eiitircly equivalent to that of
mature adult niales (0.9). Thc dosage of 0.2 ing. WRS more
than sufficient for testis substitution (seminal vcsicle wciglit
352% above coiitrol ) aiid gave it ratio value approximating
tliai of maturity. Whereas i n this particnlar litter an exact
~i.offth-substitutioiidosage WRS not injected, other litters have
sliowii that similar t o the cff s of androsterone, testosterone
a n d tlie propionate in substitioiial tloscs proclncecl a prostateseminal vesicle ratio value equivaleiit to normal litter mates.
This again emphasizes the effect of the chemical androgeiis
as equivalmt to that of the natnrally secreted hormone insofar.
a s these methods a r e capable of demonstrating. Wit11 adequate replacing dosages they fail to exhibit a more selectivc
stimulation on one end organ than does norinally secreted
testis hormone.
P r ol o uged o f w t s . T h e (1 u e st i on 1 v . hth
~ e 1- oiie compound
exerts a prolonged effect on the mammaliaii end organs mas
briefly investigated by a study of the microscopic condition of
tissues from forty adult males. Precautions were observed
in injecting dosages of androsterone, testosterone and tpropionate into castrates for periods of 20 days that would
EFFECTS O F TESTORTRROWE I N THE RAT
65
maintain the iiormal semiiial vesicle weight and not represent
many times the actual requirements for this purpose.
Wliereas weights of tissues mere cilrefdly recorded, cliief
dependence was placed upon the histological state of the
prostate and seminal vesicles.
In ordinary mitreated castrates, i n which the hormone
soiirce is completely eliminated at oiice, marked castration
caliaiiges appear within 4 days in the prostate and earlier i n
seminal vesicles. Injection of chemical androgeiis in an oil
solution naturally provides residual unabsorbed active
material for some time after thc last injection.
Castration chaiigcs similar to the 4 - h untreated
~
castrates
appeared usnally by the sixth to seventh day after the last
injection of androsterone and testosterone but injections of
testosterone pi’opionate produced effects observable for
slightly longer periods after discontiriuaiice of injection.
Thus in one group of twelve adult males of similar age
and size, but not litter mates, ten were castrated and injected
immediately with 0.2 nig. l-propionate daily f o r 20 days.
Two injected castrates and two untreated normals were sacrificed 1day after the last injection when it was determined that
seminal vesicles of injected castrates ~ w r e70% heavier than
those of the untreated males (avcrages of two each) ; thus
the dosage f o r all iujected animals wab slightly in excess of
a replacing close. Histologically the prostates and seminal
vesicles of the normals a i d injected castrates were indistinguishable. Two injected castrates were sacrificed thereafter on days 5, 10, 13 and 17 after the last injection. The
prostates and seminal vesiclrs of atiininls killed 5 clays after
the last injection mere histologically normal but those sacrificed on day 30 sliowcd decided castration changes ; those killed
13 and 17 days after the last injection revealed castration
changes approximating those found in ordinary castrated
males on about day 10 following operation.
In a second group of eight males (litter mates) six were
castrated on day 70 and injected daily until day 89 with
0.1 5 mg. t-propionate, n-ith sacrifice of two untreated normal
66
CARL El. MOORE AND DOROTHY PRICE
and two injected castrates on day 90 (1 day after last injection). This dosage proved to be almost an exact replacement
dose since average weight of injected castrate seminal vesicles
was only 19.h heavier than those from untreated normal
males. Histologically, prostates and seminal vesicles from
the normal and injected males were indistinguishable. Two
injected castrates were sacrificed on days 8 and 11 after the
last injection. By the eighth day definite castration changes
were evident and by the eleventh day a grade of involution
was present that would correspond to approximately the
eighth day of castration in ordinary untreated males.
Thus testosterone-propionate administered in approximate
replacement doses, and not in large overdoses, shom-ed but a
slight prolongation of effect. Ordinary untreated castrate
males attain a degree of castration change on the sixth to
eighth day in the prostate and seminal vesicles that makes its
appearance on approximately 8 to 11 days after the last of a
series of injections. This slightly prolonged effect of not
more than 5 to 6 days at most is probably due in part at least
to slow resorption from oil residues in subcutaneous pockets
hence it appears fair t o conclude that prolonged effects in
the castrate rat are not evident for more than approximatel>3 days.
Iwitiafion of copzclation. Testosterone-propionate mill not
only maintain or repair accessory reproductive organs in
castrates but its administration results also in the awakening
of desire and ability to copulate when castration has been
performed before germ cell production.
Three males of a group of five mcre castrated on the
thirtieth day of life and caged with two normal controls for
a period of 6 months. TWOof the three received 22 daily
injections of t-propionate, one 0.5 mg., the second 1.0 my.
daily; the third castrate was maintained as an untreated
control. Within 2 weeks from the first injection the two
treated males exhibited a normal response to females in heat
and executed repeated and vigorous copulations with pjaculation; the untreated castrate showed no interest in females.
67
EFFECTS O F TESTOSTERONE IIS THE BAT
When sacrificed the day following the twenty-second injection
average seminal vesicle weight of the two treated castrates
was found to be 828 mg. as compared with 5 mg. for the UIIinjected castrate (increase of 16,00070) and 740 mg. for normal
controls (increase of 11%).Daily treatments with 0.5 mg.
apparently induced a maximal growth response since 1.0 mg.
doses gave a similar seminal vesicle weight.
I n this group, therefore, males castrated prior to the onset
of hormonal activity arid remaining as castrates from 30 days
to an age of 7 months, were induced t o develop into a state
such that the copulation pattern was entirely characteristic
of normal males and the accessory organs had developed
slightly above the normal controls a s a result of the 3 weelis
of treatmen 1.
TABLE 3
Effects of t propionate i n normal male ruts. Injections, days 20 to 99;
sacrifice, day 40
Dad# dose
0.05 mg.
0.10 mg.
0.80 mg.
1.00 mg.
Control
Control
T'estG
weight,
Per rent
ilecrpaRe
PPnt.
from
pro>t.,
rant rol
gram3
0.3538
0.3140
0.7474
1.0228
1.2110
1.3146
-72
-75
4
-s9
0
grnm-?
0.0664
0.1026
0.1824
0.1848
0.0432
0.0386
Per c e n t
increaae
over
control
61
150
300
350
Sem. v e s .
w?iEht,
gromv
0.0910
0.3126
0.7090
0.8156
0.0106
0.0118
Per cent
increase
0 7 ~ -
co7rtrol
712
2691
6230
7182
B. EFFECTS ON THE TESTICLE
Data were obtained on thc effects of tlicse chemical anclrogens on the testicle from eighteen littcrs of animals consisting
of more than eighty-five males, the majority of which receirrcl
treatments with testosterone propionate. I n each litter the
injected members were compared with their normal brothers
and the 20-day periods of treatment were so ari-aiiged as t o
terminate within the first 80 days of life which covers the
prepuberal pcriod.
I n table 3 will be found sonie details from one litter sacrificed on the fortieth day of life subsequent to a 20-day period
of injection with four dosagc levels of tedtoRteroiie-prop ion at^.
68
CARL B. 1IOOP.E AND DOROTHY P R I C E
It can be noted that testis mcights f o r each of the four treated
males were appreciably below either of two untreated litter
mates. Compared with tlie average normal testis weight that
of the male rewiviiig 0.05 mg. clailp sliowed a recluctioii of
72%, 01- weighed 28% of normal, d i e r e a s treatments with
1 .O rng. daily reduced testis weight by but 19%). This production of less and less damage as the dosage is increased has
been quite characteristic especially f o r the propionate. The
80
,
1
I
20
30
40
50
_ _- - 7
60
70
80
DAYS
Fig. 1 Effect of testosterone proIiionate i n suppression of testis gromtli.
Ordinate represents yerceiitage dccreake in freali weight of testis ; abscissa.
r e p = s e n t s age in d : r y at autopsy, precrtl~d1))- x 20-day pcriod of injeetion. Each
point sl~owspercentage decrease in testis weight i n treated males a s compared
with normal u n t r e a t e d litter mates. Amoiint n f daily adinini~trationindicated
611
curves.
effects 011 the accessory organs have berii usually one of increased effect with increased dosage. In the litter under eonsidcration ventral prostate -creight increascs above normal
controls were from 6lF1to 350% and serriiizal vesicle increases
were from 712% to 7182%,.
The effects on the testicle of four dosage levels of t-propiouate €or diffcreiit 20-day periods h a r e been summarized in a
graph (fig. 1) each point 011 which represents percentage
EFFECTS O F TESTOSTERONE I N THE BAT
69
change in testis weight determined from comparisons with
normal litter mates.
Coiisicleriiig tlie general aspects of this graph, and that of
numerous cases with a dosage range from 0.05 mg. to 1.0 mg
and riot represented on the graph, it becomes evident 1) that
testosterone-propiorlate in illis dosage range iiiduces niarked
loss in testis weiglit. This is evident in twenty-one of the
twenty-two treated males represented. One litter exception
occurred in which the injection period was 11 instead of 20
days (8 to 19) ; in this litter tcstes i'roni three treated males
were slightly heavier than those from the two control males.
2 ) In general tlie injurious effects appear iii the reverse order
rather tlian parallel with dosage since usually 0.05 mp. tpropionate induced iiiore severe injury than 1.0 nig. daily
doses. With ordinary testosterone, iiijuries a r e iriducetl with
similar dosages but the reverse order of effects with dosage
is less appzirent. 3) Tlie harmfiil influences npon the testis
appear to climiiiish as the animal approaches maturit!:.
This
is evident not only from the qraph of effects after propionate
treatment but it is likewise evident after ordinary testosterone.
1'11~stestosterone in daily dosagc.s of 0.1 rng. 0.5 mg. and
1.0 mg. aiitl sacrifice on day tjO canset1 a decrease in testis
to 67% in contrast to sacrifice on day 70
weiglit of from
in whicli decreases of but 9% a i d 13% were recorded.
Two males receiring 2.0 mg. t-propjonate daily froin days
70 to 90 registered deereases of but 1%and 10%).
The effect upon tlie testicle indicated by decrease in weight
iiivo1.i.e~real tissue damage i n the more severe cases. In
testes just approacliing the period of spermatozooji differentiation tubul es a r e much reduced in size and show considerable
sloughiiig of cells into the lunien. Treated males having atlaiiiccl the age of spermatozoon differentiation may show proiiouncecl delay in devclopmeiit as well as considerable actual
injury. The treatnient does not prevent the testes from ultimately diffcreiitiating spermatozoa since considcrable weight
reduction may he accompaniccl b:! a few tubules with spermatozoa though the percentage of tubules reprcsenting such clcvelopnient is marItecllp less tllaii the controls.
TO
CSRL R. MOORE AND DOROTHY P R I C E
In order to determine wliether testosterone or t-propionate
exhibited any tendency to stimulate spermatogenesis a number
of litters were SO injected a s to provide sacrifice on approximately day 32 since by day 36 untreated males possess tubules
showing the ‘sperm-head’ stage (Moore, ’36). No evidence
has been forthcoming that either of these chemical aiidrogens
stimulated spermatogerietic activity and detectable inflneiices
in every case 2iare heen of an injurious ratlicr than a stimulating nature.
DISCUSSIOS
The comparative effects of the chemical aiidrogeiis, testosterone and testosterone-propioIiate, and normally secreted
testis hormone are remarkably similar when prostate gland
and seminal vesicles of rats are used as the test objects. These
substances are capable of producing any grade of effect from
barely detectable responses of the end organs7 t o conditions
indistinguishable from iiormal litter mates, or to marked
precocious growth and secretory responses when appropriate
daily dosages are employed. Whereas qnttlitative differences
in effects of these two chemical substances have failed to he
noted in this study the quantitative cliff erences noted hy
numerous investigators have loeeii evident. Testosteronepropionate per unit weight has shown a11 activity approuimate17 four times greater than testosterone.
dosages of these two sd>Adequate ~1.o~rth-substitntiorial
stances have hemi found to promote types of relationships
between the weight of the prostate and seminal vesicle that
exist in normal litter-mate controIs of young or adult
ages. These findings are in agreement with those obtained
from treatments of castrate rats with androsterone and it is
t o be emphasized that though dosages below requirements for
testis substitution on growth maintenance of seminal vesicles
will appear to selectively stimulate the prostate because of its
lower threshold of response, adequate substitutional dosages
provide a prostate-seminal vesicle ratio equivalent for the age.
Reports that the chemical androgens exert a selective stimuIation on one end organ rather than a general stimulation
EFFECTS O F TESTOSTERONE 1 N T H E RAT
71
characteristic o f testis-secreted liormonc arc believed t o be
based upon the usc of dosage levels too low to adequately
stimulate semiiial vesicles, m-liile being sufficiently high to perinit the lowcr thresholcl reacting prostate to develop norrnallp
(Callow and I)eaiicsly, '35 : Xorenchevskp et al., '35 ; Deanesly
and P a r k s , '36; Parkes, '36 : Niescher, J&7ettstein and
Tschopp, '36; Tschopp, '36). The sliiftiiig of the ratio value
by different closages of t e s l osterone is illustrated i n table 1
whcrciii for the teriniiial age of 50 days 0.1 mg. would selectively stimulate the prostate and give a n aberrant ratio value
higher than normal, 0.2 and 0.4 nig. representing morr than
substitutional dosages, reduce the value lower than normal
and shift relative vwiglits to those o f normal adults rather
than those cliaracteristic for the real age of the litter.
Tlie adeqnacy w i t h wl1ich these chemical androgens substi tute for the testis and the qnaiititatire variation in growthreplacing doses f o r rarping ages, suggests that such procedures proridr a rough measure of secretory intensity of
normal t cstcs. It has been pointed out (Price, '36 ; Moore and
Price, '37) that seminal vesicles of normal malc r a t s grow
slowly for approximately ihe first 35 or 40 claps of life wheii
tlie curve o f weights ascends sharply until approximately 80
t o 90 days of age when the ascent is more gradual. Data on
I-eplacemcnt closagcs licrcin presented indicate that secretory
activity of testes gradually iiicreases during prepuheral development LIP to the level maintained i n adlilts and that such
a stage is reached at about 80 claps of age. The samc line
of reasoning sug-gests tliai the pituitary glaiid, the normal
incitor of testis activity, liliewise begins to release more and
more gonad activating hormones. Clark ( ' 3 5 ) demonstrated
that the pituitary of male r a t s gradually increased in
gonadotropic potency from birtli to puberty. As shown by
lreatmeiits with gonadotropic liormoiie iiijectioiis the amount
Tseleased is hy n o meails sufficient to induce the full secretory
capacity of the testes.
These considerations sugyrst that puberal development is
z process cliaracterized by a gradual incremental increase in
72
CARL R. MOORE AND D O R O T H Y P R I C E
lestis liorrnone secretion and that as the higli level of secretion is attained a t approximatelj- 80 clays i t fails to increase
further, normally, bnt is capable of being increasecl by proper
treatments. With the establishment of this noriiial peak level
of activity, regulatory forces williiii the organism appear to
become operative and l-robablp consist a t least in part of a
cliecli on pituitary activity by high testis hormone levels.
IIooker ( ' 3 7 ) extracted testicles of difierent aged bulls and
coiisiders that hormone secretion i s a gradually iiicreasiriy
function from 1+months to 3 years of age, after which the
function gracliially declines. I n the rat the high point is
attained within 3 months and appears to remain fairly constan t during reproductive life.
It has been indicated tliat testoste~oiie-p~opioilntc
exhibits
effects of longer duration tliari other androgens (lfiesclier,
Wettstein and Tschopp, '36; I'arlies, '36) and it has been
of interest to compare its effects not oiily with those from
testosterone and androsterone bnt also wit11 the iiormalljsccre t ed hormone.
Castration of normal atliilt male r a t s is followed hj- such
rapid reduction of the hormone level as to induce definite
castration cliaiiges within a period of 4 claps on the prostate
gland and even earlier on seminal resides. In this case the
completrll; and no
source oi' hormone is removed suddeiily ~ i i d
storage in the organism is apparent. liijections of chemical
androgens in an oil medium 1)rovide a residual s o wce of
hormone for approximately 2 days since a grade of castration cliange appears after cessation of injectioiis of testosterone and androsterone about days 6 t o 7 that appears after
ortliary castratioii on clays 4 to 5.
Tii experiments liere reported care has lieen exercised to
employ growth-suhstitntional doses in order that the end
organ developrnent moulcl be equivalent to that in the normal
animal. Activity of secreting cells in the end organs has
served as the principal criterion of effect instead of gross
weight of organs. By these methods castration changes following the last of a series of iiijcctioiis with the propionate
EFFECTS O F TESTOSTNROSE IN THE; BAT
73
appear. to have I)ecln delayed f o r approximately 3 t o 4 clays
longer than after treatments with other chemical aiiclrogens
o r after ordinary castrrttioii. This short prolongation of
effectiveiiess is presumed t o represent slomcr absorption of
t-propionate from the oil.
The rapictitv with which full-sizcd sclminal vesicles can be
produced in prepiiherallp castrated males untreated f o r
6 months is reniarkalole. Within 3 wceks f roni beyinniiig
treatnieiit wjth propionate active secretion lias heen initiated
as ~ w l a
l s an actual illcrease in weight of 160 times a s compared with iintreated castrates ; the vesicles attained a size
and weiglit i n 3 weeks that Iiad heen attaiiiecl in the normal
control a t the aye of 7 months.
Copulatory ability was cle\~lopedto its fnll capacity within
the 3-meek period of injections. This is real copulatory
awakening since normal males on the ave1.age experience first
copulation only about 60 clays of age (Stone, '24, '27) ant1
castration liad been performecl oil clap 30. Despite the fact
S tone ( '27) determined copulatory ability was evideiicecl
S months after castration in one rat, his animals \\-ere castrated about clay 90 a n d after they liad experienced copiilation.
Even so, 74F of a group of forty-five males castrated a t the
age of 90 clays ha(l lost copulatory ability by the end of the
fourth month after castration. The absolute pcrfection of
the copulatory act on tlie part of malcs treated n-ith testosterone-propionate, ancl tlie fact ejaculations occni*red, leare
no doubt of tlie entirely normal character of the reaction developed at the end of a castration pcriotl of more than 6 m o n t h
and devclopecl for the first time. De Fremerj- and Taask
'37) fouiid that prepuhei.allp castrated rabbits developed
copnlatoryv ahilitp 7 inoritlis after castration after injections of
10 mg. of t-propionatc daily for a period of 11 to 13 clays.
Uiipublishcd observations (Moore) show that guinca pigs
castrated at 30 days of age and injwlecl 6 months later deTTeloped copnlatory ability (with ejaculations) after daily
injections of 0.3 mg. ancl 0.5 mg. testostcronc-propioilate.
74
CAlZL 13. MOOBE AND 1)OItOTHY P R I C E
The injurious effect of testosterone and t-propionate upon
the testes of males during the rapidly growing period and
lheir stimulating effect on the accessory organs coincides with
earlier findings on tlie effect of bull testis extracts (Aioore
and Price, '32) and the effects of androsterone (Noore and
Prjce, '37). Testes from treated males were materially reduced i n weight ; differentiation was arrested ; destruction
and sloughing of cells of the gerriiiiial line into the seminiferous tubules was prominent ; tubule diameter was reduced
and spermatozoon formation completely inhibited or greatly
delayed. Two points of similarity of effects with those after
androsterone treatments were 1) that the harmful influences
from givcii dosages beconie less evidence as the animal approaches maturity and 2) relative1~-large dosages fail to
materially affect the testes of mature adults. Differing at
least i n degree from other antlrogens the propionate exhibited
tlie soniewliat pel-plexing property of being more injurious
iii lower dosages. The figure shows that f o r most periods
during prepuheral life daily doses of 0.03 mg. induce testis
decline and injury to a greater extent than those of 1.0 mg.
Iiiterprctatioiis of these phenomena are not clear at the
present time. Our earlier suggestions (Moore and Price,
'32) were to the effect that deleterious action of androgens
upon tlie tcsticle rather than being a direct effect was iiidirect
by virtue of a suppressive action upon the pituitary, or one
~vliichled l o an insufficient amount of pituitary hormone being
available to stiiiiulate normal testis function. Pituitary glands
from normal rats treated with androsterone, which resulted
in testis damage, were found to have diminished gonadotropic activity j i i infantile fcmale mice (31oore and Price, '37).
Hertz and i\leycr ( '3i) have sliowii also that chemical aiidrogens injected into the castrate 1xwtiier of a parabiotic pair
effectively prevented tlie usual stimulation of tlie normal
female of tlie pair, presuiiiably 11~-virtue of preventing excessive pituitary activity that follows in the castratc partner
and expressed in tlie normal parabioiit partner. These and
numerous other data, considerable of which are cited in
EFFECTS O F TESTOSTERONE IX- THE BAT
75
former papers, suggest tlie effect a s one of pituitary modification, and tlie dccliiiing effects with ageing can be niiderstood as perhaps due t o w less easjla nioclifietl pituitary gland.
The general hypothesis contains no element of explanation,
however, for the clecliiie in effectiveness with elevation of
dosage as has been foulid after treatments with the propionate.
The suggcstiori o i abseiice of direct effect of the androgenic
substaiiecs upon thc testis might appear to deserve modifieaiion when consideration is giv-cii to the fact that 1) androgenic
substances prevent testis involution s~he11injected immediately
after hypophysectomy (\Val&, Cuyler and 3ZcCullagh, '34 j
Nelson aiid Gallagher, '36 ;Wells arid Gornez, '37) and 2 ) that
treatment with androgenic suhstances results in heightened
testis actirity in the seasonal breeding mammal (Citellus),
leading t o unusuall? early production of spermatozoa (Wells
and Moore, ' 3 6 ) .
With regard to treatments of liy~ophyseetoniizeclmales with
various aiidrogens it should be mentioned first that, in agreement with the early unpublished findings of Vatna (Moore
and Price, '32) using bull testis extract, repair of hypophysectomy damage to the testis was n o t effected. h consiileralion 1) of the capacity of androgens to prevent involution
after hypoplij-sectonly but iiiability to correct damage to the
testis after its development, and 2) the fact that progestin
(Kelsoii, '36) or yeast extract (Ilisaw, Grccp and E'evold,
'36) lilrewise prevent tcsti s damage wheii given immediately
alter liypophyscctomy raises the question wlictlier androgens
have a direct effect upon the testicle.
Reproductive conditions in seasonally active forms admittedly diEer fyom those in continuous breeders such a s the
rat. It x7as deterrniiicd that administration of androgens to
the normal but sexually iiiactive g r o u i d squirrcl was follomed
by heightened testienlar activity and germ cell production
(TI7ells and 3Ioore, ' 3 6 ) even in case the animal had been
subjected to hppophysectomy (Wells and Goniez, ' 3 7 ) . Ordin a r y pregnancy urine and esiracts of uriiie likewise proved
to be effectivti agents. At the same time adniiiiistratioii of
76
CARL B. MOORE APU'D DOE O TH Y PRICE
androgens t o sexually active ground squirrels induced liarmfnl
effects (Wells, '35).
A considcration of these various findings and the facts with
reference t o the effects of t-propionate cited above leaves one
searching for an apparently acceptable hypothesis that will
bring the various findings into a common explanation. Without doubt too little is linown of the metabolism of hormoiial
snbstances by the organism to warrant further speculation at
the present time.
SUMMARY AND CONCLUSIONS
1. The pure chemical androgens testosteroiic and t-propionate induce secretory activity in the prostate gland and
semiiial vesicles of castrates that is indistinguishable from
normal activity. These substances a ) maintain normal histnlogical conditions o r repair damages in castrate males : 13)
induce precocious secretory activity ; c) maintain the normal
growth rate of accessory organs of reproduction in castratcs
during the most rapidly growing period of life and d ) promote a normal prostaic-seminal vesicle ratio when administered in dosages adequate to maintain normal growth of
seminal vesicles ; inadequate dosages for seminal vesicle
growth maintenance naturally appear to favor prostate activity clue to its lowcr tlireshold of response.
2. By weight t-propionate proved approximately four times
as active as tpsosteronc. Substitutional dosages for maintenance of growth rate of seminal vesiclcs was approximately
three times dosage requirerncnts f o r mainteiiance of histological normality.
3. T-propionate exhibited only slight prolongation of effectiveness after injection (approximately 3 days) as compared
with testosterone, androsterone or ordinary castration of
normal males.
4. T-propionate injectioiis into rats castrated prepberally
and injected only aftcr 6 months induced the animals to esecute repeated and vigorous copulations, including ejaculations,
within a period of 3 weeks. Seminal vesicle weight exceeded
that of normal 7-month-old control males.
5. Testosterone and t-propionate cause grave retardation
and injury t o the testes of young normal males hut this eEect
gradually declines with age. The propioilate, especially, exhibited a reverse order of effects with increased dosage, 0.05
mg. often hciiig more injurious than 1.0 nig. daily doses.
LITERATI,TRE CITED
CALLOW,R. I<., AKD RUTII DEANERLP 1935 Effect of androsterone and of male
hormone concentrates on the acce3sor~reproductive orgaris of castrated
rats, mice and guiiica pigs. Biocheni. J., 101. 29, pp. 1424-1445.
CLARK,HELENhl. 1935 A prepubertal reiersal of the sex difference in t h e
gonadotropic hormone content of the pituitary gland of t h e rat.
Anat. Rec., vol. 61, pp. 175-192.
1935 A sex difference in the change in potency of the anterior
hrpophysis following hilateral castration in newborn rats. Anat. Kee.,
61, PP. 193-202.
UEAVESLTT,
It., AKI) A . 8. PARKES7936 Comparative activities of compounds
of t i l e androsteronc testosterouc series. Biocheni. J., vol. 30, yp.
291-303.
Dn FREXERY,
P., AND 31.T a u s a 1937 Geschlechtliche Alrtivitiit kastrierter n i m i i liclier Raninchen nach Bcbandlung niit Tc-3tostcronpropiona. Bcta
brev. Seer., vol. 7, nos. 8/10.
HEKTZ, ROY, AND H. K. N E Y ~ : R1937 The effect of testosterone, tcstosteronc
propionate and dehgdroandrosteronc on the secretion of the gonadotropic complex as evidenced in parahiotie rats. Endorrinohgy, vol. 21,
pp. $56-761.
HISAW,>'. L., €3. 0. GREW AND H. L. FEVOLD
19.36 Pituitary-like effects of
peast extracts. Anat. Rcc., vol. 67 (Suppl.), p. 50.
HOOKER,
CFTAS. W.
1937 Testis horinonr iii relation t o age. Endocrinolog-y,
vol. 21, pp. 655-658.
KORESCHEVSKY,
V., AND 1\1. DEXXISOX 1935 The assay of f a t soluble androsteronr-iliol. Biochem. J., rol. 29, pp. 2122-2130.
KORENCHEVSKP,
V., 31. DENNISOWA N D S. L. SIMPSON 1933 The effects of
water-soluble preparations of androsterone arid androsteronc-diol 011
castrated rats. Hiochern. J., vol. 29, pp. 2131-2142.
MICSCHER,I<., d. T V m w m r N A N D E. TSCHOPP1936 The activation of the male
sex hormones. I. and 11. Blochem. J., vol. 40, pp. 1970-1990.
MOORE,C-4RL R. 1936 Responses of immature rat testes t o gonadotropic agents.
Am. J. Anat., 101. 59, pp. 63-88.
I\fOORn, CART R., w.I ~ l I G I I E b AND T. F. ~ A L L h G F i L R 1930 Rat seminal Iesicle
cytology as a testis hormone indicator and the prevention of castration changes by testis extract injection. Am. J. Anat., 101. 45, pp.
109-13s.
XOORF,
CARL R., I)OXO~'HY
PRICE
AND T. F. GALLAGHER1930 Rat prostate
cytology- as a testis hormoiie indicator and the prevention of castration
ehaiiges hy testir extract iqjection. A m . *J. Anat., rol. 45, pp. 51-10;.
1701.
-( 8
CARL Ti. ’AIOORF, A N D DOROTHY PRICE
NOORE,CARL R., AND DoRoTIiP PRWE1932 Gonad horiiioiie functions and the
recipioeal influence between goriads arid hjpophysis with its bearing
on the problem of sex-liormonr antagoaisui. Am. J. Anat., vol. 50,
pp. 1 3 - i l .
1937 Some eflects of synthrtically prepared m a l e hornitrnr (androsterone) in the rat. Endocrinology, vol. 21, pp. 313-329.
XELSON,W. 0. 1936 The effect of various sex hormones on the testes of hypophyscctoinieed rats. Anat. Rec., vol. 67 (Suppl.), TI. 110.
KELSON,W. O., AND T. F. GILLAGIIER 1936 Some effects of androgenic substances in the rat. SLience, 1-01. 54, pp. 230-232.
PARKES,
A. 8. 1936 Inercasing of effecti\encss of tcstostrrone. The Lancet,
\ O l . 3, p. 674.
PRICE,
DOROTHY 1936 Norrnal clcvciopinrnt of the prostatr arid scniiiial Teuicles
of the r a t with a study of rspeiiinental post-n:rt:ri modifications. Am.
J. Anat., vol. G O , pp. is-127.
STONE,CALVIN P. 1924 The awakening of copulatory ability i n the rnale
albiiio rat. Am. .T. Yhysiol., r o l . 68, pp. 407-424.
- 1927 The retention of copulatory ability in male r a t s following
castration. J. Comp. Psychol., vol. 7, pp. 369-.?Xi.
‘L’SCHOPP, E. 1936 Untersuclinngen iibcr die Wirkung der ni$nnlichen Sexnalhormone uiid dire Derivate. A4rch. l n t . Pharnincod. et. Ther., Ed. 52,
S . 351-403.
\VALYH, E. L., W. K. &TYLER ABD D. R. ~\.ICCUIJLAGH 1934 The physiologic
niaintena~ier of the nialr sex glands. Am. J. Phjsiol., \ol. 107, pp.
505-512.
WELLS,L. J. 1935 Seasonal sexual rhythms and its expeiirnerital modification jn
the malr of the thirteen-lined ground syuiircl (Citcllus tridrecnlineatus). Anat. Rrr., aol. 62, pp. 409-447.
WELLS, L. J., AND E. T. GONEZ 1937 IIypophjscetoinj and its effects ov- male
reproductive organs in a wild mammal with annual r u t (Citellus).
Anat. Rec., pol. 69, pp. 213 227.
WELLS, L. J., AND CARL E. MOORE 1936 IIormonnl stimulation of spermatogenesis in the testis of the ground squirrel. Anat. Rw., vol. 66,
pp. 191-200.
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