growth hormone secretion in organ culture. The solvent of the ET containing tartaric acid had no effect on prolactin secretion in a 24-hr organ culture experiment.
BIOLOGY
OF
5, 59-66
REPRODUCTION
Effects
(1970)
of Ergotamine
Tartrate
Secretion CHARLES
of
and
by Rat Adenohypophysis
S. NICOLL,’
Department
on Prolactin
ZVI
YARON,3
Physiology-Anatomy
NAN
U,ziverszty
Growth
Hormone
in vitro1
NUTT,
AND
of California,
ELLEN
Berkeley,
DANIELS
Califor,’ia
94720
The
effects of ergotamine tartrate (ET) on prolactin secretion by rat adenohypophysis were investigated to ascertain the site of inhibitory action of the drug on the secretion of this hormone. Prolactin levels in incubation medium were estimated by disc electrophoresis and densitometry. Intraperitoneal injection of 1 mg ET 4 hr or 15 hr prior to incubation of the adenohypophyses of the recipient female rats resulted in significant inhibition of prolactin release in vitro. The drug was more effective after 4 hr than after 15 hr. Addition of ET to incubation medium at concentrations ranging from 2.5 to 20 ug/ml resulted in significant inhibition of prolactin release in a 4-hr incubation experiment. A dose-related effect was obtained over a narrow range of ET concentrations. Concentrations of the drug ranging from 0.005 to 5.0 g/ml significantly inhibited prolactin secretion in two organ culture experiments of 24-hr duration with male rat adenohypophyses. In the first experiment about 40% inhibition of prolactin secretion was obtained at all concentrations of ET. In the second organ culture study, all concentrations of the drug inhibited secretion by more than 95%. Thus, no dose-related effect was obtained in either organ culture experiment. None of the concentrations of ET significantly affected growth hormone secretion in organ culture. The solvent of the ET containing tartaric acid had no effect on prolactin secretion in a 24-hr organ culture experiment. Neither the ET nor its solvent containing tartaric acid had any effect on the detectability of prolactin in the disc electrophoretic-densitometric assay system. The results indicate that ergot drugs inhibit prolactin-dependent reproductive processes by depressing the secretion of the hormone by acting directly on the adenohypoph. yseal lactotropes. in vitro
Several
ergot
dependent mice.
alkaloids
physiological
In intact
block
in rats
and
inhibit
mals maker and
they
reduce
dependent sawa and 1Supported
when (see
and Carlsen, the
mammary Meites, by
Buchanan, 1962;
development
1955; Mantle, of
prolactin drugs
Zeil-
1958),
1968) prolactin-
Council
of the
ergot
drugs
indicate
that
1956, can
1957a,
overcome
in blocking in inducing
1958). the
Injection
action
pregnancy degenerative
of
of these
(Shelesnyak, changes
in
rat corpora lutea (Lamprecht et a!., 1969), and in reducing milk secretion in rats (Zeil. maker and Carlesen, 1962). This indicates that the ergot derivatives may depress pro-
tumors in rats (Naga1970) and preneoplastic Population
of action
(Shelesnyak,
1957a; Carlesen et a!., 1961). In depress lactation in these ani-
(Sommer and
site
the mammary glands of mice Nagasawa, 1970). Studies on the
in and
they do not act directly on the ovary, the uterus, or the mammary gland and that the adrenal cortex is not involved in their effects
deciduoma
formation and interrupt pregnancy given during the first week postcoitus Shelesnyak, addition,
and
these drugs terminate
animals
pseudopregnancy
lesions (Yanai
prolactin-
processes
Grant
lactin secretion. Moreover, tory action of ergot drugs
M70.69.C and by funds from the Committee on Research of the Univ. of Calif. at Berkeley. ‘Send reprint requests to C. S. Nicoll. ‘Visiting investigator on leave from the Department of Zoology, Tel Aviv University, Israel, August 1969 to August 1970.
trope cornine
is suggested by methansulfonate
pregnancy hypophyseal 59
the
a direct inhibion the rat lactoreport terminates
that
which is maintained by transplants, (Zeilmaker
ergopseudoadenoand
60
NICOLL
Carlsen,
1962)
and
action suitably
of prolactin prepared
1971). (1963)
However, concluded,
volving
direct
blocks
AL.
In the organ-culture
luteolytic
experiments
from such transplants in rats (Malven and Hoge,
hypophyses,
Shelesnyak from
in these studies. It was
and experiments
application
the ovaries, uterus, and nant and pseudopregnant did
the
ET
in-
glycerine
to
and
4.5%
Experiment
I:
Irate (ET) in vilro
Effects
Multiparous intraperitoneal
tartrate on prolactin hypophyses in vitro.
either
4 hr
their glands
adenohypophyses. were incubated
MATERIALS
AND
adeno.
METHODS
Ergot
female
adenohypophysis, Data on the dium Fig. with
in
15 hr
before
were
40%
experiments
less
Total
incubation
of
are
prolactin
prolactin
secretion
hr of incubation was by the ET injection.
of the a change
reduced
flasks, to one
shown
in
rats injected of glands re-
during
hour, compared with explants control rats. In the subsequent was a 50% decrease, compared trols.
single of ET
in each group. into the me-
1. Adenohypophyses of ET 4 hr prior to removal
leased
a mg
1 hr. Eight equivalent
used released
Tar-
Secretion
Explants for 4 hr with
prolactin
these
amine
received of 1.0
of medium at the end of each containing explants
and male rats of the Sprague-Dawley or Long-Evans strains were used. The former strain was used in all experiments except where indicated otherwise. The animals were killed by stunning and decapitation and their adenohypophyses were rapidly removed. The glands were cut into eight pieces and these explants were incubated in synthetic medium 199 at 37 C in an atmosphere of 5% CO2 in 02 in short-term experiments or in 24-hr organ-culture studies using procedures described previously (NicoIl, 1965; Parsons, 1970). A gyrotory shaker was used for the short-duration incubations. In most experiments the incubation flasks or culture dishes contained 0.5 ml of the medium. The prolactin levels in the medium samples were estimated by disc electrophoresis and densitometry (Nicoll et al., 1969). Mature
or
RESULTS
on Prolactin
females injection
of 14%
3.85.
of
Injection
procedure. was used
in a solution
at pH
AND
tion on the site of action of the ergot drugs, we have investigated the effects of ergotamine by rat
in the medium
levels
contained
ethanol
EXPERIMENTS
of pregthe drug
not directly affect any of these organs. In order to gain more definitive informa-
secretion
with male rat adeno-
hormone
samples were also determined by the same Ergotamine tartrate (Gynergin, Sandoz)
Barnea
of ergocornine hypophysis rats, that
the growth
the taken 3 hr with
during by about
first from there conthe
0
0 15
E 10
E C C
5
U 0
0 L
00 0-1
1-4
0-1
Hours FIG.
I. Effects of intraperitoneal
by female
rat
adenohypophyses
of
injection of ergotamine
4 and 15 hr later.
N
=
1-4
incubation tartrate (1 mg per rat) on prolactin 8 in each group.
secretion
4
44 %
in vitro
ERGOTAMINE
The adenohypophyses with the ET 15 hr a comparable as the controls
but
subsequent
the
during Total the
amount during
of prolactin the first hour
secretion
of the
ments
was reduced confirm the
from
ergot rats
which
it
was
that
fective 15 hr.
in this
concluded
regard
4 hr after injection However, they do
ingful information of action of the Experiment
II:
The effects prolactin
experiment a direct
on the drug. Effects
ET
%.
of
that
was
in they
more
mechanism
or site
in vitro
of several
concentrations
secretion
in
a 4-hr
were investigated dose-related inhibitory
milliliter
of
which
of ET incubation
to determine if effect could
contained
the ET solvent with tartaric Thus, the control medium
20
l
of
acid at pH 3.85. contained 10 rg
of tartaric acid per milliliter. The experimental medium contained the ET at concentrations of 2.5, 5.0, 10.0, or 20.0 g/ml. The the The
medium
was
changed
after
incubation was terminated results of this experiment
I
I
I
I
I
I
C)
E
E D
a’
E
10
(0-1
1 hr,
and
hr)
C C
(1-4hr)
0 L
I
I
0
5 jg
I
I
I 15
I
10
El
per
ml
-
I
I
20
medium
FIG. 2. Effects of different concentrations of ergotamine tartrate added in vitro on prolactin secretion by female rat adenohypophyses in a 4-hr incubation experiment. N = 6 in each group.
ingly,
be obtained at the pituitary level. Explants of the adenohypophyses of multiparous female rats were incubated in control medium, each
I
4
ef-
that it was after not provide mean-
of ET
0.
61
20
by about 18 %. in vivo experi-
alkaloids inhibit prolactin secretion (see introduction). In addition,
indicate
PROLACTIN
hormone
hours 1-4 was reduced by about 40 prolactin secretion over the 4 hr
experiment These results
on
of the rats treated to incubation re-
prior
leased in vitro
AND
no
dose-related
effect
was
evident
these two incubation intervals. The ET on the total secretion of prolactin
in
effect of during
the 4 hr of incubation, also presented in Fig. 2, does show a dose-related inhibitory action, but over a very narrow range. The 2.5 pg/mI concentration tin secretion by about
inhibited total 31 % and the
prolac5 pg/mI
concentration inhibited secretion by about 45 %. The higher concentrations did not inhibit prolactin secretion significantly more than
the
5 pg/mI
Experiment Prolactin
III: Effects and Growth
in Organ
after 4 hr. are shown in
The
of ET and Hormone
its Base on Secretion
Culture
direct
effect
on
prolactin
During the first hour of incubation, the lowest concentration of ET had no significant effect but the 5.0 zg/ml level and
vitro was further tested using 24-hr organ culture experiments. The effect of the tartaric acid base in the ET solvent was also tested and the levels of growth hormone in
(between 30 and hr of incubation, inhibited and the processes
to
significantly about the
40%). In the the 2.5 sg/ml
prolactin secretion higher concentrations to a comparable
same
inhibited extent
subsequent 3 level of ET by
about 50% inhibited the degree. Accord-
the same ascertain prolactin periment mature with
adenohypophyseal
secre-
tion
concentrations release
rat
of ET
Fig. 2.
higher prolactin
by
level.
medium samples were measured the specificity of the effect secretion. In the first culture (III male
ET
explants
A) adenohypophyses Sprague-Dawley rats
concentrations
of 0, 0.05,
were 0.5,
in
to on exfrom used and
62
NICOLL
ET
AL.
E
I 2O
E 0)
15 0 C
0
a. )1O 0 0)
z
5
a0
0.050.550
o
0.050.550
jig
El
pr
.005.05
ml
of
05
50
0
FIG. 3. Effects
of different concentrations of ergotamine tartrate on prolactin secretion by adenohypophyses of male rats in two organ culture experiments Dawley rats were used in Exp. lilA and Long-Evans rats were used in IIIB. N
In the
second
study
(III
B), glands
of mature male Long-Evans rats were employed and the same concentrations of FT were used in addition to a lower level (0.005 pg/ml).
The
effects
of the
tartaric
were also tested in this experiment tartaric acid in 20 pl of solvent liter
acid
base
at 10 pg per milli-
results of both 3. In experiment
of FT
inhibited
experiments are shown III A, all three levels
prolactin
55 %. Accordingly, was obtained. The
no ET
secretion
by about
dose-related had no
effect
growth hormone secretion. III B with Long-Evans rats, centrations tion to such
ble by the Inasmuch
of ET inhibited a degree that
effect on
In experiment all four con-
prolactin it was not
secredetecta-
5.0
(PL) and growth of 24-hr duration. =
hormone Sprague-
6 in each group.
disc-electrophoresis assay method. as this assay procedure can detect
prolactin levels as low as 1 Mg, the degree inhibition of release was greater than 95 None
of the concentrations
cantly altered growth In addition, the tartaric vent
of medium.
The in Fig.
0.5
medium
(OH)
5.0 pg/mI.
005.05
had
no
effect
signifi-
hormone secretion. acid in the ET solon
either
growth hormone. Thus, the effect of the ET on prolactin ascribed to the ergotamine the other constituents of the ration. degree between parent
of ET
of %.
prolactin
or
direct inhibitory secretion can be itself,and not to gynergin prepa-
The reason for the difference in the of inhibition of prolactin secretion these two experiments is not apto us. Although different strains of
rats were
used,
we
are not
aware
of any
AND
ERGOTAMINE
reason
why
the
rats should by FT than
lactotropes
of
pophyses
Long-Evans
63
PROLACTIN
is evidently
Experiment ET on The prolactin
IV: Effects of Tartaric Prolactin Detectability
apparent secretion
of
an
inhibitory in vitro
artifact
densitometric tion. For
of
procedure example, the
change medium
in
the which
affinity
for
prolactin would
the
Acid
and
The
that
alkaloids
productive plantation,
of
on
prolactin-dependent
reima direct
of
action
of prolactin drug could
estimacause a
tion
of the
seal
lactotropes.
molecules alter their
in the binding
(EC) to terminate implantation in
blue-black
stain.
directly
lactotropes distribution
to of
of tartaric acid in the solvent on rat prolactin, which was previously secreted into the 199 medium, were examined. Explants of
combination
adenohypophyses for
of six male 2 hr
in six
flasks
rats
were
(one
gland
incuper
flask) containing 1.5 ml of medium. A 0.5. ml aliquot of the medium from each flask was then transferred to each of three additional flasks was added The tartaric second group
for further incubation. to one group of these acid base of medium
Nothing aliquots.
concentration of 10 pg/mI. The third group contained ET at 10 pg/ml. These groups were incubated for an additional 3 hr, then prolactin
levels
were
determined
in
0.3-mi aliquots of the medium samples. The control samples contained prolactin at a level of 3.4 ± 0.3 pg/mg of incubated adenohypophyses. with tartaric acid
The in
the
samples solvent,
or
incubated with ET,
had levels of prolactin of 3.4 ± 0.2 and 3.2 ± 0.1 pg/mg, respectively. Thus, neither the ET nor its base had a significant effect on the detectability of prolactin phoretic system. Accordingly, ing effect medium
of ET on prolactin from incubates of
in this electrothe depreciatlevels in the rat adenohy-
of
ergocornine
block injected
or
was
(Shelesnyak
the drug it within
or to the gland
these
factors.
that
a single
reported
due to of the restricted or to
content
of
or
Pasteels
and
et a!. (1970) ours using obtained
hormone
Ectors
prolactin
estrous action addition
eminence levels
the
adeno-
reflect
(1970)
and
the
Wuttke
results similar to The former group
of a toxic
EC on the lactotropes, as electron microscopy. Wuttke also reported that implants median
although pseudoHow-
necessarily
have obtained EC in vitro.
no evidence
in
effect
of the
determined et a!. of EC
by (1970) in the
of females depressed but did not disturb
serum their
cycles. This suggests an inhibitory of EC at the hypothalamic level, to an effect on the lactotropes.
However,
fused from hypothalamus
of
rats did prolactin
content of their adenohypophyses, this dose is effective in terminating pregnancy and blocking implantation. the
a
Shelesnyak injection
mg of EC into pseudopregnant alter the gonadotropin
ever,
secre-
may have been of exposure
hypophysis does not amount being secreted.
was added to the samples to a final
failure
hypophyses
preted as reduced secretion into the medium. To test this possibility, the effects of ET and
1.5 not
the
adenohypophy-
pseudopregnancy rats when it
the
of
on
drug
by the The
into
(1957b)
the
hormone
1963) duration
result in a lower denwhich would be inter-
provide effect of
processes (pseudopregnancy, and lactation) involves
and Barnea, insufficient
the
inhibition
experiments the blocking
these
evidence
inhibitory
electrophoretic-
of
results
cogent
ergot
effect of ET on could be the re-
the
aniline
This change could sitometric reading
bated
to
DISCUSSION
strain.
suit
due
secretion.
be more sensitive to inhibition those of the Sprague-Dawley
in
the possibility that the EC difthe site of implantation in the to the hypothalamohypophys-
eal portal vessels, and was then carried to the adenohypophyses, must be kept in mind (Bogdanov, 1963). Grosvenor and Turner
64
NICOLL
(1956, drugs
1957) reported block oxytocin
suckling
in
inhibitory and
lactating
action
the on
several
on
and
some
actions,
an
increase
to
Accordingly,
the of
in the
AL.
of 5-200 pg/l00 rats in the early pressed
their
In
involve 1965). be medi-
secretion
the
normally ever, the
oxytocin
may
CNS (see Nickerson, prolactin may thus
by either
ergot
response
in
drugs
secretion,
pharmacological
effects in The effect ated
rats.
of these
prolactin
other
that release
ET
of
rise
contrast
to
addition lactotropes
the preovulatory ever, the site
A recent
report
by Fluckiger
and
(1968) suggests that the ergot not have a single mechanism blocking prolactin-dependent processes.
They
reported
that
was slightly less effective plantation and substantially depressing lactation than derivative (2-Br-a-ergocryptin). the difference in potency depressing lactation that bromination reduces its ability lease 1957)
(see while
a-ergocryptin
in blocking immore effective in its brominated of
these
However, drugs
Grosvenor slightly
and increasing
Turner, 1956; its inhibitory
effect on prolactin secretion. This bility clearly warrants investigation. cordingly, the results of Fl#{252}ckiger and ner (1968) do not prove that ergot inhibit
in
may simply indicate of the a-ergotcryptin to depress oxytocin re-
prolactin-dependent
possiAcWagdrugs
reproductive
processes by means other than by reducing the secretion of this hormone. The inhibitory effects of ergot drugs on adenohypophyseal hormone secretion is evidently not lactin. Although culture
of
consistent secretion, that EC eta!.
(1970)
completely specific our results with
male
rat
pituitaries
effect of ET on growth other in vivo experiments can depress LH release. reported
that
injection
for prothe 24-hr showed
no
this
report,
when
given
with
regard
they
both
Howtime. and
is not
the
ing
crude
Nicoll Leod,
by EC,
drug
suppresses
established. have now secretion
extracts
activity
been shown to by rat adenoin
experiThese
vitro
ergot
and
of mammalian PIF
in
rise in LH secretion. Howof action of the EC in this re-
hypophyses in short-term ments, in addition to the include
or
of ovulation
that
Several agents inhibit prolactin
tions
before
“critical period.” in these two studies
to blockade indicate
drugs.
purified
prepara-
hypothalamus (see
et a!., 1970), 1969; Birge ci’
Meites
contain-
& NicoIl,
catecholamines a!., 1970), and
1966; (Mac.
reserpine
(MacLeod, the structure
1969). Nothing is known about of PIF and there are no obvious
similarities
among
wolfia which
alkaloids, would
the
ergot
and permit
and
the
the
inferences
to
be
the may
cells not
and Shelesnyak, 1968). These which secrete have the same
Wuttke
reproductive
processes
this
suggest
hormone,
facts
this
in termihas a!.,
ci’
pseudotissue in
1968) or suggest
placental “receptors”
mice that
prolactin as those
lactotropes. of the ergot and
made
of
nating pregnancy after implantation occurred (Shelesnyak, 1957; Carlsen 1961), and they do not interrupt pregnancy maintained by placental rats (Kisch (Zeilmaker,
rau-
catecholamines
regarding the possible structure hypophysiotropin. The ergot drugs are not effective
indicate
of doses
which
Kraicer
shortly the
of the adenohypophyseal The inhibitory action on prolactin secretion,
hormone
LH
in the afternoon. at the expected
the early portion of Despite the discrepancy
gard
Wagner
drugs may of action in reproductive
and
into de-
Strauss (1970) found that a single injection of I mg of EC on the day of proestrus was highly effective in blocking ovulation, especially
on the
weight of EC of proestrus
in prolactin
occurs later rats ovulated
the prolactin inhibitory factor (PIF; see Meites and Nicoll, 1966) or by a decrease in the secretion of a prolactin-stimulating factor (PSF; see Nicoll et a!., 1970; Grosvenor et a!., 1970) by the hypothalamus, in to a direct inhibitory action at the pituitary level.
g body afternoon
drugs
consequently
which additional
depend therapeutic
on
on
AND
ERGOTAMINE
uses
for
them.
It
that the ergot of mammary
has
already
been
Meites, 1970) and preneoplastic lesions
reduce in the
KISCH,
growth and
the incidence of mammary glands
of mice (Yanai and Nagasawa, 1970). Accordingly, they may be effective in controlling prolactin-dependent metastatic breast cancer in women. In addition, the drugs may have
utility
in
women after contraceptive
terminating
lactation
weaning and they value if implantation
is dependent on adenohypophyseal tin, as it is in rats and mice. though
EC
was
effective
gesterone synthesis and Shelesnyak,
phase
of 1967).
the
may be of in women prolaca!-
in depressing
by rat ovaries 1967), the drug
alter plasma progesterone nanediol levels in women a!.,
in
However,
pro(Lindner did not
or urinary during the
menstrual
cycle
pregluteal
(Lindner
et
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