Effects of Ergotamine Tartrate on Prolactin and Growth Hormone ...

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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esEn-

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E., AND WAGNER, H. R. (1969). 2-Br-aErgokryptin: Beeinflussing von Fertilitat und Laktation bei der ratte. Experientia 24, 1130-1131. GROSVENOR, C. E., AND 1’URNER, C. W. (1956). Ergotamine, oxytocin, and milk let-down in lactating rats. Proc. Soc. Exp. Biol. Med. 93, 466-468. GROSVENOR, C. E., AND TURNER, C. W. (1957). Evidence for adrenergic and cholinergic components in milk let-down reflex in lactating rats. Proc. Soc. Exp. Biol. Med. 95, 719-722. GROSVENOR, C. E., MENA, F., MAIWEG, H., DHARIw, A. p. 5., AND MCCANN, S. M. (1970). Effect of hypothalamic extracts and exogenous prolactin reaccumulation

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H. R., At4t SHELESNYAK, M. C. (1967). Effect of ergocornine on ovarian synthesis of progesterone and 20a-hydroxy-pregn-4-en-3-one in the pseudopregnant rat. Acta Endocrinol. 56, 27-34. LINDr.JER, H. R. LUNENFELD, B., AND SHELESNYAK, M. C. (1967). Plasma levels of progesterone and cortisol, and urinary pregnanediel excretion, during the post-ovulatory phase of the cycle in normal and ergocornine-treated women. Ada Endocrinol. 56, 35-42. MACLEOD, R. (1969). Influence of norepinephrine and catecholamine-depleting agents on the synthesis and release of prolactin and growth hormone. Endocrinology 85, 916-923. MALVEN, P. V., AND HOGE, W. R. (1971). Effect of ergocornine on prolactin secretion by hypophysial homografts. Endocrinology 88, 445-449. MANTLE, P. 0. (1968). Inhibition of lactation in mice

LINDNER,

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ergot from

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H., AND MELTES, J. (1970). Suppression by ergocornine and iproniazid of carcinogen-induced mammary tumors in rats: Effects on pituitary and serum prolactin levels. Proc. Soc. Exp.

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