Further acquisitions on gonadal function in bromocriptine treated hyperprolactinemic male patients

Pharmacological

Research

FURTHER

Communications,

ACQUISITIONS

ON

TREATED

D.

Zini,

C.

Department

of

GONADAL

FUNCTION

HYPERPROLACTINEMIC

Carani,

A.

Baldini,

C.

Endocrinology,

601

Vol. 18, No. 7, 1986

MALE

Cavicchioli,

D.

University

Received

IN

of

in final

BROMOCRIPTINE

PATIENTS.

Piccinini

Modena,

and

P.

Marrama.

Italy.

form

2 May

1986

total

and

free

SUMMARY The and

the

diurnal

variation

gonadotropinemic

hyperprolactinemic during

treatment,

basal

the

variation

test

levels

bromocriptine,

diurnal showed

of

LH.

response

(basal

to

of

of in

the

LH-RH

diurnal

PRL

various

dopamine

agonist

tT

but

also

both

tT

and

fT

was

absent.

response

peak,

caused the

of

the

were

with

pattern

normal both

of

possible

and

fT

of

significant The

of

Moreover,

normalization

a

function.

of

together

secretion

besides

levels

group

drug.

of

of

a

fT)

before

only

and

and

in

not

LH

sexual

evaluated

(tT

microprolactinoma

known

variation) in

at

pituitary

well

testosterone

were

therapy

improvement

levels are

LH

LH-RH

levels

Bromocriptine

and

an

a

a delay

of

levels

and

plasma axis

with

Before

LH-RH

levels

males

with

secretion fT

to

therapy

and

basal

plasma

response impotent

decreased the

of

tT

the and

of

decrease

in

PRL

effects

of

high

hypothalamus-pituitary-testicular

discussed.

INTRODUCTION Hypogonadism 1978;

Marrama

et

infertility

(Carter

literature

are

levels

of

pins

(Carter

has

been

tT

is al,

not and et

little

al,

in

agreement;

1978;

0031-6989/86/07060149/S03.00/0

in

and

et

research

known

1984)

normal, al,

well

1978).

low

it Its

is origins

et the

are

even al,

diurnal

(Carter

accompanied

studies

sometimes

Lafuenti

hyperprolactinemia

often

many or

into

male

1981;

by

still

unclear

have

shown

increased MC variation

and

of

and in plasma

gonadotro-

al,

1983).

testosterone,

The Italian

al,

findings

decreased

et of

0 1986

impotence

levels

Neilly

et

There which

Pharmacological

Society

602

Pharmacological

appears

to

1976,

1978)

be

absent

and

is

during maintained

Research

Communications,

Vol. 78, No.

7, 1986

acute

induced

hyperprolactinemia

(Rubin

et

al,

during

chronic

hyperprolactinemia

(Murray

et

al,

1984). The

results

hypogonadism testes,

is

or

itself

if

at

the

literature

attributable

it

the

in

is

secondary

have

to

a

to

a dysfunction

left

primary

hypothalamus-pituitary

unanswered

effect

of

high

induced

axis

or

to

levels

by

a

the

the

question

of

PRL

if on

the

hyperprolactinemia

modification

in

dopaminergic

tone. Our patients as

study

with

well

as

pattern, et

at

al,

before

aimed

at

a

microprolactinoma the

which

ma

was

study

we 1984).

and

by of

have

the

an

already

in

of

of

variation

studied of

characterization

evaluation

diurnal

Evaluation

during

further

the

of

and

with

of

the

bromocriptine,

of

LH

(Marra-

patients

a

well

fT,

secretory

work

male

in

variation

preliminary

hyperprolactinemic

treatment

diurnal

tT

a previous

hypogonadism

was

known

made

dopamine

agonist.

MATERIALS

AND We

38

yrs)

group

studied

with of

adult

or

any

The from

ne,

which

period

was

To

in

testosterone ma

et

preceded was

sexual

the

al, by

measured

at

7.45, in and

performed

1984).

The

an

ultrafiltration a

commercial

by

CT

which

the

before

did

subjects

and in

scan, not

were

during

doses

of

and

have

a

any

age control

endocrine

hospitalized.

treatment between

(mean

5 and

axis

was

with

bromocripti-

15

evalua-

mg/day

for

a

months. levels,

8.00 this

and

8.15

report

of

the

according assay

patients

hypothalamus-pituitary-gonadal

orally, 8

yrs),

testosteronemic

morning

by

35 All

the

3 to

value

was

hyperprolactinemic diagnosed

age

viewpoint

taken fT

male

alteration. of

from

and

16

(mean

administered,

were

samples

males

determine

tT

of

microadenoma,

hormonal

varying

Each

group

functioning an

samples

a

pituitary

12

pathology

ted

METHODS

of

is 3

step,

and

the

average in

free

(Biodata

5.45,

men and

the

evening.

Vlahos Ltd.

et

RIA method

serum al, Milan,

blood

6.15

measurement

of

Co.

of 6.00

described

fraction to

groups

at

a previously

according kit

both

a.m.

samples to

the

in

p.m.

of

the

3

of

serum (Marra-

testosterone

was

1982.

PRL

Italy),

Serum using

a

Pharmacological

Research

Hyperprolactinemic - before - during Control

Communications,

Vol. 18, No.

fT

tT

(ng/dl)

treatment treatment

4.5 9.8

subjects

12.6

*

1:

serum

levels

and

during

+ 19.1** i 45.0

8.8 9.9

+ 1.3 il.35

+

607

+ 42.4

7.8

+

1.3

p CO.01 treatment p
vs

fT,

LH

of

hyperprolactinemic and vs control vs control subjects

tT,

and

bromocriptine

Hvoerorolactinemic treatment treatment

4.5 9.8

subjects

2:

double

12.6

the

morning-evening re and during

antibody

London)

as

men

+ 79.8** i 6.85*

8.0

during

+

1.0

bromocriptine

subjects (mean

hyperprolactinemic

and

in

men

control

+ SE)

before

subjects.

tT evening

(ng/dl)

morning

evening

high

was

assessed

in

basal

i.v.,

sampled

at

0,

antibody mUl/ml,

+ 0.5 + 0.7

NS **

206 482

+ 19.1 +_ 45.0

196 352

+ 13.1 +_ 34.2

NS **

+

8.5

+ 0.6

+*

607

+ 42.4

471

+ 32.3

**

1.3

vs

morning

of

dose

15,

30,

using

coefficients

1.5

interassay they and

45,

tT

(mean

in hyperprolactinemic and in controls.

MCR-222/71 was

and

levels

fT and treatment

with

conditions

technique, the

5.1 7.1

Sensitivity intra-

the

+ 0.5 + 1.1

peO.01

of for

0.5

in

345.0 40.2

1.2

(ng/dl)

method

a standard.

respectively,

was

PRL

treatment

variation bromocriptine

RIA

coefficients

double

(ng/dl)

men

**

Tab.

PRL

206 482

fT

Control

(mUl/ml)

+ 0.5** +_ 1.1

morning

- before - during

LH

(ng/dl)

men

**

Tab.

603

7, 1986

60, the of

For

9.4%

after 120

interassay

LH-RH was

as

serum and

8.3%,

respectively.

with RIA

befo

Council,

control 5.3%

ll.O%,

IRP-HMG and

Research

were

and

mins);

men

low-dose

stimulation

second intra-

rig/ml. variation

were

90,

(Medical

+ SE)

LH

(100

performed

mcg, by

standard.

Sensitivity

variation

were

5.3%

a

604

Pharmacological

Research

Communications,

Vol. 18, No. 7, 1986

Pharmacological

Research

Communications,

libido

Hyperprolactinemic - before - during

subjects

1.4 3.1

+ 0.4** + 0.4

3.5

+ 016

** ’

Tab.

4:

and

9.89/o,

sexual criptine

behavior treatment

means

score

of

to

libido

4 = always). All

t-0.4** + 0.4

3.4

+ 0.6

patients subjects.

1

were

area

Student’s

t

and test

of

Results

O

1.5 2.5

+ os* + 0.4

3.6

+ 0.8

o

hyperprolactinemic treatment

before

Whitney’s

U

sexual

=

and

during

bromo-

the

paired

and 3

mean

+

under to

evaluate

hyperprolactinemic evaluation

were

The

the

4

was

patients

as

each

of

curve

the

corrected between the

well

=

LH

subject,

unpaired

employed

by

very 3

difference

test

analyzed

=

response

patients, t

a

sometimes,

response

hyperprolactinemic Student’s

=

for the

attributing

strong,

2

SE.

therapy

by

=

rarely,

calculating,

area

in

bromocriptine

moderate, 1 =

by

order

during patients

never,

as

In

the in

of

=

analyzed

shown

used;

bromocriptine

2

integrated

values

was

variation.

slight, (0

area).

and

individual

expressed

the

(delta

values

=

was and

before

with

ejaculation

results

attained

basal

evaluated

absent,

administration

level

effects

= and

the

LH-RH

control

1.4 3.1

* ~~0.05 vs p
interviews

(0

often,

for

o

hyperprolactinemic and in control

was

guided

erection

peak

in

adequacy

strong),

to

ejaculation

respectively.

Sexual by

erection

men

treatment treatment

Control

605

Vol. 18. No. 7, 1986

as

means

to fT

study and

of

Mann

test.

RESULTS Basal

levels

of

both

tT

and

fT

were

significantly

decreased

tT

during

606

Pharmacological

hyperprolactinemia, 1,

2).

with

Therapy

PRL,

induced

ning

biorhythm.

It

was

after before

analogous

and

delay

in

to

during

preceding drop

peak drug

in

substantially

all

leading,

in

improved

not

by

variation

with

levels

not

levels

to

LH-RH

of

bromocriptine

The

secretion

serum

pattern

LH

found

a

and

those

to

3).

to

In

the

a

progressive

impotence,

(Table

both

tendency

reported

treatment

inverse

modification

(Table

cases,

plasma

morning-eve-

significant

only

interviewed

majority

the

significant

(Tables of

a

of

we

patients

the

that

any

LH

of

emerge.

basal show

of

the

decreased

restoration

bromocriptine;

response

therapy,

did

Vol. 18, No.

morning-evening

with

The

did

Communications,

however,

fT.

with

the

fT

PRL

of

LH-RH

of

desire,

and

that

therapy

in

emphasized,

levels

with

the

be

fT

of

together

increase

should

stimulation

loss

bromocriptine,

between

tT

complete

a significant

correlation of

with

a

Research

period

which

was

incidence

of

4).

DISCUSSION The

group

hypogonadism

of

and

agonist,

impotence,

bromocriptine.

(Marrama

et

function,

were

al,

1984),

in

testosterone,

is between

the

med

but

also

our

previous

observations

Murray

et

the

by

Rubin

other et

haloperidol tT.

hand, al,

our (1976, with

TRH

The

lack

of might

level,

are

1978)

and

hyperprolactinemia peripheral

findings

who and

be

due

hyperprolactinemia

1984).

in

observed

the

various

the

testicular

incidence levels

of

of

serum

to we

be also

altered confir-

diurnal

variation

of

This

finding

contrasts

with

the

levels

acute .loss fT

central may

of

appeared

with

of

studies

1984). fT

agreement

variation to

index

of

serum

prolactinoma

an

dopamine

previous

diminished

of

pituitary

induced

diurnal

loss

the

in

microadenoma;

evaluated

with

as

al, of

the

al,

who

patients

et

pattern

et

with

authors, by

pituitary

high

sensitive

various

(Murray

to

(Marrama

male

levels,

demonstrated 90%

a

therapy

a more to

with

1984,

tT

levels,

relating

al,

by

only

secretory males

hyperprolactinemic On

fT

and

diurnal

men

of

not

as

63%

hyperprolactinemic

results

the

fact,

patients,

the

hyperprolactinemic

serum

In

showed

corrected

According

these

Moreover,

males

mostly

decreased.

hypogonadism

in

hyperprolactinemic

cause

of the

tT

tT

the in

varying

the

observations

made

of

and

peripheral

some

with

diurnal

and

tT

10

sizes.

hyperprolactinemia of

in

rhythm during

modifications

of

chronic

causes.

At in

the

7, 1986

Pharmacological

Research

autonomous also

nervous

alter

the

Miyatake of

et

PRL

the

1980).

LH

morning of

the

also

PRL

and/or

that

suprahypothalamic and

1978;

(MC fT

The

1978).

It

circadian

al,

DA,

and

1982;

be

receptor

Lloyd

the

al,

pituitary

we

found

of

fT

1975,

basal

of of

response

of

tT,

content

These

results or

al,

the

as pulse

restoration

bromocriptine

be

played

by

the

hypothalamic

and

events, al,

such

1973;

as

Boyd

and

1984). ergot well

nervous and

(Goldstein

system

level,

reduces

Johansen

et

reduces

derivative,

known

the

hypoprolactinemic

1978;

the

vivo

and 1985;

were a

may

al, the

hyperprolactinemic

normal

changed

to

et where

turn-over

of

effects

seem

1985).

Moreover,

mitosis

rate

pattern

,

and Glowinski, Vierhapper,

in

partially

due

to

to

of

1972; 1985).

even

LH

et

al,

tone

has

been

if

reports

Rotszejn

et

al,

feed-back

by

therapy

with

the

hypothalamic

1983).

turn,

Both cause to

Judd

in

the

hyperproan

altered

stimulate

conflicting 1977;

levels

peak

in

reported are

lower

a delayed

or,

may

regarded,

the

found

in

of

Neilly

DA

of

modifications

dopaminergic

vitro,

threshold we

is of

corrected

content (MC

as

presence

Moreover,

LH-RH in

men

the

central

pituitaric

changes

in

was be

the

latter

and

in

LH

in

which

in

secretory

Kordon et al,

its

pattern

the with

et

is

testosterone.

LH-RH,

itself

both

nocturnal

semi-synthetic

bromocriptine

suggests

to

of

gonadotropin

of

circulating

LH-RH,

responsiveness lactinemia

levels

to

LH

of

to

may

al,

receptors

secretion

which

LH

bromocriptine.

related

in

central

where

that

gonadotropin

that

response

1970; Tasaka

found

the

et

emphasized,

1975;

cells.

for

and

level,

be

(Sassin et

the

(DA)

(Goldstein

lactotrope As

dopamine

peripheral

mediated

et

release,

to

at

should

Finally,

may

al,

altered

treatment

PRL

Murray of

both

et

chronobiological

of

it

an

involved

important

testis;

level,

role

be

the (Rowe

1983).

(bromocriptine),

binds at

al,

during

to

secretion

place

LH

been

primary

activity

takes

bromocriptine

tT

known

2-Br-alpha-ergocriptine-mesylate al,

et

important

et

to

has

of

of

dopaminergic

cells

Neilly

and

is

Marrama

of

hyperprolactinemia

regulation

phases

vascularization

testosterone

an

which

607

7, 1986

hypothalamus-pituitary

LH of

tone,

Reicklin,

the

of

variation

the Leydig

during

secretion

dopaminergic

dream

in of

At

peak

suggest

Vol. 18, No.

and

secretion

diurnal

does

system responsiveness

al,

and

secretion of

Communications.

LH

(Kambery, et

al:

1979;

608

Pharmacological

Research

Communications,

Vol. 18, No. 7, 1986

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