BIOLOGY

OF

REPRODUCTION

45,

523-532

(1991)

REVIEW Effect

of

Stress

on

the

Activity

of

Peripheral

Foundation

Laboratories

Hypothalamic-Pituitary-Gonadal

and Central

CATHERINE

The Clayton

the

RIVIER2

for

Peptide

Axis:

Mechanisms1

and

SERGE

Biology,

RWEST

The Salk

Institute,

La Jolla,

92037

Ca4fornia

ABSTRACT This article

reviews

sites at which

ical

rotransmitters level

are

are

a variety

gonads, may

of hormones

inhibitory

adrenal

the

or

strcssinduced

emphasis

action

ability

of stress

chiatric disorders, to interfere with

pituitary

responsiveness

in mediating

neurotransmitters, of both

the

been

recognized

and

where

[1-4].

possible

effect

relationship gators

POMC

stresses

sex

steroid

the

rat

on

secretion,

early

panied

sought

stress

alters

observation

by both

an

ductive tex gested

at the

axis

in the axis

(which

are

released

during

June

Received

January

‘This Clayton ical

by the

Foundation

Research

Council

2Correspondence:

Pepride

Biology,

The

stress)

the cor-

had

axis.

sugof the

and

22,

those

of

Indeed,

cor-

pro-opiomelanocortin

grants

by NIH Foundation

Investigator.

SR

for

as ACTh and 13-endorplay a very important role on reproductive functions.

holds

DK26741

and

Research,

California

a postdoctoral

HD13527 fellowship

and was Division.

C.R

con-

Catherine

Rivier,

The

Clayton

10010

North

Torrey

Foundation

Laboratories

Pines Road, La Jolla,

CA

circulating

evidence

acute

that

stimulus.

act within

the

these

In contrast,

brain

to mediate

hormones can influence of the HPG aXiS: the brain pituitary the

(to

interfere

gonads

(to

sexual functions (to inhibit GnRH

with

alter

and

all the

the

mechanisms

GnRH-induced stimulatory

review inhibits

will discuss gonadotropin

to the rat. We the word “stress”

the

homeostasis

that

various

the

nomenon

well

However,

we

each

study

Thus

the

through steroids at

would

recognize,

case

HPA

type

of stress

the

needlessly

lengthen

remember without

that

by

androgen

values exercise

teration

in plasma

caused appear

rate,

The

decrease

to result with

to be

volume

clearance

from strenuous

than

in metabolic a decrease exercise

inor

to an acute increase changes

but

short-lived

primarily

by an

as a decrease

a true

for

review.

otherwise

short-lived In humans,

strenuous

[7-9].

used

to physical

intensity. exposed

caused

as well

rather

unless

often levels.

a pheaxis

this

differentiation

in

of course,

pathways,

of the

stimuli of various length and and intact rodents [10-131

physical

occurs 523

to mention

refers

mechanisms and/or sex

We

and

ered

for

felt that should

in-

to provide The first

different

stress respond with a small in plasma LH and testosterone

[14-161.

92037.

in the

reader

been

mentioned discussed.

alterations of GnRH reof the work reviewed

activate

studied

“stress”

have

does pub-

the second part will be desystem (CNS) pathways in-

organism.

may

quoted

effect

review of the

would also like to emphasize that to mean any stimulus that disturbs

of the stimuli

that

will be phenomena

in mediating stress-induced In both parts, the majority

bolic

is a

of Canada.

Salk Institute,

amities

and

emotional Humans

the Med-

from

of an

factor

Increased

increasing

those

biogenic

literature

dicated,

1991.

Clayton

not

the

pertains we use

1991.

was supported

work in part

ducted

14,

to

hormones

(HPG) (CRF),

hypotha-

adrenal

activity)

between

(POMC)-derived peptides (such phin), and adrenal corticosteroids in modulating the effect of stress

Accepted

neu-

function.

volved lease.

in repro-

attributed

of gonadal

factor

of the

cells.

the pituitary and gonadal level; voted to the central nervous

is accom-

a decrease he

hypothalamic-pituitary-gonadal

ticotropin-releasing

activity and

of preserving

relationship

in

mechanisms

stress

and

part of this which stress

functions.

phenomenon

expense

or

corticotropin-releasing

voked. Selected references illustrative examples of the

investi-

process,

the

peptides,

and

is, however, but

reproductive

lished

the

on LH and

ovulatory

[6] that

of emergency,

a possible

HPA the

(a

and the anatom

of hormones

of gonadotropins on sex steroid secretion). This not pretend to present an exhaustive overview

reproductive

stresses

reproductive

(HPA)

in case

function

as the

increase

functions

necessity,

discussed

determine

by Selye

lamic-pituitary-adrenal

of the

many

of various

to

role

steroid-producing

There stress,

LH release),

studies and

GnRH.

peptides,

sex

secretion),

exercise) has long else-

Subsequently,

as well

have

which

The

effects

functions

modulating

Stress-related at all three levels

psy-

reviewed

functions density

[51.

the

been earliest

sexual

rodents

studied

and

through

on

of the

diseases,

strenuous functions

has

population

in wild have

and

one

of stress between

efficiency

trauma, and reproductive

In animals,

of reproductive

potential

on

of prolonged

CRF,

prolonged

infectious

by clinicians

the

(POMC)-like to

effects

including

acute

(including

surgical human

on

of gonadotropins

INTRODUCTION The

inhibition

is placed

pro-opiomelanocortin

stimulatory

decrease

involved

influence

to mediate

Particular

corticoids,

with

also

primarily

place.

stress.

to interfere

levels

mechanisms

believed

take

during

of the

reported

corticosteroid

the

effects

released

At the (CRF)

the mechanisms

these

alteration clearance

of release was

in hepatic

blood

of short

duration

al-

in metaconsidflow [17].

that In

R1VIER AND RIVEST

524

rodents,

the

release

are

mechanisms not

responsible

well

for

understood,

but

the

one

increased

hypothesis

LH con-

antagonist inhibitory

into action

port

[20,21] increase in basal

parable to that seen in rats with intact adrenals unpublished results). Stress-induced changes in pituitaiy and/or

membered

that

neurons, hibitory

stress

which effects

activates

hypothalamic

in turn exert complex on GnRH release [25].

that circulating sex steroids to stress [10, 19, 26], possibly renergic neurons [27]. Prolonged stress, to inhibit LH release

on the other [11,20,28-351

stimulatory and inThus it is possible the LH response effects on a-ad-

hand, is consistently found and to block ovulation

[31, 35]. Because stress effort has been devoted

also activates to determining

derived peptides, and/or stress-induced inhibition pretation of the results,

adrenal corticosteroids modulate of reproductive functions. Interhowever, is often complex because

experimental docrine

manipulations changes.

For

the HPA axis, much whether CRF, P0MG-

usually

example,

result

removal

in multiple of circulating

encor-

ticosteroids by adrenalectomy also increases AGTH and possibly CRF release [36-39]; administration of exogenous CRF, which acts within the brain to inhibit LH and GnRH secretion axis; and

[40-42], increases

sequences induced

also alters the in corticosteroid

at the level of both LH release) and the

cretion). Nevertheless, while the immediate on

central

activity of the levels can have

HPA con-

the pituitary (to alter GnRHbrain (to modulate GRE se-

currently response

mechanisms,

overall

available to stress

prolonged

results depends

exposure

suggest that primarily to a stimulus

is additionally modulated fects of hormones from involving chronic stress

by pituitary and/or gonadal efthe HPA axis. Because situations are most pertinent to human pa-

thology,

focus

diate

this the

review

will

consequences

on the

of such

mechanisms

a stress

on

that

often

of the

GNS,

rather

than

peripheral

humans,

observed

the

during

by elevated as Gushing’s

inhibition

gonadal

Sites

MEDIATE THE INHIBITORY EFFECT STRESS ON REPRODUCTIVE FUNCTION

of Action

observation

that

GRE

is released

during

stress

[43]

into the brain GnRH secretion physiological

ventricles (discussed relevance

by experiments

of rodents and primates inhibits in detail later in this paper). The of this observation was demonshowing

that

the

injection

of a GRE

refunc-

circumstances

of circulating

syndrome)

Rivier,

of sexual

pathological

levels

(C.

usually

ac-

corticosteroids

disappears

after

re-

turn to normal of exogenous in the activity

adrenal function. Treatment with large doses corticosteroids often causes adverse changes of the HPG axis [45]. In animals, adrenalec-

tomy

known

is well

to

alter

reproductive

parameters

in

general [46] and LH secretion in particular [47, 48]. Furthermore, the adrenals are necessary for the immediate occurrence of castration-induced LH and FSH rises [49, 50]. These observations have suggested the involvement of adrenal corticosteroids as regulators of sexual functions and have prompted studies aimed at determining whether such effects take place at the pituitary or the gonadal level. In the

rat,

pharmacological

doses

terfere with GnRH-induced part of the inhibitory effects at the

pituitary

level

published results) tuitary responsiveness

of dexamethasone

LH secretion of corticosteroids

[52-58].

However,

[511,

acute

in-

and at least are mediated

(G. Rivier,

or chronic [59] stress does not to GnRH, and adrenalectomized

un-

alter

pirats

also respond to prolonged stress by a significant decrease in plasma LH levels (C. Rivier, unpublished results). This suggests that at least in the rodent, increased levels of circulating corticosteroids lators of stress-induced there

is little

doubt

tion

of GnRH

itself

Gonadal above,

and the close anatomical proximity of GRE- and GnRH-secreting neurons [44], suggested the possible involvement of endogenous GRE as a mediator of stress-induced inhibition of reproductive functions. Indeed, injection of GRE

strated

In

companied (such

role

the sup-

in mediating the early response to stress observation that adrenalectomized rats rewith a decrease in plasma LH levels Com-

that

do not inhibition that

represent the sole moduof LH secretion. Indeed,

corticosteroids

[48,49,

site

of action.

stress

lowers

can

alter

the

secre-

53, 60-63]. The observation, plasma testosterone

discussed levels, has

prompted discussions as to whether such changes by decreased LH secretion or by the direct effect

MECHANISMS THAT OF PROLONGED

The

tions

me-

reproductive

functions.

Peripheral

corticosteroids, came from the spond to stress

sponsiveness.

noradrenergic

may modulate through their

primary

brain reverses [33]. Further

cerns the direct stimulatory effect of AGTH on GnRH-secreting neurons [121. The response of gonadectomized rats to acute stimuli appears less consistent, with reports of transient increased [18, 19], decreased [10], or unchanged release. While it is possible that a modest initial might be masked by the large episodic fluctuations gonadotropin secretion [22-24], it should be re-

for the

the ventricle of the rat of stress on LH secretion

derived

peptides,

corticosteroids,

and/or

al level

[64-68].

It is important

to emphasize

are caused of P0MG-

GRE at the that

gonadsimple

comparisons between plasma LH and testosterone levels in the rat can be misleading. First, testosterone is secreted episodically [22], and its marked individual fluctuations render single measurements cussed above, stress can increase LH and correlated.

in LH values, testosterone Caution

sults unless ing stress. secreted on

the

followed values should

they represent Nevertheless, during

gonads,

mostly initially

stress

invalid. Second, be accompanied by a decrease.

as disby an

Thus

may or may not appear be exerted in interpreting

serum to be re-

longitudinal measurements durthere is evidence that hormones might

in particular

exert through

direct

inhibitory

decreases

effects in gonadal

INFLUENCE

sensitivity for

to gonadotropins

GRE

found adrenal

[70-73]

[66, 69].

and

Obviously,

each

mediating

the

adrenal

glands,

reduces

basal

testicular

effect

to regulate [1, 81-83].

of stress

levels

contain could

[79].

In the

infusion

testosterone

The

are for

a role

presence

in

peptides

[683, and

the

potential

role

of such peptides, some of which are produced by Leydig cells [84], is suggested by the observation that testicular opiates appear to regulate Leydig cell function [65, 85]. CRF is also present in the rat testes [70], where it exerts inhibitory effects on steroidogenesis increases GRE biosynthesis intriguing possibility might similarly be play a physiological bition

of sex

As a final

[71,73]. The observation that in the brain [86] suggests

stress the

that the production of testicular stimulated and that this peptide role in mediating stress-induced

steroid note,

GRE might inhi-

results

response

present

has

in the

been

literature

tially explained by the ranking position specific experiment, such as has been and rhesus monkeys [87-89]. Stress-induced Stress

decreases

discuss (in

Changes

possible

particular,

those

peptides, stress

and/or and

The

have

reported

an

of

throughout

female the

septal

and

pothalamus. More than project to the median ence

LH secretion

and

this

section

of various

that

are

In the

during

neurons. cell

preoptic

will opioid

bodies

are

widely

areas

and

rat basilar

in the scattered

anterior

70% of these cells are eminence (ME), where

[90,91].

par-

pathways

activated

GnRH-secreting

(1200-1400)

exert in the

GNS

ism’s

responses

[90,91,93-95],

the

precise

hy-

thought to they influ-

forebrain,

medially, descending

see Page has been

mechanisms

tem can be altered under several from being completely understood. eral factors itory action roanatomical

[44].

terminals,

GRE

since

the level ever, the

and

main

factors on

stress

that

at what

an-

recognized

GnRI-l

to

secretion

is

or neuromodulator

in the

integration

[8,33,42,96,

which

it

GRE

could

effects

also

inhibits

of neurosecretory physiological the

of an organ-

97].

However,

influences

GnRH

the release

directly

the

act

in vitro

on

GnRH

release

nerve

of GnRH

at

terminals in the ME [40]. Howrelevance of these pathways in me-

of stress

on

the

Indeed,

HPG

axis

whereas

activity

the

iv.

seems injection

of GRE does not influence the activity of the HPG axis in the rat [42], it significantly decreases plasma LH levels in primates [104]. In addition to the parvocellular neurons of the paraventricular nucleus (PVN) of the hypothalamus the majority of the GRE fibers reaching ME),

GRE-immunoreactive

cells

(which external

the and

contains lamina

fibers

have

GnRI-l-

periventricular nuclei of the preoptic area [105]. recently observed that infusion of GRE into both the medial preoptic area (MPOA) GnRH release and plasma LII levels female

rats

bearing

a push-pull

Plotsky

and

Rivier,

unpublished

GRE axon terminals resent the primary axis

during

and

a lat-

in the

me-

[92]). Although well described

by which

that

stressing conditions Moreover, while

in the brain are recognized on the secretion of GnRI-I organization that underlies

ons

the

forming

also

participate stressed

is far sev-

The medial

however,

location the

the MPOA,

significantly in ovariectomized

cannula

remains

ME (Rivest,

Whether

or

GRE-GnRH

since

to be determined. from

GRF-immunoreactive

regulation

106].

the

synapses

The CRF-GnRH synapses connections from GRE cell

neuronal

axare

could, in body cells bodies

Afferents from other GRE neurons could

of GnRI-I

not repHPG Fur-

which

immunoreactive

activity

were hyalso in

animals. activity of the GRE neurons located in the ventroparvocellular neurons of the PVN varies during the

estrous cycle [1073, which suggests role for the PVN in the regulation stress

decreases (O()

in the

results).

of GRE perikarya

in this area [105, or extrahypothalamic in the

We have sides of

in the MPOA of the hypothalamus mechanism for the alteration of the

is still unknown. represent local

identified pothalamic

sys-

as having an inhibneurons, the neutheir influence on

stress,

thermore,

within

originating

dial forebrain bundle (for review, the GnRH system of the rat brain

through

neurons

system

and

brain,

influence

stress

the

es-

be confollowing

act?

of the

a role

to

still

are not fully understood and are likely to involve the activation of other pathways, such as those dependent on endogenous opiates [98-1011 and/or catecholamines [102, 103]. Additionally, there are direct anatomical connections between GRE axon terminals and dendrites of GnRH-secreting

ME: a periventricular

laterally

plays

to be

can during

as a neurotransmitter

and

mechanisms

derived theory,

originating

acts

in the

they

One

remains

secreted

system

inhibitory

which

are arranged in the shape of an inproject caudally and ventrally to the

system

factors

do

CRE.

a potent

containing perikarya verted V. Two systems eral

the

location(s) of

stress reached addresses

been identified in a number of other telencephalic, diencephalic, and brainstem structures, including the medial and

GnRH-containing

rats

be

used in any in baboons

on GRE, endogenous on

GnRH

of the

effect

amines)

impact few

might

of rats reported

secretion,

dependent biogenic

the

affect

a severe

conclusions This section

to be species-dependent.

Function

modulating

relatively

brain

in CNS GnRH

the

may

diating

production. testosterone

to increase under “fight-flight” types of stimuli and to decrease during stresses accompanied by depression [1]. It would therefore be of interest to determine whether the conflicting

are

CRF,

of corticosteroids

during

what

Role

in

system

Thus many speculative.

questions: atomical

functions directly is generally accepted is reported to increase intratesticular

of P0MG-derived

GnRH

rats

alteration

FUNCTIONS

tablished. sidered

of the

to male

an

ability

the

mRNAs

[74-76]

play

through

REPRODUCTIVE

ON

receptors

of AGTH

levels

to LH [80].

gonadal Restraint

also

hormones

prolonged

and

peptides

which [77,78].

of these

sensitivity

Receptors

P0MG-derived

in rodent gonads, corticosteroids

OF STRESS

conditions.

However,

we

a possible physiological of LH surge under nonhave

recently

observed

that

526

R1VIER

complete with This

destruction

of the

the inhibitory observation

ence

of the

served

failed

PVN

effect of stress is not consistent

on with

in the

of HPG

PVN

during

whole

decrease

physical

and

chronic

AND

axis

stress.

rat contain

to interfere

LH secretion a substantial

[108]. influ-

male

rat

[127],

our

ence

on

the

without

neurons Another functional is the

having

during

anatomical relationship

central

tains a large minals [109] secretion the GeA

a major

effect

on the

activity

region between

amygdaloid

of potential GRE and

nucleus

number and has

(CeA).

of GRE-containing been implicated

of corticosterone cause a striking

This

two

efferent

pothalamus the

are

amygdala

the

the

the

and

preoptic

dalofugal project

pathway [113]. The to the dorsal medial The

area

(ST)

that

connects

POA, division

in turn, of the

in plasma

regions,

which

activate

(EOP)

interaction and

between

endogenous

GnRH-secreting

neurons

has

detail elsewhere [79, 118]. Opiate concentrations in the hypophyseal naloxone increases GnRH release thalamic fragments [120, suppress the proestrous physeal portal system of trophysiological activity generator in the rhesus cepted that EOP exert a HPG axis and that the rat mediobasal

opioid been

peptides portal from

reviewed

the

infundibular

because metrical [125].

in this synapses Furthermore,

on GnRH

neurons

lip,

just

in

decrease GnRH blood [119], and superfused hypo-

121]. Morphine is also known to release of GnRH into the hypothe rat [1221 and to alter the elecof the hypothalamic GnRH pulse monkey [123]. It is generally actonic inhibitory influence on the

below opioid GnRH

almost present

the

arcuate

peptide somata

10% in the

of the diagonal

a direct generator occur at

nucleus

(ARC),

axons formed and proximal synapses band/POA

exerts

Despite

a robust

neurons

the

fact that

are

gland,

tractus [128].

solitarius The highest

has

been

ARG

in the

of the

in the

innervate

brainstem, and of P0MG-de-

ARC

other

POA [125, 126, by horseradish

anterior

hypothalamus,

(NTS) of the concentration

found

influ-

sexes.

synthesized

the

neurons

as the labeled

monosynaptic

of both

pituitary

these

gions such trogradely

[129],

and

it is

hypothalamic

130]. Indeed, peroxidase

re-

perikarya (HRP)

rewere

observed injection suggest

throughout the ARC of the hypothalamus after the of HRP into the MPOA [130]. These observations that P0MG peptide-producing neurons in the yen-

tromedial neurons

ARC project to the MPOA and that some of these establish direct synaptic contacts with GnRH-im-

munoreactive

cells

maturation for p. and

in the

participate the

the

13-END,

Influence

of GRE

directly

P0MG

CRE

or

on

the

GRE stimulates

ligand highly

Thus

there

ARC to the via

is

MPOA

p. receptors

during

in

stress.

prodynoiphin-derived regulator

within

of the the are

132].

activity

POMC-and

above,

product

the

indirectly

important

molecule

and

from

neuronal

is an

13 5]. As mentioned

[128,

neurons

of GnRH

peptides.

a major

[131], represents and p. receptors

hypothalamus

P0MG

either

inhibition

of the

[130].

process of P0MG receptors [131], that

to increase However,

opiates act directly on GnRH neurons in hypothalamus through specific recep-

region with

[126].

the

of the

hypothalamus the

synthesis

adenohypophysis

[133-

contains

release

P0MG

of 13-END

from

hy-

pothalamic slices in vitro [136]. Because the ARC is the major hypothalamic zone that synthesizes P0MG-derived peptides [128], it is conceivable that GRE acts within this area

peptides

tors [121, 124]. In juvenile female rhesus macaques, inhibitory influence of EOP on the GnRH pulse neurons of the ventral hypothalamic tract could

that

neurons,

secre-

tion. Consequently, it is possible that the GeA, through activation of the GRE neurons in the MPOA, modulates GnRH neuronal activity during severe stress. Role of endogenous opiates/POMC-derived peptides. The

peptides

cor-

was inhibited that the structo other hy-

adrenocortical

rived known

evidence

amyg-

rise

nucleus placenta

concentrated

a ventral

ticosterone that follows amygdala stimulation by a bilateral MPOA lesion [114], suggested ture in the MPOA transmits neural impulses pothalamic

hy-

terminalis

the

the

the

stria

and

BNST and parvocellular

to

(which

of the

[POA])

observation

whereas dehyperse[112]. In rats,

amygdala

nucleus

[BNST]

PVN [114-117].

the

terminalis bed

ter-

[110]. Bilateral lesions of in the GRE-like immu-

from

stria

with

con-

cell bodies and in the stress-induced

in rats decrease

pathways

in the stress

nucleus

13-END

peptides

of the

the the

of GnRH

importance GnRH during

noreactivity in the median eminence [111], struction of the amygdala attenuates compensatory cretion of AGTH resulting from adrenalectomy the

lobe

stress.

(13-END)

GnRH

P0MG-derived

study was performed in male rats and it remains possible that the PVN participates in the regulation of the estrous cycle

3-endorphin

there is an approximately 3-4-fold greater 13-END input to the GnRH cells and processes in the female than in the

ob-

activity

However,

RIVEST

symaxons

impinging of the

ulate

the

the production there is no evidence activity

of P0MG

of

P0MG-derived that GRE can

neurons

in the

peptides. directly stim-

ARC,

and

do not appear to be any GRE binding sites in this lamic area [137]. Nevertheless, an indirect influence on

P0MG

perikarya

located

in the

ARC

plain the interaction exerted by these activity of GnRH neurons during stress

could

there

hypothaof GRE

in part

ex-

two (see

systems on the Fig. 1). Another

possibility is that GRE stimulates the release P0MG terminal nerves at the level of GnRI-I

of 13-END from neurons. In the

MPOA,

the suppressive

agonist, but not lins [138]. These GnRH

neurons

prior gested rectly

of GRE are

by a GnRH

reversed

may

be

due

to a direct

action

and

not

activation of 13-END systems. It has also been that both GRE and 13-END neurons may synapse with the GnRH neurons of the MPOA to reduce

activity that

effects

by naloxone or anti-13-END-gammagloburesults indicate that the effects of GRE on

of the

GRE and

GnRH

neurons

P0MG-derived

[138]. peptides,

It is therefore acting

possible

in a synergistic

and additive way within the MPOA, may exert a direct synaptic effect on the GnRH neurons and influence secretion

during

various

stresses.

However,

to sugdithe

there

postGnRH

is as yet

INFLUENCE

OF STRESS

ON REPRODUCTIVE

527

FUNCTIONS

STRESS

CRF

Intermediate factor

CRF

CRF

ACTH/3-END J,LH

,

FIG. 1.

indirectly

Synthesis

,

involved

increase;

model

in the

decrease;

to explain

?,

alteration

of the

mechanisms

the main effects of physical stress on different brain areas and peptidergic or aminergic pathways activity of GnRH neurons. DYN, dynorphin; E, epinephrine; PRODYN, prodynorphin; +, stimulation;

unclear and remain to be fully

investigated.

directly -,

inhibition;

or

528

RIVIER

no clear neurons on

demonstration affect GnRH

GnRH

their

that during secretion via

neurons.

actions

Thus

on

other

their

effects

may

hypothalamic

tems. In addition

to

the

dent

in

modulating

pathways

stress, GRE the synapses

AND

and P0MG that exist

be

indirect

via

neurotransmitter

influence

of GRE

and

sys-

P0MG-depen-

stress-induced

inhibition

of

GnRH secretion, dynorphin also represents a possible mediator of reproductive functions during stress. Indeed, blockade of the activity of dynorphin/K receptors reverses footshock-induced indicates the system

decreases participation

in

this

containing the striatum,

the

in plasma W level of the prodynorphin

neuroendocrine

stress-response.

proDYN are the amygdala, [139].

located in the the hippocampus,

hypothalamic

nuclei

the MPOA However,

significantly the mechanisms

alters

during

ways

could

be activated

The

amygdala

could

of GRE on the the GeA (which [141]) contains [111]. However,

in the

the

not

systems

injection

of dynorphin

stress

remain

a potential

of the

effects

the role

inhibitory GRE on

played

essential,

but

involved

in the

effect of secretion

LH

by the

central

effects

of GRE during

may

dynorphinergic

be additive

complex

of stressed animals. Role of biogenic amines. described the involvement

intracerebro[101]. Consesystem

stress

to the

is prob-

other

regulation

the basal ever, the nergic,

cholinergic

activity

systems

during

stress

cholaminergic system and there is extensive cholamines

in the

particular, hibit GRE and

regulation

13-receptors

activate

noradrenergic

of the

20% arises from A2 cell from the locus coeruleus

anism involved footshock stress. while a complete inhibits

in

the

of the

have

led

of the

noradrenergic concept

exert an excitatory influence is mediated by a-adrenergic

gonadotropin release. coeruleus or A1 neurons concentrations

patterns

and

its stimulatorv effects animals [147, 148].

anisms

underlying

increase

[150, 151] trochemically

by

LG blocked

LH

release

stress [8], of cate-

estrogen-primed transacting

the

induced the

to amplify

in

These observations, of an inhibitory axis. Indeed,

the

stimulation norepinephrine

on GnRH Moreover,

stimulation [149]. clude the existence catecholamine-GnRH

cate-

in non-

catecholamines

ventricle stimulates LH rethat interrupt noradrenare generally thought to

adequate

the

re-

release of LH, which Whereas injection

Electrical releases

tion via gen-treated

observed or

system that

on the receptors.

of norepinephrine into the third lease, experimental procedures ergic inputs to the hypothalamus inhibit locus

or adrenergic,

to the

have in

of the in secre-

LII

neurons in estroone of the mechthe

noradrenergic

time of the preovulatory surge of LH neuronal response to a1 adrenergic

that stimulation interrupting LH surge by

however, do not precomponent within the Dotti and Taleisnik the

of the LG, either elecadrenergic inflow to

during

stimulation

proestrus, in the

as well MPOA

of

rats. Furthermore, in these experiments, ascending noradrenergic pathways or

of GRE by parvocellular Plotsky et a!. [8]). Morehypothalamic region

the effects of the noradrenergic system in the MPOA seem to be estrogen-dependent.

on

GnRH Thus

neurons the con-

sensus

is excitatory

in the

in

fact,

arises

70% from

of

the

A1 cell

bodies, and the balance (LG) [94]. However, the pathways to be a primary

on the mech-

HPA axis

in stressed

rats,

view

holds

agents

that

that

norepinephrine

block

the

synthesis

in-

norepinephrine, prevented this inhibition. Interestingly, activation of the central noradrenergic system may inhibit as well as facilitate LH release since in nonstressed animals,

activity.

pharmacological

as OVX

ina1

axis

the alteration of the HPG axis during Indeed, we have recently observed that bilateral destruction of the PVN signifiactivation

rats

and dendrites level of the or-

lamina terminalis [146], but terminals described by this

noradrenergic,

manipulations

of GnRH

are thought to a2-receptor, while

PVN

of catecholaminergic does not seem

Acute stressed

perikarya at the

jecting

HPA

innervation;

innervation

stimulatory influence PVN neuronal activity

cantly

release

review, see characterized

are dopaminergic, to be determined.

projections to A1, A2 cell bodies terminals were

In

of the

the

known.

vasculosum of the the tvrosine-hydroxylase

The

inhibition

well

activated during for the involvement

catecholaminergic neurons release via a hypothalamic

noradrenergic bodies, arises

in the is less

is highly evidence

neurons of the PVN (for over, the PVN is the best receiving

previous reviews neurotransmitters

regulation of the HPG axis [118, 142-144]. Howrole played by the catecholaminergic, serotoni-

and

neuronal

found to innervate both the GnRH in the MPOA of the hypothalamus

neu-

rons

Several of classic

is probably not mediated by catecholamifrom the A1, A2, and/or LG to the PVN. On it is likely that catecholamines act directly

excitatory drive at the is an increase in the

multiple

of GnRH

not alter the antireproductive effects of exposure in male rats [1081. Thus the of GRE on stress-induced inhibition of

at the POA level, and indeed, noradrenergic the POA are known to arise mainly from [145]. Recently, tyrosine-hydroxylase-positive

into [140]. path-

to be clarified. site

GnRH release nergic neurons the other hand,

group mains

cortex, several

reproductive behavior by which dynorphinergic

represent

antireproductive

ably

The

cerebral and

this treatment does long-term footshock modulating action

ganum whether

Neurons

activity of dynorphin neurons, and indeed, is known to be highly activated during stress a high concentration of GRE-like material anti -dynorphin serum does not signifi-

cantly reverse ventricular-injected quently,

[101], which (proDYN)

RIVEST

of

presence of estrogen and inhibitory in its absence [144]. As mentioned earlier, GRE released by PVN neurons does not represent a potential mechanism mediating the inhibitory effects of norepinephrine on LH secretion during stress. However, ing stress,

GRE could activate the noradrenergic which in turn acts directly on

GnRH

system durneurons.

GRE has indeed recently been found to directly activate catecholaminergic neurons in the LC [102]. Thus the servation that stress markedly increases GRE concentration

the ob-

INFLUENCE in the fibers the

LG [152] and the visualization [105] and GRE binding sites

anatomic

mitter rons neurons the

substrates

within lie in

this close

in the

LG could

ation

serve

[103].

of the

are

to

a rise and

axons arriving nucleus, acts producing

see

a facilitory on

the

stress,

While

steroid

decrease ported

the

[154].

and 5-HI Serotonin,

Thus

authors

under

environment

nuclei

activity. that the

to the

This 5-HI

raphe GnRHa per-

effects studied,

seem

of the type

mechanisms

mediating

these

reproductive effects

duration, and the influence

frequency of the stimulus of the steroid milieu on

iate [25,

that have In particular,

components 159-161].

depend

is supsystem

R, Gibb

on

the

there

is strong

evidence

that

immediate

and the

the

to stress,

in the

in LH

W, Ducharme 1984;

of

the

antireof ago-

render several often conflicting be of great in-

particularly stress.

with

As a basis

regard for

such

central

mechanisms

by stress

of the

(Fig.

1).

on

the gonadal

GnRH

D, Gold and

axes.

Adv

Exp

physiology

and

J J.

stress

1988;

J

function.

En-

GP.

due

to

and

Stress the

reproduction:

stress

and

phys.

reproductive

CNS-hypothalamic.pituirarv

Reproductive

Management.

density

Population

a review.

reproduction:

245:377-387.

RB (Eds.),

Clinical

male

between

interactions

Biol

on

AN, Chrousos

anovulation

Jaffe

of stress

13:1-7.

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Med

SSC,

500-545. 5. Christian

1984;

PW,

Chronic

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of psychological

pathophvsiologic

SSC. Yen

JR

7:529-537.

Effects

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Patho-

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efficiency.

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4:248-294. 6. Selye

8.

H.

Effect

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in the

Plotskv

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P. Neural

Rivier

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Endocrinology coding

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1939;

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Inc.;

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1990:

factor

and

AUTH

and (in

ETJ, Widmaier

agents

on

the

female

sex

25:615-624.

of stimulus-induced

G (eds,),

icotropin-releasing

type,

HPG axis that “the re-

changes

mediate

have attempted to illustrate the various known and still open to question) that

of Andrologv

3. Rabin

In:

[67]. Though much remains to a better understanding of the stress response of the HPG axis, the

involved

understanding

that

of the

induced

Invest

Archives

4. Yen

activated

sponse of the pituitary-testicular system to aversive stimuli is potentially biphasic, with an initial stimulatory phase and, if the stress is prolonged or of sufficient magnitude, a subsequent inhibitory phase” be done before we gain mechanisms mediating the

axis

duration

alteration

2. McGradv

in the

[1], as well as on adrenergic and op-

an impact on there is evidence

HPG

and

docrinol

physical

involved

functions

interactions

a good

of stress is still lacking. The diversity as well as the use of peptidergic

to participate

neuron

7.

on

of the

neurons,

mechanisms

future studies, we interactions (both

CONCLUSION of stress

have

to obtain a better understanding of the precise role by various mechanisms in mediating the temporal

organs

effects

may

nists or antagonists with arguable specificity, studies difficult to interpret. In view of the results available in the literature, it would

1. Collu

during stresses [157] and that 5-HT is able to inhibit GnRH secretion [158]. However, the precise role played by the serotoninergic pathways in the stress-induced inhibition of GnRH neuronal activity remains to be fully clarified.

The

a suppression

phenomenon

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