www.elsevier.comrlocateranireprosci
Neuroendocrine regulation of gonadotropins in the
male and the female
N. Parvizi
( ) Department of Physiology, Institute for Animal Science and Animal BehaÕiour FAL ,
Neustadt a. Rbg. 31535, Germany
Abstract
For the past decade, neuroendocrinology, in general, and neuroendocrine regulation of repro-duction, in particular, were strongly dominated by molecular genetics and molecular endocrinol-ogy. In very recent years, however, neuroendocrinology is taking back its place. Beyond doubt GnRH is the neuroendocrine signal for ovulation. But there are still many unexplored pathways within the ‘black box’ triggering and regulating this signal. Neuroendocrine control of reproduc-tion starts very early in life, well before birth. Hypophyseal gonadotropin secrereproduc-tion is under hypothalamic control at around mid-gestation in the fetal sheep and the fetal pig. These two species could be considered as best-studied farm animals considering neuroendocrinology. This minireview thus will give in the first part a short survey of developmental processes of some of the neuroendocrine systems in the pig and sheep. In the second part, the opioidergic and catecholaminergic control of gonadotropins in adults will be briefly discussed. The last part will focus on the new less known pathways mediating effects on hormones which regulate the reproductive functions.q2000 Elsevier Science B.V. All rights reserved.
Keywords: Neuroendocrine regulation; gonadotropins
It has been said that the great events of the world take place in the brain. It is in the brain, and the brain only, . . .
Oscar Wilde
1. Neuroendocine regulation of gonadotropins in the fetus
The fetal hypothalamo-pituitary–gonadal axis possesses the components of the regulatory mechanisms to perform most of its endocrine functions. In the pig, LH gene
Ž .
expression starts around day 45 p.c. post-coitus, Granz et al., 1997; Ma et al., 1996 .
Ž
Pituitary LH release is measurable in the fetal pig around day 60 of gestation Elsaesser
0378-4320r00r$ - see front matterq2000 Elsevier Science B.V. All rights reserved.
Ž .
Ž .
Howe 1996 , which show no age-dependent difference in fetal LH response to the
Ž
neuroactive aminoacid, N-methyl-D-aspartate and GnRH itself Thomas and Brooks,
.
1997 , indicate that the decline in gonadotropin secretion shortly before birth and the sex difference in fetal gonadotropin release are not a sole matter of gonadal steroid feedback. It is noteworthy, however, that at 2 weeks postnatal age in male lambs and 5 weeks postnatal age in female lambs, LH secretion is significantly higher in fetally
Ž .
castrated animals in comparison to the intact controls Bremer et al., 1981 . Further, it seems that in the sheep, males are, because of in utero exposure to androgens, less
Ž . Ž
sensitive to steroid feedback in particular, progesterone than females Robinson et al.,
.
1999 .
Ž .
GnRH perikarya are visible at around day 40 in the pig Danchin and Dubois, 1982
Ž .
and day 50 in the sheep Mueller et al., 1981 fetal hypothalamus. An accumulation of GnRH in nerve terminals contacting the eminentia mediana has been shown on day 70
Ž .
p.c. in the pig Polkowska, 1995 . Pituitary LH secretion goes under the control of hypothalamus between days 60 and 80 p.c. in the pig. Electrical stimulation of hypothalamus induces LH release in 80-day-old fetuses but not in 60-day-old ones
ŽBruhn et al., 1983 . In vitro hypophyseal cell culture studies suggest that the go-.
nadotropin secretion of the pituitary develops earlier in the female than in the male fetus. Mechanisms leading to the brain sexual differentiation, which in turn result in appropriate male and female type of reproductive performance throughout the lifespan, are probably the best-studied developmental neuroendocrine event. This has been the
Ž .
subject of many reviews for a recent review, see Wood and Foster, 1998 and thus will not be addressed in further details here.
GnRH, itself, seems to be actively involved in the development of gonads. Prolonged
Ž
fetal treatment with buserelin after day 110 p.c. this stage seems to be a critical period,
.
since earlier treatments are ineffective causes an impaired testosterone secretion in
Ž .
lambs after postnatal age of 28 weeks Brooks et al., 1995; Thomas et al., 1993 . Similar treatments have no or very little effects in female fetuses. Comparable observation has been reported in the pig where the pulsatile administration of GnRH at 2 h intervals over
Ž .
10 days reduced the number of pituitary LH cells Meijer et al., 1985 in male fetuses
It is interesting to note that GnRH antibodies applied to the mother’s circulation cross the ovine fetal–placental barrier and suppress fetal plasma LH and FSH values in male
Ž .
and LH values in female fetuses Miller et al., 1998 .
Our current knowledge about the systems modulating GnRH and subsequently gonadotropin release in the fetus is rather spare. Most of the existing data are concentrating on the opioid system.
Components of the opioidergic system are present in the brain and pituitary already at an early stage of development. Pro-enkephalin and pro-dynorphin genes switch on
Ž .
producing opioid precursors as early as day 35 p.c. in the pig Pittius et al., 1987 . At
Ž .
the same time, pro-opiomelanocortin POMC gene expression begins in the pituitary
Ž .
with increasing intensity towards the end of pregnancy Ma et al., 1994 . In the sheep
Ž
fetus, POMC gene expression is first shown around day 70 p.c. earlier ages are not
.
studied . Originally, a decrease in the pituitary expression of POMC gene was reported
Ž .
by McMillen et al. 1988 , which is not confirmed by later works. In fact, recent data by
Ž . Ž .
Yang et al. 1991 and Bell et al. 1998 indicate an increase in POMC mRNA levels in fetal sheep pituitary during late gestation.
Opioid receptors are not detectable until day 50 p.c. in the fetal pig brain. The predominant receptors at this age appear to be of thek- andm-types. The delta receptor
Ž .
is virtually absent before birth Kahle and Parvizi, 1993 . This is different from sheep in
Ž
which the delta receptor is apparently the major opioid receptor in the fetus Yang and
.
Challis, 1991 .
This species difference is possibly responsible for the differences in the opioidergic control of LH release in the fetal pig and the fetal sheep. Naloxone given into the chronic catheterized fetal lamb induces a prompt increase in plasma LH levels. The increment is higher in fetuses younger than 115 days than those older than 126 days
ŽCuttler et al., 1985 . In contrast, the opioidergic control of pituitary gonadotropin is.
questionable in the pig fetus. In this species, opioid receptors are functioning well before the birth. This is evident by inhibitory action of morphine on LH release in male and
Ž .
female fetuses Behrens-Herrler and Parvizi, 1992 , whereas naloxone has no short-term or acute effects. An inhibitory naloxone effect, however, can be induced by treating
Žpriming male fetuses with daily naloxone injections. It is interesting that this sex-dif-.
ferentiated effect, paradoxically, resembles that of morphine. This paradoxical
sex-de-Ž .
pendent effect of naloxone can be also seen in newborn piglets Prunier et al., 1990 . Thus, the naloxone effector mechanisms in fetal and neonatal pig differ from those in adults.
A close relationship between cytokines and opioids has been reported repeatedly. Interleukin-1b can stimulate opioid synthesis in the brain and a binding of interleukins
Ž .
to brain opioid receptors has been reported to be feasible Jiang et al., 1998 . Any kind of so-called tissue ‘stress’ evokes activation of the opioid and the interleukin system. Phases of rapid growth, e.g. fetal growth, are considered as such physiological ‘stress-ful’ situations for cells.
Ž .
Our recent work Parvizi and Rohwedder, unpublished data shows that intravenous as well as intracerebral applications of an interleukin-1b antagonist are associated with
Ž .
Ž . Ž . Ž .
Fig. 1. Effects of intracerebral A and i.v. B injections of interleukin-1bin fetal male and female pigs. C
Ž . Ž .
illustrates plasma LH values before and after microinjections of 60 ng I or 120 ng B interleukin-1bmor
Ž .
2ml saline v into the MBH in ovariectromized pigs.
Fetal hypothalamic–pituitary axis obviously plays a central role in initiation of parturition in some species such as sheep. The neuroendocrine trigger chiefly stems in
Ž .
the nucleus paraventricularis PVN and CRH is the primary neuropeptide. Destruction of fetal PVN around gestational day 120 prolongs pregnancy in the sheep. Parturition does not occur in ewes with treated fetuses until 157 days gestation at which the fetuses
Ž .
must be removed by caesarian section McDonald and Nathanielsz, 1991 . Oxytoxin and vasopressin, together with the dopaminergic system, are assumed to regulate
hypothala-Ž .
mic CRH secretion Matthews, 1999; Matthews et al., 1996 . There seems to be a fine regulated interplay among prostaglandin E , placental CRH, and the fetal hypothala-2
Ž
mic–hypophyseal–adrenocorticotropic axis to control and initiate parturition Chan et
.
al., 1998; Keller-Wood, 1998; Thorburn et al., 1991 .
2. Neuroendocrine regulation of gonadotropins in adults
The brain sexual differentiation, which gives the females the ability to induce a gonadotropin surge in response to estradiol, is a quantitative rather than qualitative phenomena in domestic animals. The incompetence of males for LH surge secretion is due to the failure of estrogens to activate the hypothalamic pulse generator for surge release of GnRH. Male characteristics including sexual behaviour are imposed on the developing brain by organizational action of gonadal testosterone during a critical period which is around mid-gestation in domestic animals. The active steroid molecule is possibly the brain estradiol which can be synthesized by aromatization of testosterone in situ. Distinct structural properties, such as the sexually dimorphic nucleus of the preoptic
Ž .
area, are results of the organizational effects of steroids Jacobson et al., 1985, 1989 . The lack of estradiol-induced synaptic plasticity of arcuate neurones in males is also attributed to the inability of males to display an estrogen positive feedback. Long-term estrogen deprivation induced by long-term ovariectomy causes a brain desensitization
Ž .
for estrogen positive feedback Stickan et al., 1999 . Estradiol results in a LH surge in
Ž . Ž .
short-term ovariectomized 30 days but not in long-term ovariectomized 100 days
Ž .
sows Fig. 2 . Interestingly, estradiol appears to increase the sensitivity of castrated male
Ž .
pigs to GnRH at the pituitary level Fig. 2 . Our previous studies confirm the selective
Ž
alteration of brain sensitivity to oncoming stimulations by steroids Parvizi and
Ellen-.
dorff, 1980 . Priming of the amygdala with microinjections of testosterone changes the responsiveness of the amygdala to electrical stimulation from inhibition to stimulation of LH. For this, two mechanisms are conceivable, one of which alters the sensitivity of amygdaloid neurones to regulatory inputs arriving from extra amygdaloid structures such as the olfactory system or hypothalamus. The other may alter the outgoing signal from the amygdala to such structures. Reciprocal functional connections between such
Ž .
systems are known Dyer et al., 1976; Renaud, 1976 . The action of steroids can be alternatively explained on the basis of ‘two neuron pool’ theory suggested by Sawyer
Žsee Sawyer, 1991 , now more than 25 years ago. The selective inhibition or facilitation.
Fig. 2. Plasma concentrations of LH in 250-day-old gilts ovariectomized 30 days or 100 days before treatments
Ž . Ž . Ž . Ž .
and in male pigs castrated during the neonate period c, d, e and f . Treatments: a , b and c 10mg estradiol
Ž . Ž . Ž . Ž .
benzoate OB kg bodyweight BW ; d 10 mg OB kg BW and metallibure; e OB and metallibure and
Ž . Ž .
pulses of GnRH at 1 h intervals; f seamioil vehicle and metallibure and GnRH.
fashionable issue in the late 1970s. The subject received a new name ‘brain steroids’ in the 1990s, and is an often discussed topic at present.
Catecholestrogens can be considered as such brain steroids. These hydroxylated estrogens modify LH secretion in fetal as well as in adult pigs. However, their effect does not always resemble that of estradiol. This is particularly obvious in the fetus
ŽParvizi, 1986; Parvizi and Ellendorff, 1975, 1983 . Although catecholestrogens bind to.
Ž .
brain sites Parvizi et al., 1985 , their modulatory effect on LH secretion is most
Ž .
probably due to the modification of central neurotransmitter mainly catecholaminergic systems. This capability of catecholestrogens is receiving increasing attention particu-larly in relation with the endocrine active environmental substances. In this context, it is necessary to emphasize that some of the so-called ‘xenoestrogens’, which are found in the environment, do not act directly as estrogens or antiestrogens by binding to estrogen
Ž .
receptors. They rather influence the estrogen metabolism Hanf, 1997 . Most of these compounds, although biologically quite active, have a very low affinity for estrogen receptors. Catecholestrogen production can be enhanced in the present of xenoestrogens. Catecholestrogen, which can be produced in the brain, accumulates in specific brain
Ž .
nuclei Parvizi et al., 1985 . Furthermore, they modulate catecholamine turnover rate
ŽParvizi and Wuttke, 1983 by modifying catechol-o-methyltransferase, thyrosin hydrox-.
ylase activity and catecholamine reuptake.
Catecholaminergic-mediated control of gonadotropin secretion was long assumed to be exclusively of stimulatory nature. It is now, however, generally accepted that catecholamines have dual effects on LH secretion. Their stimulatory or inhibitory action is obviously dependent to the brain site actively involved, e.g. microinjections of norepinephrine into the third ventricle enhances LH release in both male and female
Ž .
Ž .
basolateral amygdala attenuates LH secretion Parvizi and Ellendorff, 1982 . The stimulatory effect is apparently dominant when the signal for the preovulatory LH surge is in process. In contrast, the inhibitory route is only active during stages of tonic LH
Ž .
secretion. Catecholamine synthesis inhibitors, DDC diethyldithiocarbamate and
Ž
methallibure, completely abolish the estradiol-induced LH surge Elsaesser et al., 1998;
.
Kraeling and Barb, 1990; Kesner, 1988 . It is noteworthy that both DDC and methal-libure are carbamate compounds. Carbamates, closely related to DDC, are worldwide used as pesticides. Thus, it is conceivable that environmental pollution with these compounds can prominently and directly modify the neuroendocrine events and conse-quently the reproductive function in animals and in the human.
Another important neuroendocrine pathway is composed by opioids. Currently, it is agreed that in mammals, the endogenous opioid peptides are derived from four
precur-Ž .
sors Table 1 . Pro-dynorphin, pro-enkephalin and POMC are the classic ones. The new generation of endogenous opioids, nociceptinrorphanin FQ, is processed from
pro-Ž .
nociceptinrOFQ and is the endogenous ligand for ORL1 opioid-receptor-like receptor
ŽMeunier et al., 1995 . Another mammalian opioid family is presumed to be driven from.
yet discovered pro-endomorphin, which gives rise to endomorphin-1 and endomorphin-2. These latter two opioid families are not studied in farm animals yet. Endomorphins, which are shown in discrete rat brain areas, are the only very selective endogenous
Ž .
mammalian opioids. They are endogenous ligands for them-receptor Table 2 .
Genes encoding the three well-known classical opioid receptors are already cloned. The Mor-1, Dor-1 and Kor-1 genes give rise to m-, d- and k-opioid receptors, respectively, and possibly also to their subtypes. An orphan receptor called ORL, which has a very high homology with the other three opioid receptors, was identified in recent
Ž .
years Mollereau et al., 1994 . All cloned opioid receptor types, in common with the somatostatin receptor, belong to GirG -coupled super family of receptors. They allo possess the same general structure consisting of an intracellular C-terminal tail, seven-transmembrane regions and an extracellular domain.
Opioidergic neurones are in close relation or co-existence with the other peptidergic or neurotransmitter systems. In the rat, co-operations between the inhibitory neurotrans-mitter GABA, catecholamines, oxytocin, vasopressin and opioids have been shown
ŽChieng and Williams, 1998; Dyer et al., 1991; Summy-Long, 1989 . Very little is.
known about the mode of action of opioids in farm animals. But, it is well known that they strongly modulate the gonadotropin and neurohypophyseal hormone secretion in
Ž
different reproductive phases. Our previous results and those of other investigators Barb
Table 1
Pro-dynorphin Dynorphin A, B and A 1–8 aandbneoendorphin
Pro-nociceptinrOFQ Nociceptin
Ž .
Met-enkephalin inhibits LH secretion in males but has no effects in females, whereas
b-endorphin and Leu-enkephalin may modify LH secretion independent of gonadal steroids in male and female pigs. Naloxone enhances plasma LH values when given into
Ž .
the mediobasal hypothalamus of cyclic diestrous sows with high circulating
proges-Ž .
terone but not in ovariectomized sows Parvizi et al., 1993 . Furthermore, opioids
Ž . Ž
amplify feedback MBH-mediated control of gonadal steroids on LH secretion Parvizi,
.
1988; Sribhen and Parvizi, 1986 . Recently, it has been shown that treatment with an
Ž .
opioid antagonist WIN 44, 441–443 causes a nearly sixfold increase in the percentage
Ž .
of GnRH neurons in the mediobasal hypothalamus MBH expressing Fos in ewes in
Ž .
luteal phase Boukhliq et al., 1999 .
Albeit the general notion that opioids act via central neuroendocrine pathways, there are some indications for a role of peripheral opioidergic mechanisms in the control of hormone secretion. Plasma b-endorphin levels are two to three times higher during
Ž .
pregnancy than during estrous cycle Fig. 3 and the level can be enhanced by
Ž .
cloprostenol a prostaglandin analog . Noteworthy, there are no significant changes in
Ž .
peripheral blood levels of opioids during the estrous cycle Aurich et al., 1993 . Interestingly, there are also no cycle-dependent fluctuations in opioid receptor
concentra-Ž
tions in the hypothalamus, amygdala, hippocampus and striatum Kahle and Parvizi,
.
1993 . A direct opioidergic action on adenohypophyseal hormone secretion is evident in vitro. Interestingly,b-endorphin increases the basal LH release from male and female
Ž . Ž
pituitary cells in culture, but it blocks GnRH-induced LH surge Fig. 4 Baratta and
. Ž .
Parvizi, unpublished . In contrast to these findings, Barb et al. 1990 reported that
b-endorphin decreases pituitary LH release in vitro.
The neuroendocrine bases of lactational anestrus are still not elucidated in whole, but
Ž .
accumulating pieces of evidence urge the involvement of both neuro endo crine and
Ž .
circulating nutrients Quesnel and Prunier, 1995 . Suckling per se seems to play a major part. Immediately post-partum, sows have relatively high plasma LH concentrations
Ž
until a suckling-induced inhibition of LH release occurs 24–55 h post-partum Sesti and
.
Britt, 1993; De Rensis et al., 1999 . Furthermore, a transient weaning of piglets for 6–24
Ž
h results in concomitant rise in plasma LH values Parvizi et al., 1976; Mattioli et al.,
.
1986; Armstrong et al., 1988a .
It is postulated that the low gonadotropin secretion during the first half of lactation is an outcome of low GnRH secretion and depressed sensitivity of the pituitary. Opioids are supposed to be one of the key neuropeptides lowering the GnRH input during
Ž . Ž .
Fig. 4. In vitro LH release from perfused pituitaries female pigs in response tob-endorphin v, panel A .
Ž . Ž . Ž .
.
Herbison, 1995; Alonso-Solis et al., 1996; Gallegos-Sanchez et al., 1998 . A large body
´
Ž .
of evidence supports the unequivocal action of dopamine. Surgical Havern et al., 1991
Ž .
or chemical Thiery et al., 1989 disruption of dopaminergic neurones of A15 nucleus as
`
well as dopamine receptor antagonists results in a significant increase in pulsatile release of LH in sexually inactive animals during off season. Dopaminergic A14 and A15 neurones can be activated by estradiol during anestrus, but not in breeding season. Estradiol receptors have been localized on dopaminergic and opioidergic neurones in theŽ .
infundibular A12 cells Lehman et al., 1993 and on GABA neurones in the preoptic
Ž .
area Skinner and Herbison, 1997 . All these receptors seem to be photoperiod-depen-dent. Previous work did not show localisation of estradiol receptors on A14rA15
Ž .
dopaminergic neurones Lehman and Karsch, 1993 . This has led to cascade theory, postulating that a cascade of events reaches A14 then A15 and from there, the GnRH
Ž .
system Havern et al., 1994 . Recent works demonstrating direct effects of estradiol on
Ž .
A15 neurones Gallegos-Sanchez et al., 1997 weakens, however, this postulation. In the
´
ewe, dopamine antagonists enhance, while dopamine receptor agonists inhibit, theŽ .
amplitude of LH pulses during non-breeding season Gallegos-Sanchez et al., 1998 .
´
Likewise, in the ram, dopamine antagonist, sulpirid, slightly stimulates LH release andŽ
markedly enhances the stimulatory effect of naloxone only under long days Torotonese,
.
1999 , showing that dopamine pathways inhibit both GnRH and opioid neurones as part of photoperiodic control of gonadotropin release.
The situation in the horse seems to be different. There is apparently no interplay
Ž
between dopamine and opioids in the control of LH release in stallions Aurich, Gerlach,
.
Aurich and Parvizi, unpublished data . In the mare, sulpiride treatment during late seasonal anestrus advances the first ovulation in the year and increases plasma FSH
Ž
concentration; however, the treatment has no effect on LH secretion Besognet et al.,
.
1996 . Conversely, opioids inhibit LH secretion during the breeding season in luteal
Ž .
phase in mares Behrens et al., 1993 and outside the breeding season in stallions
ŽAurich et al., 1996 ..
GABA neurones are probably playing an ample role in mediating the gonadal steroid feedback control on gonadotropin release. During the breeding season, preoptic GABA
Ž
.
1992; Blache et al., 1996 in the sheep. These neurones mediate the inhibitory action of
Ž .
estrogens in non-breeding season Scott and Clarke, 1993 .
Disruption of photoperiod causes changes in melatonin secretion and seasonal estrous
Ž .
cycle. Immunization against melatonin in ewes O’Callaghan et al., 1999 and
hypotha-Ž
lamo-pituitary disconnection in rams exposed to long days and short days Lincoln and
.
Clarke, 1998; Lincoln et al., 1996 confirm that melatonin acts on hypothalamus to mediate effects of photoperiod on GnRH-induced gonadotropin release. But, melatonin action on prolactin is brought about by Mel-1 a receptors within the pars tuberalis. This
Ž
section of pituitary has been shown to secrete a factor called ‘tuberalin’ Hazelrigg et
.
al., 1996; Morgan et al., 1996 , which is a candidate for a paracrine mediator of melatonin actions such as modulation of prolactin secretion within the hypophysis.
The sensitivity of the hypothalamic–hypohyseal system seems to be fundamentally different in the mare and the ewe. Comparative studies evaluating gonadotropin response to GnRH administration revealed a unique hypothalamic–hypophyseal axis in mares
Ž .
resistant to GnRH receptor downregulation Porter et al., 1997 .
4. Future explorations and less known pathways
The discovery of opiate receptors and endogenous opioids in mid 1970s was the start of a new era not only in neuroendocrinology. Future works will not only focus on new opioid generations, but there are at least three other less explored neuroendocrine
Ž . Ž .
pathways to be traced. These are: 1 gaseous transmitters such as nitric oxide NO and
Ž . Ž . Ž .
carbon monoxide CO ; 2 cytokines; and 3 neuroendocrine-active environmental substances ‘xenohormones’, which are in close relation to gaseous transmitters.
One of the most striking discoveries in the recent years is the finding that the environmental pollutants such as toxic gaseous, NO and CO are produced in mammals and eventually mediate functions such as neurotransmission, endocrine signalling, immunological defense and a few more. They are in many ways unusual; unlike all other
Žclassical neurotransmitters, CO and NO have no receptor protein molecules and they.
are not stored in synaptic vesicles. NO neurones have been located in the vicinity of GnRH neurones and it has been suggested that NO stimulates GnRH release directly
ŽBhat et al., 1996 as well as indirectly Bonavera and Kalra, 1996 . Systemic applica-. Ž .
Ž .
tions of nitric oxide synthase NOS inhibitor prevent the steroid-induced and
preovula-Ž .
tory LH surge Bonavera et al., 1994 . Injection of n-NOS antisense oligonucleotides into the third ventricle also inhibits the steroid-induced LH surge in ovariectomized rats
ŽAguan et al., 1996 . A hypothetical model elucidating the role of NO in the control of.
Ž . Ž .
the preovulatory LH peak has been proposed by Brann et al. 1997 Fig. 5 .
Cytokines have been long shown to play a major role in reciprocal connections between immune and neuroendocrine system. Little is known about cytokine regulation of gonadotropins in farm animals. Our findings indicate that interleukin-1b modulates LH release in an age-dependent manner in female pigs. Microinjections of interleukin-1b
into the MBH lowered LH levels in eight out of 10 castrated female pigs, while identical
Ž .
Ž .
Fig. 5. A proposed model for central role of NO in the preovulatory LH surge Brann et al., 1997, modified . GCsguanylate cyclase, Coxscyclooxygenase, NEsnorepinephrine, E2sestradiol-17b, P4sprogesterone.
Ž
of LH release is also the assumed effect of interleukin in adult rats for review, see
.
McCann et al., 1998; Kalra et al., 1998 .
5. Conclusion
On the verge of the new century, we know that GnRH is the neuroendocrine signal for ovulation but it seems that we still have not explored all feasible routes triggering this signal.
References
Aguan, K., Mahesh, V.B., Ping, L., Bhat, G., Brann, D.W., 1996. Evidence for a physiological role for nitric oxide in the regulation of the LH surge: effect of central administration of antisense oligonucleotides to nitric oxide synthase. Neuroendocrinology 64, 449–455.
Alonso-Solis, R., Abreu, P., Lopez-Coviella, I., Hernandez, G., Fajardo, N., Hernandez-Diaz, F., Diaz-Cruz, A., Hernandez, A., 1996. Gonadal steroid modulation of neuroendocrine transduction: a transynaptic view. Cell. Mol. Neurobiol. 16, 357–382.
Armstrong, J.D., Kraeling, R.R., Britt, J.H., 1988a. Effects of naloxone or transient weaning on secretion of LH and prolactin in lactating sows. J. Reprod. Fertil. 83, 301–308.
Armstrong, J.D., Kraeling, R.R., Britt, J.H., 1988b. Morphine suppresses luteinizing hormone concentrations in transiently weaned sows and delayed onset of estrus after weaning. J. Anim. Sci. 66, 2216–2223. Aurich, C., Burgmann, F., Hoppen, H., 1996. Opioid regulation of LH and prolactin release in the
horse-identical or independent endocrine pathways? Anim. Reprod. Sci. 44, 127–134.
Barb, C.R., Barrett, J.B., Wright, J.T., Kraeling, R.R., Rampacek, G.B., 1990. Opioid modulation of LH secretion by pig pituitary cells in vitro. J. Reprod. Fertil. 90, 213–219.
Barb, C.R., Kraeling, R.R., Rampacek, G.B., 1992. Opioid modulation of FSH, growth hormone and prolactin secretion in the prepubertal gilt. Endocrinology 133, 13–19.
Behrens, C., Aurich, J.E., Klug, E., Naumann, H., Hoppen, H.-O., 1993. Inhibition of gonadotrophin release in mares during the luteal phase of the oestrous cycle by endogenous opioids. J. Reprod. Fertil. 98, 509–514. Behrens-Herrler, S., Parvizi, N., 1992. Long-term treatments with morphine and naloxone have sex-differenti-ated effects on luteinizing hormone secretion in chronically catheterized fetal pigs. J. Neuroendocrinol. 4, 114–118.
Bell, E., Myers, T.R., Myers, D.A., 1998. Expression of pro-opiomelanocortin and pro-hormone convertase-1 and -2 in the late gestation fetal sheep pituitary. Endocrinology 139, 5135–5143.
Besognet, B., Hansen, B.S., Daels, P.F., 1996. Dopaminergic regulation of gonadotrophin secretion in seasonally anoestrous mares. J. Reprod. Fertil. 108, 55–61.
Bhat, G., Mahesh, V.B., Aguan, K., Brann, D.W., 1996. Evidence that brain nitric oxide synthase is the major nitric oxide synthase isoform in the hypothalamus of the adult female rat and that nitric oxide potently regulates hypothalamic cGMP levels. Neuroendocrinology 64, 93–102.
Blache, D., Fabre-Nys, C., Venier, G., 1996. Inhibition of sexual behaviour and the luteinizing hormone surge by intracerebral progesterone implants in the female sheep. Brain Res. 741, 117–122.
Bonavera, J.J., Kalra, S.P., 1996. L-Argininernitric oxide amplifies the magnitude and duration of the luteinizing hormone surge induced by estrogen: involvement of neuropeptide. Endocrinology 137, 1956– 1962.
Bonavera, J., Sahu, A., Kalra, P., Kalra, S.P., 1994. Evidence in support of nitric oxide involvement in the cyclic release of prolactin and LH surges. Brain Res. 660, 175–179.
Boukhliq, R., Goodman, R.L., Berriman, S.J., Adrian, B., Lehman, M.N., 1999. A subset of gonadotropin-re-leasing hormone neurons in the ovine medial basal hypothalamus is activated during increased pulsatile luteinizing hormone secretion. Endocrinology 140, 5929–5936.
Brann, D.W., Bhat, G.K., Lamar, C.A., Mahesh, V.B., 1997. Gaseous transmitters and neuroendocrine regulation. Neuroendocrinology 65, 385–395.
Bremer, W.J., Cumming, I.A., Williams, D.M., DeKretser, D.M., Lee, V.W.K., 1981. The effect of intrauterine gonadectomy on fetal and neonatal gonadotrophin secretion in the lamb. J. Reprod. Fertil. 30, 61–66.
Brooks, A.N., Howe, D.C., 1996. Adrenocorticotrophin and luteinizing hormone responses to N-methyl-D-aspartate during fetal development in sheep. J. Neuroendocrinol. 8, 315–321.
Brooks, A.N., McNeilly, A.S., Thomas, G.B., 1995. Role of GnRH in the ontogeny and regulation of the fetal hypothalamo-pituitary-gonadal axis in sheep. J. Reprod. Fertil. 49, 163–175.
Bruhn, T., Parvizi, N., Ellendorff, F., 1983. Ontogeny of hypothalamo-pituitary function in the fetal pig: gonadotropin release in response to electrical and electrochemical stimulation of the hypothalamus. Endocrinology 112, 639–644.
Chan, E.C., Falconer, J., Madsen, G., Rice, K.C., Webster, E.L., Chrousos, G.P., Smith, R., 1998. A corticotropin-releasing hormone type I receptor antagonist delays parturition in sheep. Endocrinology 139, 3357–3360.
Chieng, B., Williams, J.T., 1998. Increased opioid inhibition of GABA release in nucleus accumbens during morphine withdrawal. J. Neurosci. 18, 7033–7039.
Cosgrove, J.R., Bootz, P.J., Foxcroft, G.R., 1991. Opioidergic control of gonadotrophin secretion in the prepubertal gilt during restricted feeding and realimentation. J. Reprod. Fertil. 91, 277–284.
Cuttler, L., Egli, C.A., Styne, D.M., Kaplan, S.L., Grumbach, M.M., 1985. Hormone ontogeny in the ovine fetus: XVIII. The effect of an opioid antagonist on luteinizing hormone secretion. Endocrinology 116, 1997–2002.
Danchin, E., Dubois, M.P., 1982. Immunocytological study of the chronology of pituitary cytogenesis in the
Ž .
domestic pig Sus scrofa with special reference to the function of the hypothalamo-pituitary-gonadal axis. Reprod. Nutr. Dev. 22, 135–151.
Gallegos-Sanchez, J., Delaleu, B., Caraty, A., Malpaux, B., Thiery, J.C., 1997. Estradiol acts locally within the´ ´ retrochiasmatic area to inhibit pulsatile LH release in the female sheep during anestrus. Biol. Reprod. 56, 1544–1549.
GallegosSanchez, J., Malpaux, B., Thiery, J.C., 1998. Control of pulsatile LH secretion during seasonal´ ´ anoestrus in the ewe. Reprod. Nutr. Dev. 38, 3–15.
Granz, S., Ellendorff, F., Grossmann, R., Kato, Y., Muhlbauer, E., Elsaesser, F., 1997. Ontogeny of growth¨ hormone and LH-b-, FSH-b- and a-subunit mRNA levels in the porcine fetal and neonatal anterior pituitary. J. Neuroendocrinol. 9, 439–449.
Hanf, V., 1997. Effects of xenoestrogens on reproductive functions. Reprod. Domest. Anim., Suppl. 4, 29–32. Havern, R.L., Whisnat, C.S., Goodman, R.L., 1991. Hypothalamic sites of catecholamine inhibition of
luteinizing hormone in the anestrous ewes. Biol. Reprod. 44, 476–482.
Havern, R.L., Whisnat, C.S., Goodman, R.L., 1994. Dopaminergic structures in the ovine hypothalamus mediating estradiol negative feedback in anestrous ewes. Endocrinology 134, 1905–1914.
Hazelrigg, D.G., Hastings, M.H., Morgan, P.J., 1996. Production of a prolactin releasing factor by the ovine pars tuberalis. J. Neuroendocrinol. 8, 489–492.
Herbison, A.E., 1995. Neurochemical identity of neurones expressing oestrogen and androgen receptors in sheep hypothalamus. J. Reprod. Fertil. 49, 271–283, Supplement.
Jacobson, C.D., Davis, F.C., Gorski, R.A., 1985. Formation of the sexually dimorphic nucleus of the preoptic area: neuronal growth, migration and changes in cell number. Brain Res. 353, 7–18.
Jacobson, C.D., Adam, D.E., Fields, J., Sladek, J.R. Jr., 1989. Simultaneous catecholamine histofluorescence and thymidine autoradiography of the sexually dimorphic nucleus of the preoptic area in the rat. Exp. Neurol. 104, 257–263.
Jiang, C.-L., Lu, C.-L., Liu, X.-Y., 1998. The molecular basis for bidirectional communication between the immune and neuroendocrine systems. Domest. Anim. Endocrinol. 15, 363–369.
Ž .
Kahle, H., Parvizi, N., 1993. Development of the opioid system in the pig. In: Parvizi, N. Ed. , Opioids in Farm Animals. Landwirtschaftsverlag, Munster S., pp. 167–180.¨
Kalra, P.S., Edwards, T.G., Xu, B., Jain, M., Kalra, S.P., 1998. The anti-gonadotropic effects of cytokines: the role of neuropeptides. Domest. Anim. Endocrinol. 15, 321–332.
Keller-Wood, M., 1998. ACTH responses to CRF and AVP in pregnant and nonpregnant ewes. Am. J. Physiol. 274, 1762–1768.
Kesner, J.S., 1988. Site of action for the estradiol-induced luteinizing hormone surge in farm animals and primates. Domest. Anim. Endocrinol. 5, 265–281.
Kraeling, R.R., Barb, C.R., 1990. Hypothalamic control of gonadotrophin and prolactin secretion in pig. J. Reprod. Fertil. 40, 3–17.
Lehman, M.N., Ebling, F.J.P., Moenter, S.M.M., Karsch, F.J., 1993. Distribution of estrogen receptor-im-munoreactive cells in the sheep brain. Endocrinology 133, 876–886.
Lincoln, G.A., Clarke, I.J., 1998. Absence of photoperiodic modulation of gonadotrophin secretion in HPD rams following chronic pulsatile infusion of GnRH. J. Neuroendocrinol. 10, 461–471.
Lincoln, G.A., Clarke, I.J., Sweeney, T., 1996. ‘‘Hamster-like’’ cycles in testicular size in the absence of gonadotrophin secretion in HPD rams exposed to long-term changes in photoperiod and treatment with melatonin. J. Neuroendocrinol. 8, 855–866.
Ma, E., Milewski, N., Grossmann, R., Ivell, R., Kato, Y., Ellendorff, F., 1994. Pro-opiomelanocortin gene expression during pig pituitary and brain development. J. Neuroendocrinol. 6, 201–209.
Ma, E., Klempt, N., Grossmann, R., Ivell, R., Kato, Y., Ellendorff, F., 1996. Expression of GH, TSH-b, LH-b and FSH-b genes during fetal pituitary development in the pig. Exp. Clin. Endocrinol. Diabetes 104, 464–472.
Matthews, G., Fraser, M., Challis, J.R.G., 1996. Dopaminergic regulation of pituitary function in the late gestation fetal sheep. J. Endocrinol. 150, 187–194.
Matthews, S.G., 1999. Hypothalamic oxytocin in the developing ovine fetus: interaction with pituitary– adrenocortical function. Brain Res. 820, 92–100.
Mattioli, M., Conte, F., Galeati, G., Seren, E., 1986. Effect of naloxone on plasma concentrations of prolactin and LH in lactating sows. J. Reprod. Fertil. 76, 167–173.
McCann, S.M., Kimura, M., Walczewska, A., Karanth, S., Rettori, V., Yu, W.H., 1998. Hypothalamic control of gonadotropin secretion by LHRH, FSHRF, NO, cytokines, and leptin. Domest. Anim. Endocrinol. 15, 333–344.
McDonald, T.H., Nathanielsz, P.W., 1991. Bilateral destruction of the fetal paraventricular nuclei prolongs gestation in sheep. Am. J. Obstet. Gynecol. 165, 764–770.
McMillen, I.C., Mercer, J.E., Thorburn, G.D., 1988. Pro-opiomelanocortin mRNA levels fall in the fetal sheep pituitary before birth. J. Mol. Endocrinol. 1, 141–145.
Meijer, J.C., Colenbrander, B., Poot, P., Wensing, C.J.G., 1985. Development of pituitary gonadotrophic cells in the pig fetus and the effect of luteinizing-hormone-releasing hormone administration. Biol. Reprod. 32, 137–143.
Messaoud-Toumi, L.H., Taragnat, C., Durand, P., 1993. Heterogeneity in the storage of gonadotropins in the ovine fetus and evidence for luteinizing hormone follicle-stimulating hormone cells in the fetal pituitary. Biol. Reprod. 48, 1239–1245.
Mesiano, S., Hart, C.S., Heyer, B.W., Kaplan, S.L., Grumbach, M.M., 1991. Hormone ontogeny in the ovine fetus: XXVI. A sex difference in the effect of castration on the hypothalamic-pituitary-gonadotropin unit in the ovine fetus. Endocrinology 129, 3073–3079.
Meunier, J.C., Mollereau, C., Toll, L., Suaudeau, C., Moisand, C., Alvinerie, P., Butour, J.L., Guillemot, J.C., Ferrara, P., Monsarrat, B., 1995. Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor. Nature 377, 532–535.
Miller, D.W., Fraser, H.M., Brooks, A.N., 1998. Suppression of fetal gonadotrophin concentrations by maternal passive immunization to GnRH in sheep. J. Reprod. Fertil. 113, 69–73.
Mollereau, C., Parmentier, M., Mailleux, P., Butour, J.L., Moisand, C., Chalon, P., Caput, D., Vassart, G., Meunier, J.C., 1994. ORL1, a novel member of the opioid receptor family. Cloning, functional expression and localization. FEBS Lett. 341, 33–38.
Morgan, P.J., Webster, C.A., Mercer, J.G., Ross, A.W., Hazelrigg, D.G., MacLean, A., Barrett, P., 1996. The
Ž .
ovine pars tuberalis secretes a factor s which regulates gene expression in both lactotrophic and non-lactotrophic pituitary cells. Endocrinology 9, 4018–4026.
Mueller, P.L., Sklar, C.A., Gluckman, P.D., Kaplan, S.L., Grumbach, M.M., 1981. Hormone ontogeny in the ovine fetus: IX. Luteinizing hormone and follicle-stimulating hormone response to luteinizing-hormone-re-leasing factor in mid- and late gestation in the neonate. Endocrinology 108, 881–886.
O’Callaghan, D., Sweeney, T., Taylor, L., Roblot, G., Wylde, R., 1999. Effect of immunization against melatonin on prolactin concentrations and the timing of reproductive transitions in ewes. Domest. Anim.
Ž .
Endocrinol. 16 4 , 207–217.
Parvizi, N., Wuttke, W., 1983. Catecholestrogens affect catecholamine turnover rates in the anterior part of the mediobasal hypothalamus and medial preoptic area in the male and female castrated rat. Neuroendocrinol-ogy 36, 21–26.
Pittius, C.W., Ellendorff, F., Hollt, V., Parvizi, N., 1987. Ontogenetic development of pro-enkephalin A and¨ pro-enkephalin B messenger RNA in fetal pigs. Exp. Brain Res. 69, 208–212.
Polkowska, J., 1995. Development of the gonadotrophic and somatotrophic axes of sheep. J. Reprod. Fertil. 49, 187–195.
Ponzilius, K.-H., Parvizi, N., Elsaesser, F., Ellendorff, F., 1986. Ontogeny of secretory patterns of LH release and effects of gonadectomy in the chronically catheterized pig fetus and neonate. Biol. Reprod. 34, 602–612.
Porter, M.B., Cleaver, B.D., Peltier, M., Robinson, G., Thatcher, W.W., Sharp, D.C., 1997. Comparative study between pony mares and ewes evaluating gonadotrophic response to administration of gonadotrophin-re-leasing hormone. J. Reprod. Fertil. 110, 219–229.
Prunier, A., Ellendorff, F., Parvizi, N., 1990. Opioid action on luteinizing hormone secretion in newborn pigs: paradoxical effect of naloxone. J. Dev. Physiol. 14, 221–227.
Quesnel, H., Prunier, A., 1995. Endocrine bases of lactational anoestrus in the sow. Reprod. Nutr. Dev. 35, 395–414.
Renaud, L.P., 1976. An electrophysiological study of amygdalohypothalamic projections to the ventromedial nucleus of the rat. Brain Res. 105, 45–58.
Robinson, J.E., Kendrick, K.M., 1992. Inhibition of luteinizing hormone secretion in the ewe by progesterone: associated changes in the release of gamma-aminobutyric acid and noradrenaline in the preoptic area as measured by intracranial microdialysis. J. Neuroendocrinol. 4, 231–236.
Robinson, J.E., Rachel, A., Forsdike, A., Taylor, J.A., 1999. In utero exposure of female lambs to testosterone reduces the sensitivity of the gonadotropin-releasing hormone neuronal network to inhibition by proges-terone. Endocrinology 140, 5797–5805.
Sawyer, C.H., 1991. Remembrances of contributions of Philip Smith and Bernardo Houssay to the
develop-Ž .
ment of neuroendocrinology. Endocrinology 129 2 , 577–578.
Scott, C.J., Clarke, I.J., 1993. Evidence that changes in the function of the subtypes of the receptors for g-aminobutyric acid may be involved in the seasonal changes in the negative feedback effects of oestrogen on gonadotropin-releasing hormone secretion and plasma luteinizing hormone levels in the ewe. En-docrinology 133, 2904–2912.
Sesti, L.A.C., Britt, J.H., 1993. Influence of stage of lactation, exogenous luteinizing-hormone-releasing hormone, and suckling on estrus, positive feedback of luteinizing hormone, and ovulation in sows treated with estrogen. J. Anim. Sci. 71, 989–998.
Sribhen, C., Parvizi, N., 1986. Endogene Opiate: 1. Enkephaline und ihre Rolle bei der Regulation der Gonadotropin-Sekretion. Tierarztl. Wschr. 99, 236–242.¨
Stickan, F., Parvizi, N., Elsaesser, F., 1999. Compensation by pulsatile GnRH infusions for incompetence for oestradiol-induced LH surges in long-term ovariectomized gilts and castrated male pigs. J. Reprod. Fertil. 115, 333–339.
Summy-Long, J.Y., 1989. Cross-inhibition of oxytocin neurones during activation of the vasopressin system.
Ž .
In: Dyer, R.G., Bicknell, R.J. Eds. , Brain Opioid Systems in Reproduction. Oxford Univ. Press, Oxford, pp. 271–287.
Thiery, J.C., Martin, G.B., Tillet, Y., Caldani, M., Quentin, M., Jamain, C., Ravault, J.P., 1989. Role of` hypothalamic catecholamines in the regulation of LH and prolactin secretion in the ewe during season anoestrus. Neuroendocrinology 49, 80–87.
Thomas, G.B., Brooks, A.N., 1997. Pituitary and gonadal responses to the long-term pulsatile administration of gonadotrophin-releasing hormone in fetal sheep. J. Endocrinol. 153, 385–391.
Thomas, G.B., McNeilly, A.S., Brooks, A.N., 1993. Development of gonadotrophs and thyrotrophs in the female foetal sheep pituitary: immunocytochemical localization studies. J. Neuroendocrinol. 5, 157–161. Thorburn, G.D., Hollingworth, S.A., Hooper, S.B., 1991. The trigger for parturition in sheep: fetal
hypothala-mus or placenta? J. Dev. Physiol. 15, 71–79.
Torotonese, D.J., 1999. Interaction between hypothalamic dopaminergic: opioidergic systems in the photoperi-odic regulation of pulsatile luteinizing hormone secretion in sheep. Endocrinology 140, 750–757. Wood, R.I., Foster, D.L., 1998. Sexual differentiation of reproductive neuroendocrine function in sheep. Rev.
Reprod. 3, 130–140.
Yang, K., Challis, J.R.G., Han, V.K.M., Hammond, G.L., 1991. Pro-opiomelanocortin messenger RNA levels increase in the fetal sheep pituitary during late gestation. J. Endocrinol. 131, 483–489.
