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Endocrinologie Cellulaire et Moléculaire de la Reproduction (G.G., Y.L., C.S., A.B., R.C.), Université Pierre & Marie Curie, CNRS-URA 1449, Paris, France; Université Française du Pacifique, Tahiti (Y.L.); Différenciation de la Gonade (S.M.), Université Pierre & Marie Curie, CNRS-URA 1449, Paris, France; and Institut des Neurosciences (C.B.), Université Pierre & Marie Curie, CNRS-URA 1488, Paris, France
Address all correspondence and requests for reprints to: Dr. Raymond Counis, Endocrinologie cellulaire et Moléculaire de la Reproduction, Université Pierre et Marie Curie, URA CNRS 1449, Case 244, 75252 Paris cedex 05, France. E-mail: Raymond.counis{at}snv.jussieu.fr
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Introduction |
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At the pituitary level, GnRH interacts with specific seven-transmembrane G protein-coupled receptors located at the surface of gonadotrophs and triggers the generation of an array of second messengers and activation of several intracellular pathways to regulate in an integrated manner the synthesis and release of gonadotropins. These include the activation of the phosphoinositidase C with the ensuing production of diacylglycerol and inositol-trisphosphate, which are responsible for the activation of protein kinase C and the mobilization of intracellular Ca2+ respectively (4, 5). GnRH also induces the activation of phospholipases D and A2 (4), production of cAMP and cGMP (2, 6, 7) and under some circumstances, activation of tyrosine kinases and the MAP kinase cascade (8, 9).
Previous data have identified the presence of nitric oxide synthase
(NOS), which catalyzes the production of nitric oxide (NO) from
L-arginine (10, 11), in diverse hypothalamic areas (12, 13, 14, 15, 16)
and in pituitary lobes (17, 18, 19), raising the possibility that NO may
act in both the brain and pituitary as a neuroendocrine regulator of
reproductive function. NO is a diffusive free radical that plays an
important role as an inter or intracellular messenger and is involved
in many physiological and pathological processes. Three forms of NOS
coded by distinct genes have been described to date: neuronal (type I)
and endothelial (type III) NOS are constitutive,
Ca2+-calmodulin-dependent enzymes, whereas the type II,
primarily found in macrophages, is inducible and Ca2+
independent (10, 11). A line of evidence suggests that NO is a
determinant in the hypothalamus for both 
1-adrenergic and
N-methyl-D-aspartate (NMDA)-induced release of
GnRH (14, 20). NOS is also expressed in the immortalized hypothalamic
GnRH-producing GT1–1 neurones (13, 21); however, in the normal rat
hypothalamus, data indicate that NO involved in the NMDA-induced
release of GnRH is produced in neuronal cells adjacent but distinct
from GnRH neurones (15).
In the rat anterior pituitary, NOS I has been identified in gonadotrophs and folliculo-stellate cells (18). Disregarding the nature of the cells concerned, elevated messenger RNA (mRNA) as well as increased cell immunostaining was reported post castration, suggesting that NOS I is negatively regulated by gonadal steroids. The intriguing presence of NOS I in gonadotrophs, and the similarity that appears to exist in response to castration of both pituitary NOS and gonadotropins (1, 2), has led us to question the site and the mechanism of action of gonadal steroids. More specifically, we are interested to establish whether GnRH may alter NOS expression in gonadotrophs.
To assess this possibility, we have reexamined the effects of steroid ablation or replacement on NOS I expression in rats treated with a potent GnRH antagonist to separate the pituitary gland from the influence of endogenous GnRH. Complementary to this, we have tested the effects of the direct stimulation in normal rats with a potent GnRH agonist. Effects on NOS I protein and mRNA levels were evaluated by Western analysis and RNA dot hybridization, respectively. We also used NADPH-diaphorase staining combined with the specific immuno-identification of pituitary cell types to examine whether changes in NOS I levels were associated with appropriate variations in enzymatic activity because it is known that the latter is closely dependent on subunit homodimerization (10, 11). Together, the data reveal a clear stimulatory action of GnRH on gene expression, protein accumulation, and enzymatic activity of NOS I in gonadotrophs. As such, this action appears affected by the mode of GnRH exposure and indirectly by gonadal steroids via modulation of GnRH secretion.
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Materials and Methods |
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Preparation of tissue extracts and Western blotting
Preparation of protein extracts and Western blotting analysis of
NOS were performed essentially as previously described (22). The
anterior pituitary, or in some cases the posterior lobe, was
homogenized in 10 mM Tris-HCl, pH 7.4, containing 2
mM EDTA, 1% Triton X-100, 1 mM
phenyl-methylsulfonyl fluoride, and 20 µg/ml leupeptin. Homogenates
were centrifuged for 45 min at 20,000 x g at 4 C, the
supernatant collected, and protein concentration determined according
to Bradford (23). Protein extracts were subjected to slab gel
electrophoresis using a 7% polyacrylamide separating gel and a 4.5%
polyacrylamide stacking gel. Colored protein molecular weight markers
(Rainbow Marker, Amersham, Arlington Heights, IL) and NOS reference
markers (Transduction Laboratories, Lexington, KY) were
coelectrophoresed.
After electrotransfer onto nitrocellulose membrane (Hybond-ECL, 0.45-µm pore size; Amersham), NOS I, NOS II, or NOS III subunits were immunodetected using specific, affinity-purified antibodies (Transduction Laboratories) at dilutions 1/200 for NOS I, 1/1000 for NOS II and 1/1000 for NOS III and the Enhanced Chemiluminescence System (ECL-Western blotting system, Amersham). Blots were exposed to Kodak XAR-5 films (Eastman Kodak, Rochester, NY).
NADPH-diaphorase histochemistry and immunohistochemistry
After the rats were killed, the pituitaries were fixed by
immersion for 2 h in 4% paraformaldehyde, then rinsed 2 h in
PBS and placed successively for 30 min each in PBS containing 12%,
15%, and 18% sucrose at 4 C. Transverse sections of 5 µm using a
Bright cryostat (Huntingdon, UK), were collected on slides and stored
at -20 C. The histochemical procedure was as described by
Scherer-Singler et al. (24) with minor modifications.
Incubation was carried out in the dark at 37 C for 15–30 min.
Incubation medium contained 1 mg/ml ß-NADPH, 0.1 mg/ml nitroblue
tetrazolium salt, and 0.3% Triton X-100 in 50 mM Tris-HCl
buffer, pH 8. The reaction was stopped by rinsing slides with 100
mM phosphate buffer, pH 7.2. To determine the specificity
of the diaphorase staining for NOS several controls were performed.
First, omission of NADPH (enzyme substrate) resulted in loss of
staining. Second, total inhibition of staining was observed following
incubation in presence of NOS inhibitor L-NMMA (a methylated analog of
L-arginine). The above controls confirmed the notion that
NADPH-diaphorase activity corresponds to NOS activity in these fixed
tissues (17, 25, 26, 27).
After histochemistry, the same sections were further processed for immunochemistry. Sections were rinsed in PBS and incubated for 30 min in 3% BSA-PBS at room temperature. Specific antibodies used were the following: mouse monoclonal immuno-affinity purified antibovine LHß antibody (no. 518 B7) that recognized an epitope common to several species including rat (28), at a 1/300 dilution; rabbit polyclonal antihuman FSHß (NIDDK, Baltimore, MD; no. 51) at a 1/900 dilution; and rabbit anti-S100 protein (Immunotech, Marseille, France) at a 1/600 dilution for staining the folliculo-stellate cells. We also used a rabbit polyclonal antirat PRL (29) at a 1/800 dilution, a rabbit polyclonal antisynthetic human GH (NIDDK, no. IC-4, AFP-1613102481) at a 1/100 dilution and a rabbit polyclonal antirat TSHß (NIDDK, #IC-1, AFP-1274789) at a 1/200 dilution (data not shown). After 1 h incubation, sections were extensively washed in PBS and further incubated for single immunostaining in the presence of biotinylated donkey antirabbit Ig F(ab')2 fragments (dilution 1/500) or biotinylated sheep antimouse Ig antibodies (dilution 1/200) followed by 30 min contact with streptavidin-fluorescein complex (dilution 1/100), the latter three provided by Amersham-France. For double immunostaining, sections were incubated overnight at 4 C with a mixture containing anti-LHß and anti-FSHß and then sequentially incubated at room temperature with biotin-conjugated antimouse Ig (dilution 1/200), TX-Red-conjugated antirabbit Ig (dilution 1/100) and streptavidin-fluorescein complex (Amersham), for 45 min each. The sections were then washed in PBS and mounted with Vectashield (Biosys, Compiègne, France). Controls omitting the primary antibody or using saturated primary antibody were also performed.
Extraction of RNA and dot blot hybridization
Total RNA was prepared from anterior pituitary using standard
techniques (30). Dots and hybridization were performed as previously
described (31) using as probe a 1.2-kb rat NOS I complementary DNA
(cDNA) (Alexis Corporation, San Diego, CA) and standardization of data
to cyclophilin mRNA.
Determination of serum LH and FSH
Serum LH and FSH were assayed using RIA kits provided by the
NIDDK (Baltimore, MD) with highly purified rat LH (NIDDK I-9) and FSH
(NIDDK I-8) for iodination (32), and reference preparations (rLH-RP3,
rFSH-RP2) and appropriate antisera (anti-rLH-S11 and anti-rFSH-S11).
Bound and free hormone were separated with immobilized protein A
(33).
Statistical analysis
Western and RNA dot blots were analyzed with a computer image
processing system (COHU high performance CCD camera and One-Dscan
software, Scanalytics, Billeria, MA). Values are the mean ±
SEM of at least three separate experiments typically with
three replicates for each experimental group. Differences between means
were assessed by ANOVA followed by Dunnett’s t test.
P 
0.05 was considered significant.
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Results |
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) revealed that only the NOS I
protein was detectable in the anterior lobe of either intact or
castrated rat. The concentration of NOS I was about one tenth of that
found in the posterior lobe used as reference in the analysis.
Castration specifically enhanced NOS I protein levels in the anterior
lobe, whereas it caused neither an alteration of NOS I levels in the
posterior lobe nor the detection of NOS II or NOS III in either
lobe.
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) shows an
important, time-dependent increase in NOS I protein levels following
orchidectomy. A significant 2-fold elevation was seen at 24 h post
castration, and a maximal 4- to 5-fold increase was attained by days
3–7. This concentration of NOS I was retained until at least day 14
and declined thereafter but remained above that of intact rats.
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and 2, we set up an experiment designed
to compare the effects of different steroid treatments in intact and
castrated rats with or without chemical hypothalamo-pituitary GnRH
disconnection. Groups of intact and castrated rats were treated on the
day of castration with daily injections of either testosterone (1
mg/day) or estradiol (20 µg/day), with or without the administration
of a GnRH antagonist (injections at days 0 and 3). Control (intact and
castrated) rats received vehicle only. The level of NOS I protein was
examined on day 4 by Western blot in anterior and posterior pituitary
lobes.
Figure 3 demonstrates that estradiol or
testosterone replacement in orchidectomized rats resulted in the total
abolition of the postcastration increase in NOS I, thus establishing
the preponderant role of steroids in this process. The postcastration
increase in NOS I was also completely abolished by treatment with the
GnRH antagonist, indicating the requirement for a functional
hypothalamo-pituitary connection via GnRH receptor,
i.e. stimulation by endogenous GnRH. As shown in Fig. 3, testosterone plus GnRH antagonist had no specific effect as compared
with treatment with GnRH antagonist alone.
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In contrast to the anterior lobe, neither steroids nor GnRH antagonist
had any effect on the level of NOS I in the posterior lobe as
illustrated in the autoradiogram of an ECL-Western blot (Fig. 3).
The concentration of serum LH and FSH, as determined under the different conditions, revealed an expected 8.2-fold and 4.1-fold increase, respectively, after castration. As predicted, this effect was totally abolished in steroid replaced animals or in castrated animals treated with the GnRH antagonist (not shown).
Effects of exogenous GnRH
To determine if GnRH was able to modulate the level of NOS I
subunit, (intact) rats were injected with the potent GnRH agonist,
Triptorelin. Initial experiments revealed a high potency of the agonist
(soluble form) to increase NOS I levels as illustrated in both the
histogram and the autoradiogram in Fig. 3 (12 h after a 20 µg
injection). We also used the long-lasting formulation of Triptorelin,
under conditions known to cause, after an initial stimulation,
homologous desensitization of gonadotrophs (injection of 60 µg) and
examined the effects on NOS I levels as a function of time (Fig. 4). As shown in the figure, this
treatment induced a rapid, transient increase in LH and FSH release,
whereas a substantial, slightly delayed but prolonged rise in NOS I
level was seen under the same conditions. A 2-fold increase in NOS I
was detectable 8 h post injection, in the descending phase of the
gonadotropin release peak, and a maximal 4.5-fold increase in NOS I was
seen at 48 h when serum gonadotropins were at their nadir. The NOS
I levels then declined dramatically, whereas no change in either LH or
FSH was detectable, demonstrating dissociated variations with time of
NOS I and gonadotropin levels.
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shows that the 3.4-fold increase in NOS I mRNA level in the anterior
lobe of rats 4 days post orchidectomy was totally abolished by
testosterone or GnRH antagonist administration. In intact rats,
testosterone or antagonist treatments also significantly depressed mRNA
levels (by 50–65%). In contrast, a 2.6-fold mRNA increase was
observed in response to a 48-h administration of GnRH agonist
(long-lasting formulation). Thus, these data indicate that variations
in the concentration of NOS I protein are associated with concomitant
changes in NOS I mRNA, implicating an action of GnRH at the NOS I gene
level.
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revealed that, in intact
anterior pituitary (Aa), a faint cytoplasmic diaphorase activity was
detectable in two types of cells that were morphologically different:
1) large, individualized glandular cells (depicted by the
arrowheads); and 2) small cells with long and thin processes
(depicted by complete arrows). After castration (4 days),
the former cells were considerably more numerous and intensely colored
(Ba), in contrast to the latter cells, the staining of which was
unaffected. Treatment of castrated rats with the GnRH antagonist (Ca)
completely abolished NADPH-diaphorase staining in glandular cells (Ca
vs. Ba) to a lesser degree than even in intact rats (Aa). In
contrast, the administration of the GnRH agonist Triptorelin
(long-lasting form, 48 h-treatment) to intact animals resulted in an
intense staining of these cells (Da). Ab, Bb, Cb, and Db showed that
variations in diaphorase staining exclusively concerned
LHß-immunoreactive cells (although all the LHß-immunoreactive cells
were not NADPH-diaphorase-reactive). B’a, B’b, B’c illustrates at a
higher magnification, a section of the anterior pituitary from
castrated rats successively analyzed for diaphorase activity (B’a) and
double immunostaining for LHß (B’b) and FSHß (B’c). It is
apparent that the blue-staining of glandular cells colocalized with
cells containing either (•) or both (
) LHß and FSHß, thus
suggesting an exclusive association of NOS I with mono- or bi-hormonal
gonadotrophs. In addition using several different antibodies (including
anti-TSHß, anti-PRL or anti GH, not shown), no
NADPH-diaphorase-positive cell was detected unassociated with either
form of gonadotroph, whereas NADPH-diaphorase-negative gonadotrophs
were found (depicted by arrow ending with 
). This
suggests the existence of gonadotrophs unable to express the enzyme
or/and to respond to GnRH, or may simply reflect the limit of assay
sensitivity. Finally, immunostaining with S-100 antibody (A’d)
identified folliculo-stellate cells, the small cells exhibiting the
NADPH-diaphorase activity (A’a) unaffected by castration or other
treatment (Aa, Ba, Ca, Da).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Indeed, an exclusive participation of gonadotrophs in the steroid/GnRH regulation of NOS I is demonstrated by our histochemical study using the NADPH-diaphorase reaction coupled to cell identification. It is well established that under the conditions used (especially paraformaldehyde fixation of tissues), the NADPH-diaphorase reaction represents only the NOS activity (17, 25, 26, 27) and this was confirmed by our controls. Interestingly, in the absence of detectable levels of NOS II or III isoforms in the rat anterior pituitary, it can be assumed that NADPH-diaphorase staining readily reflects NOS I activity only. Thus, this approach offered the double advantage compared with the immunodetection of the enzyme, to identify cells expressing NOS I and to demonstrate that changes in NOS I levels under the various treatments were associated with parallel alterations of enzyme reactivity in the gonadotrope cells. This is of interest because it has been established that NOS I is an enzyme that requires homodimerization to be active (10, 11). This process requires several cofactors including Ca2+, which is known to be mobilized under GnRH stimulation in gonadotrophs, and calmodulin, which is abundant in these cells (4). In addition, a specific inhibitor of NOS I (for homodimerization) has been described (37). Taking all these and present data into consideration, the presence of a NOS-diaphorase activity in gonadotrophs and consequently precisely linked to GnRH stimulation, even in intact rats, where exists a basal stimulation by GnRH, implies that GnRH may affect NOS on two levels: 1) enzymatic activity, at least, in part through convergent GnRH-induced increased formation of the Ca2+/calmodulin complex (the latter acting as cofactor); and 2) increased gene expression. The exact role of intracellular GnRH-induced Ca2+ rise in the formation of Ca2+/calmodulin and the ensuing activation of gonadotropic NOS I remains to be elucidated, as are the mechanisms, signaling, and functions of the GnRH-induced stimulation of NOS I gene expression.
In this respect, it is interesting to note that the administration of a
long-lasting GnRH agonist under conditions known to induce
desensitization, as reflected by the rapid increase and then
paradoxical abolition of gonadotropin release seen in Fig. 4, had no
major incidence on NOS I elevation for at least the first 48 h.
The mechanisms that are responsible for the GnRH activation and
desensitization of NOS I gene expression, synthesis, and protein
turnover thus differ from those governing gonadotropin release. It has
been previously shown that a similar desensitizing treatment altered
gene expression and synthesis of the gonadotropin subunits and GnRH
receptor (31). In particular, homologous desensitization readily
depressed FSHß and GnRH receptor mRNA levels in a few h and LHß in
two days, whereas -subunit mRNA increased and remained stable,
illustrating the fact that elements under GnRH regulation in
gonadotrope cells each respond to desensitization with distinct
characteristics. Mechanisms for such differential regulations are not
yet well understood. A dissociated regulation of transcriptional
stimulation and mRNA stability was shown for the -subunit (38).
Disregarding mechanisms involved, the delayed alteration of NOS I
raises questions concerning its possible contribution in the
desensitization process.
Indeed, because gonadotrophs express an active NOS I under the control of GnRH, the question arises as to the role and the mechanisms of action of NO in the different cellular functions. A line of evidence indicates that NO is an intracellular mediator of several brain functions through activation of a soluble guanylate cyclase (10, 11, 39). This is even apparent in the reproductive axis for the NMDA stimulation of GnRH release at the hypothalamus level (13, 21, 40). In fact, it has been known for years that GnRH can induce a Ca2+-dependent increase in the production of cGMP in gonadotrophs (6, 7, 41) and our data implicitly suggest that this effect is mediated through NO production. It has been proposed previously from in vitro experiments with a NO donor or NOS inhibitor that NO may inhibit, in gonadotrophs, GnRH-induced release of LH (18), and may even contribute to the inhibition of GHRH-induced release of GH by somatotropes (18, 42). It is well established that NO is a diffusive molecule and may operate as a paracrine modulator to affect neighboring cells of the similar or different types. For gonadotrophs, the real relationship between LH release and NO remains to be clarified. In particular, an inhibitory action of NO on GnRH-induced gonadotropin release is inconsistent with the well characterized rise in both LH and FSH secretion following castration, especially because it is associated in this experimental model with a concomitant, large increase in NOS I (mRNA and protein). In addition, it is known that gonadotropins remain elevated in the blood even after 2 weeks, whereas NOS levels decreased as seen in this study. Similar considerations are provided by the effects of GnRH agonist in intact rats because, although an inhibition of gonadotropin release was seen to develop within the period during which NOS I levels increased, no elevation in LH release was observed when NOS I levels declined (after 48 h). Conversely, although gonadotrophs contain a soluble guanylate cyclase activatable by GnRH, it should be recalled that a clear dissociation between its activation and the GnRH-induced release of LH has been demonstrated several years ago (43). Therefore, it is likely that if NO alters gonadotropin release, the mechanism would not involve the cGMP production. Nevertheless this cyclic nucleotide, the role of which in gonadotrophs is still unclear, seems important because its production is enhanced in these cells not only by the GnRH activation of soluble guanylate cyclase but also via the activation of C-natriuretic peptide receptors that possess an intrinsic guanylate cyclase activity (44). These points thus need to be further elucidated.
In conclusion, we have provided evidence for a GnRH-dependent regulation of NOS I in the anterior pituitary gonadotrophs. GnRH stimulates gene expression and the synthesis of NOS I subunits with subsequent association into an active enzyme. As such, this process appears to be affected by prolonged exposure to GnRH that induces desensitization, and by the indirect action of gonadal steroids on the hypothalamus which results in the modulation of GnRH release. NOS I thus appears to be a new target gene for GnRH action, the mechanisms and signaling of which remain to be elucidated. This action of GnRH at the genomic level differs from, but is functionally consistent with, and complements the possible role of NO, the product of NOS I, on the GnRH-induced release of LH previously reported by others. The exact role(s) and mechanism(s) of action of NO within gonadotrophs and possible paracrine actions on neighboring cells remain to be answered. Nonetheless, that GnRH can induce NOS I and regulate its concentration, represents a novel aspect of its signaling and requires further investigation.
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Acknowledgments |
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Footnotes |
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2 Recipient of a fellowship from the Fondation pour la Recherche
Médicale, Paris.
Received October 9, 1997.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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