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Reproductive Sciences Program, Departments of Physiology (D.F.B., F.J.K.) and Biostatistics (M.B.B., N.E.C.), University of Michigan, Ann Arbor, Michigan 48109-0404
Address all correspondence and requests for reprints to: Dr. Fred J. Karsch, Reproductive Sciences Program, University of Michigan, 300 North Ingalls Building, Room 1101 SW, Ann Arbor, Michigan 48109-0404. E-mail: fjkarsch{at}umich.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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. In Exp 3, flurbiprofen in the absence of
endotoxin had no effect on pulsatile LH secretion. In Exp 4,
flurbiprofen failed to prevent suppression of pulsatile LH secretion
induced by luteal phase levels of the ovarian steroids progesterone and
estradiol, which produce a nonimmune suppression of gonadotropin
secretion. In Exp 5, flurbiprofen prevented the endotoxin-induced
inhibition of pulsatile GnRH release into pituitary portal blood. Our
finding that this PG synthesis inhibitor reverses the inhibitory effect
of endotoxin leads to the conclusion that PGs mediate the suppressive
effects of this immune/inflammatory challenge on pulsatile GnRH and LH
secretion. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(TNF)-induced inhibition of LH secretion in the
gonadectomized rat (2, 10). Of interest, however, PG synthesis
inhibition failed to reverse the endotoxin-induced inhibition of LH
secretion in the castrated male rat (2). It thus remains an open
question as to whether PGs play an essential role in mediating the
inhibitory effects of endotoxin, an immune challenge that induces a
cascade of pathophysiological responses analogous to a true infection
(11).
This study tested the hypothesis that PGs mediate the inhibitory
effects of endotoxin on reproductive neuroendocrine activity in the
ewe, a model species in which the reproductive neuroendocrine axis has
been particularly well characterized, and GnRH secretion can be
monitored directly in conscious, noncompromised subjects. Our approach
was to test whether the PG synthesis inhibitor, flurbiprofen, could
reverse the inhibitory effects of endotoxin on pulsatile LH and GnRH
secretion. In addition to reproductive neuroendocrine function, we
monitored the effects of the PG synthesis inhibitor on three other
pathophysiological responses to endotoxin: activation of the
hypothalamo-pituitary-adrenal axis, generation of fever, and secretion
of the cytokine TNF.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Escherichia coli endotoxin (E. coli
lipopolysaccharide, serotype 055 B5; Sigma, St. Louis, MO)
was dissolved in nonpyrogenic saline (10 µg/ml) and injected iv (400
ng/kg). This treatment induces fever, inhibits pulsatile GnRH and LH
secretion, stimulates the neuroendocrine stress axis, and provokes
transient sickness behaviors (e.g. lethargy, labored
breathing, and diarrhea) in the ewe (4). The PG synthesis inhibitor,
flurbiprofen (Sigma), was dissolved in 95% ethanol (200
mg/ml) and injected iv (2 mg/kg). Flurbiprofen inhibits both the
cyclooxygenase-1 and -2 enzymes (13), and prior work in goats indicates
that the 2 mg/kg dose of flurbiprofen blocks endotoxin-induced fever
(14). Progesterone was administered via intravaginal
progesterone-impregnated devices (Controlled Internal Drug Release,
CIDR, InterAg, Hamilton, New Zealand; two devices per ewe).
17ß-Estradiol (Sigma) was administered via a 1-cm sc
implant constructed of SILASTIC brand tubing (Dow Corning Corp., Midland, MI). These steroid treatments produce luteal
phase levels of circulating estradiol (1–2 pg/ml) and progesterone
(
4 ng/ml) in the ovariectomized ewe (15, 16).
All procedures were approved by the Committee for the Use and Care of Animals at the University of Michigan.
General experimental protocol
The study consisted of five experiments. Exp 1–4 (Nov-Apr) were
conducted on the same five ewes using a cross-over design. Each
replicate of the cross-over was conducted during a 9-h period according
to the general protocol illustrated in Fig. 1
. The first 3.5 h were a
pretreatment period, after which all ewes received either flurbiprofen
or the equivalent volume of vehicle. This was followed 30 min later by
endotoxin, saline, or ovarian steroids, depending on the purpose of
each experiment. Ewes receiving flurbiprofen in the first replicate
received vehicle during the second and vice-versa, enabling
each ewe to act as her own control. LH was the primary reproductive
neuroendocrine variable monitored in Exp 1–4. GnRH was the primary
variable in Exp 5, which was conducted (November to May) according to
the general experimental protocol (Fig. 1), but not as a cross-over
design to avoid performing repeated pituitary portal blood collections
on the same animals.
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).
Jugular blood samples for LH assay were taken, and body temperature was
monitored at 30-min intervals.
Exp 2: can flurbiprofen prevent endotoxin-induced inhibition of
pulsatile LH secretion?
The main aim of this experiment was to test the hypothesis that
PGs mediate the endotoxin-induced suppression of pulsatile LH
secretion. Ewes were treated with flurbiprofen or vehicle as described
in Fig. 1, and jugular blood was sampled at 6-min intervals for LH
analysis. Further, treatment effects on plasma concentrations of
TNF, cortisol, progesterone, and body temperature were assessed at
30-min intervals.
Exp 3: can flurbiprofen alter pulsatile LH secretion in the absence
of endotoxin?
The goal of this experiment was to determine whether
flurbiprofen alone alters pulsatile LH secretion. Ewes were treated
with flurbiprofen or vehicle according to the general protocol,
followed by saline rather than endotoxin 30 min later (Fig. 1). Jugular
blood samples were taken at 6-min intervals to monitor LH pulses.
Exp 4: can flurbiprofen prevent a nonimmune induced inhibition of
pulsatile LH secretion?
This experiment examined whether PG synthesis is a general
requirement for any inhibitory effect on the reproductive
neuroendocrine axis. Accordingly, we tested the hypothesis that PGs
mediate the negative feedback actions of ovarian steroids on pulsatile
LH secretion. Ewes were treated with flurbiprofen or vehicle, followed
30 min later by estradiol and progesterone, rather than endotoxin (Fig. 1).
Exp 5: can flurbiprofen prevent endotoxin-induced inhibition of
pulsatile GnRH secretion?
Exp 2 revealed that flurbiprofen blocked the inhibitory effect
of endotoxin on pulsatile LH secretion. In this final experiment we
tested the hypothesis that flurbiprofen also prevents the
endotoxin-induced inhibition of pulsatile GnRH secretion. This is
particularly relevant given the recent findings that endotoxin can act
both at the brain to inhibit pulsatile GnRH secretion (4) and at the
pituitary to suppress GnRH receptor expression as well as pituitary
responsiveness to GnRH (17, 18). Ewes were treated with flurbiprofen or
vehicle followed by endotoxin 30 min later. As this experiment was not
conducted as a cross-over, separate ewes were used for control (n
= 7) and flurbiprofen (n = 6) groups. On any given experimental
day, samples were obtained from two to four ewes, which included at
least one animal from the control and flurbiprofen-treated groups. Both
jugular and pituitary portal blood were collected at 10-min intervals
for 6 h, instead of 5 h, after endotoxin. Body temperature
was recorded at 30-min intervals.
Assays
LH was measured in duplicate aliquots of plasma (10–200 µl)
using a modification of a previously described RIA (19, 20). Values are
expressed in terms of NIH LH-S12. Mean intra- and interassay
coefficients of variation were 5.3% and 5.8%, respectively, and the
assay sensitivity for 200-µl aliquots averaged 0.7 ng/ml (21 assays).
Cortisol was measured in duplicate 50-µl aliquots of plasma using the
Coat-a-Count cortisol assay kit (Diagnostics Products, Los
Angeles, CA), previously validated for use in the sheep (4). Mean
intra- and interassay coefficients of variation were 4.7% and 11.1%,
respectively, and assay sensitivity averaged 0.6 ng/ml (three assays).
Progesterone was determined in duplicate 100-µl aliquots using the
Coat-a-Count progesterone assay kit (Diagnostics Products), previously validated for use in the sheep (21).
Intra- and interassay coefficients of variation both averaged 4.8%,
and assay sensitivity averaged 0.03 ng/ml (two assays). GnRH was
measured in duplicate in methanol extracts of portal plasma samples
(650 µl portal plasma and 100 µl bacitracin) using a previously
described RIA (22, 23). Intra- and interassay variation averaged 10.6%
and 14.2%, respectively, and assay sensitivity averaged 0.16 pg/ml.
Plasma TNF was monitored by a specific two-site ELISA previously
validated for use in the sheep (24, 25). The procedure was modified to
use a recombinant human, rather than ovine, TNF standard (R&D
Systems, Minneapolis, MN; range, 15.6-2000 pg/well). Parallelism was
confirmed for use of the human standard to assess TNF in ovine
plasma samples. Each sample was diluted 1:10 in ovine plasma
(containing no detectable TNF) and analyzed in duplicate 50-µl
aliquots. Mean intra- and interassay coefficients of variation were
5.9% and 13.0%, respectively (three enzyme-linked immunosorbent assay
plates), and assay sensitivity averaged 4.2 ng/ml.
Data analysis
For analysis, all data were allocated to two 3.5-h periods:
preendotoxin (-4 to -0.5 h from endotoxin) and postendotoxin (+1.5 to
+5 h from endotoxin). LH pulses during these periods were detected by
Pulsefit (26), with the model fit assuming constant variance and using
a critical value of 1.0. LH pulse frequency data were square root
transformed before statistical analysis to normalize variability. All
other summary LH measures were log transformed before analysis. LH
pulse amplitude was defined as the difference between the peak of a
pulse and its preceding nadir. Total pulsatile LH output was calculated
as the product of the number of pulses x the mean pulse
amplitude. Mean LH was determined as the average LH concentration per
3.5-h period (see above).
GnRH in pituitary portal blood was assessed as the collection rate (picograms per min) rather than as picograms per ml. This measure minimizes errors due to contamination of portal samples with peripheral blood or cerebrospinal fluid (judged to be negligible in this study) or due to changes in the rate of pituitary blood flow. GnRH pulses were detected by the Cluster analysis of Veldhuis and Johnson (27). Cluster sizes for peaks and nadirs were defined as 1 and 2. The t statistic used to identify a significant increase and decrease was 3.8. GnRH pulse frequency, mean pulse amplitude, and mean GnRH values were determined for each ewe within both the preendotoxin (-4 to -0.5 h before endotoxin) and postendotoxin (+1.5 to +5 h after endotoxin) periods.
Plasma cortisol, progesterone, TNF, and body temperature values were
log transformed before statistical analysis.
Repeated measures ANOVA (treatment x time) was used to identify
significant interactions for all hormonal, TNF, and body temperature
values between control and flurbiprofen groups. When a significant
treatment x time interaction was obtained, post-hoc multiple
comparison analysis with Bonferroni adjustment was used to ascertain
differences between the specific groups. A paired t test was
used to compare treatment effects on the percent increase in cortisol
and progesterone between the control and flurbiprofen-treated groups in
Exp 2. The level of significance was established at P
0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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; mean LH pre- vs.
postendotoxin: control, 23.6 ± 5.3 vs. 11.2 ±
2.17 ng/ml (P < 0.01); flurbiprofen, 27.7 ± 4.9
vs. 25.3 ± 4.5 ng/ml (P = NS)].
Further, endotoxin induced a significant rise in body temperature;
this, too, was prevented by flurbiprofen [Fig. 2b; mean temperature
pre- vs. post endotoxin: control, 40.0 ± 0.2
vs. 41.6 ± 0.3 C (P < 0.01);
flurbiprofen, 39.9 ± 0.1 vs. 39.7 ± 0.1 C
(P = NS)].
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for two representative
ewes during both the control and flurbiprofen treatments of the
cross-over experiment. Endotoxin alone markedly suppressed LH pulsatile
secretion; this response was prevented by flurbiprofen. Statistical
analysis indicated that endotoxin significantly (P <
0.05) suppressed total pulsatile LH output and mean LH concentrations
(Table 1; Exp 2). Flurbiprofen completely
reversed inhibition of both variables (note: underlined
values in Table 1 depict a significant treatment x time
interaction in Exp 2, indicating the effect of flurbiprofen).
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and 4a). Endotoxin
significantly stimulated plasma cortisol and progesterone, presumably
of adrenal origin as the ewes were ovariectomized (P <
0.01; Figs. 3 and 4, b and c). Flurbiprofen did not block the
endotoxin-induced cortisol and progesterone rises, but it did diminish
their magnitude (P < 0.05, percent increase when
comparing pre- vs. postendotoxin; Figs. 3 and 4, b and c).
Endotoxin also stimulated plasma TNF concentrations
(P < 0.05); this increase was not affected by
flurbiprofen (Figs. 3 and 4d).
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. Statistical analysis indicated
flurbiprofen alone had no effect on any aspect of pulsatile LH
secretion (Fig. 5 and Table 1, Exp 3). The total pulsatile LH output
and mean LH did increase over time in both groups, but, importantly,
there was no treatment effect (bold values in Table 1
indicate a significant time effect).
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. Statistical analysis indicated a
significant decrease in total pulsatile LH output and mean LH values
over time in both groups, but no interaction of time with treatment.
Thus, flurbiprofen did not prevent the ovarian steroid-induced
suppression of pulsatile LH secretion (Table 1, Exp 4; bold
values in Table 1 indicate a significant time effect).
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. In vehicle-treated controls, endotoxin
markedly inhibited pulsatile GnRH and LH secretion (Fig. 7, a and c).
This effect was reversed by flurbiprofen (Fig. 7, b and d). Statistical
analysis indicated a significant treatment x time interaction
(Table 2, underlined
text). Specifically, in vehicle-treated controls, endotoxin
induced a significant inhibition of GnRH pulse amplitude and mean GnRH
values (P < 0.05). This effect was prevented by
flurbiprofen. Although endotoxin alone did not significantly inhibit
GnRH pulse frequency, pulses appeared to become less regular after
endotoxin. In ewe 9001, for example (Fig. 7a), the highly regular
interpulse interval of 50–60 min before endotoxin was no longer
evident after endotoxin. Rather, GnRH pulses initially occurred very
frequently (interpulse interval of 40–50 min) followed by a 150-min
period when no pulses occurred. A similar disruption of GnRH pulse
regularity was seen in other ewes treated with endotoxin plus vehicle
(e.g. Fig. 7c). Such irregularity of GnRH pulse frequency
after endotoxin was not observed in ewes pretreated with flurbiprofen
(e.g. Fig. 7, b and d). As in Exp 1 and 2, flurbiprofen
prevented the endotoxin-induced suppression of LH secretion and the
production of fever (statistical analyses not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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This conclusion contrasts with the finding that the suppressive effect
of systemic endotoxin on tonic LH secretion in the orchidectomized rat
was not reversed by indomethacin (2), a competitive inhibitor of
cyclooxygenase that acts in much the same manner as flurbiprofen (13).
This could be taken as evidence that PGs are not obligatory mediators
of endotoxin action on the reproductive neuroendocrine axis in the rat,
although PGs have been shown to mediate the effects of the cytokines
interleukin-1 and TNF in this species (2, 10). Alternatively, the
indomethacin treatment used in the rat might not have been adequate for
full blockade of PG production after systemic endotoxin, a possibility
that remains open, as the efficacy of the PG synthesis inhibitor was
not assessed. In our study, flurbiprofen prevented endotoxin-induced
fever. Because fever is driven by an increase in PGs (28, 29), it is
most likely that PG synthesis was effectively blocked in the present
study. This strengthens our conclusion that PGs mediate
endotoxin-induced suppression of pulsatile GnRH and LH secretion, at
least in the ewe.
One unexpected finding was the increase in LH pulsatility across time in both the control and flurbiprofen groups of Exp 3, in which we examined the response to flurbiprofen in the absence of endotoxin. Three explanations may account for this increase: a diurnal change in the LH pulse-generating mechanism, an effect of ethanol (vehicle for flurbiprofen), or an effect of saline (vehicle for endotoxin). This finding, although unexplained, does not weaken the overall conclusion that PGs mediate the suppressive effects of endotoxin. Each of these explanations (diurnal rhythm, ethanol, and saline) would have applied to both the flurbiprofen and vehicle groups in the other experiments of this study, yet flurbiprofen still prevented the endotoxin-induced inhibition of pulsatile GnRH and LH secretion.
Our conclusion that PGs mediate the suppressive effects of endotoxin on pulsatile GnRH and LH secretion might seem unexpected based on evidence that PGs can actually stimulate the secretion of these hormones (30, 31). For example, central delivery of PGE stimulated LH release on the afternoon of proestrus in rats in which the spontaneous LH surge was blocked by pentobarbital (32). That this may reflect direct stimulation of GnRH neurons is suggested by the findings that PGE and PGI stimulate GnRH release from a GnRH cell line in culture (33, 34). These findings, however, do not conflict with the present conclusion that PGs mediate GnRH pulse suppression, because none of the aforementioned studies addressed mediation of GnRH suppression by an immune/inflammatory challenge.
In considering how PGs may stimulate GnRH/LH secretion, on the one hand (30, 31), and mediate GnRH/LH suppression, on the other hand (this study and Refs. 2, 10), it is useful to address how and where PGs may act to mediate the inhibitory effect of endotoxin on reproductive neuroendocrine activity. In this regard, it is important to note that this immune challenge stimulates an increase in circulating PGs (35, 36) from a number of sources, most notably immune cells such as macrophages and liver Kupffer cells (35, 36, 37). PGs produced in the liver also appear to stimulate hepatic neural afferents, which activate the temperature-regulating center in the hypothalamus (37). After an immune challenge, PG synthesis is also stimulated centrally and, of particular interest, in the vicinity of the hypothalamo-hypophyseal area. Specifically, endotoxin induces cyclooxygenase-2 messenger RNA expression within microglial cells along small penetrating blood vessels around the brain and in macrophages within the meninges (38). Further, the number of cyclooxygenase-2-producing cells, as recognized by immunocytochemistry, is also enhanced within this region after endotoxin treatment (39). Interestingly, neurons containing cyclooxygenase-1 (the constitutive form of the enzyme) have been identified within the sheep brain (40). Thus, either systemic or centrally produced PGs could suppress pulsatile GnRH and LH secretion. They could act either directly on the GnRH neurons and/or pituitary gonadotropes or indirectly by inducing other pathophysiological responses that, in turn, inhibit GnRH and LH secretion.
The possibility that PGs act directly on GnRH neurons to mediate the inhibitory effect of endotoxin has not yet been tested. Consistent with this possibility are recent findings that PGE concentrations within cerebrospinal fluid increase dramatically after an immune challenge in the ewe (41), that GnRH neurons contain PGE receptors (30), and that the preoptic area where most GnRH neurons reside contains one of the highest densities of PG receptors in the brain (42). It is important to reiterate, however, that PGs can stimulate GnRH secretion (30, 31) as well as mediate the suppressive effects of endotoxin. Thus, PG receptors within GnRH neurons may relay stimulatory signals rather than mediate inhibitory inputs, such as the inhibition arising from an immune/inflammatory challenge.
Rather than acting directly, PGs may mediate pulsatile GnRH and LH
inhibition indirectly, via one or more of the pathophysiological
responses induced by immune/inflammatory challenge. Such responses
include fever, cardiovascular effects, sickness behaviors, and the
stimulation of the hypothalamo-pituitary-adrenal axis (1, 43, 44, 45, 46).
Further, GnRH secretion may be inhibited by central neurotransmitter
systems that induce these pathophysiological responses. Among these,
the noradrenergic, 
-aminobuteric acid-ergic, opioidergic, and
tachykinergic neurons have all been implicated in GnRH inhibition (3, 7, 8, 28, 47, 48).
The possibility that PGs mediate reproductive neuroendocrine suppression indirectly via the neuroendocrine stress axis is worthy of further consideration. Systemic endotoxin promptly and profoundly stimulates the secretion of CRH, arginine vasopressin, ACTH, the adrenal steroids, cortisol, and progesterone in the sheep (1, 46, 49). Each of these stress hormones may inhibit the reproductive neuroendocrine axis (50, 51, 52, 53). Recent work in sheep suggests that a chronic elevation of circulating cortisol, to a level similar to that induced by endotoxin, can inhibit pulsatile LH secretion under certain endocrine conditions (50, 54) and can interrupt the follicular phase of the estrous cycle (55). In the present study, flurbiprofen partially suppressed the endotoxin-induced stimulation of adrenal cortisol and progesterone secretion. One intriguing possibility, therefore, is that this decrease in hypothalamic-pituitary-adrenal axis activation prevented the inhibition of pulsatile GnRH and LH secretion. We are currently investigating whether PGs mediate the suppressive effects of endotoxin on reproductive neuroendocrine activity via stimulation of adrenal steroid production or other components of the neuroendocrine stress axis.
Yet another indirect pathway through which PGs may act is via the neural mechanisms that generate fever and/or the associated increase in body temperature. In our study, GnRH and LH pulses were markedly suppressed in those animals in which endotoxin induced fever, whereas pulses were unaffected when fever was blocked by the PG synthesis inhibitor. The reproductive neuroendocrine axis can be influenced by an increase in body temperature that results from alterations in the external environment (56, 57, 58). Further work is required to test whether an internally driven increase in body temperature, as is the case with fever, may also affect GnRH/LH release.
Our present observations on TNF provide insight as to where in the
cascade of neuroimmune events PGs may act to mediate suppression of
pulsatile GnRH and LH secretion. As in earlier studies in sheep (1, 41), we observed a prompt increase in circulating TNF after
endotoxin, coinciding with the suppression of reproductive
neuroendocrine function. Observations in rodents provide strong
evidence that this cytokine inhibits LH secretion (8, 10). Further,
TNF may mediate the endotoxin-induced inhibition of LH secretion in
the rat (59). If TNF also mediates the inhibitory effects of
endotoxin on LH in the sheep, two general steps may be envisioned for
where, in the neuroimmune cascade, PGs act. First, endotoxin may
stimulate PG synthesis, which subsequently enhances TNF release,
which, in turn, inhibits pulsatile GnRH/LH secretion. Alternatively
endotoxin may stimulate TNF release that, in turn, induces the PG
synthesis that suppresses reproductive neuroendocrine activity. If
TNF is a key player in mediating the endotoxin-induced inhibition of
GnRH/LH pulses in the ewe, our present findings that TNF
remains elevated despite the lack of GnRH/LH pulse inhibition in
flurbiprofen-treated ewes, favors the second possibility. Namely PGs
act downstream of endotoxin-induced TNF release to inhibit the
reproductive neuroendocrine axis of the ewe. This view is substantiated
by observations that TNF inhibits reproductive neuroendocrine
function in rodents via PG-dependent mechanisms (10).
Finally, in the broader context of the estrous cycle, recent work suggests immune challenge can interrupt cyclicity by at least three mechanisms: suppression at the level of the ovary (5, 60, 61), disruption of the process by which estradiol generates the preovulatory GnRH/LH surge (62), and inhibition of pulsatile GnRH/LH secretion (1, 2, 3, 5, 6, 52, 53). The present findings provide strong evidence that PGs mediate one of these disruptive effects, namely the endotoxin-induced suppression of pulsatile GnRH/LH secretion. It would now be keenly interesting to determine the importance of PGs in mediating the inhibitory effects of endotoxin on other components of the reproductive axis and whether the disruptive influence of endotoxin on the estrous cycle could be reversed by the inhibition of PG synthesis.
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Acknowledgments |
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assay reagents. |
Footnotes |
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2 Present address: INSERM U-501, Faculté de Médecine Nord,
Boulevard Pierre Dramard, 13916 Marseille Cedex 20, France.
Received September 24, 1999.
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References |
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the release of luteinizing hormone-releasing hormone. Endocrinology 138:19–25-induced decrease in luteinizing hormone
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gonadotropin release in the ovariectomized rhesus monkey: reversal by a
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