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Endotoxin Inhibits the Surge Secretion of Gonadotropin-Releasing Hormone via a Prostaglandin-Independent Pathway

Reproductive Sciences Program and Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109

Address all correspondence and requests for reprints to: 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.

	Abstract

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Immune/inflammatory challenges, such as bacterial endotoxin, disrupt gonadotropin secretion and ovarian cyclicity. We previously determined that endotoxin can block the estradiol-induced LH surge in the ewe. Here, we investigated mechanisms underlying this suppression. First, we tested the hypothesis that endotoxin blocks the estradiol-induced LH surge centrally, by preventing the GnRH surge. Artificial follicular phases were created in ovariectomized ewes, and either endotoxin or vehicle was administered together with a surge-inducing estradiol stimulus. In each ewe in which endotoxin blocked the LH surge, the GnRH surge was also blocked. Given this evidence that endotoxin blocks the estradiol-induced LH surge at the hypothalamic level, we began to assess underlying central mechanisms. Specifically, in view of the prior demonstration that prostaglandins mediate endotoxin-induced suppression of pulsatile GnRH secretion in ewes, we tested the hypothesis that prostaglandins also mediate endotoxin-induced blockade of the surge. The prostaglandin synthesis inhibitor flurbiprofen was delivered together with endotoxin and the estradiol stimulus. Although flurbiprofen abolished endotoxin-induced fever, which is a centrally generated, prostaglandin-mediated response, it failed to reverse blockade of the LH surge. Collectively, these results indicate endotoxin blocks the LH surge centrally, suppressing GnRH secretion via a mechanism not requiring prostaglandins. This contrasts with the suppressive effect of endotoxin on GnRH pulses, which requires prostaglandins as intermediates.

	Introduction

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IMMUNE/INFLAMMATORY CHALLENGES, such as bacterial endotoxin, potently suppress gonadotropin secretion (1, 2, 3, 4) and disrupt the ovulatory cycle in a number of species (5, 6, 7). In terms of its effects on gonadotropin secretion, endotoxin inhibits both pulsatile LH release and the estradiol-induced LH surge. Considerable insight has been gained into mechanisms whereby endotoxin suppresses pulsatile LH secretion. For example, endotoxin disrupts both hypothalamic and pituitary function, inhibiting pulsatile GnRH secretion and pituitary responsiveness to GnRH (2, 8). Furthermore, endotoxin appears to suppress pulsatile GnRH and LH secretion indirectly, via a cascade of intermediates that include cytokines, such as IL-1 and TNF-, as well as prostaglandins (3, 9, 10).

Surprisingly few studies have addressed mechanisms whereby endotoxin blocks the estradiol-induced LH surge, and those that have suggest the basis for inhibition of LH pulses and surges may not be entirely the same. For example, recent observations in ewes indicate that, unlike its acute suppression of pulses, which occurs within 1 h (2, 8, 9), endotoxin does not acutely inhibit LH release at the time of the surge. Rather, endotoxin acts to block the LH surge some 10–20 h in advance of the LH surge itself (7). During this early period in the surge induction process, the estradiol stimulus activates estrogen-sensitive neurons and the positive feedback signal is transduced by processes that ultimately lead to onset of the GnRH surge (11).

The present study consisted of two experiments to investigate mechanisms whereby endotoxin blocks the estradiol-induced LH surge in the ewe. First, we determined whether endotoxin blocks the LH surge centrally, interfering with the ability of estradiol to induce the surge of GnRH monitored in the hypophyseal portal circulation. Second, given prior evidence that prostaglandins are essential mediators of endotoxin-induced suppression of pulsatile GnRH and LH secretion in ovariectomized ewes (9), we tested the hypothesis that prostaglandins also mediate endotoxin-induced blockade of the LH surge. Our approach was to test whether the prostaglandin synthesis inhibitor flurbiprofen reverses the suppressive effects of endotoxin on the estradiol-induced LH surge.

	Materials and Methods

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General methods
Experiments were conducted from November, 1999, through July, 2001, on mature, ovariectomized Suffolk ewes maintained under standard husbandry conditions at the Sheep Research Facility in Ann Arbor, MI. All procedures were approved by the Committee for the Use and Care of Animals at the University of Michigan. This study consisted of two experiments. Experiment 1 was conducted during the nonbreeding season and experiment 2 during the breeding season. Our prior work has shown that estradiol induces a GnRH and LH surge in both the breeding and nonbreeding seasons and that there is no seasonal difference in sensitivity to the positive feedback action of estradiol (12, 13). In addition, endotoxin blocks both pulsatile and surge LH secretion in either season (Refs. 7, 9 and 14 ; and Breen, K., and F. Karsch, unpublished). Thus, interpretations in the present study are not compromised by having conducted the two experiments in different seasons. Furthermore, each experiment was internally controlled justifying conclusions made within each.

We used an artificial follicular phase model (13) that is well characterized in terms of estradiol signaling requirements for the GnRH and LH surge (11, 12, 15). To set up the model, ewes were ovariectomized aseptically under general anesthesia at least 4 wk before use. Then, an artificial luteal phase was simulated by treating ewes for 10 d with a 1-cm, sc, estradiol-filled Silastic implant (16) (Dow Corning Corp., Midland, MI) and two intravaginal progesterone-releasing devices (17) [controlled internal drug-releasing (CIDR), InterAg, Hamilton, New Zealand]. These treatments maintain luteal phase serum concentrations of estradiol and progesterone (1 pg/ml and 2–4 ng/ml, respectively) (11, 13, 17). After 10 d (approximate length of progesterone elevation during the natural luteal phase), an artificial follicular phase was created by removing progesterone to mimic corpus luteum regression. Sixteen hours later, four 3-cm estradiol implants (peak estradiol implants) were inserted sc into the axillary region. These implants raise serum estradiol to the peak follicular phase level (5–8 pg/ml) within 1–2 h and induce GnRH and LH surges beginning 18–24 h later (11, 12, 15). Escherichia coli endotoxin (E. coli lipopolysaccharide, serotype 055 B5; Sigma Chemical Co., St. Louis, MO) was dissolved in nonpyrogenic saline (20 µg/ml) and injected as a bolus (400 ng/kg, iv) 45 min in advance of the estradiol stimulus. Prior work indicates this endotoxin dose induces fever, provokes transient sickness behaviors (e.g. lethargy, labored breathing, and diarrhea), activates the hypothalamo-pituitary-adrenal axis, inhibits pulsatile GnRH and LH secretion, and can block the LH surge (1, 2, 7).

Experiment 1: does endotoxin disrupt the GnRH surge?
Eighteen ovariectomized ewes were surgically prepared for pituitary portal blood collection and sampled 2 wk later using the procedure of Caraty et al. (18), which permits sampling from fully conscious, minimally stressed animals. Before portal blood collection, ewes were set up in the artificial follicular phase model and given one of two treatments as illustrated in Fig. 1A: vehicle (n = 7) or endotoxin (n = 11). The peak estradiol implants were removed 12 h after their insertion to provide a stimulus close to the minimal duration needed to induce the LH surge in our animals (11). We selected this relatively short estradiol stimulus based on the logic that the GnRH/LH surge might be more susceptible to blockade than would be the case with a more prolonged (and presumably more powerful) estradiol stimulus. We previously observed that endotoxin blocks the LH surge in approximately 70% of ewes treated with a 12- to 14-h estradiol signal (Ref. 7 ; and Breen, K., and F. Karsch, unpublished). Jugular blood was sampled at 1-h intervals. Pituitary portal blood was withdrawn continuously, dispensed into tubes containing bacitracin to minimize GnRH degradation, and separated into hourly fractions from 15–36 h after insertion of peak estradiol implants. Rectal temperature was monitored hourly from 2 h before to 4 h after endotoxin to provide an independent assessment of efficacy of the endotoxin challenge. After sample collection, ewes were killed with a barbiturate overdose (Beuthanasia, Schering Plough Animal Health Corp., Kenilworth, NJ), and the pituitary was inspected to confirm appropriate placement of the lesion for sampling portal blood.

View larger version (23K): [in this window] [in a new window]   FIG. 1. Designs for experiment 1 (A) and experiment 2 (B). Time is depicted as hours relative to the insertion of the peak follicular phase estradiol (Peak E) implants. The dashed and solid lines designate the expected profile of serum progesterone (P) and estradiol (E) concentrations, respectively. Arrows indicate the time of endotoxin (400 ng/kg, iv bolus, given 45 min before estradiol) or its vehicle, and flurbiprofen (2 mg/kg, iv bolus given 30 min before endotoxin and 6 h later) or its vehicle. Solid bars indicate the expected period of the GnRH and LH surges in vehicle-treated ewes.

Hormone assays
LH concentrations were determined in duplicate aliquots (5–200 µl) of plasma using a modification (24) of a previously described RIA (25, 26). Values are expressed in terms of NIH-LH-S12. Mean intra- and interassay coefficients of variation were 6.0 and 5.8%, respectively, and assay sensitivity averaged 0.9 ng/ml. GnRH was measured in duplicate in methanol extracts of portal plasma (250 µl of plasma extract per assay tube) using a previously described RIA (12, 27). Intra- and interassay coefficients of variation were 3.0 and 6.4%, respectively. Assay sensitivity averaged 0.14 pg/ml.

Data analysis
GnRH or LH surges were considered to have occurred if hormone values increased 3-fold above the mean of the presurge baseline and remained so for at least 5 h. The surge period was defined as the interval between the hour GnRH or LH concentration increased and remained above 3-fold the presurge baseline and the hour GnRH or LH concentration decreased and remained below 3-fold the presurge baseline. Before statistical analysis, plasma hormone concentrations were log transformed to normalize variability across a broad range of values. Significance level was set at P 0.05. In experiment 1, GnRH or LH peak height (maximal value during the surge period) and total integrated surge amount (sum of all values during the surge period) were analyzed by ANOVA. Technical difficulties precluded accurate GnRH assessment in one of the seven control ewes; data from this animal were excluded from further analysis. Experiment 2 was a crossover experiment in which each animal received three treatments: estradiol plus vehicle (positive control), estradiol plus endotoxin, and estradiol plus endotoxin plus flurbiprofen. The LH surge period (as defined above) during the positive control run was used to identify the expected surge period of each ewe during the other two runs when endotoxin was given to block the surge. Values for total integrated amount of LH and maximal concentration during the surge period, and LH concentrations during the presurge period (0–10 h relative to insertion of peak estradiol implants) were compared across treatments using repeated-measures ANOVA. In addition, Fisher’s exact probability test was used to identify treatment effects on the proportion of ewes exhibiting the LH surge.

	Results

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Experiment 1: does endotoxin block the LH surge by preventing the GnRH surge?
Figure 2 presents GnRH and LH profiles during the surge period in vehicle- and endotoxin-treated ewes. All six vehicle-treated controls exhibited a robust LH surge accompanied by an unambiguous and sustained GnRH surge beginning approximately 20–22 h after onset of the estradiol stimulus and lasting 9–18 h (Fig. 2A, composite results). Endotoxin blocked the LH surge in 4 of 11 ewes, fewer than anticipated based on our prior studies (see Discussion). Of prime importance in terms of the experimental goals, endotoxin abolished the GnRH surge in all four ewes in which the LH surge was blocked (Fig. 2, B–E, depicts results in each of these four ewes). GnRH was invariably undetectable during the entire 22-h period of portal blood collection. The remaining endotoxin-treated ewes exhibited GnRH and LH surges comparable to those in control ewes in terms of time course, peak height, and total integrated hormone released during the surge period (Fig. 2F and Table 1). Endotoxin induced fever in all ewes (maximal rectal temperature: endotoxin, 40.4 ± 0.3 C; controls, 38.9 ± 0.2 C, P < 0.01). Maximal rectal temperature in response to endotoxin was no different among ewes that expressed the LH surge (40.4 ± 0.2 C) and those that did not (40.4 ± 0.4 C).

View larger version (27K): [in this window] [in a new window]   FIG. 2. GnRH in pituitary portal blood (closed circles) and LH in peripheral blood (open circles) in vehicle-treated control ewes (A) (mean ± SEM of six ewes), individual endotoxin-treated ewes in which the LH surge was blocked (B–E), and endotoxin-treated ewes in which the LH surge was not blocked (F) (mean ± SEM of seven ewes) in experiment 1. Data are normalized to the LH peak in A and F and to insertion of peak estradiol implants in B–E.

View larger version (35K): [in this window] [in a new window]   FIG. 3. Circulating LH concentrations in three representative ewes treated with vehicles for both endotoxin and flurbiprofen (A), endotoxin (B), and endotoxin plus flurbiprofen (C) in experiment 2. This was a crossover experiment in which each ewe received all three treatments. The horizontal bar in each panel depicts the surge period during the control run (see Materials and Methods for details). See Fig. 1 for design details.

View larger version (33K): [in this window] [in a new window]   FIG. 4. Number of ewes expressing the LH surge (A), mean (± SEM) maximal LH value (B), and total integrated LH during the surge period (C) in vehicle, endotoxin, and endotoxin plus flurbiprofen ewes in experiment 2 (n = 10/treatment, crossover experiment). *, Significant differences between vehicle and endotoxin or between vehicle and endotoxin plus flurbiprofen-treated ewes (P < 0.05). Values between endotoxin and endotoxin plus flurbiprofen-treated ewes are not significantly different (NS).

View larger version (24K): [in this window] [in a new window]   FIG. 5. Mean (± SEM; n = 10/treatment) rectal temperature values in response to vehicle (open circles), endotoxin (closed circles), or endotoxin plus flurbiprofen (shaded boxes) in experiment 2. Note that flurbiprofen blocked endotoxin-induced fever.

View larger version (22K): [in this window] [in a new window]   FIG. 6. Mean (± SEM; n = 10/treatment) plasma LH in ewes treated with vehicle (open circles), endotoxin (closed circles), or endotoxin plus flurbiprofen (shaded boxes) during the presurge period in experiment 2. LH is plotted on a logarithmic scale to facilitate illustration of the suppression of LH concentrations before the surge.

	Discussion

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Our conclusion that endotoxin blocks the LH surge by suppressing GnRH secretion is reinforced by the finding that another type of immune/inflammatory challenge, the cytokine IL-1ß, inhibited GnRH secretion and fos induction in GnRH neurons at the time of the preovulatory LH surge in rats (28). Nonetheless, it is puzzling why the LH surge was blocked by endotoxin in only four of the 11 ewes in experiment 1. Our earlier work (Ref. 7 ; and Breen, K., and F. Karsch, unpublished) indicated that endotoxin blocked the surge in approximately 70% of ewes receiving a 12- to 14-h estradiol stimulus, similar to the estradiol treatment in experiment 1. That the GnRH/LH surge was truly blocked in the four ewes of experiment 1 is substantiated by the absence of any trace of a GnRH or LH increase during the entire 22-h period of hourly portal blood collection (Fig. 2, B–E). Furthermore, that this blockade was due to endotoxin, rather than some unknown variable, is substantiated by our collective present and prior work in the artificial follicular phase model. Specifically, in a total of 48 ewes not receiving endotoxin, an estradiol stimulus of 12 h or longer was 100% effective in eliciting the GnRH/LH surge (six of six in experiment 1 and 42 of 42 in Refs. 12, 15 and 29, 30, 31). Our best explanation for the lower incidence of surge blockade in experiment 1 is that the 12-h estradiol stimulus was sufficiently strong that, in some ewes, it overcame the suppressive effect of the endotoxin preparation used in the present experiment. This possibility is reinforced by the outcome of experiment 2, in which the estradiol stimulus was 1.5 h shorter (10.5 h in duration) and endotoxin blocked the LH surge in eight of 10 ewes. Another possible factor contributing to the variable surge blockade in experiment 1 relates to individual prior histories of infection and disease, and the consequent exposure to immune and inflammatory stimuli, all of which can lead to tolerance and desensitization (32). These histories were not known for our animals. Regardless of the explanation, our findings in experiment 1 indicate that endotoxin blocks the GnRH surge in ewes in which the LH surge is blocked. This provides strong evidence that endotoxin-induced blockade of the LH surge is mediated centrally, via inhibition of GnRH secretion.

The conclusion that endotoxin blocks the LH surge via a central mechanism does not, in itself, discount the possibility of an additional inhibitory effect at the pituitary gland. In this regard, prior work in ovariectomized ewes demonstrates that endotoxin reduces pituitary responsiveness to the brief (5 min) stimulus of a GnRH pulse (8). Although the present study did not directly test the influence of endotoxin on pituitary responsiveness to the more powerful and prolonged (9–18 h) stimulus of the GnRH surge, our results provide strong evidence that the inhibitory effect of endotoxin on the LH surge cannot be explained by suppression at the level of the pituitary gland. The LH surge, when it escaped blockade by endotoxin, was comparable to that in vehicle-treated controls (see Table 1). This might reflect the finding that the vast amount of GnRH secreted during the surge greatly exceeds that needed to stimulate a full-amplitude LH surge (29), such that any suppressive effect of endotoxin at the pituitary level might be masked. Additional evidence that endotoxin does not block the LH surge at the pituitary level is provided by the earlier observation that endotoxin failed to attenuate the LH surge when treatment was initiated just before the surge and continued throughout the period of LH release (7).

Our finding that the prostaglandin-synthesis inhibitor, flurbiprofen, failed to reverse the inhibitory effect of endotoxin on the estradiol-induced LH surge is keenly interesting in light of strong evidence that prostaglandins are obligatory mediators of other central responses to immune/inflammatory challenge, such as the generation of fever (22, 23). Of particular note, prostaglandins are essential for the suppressive actions of endotoxin on the pulsatile mode of GnRH and LH release (9). It is unlikely that the failure of flurbiprofen to reverse blockade of the LH surge was due to ineffective suppression of prostaglandin synthesis because the dose was the same as that used previously to reverse endotoxin-induced suppression of GnRH and LH pulses. Further, flurbiprofen prevented endotoxin-induced fever in the same ewes that it failed to reinstate the LH surge (Fig. 5), again suggesting prostaglandin synthesis was effectively blocked. The more likely explanation of our results, therefore, is that prostaglandins are not essential mediators of the suppressive effects of endotoxin on the estradiol-induced LH surge.

The foregoing discussion implies important differences exist between the mechanisms whereby endotoxin blocks the estradiol-induced LH surge and suppresses pulsatile LH secretion in ovariectomized ewes. With regard to pulses, both a mediatory role of prostaglandins and suppression of pituitary responsiveness to GnRH are important components of the inhibitory process (8, 9), but neither of these is needed to block the LH surge. Another fundamental difference is suggested by the timing of endotoxin effects on the two modes of gonadotropin secretion. Endotoxin inhibits LH pulses acutely, within 1 h (2, 8, 9), whereas its suppressive effects on the LH surge are delayed. In this regard, endotoxin blocks the surge when delivered at onset of the estradiol signal, which precedes the LH surge by approximately 20 h, but it is ineffective when given during the period that the LH surge is actually taking place (7). Thus, rather than inhibiting secretion per se, as is the case with LH pulses, endotoxin blocks the LH surge by preventing either the early activating effects of estradiol on estradiol-sensitive neurons or transduction of the positive feedback signal into subsequent surge secretion of GnRH and LH. Our findings, therefore, imply the neuroendocrine processes that mediate the regulatory input of this stress on GnRH pulses and surges are separable and fundamentally different.

Returning to the potential mediatory role of prostaglandins, it is pertinent to note that endotoxin stimulates production of several other inhibitors of gonadotropin secretion, notably endogenous opioid peptides, cytokines, and hormones of the hypothalamo-pituitary-adrenal axis (33, 34, 35, 36, 37). Whether or not prostaglandins are essential mediators under any given condition could be a function of these other inhibitory factors, and this, in turn, could depend on the gonadal steroid milieu. For example, ovarian steroids, most notably estradiol, enhance production of the inflammatory cytokines and the extent to which endotoxin stimulates cytokine synthesis (38, 39). Our present evidence that prostaglandins are not essential for endotoxin to block the LH surge was obtained in ovariectomized ewes treated with estradiol and progesterone to create an artificial follicular phase, whereas prior evidence that prostaglandins mediate the suppression of GnRH and LH pulses (9) was obtained in ovariectomized ewes devoid of gonadal steroids. Of interest, we observed here that flurbiprofen did not reverse endotoxin-induced suppression of LH secretion before the surge (Fig. 6), when GnRH and LH are released as pulses (20, 21). Perhaps under the endocrine milieu of falling progesterone and rising estradiol, the influence of other inhibitory intermediates prevails, such that prostaglandins are no longer essential for endotoxin to suppress reproductive neuroendocrine activity. Additional work is warranted to investigate this possibility and to identify mediators of endotoxin-induced suppression of gonadotropin pulses and surges within the endocrine setting of the follicular phase.

In summary, this study allows two novel conclusions regarding mechanisms whereby endotoxin blocks the estradiol-induced LH surge. First, endotoxin blocks the LH surge centrally, preventing the GnRH surge in hypophyseal portal circulation. Second, the suppressive effect of endotoxin on the LH surge does not require prostaglandin synthesis. Beyond these conclusions, we have gathered initial evidence that the inhibitory effect of endotoxin on pulsatile gonadotropin secretion before the surge may also not require prostaglandins. This contrasts with our earlier finding (9) that prostaglandins are essential for endotoxin to suppress pulsatile GnRH and LH secretion in ewes devoid of ovarian steroids. Collectively, our findings prompt additional work to identify stress-related regulatory inputs to neuroendocrine processes that generate GnRH pulses and surges, where these inputs converge, and how the changing endocrine environment of the ovarian cycle influences pathways inhibiting reproductive neuroendocrine function during immune/inflammatory stress.

	Acknowledgments

 
We sincerely appreciate Doug Doop and Gary McCalla for their expertise in animal care. We also thank Emily Adams, Dr. Graham Barrell, Marty Brown, Emily Wessinger, and April Yasunaga for their endless hours of experimental support and Dr. Tom Harris for his contribution to the design of this study. Finally, we are grateful to Drs. Gordon D. Niswender and Leo E. Reichert, Jr., for supplying RIA reagents.

	Footnotes

 
This work was supported by NIH-HD-30773, T32-HD07048, and the Office of the Vice President for Research at the University of Michigan. N.D. was supported by la Fondation pour la Recherche Médicale (SE000738-01) (France).

Present address for H.J.B.: Department of Cell Biology, Neurobiology and Anatomy, University of Cincinnati College of Medicine, P.O. Box 670521, Cincinnati, Ohio 45267-0521.

Present address for N.D.: UMR868, Elevage des Ruminants en Régions Chaudes, 2 place P, Viala, 34060, Montpellier Cedex 1, France.

A preliminary report has appeared in Biology of Reproduction (Vol. 64, Supplement 1, 2001 Abstract 29).

Received August 22, 2003.

Accepted for publication September 29, 2003.

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