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Departments of Physiology (D.F.B., J.M.B., F.J.K.) and Biology (L.A.T.), Reproductive Sciences Program (D.F.B., J.M.B., H.B.K., L.A.T., C.V., F.J.K.), 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
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Introduction |
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In a number of species, endotoxin and cytokines have been shown to inhibit tonic LH secretion (4, 5, 6, 7) and block the preovulatory LH surge (1, 8, 9). A large body of evidence suggests this inhibition occurs at the level of the hypothalamus. Indeed, in the female rat, systemic endotoxin can inhibit the percentage of GnRH neurons expressing Fos protein on the afternoon of proestrus and can reduce the afternoon proestrous rise in GnRH primary transcript (10). Additionally, the cytokine interleukin-1 (IL-1) can decrease GnRH release in vitro from medial basal hypothalamic tissue (9) and, when given centrally, can suppress the normal increase in c-fos expression in GnRH neurons on the afternoon of proestrus (11). Push-pull perfusion studies have also shown that IL-1 given centrally can inhibit GnRH release into the median eminence in the proestrous rat (11, 12). In these in vivo studies directly assessing GnRH release, however, an anesthetized animal and acute surgical preparation were used, procedures that in and of themselves could be stressors that inhibit the reproductive axis.
At present, there is no direct evidence that a systemic immune stressor such as endotoxin actually inhibits GnRH secretion into the hypothalamic-pituitary portal blood in alert, normally behaving animals. In the sheep, such studies are possible; hypophyseal portal blood can be sampled from conscious and undisturbed animals at frequent intervals and for prolonged time periods. This approach thus allows direct assessment of hypothalamic neuroendocrine responses to immune challenge. Using the hypophyseal portal sampling methodology, we tested the hypothesis that endotoxin inhibits the reproductive axis centrally by suppressing pulsatile GnRH secretion.
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Materials and Methods |
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Pilot studies
Pilot studies were conducted for two purposes: to establish a
model in the ewe to study the effects of endotoxin on the reproductive
and stress neuroendocrine axes, and to characterize basal, nonstress
profiles of cortisol and temperature. Studies were carried out on seven
ovariectomized ewes in the anestrous (n = 3) and breeding seasons
(n = 4) (ovariectomy performed at least 1 week before
experiments). Core body temperature was monitored with
battery-operated, temperature-sensitive telemetry transmitters
(MiniMitter, model CH-3, Sunriver, OR) implanted ip at the time of
ovariectomy and tied to the broad ligament of the uterus. Jugular blood
samples were taken remotely for measurement of LH and cortisol at 5- to
15-min intervals over 8–10 h. Following a baseline period of 2–4 h,
either endotoxin (400 ng/kg, iv bolus) or an equivalent volume of
saline vehicle was administered. Temperature and hormonal responses to
endotoxin were compared with pretreatment values within the same ewe,
determined either during the baseline period or on a preceding control
day. [Statistical analyses were not employed to assess treatment
effects because experimental conditions varied slightly among ewes.]
In these pilot studies and in the main experiment, endotoxin
(Escherichia coli 05:B55, Sigma, St. Louis, MO) was
reconstituted in sterile saline to a stock concentration of 0.01 mg/ml.
Final injection volume averaged 2.6 ml and was followed by a saline or
heparinized saline (100 U/ml) flush of 6–8 ml. The dose of endotoxin
(400 ng/kg, iv) was chosen based on a previous study in gonadectomized
rams showing it induced reproductive and stress neuroendocrine
alterations but did not cause severe adverse side effects (4).
Main experiment
The main experiment was conducted during the mid-breeding season
(Oct.-Nov.) on 12 ewes, all ovariectomized and surgically fitted with
the apparatus for hypophyseal portal blood collection 2–4 weeks before
blood sampling. The surgical preparation and system for remote
automated sampling of hypophyseal portal blood were modified from the
technique of Caraty and Locatelli (13) and are described elsewhere
(14). This procedure allows sampling in undisturbed, normally behaving
ewes. Six ewes were randomly assigned to receive endotoxin (400 ng/kg,
iv bolus; between 1730 and 2000 h); the remaining six were
controls (saline vehicle, iv). In the endotoxin-treated ewes,
MiniMitters were implanted ip at the time of ovariectomy to monitor
core body temperature. Animals were sampled in pairs, one control and
one endotoxin-treated. Portal and jugular blood were collected
simultaneously (portal blood into ice-cold bacitracin 3 x
10-3 M) at 10-min intervals beginning 4 h
before and continuing 10 h after endotoxin or saline. Technical
difficulties prevented successful portal blood collection from one
control and one endotoxin-treated ewe. Thus, to attain final group
sizes of six, the protocol was repeated at least 2 weeks after the
first sampling in two ewes (endotoxin and control treatments switched
for the second sampling). We have previously shown that repeat sampling
of the hypophyseal portal blood is possible and provides a valid
description of GnRH secretion (14). 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 cut for sampling hypophyseal
portal blood.
Assays
GnRH was measured in portal plasma using a previously described
RIA (15, 16). Briefly, a 750-µl aliquot of sample (
600 µl portal
plasma and 150 µl bacitracin) was extracted in 2 ml of methanol, and
duplicate aliquots of the reconstituted extract (equivalent to 240
µl portal plasma) were assayed. To minimize the effect of
between-assay variation, all samples from a given animal were measured
in a single assay. Intraassay variation (eight assays), as determined
by the median variance ratio of assay replicates (17), averaged 0.062,
and assay sensitivity averaged 0.23 pg/tube.
LH was measured in duplicate aliquots of plasma (25–200 µl) using a modification (18) of a previously described RIA (19, 20) and is expressed in terms of NIH-LH-S12. All samples for a given ewe were measured initially at 100 µl in a single assay; reassays were done as necessary using smaller plasma volumes (25–50 µl) to assess peaks of LH pulses and using a larger volume (200 µl) to assess low LH concentrations. Mean intra- and interassay coefficients of variation (seven assays) were 7.8% and 7.7%, respectively, and assay sensitivity for 200 µl averaged 1.10 ng/ml.
Cortisol concentrations were determined in duplicate 50-µl aliquots of unextracted plasma by use of the Coat-A-Count Cortisol assay kit (DPC, Los Angeles, CA), validated in our laboratory for use in the sheep. Modifications of the kit protocol included adding a low point on the standard curve and increasing the incubation time with tracer to 1 h at 37 C. Samples from hypophysectomized ewes produced values below or at the sensitivity of the assay (0.86 ng/ml). Parallelism between serial dilutions of ovine samples and cortisol standard was confirmed. Accuracy averaged 96% when assay buffer was spiked with a known amount of cortisol. All samples from a given ewe were initially measured in a single assay. Mean intra- and interassay coefficients of variation (13 assays) were 15% and 9%, respectively, and assay sensitivity averaged 0.86 ng/ml.
Progesterone concentrations were measured in duplicate 100-µl aliquots taken from one sample every hour using the Coat-A-Count Progesterone kit (DPC) validated previously (21). In this study, we also determined that cortisol deoxycortisol, corticosterone and deoxycorticosterone did not appreciably cross-react. Mean intra- and interassay coefficients of variation (two assays) were 9.7% and 7.9%, respectively, and assay sensitivity averaged 0.08 ng/ml.
Data analysis
GnRH values are expressed as a collection rate (picograms per
minute) rather than as a concentration to minimize error due to
potential contamination of portal samples with peripheral blood or
cerebrospinal fluid (judged minimal), or due to changes in flow of
portal blood caused by positioning of the head. Pulses of GnRH and LH
were identified using the pulse detection algorithm of Veldhuis and
Johnson (22). Cluster sizes for peaks/nadirs were defined as 1/2 and
2/2 for GnRH and LH, respectively. The t statistics used to
identify significant increases and decreases were 3.8/3.8 for GnRH and
2.6/2.6 for LH.
For GnRH and LH, average pulse amplitude, pulse frequency (number of
pulses per collection period), and mean concentration (for LH) or
collection rate (for GnRH) were calculated for each ewe before and
after endotoxin or saline injection. Similarly, mean cortisol,
progesterone, and temperature values during the pre- and posttreatment
periods were calculated for each ewe. Treatment effects, comparing
values before vs. after endotoxin or saline, were identified
by paired t test. Hormonal values were transformed before
statistical analysis (log transformed for concentration, collection
rate and pulse amplitude, and square root transformed for pulse
frequency). Level of significance was set at P 
0.05.
Of note, the final 3 h of sampling (h 7–10) were excluded from statistical analyses due to suspected technical problems in the portal blood collection procedure. Specifically, three of the six control ewes exhibited an unexplained drop in GnRH pulse amplitude during this time period with no change in LH pulse amplitude. Further, in one endotoxin ewe, no clear GnRH pulses were exhibited during h 7–10, yet detectable LH pulses were evident. Adding to our suspicion of technical problems, we have obtained no indication of a diurnal change in GnRH pulse amplitude in ovariectomized ewes nor have we observed LH pulses that were not preceded by GnRH pulses (15, 23). Therefore, we excluded hormonal data between h 7–10 from statistical analyses in both the control and endotoxin groups. Likewise, data summaries in the Results compare the baseline period to the first 7 h after saline or endotoxin. Individual profiles for the full 10-h period, however, are illustrated graphically in the Results.
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Results |
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depicts plasma LH and
cortisol concentrations and body temperature profiles during a control
day (saline, 8 ml iv) and the following endotoxin treatment day
(endotoxin, 400 ng/kg iv) in an ovariectomized ewe sampled at 15-min
intervals during the anestrous season. Among all ewes in the pilot
studies, saline had no effect on plasma cortisol (before vs.
after; 6.59 ± 3.82 vs. 6.89 ± 4.39 ng/ml) or
core body temperature (before vs. after; 39.0 ± 0.2
vs. 38.9 ± 0.3 C). In contrast, endotoxin consistently
induced marked increases in cortisol and body temperature (before
vs. after: cortisol, 6.75 ± 4.74 vs.
56.84 ± 7.61 ng/ml; temperature, 38.8 ± 0.2 vs.
39.6 ± 0.3 C). Coincident with this stimulation, endotoxin
inhibited mean LH levels by an average of 38% compared with
pretreatment values (calculated as a percent rather than a mean due to
marked variability among ewes in LH concentrations before endotoxin,
which ranged from 4–35 ng/ml). Also attesting to endotoxin efficacy,
ewes developed transient sickness behaviors such as labored breathing,
cough, diarrhea, shivering, and lethargy. These hormonal and
pathophysiological responses to endotoxin in ovariectomized ewes
confirmed observations of Coleman et al. (4) in
gonadectomized rams and established a model system to study the effects
of immune challenge on hypothalamic neurosecretion.
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depicts the GnRH, LH, and
cortisol profiles of three representative control ewes receiving saline
iv at h 0. All control ewes exhibited regular pulsatile discharges of
GnRH and LH typical of ovariectomized ewes (15, 23). Each pulse of GnRH
corresponded to a pulse of LH. GnRH and LH pulse amplitude, pulse
frequency, and mean collection rate (GnRH) or concentration (LH) were
not significantly different when comparing the 4 h before to
7 h after saline (Fig. 3). Cortisol
levels remained low throughout sampling (before vs. after
saline; 11.53 ± 1.70 vs. 9.57 ± 1.60 ng/ml) and
were within the same range as those in ewes not undergoing portal
sampling (pilot studies). Cortisol followed a regular, low amplitude,
oscillatory pattern in all control ewes; peaks of cortisol oscillations
did not correspond with pulses of GnRH/LH. Although temperature was not
monitored in these ewes (MiniMitters not implanted), control data were
obtained in the ewes allocated for endotoxin treatment (MiniMitters
implanted) on a day before treatment and at a corresponding time of
day. In these ewes, saline had no effect on core body temperature
(before vs. after saline; 39.5 ± 0.1 vs.
39.5 ± 0.1 C).
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and 5 depict the hormonal and temperature
profiles of all six endotoxin-treated ewes. In contrast to control
animals, endotoxin profoundly inhibited pulsatile GnRH secretion. The
pattern of the inhibitory response, however, differed among ewes. Four
of the six ewes showed immediate GnRH suppression with a variable
return in pulsatility (Figs. 4a-c, and 5a). One ewe showed a disruption
in the regularity of GnRH pulses (Fig. 5b), and another showed a
gradual drop in pulse amplitude with total inhibition late in the
sampling (Fig. 5c). Endotoxin significantly suppressed mean GnRH
collection rate (P < 0.05) and GnRH pulse amplitude
(P = 0.01). Although GnRH pulse frequency was reduced
in some of the ewes, an overall significant effect was not observed
(Fig. 6).
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and 5). Mean concentration of LH (P = 0.001), LH pulse
amplitude (P < 0.05), and LH pulse frequency
(P = 0.01) were all significantly inhibited by
endotoxin (Fig. 6).
Of note, in several of the endotoxin-treated ewes, there was an
uncoupling of the GnRH and LH pulse patterns. For example, in ewes 2
and 10 (Fig. 5, b and c), LH levels declined precipitously during h
1–2 despite the continuation of robust GnRH pulses. Further, GnRH
pulsatility escaped inhibition, whereas LH pulses remained suppressed
in some of the animals. In particular, ewe 6 (Fig. 4c) showed a return
of GnRH pulsatility before that of LH; ewes 10 and 13 (Fig. 5, a and b)
showed transient bursts of GnRH pulses interspersed with periods of
suppression, but no corresponding detectable LH pulses.
Coincident with the inhibition of GnRH and LH, endotoxin significantly stimulated cortisol and temperature in all ewes. Within 4 h of endotoxin, cortisol reached peak values 8- to 15-fold above baseline (before vs. after; 8.39 ± 0.81 vs. 75.10 ± 8.89 ng/ml, P < 0.001). Core body temperature also increased rapidly, although it rose more gradually than cortisol, and peaked 5 h after endotoxin (before vs. after; 39.4 ± 0.2 vs. 41.1 ± 0.2 C, P < 0.001). As in the pilot studies, animals exhibited transient sickness behaviors such as labored respiration, diarrhea, shivering, and lethargy, which generally subsided by the end of the experiment.
Progesterone, assessed in one 10-min sample every hour, was
significantly stimulated by endotoxin (before vs. after;
0.11 ± 0.02 vs. 0.51 ± 0.14 ng/ml,
P < 0.01) (Fig. 7). Peak
response averaged 0.78 ± 0.22 ng/ml.
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Discussion |
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Our study supports and expands on the work of Coleman et al. (4) showing that endotoxin suppresses LH pulsatile secretion in gonadectomized rams. Interestingly, in their study, endotoxin inhibited LH pulse frequency but did not affect LH pulse amplitude. In the present study, we observed a significant drop in both LH pulse frequency and amplitude. Although a reason for the different results is not known, it is noteworthy that Coleman et al. sampled peripheral blood intermittently at 10- to 15-min intervals, whereas we withdrew blood continuously and separated it into 10-min fractions. This difference in sampling procedure could alter the pattern of LH observed.
Although endotoxin inhibited all parameters of LH secretion, analysis of the GnRH data indicated a significant inhibition in the mean GnRH collection rate and GnRH pulse amplitude but not GnRH pulse frequency. The disparity in achieving comparable statistically significant inhibition of GnRH and LH pulsatility for all parameters points to two important issues. First, in physiological studies such as ours, it is important to pay particular attention to profiles in individual animals and to evaluate the time course of the responses. For example, each of our ewes did experience a period when no GnRH pulses were observed but the nature and timing of the disruption differed. Second, the LH response to a given treatment does not necessarily correspond to the effect on GnRH secretion. This issue becomes critical if it is presumed that pituitary hormone changes simply mirror changes in hypothalamic hormone secretion.
An uncoupling between GnRH and LH pulsatile secretion was clearly
observed in at least half of the ewes treated with endotoxin.
Importantly, all control ewes and all endotoxin ewes before treatment
had robust rises in LH, which met the criteria for pulses and which
occurred in response to detected GnRH pulses. This confirms our
previous observations of a one-to-one relationship between GnRH and LH
pulses in ovariectomized ewes (15, 23). Following endotoxin, however,
this one-to-one relationship was no longer observed in all ewes. In two
animals, LH declined during the first few hours after endotoxin despite
continued robust GnRH pulses. Further, GnRH secretion escaped from
inhibition before LH recovery in several of the ewes (Figs. 4 and 5).
This provides circumstantial evidence that the pituitary response to
GnRH may have been compromised. Our results thus raise the question
whether endotoxin, and/or the mediators it induces, act at two levels
within the hypothalamic pituitary axis: centrally to inhibit GnRH
release, and at the pituitary to inhibit the response to GnRH. Of
interest in this regard, systemic endotoxin can reduce GnRH receptor
gene expression in the anterior pituitary of female rats (10), although
in vitro studies suggest cytokines can act at the pituitary
to stimulate LH secretion (24, 25). Clearly additional studies are
necessary to test for suppression at the pituitary level in the ewe.
Such an effect could, however, help to explain the significant
inhibition of LH pulse frequency but not GnRH pulse frequency we
observed.
In addition to the profound suppressive effects of endotoxin on the reproductive neuroendocrine axis, our data show coincident elevation of body temperature and stimulation of the steroids, cortisol and progesterone. Of note, the elevated progesterone was presumably of adrenal origin, because the ewes were ovariectomized. Such a rise in progesterone has also been observed in ovariectomized monkeys following central delivery of the cytokine IL-1 (26). Because the temperature and adrenal hormone responses were temporally associated with reproductive suppression, it is of interest to consider whether any or all may mediate the suppressive effects of endotoxin on GnRH secretion. With regard to temperature, we are not aware of studies that have systematically examined its potential influence on GnRH and LH secretion. It is of interest, however, that subpyrogenic doses of endotoxin in rodents can still activate the neuroendocrine stress axis, as indicated by ACTH and corticosterone responses (27). Such doses could be useful in teasing apart a role for fever as a mediator of reproductive suppression.
Although the potential influence of temperature remains to be systematically examined, an interaction between the stress and reproductive axes has been studied extensively. A large body of evidence suggests that the reproductive axis can be suppressed by hormones from all levels of the stress axis (7, 28, 29, 30, 31, 32, 33, 34). For example, the adrenal glucocorticoid cortisol has been shown to inhibit LH and FSH secretion in the monkey (28). Such suppression, however, takes days to become evident, suggesting a more chronic role for this adrenal steroid. In contrast, the hypothalamic hormones CRH and arginine vasopressin (AVP) appear to play a pivotal role in reproductive suppression in the acute setting. CRH and AVP administered centrally can inhibit tonic LH secretion in several species (7, 29, 30). In addition, CRH given into the lateral ventricle can inhibit GnRH release into the portal blood on the afternoon of proestrus in the anesthetized rat (31). Finally, anatomical evidence suggests that, in the monkey, AVP-immunoreactive boutons synapse with GnRH-immunoreactive neurons (32) and, in the rat, CRH-immunoreactive elements contact GnRH-immunoreactive elements (33).
Despite this strong evidence that the central hormones of the stress axis can acutely suppress the reproductive neuroendocrine axis, it is unclear whether CRH and/or AVP specifically mediate the suppression of pulsatile GnRH and LH secretion induced by immune stress. We have observed that endotoxin markedly stimulates CRH and AVP in hypophyseal portal blood of the ewe coincident with the GnRH and LH suppression reported in the present studies (35). Thus, terminals of GnRH neurons in the median eminence may be exposed to elevated CRH and AVP following endotoxin. It is important to recognize, however, that this does not necessarily apply to the region of GnRH perikarya. In fact, in the rat, the evidence points away from a mediatory role, at least for CRH, because CRH antagonists and antibodies fail to prevent suppression of LH following central delivery of IL-1 (11, 36). Additionally, in the male rat, ablation of the paraventricular nucleus, a major source of neuroendocrine CRH and AVP, does not prevent the suppression of LH secretion following central delivery of IL-1 (37). This argues against a mediatory role for CRH and AVP of paraventricular origin, at least in this rodent species. In ovariectomized rhesus monkeys, however, antagonists to either CRH or AVP can overcome the suppression of pulsatile LH secretion induced by central delivery of IL-1 (7, 38). Finally, it is important to note that, in sheep, CRH given centrally may actually stimulate LH secretion under some conditions (39, 40). Collectively, these findings suggest species differences and warrant further investigations to assess a possible role for CRH and/or AVP in mediating the reproductive effects of endotoxin in the sheep.
In addition to the potential inhibitory actions of CRH and AVP, the stimulation of progesterone may also contribute to suppression of GnRH and LH pulsatile secretion induced by endotoxin. Strong evidence demonstrates that progesterone inhibits GnRH and LH pulsatile secretion in the ewe (41). However, to suppress GnRH and LH in ovariectomized sheep in the breeding season, as in our study, progesterone must reach higher concentrations than those we observed in response to endotoxin (42, 43). Additionally, progesterone is known to inhibit pulse frequency not pulse amplitude (43, 44), the latter of which we observed in this study. Thus, progesterone alone cannot account for the GnRH and LH suppression we observed. However, in conjunction with other responses to the immune stress (e.g. cortisol, CRH, AVP), progesterone may well contribute. Of interest, endotoxin has been shown to stimulate progesterone secretion in ovariectomized cows, much as we observed in the sheep, and this stimulation was coincident with tonic LH suppression (5).
As a final note, two procedural issues must be addressed in conducting and interpreting studies such as ours. First, the absolute amount of GnRH quantified by our method can vary with the location and extent of the portal vasculature cut (14), which is difficult to standardize among sheep. This makes it problematic to compare absolute amounts of GnRH among animals. In fact, in the present study, the amount of GnRH collected per minute during the baseline period appeared to be higher, on average, in the control ewes vs. the endotoxin-treated ewes. This caveat, however, does not weaken our overall conclusions because we used each animal as its own control, comparing values before and after treatment. The second issue is whether the experimental procedure of portal blood collection could be a stressor that inhibits the reproductive axis in and of itself. This is unlikely in our study for three reasons. First, GnRH and LH secretion were not inhibited in vehicle-treated controls. Second, cortisol levels remained within the range of basal values we observed in our pilot studies in which portal samples were not taken. Finally, cortisol in the control animals showed a clear rhythmic oscillation of its own, a pattern characteristic of glucocorticoid secretion in the basal state (45).
In conclusion, we have shown that systemic immune challenge with endotoxin dramatically inhibits GnRH and LH pulsatile secretion coincident with stimulating adrenal cortisol and progesterone secretion and elevating body temperature. The temporal association between the stress and reproductive responses provides a basis to consider if activation of the adrenal axis contributes to reproductive inhibition induced by this immune challenge in the ewe. Of additional interest, the suppressive effects of endotoxin on pulsatile GnRH and LH secretion may have implications for female cyclicity. Indeed, we have found that endotoxin interrupts the normal progression of the natural follicular phase of the ewe, interfering with the preovulatory estradiol rise and delaying the LH surge (46). This prompts an intriguing question: Can the suppression of GnRH pulsatile secretion induced by this immune stress, as described in the present study, disrupt the follicular phase of the estrous cycle?
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Acknowledgments |
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Footnotes |
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Received April 1, 1997.
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References |
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concentrations. Biol Reprod 50:1297–1302[Abstract]
and -1ß in endotoxin-induced
suppression of plasma gonadotropin levels in rats. Endocrinology 130:3307–3313[Abstract]
on basal
gonadotropin release in the ovariectomized rhesus monkey: reversal by a
corticotropin-releasing factor antagonist. Endocrinology 128:2077–2082[Abstract]
-induced decrease in luteinizing hormone secretion
in the ovariectomized rhesus monkey. Endocrinology 131:153–158[Abstract]
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K. M. Breen, H. J. Billings, N. Debus, and F. J. Karsch Endotoxin Inhibits the Surge Secretion of Gonadotropin-Releasing Hormone via a Prostaglandin-Independent Pathway Endocrinology, January 1, 2004; 145(1): 221 - 227. [Abstract] [Full Text] [PDF]
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C.A. Stackpole, A.I. Turner, I.J. Clarke, G.W. Lambert, and A.J. Tilbrook Seasonal Differences in the Effect of Isolation and Restraint Stress on the Luteinizing Hormone Response to Gonadotropin-Releasing Hormone in Hypothalamopituitary Disconnected, Gonadectomized Rams and Ewes Biol Reprod, October 1, 2003; 69(4): 1158 - 1164. [Abstract] [Full Text] [PDF]
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N. Debus, K. M. Breen, G. K. Barrell, H. J. Billings, M. Brown, E. A. Young, and F. J. Karsch Does Cortisol Mediate Endotoxin-Induced Inhibition of Pulsatile Luteinizing Hormone and Gonadotropin-Releasing Hormone Secretion? Endocrinology, October 1, 2002; 143(10): 3748 - 3758. [Abstract] [Full Text] [PDF]
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C. Y. Williams, T. G. Harris, D. F. Battaglia, C. Viguié, and F. J. Karsch Endotoxin Inhibits Pituitary Responsiveness to Gonadotropin-Releasing Hormone Endocrinology, May 1, 2001; 142(5): 1915 - 1922. [Abstract] [Full Text]
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saline iv) and following endotoxin-treatment day (•, 400 ng/kg,
iv).
