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Departments of Physiology (J.M.B., F.J.K.), Biology (L.A.T.), and Biostatistics (Y.W., M.B.B.), and Reproductive Sciences Program, University of Michigan, Ann Arbor, Michigan 48109
Address all correspondence and requests for reprints to: Dr. F. 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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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Although the existence of the GnRH surge cannot be refuted, there is considerable controversy surrounding its functional significance. Studies in rhesus monkeys suggest that enhanced GnRH secretion over and above the pulsatile secretion seen during the early to midfollicular phase is not essential for LH surge generation (20). One study in the monkey even suggests that the LH surge can be induced by estradiol in the absence of concurrent GnRH stimulation (21). Further, the view that the LH surge can occur independent of increased GnRH secretion is strengthened by a recent study in women that led to the conclusion that GnRH secretion actually decreases at the time of the preovulatory LH surge (22). However, in other species, such as sheep, generation of the LH surge appears to require an abrupt increase in GnRH over and above the high frequency pulses of the midfollicular phase (4, 23, 24, 25, 26). To date, however, the requirements of the GnRH signal actually delivered to the anterior pituitary have not been quantified for any species.
In an initial study to address this point, we assessed the duration of the endogenous GnRH signal required to stimulate a normal LH surge in the ewe by administering a GnRH antagonist at various points during the LH surge (27). GnRH stimulation was found to be required through the entire course of the LH surge. Given that the GnRH surge of the ewe extends well beyond the LH surge, it was found that a vast excess of GnRH is secreted in terms of the duration needed to initiate and sustain the LH surge.
In the present study, we addressed the amplitude of the GnRH surge needed to induce the LH surge, and whether the amplitude of the endogenous GnRH surge may also be in excess of that required for production of a normal LH surge. Our approach was to induce LH surges with exogenous GnRH and to assess the dose-response relationship between the amplitude of the GnRH surge and the amplitude of the LH response in relation to the endogenous surges of both hormones. For this purpose, we used an animal model in which endogenous GnRH secretion was blocked (28, 29) and infused artificial GnRH surges of normal contour and duration but varying amplitudes.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Artificial GnRH surges were created by administering a solution of constant GnRH concentration at varying rates via a peristaltic pump (Gilson Minipuls 2, Gilson Medical Electronics, Middleton, WI). Flow rate was manually adjusted at 60- or 120-min intervals. Synthetic GnRH (Sigma Chemical Co., St. Louis, MO) was dissolved in sterile water to form a stock solution (2 mg/ml). Infusion solutions for preliminary and main experiments were prepared by adding GnRH stock to BSA-saline. Control animals were infused with BSA-saline alone. Infusions were administered via an indwelling catheter into one jugular vein, and blood was sampled from a catheter in the contralateral jugular vein. All artificial GnRH surges administered in the main experiment were of the same contour and duration and varied only in amplitude. The test doses in all experiments were confirmed by assay of GnRH in aliquots of infusion solutions.
Preliminary studies
Three preliminary studies were performed to determine suitable
doses and pump speeds for delivering artificial GnRH surges and to
validate a method to monitor the amount of GnRH delivered to the
anterior pituitary gland during the infusion of artificial GnRH
surges.
Preliminary Exp 1. The objective of this study was to gain an initial estimate of the amount of infused GnRH required to restore a full amplitude GnRH surge in the portal blood (definition of a full amplitude GnRH surge based on the average of eight estradiol-induced GnRH surges in one of our recent studies performed during the breeding season) (30). Three ewes in midanestrus (June) were surgically prepared for sampling hypophyseal portal blood (31) and treated with one 30-mm sc estradiol implant (32) to ensure the virtual cessation of GnRH secretion (33). A broad range of GnRH doses was infused in a pattern designed to mimic the rising edge of the GnRH surge (doses ranged from 0.48–350 µg/h at maximal infusion rates). Three infusions, separated by 2 h of no treatment, were carried out in each of the three sheep. Each infusion period lasted 5 h, with the rate of infusion increased each hour. To measure GnRH concentrations achieved by this treatment regimen in hypophyseal portal and jugular plasma, respective blood samples were collected continuously into ice-cold bacitracin and separated into 10-min fractions according to procedures previously described (7).
Preliminary Exp 2. Doses administered in the first preliminary experiment proved to be too high. Therefore, the second preliminary experiment had two objectives. The first objective was to identify a dose range for the main experiment. The second was to determine whether the amount and pattern of GnRH measured in pituitary portal blood were identical to those in jugular blood during peripheral infusion of GnRH. If equivalent, then the time course of GnRH in jugular blood could be used to quantify the precise GnRH signal delivered to the anterior pituitary gland during the infusion of artificial GnRH surges. Anestrous ewes (n = 3) were prepared as described for the first preliminary study (estradiol implant and surgery for pituitary portal blood collection). Three 5-h infusions, separated by 2 h, were carried out in each of the three ewes (infusion pattern identical to that in the first preliminary experiment). Each ewe received three doses of GnRH in randomly determined order, with all three doses represented in each of the three infusion periods. Peak infusion rates were 0.42, 4.2, and 42 µg GnRH/h. Both pituitary portal and jugular blood were withdrawn continuously into ice-cold bacitracin and pooled as 30-min fractions for assay of GnRH.
Preliminary Exp 3. There were two objectives in this preliminary study. First, we identified specific GnRH delivery rates needed to create artificial GnRH surges that reproduced the full contour and amplitude of the endogenous GnRH surge (endogenous surge characterized in one of our previous studies) (30). Second, we determined whether concentrations of GnRH in integrated samples (i.e. continuous withdrawal as used to characterize the endogenous GnRH surge) were the same as those in samples taken at a single time point. Three anestrous ewes were implanted with one 30-mm estradiol capsule to block GnRH secretion (33) and infused with a solution containing 6 ng GnRH/ml BSA-saline. Infusion was carried out for 24 h, with the rate adjusted every 1 or 2 h to recreate the full profile and duration of the endogenous GnRH surge. Animals were heparinized, and jugular blood was withdrawn continuously into ice-cold bacitracin and pooled as 60-min fractions for assay of GnRH and LH. At three time points, additional samples were withdrawn rapidly from the collection line in the middle of a 60-min integrated sample and immediately placed in ice-cold bacitracin (point samples).
Main experiment
Twelve sheep were ovariectomized 3 weeks before the study,
immediately treated sc with a 10-mm estradiol capsule (32), and
implanted with two 4- x 7-cm SILASTIC brand packets (Dow Corning,
Midland, MI) containing crystalline progesterone (34) 1–2 weeks later.
These steroid treatments result in plasma estradiol and progesterone
levels similar to those seen during the luteal phase of the estrous
cycle (35) and block GnRH secretion in anestrous ewes without, in
themselves, impairing pituitary responsiveness to surge-inducing
amounts of exogenous GnRH (28, 29, 36). The 12 ewes were separated into
2 groups and run through 3 consecutive artificial estrous cycles of
approximately 16-day duration (total of 36 cycles). To facilitate the
conduct of the study, the cycles in the 2 groups were staggered such
that the artificial follicular phase was reached in alternating weeks
by each group (cycles were designated sequentially A, C, and E in group
1 and B, D, and F in group 2).
During each artificial estrous cycle, circulating concentrations of progesterone and estradiol characteristic of the luteal and follicular phases were alternated by successive insertion and removal of the sc steroid-containing implants. The artificial luteal phase consisted of a 2-week treatment with both estradiol and progesterone implants. To maintain releasable LH stores in the pituitary during the artificial luteal phase, ewes received injections of a low dose of GnRH (1.6–2.2 ng/kg, iv) approximately every 12 h. This GnRH treatment was selected to restore the naturally occurring GnRH pulse pattern during anestrus (37). Without such treatment, pituitary responsiveness to GnRH can deteriorate when GnRH secretion is chronically blocked (38), as in our model.
Treatment during the artificial follicular phase varied as follows. In each cycle, 2 of the 6 ewes were randomly allocated as controls (1 positive and 1 negative control). In the positive control, progesterone was removed, and four 3-cm estradiol capsules were inserted 16 h later to increase circulating estradiol to the peak follicular phase level (39). Beginning just before the expected onset of the GnRH surge, 16 h after placement of the estradiol implants, ewes received a 24-h vehicle (BSA-saline) infusion. Negative controls received the same steroid treatment and vehicle infusion as positive controls, except progesterone was not withdrawn. The sustained high level of progesterone blocks the LH surge by inhibiting GnRH secretion (28, 29). The remaining 4 ewes in each cycle were designated experimental. They received the same steroid treatment as the negative controls, but were infused with artificial GnRH surges of normal contour and duration but differing amplitude. The amplitude of the infused GnRH surges was varied by changing the concentration of GnRH solution with which the animals were infused (<0.05 to 20.0 ng/ml). As GnRH can restore LH surges in the face of progesterone blockade (28), the artificial GnRH surges were expected to induce LH surges provided sufficient GnRH was delivered. There were a total of 6 positive control cycles, 6 negative control cycles, and 24 experimental cycles.
Beginning 10 h after insertion of the four estradiol implants, hourly blood samples (5 ml) were collected for 31 h through a catheter in the jugular vein contralateral to that being infused. Samples were collected into 0.5 ml heparinized, ice-cold bacitracin to minimize degradation of GnRH and were centrifuged immediately. An aliquot of plasma was extracted for GnRH assay immediately after centrifugation, and the remainder was stored at -20 C until LH analysis.
Hormone assays
GnRH was measured in duplicate in methanol extracts of plasma
(750 µl; containing 600 µl plasma and the remainder bacitracin) or
infusion solution using a RIA described previously (3, 40). Samples
from each preliminary study were included in single assays (except
samples taken during infusion of the highest GnRH dose in the second
preliminary study, which were diluted and reassayed separately). For
the main experiment, intraassay variation (six assays), determined by
the median variance ratio of assay replicates (41), averaged 0.062, and
assay sensitivity averaged 0.34 pg/ml. Surge peaks in the main
experiment were reassayed in a single assay to eliminate interassay
variation, as these values were compared in statistical analyses.
LH was measured in duplicate aliquots of plasma (5–200 µl) using a modification (42) of a previously described RIA (43, 44) and is expressed in terms of NIH LH-S12. Results were adjusted for bacitracin dilution. Mean intra- and interassay coefficients of variation were 12.3% and 16.5%, respectively (seven assays), and assay sensitivity averaged 0.82 ng/ml. Surge peaks were reassayed in a single assay with an intraassay coefficient of variation of 8.9%.
Data analysis
Data from 2 of the 24 experimental cycles were eliminated due to
technical difficulties during GnRH infusion. Three cycles, 1 each in 3
different ewes receiving the lowest GnRH doses (<20 ng/h at the peak
infusion rate), did not have detectable amounts of GnRH or LH in plasma
and were not included in the data analysis. Thus, statistical analyses
were limited to 19 experimental cycles.
Dose-response relationships were determined between the amplitude of the GnRH surge and three measured response variables: LH surge amplitude, area under the LH curve, and duration of the LH response. To reduce the weight of any one data point, all GnRH and LH surge amplitudes were defined as the averages of the three highest contiguous values. The area under the curve was assessed using a compensating polar planimeter (model no. 620000, Keuffel and Esser Co., Morristown, NJ). The duration of the LH response was defined as the continuous interval for which plasma LH concentration exceeded 5% of the maximal value for a given response.
A preliminary analysis using simple linear regression suggested that the dose-response relationships between amplitudes of the GnRH and LH surges for different ewes were linear with the same slope but had different intercepts. These different intercepts may reflect different responsiveness to GnRH among ewes. To take such individual variations into account, we fitted linear, mixed effects models with random intercepts. These random intercepts represented the possible responsiveness of a population of ewes (ewes in our experiment are considered random samples from this population). The SAS procedure "proc mixed" (45) was used to estimate the parameters (mean, slope, and variance components).
In addition to this dose-response analysis, we determined whether each GnRH-induced LH surge was of full amplitude relative to the endogenously generated LH surges in positive control ewes. A full amplitude LH surge was defined as an increase in LH for which the amplitude fell within the 95% confidence interval for an observation, based on LH surge amplitude in the six positive control cycles in this study.
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Results |
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0.01–5.6 µg/h at the highest point
of the artificial GnRH surge). Further, the time course and maximal
GnRH concentrations in pituitary portal and jugular blood samples were
virtually identical. This is illustrated in Fig. 1
, in which results for the middle dose
of GnRH (15 ng/ml solution infused at 4.2 µg/h at peak; Fig. 1A) are
shown alongside the average maximal GnRH concentrations in pituitary
portal and jugular plasma for the low and middle doses (Fig. 1B; values
for the highest dose exceeded the endogenous range; not shown).
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depicts a representative artificial
GnRH surge achieved using this delivery method compared with the
endogenous GnRH surge (Fig. 2B; note values are plotted as a percentage
of the highest point to emphasize contour over amplitude). Although the
contours of the ascending limb of the artificial and endogenous GnRH
surges were indistinguishable, the descending limb of the artificial
GnRH surge was slightly protracted relative to the endogenous surge.
The GnRH infusion rates were thus altered slightly for the main
experiment to those shown in Fig. 2C. No significant difference in the
plasma GnRH concentration was found between GnRH values obtained by
point vs. continuous sampling (Table 1).
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. In the 6 negative control cycles
(progesterone maintained, vehicle infused), LH values were very low to
undetectable (cycles 3C and 4E). In sharp contrast, LH surges were
observed in all 6 positive control cycles in which progesterone was
withdrawn 16 h before the estradiol stimulus (cycles 3E, 6A, and
9F). Amplitude of the LH surge ranged from 16.2–65.1 ng/ml when the
three contiguous highest values were used to calculate amplitude (see
Data analysis above).
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), there was an
unambiguous LH response (cycles 3A, 4A, 4C, 6C, 6E, 9B, and 9D). The
contour of these responses resembled that of the LH surge in positive
controls. Amplitude of these surge-like LH responses depended on the
plasma level of GnRH produced by the infusion and ranged from barely
detectable to 167 ng/ml. In some instances, the amplitude of these
experimentally produced LH surges was indistinguishable from that of
positive control cycles in the same animal (cycles 3A vs.
3E).
Dose-response analyses. A dose-response relationship between
the GnRH infused and the LH response was clearly apparent within each
animal (Fig. 3, cycles 4A, 4C, 6C, 6E, 9B, and 9D). Analyses of the
relationships between measured amplitude of the artificial GnRH surge
in plasma of experimental ewes and three measured aspects of the LH
response (amplitude, area, and duration) are illustrated in Fig. 4. A significant positive relationship
was observed between the amplitude of the artificial GnRH surge and
both the area under the LH curve and the amplitude of the LH response
(Fig. 4, A and B; P < 0.001 for both variables;
amplitude is the mean of three highest contiguous points). In contrast,
there was no significant relationship between the amplitude of the GnRH
surge and the duration of the LH response (Fig. 4C). Responsiveness to
GnRH differed significantly among ewes for LH area (P
< 0.05; data not shown), but not for the other two variables.
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, the relationship between the
amplitude of the artificial GnRH surge and the LH response is replotted
together with the 95% confidence belt of the LH surges generated
endogenously in the positive controls (n = 6; dashed
horizontal lines). Sixteen of the 19 artificially produced LH
surges fell within this confidence belt and are thus considered full
amplitude LH surges relative to the 6 positive control responses in
this study. These LH surges were induced by artificial GnRH surges with
a wide range of amplitudes. Of interest, some full amplitude LH surges
were produced by artificial GnRH surges far smaller than the endogenous
GnRH surges observed in the artificial follicular phase model in this
laboratory (bar along x-axis in Fig. 5). One
example of this point is the LH response in cycle 3A of Fig. 3
(depicted in Fig. 5 by the open circle). This full amplitude
LH surge was induced by an artificial GnRH surge with an amplitude of
17.6 pg/ml, which is below the 95% confidence interval of the
endogenous GnRH surge and approximately 12% of the mean endogenous
GnRH surge of 145 pg/ml (both amplitudes expressed as the mean of the
three highest contiguous values).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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These observations lead to an intriguing question: is there a function for the apparent excess GnRH secreted at the time of the LH surge? On the one hand, there may be no immediate function, and the ability of seemingly small amounts of GnRH to stimulate full amplitude LH surges may merely represent a safeguard, ensuring that ovulation will occur even if GnRH secretion is less than usual. On the other hand, the excess GnRH may be involved in functions separate from the LH surge, such as the onset and maintenance of sexual behavior. A role for GnRH in sexual receptivity has been demonstrated in rodents (46, 47, 48, 49, 50); we are currently testing whether this also holds true in sheep. Other possible roles for the apparent excess in GnRH include stimulation of the secondary FSH surge or gonadotropin synthesis, replenishing stocks of LH and FSH for the following luteal phase. Another possibility is that the large quantities of GnRH may desensitize the pituitary gland to continuing GnRH stimulation and thus act to end the LH surge. In this sense, the massive and prolonged GnRH surge may serve to break the so-called positive-feedback loop.
Although this last possibility might seem appealing, our present and previous observations argue against a role for the excess GnRH in terminating the surge. Specifically, the pituitary is still responsive to exogenous GnRH during the descending limb of the LH surge, and endogenous GnRH stimulation is required for LH release even at the very end of the LH surge (24, 27). Thus, although responsiveness to GnRH may diminish as the LH surge progresses, some GnRH receptors must still be present and functional throughout the duration of the LH surge. Of particular interest, we did not observe a dose-response relationship between the amplitude of the GnRH surge and the duration of the LH responses in this study. This leads to the conclusion that the large quantities of GnRH secreted during the surge are not required to desensitize the pituitary and thus terminate the LH surge.
The foregoing conclusions must be tempered by several potential limitations that inevitably apply to quantitative physiological studies such as this. One consideration relates to the animal model: the ovariectomized, progesterone-suppressed, anestrous ewe. Because progesterone can decrease the GnRH receptor population in the anterior pituitary gland of the ewe (51, 52), treatment with this steroid throughout the experiment may have reduced pituitary responsiveness to GnRH. The results of our study, however, suggest that pituitary responsiveness to a surge pattern of GnRH was not compromised. When exogenous GnRH surges within the physiological range were administered, LH surges of physiological amplitude resulted.
A second potential limitation is that the mean amplitude of the LH surge in the six positive control cycles tended to be lower than those we typically observe in the follicular phase model during anestrus (39.1 ± 8.1 ng/ml in this study compared with 56.1 ± 14.8 ng/ml in Ref. 3 and 48.0 ± 7.6 ng/ml in Ref. 29; all amplitudes calculated as the mean of the three highest contiguous LH values). This tendency could reflect long term suppression of GnRH pulsatility by the luteal phase level of progesterone during the artificial luteal phases that separated artificial follicular phases (36). Although we injected GnRH twice daily to overcome this problem, this may not have been sufficient. We do not, however, believe that this discredits our conclusions, because the same conditions applied for both experimental and positive control cycles, and each replicate of the study included both experimental and positive control treatments. Further, we observed no time-dependent decrease in the amplitudes of LH surges in the positive controls across the experiment, suggesting that the tendency for lower amplitude surges in this study is not related to the length of time under progesterone suppression. Measurement of endogenous GnRH in these animals would have been interesting in light of these results, but this was not feasible.
A third potential limitation of this study is that the artificially produced GnRH surges did not exactly replicate the endogenous GnRH surge, which is highly complex in its time course. The endogenous GnRH surge in the follicular phase model is marked by a characteristic progressive change in the GnRH pattern in pituitary portal blood (53). As the surge develops, a strictly episodic pattern of GnRH is replaced by pulses superimposed on a continuously elevated baseline. This is followed by amplification of both the episodic and continuous components and, finally, a period of extremely high and variable secretion that persists for many hours. Although not duplicating this pattern, the artificial GnRH surges delivered in our study were able to elicit LH responses that closely resembled the endogenous LH surge in duration, contour, and amplitude. Thus, there is no reason to suspect that a major component of the GnRH signal was missing, although the fluctuating values of the endogenous surge might provide additional information to the pituitary gland.
Yet another precaution pertains to our comparison of the amount of GnRH delivered to the pituitary during endogenous and artificially produced GnRH surges. In this regard, our procedure for collecting pituitary portal blood obtains an unknown fraction and possibly a selected pool of GnRH delivered to the pituitary. Thus, we cannot quantify the total endogenous GnRH signal at the time of the surge. The present finding that jugular and pituitary portal blood contain equal GnRH concentrations during the artificially produced surges helps us assess these GnRH stimuli in relation to the endogenous surge. Yet, they do not allow for the possibility of selective delivery of GnRH to different parts of the pituitary during the endogenous surge. Thus, our conclusion that the amplitude of the endogenous GnRH surge may exceed that needed for a full LH surge must be tempered by this limitation in our quantitative comparison between endogenous and artificial GnRH surges.
Also pertinent to the conclusion that the amount of GnRH secreted exceeds that needed to generate the LH surge are individual differences in response to GnRH. Because responsiveness to GnRH may differ among individuals, a GnRH surge effective in inducing a full amplitude LH surge in one ewe may be ineffective in another. Thus, the excess may not be as great as it might appear. Nevertheless, the amount of LH secreted during the surge appears to be greater than that required for ovulation, as shown in the rat (54) as well as the sheep (55). Thus, the excess in GnRH might be even greater with respect to the amount needed to generate the estrous cycle.
The absolute dependence of the LH surge on an abrupt increase in GnRH secretion in sheep contrasts with the situation in rhesus monkeys and humans, in which the LH surge does not appear to require such an increase (20, 21, 22). In both of these primates, normal LH surges and repeated menstrual cycles can be restored, under conditions in which endogenous GnRH release is absent, by an unvarying pulsatile delivery of GnRH (20, 56, 57, 58, 59). It is important to note, however, that a GnRH surge does accompany the LH surge in the rhesus monkey (17, 18). It would be of interest to determine whether this preovulatory increase in GnRH secretion serves a function other than LH surge generation in the reproductive physiology of the primate.
In summary, we have demonstrated a dose-response relationship between the amplitude of the GnRH surge and the amplitude of the resulting LH surge in the sheep. In conducting this analysis, we have obtained evidence that the amplitude of the GnRH surge is greater, on the average, than that required to generate the full LH surge. This complements recent findings that the duration of the GnRH surge also exceeds that needed to generate the LH surge, and it reinforces questions related to other roles that GnRH may play during the periovulatory period.
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Acknowledgments |
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Footnotes |
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2 Present address: Department of Animal and Avian Sciences, University
of Maryland, College Park, Maryland 20742-2311.
3 Present address: Department of Veterinary Preclinical Sciences,
University of Glasgow Veterinary School, Glasgow, United Kingdom G61
1QH.
4 Present address: Department of Internal Medicine, Division of
Endocrinology and Metabolism, 5560 MSRB II, University of Michigan, Ann
Arbor, Michigan 48109-0678.
5 Present address: Department of Statistics and Applied Probability,
University of California, Santa Barbara, California 93106-3110.
Received August 18, 1997.
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References |
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ski E, Chomicka LJ, Ostrowska A, Gajewska A,
Mateusiak K 1991 Release of luteinizing hormone-releasing hormone,
ß-endorphin and noradrenaline by the nucleus infundibularis/median
eminence during periovulatory period in the sheep. Neuroendocrinology 54:151–158[Medline]
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