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Reproductive Sciences Program (N.P.E., G.E.D.), and Departments of Physiology (F.J.K.), Biology (L.A.T.), and Pediatrics (V.P.), University of Michigan, Ann Arbor, Michigan 48109-0404
Address all correspondence and requests for reprints to: F. J. Karsch, Reproductive Sciences Program, University of Michigan, 300 North Ingalls Building, Room 1101 SW, Ann Arbor, Michigan 48109-0404.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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These results indicate that, once the GnRH/LH surges of the ewe have begun, elevated estradiol is not required for surge maintenance. Development of a full GnRH surge requires elevated estradiol for only a portion of the presurge period. More prolonged exposure to estradiol, however, is needed to maximize pituitary responsiveness to GnRH. Since the estradiol signal for the GnRH surge is relatively short (7–14 h) and temporally located well in advance of the surge itself, these results are consistent with the hypothesis that estradiol is required only to activate the steroid-responsive neuronal elements and not for progression of the signal from these elements to the actual surge process of GnRH release.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Despite the importance of increased estradiol in stimulating the GnRH surge, estradiol concentrations do not remain elevated throughout the period of the natural preovulatory GnRH surge. In the ewe, for example, circulating estradiol concentrations decrease abruptly within 4 h after onset of the GnRH and LH surge (2, 21, 22). Yet, the GnRH surge itself can persist for an additional 15–20 h in this species (12, 22). This temporal separation between the preovulatory GnRH surge and the estradiol signal suggests that the GnRH neurosecretory system need only be exposed to estradiol during the period that the estrogen-sensitive neuronal elements are activated, i.e. a period in advance of the GnRH surge. Once the GnRH surge begins, however, estradiol would no longer appear necessary to sustain the surge pattern of release.
In the experimental model we and others have used extensively to study regulation of the GnRH surge (artificial follicular phase model), elevated estradiol is typically maintained throughout the surge (12, 23, 24, 25). This model has been criticized as being nonphysiological, possibly producing artifactual results, because the estradiol signal is not withdrawn at the time of surge onset, as occurs naturally (26). The first goal in this study, therefore, was to refine the model and assess the effect of withdrawing the estradiol signal at surge onset on development and maintenance of the GnRH surge. Having established that the massive and sustained GnRH surge was still produced when estradiol was withdrawn at surge onset, our second goal was to assess the duration of the estradiol signal needed to induce and sustain a full GnRH surge.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Exp 1
In this experiment, we tested the effect of withdrawing the
estradiol signal at surge onset on development and maintenance of the
GnRH surge. As variation in surge timing relative to estradiol implant
addition is less within an animal over repeated artificial cycles than
between animals in any one particular cycle, all animals were run
through two artificial follicular phases, the first of which determined
the time of LH surge onset for each ewe. This information was then used
in the second artificial follicular phase to determine the time of
estradiol implant removal.
The design was as follows. Fourteen midluteal phase ewes were ovariectomized and immediately treated with a 1-cm sc Silastic capsule containing estradiol (27) and two 4 x 7 cm sc Silastic packets containing progesterone (28). These implants maintain serum concentrations of estradiol and progesterone equivalent to those observed in the midluteal phase of the estrous cycle, approximately 1 pg/ml and 3 ng/ml, respectively (31). Approximately 1 week later, when luteolysis would have occurred, progesterone implants were removed simulating luteal regression. Sixteen hours later, four 3-cm estradiol implants were inserted sc to simulate the preovulatory rise in serum estradiol concentrations (estradiol implants presoaked in water for 24 h to prevent an initial burst of steroid release (27)). This treatment regimen raises estradiol levels to approximately 8 pg/ml (31) and induces preovulatory-like surges of GnRH and LH approximately 20 h after estradiol addition (12) (note, the model used in this study was modified in that two rather than three progesterone packets were used for progesterone delivery; this treatment regimen produces circulating progesterone concentrations within the range seen during the natural luteal phase). During this first artificial follicular phase, the times of LH surge onset were determined for each ewe from hourly samples of jugular blood collected over a 20-h period beginning 10 h after placement of the four estradiol implants. Within 24 h after completion of blood sampling, these estradiol implants were removed and, after a further 24 h, progesterone implants were reinserted to generate a second artificial luteal phase. During this artificial luteal phase, animals underwent surgery for placement of the portal blood collection apparatus (30). Approximately 16 days after their insertion, progesterone implants were removed, and the animals were allocated to two groups for a second artificial follicular phase: controls (n = 6), estradiol implants retained throughout the expected duration of the GnRH surge; experimental (-E, n = 8), peak follicular phase estradiol implants removed approximately 2 h before the expected start of the GnRH surge (onset estimated from the first artificial follicular phase). Hourly samples of pituitary portal and jugular blood were collected for 35 h starting 5 h before the expected GnRH/LH surge. Pituitary portal blood was collected into 5 ml 3 x 10-3 M bacitracin (Sigma, St. Louis, MO) in ice-cold saline to inhibit endopeptidase activity.
Exp 2
In this experiment, we tested the hypothesis that, to induce the
GnRH surge, estradiol need be present only during a certain limited
time during the presurge period. The approach was similar to that of
Exp 1. Twenty ewes were allocated to four groups as shown in Fig 1
. Controls received the estradiol
stimulus until the approximate time of GnRH surge onset (21 h, n =
5). Experimental ewes were split into three groups and received an
estradiol stimulus either during a period equivalent to the last
14 h of estradiol treatment in controls (14 h, n = 5), the
last 7 h (7L, n = 5), or the earliest 7 h of estradiol
treatment (7E, n = 5). Pituitary portal and jugular blood were
sampled hourly for 36 h starting 5 h before the expected
start of the GnRH surge, estimated from LH responses in a previous
artificial follicular phase (data not shown). Peripheral blood was
collected at selected time points before, during, and after estradiol
treatment to characterize the experimentally produced rise in
circulating estradiol.
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680 µl portal plasma and
70 µl bacitracin) were extracted in methanol, and duplicate
aliquots of the extract were assayed. To minimize the effect of
between-assay variation, all samples for a given ewe were measured in a
single assay. Intraassay variation (six assays), as determined by the
median variance ratio of assay replicates (32), averaged 0.045; assay
sensitivity averaged 0.11 pg/tube. LH was measured in duplicate
aliquots of plasma (10–200 µl) using a modification (33) of a
previously described RIA (34, 35) and is expressed in terms of
NIH-LH-S12. Mean inter- and intraassay coefficients of variation (CV)
were 7.25% and 8.01%, and assay sensitivity averaged 0.14 ng/tube.
Estradiol concentrations were estimated in duplicate diethyl ether
extracts of 200 µl of plasma using a modification (36) of the Serono
Diagnostics Estradiol MAIA assay (Serono-Baker Diagnostics Inc.,
Allentown, PA). Intraassay CV (six assays) at 50% bound was 12%, and
assay sensitivity averaged 0.36 pg/ml.
Data analysis
GnRH values are expressed as rate of collection (picograms per
min) rather than concentration. This minimizes potential errors caused
by contamination of portal blood with either peripheral blood or
cerebrospinal fluid or errors due to changes in sample volume that may
occur after lifting and lowering of the ewe’s head. In both
experiments, presurge baselines for GnRH and LH were calculated as the
mean of the first four samples, unless a consistent trend was seen for
hormone concentrations to increase, in which case the mean of the first
three samples was used. Surge onset was defined as the time GnRH/LH
rose above two times the presurge baseline and remained at or above
this level for a minimum of 4 h. The end of the surge was defined
as the time GnRH/LH fell to values that remained below twice the
presurge baseline. Surge duration was the interval between the start
and end of the surge. If the surge had not ended (as defined above)
when sampling was terminated, surge duration was taken as the interval
between surge onset and the end of the collection. Surge magnitude
(GnRH and LH) was taken as the highest point assayed. GnRH and LH surge
magnitude and duration were compared by Student’s t tests
(control vs. -E in Exp 1, and controls (21 h) vs.
14 h in Exp 2). Peak estradiol concentrations in Exp 2 were
compared across groups by ANOVA. After ANOVA, mean comparisons were
made between control and treatment groups using Dunnett’s t
test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. In the -E group, estradiol implants
were removed at the expected onset of the GnRH surge (actually removed
at or shortly before surge onset in six of eight animals and just after
surge onset in the remaining two ewes). On average, implants were
removed 45 min before surge onset (range -5 to +2 h, individual times
shown as filled circles in bottom panel Fig. 2).
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). Mean GnRH surge
amplitude did not differ significantly between treatments (Fig. 3b). In
both control and -E groups, GnRH remained elevated well beyond the end
of the LH surge. GnRH surge duration, however, was significantly
(P < 0.05) longer in the control relative to the -E
group (Fig. 3b). Although the GnRH surge had ended in seven of the
eight -E animals by approximately 20 h after surge onset,
values were still elevated in all control ewes upon termination of the
experiment (30 h after surge onset, Fig. 2
).
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, along with
the mean estradiol concentrations (dashed line). In both
groups, estradiol concentrations increased within 1–2 h of addition of
the four 3-cm implants, to levels that did not differ significantly
between groups, and remained elevated while the implants were in place
(indicated by the hatched bar). Within 1 h after
removal of the four estradiol implants, circulating estradiol
concentrations started to fall precipitously back to the basal level
(1 pg/ml) provided by the remaining 1-cm estradiol implant.
Estradiol exposure for either 14 or 21 h induced GnRH and LH
surges in all animals. In every ewe, the GnRH surge began coincident
with the LH surge and outlasted the LH surge by many hours. No
differences were noted between these two groups in either GnRH surge
amplitude or duration (Fig. 5b). Further,
there was no difference in the duration of the LH surge between the two
treatments (Fig. 5a). LH surge amplitude, however, was significantly
(P < 0.01) reduced in the 14 h animals relative
to the controls (Fig. 5a). Time to surge onset was consistent in both
groups relative to the start of the estradiol signal (21 h) but
differed with regard to the interval from estradiol implant removal.
Surges began around the time of implant removal in the control group
but approximately 7 h after implant removal in the 14 h ewes
(Fig. 4).
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. As in the control and
14 h groups, peripheral estradiol increased and decreased rapidly
upon implant addition and removal. Peak estradiol concentrations in the
two 7 h groups did not differ from each other (7E: 8.5 ± 2.8
pg/ml, 7L: 4.3 ± 0.5 pg/ml), or the 14 h group (7.0 ±
0.8 pg/ml). The peak estradiol concentration achieved in the 7L group,
however, was statistically lower (P < 0.05) than in
the 21-h controls (10.0 ± 1.4 pg/ml).
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depicts group means for nonresponders coplotted with
values for the single responder for both the 7E and 7L groups.) The
single animal that responded in the 7E group (Ewe 3) mounted a GnRH
surge quantitatively similar to that seen in the control group, but the
pattern was unusual in that the GnRH surge was temporarily interrupted
approximately 4 h after its onset. Of interest, the LH response in
this ewe was barely evident (Figs. 5a and 6). The ewe that responded in
the 7L group (Ewe 17) had a GnRH surge within the range of that seen in
the controls and an LH surge that, although small relative to the
controls, was similar to the LH responses in the 14 h group (Figs. 5a and 6). The ability of this one animal to surge was not due to a
relatively high level of estradiol, as concentrations in this ewe were
actually less than in the others of this group that did not mount a
GnRH/LH surge. The GnRH and LH responses in the two ewes that expressed
a surge in response to a 7-h estradiol treatment began approximately
21 h after the addition of estradiol, much as in the control and
14 h groups. Thus, the interval from withdrawal of the estradiol
stimulus to surge onset was approximately 14 h (Fig. 6). |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Of interest, not all laboratories have consistently observed a large and sustained estradiol-induced GnRH surge in the ewe (26). It has been suggested (26) that the reported differences between laboratories can be attributed to an artifact of the extended period of estradiol treatment in the artificial follicular phase model used extensively by our group. The results of Exp 1 argue strongly against this proposal. The amplitude of the GnRH and LH surges observed in this experiment, whether the estradiol signal was withdrawn or maintained, resembled those of the preovulatory surges we observed in intact animals (22).
Although removal of the estrogenic stimulus at the time of surge onset was without effect on both GnRH surge amplitude and the existence of an extended GnRH surge, it is noteworthy that maintenance of the estradiol signal (control group of Exp 1) did prolong the duration of the GnRH surge compared with that seen in the -E group. This extension, however, was not sustained indefinitely, as GnRH values were declining in all animals in which estradiol was maintained but had not reached baseline when sampling ended. This eventual decline in GnRH in the face of continuously elevated estradiol could reflect desensitization/refractoriness of the hypothalamus to the stimulatory estradiol signal or depletion of the hypothalamic stores of releasable GnRH.
In the second experiment, the period of exposure to estradiol was further shortened to either 14 or 7 h, and the LH responses were compared with those in animals receiving estradiol for 21 h (i.e. when the estradiol stimulus was terminated at or near GnRH surge onset). Abbreviation of the estradiol signal to 14 h neither diminished its ability to stimulate a GnRH surge nor altered the GnRH surge characteristics. Further shortening of the signal to 7 h, however, produced a mixed response. Most animals (eight of 10) did not respond to this greatly shortened estradiol signal with a GnRH surge. In the two animals that did respond, however, the observed GnRH surges had an amplitude and duration within the range of surges produced by exposure to estradiol for longer periods (14 and 21 h). In all animals that responded to the 7-h and 14-h estradiol treatments, the GnRH surge developed and persisted many hours after removal of the stimulatory signal. For example, with the 14-h signal, the GnRH surge began approximately 7 h and ended approximately 25 h after the fall in circulating estradiol. Thus, to stimulate and indeed maintain the extended GnRH surge, elevated estradiol need not be present for the entire presurge period.
Collectively, the results of the two experiments lend insight into the mechanism for estradiol activation of the GnRH neurosecretory system. Our finding that estradiol is not needed for the whole presurge period is consistent with the view that elevated estradiol is required only during the time the estradiol-receptive neuronal system is activated. Neuroanatomical studies have demonstrated that the vast majority of GnRH neurons of sheep, like other mammals, do not contain detectable amounts of nuclear estradiol receptors (18, 19). It has thus been proposed that the influence of estradiol on GnRH neuronal activity is mediated by a system of interneurons. As such, the GnRH neurosecretory system is composed of GnRH neurons that are linked to estradiol-receptive neurons either directly or by means of at least one set of interneurons. Given this organization, the stimulatory effect of estradiol would be expected to occur in advance of the surge when the estradiol-receptive neurons are activated. According to this logic, estradiol would not necessarily be required during the period of the increased GnRH secretion that makes up the surge. Our finding that estradiol is not needed for the entire presurge period is consistent with the view that the steroid is needed only to activate the estradiol-responsive neuronal elements and not for progression of the signal from these elements to the surge process of GnRH release.
In addition to its effects at the hypothalamus, estradiol also has important actions at the level of the pituitary in LH surge induction (4, 5, 6, 8, 37). Our study reinforces the importance of the pituitary actions of estradiol and suggests that the temporal requirements for the pituitary and hypothalamic actions of estradiol differ. Although the shortened estradiol signals (14 and 7 h) induced GnRH surges that were not different from those seen in the control group in this study [or of natural surges or estradiol-induced surges in the artificial follicular phase model of previous studies (12, 22)], the LH surges produced in response to the 7- and 14-h estradiol stimuli were greatly reduced in amplitude. Presumably, this was due to decreased pituitary responsiveness to GnRH. The sensitizing effect of estradiol on the pituitary is well documented in a variety of species including the rat (5), sheep (4, 7, 8, 37), cow (38), and monkey (6). This action reflects the ability of estradiol to enhance GnRH receptor number and GnRH receptor messenger RNA (mRNA) in pituitary cells (14, 15, 16, 17). We are not aware of previous information concerning the duration or pattern of estradiol exposure required to induce these changes. The differing hypothalamic and pituitary requirements for estradiol to generate full GnRH and LH surges may be interpreted in two ways. First, the duration and timing of the estrogenic signal required by the hypothalamus and the pituitary may differ, the pituitary requiring a longer exposure than the hypothalamus. Second, the sensitizing effects of estradiol at the level of the pituitary may be short lived, in which case the steroid would have to be elevated immediately before onset of the LH surge for pituitary responsiveness to be maximized. The former possibility is supported by the finding of Clarke and Cummins (7), who observed that peak pituitary responsiveness to GnRH did not develop until 18–24 h after treatment with a bolus of estradiol.
In considering the different pituitary responses to the 14- and 21-h
estradiol signals, we must question whether the amplitude of the
induced estradiol rise was a factor. In the 21-h control group, the
circulating estradiol concentration increased abruptly for the first
1–2 h after implantation and then gradually increased over the
remainder of the 21-h treatment period (Fig. 4). Since the estradiol
stimulus was terminated 7 h earlier in the 14-h group, the
perceived amplitude of the estradiol signal may have been less than in
the 21-h controls, thus reducing pituitary responsiveness to GnRH. Two
points argue against this possibility. First, there was no significant
difference in peak estradiol concentration between groups. Second,
within the range of plasma estradiol concentrations in the two groups,
no difference in amplitude of the LH surge was observed in a previous
extensive dose-response study (31). Thus, the group difference in LH
surge amplitude was most likely due to the different durations rather
than size of the estradiol signal.
Interestingly, in both experiments, the timing of the GnRH surge was consistent relative to the time of addition of the estradiol implants and bore no relation to the time of withdrawal of the stimulus. The GnRH and LH surges invariably began approximately 21 h after estradiol was applied, irrespective of both the duration of estradiol treatment and the time of the stimulus relative to progesterone withdrawal. This observation has two implications. First, although we do not know how long the activational response to estradiol persists or how long estradiol remains bound to its receptor, our findings are consistent with the concept that estradiol triggers a neuronal cascade. This cascade requires a finite time for the signal to be perceived and transmitted to the GnRH release apparatus and for the surge to occur. Second, the temporal separation of surge onset from the drop in estradiol (Exp 2) and the fact that full amplitude surges can develop when estradiol is not withdrawn (Exp 1), indicate that the preovulatory GnRH/LH surge results from the elevation in estradiol rather than from the drop in estradiol that coincides with surge onset. The surge, therefore, is not a rebound response from the intense negative feedback of the previously high level of estradiol.
Finally, it is interesting to note that neither the reduction in estradiol-signal length from 21 h to 14 h, nor the further reduction to 7 h in those animals that mounted a surge, led to a change in amplitude or duration of the GnRH surge. In the artificial follicular phase model, therefore, the GnRH surge appears to be an all-or-none phenomenon, which can then be extended further if stimulation is continued as in the controls of Exp 1. This contrasts dramatically with generation of the LH surge by the pituitary which, in the ewe, requires continued stimulation by GnRH (39). Removal of the stimulatory GnRH signal at any point along the LH surge abruptly terminates the LH surge. This differing temporal dependency of the LH surge upon GnRH, and the GnRH surge upon estradiol, again may reflect the direct vs.indirect means by which the two secretory systems are activated.
In summary, once the GnRH surge of the ewe has begun, continued exposure to elevated estradiol is not required for surge maintenance, although such treatment may prolong the GnRH surge. The period during which the estradiol signal is required to stimulate a GnRH surge is relatively short, between 7 h and 14 h, and temporally located well in advance of the GnRH surge itself. The ability of a temporally remote estrogenic signal to induce a subsequent GnRH surge complements the hypothesis that the surge-inducing effects of estradiol are mediated indirectly via one or more sets of interneurons that are linked to GnRH neurons, and that estradiol need only be present when the estradiol-responsive neurons are activated. Although 7–14 h of exposure to elevated estradiol is sufficient for the GnRH surge, a longer estradiol stimulus is essential for maximal pituitary response and development of a full amplitude LH surge.
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Acknowledgments |
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Footnotes |
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2 Present address: Department of Veterinary Physiology, University of
Glasgow Veterinary School, Bearsden Rd., Glasgow G61 1QH, Scotland,
United Kingdom.
3 Present address: Department of Animal and Avian Sciences, University
of Maryland, College Park, Maryland 20742-2311.
4 Present address: Department of Internal Medicine, Division of
Endocrinology and Metabolism, 5570 MSRB II, University of Michigan, Ann
Arbor Michigan 48109-0678.
Received June 9, 1997.
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