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Laboratory of Neuroendocrinology, The Babraham Institute, Babraham Hall, Babraham, Cambridge, United Kingdom CB2 4AT
Address all correspondence and requests for reprints to: Neil P. Evans, Department of Veterinary Preclinical Studies, University of Glasgow Veterinary School, Bearsden Road, Glasgow, G61 1QH, United Kingdom. E-mail: n.evans{at}vet.gla.ac.uk
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Abstract |
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Introduction |
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Immunocytochemical studies in sheep, as well as a number of other species, have been unable to locate classical steroid receptors within GnRH neurons (11, 12, 13, 14, 15). This has led to the proposal that steroids influence GnRH secretion indirectly, either via a single steroid-responsive neuronal input, or through a system of interneuronal pathways activated or inhibited by estradiol and progesterone, respectively. An indirect route of transmission for steroidogenic information to the GnRH neurons responsible for the regulation of the surge is supported by the recent observations of Evans et al. (16), who described the estrogenic requirements for stimulation of a GnRH surge in the ewe. The results of these studies demonstrated that, although the GnRH/LH surge occurs approximately 21 h after exposure to follicular phase concentrations of estradiol, removal of the stimulatory signal after 14 h (7 h in a small number of ewes) does not result in any adverse effects on the GnRH surge, which still begins approximately 21 h after the initiation of estradiol treatment. This temporal delay between the stimulatory period of estradiol exposure and the GnRH surge could occur if information about steroidal conditions were conveyed to the GnRH neurons by an indirect or relayed transmission pathway. The existence of such a mechanism would allow the definition of at least three phases of GnRH surge generation: 1) an initial estradiol-dependent period, in which the stimulatory estradiol signal is read by the surge generating mechanisms; 2) an estradiol-independent period, in which the stimulatory signal is transmitted between the estradiol-responsive and GnRH neurons; and 3) a second estradiol-independent period, in which the GnRH neurosecretory neurons are activated and the GnRH surge occurs. The inhibitory effects of progesterone on the estradiol-induced GnRH/LH surge could theoretically be applied at each, or all, of these phases of surge generation. In this series of experiments, we seek to address the hypothesis that progesterone can block the LH surge by an action that occurs during the estradiol-independent phases of GnRH surge generation, namely, the transmission of the estradiol signal and the GnRH secretory event.
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Materials and Methods |
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Poll Dorset ewes (n = 10) were ovariectomized (OVX) by surgical laparotomy and run through a series of repeated artificial estrous cycles by the timed insertion and removal of exogenous estradiol and progesterone, as described previously (16, 17). Briefly, immediately after ovariectomy, ewes were given a 1-cm sc SILASTIC capsule containing crystalline estradiol and two intravaginal progesterone delivery devices (CIDR-G, InterAg, Hamilton, New Zealand). These steroid treatments produce average luteal phase levels of estradiol and progesterone in adult OVX ewes (17, 18). After 11 days, CIDR-Gs were removed to simulate luteolysis, and peripheral estradiol concentrations were raised to a peak follicular phase level by the sc insertion of 4 x 3-cm estradiol implants (17). The interval between simulated luteolysis and administration of the estradiol increment varied between 24–27 h, depending on the experiment. Specific times are given in the detailed experimental descriptions below. After each artificial follicular phase, the 4 x 3-cm estradiol implants were removed, and ewes were retreated with 2 new CIDR-G devices. The duration of each artificial estrous cycle was approximately 14 days. In total, ewes were run through nine artificial cycles. For reasons of clarity, the exact steroidal treatments employed in each study (two pilot studies and two complete studies) are described below, in combination with the results achieved. All animal procedures were conducted under Home Office licence (PPL80/1037).
Measurement and analysis of LH secretion
In each study, peripheral LH concentrations were assessed in
hourly samples of jugular blood, collected by venipuncture, from 10–40
h after addition of the 4 x 3-cm estradiol implants. Pituitary
responsiveness (see study 1) was investigated, in one artificial cycle,
by the collection of additional plasma samples, at 5-min intervals for
30 min, after administration of a 500-ng iv GnRH bolus.
LH was measured in duplicate 100-µl aliquots of plasma using a previously described double-antibody RIA procedure (19). LH concentrations are expressed relative to NIH-S11. Inter- and intraassay coefficients of variation were 9.0% and 6.8% at 1 ng/ml, and 8.8% and 6.2% at 10 ng/ml, respectively. The mean detection limit of the assays (n = 8) was 0.34 ng/ml.
All LH profiles were subjected to the following analysis to determine whether animals had responded to the experimental treatments with an LH surge. To be termed a surge, five criteria had to be met; LH secretion was required to: 1) increase above the mean plus 2SD of the baseline (mean of the first five samples taken). This time point was taken as the time of LH surge onset; 2) remain elevated for at least 4 h; 3) exhibit a peak that was greater than twice the concentration of LH at the start of the surge; 4) after the peak, decrease below twice the LH concentration at the start of the surge; and 5) remain at or below this level for at least 3 h.
After identification of LH surges, qualitative aspects, such as latency from the estradiol increment to surge onset (latency) and peak concentration (peak), were calculated. LH surge characteristics were statistically analyzed by paired (study 1) or unpaired (pilot study, study 2) Student’s t tests. To examine overall differences in the total amounts of LH secreted between treatment groups during a sampling period, the sum of LH concentrations seen in all samples that exceeded the presurge baseline was calculated and compared between groups, using a Mann-Whitney U test. Where split responses were seen after experimental treatments, the numbers of animals that did or did not surge were compared with controls, using a two-tailed Fishers exact-probability test.
Measurement and analysis of progesterone released from CIDR-G
devices
Progesterone concentrations were measured in a single assay
(sensitivity 0.01 ng/ml) using a commercial kit (DPC, Los Angeles, CA)
that had been validated for use in the sheep (20). Progesterone
concentrations in ewes that did or did not respond to treatment with
estradiol (see study 1) were compared by unpaired Student’s
t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Pilot study 1 results
Mean LH profiles, after 14 and 10 h exposure to follicular
phase estradiol concentrations, are shown in Fig. 1
, a and b, respectively. All ewes
exhibited an LH surge, the characteristics of which did not differ
between groups [latency (14 h): 18.8 ± 1.3 h, (10 h):
17.0 ± 1.0; peak (14 h): 7.7 ± 0.9 ng/ml, (10 h): 5.9
± 0.7 ng/ml].
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, upper panels): a, Positive control (exposed to estradiol for
10 h); b, negative control (same as for positive controls, except
that progesterone was maintained at a luteal phase level throughout);
c, experimental treatment (same as for positive controls, except that
circulating progesterone concentrations were raised to a luteal phase
level immediately after removal of the estradiol signal, by treatment
with 2 new CIDR-G devices).
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Study 1 results
Mean LH secretory profiles observed in response to the three
steroid treatments are shown in Fig. 2
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The positive control treatment stimulated an LH surge in all animals
(latency, 18.3 ± 0.8 h; peak, 11.2 ± 1.9 ng/ml). As
expected, all LH surges were blocked in response to the negative
control treatment (n = 9), in which progesterone remained elevated
throughout. Reintroduction of progesterone, after the stimulatory 10-h
estradiol signal (experimental treatment), generated a split response.
The LH surge was blocked in the majority of animals (six of nine), and
LH concentrations remained low throughout the experimental period. In
the remaining three animals, an increase in circulating LH was seen. In
two of these ewes, the increase in LH was similar to the LH surges
observed in the positive controls (latency, 18.0 ± 1.5 h;
peak, 5.9 ± 2.0 ng/ml). In the remaining ewe, the increase in LH
did not meet our criteria for an LH surge; rather, concentrations
exhibited random fluctuations with no sustained period of elevated LH
secretion (individual data not shown). Statistical analysis indicated
that the number of animals in which the surge was blocked, in response
to the experimental treatment, did not differ from the negative
controls. Further, the number of animals in which an LH surge was seen,
after the experimental treatment, was significantly less
(P < 0.005, Fishers exact-probability test) than in
the positive controls.
To determine whether there were between-animal differences in circulating progesterone concentrations that could explain the split response observed in the ewe exposed to the experimental treatment, circulating progesterone concentrations were monitored in a subgroup of animals after all three treatments. Progesterone concentrations were measured in the samples that had been collected 1, 3, 6, and 10 h after the removal of estradiol from all animals and reinsertion of CIDR-Gs in the ewes that received the experimental treatment. As expected, progesterone concentrations were significantly (P < 0.001) greater in animals treated with CIDR-Gs (7.4 ± 0.9 ng/ml, n = 9), relative to the positive controls in which CIDR-Gs had been removed (0.2 ± 0.02 ng/ml, n = 2). Within the ewes that received the experimental treatment, progesterone concentrations did not differ statistically (P = 0.41) between the ewes that did (7.8 ± 0.6 ng/ml, n = 3) or did not (8.9 ± 1.0 ng/ml, n = 4) exhibit an LH surge.
Examination of pituitary responsiveness in animals that received the
experimental treatment demonstrated that, although the treatment
blocked the LH surge in all ewes, their pituitary glands remained
responsive to exogenous GnRH (Fig. 3). LH
concentrations rose rapidly after administration of GnRH and reached a
peak after approximately 10 min (mean amplitude, 5.3 ± 0.6
ng/ml), after which, they declined and returned to basal concentrations
within 120 min of the GnRH challenge.
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Pilot study 2 results
Mean LH profiles, after 8 and 6 h exposure to follicular
phase estradiol concentrations, are shown in Fig. 1, c and d,
respectively. All animals treated with estradiol for 8 h exhibited
an LH surge (latency, 19.0 ± 1.4 h; peak, 6.5 ± 0.7
ng/ml) that was not different from those seen after treatment for
either 10 or 14 h (pilot study 1). Treatment with estradiol for
6 h resulted in stimulation of a surge in only one of five ewes. A
small increase in LH secretion was noted in the remaining four animals;
however, it did not meet the criteria required for classification as an
LH surge.
Study 2 design
The results from study 1 demonstrated that progesterone can block
the LH surge by an action within the two estradiol-independent phases
of GnRH/LH surge generation. The aim of this study was to more
accurately define when progesterone inhibits the surge, by testing the
hypothesis that the ability of progesterone to block the surge is
limited to a specific window of time that corresponds to the time
during which progesterone-receptive afferents must be activated to
block either the transmission of the signal or the release of GnRH,
i.e. the two estradiol-independent periods of GnRH surge
generation.
To test this hypothesis, it was important to maximize the duration of the estradiol-independent phases of GnRH/LH surge generation that were examined. The shortest estradiol exposure found to reliably stimulate an LH surge in the pilot study (8 h) was, therefore, used as the surge-inducing stimulus. Positive and negative control treatments were the same as those described in study 1, except that the duration of estradiol treatment was reduced from 10 to 8 h. There were two experimental treatments. In the EARLY P treatment, animals were treated with progesterone (2 x CIDR-G) for the 5 h immediately after removal of the stimulatory estradiol signal (8–13 h after the estradiol rise). In the LATE P treatment, ewes were treated with progesterone (2 x CIDR-G) from 13–18 h after the estradiol rise, i.e. during the 5 h immediately before the expected time of LH surge onset.
Study 2 results
Results from this study are presented in Fig. 4. All ewes that received the positive
control treatment responded with an LH surge (n = 3; latency,
15.0 ± 0.0 h; peak, 7.4 ± 0.6 ng/ml). As expected, no
LH surges were produced in animals that received the negative control
treatment (n = 5). After EARLY P treatment, the LH surge was
blocked in seven of eight animals. The converse was seen in the LATE P
group, in which the LH surge was blocked in only one of eight animals.
The remaining ewes exhibited LH surges that were similar to those in
the positive controls (latency, 18.0 ± 0.6 h; peak,
11.0 ± 3.0 ng/ml). Interestingly, in the eight ewes in which an
LH surge was not produced after either EARLY or LATE P treatment, an
increase in LH was observed over the course of the sampling period.
Analysis of the total amount of LH secreted in samples in which the LH
concentration exceeded baseline was found to be significantly higher
(29.1 ± 5.4 ng/ml; n = 8) in the ewes that received the
experimental treatment, relative to the negative controls (2.7 ±
0.9 ng/ml; n = 5; P < 0.001), in which luteal
phase progesterone remained in place throughout the follicular
phase.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the course of the studies included in this report, we have refined and extended the model of Evans et al. (16). Our results confirmed the ability of a discrete 14-h estradiol signal to induce an LH surge, and they demonstrated that the duration of estradiol exposure can be reduced to 10 h, and even 8 h, without affecting surge generation but that any further reduction in the length of estradiol exposure (e.g. 6 h) severely affected the proportion of animals that respond with an LH surge. As in the studies of Evans et al. (16), the amplitude of the LH surges induced by the short estradiol signal in the current study was low, relative to an endogenous preovulatory LH surge stimulated by a full estradiol signal. Given the known effects of estradiol on pituitary responsiveness (22), and the all-or-none nature of the GnRH surge (16), the available evidence would suggest that this reduction in LH surge amplitude is a consequence of reduced estrogenic priming of the pituitary gland before the GnRH surge.
In this model, activation of the system (period of estradiol exposure) is separated from the start of the surge (GnRH and LH, Ref. 16 ; LH, current study) by approximately 8 h during which, estradiol concentrations are basal (16). It is possible, therefore, to divide GnRH/LH surge generation into three separate phases: an estradiol-dependent phase (during which the stimulatory estradiol signal is read and the surge generating mechanism is activated); and two estradiol-independent phases (the first, when the stimulatory signal is transmitted from the estradiol responsive elements to the GnRH neurons; and the second, during which GnRH neurons are activated to release GnRH into the pituitary portal vasculature).
The results of study 1 demonstrate that progesterone can block the LH surge when administered after a discrete stimulatory estradiol signal and, therefore, can act during the estradiol-independent phases of LH/GnRH surge generation, to inhibit transmission of the estradiol signal and/or the secretory events associated with the surge. It is worthy of note that two of nine animals that received this treatment, however, were able to respond with an LH surge. There are a number of possible explanations for the observed LH surges in these animals: first, that progesterone concentrations differed among the sheep that surged, compared with those that did not, and that in some animals, progesterone concentrations were below a critical level that is required to block the activational effects of estradiol. Though little information is currently available on the levels of progesterone that are required to block the stimulatory effects of estradiol in the ewe, no significant differences were noted in the progesterone concentrations in the ewes that did or did not surge in the current study. We feel, therefore, that it is unlikely that differences in progesterone delivery from the CIDR-Gs and consequent peripheral concentrations could explain the observed differential responses in study 1. Second, the split response could be caused by between-animal differences in the response of the pituitary glands to progesterone. Although progesterone has been shown to have inhibitory effects on pituitary responsiveness to pulsatile GnRH in the ewe (23, 24), no data are available to indicate that progesterone has any inhibitory effect on the LH surge. Indeed, an LH surge can be induced in progesterone-treated ewes if GnRH is administered in an appropriate pattern (25, 26), and progesterone does not seem to adversely affect pituitary responsiveness when administered with a peak follicular phase concentration of estradiol (current study and Ref. 10). Effects of progesterone on pituitary responsiveness to GnRH in the ewe, therefore, may be limited to the regulation of the response to pulsatile (but not surge) patterns of GnRH release and, as such, also cannot explain our observed split response. Alternatively, the blockade of the surge in seven of nine ewes and observation of a surge in 2 ewes in study 1, in response to identical steroid treatments, could occur if there was natural between-animal variation in the speed of the neuronal events involved in LH surge generation. If this was the case, introduction of progesterone at one specific time point, namely 10 h after estradiol insertion, may not represent the same stage of surge generation in each individual and, therefore, may not have the same effect. This possibility is supported by the observation of between-animal variation in the time of the LH surge after exposure to an exogenous estradiol signal, and the observation that, when run through repeated artificial estrous cycles, the variance in surge latency is less within-animal that between-animal (personal observation).
The results of the second study included in this report confirmed our second hypothesis that the sensitivity to the inhibitory effects of progesterone, when applied after the surge-generating system has been activated by estradiol, are confined to a specific stage of the transmission of the estradiol signal. The results indicated that the ability of progesterone to inhibit the estradiol-induced surge is restricted to the EARLY part of the estradiol-independent period of surge generation. That is, the effects are limited to the period of time that corresponds to the transmission of the stimulatory signal through the interneuronal systems that link the estradiol-receptive neurons with the GnRH neurons. The period immediately before the LH surge, during which progesterone theoretically could have acted directly upon the GnRH neurons being insensitive to the inhibitory effects of progesterone. This finding will exacerbate the effects of any differences in the rate of transmission of the surge generation signal that is initiated by estradiol, discussed above, because the temporal location of the progesterone sensitive period, during which the surge can be blocked by progesterone, will differ between animals. This possibility could provide an explanation for the observation of an LH surge in a few animals in which the progesterone treatment was principally inhibitory (experimental treatment, study 1; EARLY P, study 2), and lack of a surge in one animal in which the experimental treatment was principally stimulatory (LATE P, study 2). Animals that expressed a surge, when the majority were blocked, having had progesterone applied after they had passed from the progesterone-sensitive period that occurs immediately after activation of the surge-generating system, into the progesterone insensitive period that precedes the surge. Whereas, in the LATE P-treated animal that surged, progesterone treatment must have been applied over a sufficient portion of the progesterone sensitive period to prevent expression of the surge.
In discussion of the effects that the different steroid treatment regimes had upon LH secretion and the generation of a surge, it is worthy of note that the experimental ewes that did not produce an LH surge in study 2 (EARLY P, n = 7; LATE P, n = 1) secreted significantly more LH than the negative controls, who also did not exhibit an LH surge. This result could be explained by the prolonged exposure to progesterone in the negative controls and release from steroid negative feedback in the experimental animals. An alternative explanation, however, would be that LH secretion was increased in the experimental animals because of a stimulatory effect of estradiol on the GnRH neurosecretory system but that the effect was limited by progesterone, and insufficient GnRH was released to induce a normal LH surge. Given the known effects of steroids on tonic LH secretion and the relatively small amounts of GnRH that are required to stimulate an apparently normal LH surge (26), the available data would tend to support the former possibility.
The ability of progesterone to block the LH surge, when applied for a short period of time immediately after the estradiol signal but not before the LH surge, is intriguing. Though the experiments included in this report do not address the specific mechanisms through which progesterone could act, they do, in conjuction with published data, allow us to speculate upon how and where (in the GnRH surge-generating system) progesterone is able to act. The finding that progesterone, like estradiol, exerts its effects on GnRH secretion well in advance of the secretory process suggests that progesterone also regulates GnRH neuronal activity indirectly. Mechanistically, this could be via direct involvement in the process of signal transmission, e.g. the presence of progesterone-responsive interneurons within the neural circuits that link the estradiol responsive and GnRH neurons, via a progesterone-receptive neuronal population that impinges upon the surge-generating system(s) activated by estradiol, or finally, via a nonreceptor-mediated action of progesterone upon the GnRH neurons themselves.
An indirect action of progesterone on GnRH secretion is supported by the findings of immunohistochemical studies, which have shown that, though progesterone receptors exist in a variety of different neuronal phenotypes, classical progesterone receptors, in the majority of species, are not found within GnRH cell bodies (27, 28). Which (if any) of these progesterone-receptive neurons are involved in the inhibitory effects of progesterone on the generation of the GnRH surge and whether they lie within, or impinge upon, the estradiol signal transmission pathway, however, remains to be elucidated. As stated above, although the majority of reports have been unable to locate progesterone receptors within GnRH neurons, it is worthy of note that one group, working in the guinea pig, has consistently found progesterone receptors in a small subpopulation (10%) of GnRH neurons (29), the physiological role of which is unknown. The existence of a similar subpopulation of progesterone receptive GnRH neurons, in the ewe, cannot be ruled out. However, given the recent demonstration that the GnRH surge, in the ewe, is associated with a change in GnRH synthesis across the entire population of GnRH neurons within the POA (30), we do not feel that such a limited progesterone receptive population of GnRH neurons could block the estradiol-induced GnRH surge. The results of the second study described in this report demonstrate that the surge-generating process is insensitive to the inhibitory effects of progesterone near the time of the LH surge. Given the potential ways that progesterone-receptive neurons could be involved in the signal transduction process, described above, this would suggest two things: first, that if progesterone-receptive neurons were an integral part of the signal transduction system, they are not located near the GnRH neurons; and second, that progesterone is unlikely to have any direct inhibitory effects upon GnRH release from the GnRH neurons themselves.
One final possible mechanism through which progesterone could act would be that progesterone inhibits transmission of the surge-generating signal through nongenomic postsynaptic effects. This possibility has been lent credence by a number of studies that have demonstrated that progesterone metabolites can activate and inhibit the activity of a number of neurotransmitter receptors in the brain, e.g. NMDA receptors, GABAA receptors, and oxytocin receptors (31, 32). In this regard, progesterone, through its metabolites, could disrupt transmission of the surge-inducing estradiol signal by blocking activation of a receptor population that is essential for signal progression. This possibility and the identity of the receptor population(s) involved, however, will have to remain speculative until a more definitive understanding of the neurotransmitter pathways involved with the transmission of the estradiol-induced surge-generating signal is attained.
In conclusion, this study provides important new information, with regard to the neural mechanisms through which progesterone acts to block the estradiol-induced GnRH surge. Exposure of ewes to elevated estradiol, for as little as 8 h, is shown to be sufficient to activate neuronal events that result in the secretion of an LH surge. The neural events that precede the LH/GnRH surge are shown to be sensitive to the inhibitory actions of progesterone, even when progesterone is applied after application of a stimulatory estradiol signal. Further, the ability of progesterone to block the surge during this estradiol-independent period of surge generation is not uniform, because the surge can be blocked only if progesterone is applied immediately after the estradiol signal. The timing of this progesterone-sensitive period is consistent with an action of progesterone on an interneuronal system that is downstream of the estradiol-responsive neurons but does not directly impinge upon the GnRH neurons themselves. Future work is necessary to assess the neural mechanisms through which progesterone inhibits the transmission of the estrogenic surge-generating signal, and to ascertain whether progesterone may also act during the estradiol-dependent phase of GnRH surge generation to affect or block the ability of the system to read the stimulatory estradiol signal.
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Acknowledgments |
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Footnotes |
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2 Supported by a Medical Research Council graduate student award.
Current address: Reproductive Sciences Program, 300 North Ingalls
Building, University of Michigan, Ann Arbor, Michigan 48109.
3 Supported by a St. Catharine’s College, Cambridge Research
Fellowship. Current address: Institut National de la Recherché
Agronomique, Physiologie de la Reproduction des Mammiferes Domestiques,
Nouzilly, 37380, France.
Received June 3, 1998.
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