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Biology of Reproduction 63, 1135-1142 (2000)
© 2000 Society for the Study of Reproduction, Inc.

ARTICLES

Duration and Amplitude of the Luteal Phase Progesterone Increment Times the Estradiol-Induced Luteinizing Hormone Surge in Ewes1

Donal C. Skinner2,a, Thomas G. Harrisb, and Neil P. Evansc

a Department of Clinical Veterinary Science, University of Bristol, Langford, BS40 5DU, United Kingdom b Laboratory of Neuroendocrinology, The Babraham Institute, United Kingdom, CB2 4AT, United Kingdom c Department of Veterinary Preclinical Studies, University of Glasgow Veterinary School, Glasgow, G61 1QH, United Kingdom


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Progesterone (P) powerfully inhibits the neuroendocrine reproductive axis, but the mechanisms and site or sites of action of this steroid remain poorly understood. Progesterone exposure during the luteal phase also alters the responsiveness of the hypothalamus to increased concentrations of estrogen (E) during the follicular phase. Using an ovariectomized ovine follicular phase model, we investigated whether the amplitude and duration of the luteal phase increase in circulating P affects the E-induced surge in LH. Treatment of ewes for 10 days with two, one, or half an intravaginal P-releasing implant or with an empty implant demonstrated that P concentrations significantly (P < 0.0001) delayed the time to surge onset upon exposure to an equal concentration of E. This delay was not due to a time-related difference in responsiveness to E after P clearance because the time of surge onset was not different when E treatment began 6, 12, or 24 h after the withdrawal of two P implants that had been present for 10 days. The final study demonstrated that the duration of P before treatment (5, 10, or 30 days) significantly (P < 0.0001) delayed the responsiveness of the estradiol-dependent surge-generating system. There was no effect on surge amplitude or duration in any experiment. Thus, the amplitude and duration of exposure to luteal phase P significantly affect the neural elements targeted by E to induce the preovulatory LH surge.

corpus luteum, corpus luteum function, hormone action, hypothalamus, LH, ovulatory cycle, progesterone


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Progesterone (P), in terms of the cumulative duration of its effects, is the most important ovarian steroid secreted during the lifetime of the female mammal and is central to the complex regulation of normal reproductive function. This occurs principally by regulatory effects on GnRH secretion from the hypothalamus [1, 2], but how and where these effects of P are transduced remain poorly understood. During the luteal phase of the estrous cycle, P produced by the corpus luteum inhibits hypothalamic GnRH secretion, and consequently, peripheral gonadotropin concentrations are low. The follicular phase, which is initiated by the decline in circulating P concentrations that occurs after luteolysis, is characterized by increased gonadotropin and estrogen (E) secretion. This rise in circulating E induces the preovulatory LH surge, which is caused by a robust, abrupt, and continuous increase in GnRH secretion [3–6].

The acute effects of E and P on gonadotropin secretion, both alone and combined, have been studied extensively in several species [2, 7–10]. These studies have shown that E and P both have independent regulatory effects on LH secretion [7–9] and that the actions of P can also be influenced by prior or concurrent E treatment [1, 7, 9, 10]. The possibility that P could have long-term central effects has long been recognized in terms of reproductive behavior, in which pre-exposure of the system to P, prior to stimulation by E, is required for the expression of E-induced aspects of sexual behavior [11–13]. Few studies, however, have investigated the long-term effects of P on the ability of the hypothalamo-pituitary gland complex to subsequently respond to E in terms of gonadotropin secretion. In support of an effect of luteal phase P exposure on the functionality of the system during the follicular phase, it has been shown that P priming delays the E-induced LH surge [12, 13] and that the magnitude of the E-induced GnRH surge is significantly reduced in the absence of P-priming [14]. Recent work has also suggested that the long-term effects of P may be more complex because the amount of P, rather than its mere absence or presence, can influence the time of onset of the preovulatory LH surge during the subsequent follicular phase [15].

The possibility that the timing of the E-induced preovulatory LH surge could be manipulated using gonadal steroids and the mechanisms responsible for this effect are of great interest for fertility research from both agricultural and human perspectives because the timing of ovulation may prove critical for successful fertilization and/or implantation. Recent studies in the ewe have demonstrated that premature expression of the LH surge and, therefore, forced ovulation early in the follicular phase, significantly reduces P secretion during the ensuing luteal phase; this corpus luteum insufficiency leads to a reduction in fertility [16, 17]. A similar effect is also seen after the induction of ovulation in anestrous ewes by introduction of a ram; the lack of P pre-exposure (no preceding luteal phase) results in a short luteal phase, and the associated conception rates are low [18]. These findings are also not limited to the sheep because luteal phase insufficiency, be it due to either the duration of P secretion [19] or the level of P secretion [20, 21], is associated with infertility in humans.

In the present study, we sought to investigate directly how the amplitude and length of the luteal phase elevation in circulating P concentrations could affect the E-induced LH surge using a well-described ovariectomized, steroid-treated, follicular phase ewe model [22].


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animals

Sexually mature Dorset Horn ewes were ovariectomized 1 mo before the start of the first experiment. Animals were maintained in outdoor barns on natural photoperiod, fed daily with hay, straw, and concentrate and had free access to water. At the time of ovariectomy, a 1-cm Silastic capsule containing 17ß-estradiol was implanted s.c. to produce basal (2.4 pg/ml) concentration of E [3]. Luteinizing hormone surges were induced in all experiments by s.c. insertion of four additional 3-cm Silastic capsules containing 17ß-estradiol. This treatment raises circulating E concentrations to peak follicular phase values (approximately 7.1 pg/ml) [3, 23]. Hourly jugular blood samples for LH analysis were collected by venipuncture for 30–38 h, starting 8 h after the insertion of the E capsules. All animal procedures were conducted under Home Office license (PPL/1037).

Experiment 1: Effect of Amplitude of Luteal Phase P Elevation on LH Surge

Part 1 The aim of this experiment was to investigate the effects of different concentrations of luteal P on the E-induced LH surge during the subsequent follicular phase. The experiment was conducted on 15 ewes, during the midbreeding season (December to January), over the course of four artificial estrous cycles. To counteract any carryover effect of the different treatments, we used a randomized crossover design to treat each ewe with two, one, or half an intravaginal P-releasing implant (CIDR, InterAg, Hamilton, New Zealand; [24]) or received a non-P-impregnated implant. On the basis of our previous experience with these steroid delivery devices, we expected two CIDRs to produce circulating progesterone concentrations of 3–4 ng/ml and one CIDR to produce levels of 1–2 ng/ml, which correspond to high-mid luteal and mid-low luteal phase levels in this breed [25]. Half a CIDR was therefore expected to produce a sub-luteal phase concentration, and progesterone concentrations were expected to remain basal in the ewes treated with a blank CIDR. In all treatments, the LH surge-inducing E treatment was administered 24 h after implant removal. Elevating P levels to those produced by two CIDRs followed by E treatment 24 h after P removal has been shown to produce LH and GnRH surges qualitatively similar to those occurring spontaneously in intact ewes [4, 26].

Part 2 Circulating P concentrations after the removal of two P implants fall to baseline within 8 h (range: 2–12 h; unpublished results). It is, however, probable that mean P concentrations after each treatment reach baseline at differing times and that the results obtained in Part 1 of the experiment reflect this difference. To test this hypothesis further, a second study was carried out in which the time of insertion of the E capsules following the removal of P was varied. If the effects observed in Part 1 were a function of P clearance, then the time of onset would depend on the length of time that P concentrations had reached baseline levels. In contrast, if no difference was found, this would provide strong support for a specific effect of P pretreatment concentration on the sensitivity of the hypothalamus to E.

The experiment was conducted on 16 ewes, during the late breeding season (January to February), over the course of four artificial estrous cycles. Animals were treated with two P implants for 10 days. Using a randomized crossover design, E capsules were then inserted 6, 12, or 24 h after P removal.

Experiment 2: Effect of Duration of P Pre-Exposure on the Subsequent LH Surge

The aim of this experiment was to determine the effect of the duration of pre-exposure to circulating P concentrations on the subsequent E-induced LH surge. The experiment was conducted on 15 ewes over three successive artificial estrous cycles (September to November) using a randomized crossover design. During the artificial luteal phases, P was administered by intravaginal insertion of two P implants for 5, 10, or 30 days. To examine the effects of the duration of P treatment on the LH surge, the time of P treatment was either halved (5 days) or increased three times (30 days). To prevent potential effects of decreased P release from the implants in ewes during the 30-day treatment, implants were replaced every 10 days. These treatments were expected to produce mid-high luteal phase levels over the duration of the P treatment. In all treatments, the surge-inducing E treatment was administered 24 h after P implant removal.

Radioimmunoassay

Plasma P concentrations were determined in a single RIA [27]. The intra-assay coefficient of variation was 9%, and assay sensitivity was 0.05 ng/ml.

Concentrations of LH were determined in duplicate 100-µl jugular plasma samples using the method of Niswender et al. [28], and all samples from an individual ewe within an experiment were measured in the same assay. The primary antiserum was purchased from Dr G.D. Niswender (CSU204, Colorado State University, Fort Collins, CO), iodination grade ovine LH was obtained from Biogenesis (Bournemouth, UK), and National Institutes of Health LH standard S11 was used for reference preparations. The intra- and interassay coefficients of variation averaged 8% and 11%, respectively, and assay sensitivity was 0.15 ng/ml (nine assays).

Analysis

The onset of the LH surge was defined as the first sample in which LH concentrations exceeded the presurge baseline (mean of first four samples) by two SDs and remained elevated for 4 h. The amplitude of the surge was defined as the average of the three highest consecutive values minus the presurge baseline. To obtain an estimate of the duration of the LH surge, the period during which samples exceeded the half-maximal concentration was calculated. This estimate was used because on several occasions, LH concentrations were still above the presurge baseline at the end of the experiment. All data within each experiment were analyzed by ANOVA using a Latin square design (SuperANOVA, Abacus Concepts, Berkeley, CA) that included animal as a within factor and cycle and treatment as between factors in the model. Post hoc analyses were performed using a Tukey-Kramer test.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Experiment 1: Effect of Amplitude of Luteal Phase P Elevation on LH Surge

Part 1 As expected, P levels remained basal (0.14 ± 0.03 ng/ml; range: undetectable–0.4 ng/ml) in ewes treated with blank implants. Treatment of ewes with half (0.86 ± 0.07 ng/ml; range: 0.5–1.4 ng/ml), one (1.45 ± 0.08 ng/ml; range: 1.0–2.2 ng/ml) or two (2.57 ± 0.13 ng/ml; range: 1.8–3.7 ng/ml) P implants produced increasing concentrations of circulating P. The progesterone concentrations achieved with the two-CIDR treatment were less than anticipated and fell more within the mid-high than the high luteal range. Despite being lower than expected, the concentrations achieved were significantly (P < 0.001) different from those observed following treatment with one CIDR. P concentrations were very stable over the 10-day treatment period within each group.

In comparison to treatment with blank implants (16.0 ± 0.9 h), P pretreatment with half (17.4 ± 0.8 h), one (19.5 ± 1.0 h), or two (22.6 ± 1.3 h) implants significantly (P < 0.0001) delayed the onset of the LH surge, and this effect was dose dependent (Fig. 1). The level of P pretreatment received by the animals during the preceding luteal phase did not affect any other aspect of the LH surge, such as surge amplitude or duration.



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  		FIG. 1. The amplitude of the increment in P during the luteal phase affects the timing of the estradiol-induced LH surge. Top: Mean results (+SEM) from 15 ewes showing responses to E after pretreatment with blank, half, one, or two P-releasing implants (CIDR). Middle: Representative results from three ewes following treatments with blank (open squares), half (solid circle), one (open circle), or two (solid square) CIDRs. Bottom: Mean data (+SEM) from all 15 ewes shown centered on the time of surge onset. Horizontal SEM bars mark the time of onset in each treatment. Insert shows the mean circulating P concentration for each treatment. Differing letters note significant differences at P < 0.001; repeated measures ANOVA with Tukey's post hoc test

Post hoc analysis of the results also revealed a significant (P < 0.0001) individual effect on time to surge onset that was independent of steroid treatment; in other words, the level in some animals appeared to surge earlier than that of others, but the time to surge onset was related to the circulating P level.

Part 2 Altering the time at which E was administered following the removal of two P implants had no significant effect on the timing, amplitude, or duration of the E-induced LH surge (Fig. 2).



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  		FIG. 2. The clearance rate of P does not appear to affect the timing of the estradiol-induced LH surge. Top: Mean results (+SEM) from 16 ewes showing responses to a 10-day pretreatment with 2 P-releasing implants, followed by a steroid-free interval of 6, 12, or 24 h after which E was inserted. Middle: Representative results from three ewes following intervals of 6 h (open square), 12 h (closed circle), or 24 h (open circle). Bottom: Mean data (+SEM) from 16 ewes shown centered on the time of surge onset. Horizontal SEM bars mark the time of onset for each treatment

Experiment 2: Effect of Duration of P Pre-Exposure on the Subsequent LH Surge

Duration of the artificial luteal phase P treatment (5, 10, or 30 days) had a significant (P < 0.0001) effect on the time of LH surge onset (Fig. 3). The length of P treatment did not significantly affect either the amplitude or duration of the LH surge.



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  		FIG. 3. The duration of the luteal phase progesterone increase affects the timing of the estradiol-induced LH surge. Top: Mean results (+SEM) from 16 ewes showing responses to a 5-, 10- or 30-day pretreatment with two P-releasing implants followed by E-insertion 24 h after P withdrawal. Differing letters note significant differences at P < 0.001; repeated-measures ANOVA with Tukey's post hoc test. Middle: Representative results from three ewes after P pretreatment periods of 5 days (open square), 10 days, (closed circle) and 30 days (open circle). Bottom: Mean data (+SEM) from 15 ewes after these treatments. Horizontal SEM bars mark the time of onset for each treatment

Because each experiment included a treatment group of two CIDRs and an interval of 24 h before E insertion, it was possible to carry out a preliminary analysis as to whether phase of the breeding season (either early to mid or late) influenced the E-induced LH surge. Although the mean amplitude tended to be lower in the experiment carried out during late breeding season, post hoc analysis did not show any statistical differences between the studies. The duration was also unaffected. However, surges in the experiment carried out during the late breeding season were significantly later (P < 0.005) than those carried out during the early to mid breeding season.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study demonstrates that specific components of the luteal phase elevation in P release have highly significant effects on an LH surge induced by exposure to E after P concentrations within the animal have decreased to basal levels. Because both the duration and amplitude of P exposure affected the way in which the LH surge-generating system responded to a constant E signal, it would appear that the role of P in modulating GnRH release is more complex than solely a presence/absence effect, as previously suggested [29].

Our study provides novel information as to the relationship between the duration of exposure to P and the ability of the LH surge-generating mechanism to respond to E. The results concur with previous investigations that have suggested a relationship between the amplitude of the luteal phase increase in P and the timing of the subsequent LH surge but extend these findings by demonstrating that this effect of P on the timing of the LH surge is dose dependent. An inhibitory effect of P pretreatment on the timing of the LH surge has been suggested by a number of studies that have investigated the effects of P pretreatment on both the GnRH- [16, 29] and E-induced [12–14] LH surge and the neutralization of P action by P immunization [30]. The possibility of a dose-dependent inhibitory effect of P on the timing of the LH surge has also been raised recently by the results of a nonrandomized study in intact ewes in which it was shown that the E-induced LH surge occurred later in ewes treated with two implants, relative to animals that only received one implant [15].

A number of lines of experimental evidence exist that have linked P priming during the luteal phase with fertility. For example, in sheep, the reduction in fertility that is seen when ovulation is induced during the anestrous season by introduction of a ram is associated with a reduction in the duration of the luteal elevation in P and can be prevented if exogenous P is administered to counteract the luteal insufficiency [18]. In addition, the absence of P priming in the ewe has been reported to result in decreased ovulation, despite an E-induced LH surge [31]. The importance of full-length, normal-amplitude P elevations during the luteal phase for successful reproduction has also been recognized in human medicine by the observation that short luteal phases [19] and reduced luteal phase P secretion [20, 21] are associated with an increased incidence of infertility.

Our data may provide a physiological explanation, or at least part thereof, for the apparent link between P priming and fertility. Prior P exposure will delay the timing of the LH surge and consequently may affect the maturity of the ovulated oocyte or the ability of the ruptured follicle to undergo normal luteinization. This effect of progesterone at the level of the hypothalamus is in addition to the other well-known effects of P at the level of the uterus, such as development of endometrial tissue [32], which will also affect implantation and therefore fertility. Strong support for our hypothesized hypothalamic effects of P are provided by a recent study that showed that early follicular phase preovulatory LH surges, induced by exogenous GnRH treatment, resulted in increased gestational failure. The decrease in fertility was associated with incompetent corpus luteum formation after the surge [17]. Similarly, McLeod and colleagues [16] showed that only ewes pretreated with P developed functionally normal corpora lutea following pulsatile GnRH treatment in anestrus.

Where is P exerting these effects on the LH surge? In sheep, it is well established that increased GnRH release is required to stimulate LH secretion and that LH and GnRH surge onsets are tightly coupled [3–5]. Furthermore, because we and others [15] have shown that various P treatments have no effect on any other parameter of the LH surge, it would appear that the effect of P on timing the LH surge is transduced through a neural and not a pituitary site of action. This hypothesis is supported by reports that P has little effect on GnRH-stimulated LH release from the ovine pituitary [16, 33, 34] and the inhibition of tonic [1, 35] and surge [2, 36] LH is transduced through an action of P on GnRH release. Our recent study, showing that the magnitude of the cerebrospinal fluid-GnRH surge, but not the LH surge, is significantly greater in P-treated ewes [14], provides further strong support for a neural site of action. It is generally held that in species apart from the guinea pig [37], GnRH neurons do not have classical nuclear steroid receptors [38–41]. Indeed, our laboratory has recently shown that GnRH neurons in the ewe brain do not contain nuclear P receptors (unpublished results). Thus, it would appear most likely that P acts indirectly on ovine GnRH neurons through a system of interneurones.

There is little data available to determine which neurotransmitter systems the P priming in the present study affects. Several investigations have implicated the opioidergic [42–44], noradrenergic [45], and GABAergic systems [45] in transducing the inhibitory effects of P on tonic GnRH secretion. In both sheep [36] and monkeys [46], the continued presence of P during the follicular phase inhibits the preovulatory LH surge, and we have shown recently that both the surge and tonic inhibition of GnRH release by P are transduced by the classical nuclear P receptor [2]. It is tempting to speculate, therefore, that the same neural systems may also mediate the effects observed in the present study but support for this hypothesis must be tempered in light of recent studies. Specifically, in sheep [47] and monkeys [46], the surge-inhibiting effect of P is independent of the effects of the endogenous opioids, whereas antagonism of the endogenous opioids by naloxone administration during the luteal phase reverses the effects of P on tonic GnRH release [42, 48]. It is possible that two systems, therefore, may transduce the effects of P on GnRH secretion: one affecting GnRH pulses and another influencing the preovulatory GnRH surge. It is noteworthy, therefore, that it has been suggested that E may act through two separate systems to affect tonic and surge GnRH release [49–51].

The increased or longer exposure to P could affect the neural mechanisms responsible for transducing the effects of E on GnRH release in several ways. The most obvious is by affecting the sensitivity to E itself. In this respect, P priming appears to decrease the responsiveness of the LH surge system to a surge-inducing E signal [11, 31], and this could be due to a P-induced down-regulation in E receptor expression [52, 53]. Alternatively, P may affect the synthesis and/or secretion of the neurotransmitter systems that are targeted by E to induce the LH surge. In ovariectomized ewes, P has been shown to increase proopiomelanocortin mRNA expression in the arcuate nucleus and decrease preproenkephalin mRNA in the ventromedial nucleus [44]. P could also affect synaptic plasticity, either by decreasing the contacts between stimulatory E-receptive neurons on GnRH cells or by increasing the contacts of inhibitory E-receptive cells [54, 55]. Last, P could influence the actual contact between GnRH neurons and hypophyseal portal capillaries by affecting the glial sheath surrounding the GnRH terminals [56–58].

Two further noteworthy points that came out of this study were that both the individual and season affected the time to surge onset. For example, it was noted that if a ewe expressed a short latency to surge onset after addition of E, although the effects of P exposure noted above were always evident, latency in that ewe would always be shorter than others that received the same treatment. This effect does not appear to be a result of either P uptake from the CIDRs or its subsequent degradation; there was no significant effect of individual on the concentration of circulating P. It is plausible to speculate, therefore, that this could be due to an interindividual variability in the neuronal sensitivity to P or E. Such interanimal variation in sensitivity to steroids was also suggested in our recent work that investigated the ability of P to block the E-induced surge because short duration exposure to P at specific times relative to E exposure was found to block the E-induced LH surge in most, but not all, ewes [59]. Similarly, the phase of the breeding season also appeared to affect the timing of the E-induced LH surge. Although our study was not designed to investigate the affect of phase of the breeding season on the LH surge, it agrees with previous trends that we have noted in the affects of season on the latency from E addition to surge onset [60]. The effects of these two variables emphasize the importance of the randomized crossover experimental designs that we employed in the conduct of these studies to reveal the effects of P pre-exposure on the E-induced LH surge.

In summary, this is the first study to demonstrate that the duration and level of P pre-exposure have a highly significant effect on the E-dependent mechanisms that drive the LH surge. Furthermore, because there is a tight coupling between the time of onsets of the GnRH and LH surges, this effect would appear to be neurally mediated. The ability of P to regulate the timing of the LH surge may be important in the control of fertility: low amplitude or short duration luteal phases would cause premature LH surges, possibly providing insufficient time for adequate follicular development.


   ACKNOWLEDGMENTS
 
We thank Sandra Dye for some of the assays performed in this study and Drs. Alain Caraty and Benoît Malpaux for constructive comments on an earlier version of this paper.


   FOOTNOTES
 
First decision: 30 March 2000.

1 D.C.S. was funded by a Wellcome Trust International Prize Travelling Research Fellowship (046910/Z/96/Z/JMW/JPS/CG) and T.G.H. by a MRC Research Studentship. Back

2 Correspondence: Donal C. Skinner, Department of Clinical Veterinary Science, University of Bristol, Langford House, Langford, BS40 5DU, UK. FAX: 44 117 928 9582; donal.c.skinner{at}bristol.ac.uk Back

Accepted: May 24, 2000.

Received: March 7, 2000.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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