J. Anim. Sci. 2002. 80:2681-2687
© 2002 American Society of Animal Science
Pituitary responsiveness to GnRH in mares following deslorelin acetate implantation to hasten ovulation1
C. A. Johnson,
D. L. Thompson, Jr.2 and
J. A. Cartmill
Department of Animal Science, Louisiana Agricultural Experiment Station, Louisiana State University Agricultural Center, Baton Rouge 70803-4210
2 Correspondence:
Phone: 225-578-3445; fax: 225-578-3279; E-mail:
dthompson{at}agctr.lsu.edu.
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Abstract
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The present experiment characterized the pituitary responsiveness to exogenous GnRH in the first 10 d after ovulation following commercially available deslorelin acetate implantation at the normal dosage for hastening ovulation in mares. Twelve mature, cyclic mares were assessed daily for estrus and three times weekly for ovarian activity starting May 1. Mares achieving a follicle at least 25 mm in diameter or showing signs of estrus were checked daily thereafter for ovarian characteristics. When a follicle >30 mm was detected, mares were administered either a single des-lorelin acetate implant or a sham injection and then assessed daily for ovulation. On d 1, 4, 7, and 10 following ovulation, each mare was challenged i.v. with 50 µg GnRH, and blood samples were collected to characterize the LH and FSH responses. The size of the largest follicle on the day of treatment did not differ (P = 0.89) between groups. The number of days from treatment to ovulation was shorter (P < 0.001) by 2.0 d for the treated mares indicating a hastening of ovulation. The size of the largest follicle present on the days of GnRH challenge was larger in the treated mares on d 1 (P = 0.007) but smaller on d 10 (P = 0.02). In addition, the interovulatory interval was longer (P = 0.036) in the treated mares relative to controls by 4.4 d. Concentrations of FSH in plasma of the treated mares were lower (P < 0.05) than control concentrations from d 3 to 12; LH concentrations in the treated mares were lower (P < 0.05) relative to controls on d 0 to 5, d 7, and again on d 20 to 23. Progesterone values were the same (P = 0.99) for both groups from 2 d before ovulation though d 23. There was an interaction of treatment, day, and time of sampling (P < 0.001) for LH and FSH concentrations after injection of GnRH. Both the LH and FSH responses were suppressed (P < 0.009) in the treated mares relative to controls on d 1, 4, and 7; by d 10, the responses of the two groups were equivalent. In conclusion, deslorelin administration in this manner increased the interovulatory interval, consistently suppressed plasma LH and FSH concentrations, and resulted in a complete lack of responsiveness of LH and FSH to GnRH stimulation at the dose used during the first 7 d after the induced ovulation. Together, these results are consistent with a temporary down-regulation of the pituitary gland in response to deslorelin administered in this manner.
Key Words: Gonadotropins • Mares • Ovulation
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Introduction
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Previous investigation (Johnson et al., 2000) into field reports of prolonged interovulatory intervals in mares following use of a commercially available implant of deslorelin acetate (Ovuplant) to hasten ovulation revealed that treated mares not only had a greater interovulatory interval but also had greatly reduced plasma LH and FSH concentrations for approximately 10 d after ovulation. Although the mares in that experiment (Johnson et al., 2000) were short-cycled with prostaglandin-F2
(PGF2), similar effects were noted for estrous cycles not altered by PGF2 administration by Mumford et al. (1995) in mares administered three or five times the recommended dose of deslorelin implants and by Farquhar et al. (2001) for mares administered one implant.
The prolonged suppression of gonadotropin secretion after ovulation in deslorelin-treated mares was characteristic of pituitary down-regulation induced by constant high GnRH input (Heber and Swerdloff, 1981; Nett et al., 1981; Sandow, 1983), generally characterized by a reduced sensitivity of pituitary gonadotropes to further GnRH stimulation (desensitization; Belchetz et al., 1978; Zilberstein et al., 1983). The results of Farquhar et al. (2001), who reported a reduced gonadotropin response to GnRH at 10 d after ovulation in deslorelin-treated mares, are consistent with the concept of down-regulation. Alternatively, the observed reduction in gonadotropin secretion may have been due to reduced endogenous GnRH input to the pituitary in treated mares (Crowder et al., 1986). The objective of the present experiment was to characterize the pituitary responsiveness to exogenous GnRH in the first 10 d after ovulation following deslorelin acetate implantation at the normal dosage for hastening ovulation in mares.
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Materials and Methods
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Twelve nonlactating, light horse mares between 4 and 16 yr of age were used. All mares were in good body condition (6 to 8, Henneke et al., 1983) and were maintained on a combination of ryegrass (winter) and native grass pastures. Mares were determined to have completed the vernal transition period and cycling normally before use. All mares were checked daily with a vigorous stallion throughout the experiment for signs of behavioral estrus. In addition, the ovaries of each mare were examined via transrectal ultrasonography three times weekly (Monday, Wednesday, and Friday) until detection of a follicle at least 25 mm in diameter or until the mare showed signs of estrus, at which time daily examinations, as well as daily blood sampling via jugular venipuncture, were initiated. Once a follicle >30 mm was detected for a given mare, she was administered either a single Ovuplant implant (Fort Dodge Animal Health, Overland Park, KS; n = 6) s.c. in the neck region or a sham injection (same needle size, no implant; n = 6) given in the same manner. Assignment to treatment group and administration of treatment were unknown to the personnel involved with on-farm data collection. After treatment, mares were followed with daily ultrasound exams until ovulation.
On d 1, 4, 7, and 10 following the first ovulation, each mare was challenged i.v. with 50 µg GnRH (Sigma Chem. Co., St. Louis); 7-mL blood samples were collected via an indwelling jugular catheter at -10, 0, 10, 20, 30, 45, 60, 90, and 120 min relative to GnRH injection. The dose of GnRH (50 µg) was determined in preliminary trials to be the smallest amount that consistently caused a measurable response in both LH and FSH concentrations. Ultrasound examinations were also performed on the day of each GnRH challenge, after all blood samples had been collected, to determine follicular activity. Daily ultrasound exams were resumed once a mare subsequently returned to estrus and were continued through the second ovulation. Daily blood sampling was continued for 4 d after the second ovulation to confirm ovulation via progesterone concentrations.
All blood samples in the experiment were placed on ice until centrifugation at 1,200 x g for 20 min at 5°C. Plasma was harvested and was stored at -15°C until assayed via RIA for LH (Thompson et al., 1983a), FSH (Thompson et al., 1983c), and progesterone (Diagnostic Systems Laboratory, Webster, TX, USA). Intra- and interassay coefficients of variation and assay sensitivities were 6%, 9%, and 0.2 ng/mL for LH; 7%, 11%, and 1.4 ng/mL for FSH; and 5%, 8%, and 0.05 ng/mL for progesterone.
Data were analyzed via the GLM procedure of SAS (SAS Inst. Inc., Cary, NC). Data from repetitive sampling over time (daily samples) were analyzed in a split-plot ANOVA (Gill and Hafs, 1971) for a completely randomized design (Steel and Torrie, 1980). The main effect of treatment was tested with the mare within treatments term; the time factor and its interaction with treatment were tested with the residual error term. For data from the repeated GnRH challenges, a second sub-plot effect was included (day of challenge), and the data were analyzed as a split-split-plot design (Steel and Torrie, 1980) with all appropriate interactions. Differences between treatment groups in the treatment x day x minute interaction were assessed by the LSD-test (Steel and Torrie, 1980). Net areas under the GnRH-response curves for LH and FSH were calculated by summing the time x concentration increments after subtracting the pre-GnRH average for each mare in each challenge; areas were analyzed separately for each day by one-way ANOVA (Steel and Torrie, 1980) due to heterogeneity of variances among the four challenge days.
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Results
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The size of the largest ovarian follicle on the day of treatment (P = 0.89) and 1 d before ovulation (P = 0.36) did not differ between groups (Table 1
). Mares receiving a deslorelin implant ovulated an average of 2.0 d earlier (P = 0.0003) and had an interovulatory interval 4.4 d longer (P = 0.0361) than control mares (Table 1). After the first ovulation, the size of the largest follicle present on the GnRH challenge days was larger in deslorelin-treated mares on d 1 (P = 0.0067) but smaller (P = 0.021) on d 10 (Table 1) relative to controls.
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Table 1. Intervals from treatment to ovulation, between the first and second ovulation, and sizes of the largest follicle on selected days relative to the first ovulation in control mares and mares receiving deslorelin acetate implants to hasten ovulation
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Plasma LH concentrations from daily blood samples in control mares followed the expected rise and fall around ovulation and into diestrus (Figure 1a). In mares receiving deslorelin, LH concentrations were lower (P < 0.05) relative to those in control mares from d 0 to 5, on d 7, and again on d 20 to 24 (Figure 1a). Daily plasma concentrations of FSH in control mares were low in estrus and followed the expected rise after ovulation (Figure 1b). Plasma FSH concentrations in deslorelin-treated mares were lower (P < 0.05) relative to controls on d 3 to 12 (Figure 1b). Plasma progesterone concentrations were not altered (P = 0.99) by deslorelin treatment (Figure 1c).
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Figure 1. Plasma concentrations of LH (a), FSH (b), and progesterone (c) in mares administered a deslorelin implant or sham injection (control) during the first estrus. Data are expressed relative to the day of the first ovulation (d 0). Asterisks indicate differences (P < 0.05) between groups on specific days. The pooled SEM from the analyses of variance were 0.94, 2.9, and 3.6 ng/mL for LH, FSH, and progesterone concentrations, respectively.
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There were interactions (P < 0.001) among treatments, days, and minutes of blood sampling in the ANOVA for both LH and FSH concentrations in the four GnRH challenges. Relative to control mares, the LH (Figure 2) and FSH (Figure 3) responses to exogenous GnRH were suppressed in the deslorelin-treated mares on d 1, 4, and 7. In agreement, net areas under the curve for the LH (P < 0.008) and FSH (P < 0.009) responses to GnRH were lower in deslorelin-treated mares on d 1, 4, and 7 (Figure 4).
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Figure 2. Plasma LH concentrations for GnRH challenges on d 1, 4, 7, and 10 following ovulation for mares administered a deslorelin implant or sham injection (control). There was an interaction of treatment, day, and minute (P < 0.001). The pooled SEM was 0.32 ng/mL.
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Figure 3. Plasma FSH concentrations for GnRH challenges on d 1, 4, 7, and 10 following ovulation for mares administered a deslorelin implant or sham injection (control). There was an interaction of treatment, day, and minute (P < 0.001). The pooled SEM was 2.8 ng/mL.
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Figure 4. Area under the curve for LH (a) and FSH (b) responses to GnRH challenges performed on d 1, 4, 7, and 10 following ovulation for mares administered a des-lorelin implant or sham injection (control). Each day was analyzed separately due to heterogeneity of variances; P-values for the differences between groups are shown. The SEM were 0.69, 1.5, 0.81, and 0.31 ng•mL-1•h-1 for LH and 3.3, 12.4, 7.3, and 9.5 ng•mL-1•h-1 for FSH for d 1, 4, 7, and 10, respectively.
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Discussion
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Deslorelin acetate, as the commercially available implant, Ovuplant, has been proven many times to be effective at hastening ovulation in mares with preovulatory follicles larger than 30 mm (McKinnon et al., 1993; Meinert et al., 1993; Jöchle and Trigg, 1994). Shortly after its commercial release in the United States, there were field reports that some treated mares displayed either prolonged interovulatory intervals or complete anestrus. A previous experiment (Johnson et al., 2000) confirmed, under controlled conditions, the deslorelin effect on interovulatory interval for mares short-cycled on d 7 with PGF2 and extended the observations to include the reduction in LH and FSH concentrations following treatment. Similar results were reported by Farquhar et al. (2001) for mares not short-cycled with PGF2, except that those authors found no significant suppression of daily LH concentrations.
The effects of deslorelin implant on time to ovulation, interovulatory interval, and plasma concentrations of LH and FSH observed in the present experiment were virtually identical to previous results (Johnson et al., 2000) from our laboratory. Because the mares in that experiment had been short-cycled with PGF2 injection on d 7 after ovulation, it could not be determined whether the shortened diestrous period affected the results. It is now apparent that the normal, recommended dose of deslorelin has profound effects on gonadotropin secretion in mares not administered PGF2 as well.
For both gonadotropins, there was an initial stimulation of plasma concentrations in response to deslorelin implantation. Although only daily samples were drawn in the present experiment, we have previously characterized the short-term release of LH and FSH after deslorelin implantation (Donadeu, 1997; Johnson et al., 2001) and found that peak concentrations occurred at 6 to 8 h after administration. This initial rise in both gonadotropins corresponds with the release of deslorelin: peak concentrations of deslorelin (about 400 pg/mL) occur at 3 to 6 h after implantation and decline to near baseline within 24 h (Donadeu, 1997). As in the present and previous (Johnson et al., 2000) experiments, concentrations of both gonadotropins decreased continuously for several days after the initial peak.
The size of the largest follicle on the ovaries did not differ between treatment groups on the day of treatment or 1 d before ovulation; however, the interval from treatment to ovulation was shortened by 2 d. These data are consistent with previous studies with deslorelin implants (Jöchle and Trigg, 1994; Mumford et al., 1995). The size of the largest follicle was larger in the deslorelin-treated mares on d 1 following ovulation. This may have been due to incomplete suppression from the dominant follicle ovulating earlier or to the initial temporary rise in LH and FSH following implant administration. By d 10, the size of the largest follicle on the ovaries of the deslorelin-treated mares was smaller than on the ovaries of the control mares, which was likely due to the long-term gonadotropin suppression.
Both the pre-GnRH concentrations of LH and the LH response to GnRH in control mares were characteristic of the stage of the estrous cycle (Alexander and Irvine, 1986; Ginther, 1992). Immediately after ovulation (d 1), plasma LH concentrations were at their peak, and the response to GnRH was minimal due to the high rate of secretion already occurring. With the drop in LH secretion as progesterone concentrations increased, the LH response to GnRH increased, and maximal response occurred on d 4. Later, as the inhibitory effects of progesterone become greater, the LH response to GnRH diminished and was very low by d 10. The elevated LH concentrations seen in control mares on d 20 to 24 coincided with their impending second ovulation, which was delayed in the deslorelin-treated mares.
Similar to LH, the pre-GnRH concentrations of FSH and the FSH response to GnRH in control mares were characteristic of the stage of the estrous cycle. Plasma FSH concentrations were low on d 1, due to residual effects of estradiol and inhibin from the dominant follicle (Ginther, 1992). On d 4 and 7, FSH had been freed of those inhibitory effects, and the response to GnRH was characteristic of diestrus. By d 10, the response had begun to diminish, likely due to the onset of the next follicular phase.
For mares receiving a deslorelin implant, there was virtually no LH or FSH response to the GnRH injections on d 1, 4, and 7 after ovulation. These results indicate that the pituitary glands of these mares were indeed relatively insensitive to the injected GnRH, which would support the concept of down-regulation as described in other species. The small dose of GnRH used for these challenges was chosen to approximate the endogenous (physiologic) amount of GnRH normally reaching the pituitary gland, as opposed to a saturating dose. In addition, it was desired to keep each challenge to a minimum to avoid carryover effects from injection to injection (such that the challenges might become similar to replacement therapy for a quiescent hypothalamus). Although Alexander and Irvine (1986) calculated even smaller doses as physiologic, similar methods were used herein to determine the smallest dose that would give consistent responses for both LH and FSH, which turned out to be 50 µg per mare.
Although down-regulation is a common complication in using GnRH and its analogues in other species, the horse was thought to be less susceptible to down-regulation (Irvine and Alexander, 1993). That is, horses continually infused with GnRH for 24 h had a steady increase in LH concentrations (Garcia and Ginther, 1975). Osmotic minipumps designed to deliver GnRH to horses constantly for 28 d maintained LH secretion (Hyland et al., 1987). Allen et al. (1987) administered long-term (28-d) GnRH agonist implants to horses and reported a prolonged gonadotropin secretion without refractoriness; Turner and Irvine (1992) reported similar results using higher doses. Daily administration of high levels of a GnRH agonist did not suppress LH levels in stallions and luteal levels of LH were maintained in mares; however, follicular activity was diminished after 30 d of treatment (Montovan et al., 1990).
By d 10 after ovulation, the LH and FSH responses to GnRH were similar for the two groups of mares, indicating that the deslorelin effects were waning. No further GnRH challenges were performed after d 10 because soon thereafter the control mares began to return to estrus with the associated changes in LH and FSH concentrations, which would have confounded the responses to GnRH. One model that might be useful for determining the actual length of the deslorelin effect and the characteristics of recovery from it would be similar experiments in stallions or steroid-treated geldings (Johnson and Thompson, 2000), which exhibit the same long-term inhibition of LH and FSH secretion in response to deslorelin implantation.
Other than the hastening of the first ovulation (Jöchle and Trigg, 1994; Mumford et al., 1995) and a few days’ delay in ovulation on the estrus subsequent to deslorelin administration, no other effects on the estrous cycle were observed. Given the major perturbation in plasma LH and FSH concentrations, one might expect a greater effect on follicular populations and onset of the next estrus. The lack of effect on plasma progesterone concentrations after the first ovulation indicates that corpus luteum formation and subsequent function is not dependent upon the normally high LH concentrations from the day of ovulation onward. We reported similar results for mares treated with testosterone propionate during midestrus (Thompson et al., 1983b) and the subsequent diestrus, in which LH concentrations during estrus were reduced by about 50%, whereas the timing of ovulation and the function of the subsequent corpus luteum were unaffected.
In conclusion, we have shown that the reductions in plasma LH and FSH concentrations following Ovuplant administration to mares are accompanied by an insensitivity to exogenous GnRH challenge for up to 7 d. Such insensitivity to exogenous GnRH has been shown in other species to involve a reduction in GnRH receptor numbers and(or) a perturbation of postreceptor mechanisms (Smith et al., 1983; Conn et al., 1987). Further research is needed to determine if the deslorelin-induced insensitivity observed herein is associated with a down-regulation of GnRH receptors like in other species. Whether endogenous GnRH secretion is altered in these mares, as has been suggested for ewes (Crowder et al., 1986), and whether pituitary LH and FSH content is reduced, needs to be determined in future experiments.
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Implications
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These data indicate that mares induced to ovulate with the commercially available implant of deslorelin acetate (a gonadotropin-releasing hormone agonist) experience suppressed gonadotropin secretion and a desensitization to exogenous gonadotropin-releasing hormone for at least 7 d after ovulation. This effect on pituitary function results in an extended interval between the induced ovulation and the subsequent one, if the mare does not get bred or does not become pregnant.
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Footnotes
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1 Approved for publication by the Director of the Louisiana Agric. Exp. Sta. as manuscript no. 02-11-0046. We thank A. F. Parlow, Harbor-UCLA Medical Center, Torrance, CA, and the NIDDKD, National Hormone and Pituitary Program, Rockville, MD, for reagents. 
Received for publication January 22, 2002.
Accepted for publication May 28, 2002.
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C. A. Johnson, D. L. Thompson Jr., and J. A. Cartmill
Effects of deslorelin acetate implants in horses: Single implants in stallions and steroid-treated geldings and multiple implants in mares
J Anim Sci,
May 1, 2003;
81(5):
1300 - 1307.
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Abstract
Introduction
