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ANIMAL GROWTH, PHYSIOLOGY, AND REPRODUCTION |
,
,2
* Departments of Animal Science and
and
Physiology, and
and
Laboratory for Mammalian Reproductive Biology and Genomics, Michigan State University, East Lansing 48824-1225
Abstract
Ultrasound-mediated intrafollicular injection and aspiration procedures were used to investigate the ability of the selective cyclooxygenase-2 inhibitor, NS-398, to inhibit intrafollicular PGE2 synthesis and suppress ovulation in dairy cattle. Follicular growth and timing of the preovulatory gonadotropin surge were synchronized in 55 Holstein cows and the position of the ovulatory follicle was determined by daily ultrasound scanning. Preovulatory follicular fluid was aspirated from the largest follicle in four animals at 0, 6, 12, 18, and 24 h after GnRH injection (n = 20). The remaining 35 animals were subjected to ultrasound-mediated intrafollicular injection of NS-398 (10 µM final concentration; n = 19) or diluent (n = 16; controls). At 24 h after GnRH injection, follicular fluid was harvested from a subset of NS-398- (n = 9) and diluent-treated animals (n = 6). The remaining NS-398- and diluent-treated animals were subjected to ultrasonography every 6 h for 36 h after intrafollicular injection, and then daily through d 7 of the subsequent luteal phase to monitor ovulation and corpus luteum development. Follicular fluid PGE2 concentrations were increased following GnRH injection and reached a maximum at 24 h (P < 0.05). Follicular fluid PGE2 concentrations were decreased in NS-398- vs. diluent-treated follicles (7.2 vs. 52.2 ng/mL respectively; P < 0.05), but progesterone concentrations did not differ. Intrafollicular injection of NS-398 also inhibited follicle rupture (P < 0.001). All 10 control animals ovulated within 30 h of GnRH injection. Nine out of the ten NS-398-injected animals failed to ovulate. The NS-398-injected follicles developed morphological and endocrine characteristics resembling luteinized, unruptured follicles. Thus, intrafollicular PGE2 synthesis and follicle rupture, but not luteinization, were inhibited in cattle following ultrasound-mediated intrafollicular injection of NS-398. Ultrasound-mediated intrafollicular injection of NS-398 is a useful tool for mechanistic studies of intrafollicular regulation of the ovulatory process in cattle.
Key Words: Bovine • Follicle • Luteinization • Ovulation • Prostaglandin
Introduction
Successful ovulation is a prerequisite for fertility. Intrafollicular PG are widely implicated in the mechanism of ovulation. Mice with a null mutation in the gene for cyclooxygenase-2 (COX-2, a key regulator of PG synthesis) fail to ovulate (Dinchuk et al., 1995
; Lim et al., 1997), potentially due to a deficiency in extracellular matrix (ECM) proteolysis. Cyclooxygenase-2 has been proposed to be a key determinant of the length of the ovulatory process (Sirois, 1994; Sirois and Dore, 1997). Induction of COX-2 precedes ovulation by approximately 10 h in rats (Sirois et al., 1992), horses (Sirois and Dore, 1997), and cattle (Sirois, 1994). However, the mechanisms by which the preovulatory increase in intrafollicular PG promotes ovulation are unclear.
Two families of proteinases that regulate the follicular ECM degradation required for ovulation are the matrix metalloproteinases (MMP) and the plasminogen activator/plasmin family (PA). Studies in cattle indicate the LH surge promotes a temporally and spatially specific increase in the expression of specific MMP and PA in preovulatory follicles (Bakke et al., 2002; Dow et al., 2002), which presumably helps to mediate subsequent ECM degradation and follicle rupture. However, the intrafollicular-signaling pathways downstream of the LH surge that promote increased expression of the MMP and PA in bovine follicles are not known. Studies of intrafollicular regulation of ovulation and mechanisms by which PG promote bovine follicle rupture are limited by a lack of suitable in vivo model systems.
The objectives of this study were to determine the effect of the selective COX-2 inhibitor, NS-398, on intrafollicular PGE2 synthesis, bovine follicle rupture, and the luteinization process and, hence, the utility of ultrasound-mediated intrafollicular injection and aspiration procedures for use in mechanistic studies of intrafollicular regulation of ovulation in cattle.
Materials and Methods
Animal Care
Mature, nonlactating Holstein cows (Bos taurus; 
2 yr old) were fed a balanced corn silage-based diet (restricted). During the course of the experiments, animals were housed either in 6 x 40 ft pens (four animals per pen) at the Michigan State University (MSU) Beef Cattle Research Center or in tie stalls at the MSU Dairy Teaching and Research Center. All animal-related procedures were approved by the All-University Committee on Animal Use and Care at Michigan State University.
Experimental Model
Follicular development and timing of the preovulatory gonadotropin surge were synchronized in Holstein cows (n = 55) using the Ovsynch procedure (100 µg of GnRH, followed 7 d later by 25 mg of PGF2
and 100 µg of GnRH 36 h after PGF2; Pursley et al., 1995). In this model, ovulation occurs an average of 28 h after the second GnRH injection (Pursley et al., 1995). Daily ultrasound analyses were performed after initiation of the Ovsynch procedure to exclude animals that turned over a new follicular wave before the second GnRH injection and to confirm regression of the corpus luteum.
Ultrasound-Mediated Intrafollicular Injection Procedures
The ultrasound-guided, transvaginal intrafollicular injection procedure was conducted as described by Kot et al. (1995), with the modifications described below. For injections, a Pie medical 200 SLC scanner (Classic Medical, Tequesta, FL) equipped with a 5.0-/7.5-MHz vaginal probe was utilized with a single-channeled needle system consisting of a sterile 20-gauge needle (5.08 cm long) attached to 16-gauge silicone tubing by means of a stainless steel connector. A tubing adapter was placed on the opposite end of the silicone tubing and a tuberculin syringe was attached. Separate new needles were used for each animal. Epidural anesthesia was administered and vaginal lavage was performed before injections. The transducer was mounted in a stainless steel device containing a 40-cm-long needle guide. The transducer was covered with a sterile plastic sleeve, coated with sterile lubricant, and placed in the vaginal fornix. The ultrasound system projects a dashed line through the image to represent the path that will be followed by the needle. The ovary containing the follicle of interest was positioned transrectally against the vaginal wall over the transducer face so that the needle line on the ultrasound monitor transects the follicle. The ovary was manipulated so that the needle entered the follicle via penetration of the ovarian stroma at the base of the follicle, rather than directly through the preovulatory follicle apex. The needle path to the injected follicle contained ovarian stroma and no additional follicles or corpora lutea.
Immediately before injection, the needle was filled with appropriate treatments or diluent. An additional 0.2 mL was retained in the needle so that approximately 0.1 mL of solution was delivered into the follicle when the syringe plunger was advanced. The needle was then inserted into the needle guide of the transvaginal probe. When the ovary and follicle of interest were in position and tight against the vaginal wall, the needle was advanced until the image of its tip became visible on the screen, approximately 1 cm from the follicle, indicating that the vaginal wall and peritoneum had been penetrated. The needle was then pushed forward until the image of the needle tip was visible within the follicle. Treatments were then injected into the follicle. Swirling of the fluid entering the follicle indicated that the injection was successful. The probe and needles were withdrawn immediately after injection to minimize pressure on the newly punctured follicle. At the first ultrasound after injection (1 h), animals with injected follicles that decreased in diameter >10%, had a blood-filled antrum, or that collapsed were immediately excluded from experiments.
To validate efficacy in performing ultrasound mediated intrafollicular injections, the effect of intrafollicular injection of hCG or diluent into first-wave dominant follicles was determined basically as described by Kot et al. (1995). First-wave dominant follicles were injected on d 7 postovulation with either 100 µL of hCG (100 IU; n = 7; Sigma, St. Louis, MO) or vehicle (saline) alone (n = 9). Animals were then subjected to ultrasonography every 6 h for 36 h, and then twice daily for 5 d to verify ovulation of the dominant follicle in response to hCG injection, and atresia of diluent-treated follicles at the expected time. All seven (100%) of the follicles treated with hCG ovulated within 30 h of injection, whereas the dominant follicle turned over by d 12 of the wave in all nine vehicle-injected animals. In this and forthcoming described experiments, <10 % of the follicles injected were lost or excluded from experiments due to leakage, rupture, or intrafollicular hemorrhage.
Effect of the Preovulatory Gonadotropin Surge on Follicular Fluid PGE2 Concentrations
Follicular growth and timing of the preovulatory gonadotropin surge were synchronized in 20 animals. Follicular fluid was collected from the dominant ovulatory follicle by transvaginal follicle aspiration at 0, 6, 12, 18, and 24 h (n = 4 each) after the second GnRH injection. Follicular fluid was processed for PGE2 assay as described below.
Effect of Intrafollicular Injection of the Selective COX-2 Inhibitor NS-398 on Bovine Follicle Rupture and Follicular Fluid Concentrations of PGE2
Follicular growth and timing of the preovulatory gonadotropin surge were synchronized in 35 animals. Within 2 h after the second GnRH injection of Ovsynch, the diameter of the preovulatory follicle was determined by ultrasonography. The volume of the preovulatory follicle was then calculated, and animals (n = 19) were injected intrafollicularly with 100 µL of the selective COX-2 inhibitor, NS-398 (Cayman Chemical, Ann Arbor, MI; solubilized in dimethyl sulfoxide [Fisher Scientific, Pittsburgh, PA] and diluted in saline), to achieve a final concentration of approximately 10 µM in follicular fluid. This approach was selected to potentially allow for greater control of the final NS-398 concentration in follicular fluid than if a fixed amount were infused into all preovulatory follicles irrespective of follicle size at time of injection. Additional follicles were injected with diluent alone (n = 16; controls). Preliminary experiments were done to determine optimal dose and time for NS-398 administration relative to the gonadotropin surge. To determine the effects of intrafollicular injection of NS-398 on follicular fluid PGE2 and progesterone concentrations, follicular fluid was collected from NS-398- (n = 9) and diluent-treated animals (n = 6) by transvaginal follicle aspiration at 24 h after the second GnRH injection. For determination of intrafollicular NS-398 injection effects on follicle rupture, all remaining animals were subjected to ultrasonography every 6 h for 36 h after intrafollicular injection, and then daily through d 8 after intrafollicular injection to confirm the disappearance of the ovulatory follicle (ovulation) and subsequent corpus luteum development. Serum samples were also collected from a subset of NS-398-injected animals (n = 4) on d 8 after intrafollicular injection to confirm circulating progesterone concentrations, which indicate that a functional corpus luteum is present.
Assay of Follicular Fluid PGE2 Concentrations
After collection, follicular fluid was centrifuged to pellet cells and debris, supernatant was decanted, and indomethacin was added to the supernatant to achieve a final concentration of 10 µM. Follicular fluid PGE2 concentrations were determined using a commercially available ELISA (Cayman Chemical). Sensitivity of the assay was 7.8 pg/mL. Intra- and interassay CV were 5.3 and 12.9%, respectively. The assay displays less than 18.7% cross-reactivity with PGE1, and less than 0.1% with other PG.
Assay of Serum and Follicular Fluid Progesterone
Progesterone concentrations in serum and follicular fluid were measured by RIA (Diagnostic Products Corp., Los Angeles, CA), as previously described (Xu et al., 1995). Intraassay and interassay CV were 5.6 and 9.1%, respectively.
Statistical Analysis
The effects of the preovulatory gonadotropin surge or NS-398 administration on follicular fluid PGE2 and progesterone concentrations were determined by one-way ANOVA using the GLM procedure of SAS (SAS Inst., Inc., Cary, NC). Individual comparisons of mean PGE2 concentrations were performed using Fisher’s protected LSD test. The effect of intrafollicular NS-398 administration on the proportion of cows ovulating was determined by 
2 analysis.
Results
Effect of the Preovulatory Gonadotropin Surge and Intrafollicular NS-398 Injection on Follicular Fluid PGE2 Concentrations
Follicular fluid PGE2 concentrations were markedly increased following GnRH injection (P < 0.05) and were maximal at 24 h (Figure 1). Intrafollicular injection of NS-398 resulted in reduced concentrations of PGE2 in follicular fluid collected 24 h after GnRH injection (P < 0.05). The concentration of PGE2 in NS-398-treated follicles was less than one-seventh of that of the diluent-treated follicles (Figure 1).
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). However, NS-398 administration did have a pronounced effect on luteal morphology. Morphological signs of luteinization were apparent within 48 h of NS-398 injection, and distinct structures were present in the location of the dominant ovulatory follicle 8 d after NS-398 injection. Such structures showed prominent characteristics of luteinized, unruptured follicles (Figure 4), including a prominent and clearly detectable large antrum and tissue outside of the antrum (follicle wall) of an echo texture characteristic of luteal tissue. In contrast, corpora lutea of normal morphology were detected by ultrasonography in diluent-treated control animals (Figure 4). Serum progesterone concentrations in NS-398-injected animals that are characteristic of functional corpora lutea were also detected in samples collected on d 8 after NS-398 administration (2.7 ng/mL).
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In the present experiment, ultrasound-mediated intrafollicular injection and aspiration procedures were used to study the ability of the selective COX-2 inhibitor NS-398 to inhibit LH surge-induced increases in intrafollicular PGE2 synthesis and follicle rupture. Our results illustrate the utility of the ultrasound-mediated intrafollicular injection system for mechanistic studies of the ovulatory process in cattle and support previous studies demonstrating a key role for intrafollicular PG in the ovulatory process.
Injection of hCG into first-wave dominant follicles and subsequent monitoring of ovulation rate were used to successfully validate the procedure. The low rates of follicle rupture and leakage (<10%) observed in validation experiments were amenable to use of this approach in mechanistic studies of the regulation and role of intrafollicular PG in bovine follicle rupture. Ultrasonography and examination of follicular fluid aspirated 24 h after intrafollicular injection of NS-398 (for PGE2 and progesterone measurements) revealed no signs of significant intrafollicular hemorrhage. Collectively, advantages of the described bovine model system include the ability to 1) closely synchronize follicular growth and timing of the preovulatory LH surge and subsequent follicle rupture using the Ovsynch procedure (Pursley et al., 1995); 2) nonsurgically administer treatments (hormones, inhibitors) directly into preovulatory follicles at specific time points relative to the LH surge using ultrasound-mediated intrafollicular injection procedures; 3) carefully monitor the ovulatory process and time of ovulation using ultrasonography; and 4) collect ample amounts of tissue from individual dominant ovulatory follicles for molecular and biochemical assays due to the large follicle size (>12 mm). Future intrafollicular injection studies, coupled with tissue collections for molecular and biochemical assays, will be of utility for identification of the LH surge-induced changes in expression and activity of the MMP and PA and their cognate inhibitors, which are dependent on an increase in intrafollicular PG and potentially obligatory for follicle rupture.
In the present study, intrafollicular injection of the selective COX-2 inhibitor NS-398 resulted in a greater than sevenfold reduction in follicular fluid PGE2 concentrations and inhibited follicle rupture in 90% of the animals treated. Treatment with NS-398 can also effectively inhibit ovulation of rat follicles in vitro and in vivo (Mikuni et al., 1998). To our knowledge, the effect of intrafollicular injection of a selective COX-2 inhibitor, such as NS-398, on intrafollicular PGE2 concentrations, follicle rupture, and luteinization in cattle have not been reported previously.
Previous reports in cattle also indirectly support a requirement for intrafollicular PG in mediating the ovulatory process. De Silva and Reeves (1985) examined the effect of intramuscular, intrauterine, and surgical (intraovarian) administration of indomethacin (an inhibitor of COX-1 and COX-2) on the incidence of ovulation in cattle. For the intraovarian group, treatments could not be administered directly into the antrum of the preovulatory follicle due to the surgical procedure used, but rather were administered into the ovarian stroma near the base of the preovulatory follicle. Intraovarian injection of indomethacin, but not systemic or intrauterine administration, inhibited ovulation in all six (100%) treated animals (as determined by morphological examination of ovaries at slaughter 3 to 12 d after indomethacin treatment). The effects of i.m. indomethacin administration on follicular fluid PG concentrations and ovulation rate in superovulated animals ovariectomized at 48, 56, 64, 72, and 80 h after PGF2 injection have also been examined previously. Only a small number of animals per timepoint was used in this study, and a significant effect of indomethacin administration on ovulation rate and follicular fluid PGE2 concentrations was not detected (Algire et al., 1992). The results of the present study conclusively demonstrate that ultrasound-mediated intrafollicular injection of NS-398 effectively inhibits intrafollicular PGE2 synthesis and subsequent follicle rupture in cattle.
The experimental approach used in our experiment to study of the role of intrafollicular PG in the ovulatory process in cattle has clear advantages over previous reports in the literature beyond purely efficacy. Use of frequent ultrasound scanning after treatment administration allowed for conclusive documentation of dominant ovulatory follicle (ovulation) disappearance and subsequent corpus luteum formation in vivo, and could even be used to determine effects of treatments on the length of the ovulatory process (time of ovulation after the LH surge). The current approach also allowed for more precise control over the dose of treatments that reached the ovulatory follicle than did systematic or intraovarian (stromal) administration. The volume of the follicle was calculated based on ultrasound measurements of follicle diameter and precise doses thereby delivered directly into the antrum of the preovulatory follicle to achieve the desired concentration of inhibitor (10 µm) at its site of action (granulosal cells). The currently utilized procedure did not require surgical manipulation for treatment administration and allowed for nonsurgical sample (follicular fluid) collection at precise time points after treatment administration.
The effects of NS-398 injection on follicular fluid PGE2 and the ovulatory process in cattle were most likely mediated by inhibition of COX-2. The COX-2 mRNA and protein are induced in the granulosal cells in response to the preovulatory LH surge in cattle (Sirois, 1994; Tsai et al., 1996; Liu et al., 1997) and presumably mediate the periovulatory rise in follicular fluid PGE2 observed in this and other studies (Algire et al., 1992; Sirois, 1994; Liu et al., 1997). The timing of the pronounced elevation of intrafollicular PGE2 observed in this study clearly follows the preovulatory rise in intrafollicular COX-2 reported for cattle (Sirois, 1994; Tsai et al., 1996; Liu et al., 1997). Although NS-398 is a selective COX-2 inhibitor, it also inhibits COX-1 when used at higher concentrations. The median inhibitory concentration of NS-398 for ovine COX-1 = 220 µM (Johnson et al., 1995). However, immunoreactive COX-1 levels are low or undetectable in bovine preovulatory follicles (Sirois, 1994). Furthermore, gene-targeting studies in mice do not support a requirement of COX-1 for successful follicle rupture (Langenbach et al., 1995).
Although progesterone receptor signaling pathways are also obligatory for follicle rupture (Lydon et al., 1995, 1996), effects of NS-398 administration on follicle rupture in cattle are clearly distinct and not mediated through direct regulation of intrafollicular progesterone production. In the present studies, intrafollicular NS-398 administration had no effect on follicular fluid progesterone concentrations in samples collected 24 h after GnRH injection. Furthermore, systemic indomethacin treatment in rats (Espey et al., 1989) and sheep (Murdoch and McCormick, 1991) does not decrease preovulatory follicular fluid progesterone concentrations nor does NS-398 treatment of rat follicles in vitro influence progesterone production (Mikuni et al., 1998).
Collectively, our results clearly indicate that NS-398 administration does not affect the luteinization process in cattle, but does lead to the development of luteinized, unruptured follicles. Ultrasonographic analysis of ovaries containing NS-398-treated follicles revealed the presence of structures with morphological characteristics consistent with luteinized, unruptured follicles. Serum progesterone levels indicative of a functional corpus luteum were also detected in NS-398-treated animals on d 7 after the expected time of ovulation. Previous studies in cattle also suggest that luteinization, but not ovulation occurs in bovine follicles subjected to intraovarian (surgical) injection of indomethacin. Follicles from cows in which ovulation had been blocked by indomethacin administration had a smooth and round appearance and visually appeared to be luteinized, but serum and follicular fluid progesterone concentrations in such animals were not reported (De Silva and Reeves, 1985). Intrafollicular injection of indomethacin into monkey preovulatory follicles also blocks follicle rupture without alteration of normal luteal function (Duffy and Stouffer, 2002). Furthermore, luteinized, unruptured follicles are induced in healthy women following indomethacin administration (Killick and Elstein, 1987), and follicle rupture is significantly delayed in women taking the selective COX-2 inhibitor, rofecoxib (Pall et al., 2001). Future studies will be required to delineate the key preovulatory changes in gene expression (MMP and PA) independent of the luteinization processes that are regulated by intrafollicular PG and obligatory for ovulation in cattle.
Footnotes
1 Supported by the Michigan Agric. Exp. Stn. and National Research Initiative Competitive Grants 98-35203-6226 and 03-35203-12841 from the USDA Cooperative State Research, Education, and Extension Service to G. W. Smith. 
2 Correspondence: 1230D Anthony Hall (phone: 517-432-5401; fax: 517-353-1699; e-mail: smithge7{at}msu.edu).
Received for publication December 31, 2003. Accepted for publication March 1, 2004.
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