Ovarian follicular dynamics after cauterization of the dominant follicle in anestrous ewes

Animal Reproduction Science 98 (2007) 225–232

Ovarian follicular dynamics after cauterization of the dominant follicle in anestrous ewes J.A. Martinez-Garcia a , M.T. Sanchez-Torres a,∗ , J.L. Cordero a , G.D. Mendoza a , C.M. Garcia-Bojalil a , M. Garcia-Winder b a

b

Programa de Ganader´ıa, IREGEP, Colegio de Postgraduados, Carretera M´exico-Texcoco, km. 36.5, Montecillo, Estado de M´exico, M´exico 56230, M´exico Inter-American Institute for Cooperation in Agriculture (IICA), Directorate for Agribusiness Development, 5757 Blue Lagoon Dr., Miami, FL 33126, USA Received 25 March 2002; received in revised form 1 December 2005; accepted 30 December 2005 Available online 18 April 2006

Abstract An experiment was conducted to ascertain if follicles could reach ovulatory size after the largest follicle (dominant) has been removed at different times during a progestin treatment in anestrous ewes, and secondly to determine if these new follicles could respond to an hCG-induced ovulation and have similar function as corpora lutea. Mature crossbred sheep (n = 44) in anestrous were treated with an intravaginal sponge containing 40 mg of FGA (day 0 = sponge insertion) for 9 days. Treatments consisted of cauterization of the largest follicle on the experimental day 3 (T1), day 6 (T2) and day 9 (T3); day 12 to ascertain the size of the largest follicle in control ewes. During laparotomies, the diameters of the largest follicle (DF), and those of the second and third largest follicles (SF1 and SF2, respectively) were determined. On day 12, a second laparotomy was performed for those ewes which had their DF cauterized on days 3, 6 and 9, a fourth group was left intact and only laparotomized on day 12. At this time, the size of the new DF, SF1 and SF2 were determined. Immediately after the laparotomy on day 12, all the ewes were treated with 1000 i.u. of hCG to induce ovulation. Blood samples were collected daily from day 0 to 50 and samples were analyzed for progesterone concentrations. The size of the DF at the time of sponge removal was smaller that those observed on day 3 or 6 of sponge suggesting that follicles in ewes treated with this progestin regress and a new wave of follicular development ensues between day 6 and the time of sponge removal. The size of the DF on day 12 was also smaller in ewes that have the largest follicle removed at the time of sponge removal reflecting that these follicles had a shorter period of growth; however, the rate of growth was greater for these follicles than for follicles arising after cauterization on day 3 or 6 after sponge insertion. There were no differences among treatments, in the number of ewes that formed a corpus luteum (CL) in response to hCG. Life span of the corpora lutea did not differ among ewes having their DF removed on day 6 or 9 or those that ∗

Corresponding author. Tel.: +52 595 95 202 00x1705. E-mail address: [email protected] (M.T. Sanchez-Torres).

0378-4320/$ – see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.anireprosci.2005.12.018

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served as controls, however, ewes that had their DF removed on day 3 developed longer lived CL in a larger proportion of animals. Average progesterone concentration during the life span of the induced corpora lutea was greater in control ewes than in any other experimental group. These observations allow us to conclude that, (a) the follicular dynamics observed in anestrous ewes treated with a progestin intravaginal sponge resembles that observed during the normal estrous cycle in the ewe; (b) the effects of progesterone on life span of the corpus luteum could not be only related to direct effects at the follicle but also involve changes in other components of the uterine–ovarian–hypothalamic axis; (c) the mechanisms controlling luteal life span seem to be different to those mechanisms controlling the function of the induced corpus luteum. © 2006 Elsevier B.V. All rights reserved. Keywords: Follicular dynamics; Corpus luteum; Ewes; Anestrous

1. Introduction During the last two decades, there has been abundant literature regarding the physiology and the dynamics of ovarian follicle growth in farm animals. Also there has been abundant literature and experimental repots that progestin treatment of anestrous females influences ovarian follicle development and the life span of the resulting corpus luteum (Garcia-Winder et al., 1987; Driancourt, 1991; Fortune, 1994; Bartlewski et al., 1998, 1999, 2000, 2001b; Niswender et al., 2000). When this information is analyzed together, it is possible to conclude that progestin treatments exert their effects by affecting gonadotropin release, follicle growth and response to gonadotropins, and the uterine environment, all of which are essential for the development of normal corpora lutea. There are however several questions that need to be ascertained, some of which have to do with issues such as length the follicle needs to be exposed to progesterone before ovulation to result in a normal corpus luteum. Another question is the rate a follicle can develop in the presence of a progestin sponge. A third question is whether follicles that had different growth rates before an induced ovulation can develop into corpora lutea of similar functionality. The present experiment was conducted as part of our efforts to understand the relationships that exist between the endocrine environment, the uterine milieu, and ovarian follicular growth to ensure successful reproduction in farm animals. Specifically, it was designed to ascertain if follicles could reach ovulatory size after the largest follicle has been removed at different times during a progestin treatment in anestrous ewes, and secondly to determine if these newly developed follicles could respond to an hCG-induced ovulation and function in a similar manner as corpora lutea. 2. Materials and methods 2.1. Animals and experimental procedures Mature anestrous crossbred ewes (n = 44; P ≤ 0.5 ng/ml, on two consecutive weekly blood samples) belonging to the experimental flock of the Colegio de Postgraduados, M´exico (Montecillo Estado de M´exico, M´exico), were treated with a vaginal sponge containing 40 mg of fluorogestrone acetate (FGA, Chrona-Gest, Intervet, M´exico) for 9 days (day 0 = day of insertion of the sponge). These ewes were randomly assigned to one of four experimental treatments, consisting on cauterization of the largest follicle (DF) visible at the surface of the ovary on day 3 (T1), day 6 (T2) of day 9 (T3) or to serve as non-cauterized control (T4). All animals received an i.m. injection of 1000 IU of hCG (Sigma Chemical, St. Louis MO, USA), on day 12 to induce ovu-

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lation. Cauterization of the largest follicle was performed via mid ventral laparotomy. A second laparotomy was conducted on day 12 for ewes in T1, T2 and T3; for ewes in T4 the laparotomy on day 12 was conducted to determine the size of the follicles under normal treatment conditions and no other manipulation to the ovaries was conducted. During the first laparotomy, the three largest follicles visible at the surface of the ovary were identified and measured, the second (SF1) and third (SF2) largest were marked using black and blue India ink, respectively, and the position was recorded in an ovarian map to allow for following the fate this follicle at the second laparotomy. All the procedures using in this experimental protocol have been previously reported (Coleman and Dailey, 1983; Villa-Godoy et al., 1985; White et al., 1987; Ko et al., 1991). For ewes assigned to T4, the size of DF, SF1 and SF2 were also recorded at laparotomy on day 12, this group was considered to serve as the control. Blood samples were collected daily from day 0 to 50. Samples were maintained at 5 ◦ C, and blood serum was separated by centrifugation at 1800 × g for 15 min within 1 h of collection. Serum samples were kept at −20 ◦ C until assayed for progesterone by radioimmunoassay (CoatA-Count, Diagnostic Product Corp., Los Angeles, CA, USA). Intra- and inter-assay coefficients of variation were 7.7 and 9.1%, respectively. Statistical analyses were conducted using ANOVA for a completely randomized design, using the GLM procedure of the SAS program (1988). Differences between treatments were analyzed using preplanned orthogonal contrast. 3. Results and discussion 3.1. Follicular dynamics As part of our general observations, the volume of each ovary at the time of the first laparotomy was estimated by multiplying the length × width × height from each ovary. As expected, the volume of the ovary that contained the largest follicle was greater than the volume of the other ovary, however, there were no differences associated with the day at which the measurements were taken. Also, as previously reported, the DF was present on the right ovary in a slightly greater percentage than on the left ovary (54.5% compared with 45.5%). Data for the size of the DF, SF1 and SF2 on days 3, 6 and 9 of the progestin treatment and on day 12 for the control group are included in Table 1. With regard to the size of the DF, the smaller diameter was observed at the time of sponge removal (day 9), this diameter was smaller than that observed on day 3 of treatment. To some extent this was a surprising observation because based on previous reports in cows (Ko et al., 1991; Cupp et al., 1992, 1993, 1995; Bergfeld et al., 1994; Fike Table 1 Size (mm) of the largest follicle (DF), second largest (SF1) and third largest (SF2) follicle present at the surface of the ovary on day 3 or 6 of progestin sponge treatment, at the time of sponge removal (day 9) or in those ewes that served as controls on day 12, just prior to hCG treatment Size (mm)

DF SF1 SF2

Treatments* 1

2

3

4

6.18 ± 0.84 5.41 ± 1.01 4.01 ± 0.66

5.95 ± 1.39 5.16 ± 1.48 3.40 ± 1.09

5.68 ± 1.01 4.95 ± 1.34 3.55 ± 1.01

6.81 ± 1.33 5.73 ± 1.76 3.61 ± 0.98

* Treatments 1, 2 and 3, cauterization of the DF on the experimental days 3, 6 and 9, respectively, and laparotomy in all treatments (T4) at 12 day.

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Table 2 Size (mm) of the largest follicle (DF), second largest (SF1) and third largest (SF2) follicle present at the surface of the ovary on day 12 just prior to hCG for ewes that had the largest follicle removed on day 3 or 6 of progestin implantation, at the time of sponge removal (day 9) or in ewes that served as controls Size (mm)

T1

DF SF1 SF2 OF Growth (mm) Growth rate (mm/day)

7.27 4.11 5.34 3.21 4.06 0.23

T2 ± ± ± ± ± ±

0.78a 0.69a 1.80a 1.78a 2.33a,b 0.09a

7.36 3.93 4.50 3.04 4.32 0.54

T3 ± ± ± ± ± ±

1.03a 1.19a 1.62a,b 1.31b 1.42a 0.23a

6.14 4.02 3.89 3.45 2.60 0.70

± ± ± ± ± ±

0.90b 0.73a 1.59b 1.03b 1.28b 0.40b

Lines with different superscript literal (a and b) are different (P > 0.05). DF: diameter of the dominant follicle on experimental day 12. OF: diameter of the follicle at cauterization that later occupied the site on the ovary of the dominant follicle on experimental day 12. Growth: original diameter minus diameter of the dominant follicle. Growth rate (mm/day) = growth of the dominant follicle, the cauterization to day 12 divided of days of the hCG application.

et al., 1997; Quintal-Franco et al., 1999; Kojima et al., 2003) the largest diameter of the DF was to be observed at the time of sponge removal and the smaller on day 3 of the progestin treatment. This observation suggests that in the present study, there is a regression and development of a new wave of follicular growth between day 6 and the time of sponge removal, similar to what happens during the normal estrous cycle around the time of luteolysis. If this assumption is correct, the differences in results between the present experiment and those with cows where it appears that the dominant follicle present at the time of insertion of the sponge is maintained throughout the duration of progestin implantation, may be related to the type of progestin used, dose, species, or more a complex combination of these factors. There were no differences in the sizes of SF1 and SF2 follicles on the surface of the ovary on days 3, 6 and 9 of progestin treatment (Table 1). It would have been interesting to make an endocrine characterization of these follicles to ascertain if there is a change in the physiological function of the subordinate follicles as the duration of progestin treatment progressed, particularly at the time of sponge removal where the dominant follicle appeared to be of smaller size than at other times. Data in Table 2 include the diameter of the DF, SF1 and SF2 on day 12 prior to hCG injection for ewes that had the previously largest follicle removed on days 3, 6 and 9 of the treatment with a progestin sponge and for the ewes that served as controls, with no previous laparotomy performed. Although the size of the DF on day 12 for the ewes that had the largest follicle removed on day 9, was smaller than the size of the DF for the rest of the ewes, the rate of growth (expressed as the number of mm increase is size per day for the follicle that became the DF after the removal of the largest follicle) from the day of removal to day 12 was the greatest for ewes laparotomized on day 9 (0.70 ± 0.40 mm/day compared with 0.23 ± 0.09 and 0.54 ± 0.23 the other treatments). These results, therefore, substantiate previous observations that indicate the most rapid growth rate of a follicle takes place after the decrease in circulating progesterone concentrations. Furthermore, when this observation is put in the context of the life span and progesterone production of the ensuing corpora lutea observed in the present experiment and discussed in a later section, it appears as thought the follicle acquires full capacity to become a normal corpus luteum in a very short period of time and that the beneficial effects of progestin on CL function are due to effects not only at the ovary but also at the uterus. With regard to the question of what follicle acquired dominance after the largest and presumably dominant follicle, had been removed the existing literature is rather consistent in suggesting that

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normally the second largest follicle present on the surface of the ovaries becomes the dominant follicle (Souza et al., 1996, 1997; Barrett et al., 2004; Duggavathi et al., 2005). In the present experiment, with exception of one of the experimental ewes in which the DF on day 12 came from the pool of follicles of less than 1 mm at the surface of the ovary in the rest of the ewes (23 out of 33) the DF on day 12 came from the second largest follicle (SF1) identified on the surface of the ovary at the time of laparotomy, and there were no differences due to the day of laparotomy. In general, it can be concluded that the follicular dynamics observed in anestrous ewes treated with a progestin sponge resembles what has been reported to be normal pattern during the estrous cycle. Additionally, the most rapid growth rate appears to take place after progestin withdrawal and the second largest follicle becomes the dominant follicle in the vast majority of the ewes, however, it still remains to be explained why some of these follicle failed to develop to become the DF with a smaller follicle establishing dominance. 3.2. Characteristics of the resulting corpora lutea Due to the stress inflicted by the performance of two laparotomies in such a short period of time, five ewes were removed from the experiment and not included in the characterization of the response to hCG. There were no differences among treatments, in the number of animals that responded to hCG with the formation of a corpus luteum (30/39). This response is consistent with the response observed in a wide variety of studies both in sheep (Lauderdale, 1986; Hunter, 1991; Baird, 1992; Bartlewski et al., 2000; Acosta and Miyamoto, 2004) and cows (Kesler et al., 1981; Garverick et al., 1992; Fortune et al., 2004). The average life span and the progesterone concentration during the life span of the induced CL in ewes that had the largest follicle cauterized on days 3, 6 or 9 of a progestin treatment or those that served as controls are depicted in Figs. 1 and 2. It was surprising to find that the ewes that formed a corpus luteum after they had the DF cauterized on day 3 of progestin treatment, had progesterone concentrations greater than 0.5 ng/ml for an average of 22.5 ± 3.2 days, resulting from seven ewes developing extended life corpora lutea, which persisted for more than 25 days. There is not an explanation for this observation. With regard to the rest of the treatments, there were no differences in life span of the induced corpora; this was expected for ewes that served as controls and to some extent for those in which the largest follicle was removed on day 6 of the

Fig. 1. Life span of the corpus luteum (days) formed after hCG in ewes that had the largest follicle removed on day 3 (T1), day 6 (T2) or at time of sponge removal (T3) and those ewes served as controls (T4).

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Fig. 2. Average progesterone production (ng/ml) by the corpus luteum formed in response to hCG in ewes that had the largest follicle cautherized on day 3 (T1) or day 6 (T2) of progestin implantation, at time of sponge removal (T3), or served as controls (T4).

progestin treatment, because the second dominant follicle had the opportunity to be exposed to at least 3–4 days of progesterone. However, the observation that corpora lutea of normal life span developed in ewes which had their largest follicle present at the time of sponge removal, raises questions as to what are the primary mechanisms for the positive effects of progestin treatments on life span of the corpus luteum and suggest that the effects of the progestin treatment does not exclusively occur at the single follicle, but rather the whole population of antral follicles in the ovary. Another possibility is that the primary effect of progestin treatments has to do with the endocrine changes that take place after the removal of the sponge and especially to the “synchronizing” effects of progesterone at the uterus (Deaver et al., 1986; Hawkins et al., 1993; Bartlewski et al., 1998, 2001a, 2004; Duggavathi et al., 2005). The average progesterone production during the life span of the induced corpora lutea did not differ between those ewes with the dominant follicle removed on day 3 or 6 of progestin treatment or on day 9 at the time of removal of the sponge (1.4 ± 0.2; 1.2 ± 0.2; 1.6 ± 0.3 ng/ml, respectively), however, the average progesterone concentrations were less than in those ewes that served as controls (2.1 ± 0.3 ng/ml). These observations indicate that extent of development of the follicle is important for progesterone production of the ensuing corpus luteum. This has been reported by Farin et al. (1986), O’Shea et al. (1986, 1989), Hunter (1991), Niswender et al. (1994, 2000), Niswender (2002) where it has been demonstrated that the amount of progesterone production in vitro is related to the number and health of the thecal and granulosal cells. However, the fact that in the present study there were not differences between the corpora lutea derived from follicles that had grown for only 3 days (cautherization on day 9) and those coming from follicles with longer periods of growth indicate that full stereoidogenic capacity is acquired by follicles in a short period of time, and probably within the period of time from progesterone demise to the time of ovulation. 4. Conclusions The results of this experiment taken in the context of other results published in the literature, allow us to conclude that: (a) The follicular dynamics observed in anestrous ewes treated with a progestin intravaginal sponge resembles those changes observed during the normal estrous cycle in ewes.

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