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BOR - Papers in Press, published online ahead of print February 19, 2003.
Biol Reprod 2003, 10.1095/biolreprod.102.013755
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BIOLOGY OF REPRODUCTION 69, 99–105 (2003)
DOI: 10.1095/biolreprod.102.013755
© 2003 by the Society for the Study of Reproduction, Inc.

Ovary

Differential Effects of RU486 and Indomethacin on Follicle Rupture During the Ovulatory Process in the Rat1

Francisco Gaytán2,3, Carmen Bellido3, María Gaytán3, Concepción Morales4, and José Eugenio Sánchez-Criado3

Department of Cell Biology, Physiology and Immunology3 Department of Pathology,4 School of Medicine, University of Cordoba, Spain


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Ovulation (i.e., the release of mature oocytes from the ovary) requires spatially targeted follicle rupture at the apex. Both progesterone and prostaglandins play key roles in the ovulatory process. We have studied follicle rupture and ovulation in adult cycling rats treated with a progesterone receptor antagonist (RU486), an inhibitor of prostaglandin synthesis (indomethacin, IM), or both. All rats were treated with LHRH antagonist on the morning (0900 h) of proestrus to inhibit endogenous gonadotropins and with 10 µg of ovine LH (oLH) at 1700 h in proestrus to induce ovulation. Animals were treated from metestrus to proestrus with 2 mg/day of RU486 or vehicle (olive oil) and on the morning of proestrus (1200 h) with 1 mg of IM or vehicle (olive oil). Some rats treated with vehicle or RU486 were killed on the morning of proestrus to assess preovulatory follicle development. The remaining rats were killed on the morning of estrus to study follicle rupture and ovulation. In vehicle-treated rats, oLH induced ovulation in 98% of follicles. In IM-treated rats, spatial targeting of follicle rupture was disrupted. Most oocytes were released to the ovarian interstitium (50%) or to the periovarian space (39%), and a smaller percentage (11%) of oocytes remained trapped inside the luteinized follicle. RU486-treated rats showed, on the morning of estrus, unruptured luteinized follicles. Only occasionally (2.8%), the oocytes were released to the periovarian space. IM treatment induced follicle rupture in RU486-treated rats, and 25% of oocytes were released to the ovarian interstitium. However, the number of oocytes released to the periovarian space (i.e., ovulated) was not increased by IM treatment in rats lacking progesterone actions. Overall, these data indicate that RU486 and IM have opposite effects on follicle rupture and suggest that both progesterone and prostaglandins are necessary for the spatial targeting of follicle rupture at the apex.

follicle, ovary, ovulation, progesterone, progesterone receptor


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Ovulation is a complex, multistep process that is triggered, in cycling rats, by the preovulatory LH surge on the evening of proestrus. LH surge induces the expression of multiple genes whose products are involved in the ovulatory process. Two essential LH-induced genes are those encoding progesterone receptor (PR) and prostaglandin synthase-2 (PGS-2) or cyclooxygenase-2 (COX-2) [1–3], and several lines of evidence indicate that both progesterone and prostaglandins are required for successful ovulation.

The LH surge stimulates progesterone secretion [4] and induces the transient expression of PR [1, 2] in granulosa cells of preovulatory follicles. Treatment with progesterone antiserum [5] or inhibitors of progesterone synthesis such as epostane [6] or trilostane [7] causes ovulatory inhibition that is overcome by concomitant progesterone administration. Treatment with progesterone receptor antagonists such as RU486 [8, 9], ZK299 [10], or ORG 31710 [11] also inhibits ovulation. Furthermore, PR knockout female mice lacking PR fail to ovulate and are completely infertile [12].

On the other hand, inhibitors of prostaglandin synthesis, such as indomethacin (IM) (reviewed in [13, 14]), NS-398 [15], or selective COX-2 inhibitors [16], have been repeatedly reported to inhibit ovulation. Mice carrying a null mutation for COX-2 [17] or prostaglandin E receptor (EP2) [18] genes also show defective ovulation. Furthermore, exogenous prostaglandin supplementation restores ovulation in both IM-treated rats [19, 20] and COX-2-deficient mice [17]. However, the mechanisms and the precise site of action of progesterone and prostaglandins in preovulatory follicles are not fully understood.

Ovulation is often referred to as follicle rupture. However, these terms are not equivalent and deserve precise definition. Follicle rupture consists of the breakdown of the theca layers at one or several sites, allowing the release of granulosa cells, the oocyte, and/or follicular fluid. Ovulation is the release of mature oocytes to the periovarian space and requires, therefore, spatially targeted follicle rupture. In physiological conditions, proteolytic degradation of the theca layers and extracellular matrix is limited to the zone of the follicle wall facing the ovarian surface [13, 14]. Nevertheless, the mechanisms determining the site of follicle rupture at the apex are not known. Recent studies [20, 21], using a morphological approach, have shown that ovulation but not follicle rupture is inhibited in IM-treated rats. In these animals, follicle rupture seems to occur at random, at any site of the follicle surface, and oocytes are consequently released to either the ovarian interstitium or the periovarian space. This indicates that the mechanisms underlying spatial targeting of follicle rupture are disrupted in IM-treated rats.

Detailed histological analysis allows evaluation of both follicle rupture and ovulation. We have studied, by a morphological approach, follicle rupture and ovulation in rats lacking progesterone and/or prostaglandins actions. For this, cycling rats were treated with a progesterone receptor antagonist (RU486) and/or an inhibitor of prostaglandin synthesis (indomethacin).


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

Female cycling Wistar rats (250 g body weight [BW] on average), purchased from Panlab (Barcelona, Spain), were used. Animals were maintained under standard light (14L:12D) and temperature (22°C) conditions and had free access to pelleted food and tap water. Vaginal smears were taken daily, and only animals displaying at least two consecutive 4-day estrous cycles were used. Experimental designs were established according to the Guide for the Care and Use of Laboratory Animals and were approved by the Ethical Committee of the University of Córdoba. The progesterone antagonist RU486 was obtained from Exlegin (Paris, France). Indomethacin (IM) was purchased from Sigma (St. Louis, MO), LHRH antagonist (ORG 30276, Organon, Oss, The Netherlands), and ovine LH (oLH) from the National Institutes of Health (Bethesda, MD).

Experimental Design

All animals were treated, on the morning of proestrus (0900 h), with an s.c. injection of 1 mg of LHRH-a to blunt endogenous LH secretion and on the evening (1700 h of proestrus) with an intrajugular injection of 40 µg of oLH to induce ovulation. This was performed to synchronize preovulatory gonadotropin surge, which has been reported to be altered in rats treated with PR antagonists [9, 22]. Rats were injected from metestrus to proestrus with an s.c. injection of 2 mg of RU486 or vehicle (olive oil) at 0900 h. This treatment schedule induced, in a pilot experiment, nearly complete ovulation inhibition, without altering the morphological features of preovulatory follicles (data not shown). At 1200 h in proestrus, rats were injected with either an s.c. injection of 1 mg of IM to inhibit prostaglandin synthesis, according to previous studies [20], or vehicle (olive oil). Some rats treated with RU486 or vehicle (five rats per group) were killed on the morning (0900 h) of proestrus to analyze the morphological features of preovulatory follicles. The remaining animals (n = 5 for vehicle- and IM-treated rats, n = 6 for RU486-treated rats, and n = 8 for RU486-plus-IM-treated rats) were killed on the morning (0900 h) of estrus for the evaluation of follicle rupture and ovulation.

Tissue Processing and Histological Analysis

The ovaries were fixed for 24 h in Bouin-Hollande fluid and routinely processed for paraffin embedding. Serial 6-µm-thick sections were cut and stained with hematoxylin and eosin. This stain allows the identification of the granulosa and theca layers. The location of the oocyte was recorded in each luteinized follicle (LF) or corpus luteum (CL). Newly formed CL were clearly distinguished from those of previous cycles by the presence of remnants of the follicular antrum and basophilic, non-fully luteinized granulosa cells in addition to the presence of regressive changes in CL of previous cycles. Oocytes were found in the oviducts or, occasionally, in the bursal cavity when released to the periovarian space (i.e., ovulated), in the ovarian stroma or inside blood or lymphatic vessels when released to the ovarian interstitium, or trapped inside the LF. The proportion of oocytes in each location was expressed with respect to the total number of CL or LF per rat.

Statistical Analysis

Statistical analysis was performed by ANOVA followed by the Student-Newman-Keuls method for multiple comparison among means. Significance was considered at the 0.05 level.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
On the morning of estrus, vehicle-treated rats showed newly formed CL and the oocytes surrounded by cumulus cells were found in the oviducts. In these animals (Fig. 1), all (or nearly all) preovulatory preovulatory follicles ovulated (98.3 ± 1.65%, mean ± SEM for n = 5). Rats treated with IM showed, on the morning of estrus, different types of CL, depending on the fate of the oocyte (Fig. 1). In 39% of the CL, rupture had occurred at the ovarian surface, and the oocytes were found in the oviducts or, occasionally, in the bursal cavity. However, in most cases (50%), follicle rupture had happened at the basolateral sides, and oocytes were found in the interstitium, in lacunae containing blood and follicular fluid, or inside blood or lymphatic vessels (Fig. 2A). The remaining oocytes (11%) were trapped inside the CL. The cumulus was dispersed, and the oocyte was in the metaphase II stage (Fig. 2C).



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  		FIG. 1. Percentage of oocytes released to the periovarian space (i.e., ovulated), trapped inside the corpus luteum, or released to the ovarian interstitium, in rats treated with RU486 (RU), indomethacin (IM), or both. Different superscripts mean significant (P < 0.05) differences; n = 5 for vehicle- and IM-treated rats, and n = 6 and 8 for RU- and RU-plus-IM-treated rats, respectively



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  		FIG. 2. Representative micrographs from the ovary of rats on the morning of estrus, treated with indomethacin (A and C) or RU486 (B and D). A) Interstitial oocytes surrounded by cumulus cells can be observed in the ovarian stroma near to a corpus luteum (CL) or inside blood vessels. B) Unruptured luteinized follicles (ULF) containing the oocyte (arrows). C and D) Details of the dispersed cumuli (arrows). Scale bars = 100 µm in A, C, and D; 500 µm in B

RU486-treated rats showed, on the morning of proestrus, before treatment with an ovulatory dose of oLH, preovulatory follicles displaying normal morphological features. The cumulus was compact, and the oocyte was in the germinal vesicle stage. On the morning of estrus, these animals showed unruptured LF, in which the oocyte was trapped (Figs. 1 and 2B). The cumulus was dispersed (Fig. 2D), and the oocyte was in the metaphase II stage. Only 2.8% of oocytes had been released to the periovarian space (Fig. 1). The total number of LF or CL per rat was equivalent in RU486 and vehicle-treated rats (13.8 ± 0.79 vs. 14.0 ± 0.58, mean ± SEM for n = 5 and 6, respectively), indicating that the development of preovulatory follicles was not affected in RU486-treated rats.

IM treatment induced abnormal follicle rupture in RU486-treated rats (Fig. 1). About 25% of the oocytes were released to the ovarian interstitium (Fig. 3, A and B). In some cases, the released oocyte was found under the ovarian surface in lacunae containing blood and follicular fluid, but the ovarian surface epithelium was apparently intact (Fig. 3B). Erosion of the blood vessel walls and formation of emboli of granulosa cells and follicular fluid, similar to that found in IM-treated rats, were also observed. About 73% of the oocytes remained trapped in the antrum, although some of these follicles showed rupture of the follicle wall with release of granulosa cells and follicular fluid to the ovarian interstitium (Fig. 3, C and D). However, IM treatment did not increase the number of oocytes released to the periovarian space (2.2% in average) in RU486-treated rats (Fig. 1).



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  		FIG. 3. Micrographs from the ovary of rats on the morning of estrus, treated with RU486 plus indomethacin. A and B) Ruptured luteinized follicles (RLF). Oocytes surrounded by cumulus cells (arrows in A and B) in the ovarian interstitium and absence of breakdown of the ovarian surface tissues (open arrows in B) can be observed. C and D) Nonconsecutive serial sections showing a luteinized follicle in which the oocyte was trapped (arrow in C) but showing a rupture site (open arrows in D) with release of cumulus cells. Scale bar = 125 µm


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The nature of the ovulatory process, involving the breakdown of the collagenous tissues of the theca layers, the tunica albuginea, and the ovarian surface epithelium, implicates proteolytic degradation of the extracellular matrix [23, 24]. The PA [25–27] and MMP [27–31] protease systems, as well as the PR-dependent proteases ADAMTS-1 and cathepsin-L [32, 33], have been proposed to play key roles in ovulation. The histological data of this study, based on the presence of follicle rupture, constitute an objective evidence of the existence in vivo of proteolytic activity high enough to cause the breakdown of the theca layers. The absence of follicle rupture in RU486-treated rats is consistent with previous studies suggesting a role for progesterone in the regulation of proteolytic activity [34, 35]. Although morphological alterations were not observed in the preovulatory follicles in RU486-treated rats on the morning of proestrus, its full competence to ovulate cannot be ascertained. However, the ovulatory inhibition reported after acute treatment with progesterone antiserum [5] or progesterone synthesis inhibitors [6, 7] suggests that ovulatory inhibition was due to the lack of progesterone actions rather than to defective preovulatory follicles. Furthermore, IM treatment induced follicle rupture in RU486-treated rats. This indicates that effective proteolytic activity (due to either basal levels of PR-dependent [32, 33] or non-PR-dependent [25–31] proteases) was present in the absence of PR activation.

The mechanisms underlying spatial targeting of follicle rupture at the apex were disrupted in IM-treated rats. In these animals, follicle rupture seems to occur at random at any site of the follicle surface [20, 21]. The probability of a follicle to undergo rupture at the ovarian surface should be dependent, at least in part, on the proportion of the follicle wall facing the ovarian surface that shows large interfollicle variation. This model predicts that a variable number of follicles would be ruptured at the ovarian surface, and therefore some oocytes would be released to the periovarian space. This contention was supported by the data of the present study and previous [20, 21] studies, in which up to 39% of oocytes were effectively ovulated. Previous studies have also reported that complete inhibition of ovulation cannot be achieved, even with the higher possible IM doses [13], and that a limited number of ovulations also occur in COX-2-deficient mice [36]. Surprisingly, IM treatment did not increase the number of oocytes released to the periovarian space in rats lacking progesterone actions, in spite of the induction of follicle rupture in more than 25% of follicles and the degradation of interstitial extracellular matrix and blood vessel walls by granulosa cells and follicular fluid that indicates effective proteolytic activity. This suggests that PR-mediated mechanisms play a key role in the breakdown of the ovarian surface tissues. Although mechanical factors likely play a role in stigma formation and final follicle rupture [37], previous proteolytic breakdown of the extracellular matrix seems to be necessary for the softening of the apical tissues. A role for the ovarian surface epithelium (OSE) in ovulation, involving PA secretion by OSE cells, has recently been demonstrated in the sheep [38]. Plasminogen activators increase preferentially within the apices of rat preovulatory follicles [39], and intrabursal administration of inhibitors of the PA-plasmin system decreases ovulation in rats [25]. This could be related to the results reported by Tsafriri et al. [40], indicating the presence of eggs released into the theca layer after intrabursal administration of antibodies against PA and {alpha}2-antiplasmin. Inhibition of the PA-plasmin system at the ovarian surface would prevent stigma formation and could cause "herniation" of the follicle at the basolateral sides. Furthermore, treatment with progesterone synthesis inhibitors [35] or PR antagonists [11] decreases PA activity in the rat ovary. However, whether progesterone mediates the secretion of proteolytic enzymes by OSE cells is, to our knowledge, unknown.

In summary, the differential effects of RU486 and indomethacin on follicle rupture support the hypothetical model that is presented in Figure 4. During follicle growth, continuous remodeling of the follicle basement membrane, as well as of the surrounding ovarian stroma, has to occur in order to allow follicle growth. This is likely due to the presence of proteolytic enzymes and its associated inhibitors that maintain basal proteolytic homeostasis just allowing controlled tissue remodeling [26–31]. This tissue remodeling process seems to be independent of both progesterone and prostaglandins, as indicated by the existence of follicle growth in rats treated with PR antagonists or in PR knockout female mice [12, 32, 33], as well as in rats treated chronically with IM (unpublished data). At the time of ovulation, PA and MMP protease systems are up-regulated by the preovulatory LH surge [25–31]. In addition, LH-induced secretion of follicular progesterone [4], together with the transient expression of PR in granulosa cells [1, 2], determines the expression of additional (PR-dependent) proteases [32, 33]. This is counteracted by COX-2-derived prostaglandins that modulate proteolytic activity by activation of protease inhibitors or by increasing the concentration of plasma-derived protease inhibitors [41] through changes in blood flow and vascular permeability. This would maintain proteolytic homeostasis, allowing degradation of the follicular basement membrane but not the breakdown of the theca layers throughout the follicle wall. At the apex, interactions between the preovulatory follicle and the ovarian surface tissues lead to local disruption of the proteolytic homeostasis that is tilted toward proteolytic activity. Progesterone seems to play a permissive role in ovarian surface events. Edematization [21] and breakdown of the ovarian surface tissues would create a vulnerable region for stigma formation. Thereafter, mechanical factors [37] would facilitate follicle rupture and oocyte release at the apex.



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  		FIG. 4. Hypothetical model on the role of progesterone (P) and prostaglandins (PGs) on the modulation of proteolytic activity during the ovulatory process. The LH preovulatory surge induces the transient expression of progesterone receptors (PR) and COX-2 in preovulatory follicles. P, through activation of PR, induces the expression of PR-dependent proteolytic enzymes. COX-2-derived PGs modulate proteolytic activity by the secretion/activation of proteolytic inhibitors or by increasing the concentrations of plasma-derived protease inhibitors through changes in blood flow and vascular permeability. This would maintain proteolytic homeostasis just preventing breakdown of the theca layers throughout the follicle wall. At the apex, interactions between the preovulatory follicle and the ovarian surface tissues cause a local disruption of the proteolytic homeostasis, leading to tissue breakdown, favoring stigma formation and follicle rupture, driven by follicle pressure. P seems to play some undefined role in apical changes. The effects of blocking prostaglandin synthesis with indomethacin (IM), progesterone receptor activation with RU486 (RU), or both and the most frequent locations of the oocytes (indicated as percentages) are depicted


   ACKNOWLEDGMENTS
 
The authors are very grateful to J. Molina, P. Cano, and E. Tarradas for their technical assistance.


   FOOTNOTES
 
1 This work has been subsidized by Grant BFI2002-00485 from the DGI, Spain. Back

2 Correspondence: F. Gaytán, Department of Cell Biology, Physiology and Immunology, School of Medicine, University of Cordoba, 14004-Cordoba, Spain. FAX: 57 34 218288; bc1galuf{at}uco.es Back

Received: 21 November 2002.

First decision: 11 December 2002.

Accepted: 6 February 2003.


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TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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F. Gaytan, M. Gaytan, J. M. Castellano, M. Romero, J. Roa, B. Aparicio, N. Garrido, J. E. Sanchez-Criado, R. P. Millar, A. Pellicer, et al.
KiSS-1 in the mammalian ovary: distribution of kisspeptin in human and marmoset and alterations in KiSS-1 mRNA levels in a rat model of ovulatory dysfunction
Am J Physiol Endocrinol Metab, March 1, 2009; 296(3): E520 - E531.
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 FASEB J.Home page
E. Gershon, A. Hourvitz, S. Reikhav, E. Maman, and N. Dekel
Low expression of COX-2, reduced cumulus expansion, and impaired ovulation in SULT1E1-deficient mice
FASEB J, June 1, 2007; 21(8): 1893 - 1901.
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 Hum Reprod UpdateHome page
D. L. Russell and R. L. Robker
Molecular mechanisms of ovulation: co-ordination through the cumulus complex
Hum. Reprod. Update, May 1, 2007; 13(3): 289 - 312.
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 ReproductionHome page
M Gaytan, C Bellido, C Morales, J E Sanchez-Criado, and F Gaytan
Effects of selective inhibition of cyclooxygenase and lipooxygenase pathways in follicle rupture and ovulation in the rat.
Reproduction, October 1, 2006; 132(4): 571 - 577.
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 J. Clin. Endocrinol. Metab.Home page
E. L. Escudero, P. J. Boerrigter, H. J. T. C. Bennink, R. Epifanio, J. A. Horcajadas, F. Olivennes, A. Pellicer, and C. Simon
Mifepristone Is an Effective Oral Alternative for the Prevention of Premature Luteinizing Hormone Surges and/or Premature Luteinization in Women Undergoing Controlled Ovarian Hyperstimulation for in Vitro Fertilization
J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2081 - 2088.
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 ReproductionHome page
M Gaytan, M A Sanchez, C Morales, C Bellido, Y Millan, J Martin de las Mulas, J E Sanchez-Criado, and F Gaytan
Cyclic changes of the ovarian surface epithelium in the rat
Reproduction, March 1, 2005; 129(3): 311 - 321.
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