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BOR - Papers in Press, published online ahead of print October 1, 2003.
Biol Reprod 2003, 10.1095/biolreprod.103.018853
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BIOLOGY OF REPRODUCTION 70, 313–318 (2004)
DOI: 10.1095/biolreprod.103.018853
© 2004 by the Society for the Study of Reproduction, Inc.

Ovary

Differential Regulation of Apoptosis in the Corpus Luteum of Pregnancy and Newly Formed Corpus Luteum after Parturition in Rats1

Shuji Takiguchi3, Norihiro Sugino2,3, Kikue Esato3, Ayako Karube-Harada3, Aki Sakata3, Yasuhiko Nakamura3, Hitoshi Ishikawa4, and Hiroshi Kato3

Division of Obstetrics and Gynecology,3 Department of Reproductive, Pediatric, and Infectious Science, Yamaguchi University School of Medicine, Yamaguchi 755-8505, Japan Department of Public Health,4 Mie University School of Medicine, Mie 514-8507, Japan


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Apoptosis contributes to luteal regression in many species. In the postpartum rat, there are two different types of corpora lutea (CL) in the ovary: CL of pregnancy (CLP) and newly formed CL (NCL). To investigate the regulation of apoptosis in the two different types of CL during luteal regression, apoptosis and caspase-3 activity were examined in the CL obtained on Days 7, 15, and 21 of pregnancy and Days 0, 1, 3, 5, 7, and 9 postpartum. Furthermore, the effect of lactation on apoptosis in the CL was examined in two groups of postpartum rats: lactating rats that nurse more than 10 pups, and nonlactating rats that nurse no pups. Apoptotic cells were detected after Day 21 of pregnancy. In the CLP, remarkable increases in the number of apoptotic cells on Days 5 and 9 postpartum were observed in nonlactating rats (P < 0.01), but not in lactating rats. Changes in caspase-3 activity in the CLP were not consistent with those in number of apoptotic cells. In the NCL, an increase in apoptosis was found only on Day 5 postpartum in nonlactating rats (P < 0.01), but not in lactating rats. Changes in caspase-3 activity in the NCL were consistent with those in number of apoptotic cells. In conclusion, apoptosis is, at least in part, involved in luteal regression after parturition, and lactation appears to inhibit apoptosis. This study also suggests the presence of a caspase-3-independent mechanism for apoptosis in CLP regression in the rat.

apoptosis, corpus luteum, corpus luteum function, lactation, prolactin


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Ovulation occurs immediately after parturition in rats [1], and two different types of the corpus luteum (CL) are, therefore, present in the postpartum ovary: one is CL of pregnancy (CLP) and the other is newly formed CL after parturition (NCL). CLP generally undergoes regression. In contrast, the fate of the NCL is responsive to environmental cues such as lactation. Accumulating evidence has shown that apoptosis contributes to luteal regression and is controlled by a number of regulatory factors in many species, including Bcl-2 family members and caspases [2–14]. However, little is known about the regulation of apoptosis during luteal regression after parturition in the rat. After parturition, the CL exist within one of two different environments, lactation or nonlactation, and there is a possibility that apoptosis in the CL is regulated differently in these two situations. Serum prolactin (PRL) levels are elevated by pup suckling in lactating rats [15]. On the other hand, ovulation occurs every 4 days with preovulatory PRL surges in nonlactating rats. PRL can act luteotropically or luteolytically [16–18]. For example, PRL not only increases progesterone production by the CL of pregnancy [17], but also induces apoptosis in the CL of cycling rats [19, 20]. However, it is unclear how lactation influences luteal regression of the CLP and NCL after parturition. In the present study, we investigated the regulation of apoptosis in the different types of the CL after parturition. We further examined how the apoptosis in the postpartum CL is influenced by the different environments, lactation or nonlactation.


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

Sprague-Dawley rats (Japan SLC Inc., Hamamatsu, Japan) weighing 220–270 g were housed at 24°C under controlled conditions (lights on from 0500 to 1900 h) with free access to standard rat chow and water. Vaginal smears were obtained daily, and only rats showing at least two consecutive 4-day estrous cycles were used. Proestrous rats were housed with males overnight, and Day 1 of pregnancy was defined as the day on which sperm were found in the vaginal smear. The experiments were approved by the Committee for the Ethics on Animal Experiments in Yamaguchi University School of Medicine under the Law (No. 105) and Notification (No. 6) of the Government (Japan).

Experimental Procedures

Rats were killed between 1600 and 1900 h on Days 7, 15, and 21 of pregnancy and on Days 0, 1, 3, 5, 7, and 9 postpartum. Postpartum rats (n = 105) were divided into two groups: lactating rats that nurse more than 10 pups (n = 53), and nonlactating rats that nurse no pups (n = 52). Rats were laparotomized under light ether anesthesia, and blood samples were obtained from the portal vein. The ovaries were perfused with saline via the portal vein during draining of the inferior vena cava to remove the blood, as described previously [21–23], and removed. CL were dissected and cleaned of adhering tissue in a watch glass. In postpartum rats, two different types of CL, CLP and NCL, were easily recognized under stereoscopic microscope as shown in Figure 1. In short, CLP were larger than NCL. They appeared whitish and contained thin veins, whereas the NCL appeared red and had thicker veins. In nonlactating rats, NCL were formed every 4 days from cyclic ovulation, and there were two different generations of NCL in the ovary on Day 9 postpartum. In the present study, NCL formed by the first postpartum ovulation were investigated; the day of estrus was confirmed by the presence of NCL and oocyte-containing cumulus in the oviduct. We obtained approximately 10–15 CLP per rat in both lactating and nonlactating rats. In regard to the NCL formed by first postpartum ovulation, we also obtained the same number of NCL as the CLP in both lactating and nonlactating rats. Those different types of the CL were weighed, immediately frozen in liquid nitrogen, and stored at -80°C until caspase-3 activity assay. For the TUNEL method, ovaries were fixed in 4% paraformaldehyde in PBS buffer, pH 7.4, for 24 h and then embedded in paraffin. As shown in the figures, the number of animals between the investigating factors was different in each group; therefore not all of the rats showed all investigating factors.



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  		FIG. 1. Stereoscopic micrographs of the ovaries derived from postpartum rats. A) The ovary derived from the lactating rat on Day 7 postpartum. There are two different types of corpora lutea (CL): CL of pregnancy (CLP, asterisks) and newly formed CL after the first postpartum ovulation (NCL, arrowheads). B) shows the ovary derived from the nonlactating rat on Day 7 postpartum. There are three different types of CL: CLP (asterisks), NCL formed after the first postpartum ovulation (arrowheads), and NCL formed after the second postpartum ovulation (arrows). In this study, CLP and NCL after the first postpartum ovulation were examined. Magnification x12

TUNEL Method

As shown in Figure 2, apoptotic cells were detected by the TUNEL method with the In Situ Cell Death Detection Kit, POD (Roche Molecular Biochemicals, Mannheim, Germany), according to the manufacturer's instructions as described previously [24] with modifications. Briefly, paraffin-embedded ovaries were serially sectioned (4 µm-thick). The tissue sections were deparaffinized in xylene and dehydrated in a graded series of ethanol. Endogenous peroxidase was blocked by incubation with 2% H2O2 in methanol for 30 min. After being washed with PBS buffer, the tissue sections were incubated with two different proteases: proteinase K (5 mg/ml in 20 mM Tris HCl buffer, pH 7.4, for 20 min at 37°C; Roche) and protease XIV pronase E (0.1% w:v in 50 mM PBS buffer, pH 7.2, for 5 min at room temperature; Sigma Chemical Co., St. Louis, MO). Sections were washed again and treated with TUNEL reaction mixture containing terminal deoxynucleotidyl transferase and label solution for 60 min at 37°C. After being washed in PBS buffer, sections were incubated with the antifluorescein antibody conjugated with horseradish peroxidase. Negative controls were incubated with label solution lacking terminal deoxynucleotidyl transferase. Nuclei with DNA cleavage were visualized by incubation with 3,3'-diaminobenzidine tetrahydrochloride (Nacalai Tesque Co., Ltd., Tokyo, Japan), and sections were counterstained with methyl green.



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  		FIG. 2. Apoptotic cells in the CL in nonlactating rats on Day 5 postpartum. Apoptotic cells (arrowheads) were determined by TUNEL method. Magnification x400

Apoptotic cells were counted in three different sections in each CL, and in three different CL in each rat, independently by three observers. The number of apoptotic cells was expressed as the number of apoptotic cells per 1000 luteal cells. An observer-related mean was calculated for each slide, and the mean of the three observer-related means was used as a single observation.

Caspase-3 Activity Assay

Caspase-3 activity in the CL was measured using the CaspACE Assay System, Colorimetric (Promega Co., Madison, WI), according to the manufacturer's instructions. CL were homogenized in cell lysis buffer (included with the CaspACE Assay System, Colorimetric) and centrifuged at 15 000 x g for 20 min at 4°C, and the supernatant was used for the determination of caspase-3 activities. All data were expressed in picomole p-nitroaniline liberated per µg protein per hour. Protein concentrations were determined by the method described by Lowry et al. [25]. The sensitivity of the assay was 100 pg of purified caspase-3 enzyme, and the intra- and interassay coefficients of variation were 2.6% and 6.6%, respectively.

Statistical Analyses

Two-way ANOVA was conducted to examine the separate effects of lactating condition of mother (lactating or nonlactating) and postpartum day on each parameter. This was followed by Duncan's new multiple range test in case of the presence of significant difference. To test for trend of each parameter in pregnant and postpartum rats, linear trend analysis was conducted [26]. Correlation analysis was performed using Pearson correlation test. P < 0.05 were considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Weight of CL

In the CLP of postpartum rats, there was no significant effect of group factor (lactating rats, n = 53, vs. nonlactating rats, n = 52) for weight of CL (P = 0.30, by two-way ANOVA), as shown in Figure 3A; however, a significant effect of time factor (days after parturition) was observed (P < 0.0001, by two-way ANOVA). The weight of CLP significantly decreased in both lactating (test for trend, P < 0.0001) and nonlactating rats (test for trend, P < 0.0001) throughout the days following parturition.



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  		FIG. 3. Changes in weight of CL (A), number of apoptotic cells (B) and caspase-3 activity (C) in CLP during pregnancy and after parturition. CL were weighed on Days 7, 15, and 21 of pregnancy, the day of parturition, and Days 1, 3, 5, 7, and 9 postpartum. Apoptotic cells were detected by the TUNEL method. Each bar represents the mean ± SD (A) or the mean ± SEM for the number of animals given in parentheses (B and C). a, P < 0.01 vs. Day 5 postpartum in lactating rats; b, P < 0.01 vs. Day 9 postpartum in lactating rats.

In the NCL of postpartum rats, there was a significant effect of group factor (lactating rats, n = 54, vs. nonlactating rats, n = 41) for weight of CL (P < 0.0001, by two-way ANOVA), and a significant effect of time factor was also observed (P < 0.0001, by two-way ANOVA). The weight of NCL significantly increased in both lactating (test for trend, P < 0.0001) and nonlactating rats (test for trend, P < 0.0001) throughout the days following parturition. The weight of NCL in nonlactating rats were significantly lower than that in lactating rats on Day 7 (P < 0.01, by Duncan's new multiple range test) and Day 9 (P < 0.01, by Duncan's new multiple range test) postpartum, as shown in Figure 4A.



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  		FIG. 4. Changes in weight of CL (A), number of apoptotic cells (B), and caspase-3 activity (C) in NCL after parturition. CL were weighed on Days 1, 3, 5, 7, and 9 postpartum. Apoptotic cells were detected by the TUNEL method. Each bar represents the mean ± SD (A) or the mean ± SEM for the number of animals given in parentheses (B and C). a, P < 0.001 vs. Day 7 postpartum in lactating rats; b, P < 0.001 vs. Day 9 postpartum in lactating rats; c, P < 0.01 vs. Day 5 postpartum in lactating rats; d, P < 0.01 vs. Day 5 postpartum in lactating rats.

In the CL of pregnant rats (n = 43), the weight of CL significantly increased during pregnancy (test for trend, P < 0.0001).

Number of Apoptotic Cells

In the CLP of postpartum rats, there was a significant effect of group factor (lactating rats, n = 32, vs. nonlactating rats, n = 32) for number of apoptotic cells (P = 0.0006, by two-way ANOVA), and a significant effect of time factor was also observed (P < 0.0001, by two-way ANOVA). The number of apoptotic cells significantly increased in both lactating (test for trend, P = 0.048) and nonlactating rats (test for trend, P = 0.023) throughout the days following parturition. Of interest, nonlactating rats showed significant increases in number of apoptotic cells on Day 5 (P < 0.01, by Duncan's new multiple range test) and Day 9 (P < 0.01, by Duncan's new multiple range test) postpartum compared with lactating rats, as shown in Figure 3B.

In the NCL of postpartum rats, there was a significant effect of group factor (lactating, n = 31, vs. nonlactating rats, n = 32) for number of apoptotic cells (P = 0.0006, by two-way ANOVA). However, no significant effect of time factor was observed (P = 0.060, by two-way ANOVA). No significant trend in number of apoptotic cells was observed in lactating rats (test for trend, P = 0.13), but a significant increase in apoptosis in nonlactating rats (test for trend, P = 0.023) was observed throughout the days following parturition. The number of apoptotic cells in nonlactating rats were significantly lower than that in lactating rats on Day 5 postpartum (P < 0.01, by Duncan's new multiple range test), as shown in Figure 4B.

In the CL of pregnant rats (n = 19), apoptotic cells were not detected until Day 21 of pregnancy.

Caspase-3 Activity

In the CLP of postpartum rats, there was no significant effect of group factor (lactating rats, n = 29, vs. nonlactating rats, n = 27) for caspase-3 activity (P = 0.45, by two-way ANOVA), as shown in Figure 3C. A significant effect of time factor was observed (P < 0.0001, by two-way ANOVA). The caspase-3 activity significantly decreased in both lactating (test for trend, P = 0.0002) and nonlactating rats (test for trend, P = 0.0023) throughout the days following parturition. There were no significant correlations between number of apoptotic cells and caspase-3 activity in both CLP of lactating rats (r = -0.26, P = 0.09, by Pearson correlation test) and CLP of nonlactating rats (r = -0.33, P = 0.23, by Pearson correlation test).

In the NCL of postpartum rats, there was a significant effect of group factor (lactating rats, n = 25, vs. nonlactating rats, n = 22) for caspase-3 activity (P = 0.013, by two-way ANOVA), and a significant effect of time factor was also observed (P = 0.0002, by two-way ANOVA). Caspase-3 activity significantly increased in both lactating (test for trend, P = 0.0005) and nonlactating rats (test for trend, P = 0.001) throughout the days following parturition. Caspase-3 activity in lactating rats was constant after Day 3 postpartum, whereas that in nonlactating rats increased and was significantly higher than that in lactating rats on Day 5 postpartum (P < 0.01, by Duncan's new multiple range test), as shown in Figure 4C. Caspase-3 activity in NCL increased in parallel to the increases in number of apoptotic cells, and there was significant correlation between number of apoptotic cells and caspase-3 activity in both NCL of lactating rats (r = 0.50, P = 0.0036, by Pearson correlation test) and NCL of nonlactating rats (r = 0.75, P = 0.001, by Pearson correlation test).

In the CL of pregnant rats (n = 18), there was no significant trend in caspase-3 activity (test for trend, P = 0.066) during pregnancy.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this study, observation of apoptosis in the CL of both lactating and nonlactating rats and the gradual decrease in CL weight after parturition showed that apoptosis, at least in part, contributes to structural regression of CLP after parturation despite lactation. Regarding the steroidogenic capacity of the CLP after parturition, it is reported that progesterone production is low in the CLP after parturition [15]. In addition, absence of lactation seemed to facilitate luteal regression because the CL weight in nonlactating rats was lower than that in lactating rats after Day 7 postpartum. This could be the result of a burst in apoptosis observed on Days 5 and 9 postpartum in nonlactating rats. Recently, Gaytán et al. [19] reported that cellular atrophy is one of the mechanisms for CLP regression after parturition. In our unpublished data, the size of luteal cells in CLP gradually decreased after parturition. Therefore, cellular atrophy may be another factor involved in luteal regression of CLP after parturition.

In the present study, the change in number of apoptotic cells was not consistent with that in caspase-3 activity in the CLP during pregnancy and after parturition. In our unpublished data, there was also no relationship between poly ADP-ribose polymerase (PARP), Bcl-2, and Bax mRNA expression, and number of apoptotic cells in the CLP. In addition, although the caspase-3 activity of CLP in pregnant rats was the same level as that of NCL on Day 5 postpartum in nonlactating rats, there were no apoptotic cells in CLP on Days 7 and 15 of pregnancy, whereas a remarkable increase in apoptosis was observed in the NCL on Day 5 postpartum. These findings suggest the presence of a caspase-3-independent mechanism for apoptosis in structural luteal regression of the CLP after parturition. Recent studies have shown that some types of programmed cell death can take place in the absence of caspase activation. For example, endonuclease G [27–29], granzyme B [30, 31], Ras [32, 33], apoptosis-inducing factor [34, 35], survivin [36], and Bcl-x [37] have been suggested to be involved in caspase-independent programmed cell death. Recently, Abdo et al. [38] reported that in the rat CL, tumor necrosis factor-{alpha}-induced apoptosis could not be completely inhibited by either inhibitors of caspase-3, 6, and 8 or general inhibition of caspases, suggesting the presence of a caspase-3-independent mechanism for apoptosis in the rat CL.

The present study also suggests that luteal regression of the NCL in nonlactating rats is, at least in part, due to apoptosis because the NCL weight decreased with the increase in apoptosis after Day 5 postpartum in nonlactating rats. Also, steroidogenic capacity of the NCL in nonlactating rats is low because serum progesterone levels remained low after parturition in nonlactating rats in our unpublished data. On the other hand, the increase in apoptosis and the decrease in NCL weights were not seen in lactating rats. This finding shows that lactation prevents luteal regression in the NCL by inhibiting apoptosis and agrees with the recent study reported by Goyeneche et al. [39] in which the authors stated lactation works luteotropically by preventing apoptosis in the rat CL.

In the NCL, apoptosis is likely to be induced by a caspase-3-dependent pathway because the change in number of apoptotic cells is consistent with that in caspase-3 activity, and there was a significant correlation between them. Thus, apoptosis may be differently regulated during regression of different generations of CL, such as CLP and NCL in postpartum rats.

In nonlactating rats, remarkable increases in number of apoptotic cells were found in the CLP on Days 5 and 9 postpartum, but not in lactating rats. This finding suggests the possibility that a preovulatory PRL surge is involved in the increase in apoptosis, since the surge occurs neither in lactating rats nor on Day 7 postpartum in nonlactating rats. In fact, this phenomenon has been reported in cycling rats [19, 20, 40–42]. It is also reported that PRL activates caspase-3 to induce apoptosis [43, 44]. If PRL surge would induce apoptosis in the CLP and NCL, it is difficult to explain why the second PRL surge did not increase apoptosis in the NCL in nonlactating rats. The different response to PRL may be due to the difference in the nature of the CL in postpartum rats. Recently, Bowen et al. [45] reported that repeated exposure to PRL was required to induce luteal regression in gonadotropin-treated and hypophysectomized rats. In contrast, there are some reports showing that one proestrous PRL surge or single injection of PRL induces luteal regression in the cycling rat [16, 40]. These findings may suggest that the response to PRL is dependent on the nature of the CL.

Figure 5 shows our hypothesis on a differential regulation of apoptosis between CLP and NCL after parturition. In lactating rats, high and constant levels of PRL, maintained by suckling, suppress apoptosis in both CLP and NCL. Therefore, NCL in lactating rats develop as long as pups suckle. On the other hand, in nonlactating rats ovulation occurs every 4 days. In CLP, preovulatory PRL surges induce a burst in apoptosis through a caspase-3-independent pathway on every estrous day. In NCL, the first preovulatory PRL surge may induce apoptosis through a caspase-3-dependent pathway. To further elucidate the mechanism of apoptosis in structural luteal regression, especially that of caspase-independent apoptosis, detailed investigation of regulatory factors of apoptosis will be required.



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  		FIG. 5. Hypothesis on a differential regulation of apoptosis between different generations of the rat CL after parturition. In lactating rats, high and constant levels of prolactin (PRL) by suckling suppress apoptosis in both CL of pregnancy (CLP) and newly formed CL (NCL). Therefore, lactating rat CLP slowly undergo regression compared with nonlactating rats, and NCL develop as long as pups suckle. On the other hand, in nonlactating rats, ovulation occurs every 4 days. In CLP, preovulatory PRL surges induce a burst in apoptosis through a caspase-3-independent pathway on every estrous day, and the regression of CLP of nonlactating rats is more rapid than that of lactating rats. In NCL, only the first preovulatory PRL surge induces apoptosis through a caspase-3-dependent pathway.


   FOOTNOTES
 
1 Supported in part by Grant-in-Aid for Scientific Research 11671623 and 13671721 from the Ministry of Education, Science, and Culture, Japan. Back

2 Correspondence: Norihiro Sugino, Division of Obstetrics and Gynecology, Department of Reproductive, Pediatric, and Infectious Science, Yamaguchi University School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi 755-8505, Japan. FAX: 81 836 22 2287; obgyn{at}yamaguchi-u.ac.jp Back

Received: 1 May 2003.

First decision: 20 May 2003.

Accepted: 12 September 2003.


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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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