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Ovary |
a Institute of Medicine and Experimental Biology of Cuyo, LARLAC-CONICET, 5500 Mendoza, Argentina
b Department of Physiology and Biophysics, University of Illinois, Chicago, Illinois 60612
c Department of Morphophysiology, Faculty of Medicine, University of Cuyo, 5500 Mendoza, Argentina
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. In the present study, we evaluated whether progesterone is also capable of interfering with the process of structural luteal regression, which is characterized by a decrease in weight and size of the gland because of programmed cell death (i.e., apoptosis). We have found that a low number of luteal cells undergo apoptosis throughout gestation. On the day of parturition, but following the initial decline in endogenous progesterone production, a small increase in the number of luteal cells undergoing cell death was observed. This increase in apoptotic cells continued postpartum, reaching dramatic levels by Day 4 postpartum, and was accompanied by a marked decrease in average luteal weight. We have established that the exogenous administration of progesterone significantly reduces the decline in luteal weight observed during structural luteal regression postpartum. This effect was associated with a decrease in the number of cells undergoing apoptosis and with enhanced circulating levels of androstenedione. Furthermore, in vivo administration of progesterone delayed the occurrence of DNA fragmentation in postpartum CL incubated in serum-free conditions. Finally, we have shown that neither the CL of gestation nor the newly formed CL after postpartum ovulation express the classic progesterone-receptor mRNA. In summary, the present results support a protective action of progesterone on the function and survival of the CL through inhibition of apoptosis and stimulation of androstenedione production. Furthermore, this effect is carried out in the absence of classic progesterone receptors.
apoptosis, corpus luteum, corpus luteum function, progesterone
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-hydroxysteroid dehydrogenase, an enzyme involved in progesterone catabolism whose expression is a hallmark of ongoing functional luteal regression [3]; 5) in CL incubated in vitro as well as in a luteal cell line, progesterone also inhibited the expression of 20-hydroxysteroid dehydrogenase mRNA [5]; and 6) progesterone locally administered into the ovary during functional luteal regression prevented the decrease in luteal activity of 3ß-hydroxysteroid dehydrogenase, an enzyme involved in progesterone biosynthesis [3]. Taken together, these previous findings support a role for progesterone in the inhibition of functional luteal regression. However, it is not clear whether progesterone is also capable of regulating the second facet of luteal regression, structural regression, which is characterized by a decrease in the weight and size of the CL [6, 7]. In the ovary, apoptosis, or programmed cell death, has been extensively associated with follicular atresia. The initiation of apoptosis in granulosa cells is one of the earliest signs of follicular demise [8], occurs rapidly and in a very synchronized fashion, and has been documented by both morphological [9] and biochemical criteria [10, 11]. In rodents, in contrast to the ovarian follicle and the transient CL of the estrual cycle, the process of cell death in the long-lived CL of pregnancy has received little attention. In the CL of the estrual cycle in hamsters, extensive apoptosis was observed concomitant with the dramatic drop in luteal progesterone production during luteal regression [12]. In that species, the CL of the estrual cycle lasts only one cycle and virtually disappears afterward [12]. The short-lived CL of the estrual cycle in rats also undergoes structural regression through a process of programmed cell death, apparently induced by prolactin [13–15]. As opposed to the hamster, however, consecutive estrual cycles are needed to complete the process of structural luteal regression in the rat [16]. In keeping with this, repeated exposure to prolactin was needed to induce luteal regression in hypophysectomized rats, suggesting that continued exposure to prolactin, over several cycles, is necessary to induce full luteal regression [17].
Less information is available for rats regarding apoptosis in the long-lasting CL of pregnancy. We recently reported that a significant number of luteal cells undergoing apoptosis can be observed during luteal regression induced by the antigestagen RU486 or by the luteolysin prostaglandin F2 at the end of pregnancy [6]. However, whether apoptotic cell death also occurs during normal luteal function in pregnancy is unknown. In the present study, therefore, we quantified the number of cells undergoing apoptosis within the CL throughout pregnancy and after parturition, during structural regression. We also studied whether progesterone is capable of preventing the apoptotic changes associated with structural luteal regression in the postpartum ovary, which is composed of two generations of CL: the CL of pregnancy and the new CL formed after postpartum ovulation [7]. To evaluate further the effect of progesterone as a survival factor in the rat CL, we also used a previously established approach in which CL incubated in serum-free conditions accumulates a large number of cells at different stages of apoptosis and undergoes extensive DNA fragmentation [18].
Expression of a classical progesterone receptor (PR) has been reported in the CL of several mammalian species, including cows [19], sheep [20], nonhuman primates [21, 22], and humans [23]. Conversely, in the rat, expression of PR mRNA and protein has been demonstrated within the granulosa cell layer of preovulatory follicles in the estrual cycle [24], but no expression whatsoever has been found in the CL during the estrual cycle or throughout pregnancy [25]. There is no information, however, regarding whether the PR gene is expressed in CL undergoing structural regression postpartum. Therefore, in addition to the previously described studies, the expression of luteal PR was assessed after parturition, when structural luteal regression and apoptosis take place.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Adult female rats bred in our laboratory (originally Wistar strain) and weighing 180–220 g were used. The rats were housed under controlled light (lights-on from 0600 to 2000 h) and temperature (22–24°C) conditions and had free access to standard rat chow (Cargill, Mendoza, Argentina) and tap water. To induce pregnancy, female rats were caged individually with fertile males on the afternoon of proestrus. Positive mating was verified on the following morning by identifying sperm or copulation plugs in the vagina. This day was designated as Day 0 of pregnancy. In our laboratory, rats usually give birth on Day 22. Animals were handled according to the procedures approved in the Guide for the Care and Use of Laboratory Animals [26].
Experimental Procedure
In the first experiment, six rats per group were sacrificed at 1300 h on Days 5, 7, 12, 15, 21, and 22 of pregnancy and on Day 4 postpartum. The CL from three animals were isolated from the ovaries under a stereoscopic microscope, weighed, frozen in liquid nitrogen, and stored at -80°C until processed for RNA isolation. In the remaining three animals of each group, the ovaries were removed and fixed for 1 h at room temperature in a solution of 10% (v/v) phosphate-buffered neutral formalin, dehydrated in ethanol series, cleared in xylene, and embedded in paraffin for routine hematoxylin and eosin (H&E) staining.
In the second experiment, three rats per group were sacrificed on Days 1, 2, 3, and 4 after parturition, and the ovaries were obtained and processed for routine optic microscopy. The CL from the previous pregnancy and the newly formed CL after postpartum ovulation were separately studied for in situ detection of apoptosis in paraffin sections by H&E staining and by in situ 3' end-labeling (i.e., TUNEL).
To determine the effect of progesterone on luteal apoptosis, a third experiment was conducted using two groups of postpartum rats, each composed of six to eight animals. The pups were removed immediately after delivery to avoid the establishment of lactation. The rats were injected with either progesterone (8 mg/rat s.c.) or vehicle (sunflower seed oil) at 1000 h on Days 1, 2, 3, and 4 postpartum. Animals were killed by decapitation at 1300 h on Day 4 postpartum. Trunk blood was obtained to determine hormone concentrations. The ovaries were removed and fixed for 1 h at room temperature in a solution of 10% phosphate-buffered neutral formalin, dehydrated in ethanol series, cleared in xylene, and embedded in paraffin for H&E staining. In two other groups of animals similarly treated (six to eight rats per group), the CL were isolated under a stereoscopic microscope, classified as old (CL of the previous pregnancy) or new (newly formed CL after postpartum ovulation), weighed, and used for in vitro incubation.
Optic Microscopy and Counting of Apoptotic Cells
Serial paraffin sections (thickness, 5 µm) were mounted on 3-aminopropyltriethoxy-silane (Sigma Chemical Co., St. Louis, MO)-coated slides and used for routine H&E staining. The tissue samples were observed and photographed with a Zeiss IM 35 microscope (Carl Zeiss; Oberkochen, Germany). Apoptotic cells were recognized in H&E-stained tissue sections on the basis of morphological criteria following the procedure described by Van der Schepop et al. [27] with slight modifications. Only cells with advanced signs of apoptosis (i.e., containing multiple nuclear fragments) were counted. A microscope with a 100x objective was used, and as many fields as possible were analyzed in each CL for the presence of fragmented nuclei. All the CL in each section were studied, and an average number of apoptotic nuclei per high-power field was obtained. The expression of apoptosis per unit area rather than on a per CL basis more accurately reflects the dynamic of the apoptotic process within each CL, in a size-independent manner at any given time during pregnancy and after parturition.
Nuclei exhibiting DNA fragmentation were also confirmed by using the DeathEnd Colorimetric Apoptosis System (Promega, Madison, WI), which end-labels the fragmented DNA of apoptotic cells using a modified TUNEL assay in paraffin-embedded sections as previously described [6].
Incubation of CL
The CL (four to six per milliliter per well in a 24-well tissue-culture plate) were incubated in serum-free medium (McCoy 5A:Ham F12, 1:1, v/v; Sigma) containing 25 mM Hepes, 200 IU/ml of penicillin G, 200 µg/ml of streptomycin, and 0.5 µg/ml of amphotericin B at 37°C for various periods of time in an atmosphere of 95% air/5% CO2. After incubation, the CL were immediately frozen in liquid nitrogen and stored at -80°C until genomic DNA isolation.
DNA Fragmentation
The internucleosomal cleavage of DNA was analyzed as follows: The CL were homogenized in digestion buffer composed of 100 mM NaCl, 10 mM Tris-Cl (pH 8.0), 25 mM EDTA (pH 8.0), 0.5% SDS, and 0.1 mg/ml of proteinase K (Life Technologies, Rockville, MD) and incubated overnight at 50°C. The DNA was extracted from the digested tissues with phenol:chloroform:isoamyl alcohol (25:24:1, v/v/v). The DNA was precipitated and digested for 1 h at 37°C in 1 µg/ml of ribonuclease (deoxyribonuclease-free; Roche, Indianapolis, IN). After extraction and precipitation, an equal amount of DNA for each sample (5 µg) was separated by electrophoresis on a 1.8% agarose gel (FMC Corp., BioProducts, Rockland, ME) impregnated with ethidium bromide, examined using a ultraviolet transilluminator (UVP, Upland, CA), and photographed with a photodocumentation camera (Fisher Scientific, Pittsburgh, PA). The NIH Image software was used to semiquantitate the fragmented DNA. The densitometry of the DNA fragments that appeared below 1500 base pairs (bp) was recorded. This measurement was normalized against the density of the total genomic DNA of the sample (to correct for DNA loading). In addition, the densitometric values were expressed relative to fragmentation at time zero of incubation to allow comparisons between different gels.
Hormone Assays
Serum prolactin was determined by double-antibody RIA with reagents provided by the National Institute of Diabetes, Digestive, and Kidney Diseases (Bethesda, MD). Results are expressed in terms of the rat prolactin RP-3 standard. The sensitivity of the assay was 0.5 ng/tube. Inter- and intraassay coefficients of variation were less than 10%.
Progesterone concentrations were measured using a commercially obtained kit (Diagnostic Products Corporation, Los Angeles, CA). The sensitivity of the assay was 0.02 ng/ml, and the inter- and intraassay coefficients of variation were 5% and 6%, respectively.
Androstenedione was assayed using an RIA developed in our laboratory with an antiserum raised against 4-androsten-3,17-dione 3-CMO:BSA (Steraloids, Wilton, NH). The sensitivity, variability, and cross-reactivity of this assay have been reported previously [7].
RNA Isolation and Reverse Transcription-Polymerase Chain Reaction
Total RNA from CL was purified using TRIzol (Life Technologies) according to the manufacturer's instructions. One microgram of total RNA was reverse transcribed using the Advantage RT for PCR kit (Clontech Laboratories, Inc., Palo Alto, CA). For amplification of the reverse transcription (RT) products, the reaction mixture consisted of 1x polymerase chain reaction (PCR) buffer (ExTaq buffer; Panvera, Madison, WI), 150 µM deoxynucleoside triphosphates, 50 pmol of specific oligonucleotide primers, and 0.8 U of ExTaq (Panvera) in a final volume of 40 µl. The samples were overlaid with light mineral oil, and PCR was carried out in a PTC-1000 thermal cycler (MJ Research, Waltham, MA). Oligonucleotide primer pairs were based on the sequence of the rat PR (5'-CCACAGGAGTTTGTCAAGCTC-3' and 5'-TAACTTCAGACATCATTTCCGG-3') gene as previously described [28]. Primers for L19 (5'-CTGAAGGTCAAAGGGAATGTG-3' and 5'-GGACAGAGTCTTGATATCTC-3') ribosomal protein mRNA were included to normalize the data [29]. The predicted sizes of the PCR-amplified products were 325 and 120 bp for PR and L19, respectively. Reaction products were electrophoresed on 1.8% agarose gel, visualized with ethidium bromide, and examined by ultraviolet transilluminator.
Statistical Analysis
Comparison between means of two groups was carried out using Student t-test. For multiple comparison, one-way analysis of variance was followed by either the Tukey or Dunnett multiple-comparison test. A difference was considered to be statistically significant at P < 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In the first experiment, we studied developmental changes in the number of cells undergoing apoptosis within the CL at various stages throughout gestation and after parturition. The number of luteal cells undergoing cell death declined from Days 5 to 7 of pregnancy, became very low at midpregnancy, and increased slowly but significantly at the end of gestation (Day 22) when compared with the values on Days 12, 15, and 21. A further and robust increase in the number of apoptotic cells was observed by Day 4 postpartum compared with either the day before parturition or the day of parturition (Fig. 1).
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The change in the average weight of the CL throughout gestation and after parturition (Fig. 1) reveals an inverse relationship with the number of apoptotic cells. During the first week of gestation, the CL increase slowly in weight while the number of apoptotic cells declines. From mid to late pregnancy, when the CL reach maximal weight, very few apoptotic cells were observed. On the day of parturition, a small increase in the number of cells undergoing apoptosis correlated with the beginning of the decline in luteal weight. By Day 4 postpartum, a large decline in average CL weight occurred together with a large increase in the number of luteal cells undergoing apoptosis as compared with preparturition CL.
When apoptosis was studied in detail in CL of postpartum ovaries, two generations of CL were observed: the CL of the previous pregnancy and the newly formed CL derived from the postpartum ovulation [30]. We were able to differentiate in situ both generations of CL and to study them separately to score apoptosis. Evaluated under a stereoscopic microscope, the old CL of the previous gestation were larger and less vascularized than the newly formed CL. Under the light microscope, the old CL of pregnancy presented well-organized cell distribution and closed capillaries (Fig. 2, A and C). Conversely, the newly formed CL displayed a less organized cell distribution with open capillaries (Fig. 2, A and B). Both subtypes of CL stained positive for in situ apoptosis evaluated by TUNEL (Fig. 2, D and E). An atretic follicle containing an abundant number of granulosa cells undergoing cell death was used as a positive control for in situ apoptosis evidenced by TUNEL (Fig. 2F).
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We separately quantified the number of apoptotic cells located within the old CL of gestation and the newly formed CL after postpartum ovulation. On Day 1 postpartum, only the old CL of pregnancy could be studied, because the newly formed CL was not clearly visible until 48 h after parturition. We observed that within a period of 3 days, both subtypes of CL contained a similar number of cells undergoing apoptosis per unit area, with a gradual increase from Days 2 to 4 postpartum (Fig. 3).
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Interference of Structural Luteal Regression by Progesterone
To study the effect of progesterone on structural luteal regression, we injected nonlactating rats with progesterone for 4 days after parturition and then killed them on Day 4 postpartum. The pups were removed immediately after delivery to avoid the establishment of lactation and the consequent secretion of prolactin and stimulation of the CL by this tropic hormone. Luteal regression was evaluated separately in the two generations of CL by studying in situ the number of nuclei undergoing apoptosis and by recording the average luteal weight for each type of CL. As expected, animals that were treated with progesterone displayed very high circulating levels of the steroid (Fig. 4A). The dose of progesterone injected in the peripheral circulation elevates the level of circulating progesterone but does not elevate the level of progesterone in the CL to higher than normal in pregnant rats, which is approximately 80 ng/mg protein [31]. Prolactin, one of the main hormones involved in CL function in rats, did not change with treatment, displaying very low circulating levels in both vehicle- and progesterone-treated animals (Fig. 4B). The concentration of the main circulating androgen in pregnant rats, androstenedione [32], was augmented after progesterone treatment (P < 0.01) (Fig. 4C). The number of apoptotic nuclei within both generations of CL was significantly reduced by treatment with progesterone (Fig. 5, A and B). In addition, the decrease in average weight of the CL observed in control animals by Day 4 postpartum was prevented by treatment with progesterone in both generations of CL (Fig. 5, C and D).
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To further study the effect of progesterone on cell survival in the rat CL, we used a previously established in vitro approach [33]. Old CL obtained from nonlactating rats on Day 4 postpartum and incubated in serum-free conditions displayed extensive DNA fragmentation in a time-dependent manner (Fig. 6, A and C). However, in nonlactating rats that had received a daily dose of progesterone from Days 1 to 4 postpartum, the in vitro-induced luteal DNA fragmentation was markedly delayed (Fig. 6, B and C).
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Absence of PR mRNA in CL Postpartum
In the present study, we did not detect the classic PR mRNA on Day 4 postpartum in either the old CL of pregnancy or the newly formed CL after postpartum ovulation (Fig. 7). Decidua obtained from rats killed on Day 9 of pseudopregnancy was used as positive PR mRNA-expressing tissue. The CL obtained from rats on various days of pregnancy were used as a negative control for PR mRNA, although only results from Day 15 CL are shown.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-hydroxysteroid dehydrogenase on Day 21 of gestation, 1 day before parturition, allows the conversion of progesterone into 20-didydroprogesterone, a metabolite devoid of progestational activity [5, 34]. Therefore, even though the CL is still steroidogenic at the time of parturition, the final product is not longer progesterone. After progesterone drops in circulation, indicating the occurrence of functional luteal regression, several days are needed to reduce the size of the long-lasting CL of pregnancy (see Fig. 1). Thus, the removal of cells by apoptosis in this endocrine gland does not appear to be as synchronized and fast as in ovarian follicles undergoing atresia. Whereas Guo et al. [35] demonstrated multiple apoptotic cells in CL evaluated by in situ end-labeling of the fragmented DNA (TUNEL) on Day 3 postpartum, they did not specify on which type of CL the study was performed. In the present study, the detailed and quantitative examination of apoptosis in both CL populations found after parturition revealed that both the old CL of pregnancy and the newly formed CL after postpartum ovulation undergo extensive apoptosis by Days 3–4 postpartum. Most interestingly, both types of CL reached similar levels of apoptosis per unit area within the same period of time. This occurred despite the fact that before the animals were killed, the old CL of pregnancy underwent a very long period of growth and differentiation compared with that of the new CL formed after postpartum ovulation (see Fig. 3). This result led us to speculate that the hormonal environment, which is similar for both CL types, is responsible for the fate of the CL in an age-independent manner. Supporting this hypothesis is the fact that progesterone administered to nonlactating mothers after parturition interfered with apoptosis and with the decline in luteal weight in both CL types evaluated on Day 4 postpartum.
The low apoptotic rate in the CL during gestation correlates with elevated circulating concentrations of progesterone, which has been proposed as a luteal survival factor. In a previous study [6], we found that reduction of progesterone production through the administration of exogenous agents, such as RU486 or prostaglandin F2, significantly increased luteal apoptosis, supporting the idea that progesterone has a protective role in the function and survival of the CL. Progesterone has also been shown to be a survival factor for luteal cells obtained from rats at proestrus and induced to undergo apoptosis by treatment with prolactin [36]. In agreement with this luteal survival effect of progesterone, the inhibition of progesterone biosynthesis in bovine luteal cells with aminoglutethimide increased apoptosis, whereas supplementation with progesterone prevented this effect [19]. In luteinized rat granulosa cells, which express the classic PR in response to in vivo exposure to hCG, the PR-antagonist Org 31710 was capable of inhibiting the survival effect elicited by hCG [37], suggesting that progesterone is involved in regulating the susceptibility to apoptosis. In the present study, we have shown that administration of progesterone to rats after parturition significantly interfered with the process of luteal cell removal. This was demonstrated by the finding that progesterone prevented both luteal weight loss and the increase in number of apoptotic cells in regressing CL after parturition and by the delayed capacity to undergo DNA fragmentation in vitro displayed by the CL obtained from progesterone-treated animals. Taken together, these results support the hypothesis that progesterone is a major survival factor for the rat CL, regardless of the age of the gland.
Progesterone has been reported to be a survival factor in the rat ([36]; present study) and bovine [19] CL as well as in luteinized rat and human granulosa cells [37, 38]. This action of progesterone was generally reported to be mediated through the classic PR [37–39]. However, the antiapoptotic effect of progesterone could also be mediated through alternative mechanisms. For example, in immature rat granulosa cells obtained from animals that were not exposed in vivo to hCG and, therefore, that do not express the classic PR, the antiapoptotic effect of progesterone appeared to be mediated through membrane-associated progesterone-binding sites located on the granulosa cells, which in turn produce basic fibroblast growth factor to maintain granulosa cell viability [40]. Because neither during pregnancy nor after parturition does the rat CL express classic nuclear PR ([3, 25]; present study), the possibility of progesterone mediating its survival effect in the rat CL through a similar membrane-mediated mechanism needs to be tested. On the other hand, because of the high concentrations of progesterone found within the luteal cells, the possibility of progesterone impacting the glucocorticoid receptors to elicit antiapoptotic actions also cannot be ruled out. The rat CL of pregnancy expresses high levels of mRNA encoding the glucocorticoid receptor [5]. In addition, in the absence of PR, progesterone can inhibit 20-hydroxysteroid dehydrogenase mRNA expression in rat luteal cells through the glucocorticoid receptor [5]. Thus, the final effectors of progesterone's survival actions are yet to be determined.
In a recent report, we have shown that the major circulating androgen in pregnant rats, androstenedione [32], is a potent antiapoptotic factor in the CL [7]. We have also demonstrated that treatment with progesterone increases serum levels of androstenedione (see Fig. 4), suggesting that this androgen could indirectly mediate progesterone survival actions. It is tempting to speculate that progesterone may be a substrate for P450c17, a cytochrome P450 enzyme that catalyzes two sequential steroidogenic steps, 17-hydroxylase activity and 17,20-lyase activity, thus converting C21 progesterones to C19 androgens. In the rat, androgens are synthesized via the 
4 pathway from progesterone [34]. P450c17 is expressed in the rat CL during the first half of gestation [34]. At midpregnancy, however, luteal androgen production declines, concomitant with a substantial decline in P450c17 mRNA levels, and the placenta becomes the primary source of androgens [34]. Nevertheless, the CL remains capable of secreting androgens when stimulated with LH [41]. Because we injected progesterone to postpartum mothers, the source of androstenedione cannot be the placenta; however, it could be either of the two CL populations that are present postpartum—or even the adrenal glands.
Recent observations have revealed the involvement of the Fas and Fas ligand system in prolactin-induced apoptosis of luteal cells obtained from cycling rats on the day of proestrus [42]. In such a system, progesterone attenuated the prolactin-induced luteal cell death by down-regulating Fas expression [36]. However, because in the estrual cycle prolactin is a "death factor" rather than a "survival factor," as it is in pregnancy, the involvement of the Fas/Fas ligand system in the antiapoptotic effect of progesterone should be studied in the pregnant rat CL. In fact, spontaneous apoptosis of CL obtained from pregnant rats and placed in an in vitro-culture system with serum-free medium was reduced by treatment with an anti-rat Fas monoclonal antibody, supporting a role for Fas receptor and Fas ligand in apoptosis of the long-lasting CL of pregnancy [43]. Therefore, determining whether progesterone alters the influence of the Fas system on luteal regression may help us to understand the role of progesterone in luteal cell fate.
In summary, through in vivo as well as in vitro approaches, we have demonstrated that progesterone is a potent survival factor for the rat CL. However, because of the absence of classic PR within the pregnant and postpartum rat CL, the signaling mechanism whereby progesterone promotes luteal cell survival and influences luteal cell fate in this species remains to be explored.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Correspondence: Carlos M. Telleria, University of South Dakota School of Medicine, Division of Basic Biomedical Sciences, 414 East Clark Street, Lee Medical & Sciences Building, Vermillion, SD 57069. FAX: 605 677 6381; ctelleri{at}usd.edu
3 Current address: Division of Basic Biomedical Sciences, University of South Dakota, Vermillion, SD 57069
Received: 29 May 2002.
First decision: 11 June 2002.
Accepted: 16 July 2002.
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P < 0.05 compared with Days 7 and 21; **P < 0.01 compared with Days 12 and 15; ***P < 0.001 compared with all previous days studied; aP < 0.05 compared with Days 5 and +4; bP < 0.05 compared with Day 22 and P < 0.01 compared with Days 5, 7, 12, and +4; cP < 0.05 vs. Day 22 and P < 0.01 vs. Days 5, 7, 12, 15, and +4; dP < 0.01 vs. Days 5, 7, 12, 15, and +4. Statistical differences were determined by one-way analysis of variance followed by the Tukey multiple-comparison test
