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RESEARCH |
School of Biological Sciences, University of Reading, Whiteknights, Reading RG6 6AJ, UK
Correspondence should be addressed to P G Knight; Email: p.g.knight{at}reading.ac.uk
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Abstract |
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-5-steroid dehydrogenase, 3 β- and steroid -isomerase 1 (HSD3B1). In granulosa-lutein cells, STAR transcript abundance was not affected by BMP6, whereas forskolin-induced expression of CYP11A1, HSD3B1, CYP19A1 and oxytocin transcripts was reduced. In both cell types, follistatin attenuated the suppressive effect of activin A and BMP6 on forskolin-induced P4 secretion but had no effect alone. Granulosa-lutein cells secreted low levels of endogenous activin A (
1 ng/ml); BMP6 reduced this, while raising follistatin secretion thus decreasing activin A:follistatin ratio. Collectively, these findings support inhibitory roles for BMP/activin signalling in luteinization and steroidogenesis in both TC and GC. |
Introduction |
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-5-steroid dehydrogenase, 3 β- and steroid -isomerase 1 (HSD3B1) and CYP11A1 (Ireland et al. 1980, Rodgers et al. 1987, Couet et al. 1990, Stocco 2000) Conversely, expression of cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17A1), required for androgen synthesis by TC, and P450 aromatase (CYP19A1) required for conversion of androgens to oestrogens by GC, decrease sharply after the preovulatory LH surge (Rodgers et al. 1987). Other changes in sheep and cattle include decreased secretion of inhibin (Martin et al. 1991) and increased secretion of oxytocin (Schams 1987, Luck et al. 1990) by GC. It is well established that intraovarian factors belonging to the transforming growth factor β (TGFβ) superfamily, including activins, inhibins and bone morphogenetic proteins (BMPs), are synthesized by follicular GC and TC cells and these proteins have been assigned roles as local autocrine/paracrine regulators of follicle growth and development (Shimasaki et al. 2004, Juengel & McNatty 2005, Knight & Glister 2006). However, relatively little is known regarding the expression and role of BMPs in luteinization and CL function.
The biological effects of BMPs are mediated by specific cell-surface receptors, which exist as two subtypes: type I and type II (Massague 1996), both with intrinsic serine/threonine kinase activity. BMP signalling requires binding to and formation of heteromeric complexes with the type I and type II receptors on the cell surface (Massague & Chen 2000, Miyazono et al. 2000, Miyazawa et al. 2002). Once the BMPR–ligand complex is formed, the type II receptor phosphorylates and activates the type I receptor, which in turn activates transcriptional regulators called Smads. BMPs can bind to one of three type II receptors (BMPRII, ActRIIA or ActRIIB) and one of three type I receptor (BMPRIA, BMPRIB or ActRIA). BMP4 and -7 are expressed in rat (Shimasaki et al. 1999, Lee et al. 2001) and bovine (Glister et al. 2004) TC while BMP6 expression has been reported in mouse (Elvin et al. 2000) and bovine (Glister et al. 2004) oocytes. Ovine GC have been reported to express BMP2 (Souza et al. 2002) while BMP6 immunoreactivity was detected in bovine GC (Glister et al. 2004). Treatment of non-luteinized bovine GC with BMP4, -6 and -7 enhanced basal and IGF-induced secretion of oestradiol, inhibin A, activin A and follistatin but inhibited basal and IGF-induced secretion of (Glister et al. 2004). Treatment of non-luteinized bovine TC with the same three ligands potently suppresses basal and LH-induced androgen secretion and CYP17A1 mRNA and protein expression (Glister et al. 2005).
Such evidence from functional studies on non-luteinized GC and TC suggest a role of these locally derived BMPs in follicular steroidogenesis. With this in mind, the aim of the present study was to extend these observations to the follicular–luteal transition: 1) by using real-time quantitative PCR to compare ex vivo expression of mRNA transcripts encoding selected BMP ligands and receptors in bovine CL, granulosa and theca tissue and 2) by examining the effect of selected ligands (BMP6, activin A) and an associated-binding protein (follistatin) on steroid production and steroidogenic gene expression by bovine GC and TC undergoing serum-induced luteinization in vitro.
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Results |
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10-fold higher in serum-treated cultures than in serum-free cultures (Fig. 1A). Treatment with an optimal dose-level of FSH (0.33 ng/ml) promoted a marked (20-fold) rise in oestradiol secretion by serum-free GC cultures but had no effect on oestradiol secretion from serum-treated GC cultures (data not shown).
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11-fold; P<0.01), CYP11A1 (2-fold; P>0.05) and HSD3B1 (5-fold; P<0.05) mRNA were also reduced in serum-treated TC but to much lesser extents than CYP17A1 mRNA. Androstenedione concentration in TC-conditioned medium was >100-fold lower in serum-treated cultures (reduced below assay detection limit) while P4 concentration was 3-fold higher than in serum-free cultures. Viable cell number was 6-fold higher in serum-treated TC cultures than in serum-free cultures.
In vitro-luteinized GC and TC: effects of BMP6 and activin A on progesterone secretion
Treatment with BMP6 dose-dependently reduced forskolin-induced P4 secretion from luteinized GC (P<0.001) and TC (P<0.0001) without affecting viable cell number at the end of culture (Fig. 2). BMP6 did not significantly affect ‘basal’ P4 secretion in the absence of forskolin stimulation. As shown in Fig. 3, activin A also reduced forskolin-induced P4 secretion from both GC (P<0.0001) and TC (P<0.001) without affecting cell number. ‘Basal’ P4 secretion by GC, but not TC, was also suppressed by activin A.
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Discussion |
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TopAbstractIntroductionResultsDiscussionMaterials and MethodsDeclaration of interestReferences |
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75-fold lower than in GC), indicating that little activin A (or inhibin-A) is synthesized by bovine CL and that the endogenous ligand(s) which bind to the type I and -II receptors shown to be expressed in this tissue is more likely to be BMP(s). This finding of greatly reduced activin βA expression in CL agrees with previous reports of a marked fall in GC expression of inhibin/activin 
and βA subunits after the LH surge in cattle (Rodgers et al. 1989, Ireland & Ireland 1994) but, to our knowledge, this is the first comparison of relative expression of BMPs and their receptors in bovine follicles and CL. In contrast to the bovine ovary, expression of inhibin/activin and βA subunits by granulosa-lutein cells is maintained in humans and primates (Fraser et al. 1993, Roberts et al. 1993). Indeed, circulating levels of inhibin-A are maximal during the luteal phase of the human menstrual cycle (Muttukrishna et al. 1994). Low levels of activin A were detectable by ELISA in bovine luteinized GC-conditioned media but, in the absence of suitable BMP immunoassays, the extent to which different BMPs are secreted by the cultured cells is unknown at this stage. Recent studies utilizing chemically-defined, serum-free culture systems for bovine and ovine GC (Campbell et al. 1996, 2006, Gutiérrez et al. 1997, Glister et al. 2001, 2004) and TC (Glister et al. 2005, Campbell et al. 2006) have provided useful insights into the ‘follicular’ phenotype in which GC express CYP19A1 and are responsive to FSH in terms of upregulation of CYP19A1 expression and oestrogen production; correspondingly TC expression of CYP17A1 is maintained and the cells are responsive to LH in terms of upregulation of CYP17A1 expression and androgen production. In the present study, aimed at exploring the potential actions of BMPs in the follicular–luteal transition and CL function in the bovine, we utilized a serum-supplemented culture model (Channing & Ledwitz-Rigby 1975, Skinner & Osteen 1988, Luck et al. 1990, Engelhardt et al. 1991, Wrathall & Knight 1993) in which both GC and TC undergo phenotypic changes in vitro that, in many respects, mimic those associated with luteinization in vivo. Foetal bovine serum (FBS) was able to induce such changes characteristic of luteinization in both cell-types as evidenced by increased P4 secretion and cell proliferation (GC and TC), greatly diminished ‘basal’ expression of CYP17A1 and androgen secretion by TC, and reduced expression of CYP19A1 and oestrogen secretion by GC. FBS-treated GC also displayed a sevenfold increase in ‘basal’ HSD3B1 expression consistent with an increased production of P4. In the case of TC, however, ‘basal’ expression levels (normalized to β-actin) of several components of the steroidogenic pathway (STAR, CYP11A1, HSD3B1) necessary for P4 synthesis were lower in FBS-treated cultures than in serum-free cultures, albeit not to the extent observed for CYP19A1 expression which was reduced by three orders of magnitude. To our knowledge the relative contributions of granulosa-lutein cells (‘large luteal cells’) and theca-lutein cells (‘small luteal cells’) to CL output of P4 in vivo has not been established and so it is difficult to ascertain the significance of this observation in relation to the validity of our in vitro luteinized TC model.
Based on viable cell number at the end of the 6-day culture period, it is clear that proliferation and/or survival of both GC and TC is much greater in the presence of FBS. Whilst intense cellular proliferation accompanies the rapid growth of ruminant CL tissue in vivo much of this is believed to involve endothelial cells and fibroblasts. However, both TC-derived ‘small luteal cells’ and, to a lesser degree, GC-derived ‘large luteal cells’ also proliferate, particularly in the early stages of CL formation (Jablonka-Shariff et al. 1993, Zheng et al. 1994). It is possible that FBS-stimulated proliferation of ‘contaminating’ endothelial cells and/or fibroblasts during the 6-day period of TC culture could account, at least in part, for the apparently lower relative expression of STAR, CYP11A1 and HSD3B1, compared with expression in serum-free TC cultures.
Of several BMP members found to be expressed in bovine CL we selected BMP6 for testing in our luteinized GC and TC model. Since activin A has been used in previous studies on human/primate granulosa-lutein cells (see below), we also included activin A in many of our experiments. The observation that both BMP6 and activin A inhibit forskolin-induced P4 secretion by luteinizing TC and GC suggests a negative autocrine/ paracrine action of these, or related, TGFβ superfamily ligands on luteal steroidogenesis in cattle. Previously, activin A has been shown to reduce basal and hCG-induced P4 secretion by human (Rabinovici et al. 1990, Di Simone et al. 1994) and macaque (Brannian et al. 1992) granulosa-lutein cells in a follistatin-reversible manner (Cataldo et al. 1994) but, to our knowledge, effects on theca-lutein cells have not been reported previously.
Consistent with its negative effect on P4 secretion by luteinizing GC, BMP6 also reduced forskolin-induced upregulation of CYP11A1 and HSD3B1 mRNA expression. Likewise, forskolin-induced upregulation of CYP19A1 and oxytocin expression were reduced. Previously activin A was shown to reduce oxytocin secretion by bovine GC in vitro (Shukovski & Findlay 1990). Although we did not measure oestradiol secretion in this experiment, the observation that luteinizing GC express low but detectable amounts of CYP19A1 mRNA and that forskolin treatment augments CYP19A1 expression is consistent with reported ability of bovine CL to produce small amounts of oestradiol (Okuda et al. 2001). In the case of luteinizing TC, the inhibition of forskolin-induced P4 production by BMP6 appeared to operate through a different mechanism from that in luteinizing GC; forskolin-induced upregulation of STAR mRNA was abolished but neither CYP11A1 nor HSD3B1 transcript levels were affected. In addition, BMP6 upregulated basal expression of CYP17A1, consistent with an anti-luteinization role, since thecal androgen synthesis is known to fall sharply during luteinization (Meidan et al. 1990, Mamluk et al. 1998) and androstenedione levels were undetectable in ‘basal’ conditioned media from these cells.
The proposed role for activin in delaying the onset of follicle atresia and/or luteinization referred to above was based on the finding that activin enhanced CYP19A1 activity and oestradiol production, while inhibiting P4 secretion by non-luteinized GC (Hutchinson et al. 1987, Shukovski et al. 1991). In a similar manner BMP4 and -7 enhanced FSH-stimulated steroidogenesis in cultured rat GC (Shimasaki et al. 1999) and BMP2 enhanced oestradiol production in cultured sheep GCs (Souza et al. 2002). Likewise, BMP2, -4, -6 or -7 increased basal and IGF-induced oestradiol production by non-luteinized bovine (Glister et al. 2004) and ovine (Campbell et al. 2006) GC while suppressing P4 production (Glister et al. 2004).
Experiments on non-luteinized human, rat and bovine TC have shown reduced LH- and/or forskolin-induced androgen production following treatment with activin (Hsueh et al. 1987, Hillier & Miro 1993, Wrathall & Knight 1995). More recently several BMPs were also shown to suppress androgen production by non-luteinized TC in a manner similar to activin A (human: Dooley et al. 2000, bovine: Glister et al. 2005; ovine: Campbell et al. 2006). In two of these reports (Dooley et al. 2000, Glister et al. 2005) decreased androgen production was associated with an increase in P4 production, evidently due to a profound reduction in CYP17A1 expression and 17 hydroxylase activity.
The ability of BMP6 to reduce P4 secretion by luteinized bovine GC accords with studies showing anti-P4 effects of several BMPs (including BMP6) on non-luteinized bovine GC (Glister et al. 2004). However, the negative effect of BMP6 on P4 output by luteinized TC contrasts with the positive effect of BMP4, -6 and -7 on P4 output by non-luteinized TC (Glister et al. 2005). The likely explanation for this is the divergent effect on expression of CYP17A1 that was upregulated by BMP6 in luteinized TC (present study) but downregulated by BMPs in non-luteinized TC (Glister et al. 2005). By blocking conversion to androgen, an acute loss of CYP17A1 could lead to a net increase in P4 despite a partial reduction in STAR, CYP11A1 and HSD3B1. In contrast to the positive effect of BMP6 on cell number in non-luteinized bovine GC and TC cultures (Glister et al. 2004, 2005), no effect of BMP6 on cell number was observed in this study on luteinized GC and TC. Consistent with the activin A effects on luteinized GC and TC cells similar inhibitory effects of activin have been reported on P4 secretion by cultured monkey luteal cells (Brannian et al. 1992) and on basal and hCG-induced P4 secretion from human granulosa-lutein cells (Rabinovici et al. 1990, Di Simone et al. 1994).
It is well established that follistatin, through its activin-binding ability, can oppose the effects of activin; more recent evidence indicates that follistatin can also bind to and neutralize the effects of several BMPs (see Shimasaki et al. (2004), Knight & Glister (2006)). The present finding that follistatin antagonized the suppressive effect of activin A and, to a lesser degree, BMP6 on P4 secretion by both cell-types supports this. It should be noted, however, that addition of follistatin alone did not enhance either ‘basal’ or forskolin-induced P4 secretion by luteinizing GC or TC. While this seems to contradict the earlier suggestion that follistatin has a positive role in promoting follicular atresia and/or luteinization (Shukovski et al. 1991, Findlay 1993, Knight & Glister 2003) it is possible that endogenous levels of follistatin were already sufficiently high to neutralize endogenous activin A (or related ligand?) produced by these in vitro luteinized cells. Direct measurement of immunoreactive activin A and follistatin concentrations in luteinized GC-conditioned media indicated a 50% excess of follistatin over activin A lending some support to this explanation.
The ability of follistatin to reduce the activin A-induced decline in P4 production by luteinizing bovine GC and TC concurs with findings in human granulosa-lutein cells (Cataldo et al. 1994) and with the ability of follistatin to block activin A-induced phosphorylation of Smad-2 in non-luteinized bovine GC (Glister et al. 2004). Taken together with the abundant expression of follistatin transcript in both luteinized GC and bovine CL, this suggests a role of this activin-binding protein in promoting P4 production.
BMP6 increased follistatin production from luteinized GC resulting in a decreased activin A:follistatin mass ratio. This is in accordance with a previous study on non-luteinized bovine GC showing that BMPs enhanced basal and IGF-induced secretion of follistatin while inhibiting basal and IGF-induced P4 secretion (Glister et al. 2004). Previously Tuuri et al. (1994) reported that the expression of follistatin was up-regulated by hCG in human granulosa-lutein cells, known to express considerable amounts of activin βA, and presumably activin protein. In future studies, it would be of interest to examine whether expression of other binding proteins (such as noggin, chordin and gremlin) is regulated by LH/forskolin and BMP ligands in bovine granulosa-lutein and theca-lutein cells since these are likely to play a more prominent role than follistatin in modulating BMP action in these relatively activin-deficient cells. It would also be of interest to corroborate the present findings from the in vitro luteinization model used here, by evaluating the actions and interactions of BMPs, activins and their binding proteins on primary luteal cell cultures (i.e. derived from tissue in which luteinization has occurred in vivo).
In conclusion, these findings provide evidence to support inhibitory roles for BMP/activin signalling in the follicular-luteal transition in cattle. Both BMP6 and activin A inhibited P4 production by luteinizing TC and GC but BMP(s) are likely to play a more prominent role as their expression is maintained in bovine CL tissue whereas expression of activin βA subunit is greatly diminished relative to that in follicular GC.
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Materials and Methods |
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Ovaries and isolation of GC and TC
Ovaries from cattle slaughtered at random stages of the oestrous cycle were collected from an abattoir and transported to the laboratory in medium-199 supplemented with 1% (v/v) antibiotic antimycotic solution. Samples of CL tissue (early, mid- and late-luteal phase based on criteria of Ireland et al. 1980) were removed and snap frozen for subsequent RNA isolation. Follicles, 4–6 mm in diameter, were dissected out, hemisected and GC and theca interna layers were recovered as described previously (Glister et al. 2005). For ex vivo analysis of mRNA transcripts, individual samples of granulosa and theca interna were snap frozen for subsequent RNA purification. For cell culture experiments, GC and theca interna layers pooled from 50 follicles per culture were further processed as described by Glister et al. (2001, 2005) to obtain individual cell suspensions.
Cell culture
Culture medium used was McCoy's 5A modified medium supplemented with 1% (v/v) antibiotic–antimycotic solution, 10 ng/ml insulin (bovine pancreas), 2 mM L-glutamine, 10 mM HEPES, 5 µg/ml apo-transferrin, 5 ng/ml sodium selenite, 0.1% (w/v) BSA and 5% (v/v) FBS. Culture medium used for GC was also supplemented with 10–7 M androstenedione. GC and TC were routinely seeded at a density of 104 viable cells/50 µl culture medium, into 96-well tissue culture plates (Nunclon, Life Technologies Ltd) containing 200 µl/well pre-equilibrated culture medium. Culture plates were incubated in a water-saturated atmosphere of 5% CO2 and 95% air at 38.5 °C for a period of six days. Cell-conditioned medium was removed every 48 h and wells replenished with fresh medium containing treatments (see below). Conditioned media was stored at –20 °C for hormone immunoassays. At the end of the 144 h culture period viable cell number was determined using neutral red assay (Campbell et al. 1996, Glister et al. 2001). To provide a comparison between ‘luteinized’ (serum-treated) and ‘non-luteinized’ (serum-free) phenotypes, in several experiments GC and TC were split into two batches, one of which was cultured as described above, while the other was cultured in the same medium without FBS.
RNA isolation from cultured cells
In culture experiments in which total RNA was to be extracted for PCR analysis, cells were seeded into 24-well plates (105 cells/ml) with three replicate wells per treatment. At the end of culture cell lysates were prepared using Tri-reagent and pooled lysates from replicate wells were stored at –80 °C until total RNA isolation.
Preparation and addition of treatments
Forskolin (10 mM stock solution) was prepared in DMSO and further diluted in sterile culture medium (without serum and androstenedione) to a final concentration of 10 µM. Control wells received an appropriately matched volume of DMSO. Other treatments included recombinant human (rh) BMP6 (0, 2, 10 and 50 ng/ml; R&D Systems, Abingdon, Oxfordshire, UK), rh activin A (0, 2, 10 and 50 ng/ml; R&D Systems), and rh follistatin-288 (0, 20, 100 and 500 ng/ml; National Hormone and Pituitary Program, Torrance, CA, USA). Follistatin was tested in the presence and absence of 50 ng/ml activin A and 20 ng/ml BMP6. All treatments, except forskolin, were sterilized by passing through 0.2-µm filters before further dilution in sterile culture medium. Each treatment was added at 25 µl per culture well and an equal volume of culture medium alone was added to the control wells.
Hormone assays
Concentrations of P4 in luteinized GC- and TC-conditioned media were determined by competitive ELISA (Sauer et al. 1986, Bleach et al. 2001). The detection limit was 20 pg/ml and intra- and inter-assay coefficients of variation (CV) were 8% and 10% respectively. Concentrations of oestradiol-17β and androstenedione in selected cell-conditioned media samples were determined by direct RIA as described previously (Glister et al. 2001, 2005). Detection limits were 2 and 50 pg/ml respectively and intra-and inter-assay CV were less than 10%. Activin A concentrations in selected GC-conditioned media samples were measured using the two-site ELISA (Knight et al. 1996). The detection limit of the assay was 4 pg/ml and intra- and inter-plate CV were less than 10%. Follistatin concentrations in selected GC conditioned media samples were determined using two-site ELISA (Tannetta et al. 1998). The detection limit of the assay was 60 pg/ml and intra- and inter-plate CV were less than 11%.
Purification of RNA, cDNA synthesis and real-time PCR
Total RNA was isolated from cultured cells and tissue samples using a standard acid guanidium thiocyanate–phenol–chloroform extraction method. Briefly, cell monolayers were directly lysed in 0.5 ml/well Tri Reagent (Sigma UK Ltd) while frozen tissue samples were homogenized (Ultra-Turrax T8;) for 15–20 s in 20 volumes of Tri-Reagent. After aqueous phase separation, RNA was precipitated in isopropanol, washed in 75% (v/v) ethanol and the RNA pellet was re-suspended in 50 µl nuclease-free water. Potential genomic DNA contamination was removed with an RNase-free DNase kit (RQ1; Promega UK Ltd). The Tri Reagent extraction process was repeated and the final RNA pellet re-suspended in 20 µl nuclease-free water; RNA quantity and quality were evaluated by spectrophotometry at 260/280 nm. First strand cDNA was synthesized from 1 µg RNA template using the Reverse-iT RT kit (used according to manufacturers protocol; Abgene, Epsom, Surrey, UK) in a 20 µl reaction primed with random hexamers.
Primers were designed to amplify target sequences based on criteria set by the ABI PRISM primer express software (version 1.5). Primer sequences and Entrez accession numbers are shown in Table 2. In primer validation experiments dissociation curve analysis and agarose gel electrophoresis were used to verify that each selected primer pair generated a single amplicon of the predicted size. cDNA template log-dilution curves were used to demonstrate satisfactory PCR efficiency (>85%) and linearity. PCR assays were carried out in a volume of 25 µl, comprising 10 µl cDNA template (equivalent to 20 ng reverse-transcribed RNA), 1 µl each forward and reverse primers (final concentration 0.4 µM) and 12 µl QuantiTect SYBR Green QPCR 2x Master Mix (Qiagen). Samples were processed for 40 cycles on an ABI PRISM 7700 Sequence Detection System (Perkin–Elmer-Applied Biosystems, Warrington, UK) with the following thermal cycling conditions: 2 min at 50 °C, 15 min at 95 °C, 15 s at 95 °C and 1 min at 60 °C.
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Ct method was used for semi-quantitative comparison of the abundance of each mRNA transcript. Ct values for each transcript in a given sample were first normalized to β-actin Ct value (which was uniform across experimental all groups: ANOVA P>0.1). For cell culture experiments the resultant Ct values for each treatment were then normalized to the Ct value of the respective vehicle-treated control group. For ex vivo tissue samples (GC, TC, CL) Ct values for each transcript in a given sample were normalized to the mean Ct value for that transcript in all tissue samples. For graphical presentation Ct values were finally converted to fold-differences using the formula: 
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Statistical analysis
To reduce heterogeneity of variance, hormone data were log-transformed prior to statistical analysis. QPCR data were analysed as Ct values before conversion to fold-difference values. Combined results from three or four independent culture experiments were analysed using ANOVA and provided a significant F ratio was obtained, post hoc pair-wise comparisons were made using Fisher's protected least significant difference test. Unless otherwise stated, results are presented as arithmetic means±S.E.M.
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Declaration of interest |
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Funding |
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Received May 9, 2008
First decision September 24, 2008
Revised manuscript received June 6, 2008
Accepted October 17, 2008
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References |
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