Hum. Reprod. Advance Access originally published online on March 8, 2007
Human Reproduction 2007 22(6):1526-1531; doi:10.1093/humrep/dem029
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High bone morphogenetic protein-15 level in follicular fluid is associated with high quality oocyte and subsequent embryonic development
Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
1 To whom correspondence should be addressed at: Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, 2 Xue Shi Road, Hangzhou, Zhejiang 310006, People's Republic of China. E-mail: huanghefg{at}hotmail.com
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Abstract |
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BACKGROUND: Bone morphogenetic protein-15 (BMP-15) has been shown to influence oocyte maturation and quality. However, no relationship has been established between BMP-15 and oocyte quality/embryonic development in humans. The aim of this study is to investigate BMP-15 level in human follicular fluid (FF) and its possible role in determining oocyte quality and developmental potential.
METHODS: A total of 79 occytes and their corresponding FF from 79 women undergoing ICSI were examined. Individual oocytes were inseminated and subsequently assessed on the basis of their fertilization, cleavage and preimplantation development. BMP-15, FSH, estradiol (E2) and progesterone levels of FF were also analysed via the techniques of western blot or radioimmunoassay.
RESULTS: Higher FF BMP-15 levels were observed in the fertilized and cleaved groups versus the unfertilized and uncleaved groups, respectively (P < 0.05). The best (Grade I) embryo morphology was associated with higher FF BMP-15 levels than Grade II or III embryos (P < 0.01). A significant positive correlation was found between BMP-15 and E2 levels in the same follicle.
CONCLUSION: The present study demonstrates that the BMP-15 level in FF appears to be a potential factor in predicting oocyte quality and subsequent embryo development, and is correlated with E2 level, which may additionally be a valuable predictor of oocyte fertilization.
Key words: bone morphogenetic protein-15/embryonic development/follicular fluid/IVF/oocyte
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Introduction |
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There is accumulating evidence that the oocyte plays an important role in regulating the function of neighbouring somatic cells during mammalian folliculogenesis (Erickson and Shimasaki, 2000
; Moore and Shimasaki, 2005). The oocyte was demonstrated to be able to regulate its own maturation and affect the functions of neighbouring somatic cells and the ovulation rate (Galloway et al., 2000; Hanrahan et al., 2004; Juengel and McNatty, 2005).
Bone morphogenetic protein-15 (BMP-15) is an extremely important oocyte-derived growth factor which is obligatory for normal folliculogenesis and female fertility of mammals (Juengel et al., 2002; Di Pasquale et al., 2004; Shimasaki et al., 2004; Moore and Shimasaki, 2005). BMP-15 is a member of the transforming growth factor-
(TGF-) superfamily, and within the ovary its mRNA and protein are found exclusively in the oocyte in most species (Juengel and McNatty, 2005). In the human, BMP-15 is initially detected in oocytes of primordial follicles and progressively expressed by oocytes in growing follicles throughout folliculogenesis and in 0.5-day post-ovulatory oocytes (Dube et al., 1998, Galloway et al., 2000; Shimasaki et al., 2004). BMP-15 is synthesized as a pre-proprotein comprised of a signal peptide, a large proregion and a biologically active mature region (Dube et al., 1998; Laitinen et al., 1998). After removal of the signal peptide, the proprotein undergoes proteolytic cleavage and separates from the mature region. One of the characteristics of TGF- superfamily members is the formation of dimers through covalent binding of a conserved cysteine residue in the mature region (Chang et al., 2002). Interestingly, in BMP-15, this conserved cysteine is substituted by serine, and dimers are formed through non-covalent interactions (Dube et al., 1998; Laitinen et al., 1998). It has been found that BMP-15 could bind to several receptors in granulosa cells such as BMPR-II, activin receptor type II, activin like kinase-2 (ALK-2) and ALK-6. Of these receptors, ALK-6 is most efficient in binding to BMP-15 and BMPR-II is most effective in BMP-15 bioactivity (Moore et al., 2003).
The in vitro studies indicated that BMP-15 was mitogenic for somatic cells and a stimulator of granulosa cell proliferation (Otsuka et al., 2000). Moreover, it has been reported that BMP-15 was an important determinant of the FSH biological response through inhibiting FSH receptor expression (Otsuka et al., 2001). BMP-15 knockout female mice are subfertile and demonstrate a reduced ovulation, fertilization and developmental potential (Yan et al., 2001). In the human, a BMP-15 mutation has been found to be associated with hypergonadotropic ovarian failure in women (Di Pasquale et al., 2004). Taken together, BMP-15 plays important roles in normal follicular development and ovulation.
The follicular fluid (FF) is the environment of the oocyte during its development and maturation. The composition of FF may influence and/or determine oocyte quality. The concentrations of steroid hormones, pituitary hormones, cytokines and growth factors in FF have been demonstrated to correlate with oocyte development, fertilization outcome and early post-fertilization development (Chang et al., 2002; Mendoza et al., 2002; Salmassi et al., 2005); however, a similar correlation for BMP-15 levels in FF of human and other species has not been reported. It is unclear whether BMP-15 levels in FF correlate to oocyte quality in the human follicle. In the present study, an investigation was undertaken to assess the correlation between the concentration of BMP-15 in FF and fertilization, cleavage capacity and preimplantation embryo morphology for each matching oocyte that was retrieved within the same follicle. The relationship between BMP-15 and estradiol (E2), progesterone and FSH in FF during human ovarian stimulated cycles was also assessed.
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Materials and Methods |
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Patients
This study involved 79 infertile couples enrolled in the ICSI programme of the Women's Hospital of Zhejiang University between May 2004 and August 2005. All couples were undergoing the first ICSI treatment for male factors, and ranged from 20 to 35 years. Informed consents were obtained from the couples for the use of the FF samples obtained during oocyte retrieval for the ICSI treatment. Approval by the Institutional Review Committee of the Medical School of Zhejiang University was also obtained for this study.
Ovarian stimulation, FF sampling and oocyte collection
Patients were stimulated with recombinant FSH (rFSH, Serono, Geneva, Switzerland) after being down-regulated with GnRH agonists (GnRH-a, Serono, Geneva, Switzerland) according to the long protocol. Monitoring of follicular development by real-time ultrasound scans was performed from day 5 of rFSH until the day of follicular puncture. When at least one ovarian follicle had reached 18 mm diameter, 10 000 IU of HCG (Serono, Geneva, Switzerland) were administered 34–36 h before follicular aspiration.
FF was sampled by trans-vaginal ultrasound-guided puncture and aspiration of 18–20 mm diameter follicles. Fluid from the first aspirated follicle of each patient was carefully collected, and the oocyte-cumulus complex that was used for ICSI was identified in the fluid sample coming from the same follicle and maintained in isolation from that coming from other follicles. Those FF samples in which an expanded cumulus-oocyte complex had been identified and that did not contain any visible blood contamination were used in this study. FF samples were centrifuged at 1300 g for 10 min and stored at –70°C prior to measurement.
Evaluation of fertilization, cleavage and embryo grading
IVF and subsequent culture of embryos were performed in a humidified atmosphere of 5% CO2, 5% O2, at 37°C. Fertilization results were assessed 14–16 h after insemination. Fertilization was considered normal when the oocytes contained 2 pronuclei (PN). If the fertilized oocytes contained either 1PN or 3PN, it was considered abnormal. Oocytes lacking PN were considered unfertilized (Mendoza et al., 1999). Embryo cleavage and embryo quality were evaluated three days after insemination. Embryo quality was divided into three groups according to embryo morphology: Grade I = symmetrical blastomeres and no fragmentation; Grade II = slightly uneven blastomeres and <20% fragmentation; Grade III = uneven blastomeres and >20% fragmentation. Only one oocyte from one patient was analysed in the present study. According to the fertilization outcome of oocytes analysed, patients were divided into a fertilized group and an unfertilized group. Oocyte groupings were based on the outcome of fertilization, cleavage and embryo grading.
Determination of BMP-15, E2, progesterone and FSH concentrations in FF
BMP-15 protein in FF was estimated by western blot based upon the method described by Ramsay (1998). Briefly, 1.0 µl of FF were diluted in PBS and electrophoresed using 12% sodium dodecyl sulphate polyacrylamide gel electrophoresis under non-reducing conditions. The separated proteins were transferred onto nitrocellulose membranes by applying 100 V for 2 h with a plate electrode apparatus. The blots were blocked for 1 h in Tris-buffered saline (TBST, 0.2 M NaCl, 0.1% Tween 20, 10 mM Tris, pH 7.4) containing 5% non-fat dry milk. Subsequently, the blots were incubated for 1 h with an antibody against BMP-15 (1:1000; Santa Cruz Biotechnology, Santa Cruz, USA) in TBST followed by incubation for 2 h with anti-goat immunoglobulin G (1:10 000; Santa Cruz Biotechnology, Santa Cruz, USA) in TBST. The blots were washed several times with TBST after each step. The bound antibody was detected with an enhanced chemiluminescence system (Amersham Pharmacia Biotech, Freiburg, Germany). Images were scanned with the Bio-Rad GS800 densitometer (Bio-Rad Laboratories, Hercules, CA, USA) and analysed using the Quantity One software (Bio-Rad). The relative densities of the bands were expressed as arbitrary absorbence units per area. All steps were performed at room temperature. Granulosa cells were used as a negative control. FF of three random patients were mixed to generate a standard which was included on all blots to permit comparison between blots. Densitometric values for individual FF samples were standardized against the standard sample. All samples were electrophoresed and analysed in duplicate and values were averaged before statistical analysis.
E2, progesterone and FSH in FF were all determined by a radioimmunoassay kit (Nine Tripods Biotech, Tianjin, China). The sensitivity of the E2 assay was 7.71 pmol l –1, and the intra- and interassay coefficients of variation (CVs) were 7.7% and 9.8%, respectively. The sensitivity of the progesterone assay was 0.0636 nmol l –1, and the intra- and interassay CVs were 7.2% and 8.9%, respectively. The sensitivity of the FSH assay was 1.0 ng ml –1, and the intra- and interassay CVs were 5.5% and 8.7%, respectively.
Statistical analysis
Data were analysed using of one-way analysis of variance and non-parametric test. Linear regression analysis was used and spearman's correlation coefficient was calculated to detect any correlation between the individual BMP-15 and hormone concentrations in FF. For all analyses, significance was set at P < 0.05. Statistics were calculated using the Statistical Package for Social Sciences program.
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Results |
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Seventy-nine FF samples and matched metaphase II (MII) oocytes were collected from 79 women with male factor infertility who participated in this study. The basic characteristics and treatment of ICSI according to the result of fertilization are summarized in Table 1. There were no differences regarding the clinical characteristics of oocytes between the fertilized group and unfertilized group. Moreover, no differences were found regarding the number of rFSH ampoules, the length of induction in days and the numbers of follicles, retrieved oocytes and embryos in all patients.
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In the present study, a single band at 45 kDa which represents BMP-15 was detected in all FF samples examined by western blotting (Fig. 1). As a negative control, granulosa cells lysates produced no positive band. The mean normalized level of FF BMP-15 in ICSI cycles was 0.87 ± 0.29. Seventy-nine MII oocytes underwent the ICSI procedure and were examined for fertilization, cleavage and embryo development on the corresponding day in culture. Sixty of 79 (75.9%) examined oocytes were fertilized 16–18 h after insemination, of which two oocytes were 3PN, and 53 of 58 (91.4%) were cleaved the next day. The quality of embryos was evaluated on day 3 of culture. In 53 cleaved embryos, 25 (47.2%) were Grade I embryos, 21 (39.6%) were Grade II and 7 (13.2%) embryos were Grade III. According to the fertilization, cleavage and embryo development results, the mean level of BMP-15 in FF samples of the fertilized group was significantly higher than that of the unfertilized group (0.90 ± 0.31 versus 0.77 ± 0.17; P < 0.05, Fig. 2A), and significant differences in BMP-15 levels were also observed between the cleaved and the uncleaved group (0.92 ± 0.23 versus 0.77 ± 0.06; P < 0.01; Fig. 2B). FF BMP-15 levels corresponding to embryo quality are shown in Figure 2C (Grade I 0.98 ± 0.32; versus Grade II 0.76 ± 0.17 and Grade III 0.69 ± 0.15: P < 0.01, respectively). One interesting point to note was that the high quality embryos (Grade I) were associated with higher FF BMP-15 levels in comparison with the low quality (Grades II and III) embryos.
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Linear regression analysis showed that BMP-15 levels were significantly correlated with E2 concentrations (r = 0.319; P < 0.01). On the contrary, BMP-15 levels were significantly negatively correlated with FSH concentrations in FF (r = –0.224; P < 0.05). There was no significant association between BMP-15 levels and progesterone in FF.
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Discussion |
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In the present study, we found that the oocytes retrieved from follicles with a significantly higher FF level of BMP-15 had a higher fertilization rate, better cleavage and better quality embryo development. BMP-15 levels also displayed a significant positive correlation with E2 levels and a negative correlation with FSH concentrations in FF. To our knowledge, this is the first report concerning the relationship between oocyte quality and BMP-15 levels in the human.
As we know, oocyte quality is a key factor in determining the development of an embryo. Our data here showed that the oocytes from follicles with relatively high BMP-15 levels had a better developmental potential than those from follicles with relatively low BMP-15 levels. Since the oocytes in the present study were all of nuclear maturity, it is proposed that BMP-15 may serve as an indicator of cytoplasmic maturity of oocytes.
Synchronization of nuclear and cytoplasmic maturation is essential for establishing full oocyte developmental capacity (Nogueira et al., 2006). Clearly, criteria of nuclear maturation are the germinal vesicle breakdown of oocytes and the presence of the first polar body, however, there is no straightforward criterion for cytoplasmic maturation. At the present time, oocyte cytoplasmic maturation is generally assessed by investigating its subsequent fertilization, cleavage and embryonic development (Takehara et al., 1994). Cortical granule migration, mitochondria distribution and cytoplasmic factor levels, such as cyclin B1 protein, are also used as criteria for cytoplasmic maturation, but these criteria can not be used for in vivo situations and are clearly impractical for clinical use (Craig et al., 2004; Caillaud et al., 2005).
Is BMP-15 in FF a reasonable predictor of oocyte maturation? Previous studies have shown that BMP-15 plays a central role in follicle development and normal fertility in mammals. First, BMP-15 is a mitogen for granulosa cells (Shimasaki et al., 2004), and BMP-15 has been reported to be an inhibitor of luteinization (Shimasaki et al., 2004). It is indicated that BMP-15 may promote oocyte maturation. Secondly, BMP-15 can markedly inhibit the FSH stimulation of pregnancy-associated plasma protein-A (PAPP-A) production in a dose-dependent manner. PAPP-A is the major insulin-like growth factor binding protein-4 protease in FF and deduced to play a role in the dynamics of dominant follicle development owing to its selective expression in granulosa cells of healthy but not atretic follicles (Hourvitz et al., 2002; Matsui et al., 2004). BMP-15 and FSH form a controlling network that ensures the spatio-temporal pattern of granulosa cell PAPP-A expression, indicating that BMP-15 may play a role in selection of the dominant follicle and oocyte maturation (Choi et al., 2003). Moreover, BMP-15 is able to maintain the low incidence of cumulus cell apoptosis by establishing a localized gradient, suggesting that it may be involved in follicle development (Hussein et al., 2005). Thus high levels of BMP-15 may predict strengthened control on the surrounding environment and a better response to nonphysiological endocrine conditions during stimulation cycles.
It is well known that the intrafollicular environment, including hormones and cytokines at appropriate concentrations, is critical for follicular development and oocyte maturity. Studying FF is reasonably straightforward in terms of obtaining ethical approval and ease of collection and analysis. Many reports have described hormones and other factors in FF and their roles in evaluating oocyte maturation. It has been shown that FF concentrations of progesterone, LH, growth hormone, prolactin, interleukin-1, inhibin B and tumour necrosis factor 
were related with the rate of normal fertilization and good embryo development (Enien et al., 1995; Mendoza et al., 1999, 2002; Verpoest et al., 2000; Chang et al., 2002). However, some reports did not replicate these findings (Verpoest et al., 2000; Chang et al., 2002). In contrast to all of the factors mentioned above, BMP-15 is locally derived, from the oocyte itself, so it may be a more direct and valuable index than others for predicting oocyte quality.
In the present study, BMP-15 levels in FF showed a significant correlation with E2 concentrations but not with progesterone. This result is consistent with the report that BMP-15 might promote granulosa cell mitosis and proliferation (Otsuka et al., 2000). It is known that granulosa cells are able to synthesize and secrete E2. Activation of granulosa cell mitosis and proliferation by BMP-15 may indirectly promote the synthesis and secretion of E2 in granulosa cells. However, a previous study also showed that BMP-15 produced a decrease in FSH-induced progesterone production, but had no effect on FSH-stimulated E2 production (Otsuka et al., 2000). The difference may be due to different materials and methods used in the two studies. As mentioned above, BMP-15 participates in the oocyte-somatic cell negative feedback loop through its interaction with kit ligand, which is also a key player in female fertility (Otsuka and Shimasaki, 2002; Hutt et al., 2006). Granulosa cells cultured in vitro without the presence of oocytes were used in Otsuka's study (2000), which abolished the oocyte-somatic interaction and in vitro culture could not replicate the intrafollicular environment in vivo. However, the present in vivo study, is more direct.
Additionally, we found that BMP-15 levels were negatively correlated with FSH concentrations. This result is consistent with a recent report that only a low FSH level promotes oocyte growth (Thomas et al., 2005). Low FSH had no significant effect on BMP-15 mRNA expression, whereas a high FSH level was shown to inhibit BMP-15 expression in in vitro culture of oocyte-granulosa cell complexes. A feedback loop was proposed to explain this: FSH-stimulated kit ligand expression results in suppression of BMP-15, causing an increase in FSH receptor expression and increased FSH sensitivity that enhances FSH-induced kit ligand expression (Thomas et al., 2005). Because rFSH is now used for ovarian stimulation in clinics, the inverse correlation we observed between BMP-15 and FSH in FF suggests that an optimal concentration of rFSH may exist for obtaining mature oocytes. It implies that stimulation protocols should be adapted to avoid exposure of follicles and oocytes to too high concentrations of rFSH. Further study is needed to clarify the effect of rFSH on BMP-15 levels in ovarian follicles.
In the present study, only the first-puncture, clear FF samples from each patient were analysed in order to avoid blood contamination. Usually, two embryos will be transferred into the uterus of each patient in IVF-embryo transfer. Pregnancy rate is one of the valuable indices for evaluation of embryo quality. We did not analyse the correlation between BMP-15 levels in FF and pregnancy rate in the present study, because it was difficult to identify whether the fetus in the pregnant patient had developed from the analysed follicle.
In conclusion, high cleavage rate and good morphology embryos were obtained from follicles with comparatively high BMP-15 levels. Our results indicate that BMP-15 levels in FF may be a reliable marker for quality and developmental potential of the matching oocyte. Further experiments will be needed to determine whether BMP-15 is a predominant factor related to the quality of each oocyte.
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Acknowledgments |
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This study was supported by the research grants from the National Basic Research Program of China (973 program, No.2006 CB504004), the National Natural Science Foundation of China (No. 30471642), Specialized Research Fund for the Doctoral Program of Higher Education (No.20040008931).
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Footnotes |
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* The authors equally contributed to this work
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References |
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Submitted on August 30, 2006; resubmitted on November 22, 2006; resubmitted on December 8, 2006; accepted on December 15, 2006.
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