Conference on Very Large Data Bases, pp. Infertility associated with tubal pathologies usually would not interfere with ovarian response to stimulation and was, therefore, included in the study group. Nie, Z. Abstract It has recently become practical to construct Markov state models MSMs that reproduce the long-time statistical conformational dynamics of biomolecules using data from molecular dynamics simulations.
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Abstract Oestrogen plays an important role in follicular formation and oocyte maturation via its receptor ER. Table I. Incidence of Pvu II genotypes in patients and controls. Frequency of P.
Open in new tab. Table II. Follicle number Table III. Pvu II genotypes. Pregnancy no. Issue Section:. Download all slides. View Metrics. Email alerts Article activity alert. Advance article alerts. New issue alert. In progress issue alert. Advanced Science, , 8. Zhang, C. Design and optimization of well-ordered microporous copper structure for high heat flux cooling applications. International Journal of Heat and Mass Transfer, , Kwon, H. Liu , T. Applied Mechanics Reviews, 73 1 , Jung , K.
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Abstract The paper examines a modified real business cycle model of a small open economy such as the Korean economy. Language English. References Backus, D. Backus, D. Cooley ed. Frontiers of Business Cycle Research, Ch. Kehoe and F. Barro, R. Mankiw, and X. Baxter, M. Benabib, J. Meng, and K. Brock, P. Cardia, E. Cheong, Yongseung. Cho, Ha-Hyun. Cooley, T. Princeton University Press. Farmer, R. Finn, M. The female sex hormone synthesized from androgen by LH, contributes to oocyte maturation and plays a relevant role in optimizing fertilization and embryo quality Filicori, FSH and oestrogen stimulate antral and pre-antral follicular growth which is believed to be mediated by insulin-like growth factors Yuan and Giudice, Oestrogen receptors have been identified within the oocyte Wu et al.
Both male and female mice were infertile. The Pvu II and Bst UI polymorphisms in particular have been found to have a strong association with breast cancer and spontaneous abortions Lehrer et al. Only patients who had normal cycles with unexplained infertility, and with no pathological conditions that would affect their ovarian response, e. There was one patient who had a past history of benign tubal cyst. However, this cyst, of unknown aetiology, was not the cause of her infertility and had been removed surgically 5 years previously.
Infertility associated with tubal pathologies usually would not interfere with ovarian response to stimulation and was, therefore, included in the study group. In all patients, the cause of their infertility could not be diagnosed in spite of extensive evaluation, e. In each of the controls, the pregnancy was natural without any induction therapy or stimulation. Approval by ethical committee was obtained.
The following long protocol was followed for follicular growth stimulation. Buserelin Hoechst, Allemagne, Frankfurt, Germany at a dose of 0. The dose was maintained if follicular size and numbers were adequate and if the serum oestradiol concentration was satisfactory. Otherwise, Metrodin was increased to IU daily from day 6. When the dominant follicle reached 17 mm, human chorionic gonadotrophin HCG, Profasi; Serono IU was administered and oocyte recovery was carried out 36 h later.
The luteal phase was supported by the administration of progesterone Cyclogest, vaginal pessary; Hoechst mg per day. Serum oestradiol values were measured by radioimmunoassay and were recorded 2 days prior to oocyte recovery. Follicular number, mature oocyte number and follicular size were measured by transvaginal ultrasonography.
Follicular sizes were recorded on the day of oocyte aspiration. The sizes of leading follicles were calculated as the average of the two dimensions in mm as seen in ultrasonography. Follicular numbers and oocyte numbers were recorded immediately after aspiration. Only oocytes that showed features of maturity by microscopic analysis were selected. The number of embryos obtained and replaced in each of the three groups was recorded. Clinical pregnancies were evaluated by HCG measurement and abdominal ultrasonography.
Serum HCG values were measured by enzyme immunoassay. Peripheral blood was drawn from the patients on the day of oocyte aspiration. Nuclear DNA was extracted from the peripheral leukocytes by a standard procedure.
The patients were classified into three groups according to their ER polymorphisms. One-way analysis of variance ANOVA was used for the statistical comparison of the mean follicular numbers, mean oocyte numbers, mean ratios of follicular to oocyte numbers, mean embryo numbers, mean oestrogen values and mean follicular sizes between genotypes.
Among the patients, 36 had no polymorphism, 68 were homozygous and 96 were heterozygous. Among the controls, 43 had no polymorphism, 67 were homozygous and 90 were heterozygous Table I. On the other hand, the Bst UI polymorphism was seen neither in the cases nor in the controls studied. The mean number of follicles in the no-polymorphism group was The mean number of mature oocytes in the no-polymorphism group was 9.
The mean size of leading follicles for the no-polymorphism group was Of these, 32 pregnancies were in the no-polymorphism group It was highest in the no-polymorphism group and lowest in the homozygous group.
Hence, the pregnancy rate also showed a strong negative correlation to the severity of Pvu II polymorphism. In the 72 pregnant patients, the number of embryos obtained and replaced in each of the three Pvu II genotypes showed a highly significant negative correlation with the severity of the polymorphism.
The mean number of embryos obtained in the no-polymorphism group was 9. The mean number of embryos replaced in the no-polymorphism group was 3. IVF involves artificial stimulation of the follicles, aspiration of mature follicles, oocyte retrieval, fertilization of the ova in vitro and transfer of the fertilized embryo inside the uterus.
Although all the patients were exposed to the same protocol of follicular stimulation, follicular responses among the patients differed significantly. Numerous factors have been postulated to influence the success of IVF for alleviating human infertility Edwards et al.
The outcome of this programme depends very much on the factors affecting follicular growth, steroidogenesis and maturation of oocytes Testart et al.
FSH plays a crucial role in affecting the growth of follicles. It stimulates proliferation of granulosa cells, aromatizes androgens to oestrogens, augments FSH receptors and induces LH receptors. On the other hand, oestrogen has a local regulatory effect. It augments the action of FSH, promotes granulosa cell proliferation and increases the number of oestrogen and FSH receptors. Oestrogen and FSH thus act in synergism in the ovary to increase the number of FSH receptors in the granulosa cells, resulting in follicular growth and maturation Ireland and Richards, Oestrogen has a direct affect on granulosa cell function.
It exerts direct trophic effects on folliculogenesis Greenwald and Roy, and protects the growing follicle from androgen-induced atresia Filicori, The hormone affects maturation of oocytes. Its action is required for optimal oocyte cytoplasm and oolemma maturation Filicori, Thus, it plays a crucial role in determining the quality of oocytes Kreiner et al. It has been documented that, in oestrogen-poor follicles, the quality of oocytes may be adversely affected Fishel et al.
Fertilization rates were proved to be higher with mature oocytes Edwards et al. In our study, follicular and mature oocyte numbers showed a significant negative association with the severity of the Pvu II polymorphism.
It is possible that this polymorphism down-regulates the ER gene, interfering with the effective mediation of oestrogen and its functions, on the follicle—oocyte unit. This down-regulation could vary with the severity of the polymorphism, leading to variation in follicle and oocyte numbers in each of the three polymorphic groups.
It was found that these polymorphisms were associated only with the ratio of follicles to oocytes and not with the number of follicles or number of oocytes. The polymorphisms appeared to affect the ovarian response by changing the final number of mature oocytes.
In the present study, however, strong negative associations were found between severity of Pvu II polymorphism in the ER gene, with both the follicular and mature oocyte numbers, and their ratios.
A major contributing factor to the high follicular number and oocyte number in our study and their significant association with Pvu II polymorphism could be due to the difference in stimulation protocol, the criteria used to select follicular size for HCG administration, and for oocyte aspiration. Difference in ethnicity of the population group studied could also play some role in contributing to the variation.
Screening of this polymorphism in other populations and their responses to stimulation may have to be carried out to substantiate these findings. The ratio of mean follicle number to mean mature oocyte number was lowest in the no-polymorphism group indicating that this group had the highest number of mature oocytes per follicle.
Moreover, the homozygous polymorphic group showed highest ratios with the lowest number of mature oocytes per follicle. ER polymorphisms may thus affect the ovarian response by changing the final number of mature oocytes in relation to the number of follicles. In our study, a significant negative association was also seen between follicular sizes and severity of the polymorphism.
Oestrogen receptors are present in human granulosa cells and play an important role in human follicular development Hurst and Leslie, Ovarian surface epithelial OSE cells participate in the formation of ovarian cortex and granulosa cells in early embryonic life Auersperg et al. These cells continually proliferate, re-colonize the ovarian surface in the wake of each ovulation and participate in cyclic rupture of the Graffian follicle and formation of the corpus luteum in adult life Murdoch, Oestrogen has also a crucial local positive feedback role in promoting the development of the follicle Korach, The Pvu II polymorphism could disrupt the effectiveness of the oestrogen receptor in mediating the functions of oestrogen.
This might affect the development or growth of the follicles, resulting in smaller sizes. The degree of disruptiveness could vary with the severity of the polymorphism which might be the underlying cause of the association of homozygous group with small follicular sizes and no-polymorphism group with large follicular sizes.
Large follicular sizes have been documented to have a beneficial effect on the outcome of IVF. Embryo quality as reflected by decreased fragmentation, increased cleavage, and increased implantation rate appears to be improved when HCG is delayed until two or more follicles reach at least 20 mm in diameter Miller et al.
It has been proven that in follicles of large sizes, the follicular fluid FF concentration of oestradiol suggesting an increased aromatase activity is high and high oestradiol values in the FF were associated with the recovery of fertilizable oocytes Fishel et al.
Oestradiol concentrations are related inversely to zona pellucida thickness and a thicker zona pellucida is present in unfertilized oocytes Bertrand et al. Further, many studies have shown that in patients undergoing IVF, FF oestradiol:androstenedione ratios are correlated with pregnancy potential Botero-Ruiz et al. It was found that addition of oestradiol to human oocyte maturation medium increased the fertilization and cleavage rates of in-vitro matured oocytes Tesarik et al.
In our study, the number of embryos fertilized and the pregnancy rate were remarkably different in the three genotypes. The lowest rate was in the homozygous polymorphic group and the highest in the no-polymorphism group.
Thus, our study shows that genetic variability of ER gene could play an important role in affecting pregnancy rates through their mediation of follicular sizes. In oestrogen resistance, oestrogen receptors in the follicles fail to respond appreciably to the gonadotrophin stimulation with subsequent reduction in the negative feedback response Chakravorty et al.
In this study, the serum oestradiol concentrations were lowest in the no-polymorphism group and highest in the homozygous polymorphic group. It is possible that the no-polymorphism group, in terms of better efficacy of its receptor, shows more resistance and the homozygous group shows lower resistance. This could contribute to the varying serum oestradiol concentrations. Resistance to hormonal therapy has been seen in breast cancer patients carrying the Pvu II polymorphism in ER gene Yaich et al.
In a recent study, a nonsense mutation of ER gene was identified in a man Smith et al. He showed elevated serum oestrogen concentrations, and no target tissue responses to oestrogen therapy. Similar syndromes of hormone resistance have been reported in mutations of glucocorticoid, androgen, thyroid hormone, and vitamin D receptors Brooks et al.
Analysis of all findings from our study implies that polymorphism can affect the outcome of IVF by affecting folliculogenesis, oocyte maturation, embryo quality and endometrial receptivity. Neither was any significance seen in the occurence of Pvu II polymorphism between homozygous and heterozygous groups in the patients and controls 0. Though the polymorphism was seen in the same proportion in both patients and controls, the women in the control group had at least one natural pregnancy.
This shows that the mere presence of this polymorphism does not lead to infertility. This polymorphism might only alter the ovarian response to stimulation; the more severe the polymorphism, the poorer the quality of ovarian follicles and oocytes.
Thus this polymorphism may play an indirect role in affecting the pregnancy rates of patients undergoing stimulation. The Pvu II polymorphism, localized in intron 1, 0. The location of the polymorphism in the intron makes it unlikely that the polymorphism may affect ER expression. However, the possibility that the polymorphism is in linkage disequilibrium with other ER mutations which do affect ER expression or function cannot be ruled out Yaich et al.
Some human infertility may arise from ER gene mutations Korach, , but the rare Bst UI polymorphism was not found either in the patients or in the control subjects studied. In conclusion, genetic variability of the ER gene may exert an indirect effect on the pregnancy outcome of IVF patients by affecting the development of the follicles, oocytes and embryos.
Certain ER genotypes may show their side-effects more on the patients exposed to ovarian stimulation regimes, as seen by the reduction of pregnancy rate only in IVF patients. Follicle number, oocyte number, ratio of follicles to oocytes and follicular size in each of the three Pvu II genotypes. Distribution of number of embryos obtained, replaced, and number and percentage of in-vitro fertilization IVF pregnancies in each of the three Pvu II genotypes.
Adashi, E. Anderson, C. Anderson, T. R, Skrede, M. Auersperg, N.