Single nucleotide polymorphisms in the Anti-Mullerian hormone (AMH Ile(49)Ser) and Anti-Mullerian hormone type II receptor (AMHRII -482 A>G) as genetic markers in assisted reproduction technology.
ABSTRACT: The aim of the study was to evaluate whether the presence Antimullerian hormone (AMH) and Antimullerian hormone type II receptor (AMHRII) single nucleotide polymorphisms (SNPs) Ile(49)Ser and -482A>G respectively are related to the assisted reproduction outcome.A prospective cross-sectional observational study was conducted in order to assess the distribution of AMH and AMHRII SNPs in two cohorts, one of healthy women (N?=?100) and the control group and the IVF/ICSI group (N?=?151) consisted of women undergoing IVF/ICSI treatment for infertility. Furthermore, a prospective longitudinal observational study was performed on the latter group to assess possible associations of these SNPs with patients' characteristics and controlled ovarian stimulation (COS) and pregnancy outcome.Among non-carriers of the AMH (Ile(49)Ser) polymorphism, basal FSH levels were lower in those with more than two of previous IVF attempts and fertilization rate was statistically higher in those with peak serum E2 levels below 1500 pg/ml, whereas among non-carriers of the AMHRII (-482 A>G) polymorphism, number of follicles was higher in those with more than two previous IVF attempts and total dose of gonadotropins was lower in those with peak serum E2 levels above 1500 pg/ml.There was evidence that in specific subgroups of women undergoing IVF/ICSI, AMH and AMHRII SNPs may be related to patients' characteristics and controlled ovarian stimulation and pregnancy outcome and thus may provide a means for the prediction of ovarian response in specific subgroups of women entering an IVF/ICSI program.
Project description:The aim of this study was to examine the effects of single-nucleotide polymorphisms (SNPs) in the anti-Müllerian hormone (AMH) and AMH type II receptor (AMHRII) genes on in vitro fertilization (IVF) outcomes. In this prospective cohort study, we genotyped the AMH 146 T > G, AMHRII -482 A > G and AMHRII IVS1 +149 T > A variants in 635 women undergoing their first cycle of controlled ovarian stimulation for IVF. DNA was extracted from the peripheral blood of all participants, and the SNPs were genotyped by real-time polymerase chain reaction. The distributions, frequencies of genes, and correlation with clinical pregnancy of IVF were analyzed. The AMH 146 T > G G/G genotype in women was associated with a lower clinical pregnancy rate (T/T: 55.0%, T/G: 51.8%, G/G: 40.0%; p < 0.05). Women with the AMH 146 T > G GG genotype were half as likely to have a clinical pregnancy compared with women with TT genotypes (OR = 0.55, 95% CI: 0.34⁻0.88, p = 0.014). With multivariate analysis, the AMH 146 T > G GG genotype remains as a significant independent factor to predict clinical pregnancy (p = 0.014). No significant difference was found between AMHRII polymorphisms and clinical pregnancy outcomes of IVF. In conclusion, our results show that AMH 146 T > G seems to be a susceptibility biomarker capable of predicting IVF pregnancy outcomes. Further studies should focus on the mechanism of these associations and the inclusion of other ethnic populations to confirm the findings of this study.
Project description:To investigate the possible relationship between single nucleotide polymorphisms (SNPs) in the anti-Müllerian hormone (AMH) signaling pathway and the incidence of early OHSS, the genomic DNA was isolated from peripheral blood leukocytes of 122 participants (62 patients with early OHSS and 60 patients without OHSS who underwent IVF/ICSI), and SNPs of the AMH and AMHR2 exons were detected directly. Further more, genotype distribution and allele frequency were analyzed. We found seven types of SNPs in the AMH exons, and two of them were missense mutations (rs10407022 and rs182295886). However, these two missense mutations did not increase the risk of early OHSS (rs10407022, P=0.307, OR=1.552, CI 0.668, 3.608; rs182295886, P=0.442, OR=0.359, CI 0.026, 4.883). While it was observed that participants with the SNP (rs10407022) had a relatively higher ovarian response than those without the SNP. Further more, we did not find any SNPs in exons of AMHR2. In conclusion, we analyzed the pathogenesis of OHSS by first investigating the SNPs in the AMH signaling pathway. There is no association between SNPs in the AMH/AMHR2 signaling pathway and early OHSS in Han Chinese women.
Project description:Anti-Müllerian hormone (AMH) is responsible for the Müllerian ducts' regression in male fetuses. In cells of cancers with AMH receptors (AMHRII), AMH induces cell cycle arrest or apoptosis. As AMH occurs naturally and does not exhibit significant side effects while reducing neoplastic cell colonies, it can be considered as a potential therapeutic agent for cancer treatment. The purpose of this study was to assess the AMHRII expression in endometrial cancer (EC) in correlation to various demographic data and clinical conditions. Immunohistochemical analysis was used to assess AMHRII expression in EC tissue samples retrieved from 230 women with pre-cancerous state of endometrium (PCS) and EC. AMHRII was detected in 100% of samples. No statistical difference was observed for AMHRII expression depending on the histopathological type of EC, cancer staging, body mass index, and age, as well as the number of years of menstruation, births and miscarriages, and average and total breastfeeding time. Diabetes mellitus type 2 is the only factor that has an impact on AMHRII expression in EC tissue. Thus, this study supports the idea of theoretical use of AMH in EC treatment because all histopathological types of EC at all stages of advancement present receptors for AMH.
Project description:The objective of the study was to investigate whether genetic polymorphisms of the anti-Müllerian hormone (AMH) and its specific receptor anti-Müllerian hormone type II receptor (AMHRII) were associated with the hormone disorder and phenotype of polycystic ovary syndrome (PCOS).This case-control study included 141 PCOS patients and 123 normal women. Two polymorphisms of AMH and AMHRII and the clinical characteristics of participants such as body mass index (BMI), serum luteinizing hormone (LH), estradiol levels (E2), total testosterone levels (T), and homeostasis model assessment of insulin resistance (HOMA-IR) were analyzed with the case-control sample. Gene-gene interactions of AMH and AMHRII genes were analyzed based multifactor-dimensionality reduction method.A significant difference of AMH gene polymorphisms were observed in IR-PCOS women and controls. The AMH and AMHRII gene polymorphisms were not found a significant difference in non-IR-PCOS and normal groups. To IR-PCOS women, genotypes of AMH were closely related to the serum levels of LH (P = 0.000), testosterone (P = 0.000) and HOMA-IR (P = 0.038), while in the non-IR-PCOS and normal groups, no relationship was found. No impact of AMH and AMHRII gene-gene interactions was demonstrated.Our research suggests that the diversity of AMH genotypes in the AMH signal pathway may be connected with the susceptibility and phenotype of PCOS with insulin resistance.
Project description:Müllerian inhibiting substance/anti-Müllerian hormone (MIS/AMH) is a regulator of the female reproductive system, an indicator of ovarian reserve and a growth inhibitor of Müllerian duct-derived tumors in vivo and in vitro. The objective of the present study was to analyze MIS/AMH type II receptor (MIS/AMHRII) protein and mRNA expression in healthy human endometria compared with patients with endometrial hyperplasia and endometrial cancer, providing a foundation for MIS/AMH as a biological modifier for treatment of endometrial hyperplasia and endometrial cancer. The present study included healthy endometrial tissues (n=20), simple endometrial hyperplasia tissues without atypia (n=17), complex endometrial hyperplasia tissues without atypia (n=24) and endometrial cancer tissues (n=8). The location and variation of MIS/AMHRII protein expression was observed by immunohistochemistry. The expression was graded by two pathologists and was categorized as follows: Negative, weakly positive, moderately positive or strongly positive. Reverse transcription-quantitative polymerase chain reaction was used to quantify MIS/AMHRII mRNA expression. The expression of MIS/AMHRII protein was observed in the cytoplasm of healthy human endometria, endometrial hyperplasia and endometrial cancer cells. The frequency of MIS/AMHRII protein expression was 20.22±10.35% in the proliferative phase of the healthy endometrium and 24.09±11.73% in the secretory phase of the healthy endometrium. However, no differences were observed in the menstrual cycle phases. The frequency was 54.50±16.59% in endometrial hyperplasia without atypia, 55.10±15.87% in endometrial hyperplasia with atypia and 73.88±15.70% in endometrial cancer, indicating that expression was enhanced as the disease progressed from healthy to malignant status. In endometrial hyperplasia, MIS/AMHRII protein expression was significantly associated with histological complexity compared with atypia status. The present study demonstrated that MIS/AMHRII is present in healthy endometria, endometrial hyperplasia and endometrial cancer. The low expression frequency of MIS/AMHRII was not significantly different among normal endometrial tissues, however, the protein expression was elevated in endometrial hyperplasia and endometrial cancer. These findings indicated that the study of bioactive MIS/AMH, as a possible treatment for tumors expressing the MIS/AMH receptor, is essential.
Project description:BACKGROUND:To determine the effects of age and the serum anti-Müllerian hormone (AMH) level on in vitro fertilization (IVF) outcomes, especially among young women with low serum AMH levels and older women with high AMH levels. METHODS:This study was a cohort study in which a total of 9431 women aged 20-51 years who were undergoing their first IVF cycles were recruited. Ovarian response parameters included the number of retrieved oocytes, the number of 2 pronuclear zygotes (2PN), and the frequency of good-quality embryos (GQE). Pregnancy outcomes included the clinical pregnancy rate (CPR), live birth rate (LBR), miscarriage rate (MR), and cumulative CPR and LBR (CCPR and CLBR). RESULTS:Among women under 35 years of age, the ovarian response, CPR, CCPR, LBR and CLBR (p < 0.01) were significantly lower in the low-AMH group than in the average-AMH and high-AMH groups. In women above 35 years of age, the ovarian response, CPR, CCPR and CLBR (p < 0.01) were significantly higher in the average-AMH and low-AMH groups. The LBR in the older high-AMH group was significantly higher (37.45% vs 20.34%, p < 0.01) than that in the older low-AMH group, but there was no difference (37.45% vs 32.46%, p = 0.11) compared with the older average-AMH group. When there was a discrepancy between age and the AMH level, the young low-AMH group showed a poorer ovarian response but a better CPR (58.01% vs 49.44%, p < 0.01) and LBR (48.52% vs 37.45%, p < 0.01) than the older high-AMH group. However, the CCPR (65.37% vs 66.11%, p = 0.75) and CLBR (56.35% vs 52.89%, p = 0.15) between the two groups were comparable. The conservative CLBR in the two discrepancy groups increased until the third embryo transfer and reached a plateau thereafter. CONCLUSION(S):Even with a relatively low AMH level, young women still had better pregnancy outcomes following IVF than older women. However, increasing the AMH level improves the cumulative outcomes of the older group to a comparable level through a notable and superior ovarian response.
Project description:We aimed to determine whether intraovarian injection of autologous platelet rich plasma (PRP) improves response to ovarian stimulation and in vitro fertilization (IVF) outcome in women with primary ovarian insufficiency (POI). Women (N=311; age 24-40) diagnosed with POI based on ESHRE criteria underwent intraovarian PRP injection. Markers of ovarian reserve, and IVF outcome parameters were followed. PRP treatment resulted in increased antral follicle count (AFC) and serum antimullerian hormone (AMH), while serum follicle stimulating hormone (FSH) did not change significantly. After PRP injection, 23 women (7.4%) conceived spontaneously, 201 (64.8%) developed antral follicle(s) and attempted IVF, and 87 (27.8%) had no antral follicles and therefore did not receive additional treatment. Among the 201 women who attempted IVF, 82 (26.4% of total) developed embryos; 25 of these women preferred to cryopreserve embryos for transfer at a later stage, while 57 underwent embryo transfer resulting in 13 pregnancies (22.8% per transfer, 4% of total). In total, of the 311 women treated with PRP, 25 (8.0%) achieved livebirth/sustained implantation (spontaneously or after IVF), while another 25 (8.0%) cryopreserved embryos. Our findings suggest that in women with POI, intraovarian injection of autologous PRP might be considered as an alternative experimental treatment option.
Project description:OBJECTIVE: To evaluate ovarian response and cumulative live birth rate of women undergoing in-vitro fertilization (IVF) treatment who had discordant baseline serum anti-Mullerian hormone (AMH) level and antral follicle count (AFC). METHODS: This is a retrospective cohort study on 1,046 women undergoing the first IVF cycle in Queen Mary Hospital, Hong Kong. Subjects receiving standard IVF treatment with the GnRH agonist long protocol were classified according to their quartiles of baseline AMH and AFC measurements after GnRH agonist down-regulation and before commencing ovarian stimulation. The number of retrieved oocytes, ovarian sensitivity index (OSI) and cumulative live-birth rate for each classification category were compared. RESULTS: Among our studied subjects, 32.2% were discordant in their AMH and AFC quartiles. Among them, those having higher AMH within the same AFC quartile had higher number of retrieved oocytes and cumulative live-birth rate. Subjects discordant in AMH and AFC had intermediate OSI which differed significantly compared to those concordant in AMH and AFC on either end. OSI of those discordant in AMH and AFC did not differ significantly whether either AMH or AFC quartile was higher than the other. CONCLUSIONS: When AMH and AFC are discordant, the ovarian responsiveness is intermediate between that when both are concordant on either end. Women having higher AMH within the same AFC quartile had higher number of retrieved oocytes and cumulative live-birth rate.
Project description:Objective:We compared the expression levels of Müllerian inhibiting substance (MIS)/anti-Müllerian hormone type II receptor (AMHRII) in uterine myoma and adenomyosis to evaluate the possibility of using MIS/anti-Müllerian hormone (AMH) as a biological regulator or therapeutic agent in patients with uterine leiomyoma and adenomyosis. Methods:We studied normal uterine myometrium, leiomyoma, endometrial tissue, and adenomyosis from 57 patients who underwent hysterectomy for uterine leiomyoma (22 cases) or adenomyosis (28 cases) and myomectomy for uterine myoma (7 cases). Immunohistochemical staining was used to confirm the MIS/AMHRII protein expression level in each tissue. Reverse transcription-polymerase chain reaction was performed to quantify MIS/AMHRII mRNA expression. Results:The MIS/AMHRII protein was more strongly expressed in uterine myoma (frequency of MIS/AMHRII expressing cells: 51.95%±13.96%) and adenomyosis (64.65%±4.85%) tissues than that in the normal uterine myometrium (3.15%±1.69%) and endometrium (31.10%±7.19%). In the quantitative analysis of MIS/AMHRII mRNA expression, MIS/AMHRII mRNA expression levels in uterine myoma (mean density: 4.51±0.26) and adenomyosis (6.84±0.20) tissues were higher than that in normal uterine myometrial tissue (0.08±0.09) and endometrial tissue (1.63±0.06). Conclusion:This study demonstrated that MIS/AMHRII was highly and strongly expressed on uterine myoma and adenomyosis. Our data suggest that MIS/AMH may be evaluated as a biological modulator or therapeutic agent on MIS/AMHRII expressing uterine myoma and adenomyosis.
Project description:Women undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) who have a predicted poor ovarian response (POR) present a challenge for reproductive medicine specialists. Traditional Chinese medicine (TCM) is commonly used in China for such patients, in the belief that it will improve the ovarian response and ultimately increase pregnancy rates. However, there is a lack of high-quality evidence about the effect of TCM on improving ovarian response in such patients. The purpose of this study is to evaluate ongoing viable pregnancy rate at 12 weeks' gestation and related indicators of ovarian response in fertile women who have a predicted poor ovarian response having immediate versus delayed IVF/ICSI after 3 months of Ding-Kun-Dan (DKD) pre-treatment.This study is a multicenter, randomized controlled, parallel-group, phase III, superiority clinical trial. Two hundred and seventy-eight eligible female infertility patients with POR will be included in the study and randomly allocated into an immediate treatment group and a DKD group in a 1:1 ratio. Both groups will receive IVF or ICSI as a standard treatment while in the DKD group, a commercially available Chinese medicine, DKD, will be administrated for 3 months before the IVF/ICSI cycle starts. The primary outcome of the study is the ongoing pregnancy rate at 12 weeks' gestation. The secondary outcomes include total gonadotropin dosage, duration of stimulation, estradiol (E2) and progesterone (P) levels on human chorionic gonadotropin (hCG) trigger day, cycle cancellation rate, number of oocytes retrieved, high-quality embryo rate, biochemical pregnancy rate, the change of serum anti-Müllerian hormone (AMH), follicle-stimulating hormone (FSH), and E2 levels and all side effects, safety outcomes, and any adverse events. The protocol was approved by the Ethics Committee of the First Teaching Hospital of Tianjin university of TCM (approval no. TYLL2017[K] 004).IVF/ICSI is increasingly used to treat couples desiring a baby. Many of these women will have poor ovarian function. In China, DKD is commonly used for these patients prior to undergoing IVF/ICSI. There is no effective treatment for poor ovarian response in Western medicine currently. It is important, therefore, to undertake this randomized control trial to determine whether DKD is effective or not.Chinese Clinical Trial Registry, ID: ChiCTR-IOR-17011697 . Registered on 19 June 2017.