Efficacy of oocytes donated by older women in an oocyte donation programme

Population and insemination studies indicate that women experience declining fertility with ageing. The question therefore arises whether older women are suitable oocyte donors. This study addresses this issue by examining the relationship between oocyte donor age and clinical outcome in a large oocyte donation programme. We retrospectively reviewed data from 458 consecutive oocyte donation cycles completed by 164 different designated oocyte donors. Data were divided into two groups: group A, cycles with donors aged 21–30 years at the time of follicular aspiration (193 cycles, 88 donors); and group B, cycles with donors aged 31–40 years at the time of follicular aspiration (265 cycles, 86 donors). Five donors, because of ageing during repetitive donations, contributed data to groups A and B. In a given cycle, all oocytes for a recipient came from only one designated donor. Comparing the two donor groups, there was no difference in the amount of gonadotrophin used to achieve optimal stimulation; however, more oocytes were obtained from group A than group B donors (16.8 ± 6.9 and 15.1 ± 8.1 respectively, P < 0.05). Similar percentages of oocytes were fertilized in each group, resulting in the transfer of comparable numbers of embryos (4.5 ± 1.1 and 4.4 ± 13 respectively). Comparable clinical pregnancy rates were achieved (group A, 36%; group B, 37%). The spontaneous abortion rates were also similar (group A, 20%; group B, 12%), resulting in comparable ongoing and delivered pregnancy rates per cycle (group A, 29%; group B, 32%) and per embryo transferred (group A, 6.4%; group B, 7.3%). In conclusion, women of proven fertility should not be excluded from donating oocytes simply because of their age. There exists a cohort of fertile women who resist the decreasing fecundity and increasing spontaneous abortion rates associated with ageing. With careful screening, many women of proven fertility can donate oocytes until the age of 40 years with an efficacy equal to that of younger women. Given the relative shortage of suitable oocyte donors, and increasing requests from recipients with previous donor oocyte babies to obtain oocytes from the same, now older, donor, the findings of this study are of practical clinical importance

FTO and MC4R Gene Variants Are Associated with Obesity in Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility in women. It is also associated with metabolic disturbances that place women at increased risk for obesity and type 2 diabetes. There is strong evidence for familial clustering of PCOS and a genetic predisposition. However, the gene(s) responsible for the PCOS phenotypes have not been elucidated. This two-phase family-based and case-control genetic study was designed to address the question of whether SNPs identified as susceptibility loci for obesity in genome-wide association studies (GWAS) are also associated with PCOS and elevated BMI. Members of 439 families having at least one offspring with PCOS were genotyped for 15 SNPs previously shown to be associated with obesity. Linkage and association with PCOS was assessed using the transmission/disequilibrium test (TDT). These SNPs were also analyzed in an independent case-control study involving 395 women with PCOS and 176 healthy women with regular menstrual cycles. Only one of these 15 SNPs (rs2815752 in NEGR1) was found to have a nominally significant association with PCOS (χ2 = 6.11, P = 0.013), but this association failed to replicate in the case-control study. While not associated with PCOS itself, five SNPs in FTO and two in MC4R were associated with BMI as assessed with a quantitative-TDT analysis, several of which replicated association with BMI in the case-control cohort. These findings demonstrate that certain SNPs associated with obesity contribute to elevated BMI in PCOS, but do not appear to play a major role in PCOS per se. These findings support the notion that PCOS phenotypes are a consequence of an oligogenic/polygenic mechanism

Live birth after fresh embryo transfer vs elective embryo cryopreservation/frozen embryo transfer in women with polycystic ovary syndrome undergoing IVF (FreFro-PCOS): study protocol for a multicenter, prospective, randomized controlled clinical trial

BACKGROUND: Polycystic ovary syndrome (PCOS) patients are at increased risk of pregnancy complications, which may impair pregnancy outcome. Transfer of fresh embryos after superovulation may lead to abnormal implantation and placentation and further increase risk for pregnancy loss and complications. Some preliminary data suggest that elective embryo cryopreservation followed by frozen–thawed embryo transfer into a hormonally primed endometrium could result in a higher clinical pregnancy rate than that achieved by fresh embryo transfer. METHODS/DESIGN: This study is a multicenter, prospective, randomized controlled clinical trial (1:1 treatment ratio of fresh vs. elective frozen embryo transfers).. A total of 1,180 infertile PCOS patients undergoing the first cycle of in vitro fertilization (IVF) or intracytoplasmic sperm injection will be enrolled and randomized into two parallel groups. Participants in group A will undergo fresh embryo transfer on day 3 after oocyte retrieval, and participants in group B will undergo elective embryo cryopreservation after oocyte retrieval and frozen–thawed embryo transfer in programmed cycles. The primary outcome is the live birth rate. Our study is powered at 80 to detect an absolute difference of 10 at the significance level of 0.01 based on a two-sided test. DISCUSSION: We hypothesize that elective embryo cryopreservation and frozen–thawed embryo transfer will reduce the incidence of pregnancy complications and increase the live birth rate in PCOS patients who need IVF to achieve pregnancy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT0184152

Treatment strategies for women with WHO group II anovulation : systematic review and network meta-analysis

Funding: The work was supported by an Australian government research training programme scholarship (held by RW) and the Australian National Health and Medical Research Council funded Centre for Research Excellence in Polycystic Ovary Syndrome (APP1078444).Peer reviewedPublisher PD

Baseline AMH Level Associated With Ovulation Following Ovulation Induction in Women With Polycystic Ovary Syndrome

Anti-Müllerian hormone (AMH) reduces aromatase activity and sensitivity of follicles to FSH stimulation. Therefore, elevated serum AMH may indicate a higher threshold for response to ovulation induction in women with polycystic ovary syndrome (PCOS). This study sought to determine the association between AMH levels and ovulatory response to treatment among the women enrolled into the Pregnancy in PCOS II (PPCOS II) trial. This was a secondary analysis of data from a randomized clinical trial in academic health centers throughout the United States Participants: A total of 748 women age 18-40 years, with PCOS and measured AMH levels at baseline, were included in this study. Couples were followed for up to five treatment cycles to determine ovulation (midluteal serum progesterone > 5 ng/mL) and the dose required to achieve ovulation. A lower mean AMH and AMH per follicle was observed among women who ovulated compared with women who never achieved ovulation during the study (geometric mean AMH, 5.54 vs 7.35 ng/mL; P = .0001; geometric mean AMH per follicle, 0.14 vs 0.18; P = .01) after adjustment for age, body mass index, T, and insulin level. As AMH levels increased, the dose of ovulation induction medication needed to achieve ovulation also increased. No associations were observed between antral follicle count and ovulation. These results suggest that high serum AMH is associated with a reduced response to ovulation induction among women with PCOS. Women with higher AMH levels may require higher doses of medication to achieve ovulation

Preconceptional antithyroid peroxidase antibodies, but not thyroid-stimulating hormone, are associated with decreased live birth rates in infertile women

OBJECTIVE: To study whether preconceptual thyroid-stimulating hormone (TSH) and antithyroid peroxidase (TPO) antibodies are associated with poor reproductive outcomes in infertile women. DESIGN: Secondary analysis of data from two multicenter, randomized, controlled trials conducted by the Reproductive Medicine Network of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Multivariable logistic regression analyses were performed to assess the association between preconceptual TSH levels and anti-TPO antibodies. SETTING: Not applicable. PATIENT(S): Serum samples from 1,468 infertile women were utilized. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Cumulative conception, clinical pregnancy, miscarriage, and live birth rates were calculated. RESULT(S): Conception, clinical pregnancy, miscarriage, and live birth rates did not differ between patients with TSH ≥2.5 mIU/L vs. TSH < 2.5 mIU/L. Women with anti-TPO antibodies had similar conception rates (33.3% vs. 36.3%) but higher miscarriage rates (43.9% vs. 25.3%) and lower live birth rates (17.1% vs. 25.4%) than those without anti-TPO antibodies. Adjusted, multivariable logistic regression models confirmed elevated odds of miscarriage (odds ratio 2.17, 95% confidence interval 1.12-4.22) and lower odds of live birth (oddr ratio 0.58, 95% confidence interval 0.35-0.96) in patients with anti-TPO antibodies. CONCLUSION(S): In infertile women, preconceptional TSH ≥2.5 mIU/L is not associated with adverse reproductive outcomes; however, anti-TPO antibodies are associated with increased risk of miscarriage and decreased probability of live birth. CLINICAL TRIAL REGISTRATION NUMBER: PPCOS II NCT00719186; AMIGOS NCT01044862

Clomiphene, Metformin, or Both for Infertility in the Polycystic Ovary Syndrome

Background The polycystic ovary syndrome is a common cause of infertility. Clomiphene and insulin sensitizers are used alone and in combination to induce ovulation, but it is unknown whether one approach is superior. Methods We randomly assigned 626 infertile women with the polycystic ovary syndrome to receive clomiphene citrate plus placebo, extended-release metformin plus placebo, or a combination of metformin and clomiphene for up to 6 months. Medication was discontinued when pregnancy was confirmed, and subjects were followed until delivery. Results The live-birth rate was 22.5% (47 of 209 subjects) in the clomiphene group, 7.2% (15 of 208) in the metformin group, and 26.8% (56 of 209) in the combinationtherapy group (P\u3c0.001 for metformin vs. both clomiphene and combination therapy; P=0.31 for clomiphene vs. combination therapy). Among pregnancies, the rate of multiple pregnancy was 6.0% in the clomiphene group, 0% in the metformin group, and 3.1% in the combination-therapy group. The rates of first-trimester pregnancy loss did not differ significantly among the groups. However, the conception rate among subjects who ovulated was significantly lower in the metformin group (21.7%) than in either the clomiphene group (39.5%, P=0.002) or the combinationtherapy group (46.0%, P\u3c0.001). With the exception of pregnancy complications, adverse-event rates were similar in all groups, though gastrointestinal side effects were more frequent, and vasomotor and ovulatory symptoms less frequent, in the metformin group than in the clomiphene group. Conclusions Clomiphene is superior to metformin in achieving live birth in infertile women with the polycystic ovary syndrome, although multiple birth is a complication. (ClinicalTrials.gov number, NCT00068861.

Cardiometabolic health in offspring of women with PCOS compared to healthy controls: a systematic review and individual participant data meta-analysis

BACKGROUND: Women diagnosed with polycystic ovary syndrome (PCOS) suffer from an unfavorable cardiometabolic risk profile, which is already established by child-bearing age. OBJECTIVE AND RATIONALE: The aim of this systematic review along with an individual participant data meta-analysis is to eva

Letrozole versus Clomiphene for Infertility in the Polycystic Ovary Syndrome

BACKGROUND Clomiphene is the current first-line infertility treatment in women with the polycystic ovary syndrome, but aromatase inhibitors, including letrozole, might result in better pregnancy outcomes. Full Text of Background... METHODS In this double-blind, multicenter trial, we randomly assigned 750 women, in a 1:1 ratio, to receive letrozole or clomiphene for up to five treatment cycles, with visits to determine ovulation and pregnancy, followed by tracking of pregnancies. The polycystic ovary syndrome was defined according to modified Rotterdam criteria (anovulation with either hyperandrogenism or polycystic ovaries). Participants were 18 to 40 years of age, had at least one patent fallopian tube and a normal uterine cavity, and had a male partner with a sperm concentration of at least 14 million per milliliter; the women and their partners agreed to have regular intercourse with the intent of conception during the study. The primary outcome was live birth during the treatment period. Full Text of Methods... RESULTS Women who received letrozole had more cumulative live births than those who received clomiphene (103 of 374 [27.5%] vs. 72 of 376 [19.1%], P=0.007; rate ratio for live birth, 1.44; 95% confidence interval, 1.10 to 1.87) without significant differences in overall congenital anomalies, though there were four major congenital anomalies in the letrozole group versus one in the clomiphene group (P=0.65). The cumulative ovulation rate was higher with letrozole than with clomiphene (834 of 1352 treatment cycles [61.7%] vs. 688 of 1425 treatment cycles [48.3%], P Full Text of Results... CONCLUSIONS As compared with clomiphene, letrozole was associated with higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT00719186.

Novel Genetic Risk and Metabolic Signatures of Insulin Signaling and Androgenesis in the Anovulation of Polycystic Ovary Syndrome

Funding Information: The authors are grateful to all staff in the PCOSAct group for their effort in the collection of blood samples and clinical dataset which used in current study. Special thanks to Prof. Attila Toth from Institute of Physiological Chemistry, Dresden, Germany for the REC114 antibody. This study was supported by the National key Research and Development Program of China (2019YFC1709500); the National Collaboration Project of Critical Illness by Integrating Chinese Medicine and Western Medicine; the Project of Heilongjiang Province Innovation Team “TouYan;” the Yi-Xun Liu and Xiao-Ke Wu Academician Workstation; the Innovation Team of Reproductive Technique with Integrative Chinese Medicine and Western Medicine in Xuzhou City, China; Heilongjiang University of Chinese Medicine from the National Clinical Trial Base; Heilongjiang Provincial Clinical Research Center for Ovary Diseases; the Research Grant Council (T13-602/21-N, C5045-20EF, and 14122021); and Food and Health Bureau in Hong Kong, China (06171026). Ben Willem J. Mol is supported by a National Health and Medical Research Council (NHMRC) Investigator grant (GNT1176437). Ben Willem J. Mol reports consultancy for ObsEva and Merck and travel support from Merck. Xiaoke Wu, Yongyong Shi, and Chi Chiu Wang developed the research question and designed the study. Xiaoke Wu, Yongyong Shi, Yijuan Cao, and Chi Chiu Wang designed the analysis. Yongyong Shi and Zhiqiang Li contributed to the design of the experiment of whole-exome plus targeted SNP sequencing and the analysis, and interpreted the results. Jingshu Gao, Hui Chang, Duojia Zhang, Jing Cong, Yu Wang, Qi Wu, Xiaoxiao Han, Pui Wah Jacqueline Chung, Yiran Li, and Lin Zeng contributed to the experiment of metabolic profile and immunofluorescent staining and the analysis, and interpreted the results. Astrid Borchert and Hartmut Kuhn provided antibody support and advice. Xu Zheng and Lingxi Chen contributed to create the predictive model with deep machine learning. Jian Li, Qi Wu, Hongli Ma, Xu Zheng, and Lingxi Chen contributed to the analysis of the clinical characteristics and interpreted the results. Jian Li, Hongli Ma, Hui Chang, Jing Cong, and Chi Chiu Wang drafted the manuscript. All authors reviewed and revised the manuscript. Xiaoke Wu is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Xiaoke Wu, Chi Chiu Wang, Yijuan Cao, Jian Li, Zhiqiang Li, Hongli Ma, Jingshu Gao, Hui Chang, Duojia Zhang, Jing Cong, Yu Wang, Qi Wu, Xiaoxiao Han, Pui Wah Jacqueline Chung, Yiran Li, Xu Zheng, Lingxi Chen, Lin Zeng, Astrid Borchert, Hartmut Kuhn, Zijiang Chen, Ernest Hung Yu Ng, Elisabet Stener-Victorin, Heping Zhang, Richard S. Legro, Ben Willem J. Mol, and Yongyong Shi declare that they have no conflict of interest or financial conflicts to disclose. Funding Information: This study was supported by the National key Research and Development Program of China ( 2019YFC1709500 ); the National Collaboration Project of Critical Illness by Integrating Chinese Medicine and Western Medicine ; the Project of Heilongjiang Province Innovation Team “TouYan;” the Yi-Xun Liu and Xiao-Ke Wu Academician Workstation; the Innovation Team of Reproductive Technique with Integrative Chinese Medicine and Western Medicine in Xuzhou City , China; Heilongjiang University of Chinese Medicine from the National Clinical Trial Base ; Heilongjiang Provincial Clinical Research Center for Ovary Diseases ; the Research Grant Council ( T13-602/21-N , C5045-20EF , and 14122021 ); and Food and Health Bureau in Hong Kong, China ( 06171026 ). Publisher Copyright: © 2023Peer reviewedPublisher PD