Advanced glycation end-products and its soluble receptor are not independent predictors of incident dysglycaemia or metabolic syndrome in women with polycystic ovary syndrome: a prospective observational study.

BACKGROUND: To evaluate the association of serum advanced glycation end-products (AGEs) and its soluble receptor of AGE (sRAGE) levels with dysglycaemia and metabolic syndrome in women with polycystic ovary syndrome (PCOS). METHODS: This was an analysis of a cohort of women with PCOS who were prospectively recruited for a longitudinal observational study on their endocrine and metabolic profile between January 2010 and December 2013. The association of serum AGEs and sRAGE levels with dysglycaemia and metabolic syndrome at the second-year visit (the index visit) and the sixth-year visit (the outcome visit) were determined. Comparisons of continuous variables between groups were made using the Mann-Whitney U-test. Spearman test was used for correlation analysis. Multivariate binary logistic regression analysis was employed to identify the factors independently associated with the outcome events. RESULTS: A total of 329 women were analysed at the index visit. Significantly lower serum levels of sRAGE (both p < 0.001), but no significant difference in AGEs, were observed in those with dysglycaemia or metabolic syndrome. At the outcome visit, those with incident metabolic syndrome had a significantly lower initial serum sRAGE levels (p = 0.008). The association of serum sRAGE with dysglycaemia and metabolic syndrome at the index visit was no longer significant in multivariate logistic regression after controlling for body mass index, free androgen index and homeostatic model assessment for insulin resistance (HOMA-IR). sRAGE was also not significantly associated with incident metabolic syndrome at the outcome visit on multivariate logistic regression. CONCLUSIONS: Serum sRAGE levels are significantly lower in women with PCOS who have dysglycaemia or metabolic syndrome, and in those developing incident metabolic syndrome in four years. However, it does not have a significant independent association with these outcome measures after adjusting for body mass index, free androgen index and HOMA-IR.

Use of oral progestogen in women with threatened miscarriage in the first trimester: a randomized double-blind controlled trial.

STUDY QUESTION: Will use of oral progestogen in women with threatened miscarriage in the first trimester reduce the miscarriage rate when compared with placebo? SUMMARY ANSWER: Use of oral progestogen in women with threatened miscarriage in the first trimester did not reduce miscarriage before 20 weeks when compared with placebo. WHAT IS KNOWN ALREADY: Miscarriage is a common complication of pregnancy and occurs in 15-20% of clinically recognized pregnancies. Use of vaginal progestogens is not effective in reducing miscarriage but there is still no good evidence to support use of oral progestogen for the treatment of threatened miscarriage. STUDY DESIGN, SIZE, DURATION: This was a randomized double-blind controlled trial. A total of 406 women presenting with threatened miscarriage in the first trimester were recruited from 30 March 2016 to May 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women attending Early Pregnancy Assessment Clinics because of vaginal bleeding during the first trimester were recruited and randomly assigned to use dydrogesterone 40 mg orally, followed by 10 mg orally three times a day or placebo until 12 completed weeks of gestation or 1 week after the bleeding stopped, whichever was later. The primary outcome was the miscarriage rate before 20 weeks of gestation. MAIN RESULTS AND THE ROLE OF CHANCE: The two groups of women had comparable age, BMI, number of previous miscarriages, gestation and ultrasound findings at presentation. The miscarriage rate before 20 weeks of gestation was similar in both groups, being 12.8% (26/203) in the progestogen group and 14.3% (29/203) in the placebo group (relative risk 0.897, 95% CI 0.548-1.467; P = 0.772). The live birth rate was 81.3% in the progestogen group versus 83.3% in the placebo group (P = 0.697). No significant differences were found between the two groups in terms of obstetric outcomes and side effects. LIMITATIONS, REASONS FOR CAUTION: The primary outcome was the miscarriage rate, rather than the live birth rate. Women were recruited from Early Pregnancy Assessment Clinics and those with heavy vaginal bleeding might be admitted into wards directly instead of attending Early Pregnancy Assessment Clinic. The severity of vaginal bleeding was subjectively graded by women themselves. The sample size was not adequate to demonstrate a smaller difference in the miscarriage rate between the progestogen and placebo groups. We did not exclude women with multiple pregnancy, which increased the risk of miscarriage although there was only one set of twin pregnancy in the placebo group. WIDER IMPLICATIONS OF THE FINDINGS: Use of oral progestogen is not recommended in women with threatened miscarriage in the first trimester. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Health and Medical Research Fund, HKSAR (reference number 12132341). All authors declared no conflict of interest. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov with an identifier NCT02128685. TRIAL REGISTRATION DATE: 1 May 2014. DATE OF FIRST PATIENT'S ENROLMENT: 30 March 2016.

A randomized double-blinded controlled trial of hCG as luteal phase support in natural cycle frozen embryo transfer.

STUDY QUESTION: Does the use of hCG as luteal phase support in natural cycle frozen embryo transfer (FET) increase the ongoing pregnancy rate? STUDY ANSWER: The use of hCG in natural cycle FET did not improve the ongoing pregnancy rate. WHAT IS KNOWN ALREADY: The use of luteal phase support in stimulated cycles has been associated with higher live-birth rates and the results are similar when using hCG or progesterone. STUDY DESIGN SIZE, DURATION: This is a randomized double-blinded controlled trial of 450 women recruited between August 2013 and October 2015. PARTICIPANTS/MATERIALS SETTING METHODS: Women with regular cycles undergoing natural cycle FET were recruited. Serial serum hormonal concentrations were used to time natural ovulation and at least Day 2 cleavage embryos were replaced. Patients were randomized into either: (i) the treatment group, receiving 1500 IU hCG on the day of FET and 6 days after FET, or (ii) the control group, receiving normal saline on these 2 days. MAIN RESULTS AND THE ROLE OF CHANCE: The ongoing pregnancy rate [60/225 (26.7%) in the treatment group vs 70/225 (31.3%) in the control group, odds ratio 1.242 (95% CI 0.825-1.869)], implantation rate and miscarriage rate were comparable between the two groups. In the treatment group, there were significantly more cycles with top quality embryos transferred and a significantly higher serum oestradiol level, but a comparable serum progesterone level, 6 days after FET. However, no significant differences were observed in serum oestradiol and progesterone levels 6 days after FET between the pregnant and non-pregnant women. In the multivariate logistic regression, the number of embryos transferred was the only significant factor predictive of the ongoing pregnancy rate after natural cycle FET. LIMITATIONS REASON FOR CAUTION: This study only included FET with cleavage stage embryos and only hCG, not vaginal progesterone, was used as luteal phase support. WIDER IMPLANTATIONS OF THE FINDINGS: The findings in this study do not support the use of hCG for luteal phase support in natural cycle FET. STUDY FUNDING/COMPETING INTERESTS: No external funding was used and there were no competing interests. TRIAL REGISTRATION NUMBER: clinicaltrial.gov identifier: NCT01931384. TRIAL REGISTRATION DATE: 23/8/2013. DATE OF FIRST PATIENT'S ENROLMENT: 30/8/2013.

Serum adiponectin is independently associated with the metabolic syndrome in Hong Kong, Chinese women with polycystic ovary syndrome.

OBJECTIVE: To evaluate the association of serum adiponectin level with the metabolic syndrome in Chinese women with polycystic ovary syndrome (PCOS). METHODS: This was a cross-sectional study carried out in Hong Kong Chinese women with PCOS at a university-affiliated tertiary hospital between January 2010 and January 2011. Clinical and biochemical parameters of the women were analysed. Prediction of the metabolic syndrome was determined by receiver-operator characteristic (ROC) curves, univariate and multivariate logistic regression analyses. RESULTS: A total of 116 women diagnosed to have PCOS were analysed. The area under the ROC curve of adiponectin for the prediction of metabolic syndrome was 0.820, 95% confidence interval (CI) 0.737-0.886. Univariate binary logistic regression showed that testosterone, sex hormone-binding globulin (SHBG), free androgen index (FAI), waist circumference, body mass index (BMI), quantitative insulin-sensitivity check index (QUICKI), homeostasis model assessment of insulin resistance (HOMA-IR) and adiponectin were significantly associated with the metabolic syndrome. On multivariate logistic regression analysis, adiponectin (p = 0.020), HOMA-IR, age (p = 0.011) and BMI (p = 0.019) were independently associated with the metabolic syndrome, but not FAI (p = 0.256). CONCLUSIONS: Serum adiponectin is independently associated with the metabolic syndrome in Chinese women with PCOS. Further longitudinal follow-up studies are needed to determine whether serum adiponectin adds to the prediction of long-term cardiometabolic morbidity conferred by age, BMI and measures of insulin resistance.

The effect of endometrial injury on ongoing pregnancy rate in unselected subfertile women undergoing in vitro fertilization: a randomized controlled trial.

STUDY QUESTION: Does endometrial injury in the cycle preceding ovarian stimulation for in vitro fertilization (IVF) improve the ongoing pregnancy rate in unselected subfertile women? SUMMARY ANSWER: Endometrial injury induced by endometrial aspiration in the preceding cycle does not improve the ongoing pregnancy rate in unselected subfertile women undergoing IVF. WHAT IS KNOWN ALREADY: Implantation failure remains one of the major limiting factors for IVF success. Mechanical endometrial injury in the cycle preceding ovarian stimulation of IVF treatment has been shown to improve implantation and pregnancy rates in women with repeated implantation failures. There is limited data on unselected subfertile women, especially those undergoing their first IVF treatment. STUDY DESIGN, SIZE, DURATION: This randomized controlled trial recruited 300 unselected subfertile women scheduled for IVF/ICSI treatment between March 2011 and August 2013. Subjects were randomized into endometrial aspiration (EA) (n = 150) and non-EA (n = 150) groups according to a computer-generated randomization list. PARTICIPANTS/MATERIALS, SETTING, METHODS: Subjects were recruited and randomized in the assisted reproductive unit at the University of Hong Kong. In the preceding cycle, women in the EA group underwent endometrial aspiration using a Pipelle catheter in mid-luteal phase. All women were treated with a cycle of IVF/ICSI. Pregnancy outcomes were compared. MAIN RESULTS AND THE ROLE OF CHANCE: There were no significant differences in baseline or cycle characteristics between the groups. There were 209 subjects (69.7%) who were undergoing their first IVF cycle and 91 (30.3%) subjects who had repeated cycles. There was no significant difference in ongoing pregnancy rates [26.7% (40/150) versus 32.0% (48/150); RR 0.833 (95% CI 0.585-1.187), P = 0.375] in the EA and non-EA groups. The implantation rates [32.8% (67/204) versus 29.7% (68/229); RR 1.080 (95% CI 0.804-1.450), P = 0.120], clinical pregnancy rates [34.0% (51/150) versus 38.0 (57/150); RR 0.895 (95% CI 0.661-1.211), P = 0.548], miscarriage rates [30.3% (17/56) versus 18.6% (11/59), RR 1.628 (95% CI 0.838-3.164), P = 0.150] and multiple pregnancy rates [31.3% (16/51) versus 19.3% (11/57), RR 1.626 (95% CI 0.833-3.172), P = 0.154] were all comparable between the EA and non-EA groups. Subgroup analysis in women having first embryo transfer (n = 209) also demonstrated no significant difference in ongoing pregnancy rates, but for women undergoing repeated cycles (n = 91), the on-going pregnancy rate was significantly lower in the EA group than in the non-EA group. LIMITATIONS, REASONS FOR CAUTION: The study aimed at assessing an unselected population of subfertile women by recruiting consecutive women attending our fertility clinic. However, since the majority of the recruited women (69.7%) were having their first IVF treatments, the results may not be generalizable to all women undergoing IVF. WIDER IMPLICATIONS OF THE FINDINGS: Previous RCTs and meta-analyses have suggested improved pregnancy rates after pretreatment endometrial injury in women with repeated implantation failure. A recent RCT also showed increased pregnancy rates in unselected subfertile women after endometrial injury, although that study was terminated early and thus underpowered. Our study showed with adequate power that no significant improvement in pregnancy rates was observed after endometrial injury in unselected women undergoing IVF treatment. STUDY FUNDING/COMPETING INTERESTS: The study was supported by the Small Project Funding 201309176012 of the Committee on Research and Conference Grants, University of Hong Kong. The authors have nothing to disclose. TRIAL REGISTRATION NUMBER: HKCTR-1646 and NCT 01977976.

Ovarian sensitivity index is a better measure of ovarian responsiveness to gonadotrophin stimulation than the number of oocytes during in-vitro fertilization treatment.

PURPOSE: To validate the use of the ovarian sensitivity index (OSI) as a measure of ovarian response during in-vitro fertilization (IVF) treatment. METHODS: This is a retrospective study carried out in an assisted reproduction unit in a teaching hospital. We analysed data from 2,556 women undergoing the first IVF cycle between 2002 and 2009. OSI was calculated as the number of retrieved oocytes divided by total dose of FSH administered (per 1,000 IU). Its correlation to other parameters of ovarian response was compared to that of the oocyte number. RESULTS: The correlation coefficients of OSI with age, AFC, AMH, total dose of gonadotrophin, average daily dose of gonadotrophin and duration of stimulation were significantly higher than that of oocyte number with these respective parameters. OSI demonstrated a higher intraclass correlation coefficient (ICC) than the oocyte number when comparing the two parameters across the first and second stimulated IVF cycles. CONCLUSIONS: OSI is a better measure of ovarian responsiveness to gonadotrophin stimulation than the oocyte number, and is particularly useful when different subjects are treated with different stimulation regimens which would have confounding effect on the oocyte number.

Cumulative live-birth rate in women with polycystic ovary syndrome or isolated polycystic ovaries undergoing in-vitro fertilisation treatment.

PURPOSE: This retrospective cohort study evaluated the cumulative live birth rate in women with polycystic ovary syndrome (PCOS) and isolated polycystic ovaries (PCO) undergoing in-vitro fertilisation (IVF) treatment. METHODS: We studied 104 women with PCOS, 184 with PCO and 576 age-matched controls undergoing the first IVF treatment cycle between 2002 and 2009. The main outcome measure was cumulative live birth in the fresh plus all the frozen embryo transfers combined after the same stimulation cycle. RESULTS: Women in both the PCOS (n = 104) and isolated PCO groups (n = 184) had higher ovarian response parameters compared to age-matched controls (n = 576), and higher rates of withholding fresh embryo transfer for risk of ovarian hyperstimulation syndrome (OHSS). The actual incidence of moderate to severe OHSS was significantly higher in the PCOS (11.5 %) but not the isolated PCO group (8.2%) compared to controls (4.9%). The live birth rates in the fresh cycle were comparable among the 3 groups, but the PCOS group had a significantly higher miscarriage rate compared to the other 2 groups. Cumulative live birth rate was significantly higher in the isolated PCO group (60.3%), but not the PCOS group (50.0%), compared to controls (47.5%). CONCLUSIONS: Women in the isolated PCO group, but not the PCOS group, had a significantly higher cumulative live birth rate compared to controls. This could be explained by the quantitative effect of the higher number of transferable embryos obtained per stimulation cycle, which is uncompromised by the unfavourable embryo competence otherwise observed in PCOS.

The effect of letrozole with misoprostol for medical termination of pregnancy on the expression of steroid receptors in the placenta.

STUDY QUESTION: What is the effect of letrozole on the expression of steroid receptors in the placentae in cases of termination of pregnancies? SUMMARY ANSWER: The expression of estrogen receptor-α (ERα) and progesterone receptor (PR) transcripts, as well as ERα protein, in placentae was suppressed by letrozole pretreatment in second trimester termination of pregnancy. WHAT IS KNOWN ALREADY: There have been no data in the literature on the effect of letrozole in termination of human pregnancies. STUDY DESIGN, SIZE, DURATION: This study is part of a clinical randomized trial in which 50 subjects were recruited and 44 placentae were collected. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women (n = 50) requesting second trimester abortion between 12 and 20 gestational weeks were randomized to receive either letrozole or placebo pretreatment for 3 days before administration of vaginal misoprostol. Placentae were collected from both groups of women after the abortion. Total RNA from the frozen placenta samples was extracted and subjected to real-time RT-PCR analysis of ERα and estrogen receptor-ß (ERß), PR and glucocorticoid receptor (GR) transcripts. Immunohistochemical studies of ERα, ERß, PR and GR expression, as well as Ki67 and PCNA staining for proliferation, were performed. TUNEL assays were performed to determine the extent of apoptosis. MAIN RESULTS AND THE ROLE OF CHANCE: Real-time RT-PCR demonstrated that the median ERα {3.900 [95% confidence interval (CI): -0.643-8.443] in the letrozole group versus 4.714 (95% CI: 1.776-7.652) in the control group; P = 0.005} and the median PR [0.701 (95% CI: 0.333-1.069) in the letrozole group versus 1.774 (95% CI: 1.07-2.478) in the control group; P = 0.003] were significantly lower in the letrozole group compared with the control group. Furthermore, ERα protein levels, in both syncytiotrophoblasts and cytotrophoblasts but not in villous stromal cells, were significantly reduced [H-score of 113 (95% CI: 103-119) in the letrozole group versus 217 (95% CI: 214-290) in the control group, in syncytiotrophoblasts; 100 (95% CI: 98-105) in the letrozole group versus 210 (95% CI: 200-286) in the control group, in cytotrophoblasts; P = 0.004], while the expression levels of ERß, PR, GR, PCNA, Ki67 and TUNEL were not significantly different between the two groups. LIMITATIONS, REASONS FOR CAUTION: Only the placentae from the second trimester termination of pregnancy were collected in this study. Information from first trimester terminations is still lacking. WIDER IMPLICATIONS OF THE FINDINGS: The results shed some light on the mechanism of action of letrozole pretreatment in termination of pregnancies. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the GRF/RGC and CRCG grants of the University of Hong Kong. TRIAL REGISTRATION NUMBER: HKClinicalTrials.com with trial number HKCTR-695.

Aromatase inhibitors for ovulation induction and ovarian stimulation.

Aromatase inhibitors (AIs) were originally developed for the treatment of advanced breast cancer in postmenopausal women. Their use in reproductive medicine has been extensively studied in the past decade. We reviewed the current strategies for ovulation induction for anovulatory women, mostly women with polycystic ovarian syndrome (PCOS), and the scientific basis for use of AIs in reproductive medicine. The AI, letrozole, is effective in ovulation induction in women with PCOS resistant to clomifene citrate and ovarian stimulation for intrauterine insemination and in vitro fertilization (IVF). Letrozole is an attractive option with its oral route of administration, cost, safety profile and effectiveness in ovulation induction and ovarian stimulation. Letrozole has the potential to be the first-line treatment option for ovulation induction in PCOS women, while its use in ovarian stimulation for IVF deserves further study.

A randomized comparison of pharmacokinetics of a single vaginal dose of dry misoprostol or misoprostol moistened with normal saline or with acetic acid.

BACKGROUND: The pharmacokinetics of vaginal misoprostol as a dry tablet or as a tablet moistened with normal saline or with acetic acid were studied. METHODS: For this study, 42 women requesting termination of pregnancy at gestational age of <12 weeks were recruited and received 400 µg vaginal misoprostol tablets. They were randomized into three groups: (i) dry tablets, (ii) tablets moistened with 3 ml of normal saline and (iii) tablets moistened with 3 ml of 5% acetic acid. Venous blood samples were taken at 0, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330 and 360 min after misoprostol administration. Misoprostol acid (MPA) was determined in serum samples using gas chromatography/tandem mass spectrometry. RESULTS: The serum peak MPA concentration (C(max)) was significantly higher and the time-to-peak concentration (T(max)) was significantly shorter in the normal saline and acetic acid groups, when compared with the dry tablet group. Both areas under the curve at 240 and 360 min (AUC(240) and AUC(360)) of the normal saline and acetic acid groups were also significantly greater than that of the dry tablet group. The coefficients of variation in C(max) and T(max) were highest in the normal saline group, while that of AUC(240) and AUC(360) were highest in the dry tablet group. The C(max) was significantly higher in subjects in the dry tablet group with vaginal pH < 5 than in those with pH 5. There were no significant differences in other pharmacokinetic parameters between subjects with vaginal pH < 5 and those with vaginal pH 5 in all three groups. CONCLUSIONS: Vaginal misoprostol tablets moistened with normal saline or 5% acetic acid achieved better absorption than the dry tablet. The use of vaginal misoprostol tablets moistened with normal saline or 5% acetic acid would potentially improve the clinical efficacy of misoprostol. HKClinicalTrials.com registration: HKCTR-821.

Sequential use of letrozole and gonadotrophin in women with poor ovarian reserve: a randomized controlled trial.

Sequential use of letrozole and human menopausal gonadotrophin (HMG) was compared with HMG only in poor ovarian responders undergoing IVF. Patients (n=53) with less than four oocytes retrieved in previous IVF cycles or less than five antral follicles were randomized to either letrozole for 5days followed by HMG or HMG alone. The letrozole group had lower dosage of HMG (P<0.001), shorter duration of HMG (P<0.001) and fewer oocytes (P=0.001) when compared with controls. Live-birth rate was comparable with a lower miscarriage rate in the letrozole group (P=0.038). Serum FSH concentrations were comparable in both groups except on day 8, while oestradiol concentrations were all lower in the letrozole group from day 4 (all P<0.001). Follicular fluid concentrations of testosterone, androstenedione, FSH and anti-Müllerian hormone were higher in the letrozole group (P=0.009, P=0.001, P=0.046 and P=0.034, respectively). Compared with HMG alone, sequential use of letrozole and HMG in poor responders resulted in significantly lower total dosage and shorter duration of HMG, a comparable live-birth rate, a significantly lower miscarriage rate and a more favourable hormonal environment of follicular fluid. The management of poor ovarian responders or women with poor ovarian reserve in IVF is controversial. The use of letrozole has been studied; however, results are inconsistent. This randomized trial studied the sequential use of letrozole and gonadotrophin compared with gonadotrophin alone in poor responders undergoing IVF. The sequential use of letrozole and gonadotrophin led to a significantly lower dosage and shorter duration of gonadotrophin use, significantly fewer oocytes, comparable live-birth rate, a significantly lower miscarriage rate and a more favourable hormonal environment at a lower cost.

Impact of positive hepatitis B surface antigen on the outcome of IVF treatment.

There has been controversy about the effect of hepatitis B virus (HBV) infection on pregnancy outcome after IVF treatment. A total of 1676 couples undergoing their first IVF cycle were included in this study. The prevalence of HBV infection in the female partners of the subfertile population seeking treatment with assisted reproductive technology was 7.8-9.6% during the study period. The ongoing pregnancy rate was not significantly different between couples with HBV-seropositive wives and seronegative ones (26.7% versus 30.2%). The ongoing pregnancy rate and the live-birth rate of couples with both partners being HBV surface antigen positive was not significantly different from couples with discordant HBV serostatus and those couples with both partners being HBV surface antigen negative (23% versus 29% versus 30%, respectively; 23% versus 27% versus 27%, respectively). The percentage of normal sperm morphology in HBV-seropositive husbands was significantly lower than that of seronegative counterparts (5.0% versus 10.0%, P=0.009). In conclusion, there was no adverse effect of HBV infection on the assisted reproduction outcomes. This study was the first report on the live-birth rate of hepatitis B (HBV) seropositive couples, revealing the effect on the pregnancy outcome of IVF. The prevalence of HBV infection in the female partners of subfertile population seeking treatment with ART was 7.8-9.6%. Both the ongoing pregnancy rate and live-birth rate were not significantly different among couples with both partners being positive for HBV surface antigen, couples with discordant HBV serostatus and those couples with both partners being negative for HBV surface antigen. The percentage of normal sperm morphology in HBV-seropositive husbands was significantly lower than that of seronegative counterparts.

Preimplantation genetic diagnosis for monogenic diseases.

Preimplantation genetic diagnosis (PGD) was first reported in 1990. Thereafter, more and more indications for PGD, including monogenic diseases (MGD) and translocations, are presently available, and the list of indications of PGD is expanding from early-onset and serious conditions to late-onset diseases. Polymerase chain reaction has been used for PGD of MGD, while newer techniques, including karyomapping and next-generation sequencing, emerge in recent decade. The limitations of various methods for PGD are discussed in this review.

The effect of 7 days of letrozole pretreatment combined with misoprostol on the expression of progesterone receptor and apoptotic factors of placental and decidual tissues from first-trimester abortion: a randomized controlled trial.

OBJECTIVE: To evaluate if letrozole-induced suppression of estradiol reduces progesterone receptor expression and apoptosis in the first-trimester placenta. STUDY DESIGN: We performed a double-blinded, randomized, placebo-controlled trial. We randomized 20 women requesting first-trimester abortion with gestation up to 63 days to receive either letrozole 10 mg daily or placebo pretreatment for 7 days before administrating 400 mcg of vaginal misoprostol followed by suction abortion. We collected the placental and decidual tissues on which we performed immunohistochemical staining for progesterone receptor and apoptotic markers (active caspase 3, caspase 3, Bcl2, CD95, fas ligand) and determined H-scores of each based on the intensities of staining. We performed terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL) assay for apoptosis in the samples of four women to confirm the findings from apoptotic markers. RESULTS: We excluded one woman in the letrozole group from the analysis because she had passage of abortus after taking letrozole, leaving 19 women (9 in the letrozole group, 10 in the placebo group) for analysis. There was no significant difference in the H-scorings of progesterone receptor and apoptotic markers, as well as proportion of apoptotic cells on TUNEL assay between the two groups. The H-scores for the progesterone receptor were 8.17 ± 2.67 (mean ± SD) in the letrozole group and 9.01 ± 2.82 in the placebo group (p=0.36). CONCLUSION: We did not detect a difference in the expression of progesterone receptor and apoptotic markers in placental and decidual tissues after letrozole pretreatment for 7 days in first-trimester abortion. IMPLICATIONS: We did not confirm the hypothesis that letrozole reduces progesterone receptor expression and induces apoptosis in the first-trimester placenta. Further studies are required to allow better understanding of the mechanism by which estrogen suppression following the use of letrozole can lead to improved abortion rate in the first trimester.

A randomized double-blind controlled trial of the use of dydrogesterone in women with threatened miscarriage in the first trimester: study protocol for a randomized controlled trial.

BACKGROUND: Miscarriage is a common complication of pregnancy occurring in 15-20 % of all clinically recognized pregnancies. Currently, there is still no good scientific evidence to support the routine use of progestogens for the treatment of threatened miscarriage because the existing studies were not large enough to show a significant difference and some of them were not randomized or double-blind. METHODS: This is a double-blind, randomized controlled trial. A total of 400 patients presenting with first-trimester threatened miscarriage will be enrolled. They will be randomized to take dydrogesterone 40 mg per os, followed by 10 mg per os three times a day or placebo until twelve completed weeks of gestation or 1 week after the bleeding has stopped, whichever is longer. The primary outcome is the percentage of miscarriage before 20 weeks of gestation. DISCUSSION: We postulate that the dydrogesterone therapy will significantly reduce the risk of miscarriage in women with threatened miscarriage. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov, NCT02128685 . Registered on 29 April 2014.

Live birth and cumulative live birth rates in expected poor ovarian responders defined by the Bologna criteria following IVF/ICSI treatment.

OBJECTIVE: To determine the live birth and cumulative live birth rates of expected poor ovarian responders according to the Bologna criteria and to compare their outcomes with those of expected normal responders. DESIGN: Retrospective analysis. SETTING: University infertility clinic. PATIENTS: A total of 1,152 subfertile women undergoing their first in vitro fertilization (IVF) cycle. INTERVENTIONS: Women were classified into 4 groups according to the Bologna criteria for comparison. MAIN OUTCOME MEASURE(S): Live birth and cumulative live birth rates. RESULTS: Women with expected poor response (POR) had the lowest live birth rate than the other 3 groups (23.8%, p = 0.031). Cumulative live birth rates were significantly lower in those with expected POR than those with expected normal ovarian response (NOR) (35.8% vs 62.8%, p<0.0001). In the subgroup analysis, the cumulative live birth rates in expected PORs were significantly lower in those who had ≤3 oocytes retrieved (18.6% for ≤3 oocytes vs 44.0% for >3 oocytes, p = 0.006) whereas the live birth rates in fresh cycle did not differ (17.8% vs 30.9%, p = 0.108). CONCLUSION: Women who were expected POR according to the Bologna criteria had lower live birth and cumulative live birth than expected NOR but they still can achieve reasonable treatment outcomes and IVF treatment should not be precluded.

Ovarian response and cumulative live birth rate of women undergoing in-vitro fertilisation who had discordant anti-Mullerian hormone and antral follicle count measurements: a retrospective study.

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.

Effect of preovulatory progesterone elevation and duration of progesterone elevation on the pregnancy rate of frozen-thawed embryo transfer in natural cycles.

OBJECTIVE: To assess the incidence of P elevation (PE) in natural cycles and evaluate its effect on frozen-thawed embryo transfer cycles performed in natural cycles (FET-NC). STUDY DESIGN: Retrospective analysis. SETTING: A tertiary assisted reproductive unit. PATIENT(S): Subfertile woman who did not conceive in their stimulated IVF cycle and underwent the first FET-NC cycle. INTERVENTION(S): Achieved serum samples were assayed for P concentrations from the day of LH surge up to 3 days before the surge. The cutoff level of PE was defined as 5 nmol/L. MAIN OUTCOME MEASURE(S): Clinical and ongoing pregnancy rates. RESULT(S): The incidence of PE in natural cycles was 173 of 610 (28.4%). There were no significant differences in both clinical and ongoing pregnancy rates (39.0% vs. 37.3% and 32.5% vs. 31.7%) between those with vs. without PE on the day of LH surge. If PE lasted for 2 days or more, there was a significant reduction in the clinical pregnancy rate (39.4% vs. 20.7%). Using multivariate logistic regression, women's age, PE for 2 days or more, and the number of top-quality embryos were the significant factors for clinical pregnancy rates in FET-NC. CONCLUSION(S): The incidence of PE in FET-NC was similar to that in stimulated cycles. Progesterone elevation for 2 days or more before the LH surge impaired the clinical pregnancy rate of FET-NC, whereas PE on the day of LH surge only did not have such an adverse effect.

A randomized, controlled, pilot trial on the effect of dehydroepiandrosterone on ovarian response markers, ovarian response, and in vitro fertilization outcomes in poor responders.

OBJECTIVE: To evaluate whether pretreatment dehydroepiandrosterone (DHEA) supplementation improves ovarian response markers, ovarian response to standard low-dose gonadotropin stimulation, and in vitro fertilization (IVF) outcomes in poor responders. DESIGN: Randomized, double-blind, placebo-controlled pilot study. SETTING: Tertiary reproductive medicine unit. PATIENT(S): Thirty-two women with anticipated poor ovarian response. INTERVENTION(S): Randomization into DHEA group (n=16) receiving GNC (25 mg three times a day) or placebo (n=16) starting from at least 12 weeks before the scheduled IVF treatment according to a computer-generated randomization list. MAIN OUTCOME MEASURE(S): Measurement of monthly ovarian response markers, including antral follicle count (AFC), serum antimüllerian hormone (AMH), and follicle-stimulating hormone (FSH) levels; comparison of ovarian response to a standard dose of gonadotropin stimulation at week 8 and IVF outcomes; and AFC after 12 weeks (primary outcome). RESULT(S): The DHEA supplementation resulted in statistically significantly higher serum DHEA-S, free androgen index, and follicular DHEA-S levels. No statistically significant differences in the ovarian response markers (AFC, AMH, or FSH), the ovarian response to standard-dose gonadotropin stimulation, or IVF outcomes were found between the two groups. CONCLUSION(S): No statistically significant improvement in ovarian response markers, ovarian response to standard dose gonadotropin stimulation, or IVF outcomes was found in poor responders receiving pretreatment DHEA. CLINICAL TRIAL REGISTRATION NUMBER: HKCTR-1149 (www.hkclinicaltrials.com) and NCT01915186 (www.ClinicalTrials.org).

Luteal phase support does not improve the clinical pregnancy rate of natural cycle frozen-thawed embryo transfer: a retrospective analysis.

OBJECTIVE: To evaluate pregnancy outcomes with and without use of luteal phase support (LPS) in frozen-thawed embryo transfer (FET) performed in natural cycles (NC). STUDY DESIGN: Retrospective analysis. Before 1st July 2009, two doses of 1500 IU intramuscular human chorionic gonadotrophin were given on the day of FET and 6 days after the transfer. Such practice was stopped after 1st July 2009. The pregnancy outcomes of NC FET with and without LPS were compared. RESULTS: A total of 408 NC FET cycles were analysed. Demographic data, embryo quality, clinical pregnancy rates and miscarriage rates were comparable with and without LPS. By univariate logistic regression, the only significant factors predicting the clinical pregnancy rate were the women's age, the number of embryos transferred, the number of top quality embryos before and after cryopreservation, and the average number of blastomeres after thawing. Only the women's age (OR 0.944, 95%C.I. 0.893-0.998, p=0.044) remained to be a significant predictor of clinical pregnancy rate by multivariate logistic regression. CONCLUSION: The pregnancy outcomes of NC FET were similar with or without LPS. The women's age was the significant factor affecting the clinical pregnancy rate. A randomised trial should be carried out to confirm the results.