Comparison of antral follicle count and serum anti Müllerian hormone level for determination of gonadotropin dosing in in-vitro fertilization: randomized trial.

OBJECTIVE: To compare the proportion of women achieving a desired ovarian response following ovarian stimulation when gonadotropin dosing was determined based on antral follicle count (AFC) vs serum anti-Müllerian hormone (AMH) level, in women undergoing in-vitro fertilization (IVF) using the gonadotropin-releasing hormone (GnRH) antagonist protocol. METHODS: This was a randomized double-blind trial carried out in a university-affiliated assisted reproduction unit. A total of 200 women undergoing their first IVF cycle using the GnRH-antagonist protocol between April 2016 and February 2018 were randomized to determination of gonadotropin dosing based on either AFC or serum AMH level measured in the pretreatment cycle 1 month before the IVF cycle. Patients underwent IVF as per our center's standard protocol. The proportion of subjects achieving a desired ovarian response, defined as retrieval of six to 14 oocytes, was compared between the two study arms. Subgroup analysis of patients with baseline AFC > 5 and those with baseline AFC ≤ 5 was performed. Concordance in AFC and AMH categorization between the pretreatment cycle and the ovarian-stimulation cycle was assessed using Cohen's kappa (κ). RESULTS: There was no significant difference in the proportion of patients achieving a desired ovarian response between the AFC (54%) and AMH (49%) groups (P = 0.479). The median number of oocytes retrieved was nine vs seven (P = 0.070), and the median follicular output rate was 0.54 vs 0.55 (P = 0.764) in the AFC and AMH groups, respectively. Similar findings were observed on subgroup analysis of subjects with AFC ≤ 5 and AFC > 5 at the start of ovarian stimulation (P > 0.05 for all comparisons). There was moderate concordance between AFC and AMH measured in the pretreatment cycle and the stimulation cycle (κ = 0.478 and 0.587, respectively). CONCLUSION: The proportion of women achieving a desired ovarian response following ovarian stimulation using the GnRH-antagonist protocol is similar when the gonadotropin-dosing algorithm used is based on AFC or serum AMH level. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Comparación del recuento de folículos sinusales y el nivel de la hormona antimulleriana en el suero para la determinación de la dosis de gonadotrofina en la fecundación in vitro: ensayo aleatorizado OBJETIVO: Comparar la proporción de mujeres que logran una respuesta ovárica deseada tras la estimulación del ovario cuando se determinó la dosis de gonadotrofina en función del recuento de folículos sinusales (AFC, por sus siglas en inglés) frente al nivel de la hormona antimulleriana (HAM) en el suero, en mujeres que se sometieron a una fecundación in vitro (FIV) mediante el protocolo de antagonistas de la hormona liberadora de gonadotropina (GnRH, por sus siglas en inglés). MÉTODOS: Se trata de un ensayo aleatorizado doble ciego realizado en una unidad de reproducción asistida afiliada a una universidad. Un total de 200 mujeres que se sometieron a su primer ciclo de FIV y utilizaron el protocolo de antagonistas de la GnRH entre abril de 2016 y febrero de 2018 fueron asignadas al azar a la determinación de la dosis de gonadotrofina basada en el nivel de AFC o de HAM en suero, medidos en el ciclo de pretratamiento un mes antes del ciclo de FIV. Las pacientes se sometieron a una FIV según el protocolo estándar de nuestro centro. La proporción de mujeres que lograron una respuesta ovárica deseada, definida como la recuperación de seis a 14 ovocitos, se comparó entre las dos ramas del estudio. Se realizó un análisis de subgrupos de las pacientes con AFC de base >5 y de aquellas con AFC de base ≤5. La concordancia en la categorización del AFC y la HAM entre el ciclo de pretratamiento y el ciclo de estimulación ovárica se evaluó utilizando la medida estadística kappa de Cohen (κ). RESULTADOS: No hubo diferencias significativas en la proporción de pacientes que lograron una respuesta ovárica deseada entre los grupos de AFC (54%) y HAM (49%) (P=0,479). La mediana del número de ovocitos recuperados fue de nueve frente a siete (P=0,070), y la mediana de la tasa de producción folicular fue de 0,54 frente a 0,55 (P=0,764) en los grupos AFC y HAM, respectivamente. Se observaron hallazgos similares en el análisis de subgrupos de pacientes con AFC ≤5 y AFC >5 al comienzo de la estimulación ovárica (P>0,05 para todas las comparaciones). Se observó una concordancia moderada entre el AFC y la HAM medidos en el ciclo de pretratamiento y el ciclo de estimulación (κ=0,478 y 0,587, respectivamente). CONCLUSIÓN: La proporción de mujeres que logran una respuesta ovárica deseada después de la estimulación ovárica utilizando el protocolo de antagonistas de la GnRH es similar cuando el algoritmo de dosificación de gonadotrofina utilizado se basa en el nivel del AFC o de la HAM en suero.

Efficacy of ulipristal acetate for emergency contraception and its effect on the subsequent bleeding pattern when administered before or after ovulation.

STUDY QUESTION: Does ulipristal acetate (UPA) have similar efficacy as emergency contraception (EC) when administered before and after ovulation? SUMMARY ANSWER: The efficacy of UPA-EC was significantly better when administered before than after ovulation. WHAT IS KNOWN ALREADY: Levonorgestrel (LNG) is effective as EC only when administered before, but not after ovulation. LNG EC taken in the pre-ovulatory and post-ovulatory phase results in shortening and lengthening of the index menstrual cycle, respectively. Whether the same applies to UPA is not known. STUDY DESIGN, SIZE, DURATION: Prospective, open-label clinical cohort study conducted on 700 women between May 2011 and March 2014. PARTICIPANTS, SETTING, METHODS: Seven hundred women requesting EC within 120 h after a single act of unprotected sexual intercourse in the index menstrual cycle were recruited at a community family planning clinic in Hong Kong. Each subject received a single oral dose of UPA 30 mg, and 693 of them completed follow-up. Ovulatory status at the time of UPA administration was determined by serum progesterone level supplemented by menstrual history and ultrasound tracking. The main outcome measure was the percentage of pregnancies prevented (PPP). MAIN RESULTS AND THE ROLE OF CHANCE: The PPP was significantly higher in subjects who were pre-ovulatory (77.6%) compared with those who were post-ovulatory (36.4%) at the time of UPA administration (P < 0.0001). The observed pregnancy rate following UPA administration was significantly lower than the expected pregnancy rate only in the pre-ovulatory group (P < 0.0001), but not the post-ovulatory group (P = 0.281). The overall failure rate was 1.7% (1.4 versus 2.1% in the pre- and post-ovulatory groups, respectively). Pre-ovulatory administration of UPA resulted in a small delay (median of 3 days), whereas post-ovulatory administration resulted in a minimal advancement (median of 1 day) of the next menstruation, compared with that predicted from previous menstrual pattern. More pre-ovulatory subjects (19.1%) than post-ovulatory subjects (7.8%) had deviation of the next menses of more than 7 days (P < 0.001). LIMITATIONS, REASONS FOR CAUTION: The ovulatory status of the subjects was determined based only on menstrual history and a spot sonographic finding together with serum hormonal profile at the time of recruitment. WIDER IMPLICATIONS OF THE FINDINGS: Our findings confirmed comparable efficacy of UPA in the Asian population as in western populations. The comparison between pre- and post-ovulatory use of UPA is a novel finding, which provides insights to its possible pharmacological action. STUDY FUNDING/COMPETING INTERESTS: The UPA tablets were provided free of charge by Laboratoire HRA Pharma, who were not involved in the design and execution of the study, or the drafting and final approval of the manuscript. The authors have no other conflicts of interest to declare. TRIAL REGISTRATION NUMBER: The University of Hong Kong Clinical Trials Registry (reference number: HKUCTR-1197).

Comparative evaluation of three new commercial immunoassays for anti-Müllerian hormone measurement.

STUDY QUESTION: How do the three new anti-Müllerian hormone (AMH) assay methods, manufactured by Beckman Coulter, Roche and Ansh Labs compare with each other and with the Gen II assay? SUMMARY ANSWER: The three new AMH assays are well correlated among themselves and with the Gen II assay, although differences in calibration do exist. WHAT IS KNOWN ALREADY: The Gen II assay has been the mainstay method for AMH measurement in the past few years. Recently, a few new AMH measurement methods have come to the market. STUDY DESIGN, SIZE, DURATION: This was a prospective assay evaluation performed on 178 human serum samples. PARTICIPANTS/MATERIALS, SETTING, METHODS: AMH concentration was measured in residual serum samples donated by female patients in a reproductive medicine centre. The three new assay methods were tested in parallel and the numerical values obtained were compared among themselves and with those obtained by the Gen II assay. The assay stability upon different sample storage conditions, intra-assay and inter-assay precision, linearity and dilution recovery, and diagnostic performance for polycystic ovary syndrome (PCOS) of the three new AMH assay methods were also compared. MAIN RESULTS AND THE ROLE OF CHANCE: AMH values measured by the Gen II kit and the three new assay methods have good correlations (R > 0.9 for all pairwise correlations). Values measured by the Ansh Labs assay were significantly higher, whereas those by the Roche assay were significantly lower, than those from the Gen II and Beckman-Coulter automated assays (P < 0.05). AMH values were significantly different when measured on the fresh and frozen-thawed serum sample (at -20oC and -80oC) for all three new methods (P < 0.05), but the magnitude of difference was very small with the Beckman-Coulter automated assay and Roche assay. The intra-assay coefficients of variation (CVs) were 0.7-2.2%, 0.5-1.4%, and 1.4-5.4% for the Beckman-Counter automated, Roche and Ansh Labs assays, respectively. Their inter-assay CVs were 0.9-2.5%, 0.7-1.9%, and 6.2-13.5%, respectively. All three new assay methods showed acceptable linearity, and provided excellent discrimination of PCOS from controls. LIMITATIONS, REASONS FOR CAUTION: The precision and dilution linearity experiments involved a small sample size, although these were not the primary outcome measures and have been properly evaluated in previous publications. The study was not designed or powered for determining diagnostic cut-off values. WIDER IMPLICATIONS OF THE FINDINGS: The results demonstrate that the three new AMH assay methods are all valid methods to be adopted in the field of reproduction and are a basis for further work on their clinical application. STUDY FUNDING/COMPETING INTERESTS: The authors have no competing interest to declare. The execution of this study was funded by the Department of Obstetrics and Gynaecology, The University of Hong Kong.

Screening for dysglycaemia by oral glucose tolerance test should be recommended in all women with polycystic ovary syndrome.

STUDY QUESTION: Should fasting glucose (FG) or an oral glucose tolerance test (OGTT) be used to screen for dysglycaemia in women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: A full OGTT should be recommended as the screening method for dysglycaemia in women with PCOS, regardless of BMI or family history of diabetes mellitus (DM). STUDY DESIGN, SIZE, DURATION: A cross-sectional study on 467 Chinese women diagnosed with PCOS by the Rotterdam criteria between January 2010 to December 2013. PARTICIPANTS, SETTING, METHODS: The study was done at a university hospital in Hong Kong. All subjects underwent a 75 g OGTT after overnight fasting. We evaluated the performance of FG alone, when compared with the full OGTT, in identifying subjects with dysglycaemia (prediabetes or DM, according to the 2010 diagnostic criteria of the American Diabetes Association). MAIN RESULTS AND THE ROLE OF CHANCE: Of the 467 subjects, 58 (12.4%) had dysglycaemia, among which 46 (9.8%) had prediabetes and 12 (2.6%) had DM, including 4 with known DM. Of the 46 subjects with prediabetes, 25 (54.3%) had normal FG and of the 8 subjects with screened DM in this study, 1 (12.5%) had normal FG. The sensitivity of FG alone in screening for prediabetes, DM and overall dysglycaemia were 45.7, 87.5 and 48.1%, respectively, i.e. missing 54.3% of prediabetes and 12.5% of DM cases as defined by the OGTT. Among the 54 subjects with screened dysglycaemia, 20 (37.0%) had BMI < 25 kg/m(2) and 35 (64.8%) had no family history of DM. LIMITATIONS, REASONS FOR CAUTION: We only reported on the biochemical diagnosis of DM based on a single time point. In clinical practice, confirmatory results at another time point is required for definitive diagnosis in asymptomatic subjects. WIDER IMPLICATIONS OF THE FINDINGS: There is an ongoing debate as to whether FG or an OGTT should be used as a screening method for dysglycaemia in women with PCOS. Some guidelines also recommend glucose screening only in those who are overweight and/or having family history of diabetes (DM). There have been scarce data on this issue in the Chinese population, which the current study aims at addressing. STUDY FUNDING/COMPETING INTERESTS: The study was supported by a research grant from the Hong Kong Obstetrical and Gynaecological Trust Fund, as well as internal research funding of the Department of Obstetrics and Gynaecology, The University of Hong Kong. All authors have no competing interests.

Effect of leptin on motility, capacitation and acrosome reaction of human spermatozoa.

Leptin is a polypeptide hormone with important roles in reproduction. It has been detected in human seminal plasma as well as on human ejaculated spermatozoa. This study aimed at studying the possible role of leptin in regulating human sperm functions. Immunofluorescent staining was used to study the expression of leptin and its receptor. The correlation between the concentration of leptin and soluble leptin receptor (ObRs) in seminal plasma as measured by enzyme-linked immunosorbant assay and sperm motility parameters measured by computer-assisted sperm analysis (CASA) was determined. The effects of recombinant leptin on human sperm motility, capacitation and acrosome reaction as measured by chlortetracycline staining were also studied. Leptin immunoreactivity was demonstrated at the equatorial and neck regions of human spermatozoa, whereas that of ObRs was shown up on the tail. After Percoll separation, spermatozoa with high density had more intense leptin immunoreactivity compared with those with low density. No significant correlation was found between seminal plasma concentration of leptin/ObRs and sperm motility parameters. After incubation with recombinant human leptin for either 3 h or overnight, there was no change in all the CASA motility parameters determined and percentages of capacitated and acrosome-reacted spermatozoa. We concluded that leptin does not have a significant effect on motility and capacitation/acrosome reaction in human ejaculated mature spermatozoa. Its role in male reproduction is yet to be determined.

Possible role of adrenomedullin in the pathogenesis of tubal ectopic pregnancy.

CONTEXT: Tubal ectopic pregnancy (tEP) is currently the leading cause of pregnancy-related deaths during the first trimester. Our current knowledge on the molecular pathogenesis is limited. OBJECTIVE: The objective of the study was to find out the possible role of adrenomedullin (ADM) in the pathogenesis of tEP. DESIGN: This was an experimental in vitro study on oviductal tissue. SETTING: The study was conducted at a university teaching hospital. PATIENTS AND INTERVENTIONS: Patients included those having oviducts removed surgically during salpingectomy for tEP or hysterectomy for benign gynecological conditions. Oviductal tissues were incubated in hormonal condition mimicking early pregnancy before used for in vitro experiments. MAIN OUTCOME MEASURES: Plasma ADM concentration, oviductal expression of ADM and its receptors, ciliary beat frequency, smooth muscle contraction were measured. RESULTS: The ciliary beat frequency and frequency of muscle contraction were lower in the oviducts from patients with tEP than those from simulated normal pregnancy. The plasma and oviductal tissue ADM levels were also lower. The decreases in ciliary beat and frequency of contraction were restored to normal after ADM treatment. CONCLUSIONS: The results suggest that the lower ADM level in the oviducts of tEP may lead to the decrease in ciliary beating and muscle contraction, with the result that the embryo is retained and implanted in the oviduct. Our findings explain for the first time the etiology of tubal pregnancy on the basis of an impairment of the transport of the fertilized ovum resulting from an ADM deficiency and raise the possibility of using the plasma ADM level as a predictor for tubal ectopic pregnancy.

Effect of local lignocaine gel application for pain relief during suction termination of first-trimester pregnancy: a randomized controlled trial.

BACKGROUND: This study evaluated the effectiveness of local lignocaine gel application in pain control during first-trimester suction termination of pregnancy (STOP). METHODS: In this prospective randomized placebo-controlled double-blind trial, 131 women undergoing STOP between 7 and 10 weeks of gestation were studied. They were computer-randomized to receive 2% lignocaine gel or placebo (KY Jelly) locally applied to the cervix 1 min before cervical manipulation/dilatation. They all had cervical priming with misoprostol and premedication with diazepam and pethidine. Pain scores on a verbal analogue scale preoperative, at cervical manipulation/dilatation, intraoperative and 1 h post-operative, as well as the patients' satisfaction level towards pain control, were compared. RESULTS: The lignocaine gel group had significantly reduced overall intraoperative pain score compared with placebo group (P = 0.021). No significant difference in pain score between the two groups was demonstrated at other time points. Subgroup analysis revealed that the difference in overall intraoperative pain scores between the two groups was evident in the multiparous (P = 0.015) but not the nulliparous subjects. CONCLUSION: The use of local lignocaine gel application reduces overall intraoperative pain in multiparous women undergoing first-trimester STOP preceded by misoprostol cervical priming and premedication for conscious sedation.