Reduced FSH and LH action: implications for medically assisted reproduction.

Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) play complementary roles in follicle development and ovulation via a complex interaction in the hypothalamus, anterior pituitary gland, reproductive organs, and oocytes. Impairment of the production or action of gonadotropins causes relative or absolute LH and FSH deficiency that compromises gametogenesis and gonadal steroid production, thereby reducing fertility. In women, LH and FSH deficiency is a spectrum of conditions with different functional or organic causes that are characterized by low or normal gonadotropin levels and low oestradiol levels. While the causes and effects of reduced LH and FSH production are very well known, the notion of reduced action has received less attention by researchers. Recent evidence shows that molecular characteristics, signalling as well as ageing, and some polymorphisms negatively affect gonadotropin action. These findings have important clinical implications, in particular for medically assisted reproduction in which diminished action determined by the afore-mentioned factors, combined with reduced endogenous gonadotropin production caused by GnRH analogue protocols, may lead to resistance to gonadotropins and, thus, to an unexpected hypo-response to ovarian stimulation. Indeed, the importance of LH and FSH action has been highlighted by the International Committee for Monitoring Assisted Reproduction Technologies (ICMART) in their definition of hypogonadotropic hypogonadism as gonadal failure associated with reduced gametogenesis and gonadal steroid production due to reduced gonadotropin production or action. The aim of this review is to provide an overview of determinants of reduced FSH and LH action that are associated with a reduced response to ovarian stimulation.

Outcome of assisted reproduction in women with congenital uterine anomalies: a prospective observational study.

OBJECTIVES: To assess the prevalence of congenital uterine anomalies, including arcuate uterus, and their effect on reproductive outcome in subfertile women undergoing assisted reproduction. METHODS: Consecutive women referred for subfertility between May 2009 and November 2015 who underwent assisted reproduction were included in the study. As part of the initial assessment, each woman underwent three-dimensional transvaginal sonography. Uterine morphology was classified using the modified American Fertility Society (AFS) classification of congenital uterine anomalies proposed by Salim et al. If the external contour of the uterus was uniformly convex or had an indentation of < 10 mm, but there was a cavity indentation, it was defined as arcuate or septate. Arcuate uterus was further defined as the presence of a concave fundal indentation with a central point of indentation at an obtuse angle. Subseptate uterus was defined as the presence of a septum, not extending to the cervix, with the central point of the septum at an acute angle; if the septum extended to the internal cervical os, the uterus was defined as septate. Reproductive outcomes, including live birth, clinical pregnancy and preterm birth, were compared between women with a normal uterus and those with a congenital uterine anomaly. Subgroup analysis by type of uterine morphology and logistic regression analysis adjusted for age, body mass index, levels of anti-Müllerian hormone, antral follicle count and number and day of embryo transfer were performed. RESULTS: A total of 2375 women were included in the study, of whom 1943 (81.8%) had a normal uterus and 432 (18.2%) had a congenital uterine anomaly. The most common anomalies were arcuate (n = 387 (16.3%)) and subseptate (n = 16 (0.7%)) uterus. The rate of live birth was similar between women with a uterine anomaly and those with a normal uterus (35% vs 37%; P = 0.47). The rates of clinical pregnancy, mode of delivery and sex of the newborn were also similar between the two groups. Preterm birth before 37 weeks' gestation was more common in women with uterine anomalies than in controls (22% vs 14%, respectively; P = 0.03). Subgroup analysis by type of anomaly showed no difference in the incidence of live birth and clinical pregnancy for women with an arcuate uterus, but indicated worse pregnancy outcome in women with other major anomalies (P = 0.042 and 0.048, respectively). CONCLUSIONS: Congenital uterine anomalies as a whole, when defined using the modified AFS classification, do not affect clinical pregnancy or live-birth rates in women following assisted reproduction, but do increase the incidence of preterm birth. The presence of uterine abnormalities more severe than arcuate uterus significantly worsens all pregnancy outcomes. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

A qualitative study of the impact of endometriosis on male partners.

STUDY QUESTION: What is the impact of endometriosis on male partners of women with the condition? SUMMARY ANSWER: Endometriosis significantly impacts men across several life domains and can negatively impact emotional well-being. WHAT IS KNOWN ALREADY: Endometriosis has been shown to negatively impact women's quality of life and may strain intimate relationships. Little is known about the impact on male partners. STUDY DESIGN, SIZE, DURATION: The ENDOPART study was a cross-sectional, qualitative study of 22 women with endometriosis and their male partners (n = 44) in the UK (2012-2013). PARTICIPANTS/MATERIALS, SETTING, METHODS: Inclusion criteria: laparoscopic diagnosis of endometriosis; the presence of symptoms for at least a year; partners living together. Data were collected via face to face, semi structured interviews with partners interviewed separately. Data were analysed thematically, assisted by NVivo 10. MAIN RESULTS AND THE ROLE OF CHANCE: Men reported that endometriosis affected many life domains including sex and intimacy, planning for and having children, working lives and household income. It also required them to take on additional support tasks and roles. Endometriosis also had an impact on men's emotions, with responses including helplessness, frustration, worry and anger. The absence of professional or wider societal recognition of the impact on male partners, and a lack of support available to men, results in male partners having a marginalized status in endometriosis care. LIMITATIONS REASONS FOR CAUTION: Self-selection of participants may have resulted in a sample representing those with more severe symptoms. Couples included are in effect 'survivors' in relationship terms, therefore, findings may underestimate the contribution of endometriosis to relationship breakdown. WIDER IMPLICATIONS OF THE FINDINGS: The study extends knowledge about the impact of endometriosis on relationships, which thus far has been drawn largely from studies with women, by providing new insights about how this condition affects male partners. Healthcare practitioners need to take a more couple-centred, biopsychosocial approach toward the treatment of endometriosis, inclusive of partners and relationship issues. The findings demonstrate a need for information and support resources aimed at partners and couples. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Economic and Social Research Council (reference ES/J003662/1). The authors have no conflicts of interest.

Use of double decidual sac sign to confirm intrauterine pregnancy location prior to sonographic visualization of embryonic contents.

OBJECTIVES: To determine the diagnostic accuracy of the double decidual sac sign (DDSS) for predicting an intrauterine pregnancy (IUP) prior to visualization of embryonic contents, using modern high-resolution transvaginal sonography (TVS). METHODS: The study was conducted following STARD guidelines and participants were recruited prospectively from Nurture Fertility, Nottingham, UK, following in-vitro fertilization/intracytoplasmic sperm injection treatment between 1 January 2015 and 31 October 2015. Women were excluded if there was no evidence of intrauterine fluid collection during the index test, a yolk sac or fetal pole was visible during the index test, no outcome data were available or pregnancy location could not be determined by the reference standard. The index test consisted of TVS at 32-34 days' gestation using a high-frequency transvaginal probe. Reference standard was TVS at 7 weeks' gestation. The outcome of interest was an IUP. RESULTS: A total of 67 intrauterine fluid collections were observed and included in the analysis, of which 61 exhibited the DDSS and 65 were proven to be IUPs. Two ectopic pregnancies were included, neither of which demonstrated the DDSS. The DDSS therefore had a sensitivity of 93.9% (95% CI, 85.0-98.3%), specificity of 100% (95% CI, 15.8-100%) and overall diagnostic accuracy of 94.0% (95% CI, 88.3-99.7%) for predicting an IUP. The negative likelihood ratio and positive and negative predictive values were 0.06 (95% CI, 0.02-0.16), 100% (95% CI, 94.1-100%) and 33.3% (95% CI, 4.3-77.7%), respectively. CONCLUSION: With modern high-resolution TVS, presence of the DDSS can be used to confirm accurately IUP location prior to sonographic visualization of embryonic contents, and therefore to exclude effectively ectopic pregnancy. Absence of the DDSS, however, does not preclude an IUP. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Anxiety associated with diagnostic uncertainty in early pregnancy.

OBJECTIVES: To determine anxiety levels of women presenting to an early pregnancy assessment unit (EPAU) with abdominal pain and/or vaginal bleeding and to assess how these levels change over time and according to ultrasonographic diagnosis. METHODS: We undertook a prospective cohort study in an EPAU in a large UK teaching hospital. Women with abdominal pain and/or vaginal bleeding in early pregnancy (< 12 weeks' gestation) presenting for the first time were eligible for inclusion in the study. State anxiety levels were assessed using the standardized short form of Spielberger's state-trait anxiety inventory (STAI) on three occasions (before, immediately after and 48-72 hours after an ultrasound scan). Scores were correlated with ultrasonographic diagnosis. The diagnosis was either certain or uncertain. Certain diagnoses were either positive, i.e. a viable intrauterine pregnancy (IUP), or negative, i.e. a non-viable IUP or ectopic pregnancy. Uncertain diagnoses included pregnancy of unknown location and pregnancy of uncertain viability. Statistical analysis involved mixed ANOVAs and the post-hoc Tukey-Kramer test. RESULTS: A total of 160 women were included in the study. Anxiety levels decreased over time for women with a certain diagnosis (n = 128), even when negative (n = 64), and increased over time for women with an uncertain diagnosis (n = 32). Before the ultrasound examination, anxiety levels were high (STAI value, 21.96 ± 1.11) and there was no significant difference between the five groups. Immediately after the ultrasound examination, anxiety levels were lower in the viable IUP group (n = 64; 7.75 ± 1.13) than in any other group. The difference between the five groups was significant (P < 0.005). After 48-72 hours, women with a certain diagnosis had significantly lower anxiety levels than had those with an uncertain diagnosis (10.77 ± 4.30 vs 22.94 ± 1.65; P < 0.005). CONCLUSIONS: The experience of abdominal pain and/or vaginal bleeding in early pregnancy is highly anxiogenic. Following an ultrasound examination, the certainty of the diagnosis affects anxiety levels more than does the positive or negative connotations associated with the diagnosis per se. Healthcare providers should be aware of this when communicating uncertain diagnoses. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Strategies for improving outcome of assisted reproduction in women with polycystic ovary syndrome: systematic review and meta-analysis.

OBJECTIVES: To identify, appraise and summarize the current evidence regarding the efficacy of strategies aimed at improving assisted reproductive techniques in women with polycystic ovary syndrome (PCOS). METHODS: A comprehensive literature search of the standard medical databases was performed. The last electronic search was run in July 2015. The primary outcome measures were live birth/ongoing pregnancy and ovarian hyperstimulation syndrome (OHSS). The secondary outcome measures were clinical pregnancy and miscarriage. RESULTS: We screened 1021 records and completely assessed 173, finally including 66 studies in the quantitative analysis. Many different interventions were assessed, however the overall quality of the studies was low. We observed moderate-quality evidence that there is no clinically relevant difference in live birth/ongoing pregnancy rates (relative risk (RR), 0.95 (95% CI, 0.84-1.08)), or clinical pregnancy (RR, 1.02 (95% CI, 0.91-1.15)) when comparing antagonist and agonist protocols for ovarian stimulation. Additionally, we found low-quality evidence that metformin improves live birth/ongoing pregnancy (RR, 1.28 (95% CI, 1.01-1.63)) and clinical pregnancy rates (RR, 1.26 (95% CI, 1.04-1.53)) when compared with placebo or no intervention. We further found low-quality evidence that there is no clinically relevant difference in live birth/ongoing pregnancy rates (RR, 1.03 (95% CI, 0.80-1.34)) and clinical pregnancy rates (RR, 0.99 (95% CI, 0.81-1.22)) when comparing human menopausal gonadotropin for inducing ovulation and artificial preparation with estradiol valerate for endometrial preparation for frozen embryo transfer (FET). Low-quality evidence suggests that mannitol compared with no intervention (RR, 0.54 (95% CI, 0.39-0.77)) and antagonist protocols compared with agonist protocols (RR, 0.63 (95% CI, 0.49-0.80)) reduce rates of OHSS. CONCLUSION: There is low- to moderate-quality evidence suggesting that antagonist protocols are preferable to agonist ones, because they reduce the incidence of OHSS without interfering with clinical pregnancy and live birth for women with PCOS. Additionally there is low-quality evidence pointing to a benefit of metformin supplementation on clinical pregnancy and live birth; and that ovulation induction and administration of estradiol seem to be equally effective for endometrial preparation before FET for women with PCOS. For all other interventions, the evidence is of very low quality, not allowing any meaningful conclusions to be drawn. Estrategias para mejorar el resultado de la reproducción asistida en mujeres con síndrome de ovario poliquístico: revisión sistemática y metaanálisis RESUMEN OBJETIVOS: Identificar, evaluar y resumir la evidencia actual sobre la eficacia de las estrategias para mejorar las técnicas de reproducción asistida en mujeres con síndrome de ovario poliquístico (SOP). MÉTODOS: Se realizó una búsqueda exhaustiva de literatura en las bases de datos médicas estándar. La última búsqueda electrónica se realizó en julio de 2015. Las medidas de resultado primarias fueron los nacimientos vivos/embarazos en curso y el síndrome de hiperestimulación ovárica (SHO). Las medidas de resultado secundarias fueron el embarazo confirmado ecográficamente y el aborto. RESULTADOS: Se cribaron 1021 registros, de los que se evaluaron por completo 173, para finalmente incluir 66 estudios en el análisis cuantitativo. Aunque se evaluaron muchas intervenciones diferentes, en general la calidad de los estudios fue baja. Se observó evidencia de calidad moderada de que no hay diferencias relevantes clínicamente en las tasas de nacimientos vivos/embarazos en curso (riesgo relativo (RR): 0,95 (IC 95%, 0,84-1,08)), o de embarazos confirmados ecográficamente (RR: 1,02 (IC 95%, 0,91-1,15)), cuando se comparan los protocolos de antagonistas y agonistas para la estimulación ovárica. Además, se encontró evidencia de baja calidad en que la metformina mejora las tasas de nacimientos vivos/embarazos en curso (RR: 1,28 (IC 95%, 1,01-1,63)) y de embarazos confirmados ecográficamente (RR: 1,26 (IC 95%, 1,04-1,53)) en comparación con un placebo o la no intervención. Se encontró también evidencia de baja calidad en que no hay diferencias relevantes clínicamente en las tasas de nacimientos vivos/embarazos en curso (RR: 1,03 (IC 95%, 0,80-1,34)) y las tasas de embarazos confirmados ecográficamente (RR: 0,99 (IC 95%, 0.81-1,22)) al comparar la gonadotropina menopáusica humana para la inducción de la ovulación y la preparación artificial con el valerato de estradiol para preparar el endometrio para la transferencia de embriones congelados (TEC). La baja calidad de la evidencia sugiere que el manitol, en comparación con la no intervención (RR: 0,54 (IC 95%, 0,39-0,77)), y los protocolos de antagonistas, en comparación con los protocolos de agonistas (RR: 0,63 (IC 95%, 0,49-0,80)), reducen las tasas de SHO. CONCLUSIÓN: Hay evidencia de calidad baja a moderada que sugiere que los protocolos de antagonistas son preferibles a los de agonistas, ya que reducen la tasa de SHO sin interferir con el embarazo confirmado ecográficamente y los nacimientos vivos en las mujeres con SOP. Además, existe evidencia de baja calidad que indica un beneficio del uso de metformina como aporte suplementario en embarazos confirmados ecográficamente y en nacimientos vivos; y que la inducción de la ovulación y la administración de estradiol parecen ser igualmente eficaces para la preparación del endometrio antes de la TEC en mujeres con SOP. Para el resto de procedimientos, la evidencia es de muy baja calidad, y por ello no permite extraer conclusiones importantes.

Accuracy of first-trimester ultrasound in diagnosis of tubal ectopic pregnancy in the absence of an obvious extrauterine embryo: systematic review and meta-analysis.

OBJECTIVES: To determine the accuracy of ultrasound in the diagnosis of a tubal ectopic pregnancy in the absence of an obvious extrauterine embryo. METHODS: This was a systematic review conducted in accordance with the PRISMA statement and registered with PROSPERO. We searched MEDLINE, EMBASE and The Cochrane Library for relevant citations from database inception to July 2014. Studies were selected in a two-stage process and their data extracted by two reviewers. Accuracy measures were calculated for each ultrasound sign, i.e. empty uterus, pseudosac, adnexal mass and free fluid in the pouch of Douglas, alone and in various combinations. Individual study estimates were plotted in summary receiver-operating characteristics curves and forest plots for examination of heterogeneity. The quality of included studies was assessed. RESULTS: Thirty-one studies including 5858 women were selected from 19,959 citations. Following meta-analysis, an empty uterus on ultrasound was found to predict an ectopic pregnancy with a sensitivity of 81.1% (95% CI, 42.1-96.2%) and specificity of 79.5% (95% CI, 68.9-87.1%). The corresponding performance of the pseudosac, adnexal mass and free fluid were: 5.5% (95% CI, 3.3-9.0%) and 94.2% (95% CI, 75.9-98.8%); 63.5% (95% CI, 48.5-76.3%) and 91.4% (95% CI, 83.6-95.7%); and 47.2% (95% CI, 33.2-61.7%) and 92.3% (95% CI, 85.6-96.0%), respectively. CONCLUSION: Visualization of an empty uterus, adnexal mass, free fluid or a pseudosac has poor sensitivity for the diagnosis of a tubal pregnancy when an obvious extrauterine embryo is absent, but it has good specificity. We can therefore infer that ultrasound is more useful for 'ruling in' a tubal pregnancy than 'ruling out' one. However, the findings were limited by the poor quality of some included studies and heterogeneity in the index test and reference standard.

Maternal and neonatal outcomes in pregnant women with PCOS: comparison of different diagnostic definitions.

STUDY QUESTION: Does the prevalence of adverse maternal and neonatal outcomes vary in women diagnosed with polycystic ovary syndrome (PCOS) according to different definitions? SUMMARY ANSWER: A comparison of different criteria revealed that there is a substantial risk for perinatal complications in PCOS women, regardless of the used definition. WHAT IS KNOWN ALREADY: Pregnant women with PCOS are susceptible to perinatal complications. At present, there are three main definitions for PCOS. So far, we are aware of only one study, which found that the elevated risk for complications varied widely depending on the different phenotypes and features but only considered a relatively small sample size for some of the phenotypes. STUDY DESIGN, SIZE, DURATION: Retrospective matched cohort study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data of primiparous women with PCOS according to ESHRE/ASRM 2003 criteria and healthy controls giving birth to neonates ≥500 g were included. A total of 885 women were analysed: out of 177 women with PCOS, 85 (48.0%) met the National Institutes of Health (NIH) 1990 criteria, another 14 (7.9%) featured the additional phenotypes defined by The Androgen Excess and PCOS Society (AE-PCOS) 2006 criteria, 78 (44.1%) were classified as PCOS exclusively by the ESHRE/ASRM 2003 definition, and 708 represented the control group. MAIN RESULTS AND THE ROLE OF CHANCE: The prevalence of adverse maternal (49.4 versus 64.3 versus 60.3%, P = 0.313) and neonatal (27.1 versus 35.7 versus 23.1%, P = 0.615) outcomes did not differ within the three PCOS groups (ESHRE/ASRM, NIH, AE-PCOS, respectively). Compared with healthy controls, the risk for maternal complications was increased in PCOS patients [odds ratio (OR) 2.57; 95% confidence interval (CI) 1.82-3.64; P < 0.001] while there was no difference in neonatal complications (OR 0.83; 95% CI 0.56-1.21; P = 0.343). LIMITATIONS, REASONS FOR CAUTION: A limitation of our study is its retrospective design and the relatively small sample size, particularly in the AE-PCOS subgroup. WIDER IMPLICATIONS OF THE FINDINGS: Since women with PCOS have, regardless of the used definition, a high risk of maternal and neonatal complications they should be informed and advised to follow regular checks in units where problems can be detected early to allow specialized care. STUDY FUNDING/COMPETING INTERESTS: Marietta Blau Grant (Austrian Agency for International Cooperation in Education and Research; OeAD-GmbH) and mobility scholarship (Medical University of Graz).

Accuracy of first-trimester ultrasound in diagnosis of intrauterine pregnancy prior to visualization of the yolk sac: a systematic review and meta-analysis.

OBJECTIVES: To evaluate the diagnostic accuracy of ultrasound in predicting the location of an intrauterine pregnancy before visualization of the yolk sac is possible. METHODS: This was a systematic review conducted in accordance with the PRISMA statement and registered with PROSPERO. We searched MEDLINE, EMBASE and The Cochrane Library for relevant citations. Studies were selected in a two-stage process and their data extracted by two reviewers. Accuracy measures were calculated for each ultrasound sign, i.e. gestational sac, double decidual sac sign, intradecidual sign, chorionic rim sign and yolk sac. Individual study estimates were plotted in summary receiver-operating characteristics curves and forest plots for examination of heterogeneity. The quality of included studies was assessed. RESULTS: Seventeen studies including 2564 women were selected from 19 959 potential papers. Following meta-analysis, the presence of a gestational sac on ultrasound examination was found to predict an intrauterine pregnancy with a sensitivity of 52.8% (95% CI, 38.2-66.9%) and specificity of 97.6% (95% CI, 94.3-99.0%). The corresponding performance of the double decidual sac sign, intradecidual sign, chorionic rim sign and yolk sac were: 81.8% (95% CI, 68.1-90.4%) and 97.3% (95% CI, 76.1-99.8%); 66.1% (95% CI, 58.9-72.8%) and 100% (95% CI, 91.0-100%); 79.9% (95% CI, 73.0-85.7%) and 97.1% (95% CI, 89.9-99.6%); and 42.2% (95% CI, 27.7-57.9%) and 100% (95% CI, 54.1-100%), respectively. CONCLUSION: Visualization of a gestational sac, double decidual sac sign, intradecidual sign or chorionic rim sign increases the probability of an intrauterine pregnancy but is not as accurate for diagnosis as the detection of the yolk sac. However, the findings were limited by the small number and poor quality of the studies included and heterogeneity in the index test and reference standard.