Free thyroxine levels are associated with cognitive changes in individuals with a first episode of psychosis: A prospective 1-year follow-up study.

The results of previous cross-sectional studies suggest that free thyroxine (FT4) levels are associated with cognitive abilities (particularly attention/vigilance) during the early stages of psychosis. We aimed to explore whether hypothalamic-pituitary-thyroid hormones predict cognitive changes in a 1-year longitudinal study following first episodes of psychosis (FEP). We studied 36 FEP patients and a control group of 50 healthy subjects (HS). Plasma levels of thyroid-stimulating hormone (TSH) and FT4 were measured. Cognitive assessment was performed with the MATRICS Cognitive Consensus Cognitive Battery (MCCB). FEP patients were assessed twice (baseline and after 1year), whereas HS were assessed only once. We compared cognitive changes at 1year between three groups based on baseline FT4 levels: 1) lowest quartile (Q1, FT4<1.16ng/dL); 2) medium quartiles (Q2-Q3, FT4 1.16-1.54ng/dL); and 3) highest quartile (Q4, FT4>1.54ng/dL). No differences in TSH or FT4 levels were found between HS and FEP patients. All participants had FT4 levels within the normal range. HS outperformed FEP patients in all cognitive tasks. In relation to the relationship between FT4 levels and cognitive changes, a U-shaped pattern was observed: FEP patients from the middle quartiles (Q2-Q3) improved in attention/vigilance, whereas both extreme quartiles (Q1 and Q4) showed a worsening in this cognitive domain over time. Patients with lower FT4 (Q1) showed poorer baseline attention; therefore, lower baseline FT4 levels predicted a poorer prognosis in terms of attention performance. Our study suggests that baseline FT4 levels are associated with changes in attention and vigilance performance over one year in FEP patients.

Higher levels of procoagulant microparticles in women with recurrent miscarriage are not associated with antiphospholipid antibodies.

STUDY QUESTION: Are the levels of circulating cell-derived microparticles (cMPs) in patients with recurrent miscarriage (RM) associated with the antiphospholipid syndrome (APS)? SUMMARY ANSWER: cMPs in women with RM are not associated with antiphospholipid antibodies (aPLs). WHAT IS KNOWN ALREADY: Previous studies have focused on cMP levels in RM patients. Most studies have shown higher levels of cMPs in RM patients whereas others have reported lower levels. Data regarding cMPs in patients with the APS are scanty in the literature. STUDY DESIGN, SIZE, DURATION: A case-control study including three groups of patients. A total of 154 women were prospectively recruited from September 2009 to October 2013. Four patients refused to participate. The APS group consisted of 50 women that had been previously diagnosed with primary APS and had had ≥3 consecutive first trimester miscarriages. The uRM group included 52 couples with ≥3 consecutive first trimester miscarriages of unknown etiology. The fertile control (FER) group was composed of 52 healthy fertile women with no history of pregnancy losses. Miscarriage was defined as intrauterine pregnancy loss at <10 weeks' size on ultrasound. PARTICIPANTS/MATERIALS, SETTING, METHODS: Venous blood samples for coagulation studies and cMP determinations were obtained. All patients underwent a thrombophilia study. MAIN RESULTS AND THE ROLE OF CHANCE: cMP levels were significantly higher in the APS and uRM groups versus the FER group (P < 0.0001 and P = 0.009, respectively) (cMP number × 10(3)/ml plasma [mean ± SD]: APS: 18.5 ± 13.6; uRM: 16.3 ± 13.8; FER: 9.7 ± 4.6). There were no statistically significant differences in cMP levels between the APS and uRM groups. LIMITATIONS, REASONS FOR CAUTION: The sample size was arbitrarily decided according to previous studies analyzing cMPs in RM patients. Different cMP subtypes were not investigated. WIDER IMPLICATIONS OF THE FINDINGS: The present study adds further data on the subject showing that patients with RM, irrespective of testing positive for aPLs, have increased levels of cMPs compared with healthy fertile controls. The presence of elevated cMPs in RM women may reflect an ongoing systemic pathological, albeit asymptomatic, status that can become deleterious in the setting of pregnancy. STUDY FUNDING/COMPETING INTERESTS: This study was supported in part by grant from FIS-PI11/01560 within the 'Plan Nacional de I+D+I' and co-funded by the 'ISCIII-Subdirección General de Evaluación' and the 'Fondo Europeo de Desarrollo Regional (FEDER)'. The authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER: Not applicable.

[Detecting adverse drug events during the hospital stay]. / Detección de acontecimientos adversos producidos por medicamentos durante la estancia hospitalaria.

INTRODUCTION: The principal objective was to determine the incidence rate of adverse drug events (ADEs) in hospitalised patients and evaluate the event prevention percentage. METHODS: Multi-centre, prospective observational study lasting four months, performed in five hospitals providing different levels of care. We included all adult patients who were admitted to one of the selected centres for longer than 48 hours and who required pharmacological treatment. ADEs were identified by direct observation and the use of previously defined alarm signals. The Karch-Lasagna scale was used to determine the causality relationship, and the Schumock and Thornton questionnaire adapted by Otero was used to evaluate ADE preventability. Preventable drug-induced adverse events were classified according to the taxonomy that the Ruiz-Jarabo 2000 group defined, and coordinated by ISMP-Spain. RESULTS: We included 1,550 patients, 159 of whom experienced at least one ADE (10.3 %). The preventability percentage was 51.6 %, which represented 5.3 % of the total sample. The endocrine system (34.8 %) and the cardiovascular system (20.7 %) were the most affected by preventable ADEs. Antibiotics were responsible for 16.5 % of all ADEs. 9.3 % of all preventable ADEs were triggered by use of opiates. The vast majority of preventable ADEs (36.3 %) resulted from omitting a necessary medication. Only 4.4 % of preventable ADEs are considered to be serious. CONCLUSIONS: There is a high incidence rate of ADEs during patients' hospital stay (10.3 %), and half of them (51.6 %) could have been prevented. Implementation of an automatic alarm system and certain best practices for problem spots along the care circuit will help detect and avoid preventable ADEs.

Detección de acontecimientos adversos producidos por medicamentos durante la estancia hospitalaria / Detecting adverse drug events during the hospital stay

Introducción: El objetivo principal ha sido determinar la incidencia de acontecimientos adversos producidos por medicamentos (AAM) en pacientes hospitalizados y evaluar su porcentaje de prevención. Métodos: Estudio multicéntrico, prospectivo y observacional de 4 meses de duración, realizado en cinco hospitales de distinto nivel asistencial. Se incluyó a todos los pacientes adultos que ingresaron por más de 48 h en alguna de las unidades seleccionadas y requirieron tratamiento farmacológico. La identificación de los AAM se realizó mediante la observación directa y la utilización de unas señales de alerta, previamente definidas. Se utilizó el algoritmo de Karch-Lasagna, para determinar la relación de causalidad, y el cuestionario de Schumock y Thornton adaptado por Otero et al para evaluar la evitabilidad del AAM. Los AAM prevenibles se clasificaron siguiendo la taxonomía definida por el Grupo Ruiz-Jarabo 2000, coordinado por el ISMP-España. Resultados: Se incluyó a 1.550 pacientes, de los que 159 presentaron, al menos, un AAM (10,3 %). La tasa de evitabilidad fue del 51,6 %, lo que representa un 5,3 % de la muestra total. El sistema endocrino (34,8 %) y el cardiovascular (20,7 %) fueron los más afectados por los AAM prevenibles. Los antibióticos representaron el 16,5 % de todos los AAM. En cuanto a los AAM prevenibles, el 9,3 % de ellos se desencadenaron por la utilización de opiáceos. La gran mayoría de los AAM evitables fue consecuencia de la omisión de un medicamento necesario (36,3 %). Sólo un 4,4 % de los AAM evitables se consideró graves. Conclusiones: La incidencia de pacientes con AAM durante la estancia hospitalaria es alta (10,3 %), y la mitad de ellos (51,6 %) se podría haber prevenido. La implantación de un sistema automático de alertas y ciertas prácticas de mejoras en los puntos conflictivos del circuito sanitario ayudarían a la detección y la prevención de los AAM evitable (AU)

Introduction: The principal objective was to determine the incidence rate of adverse drug events (ADEs) in hospitalised patients and evaluate the event prevention percentage. Methods: Multi-centre, prospective observational study lasting four months, performed in five hospitals providing different levels of care. We included all adult patients who were admitted to one of the selected centres for longer than 48 hours and who required pharmacological treatment. ADEs were identifi ed by direct observation and the use of previously defi ned alarm signals. The Karch-Lasagna scale was used to determine the causality relationship, and the Schumock and Thornton questionnaire adapted by Otero was used to evaluate ADE preventability. Preventable drug-induced adverse events were classifi ed according to the taxonomy that the Ruiz-Jarabo 2000 group defi ned, and coordinated by ISMP-Spain. Results: We included 1,550 patients, 159 of whom experienced at least one ADE (10.3 %). The preventability percentage was 51.6 %, which represented 5.3 % of the total sample. The endocrine system (34.8 %) and the cardiovascular system (20.7 %) were the most affected by preventable ADEs. Antibiotics were responsible for 16.5 % of all ADEs. 9.3 % of all preventable ADEs were triggered by use of opiates. The vast majority of preventable ADEs (36.3 %) resulted from omitting a necessary medication. Only 4.4 % of preventable ADEs are considered to be serious. Conclusions: There is a high incidence rate of ADEs during patients’ hospital stay (10.3 %), and half of them (51.6 %) could have been prevented. Implementation of an automatic alarm system and certain best practices for problem spots along the care circuit will help detect and avoid preventable ADEs (AU)

Amenorrea secundaria por adherencia cervicoístmica / Secondary amenorrhea due to cervical-isthmical adhesion

La adherencia cervicoístmica continúa siendo, en algunos casos, un problema de difícil solución. El diagnóstico de esta amenorrea sin hematometra sigue siendo histeroscópico, pero en el tratamiento terapéutico, la adhesiolisis no resulta siempre suficiente. Mediante el presente artículo pretendemos aportar un nuevo caso, intentando proporcionar nuevos datos que nos permita esclarecer los mecanismos fisiopatológicos de este complejo síndrome (AU)

[Evaluation of a pharmaceutical care program to improve adherence to antiretroviral therapy]. / Evaluación de un programa de atención farmacéutica dirigido a mejorar la adherencia al tratamiento antirretroviral.

OBJECTIVE: To establish the impact of a pharmaceutical care program on the improvement of adherence to antiretroviral therapy, and on patient immunologic and virologic outcome. MATERIALS AND METHODS: A multicenter, observational, prospective study in a HIV-infected patient cohort under treatment with antiretrovirals selected by random sampling in 19 Spanish hospitals. The study lasted 12 months, in which the program was applied through a baseline preprocedural visit and 4 quarterly visits. Adherence estimation was based on pill counting. An adherence > or = 90, or > or = 95% was considered adequate (in two time points). RESULTS: 541 patients were included, most of them were males (68.8%) between 20 and 78 years of age. Major risk groups included injecting drug users (43.4%) and heterosexuals (29.4%). Sixty percent had already received treatment for more than 3 years. Mean baseline viral load and CD4 count values were 32,866 copies/ml and 485 cells/mm3, respectively. Throughout the study a slight increase in the percentage of adherent patients was seen; however, statistical significance was not reached (64.3 and 79.2% of patients showed an adherence > 95 and > 90%, respectively, during the fourth quarter, versus 59.8 and 75.5% at baseline). A statistically significant decrease in viral load and increase in CD4 cells was seen following program application. The percentage of patients with a viral load < 200 copies/ml was 72.2, 76.7, and 75.0% at the 2nd, 3rd, and 4th quarters, respectively, versus 64.2% at baseline. CD4 cell counts increased by 50 cells/mm3 on average from the start to the end of follow-up. CONCLUSIONS: Patients included in the program had a good immunologic and virologic outcome, and a trend towards an increased percentage of patients with good adherence was also seen. These results confirm the need to implement follow-up programs for patients receiving antiretrovirals in order to ensure maximum therapeutic benefits.

[Resistance to antiretroviral therapy]. / Resistencias al tratamiento antirretroviral.

OVERVIEW: After some time under treatment, HIV+ patients have a virologic failure rate of 50%, being development of resistance to therapy responsible for up to 80% of the virologic failure. In addition, resistance rates in naive patients is around 10% in developed countries. Inherent characteristics of HIV (replication cycle, viral subtype), of patients (therapy compliance, intra-/interindividual variability, genetic polymorphisms), and of therapy (genetic barrier to drug resistance, inhibitory ratio, drug interactions) are the factors involved in the development of resistance, and their interpretation requires to be studied. Resistance identification will be carried out using genotypical and/or phenotypical methods, and their adequacy has been validated by various expert panels on resistance. The role of the pharmacokinetic and pharmacodynamic monitoring of antiretroviral therapy is also crucial within the field of resistance, and concerns us directly as pharmacists. Finally, understanding the resistance patterns of currently available or experimental antiretroviral drug families will provide the necessary tools to prevent and/or manage their development. OBJECTIVES: To know and understand the mechanisms and patterns of resistance for each antiretroviral family. To identify factors involved in the development of resistance to ART, and to interpret various resistance tests. SEARCH STRATEGY: Studies were identified using Medline, the Cochrane database of systemic reviews, abstracts from international meetings on AIDS, Conference on Retroviruses and Opportunistic Infections, international meetings on resistance to antiretrovirals, and product monographs from January 1999 to February 2004. SELECTION CRITERIA: To be eligible, studies had to describe viral genome mutations responsible for resistance or hypersusceptibility to ART in relation to precipitating factors. Papers describing resistance identification techniques were also selected. DATA COLLECTION AND ANALYSIS: In all, 1,083 full articles and 64 abstracts and communications at international meetings were retrieved, of which 74 articles and 20 abstracts met the inclusion criteria for our review. PRIMARY RESULTS: Of the 94 reports selected, 86 discussed factors involved in the development of resistance and resistance test interpretation. The remaining 8 reports focused on resistance patterns to the various antiretroviral drug families. Every article described the enzymatic mechanisms induced by mutations responsible for resistance or hypersusceptibility to each antiretroviral family, the classification and nomenclature for each mutation, and the influence of each mutation on the success or failure of patient treatment. REVIEWER S CONCLUSIONS: Knowledge of the mechanisms and patterns of resistance to each antiretroviral family will allow us to overall understand the evolution and outcome of treatment for any given patient. Only thus shall we be able to play an integral role in the therapy of patients.

Evaluación de la integración del farmacéutico en equipos de atención de unidades de hospitalización / Assessing pharmacist integration within health-care teams at hospital units

Objetivo: Describir la integración de un farmacéutico en tres unidades de hospitalización y valorar el impacto clínico y económico de las intervenciones realizadas. Pacientes y método: Participación en la visita diaria a los pacientes ingresados en Medicina Interna y Otorrinolaringología durante 10 meses. Registro diario de las intervenciones y evaluación del impacto de las mismas (clínico y económico).Resultados: Se han registrado 491 intervenciones con un 96,74 por ciento de aceptación. En el 17,68 por ciento de las intervenciones se ha estimado que la eficacia del tratamiento ha mejorado y en el 45,43 por ciento que la toxicidad ha disminuido. La estimación del ahorro generado ha sido de 15.227.668 ptas. (91,520 ¤).Conclusiones: La presencia del farmacéutico en la unidad de hospitalización facilita la relación con el equipo médico y de enfermería, así como la detección y resolución de problemas relacionados con los medicamentos, con el consiguiente ahorro económico. Todo ello justifica la presencia del farmacéutico en las unidades de hospitalización (AU)

Risk factors associated with fetal losses in treated antiphospholipid syndrome pregnancies: a multivariate analysis.

PROBLEM: Pregnancies in women with antiphospholipid syndrome (APS) are associated with obstetric complications despite treatment. The present study analyzes risk factors and evaluates fetal outcome in a large sample of treated APS pregnancies. METHOD OF STUDY: Seventy-seven pregnancies in 56 women were included. Twelve selected variables potentially related to the outcome of treated pregnancies were analyzed in a multivariate logistic regression model. RESULTS: Treated women delivered 65 live infants at 24-41 weeks gestation (mean 36.7+/-0.5) but two neonatal deaths occurred. There were seven first-trimester miscarriages (9%) and five intrauterine fetal demises (6.5%). Thus, the probability of having a live baby under treatment was 82% (95% CI 71.3-89.6%), a figure significantly greater (P <0.001) than that observed before therapy (25.7%; 95% CI 18.7-33.7%). Variables related with fetal outcome in the multivariate model were: preconceptional use of aspirin and abnormal umbilical artery Doppler velocimetry at 23-26 weeks gestation. CONCLUSIONS: The present report shows that in treated APS pregnancies: i) aspirin treatment started preconceptionally is an independent and significant prognostic factor associated with favorable fetal outcome; and ii) abnormal velocity waveforms in the umbilical artery predict adverse outcome of pregnancy.

The effect of exogenous luteinizing hormone (LH) on oocyte viability: evidence from a comparative study using recombinant human follicle-stimulating hormone (FSH) alone or in combination with recombinant LH for ovarian stimulation in pituitary-suppressed women undergoing assisted reproduction.

PURPOSE: The purpose of this prospective, randomized study was to compare ovarian response and oocyte and embryo yields in women undergoing ovulation induction for IVF/ICSI using recombinant human FSH (rhFSH) alone or in combination with recombinant human LH (rhLH). METHODS: Patients were randomized to receive rhFSH alone (group F; n = 13) or rhFSH + rhLH (group L; n = 15). rhFSH was administered according to a step-down protocol; patients assigned to group L received rhLH at a fixed dose of 75 IU (1 ampoule) throughout the treatment period. RESULTS: The total dose of rhFSH, number of growing follicles, and serum concentrations of estradiol (E2) on the day of hCG administration were similar in both treatment groups. However, the percentage of metaphase II oocytes and fertilization rate were significantly higher in group F than in group L. The lower fertilization rates associated with rhLH were also seen in a subgroup of patients from group L who had undergone a previous ART cycle stimulated with FSH only and thus acted as their own controls. However, when in vitro fertilization (IVF) and intracytoplasmic sperm injection cycles were considered separately, differences in fertilization rates were statistically significant only for oocytes treated by conventional IVF. CONCLUSIONS: This study shows that the addition of recombinant LH to recombinant FSH in pituitary-suppressed women undergoing ART does not improve the ovarian response and even may have a negative impact on oocyte maturation and fertilization.

Suppression of LH during ovarian stimulation: analysing threshold values and effects on ovarian response and the outcome of assisted reproduction in down-regulated women stimulated with recombinant FSH.

BACKGROUND: It has been recently suggested that gonadotrophin-releasing hormone agonist down-regulation in some normogonadotrophic women may result in profound suppression of LH concentrations, impairing adequate oestradiol synthesis and IVF and pregnancy outcome. The aims of this study, where receiver-operating characteristic (ROC) analysis was used, were: (i) to assess the usefulness of serum LH measurement on stimulation day 7 (S7) as a predictor of ovarian response, IVF outcome, implantation, and the outcome of pregnancy in patients treated with recombinant FSH under pituitary suppression; and (ii) to define the best threshold value, if any, to discriminate between women with 'low' or 'normal' LH concentrations. METHODS: A total of 144 infertile women undergoing IVF/intracytoplasmic sperm injection (ICSI) treatment were included. Seventy-two consecutive patients having a positive pregnancy test (including 58 ongoing pregnancies and 14 early pregnancy losses) were initially selected. As a control non-pregnant group, the next non-conception IVF/ICSI cycle after each conceptual cycle in our assisted reproduction programme was used. RESULTS: The median and range of LH values in non-conception cycles, conception cycles, ongoing pregnancies, and early pregnancy losses, clearly overlapped. ROC analysis showed that serum LH concentration on S7 was unable to discriminate between conception and non-conception cycles (AUC(ROC) = 0.52; 95% CI: 0.44 to 0.61) or ongoing pregnancy versus early pregnancy loss groups (AUC(ROC) = 0.59; 95% CI: 0.46 to 0.70). To assess further the potential impact of suppressed concentrations of circulating LH during ovarian stimulation on the outcome of IVF/ICSI treatment, the three threshold values of mid-follicular serum LH proposed in the literature (<1, < or =0.7, <0.5 IU/l) to discriminate between women with 'low' or 'normal' LH were applied to our study population. No significant differences were found with respect to ovarian response, IVF/ICSI outcome, implantation, and the outcome of pregnancy between 'low' and 'normal' S7 LH women as defined by those threshold values. CONCLUSIONS: Our results do not support the need for additional exogenous LH supplementation in down-regulated women receiving a recombinant FSH-only preparation.

Mid-luteal serum inhibin-A concentration as a marker of endometrial differentiation.

BACKGROUND: Recent studies have indicated that the corpus luteum is a major source of circulating inhibin-A and serum concentrations of inhibin-A may reflect the human luteal function. The present prospective study was undertaken to determine the usefulness of mid-luteal serum concentrations of inhibin-A as markers of endometrial receptivity (as assessed by histological dating and alphavbeta3 integrin expression) and whether they are better predictors of endometrial function than serum progesterone. METHODS: Consecutive infertile women (experimental group, n = 50) with regular menstrual cycles, and fertile women who were requesting contraception and had regular menstrual patterns and normal secretory endometria (control group, n = 10) were included. In all women basal body temperature, luteal serum concentrations of oestradiol, progesterone, prolactin, and inhibin-A, and endometrial biopsies were used in the same cycle to assess luteal function. RESULTS: Out-of-phase mid-secretory endometria were detected in 17 of the 50 infertile women. Lack of alphavbeta3 integrin expression was detected in 27 of the 50 mid-luteal endometrial biopsies. Thus, hormonal concentrations were compared in the mid-luteal phase between the following eight groups of women: group 1 (n = 10), control fertile women; group 2 (n = 50), infertile women (all); subdivided into group 3 (n = 33), with in-phase biopsies; group 4 (n = 17), with out-of-phase endometria; group 5 (n = 23), expressing alphavbeta3 integrin in endometria; group 6 (n = 27), whose endometria did not express alphavbeta3 integrin; group 7 (n = 18), with both in-phase endometrial biopsy and alphavbeta3 integrin expression; and finally group 8 (n = 12), whose endometria were out-of-phase and did not express alphavbeta3 integrin. Mid-luteal serum concentrations of oestradiol, progesterone, prolactin, and inhibin-A of the seven infertile groups were similar to those of the control group of fertile women. No statistically significant difference between the infertile groups was observed for any hormonal parameter considered. CONCLUSION: Mid-luteal serum inhibin-A determination does not accurately reflect endometrial function/maturation and it is not a better indicator of endometrial luteal phase dysfunction than mid-luteal serum progesterone.

Follicular development and hormone concentrations following recombinant FSH administration for anovulation associated with polycystic ovarian syndrome: prospective, randomized comparison between low-dose step-up and modified step-down regimens.

The present study compared ovarian performance and hormone concentrations, after ovulation induction, in polycystic ovarian syndrome (PCOS) patients, using recombinant human FSH (rhFSH) in low-dose step-up and modified step-down regimens. Twenty-six women with clomiphene citrate-resistant chronic anovulatory infertility were treated with rhFSH in two consecutive cycles according to two different low-dose regimens: (i) the classic chronic low-dose step-up protocol, the starting dose being 75 IU; (ii) a modified step-down protocol where the starting dose was 300 IU followed by 3 days free of treatment, then rhFSH 75 IU daily was given and stepwise dose increments were performed exactly the same as in the step-up method. Each woman received both treatment approaches, in a randomized order, with an interval of > or = 1 month between treatments. The total number of follicles that were > 10, > 14 and > 17 mm in diameter on the day of human chorionic gonadotrophin (HCG) administration, and thus cycles with HCG cancelled, were significantly increased with the step-up approach. The total number of rhFSH ampoules tended to be higher with the step-down schedule despite the fact that both the mean duration of treatment and the threshold dose were similar with the two low-dose approaches. A physiological step-down approach for ovulation induction in PCOS patients may be more appropriate in order to avoid multifollicular cycles than the step-up approach.

Day 3 serum inhibin B and FSH and age as predictors of assisted reproduction treatment outcome.

Recent reports investigating the value of basal inhibin B determination as a predictor of ovarian reserve and assisted reproduction treatment have led to discordant results. This study was undertaken to further assess the relative power of day 3 inhibin B and follicle stimulating hormone (FSH) (defined before treatment) and the woman's age both as single and combined predictors of ovarian response and pregnancy in an in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) programme. A total of 120 women undergoing their first cycle of IVF or ICSI was included. Forty consecutive cycles cancelled because of poor follicular response were initially selected. As a control group, the nearest completed IVF/ICSI cycles before and after each cancelled cycle (i.e. the closest cycles in temporal relationship to the index cycle) were used. Mean age and basal FSH concentrations were significantly higher in the cancelled than in the control group (P: < 0.01 and P: < 0.001 respectively), whereas basal inhibin B was significantly higher in the latter (P: < 0.05). The association of basal FSH (with an accuracy or predictive value of ovarian response of 79%) with cancellation rate was significant, independent of, and stronger than the effects of age and inhibin B (P: < 0.05). Any two or all three of these variables studied did not improve the predictive value of FSH alone. Woman's age was the only variable independently associated with pregnancy rate. It is concluded that the stronger predictors of success in patients undergoing their first IVF/ICSI treatment cycle are age and basal FSH rather than inhibin B. Basal FSH concentration was a better predictor of cancellation rate than age, but age was a stronger predictor of pregnancy rate.

Circulating levels of nitric oxide in successful and unsuccessful implantation after in vitro fertilization and embryo transfer. Relationship to estradiol and progesterone.

BACKGROUND: Nitric oxide (NO) may play an important role in embryo implantation and early embryo development. This study investigated the potential role of circulating nitric oxide (NO) measurement to predict the outcome of implantation and pregnancy after IVF and ET. METHODS: Two blood samples were collected from 237 IVF patients on days 13-14 and 20-21 after ET. Serum concentration of nitrite/nitrate (the two stable oxidation products of NO metabolism), estradiol (E2), progesterone and beta-hCG were measured on days 13-14 after ET and one week later. RESULTS: No significant differences were found with respect to nitrite/nitrate serum concentrations in conception versus non-conception cycles, viable versus abnormal pregnancies, and viable pregnancy group versus non-conception cycles, respectively, despite that significant differences were observed regarding E2 and progesterone values. Nitrite/nitrate serum concentrations were similar for singleton and multiple pregnancies at both study points. In viable pregnancies, no significant change was observed for nitrite/nitrate serum concentration from days 13-14 to 20-21 after ET. No correlation was found between nitrite/nitrate serum concentration and E2 or progesterone serum levels. CONCLUSIONS: Circulating levels of nitrite/nitrate are similar in successful and unsuccessful implantation after IVF and are unrelated to the outcome of pregnancy. This precludes the use of serum NO measurement as a marker of implantation and successful pregnancy in IVF.

Follicular fluid concentrations of adrenomedullin, vascular endothelial growth factor and nitric oxide in IVF cycles: relationship to ovarian response.

Marked granulosa cell proliferation along with important changes in the vascular bed of the ovary characterize IVF cycles associated with multiple follicular growth and maturation. The present report investigated follicular fluid (FF) and circulating concentrations of adrenomedullin, vascular endothelial growth factor (VEGF) and nitric oxide (NO) in 70 IVF patients (14 of whom became pregnant); these three vasoactive substances may be implicated in extensive ovarian tissue remodelling. Serum and FF concentrations of oestradiol and progesterone were also measured in the 70 IVF cycles studied. Follicular fluid concentrations of VEGF and adrenomedullin but not nitrite/nitrate (the two stable oxidation products of NO metabolism) were significantly higher (P < 0.0001) than the corresponding circulating concentrations. Follicular fluid concentrations of oestradiol and progesterone were not correlated with those of adrenomedullin, VEGF or nitrite/nitrate. No relationship existed between circulating concentrations of adrenomedullin, VEGF or nitrite/nitrate on the day of oocyte aspiration and parameters of ovarian response to gonadotrophin stimulation. In contrast, FF adrenomedullin concentration showed a direct relationship with day 3 FSH serum concentration (r = 0.53, P < 0.01) and the number of ampoules of gonadotrophin administered (r = 0.36, P < 0.005), but an inverse correlation with the total number of oocytes retrieved (r = -0.29, P < 0.01) and the number of mature oocytes (r = -0.25, P < 0. 05). A positive correlation was found for FF VEGF concentration and chronological age (r = 0.29, P < 0.05) and ampoules of gonadotrophins administered (r = 0.30, P < 0.05). There was no relationship between nitrite/nitrate FF concentrations and parameters of ovarian response. Neither serum concentrations nor FF concentrations of adrenomedullin, VEGF or nitrite/nitrate were correlated with IVF outcome. This study suggested for the first time that increased FF concentrations of adrenomedullin can be a marker of decreased ovarian response in IVF. Our results also provide further evidence favouring an association between FF VEGF and patient's age, while on the basis of our findings NO measurements are not a useful marker of ovarian response.

Ovarian reserve test with human menopausal gonadotropin as a predictor of in vitro fertilization outcome.

PURPOSE: Our purpose was to determine prospectively, using receiver-operating characteristic (ROC) analysis, whether the ovarian reserve test with hMG could improve the predictive value of a woman's age and basal levels of follicle stimulating hormone (FSH), E2, and inhibin or any combination of them regarding ovarian response and pregnancy rate in IVF treatment following pituitary desensitization. METHODS: The hMG test was performed within 3 months of IVF treatment in 80 women undergoing the first cycle of IVF and consisted of 2 ampoules of hMG daily for 5 days starting on cycle days 2 to 3. Hormone and ultrasound evaluation was performed on cycle days 2 to 3 and 7 to 8. RESULTS: The mean age and basal FSH levels were significantly higher in the canceled (n = 28) than in the control (n = 52) group, whereas the basal inhibin level was significantly higher in the latter. Regarding ovarian response, the combination FSH plus inhibin had the better diagnostic accuracy (predictive value of 70%) among basal variables. When post-hMG parameters (alone or in combination) were analyzed, E2 alone, with a 77% diagnostic accuracy, emerged as the best predictive variable of cancellation in IVF cycles. When ROC analysis was used, the area under the ROC curve for E2 post-hMG (diagnostic accuracy of 84.5%) was significantly higher than that for the estimates based on the combination of basal FSH and inhibin (diagnostic accuracy of 71.3%). However, woman's age was the only variable independently associated with pregnancy rate. CONCLUSIONS: The predictive power of the hMG test of ovarian reserve is better than that of age and basal hormone values (FSH and inhibin) and it is based mainly on the E2 response to hMG treatment. However, given that age is the only predictor of pregnancy and considering the cost and discomfort of the hMG test, the usefulness, if any, of the test in predicting IVF performance in the daily clinical setting remains to be established.

Follicular development and hormonal levels following highly purified or recombinant follicle-stimulating hormone administration in ovulatory women undergoing ovarian stimulation after pituitary suppression for in vitro fertilization: implications for implantation potential.

PURPOSE: The main goal in the present study was to compare follicular development and estradiol levels after ovarian stimulation in pituitary suppressed normally ovulating women undergoing IVF, using highly purified urinary follicle stimulating hormone (FSH) (u-FSH-HP) and recombinant FSH (rec-FSH). A secondary variable in our study was embryo implantation potential, which is closely related to appropriate follicular development and oocyte competence. METHODS: For the main purpose of this study, 30 IVF patients (group 1) were treated during IVF consecutive cycles, using the same stimulation protocol, with u-FSH-HP in the first treatment study cycle and rec-FSH in the second one. As a control group (group 2) for implantation rates obtained in cycles treated with rec-FSH, 30 additional IVF patients were included who underwent a second IVF attempt again with u-FSH-HP. RESULTS: The total dose of FSH used and ovarian response obtained in terms of estradiol plasma levels and the total number of growing follicles on the day of human chronic gonadotropin (HCG) injection were similar in both treatment cycles in group 1 but better follicular dynamics and oocyte maturity were obtained with rec-FSH. The implantation rate was significantly higher in rec-FSH treated cycles in patients in group 1 than in control women (group 2). CONCLUSIONS: rec-FSH is more efficacious than u-FSH-HP when used in the same patient in inducing multiple follicular development in down-regulated cycles as indicated by ovarian performance and oocyte maturity. In addition, rec-FSH yields significantly higher implantation rates than u-FSH-HP when used in patients undergoing their second IVF attempt.

Revisión clínica de la utilización de los bifosfonatos / Clinical review of diphosphonate use

Los bifosfonatos son un conjunto de fármacos análogos a la molécula de pirofosfato que por tener gran afinidad por el fosfato cálcico en fase sólida se unen a la hidroxiapatita del hueso, inhibiendo la resorción ósea. Son fármacos que por vía oral se absorben con dificultad, siendo su biodisponibilidad tan sólo del 1-10 por ciento. Su avidez por el hueso hace que el 20-80 por ciento de la dosis absorbida se fije a él, y una vez fijados en el hueso su semivida de eliminación es superior a los diez años. Resisten la hidrólisis, por lo que se eliminan sin metabolizar por vía renal. En general se toleran bien, siendo sus principales efectos adversos los problemas gastrointestinales y/o fiebre. Son el tratamiento de elección en la enfermedad de Paget. Se utilizan también en el tratamiento de metástasis óseas tanto en pacientes con niveles de calcio sérico normal como en presencia de hipercalcemia de causa tumoral, y constituyen uno de los tratamientos básicos de la osteoporosis. Aunque queden muchos aspectos referentes al mecanismo de acción por esclarecer, parece que aportan un considerable beneficio en la calidad de vida de los pacientes tratados. (AU)

Recombinant human follicle-stimulating hormone for ovulation induction in polycystic ovary syndrome: a prospective, randomized trial of two starting doses in a chronic low-dose step-up protocol.

PURPOSE: The aim was to compare the follicular response to 37.5 and 50 IU of recombinant follicle-stimulating hormone (FSH) as starting doses for ovulation induction in patients with polycystic ovary syndrome (PCOS). METHODS: Prospective, randomized, crossover study including 15 women with clomiphene citrate-resistant chronic anovulatory infertility. Patients were treated with subcutaneous recombinant FSH at starting doses of 37.5 IU and 50 IU, respectively, according to a low-dose step-up protocol. Each woman received both treatments, in a randomized order, with an interval of > or = 1 month between treatments. RESULTS: All treatment cycles were ovulatory after an appropriate follicular response and hormone levels were similar with both treatments, although the total quantity of FSH required and the mean daily dose required to induce identical follicular development were significantly lower with a starting dose of 37.5 IU FSH. The mean duration of treatment to achieve ovulation was approximately 13 days with both treatments but treatment periods > or = 20 days were required in some patients. CONCLUSIONS: In women with PCOS, a starting dose of 37.5 IU recombinant FSH may be adequate to induce follicular growth. However, the use of low starting doses may result in some cases in increased treatment periods and need for monitoring.