Joaquim Calaf

Novel (60%) and recurrent (40%) androgen receptor gene mutations in a series of 59 patients with a 46,XY disorder of sex development.

BACKGROUND Androgen receptor (AR) gene mutations are the most frequent cause of 46,XY disorders of sex development (DSD) and are associated with a variety of phenotypes, ranging from phenotypic women [complete androgen insensitivity syndrome (CAIS)] to milder degrees of undervirilization (partial form or PAIS) or men with only infertility (mild form or MAIS). OBJECTIVE The aim of the study was to characterize the contribution of the AR gene to the molecular cause of 46,XY DSD in a series of Spanish patients. SETTING We studied a series of 133 index patients with 46,XY DSD in whom gonads were differentiated as testes, with phenotypes including varying degrees of undervirilization, and in whom the AR gene was the first candidate for a molecular analysis. METHODS The AR gene was sequenced (exons 1 to 8 with intronic flanking regions) in all patients and in family members of 61% of AR-mutated gene patients. RESULTS AR gene mutations were found in 59 individuals (44.4% of index patients), of whom 46 (78%) were CAIS and 13 (22%) PAIS. Fifty-seven different mutations were found: 21.0% located in exon 1, 15.8% in exons 2 and 3, 57.9% in exons 4-8, and 5.3% intronic. Twenty-three mutations (40.4%) had been previously described and 34 (59.6%) were novel. CONCLUSIONS AR gene mutation is the most frequent cause of 46,XY DSD, with a clearly higher frequency in the complete phenotype. Mutations spread along the whole coding sequence, including exon 1. This series shows that 60% of mutations detected during the period 2002-2009 were novel.

The role of matching menstrual data with hormonal measurements in evaluating effectiveness of postcoital contraception.

The effectiveness of postcoital contraception can only be estimated. The most commonly used method of calculation compares the expected pregnancy rate in the exposed population to the resultant pregnancies after treatment. Estimation of the fertile period and the day of ovulation are critical to calculate the expected pregnancies. The aim of this study was to improve the accuracy of calculations by evaluating the hormonal status on the day of contraceptive treatment. A total of 483 consecutive women requesting postcoital contraception was included in a prospective observational trial. A blood sample was obtained at the moment of consultation to measure serum luteinizing hormone, estradiol, and progesterone concentrations. An ethinylestradiol-levonorgestrel combination (100 micrograms/500 mg for two doses, 12 h apart) was then prescribed. The fertile period was estimated according to previous hormonal studies in the normal cycling population. Of 483 women, 64 (13.25%) women were excluded because they presented irregular menstrual cycles and 37 (7.6%) women were lost to follow-up. Two pregnancies occurred in the remaining 382 women. Following Wilcoxs and Trussells methods, 21.1 and 17.75 pregnancies should be expected, yielding an overall treatment effectiveness of 90.52% (95% confidence interval [CI] 62.58%-97.6%) and 88.73% (95% CI 55.93%-97.12%), respectively. Hormonal data were available in 356 women; 303 of whom presented with regular cycles. Hormonal information in this group restricted the number of exposed cases to 88 women. Of the women included in Trussells method of analysis, only 51 (51.5%; p < 0.05) were at risk using hormonal data. Fifty-six percent (95% CI 34.9%-75.6%) of women with luteinizing hormone levels > 20 IU/L were not between days-1 and +1 of the cycle. Hormonal studies suggest that methods based on pregnancy risk calculated by cycle day do not faithfully reflect the real exposure.

Safety and effectiveness of hormonal postcoital contraception: a prospective study

OBJECTIVE The aim of this study was to evaluate the demographic characteristics of the population attending our hospital requesting postcoital contraception and to determine the effectiveness of the method and its side-effects. METHODS A total of 503 women asking for postcoital contraception were included in a prospective open trial. After filling in a questionnaire dealing with demographic and contraceptive data, we prescribed an ethinylestradiol-levonorgestrel combination (100 micrograms/500 mg for two doses 12 h apart). RESULTS Only 487 women were available for analysis of demographic data. A further 77 were excluded because they presented irregular menstrual cycles and 55 cases were lost for follow-up. Mean age was 22.6 +/- 5.25 years and 35.9% of cases came to the center within the first 5 h after unprotected intercourse. Only 18.8% had previously asked for postcoital contraception. Breakage of condom was the most common reason for request (81.9%). Two pregnancies occurred in the remaining 355 women. According to Dixons method 15.5 pregnancies should be expected being the overall efficacy of 87.14%. There were no serious adverse effects. Nausea and vomiting (16.33%) were the most prevalent and 59% of the users menstruated at the expected time whilst menses were delayed in 6% of the cases. CONCLUSION The combination of ethinylestradiol and levonorgestrel in low doses is an effective and safe method of postcoital contraception.

Raloxifene use in clinical practice: efficacy and safety.

Objective and Methods: In this article, we provide an interdisciplinary concise review of the effects of raloxifene on breast, bone, and reproductive organs, as well as the adverse events that may be associated with its use. Results: Raloxifene has been shown to prevent osteoporosis in postmenopausal women (PMW) with low bone mass and prevent vertebral fractures in those with osteoporosis/low bone mass; it has not been shown to reduce the risk of nonvertebral fractures. Raloxifene reduces the risk of invasive breast cancer in PMW with osteoporosis or at high risk of breast cancer. The risk of venous thromboembolism has been consistently shown to be increased with raloxifene, so it should not be used in women at high risk of venous thromboembolism. Although raloxifene does not increase, nor decrease, the risk of coronary or stroke events overall, in the raloxifene trial of PMW at increased risk of coronary events, the incidence of fatal stroke was higher in women assigned raloxifene versus placebo. Conclusions: Based on its approved indications, it is appropriate to prescribe raloxifene to prevent or treat osteoporosis, as well as to reduce the risk of invasive breast cancer in PMW with osteoporosis or at high risk of breast cancer. Women at increased risk of both fracture and invasive breast cancer are those most likely to receive a dual benefit with raloxifene. Decision making must involve the incorporation of the womans personal feelings about the risks and benefits of raloxifene therapy, balanced with her interest in reducing risk of fractures and breast cancer through pharmacological intervention.

Prevalence and predictors of abnormal glucose metabolism in Mediterranean women with polycystic ovary syndrome

Impaired glucose tolerance (IGT) and Type 2 diabetes mellitus (DM) are common in women with polycystic ovary syndrome (PCOS) in American studies. However, whether rates are similar in other countries with a lower frequency of insulin resistance is not clear. Our purpose was to investigate the prevalence of abnormal glucose metabolism (AGM) in women with PCOS and asses the ability of clinical data and biochemical tests to predict these abnormalities within our population. One hundred and three PCOS women undergo a 75-g oral glucose tolerance test. Glucose tolerance was categorised according to World Health Organisation criteria. Glucose tolerance was abnormal in 18.5% of women: 10.7% had IGT and 7.7% had DM. Women with DM were older than those with IGT or normal glucose tolerance. Women with AGM were more obese, had a higher waist/hip ratio and free testosterone levels than normal glucose metabolism patients. QUICKI was the best predictor of AGM. Receiver operating characteristics analysis suggested a threshold value of 0.31 in quantitative insulin-sensitivity check index (QUICKI) (94.1% sensitivity, 86% specificity, 57.1 positive predictive value and 98.6 negative predictive value) for the prediction of AGM. In conclusion, Mediterranean women with PCOS are at lower risk of AGM than that published from other countries; however, the incidence is still high compared with populations of women without PCOS. We recommend that PCOS patients undergo periodic metabolic screening for AGM using QUICKI.

Ultrasound evaluation of fetal movements in pregnancies at risk for severe spinal muscular atrophy

We studied spinal muscular atrophy (SMA) during human development to identify possible delays or alterations in fetal movements detectable by ultrasound. We evaluated 29 pregnancies at risk for severe SMA performing 2D-ultrasound around 11-14 weeks, prior to prenatal molecular testing of the SMN1 gene. We charted the occurrence of generalized body movements, isolated movements of arms and legs, head movements, startle and hiccup. Fetuses were diagnosed as healthy (n=12), carriers (n=10) or affected (n=7) according to the SMN1 molecular testing results obtained. SMN2 copies were also tested in the seven affected fetuses, six of whom showed two SMN2 copies and one a unique SMN2 copy. The movements under study were observed in all recordings, regardless of group and the SMN2 copies. At the gestational age examined, we did not observe a qualitative early limitation of movements in fetuses with SMA, even in cases predicted to develop a severe neonatal form.

Evaluation of fetal nuchal translucency in 98 pregnancies at risk for severe spinal muscular atrophy: possible relevance of the SMN2 copy number

Objective: To study fetal nuchal translucency (NT) thickness as a possible early marker in fetuses at risk for severe spinal muscular atrophy (SMA). To investigate the significance of the survival motor neuron (SMN) 2 gene copy number in affected fetuses. Methods: We performed 2D-ultrasound in 98 pregnancies at risk for SMA, all of which underwent prenatal molecular testing of the SMN1 gene. Crown-rump length (CRL) and NT measurements were obtained in all cases before chorionic villus sampling. Fetuses were diagnosed as healthy, carriers or affected according to the SMN1 molecular testing results. SMN2 copies were also tested in all affected fetuses. Results: Nineteen fetuses were predicted to be affected due to the absence of the SMN1 gene, 18 of which had two SMN2 copies. Mean CRL and NT values did not differ between healthy, carrier and affected fetuses. In the remaining affected case who had only one SMN2 copy, the ultrasound examination showed a NT value of 4.98 mm and findings compatible with hypoplastic left heart. Conclusions: Most affected SMA fetuses have normal NT values. Our findings support the idea that SMN2 copy number in SMA fetuses is relevant for the development of congenital heart defects and increased NT values.

Maternal risk factors and obstetric complications in late preterm prematurity

OBJECTIVE Late preterm prematurity has been related to poorer neonatal outcomes. However, research has focused on the neonatal outcomes of late preterm infants, maternal characteristics of these births have been less evaluated. The aim of the study was to compare maternal risk factors and obstetric complications in late preterm births (LPTB) and term births. These factors were also assessed comparing spontaneous LPTB with medically-indicated LPTB. STUDY DESIGN We conducted a retrospective cohort study with two groups. All singleton LPTB occurred at our University Hospital between January 1, 2009 and December 31, 2010 were included in the first cohort (n=171). A comparison cohort of term births was configured in a ratio 2:1 (n=342). Well-dated pregnancies without congenital malformations, congenital infections or chromosome abnormalities were eligible. LPTB were classified into two groups, spontaneous LPTB and medically-indicated LPTB following delivery indications. Statistical analysis of categorical variables was performed using either χ(2) or Fishers exact. Continuous variables were compared using the Students t-test. RESULTS Women with LPTB had more medical conditions than women with term births (29% vs 15.7%; P=0.002). Prior preterm births (9.7% vs 2%; P<0.001), prior adverse obstetric outcomes (6.9% vs 2.3%; P<0.001), and obstetric complications were also more frequent in LPTB than in term births. However, no differences were found in maternal medical conditions when spontaneous LPTB and medically-indicated LPTB were compared. Women with medically-indicated LPTB were older (33.69 vs 31.07; P=0.003) and mainly nulliparous (75.8% vs 49.4%; P=0.002). Obstetric complications were more frequent in medically-indicated LPTB than in spontaneous LPTB. CONCLUSIONS Maternal risk factors and obstetric complications are significantly higher in LPTB than in term births. These factors should be considered to identify women at risk for either spontaneous or medically-indicated LPTB.

Weight decrease improves live birth rates in obese women undergoing IVF: a pilot study

Obese women have lower pregnancy rates than normal-weight women undergoing assisted reproductive treatment. We conducted a pilot study to evaluate whether a 12-week diet and exercise intervention before an IVF cycle would influence pregnancy rates in obese women. Forty-one patients were enrolled in this study. They were randomly allocated to two groups: an intervention group (n = 21), who underwent an individualized diet and physical exercise programme supervised by a dietician, and a control group (n = 20), who started IVF with no previous intervention. The primary outcome was clinical pregnancy rate after a single treatment cycle. Mean weight loss in the study group after the intervention was 5.4 kg (range 1.1-14.6 kg). The study and control groups had similar total FSH consumption, number of oocytes and embryos obtained, and number and quality of embryos transferred. There was a non-significant trend towards a higher clinical pregnancy rate after fresh embryo transfer (66.7% versus 41.2%). The intervention group had a significantly higher cumulative live birth rate (61.9% versus 30%, P = 0.045) (odds ratio for intervention group, 3.8; 95% confidence interval, 1.03 to 13.9) The data suggest that weight loss resulted in a significantly increased cumulative live birth rate.

Effect of changes to cost and availability of emergency contraception on users’ profiles in an emergency department in Catalunya

Abstract Objective Emergency contraception (EC) accessibility has evolved differently in Catalunya as compared with other autonomous communities in Spain. Free-of-charge access within the Public Health System was authorised in 2004, and over-the-counter (OTC) access was implemented in 2009. The aim of the study is to assess the impact of these measures on demand and users’ profiles at our institution. Methods A retrospective study, in our Emergency Department, was conducted to evaluate EC requests in relationship to accessibility modifications. The age of women and which days of the week they attended were analysed. Results The number of EC requests, the distribution by age and the demand over the week remained stable after access to EC became free of charge. However, requests sharply decreased following OTC access implementation. Distribution by age also changed, with a significant increase in requests from women under 25 years (72% vs 56%, p < 0.001). Demand was greatest on Sunday and Monday, and this distribution persisted over the study period. Conclusion EC requests remained unchanged following free-of-charge access to EC, but decreased after OTC implementation. Women currently seeking EC at no cost at our institution are more likely to be younger and to request it on a Monday. Chinese Abstract 摘 要 目的 与西班牙其他自治区相比，在加泰罗尼亚，紧急避孕药（emergency contraception，EC）获取途径的演变有所不同。2004年公共卫生系统批准其免费发放，2009年后将其列为非处方类药物（over-the-counter，OTC）。本研究目的在于评价不同措施对于公众需求的影响。 方法 运用回顾性研究评价紧急避孕药的需求与药物获取途径间的关系。并分析女性的年龄及一周中有需求的天数。 结果 EC免费发放，EC的需求量、使用者年龄分布及一周中有需求的天数均保持稳定。然而，将EC列为OTC后，其需求量显著减少，在小于25岁的女性中分布上升（72% VS 56%，p＜0.001）。整个研究期间还发现周日与周一的需求量始终保持最高。 结论 免费发放EC并不影响其需求量，但转变为非处方药时，其使用量明显减少。本研究中免费获取EC的女性年龄偏小且倾向于在周一使用。