Cornelis B. Lambalk

Gonadotropin-releasing-hormone-receptor antagonists

The present invention relates to Gonadotropin Releasing Hormone (“GnRH”) (also known as Luteinizing Hormone Releasing Hormone) receptor antagonists.Pulsatile gonadotropin-releasing hormone (GnRH) stimulates the pituitary secretion of both luteinising hormone (LH) and follicle-stimulating hormone (FSH) and thus controls the hormonal and reproductive function of the gonads. Blockade of GnRH effects may be wanted for a variety of reasons-eg, to prevent untimely luteinisation during assisted reproduction or in the treatment of sex-hormone-dependent disorders. Selective blockade of LH/FSH secretion and subsequent chemical castration have previously been achieved by desensitising the pituitary to continuously administered GnRH or by giving long-acting GnRH agonists. Only recently have GnRH-receptor antagonists, that immediately block GnRHs effects, been developed for clinical use with acceptable pharmacokinetic, safety, and commercial profiles. In assisted reproduction, these compounds seem to be as effective as established therapy but with shorter treatment times, less use of gonadotropic hormones, improved patient acceptance, and fewer follicles and oocytes. All current indications for GnRH-agonist desensitisation may prove to be indications for a GnRH antagonist, including endometriosis, leiomyoma, and breast cancer in women, benign prostatic hypertrophy and prostatic carcinoma in men, and central precocious puberty in children. However, the best clinical evidence so far has been in assisted reproduction and prostate cancer.

Effect of clomifene citrate plus metformin and clomifene citrate plus placebo on induction of ovulation in women with newly diagnosed polycystic ovary syndrome: randomised double blind clinical trial

Abstract Objective To compare the effectiveness of clomifene citrate plus metformin and clomifene citrate plus placebo in women with newly diagnosed polycystic ovary syndrome. Design Randomised clinical trial. Setting Multicentre trial in 20 Dutch hospitals. Participants 228 women with polycystic ovary syndrome. Interventions Clomifene citrate plus metformin or clomifene citrate plus placebo. Main outcome measure The primary outcome measure was ovulation. Secondary outcome measures were ongoing pregnancy, spontaneous abortion, and clomifene resistance. Results 111 women were allocated to clomifene citrate plus metformin (metformin group) and 114 women were allocated to clomifene citrate plus placebo (placebo group). The ovulation rate in the metformin group was 64% compared with 72% in the placebo group, a non-significant difference (risk difference − 8%, 95% confidence interval − 20% to 4%). There were no significant differences in either rate of ongoing pregnancy (40% v 46%; − 6%, − 20% to 7%) or rate of spontaneous abortion (12% v 11%; 1%, − 7% to 10%). A significantly larger proportion of women in the metformin group discontinued treatment because of side effects (16% v 5%; 11%, 5% to 16%). Conclusion Metformin is not an effective addition to clomifene citrate as the primary method of inducing ovulation in women with polycystic ovary syndrome. Trial registration Current Controlled Trials ISRCTN55906981 [controlled-trials.com][controlled-trials.com].

Assisted reproductive technology in Europe, 2009: results generated from European registers by ESHRE

STUDY QUESTION The 13th European in vitro fertilization (IVF)-monitoring (EIM) report presents the results of treatments involving assisted reproductive technology (ART) initiated in Europe during 2009: are there any changes in the trends compared with previous years? SUMMARY ANSWER Despite some fluctuations in the number of countries reporting data, the overall number of ART cycles has continued to increase year by year and, while pregnancy rates in 2009 remained similar to those reported in 2008, the number of transfers with multiple embryos (3+) and the multiple delivery rates declined. WHAT IS KNOWN ALREADY Since 1997, ART data in Europe have been collected and reported in 12 manuscripts, published in Human Reproduction. STUDY DESIGN, SIZE, DURATION Retrospective data collection of European ART data by the EIM Consortium for the European Society of Human Reproduction and Embryology (ESHRE); cycles started between 1st January and 31st December are collected on a yearly basis; the data are collected by the National Registers, when existing, or on a voluntary basis. PARTICIPANTS/MATERIALS SETTING, METHODS From 34 countries (-2 compared with 2008), 1005 clinics reported 537 463 treatment cycles including: IVF (135 621), intracytoplasmic sperm injection (ICSI, 266 084), frozen embryo replacement (FER, 104 153), egg donation (ED, 21 604), in vitro maturation (IVM, 1334), preimplantation genetic diagnosis/screening (PGD/PGS, 4389) and frozen oocyte replacements (FOR, 4278). European data on intrauterine insemination using husband/partners semen (IUI-H) and donor (IUI-D) semen were reported from 21 and 18 countries, respectively. A total of 162 843 IUI-H (+12.7%) and 29 235 IUI-D (+17.3%) cycles were included. Data available from each country are presented in the tables; total values (as numbers and percentages) refer to those countries where all data have been reported. MAIN RESULTS AND THE ROLE OF CHANCE In 21 countries where all clinics reported to the ART register, a total of 399 020 ART cycles were performed in a population of 373.8 million, corresponding to 1067 cycles per million inhabitants. For IVF, the clinical pregnancy rates per aspiration and per transfer were 28.9 and 32.9%, respectively and for ICSI, the corresponding rates were 28.7 and 32.0%. In FER cycles, the pregnancy rate per thawing was 20.9%; in ED cycles, the pregnancy rate per transfer was 42.3%. The delivery rate after IUI-H was 8.3 and 13.4% after IUI-D. In IVF and ICSI cycles, 1, 2, 3 and 4+ embryos were transferred in 24.2, 57.7, 16.9 and 1.2%, respectively. The proportions of singleton, twin and triplet deliveries after IVF and ICSI (combined) were 79.8, 19.4 and 0.8%, respectively, resulting in a total multiple delivery rate of 20.2%, compared with 21.7% in 2008, 22.3% in 2007, 20.8% in 2006 and 21.8% in 2005. In FER cycles, the multiple delivery rate was 13.0% (12.7% twins and 0.3% triplets). Twin and triplet delivery rates associated with IUI cycles were 10.4/0.7% and 10.3/0.5%, following treatment with husband and donor semen, respectively. LIMITATIONS, REASONS FOR CAUTION The method of reporting varies among countries, and registers from a number of countries have been unable to provide some of the relevant data such as initiated cycles and deliveries. As long as data are incomplete and generated through different methods of collection, results should be interpreted with caution. WIDER IMPLICATIONS OF THE FINDINGS The 13th ESHRE report on ART shows a continuing expansion of the number of treatment cycles in Europe, with more than half a million of cycles reported in 2009. The use of ICSI has reached a plateau. Pregnancy and delivery rates after IVF and ICSI remained relatively stable compared with 2008 and 2007. The number of multiple embryo transfers (3+ embryos) and the multiple delivery rate have shown a clear decline.

Natural versus induced twinning and pregnancy outcome: a Dutch nationwide survey of primiparous dizygotic twin deliveries

OBJECTIVE To compare obstetrical outcome of twin pregnancies after assisted reproduction with that of natural twin pregnancies. DESIGN Retrospective national database study. SETTING Academic Medical Centre. PATIENT(S) One thousand ninety-three primiparous mothers registered in the Dutch National Birth Registry who gave birth to a dizygotic (DZ) twin (male/female) in 1994, 1995, and 1996. We compared 613 natural twin pregnancies and 480 twin pregnancies born after assisted reproduction. MAIN OUTCOME MEASURE(S) Gestational length, mode of delivery, mode of presentation of the children, birth weight, APGAR score, congenital anomalies, perinatal mortality rate, highest recorded maternal diastolic blood pressure, and maternal postpartum complications. RESULT(S) Rates of perinatal mortality and very premature parturition (<29 weeks) were lower in natural twin mothers. Overall, induced DZ twins were born 3.5 days earlier with a lower birth weight and APGAR score compared with controls. Rates of congenital anomalies and incidence of cesarean section were not different. The highest recorded diastolic blood pressure was lower in induced twinning with a 30% lower incidence of diastolic blood pressure >90 mm Hg. CONCLUSION(S) Obstetric outcome for induced DZ twin pregnancy is less optimal than in natural DZ twin pregnancy. Twinning in assisted reproduction is known for its contribution to the high rate of premature deliveries, but in addition being a subfertile patient undergoing treatment makes an intrinsic contribution to adverse events as well.

Risk of borderline and invasive ovarian tumours after ovarian stimulation for in vitro fertilization in a large Dutch cohort

BACKGROUND Long-term effects of ovarian stimulation for IVF on the risk of ovarian malignancies are unknown. METHODS We identified a nationwide historic cohort of 19 146 women who received IVF treatment in the Netherlands between 1983 and 1995, and a comparison group of 6006 subfertile women not treated with IVF. In 1997–1999, data on reproductive risk factors were obtained from 65% of women and data on subfertility (treatment) were obtained from the medical records. The incidence of ovarian malignancies (including borderline ovarian tumours) through 2007 was assessed through linkage with disease registries. The risk of ovarian malignancies in the IVF group was compared with risks in the general population and the subfertile comparison group. RESULTS After a median follow-up of 14.7 years, the risk of borderline ovarian tumours was increased in the IVF group compared with the general population [standardized incidence ratio (SIR) = 1.76; 95% confidence interval (CI) = 1.16–2.56]. The overall SIR for invasive ovarian cancer was not significantly elevated, but increased with longer follow-up after first IVF (P = 0.02); the SIR was 3.54 (95% CI = 1.62–6.72) after 15 years. The risks of borderline ovarian tumours and of all ovarian malignancies combined in the IVF group were significantly increased compared with risks in the subfertile comparison group (hazard ratios = 4.23; 95% CI = 1.25–14.33 and 2.14; 95% CI = 1.07–4.25, respectively, adjusted for age, parity and subfertility cause). CONCLUSIONS Ovarian stimulation for IVF may increase the risk of ovarian malignancies, especially borderline ovarian tumours. More large cohort studies are needed to confirm these findings and to examine the effect of IVF treatment characteristics.

Ovarian volume and antral follicle count for the prediction of low and hyper responders with in vitro fertilization

BackgroundThe current study was designed to compare antral follicle count (AFC) and basal ovarian volume (BOV), the exogenous FSH ovarian reserve test (EFORT) and the clomiphene citrate challenge test (CCCT), with respect to their ability to predict poor and hyper responders.MethodsOne hundred and ten regularly menstruating patients, aged 18–39 years, participated in this prospective study, randomized, by a computer designed 4-blocks system study into two groups. Fifty six patients underwent a CCCT, and 54 patients underwent an EFORT. All patients underwent a transvaginal sonography to measure the basal ovarian volume and count of basal antral follicle. In all patients, the test was followed by a standard IVF treatment. The result of ovarian hyperstimulation during IVF treatment, expressed by the total number of follicles, was used as gold standard.ResultsThe best prediction of ovarian reserve (Y) was seen in a multiple regression prediction model that included, AFC, Inhibin B-increment in the EFORT and BOV simultaneously (Y = -3.161 + 0.805 × AFC (0.258-1.352) + 0.034 × Inh. B-incr. (0.007-0.601) + 0.511 BOV (0.480-0.974) (r = 0.848, p < 0.001). Univariate logistic regression showed that the best predictors for poor response were the CCCT (ROC-AUC = 0.87), the bFSH (ROC-AUC = 0.83) and the AFC (ROC-AUC = 0.83). Multiple logistic regression analysis did not produce a better model in terms of improving the prediction of poor response. For hyper response, univariate logistic regression showed that the best predictors were AFC (ROC-AUC = 0.92) and the inhibin B-increment in the EFORT (ROC-AUC = 0.92), but AFC had better test characteristics, namely a sensitivity of 82% and a specificity 89%. Multiple logistic regression analysis did not produce a better model in terms of predicting hyper response.ConclusionIn conclusion AFC performs well as a test for ovarian response being superior or at least similar to complex expensive and time consuming endocrine tests. It is therefore likely to be the test for general practise.

The influence of the type of embryo culture medium on neonatal birthweight after single embryo transfer in IVF

STUDY QUESTION Does the type of medium used to culture fresh and frozen-thawed embryos influence neonatal birthweight after single embryo transfer (SET) in IVF? SUMMARY ANSWER A comparison of two commercially available culture media showed no significant influence on mean birthweight and mean birthweight adjusted for gestational age, gender and parity (z-scores) of singletons born after a fresh or frozen-thawed SET. Furthermore, we show that embryo freezing and thawing cycles may lead to a significantly higher mean birthweight. WHAT IS KNOWN AND WHAT THIS PAPER ADDS Animal studies have shown that culture media constituents are responsible for changes in birthweight of offspring. In human IVF, there is still little knowledge of the effect of medium type on birthweight. Until now, only a small number of commercially available culture media have been investigated (Vitrolife, Cook(®) Medical and IVF online medium). Our study adds new information: it has a larger population of singleton births compared with the previously published studies, it includes outcomes of other media types (HTF and Sage(®)), not previously analysed, and it includes data on frozen-thawed SETs. DESIGN This study was a retrospective analysis of birthweights of singleton newborns after fresh (Day 3) or frozen-thawed (Day 5) SET cycles, using embryos cultured in either of two different types of commercially available culture media, between 2008 and 2011. PARTICIPANTS AND SETTING Before January 2009, a single-step culture medium was used: human tubal fluid (HTF) with 4 mg/ml human serum albumin. From January 2009 onwards, a commercially available sequential medium was introduced: Sage(®), Quinns advantage protein plus medium. Singletons born after a fresh SET (99 embryos cultured in HTF and 259 in Sage(®)) and singletons born after a frozen-thawed SET (32 embryos cultured in HTF only, 41 in HTF and Sage(®) and 86 in Sage(®) only) were analysed. Only patients using autologous gametes without the use of a gestational carrier were considered. Also excluded were (vanishing) twins, triplets, babies with congenital or chromosomal abnormalities and babies born before 22 weeks of gestation. MAIN RESULTS AND THE ROLE OF CHANCE Analysis of 358 singletons born after a fresh SET and 159 singletons born after a frozen-thawed SET showed no significant difference between the HTF and Sage(®) groups in terms of birthweight. Gestational age, parity and gender of the baby were significantly related to birthweight in multiple linear regression analyses, and other possible confounding factors included maternal age, BMI and smoking, the number of blastomeres in the transferred embryo and the type of culture medium. Maternal age, BMI and smoking, gestational age at birth, gender of the baby and the percentage of firstborns did not differ significantly between the HTF and Sage(®) groups; however, among the fresh embryos, those cultured in Sage(®) had significantly more blastomeres at the time of embryo transfer compared with the embryos cultured in HTF. Birthweights adjusted for gestational age and gender or gestational age and parity (z-scores) were not significantly different between the HTF and Sage(®) groups for fresh or frozen-thawed SETs. Mean birthweight, as well as the mean birthweight among firstborns and the mean birthweights adjusted for gestational age and gender or parity (z-scores) were significantly higher in the cryopreservation group compared with the fresh embryo transfer group. BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION Our study is limited by its retrospective design and only two commercially available types of culture media were tested. More research is necessary to investigate the potential influence of culture media on gene expression. GENERALIZABILITY TO OTHER POPULATIONS Although our data do not indicate the major influences of the HTF and Sage(®) culture media on birthweight, our results cannot be extrapolated to other culture media types. Furthermore, there remains a potential influence of embryo culture environment on epigenetic variation not represented by birthweight differences but by more subtle features.

Decreased androgen concentrations and diminished general and sexual well-being in women with premature ovarian failure

Objective: To describe general and sexual well-being in women with premature ovarian failure (POF) and to investigate whether there is a relationship between androgen levels and sexual functioning. Design: Women with POF and healthy volunteers with regular menstrual cycles participated. Participants completed a written questionnaire and underwent hormonal screening. The questionnaire included standardized measures: the Questionnaire for Screening Sexual Dysfunctions, the Shortened Fatigue Questionnaire, and the Symptom Check List-90. Serum hormone measurements included estradiol, total testosterone, bioavailable testosterone, androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone sulfate. Results: Eighty-one women with POF and 68 control women participated in the study. Compared with control women, women with POF reported more complaints of anxiety, depression, somatization, sensitivity, hostility, and psychological distress. Overall women with POF were less satisfied with their sexual life. They had fewer sexual fantasies and masturbated less frequently. Sexual contact was associated with less sexual arousal, reduced lubrication, and increased genital pain. However, the frequency of desire to have sexual contact and the frequency of actual sexual contact with the partner did not differ between women with POF and control women. Women with POF had lower levels of estradiol, total testosterone, and androstenedione. Multiple regression analysis revealed that androgen levels had only a weak influence on sexual functioning; higher total testosterone levels were associated with increased frequency of desire for sexual contact, and higher androstenedione levels were associated with elevated frequency of sexual contact. Conclusions: Women with POF have diminished general and sexual well-being and are less satisfied with their sexual lives than control women. Although women with POF had lower androgen levels, we did not find an important independent role for androgens in various aspects of sexual functioning.

Superiority of skinfold measurements and waist over waist-to-hip ratio for determination of body fat distribution in a population-based cohort of Caucasian Dutch adults

OBJECTIVE To determine which anthropometric measurement is the most reliable alternative for fat distribution as measured by dual-energy X-ray absorptiometry (DXA). DESIGN Population-based survey carried out in Amsterdam, The Netherlands. SUBJECTS AND METHODS A total of 376 individuals (200 women) with a mean age of 36.5 years and mean body mass index (BMI) of 24.0 (+/-3.1) kg/m2 underwent various anthropometric and DXA measurements of central (CFM) and peripheral fat mass (PFM). Furthermore, for the assessment of apple-shaped body composition, CFM-to-PFM ratio was calculated. Anthropometric measurements were waist and hip circumference, waist-to-hip ratio (WHR), BMI, waist/length and the skinfold thickness of biceps, triceps, suprailiacal (SI), subscapular (SS) and upper leg. We determined whether equations of combined anthropometrics were even more reliable for the assessment of fat mass. RESULTS In both women and men, reliable alternatives for CFM are central skinfolds and waist (Pearsons correlation (r) >or= 0.8). Peripheral skinfolds are the best predictors of PFM (r >or= 0.8). In contrast, WHR correlated only marginally with any of the DXA measurements. Equations based on several anthropometric variables correlate with CFM even better (R2 >or= 0.8). CFM-to-PFM ratio has the highest correlation with the ratio (SS+SI)/BMI in women (r = 0.66) and waist/length in men (r = 0.71). Equations are reasonable alternatives of CFM-to-PFM ratio (R2 >or= 0.5). CONCLUSION Waist and skinfolds are reliable alternatives for the measurement of body fat mass in a cohort of Caucasian adults. WHR is not appropriate for the measurement of fat distribution.

Apoptotic cell death in human granulosa-lutein cells: a possible indicator of in vitro fertilization outcome

OBJECTIVE To determine whether women who do not conceive during an IVF treatment despite normal FSH levels have a higher rate of apoptosis in their granulosa-lutein cells than women who do conceive. DESIGN Prospective. SETTING Large teaching hospital and fertility center. PATIENT(S) Patients with normal FSH levels undergoing an IVF treatment. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Outcome of the IVF treatment and percentage of apoptotic granulosa-lutein cells. RESULT(S) A significantly lower percentage of granulosa-lutein cells were apoptotic in patients who became pregnant compared with those who did not become pregnant. A higher basal FSH level was significantly correlated with the duration of the stimulation, and the number of follicles was significantly inversely correlated with the number of ampules of FSH used and the duration of the treatment. The number of embryos was significantly correlated with the number of oocytes, and significantly inversely correlated with the number of apoptotic granulosa-lutein cells. CONCLUSION(S) Fewer granulosa-lutein cells are apoptotic in women who have an ongoing pregnancy after IVF treatment than in women who do not conceive.