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BACKGROUND: Gonadotropin therapy and laparoscopic ovarian drilling (LOD) are treatment options for ovulation induction (OI) in clomiphene citrate (CC)-resistant polycystic ovary syndrome (PCOS) patients. The current evidence of the cost-effectiveness of both treatments is scarce, conflicting and performed from different health-economic perspectives. METHODS: A retrospective health-economic evaluation was performed from a societal perspective in which human menopausal gonadotropin (hMG) therapy (n = 43) was compared with LOD (n = 35), followed by OI with CC and/or hMG if spontaneous ovulation did not occur within 2 months. Data were collected until the patients were pregnant, with a time limit of 6 months after the onset of treatment. Outcomes were expressed as ongoing pregnancy rate and number of live-born children. RESULTS: The ongoing pregnancy rate was 21/35 (60%) after LOD and 30/43 (69.8%) after hMG treatment (relative risk 0.85, 95% CI 0.61-1.19). The societal cost per patient, up to an ongoing pregnancy, was significantly higher after LOD versus hMG treatment (adjusted mean difference EUR 1,073, 95% CI 180-1,967). CONCLUSION: This economic evaluation based on real-life data shows that the societal cost up to an ongoing pregnancy is less after hMG treatment when compared with LOD surgery in CC-resistant PCOS patients.

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This study describes patients' satisfaction with the information they received regarding the disposition of supernumerary embryos in the context of their decision making, as well as partners' roles and the involvement of others. An anonymous mail questionnaire was sent to 412 female patients from the Department of Reproductive Medicine (Ghent University Hospital, Ghent, Belgium). The questionnaire had a response rate of 79%. The majority of patients who did not want to continue the storage of their embryos (87.9%) thought the information provided was sufficient to make a decision. Patients who were not satisfied more often failed to reach a decision compared to other patients (4/25 vs. 6/173, p = 0.0248). The majority of couples (81.7%) reached a decision jointly between partners. Nonetheless, in 15.6% of couples, one of the partners had made the decision alone, mostly after consulting their partners. Only a minority of the couples (13.2%) consulted others (mostly family members or close friends), suggesting that patients view these decisions as a private matter. Only 1.1% of all patients had talked to someone at the centre about their decision. To conclude, for most patients, the information provided was adequate in light of their disposition decision making. Overall, patients' decision making appears to be a private matter which happens out of sight from medical staff, making it hard to assist patients who face difficulties.

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OBJECTIVES: This paper describes a recently identified conception of the cryopreserved embryo as a symbol of one's relationship (SOR). METHODS: A questionnaire was sent together with the embryo disposition decision (EDD) form to patients for whom embryos were cryopreserved at the department in Ghent, Belgium. We collected data on patient characteristics, their EDD attitudes and the reasons for their willingness or unwillingness to consider each of the disposition options (donation to others for reproduction, donation for science and discarding). RESULTS: The SOR view was found more often in patients who were less educated and whose last treatment was less than 3 years ago. Viewing the embryo as a SOR was not linked to more difficult decision making, but to more emotionally loaded decision making. In particular, patients with this view more often reported feelings of grief. This view was also linked to the outcome of the decision making process. CONCLUSION: The conception of the embryo as a SOR is part of an affective attitude towards embryos that has an impact on patients' disposition decisions. Alongside patients' values and principles, it is important that counselors acknowledge and clarify patients' affective conceptualizations.

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OBJECTIVE: To describe patients who at least once did not reply to correspondence of the center about embryo disposition. DESIGN: Anonymous questionnaire. SETTING: Department of Reproductive Medicine, Ghent University Hospital (Belgium). PATIENT(S): Patients whose embryos were stored for at least 2 years. INTERVENTION(S): Mail survey. MAIN OUTCOME MEASURE(S): Patients' reply behavior, their characteristics, their embryo disposition decision, and their attitudes toward this decision. RESULT(S): The response rate was 79%. Twelve percent of the patients were nonrepliers, mostly because they were not able to reach a (joint) decision. Nonrepliers were somewhat older, their last treatment cycle was longer ago, and it more often had a negative outcome. Nonrepliers were childless twice as often as other patients. They also more often experienced anticipated regret about the decision, and they valued their embryos more often in relation to the use for their own treatment. The proportion of patients who seldom thought about their embryos was the same in both groups. CONCLUSION(S): Treatment failure, anticipated regret, and valuing the embryo on the basis of probability of use influence patients' reply behavior and may be key elements for prevention measures.

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On the 50th birthday of the pill, it is appropriate to recall the milestones which have led to its development and evolution during the last five decades. The main contraceptive effect of the pill being inhibition of ovulation, it may be called a small miracle that this drug was developed long before the complex regulation of ovulation and the menstrual cycle was elucidated. Another stumbling block on its way was the hostile climate with regard to contraception that prevailed at the time. Animal experiments on the effect of sex steroids on ovulation, and the synthesis of sex steroids and orally active analogues were the necessary preliminaries. We owe the development of oral contraceptives to a handful of persons: two determined feminists, Margaret Sanger and Katherine McCormick; a biologist, Gregory Pincus; and a gynaecologist, John Rock. Soon after the introduction of the first pills, some nasty and life-threatening side effects emerged, which were due to the high doses of sex steroids. This led to the development of new preparations with reduced oestrogen content, progestins with more specific action, and alternative administration routes. Almost every decade we have witnessed a breakthrough in oral contraception. Social and moral objections to birth control have gradually disappeared and, notwithstanding some pill scares, oral contraceptives are now one of the most used methods of contraception. Finally, all's well that ends well: recent reports have substantiated the multiple noncontraceptive health benefits paving the way for a bright future for this 50-year-old product.

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BACKGROUND: Embryo transfer is a crucial step in the IVF process. Most randomized prospective studies comparing transfer catheters have demonstrated significantly higher pregnancy rates with soft versus firm catheters, but none have taken the operator effect into account. Our aim was to perform a prospective randomized clinical trial comparing two catheters and to study interactions between catheters and operators. METHODS: A prospective randomized trial comparing the Cook K-SOFT-5100 and Frydman classical catheters 4.5 was performed. Three experienced operators participated in the trial, using a fixed distance transfer protocol. Primary end-point was clinical pregnancy rate, secondary end-points were rates of difficult transfer and of catheter failure. Patients were randomized by a computer program prior to embryo transfer. RESULTS: A total of 1446 embryo transfers were performed in 1155 women undergoing IVF or ICSI treatment. A total of 723 cycles were randomized to the Cook catheter and 723 cycles to the Frydman catheter. Following intention-to-treat analysis, the adjusted odds ratio of clinical pregnancy between for the Cook versus the Frydman catheter was 1.11 [95% confidence interval (95% CI) 0.89-1.38]. Odds ratios of clinical pregnancy between the Cook and Frydman catheters for the three operators were respectively 1.19 (95% CI 0.84-1.69), 2.35 (95% CI 1.40-3.95) and 0.69 (95% CI 0.48-0.99). CONCLUSIONS: Variation in pregnancy rates between embryo transfer catheters depends on variation between operators. Results from randomized clinical trials comparing embryo transfer catheters should not be generalized, because inconsistent conclusions may be unavoidable on the account of different proportions of cycles with transfers by each type of operator. The study was registered at clinicaltrials.gov. NCT00766714.

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Artificial oocyte activation using the calcium ionophore ionomycin is applied successfully in assisted reproduction but some concern exists on the clinical use. The aims of the present study were to optimize the oocyte activation scheme and to address embryo toxicity in a mouse model. Efficiency of oocyte activation and subsequent development was evaluated and ionomycin was found to be an efficient activator at 10 micromol/l. An improved effect of a second exposure to 5 micromol/l ionomycin on blastocyst development was observed. Toxicity of ionomycin on embryos was then investigated by evaluating pre- and post-implantation development of in-vivo fertilized oocytes following exposure to ionomycin. Blastocyst development, blastocyst cell numbers in trophectoderm and inner cell mass were not different between treated and non-treated zygotes. Also implantation rates and fetal parameters such as length, weight and morphological parameters were similar between the fetuses originating from zygotes treated with ionomycin and non-treated zygotes. Furthermore, healthy offspring originating from ionomycin-treated zygotes was born. In conclusion, no adverse effects of ionomycin on in-vitro or in-vivo mouse embryo development were noticed, giving arguments in favour of the use of ionomycin, although negative long-term effects of this compound cannot be excluded at present.

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Failed fertilization after intracytoplasmic sperm injection (ICSI) can occur due to an oocyte activation defect. In these cases assisted oocyte activation (AOA) may help but efficiency is still unknown. Prior to AOA, the mouse oocyte activation test (MOAT) can be carried out by injecting human spermatozoa into mouse oocytes to evaluate their activating capacity. According to the MOAT activation percentage achieved, patients were classified into three groups: 0-20% (16 patients); 20-85% (seven patients); 85-100% (seven patients). For AOA, CaCl(2) was injected together with spermatozoa followed by a double Ca(2+) ionophore treatment. The fertilization rates before application of AOA in 50 cycles were 6%, 22% and 14% in, respectively, groups 1, 2 and 3 without any pregnancy. Fertilization and pregnancy rates after AOA in 61 cycles were significantly increased to 75% and 34% for group 1, 73% and 43% for group 2, and 75% and 17% for group 3 (P < 0.0001 and P < 0.004, respectively). Application of AOA results in normal fertilization and pregnancy rates in patients whose spermatozoa show deficient activation. When MOAT reveals no activation deficiency in spermatozoa, AOA still allows for high fertilization and acceptable pregnancy rates. The obstetric and neonatal outcomes after AOA were normal as no malformations were observed.

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BACKGROUND: Because seminal prostaglandins play a role at natural fertilization, it was hypothesized that vaginal supplementation of prostaglandins at the time of intrauterine insemination (IUI) might enhance chances of conception. We investigated the effect of misoprostol, a prostaglandin analogue, on the success rate of IUI. METHODS: A multi-center double-blind randomized controlled trial, using a cross-over design with alternating sequence, was designed. Vaginal tablets of misoprostol or placebo were used in conjunction to intrauterine insemination. In total, 199 women, comprising 466 cycles, were analyzed. Main outcome measures were pregnancy rate and prevalence of vaginal bleeding and uterine cramps. RESULTS: The misoprostol group accounted for 146 cycles with 19 pregnancies, whereas the placebo group cycles totaled 164 cycles with 21 pregnancies (13.0 vs. 12.8%, not significant). There was a statistically significant increase in vaginal bleeding (12.3 vs. 1.8%; OR 7.55; 95% CI 2.31-24.48) and abdominal cramping rates (15.1 vs. 4.3%; OR 3.98; 95% CI 1.68-9.39) after application of misoprostol. Due to these severe adverse events the study was prematurely terminated. CONCLUSION: Although prostaglandins surely play a role in natural human reproduction, vaginal administration of misoprostol at the time of IUI is associated with a high rate of side effects and does not seem to enhance the outcome.

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The present study aimed to analyze detailed morphological and functional characteristics of mouse in vitro matured oocytes after a pre-maturation culture (PMC) by temporary nuclear arrest with the specific phosphodiesterase 3-inhibitor (PDE3-I) Cilostamide. In a first experiment the lowest effective dose of Cilostamide was determined. Cumulus-oocyte complexes (COCs), isolated from small antral follicles, were exposed to different concentrations of Cilostamide (ranging from 0 (control) to 10 microM) for 24 hr. Afterwards, oocytes were removed from PDE3-I-containing medium and underwent in vitro maturation (IVM) for 16-18 hr. A concentration of 1 microM Cilostamide was the lowest effective dose for maximum level of inhibition and reversibility of meiosis inhibition. This concentration was used in further experiments to evaluate oocyte quality following IVM in relation to different parameters: kinetics of meiotic progression, metaphase II (MII) spindle morphology, aneuploidy rate, fertilization, and embryonic developmental rates. The results were compared to nonarrested (in vitro control) and in vivo matured oocytes (in vivo control). Following withdrawal of the inhibitor, the progression of meiosis was more synchronous and accelerated in arrested when compared to nonarrested oocytes. A PMC resulted in a significant increase in the number of oocytes constituting a MII spindle of normal morphology. None of the oocytes exposed to PDE3-I showed numerical chromosome alterations. In addition, fertilization and embryonic developmental rates were higher in the PMC group compared to in vitro controls, but lower than in vivo controls. These results provide evidence that induced nuclear arrest by PDE3-I is a safe and reliable method to improve oocyte quality after IVM.

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BACKGROUND: The main goal of the present study was to assess the influence of the androgen receptor gene CAG repeat polymorphism on hyperandrogenism and its phenotypical features in patients with polycystic ovary syndrome (PCOS). METHODS: CAG repeat lengths were analyzed in 97 oligo-anovulatory women with ultrasound features of PCOS. All individuals were assessed for endocrine parameters and their phenotypical features were recorded. These parameters were correlated with the CAG repeat lengths. RESULTS: PCOS patients with a bi-allelic mean lower than 21 repeats had lower dihydrotestosterone levels (p = 0.007), lower androstenedione levels (p = 0.023), lower luteinizing hormone levels (p = 0.023), a lower luteinizing hormone/follicle-stimulating hormone ratio (p = 0.021) and the highest percentage of patients with acne and/or hirsutism (p = 0.021). CONCLUSIONS: Our findings support the hypothesis that the PCOS phenotype may result from either elevated androgen levels or an enhanced sensitivity to androgens caused by a more active androgen receptor.

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OBJECTIVE: To submit different glove brands to double-quality control tests using mouse embryo assay (MEA) and the human sperm motility assay (HuSMA). Operator protection against infectious body fluid contamination is a safety issue in assisted reproductive technology (ART). When using gloves in the ART laboratory, toxic substances can be transmitted to culture media, even during brief contact. DESIGN: Quality control study of gloves in ART. SETTING: University hospital-based infertility center. ANIMAL(S): Seven- to 8-week-old female B6D2F1 hybrid mice. INTERVENTION(S): We tested two surgical, two cleanroom, and six examination glove brands. Only gloves brands that passed both HuSMA and MEA were submitted to further QC using zona-free and/or cryopreserved MEA. MAIN OUTCOME MEASURE(S): Sperm motility index, two-cell and blastocyst development, blastocyst total cell number. RESULT(S): Quality control by MEA and HuSMA identified two glove brands to be nontoxic. CONCLUSION(S): Our study shows that gloves used in ART can be toxic and should be tested as part of an ongoing quality control program.

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BACKGROUND: We postulated that impaired endometrial differentiation in women with pelvic endometriosis predisposes for pre-eclampsia. METHODS: A retrospective case-control study set at the University of Ghent IVF centre. The incidence of pre-eclampsia and pregnancy-induced hypertension (PIH) following the clinical and/or laparoscopic diagnosis of endometriosis-associated infertility (case group; n = 245 pregnancies) was compared with the incidence of these obstetric complications in pregnancies following treatment for male-factor infertility (control group; n = 274 pregnancies). Pregnancy data were obtained by searching electronic databases and postal questionnaires. The case and control groups were matched for age, parity and multiple pregnancies. RESULTS: The incidence of pre-eclampsia was significantly lower in the case group (0.8%) when compared with control group (5.8%) (P = 0.002; odds ratio (OR) = 7.5, 95% confidence interval (CI): 1.7-33.3). Analysis of obstetric outcome in the subgroup of patients with laparoscopic data confirmed the lower risk of pre-eclampsia in the case (1.2%) versus control (7.4%) groups (P = 0.032; OR = 6.6, 95% CI: 1.2-37). PIH occurred in 3.5% and 8.7% of case and control pregnancies, respectively (P = 0.018; OR = 2.6, 95% CI: 1.2-6.0). The odds of developing pre-eclampsia were 5.67 times higher in the control group than in pregnancies following endometriosis-associated infertility. In multiple pregnancies, the odds of developing pre-eclampsia increased 1.93 times per additional child, with or without endometriosis. CONCLUSIONS: We found no evidence that endometriosis predisposes for pre-eclampsia. Instead, the risk of hypertensive disorder in pregnancy is significantly reduced in women with endometriosis-associated infertility.

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BACKGROUND: The use of hormones for controlled ovarian stimulation results in follicular heterogeneity, with oocytes at diverse stages of nuclear and cytoplasmic development. This study evaluated the impact of temporary nuclear arrest by a specific phosphodiesterase 3-inhibitor (PDE3-I), cilostamide, on nuclear and cytoplasmic maturation of cumulus-free germinal vesicle (GV) human oocytes from controlled ovarian stimulated cycles. METHODS: GV oocytes (n = 234) were cultured in: (i) medium without the inhibitor (control); (ii) medium supplemented with 1 microM cilostamide and (iii) medium supplemented with 10 microM cilostamide. Oocytes in groups (ii) and (iii) were exposed to cilostamide for 24 h. The PDE3-I was subsequently removed by transfer of oocytes to fresh in vitro maturation (IVM) medium and the reversibility of GV arrest was assessed during IVM culture for maximum 48 h. RESULTS: Cilostamide (1 and 10 microM) could maintain >80% of the oocytes at the GV stage, without affecting subsequent maturation to metaphase II. Oocytes exposed to 1 microM cilostamide were more likely to have normal bipolar spindles with aligned chromosomes than control oocytes (P < 0.05). When GV chromatin configurations before and after arrest were compared, a significantly higher proportion of oocytes had acquired a nucleolus completely surrounded by a rim of highly condensed chromatin (P < 0.05). CONCLUSIONS: Temporary nuclear arrest of human GV oocytes with PDE3-I proved to be beneficial for obtaining normal spindle and chromosome configurations after IVM. It resulted also in synchronization within the population of GV oocytes.

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Somatic cloning technology involves the transfer of a somatic cell nucleus into an enucleated oocyte, followed by activation and in vitro culture. Efficiency in terms of live offspring generally remains very low. Little attention has been devoted so far to the impact of culture environment on cloned embryo development. Failure of genomic reprogramming of the donor nucleus in nuclear transfer (NT) experiments could lead to an altered phenotype in these cloned embryos that could be manifested by different medium preferences of the NT embryos. We describe here the application of sequential culture media to support preimplantation development of mouse embryos reconstructed using conventional NT techniques. Embryo-quality analysis was performed on NT blastocysts obtained. Additionally, NT embryos that arrested during development also were analyzed.

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BACKGROUND: Haptoglobin (Hp) polymorphism has been associated with blood pressure regulation and essential hypertension. We investigated Hp polymorphism in patients with preeclampsia. METHODS: A total of 60 Caucasian women with preeclampsia were prospectively followed from hospital admission until delivery. Serum Hp phenotypes 1-1, 2-1, and 2-2 were determined by starch gel electrophoresis and compared with those in 200 normotensive controls of the same geographic and ethnic origin. Blood pressure and laboratory markers (serum uric acid, alanine aminotransferase, aspartate aminotransferase, platelet count, and 24-h proteinuria) were compared according to Hp phenotypes of preeclamptic women. RESULTS: We found a higher Hp1 allele frequency in the preeclamptic group than in normotensive controls (0.517 vs. 0.400, p<0.05). The Hp 1-1 phenotype was present in 28% of preeclamptic patients vs. 16% of the controls, with an odds ratio (95% CI) of 2.08 (1.05-4.08) for Hp 1-1 vs. the other Hp phenotypes. Diastolic (p<0.005) and systolic (p<0.05) blood pressure and proteinuria (p<0.05) were highest in Hp 1-1 patients. Other laboratory markers were not significantly different between Hp phenotype subgroups. CONCLUSIONS: The Hp1 allele frequency was higher among preeclamptic patients and the Hp 1-1 phenotype was associated with more severe hypertension and proteinuria.

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BACKGROUND: Single-embryo transfer (SET) has proven efficient in reducing multiple pregnancy rates after assisted reproduction technologies (ART). This study compares outcome of singletons after SET and double-embryo transfer (DET). METHODS: We studied 404 SET and 431 DET patients, who delivered a singleton child of >500 g after fresh embryo transfer in a first, second or third cycle. Preterm birth and low birthweight incidences and gestational age and birthweight were compared between both groups. Adjustments were made for maternal age, parity, cycle rank number, treatment indication, ART method, embryo characteristics and sex of the child. RESULTS: Singletons born after DET have a significantly lower birthweight than that after SET (3204.3 +/-617.5 g versus 3324.6+/-509.7 g , P<0.01). Also preterm birth (<37 weeks) [odds ratio (OR) 1.77, 95% confidence interval (CI) 1.06-2.94] and low birthweight (<2500 g) (OR 3.38, 95% CI 1.86-6.12) are significantly more common in DET singletons. CONCLUSIONS: Singleton birth after SET is advantageous compared with DET. This sheds new light on the reasons why singleton births following ART do worse than spontaneously conceived singletons in IVF programs, where double- or multiple-embryo transfer is standard.

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BACKGROUND: The aim of our study was to review the results of microsurgically performed testicular sperm extraction (TESE) and to evaluate its possible long term effects on serum testosterone (T). METHODS: We operated on 48 men (35 +/- 8 years) with non-obstructive azoospermia (NOA). If no spermatozoa were found following a micro epididymal sperm extraction (Silber et al., 1994) and testicular biopsy, testicular microdissection was performed or multiple microsurgical testicular biopsies were taken. The mean follow-up of the serum T was 2.4 +/- 1.1 years. RESULTS: Sperm was retrieved in 17/48 (35%) of the men. The per couple take home baby rate if sperm was retrieved was 4/17 (24%). Serum T decreased significantly at follow-up (p < 0.05) and 5/31 (16%) de novo androgen deficiencies developed CONCLUSION: In patients with non-obstructive azoospermia in whom no spermatozoa were found following a micro epididymal sperm aspiration and a simple testicular biopsy, we were able to retrieve spermatozoa in 35% of the men. The take home baby rate was 24% among couples with spermatozoa present upon TESE. De novo androgen deficiency occurred in 16% of the male patients following TESE indicating that, in men with NOA, long term hormonal follow up is recommended after TESE.

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BACKGROUND: First-trimester bleeding is frequent in assisted reproductive technique (ART) pregnancies. It is unknown whether first-trimester bleeding, if not ending in a spontaneous abortion, negatively influences further pregnancy outcome in ART in singletons. METHODS: Data were obtained from our ART database (1993-2002), with 1432 singleton ongoing pregnancies being included in this study. The outcome measures-second-trimester and third-trimester bleeding, preterm contraction rates, pregnancy duration, birthweight, Caesarean section rates, intrauterine growth retardation (IUGR), preterm prelabour rupture of membranes (P-PROM), neonatal intensive care unit (NICU) admission and perinatal mortality-were compared in the groups with and without first-trimester bleeding. RESULTS: Significantly more singleton pregnancies resulted from a vanishing twin in the group with first-trimester bleeding (8.7%) than in the controls (4.0%). A correlation was found between the incidence of first-trimester bleeding and the number of embryos transferred. First-trimester bleeding led to increased second-trimester [odds ratio (OR)=4.56; confidence interval (CI)=2.76-7.56] and third-trimester bleeding rates (OR=2.85; CI=1.42-5.73), P-PROM (OR=2.44; CI=1.38-4.31), preterm contractions (OR=2.27; CI=1.48-3.47) and NICU admissions (OR=1.75; CI=1.21-2.54). First-trimester bleeding increased the risk for preterm birth (OR=1.64; CI=1.05-2.55) and extreme preterm birth (OR=3.05; CI=1.12-8.31). CONCLUSIONS: First-trimester bleeding in an ongoing singleton pregnancy following ART increases the risk for pregnancy complications. The association between first-trimester bleeding, the number of embryos transferred and adverse pregnancy outcome provides a further argument in favour of single-embryo transfer.

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