Carl Spiessens

High prevalence of endometriosis in infertile women with normal ovulation and normospermic partners.

OBJECTIVE To determine the prevalence of histologically proven endometriosis in a subset of infertile women. DESIGN Retrospective case series with electronic file search and multivariable logistic regression analysis. SETTING Tertiary academic fertility center. PATIENT(S) Two hundred twenty-one infertile women without previous surgical diagnosis for infertility with regular cycles (variation, 21-35 days) whose partners have a normal semen analysis. INTERVENTION(S) Diagnostic laparoscopy and, if necessary, operative laparoscopy with CO(2) laser excision. MAIN OUTCOME MEASUREMENT(S) The prevalence of endometriosis and of fertility-reducing nonendometriotic tubal and/or uterine pathology. RESULT(S) The prevalence of endometriosis was 47% (104/221), including stage I (39%, 41/104), stage II (24%, 25/104), stage III (14%, 15/104), and stage IV (23%, 23/104) endometriosis, and was comparable in patients with (54%, 61/113) and without (40%, 43/108) pelvic pain. The prevalence of fertility-reducing nonendometriotic tubal and/or uterine pathology was 29% in all patients (15% in women with and 40% in women without endometriosis). A multivariate logistic regression model including pain, ultrasound data, age, duration of infertility, and type of fertility was not or not sufficiently reliable for the prediction of endometriosis according to the revised American Fertility Society (rAFS) classifications I-II and rAFS III-IV, respectively. CONCLUSION(S) Reproductive surgery is indicated in infertile women belonging to the study population, regardless of pain symptoms or transvaginal ultrasound results, since half of them have endometriosis and 40% of those without endometriosis have fertility-reducing pelvic pathology.

Preimplantation genetic screening for aneuploidy of embryos after in vitro fertilization in women aged at least 35 years: a prospective randomized trial

OBJECTIVE To test the hypothesis that patients with advanced maternal age (AMA) have a higher implantation rate (IR) after embryo transfer of embryos with a normal chromosomal pattern for the chromosomes studied with preimplantation genetic screening (PGS) compared with patients who had an embryo transfer without PGS. DESIGN Prospective randomized controlled trial (RCT). SETTING Academic tertiary setting. PATIENT(S) Patients with AMA (> or =35 years). INTERVENTION(S) In an RCT, the clinical IR per embryo transferred was compared after embryo transfer on day 5 or 6 between the PGS group (analysis of chromosomes 13, 16, 18, 21, 22, X, and Y) and the Control group without PGS. MAIN OUTCOME MEASURE(S) No differences were observed between the PGS group and the Control group for the clinical IR (15.1%; 14.9%; rate ratio 1.01; exact confidence interval [CI], 0.25-5.27), the ongoing IR (at 12 weeks) (9.4%; 14.9%), and the live born rate per embryo transferred (9.4%; 14.9%; rate ratio 0.63; exact CI, 0.08-3.37). Fewer embryos were transferred in the PGS group (1.6 +/- 0.6) than in the Control group (2.0 +/- 0.6). A normal diploid status was observed in 30.3% of the embryos screened by PGS. CONCLUSION(S) In this RCT, the results did not confirm the hypothesis that PGS results in improved reproductive outcome in patients with AMA.

Low Birth Weight and Subsequent Male Subfertility

Male subfertility often remains unexplained. Severe intrauterine growth retardation has previously been linked to hypergonadotropic hypogonadism. We examined whether reduced fetal growth, as judged by low birth weight, is associated with unexplained male subfertility later in life. Birth weight and gestational age were obtained by questionnaire from male partners of couples consulting for subfertility, and were transformed into birth weight SD scores. Men with normal semen analysis (n = 128) had a median birth weight SD score of 0.0 (P25-P75 range: -0.7 to 1.0), comparable to that of men with explained subfertility (n = 28), and higher (p= 0.012) than that of men with unexplained subfertility (n = 32; median -0.5 SD score; P25-P75 range: -0.9 to -0.1). These results extend the link between reduced fetal growth and male subfertility to a range of birth weight that is well within normality. The pathophysiologic mechanism governing this association now remains to be unraveled.

Intra- and inter-observer analysis in the morphological assessment of early-stage embryos.

BackgroundThe aim of this study was to determine the intra- and inter-observer variability in the evaluation of embryo quality. Multilevel images of embryos on day 1, day 2 and day 3, were analysed using different morphological parameters.MethodsMultilevel images of embryos on day 1, day 2 and day 3, were analysed using a standard scoring system. The kappa coefficient was calculated to measure intra- and inter-observer variability before and after training sessions.ResultsGood to excellent intra-observer agreement was present for most parameters exceptions being scoring the position of pronuclei and the presence of a cytoplasmic halo on day 1, multinucleation on day 2 and the size of fragments on day 3. Inter-observer agreement was only good to excellent for the number of blastomeres on day 2 and day 3 and the orientation of the cleavage axes on day 2. Training sessions had a positive impact on inter-observer agreement.ConclusionIn conclusion, assessment of morphological characteristics of early stage embryos using multilevel images was marked by a high intra-observer and a moderate inter-observer agreement. Training sessions were useful to increase inter-observer agreement.

Multicenter study on reproducibility of sperm morphology assessments.

Sperm morphology has always been considered an important tool in evaluating a mans fertilizing potential. The objective of this multicentric study was to evaluate intra- and interindividual variability and between-laboratory variation using the same or different criteria of sperm morphology assessment. Semen samples were obtained from 20 males and 32 smears were made of all samples. Eighty coded smears (4 per patient) were sent to 8 laboratories for morphology assessment. The centers applied different classification systems (strict criteria, WHO 1987, Düsseldorf criteria) and participants were asked to analyze the 80 smears twice, with an interval of 1 week between each participants two analyses. Intraclass correlations between repeats showed that sperm morphology can be assessed with acceptable within observer reproducibility. Expected increases in imprecision were observed up to coefficients of variation of >30% with decreasing morphology scores, regardless of the classification system used. Agreement in correct classification of samples as normal/abnormal was obtained in 80% of cases. Differences in reproducibility between slides may reflect an important source of heterogeneity due to smear preparation. These results emphasize the importance of external quality control systems to improve the value of sperm morphology assessments in the investigation of the male partner in a subfertile couple.

Laparoscopic Inguinal Hernia Repair in Men With Lightweight Meshes May Significantly Impair Sperm Motility: A Randomized Controlled Trial

Objective:To compare quality of life and fertility aspects after laparoscopic inguinal hernia repair in men using a heavyweight or lightweight mesh. Summary Background Data:The use of lightweight meshes in laparoscopic inguinal hernia repair could have beneficial effects on quality of life and preservation of the spermatic structures due to a decreased foreign-body reaction. Methods:A total of 59 male patients planned for primary, unilateral or bilateral inguinal hernia repair were randomized between a standard polypropylene (Marlex) or lightweight mesh (Vypro II, TiMesh). Main outcome measures were fertility aspects, assessed preoperatively and at 1-year follow-up by semen analysis and scrotal ultrasonography. Secondary outcomes were quality of life (SF-36 and McGill Pain Questionnaire) and recurrence up to 1 year postoperatively. Results:Patients operated on with a VyproII or TiMesh mesh exhibited a decreased sperm motility (vs. preoperatively) compared with Marlex patients, respectively −9.5% and −5.5% versus +2% (P = 0.013). When the results after uni- and bilateral hernia repair were analyzed separately, this difference only remained significant in the bilateral hernia subgroup: −10% for VyproII and −17% for TiMesh versus +1% for Marlex (P = 0.037). Other fertility parameters (sperm concentration, morphology, and &agr;-glucosidase level) were unchanged. There were no differences at any study point between the 3 groups regarding quality of life. Only for resumption of sport activities was a small advantage noted for VyproII versus Marlex patients (P = 0.045). After 1 year, no recurrences were observed; 3 patients (6%) complained of chronic disabling pain. Conclusions:Our data suggest that the use of lightweight meshes for laparoscopic inguinal hernia repair in male patients negatively influences sperm motility, without any benefit on quality of life. These alterations might be important in a subgroup of young male patients operated on laparoscopically for a bilateral hernia. This study was registered in the clinicaltrials.gov database (ID number NCT00925067).

Association between CAG repeat number in the androgen receptor and male infertility in a Belgian study

To the Editor: The androgen receptor (AR) contains a polymorphic CAG repeat in the first exon coding for a polyglutamine (polyGln) tract (1, 2). Normal AR alleles contain between 11 and 31 repeats and are on average somewhat larger in Asians (3). Expansion of the CAG repeat to 40 or more causes an X-linked motor neuron disease called spinal and bulbar muscular atrophy (SMBA) or Kennedy’s disease (1, 2). These patients also show signs of progressive androgen resistance (progressive sexual disturbances, testicular atrophy and deterioration of sperm quality). Tut et al. (4) reported an association between long normal CAG repeats in the AR and impaired sperm production in Chinese men. In their study, 28 or more Gln in the AR was statistically more frequently observed in the group of men with infertility or subfertility compared to normal men (odds ratio=4.02 with 95% confidence interval (CI): 3.2–4.9). The opposite phenomenon was observed for ARs with 23 or less Gln. In 6itro expression experiments showed an inverse relation between the length of the Gln tract in the AR and trans-activation function (4). In a letter to the editor in this journal Lundberg Giwercman et al. (5) reported recently that, in Swedish men, no association could be found between defective spermatogenesis and AR CAG repeat length. They analysed 33 men with abnormal sperm samples and 294 controls. The observed alleles ranged from 8 to 30 CAG repeats with 21 as the most frequent allele. The repeat lengths in Swedish men were somewhat shorter on average than those observed in the Chinese men. The lack of an association was explained by possible differences in ethnic origin or by the small number of men with fertility problems in the Swedish study. To study the possible effect of different CAG repeats in the AR on male fertility in Belgian men, we genotyped 223 infertile men involved in an intracytoplasmic sperm injection (ICSI) treatment programme. We compared the results with data obtained from 181 unselected Belgian men. PCR was performed with primers flanking the CAG repeat in exon 1 of the AR gene. Three different CAG alleles were sequenced, containing 16, 24 and 43 CAG repeats. The number of CAG repeats in the other samples was calculated by comparing the size of PCR products of unknown alleles with the PCR products from individuals with a sequenced allele. The alleles observed contained between 14 and 30 CAG repeats, with 21 CAG repeats as median and most frequent class in both groups (Fig. 1). More individuals with long normal repeats were observed in the infertile group than in the controls (Fig. 1). In Asian men, the median and modus of the CAG repeat distribution in the AR is one CAG larger (22 CAG) than in Caucasian men (21 CAG) (3). Therefore, we chose 27 or more Gln as the cut-off value. Twenty-seven Gln in a population of Caucasians compares to 28 Gln in Asian men (4). There were 18 infertile individuals (8.1%) with CAG repeats of 26 or longer (=27 or more Gln, CAG’s are followed by one CAA) and only 4 (2.2%) in the control males. This results in an OR of 3.09 (x=5.25; p=0.022, 95% CI: 1.06–10.63). Subdividing the infertile males according to sperm counts does not result in a trend of increased frequency of longer alleles in the groups with fewer sperm counts (Table 1), as was observed in the Chinese study (4). Our data show the same range of CAG alleles as in the Swedish study and a smaller mean CAG repeat length than in the Chinese study. In our study we could confirm, however, that more males with spermatogenesis problems had longer normal CAG repeats than expected for the control population of Belgian males. The absence of a similar association in the Swedish study might be due to a lack of power (only 33 infertile males included). A long normal CAG repeat is probably only an important factor if other factors are also present

Intra- and interobserver analysis in the morphological assessment of early stage embryos during an IVF procedure: a multicentre study

BackgroundQuality control programs are necessary to maintain good clinical practice. Embryo grading has been described as one of the external quality assurance schemes. Although the evaluation of embryos is based on the assessment of morphological characteristics, considerable intra- and inter-observer variability has been described. In this multicentre study, the variability in the embryo evaluation has been evaluated using morphological characteristics on day 1, day 2 and day 3 of embryo development.MethodsFive embryologists of four different IVF centers participated in this study. Multilevel images of embryos were presented on a website at different time points to evaluate intra-and inter-observer agreement in the assessment of embryo morphology. The embryos were evaluated on day 1, day 2 and day 3 of their development and each embryologist had to decide if the embryo had to be transferred, cryopreserved or discarded.ResultsBoth intra-observer agreement and inter-observer agreement were good to excellent for the position of the pronuclei on day 1, the number of blastomeres on day 2 and day 3 and the clinical decision (transfer, cryopreservation, discard). For all other characteristics (size of pronuclei, presence of cytoplasomic halo, degree of fragmentation and size of blastomeres) the intra- and inter-observer agreement was moderate to very poor.ConclusionsMono- or multicentre quality control on embryo scoring by morphological assessment can easily be performed through the design of a simple website. In the future the website design can be adapted to generate statistical feedback upon scoring and can even include a training module.

Genetic abnormalities and male infertility. A comprehensive review.

The development of assisted reproductive technologies, such as intracytoplasmic sperm injection (ICSI) substantially improved the outlook for patients with severe male fertility problems. However this implies that for the first time genetic defects associated with male in- or subfertility might be transmitted to offspring and result in genetic disease [de Kretser DM, The potential of intracytoplasmic sperm injection (ICSI) to transmit genetic defects causing male infertility. Reprod. Fertil. Dev. 1995;7:137-142]. The knowledge of male specific fertility genes on the Y chromosome increased enormously in the last decade. The SRY gene plays a critical role in gonadal differentiation. DAZ, SPGY and related genes on the Y chromosome are very important for spermatogenesis. Interstitial Y-chromosomal microdeletions encompassing the AZFa, b or c region have become an additional class of genetic abnormalities causing male infertility. A review is given of the different genetic aspects of male infertility.

Early embryo development in a sequential versus single medium: a randomized study

BackgroundThe success of in vitro fertilization techniques is defined by multiple factors including embryo culture conditions, related to the composition of the culture medium. In view of the lack of solid scientific data and in view of the current general belief that sequential media are superior to single media, the aim of this randomized study was to compare the embryo quality in two types of culture media.MethodsIn this study, the embryo quality on day 3 was measured as primary outcome. In total, 147 patients younger than 36 years treated with IVF/ICSI during the first or second cycle were included in this study. Embryos were randomly cultured in a sequential (group A) or a single medium (group B) to compare the embryo quality on day 1, day 2 and day 3. The embryo quality was compared in both groups using a Chi-square test with a significance level of 0.05.ResultsAt day 1, the percentage of embryos with a cytoplasmic halo was higher in group B (46%) than in group A (32%). At day 2, number of blastomeres, degree of fragmentation and the percentage of unequally sized blastomeres were higher in group B than in group A. At day 3, a higher percentage of embryos had a higher number of blastomeres and unequally sized blastomeres in group B. The number of good quality embryos (GQE) was comparable in both groups. The embryo utilization rate was higher in group B (56%) compared to group A (49%).ConclusionsAlthough, no significant difference in the number of GQE was found in both media, the utilization rate was significantly higher when the embryos were cultured in the single medium compared to the sequential medium. The results of this study have a possible positive effect on the cumulative cryo-augmented pregnancy rate.Trial registration numberNCT01094314