K. Diedrich

Consensus on infertility treatment related to polycystic ovary syndrome

The treatment of infertile women with polycystic ovary syndrome (PCOS) is surrounded by many controversies. This paper describes, on the basis of the currently available evidence, the consensus reached by a group of experts regarding the therapeutic challenges raised in these women. Before any intervention is initiated, preconceptional counselling should be provided emphasizing the importance of life style, especially weight reduction and exercise in overweight women, smoking and alcohol consumption. The recommended first-line treatment for ovulation induction remains the anti-estrogen clomiphene citrate (CC). Recommended second-line intervention, should CC fail to result in pregnancy, is either exogenous gonadotrophins or laparoscopic ovarian surgery (LOS). The use of exogenous gonadotrophins is associated with increased chances for multiple pregnancy and, therefore, intense monitoring of ovarian response is required. LOS alone is usually effective in <50% of women and additional ovulation induction medication is required under those circumstances. Overall, ovulation induction (representing the CC, gonadotrophin paradigm) is reported to be highly effective with a cumulative singleton live birth rate of 72%. Recommended third-line treatment is in vitro fertilization. More patient-tailored approaches should be developed for ovulation induction based on initial screening characteristics of women with PCOS. Such approaches may result in deviation from the above mentioned first-, second- or third-line ovulation strategies in well-defined subsets of patients. Metformin use in PCOS should be restricted to women with glucose intolerance. Based on recent data available in the literature, the routine use of this drug in ovulation induction is not recommended. Insufficient evidence is currently available to recommend the clinical use of aromatase inhibitors for routine ovulation induction. Even singleton pregnancies in PCOS are associated with increased health risk for both the mother and the fetus.

Use of GnRH antagonists in ovarian stimulation for assisted reproductive technologies compared to the long protocol

Abstract The use of GnRH antagonists has revolutionized ovarian stimulation for assisted reproduction. Two GnRH antagonists are clinically available, namely, cetrorelix and ganirelix. Several studies have directly compared these new stimulation protocols against the long GnRH agonist protocol. To evaluate whether there is a reduction in cases of ovarian hyperstimulation syndrome (OHSS) and/or a reduction in pregnancy rates, a meta-analysis was performed. There was a significant reduction of OHSS cases in the cetrorelix studies (odds ratio, OR, 0.23; 95% confidence interval, CI, 0.10–0.54), but no reduction for ganirelix (OR 1.13; 95% CI 0.24–5.31). The incidence of OHSS °III cases was reduced in the cetrorelix protocols as compared to the long protocol to a nearly significant degree (OR 0.26; 95% CI 0.07–1.01). Ganirelix did not reduce the incidence of OHSS °III at all (OR 1.08; 95% CI 0.27–4.38). The pregnancy rate per cycle was significantly lower in the ganirelix protocols than in the long protocol (OR 0.76; 95% CI 0.59–0.98). The studies using cetrorelix showed quite similar, not significantly different results for the antagonist and the long protocol groups for the pregnancy rate per cycle (OR 0.91; 95% CI 0.68–1.22). From the data one can conclude that cetrorelix but not ganirelix will reduce the incidence of cases of OHSS and that cetrorelix but not ganirelix will result in the same pregnancy rates as the long protocol. Several possibilities to explain this phenomenon are discussed.

Cumulative pregnancy rates and drop-out rates in a German IVF programme: 4102 cycles in 2130 patients

Cumulative pregnancy rates are useful in counselling couples on their chance of conceiving during infertility treatment. Patients also have to be counselled about the physical and psychological stress of infertility treatment. Beside the pregnancy rates, drop-out rates are a direct, and may be the most important, marker of physician quality in an IVF programme. Data from 4102 IVF cycles in 2130 patients in Germany were analysed retrospectively. Data were analysed using descriptive statistics as well as the Kaplan-Meier procedure. A real cumulative pregnancy rate of 31.2% was achieved after four cycles with an expected cumulative pregnancy rate (ECPR) of 53.3%. Age was a significant factor regarding pregnancy rates (ECPR after four cycles: 57.1% <35 years, 44.8% > or =35 years, 35.4% > or =40 years). The drop-out rate of non-pregnant patients increased from 39.9% after the first cycle to 62.2% after the fourth cycle, indicating the enormous stress and frustration that increased during the course of treatment. The drop-out rate should be used as an important marker of quality control. The presented data give, for the first time, a good basis for this counselling procedure in Germany.

Significant reduction of the incidence of ovarian hyperstimulation syndrome (OHSS) by using the LHRH antagonist Cetrorelix (Cetrotide ® ) in controlled ovarian stimulation for assisted reproduction

Abstract A prospective, randomized study was performed to compare the efficiency of hormonal stimulation for IVF (in vitro fertilization) in either the long luteal protocol, using the LHRH agonist Buserelin, or the multiple dose LHRH antagonist protocol, using the LHRH antagonist Cetrorelix. Here we present the data on the incidence of ovarian hyperstimulation syndromes (OHSS). 85 and 188 patients were recruited for the stimulation in the LHRH agonist and in the LHRH antagonist protocol, respectively. The groups were comparable regarding anamnestic data. The incidence of WHO °II and °III OHSS was significantly lower in the Cetrorelix than in the Buserelin group (1.1% vs. 6.5%, p=0.03). Additionally 3 patients in the Cetrorelix group (1.6%) and 5 patients in the Buserelin group (5.9%) did not receive hCG because of a threatening OHSS. The follicle maturation was more homogeneous in the Cetrorelix protocol, with less small follicles on the day of hCG administration but a similar number of oocyte cumulus complexes retrieved. The pregnancy rates per cycle were not significantly different in the Cetrorelix and Buserelin protocol (22% vs. 26%). The Cetrorelix multiple dose protocol is advantageous compared to the long protocol regarding the incidence of OHSS, a potentially life threatening complication of controlled ovarian stimulation.

Transvaginal sonography of the endometrium during ovum pickup in stimulated cycles for in vitro fertilization.

The endometrium of a series of 190 in vitro fertilization patients was investigated by transvaginal ultrasound. The endometrial pattern was related to the likelihood of implantation. No such relationship was found for the thickness of the endometrium. There was not a strong correlation between the endometrium and hormonal values. However, three endometrial patterns were detected after hormonal stimulation. The predominant pattern consisted of an outer hyperechogenic layer and an inner hypoechogenic layer. This pattern correlated in a positive fashion with subsequent implantation. It is concluded that the texture of the endometrium at the time of ovum pickup has a prognostic value for the likelihood of implantation to occur.

Addition of growth hormone to gonadotrophins in ovarian stimulation of poor responders treated by in-vitro fertilization: a systematic review and meta-analysis

BACKGROUND Whether the addition of growth hormone (GH) can improve the probability of pregnancy in poor responders undergoing ovarian stimulation for in-vitro fertilization (IVF) has been examined to date by several underpowered studies, which have not provided solid conclusions. METHODS A computerized literature search in MEDLINE, EMBASE, CENTRAL and randomized controlled trial (RCT) registries was performed independently by two reviewers, aiming to identify RCTs that evaluated the following research question: does GH addition increase the probability of pregnancy in poor responders undergoing ovarian stimulation with gonadotrophin releasing hormone (GnRH) analogues and gonadotrophins for IVF? RESULTS Six relevant RCTs were identified, including a total of 169 patients. GH addition significantly increased clinical pregnancy (rate difference: +16%, 95% CI: +4 to +28; fixed effects model) (number-needed-to-treat (NNT) = 6, 95% CI: 4-25) and live birth rates (rate difference: +17%, 95% CI: +5 to +30; fixed effects model) (NNT = 6; 95% CI: 3-20). Furthermore, GH addition was associated with a significantly higher proportion of patients reaching embryo transfer (rate difference: +22%, 95% CI: +7 to +36; fixed effects model). CONCLUSIONS The present meta-analysis provides evidence that GH addition increases the probability of clinical pregnancy and live birth in poor responders undergoing ovarian stimulation with GnRH analogues and gonadotrophins for IVF. However, the total number of patients analyzed is small and thus further RCTs are warranted to prove or disprove this finding.

Ovarian stimulation for IVF has no quantitative association with birthweight: a registry study

BACKGROUND Singleton children born after IVF are of lower birthweight compared with their naturally conceived peers. It has been hypothesized that ovarian stimulation might be associated with low birthweight in children born after IVF. The aim of the present study was to explore whether or not a dose relationship exists between ovarian stimulation and birthweight in singletons born after ovarian stimulation for IVF. METHODS Using a national IVF registry database with a coverage of 65-70%, parental demographic variables, treatment cycle variables and neonatal variables were retrieved from all IVF treatment cycles in women between 25 and 35 years of age in which gonadotrophins were used for ovarian stimulation and a fresh embryo transfer resulting in singleton live birth was performed. Birthweight was standardized as a z-score, adjusting for gestational week at delivery and fetal sex, using data from a large reference population. Multivariate regression analysis was used to investigate the association between the dependent variable z-score and the independent predictor variables maternal age (years), maternal weight (kg), maternal height (cm), maternal body mass index (BMI) (kg/m(2)), duration of infertility (years), number of embryos transferred (n), duration of stimulation (days), consumption of gonadotrophins (ampoules) and number of oocytes retrieved (n). RESULTS Data retrieval yielded 32,416 singleton live births after IVF, with a mean (+/-SD) z-score of -0.25 (+/-1.0) and -0.23 (+/-1.0) for male and female neonates, respectively. Regression analysis indicated that maternal weight, maternal height, duration of infertility and the number of embryos transferred were statistically significant determinants of the birthweight of singletons after ovarian stimulation IVF. Parameters of ovarian stimulation (duration of stimulation, consumption of gonadotrophins, number of oocytes retrieved), maternal BMI and maternal age did not significantly predict birthweight. CONCLUSIONS Features reflecting ovarian stimulation do not correlate with birthweight. Therefore, ovarian stimulation is unlikely to be a factor affecting birthweight of IVF pregnancies.

Europe the continent with the lowest fertility

INTRODUCTION Although fertility rates are falling in many countries, Europe is the continent with the lowest total fertility rate (TFR). This review assesses trends in fertility rates, explores possible health and social factors and reviews the impact of health and social interventions designed to increase fertility rates. METHODS Searches were done in medical and social science databases for the most recent evidence on relevant subject headings such as TFR, contraception, migration, employment policy and family benefits. Priorities, omissions and disagreements were resolved by discussion. RESULTS The average TFR in Europe is down to 1.5 children per woman and the perceived ideal family size is also declining. This low fertility rate does not seem directly caused by contraception since in Northern and Western Europe the fertility decline started in the second half of the 1960s. Factors impacting on lower fertility include the instability of modern partnerships and value changes. Government support of assisted human reproduction is beneficial for families, but the effect on TFR is extremely small. Government policies that transfer cash to families for pregnancy and child support also have small effects on the TFR. CONCLUSIONS Societal support for families and for couples trying to conceive improves the lives of families but makes no substantial contribution to increased fertility rates.

Results of cytogenetic analysis in men with severe subfertility prior to intracytoplasmic sperm injection

Intracytoplasmic sperm injection (ICSI) is increasingly becoming the treatment of choice for severe male subfertility. Cytogenetic evaluation of men with andrological subfertility reveals an increased incidence of chromosomal abnormalities when compared with the normal population. We performed chromosomal analysis on the male partners of 32 couples referred for andrological subfertility. In two of these men, constitutional chromosomal translocations were diagnosed prior to ICSI [(45,XY,t(21;22)(p11;q11) and 46,XY,t(22;Y)(p11;q12)]. Since ICSI bypasses many potential barriers of fertilization, successful pregnancy can be achieved despite the presence of severely impaired spermatozoa in a population at high risk for chromosomal aberrations. It is well known that the presence of a chromosomal aberration plays a significant role in partial or complete spermatogenic arrest. ICSI does not seem to increase the risk of fetal chromosomal abnormalities when a spermatozoon from a chromosomally normal male is used. To exclude a higher risk for spontaneous abortion and fetal chromosomal abnormalities, we advocate cytogenetic screening of males with severe male subfertility who opt for ICSI.

Small diameter laparoscopy using a microlaparoscope

In order to determine the suitability of new microlaparoscopes of < 2.0 mm diameter for diagnostic laparoscopy, 28 small diameter laparoscopies (SDL) were performed during a 4 month period. These cases were performed under general anaesthesia with immediate follow-up confirmation with conventional laparoscopic equipment (group I). An additional 13 SDL procedures were performed under analgesic sedation plus local anaesthesia and were well tolerated by the patients (group II). For group I, the visualization results were comparable in 27 out of 28 procedures. In group II, patients were highly satisfied and reported less post-procedural discomfort and minimal scar formation due to the smaller access ports. In this study, two different types of microlaparoscopes were used; while both were adequate, the newer high-resolution microlaparoscope delivered an image much more similar to conventional laparoscopy and required little or no change in technique in order to obtain images. This new endoscopic technology, with optical performance comparable to that of conventional laparoscopy, has been demonstrated to be a useful procedure for certain clinical indications.