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STUDY QUESTION What are clinical predictors for successful medical treatment in case of early pregnancy loss (EPL)? SUMMARY ANSWER Use of mifepristone, BMI, number of previous uterine aspirations and the presence of minor clinical symptoms (slight vaginal bleeding or some abdominal cramps) at treatment start are predictors for successful medical treatment in case of EPL. WHAT IS KNOWN ALREADY Success rates of medical treatment for EPL vary strongly, between but also within different treatment regimens. Up until now, although some predictors have been identified, no clinical prediction model has been developed yet. STUDY DESIGN, SIZE, DURATION Secondary analysis of a multicentre randomized controlled trial in 17 Dutch hospitals, executed between 28 June 2018 and 8 January 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS Women with a non-viable pregnancy between 6 and 14 weeks of gestational age, who opted for medical treatment after a minimum of 1 week of unsuccessful expectant management. Potential predictors for successful medical treatment of EPL were chosen based on literature and expert opinions. We internally validated the prediction model using bootstrapping techniques. MAIN RESULTS AND THE ROLE OF CHANCE 237 out of 344 women had a successful medical EPL treatment (68.9%). The model includes the following variables: use of mifepristone, BMI, number of previous uterine aspirations and the presence of minor clinical symptoms (slight vaginal bleeding or some abdominal cramps) at treatment start. The model shows a moderate capacity to discriminate between success and failure of treatment, with an AUC of 67.6% (95% CI = 64.9–70.3%). The model had a good fit comparing predicted to observed probabilities of success but might underestimate treatment success in women with a predicted probability of success of ∼70%. LIMITATIONS, REASONS FOR CAUTION The vast majority (90.4%) of women were Caucasian, potentially leading to less optimal model performance in a non-Caucasian population. Limitations of our model are that we have not yet been able to externally validate its performance and clinical impact, and the moderate accuracy of the prediction model of 0.67. WIDER IMPLICATIONS OF THE FINDINGS We developed a prediction model, aimed to improve and personalize counselling for medical treatment of EPL by providing a woman with her individual chance of complete evacuation. STUDY FUNDING/COMPETING INTEREST(S) The Triple M Trial, upon which this secondary analysis was performed, was funded by the Healthcare Insurers Innovation Foundation (project number 3080 B15-191). TRIAL REGISTRATION NUMBER Clinicaltrials.gov: NCT03212352.

STUDY QUESTION What outcomes are important for women to decide on the day of embryo transfer (ET) in IVF? SUMMARY ANSWER The highest cumulative live birth rate (cLBR) per treatment was the most important treatment outcome for women undergoing an IVF treatment, regardless of the number of transfers needed until pregnancy and impact on quality of life. WHAT IS KNOWN ALREADY Cleavage stage (Day 3) and blastocyst stage (Day 5) ETs are common transfer policies in IVF. The choice for one or the other day of ET differs between clinics. From the literature, it remains unclear whether the day of transfer impacts the cLBR. Patient preferences for the day of ET have not been examined yet. STUDY DESIGN, SIZE, AND DURATION A discrete choice experiment (DCE) was performed to investigate female patients’ preferences and their values concerning various aspects of an IVF treatment, with a particular focus on ET policy. A multicenter DCE was conducted between May 2020 and June 2020 in which participants were asked to choose between different treatments. Each treatment was presented using hypothetical scenarios containing the following attributes: the probability of a healthy live birth per IVF treatment cycle, the number of embryos available for transfer (for fresh and frozen-thawed ET), the number of ETs until pregnancy and the impact of the treatment on the quality of life. PARTICIPANTS/MATERIALS, SETTING, METHODS Women (n = 445) were asked to participate in the DCE at the start of an IVF treatment cycle in 10 Dutch fertility clinics. Participating women received an online questionnaire. The attributes’ relative importance was analyzed using logistic regression analyses. MAIN RESULTS AND THE ROLE OF CHANCE A total of 164 women participated. The most important attribute chosen was the cLBR. The total number of embryos suitable for transfer also influenced women’s treatment preferences. Neither the number of transfers needed until pregnancy, nor the impact on quality of life influenced the treatment preferences in the aggregated data. For women in the older age group (age ≥36 years) and the multipara subgroup, the impact on quality of life was more relevant. Naive patients (patients with no prior experience with IVF treatment) assigned less value to the number of ETs needed until pregnancy and assigned more value to the cLBR than the patients who had experienced IVF. LIMITATIONS REASONS FOR CAUTION An important limitation of a DCE study is that not all attributes can be included, which might be relevant for making choices. Patients might make other choices in real life as the DCE scenarios presented here are hypothetical and might not exactly represent their personal situation. We tried to avoid potential bias by selecting the attributes that mattered most to the patients obtained through patient focus groups. The final selection of attributes and the assigned levels were established using the input of an expert panel of professionals and by performing a pilot study to test the validity of our questionnaire. Furthermore, because we only included women in our study, we cannot draw any conclusions on preferences for partners. WIDER IMPLICATIONS OF THE FINDINGS The results of this study may help fertility patients, clinicians, researchers and policymakers to prioritize the most important attributes in the choice for the day of ET. The present study shows that cLBR per IVF treatment is the most important outcome for women. However, currently, there is insufficient information in the literature to conclude which day of transfer is more effective regarding the cLBR. Randomized controlled trials on the subject of Day 3 versus Day 5 ETs and cLBR are needed to allow evidence-based counseling. STUDY FUNDING/COMPETING INTEREST(S) This work received no specific funding and there are no conflicts of interest. TRIAL REGISTRATION NUMBER N/A.

STUDY QUESTION What is the methodological validity and usefulness of randomized controlled trials (RCTs) on pain relief during oocyte retrieval for IVF and ICSI? SUMMARY ANSWER Key methodological characteristics such as randomization, allocation concealment, primary outcome measure and sample size calculation were inadequately reported in 33–43% of the included RCTs, and a broad heterogeneity is revealed in the studied outcome measures. WHAT IS KNOWN ALREADY A Cochrane review on conscious sedation and analgesia for women undergoing oocyte retrieval concluded that the overall quality of evidence was low or very low, mainly owing to poor reporting. This, and heterogeneity of studied outcome measures, limits generalizability and eligibility of results for meta-analysis. STUDY DESIGN, SIZE, DURATION For this review, a systematic search for RCTs on pain relief during oocyte retrieval was performed on 20 July 2020 in CENTRAL CRSO, MEDLINE, Embase, PsycINFO, CINAHL, ClinicalTrials.gov, WHO ICTRP, Web of Science, Portal Regional da BVS and Open Grey. PARTICIPANTS/MATERIALS, SETTING, METHODS RCTs with pain or patient satisfaction as an outcome were included and analysed on a set of methodological and clinical characteristics, to determine their validity and usefulness. MAIN RESULTS AND THE ROLE OF CHANCE Screening of 2531 articles led to an inclusion of 51 RCTs. Randomization was described inadequately in 33% of the RCTs. A low-risk method of allocation concealment was reported in 55% of the RCTs. Forty-nine percent of the RCTs reported blinding of participants, 33% of blinding personnel and 43% of blinding the outcome assessor. In 63% of the RCTs, the primary outcome was stated, but a sample size calculation was described in only 57%. Data were analysed according to the intention-to-treat principle in 73%. Treatment groups were not treated identically other than the intervention of interest in 10% of the RCTs. The primary outcome was intraoperative pain in 28%, and postoperative pain in 2%. The visual analogue scale (VAS) was the most used pain scale, in 69% of the RCTs in which pain was measured. Overall, nine other scales were used. Patient satisfaction was measured in 49% of the RCTs, for which 12 different methods were used. Occurrence of side-effects and complications were assessed in 77% and 49% of the RCTs: a definition for these was lacking in 13% and 20% of the RCTs, respectively. Pregnancy rate was reported in 55% of the RCTs and, of these, 75% did not adequately define pregnancy. To improve the quality of future research, we provide recommendations for the design of future trials. These include use of the VAS for pain measurement, use of validated questionnaires for measurement of patient satisfaction and the minimal clinically relevant difference to use for sample size calculations. LIMITATIONS, REASONS FOR CAUTION Consensus has not been reached on some methodological characteristics, for which we formulated recommendations. To prevent further heterogeneity in research on this topic, recommendations were formulated based on expert opinion, or on the most used method thus far. Future research may provide evidence to base new recommendations on. WIDER IMPLICATIONS OF THE FINDINGS Use of the recommendations given for design of trials on this topic can increase the generalizability of future research, increasing eligibility for meta-analyses and preventing wastefulness. STUDY FUNDING/COMPETING INTEREST(S) No specific funding was obtained for this study. S.B. reports being the editor-in-chief of Human Reproduction Open. For this manuscript, he was not involved with the handling process within Human Reproduction Open, or with the final decision. Furthermore, S.B. reports personal fees from Remuneration from Oxford University Press as editor-in-chief of Human Reproduction Open, personal fees from Editor and contributing author, Reproductive Medicine for the MRCOG, Cambridge University Press. The remaining authors declare no conflict of interest in relation to the work presented. TRIAL REGISTRATION NUMBER Not applicable.

STUDY QUESTION Are there more de novo mutations (DNMs) present in the genomes of children born through medical assisted reproduction (MAR) compared to spontaneously conceived children? SUMMARY ANSWER In this pilot study, no statistically significant difference was observed in the number of DNMs observed in the genomes of MAR children versus spontaneously conceived children. WHAT IS KNOWN ALREADY DNMs are known to play a major role in sporadic disorders with reduced fitness such as severe developmental disorders, including intellectual disability and epilepsy. Advanced paternal age is known to place offspring at increased disease risk, amongst others by increasing the number of DNMs in their genome. There are very few studies reporting on the effect of MAR on the number of DNMs in the offspring, especially when male infertility is known to be affecting the potential fathers. With delayed parenthood an ongoing epidemiological trend in the 21st century, there are more children born from fathers of advanced age and more children born through MAR every day. STUDY DESIGN, SIZE, DURATION This observational pilot study was conducted from January 2015 to March 2019 in the tertiary care centre at Radboud University Medical Center. We included a total of 53 children and their respective parents, forming 49 trios (mother, father and child) and two quartets (mother, father and two siblings). One group of children was born after spontaneous conception (n = 18); a second group of children born after IVF (n = 17) and a third group of children born after ICSI combined with testicular sperm extraction (ICSI-TESE) (n = 18). In this pilot study, we also subdivided each group by paternal age, resulting in a subgroup of children born to younger fathers (45 years of age at conception). PARTICIPANTS/MATERIALS, SETTING, METHODS Whole-genome sequencing (WGS) was performed on all parent-offspring trios to identify DNMs. For 34 of 53 trios/quartets, WGS was performed twice to independently detect and validate the presence of DNMs. Quality of WGS-based DNM calling was independently assessed by targeted Sanger sequencing. MAIN RESULTS AND THE ROLE OF CHANCE No significant differences were observed in the number of DNMs per child for the different methods of conception, independent of parental age at conception (multi-factorial ANOVA, f(2) = 0.17, P-value = 0.85). As expected, a clear paternal age effect was observed after adjusting for method of conception and maternal age at conception (multiple regression model, t = 5.636, P-value = 8.97 × 10−7), with on average 71 DNMs in the genomes of children born to young fathers (45 years of age). LIMITATIONS, REASONS FOR CAUTION This is a pilot study and other small-scale studies have recently reported contrasting results. Larger unbiased studies are required to confirm or falsify these results. WIDER IMPLICATIONS OF THE FINDINGS This pilot study did not show an effect for the method of conception on the number of DNMs per genome in offspring. Given the role that DNMs play in disease risk, this negative result is good news for IVF and ICSI-TESE born children, if replicated in a larger cohort. STUDY FUNDING/COMPETING INTEREST(S) This research was funded by the Netherlands Organisation for Scientific Research (918-15-667) and by an Investigator Award in Science from the Wellcome Trust (209451). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER N/A.

Introduction Infertility is a major concern for females with Turner syndrome (TS), regardless of their age. While fertility preservation is now routinely offered to girls and young women with cancer, there are currently no recommendations on fertility preservation in girls and young women with TS who generally face an even higher risk for infertility. Despite the lack of international guidelines, preservation procedures have been performed experimentally in females with TS. Methods A systematic literature search based on the PRISMA-P methodology for systematic reviews was performed in order to collect all published data on fertility preservation options in females with TS between January 1980 and April 2018. A total number of 67 records were included in this review. The records were screened for information regarding cryopreservation of mature oocytes and ovarian tissue in females with TS. Two ongoing trials on fertility preservation in young females with TS were also included. Results Cryopreservation of oocytes or ovarian tissue has been performed experimentally in150 girls and adolescents with TS over the last 16 years. The efficacy of fertility preservation options in females with TS is still unknown due to the lack of follow-up data. Conclusion The efficacy of fertility preservation procedures in females with TS is still unknown. Future studies with focus on efficacy, safety and long-term follow-up are desperately needed.

Item does not contain fulltext STUDY QUESTION: Do couples who were eligible for tailored expectant management (TEM) and did not start treatment within 6 months after the fertility work-up, have different experiences with the quality of care than couples that were also eligible for TEM but started treatment right after the fertility work-up? SUMMARY ANSWER: Tailored expectant management of at least 6 months in couples with unexplained infertility is not associated with the experiences with quality of care or trust in their physician. WHAT IS KNOWN ALREADY: In couples with unexplained infertility and a good prognosis of natural conception within 1 year, expectant management for 6-12 months does not compromise ongoing birth rates and is equally as effective as starting medically assisted reproduction immediately. Therefore, TEM is recommended by various international clinical guidelines. Implementation of TEM is still not optimal because of existing barriers on both patient and professional level. An important barrier is the hesitance of professionals to counsel their patients for TEM because they fear that patients will be dissatisfied with care. However, if and how adherence to TEM actually affects the couples' experience with care is unknown. Experiences with the quality care can be measured by evaluating the patient-centredness of care and the patients' trust in their physician. STUDY DESIGN, SIZE, DURATION: This is a retrospective cross-sectional study. A survey with written questionnaires was performed among all couples who participated in the retrospective audit of guideline adherence on TEM in 25 Dutch clinics. PARTICIPANTS/MATERIALS, SETTING, METHODS: Couples were eligible to participate if they were diagnosed with unexplained infertility and had a good prognosis (>30%) of natural conception within 1 year based on the Hunault prediction model. We used patient's questionnaires to collect data on the couples' experience with the quality of care and possible confounders for their experiences other than having undergone TEM or not. Multilevel regression analyses were performed to investigate case-mix adjusted association of TEM with the patient-centredness of care (PCQ-Infertility) and the patients' trust in their physician (Wake Forest Trust Scale). MAIN RESULTS AND THE ROLE OF CHANCE: Couples who adhered to TEM experienced the quality of care on the same level as couples who were exposed to early treatment, i.e. started fertility treatment within 6 months after fertility work-up. There were no associations between adherence to TEM and the patient-centredness of care or the patients' trust in their physician. LIMITATIONS, REASONS FOR CAUTION: Because this study is retrospective, recall bias might occur. Furthermore, we were unable to measure the difference in experience with care over time. Therefore, our results have to be interpreted carefully. WIDER IMPLICATIONS OF THE FINDINGS: Prospective research on couples undergoing TEM have to be performed to provide more detailed insight in the patients' experiences with the decision making process and subsequently the expectant period. Tackling the barriers surrounding TEM, i.e. better counselling and more patient information material, could further improve patient experiences with the quality of care for couples who are advised TEM. STUDY FUNDING/COMPETING INTERESTS: Supported by Netherlands Organisation for Health Research and Development (ZonMW). ZonMW had no role in designing the study, data collection, analysis and interpretation of data or writing of the report. Competing interests: none. TRIAL REGISTRATION NUMBER: www.trialregister.nl NTR3405.

Item does not contain fulltext Previous studies suggest that administration of follitropin-beta with a pen device (Puregon Pen(R)) is more convenient, less painful and 16-18% more efficient. The aim of this study was to perform an economic evaluation of the administration of follitropin-beta by this pen device against follitropin-alpha by multidose and highly purified (HP) HMG by conventional syringe in IVF treatment by comparing the process utilities and the costs for the Dutch setting. Conjoint analysis assessed the process utilities for the three administration modes on a scale from 0 to 1. A decision analytic model estimated the costs of an average IVF cycle from a societal perspective. Patients estimated the process utility at 0.96 for the pen, 0.53 for the multidose and 0.36 for the conventional syringe. Additional costs were estimated at 0 Euros and 194 Euros, comparing the pen with multidose or conventional methods respectively. Assuming a 16% efficiency gain of the pen, costs ranged from Euros-135 (savings) to 60 Euros (extra costs). In conclusion, patients perceive sufficient benefits to the pen device to choose it over other dosing methods. Dominance of the pen device over the multidose method was shown. Compared with the conventional administration method, the added value of the pen device was 2.7 (0.96/0.36) times higher.

Hormonale suppletietherapie (hst) wordt bij meisjes met het syndroom van Turner (ts) in de puberteit gestart, aanvankelijk met als doel borstontwikkeling te induceren en later ter preventie van klachten zoals dyspareunie door vaginale droogheid. Ook wordt hst voorgeschreven ter preventie van langetermijncomplicaties, zoals osteoporose en hyperinsulinisme. Alhoewel spontane zwangerschappen bij 3-5% van de vrouwen met ts worden gemeld, worden de meeste vrouwen geconfronteerd met een prematuur ovariumfalen (pof). Met de komst van in-vitrofertilisatie in combinatie met eiceldonatie bestaat er ook voor vrouwen met ts een reele kans op zwangerschap. Alhoewel momenteel de kans op zwangerschap bij ts even groot lijkt te zijn als bij andere oorzaken van pof, treedt vaker een miskraam op en bestaat er een groter risico op maternale complicaties. Dit heeft vooral te maken met het frequenter optreden van cardiovasculaire problematiek, zoals dissectie van de aorta. Vrouwen met ts moeten hier dan ook tevoren op worden gescreend.

Incidental findings in prenatal diagnostic testing may or may not have clear prognostic significance for the phenotype. We studied experts' opinions of the benefit and disadvantage of an incidental prenatal diagnosis of a sex chromosomal aneuploidy (SCA).We interviewed 16 experts in the field of counseling and treatment of people with SCA and asked 13 clinical geneticists and genetic associates about the clinical relevance of an incidental prenatal diagnosis of SCA.Most of the experts and clinical geneticists (87.5% and 76.9%, respectively) stated that an incidental prenatal diagnosis of SCA was a benefit for the child and the parents. They acknowledged the possibility of parental decisions to terminate pregnancy. Expert options in screening, training, and treatment of health, behavior, and fertility problems increase with an early diagnosis of SCA.Most experts favored an incidental prenatal diagnosis of SCA despite the complex counseling issues and their acknowledgment of possible parental decisions to terminate pregnancy. They believed the benefits greatly outweigh the disadvantages.

To investigate the parental perspectives of being confronted with an unforeseen fetal sex chromosomal aneuploidy (SCA), in light of the fact that this accidental finding is avoidable by rapid aneuploidy detection (RAD).Exploratory qualitative interview study. We conducted 16 semi-structured interviews with parents who decided to continue pregnancy after the unforeseen finding of a fetal SCA.The communication of the unforeseen finding of SCA; the informed decision-making process concerning the pregnancy follow-up and the child and its future were the extracted themes. Parents were not prepared to accidental findings in routine prenatal diagnostics. All started an unguided search on the Internet. It is not at all clear whether parents have preference for an RAD test with X and Y probes Parents were satisfied with the post-test professional information they received to make an informed decision, whereas after birth questions still remained to be answered.Parents' perspectives may serve as major contributors to research on the question whether or not the X and Y probes should be standard included for purposes of RAD. The fact that RAD has the possibility to avoid accidental findings of SCAs, brings up the question whether any benefits outweigh the potential harms.

In a recent article in this journal it was stated that Dutch women were sensible in having their first child between the ages of 25 and 35 years. One of the conclusions was that associated health risks increase after the age of 35 but are still acceptable even at the age of 40. We demonstrate that these conclusions were based on flawed assumptions. Postponing pregnancy until after the age of 30 increases the risks of infertility and breast cancer. Motherhood at a later age is associated with an increase in obstetrical complications, miscarriage and other adverse effects on the child. Therefore, for couples planning a family with 2 children or more, it would be sensible to have the first pregnancy not long after the mother reaches the age of 30 years, or even earlier. Couples should be informed on the risks of late parenthood in order to be able to take the right decisions concerning family planning.

Maternal age, history of miscarriage and family history relating to early pregnancy losses, are important risk factors for the development of new miscarriages. These factors may be considered in offering chromosome analysis to couples with3 miscarriages. Selective chromosome analysis would result in a more efficient care. However, the way to implement selective chromosome analysis remains a subject for debate.

The introduction ofoocyte donation has provided a new perspective on reproduction for women with premature ovarian failure. In contrast to other forms ofassisted reproductive technology, the success ofoocyte donation is not affected by the age of the future mother. This has prompted a discussion on raising the age limit to allow older women to become pregnant. The health risk for the future mother is increased in older women compared with younger women but does not appear to be a sufficient reason to disqualify older women from undergoing the procedure. Lack of information regarding the effect of very late parenthood on the medical, psychological and social well-being of the future child poses the greatest concern. Should the age limit be extended for oocyte donation, treatment should be restricted to a research setting with a protocol for single-embryo transfer and extensive follow-up regarding the well-being of the future child.

In the Netherlands, the practice of private freezing and banking of umbilical-cord blood is increasing. In a questionnaire, Dutch midwives and gynaecologists were asked about their attitude towards cord-blood collection if asked to perform this after delivery. The response rate was 35% (125/356) and 71% (71/100), respectively. Two-thirds of those asked responded that they would comply. The most common application of cord blood is in the treatment of (malignant) blood disorders. The use of autologous cord blood is, however, often not the best choice for treating leukaemia in young children and the number of stem cells is often too low in a single-cord blood sample to treat older children and adults. Although frequently suggested in the lay press, there is no proven effect in other indications, such as amyotrophic lateral sclerosis, multiple sclerosis and myocardial infarction. Information on therapeutic applications of cord blood from companies with commercial interests is leading to the exploitation ofpregnantwomen. The government should consider limiting this practice and prohibiting the activities of these companies in the Netherlands pending scientific evidence for their claims.

To identify medical and psychosocial risks that could arise from allowing older men to father children through in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI).Literature review.The databases Medline, Current Contents weekly, Current Contents archives, and PsycINFO were searched over the period 1970--June 2004 for articles with data on age limits for men entering IVF/ICSI programmes. The following inclusion criteria were used: availability in the Netherlands and written in English or Dutch.Although sperm quality decreases with age, men remain fertile up to an advanced age. The risks of having children with autosomal dominant disorders or chromosomal defects increase slightly, but the individual chance is extremely small. Studies on the psychological development of children with fathers aged50 years are lacking. Extrapolation from other studies indicates that growing up with an older father has no negative influence on child development. Although older fathers have a greater chance of dying sooner, the absence of the father does not contribute significantly to psychological problems in offspring later in life.There are no medical or psychosocial arguments to support an age limit for men entering an IVF/ICSI programme.

Fertility and sexuality are important aspects in the quality of life of long-term survivors of cancer. Adolescents in particular are in a very vulnerable period of their lives with respect to future fertility and sexuality. Special attention should be paid to preserve their fertility whenever possible. The gonadotoxic effect of chemotherapy is largely drug- and dosedependent and is related to age. The effect of radiotherapy is also dependent on dose and age and on the radiation therapy field. The prepubertal ovary is the least susceptible to gonadotoxicity. Ablative regimens for stem cell transplantation have an extremely high risk of ovarian failure. Alternative chemotherapy protocols can reduce long-term gonadotoxicity. Alkylating agents impose the highest risk in causing ovarian failure and should be avoided whenever possible. Up to now, the results of gonadoprotective hormonal therapy have been disappointing and contradictory. Transposition of the ovaries should be considered in each case of planned pelvic or whole body irradiation, where ovarian involvement is unlikely and chemotherapy not necessary. Cryopreservation of preimplantation embryos will seldom be possible in female adolescents due to the lack of a stable relationship with a male partner. Cryopreservation of mature and immature oocytes (necessitating in vitro maturation) is still assumed not to be safe for the offspring. Cryopreservation and transplantation of ovarian tissue seems to be the most promising way of future fertility preservation in female adolescents. At present, it is in its early experimental stage. Its safety and possibilities for fertility preservation in humans are not proven as yet. Additionally, technical and ethical issues need to be addressed. The counseling of female adolescents who are facing the threat of cancer needs careful consideration with regards to the psychosocial impact of the treatment and its consequences. Special attention should be paid to aspects of future quality of life, in particular: fertility and sexuality.

The importance of cryopreserving semen for young male cancer patients is illustrated in three case descriptions. A 28-year-old man with chronic myeloid leukaemia that resulted in azoospermia, later fathered a child with his semen that had been stored prior to chemotherapy. In an 18-year-old adolescent with non-Hodgkin lymphoma the possibility to store cryopreserved semen was only raised after chemotherapy had been started and had caused azoospermia. This caused the patient serious regret. A 14-year-old boy with acute lymphatic leukaemia had his semen stored despite initial hesitations due to his young age. The cancer hardly ever affects the semen quality to the extent that cryopreservation of the semen becomes impossible. The aim should be to obtain several ejaculates prior to the cancer therapy and to store multiple portions, so that later a number of fertilisation attempts are possible. The primary attending physician is initially responsible for raising the possibility of semen cryopreservation. Ideally, however, all health professionals involved should be aware of this aspect. There is a need for multidisciplinary protocols for oncology centres and sperm banks, so that the timely informing of patients is guaranteed, responsibilities are recorded--with appropriate procedures to prevent unnecessary delay--and procedures that concur with legal requirements and financial constraints are established.

The neuropeptide oxytocin (OT) has been detected in testis and epididymis of several mammals. The peptide affects steroidogenesis and sperm transport in vivo. Effects of OT on sperm motility in vitro seems to be contradictory. As no data are available on the presence of OT in human semen and on the relationship of OT with sperm characteristics, we assessed OT level in semen samples in 3 groups of patients: (I) normozoospermic, (II) astheno-/oligo-/teratozoospermic, and (III) azoospermic subjects. Furthermore, we studied the relationship between the concentration of OT in semen and the sperm characteristics. OT was measured in seminal plasma by radioimmunoassay after extraction. OT semen levels did not differ in control patients (I: 1.72 +/- 0.78 pg/mL; n = 10), patients with poor semen quality (II: 1.66 +/- 0.91 pg/mL; n = 11), or in vasectomized patients (III: 1.28 +/- 0.65 pg/mL; n = 11). No statistically significant relationships between the OT levels and sperm characteristics (density: 0.0693; total sperm count: 0.0845; percentage of motility: 0.1341; morphology: 0.3478) have been found. The neurosecretory peptide oxytocin is present in human seminal plasma of normal as well as of vasectomized subjects. OT is not only derived from the testis; OT levels in poor semen samples are not different from controls. No relationship was found between OT seminal plasma levels and sperm characteristics.

Insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) have important regulatory functions in ovarian follicular development. Although most studies have investigated the IGF system in ovarian cells in vitro, investigation of the IGF system in the peripheral circulation and in follicles of varying sizes throughout the menstrual cycle in large numbers of subjects has been lacking. In the current study we performed daily IGF-I, IGF-II, IGFBP-1, and IGFBP-3 measurements in 9 healthy regularly cycling volunteers throughout the menstrual cycle. In addition, we investigated IGF-I, IGF-II, IGFBP-1, and IGFBP-3 levels in 13 samples of androgen-dominant follicular fluid [FFa androstenedione to estradiol (AD:E2) ratio, > 4] and 19 samples of estrogen-dominant follicular fluid (FFe; AD:E2 ratio, 4) obtained from 21 regularly cycling subjects and in 18 samples of fluid from luteinizing follicles obtained from patients undergoing in vitro fertilization (IVF) treatment (FFivf). IGF-I, IGF-II, IGFBP-1, and IGFBP-3 were measured using two-site immunoradiometric assays. No significant day to day differences were observed in IGF-I, IGF-II, IGFBP-1, and IGFBP-3 levels across the menstrual cycle. Median IGF-II levels in FFe (630 ng/mL; range, 212-1000) were significantly higher compared to those in FFa (474 ng/mL; range, 272-603; P = 0.002). Median IGFBP-3 levels in FFe (2955 ng/mL; range, 388-3448) were also significantly higher than those in FFa (2352 ng/mL; range, 756-2604; P = 0.003). Median IGF-I (192 ng/mL; range, 29-256) and IGFBP-1 (12 ng/mL; range, 2-281) levels in FFe were not significantly different from those in FFa [149 (range, 22-232) and 21 (range, 5-32) ng/mL, respectively). In contrast, significantly lower IGFBP-1 levels were found in FFe compared to FFivf (79 ng/mL; range, 57-234; P = 0.002), whereas there was no significant difference between FFe and FFivfe IGF-I, IGF-II, or IGFBP-3 levels, respectively. IGF-II levels were correlated with follicle diameter (r = 0.52; P = 0.002), cycle day (r = 0.47; P = 0.0065), E2 levels (r = 0.53; P = 0.003), AD:E2 ratio (r = -0.58; P = 0.001), and P concentrations (r = 0.60; P = 0.001) in all follicles, whereas no such correlations were found with IGF-I. In conclusion, as circulating levels of IGF-I, IGF-II, IGFBP-1, and IGFBP-3 are not menstrual cycle dependent, it is unlikely that these growth factors and these binding proteins play an endocrine role in cyclic ovarian follicle development, although both cycle-dependent delivery to the ovary and modification of their actions locally within the ovary cannot be excluded. With regard to FF1 the findings that IGF-II levels in FF1 are elevated compared to those in FFa and correlate with follicular functional status support a role for IGF-II during development of the dominant follicle. In addition, as IGFBP-3 in estrogen-dominant follicles mirrors the rise of IGF-II, this IGFBP may be a primary regulator of IGF-II action within the estrogen-dominant follicle. Finally, the finding of elevated levels of IGFBP-1 in luteinizing (IVF) follicles suggests an important role for this peptide in corpus luteum regulation.

In a retrospective international study 223 pregnancies induced with pulsatile hormone-releasing hormone (LH-RH) were evaluated. In patients with hypothalamic amenorrhea (HA) and polycystic ovarian disease (PCOD) the abortion rate was similar (10% vs 8.7%). The premature delivery rate was significantly higher, however, in the patients with HA, but this could be explained by the higher incidence of multiple pregnancies in this group. Thirty multiple pregnancies were observed in the HA group (n = 174) compared with none in the PCOD group (n = 24; p less than 0.05). The incidence of multiple pregnancies in the HA group correlated to the pulse dose (p less than 0.05). The 1st treatment cycle resulted in more multiple pregnancies than did subsequent cycles (p less than 0.05). Difference in pulse interval did not affect the incidence of multiple pregnancies, nor did the route of administration (intravenous or subcutaneous). The incidence of congenital anomalies was comparable to that with spontaneously achieved pregnancies.