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Study Question: Does ovarian stimulation with the addition of tamoxifen or letrozole affect the number of cumulus-oocyte complexes (COCs) retrieved compared to standard ovarian stimulation in women with breast cancer who undergo fertility preservation?Summary Answer: Alternative ovarian stimulation protocols with tamoxifen or letrozole did not affect the number of COCs retrieved at follicle aspiration in women with breast cancer.What Is Known Already: Alternative ovarian stimulation protocols have been introduced for women with breast cancer who opt for fertility preservation by means of banking of oocytes or embryos. How these ovarian stimulation protocols compare to standard ovarian stimulation in terms of COC yield is unknown.Study Design, Size, Duration: This multicentre, open-label randomized controlled superiority trial was carried out in 10 hospitals in the Netherlands and 1 hospital in Belgium between January 2014 and December 2018. We randomly assigned women with breast cancer, aged 18-43 years, who opted for banking of oocytes or embryos to one of three study arms; ovarian stimulation plus tamoxifen, ovarian stimulation plus letrozole or standard ovarian stimulation. Standard ovarian stimulation included GnRH antagonist, recombinant FSH and GnRH agonist trigger. Randomization was performed with a web-based system in a 1:1:1 ratio, stratified for oral contraception usage at start of ovarian stimulation, positive estrogen receptor (ER) status and positive lymph nodes. Patients and caregivers were not blinded to the assigned treatment. The primary outcome was number of COCs retrieved at follicle aspiration.Participants/materials, Setting, Methods: During the study period, 162 women were randomly assigned to one of three interventions. Fifty-four underwent ovarian stimulation plus tamoxifen, 53 ovarian stimulation plus letrozole and 55 standard ovarian stimulation. Analysis was according to intention-to-treat principle.Main Results and the Role Of Chance: No differences among groups were observed in the mean (±SD) number of COCs retrieved: 12.5 (10.4) after ovarian stimulation plus tamoxifen, 14.2 (9.4) after ovarian stimulation plus letrozole and 13.6 (11.6) after standard ovarian stimulation (mean difference -1.13, 95% CI -5.70 to 3.43 for tamoxifen versus standard ovarian stimulation and 0.58, 95% CI -4.03 to 5.20 for letrozole versus standard ovarian stimulation). After adjusting for oral contraception usage at the start of ovarian stimulation, positive ER status and positive lymph nodes, the mean difference was -1.11 (95% CI -5.58 to 3.35) after ovarian stimulation plus tamoxifen versus standard ovarian stimulation and 0.30 (95% CI -4.19 to 4.78) after ovarian stimulation plus letrozole versus standard ovarian stimulation. There were also no differences in the number of oocytes or embryos banked. There was one serious adverse event after standard ovarian stimulation: one woman was admitted to the hospital because of ovarian hyperstimulation syndrome.Limitations, Reasons For Caution: The available literature on which we based our hypothesis, power analysis and sample size calculation was scarce and studies were of low quality. Our study did not have sufficient power to perform subgroup analysis on follicular, luteal or random start of ovarian stimulation.Wider Implications Of the Findings: Our study showed that adding tamoxifen or letrozole to a standard ovarian stimulation protocol in women with breast cancer does not impact the effectiveness of fertility preservation and paves the way for high-quality long-term follow-up on breast cancer treatment outcomes and women's future pregnancy outcomes. Our study also highlights the need for high-quality studies for all women opting for fertility preservation, as alternative ovarian stimulation protocols have been introduced to clinical practice without proper evidence.Study Funding/competing Interest(s): The study was supported by a grant (2011.WO23.C129) of 'Stichting Pink Ribbon', a breast cancer fundraising charity organization in the Netherlands. M.G., C.B.L. and R.S. declared that the Center for Reproductive Medicine, Amsterdam UMC (location VUMC) has received unconditional research and educational grants from Guerbet, Merck and Ferring, not related to the presented work. C.B.L. declared a speakers fee for Inmed and Yingming. S.C.L. reports grants and non-financial support from Agendia, grants, non-financial support and other from AstraZeneca, grants from Eurocept-pharmaceuticals, grants and non-financial support from Genentech/Roche and Novartis, grants from Pfizer, grants and non-financial support from Tesaro and Immunomedics, other from Cergentis, IBM, Bayer, and Daiichi-Sankyo, outside the submitted work; In addition, S.C.L. has a patent UN23A01/P-EP pending that is unrelated to the present work. J.M.J.S. reported payments and travel grants from Merck and Ferring. C.C.M.B. reports her role as unpaid president of the National guideline committee on Fertility Preservation in women with cancer. K.F. received unrestricted grants from Merck Serono, Good Life and Ferring not related to present work. K.F. declared paid lectures for Ferring. D.S. declared former employment from Merck Sharp & Dohme (MSD). K.F. declared paid lectures for Ferring. D.S. reports grants from MSD, Gedeon Richter and Ferring paid to his institution; consulting fee payments from MSD and Merck Serono paid to his institution; speaker honoraria from MSD, Gedeon Richter, Ferring Pharmaceuticals and Merck Serono paid to his institution. D.S. has also received travel and meeting support from MSD, Gedeon Richter, Ferring Pharmaceuticals and Merck Serono. No payments are related to present work.Trial Registration Number: NTR4108.Trial Registration Date: 6 August 2013.Date Of First Patient’s Enrolment: 30 January 2014. [ABSTRACT FROM AUTHOR]

Background: Testicular sperm extraction (TESE) is a surgical procedure to retrieve spermatozoa from the testes of men with azoospermia to help them achieve biological parenthood. Although effective, the surgical procedure is not without complications and haematoma, devascularization, inflammation and a decrease in testosterone levels have been described as such. The prevalence and duration of hypogonadism and associated symptoms after TESE have not been studied systematically.Objective and Rationale: In this systematic review we addressed the following research questions: Are serum testosterone levels decreased after TESE and, if so, do these levels recover over time? What is the prevalence of symptoms and signs related to hypogonadism after TESE and are they related to testosterone levels?Search Methods: We searched the databases Pubmed and Embase from 1 January 1993 to 26 June 2017. We combined subject headings with terms in title and/or abstract for participants, intervention and outcomes. We included all studies that reported on TESE, regardless of the specific technique used, that measured testosterone and/or LH, and/or had information on signs or symptoms related to hypogonadism as defined by hypogonadism guidelines. An additional inclusion criterion was that studies described these measurements both before and after TESE. The quality of the included studies was assessed using the Risk Of Bias In Non-randomized Studies-of Interventions tool.Outcomes: We identified 15 studies reporting on total testosterone levels of which five studies also reported on testicular volume and one study on erectile dysfunction. Men with Klinefelter syndrome and men with non-obstructive azoospermia had the strongest decrease in total testosterone levels 6 months after TESE, with a mean decrease of 4.1 and 2.7 nmol/l, respectively, which recovered again to baseline levels 26 and 18 months after TESE, respectively. At 6 months after TESE, some studies reported serum total testosterone concentrations below a cut-off value of 12 nmol/l, where symptoms and signs related to hypogonadism may appear. Furthermore, an increased prevalence of erectile dysfunction related to decreased total testosterone levels 6 months after TESE was reported. Also, in some men a decrease in testicular volume was reported. However, it is not clear if this is related to low testosterone levels.Wider Implications: The transient, but statistically significant, decrease in total testosterone levels indicates that men are at risk of developing a temporary hypogonadism after TESE, but there is insufficient evidence for whether patients actually experience clinical symptoms in case of decreased serum testosterone levels. To be able to properly counsel TESE patients, more large-scale monitoring on signs and symptoms of hypogonadism, in combination with testosterone measurements, needs to be performed in men undergoing TESE. [ABSTRACT FROM AUTHOR]

Study Question: Do two semen analyses predict natural conception better than a single semen analysis and will adding the results of repeated semen analyses to a prediction model for natural pregnancy improve predictions?Summary Answer: A second semen analysis does not add helpful information for predicting natural conception compared with using the results of a single semen analysis and addition of the second analysis to a prediction model for natural conception did not improve predictions.What Is Known Already: A major problem with semen analyses is the large variability of results within an individual. High-quality evidence is lacking on how many semen analyses need to be performed during the fertility workup to achieve an accurate prediction of conception.Study Design, Size, Duration: We conducted a prospective cohort study of 897 consecutive couples presenting with subfertility in two university hospitals in the period 2002-2004 in the Netherlands.Participants/materials, Setting, and Methods: The laboratories scored sperm parameters according to the 1999 WHO criteria. Sperm concentration was counted and motility was assessed in a Makler counting chamber at a magnification of ×200. All assessments were performed by trained laboratory technicians. Follow-up started at the completion of the infertility workup and ended after 12 months. Primary end-point was natural conception resulting in an ongoing pregnancy. We constructed models for three strategies for the prediction of natural conception, using univariable and multivariable Cox hazard regression analyses. We evaluated the performance of the three strategies by comparing goodness-of-fit, discrimination and calibration. First, we analysed the semen parameters only. Secondly, we analysed the semen parameters in addition to the multivariable Hunault prediction model.Main Results and the Role Of Chance: Of the 897 couples, 132 (15%) achieved a pregnancy by natural conception. Using the results of a single semen analysis only, the calculated probabilities of natural conception within 12 months across the study population ranged from 0.12 to 0.38, with a median of 0.16 (IQR: 0.16-0.17). Using the results of two semen analyses did not lead to a better goodness-of-fit. Discriminative capacity was rather poor, with an area under the ROC curve (AUC) ranging from 0.51 to 0.56. Using the Hosmer-Lemeshow test statistic we found no signs of poor calibration. Using the results of two semen analyses in combination with the Hunault model did not significantly increase goodness-of-fit compared with using a single semen analysis. The Hunault model with the addition of the semen parameters fitted the data significantly better than the Hunault model itself (difference in -2 Log likelihood: 13; 3 df; P = 0.002). Using the Hosmer-Lemeshow test statistic we found no signs of poor calibration.Limitations, Reasons For Caution: The academic setting possibly explains the relatively low natural conception rates, with only 15% achieving a natural conception within 1 year. Men with azoospermia were excluded.Wider Implications Of the Findings: Performing more than one semen analysis will not increase the prognostic power of the test in clinical practice. Adding the first semen analysis to the Hunault model for the prediction of natural conception improved performance significantly compared with using the Hunault model alone. External validation, in other populations, should follow to confirm our conclusions, and to evaluate the generalizability or transportability of the extended Hunault model.Study Funding/competing Interest(s): No external funding was involved in this study. None of the authors has any conflict of interest to declare. [ABSTRACT FROM AUTHOR]

BACKGROUND We recently reported that treatment with intrauterine insemination and controlled ovarian stimulation (IUI-COS) did not increase ongoing pregnancy rates compared with expectant management (EM) in couples with unexplained subfertility and intermediate prognosis of natural conception. Long-term cost-effectiveness of a policy of initial EM is unknown. We investigated whether the recommendation not to treat during the first 6 months is valid, regarding the long-term effectiveness and cumulative costs. METHODS Couples with unexplained subfertility and intermediate prognosis of natural conception (n=253, at 26 public clinics, the Netherlands) were randomly allocated to 6 months EM or immediate start with IUI-COS. The couples were then treated according to local protocol, usually IUI-COS followed by IVF. We followed couples until 3 years after randomization and registered pregnancies and resources used. Primary outcome was time to ongoing pregnancy. Secondary outcome was treatment costs. Analysis was by intention-to-treat. Economic evaluation was performed from the perspective of the health care institution. RESULTS Time to ongoing pregnancy did not differ between groups (log-rank test P=0.98). Cumulative ongoing pregnancy rates were 72–73% for EM and IUI-COS groups, respectively [relative risk 0.99 (95% confidence interval (CI) 0.85–1.1)]. Estimated mean costs per couple were €3424 (95% CI €880–€5968) in the EM group and €6040 (95% CI €4055–€8125) in the IUI-COS group resulting in an estimated saving of €2616 per couple (95% CI €385–€4847) in favour of EM. CONCLUSIONS In couples with unexplained subfertility and an intermediate prognosis of natural conception, initial EM for 6 months results in a considerable cost-saving with no delay in achieving pregnancy or jeopardizing the chance of pregnancy. Further comparisons between aggressive and milder forms of ovarian stimulation should be performed. [ABSTRACT FROM PUBLISHER]

BACKGROUND Although chromosomal mosaicism in human preimplantation embryos has been described for almost two decades, its exact prevalence is still unknown. The prevalence of mosaicism is important in the context of preimplantation genetic screening in which the chromosomal status of an embryo is determined by the analysis of a single cell from that embryo. METHODS Here we report a systematic review and meta-analysis of studies on the chromosomal constitution of human preimplantation embryos. In 36 studies, out of 2117 citations that met our search criteria, data were provided extensively enough to allow classification of each analysed embryo with prespecified criteria for its chromosomal makeup. The main outcome of this classification was the prevalence of chromosomal mosaicism in human preimplantation embryos. RESULTS A total of 815 embryos could be classified. Of these, 177 (22%) were diploid, 599 (73%) were mosaic, of which 480 (59% of the total number of embryos) were diploid–aneuploid mosaic and 119 (14% of the total number of embryos) were aneuploid mosaic, and 39 (5%) contained other numerical chromosomal abnormalities. The distribution of the embryos over these categories was associated with the developmental stage of the embryos, the method used for analysis and the number of chromosomes analysed. CONCLUSIONS Diploid–aneuploid mosaicism is by far the most common chromosomal constitution in spare human preimplantation embryos after IVF. This undermines the reliable determination of the ploidy status of a cleavage-stage embryo based on the analysis of a single cell. Future research should determine the origin and developmental potential of mosaic embryos. [ABSTRACT FROM AUTHOR]

Systematic reviews and accompanying meta-analyses are the cornerstones of evidence-based medicine. Systematic reviews summarize clinical evidence; meta-analyses provide summary estimates of the treatment effect or the diagnostic test accuracy. Although deemed to provide the highest level of evidence, their clinical value is limited as they can only summarize aggregated data. In these meta-analyses the true variability of the treatment effects cannot be explored to the desired extent, because the meta-analyses cannot distinguish between patients with different clinical profiles. Systematic reviews and meta-analyses based on individual patient data (IPD), described as the ‘gold standard’ for systematic reviews are a promising approach that might overcome these limitations. IPD meta-analyses allow treatment effects and diagnostic accuracy to be estimated at the level of relevant patient subgroups. This enables researchers to investigate the effectiveness of treatment in patients with different profiles. In this article, we address the opportunities of systematic reviews and meta-analyses using IPD in reproductive medicine. We discuss its potential based on three clinical examples: single versus double embryo transfer in IVF, the diagnosis of tubal pathology and the prognostic value of ovarian reserve tests. We propose to show potential advantages of IPD systematic reviews and meta-analyses in providing stratified clinical evidence, which could improve medical care. [ABSTRACT FROM PUBLISHER]

BACKGROUND: Recently, dopamine agonists were proposed as a prophylactic treatment for ovarian hyperstimulation syndrome (OHSS) in women at high risk in IVF/ICSI treatment cycles. [ABSTRACT FROM PUBLISHER]

Background: Prediction models have been developed in reproductive medicine to help assess the chances of a treatment-(in)dependent pregnancy. Careful evaluation is needed before these models can be implemented in clinical practice. Methods: We systematically searched the literature for papers reporting prediction models in reproductive medicine for three strategies: expectant management, intrauterine insemination (IUI) or in vitro fertilization (IVF). We evaluated which phases of development these models had passed, distinguishing between (i) model derivation, (ii) internal and/or external validation, and (iii) impact analysis. We summarized their performance at external validation in terms of discrimination and calibration. Results: We identified 36 papers reporting on 29 prediction models. There were 9 models for the prediction of treatment-independent pregnancy, 3 for the prediction of pregnancy after IUI and 17 for the prediction of pregnancy after IVF. All of the models had completed the phase of model derivation. For six models, the validity of the model was assessed only in the population in which it was developed (internal validation). For eight models, the validity was assessed in populations other than the one in which the model was developed (external validation), and only three of these showed good performance. One model had reached the phase of impact analysis. Conclusions: Currently, there are three models with good predictive performance. These models can be used reliably as a guide for making decisions about fertility treatment, in patients similar to the development population. The effects of using these models in patient care have to be further investigated. [ABSTRACT FROM AUTHOR]

Current algorithms for the diagnosis of ectopic pregnancy do not take into account the heterogeneity in patient profiles. Such heterogeneity can lead to differences in the pre-test probability of ectopic pregnancy. In patients with clinical symptoms, for example, the probability of presence of an ectopic pregnancy is higher than in symptom-free patients. Any additional tests should then be interpreted differently, depending on the pre-test probability. We present a diagnostic algorithm that uses probabilistic decision rules for the evaluation of women with suspected ectopic pregnancy with flexible cut-off levels for test positivity We compare it with a general algorithm that uses fixed cut-off levels. Fictitious cohorts, varying in prevalence of ectopic pregnancy were put together, using data obtained from a cohort of >800 women with suspected ectopic pregnancy. In the inflexible algorithm, ectopic pregnancy was diagnosed whenever it could be visualized at transvaginal sonography, or where serum human chorionic gonadotrophin (HCG) exceeded a rigid cut-off level; ectopic pregnancy was rejected if an intrauterine pregnancy was seen or when serum HCG decreased. In the flexible algorithm, a post-test probability was obtained after each test, using pre-test probabilities and test-based likelihood ratios. Ectopic pregnancy was diagnosed whenever the post-test probability for ectopic pregnancy exceeded 95%, whereas this diagnosis was rejected if the calculated post-test probability fell below 1%. For both algorithms, sensitivity and specificity as well as predictive values were calculated. At each prevalence, the inflexible algorithm was associated with a sensitivity of 93% and a specificity of 97%. In contrast, the sensitivity and specificity of the flexible, individualized algorithm depended on the prevalence of ectopic pregnancy. Consequently, predictive values varied strongly when the inflexible algorithm was used, whereas they were much more stable after using the flexible algorithm. For five possible valuations of false positive and false negative diagnoses, the flexible algorithm reduced the expected disutility, compared with the inflexible algorithm. It is concluded that clinicians should incorporate probabilistic decision rules in algorithms used for the diagnosis of ectopic pregnancy. [ABSTRACT FROM PUBLISHER]

In this study, we compare the prognostic significance of hysterosalpingography (HSG) and laparoscopy for fertility outcome. In a prospective cohort study in 11 clinics participating in the Canadian Infertility Treatment Evaluation Study (CITES), consecutive couples who registered between 1 April 1984 and 31 March 1987 for the evaluation of subfertility and who underwent HSG and laparoscopy were included. Unilateral and bilateral tubal occlusion at HSG and laparoscopy were related to treatment-independent pregnancy. Cox regression was used to calculate fecundity rate ratios (FRR). Of the 794 patients who were included, 114 (14%) showed one-sided tubal occlusion and 194 (24%) showed two-sided tubal occlusion on HSG. At laparoscopy, 94 (12%) showed one-sided tubal occlusion and 96 (12%) showed two-sided tubal occlusion. Occlusion detected on HSG and laparoscopy showed a moderate agreement beyond chance (weighted κ-statistic 0.42). The adjusted FRR of one-sided tubal occlusion at HSG was 0.80, whereas two-sided tubal occlusion showed an FRR of 0.49. For laparoscopy, the FRR were 0.51 and 0.15 respectively. After a normal or one-sided occluded HSG, laparoscopy showed two-sided occlusion in 5% of the patients, and fertility prospects in these patients were virtually zero. If two-sided tubal occlusion was detected on HSG but not during laparoscopy, fertility prospects were slightly impaired. Fertility prospects after a two-sided occluded HSG were strongly impaired in cases where laparoscopy showed one-sided and two-sided occlusion, with FRR of 0.38 and 0.19 respectively. Although laparoscopy performed better than HSG as a predictor of future fertility, it should not be considered as the perfect test in the diagnosis of tubal pathology. For clinical practice, laparoscopy can be delayed after normal HSG for at least 10 months, since the probability that laparoscopy will show tubal occlusion after a normal HSG is very low. [ABSTRACT FROM PUBLISHER]

In 12 cows, transvaginal interstitial laser treatment (TILT) of the ovaries was performed using a neodynium: yttrium aluminium-garnet laser to investigate the feasibility of a new treatment approach for clomiphene-resistant patients with chronic hyperandrogenic anovulation. Powers of 1 and 2 W during 5 min of exposure were used. Sonographic changes of thermal damage during TILT, the extent and healing of the lesions by light microscopy and ultrasound during a 3 month follow-up and adhesion formation were studied. During laser irradiation, a hyperechogenic zone developed around the fibre tip, with a mean ± SD diameter of 4.4 ± 2.0 mm at 1 W and 6.9 ± 1.5 mm at 2 W. The mean diameters of the histological lesions 2 days after treatment were 7.3 ± 2.5 mm at 1 W and 13.0 ± 2.1 mm at 2 W. During follow-up, the mean diameter of both the histologically and the sonographically assessed lesions decreased, although transvaginal sonography (TVS) systematically and significantly underestimated the thermal damage. Lesions healed by fibrosis and no adhesions were present TILT of the ovaries in cows is easy to perform and produces central or subcapsular necrosis without adhesions. TVS gives an indication of thermal damage but underestimates the extent of tissue damage in cow ovaries. Obviously, this study does not allow conclusions to be drawn concerning its safety and efficacy in man. [ABSTRACT FROM PUBLISHER]

The aim of the study was to estimate the inter- and intra-observer reproducibility of the interpretation of hysterosalpingography (HSG) in the diagnosis of tubal pathology, and associate reproducibility with diagnostic accuracy. Four observers evaluated 143 HSGs twice, on proximal tubal obstruction, distal tubal obstruction, hydrosalpinx and peritubal adhesions. Diagnostic laparoscopy with chromopertubation was considered to be the reference strategy. Reproducibility (inter- and intra-observer agreement) was expressed in terms of kappa-values. Accuracy was expressed in terms of sensitivity, specificity and likelihood ratios. kappa-values for reproducibility between observers were almost perfect for proximal obstruction, substantial for distal obstruction and hydrosalpinx, and moderate for adhesions. kappa-values for reproducibility within observers were almost perfect for proximal obstruction and substantial for distal obstruction, hydrosalpinx and adhesions. HSG had a high specificity for proximal obstruction, but a low sensitivity. Distal obstruction, absence of hydrosalpinx and adhesions had a poor accuracy. The likelihood ratio for the presence of hydrosalpinx was high. In conclusion, proximal tubal obstruction detected on HSG changes the pre-test probability of proximal tubal obstruction from 16 to 50%. Proximal tubal patency detected on HSG changes the pre-test probability of proximal tubal patency from 16 to 9%. It is unlikely that a lack of reproducibility of the interpretation of proximal tubal patency is responsible for the low sensitivity; alternative explanations are artefacts occurring while performing HSG or an imperfect reference strategy diagnostic laparoscopy. HSG is of limited use in diagnosing distal tubal obstruction and hydrosalpinx, and has no value in the detection of peritubal adhesions. [ABSTRACT FROM AUTHOR]

To optimize success rates of IVF, selection of the most viable embryo(s) for transfer has always been essential, as embryos that are cryopreserved are thought to have a reduced chance of implanting after thawing. Recent developments challenge this concept. Evidence is accumulating that all embryos can now be cryopreserved and transferred in subsequent cycles without impairing pregnancy rates or maybe even with an improvement in pregnancy rates. In such a scenario no selection method will ever lead to improved live birth rates, as, by definition, the live birth rate per stimulated IVF cycle can never be improved when all embryos are serially transferred. In fact, selection could then only lower the live birth rate after IVF. The only parameter that could possibly be improved by embryo selection would be time to pregnancy, if embryos with the highest implantation potential are transferred first. [ABSTRACT FROM PUBLISHER]

We performed unilateral oophorectomy (UO) in three patients with polycystic ovary syndrome (PCOS) and longstanding infertility. The indication for performing this procedure was a combination of ovarian pathology and the long-standing infertility. All three patients were resistant to clomiphene citrate and before UO all patients had been treated unsuccessfully with gonadotrophins and in-vitro fertilization. All three patients became ovulatory within the first month after UO. Two patients conceived 11 and 12 months after surgery respectively and delivered healthy babies. Testosterone concentrations decreased in two patients to upper values of the normal range and remained unchanged in one patient. We conclude that restoration of ovulation can be a beneficial side-effect of UO in clomiphene citrate resistant patients with PCOS and long-standing infertility. [ABSTRACT FROM PUBLISHER]