FSH treatment improves sperm DNA damage in men with idiopathic infertility carriers of the FSH receptor p.N680S homozygous N genotype: an interim analysis

Study question: To assess whether in men with idiopathic infertility, the sperm DNA fragmentation (sDF) improves depending on the FSH receptor (FSHR) genotype as assessed by the non-synonymous polymorphisms (SNP) rs6166 (wild type or p.N680S). Summary answer: FSH treatment improves sDF in a subgroup of idiopathic infertile men, although 40% of these men do not show any significant improve- ment. The response of sDF, a surrogate marker of sperm quality, together with the evaluation of FSHR SNP p.N680S might be useful to predict the response to FSH treatment. What is known already: FSH is fundamental for spermatogenesis and is em- pirically used to treat male idiopathic infertility. Several studies suggest that sDF could be a candidate predictor of response to FSH treatment, in terms of probability to conceive. Furthermore, it is widely accepted that the FSHR SNP p.N680S influences ovarian response in women and testicular volume in men. Study design, size, duration: Multicenter, longitudinal, prospective, open-la- bel, two-arms clinical trial. Subjects enrolled were idiopathic infertile men and received 150 IU of recombinant FSH (Gonal f®) every other day for 12 weeks and were then followed-up for further 12 weeks after FSH-withdrawal. Patients were evaluated at baseline and at the end of the two phases. Participants/materials, setting, methods: Eighty-eight men with idiopathic male infertility carrier of the homozygous FSHR p.N680S N or S genotype, FSH 15%, were enrolled. 66 patients completed the sDF analysis. sDF was centrally evaluated by TUNEL/PI assay coupled to flow cy- tometry, resolving two different sperm populations, namely: PIbrighter and PIdimmer. Main results and the role of chance: Thirty-seven men (56%) were carriers of the p.N680S homozygous-N and 29 (44%) of the homozygous-S genotype, respectively. Total sDF (PIbrighter + PIdimmer) was significantly lower at the end of the study in patients carriers of the p.N680S-N allele than patients carri- ers of p.N680S-S allele (p = 0.008). Only in patients carriers of the p.N680S-N allele, total sDF decreased significantly from baseline to the end of the study (p = 0.021) and this decrease was entirely sustained by the sperm population containing vital sperms (i.e., PIbrighter fraction) (p = 0.008). PIdimmer frac- tion, including only non-vital sperms, was significantly higher in patients car- riers of the p.N680S-S allele than in carriers of N allele (p = 0.018). Total sDF was inversely related to total sperm number (p = 0.020) and progressive sperm motility (p = 0.014). Limitations, reason for caution: The statistical power of the results obtained so far is 86.9%, with alpha-error 0.05. This is an interim-analysis. Wider implications of the findings: The study suggests that FSH treatment induces a significant improvement of total sDF in men carriers of the p.N680S homozygous N allele. This sDF decrease awaits confirmation, since the study will be completed by June 2015. Study funding/competing interest(s): Funding by commercial/corporate company(ies) – The study was supported by unrestricted grant by Merck Serono. Trial registration number: EudraCT number 2010-020240-35. Keywords: FSH treatment, male infertility, Sperm-DNA fragmentatio

A multi-centre randomised controlled study of pre-IVF outpatient hysteroscopy in women with recurrent IVF implantation failure: Trial of Outpatient Hysteroscopy - [TROPHY] in IVF

<p>Abstract</p> <p>Background</p> <p>The success rate of IVF treatment is low. A recent systematic review and meta-analysis found that the outcome of IVF treatment could be improved in patients who have experienced recurrent implantation failure if an outpatient hysteroscopy (OH) is performed before starting the new treatment cycle. However, the trials were of variable quality, leading to a call for a large and high-quality randomised trial. This protocol describes a multi-centre randomised controlled trial to test the hypothesis that performing an OH prior to starting an IVF cycle improves the live birth rate of the subsequent IVF cycle in women who have experienced two to four failed IVF cycles.</p> <p>Methods and design</p> <p>Eligible and consenting women will be randomised to either OH or no OH using an internet based trial management programme that ensures allocation concealment and employs minimisation for important stratification variables including age, body mass index, basal follicle stimulating hormone level and number of previous failed IVF cycles. The primary outcome is live birth rate per IVF cycle started. Other outcomes include implantation, clinical pregnancy and miscarriage rates.</p> <p>The sample size for this study has been estimated as 758 participants with 379 participants in each arm. Interim analysis will be conducted by an independent Data Monitoring Committee (DMC), and final analysis will be by intention to treat. A favourable ethical opinion has been obtained (REC reference: 09/H0804/32).</p> <p>Trail Registration</p> <p>The trial has been assigned the following ISRCTN number: ISRCTN35859078</p

ART results with frozen oocytes: data from the Italian ART registry (2005–2013)

PURPOSE: This study is a retrospective collection of aggregated data from all the Italian ART centers reporting to the Italian National Register from cycles started between January 2005 and December 2013. METHODS: Data from both slow freezing (SF) and vitrification (V) were assessed for the period 2007–2013, while during the years 2005–2006 cryopreservation was exclusively performed by SF. RESULTS: In the study period, a total of 2,526,024 oocytes were retrieved (from 378,543 retrievals), of which 1,346,061 (53.3 %) were inseminated in fresh cycles and 214,481 (8.5 %) were cryopreserved. Cryopreserved oocytes were used in 24,173 cycles yielding 19,453 transfer cycles (80.5 % of the thawing/warming cycles) and 3043 clinical pregnancies (15.6 % per transfer). A significant difference in implantation (8.7 vs 12.9 % OR 1.30 CI 1.20–1.40) and pregnancy rates per transfer (12.2 vs 14.9 % OR 1.34 CI 1.23–1.46) was found between SF and V. Complete outcome data was available for 2708 pregnancies (89.8 %), leading to 1882 deliveries and 2152 live births. Neonatal major congenital anomalies were 0.9 % (20/2152). CONCLUSIONS: A wide variation in pregnancy rates were found among different centers and lower rates were reported in donor cycles and in centers with more experience

Is letrozole needed for controlled ovarian stimulation in patients with estrogen receptor-positive breast cancer?

Abstract OBJECTIVE: To assess the advantages and disadvantages of using letrozole for controlled ovarian stimulation (COH) in young patients with estrogen receptor-positive (ER+) breast cancer, wishing to cryopreserve oocytes. DESIGN: Retrospective cohort analysis. SETTING: Sixteen Italian units for reproductive medicine and in vitro fertilization. METHODS: Data of 50 ER+ breast cancer patients undergoing COH to cryopreserve oocytes before gonadotoxic chemotherapy with a letrozole plus gonadotropins (Le+Gn) protocol were compared with those of 25 young women with ER- breast cancer, submitted to COH using a protocol with gonadotropins alone (Gn-only). RESULTS: The Le+Gn protocol implied a significantly lower total Gn consumption and allowed to maintain significantly lower circulating E2 levels at all checkpoints throughout stimulation (peak E2 value 446\u2009\ub1\u2009357 versus 1553\u2009\ub1\u2009908\u2009pg/ml, respectively; p\u2009=\u20090.001). On the other side, the Le+Gn protocol allowed a significantly lower yield of oocytes available for cryostorage (6.6\u2009\ub1\u20093.5 versus 8\u2009\ub1\u20095, respectively; p\u2009=\u20090.038). CONCLUSIONS: In breast cancer patients, the association of letrozole to Gn significantly reduces the number of oocytes available for cryostorage in comparison with the use of Gn alone. On the other side, it is associated with significantly lower E2 levels during the whole stimulation cycle, a safety issue that has been traditionally considered advantageous in case of ER+ cancers

Human oocyte cryopreservation with slow freezing versus vitrification. Results from the National Italian Registry data, 2007-2011

Abstract OBJECTIVE: To compare mature human oocytes cryopreservation with slow freezing (SF) and vitrification (VT) in infertile couples. DESIGN: Retrospective study of national Italian data submitted during the period 2007-2011. SETTING: National ART registry. PATIENT(S): Infertile patients with supernumerary oocytes. INTERVENTION(S): Thawing or warming of cryopreserved oocytes and ICSI. MAIN OUTCOME MEASURE(S): oocyte survival, fertilization, implantation and clinical pregnancy rate between SF and VT. RESULT(S): A total of 14,328 cycles with 11,599 transfers, 1,850 pregnancies, 1,168 deliveries and 1,342 babies born were analyzed from 146 reporting centers (range of cycles 1-1,255 per center). The SF oocytes' survival rate was lower than in VT (51.1% vs. 63.1%). Fertilization rate was significantly higher in SF than in VT (SF 71.6% vs. VT 70.1%). VT showed a significantly higher pregnancy rate, both per started cycle (14.4% vs. 12.0%) and per transfer (18.0% vs. 14.8%), and implantation rate (9.5% vs. 8.1%) than SF. However, the range and median pregnancy rate per started cycle were, respectively, 0%-50% and 7.7% in SF and 0%-100% and 6.7% in VT. CONCLUSION(S): VT showed a statistically significant higher performance than SF. As with other ART procedures, the results are not homogeneous among clinics and protocols, but the confirm the clinical value of oocyte cryopreservation in infertile patients

Human recombinant follicle stimulating hormone (rFSH) compared to urinary human menopausal gonadotropin (HMG) for ovarian stimulation in assisted reproduction: a literature review and cost evaluation.

Background Gonadotropins are protein hormones which are central to the complex endocrine system that regulates normal growth, sexual development, and reproductive function. There is still a lively debate on which type of gonadotropin medication should be used, either human menopausal gonadotropin or recombinant follicle-stimulating hormone. The objective of the study was to perform a systematic review of the recent literature to compare recombinant follicle-stimulating hormone to human menopausal gonadotropin with the aim to assess any differences in terms of efficacy and to provide a cost evaluation based on findings of this systematic review. Methods The review was conducted selecting prospective, randomized, controlled trials comparing the two gonadotropin medications from a literature search of several databases. The outcome measure used to evaluate efficacy was the number of oocytes retrieved per cycle. In addition, a cost evaluation was performed based on retrieved efficacy data. Results The number of oocytes retrieved appeared to be higher for human menopausal gonadotropin in only 2 studies while 10 out of 13 studies showed a higher mean number of oocytes retrieved per cycle for recombinant follicle-stimulating hormone. The results of the cost evaluation provided a similar cost per oocyte for both hormones. Conclusions Recombinant follicle-stimulating hormone treatment resulted in a higher oocytes yield per cycle than human menopausal gonadotropin at similar cost per oocyte

Artificial shrinkage of blastocysts prior to vitrification improves pregnancy outcome: analysis of 1028 consecutive warming cycles

PURPOSE: This study aims to compare implantation, pregnancy, and delivery rates in frozen transfer cycles with blastocysts that were vitrified either with artificial shrinking (AS group) or without (NAS group). METHODS: Retrospective comparative study of artificial shrinking of blastocysts prior to vitrification and frozen embryo transfer cycles in infertile patients undergoing frozen embryo transfer (FET) was done at the Humanitas Fertility Center between October 2009 and December 2013. Main outcome measure(s) were implantation (IR), pregnancy (PR), and delivery rates (DR) between the two groups. RESULTS: A total of 1028 consecutive warming blastocyst transfer cycles were considered. In 580 cycles (total of 822 blastocysts), artificial shrinking was performed prior to vitrification (AS group), while in the remaining 448 cycles (total of 625 blastocysts), the artificial shrinking was not performed (NAS group). There were no differences in patient age (36.4 ± 3.7 vs. 36.3 ± 3.9) and number of embryos transferred (1.41 ± 0.49 vs. 1.38 ± 0.50) between groups. The IR, PR, and DR in the AS group were significantly higher (p < 0.05) than in the NAS group (29.9 vs. 23.0 %, 36.3 vs. 27.9 %, and 26.5 vs. 18.1 %, respectively). CONCLUSIONS: Performing AS of blastocysts prior to vitrification appears to improve implantation, pregnancy, and delivery rates probably related to a decreased risk of ultrastructural cryodamages, plausible when cryopreserving expanded blastocysts