Embryo long-term storage does not affect assisted reproductive technologies outcome: analysis of 58,001 vitrified blastocysts over 11 years.

BACKGROUND: Recently, the potential detrimental effect that the duration of storage time may have on vitrified samples has raised some concerns, especially when some studies found an association between cryostorage length and decreased clinical results. OBJECTIVE: This study aimed to evaluate the effects of the storage time length of day-5 vitrified blastocysts in 2 study groups: freeze-all cycles and nonelective frozen embryo transfers. STUDY DESIGN: This was a retrospective study that included 58,001 vitrified/warmed day-5 blastocysts from 2 different populations, according to the reason for frozen embryo transfer. Elective frozen embryo transfer comprised freeze-all cycles (N=16,615 blastocysts and 16,615 patients) in which only single embryo transfers and only the first frozen embryo transfer were included. The nonelective frozen embryo transfer group included 41,386 embryos from 25,571 patients where frozen embryo transfer took place using supernumerary embryos after fresh embryo transfer. All the possible frozen embryo transfers were included. Both single embryo transfer and double embryo transfers were included. Donor and autologous oocytes were used. The period covered by this study was 11 years. The blastocyst sample was clustered into deciles, which provided specific storage duration categories. The main outcome was the live birth rate, and secondary outcomes were embryo survival, miscarriage, and clinical and ongoing pregnancy rates according to storage duration. The impact of storage time was assessed by univariable analyses in both groups. The comparison was made between each decile and the last one. A multivariable logistic regression analysis was conducted, including the variables with significant association found in the univariate analysis. Student t test and chi-square tests, or an analysis of variance, were used wherever appropriate. P<.05 was considered statistically significant. RESULTS: There were statistical differences in baseline characteristics of patients included in the study groups. Storage durations ranged from ≤0.67 to ≥4.34 and from ≤1.8 to ≥34.81 months in freeze-all and nonelective frozen embryo transfer, respectively. Embryo survival did not show statistical differences across the categories of storage time in freeze-all and nonelective frozen embryo transfer groups. Statistical differences were found for the live birth rate across some, but not all, the subgroups of storage duration. The multivariable analysis showed no association between storage time and the live birth rate in both groups (nonsignificant). Blastocyst quality, body mass index, number of retrieved oocytes, endometrial preparation, male factor, and uterine factor were related to the drop in the live birth rate in the freeze-all group (P<.05). In the nonelective frozen embryo transfer group, the variables that showed significant association with the live birth rate were age at retrieval and frozen embryo transfer, type of frozen embryo transfer (single embryo transfer or double embryo transfers), number of retrieved oocytes, body mass index, endometrial preparation, origin of sperm sample, and female factor. CONCLUSION: This large study demonstrated no association between storage time and clinical outcome. Other variables, such as the patient's age, embryo quality, body mass index, and etiology, are somewhat responsible for impacting the outcome. This provides evidence for the safety of embryo vitrification, even after long storage periods. This is reassuring for both in vitro fertilization practitioners and patients undergoing frozen embryo transfer of either elective or nonelective embryos.

The combined effect of BMI and age on ART outcomes.

STUDY QUESTION: For a woman with infertility and overweight/obesity, can infertility treatment be postponed to first promote weight loss? SUMMARY ANSWER: Advice regarding a delay in IVF treatment to optimize female weight should consider female age, particularly in women over 38 years for whom only substantial weight loss in a short period of time (3 months) seems to provide any benefit. WHAT IS KNOWN ALREADY: Body weight excess and advanced age are both common findings in infertile patients, creating the dilemma of whether to promote weight loss first or proceed to fertility treatment immediately. Despite their known impact on fertility, studies assessing the combined effect of female age and BMI on cumulative live birth rates (CLBRs) are still scarce and conflicting. STUDY DESIGN, SIZE, DURATION: We performed a multicentre retrospective cohort study including 14 213 patients undergoing their first IVF/ICSI cycle with autologous oocytes and subsequent embryo transfers, between January 2013 and February 2018 in 18 centres of a multinational private fertility clinic. BMI was subdivided into the following subgroups: underweight (<18.5 kg/m2), normal weight (18.5-24.9 kg/m2), overweight (25.0-29.9 kg/m2), and obesity (≥30.0 kg/m2). PARTICIPANTS/MATERIALS, SETTING, METHODS: The primary outcome was CLBR. The secondary outcome was time to pregnancy. To assess the influence of female age and BMI on CLBR, two multivariable regression models were developed with BMI being added in the models as either an ordinal categorical variable (Model 1) or a continuous variable (Model 2) using the best-fitting fractional polynomials. CLBR was estimated over 1-year periods (Model 1) and shorter timeframes of 3 months (Model 2). We then compared the predicted CLBRs according to BMI and age. MAIN RESULTS AND THE ROLE OF CHANCE: When compared to normal weight, CLBRs were lower in women who were overweight (adjusted odds ratio (aOR) 0.86, 95% CI 0.77-0.96) and obese (aOR 0.74, 95% CI 0.62-0.87). A reduction of BMI within 1 year, from obesity to overweight or overweight to normal weight would be potentially beneficial up to 35 years old, while only a substantial reduction (i.e. from obesity to normal BMI) would be potentially beneficial in women aged 36-38 years. Above 38 years of age, even considerable weight loss did not compensate for the effect of age over a 1-year span but may be beneficial in shorter time frames. In a timeframe of 3 months, there is a potential benefit in CLBR if there is a loss of 1 kg/m2 in BMI for women up to 33.25 years and 2 kg/m2 in women aged 33.50-35.50 years. Older women would require more challenging weight loss to achieve clinical benefit, specifically 3 kg/m2 in women aged 35.75-37.25 years old, 4 kg/m2 in women aged 37.50-39.00 years old, and 5 kg/m2 or more in women over 39.25 years old. LIMITATIONS, REASONS FOR CAUTION: This study is limited by its retrospective design and lower number of women in the extreme BMI categories. The actual effect of individual weight loss on patient outcomes was also not evaluated, as this was a retrospective interpatient comparison to estimate the combined effect of weight loss and ageing in a fixed period on CLBR. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest that there is potential benefit in weight loss strategies within 1 year prior to ART, particularly in women under 35 years with BMI ≥25 kg/m2. For those over 35 years of age, weight loss should be considerable or occur in a shorter timeframe to avoid the negative effect of advancing female age on CLBR. A tailored approach for weight loss, according to age, might be the best course of action. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was obtained for this study. All authors have no conflicts to declare. TRIAL REGISTRATION NUMBER: N/A.

Shared IVF among female couples: clinical outcomes of the Reception of Oocytes from the Partner (ROPA) method.

RESEARCH QUESTION: What is the population undergoing the ROPA (Reception of Oocytes from Partner) method and what are the outcomes of the technique? DESIGN: Case series of all ROPA treatments carried out between 2011 and 2020 in 18 fertility clinics in Spain. Demographic characteristics, cycle features, laboratory and clinical outcomes, and the intentions regarding the disposition of surplus embryos were analysed. RESULTS: Donor patients were on average 3.5 years younger than recipients (P = 0.001). No significant differences were found in body mass index or anti-Müllerian hormone. In 13% of cases, fertility issues were found: poor ovarian reserve (6.8%); endometriosis (2.9%); and polycystic ovary syndrome (2.2%). Including cases of advanced age (38 years old or older), more than one-half of couples (53.6%) had some condition that could affect fertility. Mean number of mature oocytes per cycle was 10 (+/- 5.7), and fertilization rate was 74.5% (+/- 18.8). Mean number of viable embryos was 3.2 (+/- 1.5). Surplus embryos were cryopreserved in 50.4% of cycles. Outcomes after embryo transfers from ROPA, and subsequent frozen cycles were as follows: positive pregnancy test (61.0%), clinical pregnancy (54.1%) and miscarriage rate (16.1%). Other outcomes were live birth rate per embryo transfer (44.7%); multiple pregnancy rate (5.4%); per cumulative ROPA cycle (48.6%); and per couple (61.6%). CONCLUSION: The outcomes of the ROPA method are reassuring. About one-half of the ROPA cycles resulted in a live birth and one-quarter of the cycles had surplus embryos after achieving a live birth. Main neonatal outcomes were also reassuring.

Serum progesterone concentrations are reduced in obese women on the day of embryo transfer.

RESEARCH QUESTION: Does serum progesterone concentration vary on the day of embryo transfer according to female body mass index (BMI)? DESIGN: Retrospective analysis including 3210 infertile patients undergoing an embryo transfer in the context of an artificial endometrial preparation cycle with sequential administration of oestrogens and micronized vaginal progesterone (MVP) (400 mg/12 h). Serum progesterone was measured on the day of embryo transfer, 6 ± 2 h after last MVP administration. Serum progesterone concentrations were subdivided into optimal (≥9.2 ng/ml) or suboptimal (<9.2 ng/ml) concentrations, and the cut-off point was defined according to our previous results. The primary objective was the correlation between progesterone concentrations on the day of embryo transfer and patient BMI, as a continuous variable and according to four ranges (underweight: <18.5 kg/m2; normal weight: 18.5-24.9 kg/m2; overweight: 25-29.9 kg/m2; and obesity: ≥30 kg/m2), according to the World Health Organization classification. Secondary objectives included the evaluation of reproductive outcome according to patient BMI and progesterone concentrations on the day of embryo transfer. RESULTS: Mean serum progesterone concentrations and the ratio of patients with progesterone concentrations above the cut-off point of 9.2 ng/ml fell progressively as BMI increased. Overweight and obese patients had lower mean serum progesterone concentrations than underweight and normal weight women (P < 0.001). A trend was observed towards impaired reproductive results in obese patients with suboptimal progesterone concentrations, absent when concentrations were optimal. CONCLUSIONS: Serum progesterone concentrations on the day of embryo transfer in artificial cycles with MPV decrease as BMI increases. It is highly recommended that serum progesterone concentrations are moitored to ensure optimal concentrations and reproductive outcomes.

BMI and miscarriage after IVF.

PURPOSE OF REVIEW: To summarize recent findings related to the risk of miscarriage in women with elevated BMI undergoing IVF, and the mechanisms involved in said risk. RECENT FINDINGS: Miscarriage rates are increased in overweight and obese women in both natural and assisted reproduction. Oocyte and embryo quality assessed according to classic morphological static parameters does not seem to be affected by excessive female body weight. Despite the initial lack of consensus between studies regarding embryo morphokinetics in obese women, blastocyst formation and quality have recently been shown to be similar across BMI groups, even in the case of euploid embryos. However, some metabolomic differences have been described in oocytes and embryos from obese women, thus pointing to a functional alteration. In women with elevated BMI, the percentage of aneuploid embryos is similar to that of normal weight women, and rates of miscarriage are higher, despite the transfer of euploid embryos. Therefore, the origin of the increased pregnancy loss rate after IVF in these women may be related to metabolomic, epigenetic or mitochondrial oocyte and embryo disturbances, or to the abnormal endocrine, metabolic and inflammatory uterine environment induced by obesity, which seems to be also responsible for other numerous complications during pregnancy and the in-utero fetal programming of postnatal diseases. A displacement of the window of implantation in obese women undergoing artificial endometrial preparation has recently been described and may be related to the poorer embryo implantation rates and increased risk of miscarriage observed following fresh and frozen embryo transfers with autologous oocytes, and with donated ova in recipients with extremely high BMI. SUMMARY: Female obesity is related to poorer outcome in natural and assisted conception, including an increased risk of miscarriage. Embryo morphology, assessed by conventional methods or by morphokinetics, does not seem to be affected by excess weight, with similar blastocyst formation and quality than normal weight women reported in IVF cycles. Embryo aneuploidy is not increased, and higher miscarriages rates are seen after euploid embryo transfer in obese women. Disturbances of the uterus or its environment induced by female obesity seem to be the most likely cause of the increased risk of miscarriage, although metabolomic, epigenetic or mitochondrial oocyte and embryo dysfunction cannot be ruled out as cannot congenital anomalies. In the context of all the above, weight reduction before pregnancy should be advised in obese women trying to become pregnant.

Similar reproductive outcomes between lesbian-shared IVF (ROPA) and IVF with autologous oocytes.

PURPOSE: To compare reproductive outcomes of the ROPA method (reception of oocytes from partner) to IVF with autologous oocytes. To study the impact of the absence of a genetic link between the embryo and its recipient in reproductive outcomes. METHODS: Retrospective multicentric cohort study performed from January 2011 to December 2020 in 18 fertility clinics in Spain. A total of 99 ROPA (73 couples) and 2929 non-ROPA cycles (2334 couples or single patients) of women younger than 38 years old with no known female fertility disorder were included. Clinical outcomes were compared between both groups and included positive pregnancy test, clinical pregnancy, miscarriage, ectopic pregnancy, pre-term birth, live birth, weeks of gestation at birth, and newborn weight at birth. RESULTS: No differences were found between groups in clinical outcomes. The total clinical pregnancy rates per embryo transfer were 57% and 50.2% (p = 0.15) and the live-birth rates were 46.1% and 40.9% (p = 0.14) for the ROPA and non-ROPA groups, respectively. When adjusted to age and BMI of donors and recipients, there were also no differences in live-birth rates between both groups. The cumulative live-birth rate per ROPA cycle was 73.7% and the cumulative live-birth rate per couple was 78.3%. CONCLUSION: Clinical outcomes following the ROPA method and IVF with autologous oocytes were found to be similar. These findings suggest no impact of the absence of genetic ties between the embryo and the uterus on reproductive treatments' outcomes. Data regarding the outcomes of the ROPA method are reassuring.

Blastocyst formation is similar in obese and normal weight women: a morphokinetic study.

STUDY QUESTION: Does the embryo cleavage pattern and rate of blastocyst formation differ between normal weight and obese women undergoing IVF? SUMMARY ANSWER: Embryo morphokinetic development, final blastocyst formation rate and blastocyst morphology do not differ between obese and normal weight women. WHAT IS KNOWN ALREADY: Female obesity has been related to impaired IVF outcomes. Although the mechanisms responsible for this detrimental effect are thought to include impaired oocyte and embryo quality and reduced endometrial receptivity, they are yet to be confirmed. Embryo quality has been commonly assessed using static morphological criteria. Only three studies have analysed the progress of embryos up to the blastocyst stage in women with elevated BMI, but they have used small samples of patients or have obtained contradictory results. STUDY DESIGN, SIZE, DURATION: This retrospective, cohort study, was performed from January 2016 to May 2020. A total of 3316 ICSI cycles from 2822 women were included, of which 1251 cycles were part of a preimplantation genetic testing programme. In total, 17 848 embryos were analysed. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study reports on the IVF cycles of infertile women, with a known BMI, who underwent ICSI and whose embryos were grown until the fifth/sixth day of development in a time-lapse system. Patients were grouped as follows. Underweight was defined as a BMI <18.5 kg/m2; normal weight was a BMI of 18.5-24.9 kg/m2; overweight was a BMI of 25-29.9 kg/m2; and obesity was a BMI of ≥30 kg/m2. Embryo development was assessed on an external computer with analysis software. MAIN RESULTS AND THE ROLE OF CHANCE: Despite an initial slower pattern of embryo development, the blastocyst formation rate on day 5 or on day 5 plus day 6 did not differ in obese women with respect to the other three BMI groups. Moreover, based on the evaluation of inner cell mass and the trophectoderm on both days of blastocyst development, embryo quality was similar across the BMI groups, as were the pattern of development and arrest up to blastocyst formation and the distribution of the categories of full, expanded and hatching blastocysts. LIMITATIONS, REASONS FOR CAUTION: Limitations include the retrospective analysis of data, the use of BMI as the only parameter to define normal/abnormal female body weight, and the lack of complete information about clinical outcomes. WIDER IMPLICATIONS OF THE FINDINGS: Blastocyst formation and embryo morphokinetics are not affected by female obesity, and the poorer IVF outcomes described for such women are probably due to deficient endometrial receptivity. The role of endometrial progesterone exposure on the day of embryo transfer should be analysed in future studies as a possible determining factor. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used and there are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Impact of low serum progesterone levels on the day of embryo transfer on pregnancy outcome: a prospective cohort study in artificial cycles with vaginal progesterone.

STUDY QUESTION: Is there a serum progesterone (P) threshold on the day of embryo transfer (ET) in artificial endometrium preparation cycles below which the chances of ongoing pregnancy are reduced? SUMMARY ANSWER: Serum P levels <8.8 ng/ml on the day of ET lower ongoing pregnancy rate (OPR) in both own or donated oocyte cycles. WHAT IS KNOWN ALREADY: We previously found that serum P levels <9.2 ng/ml on the day of ET significantly decrease OPR in a sample of 211 oocyte donation recipients. Here, we assessed whether these results are applicable to all infertile patients under an artificial endometrial preparation cycle, regardless of the oocyte origin. STUDY DESIGN, SIZE, DURATION: This prospective cohort study was performed between September 2017 and November 2018 and enrolled 1205 patients scheduled for ET after an artificial endometrial preparation cycle with estradiol valerate and micronized vaginal P (MVP, 400 mg twice daily). PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients ≤50 years old with a triple-layer endometrium ≥6.5 mm underwent transfer of one or two blastocysts. A total of 1150 patients treated with own oocytes without preimplantation genetic testing for aneuploidies (PGT-A) (n = 184), own oocytes with PGT-A (n = 308) or donated oocytes (n = 658) were analyzed. The primary endpoint was the OPR beyond pregnancy week 12 based on serum P levels measured immediately before ET. MAIN RESULTS AND THE ROLE OF CHANCE: Women with serum P levels <8.8 ng/ml (30th percentile) had a significantly lower OPR (36.6% vs 54.4%) and live birth rate (35.5% vs 52.0%) than the rest of the patients. Multivariate logistic regression showed that serum P < 8.8 ng/ml was an independent factor influencing OPR in the overall population and in the three treatment groups. A significant negative correlation was observed between serum P levels and BMI, weight and time between the last P dose and blood tests and a positive correlation was found with age, height and number of days on HRT. Multivariate logistic regression showed that only body weight was an independent factor for presenting serum P levels <8.8 ng/ml. Obstetrical and perinatal outcomes did not differ in patients with ongoing pregnancy regardless of serum P levels being above/below 8.8 ng/ml. LIMITATIONS, REASONS FOR CAUTION: Only women with MVP were included. Extrapolation to other P administration forms needs to be validated. WIDER IMPLICATIONS OF THE FINDINGS: This study identified the threshold of serum P as 8.8 ng/ml on the day of ET for artificial endometrial preparation cycles necessary to optimize outcomes, in cycles with own or donated oocytes. One-third of patients receiving MVP show inadequate levels of serum P that, in turn, impact the success of the ART cycle. Monitoring P levels in the mid-luteal phase is recommended when using MVP to adjust the doses according to the needs of the patient. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: NCT03272412.

Impact of chronic endometritis in infertility: a SWOT analysis.

Chronic endometritis is a pathology often associated with reproductive failure, but there are still no clear recommendations on whether its inclusion in the initial study of infertile couples is necessary. In this discussion paper, based on a SWOT (Strengths, Weaknesses, Opportunities, Threats) analysis, the different aspects of the repercussions of chronic endometritis in fertility are evaluated. To avoid possible subjectivity in the analysis and results of this study, the researchers followed the Oxford criteria for the evaluation of evidence. The results from the evaluation of the reviewed literature seem to indicate that, pending new evidence, it would be advisable not to include chronic endometritis in the initial baseline study before assisted reproduction in order not to delay other assisted reproduction treatments. However, it would be advisable in cases of repetitive implantation failure and pregnancy loss after having undergone IVF with viable embryos and before continuing with costly reproductive processes, since results could be improved. The development of randomized studies assessing the impact of antibiotic treatment as a possible therapeutic option in infertile women with chronic endometritis, as well as the possible impact on endometrial microbiota and receptivity/implantation, would allow for the establishment of more precise clinical guidelines in this regard.

Ovarian stimulation for oocyte vitrification does not modify disease-free survival and overall survival rates in patients with early breast cancer.

RESEARCH QUESTION: Does ovarian stimulation for oocyte vitrification affect disease-free survival and overall survival rates in women with early breast cancer? DESIGN: This cohort study included 259 patients with early breast cancer; 148 patients underwent ovarian stimulation, whereas 111 patients did not. Patients were treated between January 2008 and December 2016. To calculate the disease-free survival time and overall survival rate, the time of definitive surgery was defined as the starting point. The follow-up was conducted up to 5 years. RESULTS: Exposed and non-exposed groups were comparable in tumour, node and metastases classification, Nottingham grade, hormonal receptor status, tumour molecular phenotype, histology and pathology stage. The exposed group was younger than the non-exposed. Recurrences occurred in 9/148 women (6.1%) in the exposed group and 15/111 women (13.5%) in the non-exposed group, with no significant difference. The mean disease-free survival time was 63.9 months (95% confidence interval [CI]: 61.5-66.4) in the exposed group and 60.6 months (95% CI: 56.9-64.2) in the non-exposed, with no significant difference (log-rank [Mantel-Cox] test). Overall survival rates were comparable; 2/148 (1.4%) and 4/111 (3.6%) patients died, in exposed and non-exposed groups, respectively, during the period analysed. Mean overall survival times were 67.2 months (95% CI: 66.2-68.2) in the exposed group and 65.9 months (95% CI: 64.0-67.9) in the unexposed, with no significant difference (log-rank [Mantel-Cox] test). CONCLUSIONS: This study suggests that ovarian stimulation in patients with early-stage breast cancer is safe in the long term.

Second-generation preimplantation genetic testing for aneuploidy in assisted reproduction: a SWOT analysis.

Second-generation preimplantation genetic testing for aneuploidy (PGT-A 2.0) in patients with an unfavourable reproductive and IVF prognosis is becoming common practice, with the aim of improving reproductive outcomes. However, there is still no clear evidence on the possible advantages and drawbacks with regard to this procedure. In this discussion paper, based on a SWOT (strengths, weaknesses, opportunities, threats) analysis, the different aspects of this strategy are evaluated. Current evidence suggests that PGT-A 2.0 should not at present have an indiscriminate application, but it might be indicated in cases in which the risk of aneuploidy is increased.

Clinicopathological and Immunohistochemical Study of 14 Cases of Morbihan Disease: An Insight Into Its Pathogenesis.

INTRODUCTION: Morbihan disease (MORD) is rare with only 45 clear-cut cases previously reported. Histopathologic findings are supposed to be nonspecific. We report 14 patients and review the previous cases. OBJECTIVES: To characterize the clinicopathologic findings, outcomes, and immunophenotype of MORD. MATERIAL AND METHODS: Inclusion criteria were a clinical picture of persistent, nonpitting edema affecting the mid and or upper third of the face and histopathological findings fitting previous reports and exclusion of other entities. RESULTS: The majority of our patients were males (71.5%) with a male/female ratio of 10/4. The mean age when diagnosed was 58.8 years. Eyelids and forehead were the most frequently involved areas. Two of the patients presented previous rosacea. Most constant histopathological findings were lymphatic vessel dilatations in the upper dermis and the presence of mast cells (7.5 in 10 high-power field as a mean). Mild edema was also present in most of the cases. Granulomas were found in 7 of the cases, and immunostaining with CD68 and CD14 only revealed an additional case. CONCLUSIONS: MORD occurs more in middle-aged males, not associated with rosacea and mostly affects eyelids and forehead. Granulomas are not mandatory for the diagnosis. Histopathology of MORD fits within the spectrum of localized lymphedema.

GnRH antagonist for endometrial priming in an oocyte donation programme: a prospective, randomized controlled trial.

RESEARCH QUESTION: Can gonadotrophin releasing hormone (GnRH) antagonist be used in egg donation recipients with ovulatory cycles for the purpose of achieving synchronization between the donor´s and recipient´s cycle? DESIGN: Prospective randomized controlled trial to compare 7-day dosage of GnRH antagonist for endometrial priming in an oocyte donation programme with a single dose of long-acting GnRH agonist. A total of 563 women were randomized in a private single centre, and 473 women underwent embryo transfer. Ongoing pregnancy rate was the primary end point. Analysis was adjusted for embryonic stage at the time of embryo transfer; data collected included days on the waiting list; number of fresh-vitrified oocytes collected; and oocyte donor´s age at the time of retrieval. RESULTS: No statistically significant differences were found between groups in per intention-to-treat analysis: adjusted OR 1.42 (CI 0.97 to 2.09); per treatment received: adjusted OR 1.43 (CI 0.97 to 2.09); per embryo transfer: adjusted OR for ongoing pregnancy rate 1.47 (CI 1.01 to 2.13), P = 0.047. CONCLUSIONS: For women with ovulatory cycles undergoing oocyte donation, the outcomes are similar between GnRH antagonist and down-regulated hormone replacement protocols.

Implantation failure of endometrial origin: what is new?

PURPOSE OF REVIEW: To review recent findings related to possible causes of recurrent implantation failure of endometrial origin in normal uterus. RECENT FINDINGS: Recent evidences suggest that in apparently normal endometria, RIF may associate with molecular and functional changes in the uterus such as abnormal endometrial microbiota, including the presence of chronic endometritis, poor synchronization between the blastocyst and endometrium, and/or excessive uterine peristalsis. An altered endometrial microbiota detected by molecular techniques has been recently related to poorer embryo implantation, even in apparently normal endometria. The use of the endometrial receptivity analysis test to obtain an objective signature of endometrial receptivity has shown to improve the reproductive performance in RIF patients. The diagnosis of uterine peristalsis, however, remains challenging since the usual evaluation by transvaginal ultrasound is not accurate, and drugs tested to reduce uterine peristalsis and enhance embryo implantation have not been clearly beneficial. Finally, endometrial injury to improve implantation rates remains controversial being definitive well-designed trials needed to assess its benefit, if any. SUMMARY: In recurrent implantation failure of endometrial origin an altered pattern of the microbial endometrial ecosystem, a displaced window of implantation leading to desynchronization between the blastocyst and the endometrium, or an altered pattern of uterine contractions during embryo transfer may be factors to consider in our attempt to solve this clinical issue. New diagnostics for assessing these conditions and new therapies to improve these dysfunctional situations are currently under investigation to be presumably included in the near future in the work-up of affected patients.

Juvenile xanthogranuloma with angiomatous appearance and a peculiar immunophenotype.

Juvenile xanthogranuloma is the most common form of non-Langerhans cell histiocytosis in childhood. The clinical differential diagnosis of a solitary juvenile xanthogranuloma includes molluscum contagiosum, Spitz nevus, and melanoma. Lesions larger than 2 cm in diameter may be misdiagnosed as hemangiomas, but this is not typical of smaller juvenile xanthogranuloma. We report a case of solitary juvenile xanthogranuloma in a 10-year-old boy with angiomatous appearance and peculiar immunophenotype.

Polycystic ovary syndrome throughout a woman's life.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among reproductive-aged women and the main cause of infertility due to anovulation. However, this syndrome spans the lives of women affecting them from in-utero life until death, leading to several health risks that can impair quality of life and increase morbidity and mortality rates. Fetal programming may represent the beginning of the condition characterized by hyperandrogenism and insulin resistance which leads to a series of medical consequences in adolescence, adulthood, and old age. Menstrual and fertility problems evolve into metabolic complications as age advances. An early and precise diagnosis is important for an adequate management of PCOS, especially at the extreme ends of the reproductive lifespan. However, many different phenotypes are included under the same condition, being important to look at these different phenotypes separately, as they may require different treatments and have different consequences. In this way, PCOS exhibits a great metabolic complexity and its diagnosis needs to be revised once again and adapted to recent data obtained by new technologies. According to the current medical literature, lifestyle therapy constitutes the first step in the management, especially when excess body weight is associated. Pharmacotherapy is frequently used to treat the most predominant manifestations in each age group, such as irregular menses and hirsutism in adolescence, fertility problems in adulthood, and metabolic problems and risk of cancer in old age. Close surveillance is mandatory in each stage of life to avoid health risks which may also affect the offspring, since fetal and post-natal complications seem to be increased in PCOS women.

Primary dermal pleomorphic liposarcoma: utility of adipophilin and MDM2/CDK4 immunostainings.

Liposarcoma, usually arises in deep soft tissues and pleomorphic liposarcoma (PL), is the rarest histopathologic variant. However, 15 cases of entirely dermal PL have been reported. We describe a case of a 79-year-old man who developed a rapidly growing nodule on his thorax. Excisional biopsy was performed and immunohistochemical studies were carried. The lesion was a well-circumscribed dermal nodule composed of multivacuolated pleomorphic lipoblasts and atypical mitotic figures. Neoplastic cells expressed CD10 and resulted negative S100 protein, Melan-A, MITF-1, AE1/AE3, CD4, CD68 (PGM1), retinoblastoma gene family protein, pericentrine and lysozyme. Adipophilin stain showed the lipid contents in the cytoplasm of the neoplastic cells. MDM2 and CDK4 resulted both negative. A diagnosis of primary dermal PL was made. This case shows the utility of adipophilin immunostaining to prove the lipid contents in neoplastic cells, which has the advantage of using formalin-fixed paraffin-embedded tissue and making needless frozen sections and ultrastructural studies to show these findings. Negative MDM2/CDK4 staining in our case argues against the possibility of dedifferentiated liposarcoma and further supports the diagnosis of true PL.

Metformin-Induced Generalized Fixed Drug Eruption With Cutaneous Hemophagocytosis.

Fixed drug eruption (FDE) consists of recurrent dusky-red to brownish macules or patches at the same sites after the readministration of the causative drug. It usually presents as a solitary lesion, but generalized eruptions have been described. The most frequently implied drugs are antibiotics, anticonvulsants, and analgesics. Only 2 cases due to metformin have been reported. Histopathologic features of FDE include vacuolar degeneration of the basal layer, necrotic keratinocytes, and superficial and deep perivascular lymphocytic infiltrate. Cutaneous hemophagocytosis in the context of a FDE has not been previously reported. We describe the case of an 86-year-old man who developed a pruritic generalized macular eruption of reddish to violaceous patches. Skin biopsy was performed and the dermal infiltrate was immunohistochemically studied. Histopathology showed interface dermatitis with vacuolar degeneration of the basal layer, necrotic keratinocytes, and superficial and deep perivascular lymphohistiocytic infiltrate. In deep dermis, histiocytes with engulfed cells inside their cytoplasm were seen. Lymphoid enhancer binding factor 1 immunostain demonstrated that most of these cells were lymphocytes. We present the first case with cutaneous hemophagocytosis in the context of a metformin-induced generalized FDE. In this particular case, hemophagocytosis was just a histopathologic finding with no systemic consequences for the patient.

Anti-NXP2-Positive Paraneoplastic Dermatomyositis With Histopathologic Changes Confined to the Acrosyringia.

BACKGROUND: Paraneoplastic syndromes consist of a group of disorders that are not related to the extension of the primary tumor or its metastases and that might be the first manifestation of a hidden neoplasm. It is a well-known association between dermatomyositis (DM) and cancer, especially gynecological tumors in women and lung cancer in men. METHODS: We describe the case of a 67-year-old male who developed muscular weakness and pruritic skin lesions. Skin biopsies were performed and histologic findings were consistent with DM. RESULTS: Skin biopsy showed interface dermatitis with vacuolar degeneration of the basal layer, dermal mucin deposits, and necrotic keratinocytes in the acrosyringia, a finding that has been previously reported in lupus erythematous but not in DM. Autoimmunity tests showed positivity for antinuclear antibodies and anti-NXP2, a recently described antibody associated with juvenile DM and, more rarely, with paraneoplastic DM. CONCLUSION: We present the first case in the literature with histopathologic changes of DM affecting the acrosyringia. Besides, our patient autoimmunity results support the utility of the new myositis-specific autoantibodies and its relation with a clinical phenotype.

Strategies to manage refractory endometrium: state of the art in 2016.

The endometrium is one of a number of factors involved in achieving optimal outcomes after assisted reproductive treatment. Owing to its "passive" growth following adequate ovarian stimulation, it has received virtually no attention. Only when either endometrial thickness or ultrasonographic pattern seem inadequate have different strategies been assessed to try to improve it, especially in those cases where it seems difficult or impossible to make it grow. The objective of this review is to summarize the different strategies that have been investigated in patients with inadequate endometrium, to attempt to provide solid evidence of therapies that may be beneficial and to move away from empirism. A review of the existing literature was performed by searching MEDLINE, EMBASE, Cochrane library and Web of Science for publications in English related to refractory endometrium. Most current treatments are based on anecdotal cases and not on solid data, although worldwide many doctors and patients use them. In conclusion, this review found that it is not easy to provide a pragmatic, evidence-based approach to help physicians and patients confused by the available data on how to improve a poor endometrium. Honest balanced information provided to our patients is the best that we can do.