To transfer or not to transfer: the dilemma of mosaic embryos - a narrative review.

A frequent finding after preimplantation genetic diagnostic testing for aneuploidies using next-generation sequencing is an embryo that is putatively mosaic. The prevalence of this outcome remains unclear and varies with technical and external factors. Mosaic embryos can be classified by the percentage of cells affected, type of chromosome involvement (whole or segmental), number of affected chromosomes or affected cell type (inner mass cell, trophectoderm or both). The origin of mosaicism seems to be intrinsic as a post-zygotic mitotic error, but some external factors can play a role. As experience has increased with the transfer of mosaic embryos, clinical practice has gradually become more flexible in recent years. Nevertheless, clinical results show lower implantation, pregnancy and clinical pregnancy rates and higher miscarriage rates with mosaic embryo transfer when compared with the transfer of euploid embryos. Prenatal diagnosis is highly recommended after the transfer of mosaic embryos. This narrative review is intended to serve as reference material for practitioners in reproductive medicine who must manage a mosaic embryo result after preimplantation genetic testing for aneuploidies.

A 5-year multicentre randomized controlled trial comparing personalized, frozen and fresh blastocyst transfer in IVF.

RESEARCH QUESTION: Does clinical performance of personalized embryo transfer (PET) guided by endometrial receptivity analysis (ERA) differ from frozen embryo transfer (FET) or fresh embryo transfer in infertile patients undergoing IVF? DESIGN: Multicentre, open-label randomized controlled trial; 458 patients aged 37 years or younger undergoing IVF with blastocyst transfer at first appointment were randomized to PET guided by ERA, FET or fresh embryo transfer in 16 reproductive clinics. RESULTS: Clinical outcomes by intention-to-treat analysis were comparable, but cumulative pregnancy rate was significantly higher in the PET (93.6%) compared with FET (79.7%) (P = 0.0005) and fresh embryo transfer groups (80.7%) (P = 0.0013). Analysis per protocol demonstrates that live birth rates at first embryo transfer were 56.2% in PET versus 42.4% in FET (P = 0.09), and 45.7% in fresh embryo transfer groups (P = 0.17). Cumulative live birth rates after 12 months were 71.2% in PET versus 55.4% in FET (P = 0.04), and 48.9% in fresh embryo transfer (P = 0.003). Pregnancy rates at the first embryo transfer in PET, FET and fresh embryo transfer arms were 72.5% versus 54.3% (P = 0.01) and 58.5% (P = 0.05), respectively. Implantation rates at first embryo transfer were 57.3% versus 43.2% (P = 0.03), and 38.6% (P = 0.004), respectively. Obstetrical outcomes, type of delivery and neonatal outcomes were similar in all groups. CONCLUSIONS: Despite 50% of patients dropping out compared with 30% initially planned, per protocol analysis demonstrates statistically significant improvement in pregnancy, implantation and cumulative live birth rates in PET compared with FET and fresh embryo transfer arms, indicating the potential utility of PET guided by the ERA test at the first appointment.

Single-cell RNA sequencing of oocytes from ovarian endometriosis patients reveals a differential transcriptomic profile associated with lower quality.

STUDY QUESTION: Do oocytes from women with ovarian endometriosis (OE) have a different transcriptomic profile than those from healthy women? SUMMARY ANSWER: Oocytes from endometriosis patients, independently of whether they came from the affected ovary, exhibited a differential transcriptomic profile compared to oocytes from healthy egg donors. WHAT IS KNOWN ALREADY: Studies of endometriosis have sought to determine whether OE affects oocyte quality. While many reports indicate that oocytes recovered from endometriotic ovaries may be affected by the disease, other studies have found no significant differences among oocyte/embryo quality and fertilization, implantation and pregnancy rates in women with endometriosis. STUDY DESIGN, SIZE, DURATION: This prospective study compared metaphase II (MII) oocytes (n = 16) from endometriosis patients (n = 7) to oocytes (n = 16) from healthy egg donors (n = 5) by single-cell RNA sequencing (scRNA-seq). Participants were recruited between December 2016 and February 2018 at IVI-RMA Valencia and Vigo clinics. PARTICIPANTS/MATERIALS, SETTING, METHODS: Human MII oocytes were collected from healthy egg donors and OE patients aged 18-34 years, with a body mass index of <30 and >6 pre-antral follicles. RNA was extracted, cDNA was generated and libraries were constructed and sequenced. scRNA-seq data libraries were processed and statistically analysed. Selected genes were validated by quantitative real-time PCR. MAIN RESULTS AND THE ROLE OF CHANCE: Our scRNA-seq results revealed an effect of endometriosis on global transcriptome behaviour in oocytes from endometriotic ovaries. The highest number of differentially expressed genes (DEGs) was found when oocytes from women with OE were compared to oocytes from healthy donors [520 DEGs (394 upregulated and 126 downregulated)], independently of whether oocytes came from an affected or unaffected ovary. Among the top 20 significant DEGs in this comparison, most were upregulated, including APOE, DUSP1, G0S2, H2AFZ, ID4, MGST1 and WEE1. PXK was the only downregulated gene. Subsequently, functional analysis showed 31 enriched functions deregulated in endometriosis patients (Benjamini P < 0.1), being 16 significant enriched functions considering Benjamini P < 0.05, which involved in biological processes and molecular functions, such as steroid metabolism, response to oxidative stress and cell growth regulation. In addition, our functional analysis showed enrichment for mitochondria, which are an important cellular component in oocyte development. Other functions important in embryo development, such as angiogenesis and methylation, were also significantly enriched. LARGE SCALE DATA: All raw sequencing data are submitted in Gene Expression Omnibus (GEO) under accession number (PRJNA514416). LIMITATIONS, REASONS FOR CAUTION: This study was restricted only to OE and thereby other anatomical entities, such as peritoneal and deep infiltrating endometriosis, were not considered. This is a descriptive study with a limited number of samples reflecting the difficulty to recruit human oocytes, especially from women with endometriosis. WIDER IMPLICATIONS OF THE FINDINGS: This study suggests that OE exhibits a global transcriptomic effect on oocytes of patients in OE, independently if they come from an affected or unaffected ovary and alters key biological processes and molecular functions related to steroid metabolism, response to oxidative stress and cell growth regulation, which reduce oocyte quality. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by IVI Foundation, the Spanish Ministry of Economy and Competitiveness through the Miguel Servet programme (CPII018/00002 to F.D.), the Sara Borrell Program (CD15/00057 to H.F.) and the VALi+d Programe (Generalitat Valenciana); ACIF/2016/444 to A.C.). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: None.

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.

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.

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.

The human first cell cycle: impact on implantation.

The morphology of fertilization events has been related to successful implantation by subjective criteria (pronuclei score, pronuclei symmetry and position). This work first described these events by time-lapse technology and then compared the timings of fertilization events (second polar body extrusion, first and second pronuclei appearance, abuttal and fading) in implanted versus nonimplanted embryos in a 2-year cohort retrospective study. A total of 1448 transferred embryos from 842 patients undergoing intracytoplasmic sperm injection with oocyte donation were monitored, 212 embryos from treatments where the number of gestational sacs matched the number of transferred embryos and 687 embryos from treatments no biochemical pregnancy was achieved. The timings at which second polar body extrusion (3.3-10.6 h), pronuclear fading (22.2-25.9 h) and length of S-phase (5.7-13.8 h) occurred were linked successfully to embryo implantation. The other parameters were apparently not related, as determined by image acquisition and time-lapse analysis.

Reproductive outcomes of oocyte donation in patients with uterine Müllerian anomalies.

OBJECTIVE: To evaluate live-birth rates per embryo transfer in patients with uterine Müllerian anomalies (UMAs). Secondary objectives were to compare reproductive outcomes between the normal uterus group, the different UMA types, and UMA subgroups with and without required surgery. DESIGN: This retrospective study compared two cohorts, one with UMAs and other with normal uteri of our oocyte donation program at 12 Instituto Valenciano De Infertilidad/Reproductive Medicine Associates University affiliated clinics from January 2000 to 2020. The oocyte donation reduces confounding because of differences in embryo quality. The primary outcome was the live-birth rate per embryo transfer. Secondary outcomes included the rates of implantation, clinical pregnancy, miscarriage, and ongoing pregnancy. We calculated odds ratios with 95% confidence intervals. PATIENTS: Infertile women undergoing oocyte donation with UMAs. INTERVENTION: None. MAIN OUTCOME MEASURES: The rates of implantation, clinical pregnancy, miscarriage, ongoing pregnancy, and live birth. RESULTS: We analyzed 58,337 cycles of oocyte donation: 57,869 patients had no uterine malformation, and 468 women had UMAs. Compared with patients with normal uteri, patients with UMAs had lower rates of live births (36.67% [32.84-40.65] vs. 38.1% [95% confidence intervals {CI}: 37.82-38.42]) and ongoing pregnancy (39.74% [35.93-43.66] vs. 41.5% [41.24-41.83]). The miscarriage rate was higher in patients with UMAs (19.5% [16.55-22.85] vs. 16.6% [16.47-16.92]). Specifically, patients with a unicornuate uterus (n=29) had lower rates of implantation (24.07% [13.49-37.64] vs. 42.85% [95% CI: 42.6-43.09]), pregnancy (41.86% [27.01-57.87] vs. 59.51% [59.22-59.81]), ongoing pregnancy (16.67% [6.97-31.36] vs. 41.54% [41.24-41.83]), and live births (16.67% [6.97-31.36] vs. 38.12% [37.83-38.42]). In addition, patients with a partial septate uterus (n=91) had a higher miscarriage rate (26.50% [18.44-34.89] vs. 16.7% [16.47-16.92]). Compared with the normal uterus group, the live-birth rates were lower in the UMA without surgery group (33.09% [27.59-38.96] vs. 38.12% [37.83-38.42]). CONCLUSION: Among patients who received embryos derived from donated oocytes, live birth and ongoing pregnancy rates were lower in patients with UMAs compared with patients with normal uteri. A higher miscarriage rate was found in patients with UMAs. Patients with a unicornuate uterus had worse reproductive outcomes. Our results show that the uterus is less competent in patients with UMAs. TRIAL REGISTRATION: This study was registered at clinicaltrial.gov (NCT04571671).

The non-ergot derived dopamine agonist quinagolide in prevention of early ovarian hyperstimulation syndrome in IVF patients: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Ovarian hyperstimulation syndrome (OHSS) seems to be induced by the ovarian release of vascular endothelial growth factor (VEGF), which increases vascular permeability. Dopamine agonists inhibit VEGF receptor phosphorylation and thereby decrease vascular permeability. METHODS: A randomized, double-blind, placebo-controlled, multicentre study assessing three oral doses (50, 100, 200 microg/day) of the non-ergot derived dopamine agonist quinagolide started on the day of human chorionic gonadotrophin (hCG) and continued for 17-21 days without dose-titration in comparison to placebo in preventing moderate/severe early OHSS (onset < or =9 days after hCG administration) in 182 IVF patients with > or =20 but less than 30 follicles > or =10 mm. RESULTS: The incidence of moderate/severe early OHSS was 23% (12/53) in the placebo group and 12% (6/51), 13% (7/52) and 4% (1/26) in the quinagolide 50, 100 and 200 microg/day groups, respectively. The moderate/severe early OHSS rate was significantly lower with all quinagolide groups combined compared with placebo [P = 0.019; OR = 0.28 (0.09-0.81)]. The incidence of ultrasound evidence of ascites among patients with no clinical pregnancy was significantly reduced from 31% (8/26) with placebo to 11% (8/70) with all quinagolide groups combined [P = 0.033; OR = 0.29 (0.10-0.88)], although there was no difference for those with clinical pregnancy. Quinagolide did not have a detrimental effect on pregnancy or live birth rates. The incidence of gastrointestinal and central nervous system adverse events increased with increasing doses of quinagolide. CONCLUSIONS: Quinagolide appears to prevent moderate/severe early OHSS while not affecting treatment outcome. The effect is more marked in patients who did not achieve a clinical pregnancy. Quinagolide administered in high doses without dose-titration is associated with poor tolerability. ClinicalTrials.gov Identifier: NCT00329693.

Aromatase Inhibitors for Ovarian Stimulation in Patients with Breast Cancer.

BACKGROUND: Breast cancer is the most common malignancy diagnosed in women, and its treatment has a high probability of loss of fertility. Oocyte vitrification is the most commonly used technique to preserve fertility before starting oncological treatment. Aromatase inhibitors induce hypoestrogenemia while promoting the release of gonadotropins and constitute an alternative drug for ovarian stimulation in patients with breast cancer. OBJECTIVE: In this mini-review, we update and describe the current status of aromatase inhibitor use in controlled ovarian stimulation for oocyte vitrification in patients with breast cancer. RESULTS: Aromatase inhibitors are commonly used in combination with gonadotropins for ovarian stimulation in patients with breast cancer who preserve their fertility through oocyte vitrification. They achieve similar ovarian responses as conventional ovarian stimulation protocols in regards to the number of oocytes, and no additional complications after their use have been reported. Furthermore, aromatase inhibitors seem to be safe not only for offspring, as no more congenital defects occur in newborns from pregnancies achieved after their use, but also for the patients, as no more malignancy recurrence or increased mortality was found in cohort studies. CONCLUSION: Aromatase inhibitors are elective drugs for ovarian stimulation in patients with breast cancer who decide to preserve their fertility through oocyte vitrification.

The role of thrombophilia and thyroid autoimmunity in unexplained infertility, implantation failure and recurrent spontaneous abortion.

BACKGROUND: The role of thrombophilia and thyroid autoimmunity in unexplained infertility (UI), implantation failure (IF) and recurrent spontaneous abortion (RSA) is controversial and poorly understood. METHODS: From March, 2004 to January, 2007, 119 women were prospectively included: 32 oocyte donors, 31 patients with UI, 26 with IF and 30 with RSA. The IF and RSA groups presented normal preimplantation genetic screening. Protein C, protein S, antithrombin III, lupus anticoagulant, activated protein C resistance (APCR), immunoglobulin M and G anticardiolipin antibodies, homocystine, Factor V Leiden, prothrombin G20210A mutation, methylentetrahydrofolate reductase C677T mutation, thyroid-stimulating hormone (TSH), free thyroxine, anti-thyroid peroxidase (TPO) and anti-thyroglobulin (TG) antibodies were assessed. RESULTS: The prevalence of thrombophilia was high and similar among groups. In the IF group, the prevalence of APCR (15.4%), lupus anticoagulant (11.5%) and combined thrombophilia (19.2%) was higher, but not significantly different, than the other three groups. The prevalence of thyroid autoimmunity in women with IF (anti-TPO antibodies, P = 0.009; anti-TPO plus anti-TG antibodies,P = 0.04) and UI (anti-TPO, P = 0.002; anti-TG, P = 0.019; anti-TPO plus anti-TG antibodies, P = 0.005) was significantly increased in comparison to those with RSA. There was also a trend towards a higher prevalence of thyroid autoimmunity in the UI and IF groups than in the control group. TSH and free thyroxine levels all remained within a normal range. CONCLUSIONS: When embryo aneuploidy is ruled out, thrombophilia could constitute an etiologic factor in IF. Furthermore, thyroid autoimmunity is strongly related to UI and IF.

Relación entre la ubicación de la burbuja de aire en la transferencia embrionaria y las tasas de implantación y gestación evolutiva / Relationship between air bubble location at embryo transfer and implantation and ongoing pregnancy rates

Resumen OBJETIVO: Evaluar la relación entre la ubicación de la burbuja de aire que contiene los embriones y las tasas de implantación y de gestación clínica. El secundario: estudiar la relación entre la posición de la punta de la cánula, el grosor endometrial y el desplazamiento de la burbuja con esos desenlaces reproductivos. MATERIALES Y MÉTODOS: Estudio retrospectivo, observacional y de análisis de imágenes ecográficas de transferencias de embrión único en estadio de blastocisto practicadas por un mismo especialista en la Fundación IVI, Valencia, España, entre septiembre de 2013 y febrero de 2021. Criterios de selección: grosor endometrial ≥ 6 mm en el último control ecográfico, ausencia de miomas, IMC menor de 30 kg/m2, transferencias atraumáticas efectuadas por el mismo especialista. En función de la ubicación de la burbuja de aire se establecieron tres grupos de estudio (alta: mayor de 0.98 cm, media: 0.98 a 1.44 cm y baja: mayor de 1.44 cm) y para evaluar la asociación entre las categorías se aplicó el cálculo de razón de momios (OR) e IC95%. RESULTADOS: Se estudiaron 342 transferencias de embrión único. La edad media de las pacientes fue 39.70 ± 4.5 años. La relación entre la distancia de la burbuja de aire al fondo uterino y la tasa de implantación fue de 61 ± 9% en el grupo de ubicación alta, 64 ± 9% en el grupo de ubicación media, y de 56 ± 1% en el grupo de ubicación baja (p = 0.437). No se observaron diferencias en la tasa de gestación evolutiva analizada mediante probabilidad de ocurrencia entre grupos, con frecuencias de 0.60 en comparación con 0.64 (OR: 1.42; IC95%: 0.83 a 2.44; p: 0.199) y en la ubicación alta con media, y frecuencias de 0.60 en comparación con 0.56 (OR: 1.22; IC95%: 0.72-2.08; p: 0.462) entre alta y baja. CONCLUSIONES: No se encontró asociación entre la ubicación de la burbuja y las tasas de implantación y de gestación evolutiva. El mayor desplazamiento de la burbuja se asoció con mayores tasas de gestación evolutiva.

Abstract OBJECTIVE: To evaluate the relationship between the location of the air bubble containing the embryos and the implantation and clinical gestation rates. Secondary: to study the relationship between the position of the cannula tip, the endometrial thickness and the displacement of the bubble with these reproductive outcomes. MATERIALS AND METHODS: Retrospective, observational, ultrasound image analysis study of single embryo transfers at blastocyst stage performed by the same specialist at the IVI Foundation, Valencia, Spain, between September 2013 and February 2021. Selection criteria: endometrial thickness ≥ 6 mm at the last ultrasound control, absence of fibroids, BMI less than 30 kg/m2, atraumatic transfers, performed by the same specialist. Based on the location of the air bubble, three study groups were established (high: greater than 0.98 cm, medium: 0.98 to 1.44 cm and low: greater than 1.44 cm) and the odds ratio (OR) and 95%CI were used to evaluate the association between the categories. RESULTS: A total of 342 single embryo transfers were studied. The mean age of the patients was 39.70 ± 4.5 years. The relationship between the distance of the air bubble to the uterine fundus and the implantation rate was 61 ± 9% in the high placement group, 64 ± 9% in the medium placement group, and 56 ± 1% in the low placement group (p = 0.437). No differences were observed in the evolutionary gestation rate analyzed by probability of occurrence between groups, with frequencies of 0.60 compared to 0.64 (OR: 1.42; 95%CI: 0.83 to 2.44; p: 0.199) and high to medium location, and frequencies of 0.60 compared to 0.56 (OR: 1.22; 95%CI: 0.72-2.08; p: 0.462) between high and low. CONCLUSIONS: No association was found between the air bubble localization and implantation or ongoing pregnancy rates. However, a greater displacement of the bubble was associated with higher ongoing pregnancy rates.

Study of nucleation status in the second cell cycle of human embryo and its impact on implantation rate.

OBJECTIVE: To study nucleation status in two- and four-cell embryos and its effect on reproductive outcomes. DESIGN: Retrospective cohort study. SETTING: University-affiliated private center. PATIENT(S): A total of 1,679 embryos from 940 oocyte donation cycles from May 2012 to May 2014. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Implantation, morphokinetics, and nucleation status restoration. RESULT(S): Multinucleation was present in 42.53% of embryos with known implantation data at the two-cell stage; it was present in approximately 14% of them at the four-cell stage. In all, 73.4% of the embryos were multinucleated at two cells and restored their nucleation status when they cleaved into four cells. Embryos with blastomeres multinucleated (more than two nuclei) at the four-cell stage showed a lower implantation rate. The average length of S-phase in the first embryo cell cycle in the positive known implantation data (KID+) embryos was longer than in KID- (15.50 hours vs. 14.38 hours) and slightly shorter in the second embryo cell cycle (8.35 hours in KID+ vs. 8.60 hours in KID-). CONCLUSION(S): Multinucleation in two-cell-stage embryos is a frequent event, which is reversible in a high proportion of embryos, without impact on the implantation rate; and embryos with multinucleated blastomeres have a reduced outcome compared with those with binucleated blastomeres when multinucleation is present in four-cell-stage embryos.

Ovarian stimulation in patients with breast cancer.

Breast cancer is the most prevalent malignancy among women under 50. Improvements in diagnosis and treatment have yielded an important decrease in mortality in the last 20 years. In many cases, chemotherapy and radiotherapy develop side effects on the reproductive function. Therefore, before the anti-cancer treatment impairs fertility, clinicians should offer some techniques for fertility preservation for women planning motherhood in the future. In order to obtain more available oocytes for IVF, the ovary must be stimulated. New protocols which prevent exposure to increased estrogen during gonadotropin stimulation, measurements to avoid the delay in starting anti-cancer treatment or the outcome of ovarian stimulation have been addressed in this review. There is no evidence of association between ovarian stimulation and breast cancer. It seems that there are more relevant other confluent factors than ovarian stimulation. Factors that can modify the risk of breast cancer include: parity, age at full-term birth, age of menarche, and family history. There is an association between breast cancer and exogenous estrogen. Therefore, specific protocols to stimulate patients with breast cancer include anti-estrogen agents such as letrozole. By using letrozole plus recombinant follicular stimulating hormone, patients develop a multifollicular growth with only a mild increase in estradiol serum levels. Controlled ovarian stimulation (COS) takes around 10 days, and we discuss new strategies to start COS as soon as possible. Protocols starting during the luteal phase or after inducing the menses currently prevent a delay in starting ovarian stimulation. Patients with breast cancer have a poorer response to COS compared with patients without cancer who are stimulated with conventional protocols of gonadotropins. Although many centres offer fertility preservation and many patients undergo ovarian stimulation, there are not enough studies to evaluate the recurrence, breast cancer-free interval or mortality rates in these women.

Oocyte donation outcome after oncological treatment in cancer survivors.

OBJECTIVE: To study reproductive outcome in patients cured of cancer who required oocyte donation (OD) owing to iatrogenic ovarian dysfunction. DESIGN: Multicenter, unmatched, retrospective cohorts study. SETTING: Private, university-affiliated group of clinics. PATIENT(S): Women treated and cured of cancer (n = 142) who underwent 333 cycles of OD (exposed group) and women without a previous cancer diagnosis (n = 17,844) who underwent 29,778 cycles of OD (unexposed cohort) between January 2000 and January 2012. INTERVENTION(S): Retrospective chart review. MAIN OUTCOME MEASURE(S): Pregnancy, implantation, miscarriage, and ongoing pregnancy rates. RESULT(S): There were no differences in terms of pregnancy (55.7% vs. 54.7%), implantation (39.8% vs. 38.2%), miscarriage (29.5% vs. 26.9%), or delivery rates (39.3% vs. 39.9%) between the unexposed group and the patients previously diagnosed and cured of cancer, respectively. There was no correlation between OD outcome and cancer type. CONCLUSION(S): Endometrial receptivity in women treated and cured of cancer was comparable to that of general patients without previous malignancies who had received OD, based on the largest series available in the literature.

Treatment of luteal phase defects in assisted reproduction.

Abnormal luteal function is a common issue in assisted reproduction techniques associated with ovarian stimulation probably due to low levels of LH in the middle and in the late luteal phase. This defect seems to be associated with supraphysiological steroid levels at the end of follicular phase. The luteal phase insufficiency has not got a diagnostic test which has proven reliable in a clinical setting. Luteal phase after ovarian stimulation becomes shorter and insufficient, resulting in lower pregnancy rates. Luteal phase support with progesterone or hCG improves pregnancy outcomes and no differences are found among different routes of administration. However, hCG increases the risk of ovarian hyperstimulation syndrome. In relation to the length of luteal support, the day of starting it remains controversial and it does not seem necessary to continue once a pregnancy has been established. After GnRHa triggering ovulation, intensive luteal support or hCG bolus can overcome the defect in luteal phase, but more studies are needed to show the LH utility as support.

The role of LH in ovarian stimulation.

LH is a glycoprotein that plays a crucial role in folliculogenesis during the natural ovarian cycles. It has the same activity and shares receptors with hCG. However the use of LH in combination with FSH in controlled ovarian stimulation remains controversial. A practical approach concerning the usefulness of LH according to the endogenous level of LH is described herein. Specific groups of patients can benefit from ovarian stimulation with LH. New applications of LH/hCG activity are also discussed.

Ovarian response to controlled ovarian hyperstimulation in cancer patients is diminished even before oncological treatment.

OBJECTIVE: To evaluate the results of controlled ovarian stimulation before chemotherapy for oocyte vitrification to preserve fertility in women diagnosed with cancer and compare them with a historical control group. DESIGN: A retrospective, multicenter, observational study performed between March 2007 and January 2011. SETTING: University-affiliated infertility clinics. PATIENT(S): Of 272 patients affected by cancer in our Fertility Preservation Program, 223 women underwent a stimulated cycle for oocyte vitrification according to our protocols before cancer treatment. Their results were compared with a historical control group of 98 patients diagnosed with male factor infertility who were stimulated for a conventional IVF cycle. INTERVENTION(S): Controlled ovarian stimulation and oocyte retrieval. MAIN OUTCOME MEASURE(S): Days of stimulation, total dose of gonadotropins, estrogen levels, and number of oocytes retrieved and vitrified. RESULT(S): No differences were found in days of stimulation, but significant differences in E(2) levels and the number of retrieved oocytes were measured, especially in the hormone-dependent cancer group. CONCLUSION(S): Patients with hormone-dependent cancer had a weaker response to controlled ovarian stimulation compared with patients with non-hormone-dependent cancer. Whether the oncological disease already affects the ovaries before chemo-/radiotherapy remains to be elucidated.

Intravenous albumin does not prevent moderate-severe ovarian hyperstimulation syndrome in high-risk IVF patients: a randomized controlled study.

BACKGROUND: Intravenous albumin administration has been described for many years as a debatable, but probably useful preventive measure in ovarian hyperstimulation syndrome (OHSS). The present study details the largest randomized controlled trial to date of albumin infusion versus no treatment in IVF patients with a high risk of developing moderate to severe OHSS. METHODS: Between March 1999 and February 2002, women undergoing IVF at the IVI Valencia with >20 retrieved oocytes were included. A total of 988 patients was initially enrolled. Immediately after oocyte retrieval, patients were allocated to two groups based on a computer randomization: the first group received 40 g human albumin; the second group received no treatment. Subjects were weighed and a blood analysis performed immediately after oocyte retrieval and again 7 days later. Women were monitored on an outpatient basis until menstruation, or until fetal heart activity was detected. Twelve subjects were excluded due to follow-up loss, leaving 976 women (377 of them oocyte donors), with 488 in each group. RESULTS: No difference was found between the two groups in terms of patient characteristics and outcome. Moderate-severe and severe-only OHSS rates were similar. The incidence of haemoconcentration and liver and renal dysfunction at 7 days after oocyte retrieval was similar in the two groups. In women who developed moderate/severe (n = 66) or only severe (n = 46) OHSS, there was no difference based on prior albumin administration between blood parameters or body weight on the day of oocyte retrieval, 7 days later, and even when comparing variation between both measurements. Moreover, the number of patients with paracentesis, hospital admissions, complications and days of OHSS until resolution did not differ. CONCLUSIONS: Albumin infusion on the day of oocyte retrieval is not a useful means of preventing the development of moderate-severe OHSS.