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The aim of this study was to evaluate the risk of preeclampsia in women of advanced age who conceived through donated oocytes as compared with natural conceptions. A historical prospective study of singleton live births of parturients ≥ 45 years of age at four university hospitals was conducted. For the purpose of the study, the population was divided by the mode of conception into two groups: oocyte donation and natural conception. The main outcome variable in this study was preeclampsia. Secondary outcomes included pregnancy-induced hypertension and Small for Gestational Age. Two hundred and seventy pregnancies were achieved naturally and 135 women conceived by oocyte donation. Mean age at delivery for the natural conception and oocyte donation groups was 45.7 and 47.8, respectively. Preeclampsia complicated 3 out of 270 (1.1%) natural conception pregnancies and 17 out of 135 (12.6%) oocyte donation conceptions. After adjusting for confounders, oocyte donation pregnancies were found to be associated with a 12-fold increased risk for preeclampsia (P = 0.001). Among oocyte donation pregnancies, the risk of preeclampsia was not affected by parity or age. A substantially increased risk for preeclampsia was found in oocyte donation pregnancies, suggesting that the foreign oocyte may play a specific biologic role in the development of preeclampsia after the age of 45.

To look into current evidence exploring the added value of rLH supplementation to rFSH in GnRH analogues cycles, to identify groups of women that still have no evidence for adjuvant rLH therapy and to discuss ways that may advance research on this topic.Eight systematic reviews and meta-analyses exploring the benefit for pregnancy achievement of rLH supplementation, excluding other LH activity preparations, to GnRH analogues cycles in the ART setting were thoroughly evaluated.Evidence exists to show that rLH supplementation seems to have added value for pregnancy achievement in women with poor ovarian response and in women ≥35 years of age employing the GnRH agonist protocol, while the evidence is still debatable when the GnRH antagonist is administered. In the general infertile population, rLH supplementation does not have added value in the GnRH-antagonist cycles while the evidence is still controversial when the GnRH agonist is employed. Whether rLH supplementation may have a benefit in some young, normo-gonadotropic women, who may develop LH deficiency following GnRH analogues, is still to be shown. The main task remains how to identify subgroups of women that may benefit from rLH supplementation.An accurate definition of the LH threshold in GnRH analogue treated cycles may contribute to the discussion of which subgroups of women may benefit from adjuvant rLH therapy.

Research question Current knowledge of cancer risk among women who undergo IVF is based mainly on studies of women treated in their thirties, frequently with short follow-up periods. Therefore, information about cancer risk among infertile menopausal women is limited. We aimed to evaluate the risk of cancer among IVF patients treated at age 40 years and older, followed up for an extended period. Design Historical cohort study of all IVF patients treated at the age of 40 years or older at two university-affiliated IVF units in Jerusalem, Israel, between 1994 and 2002. Data were cross-linked with the Israel National Cancer Registry to 2016. Standardized incidence ratios (SIR) and 95% confidence intervals were computed by comparing the observed number of cancer cases with the expected cancer rate in the general Israeli population adjusted for age and year of birth. In addition, Kaplan–Meier analysis was conducted to account for the length of follow-up. Results A total of 501 patients were included in the analysis, with mean follow-up of 16.7 ± 3.7 years (range 2–22 years). Mean age at first IVF cycle was 42.3 years (±2.1). Mean number of IVF cycles was 3.2 ± 2.6 (range 1–15). Thirty-six women (7.2%) developed invasive cancer, compared with 47.2 expected cases; SIR 0.76 (95% CI 0.53 to 1.06); 22 women were diagnosed with invasive breast cancer, compared with 19.84 expected; SIR 1.11 (95% CI 0.69 to 1.68). Conclusions Older women undergoing IVF treatment were not significantly associated with an excess risk of cancer at long-term follow up. Further studies, however, are needed to confirm these findings.

This monograph, written by the pioneers of IVF and reproductive medicine, celebrates the history, achievements, and medical advancements made over the last 40 years in this rapidly growing field.

Context: Delay in maternal age at first birth is a significant demographic trend. Concomitantly, an extensive body of literature attempts to elucidate the observed associations between late-age childbearing and longevity. It is essential to assess individual patients’ potential for extended fertility and to convey the health consequences of childbearing at a later age.

Deleterious mutations in BRCA1 or BRCA2 genes have long been recognized as independent risk factors, mostly for breast and ovarian cancer. Numerous studies have evaluated the molecular processes involving these genes, the pathophysiology of BRCAness, follow up options and modes of prophylaxis. The fertility of BRCA carriers, however, has not been widely investigated. The aim of the present work is to review the literature pertaining to this issue.

Infertility has been increasingly recognized as a possible biomarker for cancer risk. There is significant data linking these two seemingly disparate diseases in infertile men and burgeoning data linking them in infertile women. Here we investigate the possible mechanisms whereby one shared genetic or epigenetic insult could confer increased risk for both infertility and cancer.

Aging is characterized by reduced tissue regenerative capacity attributed to a diminished responsiveness of tissue-specific stem cells. With increasing age, resident precursor cells in muscle tissues show a markedly impaired propensity to proliferate in response to damage. However, exposure to factors present in the serum of young mice restores the regenerative capacity of aged precursor cells. As pregnancy represents a unique biological model of a partially shared blood system between young and old organisms, we hypothesized that pregnancy in aged mice would have a rejuvenating effect on the mother. To test this hypothesis, we assessed muscle regeneration in response to injury in young and aged pregnant and nonpregnant mice. Muscle regeneration in the aged pregnant mice was improved relative to that in age-matched nonpregnant mice. The beneficial effect of pregnancy was transient, lasting up to 2 months after delivery, and appeared to be attributable to activation of satellite cells via the Notch signaling pathway, thus supporting the possibility that pregnancy induces activation of aged dormant muscle progenitor cells.

Successful embryo implantation depends on a well-functioning endometrium as well as a normal healthy embryo. This process might be hampered if either of these variables is defective. Repeated implantation failure (RIF) is diagnosed when good-quality embryos repeatedly fail to implant after transfer in several IVF treatment cycles. The causes of RIF originate with either the mother or the embryo. The authors discuss factors that are associated with RIF and address various treatment options.

Objective: To investigate the workup/treatment provided to pregnant motor vehicle accident (MVA) casualties in a mature trauma system. Adherence to recommendations was used to measure quality of care. Background: MVAs affect approximately 3% of pregnant women. Trauma casualty outcome improves after implementation of guidelines. Methods: A 5-year audit of clinical practice in 2 university hospitals with a trauma call system where the general surgeon is the primary care physician. Trauma guidelines (general/specific to treatment of pregnant MVA casualties) were used to examine adherence. Pregnant casualties aged >18 years, injured in a private vehicle were identified via computerized hospital databases. Data relevant to the study were extracted from ED/admission files. Results: Among the 236 casualties included there were no maternal deaths. Six casualties (2.5%) had significant injuries and 3 (1.2%) required surgery (all within 24-hours of admission). Contrary to established procedure, maternal vital signs were often not documented. In contrast, fetal viability was usually documented; most casualties underwent ultrasound fetal evaluation (233 of 236, 98.7%) and those with viable pregnancies underwent fetal heart rate monitoring (162 of 169, 96%). A sixth of the MVA casualties (16%) were examined only by an obstetrician. All casualties were admitted but only 15 (6.4%) were admitted in accordance with guidelines. Readmission rates (1.3%) were similar to those observed in nonpregnant casualties. Conclusions: Pregnant MVA casualties are underexamined and overadmitted. Concerns regarding potential obstetrical complications distract medical attention away from basic trauma guidelines. Education programs should emphasize prioritizing the mother and adhering to the basic rules of trauma care despite the presence of the fetus. (Ann Surg 2011;254:346–352)

Ambiguous feelings regarding women engaging in formal volunteering and concerns about their exploitation might explain the dearth of studies regarding the volunteering benefits specifically experienced by low socioeconomic status women. The current study examined benefits of volunteering among women participating in Women for Women's Health (WWH), a lay health volunteers (LHV) programme implemented in Jewish and Arab communities in Israel, and aiming at empowering such women to become active volunteers and promote health activities in their communities. Two years after the introduction of WWH in each community, all 45 Jewish and 25 Arab volunteers were contacted by phone and invited to participate in the focus group discussions. Five focus group discussions were conducted with 25/42 Jewish volunteers in 2003 and four with 20/25 Arab volunteers in 2005. The other volunteers could not attend the scheduled meetings or became inactive for personal reasons. Four benefit categories were identified in both ethnic groups: 1. Personal benefits of having increased knowledge, feeling self-satisfaction, mastering new skills and performing healthy behaviours; 2. Group-social benefits of social support and sense of cohesion; 3. Purposive benefits of achieving the WWH mission and goals; 4. Sociopolitical benefits of learning to accept the other and experiencing increased solidarity. However, the relatively less privileged Arab volunteers enumerated more benefits within the personal and purposive categories. They also identified the unique sociocultural category of improving women's status in the community by creating a legitimate space for women by public sphere involvement, traditionally solely a male domain. We conclude that volunteering in community-based health promotion programmes can be an empowering experience for lay women without being exploitative. Positive volunteering benefits will be even more discernable among underprivileged women who enjoy fewer opportunities in the personal and public domains. More studies need to explore volunteering benefits as reported by LHVs, making these benefits more visible and desirable.

Contemporary preoperative team briefings conducted to improve patient safety focus mainly on supplying identification details regarding the patient and the surgical procedure. Drawing on cognitive theory principles, in this study a briefing protocol was developed that presents a broader perspective model of the patient and the planned procedure. In addition to customary identification details and drug sensitivities, the new briefing also includes review of significant background information, needed equipment, planned surgery stages, and so forth. The briefing content was developed following 130 continuous, nonstructured observations conducted in gynecologic and orthopedic operating rooms. The briefing form was designed as a large poster hung in a visible position on the operating room wall. The poster guides the team members (ie, nurses, surgeons, and anesthesiologists) in their conduct. Briefing is conducted orally, and no written records are required. The number of nonroutine events (ie, situations that, if not corrected, might lead to patient harm) observed in the 130 surgeries conducted without briefing was compared with the number of events in 102 surgeries in which briefing was conducted. There was a 25% reduction in the number of nonroutine events when briefing was conducted and a significant increase in the number of surgeries in which no nonroutine event was observed. Team members evaluated the briefing as most valuable for their own work, the teamwork, and patient safety. Following the study, the new briefing format was accepted and adopted for routine use. Team briefings designed to supply a broader-perspective surgery model may be an easy-to-apply tool to reduce the number of nonroutine events during surgery and increase patient safety.

Objective To assess whether supplementation with hCG throughout the secretory phase of hormonally modulated cycles of frozen-thawed embryos might positively affect the outcome of such cycles. Design Prospective, randomized controlled trial. Setting University teaching hospital. Patient(s) Patients undergoing frozen-thawed embryo transfer cycles. Intervention(s) Patients were randomly divided into two groups by the last digit of their identification number. Group A received our standard protocol for endometrial preparation, whereas group B patients were given an additional 250 μg of recombinant hCG on day of P initiation, the day of embryo transfer, and 6 days later. Throughout the cycle, and to compare between the groups, serial ultrasound examinations and hormonal tests of E 2 and P serum levels were obtained. Main Outcome Measure(s) Implantation and clinical pregnancy rates (PR). Result(s) One hundred sixty-five patients were enrolled in this study, 78 in the control group and 87 in the hCG-treated group. Progesterone levels and endometrial thickness were similar throughout the cycle in both groups. The E 2 level was significantly higher in group B on the day of embryo transfer and 6 days later. The PRs did not differ between the two groups (28.2% and 32.2% for groups A and B, respectively). Similarly, the implantation rates were comparable between the groups (12.7% and 14.9%, respectively). Conclusion(s) No advantage was found concerning PR and implantation rate by supplementing the secretory phase with hCG in patients undergoing transfer of frozen-thawed embryo in hormonally modulated cycles.

The objective of the current report was to provide a summary of knowledge concerning the treatment of women with poor ovarian response with androgens and androgen modulating agents. This involved a review of the literature. The literature search was performed using PubMed. Information concerning the role of androgens and androgen modulating agents in treating women with poor ovarian response is limited. The search of the literature yielded five studies and one case report concerning the treatment of poor responders with androgens. The variations in patient selection, type of androgens employed and the different duration of exposure preclude drawing any definite conclusions. Aromatase inhibitors block the conversion of androgens to oestrogens, thereby promoting an androgen-rich intrafollicular environment. The evidence presented in this review suggests a potential beneficial role for the use of aromatase inhibitors in treating women who have previously experienced failure of standard IVF protocols. The optimal dose and duration of this treatment is yet to be determined. Although the results of studies concerning LH supplementation in poor responders are conflicting, the latest Cochrane review on the use of recombinant LH for ovarian stimulation supports its use in poor responders, based on pooled pregnancy estimates.

Objective To determine whether oocyte retrieval and in vitro maturation (IVM) is effective in girls undergoing fertility preservation before cancer treatment. Design Cohort study. Setting Tertiary university medical center. Patient(s) Patients ≤20 years old before gonadotoxic chemotherapy undergoing ovarian cortex cryopreservation. Intervention(s) Before ovarian cortex cryopreservation, oocytes in all observed follicles were aspirated, matured in vitro, and cryopreserved. Main Outcome Measure(s) Maturation of oocytes. Result(s) One hundred seventy-nine oocytes were detected in 17/19 patients (89%) aged 5–20 years. We found 7, 8, and 17 oocytes in patients 5, 8, and 10 years old, respectively. The median number of oocytes per patient was 9 (0–37). Maturation rate was 45/133 oocytes (34%). In total, 81 oocytes were cryopreserved. We cryopreserved 4 of 12 detected, 4 of 9 detected, 1 of 8 detected, and 4 of 9 detected IVM oocytes for patients aged 5–10, 11–14, 15–17, and 18–20 years old, respectively. Conclusion(s) Patients undergoing ovarian cryopreservation could benefit from supplementary oocyte aspiration from the cortex. Surprisingly, oocytes were detected even in young premenarcheal girls. The number of oocytes detected, matured, and cryopreserved was not age dependent. Retrieved oocytes can be matured in vitro and cryopreserved. Because no pregnancy has yet resulted from this procedure it should be considered to be experimental. We describe the youngest patients to undergo ovum collection, IVM, and oocyte cryopreservation.

Objective To describe our 2-year experience with preimplantation genetic diagnosis (PGD) for carriers of mutations in the genes BRCA1 and BRCA2, the dilemmas incurred and the lessons learned. Methods We collected data on those carriers of BRCA1/2 mutations who applied for PGD counseling and who decided to proceed. We describe the PGD procedures that were conducted and their outcome. Results Ten carriers of BRCA1/2 mutations applied for PGD counseling, seven were healthy, and three were BC survivors. Eight women needed in vitro fertilization (IVF) because of coexisting infertility. After counseling, six opted for the procedure and five of them underwent PGD for the BRCA mutation. In one of these PGD, fluorescence in situhybridization (FISH) analysis for chromosomes 21, X and Y was also performed. Three women conceived, each in the first treatment attempt. One of them gave birth to twins, the second to a singleton and the third is currently pregnant. During the pregnancies, dilemmas concerning PGD confirmation were discussed. Conclusions PGD is an acceptable reproductive option for BRCA mutation carriers, especially for those who require IVF due to fertility problems. Discussion of this option should be carried out with sensitivity, taking into account the age of the woman, her health, fertility status and emotional state. Confirmatory prenatal diagnosis may not always be encouraged. Copyright © 2009 John Wiley & Sons, Ltd.

The tendency to postpone childbearing in developed countries and the relatively high rate of infertility in older women contribute to an increase in the portion of women aged 40 years and older opting for infertility treatments. The main factor for infertility in this group is oocyte senescence, but since this process does not have a specific diagnosis many of those will be classified as having 'unexplained infertility'. The efficacy of the traditional clinical approach for 'unexplained infertility' in older women is questionable. Reviewing the current literature, clomiphene citrate seems to be inefficient in this group of patients, while delivery rates of gonadotrophins and intrauterine insemination cycles are less than 5%. Although low in absolute terms, IVF is more efficient. The chance for delivery, however, diminishes with each year of age above 40. Therefore, after a short trial of gonadotrophins and intrauterine insemination, women aged 40-41 years should be quickly referred to IVF. At an older age, IVF is the primary treatment option.

Objective To compare mitochondrial function in granulosa cells obtained from older (>40 y) low-responder IVF patients with that of young ( Design Prospective laboratory research. Setting In vitro fertilization unit in a university hospital. Patient(s) Twenty patients undergoing IVF treatment cycles. Intervention(s) Ultrasound guided oocytes pick-up. Main Outcome Measure(s) Mitochondrial function examined by using JC-1 stain for the mitochondrial membrane potential in granulosa cells of both groups and Western blots for assaying and quantification of steroidogenic acute regulatory protein (StAR) and p450scc (side-chain cleavage). Result(s) The number of granulosa cells per follicle differed between the two groups, with fewer granulosa cells isolated in the older low-responder women, compared with in the young, normal responders who were the control women. Trypan blue–negative cells showed similar undisturbed mitochondrial membrane potential, and similar ratios of apoptotic granulosa cells were observed in the two groups. In addition, there was no difference in StAR and P450scc protein levels between the two groups. Conclusion(s) Our results demonstrate a significant decrease in the number of total aspirated granulosa cells per follicle in older, poor-responder women, which probably explains the reduced hormonal production by those follicles. However, those cells demonstrate normal mitochondrial membrane potential as well as similar levels of StAR, P450scc, and de novo steroid hormone synthesis in the two groups of patients. Our results do not support mitochondrial dysfunction as a main mechanism of reproductive aging.

OBJECTIVE: To characterize the injuries incurred by involvement in terror-related multiple casualty incidents (TR-MCIs) during pregnancy and describe the maternal and fetal outcomes. METHODS: Retrospective (January 1, 2001-December 31, 2003), descriptive, multicenter study of all pregnant women injured in TR-MCIs. RESULTS: Twelve pregnant women (singletons, gestational age 20.6 +/- 10.5 weeks) who were injured during the study period. One victim was intubated on location of the event, another was hemodynamically compromised upon arrival. All women survived. Seven women required surgical intervention with general anesthesia. Four of the five women with viable pregnancies required cesarean delivery within minutes to hours of arrival. Three of these fetuses were delivered in extremis and one died. CONCLUSIONS: Women with a viable pregnancy who have been injured in TR-MCIs have a high incidence of surgical procedures and a high likelihood of undergoing cesarean delivery within minutes to hours of injury. Fetal outcome may be poor under these circumstances. Language: en

Background Human embryonic stem cells (hESCs) suitable for future transplantation therapy should preferably be developed in an animal-free system. Our objective was to develop a laser-based system for the isolation of the inner cell mass (ICM) that can develop into hESC lines, thereby circumventing immunosurgery that utilizes animal products. Methods Hatching was assisted by micromanipulation techniques through a laser-drilled orifice in the zona pellucida of 13 abnormal preimplantation genetic diagnosed blastocysts. ICMs were dissected from the trophectoderm by a laser beam and plated on feeders to derive hESC lines. Results eight ICMs were isolated from nine hatched blastocysts and gave rise to three hESC lines affected by myotonic dystrophy type 1, hemophilia A and a carrier of cystic fibrosis 405 + 1G > A mutation. Five blastocysts that collapsed during assisted hatching or ICM dissection were plated whole, giving rise to an additional line affected by fragile X. All cell lines expressed markers of pluripotent stem cells and differentiated in vitro and in vivo into the three germ layers. Conclusions These hESC lines can serve as an important model of the genetic disorders that they carry. Laser-assisted isolation of the ICMs may be applied for the derivation of new hESC lines in a xeno-free system for future clinical applications.

Study objective To investigate the actual complication rate of hysteroscopic surgery performed by experienced endoscopic surgeons in a single medical center. Design A prospective descriptive study (Canadian Task Force classification III). Setting An endoscopic gynecology unit at a tertiary care university hospital. Patients Women from 21 to 82 (median 45.0) years, undergoing operative hysteroscopy for uterine disease. Intervention Operative hysteroscopy with glycine or saline solution used as an irrigation medium. Measurements and main results Data of short-term complications were prospectively collected during surgery and at the 2-week follow-up visit. Six hundred procedures were investigated. The total complication rate was 3%, with 1% of uterine perforations. Two-thirds of the complications were related to cervical dilation or uterine entry, and infertility was found to be a risk factor. Conclusions Hysteroscopic surgery, performed by a well-trained hysteroscopic surgeon, is a safe procedure with an overall complication rate of 3%. Most complications are related to cervical dilation or uterine entry techniques. Efforts therefore should be focused on identifying the patients at risk and finding novel techniques for cervical priming.

To determine the molecular basis of familial, autosomal-recessive, non-obstructive azoospermia in a consanguineous Iranian Jewish family.We investigated the genetic cause of non-obstructive azoospermia in two affected siblings from a consanguineous family. Homozygosity mapping in the DNA samples of the patients and their normospermic brother was followed by exome analysis of one of the patients. Other family members were genotyped for the mutation by Sanger sequencing. The mutation effect was demonstrated by immunostaining of the patients' testicular tissue.The two patients were homozygous for a splice site mutation in SYCE1 which resulted in retention of intron three in the cDNA and premature stop codon. SYCE1 encodes a Synaptonemal Complex protein which plays an essential role during meiosis. Immunostaining of patient's testicular tissue with anti-Syce1 antibody revealed an undetectable level of Syce1. Histological examination of the patients' tissue disclosed immature-stages spermatocytes without mature forms, indicating maturation arrest.The significance of most synaptonemal complex proteins was previously demonstrated in a mutant mouse model. The present report underscores the importance of synaptonemal complex proteins in spermatogenenesis in humans. Our new approach, combining homozygosity mapping and exome sequencing, resulted in one of the first reports of an autosomal-recessive form of NOA.

In order to reduce total fertilization failure in unexplained infertility, sibling oocytes were submitted to both conventional IVF and intracytoplasmic sperm injection (ICSI). Two groups of ICSI embryos were compared in unexplained infertility patients: those derived from ICSI when IVF had failed to fertilize, and those derived from ICSI while their sibling oocytes were fertilized by IVF. The outcome of oocytes fertilized exclusively by ICSI (essential ICSI, n = 749) was compared with those fertilized both by IVF and ICSI (non-essential ICSI, n = 957) in all IVF patients treated for unexplained infertility at the Hadassah Hospital (1999–2002). The latter group was further subdivided into ICSI and IVF embryos. Total fertilization rate was 54%. Fertilization rates by ICSI were lower in the essential ICSI compared with the non-essential ICSI group, at 65 and 73% (P < 0.025). Pregnancy rates per embryo transfer in the essential ICSI group (49%), ICSI derived embryos group (55%) and IVF derived embryos (44%) from the non-essential ICSI group, were similar. Implantation rates were lower in the essential ICSI group as compared with the non-essential ICSI group (21 versus 32% respectively; P < 0.05) and 26% for IVF embryos. In conclusion, essential ICSI was associated with lower fertilization and implantation rates.

Objective To describe the success rate of intracytoplasmic sperm injection (ICSI) using thawed cryopreserved sperm in male cancer patients. Design Retrospective consecutive study. Setting IVF unit in a tertiary university hospital. Patient(s) Twenty-one couples treated by ICSI using the frozen-thawed sperm of husbands treated for cancer. Intervention(s) Follow-up of all treatments by ICSI. Main Outcome Measure(s) Pregnancy rate, sperm count, and fertilization rate. Result(s) Male patients being treated for cancer froze between one and 29 sperm samples. Post-thaw sperm count ranged from 1 × 10 5 to 106 × 10 6 . The mean fertilization rate by ICSI was 60% (range, 33%–100%), and the pregnancy rate was 42%. Twenty-six pregnancies were obtained resulting in 23 children (13 singleton and 10 twins) and eight spontaneous abortions (31%). Delivery was obtained in 12 of the 21 treated couples (57%). The lowest total motile sperm count that resulted in a pregnancy was 1 ⁎ 10 5 . Conclusion(s) Male cancer patients should be encouraged to freeze numerous sperm samples even when sperm count and motility are poor. In these cases, ICSI is a powerful technique compared with intrauterine injection since thawed sperm samples with poor parameters can produce relatively high fertilization rates resulting in normal pregnancies and deliveries. The possibility to repeat treatments even in the face of a limited number of sperm samples appears to be of importance.

This study sought to assess the efficacy of intravenous immunoglobulin (IVIg) in improving pregnancy rates and outcome, in a select group of patients with repeated IVF failure and human leukocyte antigen (HLA) similarity. Couples suffering from recurrent IVF failure, defined as at least seven attempts at embryo transfer with no successful implantations, who were found to share at least three HLA loci, and a negative cross-match test, were included in the study. The treatment consisted of two 30 g IVIg doses: one before oocyte retrieval, and a second as soon as a fetal pulse was identified on ultrasound. Ten couples comprised the study group. In total, these couples had undergone 98 IVF cycles with no successful pregnancies prior to initiation of the study. Following a total of 18 IVIg courses, seven women conceived, two women twice. Up to date, five women have delivered at least one live fetus, at 27 weeks or later. One woman is currently in the early third trimester of a twin pregnancy, and one woman had a late abortion at 19 weeks. The results suggest that couples with recurrent IVF failure and HLA similarity, may benefit from IVIg treatment.

Polycystic ovary syndrome (PCOS) with prolonged anovulation had resulted in endometrial carcinoma in a 43-year-old woman. Since she and her husband did not share common biological children, they requested fertility preservation. Due to the woman's age, high dose progesterone and postponing surgery were both considered inappropriate. We therefore proposed oocyte retrieval from the ovaries removed by staging laparotomy followed by in vitro maturation and ICSI. Surrogacy could then enable a future pregnancy. Fourteen of 17 (82%) retrieved oocytes matured in vitro. Following ICSI, eight embryos (two at the pronuclear stage and six cleaved) were cryopreserved. To the best of our knowledge, this is the first report of oocyte aspiration, maturation and fertilization from an ovary removed by laparotomy.

BACKGROUND: Uterine leiomyomas are the most common benign smooth muscle cell tumours in women. Formation of leiomyomas, still not completely understood, is viewed as a multistep process, with involvement of ovarian steroid hormones, cytokines and growth factors. Our study aimed to identify tyrosine kinase inhibitors as potential 'signal transduction therapeutics' for leiomyomas, underlying the effect of ovarian steroidal hormones. METHODS: The selective epidermal growth factor (EGF) receptor blocker AG1478 was evaluated as a potential target, since EGF has been shown to mediate estrogen action and to play a crucial role in regulating leiomyoma growth. Paired cultures of leiomyoma and normal myometrium samples were established and the suppressive effect of AG1478 on the cells prior and subsequent to steroidal hormone treatment was examined: cell proliferation, recovery after treatment, cell cycle analysis and immunochemical analysis of relevant proteins. RESULTS: Leiomyoma cell growth is effectively blocked by AG1478 and is unaffected by the presence of physiological concentrations of progesterone and estradiol. AG1478 (10 microM) completely suppressed proliferation and the cells did not recover after cessation of treatment. CONCLUSION: The growth-arresting properties of AG1478, unaffected by ovarian steroidal hormones, identify it as a potential lead agent for the non-surgical management of uterine leiomyomas.

Objective To characterize the reproductive history of women who delivered an infant after a spontaneous pregnancy after the age of 45 years. Design Observational study. Setting University departments. Patient(s) Two hundred nine women who conceived spontaneously and had their most recent delivery after the age of 45 years. Intervention(s) Review of all individual medical charts for a complete history of all pregnancies. Main outcome measure(s) Gravidity, parity, and spontaneous abortion (SAB) rate. Result(s) The mean (±SD) age at last delivery was 45.7 ± 0.9 years (range: 45–49). The mean parity was 9.6 ± 4 children (range: 2–20): 81% of the women were grandmultiparas (≥6 deliveries) and 46% were grand-grandmultiparas (≥11 deliveries). The mean number of SAB was 1.9 ± 1.9 (range: 0–9). Increased parity did not have a protective effect on abortion rate: 12.9% for parity 2–5, 15.6% for parity 6–10, and 21.3% for parity 11–20. Women in the study group differed significantly in their SAB rate from a general population: 11.3% vs. 17.7% at age 39, 13.2% vs. 33.8% at age 44, and 9.1% vs. 33.8% at age 45. Conclusion(s) Women who conceived at or after 45 years of age were mostly grandmultiparas. Although multiparity in itself did not affect SAB rates, this measure was remarkably low in our exceptionally fertile group as compared with the rates published for a general population. This unique group of grandmultiparous women might possess a genetic propensity that delays the normal rate of ovarian and oocyte senescence.

The authors of this Views and Reviews outline in detail the indispensable role of imaging tools—ultrasound, computed tomography, and magnetic resonance imaging—in the diagnosis and treatment of female and male factor infertility. Equipment producing diagnostic images, coupled with ever-increasing computing power, will pave the way for novel functional dynamic studies that will expand the understanding of reproductive processes and their management.

Purpose: The objective of this study was to compare the efficacy of GnRH-antagonists to GnRH-agonists in ovarian stimulation of poor responders undergoing IVF. Methods: Retrospective analysis of our data revealed that 56 patients underwent treatment with a GnRH-agonist according to the flare-up protocol. Patients failing to achieve an ongoing pregnancy (n=53) were subsequently treated in the next cycle with a GnRH-antagonist according to the multiple-dose protocol. Main outcome measures included the clinical pregnancy and implantation rates. Results: While ovulation induction characteristics and results did not differ between the two protocols, the number of embryos transferred was significantly higher (P=0.046) in the GnRH-antagonist than in the GnRH-agonist stimulation protocol (2.5 ± 1.6 vs. 2.0 ± 1.4, respectively). The clinical pregnancy and implantation rates per transfer in the GnRH-antagonist group appeared higher than in the GnRH-agonist, but did not differ statistically (26.1 and 10.7 compared with 12.2 and 5.9%, respectively). However, the ongoing pregnancy rate per transfer was statistically significantly higher (P=0.03) in the GnRH-antagonist than in the GnRH-agonist group (23.9 vs. 7.3%, respectively). Conclusion: Applying GnRH-antagonists to ovarian stimulation protocols may offer new hope for IVF poor responder patients. However, further controlled randomized prospective studies with larger sample sizes are required to establish these results.

Objective To examine the effect on pregnancy and implantation rates when highly purified, fermentation-based hyaluronic acid was the only macromolecule supplement to the transfer medium in a human IVF program. Design Prospective randomized study. Setting In vitro fertilization center in an academic medical institution. Patient(s) Eighty patients were included in this prospective randomized double blind study. Inclusion criteria were age ≤35 years, the availability of at least three embryos eligible for transfer on day 3 after fertilization, and no more than three previous embryo transfer attempts. Intervention(s) All embryos were cultured in P1 medium containing 10% synthetic serum substitute (SSS) until day 3. Patients were randomly allocated to two groups; in treatment group A (40 patients), embryos were transferred to P1 medium supplemented with 0.5 mg/mL hyaluronic acid for 5–10 min before their intrauterine transfer. In the control group B (40 patients), embryos were transferred, as routinely performed, in P1 medium containing 10% SSS. Main outcome measure(s) Clinical pregnancy and implantation rates. Result(s) The mean age of the female partner was 28.7 ± 3.3 years and 29.7 ± 3.8 years for groups A and B, respectively. In group A, 103 embryos were transferred and in group B, 97 embryos were transferred for a similar mean number of 2.6 ± 0.6 and 2.4 ± 0.5 embryos/transfer, respectively. Twenty-five pregnancies were achieved in group A, and 21 pregnancies in group B. This led to a comparable clinical pregnancy and implantation rates of 62.5% and 34% as compared to 52% and 26.8% for groups A and B, respectively. Conclusion(s) Hyaluronic acid can successfully replace albumin as a sole macromolecule in a human embryo transfer medium and result in high pregnancy and implantation rates. The use of this supplement is an important step in the development of human embryo culture media free of blood-derived additives.

Objective: Ovarian cancer is the leading cause of death from gynecologic malignancies in the United States. In an attempt to develop drugs that suppress ovarian cancer cells, we examined the effect of selective inhibitors of protein tyrosine kinases–tyrphostins, which are likely to play a role in ovarian cancer cells. Study Design: We examined the cellular and biochemical effects of tyrphostins AG1478, PP2, AGL2592, and AG490 from four different families on the ovarian carcinoma cell line OV1063. Results: We found that the AG1478, PP2, AGL2592, and AG490 tyrphostins suppressed cell proliferation and altered cell cycle distribution of the OV1063 cells in a dose- and time-dependent manner. Immunoblotting analysis indicated that AG1478 effectively inhibited epidermal growth factor receptor autophosphorylation, that AG490 decreased the level of Jak2 and phosphorylated Stat3, and that PP2 decreased the level of pp60Src protein. AGL2592 decreased the level of constitutive activated epidermal growth factor receptor and pStat3, but its molecular targets have not been identified completely. Conclusion: The growth-arresting properties of these tyrphostins identify them as possible candidates for signal transduction therapy.

Recent advances in cancer therapy have improved the long-term survival of young cancer patients who are then commonly faced with iatrogenic infertility and premature ovarian failure. Preservation of fertility potential has thus become a major goal and could be realized by preventing ovarian toxicity or by cryopreservation of reproductive cells (i.e. oocytes, embryos) and tissues (i.e. ovarian cortex). GnRH analogs prevent chemotherapy-induced-ovarian-damage in rats, however human results are controversial. Anti-apoptotic agents (i.e. sphingosine-1-phosphate) may present an innovative treatment to prevent oocyte destruction during cancer therapy. Although cryopreservation of mouse oocytes is successful, the results obtained in other mammalian species were worse, probably due to their extreme sensitivity to suboptimal conditions during the process of cryopreservation. This resulted in low oocyte survival and fertilization rates, a high incidence of polyploidy, and poor embryonic developmental ability. Ovarian tissue cryopreservation is currently considered as the optimal procedure for follicle banking. Transplantation offers the best prospect of using frozen-thawed ovarian tissue, since no reliable ovarian in-vitro culture technology exists.

To evaluate the prevalence and characteristics of complementary medical therapy (CMT) use among Israeli couples undergoing in vitro fertilization (IVF).In a cross-sectional study, men and women undergoing treatment at four IVF units in Israel were invited to complete an anonymous questionnaire between May 2010 and December 2011. Patients were considered users of CMT if they reported that either partner used at least one type of CMT for treating infertility. Stepwise backward logistic regression was used to assess the independent effects of variables on CMT utilization.Of 511 patients approached, 400 (78.1%) completed the survey and 159 (39.8%) indicated that CMT for infertility was used by one or both partners. Higher CMT use was significantly associated with the treating hospital, post high-school education, more than three previous IVF trials, being employed, and using psychosocial support (all P0.05). Most users (75/129; 58.1%) did not notify the IVF clinic medical staff about concurrent use of CMT.Use of CMTs was widely reported by Israeli patients undergoing IVF, particularly those with higher education, and those undergoing repeated IVF trials and receiving psychosocial support. IVF staff ought to be aware of the widespread utilization of CMTs because the impact of these therapies on IVF outcomes is inconclusive.

To examine the association between the mother's age at last birth and maternal long-term survival.Data from three national censuses (1972, 1983, and 1995) and national birth and death records (1972-2009) were used to examine the association between age at last birth and mortality while accounting for potential confounders, such as parity. Age-adjusted mortality rates and Cox proportional hazard models were used in the analysis.A total of 887 women who delivered their last child after 45 years of age were identified from among 178,507 women (1,592,379 person-years). Age-adjusted mortality rates from 55 years of age were highest for childless women (9.2 per 1000) and decreased linearly (P .001) for parous women with increased age at last birth (5.2 per 1000 for women aged ≥45 years at last birth). In models adjusted for age at first birth and parity, mortality risks were lowest among parous women with late-age births (≥45 years) compared with parous women with their last births before 35 years of age (hazard ratio, 0.58; 95% confidence interval, 0.40-0.86).This study provides new empirical evidence that late-age births are associated with maternal longevity, although a direct causal relation cannot be established with the information available.

Expression of the X inactivation-specific transcript (XIST:) gene has previously been shown by reverse transcription-polymerase chain reaction (RT-PCR) to be present at the 4-cell stage of female mouse embryos. This early expression, which is followed by X inactivation in the extra-embryonic tissues, is maternally imprinted. By the blastocyst stage, as the embryonic lineages begin to form, the imprint is lost and expression becomes random. By applying in-situ RT-PCR, we showed that XIST: is expressed even earlier in development, in unfertilized mouse oocytes as well as in pronuclei stage zygotes. Our data demonstrate XIST: expression in oocytes and suggest that XIST: transcripts may occur in both XX and XY zygotes. A difference in the pattern of expression (rod-like or rounded punctate signal) is found among pronuclear-stage embryos. Early expression is in agreement with findings reported in human embryos.

Purpose: To investigate the various methods of evaluationand treatment of patients with a low response to controlledovarian hyperstimulation in assisted reproductive technologies (ART). Methods: Review and analysis of relevant studies publishedin the last decade, identified through the literature and Medlinesearches. Results: While a universally accepted definition for lowresponders is still lacking, these patients are reported torepresent about 10% of the ART population. Several ovarianreserve screening techniques have been proposed; however,currently the best-characterized and most sensitive screeningtools available are the basal day 3 serum follicle-stimulatinghormone level and the clomiphene citrate challenge test.When abnormal, these tests allow physicians to counselpatients that their prognosis for conception is poor. Althoughthe presence of a normal result does indicate better long-termchances for conception, an age-related decline in fecundityremains and patient age should still be considered whencounseling patients with normal screening results. Severalstimulation protocols have been applied in the low-responsegroup with varying success. Recent studies show that theuse of a minidose gonadotropin-releasing hormone-agonistprotocol may result in significantly decreased cycle cancellationsas well as increased clinical and ongoing pregnancies,and thus is proposed as a first-line therapy. Studies evaluatingsupplementary forms of treatment to the ovulation inductionregimen show improved outcome when pretreating withoral contraceptives, whereas there seems to be no benefitfrom cotreatment with growth hormone or glucocorticoids.Blastocyst culture and transfer and assisted hatching in lowresponders are still under evaluation, whereas natural cyclein vitro fertilization may be used in cases of repeated failuresas a last option before resorting to oocyte donation or adoption.Future possible forms of treatment like in vitro maturationof immature human oocytes, cytoplasm, and nucleartransfer currently are experimental in nature and their efficacyhas still to be proven.Conclusions: The evaluation and treatment of low respondersin ART remains a challenge. Understanding of the underlyingetiology and pathophysiology of this disorder may helpthe clinician to approach it successfully.

Objective: To present our experience with a flexible and convenient protocol for artificial endometrial preparation without prior GnRH agonist suppression in patients with functioning ovaries undergoing frozen ET. Design: Case series. Setting: An IVF unit in a university hospital. Patient(s): All patients who underwent IVF with embryo cryopreservation from December 1997 to June 1998 and requested transfer of their frozen-thawed embryos. Intervention(s): Controlled endometrial preparation for ET entailed the use of a fixed dose of 6 mg/d of micronized E 2 started on day 1 of the cycle, followed by concomitant administration of micronized P placed in the vagina. Main Outcome Measure(s): Hormonal and endometrial profiles throughout the cycle, pregnancy rate per ET, implantation rate, and pregnancy outcome. Result(s): Of 185 treatment cycles in 140 patients, 8 cycles (4.3%) were canceled. In another 2 cycles, no embryos were suitable for transfer. For the remaining 175 ET cycles, the calculated pregnancy rate and implantation rate were 21.7% and 9%, respectively. The proliferative phase could be extended up to 20 days but was a mean (±SD) of 15 ± 1.9 days. Conclusion(s): For patients with functioning ovaries, controlled endometrial preparation for the transfer of frozen-thawed embryos can be done successfully by using oral E 2 from day 1 of the cycle followed by P preparation. Prior suppression with GnRH agonist is not necessary.