Cancer in IVF patients treated at age 40 years and older: long term follow-up.

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.

Forty years of IVF.

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.

Increased incidence of preeclampsia in mothers of advanced age conceiving by oocyte donation.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

BRCA mutations and reproduction.

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.

Introduction: Cancer biomarkers and fertility.

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.

Recombinant luteinizing hormone supplementation to recombinant follicle stimulating hormone therapy in gonadotropin releasing hormone analogue cycles: what is the evidence?

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Introduction: Imaging in reproduction.

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.

Introduction: Fertility and longevity.

The authors of this Views and Reviews outline the current understanding of the association between fertility and longevity. Natural fertility in populations that did not employ any contraception make up the model that attempts to define this relationship. Longevity seems to be increased in women with late-age conceptions and may be the result of genetic or environmental factors or both. A new concept is suggested that demonstrates the potential rejuvenating effect of pregnancy on older pregnant mothers. The link between infertility itself and conceptions at an older age with morbidity and mortality is summarized.

Influence of late-age births on maternal longevity.

PURPOSE: To examine the association between the mother's age at last birth and maternal long-term survival. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Deleterious mutation in SYCE1 is associated with non-obstructive azoospermia.

PURPOSE: To determine the molecular basis of familial, autosomal-recessive, non-obstructive azoospermia in a consanguineous Iranian Jewish family. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

The rejuvenating effect of pregnancy on muscle regeneration.

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.

Oocyte donation is an independent risk factor for pregnancy complications: the implications for women of advanced age.

Maternal age at first pregnancy and age-related infertility are steadily increasing, and the demand for assisted reproductive technologies (ART) to treat age-related infertility is also on the rise. The latest registry findings from Europe and the United States show that the meager results of ART in women above 43 years of age have not improved much over the past 10 years. The latest evidence shows that the demand for oocyte donation (OD) is steadily increasing. Contrary to previous belief-attributing increased perinatal complications in OD recipients to advanced maternal age and multifetal pregnancy-accumulating evidence from the past few years suggests that OD itself is a significant and independent risk factor for pregnancy complications, mostly for pre-eclampsia. The increased rate of chronic maternal disease and medical complications in pregnancy observed in advanced maternal age, coupled with the growing demand for OD, with its independent association with pre-eclampsia, create an urgent need to adopt a clear policy taking these risks into account. We present recent evidence showing that OD is an independent risk factor for pre-eclampsia and suggest recommendations for women approaching OD treatment in advanced age.

Use of complementary medical therapies by Israeli patients undergoing in vitro fertilization.

OBJECTIVE: To evaluate the prevalence and characteristics of complementary medical therapy (CMT) use among Israeli couples undergoing in vitro fertilization (IVF). METHODS: 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. RESULTS: 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 P<0.05). Most users (75/129; 58.1%) did not notify the IVF clinic medical staff about concurrent use of CMT. CONCLUSION: 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.

Introduction: MicroRNAs in human reproduction: small molecules with crucial regulatory roles.

MicroRNAs constitute a large family of approximately 21-nucleotide-long, noncoding RNAs. They emerged more than 20 years ago as key posttranscriptional regulators of gene expression. The regulatory role of these small RNA molecules has recently begun to be explored in the human reproductive system. In this issue's Views and Reviews, the authors present the current knowledge regarding the involvement of microRNAs in several aspects of human reproduction and discuss its future implications for clinical practice.