A group of experts gathered in Indianapolis in December 2011 to address lingering concerns related to uterus transplantation (UTn). They represent a multi-national group of four research teams who have worked for over 15 years on bringing UTn to reality for patients. Presented here are a set of parameters that must be considered in order for UTn to become an acceptable procedure in the human setting. UTn has been proposed as a potential solution to absolute uterine factor infertility (AUFI). Causes of AUFI include congenital uterine factors (i.e. absence or malformation) or acquired uterine factors (e.g. hysterectomy for uncontrollable hemorrhage) rendering a woman ‘unconditionally infertile’. Current estimates are that in the USA, up to 7 million women with AUFI may be appropriate candidates for UTn. As a result of a first human attempt in 2000, investigators have responded with a plethora of publications demonstrating successful UTn attempts, including pregnancies, in various autogeneic, syngeneic and allogeneic animal models. Before UTn can become an accepted procedure, it must satisfy defined criteria for any surgical innovation, i.e. research background, field strength and institutional stability. Equally important, UTn must satisfy accepted bioethical principles (respect for autonomy, beneficence, non-maleficence and justice) and their application (informed consent, appropriate assessment of risk and benefit and fair selection of individuals). Furthermore, we believe that a defined number of transplants should not be exceeded worldwide without a successful term delivery, to minimize proceeding in futility using current techniques. Even if UTns were to become relatively common, the following research objectives should be continuously pursued: (i) additional pregnancies in a variety of large animal/primate models (to search for unanticipated consequences), (ii) continuous assessment of women diagnosed with AUFI regarding UTn, (iii) continuous assessment using ‘borrowed’ psychological tools from transplant centers, adoption agencies and assisted reproductive technology centers with potential recipients and (iv) continuous careful ethical reflection, assessment and approval.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/2/288?rss=1

Recommendation and review posted by G. Smith

STUDY QUESTION

Is DNA methyltransferase 1 (DNMT1) dysfunction involved in epigenetic deregulation of placentae from embryos obtained by assisted reproduction technologies (ARTs)?

SUMMARY ANSWER

DNMT1 expression in growing placentae of in vitro produced (IVP) embryos is compromised and associated with pregnancy loss.

WHAT IS KNOWN ALREADY

DNMT1 maintains the methylation profile of genes during cell division. The methylation status of genes involved in placenta development is altered in embryos obtained in vitro. Disturbances in the epigenetic regulation of gene expression during placentogenesis could be involved in the frequent developmental arrest and loss of IVP embryos.

STUDY DESIGN, SIZE, DURATION

Forty sheep were naturally mated (Group 1, CTR). IVP blastocysts (2–4 per ewe) were surgically transferred to the remaining 46 recipient sheep 6 days after oestrus (Group 2). Twenty-one recipients from Group 1 and 27 recipients from Group 2 were allowed to deliver in order to compare embryo survival in both groups at term (150 days). From the remaining recipients (n = 38), fetuses and placentae of both groups were recovered by paramedian laparotomy at Days 20, 22, 24, 26 and 28 of gestation.

MATERIALS, SETTING, METHODS

Immediately after collection, early placental tissues (chorion-allantois) were snap frozen in liquid nitrogen and DNMT1 expression and activity was evaluated. mRNA levels (for DNMT1, HDAC2, PCNA, DMAP1, MEST, IGF2, CDKN1C, H19) and the methylation status of H19 were also analyzed. Furthermore, embryo size and survival rate were measured.

MAIN RESULTS AND THE ROLE OF CHANCE

Our study shows that DNMT1 expression was reduced in early placentae from sheep IVP embryos. This reduction was associated with growth arrest and subsequent death of the sheep embryos. Conversely, normal levels of DNMT1 and its cofactors were observed in placentae from IVP embryos that survived this developmental bottleneck. Although DNA methylation machinery was severely compromised in IVP placentae only up to Day 24, the low DNMT1 enzymatic activity that persisted after this stage in IVP placentae was not lethal for the developing embryos.

LIMITATIONS, REASONS FOR CAUTION

The studied genes represent only a small fraction of genes regulating DNA methylation. Further studies are needed to evaluate changes in the expression and methylation status of other genes that may lead to developmental arrest of IVP embryos. As this is the only study evaluating the functionality of DNMT1 machinery in placentae from ART embryos, studies on other species are needed to confirm if our observation may be applicable to all mammalian embryos produced in vitro.

WIDER IMPLICATIONS OF THE FINDINGS

The knowledge about compromised activity of DNMT1 in placentae obtained from IVP embryos should stimulate detailed studies on the metabolic requirements of oocytes and embryos in order to adequately enrich the culture media.

STUDY FUNDING/COMPETING INTEREST(S)

This work was supported by the European Research Council (FP7/2007–2013)/Programme IDEAS GA no. 210103 to G.E.P. No competing interests are declared.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/2/298?rss=1

Recommendation and review posted by G. Smith

STUDY QUESTION

Does the selection of sperm for ICSI based on their ability to bind to hyaluronan improve the clinical pregnancy rates (CPR) (primary end-point), implantation (IR) and pregnancy loss rates (PLR)?

SUMMARY ANSWER

In couples where ≤65% of sperm bound hyaluronan, the selection of hyaluronan-bound (HB) sperm for ICSI led to a statistically significant reduction in PLR.

WHAT IS KNOWN AND WHAT THIS PAPER ADDS

HB sperm demonstrate enhanced developmental parameters which have been associated with successful fertilization and embryogenesis. Sperm selected for ICSI using a liquid source of hyaluronan achieved an improvement in IR. A pilot study by the primary author demonstrated that the use of HB sperm in ICSI was associated with improved CPR. The current study represents the single largest prospective, multicenter, double-blinded and randomized controlled trial to evaluate the use of hyaluronan in the selection of sperm for ICSI.

DESIGN

Using the hyaluronan binding assay, an HB score was determined for the fresh or initial (I-HB) and processed or final semen specimen (F-HB). Patients were classified as >65% or ≤65% I-HB and stratified accordingly. Patients with I-HB scores ≤65% were randomized into control and HB selection (HYAL) groups whereas patients with I-HB >65% were randomized to non-participatory (NP), control or HYAL groups, in a ratio of 2:1:1. The NP group was included in the >65% study arm to balance the higher prevalence of patients with I-HB scores >65%. In the control group, oocytes received sperm selected via the conventional assessment of motility and morphology. In the HYAL group, HB sperm meeting the same visual criteria were selected for injection. Patient participants and clinical care providers were blinded to group assignment.

PARTICIPANTS AND SETTING

Eight hundred two couples treated with ICSI in 10 private and hospital-based IVF programs were enrolled in this study. Of the 484 patients stratified to the I-HB > 65% arm, 115 participants were randomized to the control group, 122 participants were randomized to the HYAL group and 247 participants were randomized to the NP group. Of the 318 patients stratified to the I-HB ≤ 65% arm, 164 participants were randomized to the control group and 154 participants were randomized to the HYAL group.

MAIN RESULTS AND THE ROLE OF CHANCE

HYAL patients with an F-HB score ≤65% demonstrated an IR of 37.4% compared with 30.7% for control [n = 63, 58, P > 0.05, (95% CI of the difference –7.7 to 21.3)]. In addition, the CPR associated with patients randomized to the HYAL group was 50.8% when compared with 37.9% for those randomized to the control group (n = 63, 58, P > 0.05). The 12.9% difference was associated with a risk ratio (RR) of 1.340 (RR 95% CI 0.89–2.0). HYAL patients with I-HB and F-HB scores ≤65% revealed a statistically significant reduction in their PLR (I-HB: 3.3 versus 15.1%, n = 73, 60, P = 0.021, RR of 0.22 (RR 95% CI 0.05–0.96) (F-HB: 0.0%, 18.5%, n = 27, 32, P = 0.016, RR not applicable due to 0.0% value) over control patients. The study was originally planned to have 200 participants per arm providing 86.1% power to detect an increase in CPR from 35 to 50% at α = 0.05 but was stopped early for financial reasons. As a pilot study had demonstrated that sperm preparation protocols may increase the HB score, the design of the current study incorporated a priori collection and analysis of the data by both the I-HB and the F-HB scores. Analysis by both the I-HB and F-HB score acknowledged the potential impact of sperm preparation protocols.

BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION

Selection bias was controlled by randomization. Geographic and seasonal bias was controlled by recruiting from 10 geographically unique sites and by sampling over a 2-year period. The potential for population effect was controlled by adjusting for higher prevalence rates of >65% I-HB that naturally occur by adding the NP arm and to concurrently recruit >65% and ≤65% I-HB subjects. Monitoring and site audits occurred regularly to ensure standardization of data collection, adherence to the study protocol and subject recruitment. Subgroup analysis based on the F-HB score was envisaged in the study design.

GENERALIZABILITY TO OTHER POPULATIONS

The study included clinics using different sperm preparation methods, located in different regions of the USA and proceeded in every month of the year. Therefore, the results are widely applicable.

STUDY FUNDING/COMPETING INTEREST(S)

This study was funded by Biocoat, Inc., Horsham, PA, USA. The statistical analysis plan and subsequent analyses were performed by Sherrine Eid, a biostatistician. The manuscript was prepared by Kathryn C. Worrilow, Ph.D. and the study team members. Biocoat, Inc. was permitted to review the manuscript and suggest changes, but the final decision on content was exclusively retained by the authors. K.C.W is a scientific advisor to Biocoat, Inc. S.E. is a consultant to Biocoat, Inc. D.W. has nothing to disclose. M.P., S.S., J.W., K.I., C.K. and T.E. have nothing to disclose. G.D.B. is a consultant to Cooper Surgical and Unisense. J.L. is on the scientific advisory board of Origio.

TRIAL REGISTRATION NUMBER

NCT00741494.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/2/306?rss=1

Recommendation and review posted by G. Smith

STUDY QUESTION

Do higher leptin levels and lower adiponectin levels predict subsequent development of endometriosis?

SUMMARY ANSWER

Plasma leptin and adiponectin levels were not associated with laparoscopically confirmed endometriosis when collected prior to disease diagnosis.

WHAT IS KNOWN ALREADY

Case–control studies have identified altered levels of the inflammatory adipokines leptin and adiponectin in women with endometriosis, but it remains unclear whether inflammation results in endometriosis or whether the presence of endometriosis creates an inflammatory state.

STUDY DESIGN, SIZE, DURATION

Nested, matched, case–control study within the prospective Nurses' Health Study II (NHS II) cohort. Blood samples were collected between 1996 and 1999 from 29 611 female nurses within the cohort. Women who reported endometriosis before blood collection were excluded.

PARTICIPANTS/MATERIALS, SETTING, METHODS

Plasma leptin and adiponectin levels were assayed by ELISA. Three hundred and fifty cases of laparoscopically confirmed endometriosis were matched 1:2 with 694 controls of comparable race, age, infertility history, menopausal status and time of blood draw. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression models adjusting for matching factors and BMI.

MAIN RESULTS AND THE ROLE OF CHANCE

After adjusting for BMI, there were no statistically significant associations between endometriosis and leptin [RR = 1.2; 95% CI = 0.7–2.0; P-value, test for linear trend (P_trend) = 0.72], adiponectin (RR = 0.8; 95% CI = 0.5–1.2; P_trend = 0.48) or the leptin to adiponectin ratio (RR = 0.8; 95% CI = 0.4–1.4; P_trend = 0.14) when comparing the upper with the lower quartile. Results were unaltered when analyses were stratified by BMI or restricted to cases diagnosed ≥4 years after blood draw. To evaluate statistical significance and limit the role of chance to the gold standard of 5%, we present 95% CIs about the RRs, and for P-values calculated for linear tests of trend and tests of heterogeneity, we have set the α-level to be 0.05 (i.e. <0.05 is considered to be statistically significant).

LIMITATIONS AND REASONS FOR CAUTION

A limitation of this study is the inability to differentiate the time of endometriosis ‘diagnosis’ from the time of disease ‘onset’ due to the impossibility in identifying a precise time point at which the disease process was first initiated at a molecular or cellular level. Additional limitations include lack of information regarding stage of endometriosis and the possibility of asymptomatic disease in the control population.

WIDER IMPLICATIONS OF THE FINDINGS

The mean age at diagnosis of endometriosis in the study population is 41.7, ~10 years older than the mean age of diagnosis in the general population. While this may limit the generalizability of the results, there is no reason to suspect that the association between adipokines and endometriosis risk should differ at a younger age of diagnosis in an adult population.

STUDY FUNDING

This study was supported by research grants HD48544, HD52473 and HD57210 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The NHS II is supported by the Public Health Service grant CA50385 from the National Cancer Institute, NIH, U.S. Department of Health and Human Services. H.R.H. is supported by NIH training grant T32 ES007069 and MCHB grant number 5T76MC00001 (formerly MCJ201).

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/2/315?rss=1

Recommendation and review posted by G. Smith

STUDY QUESTION

Can plasma microRNAs be used as a non-invasive diagnostic test for the detection of endometriosis?

SUMMARY ANSWER

Plasma miR-17-5p, miR-20a and miR-22 are down-regulated in women with endometriosis compared with those without endometriosis in mainland China.

WHAT IS KNOWN ALREADY

There is currently a pressing need to develop a non-invasive diagnostic test for endometriosis. Altered circulating microRNA profiles have already been linked to various disease states.

STUDY DESIGN, SIZE, AND DURATION

This was a prospective laboratory study in a tertiary-referral university hospital in Beijing, PR China, between January 2012 and May 2012. Twenty-three women with histologically proven endometriosis and 23 endometriosis-free controls were enrolled in this study.

PARTICIPANTS/MATERIALS, SETTING, AND METHODS

Laparoscopic inspection of the abdominopelvic cavity was performed for each patient, and peripheral blood samples were collected before laparoscopy. Microarray-based microRNA expression profiling was used to identify differentially expressed microRNAs in plasma samples between women with and without endometriosis, and quantification of selected microRNAs was performed using quantitative RT–PCR.

MAIN RESULTS AND THE ROLE OF CHANCE

Twenty-seven microRNAs were differentially expressed between women with and without endometriosis, of which six microRNAs (miR-15b-5p, miR-17-5p, miR-20a, miR-21, miR-22 and miR-26a) were selected for validation. MiR-17-5p, miR-20a and miR-22 were significantly down-regulated in women with endometriosis compared with controls (P = 0.011, 0.0020 and 0.0002, respectively), yielding an area under the receiver operator characteristics curve of 0.74 [95% confidence interval (CI): 0.58–0.90], 0.79 (95% CI: 0.65–0.93) and 0.85 (95% CI: 0.71–0.98) in discriminating endometriosis from controls, respectively.

LIMITATIONS AND REASONS FOR CAUTION

Our sample size was small and all cases were rAFS stage III–IV, which may limit generalization of plasma microRNAs for early diagnosis of endometriosis. Moreover, only six microRNAs were selected for validation.

WIDER IMPLICATIONS OF THE FINDINGS

Plasma microRNAs provide a promising opportunity for detection of endometriosis.

STUDY FUNDING/COMPETING INTEREST(S)

This research was supported by the National Natural Science Foundation of China (81170548) and Key Project for Clinical Faculty Foundation, Ministry of Health, China (2010). All authors declare no conflict of interest.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/2/322?rss=1

Recommendation and review posted by G. Smith

STUDY QUESTION

Is an elective single-embryo transfer (eSET) policy feasible for women aged 40 or older?

SUMMARY ANSWER

For older women (aged 40–44 years) with a good prognosis, an eSET policy can be applied with acceptable cumulative clinical pregnancy rates and live birth rates.

WHAT IS KNOWN ALREADY

Various studies have shown the effectiveness of eSET in women aged <35 years with high cumulative pregnancy rates and low rates of multiple births.

STUDY DESIGN, SIZE, DURATION

This retrospective cohort study included 628 women treated between 2000 and 2009.

PARTICIPANTS, SETTING, METHODS

Women aged 40–44 years underwent a fresh cycle of IVF or ICSI treatment with eSET (n = 264) or double-embryo transfer (DET) (n = 364). In the subsequent frozen-thawed embryo transfer cycles, SET/DET was performed in both groups according to the number of embryos available and the opinion of the couple. The study was performed at the Family Federation of Finland Helsinki Fertility Clinic.

MAIN RESULTS AND THE ROLE OF CHANCE

In the fresh cycles, the clinical pregnancy rates were 23.5 and 19.5% in the eSET and DET groups, respectively, and live birth rates were 13.6 and 11.0%, respectively. In the fresh cycles with eSET, there were no twin pregnancies, but in the DET group, there were three sets of twins (7.5%). The cumulative clinical pregnancy rates per oocyte retrieval were 37.1 and 24.2% in the eSET and DET groups, respectively (P < 0.001), and the cumulative live birth rates were 22.7 and 13.2%, respectively (P = 0.002). Cumulative twin rates were 6.7% (n = 4) in the eSET group and 8.3% (n = 4) in the DET group (P = 0.726). All of the twin pregnancies in the eSET group resulted from frozen and thawed DET embryo transfer cycles.

LIMITATIONS

The characteristics of the two patients groups are not comparable because the suitability of eSET was individually assessed by a clinician based on both clinical prognostic factors and the outcome of IVF or ICSI, i.e. the number and quality of embryos.

WIDER IMPLICATIONS OF THE FINDINGS

This study may be generalized to IVF units having experience in eSET and cryopreservation.

STUDY FUNDING/COMPETING INTEREST(S)

This study received no funding and there are no conflicts of interests to be declared.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/2/331?rss=1

Recommendation and review posted by G. Smith